Pediatric Anesthesia Bruno Bissonnette 2011

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Pediatric Anesthesia
Basic Principles—State of the Art—Future
Edited by
Bruno Bissonnette, MD
Department of Anesthesia
Faculty of Medicine
University of Toronto
President and Founder
Children of the World Anesthesia Foundation
Toronto, Ontario, Canada
Subeditors
Brian J. Anderson, MB ChB, PhD - New Zealand
Adrian Bösenberg, MB ChB - USA
Thomas Engelhardt, MD, PhD - Scotland
Linda J. Mason, MD - USA
Joseph D. Tobias, MD - USA
Illustrator: Danny Aguilar - Canada
2011
PEOPLE’S MEDICAL PUBLISHING HOUSE—USA

SHELTON, CONNECTICUT
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People’s Medical Publishing House-USA

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into a retrieval system, or transmitted, in any form or by any means (electronic, mechanical, photocopying, recording, or otherwise), without the
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11 12 13 14 15/PMPH/9 8 7 6 5 4 3 2 1
ISBN-13: 978-1-60795-093-6
ISBN-10: 1-60795-093-6
Printed in China by People’s Medical Publishing House

Editor: Linda Mehta
Copyeditor/Typesetter: David Stockhoff, Spearhead Global
Cover designer: Bruno Bissonnette and Mary McKeon
Library of Congress Cataloging‐in‐Publication Data
Pediatric anesthesia : basic principles, state of the art, future/[edited by] Bruno Bissonnette.
p. ; cm.
Includes bibliographical references and index.
ISBN-13: 978-1-60795-093-6
ISBN-10: 1-60795-093-6
1. Pediatric anesthesia. I. Bissonnette, Bruno.
[DNLM: 1. Anesthesia—methods. 2. Child. 3. Anesthetics—pharmacology. WO 440]
RD139.P418 2011
617.9′6083—dc22
2010048079
Notice: The authors and publisher have made every effort to ensure that the patient care recommended herein, including choice of drugs and
drug dosages, is in accord with the accepted standard and practice at the time of publication. However, since research and regulation constantly
change clinical standards, the reader is urged to check the product information sheet included in the package of each drug, which includes
recommended doses, warnings, and contraindications. This is particularly important with new or infrequently used drugs. Any treatment
regimen, particularly one involving medication, involves inherent risk that must be weighed on a case-by-case basis against the benefits
anticipated. The reader is cautioned that the purpose of this book is to inform and enlighten; the information contained herein is not intended as,
and should not be employed as, a substitute for individual diagnosis and treatment.
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To All the Children of the World We Care For

Also
To my dear mother Lilianne for her love and encouragement
and
to the loving memories of my father Raymond and my brother Luc Bissonnette
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Contributors
Rita Agarwal, MD, FAAP [130] Dean B. Andropoulos, MD, MHCM [106]
Associate Professor of Anesthesiology Professor of Anesthesiology and Pediatrics
Pediatric Anesthesia Program Director Baylor College of Medicine
The Children’s Hospital of Denver Chief of Anesthesiology
Aurora, Colorado, USA The Kurt D. Groten Sr Family Chair of
Pediatric Cardiovascular Anesthesiology
Swati Agarwal, MD [67] Attending Cardiovascular Anesthesiologist
Assistant Professor Texas Children’s Hospital
Virginia Commonwealth University School of Medicine Houston, Texas, USA
Pediatric Critical Care Physician
Inova Fairfax Hospital for Children Christian Apitz, MD [7]
Falls Church, Virginia, USA Pediatric Cardiologist
Pediatric Heart Centre
Asim Ali, BASc, MD, FRCSC [102] University Children’s Hospital
Assistant Professor of Ophthalmology Giessen, Germany
Department of Ophthalmology and Vision Sciences
University of Toronto Glen S. Van Arsdell, MD [94]
Attending Ophthalmologist Professor of Surgery
Director of Pediatric Ophthalmology Fellowship Program University of Toronto
Department of Ophthalmology and Vision Sciences Head, Division of Cardiovascular Surgery
The Hospital for Sick Children Department of Surgery
Toronto, Ontario, Canada CIT Chair in Cardiovascular Research
Labatt Family Heart Centre
Kanwaljeet J. S. Anand, MB BS, DPhil, FAAP, The Hospital for Sick Children
FCCM, FRCPCH [15] Toronto, Ontario, Canada
Professor of Pediatrics, Anesthesiology and Neurobiology
University of Tennessee Karim Ashenoune, MD, PhD [63]
St. Jude Children’s Research Hospital Endowed Chair of Professor of Anesthesiology and Intensive Care Medicine
Critical Care University of Nantes
Division Chief, Pediatric Critical Care Medicine Attending Anesthesiologist
Le Bonheur Children’s Medical Center Departement of Anesthesiology and Intensive Care Medicine
University of Tennessee Health Science Center Hôtel Dieu
Memphis, Tennessee, USA Centre Hospitalier Universitaire de Nantes
Nante, France
Brian J. Anderson, MB ChB, PhD, FANZCA,
FJFICM [17, 18] Hanan Azzam, MD [82]
Honorary Associate Professor of Anaesthesiology Assistant Professor of Clinical Pathology
University of Auckland School of Medicine Faculty of Medicine, Mansoura University Hospital
Paediatric Anaesthetist and Intensivist Department of Clinical Pathology
Department of Anaesthesia and Critical Care Medicine Mansoura University Hospital
Auckland Children’s Hospital Mansoura, Egypt
Auckland, New Zealand
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viii Contributors
Mette M. Berger, MD, PhD [124] Gilles Boulay, MD [1]

Professor of Anesthesia and Critical Care Medicine Faculté de Médecine, AP-HP
University of Lausanne School of Medicine Université Paris Descartes
Consultant, Service of Intensive Care Medicine and Burns Attending Anesthesiologist
Centre Hospitalier Universitaire Vaudois Hôpital Saint-Vincent de Paul
Lausanne, Switzerland Paris, France
Marc-André Bernath, MD, MER [124] Nathalie Bourdaud, MD [53, 112]
Médecin Associé Université Paris Descartes
Université de Lausanne Faculté de Médecine, AP-HP
Chef du secteur de l’Anesthésie Pédiatrique Praticien Hospitalier
Service d’Anesthésiologie Hôpital Necker Enfants-Malades
Centre Hospitalier Universitaire Vaudois (CHUV) Paris, France
Lausanne, Switzerland
Kenneth M. Brady, MD [15]
Dominique A. Bettex, MD [73]
Associate Professor, Pediatrics and Anesthesia
Assistant Professor of Anesthesiology
Baylor College of Medicine
University of Zurich
Chief, Division of Cardiac and Vascular Anesthesia Attending Anesthesiologist and Intensivist
University Hospital Department of Anesthesia and Pediatrics
Zurich, Switzerland Texas Children’s Hospital
Houston, Texas, USA
Bruno Bissonnette, MD [6]
Professor of Anesthesia Karen A. Brown, MD, FRCP(C) [62]
Department of Anesthesia Professor of Anesthesiology
Faculty of Medicine McGill University
University of Toronto Queen Elizabeth Hospital of Montreal Foundation Chair in
President and Founder Pediatric Anesthesia
Children of the World Anesthesia Foundation Attending Anesthesiologist
Toronto, Ontario, Canada Montreal Children’s Hospital
McGill University Health Center
David A. Blacoe, MbChB, MRCP(UK), FRCA [128] Montreal, Quebec, Canada
Consultant in Anaesthesia
Anaesthetist Stephen C. Brown, MD, FRCPC [16]
Monklands Hospital Associate Professor of Anesthesia
Airdrie, Scotland University of Toronto
Medical Director
Christopher M. Bolton, MB BS, FANZCA, PhD [122] Divisional Center of Pain Research and Pain Management
Attending Anaesthesiologist The Hospital for Sick Children
Department of Anaesthesia and Pain Management
The Royal Children’s Hospital
Melbourne, Victoria, Australia David Buckley, MBBChB, FANZCA, FCICM [42]
Paediatric Intensivist and Anaesthetist
Peter D. Booker, MB, BS, MD, FRCA [23, 95] Starship Children's Hospital
Senior Lecturer in Paediatric Anaesthesia Auckland, New Zealand
University of Liverpool
Honorary Consultant Sabine Kost-Byerly, MD [66]
Paediatric Anaesthetist Associate Professor of Anesthesiology
Alder Hey Children’s NHS Foundation Trust Johns Hopkins University School of Medicine
Liverpool, England Director, Pediatric Pain Management
Department of Anesthesiology and Critical Care Medicine
Alain Borgeat, MD, PhD [44] Baltimore, Maryland, USA
Professor of Anesthesiology
Chief, Department of Anesthesiology
Xavier Capdevila, MD, PhD [45]
Balgrist University Hospital
Professor of Anesthesiology and Critical Care Medicine
Zurich, Switzerland
Montpellier School of Medicine
Adrian Bösenberg, MB ChB, FFA(SA) [47,49,132] Montpellier University I
Professor of Anesthesiology Chairman, Department of Anesthesiology and
University of Washington Critical Care Medicine
Director, Division of Regional Anesthesia Lapeyronie University Hospital
Department Anesthesiology and Pain Management Montpellier, France
Seattle Children’s Hospital
Seattle, Washington, USA
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Contributors ix
Pierre Carli, MD [68] Brian Chanpong, DDS, MSc [126]

Professeur d’Anesthésiologie et de Réanimation Chirurgicale Clinical Assistant Professor
Université Paris Descartes Faculty of Dentistry
Chef, Département d’Anesthésie et de Réanimation University of British Columbia
Professor Hospitalier Attending Dental Anesthesiologist
Département d’Anesthésie-Réanimation Department of Dentistry
Directeur, SAMU de Paris British Columbia Children’s Hospital
Hôpital Necker Enfants Malades Vancouver, British Columbia, Canada
Paris, France
Pierre-Guy Chassot, MD, PhD [73]
Alison S. Carr, MB BS, FRCA, MSc, Associate Professor of Anesthesia
PGCertMEd (Dist) [99] University Hospital of Lausanne
Consultant Paediatric Anaesthetist and Head, Division of Cardiac Anesthesia
Honorary Senior Lecturer Director, Division of Intraoperative Transesophageal
Plymouth Hospitals NHS Trust Echocardiography
Derriford Hospital Lausanne, Switzerland
Plymouth, England
Farha Abd El-Aziz El-Chennawi, MD [82]
Michael J. Casas, DDS, Dip.Paed, MSc, FRCD(C) [125] Professor of Immunology
Associate Professor of Dentistry Vice-President of Mansoura University
University of Toronto Postgraduate Studies and Research
Director of Dental Clinics Faculty of Medicine, Mansoura University
Department of Dentistry Head of Immunology Unit and Clinical Pathology
The Hospital for Sick Children Mansoura University Hospital
Toronto, Ontario, Canada Mansoura, Egypt
Neroli Chadderton, BHB, MBChB, FANZCA [23] Olivier Choquet, MD [45]

Specialist Anesthetist Associate Professor of Anesthesia
Hutt Valley Hospital Montpellier University I
Wellington, New Zealand Lapeyronie University Hospital
Montpellier, France
Tristan M. B. de Chalain, MSc, MB Ch.B, FCS(SA),
FRCSC, FRACS [123] Howard M. Clarke, MD, PhD, FRCS(C),
University of Auckland FACS, FAAP [123]
Director, Auckland Plastic Surgical Center Professor of Surgery
Consultant Plastic Surgeon University of Toronto
Starship Children’s Hospital Active Staff Surgeon
Auckland, New Zealand Department of Surgery, Division of Plastic Surgery
The Hospital for Sick Children
George A. Chalkiadis, MB BS, FANZCA, Toronto, Ontario, Canada
FFPMANZCA, DA (London) [30]
Clinical Associate Professor John G. Coles, MD, FRCSC [105]
University of Melbourne Professor of Surgery
Consultant Paediatric Anaesthetist and Pain Medicine Specialist University of Toronto
Coordinator of the Children’s Pain Management Services Attending Cardiovascular Surgeon
Attending Paediatric Anaesthetist The Hospital for Sick Children
Department of Anaesthesia and Pain Management Toronto, Ontario, Canada
Melbourne, Victoria, Australia Mario J. da Conçeicao, MD, PhD [34]
Professor of Surgical Techniques and Anesthesia
John Chandler, FDSRCS, FCARCSI [10] Blumenau Regional University Foundation
Fellow in Pediatric Anesthesia Instructor of Pediatric Anesthesia
University of British Columbia Joana de Gusmao Children’s Hospital
British Columbia Children’s Hospital Florianopolis, Brazil
Vancouver, British Columbia, Canada
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x Contributors
Bairbre Connolly, MB BCh, BAO, FRCSI, MCh, Andrew Davidson, MBBS, MD, FANZCA [77]
FFRRCSI, LMCC, FRCP(C) [121] Leonard Travers Professor of Anaesthesia
Associate Professor of Radiology Clinical Associate Professor
Department of Medical Imaging Department of Pharmacology
University of Toronto University of Melbourne
Earl Glenwood Coulson Chair Associate Editor, Anesthesiology
Pediatric Interventional Radiology Head, Clinical Research Development
Department of Diagnostic Imaging—Image Guided Therapy Murdoch Children’s Research Institute
The Hospital for Sick Children Attending Anaesthetist
Toronto, Ontario, Canada Department of Anaesthesia and Pain Management
Isabelle Constant, MD, PhD [75] Melbourne, Victoria, Australia
Professeure d’Anesthésiologie et de Réanimation
AP-HP, UPMC Paris 6 Jayant K. Deshpande, MD, MPH [88]
Chef du Service d’Anesthésie-Réanimation Chirurgicale Professor of Pediatrics and Anesthesiology
Responsable du Pôle Hospital-Universitaire de University of Arkansas for Medical Sciences
Chirurgie-Anesthésie Senior Vice President/Chief Quality Officer
Coordonnateur du Centre de Traitement des Grands Brûlés Arkansas Children’s Hospital
Hôpital Armand Trousseau Little Rock, Arkansas, USA
Paris, France
John Doyle, MD, FRCPC, FAAP [113]
Robin G. Cox, MB BS, MRCP(UK), FRCA, FRCPC [36] Associate Professor of Anesthesiology
Professor of Anesthesia, University of Calgary Department of Pediatrics
Pediatric Anesthesiologist University of Toronto
Department of Anesthesia and Critical Care Medicine Head, Division of Blood and Marrow Transplant Program
Alberta Children’s Hospital The Hospital for Sick Children
Calgary, Alberta, Canada Toronto, Ontario, Canada
Peter N. Cox, MBChB, DCH, FFARCS (UK), R. Blaine Easley, MD [15, 58]
FRCP(C) [64] Associate Professor, Pediatrics and Anesthesiology
Professor of Anesthesia, Critical Care and Pediatrics Baylor College of Medicine
University of Toronto Attending in Cardiovascular Anesthesiology and Critical Care
Associate Chief, Critical Care Unit Texas Children’s Hospital
Clinical Director, Pediatric Intensive Care Unit Houston, Texas, USA
Fellowship Program Director
Department of Critical Care Medicine David Elliott, MB BS (Lon), MRCP(UK), FRCA,
The Hospital for Sick Children PgClinUs [99]
Toronto, Ontario, Canada Anaesthetic Registrar
Derriford Hospital
Mary Cunliffe, MB BS, FRCA, FFPMRCA [91] Plymouth, England
Honorary Clinical Lecturer in Anaesthesia
University of Liverpool Steven T. Elliott, MD [89]
Consultant Paediatric Anaesthetist Surgery Resident
Jackson Rees Department of Paediatric Anaesthesia University of California Davis Medical Center
Alder Hey Children’s NHS Foundation Trust Sacramento, California, USA
Liverpool, England
Thomas Engelhardt, MD, PhD [5, 57]
Sharon L. Cushing, MD, MSc, FRCS(C) [98] Consultant Paediatric Anaesthetist
Assistant Professor of Surgery (ENT) Royal Aberdeen Children’s Hospital
University of Toronto Aberdeen, Scotland
Attending Otolaryngologist
The Hospital for Sick Children Walid A. Farhat, MD, FAAP [109]
Toronto, Ontario, Canada Associate Professor of Surgery (Urology)
Department of Surgery, Division of Urology
Souhayl Dahmani, MD, PhD [19] University of Toronto
Université Paris VII Associate Surgeon-in-Chief for Education
Service d’Anesthésie-Réanimation et Douleur The Hospital for Sick Children
INSERM U676, Hôpital Robert Debré Toronto, Ontario, Canada
Paris, France
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Contributors xi
Patrick T. Farrell, MD [97] Steven Ganzberg, DMD, MS [126]

Conjoint Lecturer, University of Newcastle Professor of Clinical Anesthesiology
Director of Anaesthesia, John Hunter Hospital College of Dentistry
Newcastle, New South Wales, Australia College of Medicine and Public Health
The Ohio State University
Pierre Fayoux, MD, PhD [8] Residency Program Director
Director of the Pediatric Otorhinolaryngology Department of Dental/Maxillofacial Anesthesiology
Head-Neck Surgery Columbus, Ohio, USA
Department of Otorhinolaryngology
Jeanne de Flandre Children’s Hospital Zipporah Njeri Gathuya, MD [132]
University Hospital of Lille Specialist Anesthesiologist
Lille 2 University University of Nairobi
Lille, France Director, Pediatric Anesthesia
Department Anesthesiology
Annie Fecteau, MD [107] Mary Gertrude Children’s Hospital
Associate Professor of Surgery Nairobi, Kenya
Department of Surgery
University of Toronto J. Ted Gerstle, MD [96]
Division of General and Thoracic Surgery Associate Professor of Surgery
Sick Kids Transplant Center Department of Surgery
The Hospital for Sick Children University of Toronto
Toronto, Ontario, Canada Program Director, Division of General and Thoracic Surgery
Jean-Louis Feugeas, MD [45] Project Investigator—Program in Cell Biology
Associate Professor of Anesthesia Research Institute
La Conception University Hospital The Hospital for Sick Children
Marseille, France Toronto, Ontario, Canada
David M. Fisher, MB BCh, FRCSC, FACS [100] Peter Gibson, MBBS, FANCZA [110]
Associate Professor of Surgery (Plastics) Clinical Lecturer in Anaesthesia
University of Toronto The University of Sydney
Medical Director, Cleft Lip and Palate Program Staff Anaesthetist
The Hospital for Sick Children Specialist Paediatric Anaesthetist
Toronto, Ontario, Canada The Children’s Hospital at Westmead
Westmead, New South Wales, Australia
James Flowerdew, MD [101] Jean-Louis Giniès, MD [11]
Attending Anesthesiologist Professor of Pediatrics
Director, Medical Student Electives in Anesthesia University of Angers
Maine Medical Center Attending Pediatrician
Portland, Maine, USA Pediatric Intensive Care Medicine
Centre Hospitalier Universitaire
Christopher R. Forrest, MD, MSc, FRCSC, FACS [116] Angers, France
Professor of Surgery,
Department of Surgery Jean Godard, MD [71]
University of Toronto Praticien Hospitalier d’Anesthésie-Réanimation
Chief, Division of Plastic Surgery Service de Réanimation Pédiatrique
Medical Director, Craniofacial Program Hôpital Femme-Mère-Enfant
The Hospital for Sick Children Lyon, France
Manuel García Górriz, MD [12]
Michael J. Fredrickson, MD, MBChB, FANZCA [51] Assistant Professor of Anesthesia
Clinical Senior Lecturer Universitat Autonoma de Barcelona
University of Auckland Hospital Universitari Vall D’Hebron
Auckland, New Zealand Barcelona, Spain
Mohamed El-Gammal, MD [115] Marie Granier, MD [103]

Assistant Professor of Anesthesia Pediatric Anesthesiologist
King Saud bin Abdulaziz University for Health Sciences Centre Hospitalier Universitaire Estaing
Chairman Department of Anesthesia Clermont-Ferrand, France
Head, Division of Pediatric Anesthesia
King Abdulaziz Medical City
Riyadh, Saudi Arabia
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xii Contributors
Jean-Claude Granry, MD [11] Brendan O’Hare, MB [119]

Professor of Anesthesia and Intensive Care Senior Clinical Lecturer
University of Angers Department of Pediatrics
Chief, Department of Anesthesia and Intensive Care Trinity Medical School
Department of Anesthesia and Critical Care Medicine Trinity College
Centre Hospitalier Universitaire Consultant in Paediatric Anesthesia and Critical Care Medicine
Angers, France Our Lady’s Children’s Hospital, Crumlin
Dublin, Ireland
George A. Gregory, MD [133]
Professor Emeritus, Anesthesia and Pediatrics Jason A. Hayes, MD [25]
University of California, San Francisco Assistant Professor of Anesthesia
San Francisco, California, USA University of Toronto
Attending Anesthesiologist
Magalie Guérin, MD [40] The Hospital for Sick Children
Faculté de Médecine de Marseille Toronto, Ontario, Canada
Université de la Méditerranée
Fellow, Department of Pediatric Anesthesia and Elise Héon, MD, FRCS(C) [102]
Critical Care Medicine Professor of Ophthalmology
La Timone University Hospital Department of Ophthalmology and Vision Sciences
Marseille, France University of Toronto
Ophthalmologist-in-Chief
Jean-Daniel Guieu, MD, PhD [76] Department of Ophthalmology and Vision Sciences
Professor Emeritus of Neurophysiology Associate Surgeon-in-Chief
University of Lille II The Hospital for Sick Children
Department of Clinical Neurophysiology Toronto, Ontario, Canada
University Hospital of Lille
Lille, France Badr-Eddine Hmamouchi, MD [79]
Professor of Anesthesia and Critical Care Medicine
Walid Habre, MD, PhD [61] Hassan II – Ain Chok University of Casablanca
Associate Professor of Anesthesia Department of Anesthesia and Critical Care
University of Geneva Casablanca Children’s Hospital
Head, Division of Pediatric Anesthesia Casablanca, Morocco
University Hospitals of Geneva
Geneva, Switzerland Laura Holmes, BSc, CNIM [74]
Neurophysiology Technologist
Division of Intraoperative Neuromonitoring
Gregory B. Hammer, MD [67]
Professor of Anesthesiology and Pediatrics
Departments of Anesthesia and Pediatrics
Stanford University School of Medicine Osami Honjo, MD, PhD [94, 105]
Attending Anesthesiologist Assistant Professor of Surgery (Cardiovascular)
Director of Pediatric Anesthesia Research Department of Surgery
Lucile Packard Children’s Hospital at Stanford University of Toronto
Stanford, California, USA Staff Cardiovascular Surgeon,
Division of Cardiovascular Surgery
Jamil Hamza, MD [1] Department of Surgery
Professor of Anesthesia and Critical Care Medicine The Hospital for Sick Children
Faculté de Médecine, AP-HP Toronto, Ontario, Canada
Université Paris Descartes
Head of Pediatric Surgical Intensive Care David J. Kenny, BSc, DDS (hons), PhD, Dip Ped,
Hôpital Necker Enfants-Malades FRCD(C) [125]
Paris, France Professor of Dentistry
Raafat S. Hannallah, MD [69] Attending Pediatric Dentist
Professor of Anesthesiology and Pediatrics The Hospital for Sick Children
The George Washington University Medical Center Toronto, Ontario, Canada
Attending Pediatric Anesthesiologist
Department of Anesthesiology
Children’s National Medical Center
Washington, DC, USA
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Contributors xiii
Renée Krivosic-Horber, MD [81] Martin Jöhr, MD [31]

Professeure d’Anesthésie et Réanimation Professor of Anesthesia and Intensive Care Medicine
Université de Lille 2 Head, Division of Pediatric Anesthesia
Chef, Centre d’Hyperthermie Maligne de LilleHead, Department of Anesthesia, Intensive Care Medicine,
Lille MH Center Emergency Medicine and Pain Therapy
Centre de référence des maladies rares neuro-musculaires Luzerner Kantonsspital
Centre Hospitalier Regional Universitaire Luzerne, Switzerland
Lille, France
Daisy T. Joo, MD, PhD [25]
Rodrigo A. Iniguez, MD [111] Attending Anesthesiologist
Pediatric Surgeon North York General Hospital
Group for Improvement of Intestinal Function and Treatment Toronto, Ontario, Canada
Transplant Center, The Hospital for Sick Children
Toronto, Ontario Hans Jutzi, MD [44]
Tel-Hashomer, Israel Consultant in Anesthesiology
Richard J. Ing, MBBCh, FCA(SA) [83] Balgrist University Hospital
Associate Professor of Anesthesia and Critical Care Medicine Zurich, Switzerland
Duke University
Attending Anesthesiologist and Intensivist Chaim Kaplinsky, MD [13]
Division of Pediatric Anesthesia and Critical Care Medicine Professor of Medicine (Hematology) and Pediatrics
Department of Anesthesiology The Sackler School of Medicine
Duke University Medical Center University of Tel-Aviv
Durham, North Carolina, USA Department of Pediatric Hematology-Oncology
“Safra” Children’s Hospital
Lisa A. Isaac, MD, FRCP(C) [39] The Chaim Sheba Medical Center
Assistant Professor of Anesthesia Tel-Hashomer, Israel
Attending Anesthesiologist Cengiz Karsli, BSc, MD, FRCPC [39]
Department of Anesthesia and Pain Medicine Assistant Professor of Anesthesia
The Hospital for Sick Children University of Toronto
Toronto, Ontario, Canada Attending Anesthesiologist
Giorgio Ivani, MD [48] Toronto, Ontario, Canada
Associate Professor of Anesthesia
University of Turin Katherine Keech, MD [47]
Chairman, Department of Pediatric Anesthesia and Fellow in Pediatric Anesthesia
Intensive Care Medicine Department Anesthesiology and Pain Management
Regina Margherita Children’s Hospital Seattle Children’s Hospital
Turin, Italy Seattle, Washington, USA
Brenna L. Jacobson, MD [59] Cassandra M. Kelleher, MD [107]

Assistant Professor of Anesthesiology Instructor in Surgery
Loma Linda University School of Medicine Department of Surgery
Attending Anesthesiologist Harvard Medical School
Loma Linda, California, USA Assistant in Surgery
Mass General Hospital for Children
Justin John, MD [113] Boston, Massachusetts, USA
Assistant Professor of Anesthesiology and Pediatrics
Department of Pediatrics Gili Kenet, MD [13]
Eastern Virginia Medical School Professor of Medicine (Hematology) and Pediatrics
Attending Anesthesiologist The Sackler School of Medicine
Medical Director of Sedation Services University of Tel-Aviv
Department of Anesthesiology Institute of Thrombosis and Hemostasis
Children’s Hospital of The King’s Daughters The Thrombosis Unit and National Hemophilia Center
Norfolk, Virginia, USA Department of Hematology
Safra Children’s Hospital
The Chaim Sheba Medical Center
Tel-Hashomer, Israel
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xiv Contributors
Sonia ben Khalifa, MD [90] Wai-Ching Lam, MD, FRCS(C) [102]

Professor of Anesthesia and Intensive Care Medicine Associate Professor of Ophthalmology
Faculty of Medicine, Tunis El Manar University Program Director
Chairman Department of Ophthalmology and Vision Sciences
Department of Anesthesia and Intensive Care Medicine University of Toronto
University Children Hospital Attending Ophthalmologist
Tunis, Tunisia Department of Ophthalmology and Vision Sciences
Antoine E. Khoury, MD, FRCSC, FAAP [87] Attending Ophthalmologist
Professor and Chief of Pediatric Urology Toronto Western Hospital
University of California, Irvine University Health Network
Children’s Hospital of Orange County Toronto, Ontario, Canada
Orange, California, USA
Frédéric Lamy, MD [40]
Jarmila Kim, MD, FRCPC [37] Faculté de Médecine de Marseille
Assistant Professor of Anesthesia Université de la Méditerranée
University of Ottawa Fellow, Department of Pediatric Anesthesia and
Attending Anesthesiologist Critical Care Medicine
Children’s Hospital of Eastern Ontario La Timone University Hospital
Ottawa, Ontario, Canada Marseille, France
Vincent P. Laudenbach, MD, PhD [19]

Peter C. W. Kim, MD, CM, PhD [85] Professor of Pediatric Anesthesiology and Neonatal
Professor of Surgery Intensive Care
Department of Surgery Charles Nicolle University Hospital
University of Toronto Laboratory Deputy Head
Staff Surgeon, Lead CIGITI EA 4309 NeoVasc “Microvasculature and neonatal brain lesions”
Hospital for Sick Children Normandy University Institute
Toronto, Ontario, Canada Rouen, France
Hannu Kokki, MD, PhD [27] Emmanuèle Laureau, MD, MsC [76]
Associate Professor of Anesthesiology Staff Neurophysiologist
University of Kuopio Department of Clinical Neurophysiology
Attending Anesthetist University Hospital of Lille
Kuopio University Hospital, Lille, France
Kuopio, Finland
Peter C. Laussen, MBBS [119]
Charles D. Kurth, MD [129] Professor of Anesthesia
Professor of Anesthesia and Pediatrics Harvard Medical School
University of Cincinnati College of Medicine DD Hansen Chair in Pediatric Anesthesia
Anesthesiologist in Chief Chief, Division Cardiovascular Critical Care
Chairman, Department of Anesthesiology Children’s Hospital Boston
Cincinnati Children’s Hospital Medical Center Boston, Massachusetts, USA
Cincinnati, Ohio, USA
Charles Lee, MD [108]
Frédéric Lacroix, MD [45] Assistant Professor of Anesthesiology
Praticien Hospitalier Loma Linda University School of Medicine
Faculté de Médecine de Marseille Director of Acute/Perioperative Pain Service
Université de la Méditerranée Director of Organ Transplantation Anesthesia
Anesthésiste-Réanimateur Pédiatrique Clinical Director of Pediatric Anesthesia
Départment d’Anesthésiologie et Réanimation Loma Linda University Medical Center
Centre Hospitalier Universitaire La Timone Loma Linda, California, USA
Assistance Publique—Hôpitaux de Marseille
Marseille, France Corinne Lejus, MD, PhD [63]
Professor of Anesthesiology and Surgical
Carol L. Lake, MD, MBA, MPH [95] Intensive Care Medicine
Hummelstown, Pennsylvania, USA University of Nantes
Chief of Department of Anesthesiology and Surgical
Intensive Care Medicine
Hôtel Dieu
Centre Hospitalier Universitaire de Nantes
Nantes, France
Bissonette-000FM-(F) 4/9/11 3:33 PM Page xv
Contributors xv
Mark F. Levine, MBBCh, FRCPC [117] Barry Lyons, MB, FFARCSI [64]
Associate Professor of Anesthesia Consultant Anaesthetist
Program Director Department of Anaesthesia and Critical Care Medicine
Department of Anesthesia Our Lady’s Hospital for Sick Children
University of Toronto Dublin, Ireland
The Hospital for Sick Children Jean Mantz, MD, PhD [19]
Toronto, Ontario, Canada Professeur d’Anesthésie-Réanimation
Université Paris VII, Paris Diderot
Jonathan de Lima, MBBS, PhD (UCL), FANCZA [110] Chairman, Service d’Anesthésie-Réanimation
Clinical Senior Lecturer INSERM U676, Hôpital Beaujon
The University of Sydney Clichy la Garenne, France
Deputy, Department of Pain Medicine and Palliative Care Bruno Marciniak, MD [8]
Senior Staff Anaesthetist Attending Anesthesiologist
Specialist Paediatric Anaesthetist Jeanne de Flandre Children’s Hospital
The Children’s Hospital at Westmead University Hospital of Lille
Westmead, New South Wales, Australia Lille, France
Tsz-Yan Milly Lo, MB ChB, DCH, MRCP (UK), Peter Marhofer, MD [46]
MRCPCH, PhD [64] Professor of Anesthesiology
Honorary Senior Lecturer Medizinische Universität Wien
University of Edinburgh Univ. Klinik für Anästhesie, Intensivmedizin and
Consultant in Paediatric Intensive Care Medicine Schmerztherapie
The Royal Hospital for Sick Children Vienna, Austria
Edinburgh, Scotland
Giuseppe Marraro, MD [72]
Justin L. Lockman, MD [58] Associate Professor of Anesthesia and
Fellow in Anesthesiology and Critical Care Medicine Intensive Care Medicine II Specialization
Pediatric Critical Care Medicine and Anesthesiology School of Anesthesia and Intensive Care
The Johns Hopkins School of Medicine Faculty of Medicine and Surgery
Fellow in Anesthesiology University of Milan
Children’s Hospital Honorary Consultant in Anesthesia and
The Johns Hopkins Hospital Intensive Care Medicine
Baltimore, Maryland, USA Director of Pediatric Anesthesia and Intensive Care Medicine
Pediatric Intensive Care Unit
Per-Arne Lönnqvist, MD, DEAA, FRCA, PhD [86] Fatebenefratelli and Ophthalmiatric Hospital
Professor of Pediatric Anesthesia and Intensive Care Medicine
Milan, Italy
Department of Physiology and Pharmacology
Karolinska Institute
Lynn D. Martin, MD, FAAP, FCCM [131]
Senior Consultant, Karolinska University Hospital
Professor of Anesthesiology and Pediatrics (Adj.)
Stockholm, Sweden
University of Washington School of Medicine
Director, Department of Anesthesiology and Pain Medicine
Armando J. Lorenzo, MD, MSc, FAAP [109] Medical Director, Bellevue Clinics and Surgery Center
Assistant Professor of Surgery (Urology)
Seattle Children’s Hospital
Department of Surgery, Division of Urology
Seattle, Washington, USA
Attending Surgeon Linda J. Mason, MD [59, 95]
The Hospital for Sick Children Professor of Anesthesiology and Pediatrics
Toronto, Ontario, Canada Loma Linda University School of Medicine
Director of Pediatric Anesthesiology
Igor Luginbuehl, MD [14] Loma Linda University Medical Center
Associate Professor of Anesthesia Loma Linda, California, USA
Attending Anesthesiologist Lynne G. Maxwell, MD, FAAP [66]
The Hospital for Sick Children Associate Professor Anesthesiology and Critical Care
Toronto, Ontario, Canada University of Pennsylvania
Ruth Oelhafen Luginbuehl, MD, DTATI [2] Deputy Director, General Anesthesia Division
Pediatrician FMH The Children’s Hospital of Philadelphia
Medical Art Therapist DTATI Philadelphia, Pennsylvania, USA
Bissonette-000FM-(F) 4/9/11 3:33 PM Page xvi
xvi Contributors
Jean Xavier Mazoit, MD, PhD [28] Neil S. Morton, MD, FRCA, FRCPCH, FFPMRCA [41]
Attending Anesthesiologist Reader in Paediatric Anaesthesia and Pain Management
Département d’Anesthésie-Réanimation University of Glasgow
Hôpital Bicêtre AP-HP Consultant in Paediatric Anaesthesia and Pain Management
Laboratoire d’Anesthésie UMR788 Royal Hospital for Sick Children
Neuroprotection, régénération des axones et de la myéline Editor-in-Chief, Pediatric Anesthesia
Université Paris-Sud Glasgow, Scotland
Faculté de Medecine du Kremlin-Bicêtre
Bicêtre, France Valeria Mossetti, MD [48]
Craig D. McClain, MD, MPH, FAAP [93] Division of Pediatric Anesthesiology and
Assistant Professor of Anesthesia Intensive Care Medicine
Harvard Medical School Regina Margherita Children’s Hospital
Associate in Anesthesia Turin, Italy
Children’s Hospital Boston
Etsuro K. Motoyama, MD [9]
Boston, Massachusetts, USA
Professor Emeritus of Anesthesiology and Pediatrics
Conor McDonnell, MD, MB [20] University of Pittsburgh School of Medicine
Assistant Professor of Anesthesia Attending Anesthesiologist and Pulmonologist
University of Toronto Director Emeritus, Respiratory Physiology Laboratory
Staff Anesthesiologist Children’s Hospital of Pittsburgh
The Hospital for Sick Children University of Pittsburgh Medical Center
Toronto, Ontario, Canada Pittsburgh, Pennsylvania, USA
Patricia A. McGrath, PhD [16] Isabelle Murat, MD, PhD [127]

Professor of Anesthesia Professor of Anesthesia
University of Toronto AP-HP, University Paris 6
Scientific Director Chairman, Departement of Anesthesia and
Chronic Pain Program Psychology Critical Care Medicine
Research Institute Armand Trousseau Hospital
Senior Associate Scientist Paris, France
Neurosciences and Mental Health
The Hospital for Sick Children Laura B. Myers, MD [120]
Toronto, Ontario, Canada Assistant Professor of Anesthesia
Harvard Medical School
Olli A. Meretoja, MD [27] Research Associate in Anesthesia
Professor of Anesthesiology Children's Hospital Boston
University of Helsinki Staff Anesthesiologist
Hospital for Children and Adolescents Newton-Wellesley Hospital
Helsinki, Finland Boston, Massachusetts, USA
Hawa Keïta-Meyer, MD, PhD [19] Sif-Eddine Nejmi, MD [79]

Professor of Anesthesia Professor of Anesthesia and Critical Care Medicine
AP-HP, University Paris 7 Hassan II – Ain Chok University of Casablanca
Director, Division of Anesthesia Department of Anesthesia and Critical Care
Louis Mourier Hospital Casablanca Children’s Hospital
Colombes, France Casablanca, Morocco
Gregory Moloney, MBBS, FANZCA [43] David G. Nykanen, MD [118]

Attending Anaesthetist Associate Professor of Paediatrics (Cardiology)
Mater Children’s Hospital University of Central Florida College of Medicine
Brisbane, Queensland, Australia Director, Cardiology and Cardiac Catheterization
Arnold Palmer Medical Center
Victor H. Espinal Montoya, MD [65] Orlando, Florida, USA
Department of Anesthesia Kar-Binh Ong, MBBS (London), FRCA(UK) [56]
Cape Breton Regional Hospital Honorary Senior Lecturer (Institute of Child Health)
Sydney, Nova Scotia, Canada Consultant Anaesthetist (Great Ormond Street Hospital)
Great Ormond Street Hospital
London, England
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Contributors xvii
Gilles Orliaguet, MD, PhD [53, 112] Aurelia Peraud, MD, PhD [92]
Professeur d’Anesthésiologie et Réanimation Associate Professor of Surgery (Neurosurgery)
Université Paris Descartes Faculté de Médecine, AP-HP Ludwig-Maximilian University of Munich
Vice Chairman Chief, Division Pediatric Neurosurgery
Département d’Anesthésie et Réanimation Attending Pediatric Neurosurgeon and Epilepsy Surgeon
Hôpital Necker Enfants-Malades Department of Neurosurgery
Paris, France Klinikum Grosshadern
Munich, Germany
Nicholas Pace, FRCA, FRCP, MPhil, PhD [128]
Clinical Director Daniel A. Peters, MD, MBA, FRCSC [116]
Department of Anaesthesia Assistant Professor of Surgery (Plastic Surgery)
Gartnavel General Hospital Department of Surgery
Glasgow, Scotland Telfer School of Management
University of Ottawa
Greta M. Palmer, MBBS, FANZCA, FFPMANZCA [26] Children’s Hospital of Eastern Ontario
Clinical Associate Professor Ottawa, Ontario, Canada
University of Melbourne
Deputy Head, Children’s Pain Management Service Robert Plant, FCARCSI, FJFICM(Ireland),
Paediatric Anaesthetist and Pain Management Specialist FJFICM(Aus/NZ) [10]
Royal Children’s Hospital Director of Intensive Care
Murdoch Children’s Research Institute Cork University Hospital
Melbourne, Victoria, Australia Cork, Ireland
Blake C. Papsin, MD, MSc, FRCSC, FACS, FAAP [98] David M. Polaner, MD, FAAP [130]
Professor of Otolaryngology Professor of Anesthesiology and Pediatrics
Faculty of Medicine University of Colorado School of Medicine
The University of Toronto Chief, Acute Pain Service
Cochlear Chair in Auditory Development Anesthesia Informatics
Director of the Cochlear Implant Program The Children’s Hospital of Denver
Attending Otolaryngologist Aurora, Colorado, USA
Associate Scientist, Neurosciences and Mental Health
The Research Institute George D. Politis, MD, MPH [21]
The Hospital for Sick Children Associate Professor of Anesthesiology and Pediatrics
Toronto, Ontario, Canada University of Virginia
Catherine Paquet, MD, FRCPC [54] Co-Director of the University of Virginia
Assistant Professor of Anesthesia Outpatient Surgical Center
McGill University University of Virginia Health System
Attending Anesthesiologist Charlottesville, Virginia, USA
Montreal Children’s Hospital
Montreal, Quebec, Canada Elizabeth Prentice, MBBS, FANZCA [70]
Attending Paediatric Anaesthetist
Olivier Paut, MD [40] Department of Anaesthesia and Pain Management
Professor of Anesthesia and Critical Care Medicine The Royal Children’s Hospital
Faculté de Médecine de Marseille Melbourne, Victoria, Australia
Université de la Méditerranée
Head, Department of Pediatric Anesthesia and Carlos Hervás Puyal, MD [12]
Critical Care Medicine Consultant Pediatric Anesthesiologist
La Timone University Hospital Department of Anesthesia
Marseille, France Hospital Universitario Vall d’Hebron
Barcelona, Spain
Dilip Pawar, MBBS, DA, MD, FAMS, FAMS(S) [29]
Professor of Anesthesiology Abdullah A. Al-Rabeeah, MD, FRCSC [114]
All India Institute of Medical Sciences Minister of Health, Kingdom of Saudi Arabia
New Delhi, India Professor of Surgery
King Saud bin Abdulaziz University for Health Sciences
Senior Pediatric Surgeon
King Abdulaziz Medical City (National Guard Health Affairs)
Riyadh, Saudi Arabia
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xviii Contributors
Carmen T. Ramos, MD, MSc [85] Sophie Saindon, MD, FRCP(C) [55]
Ad Honorem Associate Professor of Surgery Clinical Assistant Professor of Anesthesia
University of Puerto Rico University of Montreal
Chief, Division of Pediatric Surgery Attending Anesthesiologist
Department of Surgery Centre Hospitalier Universitaire Ste-Justine
San Jorge Children’s Hospital Mother and Child University Hospital Center
San Juan, Puerto Rico Montreal, Quebec, Canada
Sally E. Rampersad, MD [131] Michela Salvadore, MBChB, FRCA [57]
Associate Professor of Anesthesiology Specialist Registrar in Anaesthesia
Department of Anesthesiology Royal Aberdeen Children’s Hospital
University of Washington School of Medicine Aberdeen, Scotland
Director, Quality Improvement
Department of Anesthesiology and Pain Medicine Paul J. Samuels, MD [129]
Children’s Hospital and Regional Medical Center Associate Professor of Anesthesiology and Pediatrics
Seattle, Washington, USA Director of Education
Cincinnati Children’s Hospital
Pramod P. Reddy, M.B.B.S. [87] Cincinnati, Ohio, USA
Associate Professor of Urology
University of Cincinnati Anthony D. Sandler, MBChB [89]
Director, Division of Pediatric Urology Diane and Norman Bernstein Chair
Cincinnati Children’s Hospital Medical Center Professor of Surgery and Pediatrics
Cincinnati, Ohio, USA George Washington University
Chief, Division of Thoracic and Abdominal Surgery
Andrew N. Redington, MB, BS, MRCP (UK), MD, FRCP Children’s National Medical Center
(UK), FRCP (C) [7] Washington, DC, USA
Professor of Pediatrics
University of Toronto Rosario Nuño Sanz, MD [12]
BMO Financial Group Chair in Cardiology Pediatric Anesthetist
Labatt Family Heart Centre Department of Anesthesiology
Head, Division of Cardiology Hospital Universitario Vall d’Hebron
The Hospital for Sick Children Barcelona, Spain
Senior Associate Scientist
Physiology and Experimental Medicine Frédérique Sauvat, MD, PhD [112]
The Hospital for Sick Children Research Institute Praticien Hospitalier
Toronto, Ontario, Canada Pediatric Surgeon
Centre Hospitalier Regional F. Guyon
Bénédicte Ringuier, MD [11] Saint Denis de la Réunion, France
Department of Pediatrics
University of Angers Ahmed Mohamed Shalabi, MSC, MD [80]
Attending Pediatrician Assistant Lecturer in Anesthesiology and
Pediatric Anesthesia and Intensive Care Surgical Intensive Care Medicine
Centre Hospitalier Universitaire Faculty of Medicine
Angers, France Alexandria University
Attending Anesthesiologist and Intensivist
Allison Kinder Ross, MD [83] Alexandria University Hospitals
Associate Professor of Anesthesia Alexandria, Egypt
Duke University
Chief, Division of Pediatric Anesthesia Lionel Simon, MD (Deceased) [1]
Division of Pediatric Anesthesia and Critical Care Medicine Faculté de Médecine, AP-HP
Department of Anesthesiology Université Paris Descartes
Duke University Medical Center Anesthesiologist
Durham, North Carolina, USA Hôpital Saint-Vincent de Paul
Paris, France
David A. Rowney, MB ChB, FRCA [78]
Consultant in Paediatric Anaesthesia and Craig Sims, MB BS FANZCA [35]
Intensive Care Medicine Clinical Senior Lecturer in Anaesthesia
Royal Hospital for Sick Children School of Paediatrics and Child Health
Edinburgh, Scotland University of Western Australia
Paediatric Anaesthetist
Princess Margaret Hospital for Children
Perth, Western Australia, Australia
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Contributors xix
Jonathan H. Smith, BSc (Hons), MB, BS, FRCA [56] Michael R. J. Sury, FFARCS [56]
Honorary Senior Lecturer in Anaesthesia Honorary Senior Lecturer in Anaesthesia
Portex Unit of Paediatric Anaesthesia PORTEX Unit of Paediatric Anaesthesia
UCL Institute for Child Health Institute of Child Health
Consultant Paediatric Anaesthetist University College London
Great Ormond Street Hospital for Children Consultant Anaesthetist
London, England Department of Anaesthesia
Great Ormond Street Hospital NHS Trust
Raz Somech, MD, PhD [13] London, England
Professor of Medicine (Immunology) and Pediatrics
The Sackler School of Medicine Dale F. Szpisjak, MD, MPH [54]
Tel-Aviv University Associate Professor of Anesthesiology
Director, Division of Pediatric Immunology Uniformed Services University of the Health Sciences
Department of Pediatric Interim Chair, Department of Anesthesiology
Edmond and Lily Safra Children’s Hospital Bethesda, Maryland, USA
The Chaim Sheba Medical Center
Institute of Hematology Elsa Taylor, MBChB, FANZCA [24]
The Sheba Cancer Research Center Specialist Paediatric Anaesthetist
Tel Hashomer, Israel Starship Children’s Hospital
Starship Children’s Health
Sulpicio G. Soriano, MD, FAAP [93] Auckland, New Zealand
Professor of Anesthesia
Harvard Medical School Nasrin Najm-Tehrani, MB BCh, MSc,
Children’s Hospital Boston Endowed Chair in FRCS Ed (Ophth) [102]
Pediatric Neuroanesthesia Assistant Professor of Ophthalmology
Attending Pediatric Anesthesiologist Department of Ophthalmology and Vision Sciences
Children’s Hospital Boston University of Toronto
Boston, Massachusetts, USA Attending Ophthalmologist
Leader of ROP Program
William M. Splinter, MD, FRCPC [37] Department of Ophthalmology and Vision Sciences
Associate Professor of Anesthesia The Hospital for Sick Children
University of Ottawa Toronto, Ontario, Canada
Children’s Hospital of Eastern Ontario Caroline Telion, MD [68]
Ottawa, Ontario, Canada Practicien Hospitalier
Département d’Anesthésie – Réanimation
Samuel Strantzas, MSc, D.ABNM [74] Hôpital Necker Enfants Malades
Associate Clinical Neurophysiologist Paris, France
Director, Division of Intraoperative Neuromonitoring
The Hospital for Sick Children Michael J. Temple, MD, FRCPC [121]
Toronto, Ontario, Canada Assistant Professor of Radiology
Department of Medical Imaging
Pascal Stucki, MD, MER [124] University of Toronto
Médecin Associé Attending Radiologist
Service de Soins Intensifs Médicochirurcaux de Pédiatrie Pediatric Interventional Radiology
Centre Hospitalier Universitaire Vaudois (CHUV) Department of Diagnostic Imaging—Image Guided Therapy
Lausanne, Switzerland The Hospital for Sick Children
Santhanam Suresh, MD [50]
Professor of Anesthesiology and Pediatrics Priya Thalayasingam, MBBS, FANZCA [104]
Northwestern University’s Feinberg School of Medicine Consultant Paediatric Anaesthetist
Vice Chairman Department of Anaesthesia and Pain Management
Director of Research and Pain Medicine Princess Margaret Hospital for Children
Department of Anesthesiology Perth, Western Australia, Australia
Children’s Memorial Hospital
Chicago, Illinois, USA
Joseph D. Tobias, MD [4, 15, 57]
Professor of Anesthesiology and Pediatrics
The Ohio State University
Chairman, Department of Anesthesiology and Pain Medicine
Nationwide Children’s Hospital
Columbus, Ohio, USA
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xx Contributors
Dalia Mohamed Tohlob, MD [82] Polina Voronov, MD [50]

Assistant Lecturer of Clinical Pathology Assistant Professor of Anesthesiology
Faculty of Medicine, Mansoura University Hospital Northwestern University’s Feinberg School of Medicine
Mansoura, Egypt Attending Anesthesiologist
Children’s Memorial hospital
Jon Tomasson, MD [129] Chicago, Illinois, USA
Attending Pediatric Anesthesiologist
Children’s Hospital and Clinics of Minnesota Laszlo Vutskits, MD, PhD [3]
Minneapolis, Minnesota, USA Senior Lecturer in Anesthesia
Faculty of Medicine
Peter H. Tonner, MD [22] University of Geneva Medical School
Professor and Chairman Head, Neuroscience-Oriented Anesthesia Research Group
Department of Anesthesia and Intensive Care Medicine Department of Fundamental Neuroscience
Klinikum Links der Weser, Bremen Attending Anesthesiologist
Department of Anesthesia and Intensive Care Medicine Division of Pediatric Anesthesia
Klinikum Bremen Nord Department of Anesthesiology, Pharmacology and
Bremen, Germany Intensive Care
University Hospital of Geneva
Mehdi Trifa, MD [90] Geneva, Switzerland
Associate Professor of Anesthesia Samuel H. Wald, MD [59]
Faculty of Medicine, Tunis El Manar University, Clinical Professor, Pediatric Anesthesiology
Attending Anesthetist and Intensivist Associate Vice-Chair of Education
Department of Anesthesia and Intensive Care Medicine Associate Director, Residency Program
University Children Hospital Department of Anesthesiology
Tunis, Tunisia David Geffen School of Medicine at UCLA
Los Angeles, California, USA
Pedro Paulo Vanzillotta, MD [84]
Chief, Department of Anesthesia Paul W. Wales, BSc, MD, MSc, FRCSC, FACS [111]
Hospital Municipal Jesus Associate Professor of Surgery
Rio de Janeiro, Brazil Department of Surgery
Susan T. Verghese, MD [69] Neonatal and Pediatric Surgeon
Professor of Anesthesiology and Pediatrics Director, Group for Improvement of Intestinal Function and
The George Washington University Medical Center Treatment
Department of Anesthesia Associate Scientist, Child Health Evaluative Sciences
Children’s National Medical Center Research Institute, The Hospital for Sick Children
Washington, DC, USA Toronto, Ontario, Canada
Anne Laffargue Vetter, MD [52] Robert Whitty, FCARCSI [33]

Director of Pediatric Anaesthesia Division Consultant Pediatric Anesthetist
Jeanne de Flandre Children’s Hospital Children’s University Hospital
University Hospital of Lille The Adelaide, Meath, and National Children’s Hospital
University of Lille Dublin, Ireland
Lille, France
Suzanne Wiener, MD [4]
Francis Veyckemans, MD [38, 60] FMH Pediatrics
Clinical Professor of Anesthesiology
FMH Acupuncture
Université Catholique de Louvain (Woluwé)
University of Geneva
Pediatric Pain Fellow
Cliniques Universitaires St-Luc
Department of Anesthesiology and Reanimation
Brussels, Belgium
University Hospital of Geneva, Switzerland
Geneva, Switzerland
Daniel Vischoff, MD [55]
Clinical Assistant Professor of Anesthesia
Niall Wilton, MRCP, FRCA [42]
University of Montreal
Clinical Director
Pediatric Anesthesia and Operating Rooms
Centre Hospitalier Universitaire Ste-Justine
Starship Children’s Hospital
Mother and Child University Hospital Center
Starship Children’s Health
Montreal, Quebec, Canada
Auckland, New Zealand
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Contributors xxi
William Wisden, MA, PhD [5] Myron Yaster, MD [66]

Professor of Molecular Neuroscience Richard J. Traystman Distinguished Professor of Pediatric
Imperial College South Kensington, London Anesthesia, Critical Care Medicine, and Pain Management
Head, Cell Biology and Functional Genomics Section The Johns Hopkins University School of Medicine
Blackett Laboratory Attending Anesthesiologist
London, England Division of Pediatric Anesthesia
Departments of Anesthesiology, Critical Care Medicine and
Andrew R. Wolf, MA, MBBChir, MD, FRCA [15] Pediatrics
Honorary Professor of Anaesthesia Children’s Hospital, The Johns Hopkins Hospital
Faculty of Medicine Baltimore, Maryland, USA
University of Bristol
Consultant in Paediatric Anesthesia and Intensive Care Medicine Maysaa El Sayed Zaki, MD, PhD [82]
Bristol Royal Hospital for Children (Bristol Children’s Hospital) Professor of Clinical Pathology
Bristol, England Faculty of Medicine, Mansoura University
Department of Clinical Pathology
Gordon T. C. Wong, MB BS, FANZCA [32] Mansoura University Hospital
Clinical Assistant Professor of Anesthesiology Mansoura, Egypt
University of Hong Kong
Honorary Associate Consultant
Queen Mary Hospital
Hong Kong, China
Bissonette-000FM-(F) 4/9/11 3:33 PM Page xxii
Bissonette-000FM-(F) 4/9/11 3:33 PM Page xxiii
Preface
Pediatric anesthesia is no longer a subspecialty of anesthesia; in The children of the world we care for, represented by the
the twenty-first century, it is considered a professional entity. The Children of the World Anesthesia Foundation, are the ultimate
growing complexity of this specialty is well demonstrated in this recipients of Pediatric Anesthesia: Basic Principles—State of the
major addition to the medical and surgical literature. The academic Art—Future. This international organization, which I founded in
and scientific development in recent years can be well appreciated 2005, is dedicated to the promotion and dissemination of
through the exceptional contributions of the 220 collaborators continuing education in pediatric anesthesia and critical care
who invested a great deal of time to share their knowledge medicine through the development and acquisition of basic
and expertise in writing this textbook. They have successfully principles of safe practice of anesthesia for infants and children
demonstrated, once again, that children are not “small adults” in around the world. This book will provide expanded knowledge
modern anesthesia and surgery. I take this opportunity to express and substantial clinical information to healthcare professionals
to each and every one of them my sincere thanks for their to ensure that every child can aspire to the best care possible
participation in this international venture. wherever they live. The extensive electronic version of this book is
Because of the extent of the information to be shared with available on the Foundation’s website.
the readers, Pediatric Anesthesia: Basic Principles—State of the This unique textbook would not have been possible without
Art—Future is divided into six parts: Developmental Considera- the contribution and dedication of numerous other professionals.
tions; Pharmacology; Anesthesia Management and Techniques; I would like to extend my very special thanks to Ms. Linda Mehta
Special Monitoring and Resuscitation Techniques; Anesthetic, and Mr. Martin Wonsiewicz at PMPH-USA for their enthusiasm,
Surgical, and Interventional Procedures Considerations; and support, and determination to make this project a reality. I am also
Specific Considerations. I hope that this approach will facilitate truly grateful to Mr. David Stockhoff and members of his team at
consultation and optimize reading. To further demonstrate Spearhead Global, Inc. for their dedicated support in the making
the scientific importance of each section, an international group of of a book that is beyond compare. I also express my gratitude to
subeditors was invited to assist me with the giant task of providing Mr. Danny Aguilar, medical graphic artist and illustrator, for his
the highest quality and most in-depth information. Their unique contribution to the visual beauty of this book.
exceptional knowledge, based on a well-established international Finally, on behalf of the subeditors, collaborators, and everyone
reputation and recognized wisdom in academic pediatric else involved in this venture, I would like to express to each reader
anesthesia, elevates the status of this book. I am profoundly grateful our sincere thanks for your interest in pediatric anesthesia and
to Drs. Brian Anderson, Adrian Bösenberg, Thomas Engelhardt, your intellectual curiosity. We hope you will find it a thoughtful
Linda Mason, and Joseph Tobias for their extensive investment of and useful resource in your everyday professional activities and
time and determination in making this exceptional book the immediately adopt it as your best academic friend.
premier text in pediatric anesthesia. I wish to express to them all
my deepest gratitude for their support, enthusiasm and intellectual Merci!
generosity. Bruno Bissonnette
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Bissonette-000FM-(F) 4/9/11 3:33 PM Page xxv
Contents
PART I CHAPTER 10
DEVELOPMENTAL CONSIDERATIONS 1 Renal Function, Acid-Base, and
Electrolyte Homeostasis 140
Subeditor: Joseph D. Tobias
John Chandler and Robert Plant
CHAPTER 1 CHAPTER 11
Prenatal Normal and Abnormal Development 1 Digestive System, Metabolic
Gilles Boulay, Lionel Simon, and Jamil Hamza Functions, and Nutrition 170
Bénédicte Ringuier, Jean-Louis Giniès,
CHAPTER 2 and Jean-Claude Granry
General Growth and Tissue
Development Throughout Childhood 20 CHAPTER 12
Ruth Oelhafen Luginbuehl Endocrine System 181
Carlos Hervás Puyal, Manuel García Górriz,
CHAPTER 3 and Rosario Nuño Sanz
Anesthesia and the Developing Brain 43
Laszlo Vutskits CHAPTER 13
Principles of Hematopoiesis,
CHAPTER 4 Immunity, and Coagulation 203
Nociception and Pain Perception Chaim Kaplinsky, Raz Somech, and Gili Kenet
in Infants and Children 58
CHAPTER 14
Suzanne Wiener and Joseph D. Tobias
Temperature Regulation: Physiology
CHAPTER 5 and Pharmacology 221
Central Nervous System: Igor Luginbuehl
Neurotransmitters and Anesthesia 71
CHAPTER 15
Thomas Engelhardt and William Wisden Development and Evaluation of Pain
and the Stress Response 259
CHAPTER 6
Central Nervous System: Anatomy and Physiology 80 R. Blaine Easley, Kenneth M. Brady, Andrew R. Wolf,
Kanwaljeet J. S. Anand, and Joseph D. Tobias
Bruno Bissonnette
CHAPTER 16
CHAPTER 7 Chronic and Recurrent Pain in the
Normal and Abnormal Development Pediatric Patient 273
of the Heart and the Circulation 91 Stephen C. Brown and Patricia A. McGrath
Christian Apitz and Andrew N. Redington
PART II
CHAPTER 8 PHARMACOLOGY 291
Airway Development 100
Subeditor: Brian J. Anderson
Pierre Fayoux and Bruno Marciniak
CHAPTER 17
CHAPTER 9 An Introduction to the Intricacies
Respiratory Physiology 106 of Pharmacology in Pediatrics 291
Etsuro K. Motoyama Brian J. Anderson
Bissonette-000FM-(F) 4/9/11 3:33 PM Page xxvi
xxvi Contents
Using Pharmacokinetics and Pharmacodynamic Pharmacology of Vagal Blockers and
Models to Prevent Adverse Events in Neonates, Antagonist Agents 507
Infants, and Children 297 Martin Jöhr
Brian J. Anderson
CHAPTER 32
CHAPTER 19 Anticoagulants 525
Mechanisms of Action of General Anesthetics 310 Gordon T. C. Wong
Vincent P. Laudenbach, Souhayl Dahmani,
Hawa Keïta-Meyer, and Jean Mantz CHAPTER 33
Pharmacology of Vasopressive Agents 535
CHAPTER 20 Robert Whitty
Nitrous Oxide 317
Conor McDonnell CHAPTER 34
Antiemetic Agents 544
CHAPTER 21 Mario J. da Conçeicao
Volatile Anesthetics 323
CHAPTER 35
George D. Politis
Resuscitation Agents 552
Craig Sims
CHAPTER 22
Xenon and Anesthesia: Pharmacology 347
PART III
Peter H. Tonner
ANESTHESIA MANAGEMENT
CHAPTER 23 AND TECHNIQUES 571
Intravenous Agents 355 Subeditor: Adrian Bösenberg
Peter D. Booker and Neroli Chadderton
CHAPTER 36
CHAPTER 24 Preoperative Evaluation, Laboratory Testing,
Ketamine 376 and Preparation for Anesthesia and Surgery 571
Elsa Taylor Robin G. Cox
Opioid Analgesic Agents 387 Premedication, Sedation, and Preoperative Fasting 584
Jason A. Hayes and Daisy T. Joo William M. Splinter and Jarmila Kim
CHAPTER 38
CHAPTER 26
Anesthesia Equipment 594
Non-Opioid Analgesic Agents 406
Francis Veyckemans
Greta M. Palmer
CHAPTER 39
CHAPTER 27 Induction of Anesthesia 669
Neuromuscular Blocking Agents in Children 416
Cengiz Karsli and Lisa A. Isaac
Olli A. Meretoja and Hannu Kokki
CHAPTER 40
CHAPTER 28 Maintenance of Anesthesia: Inhalational Agents 690
Pharmacology of Local Anesthetics 441
Olivier Paut, Frédéric Lamy, and Magalie Guérin
Jean Xavier Mazoit
CHAPTER 41
CHAPTER 29 Maintenance of Anesthesia: Total
Adjuvants to Local Anesthetics 473 Intravenous Anesthesia 709
Dilip Pawar Neil S. Morton
Pharmacology of Premedication Modern Modes of Ventilation in
and Sedative Agents in Children 491 the Operating Room 716
George A. Chalkiadis Niall Wilton and David Buckley
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Contents xxvii
Which Endotracheal Tube in Neonates, Sedation and Anesthesia for Procedures
Infants, and Small Children? 747 Outside Operating Theaters 886
Gregory Moloney Jonathan H. Smith, Kar-Binh Ong, and Michael R. J. Sury
Regional Anesthesia: Principles of Acute Complications During Anesthesia 905
Localization Using Manual Approaches 753 Michela Salvadore, Thomas Engelhardt, and Joseph D. Tobias
Hans Jutzi and Alain Borgeat
CHAPTER 58
CHAPTER 45 Emergence and Postoperative Care 924
Regional Anesthesia: Principles of Justin L. Lockman and R. Blaine Easley
Localization Using Electrical Stimulation 757
Jean-Louis Feugeas, Frédéric Lacroix, CHAPTER 59
Olivier Choquet, and Xavier Capdevila Anesthesia for the Patient With
Coexisting Diseases 942
CHAPTER 46 Brenna L. Jacobson, Samuel H. Wald, and Linda J. Mason
Regional Anesthesia: Principles of Localization
Using Ultrasound Techniques 767 CHAPTER 60
Peter Marhofer Anesthesia for Laparoscopic Procedures 968
Francis Veyckemans
CHAPTER 47
Regional Anesthesia: Upper Limb Blocks 783 CHAPTER 61
Katherine Keech and Adrian Bösenberg Anesthesia for Non-Cardiac Surgery
in Children With Congenital Heart Disease 981
CHAPTER 48 Walid Habre
Regional Anesthesia: Lower Limb Blocks 793
Giorgio Ivani and Valeria Mossetti CHAPTER 62
A Pragmatic Approach to Pediatric
CHAPTER 49 Obstructive Sleep Apnea 988
Regional Anesthesia: Central Neuraxial Blocks 806 Karen A. Brown
Adrian Bösenberg
CHAPTER 63
CHAPTER 50 Anesthesia for the Acutely Ill Patient 994
Regional Anesthesia: Head and Neck Blocks 823 Corinne Lejus and Karim Ashenoune
Polina Voronov and Santhanam Suresh
CHAPTER 64
CHAPTER 51 Pediatric Critical Care 1008
Regional Anesthesia: Thorax and Abdomen Blocks 833 Barry Lyons, Tsz-Yan Milly Lo, and Peter N. Cox
Michael J. Fredrickson
CHAPTER 65
CHAPTER 52 Intrahospital Patient Transportation 1043
Fluid Therapy for the Pediatric Surgical Patient 843 Victor H. Espinal Montoya
Anne Laffargue Vetter CHAPTER 66
Pediatric Pain Management 1048
CHAPTER 53
Transfusion for the Pediatric Patient 850 Sabine Kost-Byerly, Lynne G. Maxwell, and Myron Yaster
Nathalie Bourdaud and Gilles Orliaguet
PART IV
CHAPTER 54 SPECIAL MONITORING AND
Perioperative Blood Sparing Techniques RESUSCITATION TECHNIQUES 1065
in Pediatric Patients 861 Subeditor: Bruno Bissonnette
Dale F. Szpisjak and Catherine Paquet
CHAPTER 67
CHAPTER 55 Cardiopulmonary Resuscitation
Outpatient Anesthesia 873 of the Infant and the Child 1065
Daniel Vischoff and Sophie Saindon Swati Agarwal and Gregory B. Hammer
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xxviii Contents
Prehospital Cardiorespiratory Pediatric Features of Malignant Hyperthermia 1362
and Trauma Resuscitation 1081 Renée Krivosic-Horber
Pierre Carli and Caroline Telion
CHAPTER 82
CHAPTER 69 Influence of Anesthesia on the Immune
Peripheral Vascular Access 1097 System in Children 1379
Susan T. Verghese and Raafat S. Hannallah Farha Abd El-Aziz El-Chennawi, Maysaa El Sayed Zaki,
Hanan Azam, and Dalia Mohamed Tohlob
CHAPTER 70
Central Vascular Access 1114 CHAPTER 83
Specific Problems and Anesthesia Management
Elizabeth Prentice
of Extremely Low Birthweight Infants 1392
CHAPTER 71 Richard J. Ing and Allison Kinder Ross
Prolonged Vascular Access 1155
CHAPTER 84
Jean Godard Miscellaneous Techniques 1406
Pedro Paulo Vanzillotta
CHAPTER 72
Airway Management 1167
PART V
Giuseppe Marraro
ANESTHETIC, SURGICAL, AND
CHAPTER 73 INTERVENTIONAL PROCEDURES:
Transesophageal Echocardiography CONSIDERATIONS 1421
in Congenital Heart Disease 1186
Subeditor: Linda J. Mason
Dominique A. Bettex and Pierre-Guy Chassot
CHAPTER 85
CHAPTER 74 Management of the Neonate:
Principles of Neuroelectrophysiology Monitoring 1213 Surgical Considerations 1421
Samuel Strantzas and Laura Holmes Carmen T. Ramos and Peter C. W. Kim
Brain Monitoring 1245 Management of the Neonate:
Isabelle Constant Anesthetic Considerations 1437
Per-Arne Lönnqvist
CHAPTER 76
Spinal Cord Monitoring 1262 CHAPTER 87
Emmanuèle Laureau and Jean-Daniel Guieu Genitourinary Tract: Surgical Considerations 1476
Pramod P. Reddy and Antoine E. Khoury
CHAPTER 77
Depth of Anesthesia Monitoring CHAPTER 88
and Awareness 1285 Genitourinary Tract: Anesthetic Considerations 1496
Andrew Davidson Jayant K. Deshpande
CHAPTER 89
CHAPTER 78
Digestive Tract Procedures:
Cardiovascular Monitoring and
Surgical Considerations 1501
Cardiothoracic Procedures 1304
Steven T. Elliott and Anthony D. Sandler
David A. Rowney
CHAPTER 90
CHAPTER 79 Digestive Tract Procedures:
Gastrointestinal Procedures 1334 Anesthetic Considerations 1520
Sif-Eddine Nejmi and Badr-Eddine Hmamouchi Sonia ben Khalifa and Mehdi Trifa
Patient Positioning and Precautions Bone and Joint Surgery: Anesthetic
During Anesthesia and Surgery 1341 Considerations and Postoperative Management 1527
Ahmed Mohamed Shalabi Mary Cunliffe
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Contents xxix

Neurosurgery and Neurotraumatology: Heart and Lung Transplantation:
Surgical Considerations 1551 Surgical Considerations 1781
Aurelia Peraud Osami Honjo and John G. Coles

Neurosurgery and Neurotraumatology: Heart and Lung Transplantation:
Anesthetic Considerations 1569 Anesthetic Considerations 1793
Craig D. McClain and Sulpicio G. Soriano Dean B. Andropoulos

Cardiovascular Procedures: Liver Transplantation: Surgical Considerations 1807
Surgical Considerations 1589 Cassandra M. Kelleher and Annie Fecteau
Osami Honjo and Glen S. Van Arsdell CHAPTER 108
Liver Transplantation: Anesthetic Considerations 1816
CHAPTER 95
Charles Lee
Cardiovascular Procedures:
Anesthetic Considerations 1609 CHAPTER 109
Carol L. Lake, Linda J. Mason, and Peter D. Booker Renal Transplantation: Surgical Considerations 1821
CHAPTER 96 Walid A. Farhat and Armando J. Lorenzo
Thoracic Surgery: Surgical Considerations 1641
CHAPTER 110
J. Ted Gerstle Renal Transplantation: Anesthetic Considerations 1836
Jonathan de Lima and Peter Gibson
CHAPTER 97
Thoracic Surgery: Anesthetic Considerations 1655 CHAPTER 111
Patrick T. Farrell Intestinal and Pancreatic Transplantation:
Surgical Considerations 1843
CHAPTER 98
Rodrigo A. Iniguez and Paul W. Wales
Otorhinolaryngology: Surgical Considerations 1668
Blake C. Papsin and Sharon L. Cushing CHAPTER 112
Intestinal and Pancreatic Transplantation:
CHAPTER 99 Anesthetic Considerations 1850
Otorhinolaryngology: Anesthetic Considerations 1699
Nathalie Bourdaud, Frédérique Sauvat, and Gilles Orliaguet
Alison S. Carr and David Elliott
CHAPTER 113
CHAPTER 100 Bone Marrow Transplantation:
Plastic Procedures: Surgical Considerations 1722 Hematological and Anesthetic Considerations 1859
David M. Fisher John Doyle and Justin John
CHAPTER 101
CHAPTER 114
Plastic Procedures: Anesthetic Considerations 1728
Conjoined Twins: Surgical Considerations 1867
James Flowerdew
Abdullah A. Al-Rabeeah
CHAPTER 102
Ophthalmological Procedures: CHAPTER 115
Surgical Considerations 1738 Conjoined Twins: Anesthetic Considerations 1877
Asim Ali, Nasrin Najm-Tehrani, Wai-Ching Lam, Mohamed El-Gammal
and Elise Héon
CHAPTER 116
CHAPTER 103 Craniofacial Malformations:
Ophthalmological Procedures: Surgical Considerations 1891
Anesthetic Considerations 1757 Daniel A. Peters and Christopher R. Forrest
Marie Granier
CHAPTER 117
CHAPTER 104 Craniofacial Malformations:
Anesthesia for Organ Retrieval 1768 Anesthetic Considerations 1920
Priya Thalayasingam Mark F. Levine
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xxx Contents

Interventional Cardiac Catheterization Dental Procedures: Anesthetic Considerations 2080
Procedures: Cardiology Considerations 1934 Steven Ganzberg and Brian Chanpong
David G. Nykanen
PART VI
CHAPTER 119 SPECIFIC CONSIDERATIONS 2091
Interventional Cardiac Catheterization
Procedures: Anesthetic Considerations 1952 Subeditor: Thomas Engelhardt
Peter C. Laussen and Brendan O’Hare
CHAPTER 127
CHAPTER 120 Mortality, Morbidity, and
Fetal Anesthesia 1971 Outcome in Pediatric Anesthesia 2091
Laura B. Myers Isabelle Murat

Interventional Radiology: Consent, Research, and Withdrawing Treatment 2109
Radiological Considerations 2002 Nicholas Pace and David A. Blacoe
Michael J. Temple and Bairbre Connolly
CHAPTER 129
CHAPTER 122 Training and Education in Pediatric Anesthesia 2119
Interventional Radiology: Anesthetic Paul J. Samuels, Jon Tomasson, and Charles D. Kurth
Considerations and Postprocedural
Management 2015 CHAPTER 130
Christopher M. Bolton Acute Pain Service 2132
Rita Agarwal and David M. Polaner
CHAPTER 123
Burns and Post-Burn Care: CHAPTER 131
Surgical Considerations 2031 Quality Improvement 2143
Howard M. Clarke and Tristan M.B. de Chalain Sally E. Rampersad and Lynn D. Martin

Burns and Post-Burn Care: Special Problems in Developing Countries 2155
Anesthetic Considerations 2049 Adrian Bösenberg and Zipporah Njeri Gathuya
Marc-André Bernath, Pascal Stucki,
and Mette M. Berger CHAPTER 133
Implications for Humanitarian Anesthesia 2173
CHAPTER 125 George A. Gregory
Dental Procedures: Surgical Considerations 2071
David J. Kenny and Michael J. Casas Index 2183
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Developmental Considerations I
P A R T
Prenatal Normal and Abnormal

1 Development
C H A P T E R Gilles Boulay, Lionel Simon, and Jamil Hamza
INTRODUCTION following birth, have specific implications for the perioperative

care of infants and children. These normal developmental pro-
The subspecialties of pediatric anesthesiology and pediatric cesses may affect the response of infants and children to various
intensive care medicine have seen remarkable growth since the anesthetic agents.
1980s. This growth has included the establishment of fellowship Knowledge of the normal and abnormal prenatal development
programs, the establishment of guidelines for the accreditation of is necessary for the pediatric anesthesiologist who is becoming
these programs, the institution of a formal written examination increasingly involved in fetal-neonatal surgical procedures, which
process for pediatric intensive care medicine leading to board may occur immediately after birth or even before with the growing
certification, and the plans for a written examination in pediatric field of in utero surgery. The goals of this, the first chapter of this
anesthesiology. There has also been increasing recognition of the textbook on pediatric anesthesiology, are to (1) describe the
value of such training and the attainment of board certification normal and abnormal developmental stages of the embryonic and
not only by pediatricians and pediatric surgeons but also by fetal periods, (2) show how some maternal disorders (hyperten-
physicians outside of our own subspecialty. The recognition that sion, diabetes) or drug ingestions (tobacco, alcohol, cocaine)
neonates, infants, and children may require subspecialists to during this critical period can alter normal fetal development,
provide their perioperative care has partly grown from the (3) discuss the fetal and neonatal problems associated with
acceptance that the anatomy, physiology, and pharmacology of intrauterine growth retardation (IUGR) and premature birth,
pediatric patients differ from those of their adult counterparts. which remain the two primary causes of perinatal mortality and
That being said, it becomes obvious that children are not just “little morbidity, (4) explain why and how acute fetal distress can lead to
adults” and that variability in the response to many pharmaceuti- definitive neurologic impairment, and (5) develop a comprehen-
cal agents is just one of many variations that may exist in this sive approach to diagnosis and therapy.
population.
When dealing with infants and children, the anesthesiologist
is faced with variations not only in size, gestational age, and anato-
NORMAL AND ABNORMAL
mic parameters but also in metabolic, cellular, and subcellular EMBRYOLOGIC DEVELOPMENT
ones. Pediatric anesthesiologists are frequently called upon to The human pregnancy usually lasts 266 days (38 wk) from fer-
anesthetize children with various congenital anomalies and mal- tilization to birth. Prenatal growth can be divided in two periods:
formations. As outlined in the chapters that follow in this section, (1) embryonic and (2) fetal. During the embryonic period, most
a myriad of processes must occur for normal development to take major organ systems are formed (organogenesis). During the fetal
place. Given the intricacies of these processes, it is amazing that period (from 8 wk to birth), functional development of organ
the majority of these defects are relatively uncommon in the systems and maturation take place.
general population. By understanding the processes that must
occur for normal development, we can gain an understanding of Normal Embryonic Development
how defects during the embryonic period can result in devastating
anatomic abnormalities. Given that numerous processes occur (First 8 Weeks)1–5
simultaneously in various organ systems, congenital anomalies in The embryonic development begins when the zygote containing a
several organ systems may coexist. In addition to the deviations single diploid nucleus forms as a spermatocyte and an oocyte join
from normal development that may result in congenital ano- during the process of fertilization. While a series of cell divisions
malies, even the normal developmental processes, which continue occur, the embryo travels toward the uterus. Further cleavage
2 PART 1 ■ Developmental Considerations
Figure 1-1. Formation of the blastocyst.
results in the zygote with 16 cells that organize in two separate The caudal eminence and first somites form (Figure 1–3) while
groups of cells. The peripheral outer cell mass (trophoblast) will neuromeres develop into the presumptive brain vesicles. At the
yield the placenta and membranes, whereas the central inner cell end of the third week, a primitive heart tube is formed and the
mass (embryoblast) will form the embryo. By the 30-cell stage, the embryologic vasculature begins.
blastocyst cavity develops (morula). At the end of the first week, From the fourth to eighth week of gestation (organogenesis
the embryo enters the uterine cavity and implants into the period), the three primitive layers (ectoblast, mesoblast, and en-
endometrial lining of the uterine wall. At this point, it is then doderm) differentiate into different tissues and organs. The
designated a blastocyst (Figure 1–1). At the beginning of the embryonic plate folds laterally; its cranial and caudal ends expand
second week, the embryoblast splits into the epiblast or primary and the limbs begin to develop. The embryonic plate acquires a
ectoderm and the hypoblast or primary endoderm, thus creating human-like shape. The ectoderm differentiates into tissues and
a dorsoventral axis in the embryo (bilaminar embryo). The organs that will eventually have contact with the external environ-
trophoblast differentiates into two tissues: the cytotrophoblast and ment (central and peripheral nervous system, skin, sweat glands,
the syncytiotrophoblast. During the second week, the amniotic and mammary glands, teeth, and epithelial structures of the eyes, ears
chorionic cavities appear. Gastrulation begins at the third week as and neck). The mesoderm yields the somites, dermis, epidermis,
the bilaminar germ disk becomes trilaminar with the formation cardiovascular system (heart, arteries, venous and lymphatic
of the mesoblast (Figure 1–2). The neural plate and groove appear. vessels), urogenital system (kidney, gonads), spleen, and adrenal
cortex. The endoderm provides the epithelium of the digestive
system, respiratory tract, and bladder as well as forming the
parenchyma of the liver, pancreas, and some glandular structures
(thyroid, parathyroid, thymus, salivary). The myocardium de-
velops and the heart begins to beat during the fourth week. The
process of neurulation converts the neural plate into a neural tube,
which begins the differentiation of the brain and spinal cord. At
the same time, the pulmonary primordium and hepatic plate
appear. The optic system begins to form (sulci, vesicles, and pit).
The somites divide into three structures: (1) myotomes,
which provide the segmental musculature of the back and the
Figure 1-2. Formation of the trilaminar germ disk. (1) Amniotic

cavity. (2) Hensen node and primitive streak, then neural groove.
(3) Chorionic cavity. (4) Epiblast. (5) Hypoblast. (6) Migration of Figure 1-3. The development of the somites and neural tube.
epiblastic cells. (7) Mesoblast. (1) Somite. (2) Neural tube.
CHAPTER 1 ■ Prenatal Normal and Abnormal Development 3
anterolateral body wall; (2) dermatomes, which form the dermis The lung bud appears at approximately day 24. It elongates to
of the scalp, neck, and trunk; and (3) sclerotomes, which develop form the primordial trachea and branches to form the bronchial
into vertebral bodies and arches. Spinal defects such as scoliosis or tree and the epithelial lining of the lungs (including the alveoli).
spina bifida result from the abnormal induction of the sclerotome Segmental bronchi develop and the diaphragm is complete at day
and the neural tube at the level of the first five somites (from day 52. The primitive heart tube appears around day 20 and its folding
22 onward). The two opposite orifices of the neural tube are is completed by day 30. Between weeks 5 and 8, the primitive heart
termed the cranial and the caudal neuropores. The cranial neu- tube undergoes a process of looping, remodeling, and septation
ropore closes on day 24 and the caudal neuropore on day 26. that transforms the single lumen into four cavities. During the
Neural crest cells migrate to several locations in the body where fifth and sixth weeks, a pair of septa (septum primum and
they differentiate into different structures and cell types. The fifth secondum) develop to separate the right and left atria. A pair of
week is critical for the development of the peripheral nervous foramina that perforate these septa (ostia primum and secundum)
system. At day 28, motor neurons appear in the central column of allow the right-to-left shunting of blood. The mitral and tricuspid
the neural tube (starting in the cervical region). Spinal nerves atrioventricular valves develop during this period. They are
begin to sprout and grow into myotomes on day 32 and the three finalized by the third month. The coronary sinus is formed at day
main subdivisions of the brain (forebrain, midbrain, and hind- 52 (Figure 1–4). The gut tube is formed at day 24. By the fifth
brain) become identifiable. At the end of the embryonic period, week, the abdominal portion of the foregut divides into three
the gross structure of the nervous system is developed. parts: esophagus, stomach, and proximal duodenum. During the
Figure 1-4. Formation of the heart

(timeline). From Larsen WJ. Human
Embryology. 2nd ed. New York: Churchill
Livingstone; 1997. Chapter 7, p. 152.
sixth and seventh weeks, the stomach rotates. This rotation and increases from 8 g at the eighth week to 3400 g at birth (a 425-fold
the secondary fusion of the duodenum to the dorsal body wall increase) (Figure 1–6). Weight gain occurs in the third trimester,
create the lesser sac of the peritoneal cavity, and the remaining mainly in the last 2 months of pregnancy (700 g/mo). Major
cavity develops as the greater sac. By the fifth week, rapid elonga- changes in body proportions occur concomitantly. The head
tion of the ileum produces a primary intestinal loop that herniates represents half of the crown-rump length at 9 weeks, one third
through the umbilicus. This herniated organ fully retracts into the of this length at the end of the fifth month, and one fourth at
abdominal cavity during the 10th week. The rotation of the midgut birth. Fetal life is supported by the placenta, an organ with
produces the definitive configuration of the small and large maternal (decidua basalis) and fetal (chorion) components. The
intestines (Figure 1–5). The distal hindgut gives rise to the rectum placenta provides the fetus with oxygen and nutrients from
and the urogenital sinus. The major stages of the embryonic maternal blood and eliminates the metabolic waste of the fetus.
development from day 1 to day 56 are summarized in Table 1–1. By 10 weeks, there is a 180-degree counter-clockwise rotation of
the midgut returning from the umbilical cord into the abdomen,
Normal Fetal Development bringing the stomach and the small and large intestine into their
normal positions.
(From 8 Weeks to Term) By 12 weeks, the glandular stage of pulmonary develop-
The embryo becomes a fetus at the beginning of the third month. ment induces the formation of intrasegmental airways and
During the fetal period, there is an increase in cell number and associated vessels. The gender of the external genitalia becomes
size and a remodeling of several organ systems concomitant with identifiable. From the 16th to the 24th week, the canalicular stage
their maturation. The growth in length is particularly rapid from involves growth of the liquid-filled airways. The lung develops a
the third to the fifth month (~5 cm/mo). The weight of the fetus viable gas-exchanging surface and surfactant production begins.
Figure 1-5. Herniation and

rotations of intestine. (1) Primary
intestinal loop. (2) Stomach.
(3) Aorta. (4) Superior mesenteric
artery. (5) Liver. (6) Small intestine.
(7) Colon. (8) Rectum. From
Larsen WJ. Human Embryology.
2nd ed. New York: Churchill
Livingstone; 1997. Chapter 9,
p. 241.)
Bissonette-001-(F)
TABLE 1-1. Normal Embryonic Development and Malformation

Age, d Central Nervous Extremities
4/13/11
(Length, mm) Appearance System Heart Gut Lung Urologic Face and Other
4 Blastocyst
4:17 PM
7–14 (0.1) Yolk sac
19 (1) Enlargement of Allantois

anterior neural
Page 5
plate
24 (2) Neural crest cells Heart beats at Gut tube Lung bud appears Mesonephric Mandible Optic evagination
migrated 22 d ridge Hyoid arches Otic placode
30 (4) Ventral roots begin Complete folding Primary bronchi Metanephric Olfactory Upper limb bud
to form blastema appear placodes forms
Optic cup
Otic invagination
Closure of neural
tube
34 (7) Sympathetic trunks Secondary bronchi Ureteric bud enter Thyroïd and Lower limb bud
begin to form buds metanephric parathyroïds forms
blastema develop Lens invagination
CHAPTER 1
Otic vesicle
■
38 (11) Limb buds are Stomach rotation Major calyces form Nasal swellings
innervated as
they form
44 (17) Vagal fibers Aorta Duodenal lumen Tertiary bronchi Minor calyces form Secondary palate Early muscle is
innervate heart Pulmonary artery obliterated, formed present
Valves cecum rotates
Membrane right
Ventricular
septum
52 (23) Most of spinal Coronary sinus Tracheal cartilage Kidneys ascend Facial swellings
ganglia formed formed fused
55 (28) Anorectal canal
completed
Adapted from reference 6.
Prenatal Normal and Abnormal Development
5
TABLE 1-2. Relative Timing and Developmental Pathology of Some Malformations

Tissues Malformation Defect in Cause Prior to Comment
Central nervous Anencephaly Closure of anterior neural tube 26 d Subsequent degeneration of
system Meningomyelocele Closure in a portion of the 28 d forebrain
posterior neural tube 80% lumbosacral
Face Cleft lip Closure of lip 36 d 42% associated with cleft palate
Cleft maxillary palate Fusion of maxillary palatal 10 wks
shelves
Branchial sinus and/or cyst Resolution of branchial cleft 8 wk
Gut Esophageal atresia and Lateral septation of foregut into 30 d
tracheoesophageal fistula trachea and foregut
Rectal atresia with fistula Lateral septation of cloaca 6 wk
into rectum and urogenital
sinus
Duodenal atresia Recanalization of duodenum 7–8 wk
Malrotation of gut Rotation of intestinal loop 10 wk Associated incomplete or
aberrant mesenteric
attachment
Omphalocele Return of midgut from yolk sac 10 wk
to abdomen
Meckel’s diverticulum Obliteration of vitelline duct 10 wk May contain gastric and/or
Diaphragmatic hernia Closure of pleuroperitoneal pancreatic tissue
canal 6 wk
Genitourinary Extroversion of bladder Migration of infraumbilical 30 d Associated müllerian and
system mesenchyme wolffian duct defects
Bicornuate uterus Fusion of lower portion of 10 wk
müllerian ducts
Hypospadias Fusion of urethral folds 12 wk
Cryptorchidism Descent of testicle into scrotum 7–9 mo
Heart Transposition of great Directional development of 34 d
vessels bulbus cordis septum
Ventricular septal defect Closure of ventricular septum 6 wk
Patent ductus arteriosus Closure of ductus arteriosus 9–10 mo
Limb Aplasia of radius Genesis of radial bone 38 d Often accompanied by other
defects of radial side of distal
limb
Syndactyly Separation of digital rays 6 wk
Complex Cyclopia Prechordal mesoderm 23 d Secondary defects of midface
development and forebrain
Sirenomelia Development of posterior axis 23 d Associated defects of cloacal
development
Abnormal Development6–9 (incomplete separation of fingers), cleft palate (incomplete closure

of the palate), and malrotation of the gut (incomplete rotation of
Abnormal development may result from chromosomal anomalies the gut). Another type of malformation is the aberrant form,
that cause approximately 40 to 50% of spontaneous abortions which never exists at any stage of normal development. Accessory
(when the products of conception are examined) (Table 1–2). tissues such as polydactyly or accessory spleens belong to another
Many chromosomal anomalies are not lethal and lead to abnormal type of malformation. The accessory tissue is initiated at the same
developmental syndromes (Down syndrome). Other chromoso- time as the normal tissue. Hamartomas are organizational defects
mal anomalies include monosomy, trisomy, mosaic, transloca- leading to an abnormal admixture of tissues. Some—such as
tions, triploidy, or tetraploidy. They may result in any of three hemangiomas, melanomas, fibromas, and adenomas—have a
types of developmental pathology including (1) malformation malignant potential.
(poor tissue formation), (2) deformation (because of altered
mechanical forces on a normal tissue), and (3) disruption (break-
down of a previously normal tissue). Apart from chromosomal Congenital Diaphragmatic Hernia
anomalies, several types of malformations can be observed. This malformation occurs in 1 of 2500 live births, affecting the left
Incomplete morphogenesis is due to an incomplete stage in the side four to eight times more than the right side. It results from
development of a structure. To this group belong syndactyly closure anomaly of the pericardioperitoneal canal. Consequently,
abdominal organs develop in the pleural cavity, which impairs the phenomenon characterized by an inadequate maternal vascular
growth of the ipsilateral lung. Although surgical correction can be response to the development of the placenta. In normal pre-
achieved while the fetus is still in utero, in most cases, it is per- gnancies, the development of uteroplacental arteries into spiral
formed after birth. arteries should convert the uteroplacental arterial bed into a low-
resistance, low-pressure, and high–blood flow system. The
mechanism responsible for such an evolution reflects important
Esophageal Atresia
and complex interactions between the trophoblastic and the
This disorder seems to result from the failure of the esophageal maternal endothelial cells.
endoderm to proliferate rapidly enough during the fifth week to In preeclampsia, a defect in trophoblastic invasion impairs the
coincide with the elongation of the embryo. Five different types normal development of uteroplacental arteries. The development
are described, with or without an esophagotracheal fistula. This of large spiral arteries is limited to the decidua and a constricting
anomaly should be rapidly repaired at birth because of the risk of segment remains present in the external part of the myometrium.
aspiration. Damage to endothelial cells, platelets, and trophoblast cells is
responsible for an intravascular activation of the coagulation
Spina Bifida cascade and increased vascular resistance, leading to a decrease in
Spina bifida is a closure anomaly of the spinal canal during the placental blood flow. The etiology of the original defect in tro-
third week. It occurs most frequently in the lumbosacral region. phoblastic invasion is unknown, although both genetic and im-
The consequences of this defect in neural tube closure can be munologic factors may be involved. Vascular lesions are present in
severe, with the dura and/or the arachnoid protruding from the uteroplacental arteries from the 16th week of pregnancy, long
vertebral canal (meningocele and/or meningomyelocele). The before the development of maternal hypertension. It is postulated
mildest form of spina bifida is termed occulta; in this, the vertebral that placental ischemia is a very early mechanism responsible for
arches of a single vertebra fail to fuse without protrusion of neural the clinical manifestations of preeclampsia. No prophylactic
structures from the spinal canal and any defect in the skin and therapy has been shown to be effective in preventing preeclampsia.
overlying structures. The goal of the antihypertensive therapy in preeclampsia is to
avoid the occurrence of maternal complications of the hyper-
tension. However, none of these treatments has clearly been shown
Hirschsprung Disease to improve fetal outcome. Although low-dose aspirin has been
Hirschsprung disease is a congenital defect of neural crest migra- recommended to prevent preeclampsia and to improve perinatal
tion giving rise to an area of constriction and paralysis of outcome in women at risk for preeclampsia, such therapy has been
the colonic segment. The consequence of this malformation is the shown to be ineffective.10,11 Progressive deterioration in both
development of a characteristic dilated colon proximal to the maternal and fetal conditions is usual in severe preeclampsia, and
constricted area. delivery is the only effective treatment for this situation. Therefore,
cesarean section should be considered even at a very early stage to
avoid dramatic complications for both the mother and the infant.
Omphalocele Delivery of a preterm infant must be anticipated and, if the
Omphalocele occurs in 2.5 of 10,000 births and results from an hospital is not designed for this event, the mother should be
incomplete closure of the umbilicus. The gastrointestinal struc- referred to a level III obstetric center that includes a neonatal
tures protrude through an unclosed umbilical ring. The omphalo- intensive care unit. The decision to deliver the patient is often easy
cele often occurs with defects in other organ systems (cardiac, in cases of severe preeclampsia after 32 weeks of gestation.
renal) or as a part of a chromosomal anomaly. Between 28 and 32 weeks, a short delay is often utilized before
delivery to accelerate fetal pulmonary maturation through the
Gastroschisis administration of maternal steroid therapy.12
The incidence of growth retardation and perinatal morbidity
Gastroschisis occurs in approximately 1 of 10,000 births. In this
and mortality rates are increased in pregnancies complicated with
malformation, the umbilical ring closes normally. The abdominal
severe preeclampsia or eclampsia. Some authors have reported
wall defect occurs between the developing rectus muscles just
high rates of stillbirth and/or severe neonatal complications
lateral to the umbilicus, usually on the right side. The cause of this
resulting in cerebral palsy and mental retardation in neonates born
anomaly is an abnormality in the involution of the right umbilical
to eclamptic women.13,14 In spite of this, several studies have
vein during the fifth to sixth week. The visceral organs rarely
demonstrated a reduced incidence of cerebral hemorrhage in very
protrude through this defect. Gastroschisis is less often associated
low birthweight (VLBW) infants when they were born to mothers
with other defects than omphalocele and is not associated with
with preeclampsia. Nelson and Grether suggested that magnesium
chromosomal anomalies.
sulfate therapy used in preeclamptic women may be responsible
for this protective effect against cerebral palsy in VLBW infants.15
The primary factors associated with a poor neonatal prognosis
MATERNAL DISORDERS: include the early onset of preeclampsia (before 37 wk), prema-
INTRAUTERINE DEVELOPMENT turity, multiple pregnancy, severity of the disease, and previous
maternal hypertension or renal disease. Several authors have tried
Pregnancy-Induced Hypertension to test the value of Doppler-derived patterns in determining fetal
The diagnosis of preeclampsia is based on the triad of elevated prognosis in pregnancy complicated with preeclampsia.16–18 These
blood pressure accompanied by proteinuria and edema. This studies have led to contradictory results because of a difficult
pathology, which is unique to human pregnancy, is a complex interpretation caused by to the complexity of the uteroplacental
circulation. Absent or reversed end-diastolic velocity waveform in a neural tube defect in infants whose mothers are treated with
the umbilical artery seems to be associated with a poor neonatal valproic acid or carbamazepine can be assessed with ultrasound
outcome.17,19 Ultrasonography may also be useful to ensure fetal examinations27 or α-fetoprotein blood level measurements. The
well-being. Obstetric ultrasound can evaluate fetal movements, teratogenic risk of anticonvulsants is reduced by folic acid
breathing activity, and muscle tone20 as well as provide an assess- supplementation throughout pregnancy and adaptation of the
ment of fetal anatomy, fetal growth, and amniotic fluid volume. anticonvulsant treatment to the lowest effective doses. An
Identification of other conditions associated with maternal increased rate of neonatal deaths has been suspected in infants
hypertension, such as trisomy 13 and 18, is also possible with the born to epileptic mothers. These newborns are more likely to need
use of ultrasound.19 IUGR is important to quantify, and oligohy- hospitalization in a neonatal intensive care unit,21 but the inci-
dramnios appears to be associated with a neonatal outcome. dence of prematurity, low birthweight (LBW), and neonatal head
circumference seems similar to that in normal neonates. Fortu-
nately, most epileptic mothers have uncomplicated pregnancies
Epilepsy and normal babies.
Two major risks have to be considered in an epileptic woman who
wants to become pregnant: (1) an increase in the incidence of
seizures may be observed during pregnancy and (2) the anti-
Diabetes Mellitus
convulsant medications may have teratogenic effects. These two Insulin-dependent diabetes can seriously alter the prognosis of
risks may be limited if pregnancy is correctly planned with good pregnancy. Spontaneous abortions, stillborns, and congenital
patient information and counseling. An increase in the incidence malformations occur more often in fetuses of diabetic mothers.
of seizures may be observed during pregnancy in 21 to 46% of the The relative risk for major malformations in these infants is 7.9
women.21,22 Many factors have been involved to explain this times higher than in neonates born to mothers without diabetes.30
increase in the number and severity of seizures: (1) some women The percentage of newborns with a birthweight greater than the
discontinue or reduce the dose of their anticonvulsant medication 90th percentile is increased in diabetic women. The factors
to limit the risk of teratogenicity23 and (2) the pharmacokinetics of involved in maternal and fetal weight gain during pregnancy are
anticonvulsant medications can be impaired by pregnancy. How- not fully elucidated.31 Leptin, a small peptide, usually produced by
ever, the decrease in the plasma concentration of many anti- adipocytes and involved in many endocrine regulations, is also
convulsant medications during pregnancy does not involve the synthesized in the placenta. The placental production of leptin can
free fraction of these drugs,24 and when the patients are monitored, be regulated by insulin and may be involved in the fetal weight
an adjustment of these medications to maintain the plasma control. The increased rate of high birthweights is also present in
concentration of antiepileptic drugs throughout pregnancy does women with gestational diabetes and those at increased risk of
not necessarily prevent the increase in the incidence of seizures.25 diabetes including those with an abnormal oral glucose tolerance
Generalized convulsions can lead to hypoxemia and hemodyna- test during pregnancy.32 The rigorous control of the blood glucose
mic disorders and, as such, represent a serious risk to fetal well- levels in diabetic women attempting to become pregnant and
being. Therefore, the optimal control of seizure activity and strict during pregnancy can reduce these risks. One study showed that
compliance should be obtained before pregnancy. the incidence of spontaneous abortion and congenital malfor-
The incidence of congenital malformations in infants born to mations in diabetic women receiving intensive insulin therapy was
epileptic mothers is two to three times greater than in nonepileptic identical to that in nondiabetic women.33 Ideally, the intensive
mothers.21 Important differences exist in the teratogenic effects of therapy should begin before conception and maintain normal
anticonvulsant medications. Neural tube defects such as spina blood glucose levels (fasting blood glucose level of 70–100 mg/dL
bifida are associated with first trimester exposure to valproic acid and a 1-h postprandial level < 140 mg/dL).
or carbamazepine. Phenytoin21 and valproic acid26,27 are the two
treatments that appear to be associated with the higher risk of
malformation syndromes. A fetal hydantoin syndrome occurs in
Drug Abuse
10 to 30% of exposed pregnancies.23 Hydantoin exposure in pre- Alcohol
gnancy may be associated with multisystemic anomalies including Alcohol consumption impairs the pregnancy and offspring
the prenatal onset of growth deficiency, central nervous system outcome. Alcohol has a direct toxic effect on the fetus, whereas
malformations, craniofacial anomalies, and nail/digital hypoplasia. malnutrition associated with alcoholism can also impact on the
Multiple malformations including lip and palatal malformations, normal course of pregnancy. Indirect fetal toxicity may result from
congenital heart disease, and facial and digital anomalies have also zinc deficiency, alterations in placental functions, and effects on
been described after exposure to valproic acid, phenobarbital, and prostaglandins. The amount of alcohol consumption is critical for
carbamazepine.23 The risk for neural tube defect associated with fetal prognosis. Normal development is impaired when maternal
valproic acid and carbamazepine is increased by low folate consumption exceeds 1 to 2 glasses of wine per day, with major
concentrations during pregnancy.28 Genetic factors also play a role consequences when more than 3 glasses per day are consumed.
because the relative risk for giving birth to an infant with a neural These anomalies, termed the fetal alcohol syndrome, include
tube defect is increased by a factor of 10 in a woman who has IUGR, microcephaly with characteristic craniofacial anomalies,
already delivered an affected infant in a previous pregnancy.29 and central nervous system anomalies with intellectual defi-
When possible, monotherapy for seizure control is preferred ciency.34 Major congenital malformations of other organs (heart,
in a woman who may become pregnant because the risk of birth urinary tract) are also more frequent in infants of alcoholic
defects dramatically increases with multiple treatments. The risk mothers, even though they are less specific for the syndrome.
has been reported to be as high as 58% when carbamazepine, Growth retardation is linked to the amount of alcohol con-
phenobarbital, and valproic acid were combined.29 The presence of sumption. At birth, infants born to alcoholic mothers weigh up to
160 g less than those born to nonalcoholic women. Alcohol abuse associated with cocaine exposure. The mechanism involved
has also been linked to an increased incidence of placental abrup- can be either direct teratogenicity or a consequence of vas-
tion and spontaneous abortion. In utero exposition to alcohol opressor effects of cocaine in both the mother and the fetus.
impairs postnatal development and is associated with school 3. Congenital heart defects are associated with cocaine use and
problems in late childhood. can result from the lower intracardiac fetal blood flow with
subsequent impairment of the development of some parts of
Tobacco the heart.
4. An increased incidence of neonatal distress with lower Apgar
A 1995 French study showed that 25% of pregnant women smoked scores at 1 minute (but not at 5 min) has been reported in
cigarettes.35 Sixty percent of them smoked fewer than 10 cigarettes neonates exposed prenatally to cocaine.44 Cocaine exposure
per day, whereas only 10% smoked more than 20 cigarettes per during pregnancy may also produce LBW; however, this is not
day. Although this French study did not show a link between observed if exposure is limited to the first trimester of gesta-
smoking and prematurity, many other studies performed in the tion.41
United States, England, and Australia found a positive correlation 5. Hyperreflexia, prolonged periods of scanning eye movements,
between the risk of preterm birth and maternal tobacco consump- excessive irritability, and tachypnea in a neonate can reflect
tion.36,37 These discordant results may be related to quantitative acute cocaine intoxication.
differences in maternal smoking between the studied populations. 6. Differences in neurobehavioral capabilities, clinical seizures,
In the study of Schwartz and coworkers, “the stillbirth rate was and electroencephalographic abnormalities are also seen in
increased in smokers especially in those who inhaled.”38 In this neonates who were (chronically) exposed to cocaine in utero.
study, mothers who ceased smoking at the beginning of their 7. Cerebral infarctions and hemorrhages are other possible
pregnancy enjoyed the same prognosis for their pregnancy and neonatal complications that can result from alterations in
their offspring as the nonsmokers. Cigarette smoking during cerebral blood flow induced by cocaine.
pregnancy has also been related to other obstetric complications 8. Gastrointestinal tract disorders and renal dysfunction have also
including ectopic pregnancy, placental abruption, and placenta been reported in such neonates. Some authors reported a de-
previa.34 At term, the mean birthweight is usually 150 to 300 g creased incidence of respiratory distress syndrome in neonates
lower in infants born to smokers than to nonsmokers. The rate of after prenatal exposure to cocaine.45 This is supported by ex-
congenital anomalies and especially orofacial clefts may be in- perimental data showing enhanced maturation of the fetal lung
creased with maternal smoking. However, the teratogenic effects in animals exposed to cocaine.46,47
of tobacco, if present, are probably minimal. Cigarette smoking
interacts with the efficacy of dietary folate in women whose intake
is low,23 and therefore, smokers are at risk for folate deficiency, Benzodiazepines
which may increase the incidence of birth defects. Dysmorphic characteristics similar to those of fetal alcohol syn-
drome, growth aberrations, and central nervous system abnor-
malities have been reported in infants born to mothers consuming
Cocaine benzodiazepines during pregnancy.48 However, a clear link be-
Cocaine abuse is a serious health problem. In the United States, tween maternal use of benzodiazepine and teratogenicity has not
its prevalence is estimated between 7.5 and 45% in the obstetric been clearly demonstrated. Bergman and associates reported that
population, resulting in a very high incidence in both maternal 6 of 64 infants with major exposure to benzodiazepines exhibited
and neonatal morbidity and mortality.39 Adverse effects on the clinical features of developmental teratogenicity49; however, many
mother are multiple, many of them being related to hypertensive mothers exhibited other potentially confounding factors such as
effects. Women who abuse cocaine have higher rates of alcohol dependence, multiple-drugs dependence, or convulsions.
spontaneous abortion and preterm labor. Burkett and colleagues Addiction associated with other teratogenic drugs has also been
reported an incidence of 41% of spontaneous or therapeutic suspected.50 Even though more recent studies did not find any
abortions in 139 women who used cocaine during pregnancy.40 teratogenic effects of benzodiazepine,29 massive use of benzodiaze-
Cocaine abuse favors the occurrence of placental abruption even pines should be avoided during pregnancy. Sedation and with-
if the use is limited to the first trimester of gestation.41 In the drawal symptoms have been reported in neonates whose mothers
absence of placental abruption, cocaine use can be associated with took benzodiazepines up to delivery.49
chorionic villus hemorrhage and villus edema.42 The influence
of these placental abnormalities on the fetal outcome remains
to be determined. Other obstetric complications such as meco- Infectious Diseases
nium staining, prolonged membrane rupture, and precipitous Rubella
deliveries are more frequent in women who abuse cocaine. The
Primary infection with rubella virus during pregnancy can induce
development of fetus exposed to cocaine is impaired in several
fetal death, chromosomal alterations leading to IUGR, ocular
different ways:
lesions, deafness, congenital cardiomyopathy, and other malfor-
1. Cocaine induces uteroplacental vasoconstriction, resulting in mations. A rubella titer should be made in every woman before
uteroplacental insufficiency and fetal hypoxemia. This may pregnancy to know her immune status. Congenital rubella can be
cause reduced birthweight, IUGR, microcephaly, and prema- avoided with a policy of preventive immunization of all serone-
turity. The rate of premature deliveries in women exposed to gative women before pregnancy. In case of primary infection with
freebase cocaine (crack) may exceed 50%.43 rubella virus during pregnancy, the incidence of fetal infection is
2. Different authors have suspected, both in experimental and approximately 90% in the first trimester, decreasing to 25% if
in human studies, an increased rate of fetal malformations infection occurs during the 23rd and the 26th week. If maternal
infection occurs during the last trimester, fetal infection is very TABLE 1-3. Maternal Factors That Significantly Influenced
frequent (>90%), but the consequences for the neonate will be the Perinatal HIV-1 Transmission in the French Cohort
minimal or absent. The diagnosis of fetal infection is made by Study
detection of specific immunoglobulin M (IgM) antibodies in the
fetal blood after 22 weeks. Direct detection of the virus after Maternal Factors Associated With an Increased % of Infected
chorionic villus sampling using polymerase chain reaction is also Rate of HIV Transmission to the Fetus Children
possible during the first trimester. The risk of severe congenital Clinical signs, AIDS
abnormalities seems to be maximal (>90%) for the infant when CDC stage I 18
the infection occurs before the 11th week. II 19
III 26
Toxoplasmosis IV 35
Humans can be incidental hosts for Toxoplasma gondii, a pro- CD4+ lymphocyte counts
tozoan whose definitive host is the domestic cat. Toxoplasma <200/mm3 43
infection in humans is often asymptomatic and results in the 200–400/mm3 26
development of antibodies, first IgM 1 to 2 weeks after exposure, 400–600/mm3 20
then IgG after 3 to 4 weeks. In case of acute infection during >600/mm3 15
pregnancy of a nonimmune mother, the organism can be trans- P24 antigenemia
mitted to the fetus in up to 60% of cases. Fetal infection may cause Negative 19
IUGR, nonimmune hydrops, hydrocephalus, or microcephaly. Positive 46
Some infected infants are asymptomatic at birth but develop
neurologic issues later in development.51 Nonimmune pregnant Age of the mother, y
women should be advised to eat only well-cooked or “hard– <25 16
frozen” meat, wash every utensil or surface after contact with raw 25–30 21
meat, avoid contact with cats and their litterbox, and wash fruits 30–35 24
and vegetables thoroughly. When an acute infection occurs before >35 30
the third trimester of pregnancy, treatment with spiramycin if AIDS = acquired immunodeficiency syndrome; CDC = Centers for Disease
started promptly and continued until delivery reduces the risk of Control and Prevention.
fetal transmission by 50%. After pregnancy, breast feeding was also associated with an increased rate of
transmission.
Human Immunodeficiency Virus
Pregnancy is a frequent event in young women infected by HIV. 1 and 3 months of age.59 The first signs of the disease usually
Pregnancy does not appear to influence the course of HIV infec- appear at 6 months of age, and the median survival rate is
tion in asymptomatic women,52,53 although some studies have approximately 38 months.60
suggested an impairment of the outcome in women with HIV/
AIDS after pregnancy.54 Although HIV transmission to the fetus
can occur very early in pregnancy, before 15 weeks, fetal trans- Herpes
mission seems rare during the first trimester. The spontaneous Neonatal infections with herpes simplex virus have a high mor-
rate of fetal transmission of HIV from an infected mother is 12 to bidity and mortality rate. Therefore, maternal infections require
30%,52,55,56 depending largely on the characteristics of maternal special attention to prevent fetal contamination at birth. Asymp-
infection (Table 1–3).57 Cesarean section may reduce the risk of tomatic genital infections are responsible for two thirds of the
fetal contamination at delivery, but this is controversial and vagi- neonatal infections with herpes simplex virus at delivery. Four
nal delivery is generally preferred whenever possible. A double- situations can be individualized to decide the best policy to
blind, prospective study was designed in asymptomatic pregnant identify and prevent neonatal infection with herpes simplex virus
women infected with HIV with T4 lymphocyte counts of 200/mm3 (Table 1–4).
or greater to compare zidovudine therapy versus placebo during
pregnancy and delivery. The transmission rate of HIV from the
mother to the infant was significantly reduced in the zidovudine ABNORMAL FETAL DEVELOPMENT
group (8% vs 25%). Moreover, no teratogenic effect of zidovudine
has been reported despite its fetoplacental passage.58 Antiretroviral
IUGR
drugs may also be indicated for maternal therapy, and these agents IUGR complicates 3 to 7% of all pregnancies and remains one of
should not be withheld during pregnancy. HIV-infected infants the main causes of perinatal morbidity and mortality. The pro-
look normal at birth, and early on, the diagnosis of HIV infection gnosis associated with IUGR depends on its cause. Up to 8% of
is difficult because of the presence of maternal antibodies. newborns with IUGR have a major malformation that will impair
Detection of the P24 in the neonate’s serum is a very specific their outcome. Head growth is of particular concern in the
method for the diagnosis of infection at birth, but its sensitivity is determination of the prognosis, and harmonious IUGR with head
only 18%. Its presence at birth seems to be associated with poor circumference lower than the 3rd percentile is associated with
prognosis. Viral culture can also allow an early diagnosis of neo- poor neurodevelopmental outcomes.61
natal HIV infection with excellent specificity, but the technique is Hemodynamic changes and/or infectious diseases are often
not easy. Its sensitivity is around 50% at birth and 80% between involved in the pathophysiology of IUGR.62 In normal situations,
TABLE 1-4. Relationship Between the Maternal Manifestations of Herpes Infection and the Risk for the Newborn to Develop
an Infection With HSV
Clinical Manifestations Incidence in Mothers Risk for the Newborn to Develop
in the Mother of Infected Newborns an Infection with HSV Management of Delivery
Primary infection with HSV Rare 75% Cesarean section ± acyclovir for the
in the month before delivery infant
Recurrent maternal infection + 2–5% Cesarean section
Antecedent of genital infection ++ 1/1000 Vaginal delivery after disinfection
with HSV identification of HSV ± acyclovir
for the infant.
None antecedent +++ 1/10,000 No possibility of oriented prevention
2/3 of neonatal infection with HSV
HSV = herpes simplex virus.
the oxygenated blood from the umbilical vein flows through the function,62 with absent or inversed flow signs being a sign of
ductus venosus to the right atrium to the left lobe of the liver and imminent heart failure. Decreases in cardiac output and aortic and
to the portal vein, resulting in a preferentially mesenteric blood pulmonary peak velocities are directly related to the umbilical pH
flow. Impaired uteroplacental perfusion induces a reduction in at birth.69
fetal oxygen delivery responsible for a progressive hemodynamic Delivery is probably the more efficient treatment for IUGR. Its
adaptation of the fetus with differential shunting of blood to vital timing is based on an evaluation of the fetal heart rate (FHR),
organs such as brain, heart, or adrenals. The blood flow to these biophysical profile including amniotic fluid volume, Doppler
vital organs can be increased to 300%, whereas the increase in the velocimetry, and the level of fetal maturation.64 The progress of
vascular resistances in the other fetal organs can reduce the cardiac neonatal care and the benefits of antenatal corticosteroids in
output by 40%. This redistribution of flow is an adaptive pheno- reducing the risks of prematurity allow early deliveries of fetuses
menon that does not imply fetal distress but a “brain-sparing with progressively deteriorating IUGR status. Nevertheless, the
effect.” Placental insufficiency can result in metabolic disorders right time for delivery before progressive deterioration of the fetus
often associated with IUGR. In spite of low levels of insulin often represents a difficult choice for the obstetric team. Growth-
(hypoperfusion of the pancreas), hypoglycemia is often noted.63 restricted fetuses may benefit from repeated noninvasive tests such
Triglycerides and fatty acids levels are increased, whereas the ratio as FHR, ultrasound examinations with Doppler sonograms, and
of essential to nonessential amino acids is often low, reflecting occasionally, fetal blood sampling that may help in determining
the reduced anabolism of the fetus. This ratio is negatively the fetal condition and the appropriate timing of delivery.
correlated to the degree of fetal hypoxemia. Biologic signs of
hypothyroidism can appear in the hypoxemic fetus, whereas
hypervascularization of the adrenals increases cortisol levels in Prematurity: Main
response to hypoglycemia. Pathophysiologic Implications
The diagnosis of IUGR can be assessed by ultrasonographic
The incidence of prematurity is approximately 6 to 11% of all life
examination. In the first trimester, measurements of the crown-
births.70–73 These infants have a high morbidity and mortality rate
rump length and the biparietal diameter allow for precise dating
because of the incompleteness of organ maturation. They are not
of pregnancy.64 In late pregnancy, the diagnosis of IUGR is much
able to maintain their body temperature and have difficulties with
more difficult when the gestational age is not precisely known.
sucking, swallowing, eating, and sustaining ventilation. They are
Many Doppler and morphometric indices have been proposed to
detect a fetus who is small–for–gestational age (SGA). Abdominal prone to cerebral damage, intraventricular hemorrhage, respira-
circumference and estimated fetal weight appear to be accurate tory distress syndrome, and necrotizing enterocolitis. However,
predictive indicators of infants who are SGA.65 Doppler ultrasono- since the mid-1990s, major advances in the neonatal and perinatal
graphic examination also gives information on the fetal condition care of preterm infants have reduced the mortality rate, even in
and can predict fetal asphyxia.66 Compensatory redistribution of very small infants.
arterial blood flow to the brain and myocardium and decreased
flow to peripheral organs are additional physiologic adaptive Definitions
changes beneficial in preventing brain hypoxemia rather than a According to the World Health Organization nomenclature,
sign of impending brain damage.64 Loss of variability and late preterm labor (prematurity) is now defined as a gestational age less
decelerations are pejorative features. Absent or reversed end- than 37 completed weeks or less than 259 days, irrespective of
diastolic velocity waveforms in umbilical arteries of fetuses who birthweight, because decreased weight per se can be due to IUGR.
are SGA indicate a serious risk of adverse outcome with a 28% Classification according to the gestational age:74
perinatal mortality rate.64,67 Absent end-diastolic blood flow
and/or anomalies in heart rate reactivity (nonstress test) have been 1. Preterm infant: born before 37 weeks of gestation (<259 days).
associated with fetal hypoxemia and acidosis.68 Fetal cardiac 2. Moderately premature: born at 31 to 36 weeks of gestation.
function should be assessed in an IUGR infant. The ductus 3. Severely premature: born at 24 to 30 weeks of gestation.
venosus blood velocity may be used to assess the left ventricle 4. Postterm infant: born after 42 weeks of gestation.
Classification according to the birthweight: TABLE 1-5. Immediate Complications and Late Sequelae
1. An LBW infant is one weighing less than 2500 g irrespective of Preterm Infants
of the duration of pregnancy (only 54% of LBW infants are Immediate Complication Late Sequelae
preterm).
2. A VLBW infant is one weighing less than 1500 g. Hypoxia, ischemia Mental retardation, spastic diplegia,
3. VLBW is associated with maternal malnutrition, excessive microcephaly, seizures, poor
smoking, chronic alcohol ingestion, drug abuse, toxemia, or school performance
placental insufficiency. Intraventricular Mental retardation, spasticity,
hemorrhage seizures, hydrocephalus
Sensorineural injury Hearing, visual impairment,
Mortality, Morbidity, and Outcome retinopathy of prematurity,
In North America and Europe, preterm birth is the most impor- strabismus, myopia
tant cause of perinatal mortality. In Great Britain, preterm birth Respiratory failure Bronchopulmonary dysplasia, cor
accounts for 85% of early neonatal deaths not caused by lethal pulmonale, bronchospasm,
congenital malformations.72 In the United States, preterm birth malnutrition, iatrogenic cleft
occurs in 7.5% of all deliveries and accounts for 75% of the palate, recurrent pneumonia
perinatal deaths.71 In another study, preterm infants weighing less Necrotizing Short bowel syndrome,
than 750 g accounted for 41% of early neonatal deaths and 25% of enterocolitis malabsorption, malnutrition,
infant deaths.73 There is a relationship between the survival rate infectious diarrhea
of premature infants and increasing gestational age. From 1979 to Cholestatic liver Cirrhosis, hepatic failure,
1981, a survival rate above 90% was reported for neonates born disease carcinoma, malnutrition
after 32 weeks of gestation, decreasing to less than 50% when the Nutrient deficiency Osteopenia, fractures, anemia,
gestational age was less than 26 weeks.75 vitamin E, growth failure
Preterm birth is associated with a major increase in neonatal Social stress Child abuse or neglect, failure to
and infant morbidity, including neurodevelopmental disorders, thrive
chronic respiratory problems, intraventricular hemorrhage, infec- Other Sudden infant death syndrome,
tion, retrolental fibroplasias, and necrotizing enterocolitis.76,77 There infections, inguinal hernia,
is a long-term risk of neurologic and developmental impairment.78– cutaneous scars, gastroesophageal
82
In one study, McCarton and associates found that, irrespective of reflux, hypertension,
the degree of prematurity, SGA infants were at greater risk for craniosynostosis, cholelithiasis,
neurodevelopmental impairment than appropriate–for–gestational urolithiasis, cutaneous
age (AGA) infants. Cognitive impairment can be attributed to a hemangiomas
higher incidence of neurologic abnormalities in SGA infants at
each gestational age.83 Table 1–5 presents the immediate complica-
tions and the late sequelae of preterm infants. Prevention of pre-
term birth is, thus, a major public health goal in many developed capacity.94 Chest wall compliance is higher in preterm infants
countries and is cost-effective.84 In France, there was a reduction of (6.4 mL/cmH2O/kg at 32 wk vs 4.2 mL/cmH2O/kg at term.95 Air-
the preterm birth rate from 8.2% in 1972 to 6.8% in 1976 and 5.6% way resistance is increased in premature infants because of a
in 1981, with a parallel decrease in the incidence of infants smaller diameter of the bronchi.96 Accessory inspiratory muscles
weighing less than 1500 g from 0.8% in 1972 to 0.4% in 1981.85 are relatively inefficient because of an unfavorable anatomic rib
configuration, leading to easy distortion of the chest wall and
paradoxical ventilation. The diaphragm is the most important
Risk Factors for Preterm Birth respiratory muscle in preterm infants. There is a tendency for
The causes of prematurity are (1) low socioeconomic status, respiratory muscle fatigue, which results from metabolic charac-
(2) multiple gestation, (3) uteroplacental insufficiency, (4) mater- teristics of the diaphragm with a reduction of the content of type
nal illness with preeclampsia, and (5) idiopathic IUGR.86–91 These 1 muscle fibers (slow-twitch, high oxidative capacity) that account
risk factors are summarized in Table 1–6. for only 10% in preterm infant versus 20 to 30% in the full-term
infant.97,98 The diaphragmatic work to maintain tidal volume in
Problems and Complications Associated preterm infants is increased and may lead to diaphragmatic
With Preterm Birth fatigue, respiratory distress, or apnea.99,100
At the end of the canalicular stage of pulmonary differentiation
RESPIRATORY PROBLEMS: Respiratory distress is common in (16–24 wk), a reliable gas-exchanging surface appears and sur-
preterm infants because of the immaturity of the respiratory factant production begins.101–103 During the alveolar stage of
system (Table 1–7). The limit of viability is approximately 22 to differentiation (from 24 wk to term), surfactant secretion in the
24 weeks when the lungs have developed a gas-exchanging surface amniotic liquid increases, providing a useful indicator of lung
and surfactant production has begun. Anatomic issues are critical maturity.104 The insufficiency in surfactant production explains
at this stage. Breathing is exclusively nasal and nasal occlusion can why preterm infants are predisposed to develop HMD. At this
induce hypoxemia with a reduction of ventilation.92 Spontaneous stage, maternal administration of betamethasone or dexame-
neck flexion can induce an airway obstruction with apnea.93 thasone 48 hours before delivery increases surfactant production
Pulmonary compliance is decreased in cases of hyaline membrane and significantly decreases respiratory morbidity in preterm
disease (HMD) because of a reduction of the functional residual infants born after 30 weeks of gestation.74,105,106
TABLE 1-6. Risk Factors of Preterm Birth TABLE 1-7. Complications Associated With Preterm Infants
Obstetric factors Multiple gestation Respiratory Respiratory distress syndrome – hyaline
Overdistention of the uterus membrane disease
Placenta previa Bronchopulmonary dysplasia
Uteroplacental insufficiencies Pneumothorax
Intrauterine growth retardation Pneumomediastinum
Placental abnormalities Congenital pneumonia
Gestational bleeding Pulmonary hypoplasia
Cervical and uterine anomalies (multiple Pulmonary hemorrhage
fibroids, septate uterus) Apnea
In utero diethylstilbestrol exposure Cardiovascular Patent ductus arteriosus
Trauma: spontaneous, precipitous Hypotension
delivery, or iatrogenic (e.g., dilation and Hypertension
curettage) Bradycardia (with apnea)
Premature rupture of the fetal membranes Congenital malformations
Multiple second trimester spontaneous Neurologic Intraventricular hemorrhage
abortions Periventricular leukomalacia
In vitro fertilization pregnancy Hypoxic-ischemic encephalopathy
Maternal factors Infection (vaginitis, cervicitis, Seizures
chorioamniotitis, or urinary tract Retinopathy of prematurity (retrolental
infection) fibroplasia)
Preeclampsia Hypotonia
Severe cardiac disease Congenital malformations
Severe renal disease Kernicterus (bilirubin encephalopathy)
Thyrotoxicosis Hematologic Anemia
Diabetes Hyperbilirubinemia (direct or indirect)
Previous history of preterm labor Subcutaneous or organ hemorrhage (liver,
Smoking adrenal)
Cocaine use Disseminated intravascular coagulopathy
Socioeconomic African origin Vitamin K deficiency
factors Single marital status Hydrops
Low socioeconomic status Gastrointestinal Necrotizing enterocolitis
Poor antenatal care Poor gastrointestinal function or motility
Poor personal hygiene Metabolic- Hypocalcemia
Extremes of maternal age endocrine Hypoglycemia
Stress Hyperglycemia
Fetal factors Fetal anomalies Late metabolic acidosis
Iatrogenic Hypothermia
prematurity Renal Hyponatremia
Hypernatremia
Hyperkalemia
Renal tubular acidosis
Hypercapnic ventilatory response is decreased in the preterm
Renal glycosuria
infant, and hypoxia may depress this response in term or preterm
Edema
infants.107,108 There is also decreased ventilation during oral feeding
Other Infections (congenital, perinatal, or
in preterm infants.109 Clinical apneas are frequent, occurring in as
nosocomial)
many as 25% of all preterm infants, especially the most immature.
These events can be life-threatening. They are associated with a
decrease in arterial oxygen saturation, bradycardia, and loss of
concurrently with the decrease in pulmonary vascular resistance
muscle tone. Factors involved in these apneas include brainstem
associated with recovery from HMD and normal postnatal
immaturity, decreased hypercarbic and hypoxic responses, and
changes (see Table 1–7).113,114 The medical treatment of patent
respiratory fatigue precipitated by chest wall distortion.110,111
ductus arteriosus includes fluid restriction, diuretics, and the
Treatment of apnea is directed at increasing the central drive to
administration of either indomethacin or ibuprofen.115,116 Indo-
ventilation using theophylline or caffeine preparations, stabilizing
methacin and ibuprofen induce closure of patent ductus arteriosus
the chest wall (positive end-expiratory pressure), and stimulating
by inhibiting prostaglandin synthesis117; however, efficacy is not
by rocking or stroking. The risk of apnea after general anesthesia
always complete in extremely premature infants (<28 wk) and
is inversely related to the gestational age, affecting mainly infants
surgical closure may be required.118,119 Heart rate is greater in
with a postconceptional age of 50 weeks or less.112
preterm than in full-term infants (160 vs 120 beats/min) and
CARDIOVASCULAR PROBLEMS: Preterm infants often have a decreases progressively from 160 to 130 beats/min from 26 to
patent ductus arteriosus that appears 3 to 5 days after birth, 40 weeks of gestation.120 Blood pressure is lower in preterm than
in full-term infants. Cardiac output is higher in preterm than in GASTROINTESTINAL PROBLEMS: Necrotizing enterocolitis is a
full-term infants, which may reflect their higher metabolic rate major digestive problem that remains a frequent complication in
and oxygen consumption when compared with adults.121,122 preterm infants (see Table 1–7). It generally occurs after the
Diastolic function is insufficient and cardiac output is dependent beginning of enteral feedings, but may also occur in infants who
on heart rate. Therefore, any bradycardia decreases cardiac output. have never been fed.138 The usual clinical manifestations include
There is also a limited left ventricular response to volume overload abdominal distention, vomiting, bloody stools, and shock.
in preterm infants.123 Autonomic control of the heart is predomi-
nantly mediated by the parasympathetic nervous system because METABOLIC-ENDOCRINE PROBLEMS: As mentioned previously,
the sympathetic system is immature. There is a decreased respon- metabolic acidosis is common in preterm infants (see Table 1–7).
siveness to vasoconstrictor and vasodilator agents.124 Hypoxia In addition, hypocalcemia can also be seen because calcium
(apnea) produces a bradycardia with a decrease of cardiac output transfer occurs mainly during the third trimester of gestation and
associated with an increase of systemic and pulmonary resistances, because preterm infants have diminished concentrations of serum
which then further potentiates the hypoxemia. There is impair- proteins. Because of the immaturity of glucose regulation, preterm
ment of the autoregulation of cerebral blood flow.125 Perlman and infants tolerate glucose loads poorly. Therefore, excessive glucose
coworkers described a fluctuation of cerebral blood flow in infusion can be deleterious to the central nervous system. There is
preterm infants with respiratory distress syndrome that correlated also a risk of hypoglycemia that requires appropriate correction.
with an increasing rate of intracerebral hemorrhage.126 HEMATOLOGIC PROBLEMS: Anemia is frequent in preterm infants
RENAL PROBLEMS: Urine production begins in utero at 10 to because the production of red blood cells is reduced (see Table
12 weeks of gestation. Urinary flow is important to maintain the 1–7). Anemia has been shown to increase the risk of apnea.139
amniotic fluid volume. Glomerular filtration is decreased in Immaturity of hepatic function can explain the abnormalities of
preterm infants compared with full-term infants.127 Because the coagulation with decreases of vitamin K–dependent factors
fetus maintains its metabolic homeostasis through the placenta, it leading to prolongation of the prothrombin time.
is only after birth that the kidney assumes this function. Tubular INFECTION: The development of infections such as pneumonia,
function begins to develop after 34 weeks of gestation.128 The renal sepsis, or meningitis is common in the preterm infant because
tubular threshold for sodium is decreased, which explains the of significant reduction in cellular and tissue immunity (see
propensity for neonates, especially preterm ones, to develop Table 1–7).
hyponatremia (see Table 1–7).129 The tubular threshold for glucose
is low and responsible for frequent glycosuria with dehydration
induced by an osmotic polyuria.130 Metabolic acidosis is common
Prevention of Premature Birth
owing to diminished renal tubular threshold for sodium bicarbo- The strategies to prevent preterm birth are reviewed in an article
nate.131 The infusion of sodium bicarbonate may be necessary to from Goldenberg and colleagues.75 These factors are outlined in
control acidosis in preterm infants. These infants are at increased Table 1–8. Two categories of strategies are used to reduce adverse
risk of dehydration because insensible water loss is increased.132 outcomes associated with prematurity: (1) those intended to
Immaturity of distal tubular function and relative hypoaldostero- prevent or delay preterm birth and (2) those aiming at reducing
nism can explain the risk of hyperkalemia in preterm infants.133 the morbidity and mortality of prematurity. The regionalization
of perinatal care ensures that most preterm infants are delivered
NEUROLOGIC PROBLEMS: Brain development differs from that in close to a neonatal intensive care unit with appropriate equipment
other organs. The brain has two growth spurts: (1) neuronal cell and trained personnel. In these units, specialized therapies can be
multiplication between 15 and 20 weeks of gestation and (2) a used such as specific methods of mechanical ventilation, exoge-
phase of glial cell multiplication from 25 weeks of gestation to the nous surfactant therapy, and other supportive therapies (antibiotic
second year of life. Preterm blood vessel fragility is increased by treatment, and fluid and electrolyte management). Effective
several respiratory or hemodynamic factors, thereby increasing obstetric interventions include use of prenatal corticosteroids for
the risk of intracerebral hemorrhage during the first days of life fetal pulmonary maturation, intrapartum antibiotics to reduce
(see Table 1–7).125,126,134 Periventricular leukomalacia is an ischemic neonatal sepsis, and prevention or prompt treatment of fetal
cerebral complication with a risk of delayed neurologic develop- hypoxia. These interventions are effective in decreasing the
ment. Its incidence ranges from 12 to 25% in LBW infants less mortality of preterm infants.
than 1500 g to 8% in infants born after 34 weeks.135 Retrolental
fibroplasia is a complication depending on the gestational age, the
duration of oxygen therapy, and the partial pressure of oxygen in Acute Fetal Distress
the arterial blood.136
Fetal distress can be chronic (antepartum period) or acute (intra-
THERMAL PROBLEMS: Thermal regulation is immature in the partum period only). Clinical features of antenatal fetal distress
preterm infant. Exposure to cold may induce an elevation of meta- include IUGR, fetal hypoxia, increasing vascular resistance in fetal
bolic rate and oxygen consumption that increases the risks of blood vessels, and fetal acidosis. Antepartum fetal distress is
hypoxemia, acidosis, apnea, or respiratory distress (see Table 1–7). frequently associated with uteroplacental insufficiency. Acute fetal
Body heat can be dissipated by conduction, convection, radiation, distress occurs during labor. It is a nonspecific and imprecise
and also evaporation, which is the most important mechanism.137 diagnosis often associated with surgical delivery. Parer and
The surface-to-volume ratio is more important in preterm than Livingston define fetal distress as “a progressive fetal asphyxia
in full-term infants, increasing heat losses. It is essential to protect which without treatment induces a decompensation of adapted
these infants in an incubator, dry them off immediately after birth, physiological responses and causes definitive neurologic impair-
and provide them with warmed and humidified inspired gases. ment and other damage or death.”140 If birth asphyxia is defined by
TABLE 1-8. Interventions to Prevent Premature Birth Fetal oxygen delivery depends on the umbilical blood flow and
umbilical venous oxygen content and tension. Although some
Prenatal care (routine or enhanced) cases are caused to changes in cardiac output (fetal arrhythmias)
Risk-scoring systems or to modifications of fetal oxygen content (fetal anemia), major
Cervical circling acute fetal distress is mainly related to a decrease of umbilical
Progestin supplementation blood flow. Three mechanisms are responsible for this decrease:
Programs for cessation of tobacco, drug, and alcohol use (1) increase of uterine venous pressure (mainly uterine hyperto-
Psychological support nia), (2) decrease of uterine arterial pressure (mainly maternal
Nutritional interventions hypotension), and (3) increase of uterine vascular resistance
Counseling (mainly maternal hypertension). The fetal response to hypoxia is
Caloric supplementation a redistribution of blood flow to vital organs (heart and brain).
Protein supplementation Fetal hypoxia results in hypertension with bradycardia without
Vitamin or mineral supplementation initial modification of the cardiac output. In severe or prolonged
Patient education (to detect signs of preterm labor) hypoxemia, fetal cardiac output decreases. During moderate
Home uterine-activity monitoring hypoxemia, absolute umbilical blood flow tends to be maintained.
Frequent contact with a nurse Blood flow to brain, heart, and adrenals can increase from 100 to
Tocolytic therapy 200% while the cardiac output of the fetus decreases to 30%.154 The
Bed rest umbilical venous blood flow that returns from the placenta either
Hydration enters the hepatic circulation or bypasses the liver via the ductus
Screening for and treatment of infection (urinary tract infection venosus. The double phenomenon of increasing myocardial blood
or bacterial vaginosis) flow and redistribution of umbilical venous blood (increasing the
Antibiotics for preterm labor or premature rupture of proportion of oxygen-rich blood) maintains oxygen delivery to
membranes the myocardium of the fetus during hypoxemia.155–157 Autoregula-
Low-dose aspirin tion of cerebral blood flow protects the brain by increasing oxygen
Calcium supplementation delivery via vasodilatation associated with the hypertensive
From Goldenberg RL, Dwight JR. Prevention of premature birth. N Engl J Med. response to hypoxemia. Severe and prolonged hypoxemia induces
1998;339:313–320. ischemic cerebral lesions by a phenomenon of alteration of the
cerebral blood flow associated with hypotension. The evolution of
these ischemic lesions depends on the severity and timing of
an Apgar score below 7, its incidence is 5.3%.141 If the definition is cerebral hypoxemia.
the requirement of more than 1 minute of positive-pressure Antenatal fetal distress can be suspected in cases of (1) diag-
ventilation at birth, the incidence decreases to 1.16%.142 However, nosis of IUGR by ultrasound, (2) Doppler anomalies of the
if measurements of blood gas and acid-base status in the umbilical umbilical artery or fetal aorta blood flow,158–160 (3) alterations of
artery are used just after delivery, the incidence is 2%.143 the FHR (spontaneously or during contractions), and (4) diagnosis
The morbidity of acute fetal distress is most important. In 1979, of hypoxia or acidosis during percutaneous umbilical venous
a consensus conference estimated that intrapartum events ac- blood sampling. Acute fetal distress is suspected during labor
counted for 20 to 40% of cerebral palsy and 10% of severe mental when there are (1) anomalies of the FHR (tachycardia or brady-
retardation.144 Freeman in 1985 concluded that asphyxia played a cardia), (2) low variability or abnormal evolution of FHR with
major role in cerebral palsy, but not in the occurrence of mild or uterine contractions (decelerations), or (3) anomalies of the acid-
severe mental retardation with epilepsy.145 Currently, the incidence base status from fetal scalp blood sampling. A pH less than 7.25
of cerebral palsy caused by birth asphyxia is less than 10%.145–147 suggests fetal distress and a pH less than 7.20 is an indication for
The consequences of birth asphyxia are variable, because some early surgical delivery. Parer and Livingston suggest that adding
fetuses die or have severe and irreversible brain injury whereas the determination of FHR variability to the FHR pattern interpre-
others survive without apparent neurologic deficiencies.148–150 In tation is the best indicator of fetal vigor at birth.140 If FHR
the absence of any history of chronic fetal distress, there are three variability is absent, then a fetal stimulation test or fetal blood
major causes of acute fetal distress: sampling for acid-base status determination may be indicated.
1. Maternal arterial hypotension: Hypotension can occur when Chronic fetal distress can be responsible for premature delivery
analgesia for labor is established (epidural or spinal anesthesia) or IUGR. Acute fetal distress in full-term infants without a
or following uteroplacental hemorrhage. Hypotension can also previous problem can be associated with immediate or delayed
occur or be enhanced by maternal malposition.151 complications. Neurologic injuries represent the major factor in
2. Umbilical cord compression: Cord prolapse is positionally the morbidity of the child. Outcome after birth asphyxia is difficult
dependent. It is 20 times more frequent in abnormal than in to predict because it varies from intrauterine death to normal
vertex presentation.152 Abnormal presentations are more fre- survival without any apparent deficit.
quent in preterm infants. At 28 weeks, 25% of fetus are found
in breech presentation.153 Cord prolapse is, therefore, also
indirectly related to gestational age.
CONCLUSIONS
3. Uterine hypertonia: Uterine hypertonia is responsible for a The knowledge of normal and abnormal development of the fetus
decrease in umbilical blood flow. The most frequent cause is increasingly necessary for the pediatric anesthesiologists who
of hypertonia is an excessive exogenous oxytocin adminis- are involved in the care of preterm and term neonates undergoing
tration. surgical treatments of a congenital malformation or a specific
complication of prematurity. Diagnosis of major malformations is 20. Manning FA, Menticoglou S, Harman CR, et al. Antepartum fetal risk
now more predictable and effective with the development of assessment: the role of the biophysical profile score. Clin Obstet
reliable in utero evaluation techniques and better pregnancy Gynecol. 1987;1:157.
supervision. These anomalies should be evaluated as soon as 21. Sabers A, Rogvi-Hansen B, Dam M, et al. Pregnancy and epilepsy: a
retrospective study of 151 pregnancies. Acta Neurol Scand. 1998;97:
possible and can lead to the transfer of the obstetric patient to a
164.
tertiary perinatal center where a suitable therapeutic strategy can 22. Hauser WA, Hesdorffer DC. Pregnancy and teratogenesis. In: Hauser
be decided. Many innovations have been made, thus reducing the WA, editor: Epilepsy, Frequency, Causes and Consequences. New York:
mortality rate even in very small infants. Much of this decrease in Demos; 1990, pp. 147–156.
mortality can be attributed to improvements in the neonatal and 23. Chang SI, McAuley JW. Pharmacotherapeutic issues for women of
perinatal care of preterm infants. Another consequence of this childbearing age with epilepsy. Ann Pharmacother. 1998;32:794–801.
improvement in neonatal care is a reduction of the viable gestatio- 24. Yerbi MS, Friel PN, McCormick K, et al. Pharmacokinetics of
nal age compatible with long-term survival with an increase in the anticonvulsants in pregnancy: alterations in plasma protein binding.
number of preterm infants needing surgery. Therefore, the pedi- Epilepsy Res. 1990;5:223–228.
atric anesthesiologist must be fully trained in dealing with the 25. Lander CM, Eadie MJ. Plasma antiepileptic drug concentrations
problems associated with extreme prematurity. during pregnancy. Epilepsia. 1991;32:257–266.
26. Samren EB, van Duijn, Koch S, et al. Maternal use of antiepileptic
drugs and the risk of major congenital malformations: a joint
REFERENCES European prospective study of human teratogenesis associated with
maternal epilepsia. Epilepsia. 1997;38:981–990.
1. Larsen WJ. Human Embryology. 2nd ed. Churchill, New York: 27. Bradai R, Robert E. Prenatal ultrasonic diagnosis in the epileptic
Livingstone; 1997. mother on valproic acid. Retrospective study of 161 cases in the
2. O’Rahilly R, Muller F. Developmental Stages in Human Embryos. central eastern France register of congenital malformations. J Gynecol
Washington, DC: Carnegie Institution of Washington; 1987. Obstet Biol Reprod. 1998;27:413–419.
3. Kliegman RM. Fetal growth and maturity. In: Nelson WE, editor: 28. Shojania AM. Folic acid and vitamin B12 deficiency in pregnancy
Textbook of Pediatrics. 15th ed. Philadelphia: WB Saunders; 1996. and in the neonatal period. Clin Perinatol. 1984;11:433–459.
4. Needlman RD. Fetal growth and development. In: Nelson WE, editor: 29. Lewis DP, Van Dyke DC, Stumbo PJ, et al. Drug and environmental
Textbook of Pediatrics. 15th ed. Philadelphia: WB Saunders; 1996. factors associated with adverse pregnancy outcomes. Part I: anti-
5. Warshaw JB. The fetus and the newborn. General principles of epileptic drugs, contraceptives, smoking and folate. Ann Pharmaco-
growth and development. In: Oski FA, editor: Principles and Practice ther. 1998;32:802–817.
of Pediatrics. 2nd ed. Philadelphia: JB Lippincott; 1994. 30. Becerra JE, Khoury MJ, Cordero JF, et al. Diabetes mellitus during
6. Jones KL. Smith’s Recognizable Patterns of Human Malformation. 4th pregnancy and the risk for specific birth defects: a population-based
ed. Philadelphia: WB Saunders; 1988. case control study. Pediatrics. 1990;85:1–9.
7. Bergsma D. Birth Defects Atlas and Compendium. 2nd ed. The 31. Lepercq J, Cauzac M, Lahlou N, et al. Overexpression of placental
National Foundation March of Dimes. Baltimore: Williams & leptin in diabetic pregnancy: a critical role for insulin. Diabetes.
Wilkins; 1974. 1998;47:847–850.
8. Jones KL. Dysmorphology. In: Nelson WE, editor: Textbook of 32. Aparicio NJ, Joao MA, Cortelezzi M, et al. Pregnant women with
Pediatrics. 15th ed. Philadelphia: WB Saunders; 1996. impaired tolerance to an oral glucose load in the afternoon: evidence
9. Romero R, Pilu G, Jeanty P, et al. Prenatal Diagnosis of Congenital suggesting that they behave metabolically as patients with gestational
Anomalies. ed. Norwalk, Conn: Appleton and Lange; 1988. diabetes. Am J Obstet Gynecol. 1998;178:1059–1066.
10. Caritis S, Sibai B, Hauth J, et al. Low dose aspirin to prevent pre- 33. The Diabetes Control and Complications Trial Research Group.
eclampsia in women at high risk. N Engl J Med. 1998;338:701–705. Pregnancy outcomes in the diabetes control and complications trial.
11. CLASP: A randomised trial of low dose aspirin for the prevention Am J Obstet Gynecol. 1996;174:1343–1353.
and treatment of preeclampsia among 9364 pregnant women. Lancet. 34. Kaminski M. Tabac, alcool et grossesse. In: Papiernik E, Cabrol D,
1994;343:619–629. Pons JC, editors. Obstetrique. Paris : Flammarion, Médecine-Sciences,
12. Sibai BM, Mercer BM, Schiff E, et al. Aggressive versus expectant 1995. pp. 1019–1027.
management of severe preeclampsia at 28 to 32 weeks gestation: a 35. Blondel B, Du Mazaubrun C, Breart G. Enquête Nationale Périnatale
randomized controlled trial. Am J Obstet Gynecol. 1994;171:818–822. 1995. Rapport de Fin d’Étude. Paris: INSERM; 1996.
13. Brazy JE, Grimm JK, Little VA. Neonatal manifestations of severe 36. Groupe d’experts de l’INSERM. Tabac, alcool, facteurs nutritionnels
maternal hypertension occurring before the thirty sixth week of et environnementaux. In: Grande Expertise Collective INSERM
pregnancy. J Pediatr. 100:165,1982. Prématurité. Paris: INSERM; 1997, pp. 65–74.
14. Sibai BM, Anderson GD, Abdella TN, et al. Eclampsia III: neonatal 37. Shiono PH, Klebanoff MA, Roads GG. Smoking and drinking during
outcome, growth and development. Am J Obstet Gynecol. 1983;146:307. pregnancy: their effects on preterm birth. JAMA. 1986;255:82–84.
15. Nelson KB, Grether JK. Can magnesium sulfate reduce the risk of 38. Schwartz D, Goujard J, Kaminski M, et al. Smoking and pregnancy
cerebral palsy in very low birthweight infants? Pediatrics. 1995;95:263. results of a prospective study of 6989 women. Rev Eur Etudes Clin
16. Almstrom H, Axelsson O, Cnattingus S, et al. Comparison of Biol. 1972;17:867.
umbilical artery velocimetry and cardiotocography for surveillance of 39. Kain Z, Rimar S, Barash P. Cocaine abuse in the parturient and effects
small-for-gestational-age fetuses. Lancet. 1992;340:936. on the fetus and neonate. Anesth Analg. 1993;77:835–845.
17. Ducey J, Schulman H, Farmakides G, et al. A classification of 40. Burkett G, Yasin S, Palow D. Perinatal implications of cocaine
hypertension in pregnancy based on Doppler velocimetry. Am J exposure. J Reprod Med. 1990;35:35–42.
Obstet Gynecol. 1987;157:860. 41. Chasnoff IJ, Griffith DR, MacGregor S, et al. Temporal patterns of
18. Havretty K, White MJ, Rubin PC. Doppler uteroplacental waveforms cocaine use in pregnancy: perinatal outcome. JAMA. 1989;261:1741–
in pregnancy induced hypertension: a reappraisal. Lancet. 1988;1:650. 1744.
19. Uzan S, Beaufils M, Uzan M. HTA et grossesse. In: Papiernik E, Cabrol 42. Mooney EE, Boggess KA, Herbert WNP, et al. Placental pathology in
D, Pons JC, editors. Obstetrique. Paris : Flammarion, Médecine- patients using cocaine: an observational study. Obstet Gynecol.
Sciences ; 1995. pp. 793–824. 1998;91:925–929.
43. Cherukuri R, Minkoff H, Feldeman J, et al. A cohort study of venous blood gases measured at cordocentesis. Am J Obstet Gynecol.
alkaloidal cocaine (crack) in pregnancy. Obstet Gynecol. 1988;72: 1990;162:115–120.
147–151. 67. Karsdorp VHM, Van Vugt JMG, Van Geijn HP. Clinical significance
44. Oro AS, Dixon SD. Perinatal cocaine and metamphetamine exposure: of absent or reversed end diastolic velocity waveform in umbilical
maternal and neonatal correlates. J Pediatr. 1987;111:571–578. arteries. Lancet. 1994;344:1664–1668.
45. Zuckerman B, Maynard EC, Cabral H. A preliminary report of 68. Rizzo G, Arduini D. Fetal cardiac function in intrauterine growth
prenatal cocaine exposure and respiratory distress syndrome in retardation. Am J Obstet Gynecol. 1991;165:876–882.
premature infants. Am J Dis Child. 1991;145:696–698. 69. Donner C, Vermeylen D, Kirkpatrick C, et al. Management of the
46. Kain ZN, Chinoy MR, Antonio-Santiago MT, et al. Enhanced lung growth restricted fetus: the role of non invasive tests and fetal blood
maturation in cocaine exposed rabbit fetuses. Pediatr Res. 1991;29: sampling. Obstet Gynecol. 1995;85:965–970.
534–537. 70. U.S. Department of Health and Human Services, Public Health
47. Sosenko IRS. Cocaine administration to pregnant rats produces Service, The National Center for Health Statistics (NCHS). Vital
increased surfactant maturation without affecting antioxidant Statistics of the United States, 1980. Vol 1. Hyattsville, MD: 1984.
enzyme development [abstract]. Pediatr Res. 1991;29:330A. 71. Quilligan EJ, Little AB, Oh WM. 1983 An elevation and assessment
48. Laegreid L, Olegard R, Walstrom J, et al. Teratogenic effects of benzo- of the state of the science. In: Pregnancy, Birth and Infant. NIH
diazepine use during pregnancy. J Pediatr. 1989;114:126–131. Publication N8. 82-02304. Bethesda, Md: National Institutes of
49. Bergman U, Rosa FW, Baum C, et al. Effects of exposure to Health; 1983.
benzodiazepine during fetal life. Lancet. 1992;340:694–696. 72. Rush RW, Keirse MJ, Howat P, et al. Contribution of preterm delivery
50. Laegreid L, Kyllerman M, Hedner T, et al. Benzodiazepine ampli- to perinatal mortality. Br Med J. 1976;2:965–968.
fication of valproate teratogenic effects in children of mothers with 73. Overpeck MD, Hoffman HJ, Prager K. The lowest birth-weight
absence epilepsy. Neuropediatrics. 1993;24:88–92. infants and the US infant mortality rate: NCHS 1983 linked
51. Wilson C, Remington J, Stagno S, et al. Development of adverse birth/infant death. Am J Public Health. 1992;82:441–444.
sequelae in children born with subclinical Toxoplasma infection. 74. Creasy RK. Preterm labor and delivery. In: Creasy RK, Resnik R,
Pediatrics. 1980;66:767. editors. Maternal-Fetal Medicine, Principles and Practice, 2nd ed.
52. Blanche S, Rouzioux C, Moscato MLG, et al. A prospective study of Philadelphia: WB Saunders; 1989. pp 477–504.
infants born to women seropositive for human immunodeficiency 75. Goldenberg RL, Nelson KG, Hale CD, et al. Survival of infants with
virus type 1. N Engl J Med. 1989;320:1643. low birth weight and early gestational age. Am J Obstet Gynecol.
53. Gloeb DJ, O’Sullivan MJ, Efantis J. Human immunodeficiency virus 1984;149:508–511.
in women: I. The effects of human immunodeficiency virus on 76. Institute of Medicine, National Academy of Sciences. Preventing Low
pregnancy. Am J Obstet Gynecol. 1988;159:756. Birth Weight. Washington, DC: National Academy Press; 1985.
54. Lindgren S, Anzen B, Bohlin AB, et al. HIV and child bearing: clinical 77. Arias F, Tomich P. Etiology and outcome of low birth weight and
outcome and aspects of mother to infant transmission. AIDS. preterm infant. Obstet Gynecol. 1982;60:277–281.
1991;5:1111–1116. 78. Teberg AJ, Wather FJ, Pena IC. Mortality, morbidity and outcome of
55. European Collaborative Study. Children born to women with HIV 1 the small-for-gestational age preterm infant. Semin Perinatol.
infection: natural history and risk of transmission. Lancet. 1991; 1988;12:84–89.
1:253–260. 79. Vohr BR, Oh W, Rosenfield AG, et al. The premature small for
56. Delfraissy JF, Goujard C, Boue F, et al. Transmission périnatale du gestational age infant: a 2-year follow-up study. Am J Obstet Gynecol.
VIH. Rep Hum Horm. 1992;5:543. 1979;133:425–431.
57. Mayaux MJ, Blanche S, Rouzioux C, et al. Maternal factors associated 80. Commey JO, Fitzhardinge PM. Handicap in the preterm small for
with perinatal HIV-1 transmission: The French cohort study: 7 years gestational age infant. J Pediatr. 1979;94:779–786.
of follow up observation. J Acquir Immun Defic Syndr. 1995;8:188– 81. Kitchen W, Ford G, Orgill A, et al. Outcome in infants with birth
194. weight 500 to 999 gm: a regional study of 1979 and 1980 births.
58. Gillet JY, Garraffo R Abrar D, et al. Fetoplacental passage of J Pediatr. 1984;104:921–927.
zidovudine. Lancet. 1989;ii:269–270. 82. Sung IK, Vohr B, Oh W. Growth and neurodevelopmental outcome
59. Burgard M, Mayaux MJ, Blanche S, et al. The use of viral culture and of very low birth weight infants with intrauterine growth retardation:
p24 antigen testing to diagnosis human immunodeficiency virus comparison with control subjects matched by birth weight or for
infection in neonates. N Engl J Med. 1992;327:1192–1197. gestational age. J Pediatr. 1990;116:19–26.
60. Scott GB, Hutto C, Makuch RW, et al. Survival in children with 83. McCarton CM, Wallace IF, Divon M, et al. Cognitive and neurologic
perinatally acquired human immunodeficiency virus type I infection. development of the premature, small for gestational age infant
N Engl J Med. 1989;321:1791. through age 6: comparison by birth weight and gestational age.
61. Hadders-Algra M, Touwen BCL. Body measurements, neurological Pediatrics. 1996;98:1167–1178.
and behavioral development in six year old children born preterm 84. Korenbrot CC, Aalto LJ, Laros RK. The cost effectiveness of stopping
and/or small-for-gestational age. Early Hum Dev. 1991;22:1–13. preterm labor with β-adrenergic treatment. N Engl J Med. 1984;
62. Ville Y. Retard de croissance intrautérin d’origine vasculaire. 9e 310:691–696.
Séminaire Guigoz-GENEUP-RP. Paris. Guigoz et la Fédération des 85. Rumeau-Rouquette C, Du Mazaubrun C, Rabarison Y, et al. Naître
groupes d’Études en Néonatologie; 1997. en France: 10 ans d’Evolution, 1972–1981. Paris: INSERM/Doin;
63. Economides DL, Nicolaides KH. Blood glucose and oxygen tension 1984.
levels in small for gestational age fetuses. Am J Obstet Gynecol. 86. Gonik B, Creasy RK. Preterm labor: its diagnosis and management.
1989;160:385–389. Am J Obstet Gynecol. 1986;154:3–8.
64. Lepercq J, Mahieu Caputo D. Diagnosis and management of intrau- 87. McKeown T, Record R. Observations on fetal growth in multiples
terine growth retardation. Horm Res. 1998;49:14–19. pregnancies. J Endocrinol. 1952;8:386–401.
65. Chang TC, Robson SC, Boys RJ, et al. Prediction of the small for ges- 88. Linn S, Schoenbaum S, Manson R. The relationship between induced
tational age infant: which is the best? Obstet Gynecol. 1992;80:1030– abortion and outcome of subsequent pregnancies. Am J Obstet
1038. Gynecol. 1983;146:136–140.
66. Bilardo CM, Nicolaides KH, Campbell S. Doppler measurements of 89. Parisi VM. Cervical incompetence and preterm labor. Clin Obstet
fetal and uteroplacental circulations: relationship with umbilical Gynecol. 1988;31:585–598.
90. Gravett MG, Nelson HP, DeRouen T. Independent associations of 114. Thibeault DW, Emmanouilides GC, Nelson RJ, et al. Patent ductus
bacterial vaginosis and Chlamydia trachomatis infection with arteriosus complicating the respiratory distress syndrome in pre-
adverse pregnancy outcome. JAMA. 1986;256:1899–1903. term infants. J Pediatr. 1975;86:120.
91. Berkowitz GS, Papiernik E. Epidemiology of preterm birth. 115. Rudolph AM, Heymann MA. Medical treatment of ductus
Epidemiol Rev. 1993;15:414–443. arteriosus. Hosp Pract. 1977;12:57.
92. Miller MJ, Carlo WA, Strohl KP, et al. Effect of maturation on oral 116. Stevenson JG. Fluid administration in the association of patent
breathing in sleeping premature infants. J Pediatr. 1986;109: ductus arteriosus complicating respiratory distress syndrome.
515–519. J Pediatr. 1977;90:257.
93. Thach BT, Stark AR. Spontaneous neck flexion and airway obstruc- 117. Heymann MA, Rudolph AM, Silverman NH. Closure of the ductus
tion during apneic spells in preterm infants. J Pediatr. 1979;94:275. arteriosus in premature infants by inhibition of prostaglandin
94. Bancalari E, Garcia OL, Jesse ML. Effects of continuous negative synthesis. N Engl J Med. 1976;295:530.
pressure and lung mechanics in idiopathic respiratory distress 118. Merritt TA, Disessa TG, Feldman BH, et al. Closure of the patent
syndrome. Pediatrics. 1973;51:485. ductus arteriosus with ligation and indomethacin: a consecutive
95. Gerhardt T, Bancalari E. Chest wall compliance in full term and experience. J Pediatr. 1978;93:639.
premature infants. Acta Paediatr Scand. 1980;69:359–364. 119. Mellander M, Leheup B, Lindstrom DP, et al. Recurrence of symp-
96. Stocks J, Godfrey S. Specific airways conductance in relationship tomatic patent ductus arteriosus in extremely premature infants
to postconceptional age in early infancy. J Appl Physiol. 1977;43: treated with indomethacin. J Pediatr. 1984;104:419–425.
144–154. 120. Siassi B, Hodgman J, Cabal L, et al. Cardiac and respiratory activity
97. Keens TG, Bryan AC, Levison H, et al. Development pattern of in relation to gestation and sleep states in newborn infants. Pediatr
muscle fiber types in human ventilatory muscles. J Appl Physiol. Res. 1979;13:1163.
1978;44:909–913. 121. Walther FJ, Siassi B, Ramadan NA, et al. Pulsed Doppler determina-
98. Muller NL, Gulston G, Cade D, et al. Diaphragmatic muscle fatigue tion of cardiac output in neonates: normal standards for clinical use.
in the newborn. J Appl Physiol. 1979;46:688–695. Pediatrics. 1985;76:829–833.
99. Heldt GP. Development of stability of respiratory system in preterm 122. Walther FJ, Siassi B, King J, et al. Echocardiographic measurements
infants. J Appl Physiol. 1988;65:441–444. in normal preterm and term neonates. Acta Paediatr Scand. 1986;
100. Guslits BG, Gaston SE, Bryan MH, et al. Diaphragmatic work of 75:563–568.
breathing in premature human infants. J Appl Physiol. 1987;62: 123. Romero TE, Friedman WF. Limited left ventricular response to
1410–1415. volume over load in the neonate period: a comparative study with
101. Boyden EA. Development and growth of the airways. In: Hodsen adult animal. Pediatr Res. 1979;13:910–915.
WA, editor. Development of the Lung. New York: Marcel Dekker; 124. Manders WT, Pagani M, Vatner SF. Depressed responsiveness to
1977. vasoconstrictor and dilatator agents and baroreflex sensitivity in
102. Hislop A, Reid L. Lung development in relation to gas exchange conscious newborn lambs. Circulation. 1979;60:945–955.
capacity. Bull Physiopathol Respir. 1973;92:1317–1343. 125. Lou HC, Lassen NA, Friis-Hansen B. Impaired autoregulation of
103. Campiche MA, Gautier A, Hernandez EI, et al. An electron cerebral blood flow in the distressed newborn infant. J Pediatr.
microscope study of the fetal development of human lung. Pedia- 1979;94:118.
trics. 1963;32:976–994. 126. Perlman JM, McMenamin JB, Volpe JJ. Fluctuating cerebral blood
104. Gluck L, Kulovich MV. Lecithin/sphingomyelin ratios in amniotic velocity in respiratory distress syndrome. N Engl J Med. 1983;309:
fluid in normal and abnormal pregnancy. Am J Obstet Gynecol. 204–209.
1973;115:539–546. 127. Guignard JP. Assessment of renal function without urine collection.
105. Liggins GC, Howie RN. A controlled study of antepartum glucocor- Arch Dis Child. 1977;52:424.
ticoid treatment of the respiratory distress syndrome in premature 128. Arant BS. Developmental patterns of renal functional maturation
infants. Pediatrics. 1972;50:515–525. compared in the human neonate. J Pediatr. 1978;92:705–712.
106. Morales WJ, Diebel D, Lazar AJ, Zadrosny D. The effect of antenatal 129. Engelke SC, Shah BL, Vasan V, et al. Sodium balance in very low
dexamethasone administration on the prevention of respiratory birth weight infants. Pediatrics. 1984;74:259.
distress syndrome in preterm gestations with premature rupture of 130. Stonestreet BS, Rubin L, Pollack A, et al. Renal functions of low birth
membranes. Am J Obstet Gynecol. 1986;154:591–595. weight infants with hyperglycemia and glycosuria produced by
107. Rigatto H, Brady JP, Chir B, et al. Chemoreceptor reflexes in preterm glucose infusions. Pediatrics. 1981;66:561.
infants: I: the effect of gestational age and postnatal age on the ven- 131. Guignard JP, John EG. Renal function in the tiny, premature infant.
tilatory response to inhaled carbon dioxide. J Appl Physiol. 1975; Clin Perinatol. 1986;13:377–401.
55:604. 132. Wu PYK, Hodgman JE. Insensible water loss in preterm infants:
108. Rigatto H, Verduzco RT, Cates DB. Effects of O2 on the ventilatory changes with postnatal development and non ionizing radiant
response to carbon dioxide in preterm infants. J Appl Physiol. energy. Pediatrics. 1974;54:704–712.
1975;39:896–899. 133. Gruskay J, Costarino AT, Polin RA, et al. Nonoliguric hyperkaliemia
109. Shivpuri CR, Martin RJ, Carlo WA, et al. Decreased ventilation in in the premature infant weighing less than 1000 grams. J Pediatr.
preterm infants during oral feeding. J Pediatr. 1985;106:625. 1988;113:381–386.
110. Heldt GP, McIloroy MB. Distortion of chest wall and work of 134. Ment LR, Duncan CC, Ehrenkranz RA, et al. Intraventricular
diaphragm in preterm infants. J Appl Physiol. 1987;62:164–169. hemorrhage in the preterm neonate: timing and cerebral blood flow
111. Henderson-Smart DJ, Pettigrew AG, Campbell DJ. Clinical apnea changes. J Pediatr. 1984;104:419–425.
and brainstem neural function in preterm infants. N Engl J Med. 135. Fawer CL, Diebold P, Calame A. Periventricular leukomalacia and
1983;308:353–357. neurodevelopmental outcome in preterm infants. Arch Dis Child.
112. Kurtz CD, Spitzer AR, Broennle AM, et al. Postoperative apnea in 1987;62:30–36.
preterm infants. Anesthesiology. 1987;66:483–488. 136. Kinsey VE, Arnold HJ, Kalina RE, et al. PaO2 levels and retrolental
113. Siassi B, Blanco C, Cabal L, et al. Incidence and clinical features fibroplasia: a report of the cooperative study. Pediatrics. 1977;60:655.
of patent ductus arteriosus in low birth weight infants: a prospec- 137. Hammarlund K, Stromberg B, Sedin G. Heat loss from skin of
tive analysis of 150 consecutively born infants. Pediatrics. 1976; preterm and fullterm newborn infants during the first weeks after
57:347. birth. Biol Neonate. 1986;50:1–10.
138. Salle B, Berthier JC. Entéropathie aiguë nécrosante du nouveau-né. 150. Low JM, Gaibraith RS, Muir DW, et al. Motor and cognitive deficits
Pédiatrie. 1979;34:461–471. after intrapartum asphyxia in the mature fetus. Am J Obstet Gynecol.
139. Dallman PR. Anemia of prematurity. Annu Rev Med. 1981;32: 1988;158:356–361.
143–160. 151. Eckstein KL, Marx GF. Aortocaval compression and uterine
140. Parer JT, Livingston EG. What is fetal distress? Am J Obstet Gynecol. displacement. Anesthesiology. 1974; 40:92–96.
1990;162:1421–1427. 152. Johnson CE. Transverse presentation of fetus. JAMA. 1964;187:
141. Drage J, Kennedy C, Schwarz B. The Apgar score as an index of 642.
neonatal mortality: a report from the Collaborative Study of 153. Collea JV. Current management of breech presentation. Clin Obstet
Cerebral Palsy. Obstet Gynecol. 1964;24:222. Gynecol. 1980;23:525.
142. MacDonald H, Mullingan J, Allen A, et al. Neonatal asphyxia. 154. Behrman RE, Lees MH, Peterson EN, et al. Distribution of the
I. Relationship of obstetric and neonatal complications to neonatal circulation in the normal and the asphyxiated fetal primate. Am J
mortality in 38,405 consecutive deliveries. J Pediatr. 1980;96:898–902. Obstet Gynecol. 1970;108:956–969.
143. Low JA. The role of blood gas and acid-base assessment in the 155. Cohn HE, Sacks EJ, Heymann MA, et al. Cardiovascular responses
diagnosis of intrapartum fetal asphyxia. Am J Obstet Gynecol. 1988; to hypoxemia and acidemia in fetal lambs. Am J Obstet Gynecol.
159:1235–1240. 1974;120:817–824.
144. Antenatal diagnosis: Report of a Consensus Development Con- 156. Goodlin R. Fetal cardiovascular responses to distress. Obstet
ference, National Institute of Child Health and Human Development. Gynecol. 1977;49:371–381.
Vol. 79. Washington, DC: Government Printing Office; 1979. p. 1973. 157. Cohn H, Piasecki G, Jackson B. The effect of fetal heart rate on
145. Freeman J. Summary in prenatal and perinatal factors associated cardiovascular function during hypoxemia. Am J Obstet Gynecol.
with brain disorders. Washington, DC: Government Printing Office; 1980;138:1190–1199.
1985. NIH Publication no. 85-1149. 158. Burke G, Stuart B, Crowley P, et al. Is intrauterine growth retardation
146. Nelson K. What proportion of cerebral palsy is related to birth with normal umbilical artery blood flow a benign condition? Br
asphyxia? J Pediatr. 1988;112:572–574. Med J. 1990;300:1044.
147. Blair E, Stanley FJ. Intrapartum asphyxia: a rare cause of cerebral 159. Nicolaides KH, Bilardo CM, Soothill PW, et al. Absence of end
palsy. J Pediatr. 1988;112:515–519. diastolic frequencies in umbilical artery: a sign of fetal hypoxia and
148. Freeman JM, Nelson KB. Intrapartum asphyxia and cerebral palsy. acidosis. Br Med J. 1988;297:1026–1027.
Pediatrics. 1988;82:240–249. 160. Arduini D, Rizzo G, Romanini C, et al. Fetal haemodyna-
149. Paneth N, Stark R. Cerebral palsy and mental retardation in relation mic response to maternal hyperoxygenation as predictor of fetal
to indicators of perinatal asphyxia. Am J Obstet Gynecol. 1983; distress in intrauterine growth retardation. Br Med J. 1989;298:
147:960–966. 1561–1562.
General Growth and Tissue

2 Development Throughout
Childhood
C H A P T E R
Ruth Oelhafen Luginbuehl
INTRODUCTION Postnatal
The first two decades of a human life are characterized by Birth is a dramatic event during which the fetus must adapt rapidly
significant growth and changes in both form and function. As a to the abrupt change from the intrauterine to the extrauterine
human being progresses through fetal life, infancy, childhood, and environment. However, it is merely the beginning of a long process
adolescence towards adulthood, tremendous physical, cognitive, of changes during human growth and development. Physical
and emotional maturation occurs. Therefore, a physician dealing growth continues at a rapid pace during the first 6 months of
with a pediatric population will be confronted with remarkable extrauterine life and slows down gradually by about 2 years of age,
physical and psychological differences in development and maturity only to accelerate eventually again during the pubertal growth
based on the chronological age of a child. A proper understanding spurt. On average, birthweight is doubled by 6 months of age and
of this developmental progression is crucial for an anesthesiologist tripled by 1 year. Length is doubled by 4 years of age. Growth
to provide optimal care. As a detailed review in developmental curves, including head circumference and body mass index (BMI)
pediatrics is beyond the scope of this chapter, a general overview of curves, for healthy boys and girls are presented in Figures 2–2 to
issues relevant to the practice of anesthesia is presented. 2–9. Significant changes in body proportion take place over the
course of childhood. At birth the head is large relative to body size
(approximately 1/4 of total body length compared with 1/8 in
GENERAL GROWTH adulthood), the trunk is long, and the limbs are short (trunk to
limb ratio of 1:1 compared with 3:4 in adulthood). The upper body
Prenatal to lower body ratio of about 1.7:1 in newborns decreases to
The most rapid growth in human development occurs during the approximately 1:1 in adulthood.3 As Figure 2–10 shows, the total
prenatal stage.1 Although well protected in the uterus, the human body water content is almost 70% of body weight in the term
embryo may be affected in a negative way by environmental newborn (80% in the preterm baby), 62% at 1 year of age, and 65%
agents or so-called teratogens.2 Teratogens, in biological (such as in adulthood.4 The decrease in the proportion of total body water
bacterial and viral infections), chemical (such as drugs), and between the premature neonate and the older infant is attributed
physical form (such as radiation) may cause developmental to an increase in the proportion of body fat. The body surface area
disruptions following maternal exposure. The damage caused by to volume ratio is highest in the preterm newborn and decreases
these agents is very much dependent on the prenatal stage at the into adulthood. Because of their increased relative surface area,
time of exposure. During the first 2 weeks of gestation, maternal neonates may become hypothermic more quickly if they are
exposure to teratogens may result in embryonic death and unprotected. The higher relative surface area also results in greater
spontaneous abortion or full repair. During organogenesis, evaporative water loss. The skin of the premature infant is thin
which is completed by the end of the eighth gestational week, the and gelatinous, further increasing evaporative heat losses in the
embryo is most vulnerable to environmental agents. During this first few days of life.5 Figure 2–11 illustrates the nomogram for
stage, teratogenic insults may give rise to major congenital approximating body surface area based on height and weight.
malformations. The fetal period (beginning at the ninth Mosteller’s formula allows a more accurate calculation of body
gestational week and lasting until term) is characterized by a surface area6:
striking rate of somatic growth with continued differentiation
of organ systems. Environmental insults during this phase may Body surface area ⎡⎣ m 2 ⎤⎦ = Body length ⎡⎣cm⎤⎦ x body weight ⎡⎣kg ⎤⎦ 36000
cause functional defects of organ systems or impair general growth
and result in a small-for-gestational-age (SGA) infant. Other Adolescence, the developmentally transitional stage between
conditions including genetic defects, maternal illness, tobacco use, childhood and adulthood, marks a time of dramatic physical and
and malnutrition may also compromise growth. By contrast, psychological changes. Growth and physical changes including the
poorly controlled maternal diabetes mellitus may result in a baby development of secondary sexual characteristics (facial, axillary,
that is large for gestational age (LGA). Figure 2–1 illustrates the and pubic hair as well as breast, testicular, penile, and laryngeal
approximate birthweight at various gestational ages. development) are the result of endocrine maturation.7–8 The first
CHAPTER 2 ■ General Growth and Tissue Development Throughout Childhood 21
Figure 2-1. Growth percentiles for preterm neonates.

Figure 2-2. Growth percentiles for boys aged 0 to 36 months.

Figure 2-3. Growth percentiles for girls aged 0 to 36 months.

Figure 2-4. Growth percentiles for boys aged 2 to 20 years.

Figure 2-5. Growth percentiles for girls aged 2 to 20 years.

Figure 2-6. Head circumference percentiles for boys aged 0 to 36 months.

Figure 2-7. Head circumference percentiles for girls aged 0 to 36 months.

Figure 2-8. Body mass index (BMI) percentiles for boys aged 2 to 20 years.
Figure 2-9. Body mass index (BMI) percentiles for girls aged 2 to 20 years.
Figure 2-10. Age dependent changes in body composition.

sign of pubertal onset in boys is testicular enlargement, beginning needs. Around the age of 6 months, infants are generally ready for
as early as 9 to 10 years of age. The first visible sign of puberty in the introduction of complementary solid food. The timing and
girls is the appearance of breast buds, which general begins order of the introduction of solids varies considerably and is
between 8 and 12 years of age. Menarche (age of first menses) influenced by social and cultural factors. However, there are
typically follows 2.5 years later, and marks the onset of fertility. recommendations for the introduction of solid food by the
Staging of puberty is based on the sexual maturity rating (SMR) World Health Organization (WHO).12 These recommendations
criteria described by Tanner (Table 2–1).9 On average, the peak take into consideration not only the risk of nutrients to act as
growth velocity during the pubertal growth spurt occurs in girls at potential allergens, but also their potential to negatively influence
11 to 12 years of age and in boys at around 14 years of age. During the risk of cardiovascular problems later on in adulthood.13–14
the 2 years following menarche, girls gain on average another 5– Complementary food should be introduced step by step. The age
8 cm until finally reaching adult height.10 when children become entirely self-feeding varies and depends
on sociocultural factors and the willingness of the parents to
tolerate a mess at mealtimes. Caloric intake per kilogram of body
FLUIDS AND NUTRITION weight falls steadily after the age of 1 year. Table 2–2 illustrates the
Rapid growth and the relatively high maintenance rates due to recommended energy intake in a healthy and active child. Caloric
higher metabolic and nutrient turnover explain the significantly requirements in a hospitalized child vary depending on the illness
higher caloric needs in infants and children compared with and most often lie between the basal metabolic requirements
adults.11 Lack or too low a caloric intake has a negative impact on and the normal energy needs of an active child. Because the
a child’s development, causing the weight curve to decline first. metabolism of 1 calorie of energy results in net consumption of
A more chronic situation will eventually have a negative influence 1 mL of water, fluid requirements are thought to reflect caloric
on body size, and later on psychomotor development (failure to requirements. A simple formula known as the Holliday–Seger
thrive [FTT:). During the first 5 to 6 months of life, nutrition of a method for calculating daily maintenance fluid requirements
healthy infant is provided entirely by breast milk (preferably) or by based on body weight may also help to estimate the daily energy
special infant formulas, which have been adapted to age-related needs.15
Figure 2-11. Nomogram for estimation of body surface area. A: For patients of approximately normal body size, the surface area
can be estimated from the body weight alone. B: The intersection of the line connecting patient’s height (left column) with patient’s
weight (right columns) yields the patient’s body surface area.
Daily fluid Daily energy The body surface area method serves the same purpose, but is
requirement requirement based on the body surface area.16 Daily fluid requirements are 1500
0 to 10 kg body weight: 100 mL/kg 100 kcal/kg mL/m2 per 24 hours and daily energy requirements are 1500
11 to 20 kg body weight: 1000 mL 1000 kcal mL/m2 per 24 hours. Recommended daily allowances for
50 mL/kg 50 kcal/kg electrolytes, minerals, vitamins, and other nutrients can be found
20 kg body weight: 1500 mL 1500 kcal in various references.11,14–16
20 mL/kg 20 kcal/kg
TABLE 2-1. Classification of Sexual Maturity Rating in Boys and Girls

Girls Boys
Sexual Maturity
Rating Stage Breasts Pubic Hair Pubic Hair Penis Testes
1 Preadolescent Preadolescent Preadolescent Preadolescent Preadolescent
2 Brest and papilla Sparse, lightly Scanty, long, slightly Slight enlarge- Enlarged
elevated as small pigmented, straight, pigmented ment scrotum,
mound; areola medial border of labia pink texture
diameter increased altered
3 Breast and areola Darker, beginning to Darker, starts to Longer Larger
enlarged, no contour curl, increased curl, small
separation amount amount
4 Areola and papilla form Coarse, curly, abundant Resembles adult Larger; glans Larger, scrotum
secondary mound but amount less than type, but less in and breadth dark
in adult quantity; coarse, increase in
curly size
5 Mature; nipple projects, Adult feminine triangle, Adult distribution, Adult size Adult size
areola part of general spread to medial spread to medial
breast contour surface of thighs surface of thighs
Adapted from references 10, 11.
TABLE 2-2. Recommended Daily Energy Intake (kcal), surfactant are present to permit survival of some infants without
by Age exogenous surfactant. Infants born without adequate surfactant
develop infantile respiratory distress syndrome (RDS). If
Age, Years Per Kilogram Body Weight Per Day premature delivery can be anticipated 48 hours ahead of time,
0–0.5 108 650 surfactant production may be induced by the administration of
0.5–1.0 98 850 glucocorticoids to the mother. More importantly, several
1–3 102 1300 preparations of exogenous surfactant are now available and have
4–6 90 1800 improved morbidity and mortality in this population.5, 17
7–10 70 2000 Approximately 12% to 16% of the adult number of alveoli are
11–14 Males 55 2500 present at birth. The number and size of alveoli continue to
15–18 45 3000 increase until the child is about 8 years of age, after which time
11–14 Females 47 2200 lung growth occurs only by increasing alveolar size.1 Before birth,
15–18 40 2200 the lungs are filled with fluid. To make the transition to extra
uterine life and allow the lungs to take over their function, this
Adapted from reference 17. fluid must be replaced by air. The majority of the fluid is removed
from the lungs by compression of the highly compliant chest
wall in the birth canal during the birth process.18 The rest will
SPECIFIC ORGAN SYSTEMS be absorbed into the pulmonary vascular system and removed
by the pulmonary lymphatic system.5 This process may require
Airway and Respiratory System several hours in the normal infant and transient tachypnea of
The respiratory system serves the two main functions of supplying the newborn may be seen if there is ineffective removal of this
sufficient oxygen to meet metabolic demands and removing fluid. This is generally a benign process which resolves during
carbon dioxide. A variety of processes including ventilation, the first day of life. Therapy may include the administration of
perfusion, and diffusion are involved in fulfilling these functions. supplemental oxygen or continuous positive airway pressure
The development of the respiratory system begins during the (CPAP). The first breath may require a very high negative intra-
fourth week of gestation.1 The respiratory tree is formed by thoracic pressures to inflate the lung tissue and fill the alveoli with
successive branching of the airways. By 24 weeks of gestation, air. This may result in a pulmonary air leak, which may cause a
some thin-walled primitive alveoli have developed at the end of pneumothorax or pneumomediastinum.19 Asymptomatic infants
the respiratory bronchioles. These regions are well vascularized generally do not require invasive therapy such as tube thoracos-
and therefore, at this point, the conditions exist for effective gas tomy. However, ongoing observation and monitoring for signs of
exchange and breathing. However, at 24 weeks, the primitive respiratory deterioration are necessary.5
alveoli are mainly lined by type I pneumocytes, which means there The respiratory rate is highest in the newborn period and
is no surfactant production. Surfactant is produced by type II gradually falls to adult values by adolescence (Table 2–3). Young,
pneumocytes and spreads out in the form of a monomolecular especially premature, infants may normally show an irregular
film over the walls of the primitive alveoli. Its function is to respiratory pattern. Even term infants may normally display
counteract surface tension forces and to facilitate alveolar periodic breathing, which is characterized by a period of apnea
expansion. By 26 to 28 weeks of gestation, sufficient alveoli and lasting from 3 to 10 seconds followed by a period of ventilation
TABLE 2-3. Mean Respiratory Rates, by Age of carbon dioxide and almost full oxygenation of blood, which
then returns to the fetus via the umbilical vein.25 There are three
Age Respiratory Rate, breaths/min shunts bypassing organs, which during fetal life do not have a
Premature 40–70 major function. First is the ductus venosus, serving as a connection
0–3 months 35–55 from the umbilical vein to the inferior vena cava, permitting half
3–6 months 30–45 of the umbilical venous (oxygenated) blood to bypass the hepatic
6–12 months 25–40 microcirculation. Second is the foramen ovale, a direct connection
1–3 years 20–30 between the right and the left atrium, allowing blood of the highest
3–6 years 20–25 possible O2 concentration (from the umbilical vein into the right
6–12 years 14–22 atrium to the left atrium) to perfuse the cerebral circulation.
Adult 12–18 Finally, the ductus arteriosus, which directs blood from the
right ventricle to the descending aorta, thereby bypassing
Adapted from reference 23. the pulmonary circulation. Only approximately 10% of the blood
flowing through the right ventricle circulates through the lungs,
which in utero do not participate in gas exchange. As the right-
for 10 to 18 seconds. It is rarely seen during the first 24 hours sided pressures are higher than left-sided pressures in the fetus
after birth and disappears by 38 to 40 weeks of gestational age.20 It due to the high pulmonary vascular resistance, the right ventricle
is therefore important to count the respiration rate for a full is more muscular than the left ventricle.
minute in this age group when performing an assessment. At birth, the fetal circulation begins to transition to the
This normal variation in respiration must be distinguished postnatal circulation. The critical event during this transition is
from apnea of prematurity, which may require mechanical or the establishment of lung inflation. With the first breath, the lungs
pharmacological therapy. Apnea in infancy is defined as an become aerated. The contact with air containing oxygen results
unexplained episode of interruption of breathing for 20 seconds or in vasodilatation of the pulmonary resistance vessels, which is
longer, or a shorter respiratory pause of any duration associated accompanied by a tremendous increase of the pulmonary blood
with symptoms such as bradycardia, cyanosis, pallor, and/or flow as pulmonary vascular resistance acutely falls. Left atrial
significant muscular hypotonia.21 Respiratory pauses of up to pressure becomes immediately higher than right atrial pressure,
20 seconds during sleep are considered to be normal in a healthy causing the foramen ovale to functionally close. Increased
infant.22 As the lungs in an infant are noncompliant and the arterial oxygen tension causes constriction and closure of the
chest wall elastic, mild intercostal restractions may be a normal ductus arteriosus. The ductus venosus and the umbilical vessels,
occurrence and not necessarily indicative of intrathoracic or which are no longer needed, also constrict and obliterate. These
pulmonary parenchymal disease. However, this finding must be changes occur gradually over the first few days of life. Therefore,
considered pathologic in the context of other signs of respiratory establishing vascular access through umbilical veins and arteries
distress such as tachypnea, cyanosis, stridor, wheezing, grunting, for the administration of fluids and medications, or monitoring
nasal flaring, or retractions.18 Additionally, neonates and infants in severely sick neonates is only possible for a short period of time
are more dependent on the diaphragm for normal ventilatory after birth.
function. As such, they may normally display paradoxical or The higher affinity of fetal hemoglobin (HbF) for oxygen is
abdominal breathing where the abdomen moves out while the crucial in utero, allowing O2 to be extracted from the maternal
chest wall moves in and vice versa. blood. Placental oxygen transfer occurs at a much lower oxygen
The larynx in neonates and young infants differs from older tension than does alveolar oxygen transfer after birth. However,
children, adolescents and adults not only in size, but also in ex utero, this higher affinity is a disadvantage, as it impairs oxygen
relative dimensions and location.23 An infant’s glottis is relatively delivery at the tissue level. Resting cardiac output in the neonate
small compared with an adult glottis, whereas the epiglottis is is high compared with that of the older child and adult.26 This
proportionately larger. This relative difference in size and the allows the infant to meet oxygen demands in the periphery, but as
position of the larynx high in the neck are crucial in allowing a result, the ability of the newborn to further increase cardiac
infants to simultaneously suck, swallow, and breath. Therefore, output in conditions of stress is limited.
most newborn infants are obligate nasal breathers. Significant Accurate blood pressure measurement in children depends
nasal obstruction presenting at birth such as bilateral choanal on the selection of an appropriate sized cuff. As is the case with
atresia may be a life-threatening situation. The descent of the adults, it is now generally agreed that diastolic blood pressure
larynx to a lower position in the neck begins around 2 years of corresponds with the disappearance of Korotkoff sounds, also
age. This change in position results in a confluence of the digestive referred to as the fifth Korotkoff sound.27 In some children,
and the respiratory tract. Although the ability of breathing and Korotkoff sounds may be heard down to 0 mmHg. Normal blood
suckling simultaneously is lost, this change is necessary to elongate pressure in newborns correlates with gestational age and
the vocal tract, which in turn is crucial for the development of birthweight.28 Blood pressure curves for infants are provided in
complex speech and articulation.23 Figures 2–12 and 2–13. Tables 2–4 and 2–5 summarize blood
pressure levels for boys and girls from 1 to 17 years of age. Table
2–6 shows the normal range of heart rate in relationship to the age
Cardiovascular System of the infant or child.
The development of the cardiovascular system is essentially Electrocardiographic (ECG) findings in neonates and children
complete by 8 weeks of gestation, the most critical period being are different from that of adults.29 Because of the right-sided
day 20 to 50.24 During fetal life, the placenta is providing the predominance of the fetal heart, the neonatal ECG shows a
function that the lungs provide after birth. This includes removal marked right axis deviation (30 to 180 degrees) compared
Figure 2-12. Percentiles for blood

pressure in boys.
with that of adults (–30 to 105 degrees). The electrocardiogram 2) Abnormal cardiac size or silhouette or abnormal pulmonary
also shows tall R waves in the right-sided leads and deep S waves vascularity on chest x-ray
in the left-sided leads. There is a gradual shift toward the normal 3) Abnormal ECG
left axis orientation over the course of childhood. This occurs most 4) Diastolic murmur
rapidly in the first month of life. QRS duration is shorter in 5) A systolic murmur that is loud (more than 3/6 or with a thrill),
children, ranging from an average of 50 ms in neonates to 80 ms long in duration and transmits well to other parts of the body
in adults. The PR interval is shorter, increasing from about 90– 6) Abnormal heart sounds
100 ms (upper limits of normal is 120 ms) in neonates to 150–170
Innocent systolic murmurs include the vibratory Still’s
ms (upper limit of normal is 210 ms) in adults. T waves may be
murmur, the basal systolic ejection murmur, cardiorespiratory
inverted further toward the left in the precordial leads in children
murmur, and the murmur of physiologic peripheral pulmonary
than in adults.
stenosis. The venous hum is a continuous murmur heard
Innocent (or functional) heart murmurs are common in
throughout the cardiac cycle. Other innocent heart sounds that
childhood and may be heard in 80% of children at some point in
may be present in childhood include the carotid bruit and third
life.29 They emanate from cardiovascular structures in the absence
heart sound (S3).
of anatomic abnormalities and are accentuated or brought out in
a high-output state such as fever or feeding. Innocent heart
murmurs can be difficult to diagnose and have to be differentiated Gastrointestinal System
from pathologic heart murmurs. If 1 or more of the following
At birth the gastrointestinal system is almost fully capable of
criteria are present, cardiology consultation is suggested:
taking over its functions which include digestion, absorption,
1) Symptoms or physical signs of heart failure on examination and secretion, as well as endocrine and immunologic activities.
(e.g., cyanosis, dyspnea, abnormal strong or weak pulses, Meconium, the first bowel movement after birth, is of greenish-
hepatomegaly) black color and with a sticky consistency. It is normally discharged
Figure 2-13. Percentiles for blood

pressure in girls.
TABLE 2-4. Blood Pressure Levels for Boys Aged TABLE 2-5. Blood Pressure Levels for Girls Aged
1 to 17 Years 1 to 17 Years
Systolic Blood Pressure, Diastolic Blood Pressure, Age Systolic Blood Pressure, Diastolic Blood Pressure,
Age, Years mm Hg (2 SD) mmHg (2 SD) mmHg (2 SD) mmHg (2 SD)
1 98 (94–102) 53 (50–55) 1 100 (97–104) 54 (53–56)
2 102 (98–106) 57 (55–59) 2 102 (99–105) 58 (57–61)
3 105 (100–109) 61 ( 59–63) 3 103 (100–106) 62 (61–64)
4 107 (102–111) 64 (62–66) 4 104 (101–108) 65 (63–67)
5 108 (104–112) 67 (65–69) 5 106 (103–109) 67 (65–69)
6 110 (105–114) 70 (67–72) 6 107 (104–111) 69 (67–71)
7 111 (106–115) 72 (69–74) 7 109 (106–112) 70 (69–72)
8 112 (107–116) 73 (71–75) 8 111 (108–114) 71 (70–74)
9 113 (109–117) 74 (72–77) 9 113 (110–116) 73 (71–75)
10 115 (110–119) 75 (73–78) 10 115 (112–118) 74 (73–76)
11 117 (112–121) 76 (74–78) 11 117 (114–120) 75 (74–77)
12 119 (115–123) 77 (75–79) 12 119 (116–122) 76 (75–78)
13 122 (117–126) 77 (75–80) 13 121 (118–124) 78 (76–80)
14 125 (120–128) 78 (76–80) 14 122 (119–126) 79 (77–81)
15 127 (123–131) 79 (77–81) 15 124 (121–127) 79 (78–82)
16 130 (125–134) 81 (79–83) 16 125 (122–128) 80 (79–82)
17 133 (128–136) 87 (85–89) 17 125 (122–128) 80 (79–82)
Adapted from reference 33. Adapted from reference 33.
TABLE 2-6. Mean Heart Rate, by Age Colic, an episodic pattern of seemingly inconsolable crying that
tends to occur in the evenings, may be seen in babies less than
Age Heart Rate, beats/min 3 months of age. The cause of this phenomenon is not completely
Premature 120–170* understood. Although it resolves spontaneously around the end
0–3 months 100–150* of the third month of life, it must be differentiated from organic
3–6 months 90–120 causes. It may represent a source of considerable concern and
6–12 months 80–120 frustration for parents and caregivers.
1–3 years 70–110 Although tooth formation begins in utero during the 4th
3–6 years 65–110 month of gestation, the first primary (deciduous) tooth does not
6–12 years 60–95 erupt until approximately 6 to 7 months of age.36 Deciduous
Adult 55–85 dentition (with 20 teeth) is complete between the age of 2 and
3 years. The permanent teeth begin to erupt around the age of
Adapted from reference 23. 6 years, starting after the loss of the primary central incisors. The
*In sleep, infant heart rates may drop significantly lower, but if perfusion is
maintained, no intervention is required
last primary tooth is shed around the age of 12 to 14 years. The
anesthesiologist must be aware of the possibility of loose teeth at
any age during childhood when managing the airway. The set of
permanent teeth (32 teeth) may not be complete until the third
within the first 24 to 48 hours of life. Overall, the gastrointestinal decade of life. The timing of appearance of the dentition is shown
transit time in the infant is shorter than that of an adult and in Table 2–7.
increases with increasing age. The normal physiologic range of
stool frequency varies greatly (from 10 times a day to 1–2 times a
week30). Breast-fed infants usually have stools more often than Renal System
do their formula-fed counterparts. The frequency of bowel Urine production begins at approximately 12 weeks of gestation
movements gradually declines over the first years of life, reaching and continues throughout fetal life.1 The urine is excreted into the
adult habits at about 4 years of age. The abdomen of the infant and amniotic cavity and forms the major part of the amniotic fluid.
younger child is protuberant because of the relatively large volume However, because the elimination of fetal metabolic waste is a
of the abdominal viscera. In infants the edge of the liver is function of the placenta, there is no need for the kidneys to work
normally felt 1–2 cm below the right costal margin.31 The spleen
should be no more than 1 cm below the rib margin. In young
infants, an umbilical hernia is common, usually of no clinical
concern, and generally closes spontaneously as the muscles TABLE 2-7. Chronology of Human Dentition
develop toward the end of the first year. Average Age
In neonates and younger infants, the lower esophageal sphincter Tooth of Eruption
tone is physiologically decreased and may lead to gastroesophageal
reflux. Other predisposing factors include a short esophagus, Deciduous Dentition
large meals in relation to gastric capacity, frequent feeding Maxillary Central Incisor 7.5 months
regimen, supine position, and Valsalva maneuvers during bowel Lateral Incisor 9 months
movements.32 Daily vomiting or “spitting up” may be seen in one Cuspid 18 months
half of all infants between 0 and 3 months of age and up to two First Molar 14 months
thirds of 4- to 6-month-old infants.33 Most of these infants suffer Second Molar 24 months
no ill effect (“happy spitter”) and grow well.31 This condition Mandibular Central Incisor 6 months
usually begins in the first weeks of life and resolves spontaneously Lateral Incisor 7 months
by 9 to 24 months of age as solid food has been introduced and the Cuspid 16 months
child becomes more upright. Only between 1:300 and 1:1000 First Molar 12 months
infants have reflux significant enough to cause complications.34 Second Molar 20 months
Neonatal jaundice (physiologic hyperbilirubinemia) is a Permanent Dentition
common condition, which generally begins during the second Maxillary Central Incisor 7–8 years
24 hours of life, has its peak around the third day of life, and Lateral Incisor 8–9 years
resolves itself by the end of the first week.35 It is caused by a high Cuspid 11–12 years
rate of bilirubin production due to the shorter lifespan of the First Bicuspid 10–11 years
newborn’s red blood cells and by a limited ability to effectively Second Bicuspid 10–12 years
eliminate bilirubin due to immaturity of the hepatic microsomal Second Molar 12–13 years
enzyme systems. Typical physiologic newborn jaundice is an Third Molar 17–21 years
unconjugated, or indirect-reacting hyperbilirubinemia. Preterm Mandibular Central Incisor 6–7 years
and breast-fed newborn babies may show a protracted form of Lateral Incisor 7–8 years
this condition. Although it is generally a benign, self-limiting Cuspid 9–10 years
condition, its course should be monitored to prevent missing an First Bicuspid 10–12 years
indication for treatment (e.g., phototherapy). It should also be Second Bicuspid 11–12 years
differentiated from pathologic causes of jaundice such as those Second Molar 11–13 years
related to blood type incompatibility or hepatic problems such as Third Molar 17–21 years
biliary atresia. Adapted from reference 41.
before birth. The fetal kidneys receive only 2% of the cardiac and hematocrit compared to the older child. At birth the infant’s
output, compared with 20% for the mature kidney.37 One of the hemoglobin is primarily HbF, which has a higher affinity for
major functions of the kidney is to maintain extracellular oxygen than the adult type (HbA). The initially high hematocrit
homeostasis. Although the adult kidneys maintain precise balance drops dramatically during the first days of life, due to decreased
matching fluid and electrolyte excretion to intake, in growing production of hemoglobin and red blood cells combined with the
children this balance must be positive for a number of solutes to shorter lifespan of fetal erythrocytes.39 The more immature the
make growth possible. This conveys a great challenge for the neonate, the shorter is the lifespan of red cells. This and a lower
kidneys during this period of life. Although the kidneys are total body iron store result in a more exaggerated neonatal
morphologically fully developed at 34 weeks of gestation, the anemia in preterm infants compared to their term counterparts.
functional development is far from complete at birth. Postnatal The nadir of the hemoglobin level is reached at approximately 8 to
functional changes occur in renal blood flow, glomerular filtration 12 weeks of age in term infants and 4 to 8 weeks in premature
rate (GFR), and tubular function. The glomerular filtration rate is infants. This physiologic drop of hemoglobin concentration
low in newborn, increases dramatically during the first month of stimulates erythropoiesis. Hemoglobin produced postnatal is of
life, and reaches adult values, corrected to body surface area, by the adult type, which has largely replaced HbF by approximately
the age of 2 years. At birth, the serum creatinine concentration 4 months of age. Besides blood loss, there are two major types of
reflects the maternal level and declines during the first days of life. anemia including the hypo- or aregenerative anemia, where the
Since the serum creatinine at birth is a result of the placental production of red blood cells is decreased and hemolytic anemia
creatinine transfer, it does not reflect the neonatal renal func- with an increased destruction of red blood cells. Table 2–8 shows
tion. Over the course of early childhood, creatinine clearance the normal hematologic values during childhood.
increases, reaching adult values between 2 and 3 years. Due to the The white blood cell count is highest in the first days of life and
rapid growth and increase in muscular mass, normal serum drops steadily throughout childhood to finally reach adult values
creatinine values increase with age and are higher in men. In the during adolescence. Leucocytosis is a sign of a possible infectious
newborn the ability to concentrate urine is limited compared process. The younger the child, the more limited is the ability
with adults. A maximum urine concentration of 600 mOsm/kg to react with leucocytosis to an infectious agent. In neonates,
can be achieved in newborns versus 1200 mOsm/kg in adult leukopenia is generally more indicative of an infectious process.
counterparts. In young children, the relative inability to handle This age group is also more likely to develop hypothermia rather
high solute loads is offset by the low solute content of breast milk than a fever as a reaction to an infection. Table 2–9 illustrates
and infant formula. normal leukocytosis counts at different ages. The production of
platelets is regulated by thrombopoietin, which maintains a
normal blood platelet count of 150–400 109/L with no age
Hematological System related differences. Table 2–10 lists normal platelet counts and
The first blood cells produced by the embryo belong to the red Table 2–11 gives normal values for selected coagulation tests.
cell line, followed by granulocytes, platelets and lymphocytes.38 After the initial adjustment during the first hours of life, blood
The anatomic site of hematogenesis undergoes developmental volume maintains a relatively constant relationship to body weight
changes during fetal life. At about 3 to 5 months of gestation, the throughout most of the life. The average blood volume in term
liver is the chief organ of hematopoiesis and continues to produce newborns is 85 mL/kg and 90 mL/kg in preterm newborns. It
red cells into the first postnatal week. During the last 3 months increases to an average of 105 mL/kg during the first days of life
of gestation, the bone marrow becomes the chief site of blood and then decreases again over the course of the next few months.
cell formation. The term neonate has a higher hemoglobin At approximately 6 months of age, the average blood volume is
TABLE 2-8. Normal Hematologic Values in Children

Age Hemoglobin, g/dL (2 SD) Hematocrit, % (2 SD) Red Cell Count, 1012/L (2 SD)
Birth (cord blood) 16.5 (13.5–19.5) 51 (42–60) 4.7 (3.9–5.5)
1–3 days (capillary) 18.5 (14.5–22.5) 56 (45–67) 5.3 (4.0–6.6)
1 week 17.5 (13.5–21.5) 54 (42–66) 5.1 (3.9–6.3)
2 weeks 16.5 (12.5–20.5) 51 (39–63) 4.9 (3.6–6.2)
1 month 14.0 (10.0–18.0) 43 (31–55) 4.2 (3.0–5.4)
2 months 11.5 (9.0–14.0) 35 ( 28–42) 3.8 (2.7–4.9)
3–6 months 11.5 (9.5–13.5) 35 (29–41) 3.8 (3.1–4.5)
0.5–2 years 12.0 (10.5–13.5) 36 (33–39) 4.5 (3.7–5.3)
2–6 years 12.5 (11.5–13.5) 37 (34–40) 4.6 (3.9–5.3)
6–12 years 13.5 (11.5–15.5) 40 (35–45) 4.6 (4.0–5.2)
12–18 years:
Female 14.0 (12.0–16.0) 41 (36–46) 4.6 (4.1–5.1)
Male 14.5 (13.0–16.5) 43 (37–49) 4.9 (4.5–5.3)
18–49 years:
Female 14.0 (12.0–16.0) 41 (36–46) 4.6 (4.0–5.2)
Male 15.5 (13.5–17.5) 47 (41–53) 5.2 (4.5–5.9)
TABLE 2-9. Reference Ranges for Leukocyte Counts in Children

Age Leukocytes, 103/mm3 (2 SD) Neutrophils, 103/mm3 (2 SD) [%*: Lymphocytes, 103/mm3 (2 SD) [%*:
Birth 18.1 (9.0–30.0) 11.0 (6.0–26.0) [61: 5.5 (2.0–11.0) [31:
12 hours 22.8 (13.0–38.0) 15.5 (6.0–28.0) [68: 5.5 (2.0–11.0) [24:
24 hours 18.9 (9.4–34.0) 11.5 (5.0–21.0) [61: 5.8 (2.0–11.5) [31:
1 week 12.2 (5.0–21.0) 5.5 (1.5–10.0) [45: 5.0 (2.0–17.0) [41:
2 weeks 11.4 (5.0–(20.0) 4.5 (1.0–9.5) [40: 5.5 (2.0–17.0) [48:
1 month 10.8 (5.0–19.5) 3.8 (1.0–9.0) [35: 6.0 (2.5–16.5) [56:
6 months 11.9 (6.0–17.5) 3.8 (1.0–8.5) [32: 7.3 (4.0–13.5) [61:
1 year 11.4 (6.0–17.5) 3.5 (1.5–8.5) [31: 7.0 (4.0–10.5) [61:
2 years 10.6 (6.0–17.0) 3.5 (1.5–8.5) [33: 6.3 (3.0–9.5) [59:
4 years 9.1 (5.5–15.5) 3.8 (1.5–8.5) [42: 4.5 (2.0–8.0) [50:
6 years 8.5 (5.0–14.5) 4.3 (1.5–8.0) [51: 3.5 (1.5–7.0) [42:
8 years 8.3 (4.5–13.5) 4.4 (1.5–8.0) [53: 3.3 (1.5–6.8) [39:
10 years 8.1 (4.5–13.5) 4.4 (1.8–8.0) [54: 3.1 (1.5–6.5) [38:
16 years 7.8 (4.5–13.0) 4.4 (1.8–8.0) [57: 2.8 (1.2–5.2) [35:
21 years 7.4 (4.5–11.0) 4.4 (1.8–7.7) [59: 2.5 (1.0–4.8) [34:
*Percentages are proportion of leukocytes.
TABLE 2-10. Circulating Platelet Counts in Children seen in absorption, distribution, and clearance of xenobiotics.
These factors should be kept in mind when calculating and
Age Platelet Count, 109/L adjusting drug dosages in children, particularly in infants. As a
Cord blood 288 53 general rule, on a per kilogram body weight basis, drug doses are
2 days 303 48 lower in younger infants and higher in children (preadolescents)
5 days 338 59 than in adults.
1 month 343 72
2–11 months 365 49 Neurological System
1–2 years 314 78
3–4 years 304 66 Although the nervous system is anatomicly complete at birth,
5–6 years 303 65 functionally it remains immature with the continuation of
7–10 years 295 58 myelination and synaptogenesis.41 At birth, the cranial sutures are
11–15 years 251 40 still open and are easily palpable. There may be some overlapping
Adult 234 48 of skull bones for the first few days of life, caused by compression
of the head in the birth canal. This should be differentiated from
craniosynostosis (premature closure of 1 or more sutures). The
anterior fontanel is diamond shaped, less than 3.5 cm in diameter
approximately 75–77 mL/kg, similar to that of older children and at birth, soft and easily palpable. Its size gradually decreases
adults.40 following birth, but is still palpable during the first year of life. It
closes at anywhere from 12 to 18 months of age. A bulging or tense
anterior fontanel with or without separation of the sutures may be
Pharmacology and Therapeutics an indication of increased intracranial pressure. A sunken fontanel
Maturational changes in body size and composition, as well may be a sign of severe hypovolemia from any of many causes
as changes in metabolic, gastrointestinal, hepatic, and renal including dehydration. The posterior fontanel is triangular and
function may affect the way pharmacologic agents perform in much smaller in size (fingertip). It may be difficult to palpate at
infants and general and therefore how they should be prescribed birth and is usually closed by 6 weeks of age. The sutures need to
and administered. In different age groups, divergences may be stay open to allow the brain to grow. (The growth of the head
TABLE 2-11. Reference Values for Selected Coagulation Tests in Children

APTT, Fibrinogen, Bleeding Time,
Age PT, sec (2 SD) INR(2 SD) sec (2 SD) g/L (2 SD) min (2 SD)
1–5 years 11 (10.6–11.4) 1.0 (0.96–1.04) 30 (24–36) 2.76 (1.70–4.05) 6 (2.5–10)
6–10 years 11.1 (10.1–12.1) 1.01 (0.91 1.11) 31 (26–36) 2.79 (1.57–4.0) 7 (2.5–13)
11–16 years 11.2 (10.2–12.0) 1.02 (0.93–1.10) 32 (26–37) 3.0 (1.54–4.48) 5 (3–8)
Adult 12 (11.0–14.0) 1.10 (1.0–1.3) 33 (27–40) 2.78 (1.56–4.0) 4 (1–7)
PT prothrombin time; INR international normalized ratio; APPT activated partial thromboplastin time. Adapted from reference 48.
circumference is presented in Figure 2–6 for boys and Figure 2–7 TABLE 2-12. Developmental Milestones
for girls.) Further maturation of the nervous system (myelination
and synaptogenesis) continues rapidly during the first 2 years of Age
life and is accompanied by rapid development of motor and Gross Motor
behavioral skills. These advances occur in a rostrocaudal pattern. Rolls from prone to supine 4–5 months
Myelination is complete by 7 years of age. Sits without support 7 months
Primitive reflexes such as the grasp, rooting, sucking, Moro, Rolls from supine to prone 5–6 months
and asymmetric tonic neck reflex are present in the neonate infant Gets to sitting 8 months
and fade during the latter part of the first year of life in the course Pulls self to stand 9 months
of normal development. Tendon reflexes (biceps, patellar, ankle Stands without support 12 months
jerks) are present at birth. They may be exaggerated with a Walks well 15 months
tendency to clonus in newborn infants; however, they should be Up and down stairs without support 2 years
symmetric. Absent or asymmetric tendon reflexes may be an Runs 2 years
indication of a significant central or peripheral nervous system
abnormality. In the newborn, flexor tone predominates, giving the Fine Motor
infant the typical flexed posture. Brings hands together 3 months
Grasps object 3.5 months
Reaches for object 4 months
DEVELOPMENTAL PEDIATRICS Transfers object from one hand to the other 6 months
Pincer (thumb-forefinger) grasp 8 months
So far this chapter has listed the chronology of anatomic and
Turns page 12 months
physiologic changes that occur in childhood. Of equal importance
Scribbles 13 months
are the developmental and behavioral changes featured during
Tower of 2 cubes 14 months
growth of the human organism. The developmental stage of a
child has a remarkable influence on the general approach to Communication and Language
the patient, as well as specific issues related to assessment and Cooing 2–4 months
treatment. For example, knowledge of a child’s level of cognitive Monosyllabic babbling 5–8 months
maturity helps to determine which pain rating scale is most Imitates sounds made by others 9–12 months
appropriate. Patient safety may also depend on knowledge of Polysyllabic babbling 9–12 months
child development. For instance, adequately high bed rails are Follows 1-step commands 10–15 months
needed for children who might pull themselves to the standing First words other than ‘mama’ or ‘dada’ 12 months
position. Child development involves several areas including 10-word vocabulary 15–18 months
motor (fine and gross motor), communication, and socialization 2-word sentences 18–24 months
skills. Some of the major developmental milestones during Complete sentences 2–3 years
childhood are illustrated in Table 2–12. It should be kept in mind Almost completely intelligible to strangers 3–5 years
that these are only guidelines since children show considerable
Social skills
variation in timing and succession of stages during normal
Social smile 1–2 months
development. Chronic illness or frequent hospitalizations as well
Separation anxiety / stranger awareness 6–12 months
as environmental factors, such as psychosocial issues, may delay
Interactive games: e.g., peek-a-boo 9–12 months
achievements of developmental milestones.
Feeds self with cup and spoon 15–18 months
Newborn infants do not have predictable sleep schedules. Naps
Recognizes self in mirror 2 years
are interspersed with feedings and periods of crying and quiet
Dresses self (except for buttons, etc.) 3 years
wakefulness. Over time, naps coalesce and episodes of wakefulness
Parallel play 1–2 years
become longer. In general, by 18 months of age, children are only
Cooperative play 3–4 years
taking one daytime nap and by 4 years of age children no longer
Able to distinguish fantasy from reality 5 years
sleep during the day. Toilet training is a learned behavior whose
timing of onset is extremely variable. The ability to achieve Adapted from reference 50.
continence develops by about 20 months of age, so attempting toilet
training before this time is often fruitless. Most children are fully
toilet trained between the ages of 2 and 3 years. Daytime control is Although the cognitive development during childhood is a
generally achieved before nighttime control, so even children who continuous process, it has been divided into a number of discrete
are continent during the day may require diapers at night. Primary stages described by Freud, Erikson, Piaget and others. Table 2–13
nocturnal enuresis, or bedwetting of unknown etiology, may occur offers an overview of the major schools of developmental theories,
in 15% to 20% of children 5 years of age or more. Thereafter, the including those proposed by Freud, Erikson, and Piaget. Piaget
incidence decreases by about 15% of the initial rate per year and believed that children perceive the world differently than adults
becomes stable at 1% by 15 years of age.42 It is believed to be related and that their perception is different in each stage. This thesis can
to physiologic immaturity. A positive family history following aid in the understanding the actions and reactions seen in different
mainly the male lineage can often be observed. Primary nocturnal age groups. Piaget postulated that children learn through active
enuresis may be a source of considerable anxiety for some children, interaction with the environment not only through their success,
particularly when they must sleep in an environment other than but also by analyzing their mistakes.43 During the first stage of
their own home, such as in a hospital. Piaget’s theory of cognitive development (Sensorimotor stage: 0 to
TABLE 2-13. Theories of Developmental Psychology

Age Freud Erikson Piaget Acquired Skills
Birth–18 months Oral phase Basic trust vs. Sensorimotor Basic trust as feature for later bonding capacity;
mistrust Object permanence; Differentiation between
self and world
18 months–3 years Anal phase Autonomy vs. Symbolic Verbal communication more sophisticated;
shame, preoperational Predominant egocentricity; Control over body
doubt function
3–6 years Oedipal phase Initiative vs. Intuitive Rich imagination and creativity; Symbolic
guilt preoperational functioning; Confrontation with society’s moral
values
6–12 years Latency Industry vs. Concrete Higher level of social skills in peer interaction;
inferiority operational Development of reasoning
12–17 years Adolescence Identity vs. role Formal Moving out of family core to gain autonomy and
confusion operational independence; Abstract reasoning and thinking
2 years of age), a child’s view of the world is shaped by physical often leads to behaviors with unreasonable risk taking. A child’s
interaction with the environment. Infants may use their mouths understanding for the concept of illness and medical treatment is
for this purpose and their safety needs to be considered at all influenced by sociocultural and religious factors, as well as by his
times. It is the stage of establishment of basic trust between the cognitive developmental stage. Table 2–14 illustrates the age-
child and the primary caregiver, which eventually will be a basic related development of spirituality and concept of illness and death
feature for the capacity of bonding and building relationships later and accordingly the adjustment of interventions.44
in life. At around 9 months of age, a phenomenon known as
stranger anxiety may be seen when babies are confronted with
unfamiliar individuals. As the preoperative stage approaches, the APPROACH TO HISTORY AND
concept of object permanence is achieved whereby a child learns
that an object exists even though it is no longer present or visible.
PHYSICAL EXAMINATION
In the preoperative stage (2 to 6 years of age), thought is dominated The approach to history taking in pediatrics varies according to
by egocentricity and symbolism. Fantasy play is common. the age of the child. It is important for the consultant to be aware
Although toddlers have some appreciation of cause and effect, of which historical features are of greatest interest in each age
they exhibit magical thinking. They may believe that a bad deed group to avoid missing vital information and to streamline the
or thought has caused illness in themselves or in others. information-gathering process. In neonates, the history will of
This stage also sees the development and subsequent disap- course be heavily weighted toward pregnancy and delivery. During
pearance of temper tantrums, episodes of loss of control over the infancy, attainment of developmental milestones provides valuable
environment that leads to loss of internal control. These may be information on the health status of the infant. As the child ages, his
aggravated if the child is tired or in physical discomfort. As the own past medical history assumes greater and greater importance.
third stage approaches the child starts to identify with his parents’ Issues such as medication, allergies, past surgical procedures, and
and their society’s values and to develop an inner voice of self- chronic conditions must be considered. Obviously, in the very
observation and self-guidance, the conscience as the cornerstone young child, the history will be obtained entirely from a parent or
of morality. In the third stage of concrete operations (6 to 11 years caregiver. The older child will be able to provide information and
of age), children develop the ability to consider different points of should be allowed to become involved in the process. They should
view and to elaborate explanations based on observations. be given an opportunity to ask questions and raise concerns.
However, thinking still tends to be dogmatic. The child can Preadolescents and adolescents may feel uncomfortable discussing
understand causality beyond himself and his own perception. certain issues in front of their parents and therefore should
They move out of egocentricity enough to understand that others also be interviewed on their own to make sure a full history is
may have ideas, feelings and desires different from their own. obtained (e.g., drug abuse, sexual activity, potential for pregnancy,
Through social interactions with peers, the child develops ways piercings). Confidentiality must be respected in these situations.
to maintain self-esteem while developing increased ability to Children, particularly toddlers, are less able to localize symptoms
tolerate frustration. In the final stage of formal operations (11 years than are adults. Consequently, a wide range of complaints
to adulthood), the ability to think about the world in abstract including pharyngitis and pneumonia may present as nonspecific
terms evolves. Older children can weigh options and consider the abdominal pain or discomfort. Care must be taken not to miss the
consequences of different courses of action. Adolescents display true diagnosis in such cases. Toddlers are also suggestible and may
an increasing need for autonomy and independence. If not met, nod agreeably when asked about specific symptoms. It is usually
their need to participate in their own medical decision making preferable to use open-ended questions such as “Where does it
may lead to problems in patient compliance. Typical in this hurt?” as opposed to leading questions such as “Does it hurt
age group are feelings of grandiosity and invulnerability, which there?” Whereas organization of the physical examination by
TABLE 1–14 Spirituality and concepts of illness and death in children, and conclusions for interventions. Adapted from53
Age Characteristics Spiritual Development Concept of Illness and Death Interventions
0 – 2 years Sensory and motor Faith reflects trust and None Provide maximal physical
relationship with hope in others, Need for comfort, familiar
environment, Limited sense of self-worth, love persons and transitional
language skills, Object and containment objects, consistency,
permanence, Use simple language
2 – 6 years Magical and animistic Faith is magical and Believes illness and death Correct perceptions of
thinking, egocentricity, imaginative, can be caused by thoughts illness as punishment,
Thinking is irreversible, Participation in rituals, and actions, Death is Evaluate for sense of
Engages in symbolic Need for courage temporary and reversible guilt, Use precise
play like sleep, Not language
personalizing death
Interested in physiology and
6 – 12 years Concrete thinking, Faith concerns right and details of illness,
Reasoning about wrong, Accepts external Personalizes illness and Provide concrete info, Be
Causality interpretations as truth, death, truthful, Allow child to
Explores nonphysical participate in decision
12 – 18 years Generality of thinking, Accepts inner explanations for illness making
Reality becomes interpretations as truth, and death Allow child privacy,
objective, Body-image Searches for meaning, Promote child’s
and self-esteem purpose, and value of independence, Be
paramount, Sense of life, Evolution of truthful, Allow child to
invulnerability and relationship with Higher participate in decision
omnipotence power making
system or by anatomy (“head to toe” examination) may be ation, intraoperative care, postoperative management, and patient
appropriate in adults and older children, some adaptations are safety. A synopsis has been provided to assist the pediatric
required in infants and toddlers. An opportunistic approach is anesthesiologist in providing exemplary care to all infants and
usually the most effective strategy in these groups. For example, if children. With a sound knowledge of general growth and
an infant is quiet, it usually makes sense to begin by auscultating development, supplemented as appropriate with consultation from
the chest and examining the abdomen and to leave other aspects other pediatric specialists, this goal is eminently achievable.
such as examination of the extremities until later. Distraction,
either by the parent or by the examiner, is often quite useful.
The value of observation in providing important data should not REFERENCES
be underestimated. The “laying on of hands” should be the last 1. Moore K, Persaud T. The Developing Human: Clinically Oriented
part of any assessment. Whenever possible, children should be Embryology, Philadelphia: Saunders 2003.
examined in the presence of a parent or caregiver. Infants and 2. Shepard TH, Brent RL, Friedman JM, et al. Update on new developments
in the study of human teratogens. Teratology, 2002;65:153–61.
toddlers can often be examined in a parent’s lap. Finally, infants 3. Feigelman S. Overview and Assessmentt of Variability. In Nelson Textbook
should not be left exposed any longer than is absolutely neces- of Pediatrics ed. Kliegman R, Behrman R, Jenson H, et al. Philadelphia:
sary to prevent hypothermia. During the neonatal period, an Saunders, 2007, 33–41.
overhead warmer may be indicated. In older children, especially 4. Bechard L, Puig M. Body Composition and Growth. In Nutrition in
pediatrics: Basic science and clinical applications, ed. Walker W, Watkins J,
adolescents, modesty becomes an important consideration and Duggan C . Hamilton, BC: Decker Inc, 2003, 32–51.
should be respected. For the physical examination of adolescents 5. Martin R, Fanaroff A, Walsh M. Neonatal - postnatal medicine: Diseases
in the absence of a parent, a nurse as a third person should be of the fetus and infant, Philadelphia: Mosby, 2006.
present. Children of all ages should have height, weight, and head 6. Pesce M. Reference Ranges for Laboratory Tests and Procedures. In
circumference measured, recorded, and plotted on standard Nelson Textbook of Pediatrics, ed. Kliegman R, Behrman R, Jenson H, et
al. Philadelphia: Saunders 2007, 2939–54.
growth curves. These data may provide clues to an underlying 7. Delemarre-van de Waal HA. Regulation of puberty. Best Pract Res Clin
disease and they are needed for appropriate selection of equipment Endocrinol Metab, 2002;16:1–12.
and calculation of drug doses. 8. Marcell A. Adolescence. In Nelson Textbook of Pediatrics, ed. Kliegman
R, Behrman R, Jenson H, et al. Philadelphia: Saunders, 2007, 60–65.
9. Tanner J. Growth at adolescence. Oxford: Blackwell Scientific, 1962.
CONCLUSION 10. Nottelmann ED, Susman EJ, Dorn LD, et al. Developmental processes in
early adolescence. Relations among chronologic age, pubertal stage,
The challenges of childhood growth involve anatomic, height, weight, and serum levels of gonadotropins, sex steroids, and
physiologic, and cognitive-behavioral developmental changes. adrenal androgens. J Adolesc Health Care, 1987;8:246–60.
11. Heird W. Nutrition. In Nelson Textbook of Pediatrics, ed. Kliegman R,
These changes may have a profound influence on a wide variety Behrman R, Jenson H, et al. Philadelphia: Saunders, 2007, 209–14.
of aspects of anesthetic and perioperative care including choice 12. Kramer M, Kokuma R. The optimal duration of exclusive breastfeeding:
of medications and equipment, pre- and postoperative evalu- A systematic review. World Health Organization, 2001,
13. Gidding SS, Dennison BA, Birch LL, et al. Dietary recommendations for multicenter study. Philadelphia neonatal blood pressure study group.
children and adolescents: A guide for practitioners. Pediatrics, J Perinatol, 1995;15:470–9.
2006;117:544–59. 29. Park M. Pediatric Cardiology for Practioners. (St. Louis: Mosby Year Book,
14. Kleinman R. Pediatric Nutrition Handbook. American Academy of 2008).
Pediatrics, 2004. 30. Klish W. Functional Constipation and Encopresis. In Oski’s Pediatrics:
15. Cannolly MV. Nutritional assesment. In Nutrition in pediatrics: Basic Principles and practice, ed. McMillan J, Feigin R, De Angelis C, et al.
science and clinical applications, Walker W, Watkins J, Duggan C. Philadelphia: Lippincott Williams & Wilkins, 2006, 1920–23.
Hamilton, BC: Decker Inc, 2003, 817. 31. Wilkinson A, Charlton V, Phibbs R, et al. Examination of the Newborn
16. Samour P, King K. Handbook of pediatric nutrition, Sudbury Infant. In Rudolph’s Pediatrics, ed. Rudolph C, Rudolph A, Hostetter M, et
(Massachusetts) Jones & Barlett Publishers, 2005. al. New York: McGrawHill, 2002, 83–91.
17. Schwartz RM, Luby AM, Scanlon JW, et al. Effect of surfactant on 32. McEvoy C. Sucking and Swallowing Disorders and Gastroesophageal
morbidity, mortality, and resource use in newborn infants weighing 500 Reflux. In Oski’s Pediatrics: Principles and Practice, ed. McMillan J, Feigin
to 1500 g. N Engl J Med, 1994;330:476–80. R, De Angelis C, et al. Philadelphia: Lippincott Williams & Wilkins, 2006,
18. Sarnaik A, Heidemann S. Respiratory Pathology and Regulation. In 382–84.
Nelson Textbook of Pediatrics, ed. Kliegman R, Behrman R, Jenson H, 33. Rudolph C. Disorders of Esophageal Motility. In Rudolph’s Pediatrics, ed.
et al. Philadelphia: Saunders, 2007, 1719–31. Rudolph C, Rudolph A, Hostetter M, et al. New York: McGrawHill, 2002,
19. Steele RW, Metz JR, Bass JW, et al. Pneumothorax and 1388–94.
pneumomediastinum in the newborn. Radiology, 1971; 98:629–32. 34. Orenstein S, Peters J, Kahn S, et al. Gastroesophageal Reflux. In Nelson
20. Greenough A. Respiratory Disorders in the Newborn. In Kendig’s Textbook of Pediatrics, ed. Kliegman R, Behrman R, Jenson H, et al.
Disorders of the Respiratory Tract in Children, ed. V. Chernick, T. Boat, R. Philadelphia: Saunders, 2007, 1547–49.
Wilmott, et al. Philadelphia: Saunders, 2006, 317–41. 35. Stevenson D, Madan A. Jaundice in the Newborn. In Rudolph’s Pediatrics,
21. Herzinger R. Apnea. In Oski’s Pediatrics: Principles and Practice, ed. ed. Rudolph C, Rudolph A, Hostetter M, et al. New York: McGrawHill,
McMillan J, Feigin R, De Angelis C, et al. Philadelphia: Lippincott 2002, 164–69.
Wlliams & Wilkins, 2006, 318–20. 36. Kula K, Josell S. Oral Problems. In Oski’s Pediatrics: Principles and Practice,
22. Loughlin G, Carroll J. Apparent Life-Threatening Event. In Oski’s ed. McMillan J, Feigin R, De Angelis C, et al. Philadelphia: Lippincott
Pediatrics: Principles and Practice, ed. McMillan J, Feigin R, De Angelis C, Williams & Wilkins, 2006, 781–800.
et al. Philadelphia: Lippincott Williams & Wilkins, 2006, 714–22. 37. Baum M. Development of Renal Function. In Rudolph’s Pediatrics, ed.
23. Smith R, Cable B. Laryngeal Disorders. In Oski’s Pediatrics: Principles and Rudolph C, Rudolph A, Hostetter M, et al. New York: McGrawHill, 2002,
Practice, ed. McMillan J, Feigin R, De Angelis C, et al. Philadelphia: 1632–38.
Lippincott Williams & Wilkins, 2006, 1411–21. 38. Quinn C, Buchanan G. Hematopoiesis and Hematologic Disease. In Oski’s
24. Bezold L. Cardiovascular Embryology. In Oski’s Pediatrics: Principles and Pediatrics: Principles and Practice, ed. McMillan J, Feigin R, De Angelis C,
Practice, ed. McMillan J, Feigin R, De Angelis C, et al. Philadelphia: et al. Philadelphia: Lippincott Williams & Wilkins, 2006, 440–50.
Lippincott Williams & Wilkins, 2006, 325–34. 39. O’Brien RT, Pearson HA. Physiologic anemia of the newborn infant.
25. Valente A, Fleishman C, Talner N. Cardiovascular Disease in the J Pediatr, 1971;79:132–8.
Newborn. In Oski’s Pediatrics: Principles and Practice, ed. McMillan J, 40. Dallman P, Shannon K, Pearson HA. Developmental Changes in
Feigin R, De Angelis C, et al. Philadelphia: Lippincott Williams & Wilkins, Red Blood Cell Production and Function. In Rudolph’s Pediatrics, ed.
2006, 339–60. Rudolph C, Rudolph A, Hostetter M, et al. New York: McGrawHill, 2002,
26. Rudolph A. Fetal Circulation and Cardiovascular Adjustments after Birth. 1519–23.
In Rudolph’s Pediatrics, ed. Rudolph C, Rudolph A, Hostetter M, et al. New 41. Nelson C. Brain Development and Behavior. In Rudolph’s Pediatrics, ed.
York: McGrawHill, 2002, 1749–53. Rudolph C, Rudolph A, Hostetter M, et al. New York: McGrawHill, 2002,
27. Update on the 1987 task force report on high blood pressure in children 408–10.
and adolescents: A working group report from the national high blood 42. Wan J, Greenfield S. Enuresis and common voiding abnormalities. Pediatr
pressure education program. National high blood pressure education Clin North Am, 1997;44:1117–31.
program working group on hypertension control in children and 43. Dixon S. In Encounter with Children: Pediatric Behavior and Development,
adolescents. Pediatrics, 1996;98:649–58. ed. S. Dixon S, Stein M. Philadelphia: Mosby, 2006, 13–43.
28. Zubrow AB, Hulman S, Kushner H, et al. Determinants of blood pressure 44. Himelstein BP, Hilden JM, Boldt AM, et al. Pediatric palliative care. N
in infants admitted to neonatal intensive care units: A prospective Engl J Med, 2004;350:1752–62.
Anesthesia and the

Developing Brain 3
Laszlo Vutskits C H A P T E R
INTRODUCTION called neural stem cells), the direct descendants of cells of the
neural plate. Subsequent to the closure of the neural tube, intense
The normal development of the central nervous system (CNS) symmetrical proliferation of these neuroepithelial cells will give
relies on the precise temporal and spatial orchestration of several rise to a homogenous pseudostratified epithelium, which is called
molecular pathways that guide the proliferation, migration, dif- the ventricular zone (VZ).6 Early proliferation increases the surface
ferentiation, and survival of neuronal cells. Interference with these area and the thickness of the VZ. Consequently, the neural tube
finely tuned developmental mechanisms can disrupt physiologic starts to differentiate along several axes. Regional expansions
developmental patterns and may, ultimately, lead to permanent along its anteroposterior axis will shape the major subdivisions of
impairment of CNS functions. Anesthetics primarily operate via the CNS: (1) the spinal cord; (2) the rhombencephalon or hind-
ligand-gated ionotropic neurotransmitter receptors and, thus, brain; (3) the mesencephalon or midbrain; and (4) the prosence-
modulate the activity of different neurotransmitter systems.1 In phalon or forebrain. The vertical axis determines the dorsal and
turn, it is now well established that, in addition to their role in ventral sides, whereas the horizontal axis establishes medial and
synaptic transmission in the CNS, neurotransmitters act during lateral structural growth. Appropriate differentiation of the axes
development as epigenetic factors to control important biologic of the neural tube is dependent on the precise temporal and spatial
processes including progenitor cell proliferation, neuroblast gradients of highly complex gene expression during the early
migration, and neuronal differentiation.2,3 In addition, a delicate embryonic period. Defective patterns of gene expression are
balance between excitatory and inhibitory signals also has a key known to induce major developmental anomalies in the fetal
role in the functional assembly of neuronal networks.4 Because nervous system.5
even small changes in the relative amounts of excitation and During the early embryonic stages, the first neurons of the
inhibition can markedly alter information processing, the impact human brain are generated in the rostral part of the neural plate.7
of anesthesia on neuronal and CNS development is an intriguing However, the vast majority of neuronal cells are eventually derived
question. This chapter aims to provide a brief synopsis of the from neuroepithelial stem cells of the VZ. At the start of
ontogeny of the human CNS and to describe how neurotrans- neurogenesis, occurring approximately at E33 in the lateral part
mitter signaling contributes to shape the maturing brain and of the cortical wall in humans,7 these stem cells down-regulate
reviews the accumulating evidence suggesting that anesthetic their epithelial characteristics and switch from a symmetrical to an
agents may indeed interfere with neural development. asymmetrical mode of cell division. One daughter remains a
progenitor to give rise to future neuronal cells whereas the other
is a postmitotic cell that is destined to become a neuron. By
ONTOGENY OF THE HUMAN BRAIN gestational weeks (GWs) 5 and 6, the VZ is the only proliferative
Cell Proliferation, Neurogenesis, zone. In the developing hindbrain and midbrain, the majority of
neurons are generated during this period.8 In the developing
and Neuronal Migration telencephalon, the first postmitotic neurons migrate in a radial
In the earliest phase of neural development, starting on the 15th fashion out of the VZ and form the first recognizable cortical layer
postconceptional day of human embryonic life, neural tissue is (the preplate). Around the seventh and eighth GW, accumulating
induced and begins to form within the ectodermal layer of the postmigratory cells within the preplate form the cortical plate
embryo.5 As a consequence of neural induction, the ectoderm (CP). This is divided into the marginal zone on the superficial side
subsequently divides into three different regions: the neural and the subplate on the inner side. Parallel to the formation of the
ectoderm or neural plate, which will give rise to the CNS; the CP, a secondary proliferative region, the subventricular zone
nonneural ectoderm, which will form the epidermis; and the cells (SVZ) appears above the basal border of the VZ.6 By GWs 25 to 27,
at the border between neural and nonneural ectoderm, which for when the SVZ is still proliferating, the human VZ has reduced in
the most part will become the neural crest tissue. After the size to a one-cell-thick ependymal layer. The subsequent develop-
ectoderm differentiates, the neural plate border cells bend to form ment of the cerebral cortex during the second half of gestation in
the neural folds. Before the closure of the neural tube, the neural primates is mainly related to cell proliferation in the SVZ. In
folds expand considerably in the cephalad region (head) as the addition, whereas the VZ gives rise only to neurons, dividing
first indication of the future brain. In humans, the neural tube progenitors of the SVZ generate both neurons and glial cells.6
closes at around embryonic day (E) 30.6 At this stage, its wall During GWs 10 to 25, there is a major wave of generation and
consists of a single layer of columnar neuroepithelial cells (also subsequent migration of cortical neurons in the human brain. Two
major kinds of neurons can be distinguished in the cerebral cortex: 3 months (postterm) in primary sensory areas, such as the
(1) projection neurons with pyramidal morphology, containing auditory and visual cortex, and at the age of 15 months in the
the excitatory neurotransmitter glutamate; and (2) local circuit prefrontal cortex.22
neurons with extremely diverse morphology, containing gamma- Compared with the rodent brain, a distinctive feature of the
aminobutyric acid (GABA). Projection neurons are all derived primate CNS is the intricate folds of the cerebral cortex. In fact,
from the neocortical VZ and SVZ of the telecephalon. These cells during the last trimester of pregnancy, the human cerebral cortex
migrate radially to accumulate in the CP in an inside-out manner. expands tangentially and folds to accommodate a large surface
The earliest-born neurons are destined to become the future layer area, measuring 1600 to 2000 cm2 in humans, three times larger
6, and the last-born neurons will become layer 2. In humans, the than the inner surface of the skull.23,24 Although several hypotheses
majority (~65%) of local circuit neurons are also born in the VZ have been proposed to explain the folding process during develop-
and SVZ and migrate radially to populate the CP. A significant ment, the potential influence of genetic, epigenetic, and environ-
portion (~35%) of local circuit neurons are born in the VZ and mental factors is still poorly understood.
SVZ of the subcortical ganglionic eminence of the ventral
telencephalon from which they migrate tangentially above the
SVZ into the cerebral cortex.9 Peak migratory activity of both Glial Cell Development
projection and local circuit neurons is thought to occur between and Myelin Formation
the third and the fifth months of gestation. Migration is competed Glial cells in the CNS are from two ontogenetically different
during the third trimester. The period after GW 22 is the most
categories. Microglia cells are macrophages residing in the CNS.
significant time for spatial, laminar, and cytologic differentiation
These cells are immigrants of the hematopoietic system that enter
of the CP. By the seventh month of gestation, the cerebral cortex
the CNS during the early stages of development. Macroglia cells
is clearly divided into six layers.6 In humans, neurogenesis ceases
(astrocytes and oligodendrocytes) are derived from precursors cells
in most cerebral regions by the third trimester of pregnancy.
of the SVZ.25 In humans, the majority of glial cells are produced
However, newly generated neurons are still continuously added
between GWs 20 and 40.26 Astrocytes have diverse functions
into discrete regions of the adult brain, such as the hippocampus10
ranging from the regulation of extracellular matrix composition to
and the olfactory bulb.11 The functional significance of this adult
the regulation of energy metabolism in the brain.27 Oligoden-
neurogenesis is still a matter of debate, but it is thought to be
drocytes are destined to form the myelin sheet around neuronal
important for hippocampus- and olfaction-related memory
axons in the CNS. Although myelination starts at GW 12 in the
processing.12
spinal cord28 and around GW 14 in the telencephalon,29 it becomes
a vigorously active process only during the first year after term.30
Neuronal Differentiation and Synaptogenesis Following the first year of life, myelination continues at a slower
rate and becomes completed only during the fourth decade of life.31
Neuronal differentiation starts early during fetal life. By GW 8 to
9, neurons in the CP display a fusiform cell body, a descending
axon, and an apical dendrite with a dense terminal tuft in the Regressive Phenomena During Development
marginal zone. Using a variety of chemoattractor or chemore-
pellent axonal guidance cues, the growth cones of developing In addition to progressive biologic events, such as neurogenesis
axonal pathways navigate to their intermediate and final targets. and differentiation, regressive phenomena also play a major role in
For example, corticospinal axons reach the lower cervical spinal determining the form of the mature CNS.32 Among these regres-
cord by GW 26. Thereafter, they progressively and extensively sive phenomena is programmed cell death or apoptosis, which
innervate spinal neurons.13 Neuronal dendrites represent the plays a fundamental role in the control of the final number of
primary sites of synaptic contacts in developing neurons. It is now neurons and glial cells during development.33 Two apoptogenic
well established that interference with the finely tuned molecular periods take place during CNS development. The first wave,
mechanisms, guiding the formation of neuronal dendritic arbors observed between GWs 7 and 13 in the proliferative zones of the
in the developing brain, can lead to persistent dysfunctions of the human telencephalon, consists of an early neuronal death of
CNS.14 Although the type-specific morphology of CNS neurons proliferating precursors and young postmitotic neuroblasts.33,34
appears to be specified genetically,15 these intrinsic programs act The second wave affects postmitotic neurons at later stages and is
in concert with extracellular signals during the differentiation of linked to cell differentiation and synaptogenesis. In the cerebral
the dendritic arbor.16 Dendritic development accelerates from the cortex, this type of cell death peaks between GWs 19 and 33.
third trimester of gestation, remains very active till the end of the However, apoptosis in sensorimotor, prefrontal, and cingulated
first postnatal year, and continues up to 5 years of age.17–19 From cortices continues until the first month of postnatal life34,35
the very early stages of differentiation, neurons establish synaptic Axonal retraction without accompanying cell death is another
contacts with neighboring neurons. In the spinal cord, the first prominent regressive process in the CNS. Although little is known
synaptic contacts are established around GW 8, whereas synapses about the extent of this phenomenon in humans, data from
in the cerebral cortex can be detected beginning at GW 9 to 10.20,21 primates indicate a considerable postnatal reduction in the
After the formation of the CP, synaptic density steadily increases number of projection axonal fibers within the corticospinal,
with a rate of about 4% per week in all cortical regions until GW thalamocortical, and callosal pathways during the first few months
24 to 26.21 Synaptogenesis then considerably accelerates from GW of postnatal life.36–38 Physiologic data of children with congenital
28, resulting in an approximately sixfold increase in the number hemiplegia suggest that axonal elimination in the corticospinal
of cortical synapses between this period and the first few months tract may be activity-dependent, because in these children, major
of postnatal life.22 Peak synaptic density is reached at the age of parts of the ipsilateral corticospinal projections are conserved.39
CHAPTER 3 ■ Anesthesia and the Developing Brain 45
Intense synaptogenesis during the third trimester of pregnancy The GABAergic signaling system has the unique property of
and the first 2 years of postnatal life is followed by a period of “ionic plasticity,” which is based on short-term and long-term
synapse elimination during which synaptic density and number changes in the Cl– and HCO3– ion concentrations in the postsy-
significantly decrease. In the rhesus monkey, synaptic density in naptic neurons. Although short-term ionic plasticity is caused by
the primary visual and the motor cortex decline to 50 to 60% of activity-dependent, channel-mediated anion shifts, long-term
peak values following sexual maturity, whereas the extent of ionic plasticity depends on changes in the expression patterns and
synapse elimination is significantly lower in the prefrontal and kinetic regulation of molecules involved in anion homeostasis.53
cingulated cortex of these animals.40–43 Human data indicate that During development in immature neurons, activation of GABAA
there is a region-specific first phase of decline in synaptic density receptors leads to the depolarization of these cells because of the
between 3 and 5 years of age followed by a plateau phase during high intracellular Cl– concentrations. Thus, in addition to gluta-
which synaptic density remains relatively constant. This plateau mate, GABA also acts as an excitatory neurotransmitter during
phase ends around the time of puberty, and then the number of brain development. The functional switch toward the hyper-
synapses further declines to reach adult values.22 polarizing actions of this neurotransmitter and its subsequent
inhibitory properties is linked to the developmental expression of
the K+/Cl– cotransporter (KCC2), which actively extrudes intra-
NEUROTRANSMITTERS AS SIGNALS cellular Cl– from neurons.53 KCC2 appears in the early postnatal
FOR CNS DEVELOPMENT period in rodents, although no data about the expression pattern
Neurotransmitters are primarily considered as the main actors of of this protein exist in humans yet.
synaptic transmission. However, it is important to note that these Among the ionotropic glutamate receptors, AMPA and kainate
molecules are also present in the chemical microenvironment of receptors are the first to be expressed during early mammalian
neural cells beginning at the very early stages of CNS develop- CNS ontogenesis.54–56 In rodents, these receptors are expressed
ment.44,45 Furthermore, neural stem cells, migrating neuroblasts, from E10 in the neural tube57 and as early as the fifth gestational
and immature neurons express specific receptors for neurotrans- week in human embryos.54 Spatiotemporal changes in the expres-
mitters.45,46 Thus, in addition to their role in neurotransmission in sion pattern of subunits (GluR1–4) forming the AMPA receptor
mature neuronal circuits, these same molecules can also serve as complex also occur during CNS development.46,58–61 GluR1
chemical signals to orchestrate a variety of morphogenetic events subunit levels increase progressively during late embryonic and
during brain development.47,48 These effects appear to be, at least early postnatal days with varying levels of expression according to
partially, mediated through a paracrine mode of action in which specific brain areas.62 The GluR2/3 subunits are also expressed in
neurotransmitters are nonsynaptically released into the early dif- embryonic development, whereas the presence of GluR4 is mainly
ferentiating cortical environment and activate their cogent recep- restricted to the late postnatal development and adult.46 Concern-
tors.48 This type of early neurotransmitter signaling may mediate ing the isoforms of AMPA receptors, expression of the flip variants
a wide range of developmental effects including proliferation, dominates before birth and continues to be expressed in adult-
differentiation, and synapse formation. This is in contrast with the hood, whereas flop variants are in low concentration before the
more focused, rapid mode of operation at the synapse within the postnatal period and reach the same level as the flip form by
developed CNS. adulthood.63
Changes in receptor subunit composition affect the functional
properties of the receptor complex, such as Ca2+ permeability,
Ontogeny of Ligand-Gated Ion Channels single-channel conductance, desensitization, and affinity for
During development, the expression of ligand-gated ion channel agonists.64,65 For example, a developmental switch during the
receptors follows a precise spatial and temporal pattern in the postnatal period, due to the expression of the GluR2 subunit of
CNS.44–46 The specific ontogenic progression in the expression of the AMPA receptor complex in neocortical layer V pyramidal
different receptor subunit genes characterizes the subunit assembly neurons, substantially modifies the Ca2+ permeability of these
of the majority of ionotropic receptors, suggesting that these cells.65 Similarly to AMPA receptors, kainate receptors also show
protein complexes might respond differently to endogenous and a spatial and temporal expression pattern during CNS develop-
exogenous ligands at distinct stages of neural development.44–46 ment with a peak in their expression in the late embryonic and
Several GABAA receptor subunits are expressed from the early early postnatal period.46,66,67
stages of embryonic development, and anatomic mapping of these In the human embryo, functional N-methyl-D-aspartic acid
subunits in the developing rodent CNS reveals a complex, tran- (NMDA) receptors can be detected from around the 10th
sient, and region-specific expression pattern of these proteins.49–51 gestational week.56 The functional NR1 subunit is ubiquitously
In fact, it is now well established that embryonic and early postnatal present in the brain throughout pre- and postnatal development,
GABAA receptors differ markedly from those expressed in the adult although the modulatory subunits (NR2A-D) are differentially
brain.49–52 For example, in most brain areas, the ␣3 subunits, along expressed.46,68,69 The NR2A subunit is expressed mainly during the
with the β2, β3, and γ2 subunits are the most prominent postnatal time, whereas the NR2B subunit is detected throughout
components of the GABAA receptor complex throughout the pre- the embryonic period with a restricted expression to the forebrain
and early postnatal development.50 The ␣3 subunit content then at the postnatal stages. The NR2C subunit appears postnatally and
decreases, and this is accompanied by a concomitant increase in is prominent in the cerebellum; the NR2D subunit is mainly
the expression of the ␣1 subunit. For detailed region-specific and present in the diencephalons and the brainstem at embryonic and
temporal expression patterns of GABAA receptor subunit mRNAs neonatal stages. The NR3 subunit is abundant within late prenatal
in the brain, the reader is referred to references 49 and 50. and early postnatal brain development.70
Glycine receptor subunits are expressed at high levels during demonstrating the existence of nonsynaptic GABAergic signaling
early cortical development.71 In newborn rats, the GlyR is ␣2- between neuroblasts and glial progenitors in the postnatal SVZ.94
homomeric and differs from the adult form, which includes three According to these data, spontaneous depolarization-induced
␣1 and two β subunits.72 As with prenatal GABA signaling, nonsynaptic GABA release in neuroblasts activates GABAA
activation of nonsynaptic Gly receptors during the embryonic receptors on adjacent astrocytes leading to a decreased proliferation
period is excitatory.73 In the developing brain, glycine is found at of these latter cell types. Functional ionotropic glutamate receptors
very low concentrations,74 and Gly receptors are mainly activated emerge during terminal cell division and the early neuronal
by another endogenous ligand, taurine.73 differentiation of rat neuroepithelial cells.95 Activation of AMPA/
Neuronal nicotinic acetylcholine (nACh) receptors are widely kainite, but not of NMDA receptors, has been shown to shorten
distributed in both the developing and the adult mammalian the cell cycle of isolated cortical neuroblasts89 and to differentially
CNS.75,76 In rats, functional receptors are present as early as E12,77 alter cell proliferation in the ventricular and subventricular cortical
and it is now well established that, similar to the previously germinal zones.92 A similar effect of non-NMDA receptor agonists
mentioned ionotropic receptor complexes, nACh receptor subunit has also been observed in O-2A cells in culture.96 By contrast,
expression is also developmentally regulated.78–80 For example, in proliferation of striatal neuronal progenitors is promoted by an
the case of the cerebral cortex, a pair of subunit mRNAs (α3–β2) NMDA-dependent mechanism, but not through AMPA/kainate
is initially (E12–13) expressed followed by a repression of the ␣3 receptors in the ventral telencephalon.97 NMDA receptors are also
subunit (E15) and the subsequent (E17–E19) induction of the ␣4 involved in the regulation of cell proliferation in the hippocampal
subunit.80 dentate gyrus throughout life.98 A single treatment with NMDA
Serotonin (5-HT3) acts through several different receptors,81 receptor antagonists increases granule cell proliferation approxi-
but only the 5-HT3 receptor is ionotropic and mediates rapid mately twofold within 3 hours, although activation of this receptor
excitatory responses through a ligand-gated ion channel that is leads to a decrease in the proliferation rate.99 By contrast to what is
mainly permeable to Na+ and K+, with a variable permeability for known about the importance of GABAA and ionotropic glutamate
Ca2+ according to the receptor subunit assembly.82–84 Both seroto- receptors in neural progenitor proliferation, the involvement of
nin and the 5-HT3 receptors appear during early prenatal develop- Gly, nACh, and 5-HT3 receptors in this process remains to be
ment.85,86 In the rat embryonic brain, 5-HT3 receptors are detected determined.
in a number of proliferative regions as early as E12.5.86 Although
5-HT3 receptor subunits (5-HT3A–E) have now been described,87
the developmental expression pattern of these subunits remains
Neurotransmitters and Cell Migration
to be determined. Once generated, immature postmitotic cells leave the germinative
zones and migrate toward their final destination. The complex
cyto-architectural organization of the mature CNS reflects this
Neurotransmitters and Cell Proliferation highly precise pattern of cell migration. Deficiency in migration
GABAA receptor subunits α4, β1, and γ1 are expressed in the rat patterns, caused by genetic disorders, toxins, pharmacological
VZ during periods of neurogenesis, indicating that GABA may interventions, or other environmental insults, can result in major
directly regulate proliferation of CNS progenitors.88 Although the brain malformations.100 There are two major modes of neuronal
impact of GABAA receptor activation on cell proliferation remains migration in the cerebral cortex: (1) a radial mode for the principal
to be determined in vivo, activation of this receptor complex can pyramidal cells and (2) a tangential mode for the interneurons.101
control cell cycle kinetics in neuronal progenitors. GABA has been A growing body of evidence indicates that neurotransmitters and
shown to depolarize and decrease the proliferation rate of neuronal their specific receptors are involved in the complex molecular
progenitors isolated from the developing rat telencephalon during machinery that orchestrates the migration of immature neurons in
the peak period of cortical neurogenesis (E16–E19), whereas the the brain during development and adulthood.102 The GABA
administration of GABAA receptor antagonists displayed opposite system, via various receptors, is involved at distinct phases of
effects.89 The actions of growth factors and GABA are heavily radial migration of projection neurons. GABAA–C receptors are
interconnected, thereby providing a major feedback mechanism.2 required for ventricular to intermediate zone migration, GABAB
In vitro, exposure of proliferating neuroepithelial cells to basic receptors are required for intermediate zone to cortical plate
fibroblast growth factor (bFGF) increased the expression of the ␣1 migration, and GABAA receptor activation is required for proper
subunit on the cell surface. In turn, exposure of these cells to GABA termination of migration within the cortical plate.103–105 GABA-
inhibited the proliferative effects of bFGF on neural progenitors, minergic interneurons, originating in the median ganglionic
suggesting that GABA regulates cell production by providing a eminence, also require GABAA receptor signaling to migrate
feedback signal that terminates cell division.90 Trophic factors can tangentially toward the cerebral cortex.106 Although GABA is
also decrease GABA production.91 Accumulating evidence suggests present at micromolar concentrations throughout their migratory
that the modulatory effect of GABA on cell proliferation depends route, tangentially migrating interneurons show little response to
on the brain region.44,92 For example, in embryonic neocortical slice GABA stimulation upon leaving the median ganglionic eminence.
cultures from mice, GABA increases cell proliferation in the VZ However, when these cells reach the proximity of the neocortex,
but decreases it in the SVZ.92 This differential modulation of cell they change the number and the subunit composition of the
proliferation could regulate the relative contribution of VZ and GABAA receptor complex on the cell surface. Changes in the 13-
SVZ progenitors to neocortical growth and, thus, could be of subunit composition of the GABAA receptor correlates with the
significant importance for proper CNS development.92,93 Recent ability of migrating interneurons to cross the corticostriatal
results further extend our understanding regarding the regulatory junction, indicating that these cells require a specific GABAA
role of GABA on cell proliferation during development by receptor–dependent signal for entry into the cortex.106 GABA,
through activation of the GABAA receptor, also promotes the motility and neurite outgrowth via the activation of nACh
migration of young CA1 pyramidal cells and interneurons in the receptors.121 Little is known about the effects of 5-HT3 receptor–
developing hippocampus.107,108 Migrating cells, in either the radial mediated serotonin signaling during early phases of neuronal
or the tangential pathways, also express functional ionotropic differentiation. Recently, nerve growth factor (NGF)–induced
glutamate receptors on the cell surface.102 Micromolar concentra- neurite outgrowth in PC12 cells has been shown to be enhanced
tions of glutamate have been shown to stimulate the chemotaxis of by serotonin and this effect was abolished by pharmacologic
immature embryonic neurons through an NMDA-dependent and blockade of the 5-HT3 receptor.122 The biologic significance of
AMPA/kainate-independent mechanism.109 Conversely, glutamate these data remains to be determined.
released within the hippocampus by glutamatergic neurons
modulates the tangential migration of hippocampal interneurons
through AMPA receptor activation108 and promotes the migration Neurotransmitters and Activity-Dependent
of young pyramidal neurons via NMDA receptor–dependent Neuronal Network Formation
signaling.107 These latter results suggest that glutamatergic and The establishment of neuronal networks begins with growing
GABAminergic neurons could modulate their migration in a axons recognizing their postsynaptic targets with the formation of
synergistic and cooperative manner through the release of specific synaptic contacts. The most active phase of neuronal dif-
neurotransmitters. Paracrine, nonsynaptic signaling by glutamate ferentiation, synaptogenesis and functional network formation in
and presumably other neurotransmitters, are also responsible to the rodent brain take place between the first and the third postnatal
shape hindbrain development. The pharmacologic blockade of weeks (corresponding to a period extending from the last trimester
the NMDA receptors results in a reduced radial migration of of pregnancy up to the first few years of life in humans), which
granule cells.110 The role of Gly, nACh, and 5-HT3 receptors in closely parallels to the onset of sensory input to the cortex.123,124
neural progenitor proliferation remains to be determined. GABA and glutamate, as synaptically released neurotrans-
mitters, are confirmed regulators of the activity-dependent
development of functional neuronal networks during critical
Neurotransmitters and Early periods of early postnatal life.125,126 These critical periods represent
Neuronal Differentiation developmental time windows in which brain circuits are parti-
The initial formation of neuronal axons and dendrites is an im- cularly receptive to acquiring certain types of information or even
portant developmental step preceding the assembly of differentiat- need instructive signals for their continued development.45 A
ing neurons into functional networks. Axons carry efferent delicate balance between excitatory and inhibitory signals has a
information from neurons, whereas dendrites represent the key importance in appropriate network development. In addition
primary sites of synaptic contacts for developing and mature to drastic pharmacologic perturbations of neuronal activity, even
neurons. Elaboration of a highly complex and organized dendritic small changes in the relative amounts of excitation and inhibition
arbor is a prerequisite for the establishment of neuronal circuitry.16 can markedly alter information processing.4
In turn, substantial evidence supports the view that afferent Immature or developing neurons and neuronal circuits are
synaptic and network activity plays a fundamental role in shaping particularly sensitive to external stimuli during the synaptogenetic
neuronal arbor development.111–113 Although the particular mor- period. As discussed in the section on Neurotransmitters and Cell
phology of CNS neurons appears to be specified genetically,15 these Migration, endogenous GABA and glutamate are clearly key
intrinsic programs act in concert with extracellular signals during factors guiding CNS morphogenesis. Exogenous stimulation or
the differentiation of the dendritic arbor.16 In several in vitro and blockade of GABAminergic and glutamatergic signaling pathways
in vivo experimental models, exposure to GABA leads to an can also trigger cell death in the developing brain.127 It was shown
increased dendritic length with increased branching and density during the 1970s that subcutaneous injection of high doses of
of synapses, whereas antagonism of the GABAA receptor, using glutamate induces acute neuronal necrosis in several brain regions
the selective GABAA receptor antagonist bicucullin, has opposite in newborn mice and monkeys.128,129 Blockade of the NMDA
effects.2 Importantly, blockers of the Ca2+/calmodulin kinase II receptor during synaptogenesis triggers widespread apoptosis in
(CaMKII) or mitogen-activated protein kinase (MAPK) reduce the developing brain.129
the trophic effects of GABA, suggesting that GABA exerts its Generation of transgenic mice presenting deficient GABA-
effects via activation of Ca2+-dependent kinases.114 Glycine has also minergic or glutamatergic signaling pathways further improved
been shown to enhance neuritic outgrowth.115,116 However, these the understanding regarding the role of these molecules during
effects do not seem to be mediated via Gly receptors, but rather the critical periods of neuronal network development. GABA is
through the activation of the GABAA receptor complex.116 Among synthesized by glutamic acid decarboxylase, which is the product
the ionotropic glutamate receptors, activation of the NMDA of two distinct genes, Gad65 and Gad67. Although genetic
receptor has been shown to promote neurite elongation of imma- deletion of the GAD67 enzyme is lethal and eliminates most
ture cerebellar granule neurons117 as well as to enhance dendri- cortical GABA content,130 Gad65-knockout mice are viable and
tic outgrowth and branching in differentiating hippocampal show poor GABA release upon stimulation from synaptic
neurons.44,118 By contrast, in embryonic spinal motoneurons, vesicles.131 This decrease in GABA-mediated synaptic neurotrans-
AMPA and kainite, but not NMDA receptors, mediate dendritic mission results in an impairment of activity-dependent refinement
growth.119 Activation of the nACh receptor promotes neurito- of functional connections in the developing visual cortex, thereby
genesis of immature, newly formed neurons in the rat olfactory demonstrating the important role of GABAergic neurotrans-
bulb and pharmacologic blockade of the ␣7 subunit of the receptor mission in synaptic plasticity.131
complex abolishes this effect.120 Conversely, in cultured embryonic In transgenic animals lacking the NR1 subunit of the NMDA
mouse spinal cord, acetylcholine decreased both growth cone receptor, thus, having no functional NMDA receptors, there is
increased apoptosis in several brain areas during the period of reviews the existing laboratory data regarding this phenomenon
naturally occurring cell death and synaptogenesis132 and these with a focus on drugs that have been clearly shown to affect some
animals die soon after birth.133 Generation of region-specific aspects of CNS development either in vitro or in vivo.
knockouts in which nonfunctional NMDA receptors are present
only in the cerebral cortex has allowed the study of the role of this
receptor in the formation of cortical circuits during the early Specific Anesthetic Agents
postnatal life.134 These experiments have revealed the important Ketamine
role of NMDA receptors during the critical period in several
Ketamine is a noncompetitive antagonist to the phencyclidine
cortical systems including the formation of the somatosensory
(PCP) site of the NMDA receptor. By preventing excitotoxic
barrel cortex134 and the shaping of ocular dominance columns in
actions of endogenous excitatory amino acids such as glutamate
the visual cortex.125
and aspartate, it may have a neuroprotective role in ischemia-
The mammalian neocortex is densely innervated by cholinergic
induced and seizure-related brain damage.141–143 The first indica-
and serotoninergic fibers, suggesting roles for these neurotrans-
tions that, in addition to its potential benefits, ketamine can also
mitters in synaptogenesis and neural circuit formation. Both
induce pathologic changes in the CNS came from the observations
acetylcholine and serotonin have been shown to mediate fast
that subcutaneous administration of PCP to adult rats induced
synaptic transmission in the visual cortex, and the early onset of
cytopathologic changes (vacuolization of neuronal cytoplasm) in
these mechanisms suggests a role during initial stages of circuit
cerebrocortical neurons.144 These effects were detectable as soon as
formation and during subsequent experience-dependent remodel-
2 hours after drug exposure; however, neuronal morphology
ing of cortical connections.135 5-HT3 receptor activation decreases
returned to normal when only a single dose of PCP was applied.
the amplitude and lateral extent of excitation throughout postnatal
In this same work, ketamine mimicked the effect of PCP when
development. This effect peaks after eye opening, which indicates
administered subcutaneously at 40 mg/kg, although lower doses of
a function for serotonergic modulation of circuit responses during
this anesthetic did not induce vacuolar neurodegeneration.144
the period of refinement of cortical connections.136 nACh recep-
These observations were further extended to the developing brain
tors are transiently up-regulated during the early postnatal period
in a subsequent study in which a series of seven subcutaneous
in several brain areas.137 Synergistic actions mediated by α7 nACh
injections of ketamine (20 mg/kg at each dose) spaced evenly over
receptors and NMDA receptors may contribute to experience-
9 hours induced extensive apoptotic neurodegeneration in 7-day-
dependent synaptic plasticity in the sensory neocortex during
old rat pups.129 The potential relevance of these rodent data has
early postnatal life, although nicotine-induced desensitization of
recently been confirmed in primates, in which ketamine induced
presynaptic α7 nACh receptors would allow an increased gluta-
extensive neuronal cell death in the cerebral cortex of rhesus
mate release onto postsynaptic NMDA receptors.138 Importantly,
monkey fetuses when the pregnant mother was exposed to this
altered stimulation of nACh receptors specifically during the
anesthetic for 24 hours.145 These experiments thus support the
second postnatal week disrupts the development of glutamate
contention that long-term exposure to ketamine at anesthetic
synapses in the rat auditory cortex.139
concentrations could indeed exert neurotoxic effects on the
The fetal alcohol syndrome is a dramatic clinical demonstra-
developing CNS.
tion of how exogenous perturbations of GABAminergic and gluta-
Whether short-term ketamine exposure, as may be used in
matergic signaling can affect brain development. Administration
current pediatric anesthesia practice, can induce cell death in the
of ethanol, having both NMDA antagonist and GABA-mimetic
developing brain is a controversial issue. Several independent
properties, to pregnant rodents provokes disturbances of cortical
observations indicate that, by contrast to repeated injections of
lamination and neuronal ectopia, and reduces the thickness of the
ketamine aimed to produce long-term anesthesia, a single anes-
cortical mantle in the offspring.140 In fact, ethanol has been shown
thetic dose of this drug does not induce neuronal apoptosis.144–147
to inhibit proliferation of neuronal precursors, to impair their
However, these results were challenged by other experiments
migration, and to induce neuronal death thereby providing the
demonstrating that even relatively mild exposure to ketamine can
potential neurobiologic bases for the reduced brain mass and
trigger apoptosis in the developing mouse brain.148 In this latter
lifelong neurobehavioral disturbances associated with the human
study, using immunocytochemical labeling with a specific anti-
fetal alcohol syndrome.140 By contrast to immature cells, differen-
body against the early apoptotic marker, caspase 3; apoptotic cell
tiated neurons are less sensitive to pharmacologic modulation of
bodies could be detected in several brain areas as soon as 4 hours
GABAminergic and glutamatergic signaling.127 These findings
after a single subcutaneous injection of ketamine to 7-day-old
suggest that the increased vulnerability of neurons is mainly
mice at anesthetic and subanesthetic concentrations (40 mg/kg
confined to the synaptogenetic period, and once this period is
and 10 mg/kg, respectively). Although clearly further experiments
over, transient pharmacologic manipulation of neuronal activity
are needed to elucidate the impact of a single-dose ketamine ad-
will not affect neuronal survival and optimal network function.
ministration on neuronal responses, these results raise the intri-
guing possibility that even a brief apoptogenic stimulus might alter
EFFECTS OF ANESTHETICS neuronal development during the peak synaptogenetic period.
An important point of concern in terms of neurotoxicity is that
ON CNS DEVELOPMENT neuronal apoptosis is not the only parameter to be considered in
On the basis of our increased understanding regarding the evaluating the potential adverse effects of ketamine or other
important developmental role of the neurotransmitter systems, it anesthetics on neuronal development. It is now well established
is not surprising that the past few years have yielded a veritable that interference with the finely tuned molecular mechanisms,
explosion of publications claiming the potential for adverse effects which guides the formation of neuronal dendritic arbors in the
of anesthetic agents on the immature brain. The following section developing brain, can lead to persistent dysfunctions of the CNS.14
Thus, understanding whether anesthetics modify dendritic arbor Propofol

expansion during CNS development is of utmost interest. To Propofol (2,6-diisopropyl phenol) is an alkyl phenol that poten-
investigate this issue, we have developed an in vitro model in which tiates the effect of GABA in the CNS by inducing tyrosine kinase–
immature neuroblasts are isolated from the SVZ of newborn rats.149 mediated phosphorylation of the β subunits of the GABAA
This purified cell population develops into GABAminergic receptor complex.159 Selective toxicity of propofol for GABA-
interneurons in low-density cultures with a dendritic arbor. On the minergic neurons, but not for astroglial cells, has been demonst-
basis of previous experimental and clinical studies measuring rated in aggregated cell cultures of the fetal rat telencephalon.160
ketamine plasma concentrations following single-shot or repeated Propofol has also been shown to induce growth cone collapse and
administration in rodents and humans,147,150,151 we have recently to inhibit neurite outgrowth in immature peripheral, retinal, and
explored the dose- and exposure time–dependent effects of autonomic neurons in vitro.161 In line with these results, we have
ketamine on the differentiation and survival of GABAminergic shown that even low concentrations of this drug can impair
neurons in these cultures.152 We found that ketamine, but not the dendritic differentiation of GABAminergic neurons in vitro.162
noncompetititve NMDA receptor antagonist MK801, rapidly Finally, recent in vivo experiments indicate that the intraperitoneal
induced apoptosis of developing neurons when administered at injection of propofol (60 mg/kg) to 10-day-old mice pups induces
concentrations previously reported to induce cell death in vivo neuronal apoptosis in several brain areas and that these changes
(≥10 mg/mL).147 Neither survival nor long-term dendritic develop- were accompanied by persistent behavioral deficits.163
ment was altered when differentiating neurons were exposed to
lower, subanesthetic concentrations (≤2 mg/mL) of this anesthetic
for up to 8 hours. By contrast, long-term exposure (>24 h) of Benzodiazepines
neurons to ketamine at concentrations as low as 0.01 mg/mL Benzodiazepines bind selectively to the α subunits of the GABAA
severely impaired dendritic arbor development. These new data receptor and exert agonistic activity on this receptor complex.164
suggest that long-term use of even low concentrations of ketamine, GABA is among the first neurotransmitters to appear in the
such as an adjuvant to postoperative sedation and pain control, developing brain, and signaling through the GABAA receptor is
could potentially interfere with the dendritic development of present from the very early developmental stages.165,166 Chronic
immature neurons. prenatal exposure of rat fetuses to diazepam results in long-term
Little is known about the molecular mechanisms involved in functional deficits as well as alterations of stress-induced beha-
ketamine-induced neurotoxicity. Recently, ketamine has been vioral patterns in these animals.167–169 Prolonged diazepam treat-
shown to reduce phosphatidylinositol-3 kinase/Akt phosphoryla- ment during both the prenatal and the postnatal period induces
tion and, thus, increase glycogen synthase kinase-3 (GSK-3) levels long-lasting changes in GABAA receptor as well as neurosteroid
in neurons.153 In turn, GSK-3 phosphorylates Bax, a proapoptotic levels.170 In turn, diazepam-induced alterations in GABAA receptor
Bcl-2 family member that stimulates the intrinsic (mitochondrial) function result in the impaired modulation of norepineph-
death pathway by eliciting cytochrome C release from the mito- rine release from brain synaptosomes in response to stressful
chondria, promotes its mitochondrial localization.154 In fact, stimuli.171,172 In addition to the effects of chronic benzodiazepine
application of Akt phosphorylation-activating growth factors, such exposure, results indicate that, as with ketamine,148,173 a single,
as insulin-like growth factor-1 (IGF-1), as well as inhibitors of subanesthetic dose of midazolam can induce a significant neuro-
GSK-3 has been shown to protect against ketamine-induced apoptotic response in the cerebral cortex as well as in the basal
apoptosis.153 In this context, it is important to note that blockade ganglia of young mice.148 Whether this treatment paradigm also
of the NMDA receptor during the peak synaptogenetic period, induces long-term behavioral or cognitive deficits remains to be
using ethanol, delays the developmental switch from NR2B to determined.
NR2A subunits, thereby altering the function of NMDA signaling
in maturing neural networks.155,156 Another important issue to be Barbiturates
addressed in the future is whether neuronal sensitivity to ketamine
Barbiturates are also potent agonists of the GABAA receptor. In
is dependent on the subunit composition of the NMDA receptor
line with reports using midazolam or propofol, exposure of 7-day-
complex. Ketamine-induced neurotoxicity is primarily confined
old rats to barbiturates for 5 hours has been shown to induce
to the brain growth spurt period when NR1 and NR2B subunits
widespread neuronal apoptosis in numerous brain regions.174 In
predominate and the proapoptotic effects of this drug decrease
these experiments, neuronal death was associated with reduced
with the progressive increase in the amount of the NR2A subunit
expression of neurotrophins and decreased concentrations of
during this period.68,157
survival-promoting proteins in the brain.174
Little is known about the potential adverse effects of ketamine
on neuronal progenitor proliferation and cell migration. Some
observations indicate a possible role for ketamine in progenitor Volatile Anesthetic Agents
proliferation in postnatal neurogenic zones. In adult rats receiving Although the exact mechanisms of action of the volatile anesthetic
subanesthetic concentrations of ketamine for 5 consecutive days, agents remain to be determined, all of these anesthetics have
the proliferation marker, bromodeoxyuridine, demonstrates en- GABAmimetic and/or NMDA antagonistic properties. During the
hanced neurogenesis in the hippocampal subgranular zone.158 To mid-1980s, halothane was among the first of the anesthetics
our knowledge, there are no other studies regarding the role of reported to alter brain development. When rats were chronically
ketamine exposure on the immature brain before the synaptoge- exposed to halothane anesthesia during the entire gestational
netic period. Given the important role of these earlier develop- period, dendritic length and branching as well as cerebral synaptic
mental stages in the proper formation of the CNS, further research density were severely impaired.175 The effect of halothane on
is needed to clarify these issues. dendritic growth appeared to be enduring, and the delay in initial
dendritic growth caused by halothane was not compensated for increases cell proliferation in oligodendrocytes197 but inhibits
by an increased rate of dendritic growth once the drug had been mitosis in astrocytes and neuronal precursors.196,198
withdrawn. The effect of halothane treatment on dendritic growth Although morphine has been reported to reduce chemotactic
was associated with learning impairment, decreased exploratory responses in leukocytes199 and increase chemotaxis in microglia,200
behavior, and decreased nociceptive reactivity.176 the role of opioid signaling in neuronal cell migration in the
Isoflurane (1.5%) has been shown to induce neuronal dege- developing brain remains to be established. In this context, recent
neration in organotypic hippocampal slice cultures.177 In these observations reveal that by contrast to proliferative neural pro-
experiments, isoflurane-induced cell death occurred in cultures genitors, migrating neuroblasts do not express opioid receptors
obtained from postnatal 7-day-old rats (PND7) but not in those on the cell surface.198 Further work is needed to determine whether
from PND4 or PND14 rat pups. Moreover, this effect was opioids affect the migration of other cell types such as astroglial
observed only with an isoflurane exposure of at least 5 hours. cells during development.
Recent in vivo data also point to the dose, exposure time, and age- Naltrexone-induced chronic pharmacologic blockade of opioid
dependent toxicity of this volatile anesthetic agent.178,179 Altogether, signaling in the early postnatal period induces a significant
these studies further support the notion of both an age- and a increase in the extent of dendritic arborization as well as in the
duration-dependent relationship between anesthesia administra- number of dendritic spines, indicating that endogenous opioid
tion and perinatal neuronal death. Interesting new data show that systems are critical regulators of neuronal differentiation and that
even shorter exposure time (4 h) to isoflurane in neonatal rat pups, they control growth through an inhibitory mechanism.201,202 In
although not affecting survival, can induce a significant decrease vitro observations indicate a dual role for opioid signaling in
in hippocampal stem cell proliferation, leading to the long-term neurite growth. Although high-dose (1 mM) morphine inhibits
impairment of neurocognitive function revealed by the fear neurite elongation, low concentrations (<10 nM) of this drug
conditioning test.180 enhance neurite-promoting activity of NGF.203,204 Although no
Nitrous oxide (N2O) is a potent antagonist of the NMDA type data are available on whether pharmacologic blockade or enhance-
of glutamate receptor. When pregnant rats were exposed to 75% ment of opioid signaling induces cell death or survival during CNS
N2O-25% O2 mixtures on gestational days 14 and 15 for 8 hours development, application of selective μ receptor agonists increases
per day, permanently altered behavioral deficits could be detected NGF-dependent survival of embryonic chick dorsal root ganglion
in the offspring without any accompanying physical abnor- neurons, suggesting that growth factor–mediated neuronal sur-
malities.181 In line with results observed following ketamine ad- vival might be modulated by opioid signaling.205,206 Conversely, in
ministration, there is now evidence that a 3-hour exposure to N2O the adult rat brain, high doses of opioid have been shown to induce
can also trigger apoptosis in the developing brain.182 electoencephalographic seizure activity and cell death in several
brain regions.20,207
Opioid Analgesics
Opioid analgesics primarily act on μ-, δ-, and κ-types of opioid Combined Use of Anesthetic Agents
receptors on the cell surface. Upon binding, these opioid receptor During the perioperative period, patients are usually exposed to a
subtypes recruit inhibitory G proteins (Gi/o) and thereby initiate combination of different anesthetic agents either simultaneously
the activation of multiple intracellular signaling cascades.183,184 In or in a timely order. As the majority of these drugs have GABA-
addition to inducing potent analgesic effects, these signaling mimetic and/or NMDA antagonistic properties, the question as to
pathways are also implicated in a variety of other biologic events whether combined use of anesthetic agents could act additively or
including the modulation of proliferation, survival, and dif- synergistically in terms of neurotoxicity is of great clinical
ferentiation of cells expressing opioid receptors.184 In the develop- significance. Although one of the major arguments for providing
ing rodent CNS, opioid receptors are expressed from early multimodal anesthesia or balanced anesthesia is to diminish
developmental stages,185,186 suggesting a role for opioid receptor– potential side effects linked to higher concentrations of individual
mediated signaling in the developmental processes. In rats, chro- drugs, recent laboratory results would suggest the need for a risk/
nic morphine exposure during the embryonic and the early benefit reevaluation of this practice.208 Indeed, a large amount of
postnatal period induces significant reduction in brain volume, experimental evidence suggests that concurrent use of several anes-
neuronal packing density, and dendritic growth.187–191 Animals thetic agents can potentiate CNS damage. The co-administration of
subjected to this treatment paradigm show long-term impair- even low concentrations of ketamine and N2O enhances the
ments in learning abilities and motor activity.192,193 By contrast to neurotoxic reaction to a much greater degree that can be explained
the effects of exogenous opioid exposure, pharmacologic blockade by the simple additive effects of these agents.182 Recently, the co-
of endogenous opioid signaling by naltrexone induces an increase administration of sedative concentrations of midazolam and
in brain size, suggesting a modulator role for the endorphin and ketamine to the infant mouse brain was shown to be more effective
opioid receptor system during development.194 in inducing apoptosis than either of these drugs alone.148 The co-
It is now well established that opioids modulate cell prolifera- administration of ketamine with propofol or thiopental also
tion in germinative zones of the developing brain in a receptor-, potentiates apoptotic neurodegeneration in young rodents.163
brain region–, and cell type–specific manner. Activation of the μ Importantly, exposure of 7-day-old rats to a combined midazolam-
and κ opioid receptors increases proliferation rate, whereas N2O-isoflurane anesthesia for 6 hours led to widespread neuro-
agonists of the δ receptor decrease cell division in the germinal degeneration in the developing brain and this was accompanied by
zone of the late embryonic neocortex.195 Conversely, morphine- persistent learning deficits.209 Interesting new data from this same
induced μ receptor activation inhibits DNA synthesis in the research group provide some insights into the molecular mecha-
developing cerebellum.196 Finally, signaling through the μ receptor nisms of anesthesia-induced activation of apoptotic pathways in
immature neurons.210 Midazolam-N2O-isoflurane rapidly induced essential criticism concerning the significance of animal
significant changes in the expression pattern of brain-derived experiments in comparison with human anesthesia practice
neurotrophic factor (BDNF) in the brain of rat pups. BDNF is a concerns the relatively long exposure time needed to produce
member of the neurotrophin family of growth factors and is detectable neurotoxic effects in the majority of laboratory
implicated in neuronal survival, differentiation, and synaptic studies.217 In fact, from a developmental perspective, several hour-
plasticity via activation of its high-affinity receptor, TrkB.211 This long exposures to anesthetics in rodents would be equivalent to
neurotrophin also binds to the so-called low-affinity neurotrophin producing general anesthesia for days or even weeks in the human
receptor, p75NTR, leading to the activation of apoptotic cas- neonate.8 However, recent results somewhat counteract these
cades.211 In the cerebral cortex of 7-day-old rats, as little as a 2-hour- arguments, showing that even a single exposure to subanesthetic
long anesthetic exposure significantly increased the amounts of doses of anesthetics could trigger a two- to fourfold increases in
BDNF. This was accompanied by an increase in the expression of neuronal apoptosis in the mouse brain during the synaptogenetic
the p75NTR receptor. By contrast, the anesthetic induced an period.148 In addition, in vitro data indicate that short-term ex-
important decrease in BDNF levels without affecting p75NTR posure to anesthetic agents can also impair neuronal development
receptor expression in the thalamus, leading to a reduced BDNF- by interfering with dendritic growth and branching without
dependent activation of the TrkB receptor. These results suggest inducing cell death.152,162 Given the utmost importance of neuronal
that general anesthesia can perturb CNS development by interact- dendritic architecture in appropriate information processing, one
ing with the multifaceted molecular pathways of neurotrophin essential next step will be to determine how neuronal dendritic
signaling. arbor development is influenced by anesthetic agents in a more
complex and physiologic environment, using organotypic slice
cultures and in vivo animal experiments. These experiments,
Protection Against Anesthesia- combined with long-term assessment of behavioral outcome
Induced Neurotoxicity following short-term anesthesia, may help us to better understand
Deciphering the molecular pathways involved in anesthetic- the impact of anesthetic agents on CNS development.
induced adverse effects on the developing CNS would allow us to Differences in concentrations of drugs needed to produce
develop therapeutic strategies to prevent these unwanted com- anesthesia across different species further complicate the issue of
plications. In this context, administration of β-estradiol has been anesthesia-induced developmental neurotoxicity. Subanesthetic
shown to reduce anesthesia-induced apoptosis in the developing plasma concentrations of ketamine in humans vary from 0.1 to
brain.210 This sex hormone is known to activate the Akt serine/ 0.5 μg/mL,218,219 whereas intravenous administration to children
threonine kinase, which is an important factor for neuronal at doses of 3 mg/kg to induce anesthesia results in blood levels
of 1 to 2 μg/mL.150,151 Although no direct comparison in terms of
survival pathways. The midazolam-N2O-isoflurane anesthesia-
plasma concentrations exists with rodents; as much as 40 mg/kg of
induced apoptotic neurodegeneration has been reported to be
subcutaneously injected ketamine is insufficient to produce
reduced in a dose-dependent manner by the co-administration of
anesthesia in young mice.148 In laboratory animals, plasma levels
melatonin. Melatonin, in addition to its sleep-promoting activity,
of ketamine are approximately 6 μg/mL following a single 20 mg/
exerts antioxidant effects by improving mitochondrial homeos-
kg subcutaneous dose.147 These studies suggest that effective
tasis and stabilizing the inner mitochondrial membrane.212 Recent
plasma concentrations and probably “on-site” brain concentrations
data indicate that co-administration of L-carnitine, a quaternary
of ketamine needed to produce anesthesia are significantly higher
ammonium compound involved in fatty acid metabolism, also
in rodents than in humans, raising further difficulties in the
protects against N2O-isoflurane-induced neuroapoptosis.213 In
extrapolation of these experiments to human infants.
vitro, ketamine-induced neurotoxicity is prevented by the co-
Finally, one can argue that experimental conditions in these
administration of IGF-1, a growth factor known to activate the
animal experiments are very different from those associated with
phosphatidylinositol-3 kinase/Akt signaling pathway.153 Recently, surgical anesthesia and complex perioperative management.217
co-application of xenon during isoflurane and isoflurane-N2O First, based on the neuronal stimulation hypothesis,220 preopera-
anesthesia has been shown to attenuate the neurotoxic effects of tive stress and painful stimuli during surgery can activate NMDA
these latter two agents during the early postnatal period.214 These and other excitatory receptors in the immature brain and anes-
encouraging observations open a whole new line of research thetic drugs could, thus, reduce extreme degrees of neuronal
aimed to counteract anesthesia-induced neurotoxicity. Further excitation.221 In line with this hypothesis, application of ketamine
studies should be conducted to address this important issue. has been shown to reduce cell death following inflammatory pain
in the newborn rat brain.222 The average clinical situation is
Extrapolation of Laboratory Results to by contrast to experimental settings in which anesthesia was
administered without painful stimuli and, consequently, the
Clinical Practice effect of anesthetics on the suppression of basal neural activity is
It is of course extremely difficult to evaluate the clinical relevance evaluated. Second, human neonates and children routinely receive
of experimental observations claiming the possibility of anesthesia- nutritional support and metabolic monitoring in the periopera-
induced neurotoxicity in the developing brain. A first important tive period, thereby minimizing the risk for hypoglycemia and
question concerns the possibility of interspecies differences in impaired nutrition. By contrast, although this issue is contro-
terms of drug effects.215 In this context, it is important to note that, versial, rodent pups do not suckle well after general anesthesia,
in addition to rodents, anesthetic and subanesthetic doses of resulting in a prolonged decrease in weight gain compared
currently used anesthetics have now been shown to induce with nonanesthetized littermates.146,223 Given that the role of
apoptosis in other species such as pigs and monkeys.145,216 Another malnutrition in decreased brain growth and learning disabilities is
well established,224,225 one cannot fully exclude the possibility that state of our knowledge, we believe that no recommendations can
the neurotoxic effects of anesthetic agents are, at least partially, be made to change clinical practice. Nevertheless, in light of
related to impaired nutrition in the perioperative period in these accumulating experimental data, one should systematically
animal studies. consider whether elective surgical procedures in infants could be
safely postponed to later periods. Also, when surgery or a
procedure is unavoidable, every effort should be made to limit the
Anesthesia-Related Neurotoxicity and duration of the intervention. Finally, it is important to note that
Clinical Evidence there is no evidence whether one anesthetic agents is better or
Several human cohort studies have demonstrated an association worse that the others in terms of potential for toxicity to the CNS.
between surgery in the neonatal period and poor neurodevelop- Clearly, given the large number of human fetuses and infants
mental outcome. Neurodevelopmental outcome in extremely low receiving anesthesia worldwide, there is no doubt that additional
birthweight (ELBW) infants undergoing laparotomy for necro- experimental and clinical studies are needed to elucidate the
tizing enterocolitis (NEC) has been shown to be significantly impact of anesthesia on the developing brain.
worse than in ELBW infants, with or without NEC, in the absence
of anesthesia and surgery.226 Children who required major neo- REFERENCES
natal surgery performed significantly less well at 1 year of age and
in early adolescence than with their peers.227,228 Children who 1. Yamakura T, Bertaccini E, Trudell JR, Harris RA. Anesthetics and ion
underwent surgical correction for congenital diaphragmatic channels: molecular models and sites of action. Annu Rev Pharmacol
Toxicol. 2001;41:23–51.
hernia or esophageal atresia during the neonatal period have more
2. Represa A, Ben-Ari Y. Trophic actions of GABA on neuronal
learning, emotional, and behavioral problems than children in the development. Trends Neurosci. 2005;28:278–283.
general population.229,230 Recent clinical observations indicate that 3. Waters KA, Machaalani R. NMDA receptors in the developing brain
surgical closure of patent ductus arteriosus (PDA) in ELBW and effects of noxious insults. Neurosignals. 2004;13:162–174.
infants is associated with significantly worse neurodevelopmental 4. Liu G. Local structural balance and functional interaction of
and neurosensory outcome than indomethacin-induced success- excitatory and inhibitory synapses in hippocampal dendrites. Nat
ful closure without a need for surgery.231 Unfortunately, given the Neurosci. 2004:7:373–379.
high number of potentially confounding factors, none of these 5. Sarnat HB, Flores-Sarnat L. Integrative classification of morphology
studies provides evidence for an association between anesthesia and molecular genetics in central nervous system malformations. Am
per se and poor outcome. In fact, the majority of infants included J Med Genet A. 2004;126:386–392.
6. Bystron I, Blakemore C, Rakic P. Development of the human cerebral
in these studies have coexisting malformations, prematurity, cortex: Boulder Committee revisited. Nat Rev Neurosci. 2008;9:
sepsis, and associated cardiovascular instability. Also, it is virtually 110–122.
impossible to distinguish between the effects of anesthetic agents, 7. Bystron I, Rakic P, Molnar Z, Blakemore C. The first neurons of the
surgical stress, and postoperative issues in the clinical setting. human cerebral cortex. Nat Neurosci. 2006;9:880–886.
Upcoming clinical trials, attempting to focus on a specific neonatal 8. Clancy B, Darlington RB, Finlay BL. Translating developmental time
population that presents with limited comorbidity but requires across mammalian species. Neuroscience. 2001;105:7–17.
surgery, are necessary to further investigate this issue.232 9. Letinic K, Zoncu R, Rakic P. Origin of GABAergic neurons in the
One should not forget that multiple lines of evidence suggest human neocortex. Nature. 2002;417:645–649.
the necessity of providing anesthesia in infants. In preterm babies 10. Eriksson PS, Perfilieva E, Bjork-Eriksson T, et al. Neurogenesis in the
adult human hippocampus. Nat Med. 1998;4:1313–1317.
undergoing surgery, perioperative stress hormone levels as well as
11. Curtis MA, Kam M, Nannmark U, et al. Human neuroblasts migrate
postoperative complications were significantly higher when only to the olfactory bulb via a lateral ventricular extension. Science.
N2O and curare were administered peroperatively compared with 2007;315:1243–1249.
infants who also received fentanyl or halothane.233,234 In neonates 12. Ming GL, Song H. Adult neurogenesis in the mammalian central
undergoing cardiac surgery, deeper levels of anesthesia decreased nervous system. Annu Rev Neurosci. 2005;28:223–250.
the incidence of postoperative sepsis, disseminated intravascular 13. Eyre JA, Miller S, Clowry GJ, et al. Functional corticospinal projec-
coagulation, and mortality.235 Repetitive painful stimuli have been tions are established prenatally in the human foetus permitting
shown to persistently alter pain processing in humans,217,236 and involvement in the development of spinal motor centres. Brain.
epidemiologic studies reveal an association between perinatal 2000;123:51–64.
14. Webb SJ, Monk CS, Nelson CA. Mechanisms of postnatal
and neonatal complications and behavioral/emotional problems
neurobiological development: implications for human development.
in childhood, such as anxiety, depression, and even suicidal Dev Neuropsychol. 2001;19:147–171.
tendencies.237–241 15. Jan YN, Jan LY. The control of dendrite development. Neuron. 2003;
40:229–242.
16. Chen Y, Ghosh A. Regulation of dendritic development by neuronal
CONCLUSIONS activity. J Neurobiol. 2005;64:4–10.
Anesthesia-induced neurotoxicity remains a highly debated and 17. Koenderink MJ, Uylings HB. Postnatal maturation of layer V
pyramidal neurons in the human prefrontal cortex. A quantitative
controversial issue. The important role of neurotransmitter
Golgi analysis. Brain Res. 1995;678:233–243.
signaling in shaping CNS development raises the intriguing 18. Koenderink MJ, Uylings HB, Mrzljak L. Postnatal maturation of the
possibility that interference with these signaling pathways, such layer III pyramidal neurons in the human prefrontal cortex: a
as exposing the developing organism to anesthetic agents, could quantitative Golgi analysis. Brain Res. 1994;653:173–182.
potentially alter physiologic developmental patterns during brain 19. Mrzljak L, Uylings HB, Kostovic I, van Eden CG. Prenatal develop-
maturation. However, the functional impact of anesthetic agents ment of neurons in the human prefrontal cortex. II. A quantitative
on developing humans remains to be determined. At the current Golgi study. J Comp Neurol. 1992;316:485–496.
20. Molliver ME, Kostovic I, van der Loos H. The development of 44. Nguyen L, Rigo JM, Rocher V, et al. Neurotransmitters as early signals
synapses in cerebral cortex of the human fetus. Brain Res. 1973;50: for central nervous system development. Cell Tissue Res. 2001;305:
403–407. 187–202.
21. Zecevic N. Synaptogenesis in layer I of the human cerebral cortex in 45. Herlenius E, Lagercrantz H. Development of neurotransmitter
the first half of gestation. Cereb Cortex. 1998;8:245–252. systems during critical periods. Exp Neurol. 2004;190(Suppl 1):
22. Huttenlocher PR, Dabholkar AS. Regional differences in synapto- S8-S21.
genesis in human cerebral cortex. J Comp Neurol. 1997;387:167–178. 46. Lujan R, Shigemoto R, Lopez-Bendito G. Glutamate and GABA
23. Hilgetag CC, Barbas H. Role of mechanical factors in the morphology receptor signalling in the developing brain. Neuroscience. 2005;130:
of the primate cerebral cortex. PLoS Comput Biol. 2006;2:e22. 567–580.
24. Dubois J, Benders M, Cachia A, et al. Mapping the early cortical fold- 47. McMahon D. Chemical messengers in development: a hypothesis.
ing process in the preterm newborn brain. Cereb Cortex. 2007;18: Science. 1974;185:1012–1021.
1444–1454. 48. Owens DF, Kriegstein AR. Developmental neurotransmitters?
25. Liu Y, Rao MS. Glial progenitors in the CNS and possible lineage Neuron. 2002;36:989–991.
relationships among them. Biol Cell. 2004;96:279–290. 49. Poulter MO, Barker JL, O’Carroll AM, et al. Differential and transient
26. de Graaf-Peters VB, Hadders-Algra M. Ontogeny of the human expression of GABAA receptor alpha-subunit mRNAs in the develop-
central nervous system: what is happening when? Early Hum Dev. ing rat CNS. J Neurosci. 1992;12:2888–2900.
2006;82:257–266. 50. Laurie DJ, Wisden W, Seeburg PH. The distribution of thirteen
27. Pellerin L, Bouzier-Sore AK, Aubert A, et al. Activity-dependent GABAA receptor subunit mRNAs in the rat brain. III. Embryonic and
regulation of energy metabolism by astrocytes: an update. Glia. postnatal development. J Neurosci. 1992;12:4151–4172.
2007;55:1251–1262. 51. Yu ZY, Wang W, Fritschy JM, et al. Changes in neocortical and
28. Weidenheim KM, Bodhireddy SR, Rashbaum WK, Lyman WD. hippocampal GABAA receptor subunit distribution during brain
Temporal and spatial expression of major myelin proteins in the maturation and aging. Brain Res. 2006;1099:73–81.
human fetal spinal cord during the second trimester. J Neuropathol 52. Hutcheon B, Fritschy JM, Poulter MO. Organization of GABA
Exp Neurol. 1996;55:734–745. receptor alpha-subunit clustering in the developing rat neocortex and
29. Zecevic N, Andjelkovic A, Matthieu JM, Tosic M. Myelin basic hippocampus. Eur J Neurosci. 2004;19:2475–2487.
protein immunoreactivity in the human embryonic CNS. Brain Res 53. Rivera C, Voipio J, Kaila K. Two developmental switches in
Dev Brain Res. 1998;105:97–108. GABAergic signalling: the K+-Cl– cotransporter KCC2 and carbonic
30. Brody BA, Kinney HC, Kloman AS, Gilles FH. Sequence of central anhydrase CAVII; J Physiol. 2005;562:27–36.
nervous system myelination in human infancy. I. An autopsy study of 54. Bardoul M, Levallois C, Konig N. Functional AMPA/kainate
myelination. J Neuropathol Exp Neurol. 1987;46:283–301. receptors in human embryonic and foetal central nervous system.
31. Paus T, Zijdenbos A, Worsley K, et al. Structural maturation of neural J Chem Neuroanat. 1998;14:79–85.
pathways in children and adolescents: in vivo study. Science. 55. Gallo V, Pende M, Scherer S, et al. Expression and regulation of
1999;283:1908–1911. kainate and AMPA receptors in uncommitted and committed neural
32. Cowan WM, Fawcett JW, O’Leary DD, Stanfield BB. Regressive progenitors. Neurochem Res. 1995;20:549–560.
events in neurogenesis. Science. 1984;225:1258–1265. 56. Ritter LM, Unis AS, Meador-Woodruff JH. Ontogeny of ionotropic
33. Lossi L, Merighi A. In vivo cellular and molecular mechanisms of glutamate receptor expression in human fetal brain. Brain Res Dev
neuronal apoptosis in the mammalian CNS. Prog Neurobiol. 2003; Brain Res. 2001;127:123–133.
69:287–312. 57. Scherer SE, Gallo V. Expression and regulation of kainate and
34. Rakic S, Zecevic N. Programmed cell death in the developing human AMPA receptors in the rat neural tube. J Neurosci Res. 1998;52:
telencephalon. Eur J Neurosci. 2000;12:2721–2734. 356–368.
35. Rabinowicz T, de Courten-Myers GM, Petetot JM, et al. Human 58. Pellegrini-Giampietro DE, Bennett MV, Zukin RS. Differential
cortex development: estimates of neuronal numbers indicate major expression of three glutamate receptor genes in developing rat brain:
loss late during gestation. J Neuropathol Exp Neurol. 1996;55: an in situ hybridization study. Proc Natl Acad Sci U S A. 1991;88:
320–328. 4157–4161.
36. Galea MP, Darian-Smith I. Postnatal maturation of the direct 59. Gallo V, Upson LM, Hayes WP, et al. Molecular cloning and develop-
corticospinal projections in the macaque monkey. Cereb Cortex. ment analysis of a new glutamate receptor subunit isoform in
1995;5:518–540. cerebellum. J Neurosci. 1992;12:1010–1023.
37. Darian-Smith C, Darian-Smith I, Cheema SS. Thalamic projections 60. Ripellino JA, Neve RL, Howe JR. Expression and heteromeric interac-
to sensorimotor cortex in the newborn macaque. J Comp Neurol. tions of non-N-methyl-D-aspartate glutamate receptor subunits
1990;299:47–63. in the developing and adult cerebellum. Neuroscience. 1998;82:
38. LaMantia AS, Rakic P. Axon overproduction and elimination in the 485–497.
corpus callosum of the developing rhesus monkey. J Neurosci. 61. Migues PV, Cammarota M, Kavanagh J, et al. Maturational changes
1990;10:2156–2175. in the subunit composition of AMPA receptors and the functional
39. Eyre JA, Taylor JP, Villagra F, et al. Evidence of activity-dependent consequences of their activation in chicken forebrain. Dev Neurosci.
withdrawal of corticospinal projections during human development. 2007;29:232–240.
Neurology. 2001;57:1543–1554. 62. Martin LJ, Furuta A, Blackstone CD. AMPA receptor protein in
40. Zecevic N, Bourgeois JP, Rakic P. Changes in synaptic density in developing rat brain: glutamate receptor-1 expression and localization
motor cortex of rhesus monkey during fetal and postnatal life. Brain change at regional, cellular, and subcellular levels with maturation.
Res Dev Brain Res. 1989;50:11–32. Neuroscience. 1998;83:917–928.
41. Bourgeois JP, Rakic P. Changes of synaptic density in the primary 63. Hollmann M, Heinemann S. Cloned glutamate receptors. Annu Rev
visual cortex of the macaque monkey from fetal to adult stage. Neurosci. 1994;17:31–108.
J Neurosci. 1993;13:2801–2820. 64. Swanson GT, Kamboj SK, Cull-Candy SG. Single-channel properties
42. Bourgeois JP, Goldman-Rakic PS, Rakic P. Synaptogenesis in the of recombinant AMPA receptors depend on RNA editing, splice
prefrontal cortex of rhesus monkeys. Cereb Cortex. 1994;4:78–96. variation, and subunit composition. J Neurosci. 1997;17:58–69.
43. Granger B, Tekaia F, Le Sourd AM, et al. Tempo of neurogenesis and 65. Kumar SS, Bacci A, Kharazia V, Huguenard JR. A developmental
synaptogenesis in the primate cingulate mesocortex: comparison with switch of AMPA receptor subunits in neocortical pyramidal neurons.
the neocortex. J Comp Neurol. 1995;360:363–376. J Neurosci. 2002;22:3005–3015.
66. Lilliu V, Perrone-Capano C, Pernas-Alonso R, et al. Ontogeny of 89. LoTurco JJ, Owens DF, Heath MJ, et al. GABA and glutamate
kainate receptor gene expression in the developing rat midbrain and depolarize cortical progenitor cells and inhibit DNA synthesis.
striatum. Brain Res Mol Brain Res. 2002;104:1–10. Neuron. 1995;15:1287–1298.
67. Bahn S, Volk B, Wisden W. Kainate receptor gene expression in the 90. Antonopoulos J, Pappas IS, Parnavelas JG. Activation of the GABAA
developing rat brain. J Neurosci. 1994;14:5525–5547. receptor inhibits the proliferative effects of bFGF in cortical
68. Watanabe M, Inoue Y, Sakimura K, Mishina M. Distinct spatio- progenitor cells. Eur J Neurosci. 1997;9:291–298.
temporal distributions of the NMDA receptor channel subunit 91. Nguyen L, Malgrange B, Breuskin I, et al. Autocrine/paracrine
mRNAs in the brain. Ann N Y Acad Sci. 1993;707: 463–466. activation of the GABA(A) receptor inhibits the proliferation of
69. Takai H, Katayama K, Uetsuka K, et al. Distribution of N-methyl-D- neurogenic polysialylated neural cell adhesion molecule-positive
aspartate receptors (NMDARs) in the developing rat brain. Exp Mol (PSA-NCAM+) precursor cells from postnatal striatum. J Neurosci.
Pathol. 2003;75:89–94. 2003;23:3278–3294.
70. Sun L, Margolis FL, Shipley MT, Lidow MS. Identification of a long 92. Haydar TF, Wang F, Schwartz ML, Rakic P. Differential modulation
variant of mRNA encoding the NR3 subunit of the NMDA receptor: of proliferation in the neocortical ventricular and subventricular
its regional distribution and developmental expression in the rat zones. J Neurosci. 2000;20:5764–5774.
brain. FEBS Lett. 1998;441:392–396. 93. Kornack DR, Rakic P. Changes in cell-cycle kinetics during the
71. Malosio ML, Marqueze-Pouey B, Kuhse J, Betz H. Widespread development and evolution of primate neocortex. Proc Natl Acad
expression of glycine receptor subunit mRNAs in the adult and Sci U S A. 1998;95:1242–1246.
developing rat brain. EMBO J. 1991;10:2401–2409. 94. Liu X, Wang Q, Haydar TF, Bordey A. Nonsynaptic GABA signaling
72. Langosch D, Thomas L, Betz H. Conserved quaternary structure of in postnatal subventricular zone controls proliferation of GFAP-
ligand-gated ion channels: the postsynaptic glycine receptor is a expressing progenitors. Nat Neurosci. 2005;8:1179–1187.
pentamer. Proc Natl Acad Sci U S A. 1988;85:7394–7398. 95. Maric D, Liu QY, Grant GM, et al. Functional ionotropic glutamate
73. Flint AC, Liu X, Kriegstein AR. Nonsynaptic glycine receptor acti- receptors emerge during terminal cell division and early neuronal
vation during early neocortical development. Neuron. 1998;20: differentiation of rat neuroepithelial cells. J Neurosci Res. 2000;
43–53. 61:652–662.
74. Aprison MH, Shank RP, Davidoff RA. A comparison of the con- 96. Steinhauser C, Gallo V. News on glutamate receptors in glial cells.
centration of glycine, a transmitter suspect, in different areas of the Trends Neurosci. 1996;19:339–345.
brain and spinal cord in seven different vertebrates. Comp Biochem 97. Luk KC, Kennedy TE, Sadikot AF. Glutamate promotes proliferation
Physiol. 1969;28:1345–1355. of striatal neuronal progenitors by an NMDA receptor-mediated
75. Court JA, Lloyd S, Johnson M, et al. Nicotinic and muscarinic choli- mechanism. J Neurosci. 2003;23:2239–2250.
nergic receptor binding in the human hippocampal formation during 98. Cameron HA, Hazel TG, McKay RD. Regulation of neurogenesis by
development and aging. Brain Res Dev Brain Res. 1997;101:93–105. growth factors and neurotransmitters. J Neurobiol. 1998;36:287–306.
76. Paterson D, Nordberg A. Neuronal nicotinic receptors in the human 99. Cameron HA, McEwen BS, Gould E. Regulation of adult neuro-
brain. Prog Neurobiol. 2000;61:75–111. genesis by excitatory input and NMDA receptor activation in the
77. Naeff B, Schlumpf M, Lichtensteiger W. Pre- and postnatal develop- dentate gyrus. J Neurosci. 1995;15:4687–4692.
ment of high-affinity [3H]nicotine binding sites in rat brain regions: 100. Kato M, Dobyns WB. Lissencephaly and the molecular basis
an autoradiographic study. Brain Res Dev Brain Res. 1992;68: of neuronal migration. Hum Mol Genet. 2003;12(Spec No 1):
163–174. R89–R96.
78. Schuetze SM, Role LW. Developmental regulation of nicotinic acetyl- 101. Nadarajah B, Parnavelas JG. Modes of neuronal migration in the
choline receptors. Annu Rev Neurosci. 1987;10:403–457. developing cerebral cortex. Nat Rev Neurosci. 2002;3:423–432.
79. Winzer-Serhan UH, Leslie FM. Codistribution of nicotinic 102. Heng JI, Moonen G, Nguyen L. Neurotransmitters regulate cell
acetylcholine receptor subunit alpha3 and beta4 mRNAs during rat migration in the telencephalon. Eur J Neurosci. 2007;26:537–546.
brain development. J Comp Neurol. 1997;386:540–554. 103. Behar TN, Li YX, Tran HT, et al. GABA stimulates chemotaxis and
80. Zoli M, Le Novere N, Hill JAJ, Changeux JP. Developmental regula- chemokinesis of embryonic cortical neurons via calcium-dependent
tion of nicotinic ACh receptor subunit mRNAs in the rat central and mechanisms. J Neurosci. 1996;16:1808–1818.
peripheral nervous systems. J Neurosci. 1995;15: 1912-1939. 104. Behar TN, Schaffner AE, Scott CA, et al. Differential response of
81. Barnes NM, Sharp T. A review of central 5-HT receptors and their cortical plate and ventricular zone cells to GABA as a migration
function. Neuropharmacology. 1999;38:1083–1152. stimulus. J Neurosci. 1998;18:6378–6387.
82. Le Novere N, Changeux JP. LGICdb: the ligand-gated ion channel 105. Behar TN, Schaffner AE, Scott CA, et al. GABA receptor antagonists
database. Nucleic Acids Res. 2001;29:294–295. modulate postmitotic cell migration in slice cultures of embryonic
83. Derkach V, Surprenant A, North RA. 5-HT3 receptors are membrane rat cortex. Cereb Cortex. 2000;10:899–909.
ion channels. Nature. 1989;339:706–709. 106. Cuzon VC, Yeh PW, Cheng Q, Yeh HH. Ambient GABA promotes
84. Ronde P, Nichols RA. High calcium permeability of serotonin 5-HT3 cortical entry of tangentially migrating cells derived from the medial
receptors on presynaptic nerve terminals from rat striatum. ganglionic eminence. Cereb Cortex. 2006;16:1377–1388.
J Neurochem. 1998;70:1094–1103. 107. Manent JB, Demarque M, Jorquera I, et al. A noncanonical release
85. Lauder JM, Wallace JA, Krebs H. Roles for serotonin in neuroem- of GABA and glutamate modulates neuronal migration. J Neurosci.
bryogenesis. Adv Exp Med Biol. 1981;133: 477–506. 2005;25:4755–4765.
86. Tecott L, Shtrom S, Julius D. Expression of a serotonin-gated ion 108. Manent JB, Jorquera I, Ben-Ari Y, et al. Glutamate acting on AMPA
channel in embryonic neural and nonneural tissues. Mol Cell but not NMDA receptors modulates the migration of hippocampal
Neurosci. 1995;6:43–55. interneurons. J Neurosci. 2006;26:5901–5909.
87. Niesler B, Walstab J, Combrink S, et al. Characterization of the novel 109. Behar TN, Scott CA, Greene CL, et al. Glutamate acting at NMDA
human serotonin receptor subunits 5-HT3C,5-HT3D, and 5-HT3E. Mol receptors stimulates embryonic cortical neuronal migration.
Pharmacol. 2007;72:8–17. J Neurosci. 1999;19:4449–4461.
88. Ma W, Barker JL. Complementary expressions of transcripts encoding 110. Komuro H, Rakic P. Modulation of neuronal migration by NMDA
GAD67 and GABAA receptor alpha 4, beta 1, and gamma 1 subunits receptors, Science. 1993;260:95–97.
in the proliferative zone of the embryonic rat central nervous system. 111. McAllister AK. Cellular and molecular mechanisms of dendrite
J Neurosci. 1995;15:2547–2560. growth. Cereb Cortex. 2000;10:963–973.
112. Cline HT. Dendritic arbor development and synaptogenesis. Curr 135. Roerig B, Nelson DA, Katz LC. Fast synaptic signaling by nicotinic
Opin Neurobiol. 2001;11:118–126. acetylcholine and serotonin 5-HT3 receptors in developing visual
113. Wong RO, Ghosh A. Activity-dependent regulation of dendritic cortex. J Neurosci. 1997;17:8353–8362.
growth and patterning. Nat Rev Neurosci. 2002;3:803–812. 136. Roerig B, Katz LC. Modulation of intrinsic circuits by serotonin
114. Borodinsky LN, O’Leary D, Neale JH, et al. GABA-induced neurite 5-HT3 receptors in developing ferret visual cortex. J Neurosci. 1997;
outgrowth of cerebellar granule cells is mediated by GABA(A) re- 17:8324–8338.
ceptor activation, calcium influx and CaMKII and erk1/2 pathways. 137. Broide RS, Robertson RT, Leslie FM. Regulation of alpha7 nicotinic
J Neurochem. 2003;84:1411–1420. acetylcholine receptors in the developing rat somatosensory cortex
115. Furuya S, Tabata T, Mitoma J, et al. L-Serine and glycine serve as by thalamocortical afferents. J Neurosci. 1996;16:2956–2971.
major astroglia-derived trophic factors for cerebellar Purkinje 138. Aramakis VB, Metherate R. Nicotine selectively enhances NMDA
neurons. Proc Natl Acad Sci U S A. 2000;97:11528–11533. receptor–mediated synaptic transmission during postnatal develop-
116. Tapia JC, Mentis GZ, Navarrete R, et al. Early expression of glycine ment in sensory neocortex. J Neurosci. 1998;18:8485–8495.
and GABA(A) receptors in developing spinal cord neurons. Effects 139. Aramakis VB, Hsieh CY, Leslie FM, Metherate R. A critical period
on neurite outgrowth. Neuroscience. 2001;108:493–506. for nicotine-induced disruption of synaptic development in rat
117. Pearce IA, Cambray-Deakin MA, Burgoyne RD. Glutamate acting
auditory cortex. J Neurosci. 2000;20:6106–6116.
on NMDA receptors stimulates neurite outgrowth from cerebellar
140. Ikonomidou C, Bittigau P, Ishimaru MJ, et al. Ethanol-induced
granule cells. FEBS Lett. 1987;223:143–147.
apoptotic neurodegeneration and fetal alcohol syndrome. Science.
118. Wilson MT, Kisaalita WS, Keith CH. Glutamate-induced changes
2000;287:1056–1060.
in the pattern of hippocampal dendrite outgrowth: a role for
141. Albers GW, Goldberg MP, Choi DW. N-Methyl-D-aspartate antago-
calcium-dependent pathways and the microtubule cytoskeleton.
J Neurobiol. 2000;43:159–172. nists: ready for clinical trial in brain ischemia? Ann Neurol. 1989;
119. Metzger F, Wiese S, Sendtner M. Effect of glutamate on dendritic 25:398–403.
growth in embryonic rat motoneurons. J Neurosci. 1998;18:1735– 142. Bullock R. Strategies for neuroprotection with glutamate anta-
1742. gonists. Extrapolating from evidence taken from the first stroke and
120. Coronas V, Durand M, Chabot JG, et al. Acetylcholine induces head injury studies. Ann N Y Acad Sci. 1995;765:272–278; discus-
neuritic outgrowth in rat primary olfactory bulb cultures. Neuro- sion 298.
science. 2000;98:213–219. 143. Himmelseher S, Durieux ME. Revising a dogma: ketamine for
121. Owen A, Bird M. Acetylcholine as a regulator of neurite outgrowth patients with neurological injury? Anesth Analg. 2005;101:524–534,
and motility in cultured embryonic mouse spinal cord. Neuroreport. table of contents.
1995;6:2269–2272. 144. Olney JW, Labruyere J, Price MT. Pathological changes induced in
122. Homma K, Kitamura Y, Ogawa H, Oka K. Serotonin induces the cerebrocortical neurons by phencyclidine and related drugs. Science.
increase in intracellular Ca2+ that enhances neurite outgrowth in 1989;244:1360–1362.
PC12 cells via activation of 5-HT3 receptors and voltage-gated 145. Slikker WJ, Zou X, Hotchkiss CE, et al. Ketamine-induced neuronal
calcium channels. J Neurosci Res. 2006;84:316–325. cell death in the perinatal rhesus monkey. Toxicol Sci. 2007;98:
123. Miller M. Maturation of rat visual cortex. I. A quantitative study 145–158.
of Golgi-impregnated pyramidal neurons. J Neurocytol. 1981;10: 146. Hayashi H, Dikkes P, Soriano SG. Repeated administration of
859–878. ketamine may lead to neuronal degeneration in the developing rat
124. Miller M, Peters A. Maturation of rat visual cortex. II. A combined brain. Paediatr Anaesth. 2002;12:770–774.
Golgi-electron microscope study of pyramidal neurons. J Comp 147. Scallet AC, Schmued LC, Slikker W Jr, et al. Developmental
Neurol. 1981;203:555–573. neurotoxicity of ketamine: morphometric confirmation, exposure
125. Hensch TK. Critical period regulation. Annu Rev Neurosci. 2004; parameters, and multiple fluorescent labeling of apoptotic neurons.
27:549–579. Toxicol Sci. 2004;81:364–370.
126. Hensch TK. Critical period plasticity in local cortical circuits. Nat 148. Young C, Jevtovic-Todorovic V, Qin YQ, et al. Potential of ketamine
Rev Neurosci. 2005;6:877–888. and midazolam, individually or in combination, to induce apoptotic
127. Olney JW. New insights and new issues in developmental neurodegeneration in the infant mouse brain. Br J Pharmacol.
neurotoxicology. Neurotoxicology. 2002;23:659–668. 2005;146:189–197.
128. Olney JW, Sharpe LG. Brain lesions in an infant Rhesus monkey 149. Gascon E, Vutskits L, Zhang H, et al. Z. Sequential activation of p75
treated with monsodium glutamate. Science. 1969;166:386–388.
and TrkB is involved in dendritic development of subventricular
129. Ikonomidou C, Bosch F, Miksa M, et al. Blockade of NMDA recep-
zone-derived neuronal progenitors in vitro. Eur J Neurosci.
tors and apoptotic neurodegeneration in the developing brain.
2005;21:69–80.
Science. 1999;283:70–74.
150. Malinovsky JM, Servin F, Cozian A, et al. Ketamine and norketa-
130. Asada H, Kawamura Y, Maruyama K, et al. Cleft palate and de-
creased brain gamma-aminobutyric acid in mice lacking the 67-kDa mine plasma concentrations after i.v., nasal and rectal adminis-
isoform of glutamic acid decarboxylase. Proc Natl Acad Sci U S A. tration in children. Br J Anaesth. 1996;77:203–207.
1997;94:6496–6499. 151. Weber F, Wulf H, Gruber M, Biallas R. S-Setamine and S-
131. Hensch TK, Fagiolini M, Mataga N, et al. Local GABA circuit norketamine plasma concentrations after nasal and i.v. administra-
control of experience-dependent plasticity in developing visual tion in anesthetized children. Paediatr Anaesth. 2004;14:983–988.
cortex. Science. 1998;282:1504–1508. 152. Vutskits L, Gascon E, Tassonyi E, Kiss JZ. Effect of ketamine on
132. Adams SM, de Rivero Vaccari JC, Corriveau RA. Pronounced cell dendritic arbor development and survival of immature GABAergic
death in the absence of NMDA receptors in the developing neurons in vitro. Toxicol Sci. 2006;91:540–549.
somatosensory thalamus. J Neurosci. 2004;24:9441–9450. 153. Takadera T, Ishida A, Ohyashiki T. Ketamine-induced apoptosis in
133. Li Y, Erzurumlu RS, Chen C, et al. Whisker-related neuronal cultured rat cortical neurons. Toxicol Appl Pharmacol. 2006;210:
patterns fail to develop in the trigeminal brainstem nuclei of 100–107.
NMDAR1 knockout mice. Cell. 1994;76:427–437. 154. Linseman DA, Butts BD, Precht TA, et al. Glycogen synthase
134. Iwasato T, Datwani A, Wolf AM, et al. Cortex-restricted disruption kinase-3beta phosphorylates Bax and promotes its mitochondrial
of NMDAR1 impairs neuronal patterns in the barrel cortex. Nature. localization during neuronal apoptosis, J Neurosci. 2004;24: 9993–
2000;406:726–731. 10002.
155. Nixon K, Hughes PD, Amsel A, Leslie SW. NMDA receptor subunit 176. Levin ED, Uemura E, Bowman RE. Neurobehavioral toxicology of
expression following early postnatal exposure to ethanol. Brain Res halothane in rats. Neurotoxicol Teratol. 1991;13:461–470.
Dev Brain Res. 2002;139:295–299. 177. Wise-Faberowski L, Zhang H, Ing R, et al. Isoflurane-induced
156. Nixon K, Hughes PD, Amsel A, Leslie SW. NMDA receptor subunit neuronal degeneration: an evaluation in organotypic hippocampal
expression after combined prenatal and postnatal exposure to slice cultures. Anesth Analg. 2005;101:651–657.
ethanol. Alcohol Clin Exp Res. 2004;28:105–112. 178. Li Y, Liang G, Wang S, et al. Effects of fetal exposure to isoflurane on
157. Li JH, Wang YH, Wolfe BB, et al. Developmental changes in locali- postnatal memory and learning in rats. Neuropharmacology. 2007;
zation of NMDA receptor subunits in primary cultures of cortical 53:942–950.
neurons. Eur J Neurosci. 1998;10:1704–1715. 179. Johnson SA, Young C, Olney JW. Isoflurane-induced neuroapop-
158. Keilhoff G, Bernstein HG, Becker A, et al. Increased neurogenesis tosis in the developing brain of nonhypoglycemic mice. J Neurosurg
in a rat ketamine model of schizophrenia. Biol Psychiatry. 2004; Anesthesiol. 2008;20:21–28.
56:317–322. 180. Stratmann G, Bouchra H, Arora K, et al. Isoflurane increases stem
159. Bjornstrom K, Sjolander A, Schippert A, Eintrei C. A tyrosine kinase cell proliferation in adult but not in neonatal rat hippocampi. Soc
regulates propofol-induced modulation of the beta-subunit of the Neurosci Abst. 2005;826:829.
GABA(A) receptor and release of intracellular calcium in cortical 181. Mullenix PJ, Moore PA, Tassinari MS. Behavioral toxicity of nitrous
rat neurones. Acta Physiol Scand. 2002;175:227–235. oxide in rats following prenatal exposure. Toxicol Ind Health. 1986;
160. Honegger P, Matthieu JM. Selective toxicity of the general anesthetic 2:273–287.
propofol for GABAergic neurons in rat brain cell cultures. J Neurosci 182. Jevtovic-Todorovic V, Benshoff N, Olney JW. Ketamine potentiates
Res. 1996;45:631–636. cerebrocortical damage induced by the common anaesthetic agent
161. Al-Jahdari WS, Saito S, Nakano T, Goto F. Propofol induces growth nitrous oxide in adult rats. Br J Pharmacol. 2000;130:1692–1698.
cone collapse and neurite retractions in chick explant culture. Can 183. Milligan G. Opioid receptors and their interacting proteins.
J Anaesth. 2006;53:1078–1085. Neuromolecular Med. 2005;7:51–59.
162. Vutskits L, Gascon E, Tassonyi E, Kiss JZ. Clinically relevant con- 184. Tegeder I, Geisslinger G. Opioids as modulators of cell death and
centrations of propofol but not midazolam alter in vitro dendritic survival—unraveling mechanisms and revealing new indications.
development of isolated gamma-aminobutyric acid-positive inter- Pharmacol Rev. 2004;56:351–369.
neurons. Anesthesiology. 2005;102:970–976. 185. Zhu Y, Hsu MS, Pintar JE. Developmental expression of the mu,
163. Fredriksson A, Ponten E, Gordh T, Eriksson P. Neonatal exposure to kappa, and delta opioid receptor mRNAs in mouse. J Neurosci.
a combination of N-methyl-D-aspartate and gamma-aminobutyric 1998;18:2538–2549.
acid type A receptor anesthetic agents potentiates apoptotic neuro- 186. Georges F, Normand E, Bloch B, Le Moine C. Opioid receptor gene
degeneration and persistent behavioral deficits. Anesthesiology. expression in the rat brain during ontogeny, with special reference
2007;107:427–436. to the mesostriatal system: an in situ hybridization study. Brain Res
164. Rudolph U, Antkowiak B. Molecular and neuronal substrates for Dev Brain Res. 1998;109:187–199.
general anaesthetics. Nat Rev Neurosci. 2004;5:709–720. 187. Zagon IS, McLaughlin PJ. Morphine and brain growth retardation
165. Fiszman ML, Behar T, Lange GD, et al. GABAergic cells and signals in the rat. Pharmacology. 1977;15:276–282.
appear together in the early post-mitotic period of telencephalic and 188. Ford DH, Rhines RK. Prenatal exposure to methadone HCl in
striatal development. Brain Res Dev Brain Res. 1993;73:243–251. relationship to body and brain growth in the rat. Acta Neurol Scand.
166. Lauder JM, Han VK, Henderson P, et al. Prenatal ontogeny of the 1979;59:248–262.
GABAergic system in the rat brain: an immunocytochemical study. 189. Hammer RPJ, Ricalde AA, Seatriz JV. Effects of opiates on brain
Neuroscience. 1986;19:465–493. development. Neurotoxicology. 1989;10:475–483.
167. Kellogg C, Tervo D, Ison J, et al. Prenatal exposure to diazepam 190. Ricalde AA, Hammer RPJ. Perinatal opiate treatment delays growth
alters behavioral development in rats. Science. 1980;207:205–207. of cortical dendrites. Neurosci Lett. 1990;115:137–143.
168. Kellogg CK, Simmons RD, Miller RK, Ison JR. Prenatal diazepam 191. Seatriz JV, Hammer RPJ. Effects of opiates on neuronal development
exposure in rats: long-lasting functional changes in the offspring. in the rat cerebral cortex. Brain Res Bull. 1993;30:523–527.
Neurobehav Toxicol Teratol. 1985;7:483–488. 192. Zagon IS, McLaughlin PJ, Thompson CI. Development of motor
169. Simmons RD, Miller RK, Kellogg CK. Prenatal exposure to activity in young rats following perinatal methadone exposure.
diazepam alters central and peripheral responses to stress in adult Pharmacol Biochem Behav. 1979;10:743–749.
rat offspring. Brain Res. 1984;307:39–46. 193. Zagon IS, McLaughlin PJ, Thompson CI. Learning ability in adult
170. Roberts AA, Pleger GL, Kellogg CK. Effect of prenatal exposure to female rats perinatally exposed to methadone. Pharmacol Biochem
diazepam on brain GABA(A) receptor mRNA levels in rats exa- Behav. 1979;10:889–894.
mined at late fetal or adult ages. Dev Neurosci. 2001;23:135–144. 194. Zagon IS, McLaughlin PJ. Increased brain size and cellular content
171. Raol YH, Zhang G, Budreck EC, Brooks-Kayal AR. Long-term in infant rats treated with an opiate antagonist. Science. 1983;221:
effects of diazepam and phenobarbital treatment during develop- 1179–1180.
ment on GABA receptors, transporters and glutamic acid decar- 195. Reznikov K, Hauser KF, Nazarevskaja G, et al. Opioids modulate
boxylase. Neuroscience. 2005;132, 399–407. cell division in the germinal zone of the late embryonic neocortex.
172. Martire M, Altobelli D, Cannizzaro C, et al. Prenatal diazepam Eur J Neurosci. 1999;11:2711–2719.
exposure functionally alters the GABA(A) receptor that modulates 196. Hauser KF, Houdi AA, Turbek CS, et al. Opioids intrinsically inhibit
[3H]noradrenaline release from rat hippocampal synaptosomes. the genesis of mouse cerebellar granule neuron precursors in vitro:
Dev Neurosci. 2002;24” 71–78. differential impact of mu and delta receptor activation on proli-
173. Rudin M, Ben-Abraham R, Gazit V, et al. Single-dose ketamine feration and neurite elongation. Eur J Neurosci. 2000;12:1281–1293.
administration induces apoptosis in neonatal mouse brain. J Basic 197. Knapp PE, Maderspach K, Hauser KF. Endogenous opioid system in
Clin Physiol Pharmacol. 2005;16:231–243. developing normal and jimpy oligodendrocytes: mu and kappa
174. Bittigau P, Sifringer M, Genz K, et al. Antiepileptic drugs and ap- opioid receptors mediate differential mitogenic and growth
optotic neurodegeneration in the developing brain. Proc Natl Acad responses. Glia. 1998;22:189–201.
Sci U S A. 2002;99:15089–15094. 198. Sargeant T.J, Day DJ, Mrkusich EM, et al. Mu opioid receptors are
175. Uemura E, Levin ED, Bowman RE. Effects of halothane on synapto- expressed on radial glia but not migrating neuroblasts in the late
genesis and learning behavior in rats. Exp Neurol. 1985;89:520–529. embryonic mouse brain. Brain Res. 2007;1175:28–38.
199. Grimm MC, Ben-Baruch A, Taub DD, et al. Opiate inhibition of 222. Anand KJ, Garg S, Rovnaghi CR, et al. Ketamine reduces the cell
chemokine-induced chemotaxis. Ann N Y Acad Sci. 1998;840:9–20. death following inflammatory pain in newborn rat brai. Pediatr Res.
200. Takayama N, Ueda H. Morphine-induced chemotaxis and brain- 2007;62:283–290.
derived neurotrophic factor expression in microglia. J Neurosci. 223. Olney JW, Young C, Wozniak DF, et al. Anesthesia-induced develop-
2005;25:430–435. mental neuroapoptosis. Does it happen in humans? Anesthesiology.
201. Hauser KF, McLaughlin PJ, Zagon IS. Endogenous opioids regulate 2004;101: 273–275.
dendritic growth and spine formation in developing rat brain. Brain 224. Dobbing J. Undernutrition and the developing brain. The relevance
Res. 1987;416:157–161. of animal models to the human problem. Am J Dis Child. 1970;
202. Hauser KF, McLaughlin PJ, Zagon IS. Endogenous opioid systems 120:411–415.
and the regulation of dendritic growth and spine formation. J Comp 225. Lucas A, Morley R, Cole TJ. Randomised trial of early diet
Neurol. 1989;281:13–22. in preterm babies and later intelligence quotient. BMJ. 1998;317:
203. Tenconi B, Lesma E, DiGiulio AM, Gorio A. High opioid doses 1481–1487.
inhibit whereas low doses enhance neuritogenesis in PC12 cells. 226. Chacko J, Ford WD, Haslam R. Growth and neurodevelopmental
Brain Res Dev Brain Res. 1996;94:175–181. outcome in extremely-low-birth-weight infants after laparotomy.
204. Brailoiu E, Hoard J, Brailoiu GC, et al. Ultra low concentrations of Pediatr Surg Int. 1999;15:496–499.
morphine increase neurite outgrowth in cultured rat spinal cord and 227. Ludman L, Spitz L, Lansdown R. Developmental progress of
cerebral cortical neurons. Neurosci Lett. 2004;365:10–13. newborns undergoing neonatal surgery. J Pediatr Surg. 1990;25:
205. Sakaguchi M, Fujimori T, Satoh T, et al. Effects of opioids on 469–471.
neuronal survival in culture of embryonic chick dorsal root ganglion 228. Ludman L, Spitz L, Wade A. Educational attainments in early
neurons. Neurosci Lett. 1999;262:17–20. adolescence of infants who required major neonatal surgery.
206. Kofke WA, Garman RH, Stiller RL, et al. Opioid neurotoxicity: J Pediatr Surg. 2001;36:858–862.
fentanyl dose-response effects in rats. Anesth Analg. 1996;83:1298– 229. Bouman NH, Koot HM, Hazebroek FW. Long-term physical,
1306. psychological, and social functioning of children with esophageal
207. Kofke WA, Garman RH, Garman R, Rose M. Opioid neurotoxicity: atresia. J Pediatr Surg. 1999;34:399–404.
role of neurotransmitter systems. Neurol Res. 2000;22:733–737. 230. Bouman NH, Koot HM, Tibboel D, Hazebroek FW. Children with
208. Mellon RD, Simone AF, Rappaport BA. Use of anesthetic agents in congenital diaphragmatic hernia are at risk for lower levels of
neonates and young children. Anesth Analg. 2007;104:509–520. cognitive functioning and increased emotional and behavioral
209. Jevtovic-Todorovic V, Hartman RE, Izumi Y, et al. Early exposure problems. Eur J Pediatr Surg. 2000;10:3–7.
to common anesthetic agents causes widespread neurodegeneration 231. Kabra NS, Schmidt B, Roberts RS, et al. Neurosensory impair-
in the developing rat brain and persistent learning deficits. ment after surgical closure of patent ductus arteriosus in extre-
J Neurosci. 2003;23:876–882. mely low birth weight infants: results from the Trial of
210. Lu LX, Yon JH, Carter LB, Jevtovic-Todorovic V. General anesthesia Indomethacin Prophylaxis in Preterms. J Pediatr. 2007;150:229–234,
activates BDNF-dependent neuroapoptosis in the developing rat 234.e1.
brain. Apoptosis. 2006;11:1603–1615. 232. Davidson A, McCann ME, Morton N. Anesthesia neurotoxicity
211. Teng KK, Hempstead BL. Neurotrophins and their receptors: in neonates: the need for clinical research. Anesth Analg. 2007;105:
signaling trios in complex biological systems. Cell Mol Life Sci. 881–882.
2004;61:35–48. 233. Anand KJ, Sippell WG, Aynsley-Green A. Randomised trial of
212. Yon JH, Carter LB, Reiter RJ, Jevtovic-Todorovic V. Melatonin fentanyl anaesthesia in preterm babies undergoing surgery: effects
reduces the severity of anesthesia-induced apoptotic neurode- on the stress response. Lancet. 1987;1:62–66.
generation in the developing rat brain. Neurobiol Dis. 2006;21: 234. Anand KJ, Sippell WG, Schofield NM, Aynsley-Green A. Does
522–530. halothane anaesthesia decrease the metabolic and endocrine stress
213. Zou X, Sadovova N, Patterson TA, et al. The effects of l-carnitine responses of newborn infants undergoing operation? Br Med J (Clin
on the combination of, inhalation anesthetic-induced develop- Res Ed). 1988;296:668–672.
mental, neuronal apoptosis in the rat frontal cortex. Neuroscience. 235. Anand KJ, Hickey PR. Halothane-morphine compared with high-
2008;151:1053–1065. dose sufentanil for anesthesia and postoperative analgesia in
214. Ma D, Williamson P, Januszewski A, et al. Xenon mitigates neonatal cardiac surgery. N Engl J Med. 1992;326:1–9.
isoflurane-induced neuronal apoptosis in the developing rodent 236. Peters JW, Schouw R, Anand KJ, et al. Does neonatal surgery lead
brain. Anesthesiology. 2007;106:746–753. to increased pain sensitivity in later childhood? Pain. 2005;114:
215. Berde C, Cairns B. Developmental pharmacology across species: 444–454.
promise and problems. Anesth Analg. 2000;91:1–5. 237. Botting N, Powls A, Cooke RW, Marlow N. Attention deficit hyper-
216. Rizzi S, Carter LB, Ori C, Jevtovic-Todorovic V. Clinical anesthesia activity disorders and other psychiatric outcomes in very low
causes permanent damage to the fetal guinea pig brain. Brain Pathol. birthweight children at 12 years. J Child Psychol Psychiatry. 1997;38:
2008;18:198–210. 931–941.
217. Anand KJ, Soriano SG. Anesthetic agents and the immature 238. Whitfield MF, Grunau RE. Behavior, pain perception, and the
brain: are these toxic or therapeutic? Anesthesiology. 2004;101: extremely low-birth weight survivor. Clin Perinatol. 2000;27:
527–530. 363–379.
218. Roytblat L, Talmor D, Rachinsky M, et al. Ketamine attenuates the 239. Coplan JD, Andrews MW, Rosenblum LA, et al. Persistent elevations
interleukin-6 response after cardiopulmonary bypass. Anesth Analg. of cerebrospinal fluid concentrations of corticotropin-releasing
1998;87:266–271. factor in adult nonhuman primates exposed to early-life stressors:
219. Zilberstein G, Levy R, Rachinsky M, et al. Ketamine attenuates implications for the pathophysiology of mood and anxiety disorders.
neutrophil activation after cardiopulmonary bypass. Anesth Analg. Proc Natl Acad Sci U S A. 1996;93:1619–1623.
2002;95:531–536, table of contents. 240. Jacobson B, Bygdeman M. Obstetric care and proneness of offspring
220. Lipton SA, Nakanishi N. Shakespeare in love—with NMDA to suicide as adults: case-control study. BMJ. 1998;317:1346–1349.
receptors? Nat Med. 1999;5:270–271. 241. Salk L, Lipsitt LP, Sturner WQ, et al. Relationship of maternal and
221. Bhutta AT, Anand KJ. Vulnerability of the developing brain. perinatal conditions to eventual adolescent suicide. Lancet.
Neuronal mechanisms. Clin Perinatol. 2002;29:357–372. 1985;1:624–627.
Nociception and Pain Perception

in Infants and Children 4
Suzanne Wiener and Joseph D. Tobias C H A P T E R
INTRODUCTION specific receptors, transduction, peripheral sensitization, phenoty-

pic switches, transmission, ascending projections, supraspinal
The study of pediatric pain from the underlying neurobiologic centers, and the descending modulation systems. In addition
mechanisms to its effective management has grown since the early to the complex nervous pathways involved in nociception, the
1990s into an extremely active and important field. A crucial sensing of pain, which occurs only after the integration of the
change has been the realization that infants experience pain and noxious message into supraspinal centers, can be affected by
demonstrate dramatic and robust pain behaviors. Before that numerous factors. These include psychological factors (sex,
realization, there was the misconception that the immaturity of age, cognitive level, previous pain experiences, family learning,
the central and peripheral nervous systems was such that infants culture), situational factors (expectations, control, relevance), and
did not feel pain, and consequently, analgesia for painful inter- emotional factors (fear, anger, frustration). Furthermore, this
ventions was unnecessary. However, it is now fully accepted not chapter reviews how chronic pain syndromes develop and how
only that infants are capable of experiencing pain but that there painful procedures, at an early age, can have deleterious long-term
are potential acute and long-term adverse effects from the under- consequences.
treatment of pain.1
Pain sensation involves a multilayered network of nociceptors,
nerve fibers, neurons, and glial cells distributed in multiple THE NOCICEPTIVE PATHWAY
peripheral, spinal, and supraspinal areas, forming diverse feedback
and feed-forward loops. The participation, function, and neuro- Nociceptors
chemical profiles of these cellular elements are constantly modi- A nociceptor is a sensory receptor that sends signals that cause the
fied by external and internal cues.2,3 Signaling of pain at any stage perception of pain in response to potentially damaging stimulus.
of development depends not only on the context and characteris- These receptors are found in any area of the body that can sense
tics of the painful stimulus but also on the behavioral state and pain either externally (skin, cornea, mucosa) or internally (mus-
cognitive demands at that time.2 cles, joint, bladder, gut, digestive tract). They have four major
Current pain research shows that the neonate or infant is not a functional components (Figure 4–1): (1) the peripheral terminal
merely a “little adult.” Structures and mechanisms used for pain that transduces external stimuli and initiates action potentials;
processing during early development are unique and different (2) the axon that conducts action potentials; (3) the cell body that
from those used in adult pain processing. Many of these structures controls the identity and integrity of the neuron, and (4) the
or mechanisms are not maintained beyond specific periods of central terminal that forms the presynaptic element of the first
early development.4,5 Thus, the immature pain system plays a synapse in the sensory pathway in the central nervous system
signaling role during each stage of development and uses neural (CNS).7 The cell bodies of the first-order neurons are located in
elements available at that time to fulfill this role.6 This plasticity of either the dorsal root ganglia (DRGs) or the trigeminal ganglia.
the developing nervous system may allow for the greatest impact The trigeminal ganglia are specialized nerves for the face, whereas
of pain to occur in the most premature infants.5 the dorsal root ganglia are associated with the rest of the body.
To better understand the tremendous impact of pain on the Nociceptors are silent receptors and do not sense normal stimuli.
developing nervous system and its pervasive long-term effects, we Only when activated by a threatening response (high-threshold
review the uniqueness of the nocioceptive pathway including receptors) do they invoke a reflex.
Figure 4-1. Operational components of the nocioceptor including the peripheral terminal that innervates the tissue,
the axon that conducts the impulse toward the central nervous system, the cell body that lies in the dorsal root gan-
glia, and a central terminal that conducts information to the synapse with the second-order neuron.
CHAPTER 4 ■ Nociception and Pain Perception in Infants and Children 59
Nociceptors develop from neural crest stem cells. The neural is the C fiber axon, which has slower conduction because of the
crest is responsible for a large part of the early development in light or nonmyelination of the axon. Therefore, pain comes in two
vertebrates and, more specifically, for neuronal development. The phases. The first phase (“first, sharp pain”) is mediated by the fast-
neural crest stem cells form the neural tube, and nociceptors grow conducting Aδ fibers and the second (“second, dull pain”) by
from the dorsal part of this tube in a rostrocaudal progression. C fibers. If there is massive, repetitive, or prolonged input to a
They form late during neurogenesis when compared with C fiber, there is progressive buildup in the spinal cord dorsal horn.
proprioceptors (Aα) or low-threshold mechanoreceptors (Aβ), This phenomenon is called wind-up, which may increase sensiti-
which form during the early stages of gestation.5,8 These are non– vity to pain.14
pain-sensing receptors, so the development of nociceptors late in
neurogenesis allows for their different sensing capabilities. All
embryonic nociceptors express the TrkA nerve growth factor Transduction
(NGF) receptor.8 The formation of most TrkA+ neurons is de- Transduction is the first stage of the nociceptive pathway and
pendent on the proneural transcripition factor neurogenin 1 involves the process of converting a noxious or painful stimulus,
(Ngn1). The homebox gene Brn3a and the zinc finger gene Klf7 which can be mechanical, thermal, or chemical, into a nervous
are required for maintenance of TrkA expression. However, these impulse. Specific nociceptor transducers are responsible for how
transcription factors are not specific for nociceptors.9–11 Following and whether the specific nerve ending responds to stimulus.
sensory neurogenesis, differentiation occurs and two different
Members of the TRP channel family (transient receptor potential;
types of nociceptors are formed. They are classified as either
cation channels; TRPV1, TRPV2, TRPV3, TRPV4),15 all expres-
peptidergic or nonpeptidergic nociceptors. These two sets of re-
sing a particular C-terminal domain, detect noxious heat.16 The
ceptors express distinct ion channels and receptors. This specia-
extent to which all of these TRPs are involved in heat-responsive
lization allows the receptors to innervate different peripheral and
nociceptor neurons remains uncertain. Heat-evoked activity in
central targets. This differentiation occurs in both the perinatal
nociceptors may also be modulated by co-expression of heat-
and the postnatal periods.
sensitive potassium channels like TREK-1, whose activity is re-
Early embryonic nociceptors share similar molecular identity,
duced by increased heat. Cool stimuli are sensed by the TRPM8
co-expressing both TrkA and Runx1.11 The nonpeptidergic
nociceptors switch off the TrkA NGF and begin expressing Ret. channel, whereas the molecular transducers for noxious cold
Ret is a transmembrane signaling component that allows for the remain unclear, perhaps involving TRPM8, TRPA1, and others.
expression of another growth factor, the glial cell–derived growth Interestingly, although tactile sensibility and motor function
factor (GDNF). Most of these neurons bind isolectin B4 (IB4). deteriorate in the cold, pain perception persists. This is achieved
This transition is assisted by Runx1, which has proved to be vital by expression in nociceptor peripheral terminals of the TTX-R
in the development of nonpeptidergic nociceptors and in the Nav 1.8 voltage-gated sodium channel (VGSC), whose inactiva-
coordination of afferent targeting to the spinal cord. The signals tion, unlike TTX-S channels, is cold resistant.17 The ENaC/DEG
that trigger Runx1 down-regulation in the peptidergic neurons channel family (degenerin/epithelial sodium channel) detects
remain unclear. The peptidergic nociceptors continue to use TrkA, mechanical stimuli. Although there are several candidates for the
after the loss of Runx1 in the DRGs. They express a completely high-threshold (pinch) mechanotransducers, as of today, all of
different type of growth factor (calcitonin gene–related peptide those appear to be invalid. These include TRPs (TRPA1), ASICs,
[CGRP], Substance P [SP])11,12 and they do not bind IB4. Ongoing and potassium channels.18 Noxious chemicals, such as capsaicin
research is attempting to determine more specifically what creates or acid (extracellular protons, spider toxins), may be detected
the differences between these nociceptors.7 through a common transducer (TRPV1). TRPV1 appears to be a
Nociceptors sensory channels/receptors can be divided into major intergrator of diverse chemical (wasabie, mustard, raw
Runx1-dependent and Runx1-independent subgroups. Runx1- garlic, bradykinin) and perhaps even of thermal and mechanical
dependent genes are further divided into three groups: (1) Ret- noxious stimuli.19,20
dependent, (2) Ret-independent and TrkA-dependent, and A single type of stimulus can interact with multiple detectors,
(3) Ret-independent and TrkA-independent.13–14 Runx1 is selec- as seen by the ability of extracellular protons to activate not only
tively required for thermal, but not mechanical pain sensitivity in TRPV1, but also ASICs, which are also members of the ENaC/
vivo, supporting the idea that development of nociceptive mecha- DEG channel family.21 Furthermore, some nociceptors have quite
nical and thermal sensitivity is subject to separate genetic control. low thresholds with maximal responses in the noxious range
The sensory specificity of nociceptors is established by their (TRPV3-4); others have thresholds so high that they do not
high threshold to particular stimuli. Only when the high threshold normally respond to noninjurious stimuli (TRPV2) and are called
has been reached by either chemical, thermal, or mechanical sleeping or silent nociceptors because they wake and become res-
stimuli are the nociceptors triggered. The majority of nociceptors ponsive only in the presence of inflammation.7 Thus, transduction
are classified by the type of stimulus to which they respond. Some is mediated by high-threshold transducer ion channels that
nociceptors respond to more than one stimulus and are conse- depolarize the peripheral terminal activating voltage-dependent
quently designated polymodal nociceptors. Other nociceptors re- sodium channels.
spond to none of these modalities and yet may respond to Mutations in the NGF TrkA receptor that result in a failure of
stimulation under conditions of inflammation after tissue damage nociceptor survival in the embryo22 lead to loss of nociceptor
or after sensitization. This latter group is known as sleeping or neurons in patients with hereditary sensory and autonomic
silent nociceptors. neuropathy type 4, producing congenital pain hyposensitivity.
Nociceptors have two different types of axons. The first are the A congenital indifference to pain without loss of nociceptor
Aδ fiber axons. They are myelinated and allow a fast action neurons has been shown recently to occur with loss of functional
potential to be carried to the spinal cord and CNS. The other type mutations in the SCN9A gene encoding the alpha subunit of
Nav 1.7 VGSC.23,24 These two examples of mutations reveal the from the periphery appears to be a major means whereby nocicep-
crucial importance of nociceptors as a warning device. tor cell bodies change in response to peripheral inflammation.
Inflammation tends to cause an increase in the expression of spe-
cific nociceptive ion channels/receptors. The underlying transcrip-
Peripheral Sensitization tional mechanisms are unclear and may involve axonal transport
Peripheral sensitization represents a form of stimulus-evoked of transcripts and local translation.7
functional plasticity of the nociceptor. The stimulus is the sus- If the peripheral axon of nociceptors is severely injured, dis-
tained presence of inflammatory mediators released from injured rupting contact of the cell body with its terminal and its peripheral
and inflammatory cells that sensitize the nociceptor, reducing the target, profound changes in transcription are induced. Negative
threshold and increasing the responsiveness (primary hyperal- signals such as a loss of target-derived growth factors and positive
gesia). The peripheral nociceptive hyperexcitability is induced signals like retrograde protein kinase G or a vimentin-dependent
through increased receptor (autosensitization) or cell membrane translocation of activated ERK drive activation of multiple signal-
(heterosensitization) reactivity to stimuli. As a result of the change transduction pathways in the cell body that alter transcription in
in the chemical milieu produced by the disruption of cells, deg- more than 1000 genes. These molecular reactions are attempts
ranulation of mast cells, secretion by inflammatory cells, and either by the neuron to survive the major insult or for the axon to
induction of enzymes like cycloxygenase-2 (COX-2), nociceptors regrow. However, many axotomy-induced transcriptional changes
are no longer exclusively noxious stimuli detectors. They also are maladaptive and produce alterations in function that can result
become detectors of innocuous inputs. Thus, low-intensity stimuli in neuropathic pain. Injured neurons lose some normal nociceptor
gain access to the nociceptive pathway and begin to produce pain. features (a down-regulation of TRP and sodium channels),
Various sensitizers (kinins, amines, prostanoids, growth factors, although at the same time gaining a new molecular identity. One
chemokines, cytokines) combined with protons and adenosine example of this is the up-regulation in DRG neurons of enzymes
triphosphate (ATP), forming an “inflammatory soup,” are detected involved in the synthesis and recycling of tetrahydrobiopterin
by the nociceptor terminal and, as a result, change the properties (BH4) after peripheral axonal injury. BH4 is an essential cofactor
of the transducer and sodium channels, mainly as a result of for aromatic amine hydroxylases and nitric oxide synthetases. Its
phosphorylation. Transducer channel activity is, thus, heightened increase drives NO production in DRG neurons, which in turn
by the diverse inflammatory agents that bind to their cell-surface increases calcium influx in the neurons. Inhibition of BH4 syn-
receptors to stimulate phospholipase C (PLC-γ or PLC-β) signaling thesis produces analgesia, whereas increased synthesis of BH4
pathways. This, in turn, leads to hydrolysis of plasma membrane produces painlike behavior. A human variant of the rate-limiting
lipids and the subsequent stimulation of protein kinase C subforms enzyme in the BH4 pathway (guanosine triphosphate [GTP]
cyclohydrolase, which produces less BH4 in response to stress or
(PKC-ε). Both of these actions have been proposed to potentiate
injury), is associated with decreased chronic pain in patients after
TRPV1 receptor function. Prostaglandins (PGE2) and other in-
surgery. Although changes in the injured DRG neurons show a
flammatory products that activate adenylyl cyclase (AC) through
major phenotypic shift, alterations are also seen in their spared,
G-coupled receptors also enhance nociceptor excitability. This
noninjured neighbors. These cells may also be involved in the
occurs, in part, by cyclic adenosine monophosphate–dependent
genesis of chronic pain.
protein kinase (cAMP-PKA)–dependent phosphorylation of Na,
1.8, and/or 1.9. Furthermore, substance P and CGRP dilate blood
vessels, increasing the local inflammatory response and contri- Presynaptic Terminal and Transmission
buting to peripheral sensitization. Several new products have also
been identified as peripheral sensitizers including the transforming Stimuli from the periphery are transmitted to the spinal cord
growth factor-β (TGF-β) member activin,25 TNFα,26 the chemo- through the sensory afferent nerves (Figure 4–2). Afferent
kine CCL3,27 prokineticins,28 proteases that activate protease- nociceptive fibers travel back to the spinal cord where they form
activated GPCR receptors,29,30 and GDNF.31 synapses in its superficial dorsal horn (gray matter) for somatic
From multiple knockout studies, it has been shown that both neurons and in the spinal nucleus of the trigeminal nerve for those
neurons innervating the face. The nociceptive fiber located in the
TRPV1 and TRPA1 contribute to peripheral sensitization as do
periphery is known as a first-order neuron. The first-order neuron
the VGSCs, Nav1.8, Nav1.7, and Nav1.9. TRP receptor antago-
carries the sensory input to the dorsal horn of the spinal cord
nists and sodium channel selective blockers may be a useful
where they synapse with second-order neurons. This synapse
approach for reducing peripheral sensitization and thereby inflam- transfers information carried by action potentials regarding the
matory pain.32 intensity and duration of the peripheral noxious stimuli. The
rostrocaudal and mediolateral topography of the central terminal
Phenotypic Switches reflects the spatial location of the peripheral nociceptor, whereas
their dorsoventral location reflects the identity of the nociceptor.
In addition to driving peripheral sensitization, peripheral inflam- Thus, they evoke fast and slow excitatory postsynaptic potentials
mation produces retrograde signals in nociceptor neurons that that exhibit significant spatial and temporal summation.7 Unlike
increase the transcription of neuropeptides, brain-derived neuro- low-threshold primary sensory neurons that use glutamate as their
trophic factor (BDNF), and sodium channels in the cell body as unique neurotransmitter, nociceptors use various compounds
well as increase the translation of TRP channels to augment both including glutamate, neuropeptides (substance P), acetylcholine
central transmission and peripheral sensitization. Furthermore, (ACh)_, CGRP, and proteins like BDNF as transmitters and
the expression of μ-opioid receptors is increased by inflammation synaptic modulators.
via NGF enhancing sensitivity to opioids. Transport of NGF- N-Type (CaV2.2) voltage-gated calcium channels are key
activated Trk receptors and perhaps those of other growth factors mediators of nociceptive signaling. These channels control the
Figure 4-2. Schematic representation of the central regulation of pain and nocioceptive transmission.
release in the spinal cord of glutamate and neuropeptides such as tors. This mechanism of action of the cannabinoids may enable
substance P. Consequently, inhibition of N-type channels via the development of peripherally acting cannabinoid analgesics
activation of opioid receptors or by N-type channel antagonists without central side effects.
mediates analgesia. CaV2.2 RNA undergoes alternative splicing, Other agents act to increase nociceptor input to the CNS. PGE2
producing multiple CaV2.2 channel isoforms with distinct and bradykinin act to increase transmitter release at the central
electrophysiologic properties, distribution, and physiologic role. terminal. PGE2 is produced following induction of the COX-2
CaV2.2 e37a variant is responsible for thermal and mechanical enzyme in dorsal horn neurons in response to peripheral inflam-
nociception in undamaged tissues and thermal and mechanical mation, whereas bradykinin is released in the spinal cord within
hyperalgesia during both inflammatory and neuropathic pain. minutes of nociceptor input. Both agents act via their G protein–
Both N-type channel CaV2.2 e37a and e37b isoforms, differing by coupled receptors to increase transmitter release.
their proximal C terminus, contribute to tactile neuropathic
allodynia. N-Type channels and its alternative splicing of CaV2.2
are, thus, significantly involved in chronic pain. The elucidation Ascending Pathway
and better understanding of the molecular complexity in splice Following a painful stimulus, if sufficient numbers of a particular
variants and their respective locations and roles in different pain type or types of nociceptors are activated, an afferent volley will be
pathways will allow for the development of better therapeutic produced. This ascending pathway initiates the conscious sensa-
strategies for the treatment of chronic pain.33,34 tion of pain. Aδ fibers, conveying fast, spontaneous pain, form
Transmitter-modulated reductions in transmitter release from synapses in lamina I of the dorsal horn of the spinal cord
nociceptors are a prominent control mechanism in nociceptor (Hematopoietic Progenitor Cells [HPC], which are reactive to
input to the CNS. Chemicals involved in this modulation include heat, pinch, and cold) and lamina V (WDR cells [wide-dynamic-
endogenous opioids acting on μ- and δ-opioid receptors (DOR), range] neurons, which have large receptive fields and receive input
gamma-aminobutyric acid (GABA) acting on GABAB receptors, from mechanoreceptors in addition to nociceptors). In these
glycine, serotonin, norepinephrine (NE), and endogenous can- laminae, a synapse is formed with a second-order neuron. After
nabinoids acting on CB1 receptors. The density of these receptors being activated by mainly glutamate-activated AMPA (α-amino-
changes based on several dynamic factors. In the case of the μ- 3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor) type of
opioid receptor, there is an increase after inflammation and a glutamate receptors, the second-order neurons crosses the midline
decrease after axonal injury. The DOR has another form of through the anterior white commissure and travel cephalad
regulation. Very little of the receptor is normally inserted in the through the lateral spinothalamic tracts (STTs) or the neospino-
nociceptor terminal membrane. The majority of DORs are located thalamic tracts, located in the anterolateral quadrant of the
within the membrane in peptide-containing, large dense-core controlateral spinal cord white matter. The second-order neurons,
vesicles. Following nociceptor activation, fusion of the vesicles to without making connections elsewhere, terminate in the ventro-
the terminal membrane during synaptic release results in posterior nucleus of the thalamus. The ventroposterior nucleus
stimulus-triggered exocytosis and the introduction of the receptor includes the ventral posterolateral (VPL), the ventral postero-
into the terminal. Therefore, DOR-mediated analgesia requires medial (VPM) and the posterior (PO) nuclei of the thalamus.
previous activation of the nociceptor before analgesia can be Third-order neurons project from the thalamus to the cortex and
achieved. Cannabinoids exert their analgesic action primarily on synapse with the dendrites of the primary somatosensory cortex
CB1 receptors expressed on the peripheral terminals of nocicep- (S1) in the postcentral gyrus.
S1 is organized somatotopically and is subdivided into four involved in motor control. The other is directed to the medial
parallel strips: Brodmann’s areas 3a, 3b, 1, and 2. In each area, pontobulbar reticular formation and is involved in the mecha-
different receptor types predominate. In area 3a, afferents from nisms of nociception. Few branches project to the centromedian
muscle predominate, whereas in area 3b, afferents from the skin and intralaminar nuclei of the thalamus. Most fibers project
predominate. From area 3b, information is sent to areas 1 and 2, ipsilaterally, unlike the STTs. The afferents of the SRT are involved
which are important in recognizing the texture and the size/shape in the motivational and affective characteristics as well as the
of objects, respectively. The body representation (homunculus) in neurovegetative responses to pain. This tract is an important
S1 is distorted because some body parts are overrepresented pathway for the modulation of the nociceptive segmental path-
(hand, face) whereas other body parts are underrepresented ways by activating brainstem structures responsible for descending
(trunk, leg). The distorsion is related to discriminative properties suppression.
that are more prominent in some territories (hand, face) than in The neurons of the spinomesencephalic tract (SMT) originate
others. From S1, somatosensory information is then sent to in the WDR, substantia nigra (SN), and N-NOC neurons mainly
areas 5 and 7 in the posterior parietal associative somatosensory in laminae I, II, IV, V, VI, but also in laminae VII and X and in the
cortex (S2) where stereognosis takes place. Fast pain is felt within ventral horn. They terminate in several structures of the midbrain,
0.1 sec from the application of the painful stimulus and is sharp especially the periaqueductal gray (PAG) matter and the deep
and acute. Pain is detected as soon as it reaches the thalamus, layers of the superior colliculus. The projections to the PAG matter
yet physical awareness of the location, quality, intensity, and extent originate from WDR and SN and are functionally distinct. Those
of the painful stimulus becomes possible only when the soma- that reach the PAG in the portion more dorsal to the limiting
tosensory cortex is activated. This ascending path is respon- sulcus have an excitatory characteristic in afferent nociceptive
sible for the discriminative aspect of nociception. Because it has transmission, and those that project more ventral to the limiting
mainly controlateral projections, the body representation is sulcus activate inhibitory mechanisms responsible for the
contralateral. inhibition of the afferents of this same pathway. This suggests
Conveying slow, increasing pain, C fibers enter the spinal cord an autoregulatory function of the medulla and midbrain. Stimula-
and connect with interneurons in laminae I, II, and possibly III. tion of regions innervated by the SMT produces different res-
The interneurons that receive this input express different subtypes ponses involved in nociceptive processing. Responses include
of glutaminergic receptors, namely N-methyl-D-aspartic acid aversive behaviors in the presence of noxious stimuli as well as
(NMDA) and AMPA. High levels of afferent input depolarize the motor, autonomic, cardiovascular, motivational, and affective
interneuron first through the AMPA then through the NMDA responses.
receptors. The interneurons then transmit the signal, mainly The parabrachial nucleus (PN), constituting the spinopara-
by the release of substance P (essential for wind-up), to the STT brachial tract (SPBT), receives direct and indirect afferents from
cells (second-order neurons) that reside mainly in laminae I nociceptive pathways. The lateral parabrachial region receives
(nociceptive-specific [NS] neurons), IV, and V. The axons of the projection from nociceptive SN neurons originating in lamina I.
STT cells project across the spinal cord to the STT, joining fibers This area in turn projects primarily to the amygdala and hypo-
from the fast pathway. Whereas fast-pain fibers travel through the thalamus. The patterns of nociceptive connectivity suggest that
neospinothalamic tract (lateral), slow-pain fibers travel through the parabrachial area plays an important role in the motivational
the paleospinothalamic tract (anterior). Both neospinothalamic and affective components of pain sensation and/or autonomic and
tract and paleospinothalamic tract convey ascending monosynap- endocrine responses to noxious stimulation. Neurons in the inter-
tic tracts and constitute the anterolateral extralemniscal system. nal lateral parabrachial nucleus also respond to noxious stimula-
The paleospinothalamic neurons terminate in the ventrolateral tion. By contrast to the lateral parabrachial region, nociceptive
medulla, in various areas throughout the brainstem (reticular input to the internal lateral parabrachial nucleus is derived from
formation), in the periaqueductal gray matter (mesencephalon), in the deep dorsal horn (laminae V and VI). Its neurons send their
the parabrachial nucleus (pons), and in the thalamus (intralaminar axons to the medial thalamus, to the paracentral nucleus.
nucleus and other midline nuclei), where they synapse with third- The spinohypothalamic tract (SHT) originates from laminae I,
order neurons. However, C fiber impulses are not relayed to the V, X and some other regions around the central medullary canal.
somatosensory cortex, but rather to the frontal association cortex. It is composed of SN, WDR, and N-NOC neurons. These neurons
Their impulses are responsible for the affect that accompanies pain respond to noxious and innocuous stimulation coming from
and, thus, allows a cognitive appraisal of the nociceptive input. muscles, tendons, joints, skin, and viscera. Its projections contri-
The appraisal of pain is likely closely linked to one’s pain tolerance. bute to the neuroendocrine, autonomic, motivational-affective,
Slow pain is different from acute pain because it is poorly localized and alertness responses of pain of both somatic and visceral
(non-discriminative), has a bilateral body representation, and is origin.35 Two polysynaptic tracts, the spinocervicothalamic and
described as an “aching,” “throbbing,” or “burning” pain. the dorsal horn postsynaptic tracts, are also involved in ascending
The paleospinothalamic neurons include several ascending nociception. The spinocervicothalamic tract originates mainly
monosynaptic tracts involved in the nociceptive process. The from laminae III and IV and, to a lesser extent, from laminae I,
neurons of the spinoreticular tract (SRT) originate mainly in II, and V. Its neurons receive afferents from peripheral Aδ and
laminae V, VII, and VIII, and also in laminae I and X, mostly from A fibers, consisting mostly of WDR and N-NOC fibers, although
NS and WDR neurons, although also involving nonnociceptive SN neurons have also been described. Projections ascend in
(N-NOC) neurons. These neurons propagate noxious and the ipsilateral lateral cervical nucleus (LCN) where they
innocuous stimuli from skin, viscera, and muscles. The SRT has synapse. LCN neurons project to the controlateral thalamus via
two projections to the brainstem. The first of these is directed to the medial lemniscus. The functions related to this tract concern
the precerebellar nucleus in the lateral reticular formation and is the sensory-discriminative, motivational-affective, and autonomic
characteristics of pain, as well as playing a role as in sensory (VMpo) are also involved in the sensory-discriminative dimen-
integration and modulation of afferent inputs in the spinal cord. sion. The insula, being a component of the limbic system, is also
The dorsal horn postsynaptic tracts originate mainly from involved in affective processing.36
laminae III and V as well as laminae VI and VII. The input is com-
posed mainly of WDR and N-NOC neurons with a few SN neu- Medial Pain System (Affective-
rons. Ascending fibers are organized along two distinct pathways,
Behavioral-Autonomic)
close to the midline of the spinal cord and at the junction of the
gracile and cuneiform bundles, originating from the lumbar sacral The medial thalamic nuclei are the relay station for ascending
region and the thoracic column, respectively. The gracile nucleus, pathways, conveying essentially affective-motivational components
with extensive direct and indirect projections, plays an important of pain. The limbic system (amygdala, cingulated gyrus, hip-
role in sensory integration of the projections from abdominal pocampus, hypothalamus, thalamus) plays a crucial role in emo-
organs and from the skin. After crossing completely, fibers form tional behavior during painful experiences. The cingulate gyrus is
the medial lemniscus, which in turn, projects to the ventrobasal a major part of the anatomic limbic system and, thus, is involved in
nuclear complex of the thalamus. The postsynaptic pathway of the emotion related to pain. The cingulate cortex also participates in
dorsal column represents the largest afferent pathway for infor- sensory, motor, and cognitive processes related to pain. The
mation of visceral origin. This has been revealed in studies de- anterior cingulate cortex (ACC), consisting of areas 25 and 24, has
monstrating the control of visceral cancer pain by means of been implicated in a wide variety of autonomic functions including
myelotomy techniques. Lesions in this region are more effective visceromotor, skeletomotor, and endocrine outflow. These pro-
in the control of visceral pain than in interruption of the pathway cesses include responses to the painful stimuli. Because all of these
of the anterolateral quadrant of the spinal cord. This pathway also activities have an affective component, it is likely that connections
has functions related to proprioception, tactile discrimination, and with the amygdala are essential.37 ACC is also involved in rational
graphesthesia. Given its projections to various thalamic regions, cognitive functions, such as anticipation and decision-making. By
the postsynaptic pathway of the dorsal column is considered to be contrast, the posterior cingulate cortex (PCC), consisting of areas
involved in the sensory-discriminative and motivational-affective 29, 30, 23, and 31, contains neurons that monitor eye movements
components of pain.35 and respond to sensory stimuli. It is involved in spatial orientation
and memory. It is likely that connections between the PCC and the
parahippocampal cortex contribute to these processes.
Supraspinal Centers of Nociception The hypothalamus coordinates behaviors necessary for sur-
vival, including the emotional homeostasis and responses to pain.
It is now clear that there is no single pain center in the brain.
It regulates the autonomic and humoral responses to pain, stress,
Ascending pain pathways are relayed either directly or indirectly
and emotional expression. Many other areas in the brainstem
to cortical and subcortical brain regions. The regions that are
mediate homeostatic changes in bodily functions associated with
commonly activated by nociceptive stimulation are often referred
to as the pain matrix. The pain matrix is subdivided into a medial pain while receiving active regulatory inputs from cortical,
and a lateral pain system. This distinction, which is based on the subcortical, and thalamic areas. The reticular activating system
projection sites from either medial or lateral thalamic structures to (reticular formation) is involved in the arousal effects of the
the cortex, is an oversimplification of the networks involved but is painful stimuli. The arousal may activate noradrenergic neurons
a useful means for grouping brain regions that appear to have in the locus coeruleus (LC) and, thus, decrease the upward pain
similar roles in pain processing.36 The lateral pain system is transmission (see the section on “Descending Inhibitory Systems
primarily thought to have a sensory-discriminative function, com- (Endogenous Pain Modulation)”). The cathecholaminergic nuclei
prising spatial, temporal, and intensity properties. The medial pain of the brainstem receive input from lamina 1 (pain-specific)
system has an affective-motivational dimension, related to the pathways and regulate vigilance and attention through cortical
unpleasantness of the stimulus as well as the behavioral and auto- projections. Furthermore, they regulate bodily functions via the
nomic reactions it evokes. Some regions encode both sensory- autonomic nervous system and are involved in the descending
discriminative and affective pain processing. All of these areas modulation of the spinal nociceptive afferents. The parabrachial
communicate extensively and reciprocally with the prefrontal nucleus is involved in cardiovascular regulation. It has connections
cortex, which brings the situational and memory context to the to the ventral medial nucleus of the hippocampus and the central
experience (cognitive-evaluative function). We present a more nucleus of the amygdala. Both of these areas of the CNS are in-
detailed description of supraspinal centers of nociception, volved in the affective response to pain. The PAG area is involved
subdivided according to their main function. in endogenous analgesia and in automatic coping behavior such as
the fight or flight reaction. The superior colliculus may play a role
in pain-related visuomotor orientating, a reflex function that
Lateral Pain System (Sensory-Discriminative) allows turning of the upper body, head, and eyes in the direction
The lateral thalamic nuclei function as a relay station by conveying of a painful stimulus. The pretectal nuclei are involved in the
sensory information from the spinal cord and brainstem to regulation of endogenous analgesia. The red nucleus is involved in
sensory-discriminatve processing regions. The VPM and the VPL pain-related motor functions.
project to the primary somatosensory (SI) cortex and send minor
projections to the secondary somatosensory (SII) areas of the
cortex. The ventral posterior inferior (VPI) nucleus sends axons Cognitive-Evaluative Function
mainly to the SII. Reaching the somatosensory cortex, physical The intralaminar and reticular thalamic nuclei, the prefrontal
awareness of pain becomes possible. The posterior insular cortex cortex, and the ACC are involved in the cognitive dimension of
as well as its thalamic relay nucleus, the ventromedial nucleus pain.
Descending Inhibitory Systems are the source of spinal NE. NE is known to have a significant
(Endogenous Pain Modulation) antinociceptive influence through action on spinal presynaptic α2-
adrenergic receptors (subtype α2A, α2C). NE also exerts its
Modulation of nociceptive transmission occurs at multiple descending inhibition by direct catecholaminergic postsynaptic
(peripheral, spinal, supraspinal) levels. Endogenous opioids, found innervation of STT neurons and by activating, in the superficial
at the peripheral, spinal, and supraspinal levels, act at G-coupled– laminae, a population of small, low-threshold units, likely to be
protein opioid receptors by increasing potassium channel activity inhibitory interneurons. The latter enhance GABAergic and gly-
(hyperpolarization) and by inhibiting the Ca2+ voltage-gated cinergic inhibitory synaptic transmsission in the substantia gela-
channel, thereby inhbiting substance P release. These endogenous tinosa. The LC also receives projections from the central nucleus
opioids include δ-selective enkephalins, κ-selective dynorphins, of the amydgala, preoptic area, paraventricular nucleus of the
and μ-selective endomorphins. Endogenous opioids play an hypothalamus, and lateral hypothalamus. NE systems have little
important role in pain modulation and are found in the cerebral influence on baseline pain sensitivity; however, in persistent pain,
cortex, hypothalamus, thalamus, hippocampus, basal ganglia, these systems have an important role. In conditions that cause
amygdala, PAG, LC, reticular formation, and parabrachial nucleus. persistant pain (inflammation, injury), the function of descending
At the spinal level, modulation of the pain input has been pathways may change considerably. These changes may enhance
viewed as the attenuation of dorsal horn transmission. Melzack the efficacy of descending inhibition by increasing turnover of NE
and Wall’s Gate Control Theory first suggested this theory in 1965. and by increasing the number of α2-adrenergic receptors in the
Gate control regulation of pain occurs in the gelatinous substance spinal cord. Increased efficacy of glutamatergic receptors of the
(lamina II) of the dorsal horn. The selective stimulation of large medulla, accompanied by a phenotypic switch of medullary
cutaneous afferent Aβ fibers from an injured area blocks activation neurons, has also been observed following inflammation. In the
of the second-order neurons, which are stimulated by the presence of sustained pain stimulation, a decrease of descending
nociceptive Aδ and C fibers. The nociceptive input will be sensed inhibition or an increase of descending facilitation of pain may
as painful only if it can subtract itself from the inhibitory influence also be seen.
of enkephalin interneurons activated by Aβ fibers. This type of Other brainstem, diencephalic, and telencephalic structures
control modulates the pain intensity (sensory-discriminative modulate pain. The hypothalamus is involved in stress-induced
modulation). analgesia either by endocrine mechanisms (Corticotropin releasing
At the supraspinal level, multiple brain regions contribute to factor (CRF) released after activation of the hypothalamic-
the escending inhibitory pathways. These descending pain pituitary-adrenal axis) or by spinal antinociception through axonal
inhibitory controls are immature at birth and do not become projections from the hypothalamus to the PAG-RVM circuitry. The
functionally effective until postnatal day 10 in the rat, although all limbic system and the frontal cortex are closely associated with
descending projections are already present at birth. They may have memory and emotions. With other brain structures, they have an
gender-specific and genetic-specific differences contributing to important impact on pain modulation and perception (emotive-
individual variability in pain sensitivity. Each of the descending affective modulation).
inhibitory system has different neurochemistry (endogenous Another inhibitory system is the diffuse noxious inhibitory
opioids, serotonin, NE, GABA) and different neuroanatomic con- controls (DNICs). Some neurones in the dorsal horn of the spinal
nections. Both the PAG, the RVM (nucleus raphe magnus), and cord are strongly inhibited when a nociceptive stimulus is applied
adjacent reticular formation including the nucleus gigantocel- to any part of the body, distinct from their excitatory receptive
lularis pars alpha and paragigantocellularis ventralis receive direct fields. DNICs influence only convergent neurones. The other cell
projections from the spinal dorsal horn and control the ascending types that are found in the dorsal horn, including specific nocicep-
nociceptive input by a feedback mechanism, thereby modulating tive neurones, are not affected by this type of control. In normal
pain intensity (sensory-discriminative modulation). On the basis conditions, these inhibitions can be triggered only by conditioning
of their physiologic response properties, spinally projecting RVM stimuli, which are nociceptive. The inhibitions are extremely
neurons can be classified into three types. The on-cells give an potent, affect all the activities of the convergent neurones, and
excitatory response to a noxious stimulus starting just before a persist, sometimes for several minutes, after the removal of the
spinal nocifensive reflex (withdrawal reflex). The off-cells give an conditioning stimulus. In fact, only activity of Aδ or C peripheral
inhibitory response to a noxious stimulus starting just before a fibers can trigger DNICs. DNICs are sustained by a complex loop
spinal nocifensive reflex. The neutral cells give variable responses that involves supraspinal structures because, unlike segmental
or are unresponsive to noxious stimuli. Morphine suppresses on- inhibitions, they are not observed in animals in which the cord
cell activity, increases indirectly off-cell activity through a has previously been transsected at the cervical level. The ascending
GABAergic mechanism within the RVM, and has little effect on and descending limbs of this loop travel, respectively through the
neutral cell activity. A subgroup of neutral cells are serotoninergic ventrolateral and dorsolateral funiculi, respectively. DNICs result
and project to the spinal cord where its receptor contributes to from the physiologic activation of the subnucleus reticularis
descending antinociceptive action by modulating the effects in- dorsalis (SRD) in the caudal medulla.
duced by on- and off-cells.
At the spinal cord level, the dorsolateral funiculus is the main
descending pathway mediating antinocieptive effects from the
Perception and Chronic Pain
RVM to the spinal dorsal horn. The noradrenergic neuronal cell Perception is how pain actually feels to someone rather than pain
groups of the brainstem, particularly the LC (LC-A6) as well as as a sensation. It is the cerebral cortical response to nociceptive
pontine noradrenergic cell groups A5 and A7, receive projections signals that are projected by third-order neurons to the brain. The
from the PAG. Descending axons originating in these noradrener- relief of nociception, the antinociception, is simply the blockade
gic neuronal cell groups, conveyed by the ventrolateral pathway, of nociceptive inputs. This notion should be differentiated
from analgesia, the relief of perception of noxious stimulus. The means by which changes in the nervous system can modulate the
relationship between the reported pain intensity and the peri- response to any stimulus. Such plasticity or modifiability of the
pheral stimulus that evokes it depends on many factors such as sensory system characterizes pain syndromes.3,39
past pain experience, depression, distraction, expectation or Chronic pain is not just a prolonged acute pain; it is a distinct
anticipation, anxiety, the level of arousal, gender, and genetics. entity, with many functional and structural alterations of the
Therefore, people have different pain thresholds. The prefrontal peripheral nervous system (peripheral sensitization or primary
cortex and the limbic system are responsible for learning and hyperalgesia) and CNS (central sensitization or secondary hyper-
memorization of painful experiences and the way an individual, algesia). Ongoing nociceptive input from the periphery is needed
who coped with pain in the past, will cope with subsequent to maintain central hyperexcitability, the key process in the
episodes of pain. Individuals who are already suffering from an generation of chronic pain. Repetitive and intense activation of the
illness or experience depression or insomnia are more likely to high-threshold C fibers and AMPA postsynaptic receptors results
have a lower pain threshold than healthy people. In reality, the in release of excitatory substances such as glutamate and substance
experience of pain is nothing more than the interpretation of P. Early changes also include elimination of the voltage-dependent
nociceptive inputs. If a dissociation between nociception and pain magnesium blockade of NMDA receptors and Na channel
appraisal occurred, the experience of pain would not influence stimulation. These changes permit glutamate to activate NMDA
behavior because the affect is missing. This affect accounts for the and non-NMDA postsynaptic receptors and cause a gradual
variability of pain tolerance among individuals. increase in the frequency of dorsal horn neurons firing, known as
Supraspinally mediated factors that fall into the cognitive do- the NMDA-mediated wind-up phenomenon. Activated receptors
main may account for a significant amount of the interindividual increase intracellular calcium levels with subsequent activation of
differences in the subjective experience of pain. For example, calcium-dependent intracellular kinase and phosphorylation of ion
distraction’s main effect appears to be increased activity within the channels and NMDA receptors. Potential consequences of these
medial pain systems via the descending pain modulatory system changes include altered synaptic transfer and transcriptional
and a corresponding reduction in activation in the lateral pain changes with c-fos production in the second-order dorsal horn
system. Other experiments have investigated the effect of anti- projection neurons (marker of central sensitization).
cipation of an impending painful stimulus on regional brain acti- Activation of the NMDA receptors represents the first step in
vity. The main effects of anticipation were found to be activation central sensitization (the transition from acute to chronic pain). As
of rostral anterior insula and medial prefrontal cortices during the such, adequate treatment of physiologic, nociceptive pain is the
anticipation of pain, whereas during pain itself, insular activity most important goal of acute pain management because it may
was more caudal and the prefrontal focus was replaced by activity prevent subsequent central sensitization. Other neurochemical
within the ACC. The hippocampal formation (entorhinal com- changes involved in central sensitization include sensitization of
plex) is responsible for producing anxiety-induced increased pain WDR neurons to nonnociceptive stimuli and expression of
perception. substance P by A fiber presynaptic terminals. Neuroanatomic
A few genes have been identified that are associated with the modifications include sprouting of A fiber terminals into the
perception of pain in humans. Single nucleotide polymorphisms superficial layers of the dorsal horn with synapses onto the
(SNPs) in genes that code for the melanocortin-1 receptor and nociceptive second -order neurons. Additional modifications
neuronal cytochrome P450 (PY2D6) are associated with alteration include extensive reorganization of the somatosensory cortical
in opioid analgesia. Congenital insensitivity to pain (CIP) type I maps and remodeling in the brainstem, cerebellum, basal ganglia,
has been linked to the gene encoding a subunit of serine palmi- and motor cortical areas with subsequent dysfunctional descend-
toyltransferase, and type IV has been linked to the gene encoding ing inhibition. This central sensitization and neuroplastic remod-
for a NGF-specific tyrosine kinase receptor. Furthermore, a eling are responsible for all the main features of chronic pain
common SNP in codon 158 (val138met) of the gene that codes for including hypersensitivity to nociceptive stimuli (hyperalgesia),
catecholamine-O-methyltransferase (COMT) has been proposed perception of pain upon nonnociceptive stimulation (allodynia),
to contribute to differences in the human experience of pain. expansion of the pain-receptive fields to uninjured tissue (referred
Recent studies have identified three genetic haplotypes of the gene pain), and prolonged pain after a transient stimulus (persistant
encoding COMT, designated low pain sensitivity (LPS), average pain).
pain sensitivity (APS), and high pain sensitivity (HPS). These
haplotypes encompass 96% of the human population, and five
combinations of these haplotypes are strongly associated with DEVELOPMENT OF
variation38 in the sensitivity to experimental pain. The presence NOCICEPTIVE CIRCUITRY
of even a single LPS haplotype diminishes, by as much as two to
three times, the risk of developing a chronic pain condition. The Somatosensory processing comprises a fine balance of sensory
LPS haplotype produces much higher levels of COMT enzymatic afferent input, local inhibitory and excitatory control on dorsal
activity than the APS or the HPS haplotypes. As shown in rat horn projection neurons, and descending inhibitory and facili-
studies, inhibition of COMT results in a profound increase in pain tatory modulation. The development and maturation of each of
sensitivity.38 these components will affect the nociceptive responsivity.
The threshold for eliciting pain has to be high enough that it
does not interfere with normal activites but low enough that is can
be evoked before frank tissue damage occurs. This threshold is not
Primary Sensory Afferents
fixed and can be shifted either up or down, which may be either Development of primary sensory neurons is the first stage in the
adaptative or maladaptive. Shifts in pain threshold and respon- development of the somatosensory pathways that will transmit
siveness are an expression of neural plasticity, the neurobiologic sensory stimuli from the periphery to the higher areas of the CNS.
Nociceptive neurons develop without influence from either central embryonic dorsal horn cell, resulting in excitatory glutamatergic
or peripheral targets.40 Primary sensory neurons that make up the or inhibitory GABA cells.48 It is interesting to note that the genesis
DRG appear at embryonic day 12 (E12). The future, cutaneous, of projecting neurons of lamina I is completed before the local
nonnociceptive A fibers expressing the neurotrophin receptors interneuron circuitry,49 implying that direct transmission of
TrkB and TrkC appear first, followed by the C fiber cells that nociceptive activity from the spinal cord to the CNS may appear
express TrkA. The development of these two populations is under before the development of the local modulation circuitry. At
the control of separate transcription factors of the neurogenin postnatal days 18 to 27, the miniature excitatory postsynaptic
family. Ngn1) is required for small C fiber neurons and Ngn2 for current (mEPSC) frequencies of lamina I are five times higher
the larger A fibre cells.41 The number of neurons increases until the than those in the interneurons. The relatively late maturation of
time of birth and is followed by a 15 to 20% loss over the first few interneurons means that their axodendritic growth takes place
postnatal weeks,42 coinciding with the final innervation of the skin postnatally, which may be important for the activity-dependent
by the peripheral afferents of the DRG neurons. The survival of shaping of nociceptive circuits (see Section on Growth of Axons
the neurons is dependent upon the presence of neurotrophic Toward Peripheral and Central Targets).
factors produced by both the peripheral (skin) and the central
targets.43
Functional Maturation of
Nociceptive Circuitry
Growth of Axons Toward Peripheral
The appearance of connections between the afferent sensory and
and Central Targets the spinal neuronal cells leads to the first functional reflex
Toward the periphery, outgrowth of axons from DRG sensory response to tactile and nociceptive stimluli. Although these spinal
neurons occurs before birth. Large-diameter A fibers form an reflexes are not proof of the consciousness of pain, they confirm
initial nerve plexus and are followed by the smaller-diameter C the presence of a functional connectivity of somatosensory cir-
fibers.44 This growth is extremely precise with each DRG innervat- cuitry, a prerequisite of any behavioral response to a peripheral
ing somatotopically appropriate dermatomes. There is an initial sensory stimulus. The study of pain behaviors in fetal and neonatal
hyperinnervation of the skin, extending beyond the dermis into animal is restricted to examination of reflex responses that can be
the epidermal surface. These projections subsequently withdraw, elicited only once the primary afferent, dorsal horn neuron, and
resulting in a pattern of innervations similar to that found in the motor neuron circuitry synaptic connections are complete. Reflex
adult.45 The first sensory neuron–derived afferents to penetrate responses can be elicited to both tactile and noxious stimuli. The
the spinal cord are the A fibers at E15 to E17, followed by C fiber presence of these responses is not evidence of pain percep-
projections at E18 to E20. Although the peripheral target skin tion, rather, it is an indication of the degree of maturation of
influences the pattern of projections in the CNS, it does not direct somatosensory ciruitry and sensitivity to peripheral stimuli. Even
cutaneous axons to specific populations of neurons in the dorsal though prevalent in rats at E15 to E-17,50 cutaneous reflex
horn. The inhibitory growth cone collapsing molecule semaphorin responses, at birth, are diffuse and exaggerated with lowered
3A and the homeodomain protein, DRG11, seem to play an thresholds. Receptive fields of hind limb flexor muscles are large
important role in the specific growth of sensory axons.45 and disorganized in younger animals, resulting in inappropriate
Spontaneous action potentials of fetal dorsal horn ganglia cells limb withdrawal responses to noxious stimuli.51 Despite their
during this period may also be responsible for appropriate importance in early behavior, reflex responses cannot be equated
synaptic connections. with a true pain experience, which must involve the cortex and
cognitive brain function. These reflexes are likely to reflect the
absence of the normal inhibitory control that higher brain
Functional Development of Nociceptors structures exert at more mature stages of development to dampen
Determinant characteristics of C fibers such as the expression spinal excitability. These reflex responses decrease as the rat
of the neurotrophin receptor TrkA and selective binding of IB4 matures, becoming more restricted to an isolated leg or foot
can be seen at an early embryonic age. The sodium canal TTX- movement. The fine-tuning of both excitatory and inhibitory
resistant Nav 1.8 (SNS/PN3) that regulates the neuronal hyper- synaptic connections with interneurons within lamina II during
excitability is expressed in C fibers from E17 with adult levels the postnatal period allows a progressive modification and
present from the seventh day of life.46 Within days of birth, adaptation of these behaviors. The early presence and maturation
the receptor for the capsaicin TRPV1, which has a predominant of A fiber terminations witin lamina II during the first weeks of
role in the detection of thermal and chemical stimuli, is expressed postnatal life seem to influence considerably the neuronal res-
in the dorsal ganglia at a percentage similar to that found in adults. ponses of the dorsal horn, contributing to the high level of
The ATP-gated P2X3 receptor, important for thermal and cutaneous reflexes excitability. On the contrary, the activity
mechanical hyperalgesia following inflammation or nerve injury, triggered in the dorsal horn by C fibers appears gradually during
is also expressed from an early age by cells of the DRG. the postnatal period with a lower percentage of neurons conveying
a nocicepive signal during the first weeks of life compared with
those in an adult.52
Cell Determination in the Dorsal Horn
The expression of the gene homeobox Lbx1 is required for both
the correct specification of substantia gelatinosa neurons and the
Balance Between Excitation and Inhibition
appropriate sensory afferent innervation of the dorsal horn.47 The The dorsal horn cells of newborn animals are more excitable than
selection of postmitotic genes Tlx1 and Tlx3 seals the destiny of those of adults. A painful cutaneous stimulation at an early
postnatal age (P0–3) frequently results in action potentials with a activation of C fibers is observed. Nociceptive C fibers can be
prolonged activity of 30 to 90 sec beyond the end of the stimulus. sensitized by inflammatory chemicals even before birth. As soon
This effect diminishes with age in both amplitude and duration.53 as the stimulation of peripheral C fibers begins to trigger cells of
The newborn dorsal horn cells’ high-response capacity demon- the dorsal horn, a repeated stimulus creates a wind-up NMDA
strates the immaturity of excitatory and inhibitory synaptic receptor–dependent phenomenon.58 Hyperalgesia can be triggered
transmission in the spinal cord of the newborn. The elimination in the young animal from age P3 or even before, although its
of some synapses (such as the Aβ fiber input to lamina II) and the magnitude may not be as great as in adults.59 The postnatal ma-
strengthening of others (such as C fiber inputs) alter the balance turation of hyperalgesia may follow the development of signaling
of postnatal transmission. This process may be linked to the by substance P, which has been shown to be important for this
number of silent synapses which express only NMDA receptors form of central sensitization.
in neonatal superficial dorsal horn neurons.54 Repeated afferent Whereas many of the nervous system responses to local tissue
stimulation may convert silent synapses to functional ones by damage resolve after the injury is healed, tissue damage during a
rapid insertion of AMPA receptors. The parallel development of critical period in newborn rodents can cause prolonged alterations
inhibitory, organized synapses is crucial to the development of a in somatosensory function that persist into adult life. The
functional nociceptive system. The subtle equilibrium between consequences of neonatal injury depend on the type of injury and
excitation and inhibition within the CNS determines the func- the modality of sensation.60–62 The early-onset inflammatory
tionality of the system. The presence of inhibitory synpases can hyperalgesia and the later-onset basal hypoalgesia extend into
determine the impact of adjacent excitatory synapses only if they adulthood and appear only if the original inflammatory stimulus
are localized on the same dentritic branch and are activated is applied during the first 10 days of life. Although it is not known
simultaneously.55 As with the excitatory synapses, the inhibitory how these long-term changes in pain signaling develop, potential
GABA and glycinergic synapses are regulated in the dorsal horn mechanisms include alterations in synaptic connectivity and
and go through important functional modifications during the signaling in postnatal nociceptive pathways as well as changes in
postnatal period. the balance of inhibition versus excitation. In addition, tissue
injury in the newborn triggers the secretion of higher concentra-
tions of growth factors, which may have various effects on the
The Development of Descending development of peripheral nociceptors.63 The permanent expan-
Pain Pathways sion of the dorsal horn receptor field in the neonatal injured area
Descending activity from the brainstem is another factor con- is evidence for the failed development of a directed inhibitory
tributing to the balance between excitation and inhibition in spinal system within the nociceptive circuitry.
nociceptive circuits. Brainstem fibers containing serotonin
innervate the PAG at birth, yet the pattern and the density of adult
terminals are not achieved in the lumbar spine until P21. This SUMMARY
observation explains why stimulus-produced analgesia from the This chapter has concentrated on nociceptive processing and its
PAG is not effective until P21 in rats. The dorsolateral funiculus of maturation at the peripheral and spinal level, the importance of
the spinal cord, which transmits the descending inhibitory functional higher brain centers in the “pain experience” on the
pathways, grows down the spinal cord early in fetal life but does early and late consequences of pain, and issues related to the
not extend collateral branches into the dorsal horn until P10.56 The development of chronic pain. Neuroanatomic evidence demonst-
lack of descending inhibition in the neonatal dorsal horn means rates that pain and its perception are complex entities involving
that there is no endogenous analgesic system to dampen noxious multiple ascending pathways, different functional projections to
inputs as they enter the CNS, and their effects may, therefore, be the thalamic area, a cortical circuit, and a crucial excitatory and
more profound than in the adult. The late functional maturation inhibitory synaptic transmission system. Clinical and laboratory
of this system is due to either low serotonin levels in the synaptic research has elucidated many of the physiologic, pharmacologic,
terminals or a delay in receptor maturation in the early postnatal and neurobiologic/immune complex mechanisms involved in the
period. Although the low levels of serotonin may limit synaptic immature pain pathways. Research has also shown how the
transmission, they may still influence synaptic maturation, as the developing pain circuitry depends on nonnoxious sensory activity
exposure to serotonin causes rapid insertion of AMPA receptors in the healthy newborn and how early injury can permanently
into the synaptic membrane of neonatal substantia gelatinosa alter pain processing. The demonstration of interactions between
neurons. The descending noradrenergic inhibitory system seems the nervous and the immune systems and the discovery of the
to mature earlier because the administration of a α2-adrenergic synthesis and release of immune chemical messengers secondary
receptor agonist produces analgesia following nociceptive mecha- to a noxious stimulus have been crucial in our understanding of
nical or thermal stimuli in the newborn rat. Also, the intrathecal the pathophysiology of the nervous and nocioceptive systems.
administration of dexmedetomidine, a potent and selective α2- These messengers are involved in the regulation of the activity of
adrenergic agonist, reverses inflammatory hyperalgesia at all CNS neurons (mainly those in the dorsal horn of the spinal cord)
postnatal ages at doses that have no effect on baseline sensory in certain pathologic situations leading to inflammatory and
processing and that are lower than those needed in the adult.57 chronic neuropathic pain. Questions related to the affective and
cognitive aspects of the pain experience among different chronic
pain conditions in later ages still remain to be more extensively
Early and Late Consequences of Pain explored. These studies should not only help us to better prevent
Nociceptive activity is not a normal physiologic event during the and assess pain but also contribute to rational design of analgesic
neonatal period. After tissue injury, a strong and prolonged regimes that are specific to young infants.
REFERENCES 25. Goldberg YP, MacFarlane J, MacDonald ML, et al. Loss-of-function

mutations in the Nav1.7 gene underlie congenital indifference to pain
1. Fitzgerald M, Howard R. The neurobiologic basis of pediatric pain. in multiple human populations. Clin Genet. 2007;71:311–319.
In: Schechter N, Berde C, Yaster M, editors. Pain in Children and 26. Xu P, Hall AK. The role of activin in neuropeptide induction and pain
Adolescents. Philadelphia: Lippincott Williams & Wilkins; 2003. sensation. Dev Biol. 2006;299:303–309.
pp. 19–42. 27. Jin X, Gereau RW. Acute p38-mediated modulation of tetrodotoxin-
2. Price DD. Psychological and neural mechanisms of the affective resistant sodium channels in mouse sensory neurons by tumor
dimension of pain. Science. 2000;288:1769–1772. necrosis factor-α. J Neurosci. 2006;26:246–255.
3. Woolf CI, Salter MW. Neuronal plasticity:increasing the gain in pain. 28. Zhang N, Inan S, Cowan A, et al. A proinflammatory chemokine,
Science. 2000;288:1765–1768. CCL3, sensitizes the heat- and capsaicin-gated ion channel TRPV1.
4. Narsinghani U, Anand KJS. Developmental neurobiology of pain in Proc Natl Acad Sci U S A. 2005;102:4536–4541.
neonatal rats. Lab Animal. 2000;29:27–39. 29. Vellani V, Colucci M, Lattanzi R, et al. Sensitization of transient
5. Fitzgerald M. The development of nociceptive circuits. Nat Rev receptor potential vanilloid 1 by the prokineticin receptor agonist
Neurosci. 2005;6:507–520. Bv8. J Neurosci. 2006;26:5109–5116.
6. Glover V, Fisk N. We don’t know: better to err on the safe side from 30. Grant AD, Cottrell GS, Amadesi S, et al. Protease-activated receptor
mid-gestation. BMJ. 1996;313:796–800. 2 sensitizes the transient receptor potential vanilloid 4 ion channel
7. Woolf CJ, Ma Q. Nociceptors—noxious stimulus detectors. Neuron. to cause mechanical hyperalgesia in mice. J Physiol. 2007;578:
715–733.
2007;55:353–364.
31. Dai Y, Wang S, Tominaga M, et al. Sensitization of TRPA1 by PAR2
8. Marmigere F, Ernfors P. Specification and connectivity of neuronal
contributes to the sensation of inflammatory pain. J Clin Invest.
subtypes in the sensory lineage. Nat Rev Neurosci. 2007;8:114–127.
2007;117:1979–1987.
9. Ma Q, Chen Z, del Barco Barrantes I, et al. Neurogenin1 is essential
32. Malin SA, Molliver DC, Koerber HR, et al. Glial cell line–derived
for the determination of neuronal precursors for proximal cranial neurotrophic factor family members sensitize nociceptors in vitro
sensory ganglia. Neuron. 1998;20:469–482. and produce thermal hyperalgesia in vivo. J Neurosci. 2006;26:8588–
10. Ma Q, Fode C, Guillemot F, et al. Neurogenin1 and neurogenin2 8599.
control two distinct waves of neurogenesis in developing dorsal root 33. Woolf CJ, Ma Q. Nociceptors—noxious stimulus detectors. Neuron.
ganglia. Genes Dev. 1999;13:1717–1728. 2007;55:353–364.
11. Chen CL, Broom DC, LiuY, et al. Runx1 determines nociceptive sen- 34. Jarvis MF, Honore P, Shieh CC, et al. A-803467, a potent and selective
sory neuron phenotype and is required for thermal and neuropathic Nav1.8 sodium channel blocker, attenuates neuropathic and
pain. Neuron. 2006;49:365–377. inflammatory pain in the rat. Proc Natl Acad Sci U S A. 2007;104:
12. Yoshikawa M, Senzaki K, Yokomizo T, et al. Runx1 selectively 8520–8525.
regulates cell fate specification and axonal projections of dorsal root 35. Ji RR, Samad TA, Jin SX, et al. MAPK activation by NGF in primary
ganglion neurons. Dev Biol. 2007;303:663–674. sensory neurons after inflammation increases TRPV1 levels and
13. Luo W, Wickramasinghe SR, Savitt JM, et al. A hierarchical NGF maintains heat hyperalgesia. Neuron. 2002;36:57–68.
signaling cascade controls Ret-dependent and Ret-independent 36. Puehler W, Zollner C, Brack A, et al. Rapid upregulation of mu opioid
events during development of nonpeptidergic DRG neurons. Neuron. receptor mRNA in dorsal root ganglia in response to peripheral
2007;54:739–754. inflammation depends on neuronal conduction. Neuroscience. 2004;
14. Fields HL, Rowbotham M, Baron R. Postherpetic neuralgia: irritable 129:473–479.
nociceptors and deafferentation. Neurobiol Dis. 1998;5:209–227. 37. Delcroix JD, Valletta JS, Wu C, et al. NGF signaling in sensory
15. Dhaka A, Viswanath V, Patapoutian A. Trp ion channels and tempe- neurons: evidence that early endosomes carry NGF retrograde
rature sensation. Annu Rev Neurosci. 2006;29:135–161. signals. Neuron. 2003;39:69–84.
16. Brauchi S, Orta G, Salazar M, et al. A hot-sensing cold receptor: C- 38. Sung YJ, Chiu DT, Ambron RT. Activation and retrograde transport
terminal domain determines thermosensation in transient receptor of protein kinase G in rat nociceptive neurons after nerve injury and
potential channels. J Neurosci. 2006;26:4835–4840. inflammation. Neuroscience. 2006;141:697–709.
17. Alloui A, Zimmermann K, Mamet J, et al. TREK-1, a K+ channel 39. Perlson E, Michaelevski I, Kowalsman N, et al. Vimentin binding to
involved in polymodal pain perception. EMBO J. 2006;25:2368–2376. phosphorylated Erk sterically hinders enzymatic dephosphorylation
18. Zimmermann K, Leffler A, Babes A, et al. Sensory neuron sodium of the kinase. J Mol Biol. 2006;364:938–944.
channel Nav1.8 is essential for pain at low temperatures. Nature. 40. Xiao HS, Huang QH, Zhang FX, et al. Identification of gene
2007;447:856–859. expression profile of dorsal root ganglion in the rat peripheral
axotomy model of neuropathic pain. Proc Natl Acad Sci U S A. 2002;
19. Hu J, Milenkovic N, Lewin GR. The high threshold mechanotrans-
99:8360–8365.
ducer: a status report. Pain. 2006;120:3–7.
41. Tegeder I, Costigan M, Griffin RS, et al. GTP cyclohydrolase and
20. Bandell M, Story GM, Hwang, SW, et al. Noxious cold ion channel
tetrahydrobiopterin regulate pain sensitivity and persistence. Nat
TRPA1 is activated by pungent compounds and bradykinin. Neuron.
Med. 2006;12:1269–1277.
2004; 41:849–857. 42. Raingo J, Castiglioni AJ, and Lipscombe D. Alternative splicing
21. Kwan KY, Allchorne AJ, Vollrath MA, et al. TRPA1 contributes to controls G protein–dependent inhibition of N-type calcium channels
cold, mechanical, and chemical nociception but is not essential for in nociceptors. Nat Neurosci. 2007;10:285–292.
hair-cell transduction. Neuron. 2006;50:277–289. 43. Swayne LA, Bourinet E. Voltage-gated calcium channels in chronic
22. Julius D, Basbaum AL. Molecular mechanisms of nociception. pain: emerging role of alternative splicing. Eur J Physiol. 2008;456:
Nature. 2001;413:203–210. 459–466.
23. Verpoorten N, Claeys KG, Deprez L, et al. Novel frameshift and splice 44. Altier C, Dale CS, Kisilevsky AE, et al. Differential role of N-type
site mutations in the neurotrophic tyrosine kinase receptor type 1 calcium channel splice isoforms in pain. J Neurosci. 2007;27:6363–
gene (NTRK1) associated with hereditary sensory neuropathy type 6373.
IV. Neuromuscul Disord. 2006;16:19–25. 45. Mannion RJ, Costigan M, Decosterd I, et al. Neurotrophins: peri-
24. Cox JJ, Reimann F, Nicholas AK, et al. An SCN9A channelopathy pherally and centrally acting modulators of tactile stimulus–induced
causes congenital inability to experience pain. Nature. 2006;444: inflammatory pain hypersensitivity. Proc Natl Acad Sci U S A. 1999;
894–898. 96:9385–9390.
46. Kohno T, Ji RR, Ito N, et al. Peripheral axonal injury results in 55. Bromm B. Brain images of pain. News Physiol Science. 2001;16:
reduced mu opioid receptor pre- and post-synaptic action in the 244.
spinal cord. Pain. 2005;117:77–87. 56. Fitzgerald M, Koltzenburg M. The functional development of
47. Guan JS, Xu ZZ, Gao H, et al. Interaction with vesicle luminal descending inhibitory pathways in the dorsolateral funiculus of the
protachykinin regulates surface expression of delta-opioid receptors newborn rat spinal cord. J Neurophysiol. 1986;56:555–571.
and opioid analgesia. Cell. 2005;122:619–631. 57. Leong SK, Shieh JY, Wong WC. Localizing spinal-cord-projecting
48. Agarwal N, Pacher P, Tegeder I, et al. Cannabinoids mediate analgesia neurons in neonatal and immature albino rats. J Comp Neurol.
largely via peripheral type 1 cannabinoid receptors in nociceptors. 1984;228:18–23.
Nat Neurosci. 2007;10:870–879. 58. Staud R, Cannon RC, Mauderli AP, et al. Temporal summation
49. Vasko MR. Prostaglandin-induced neuropeptide release from spinal of pain from mechanical stimulation of muscle tissue in normal
cord. Prog Brain Res. 1995;104:367–380. controls and subjects with fibromyalgia syndrome. Pain. 2003;102:
50. Wang H, Kohno T, Amaya F, et al. Bradykinin produces pain 87–95.
hypersensitivity by potentiating spinal cord glutamatergic synaptic 59. Jasmin L, Tien D, Weinshenker D, et al. The NK1 receptor mediates
transmission. J Neurosci. 2005;25:7986–7992. both the hyperalgesia and the resistance to morphine in mice lacking
51. Samad TA, Moore KA, Sapirstein A, et al. Interleukin-1b–mediated noradrenaline. Proc Natl Acad Sci U S A. 2002;99:1029–1034.
induction of Cox-2 in the CNS contributes to inflammatory pain 60. Ren K, Hylden JL, Williams GM, et al. The effects of a non-
hypersensitivity. Nature. 2001;410:471–475. competitive NMDA receptor antagonist, MK-801, on behavioral
52. Almeida TF, Roizenblatt S, Tufik S. Afferent pain pathways: a hyperalgesia and dorsal horn neuronal activity in rats with unilateral
neuroanatomical review. Brain Res. 2004;1000:40–56. inflammation. Pain. 1992;50:331–344.
53. Raij TT. Pain Processing in the Hhumain Brain—Views From 61. Bantick SJ, Wise RG, Ploghaus A, et al. Imaging how attention
Magnetoencephalography and Functional Magnetic Resonance modulates pain in humans using functional MRI. Brain. 2002;125:
Imaging [thesis]. Helsinki, Finland : Brain Research Unit of Low 310–319.
Temperature Laboratory and Advanced Magnetic Imaging Centre. 62. Porro CA, Baraldi P, Pagnoni G, et al. Does anticipation of pain affect
Helsinki University of Technology. Department of Psychiatry, cortical nociceptive systems? J Neurosci. 2002;22:3206–3214.
University of Helsinki ; 2005. 63. Ploghaus A, Narain C, Beckmann CF, et al. Exacerbation of pain by
54. Brooks J, Tracey I. From nociception to pain perception: imaging the anxiety is associated with activity in a hippocampal network.
spinal and supraspinal pathways. J Anat. 2005;207:19–33. J Neurosci. 2001;21:9896–9903.
Central Nervous System:

Neurotransmitters and Anesthesia 5
Thomas Engelhardt and William Wisden C H A P T E R
INTRODUCTION the development of the CNS. Quanta of neurotransmitters

are released after membrane depolarization via an exocytotic
The conduct of general anesthesia has become safer. The incidence process. Following diffusion across the synaptic cleft and binding
of anesthesia-related mortality has decreased dramatically since to a transmembrane receptor, binding to the specific ligand-
the 1970s and is now estimated at much less than 1 in 10,000. receptor complex then determines the subsequent effect. The
However, the progress in safety has not been matched by the majority of neurotransmitters are removed from the synaptic
understanding of the molecular basis of general anesthesia. cleft via re-uptake processes, degradation, or diffusion. There
Despite considerable research efforts, the exact mechanisms of may also be neuromodulators that change the sensitivity of the
general anesthesia remain to be elucidated. This chapter reviews receptor to its (natural) ligand and are not re-absorbed by the
central nervous system (CNS) neurotransmitters and their role in presynaptic neuron. The receptors in biochemistry terms
sleep-awake states and considers aspects of neurodevelopment are proteins on the cell membrane or within the cytoplasm that
relevant to anesthesia. bind specific factors (ligands) and initiate a cellular response to
the ligand. They are divided into transmembrane and intracellular
receptors. Only the transmembrane receptors are relevant to
ANESTHETICS AND THEIR anesthesia. Transmembrane receptors are integral membrane
INTERACTION WITH CNS proteins and are normally composed of two or more subunits. In
NEUROTRANSMITTERS general, transmembrane receptors are classified according to their
function (metabotropic or ionotropic) or structure (domains)
The commonly used general anesthetic agents include both
(Figure 5–1).
inhalational and intravenous agents. The inhalational agents
include both gases such as nitrous oxide (N2O) and xenon as well
as the vapors of volatile liquids such as halothane, isoflurane, Ionotropic Receptors
sevoflurane, or desflurane. The intravenous agents include the
barbiturates (thiopental and methohexital), propofol, ketamine, The activity of ionotropic receptors is regulated by changes of
either the membrane potential (voltage-gated) or the ligands
etomidate, and benzodiazepines. Although the clinically relevant
(ligand-gated). Voltage-gated ion channels are normally closed at
anesthetic agents are often small, highly lipid-soluble molecules,
resting membrane potential, and a change in the membrane po-
the previously held hypothesis that these agents act by dissolving
tential of the cell causes conformational changes that result in the
within the membrane of nerve cells inducing structural changes of
opening of the pore and the transmembrane movement of ions. A
the lipid bilayer has now been discarded.1–5 Current thinking
transitional change leads to an inactivated state. Ligand-gated ion
hypothesizes that anesthetic agents amplify and modulate neuro- channels are primary targets for general anesthetic agents. These
transmitter signals within the CNS. In addition, some anesthetic ligand-gated ion channels contain an intrinsic ion channel and an
agents (the volatile or inhalational agents) directly open ion extracellular binding site(s) for the ligand(s). Ligand binding
channels such as two pore domain K+ channels or, in the case of causes a conformational change with an increase of opening
propofol, inhibit cyclic nucleotide–gated (HCN) channels.5 probability of the ion pore. Ligand-gated ion channels fall into two
Although these latter effects on ion channels are important families: (1) the Cys loop family, which includes the nicotinic,
anesthetic targets, this chapter focuses on how anesthetic agents serotonin (5-HT3), gamma-aminobutyric acid A (GABAA), and
interact directly with neurotransmitter receptors. Because of the glycine receptors; and (2) the glutamate-gated ionotropic recep-
huge diversity in molecular structure of the different classes of tors, which comprise the α-amino-3-hydroxy-5-methylisoxazole-
anesthetic agents, it is not surprising that these drugs interact with 4-propionic acid (AMPA), kainite, and N-methyl-D-aspartic acid
a variety of protein targets (i.e., receptors and ion channels). (NMDA) receptor subtypes. The Cys loop family is characterized
Therefore, the concurrent use of anesthetic agents, analgesic by a pentameric arrangement of subunits and can be subdivided
agents, and neuromuscular blocking agents results in the simulta- into excitatory (nicotinic, 5-HT3) and inhibitory (GABAA, glycine)
neous modulation of multiple receptors and ion channels systems ligand-gated channels. The ionotropic glutamate receptors are
during general anesthesia. encoded from an entirely different gene family that encodes sub-
Neurotransmitters are small molecules that relay, amplify, and units with a different membrane topology from those of the Cys
modulate signals between neurons and other cells. In addition, loop family. Ionotropic glutamate receptors assemble as heterome-
as discussed in Chapter 3, these agents may also control or regulate ric tetramers.
Figure 5-1. Classification of transmembrane

receptors. Only receptors potentially relevant
to anesthesia are displayed. GABAB =
gamma-aminobutyric acid B; 5-HT1A =
5-hydroxytryptamine; NMDA = N-methyl-
D-aspartic acid.
Metabotropic Receptors sleep, often associated with high level of brain activity and vivid
dreaming, and non–rapid eye movement (NREM) sleep, with a
Metabotropic receptors constitute the largest family of cell-surface reduced level of brain activity.7,8 Although not universally ac-
receptors and are a subclass of transmembrane receptors that cepted, it is likely that anesthetic agents interfere with the neuronal
amplify their signal through G proteins linked to the receptor. circuitry underlying these processes.5
Metabotropic receptors have seven membrane-spanning domains
and the signaling unit is referred to as G protein–linked receptors
(GPLRs). G proteins comprise three subunits—α, β, and γ—and Wakefulness
are “molecular switches” that transduce a signal to an amplifying
The ascending reticular activating system projects from the
enzyme whose activity produces a second messenger, resulting in
midbrain to the thalamus, hypothalamus, and neocortex. The
the activation or inhibition of an enzyme or ion channel. Agonists
cholinergic neurons that project to the thalamus originate from
bind to GPLRs that activate G proteins through the release of
the pedunculopontine and laterodorsal tegmental nuclei and fire
guanosine 5’ diphosphate (GDP) bound to the α subunit initiating
the G protein cycle (Figure 5–2).
All subunits transduce signals and regulate a range of second
messenger production or destruction. G Proteins are traditionally
classified according to their α subunits: αs, αi, αq, and α12/13. In
general, Gαs stimulates adenylate cyclase activity and regulates
calcium ion channels whereas Gαi inhibits adenylate cyclase, acti-
vates cyclic guanosine monophosphate (cGMP)–specific phos-
phodiesterases, and regulates potassium and calcium channels.
The family of Gαq G proteins activates phospholipase C (PLC-β),
and the function of Gα12/13 is likely to regulate chloride ion
channels. Individual receptors can activate more than one G pro-
tein, and variation in different stages of G protein activation and
deactivation can affect the regulation of intracellular signaling.
The guanosine triphosphate (GTP) hydrolysis and binding pro-
perties vary for individual Gα subunits, and accessory and re-
gulatory proteins affect these processes. It is likely that anesthetic
agents interfere with GPLR and dependent enzyme systems;
however, evidence so far has been inconclusive.
ROLE OF NEUROTRANSMITTERS
IN SLEEP-AWAKE STATES Figure 5-2. G protein cycle. Following agonist binding and release
of guanosine diphosphate (GDP), subsequent binding of guanosine
The principal mechanisms of natural sleep and the neurotrans- triphosphate (GTP) leads to dissociation of the heterotrimer into its
mitters involved are helpful in furthering our understanding of component subunits. The GTPase activity of the ␣ subunit determines
the mechanisms of general anesthetic agents.5,6 The natural states the lifetime of this dissociated, now active G protein. Hydrolysis of GTP
of consciousness include wakefulness and sleep. The latter is back to GDP leads to re-association of the heterotrimer and completion
commonly divided into two phases: rapid eye movement (REM) of the G protein cycle.
CHAPTER 5 ■ Central Nervous System: Neurotransmitters and Anesthesia 73
rapidly during wakefulness and REM sleep.9 Other neuronal types thesis is supported by the reciprocal neuronal activity in POA on
involved in stimulating arousal include noradrenergic, serotiner- one side and the LC, DRN, TMN, and PFLH on the other side18
gic, and histaminergic, and/or exinergic neurons. The monoami- (Figure 5–4).
nergic neurons from the locus ceruleus (LC; norepinephrine),
dorsal raphe nuclei (DRN; serotonin), and tuberomamillary
nucleus (TMN; histamine) fire rapidly during wakefulness, but CURRENT AND POTENTIAL TARGETS
only infrequently during sleep. Orexins (also named hypocretins) FOR GENERAL ANESTHESIA
are peptide neurotransmitters originating in the perifornical
Ligand-activated receptor systems are important targets for gene-
region of the lateral hypothalamus (PFLH) and are thought to be
ral anesthetic agents. Their functional classification has been
involved in the pathogenesis of narcolepsy. The orexinergic
previously discussed in the section on Ionotropic and Metabotropic
neurons display maximal activity during wakefulness and are only
Receptors in this chapter. It is likely that only a very few subtypes
minimally active during REM and NREM sleep.10,11 These neuro-
might be sensitive to general anesthetic agents when used at clinical
transmitters promote wakefulness and can be considered potential
concentrations. The principal neurotransmitter systems relevant
targets for general anesthetic agents.6,12,13
to anesthesia are the inhibitory GABA and the excitatory glutamate
systems. Other receptor types may make a smaller contribution.12
REM and NREM Sleep
REM sleep time depends on the maturity of the nervous system.7 Cys Loop Receptors (GABAA,
REM sleep time declines rapidly in early childhood from 50% at Glycine, Nicotinic, and 5-HT3)
birth to approximately 20% after 6 years.14,15 Characteristics of REM
sleep include irregular heart rate and breathing pattern as well as GABA is the major inhibitory neurotransmitter and is involved in
muscle atonia. Transsection and pharmacologic studies on animals all aspects of brain function including the regulation of wakeful-
suggest that the pons and caudal midbrain are fundamental for ness, anxiety, memory, and motor output. GABAA receptors are
REM activity, with cholinergic neurons acting as promoters and hetero-oligomeric chloride channels. The subunits are selected
monoaminergic neurons as suppressors of REM sleep.8 The from four principle families (α, β, γ, and δ) (Figure 5–5), although
switching between NREM and REM sleep is poorly understood, others have been identified. The receptors are important targets
but may be regulated by REM-on/REM-off areas in the mesopon- for many classes of drugs in clinical use including anesthetic
tine tegmentum (Figure 5–3). Both areas contain inhibitory agents. The most common mammalian CNS GABAA receptor
GABAergic neurons heavily innervating each other. The REM-on (60%) comprises two α1, two β2, and a single γ2 subunit. Each
side also contains excitatory glutamatergic neurons projecting into GABAA receptor isoform displays a distinct distribution in the
the basal forebrain, medulla, and spinal cord, which regulates elec- brain, suggesting specific physiologic functions.20,21
troencephalographic components and muscle atonia, respectively.16 Binding of GABA to the GABAA receptor complex leads to the
The existence of NREM sleep–promoting structures in the movement of chloride ions into the postsynaptic neuron, resulting
rostral hypothalamus as opposed to wake-promoting systems in in hyperpolarization of the cell membrane and inhibition.22 In the
the posterior hypothalamus was postulated almost 80 years ago.17 developing nervous system, the Cl– gradient is reversed, being
Sleep-active neurons are located in several regions of the preoptic higher on the inside than on the outside of the neurons. Thus, in
area (POA) and are concentrated in the ventrolateral POA young neurons (probably fetal stage in humans), GABAA receptors
(vlPOA) and the median preoptic nucleus (MnPN).18 Anatomic, produce depolarizing actions by opening of voltage-gated Ca2+
electrophysiologic, and immunohistochemical (c-FOS; surrogate channels and excitation. GABAA receptors produce fast (phasic)
marker of neuronal activity) evidence supports a role of these inhibition at central synapses and tonic inhibition (from ambient
neurons in promoting NREM sleep onset and maintenance by GABA) at extrasynaptic sites.23 The αβγ2 type receptors are
inhibiting and modulating multiple arousal systems.19 This hypo- localized at synapses, and the α4βδ and α6βδ receptors are
Figure 5-3. Reciprocal interaction model of

rapid eye movement (REM) sleep. 1: Positive
feedback of the REM-on neuronal population
results in gradual increased excitation of
REM-off neurons. 2: The REM-off neurons
inhibit the REM-on neurons, terminating
REM sleep (3). 4: The REM-off neurons are
self-inhibiting, terminating inhibition of
REM-on neurons and completing the cycle.
Figure 5-4. Simplified sleep switch. Reciprocal relationship between sleep-promoting area (POA) and
arousal systems (locus ceruleus [LC], dorsal raphe nucleus [DRN], tuberomamillary nucleus [TMN],
and perifornical region of the lateral hypothalamus [PFLH]). The flip-flop mechanisms prevent interme-
diate states. The cholinergic system contributes to arousal as well as rapid eye movement (REM) sleep.
GABA = gamma-aminobutyric acid; 5-HT = serotonin; IL-1b = interleukin-1β; LDT = laterodorsal
tegmental nucleus; MnPN = median preoptic nucleus; NE = norepinephrine; PGD2 = prostaglandin D2;
PPT = pedunculopontine tegmental nucleus; VLPO = ventrolateral preoptic hypothalamic area.
Adapted from reference 19 and modified after references 18 and 7.
extrasynaptic.23 The functional GABAA receptor system can be

probed with selective drugs.24 Drug specificity in vivo was esta-
blished using knockin mice with point mutations in the GABAA
receptor subunit genes and from gene knockouts.24 Zolpidem acts
preferentially at α1βγ2 receptors (producing sedation and hypno-
sis); benzodiazepines act on α1β2/3γ2 (producing sedation and
hypnosis), α2β2/3γ2 (producing anxyliolysis and myorelaxation),
α3βγ2 (producing anxyiolysis and myorelaxation), and α5βγ2
receptors (reducing memory). The latter receptor subtype is
mainly expressed in the hippocampus. Propofol and etomidate act
largely at β2- and β3-containing GABAA receptors.24 Point mutant
mice show that β2- and β3-containing GABAA receptors are lar-
gely responsible for the anesthetic actions of these two intravenous
anesthetic agents.
Other “GABAA” drugs are potent sleep inducers and act mostly
at extrasynaptic GABAA receptors. The GABAmimetic agent
gaboxodol exerts most of its effects (sleep induction) via α4βδ
receptors.25 The extrasynaptic receptors remain a potentially
important target for new drug development. Steroids, including
steroid anesthetics, activate and modulate many GABAA receptor
subtypes.26 Recombinant GABAA receptors are activated potently
by inhalational anesthetic agents,27 and GABAA receptor modula-
tion provides some component of the inhalational-induced
anesthesia. However, the in vivo contribution of these receptors
to the actions of inhalational anesthetic agents requires more
Figure 5-5. A: Subunit arrangement in γ2 (synaptic) and δ (extrasy- clarification.
naptic) containing gamma-aminobutyric acid A (GABAA) receptors. B: GABAC receptors appear to represent a relatively simple form
Schematic of an individual subunit topology. The pore-lining domain, of ligand-gated chloride channel made up of ρ subunits. Many
TM2, is shown in blue. Pink triangles represent GABA. The blue circle argue that they are really a specialized GABAA receptor subtype
represents a benzodiazepine ligand. C = cysteine; TM = transmembrane and that they should be reclassified as this. GABAC receptors are
domain. Reproduced with permission from reference 22. insensitive to bicuculline and baclofen and are most prominent in
the retina. They are not modulated by barbiturates or benzodiaze- tors are permeable only to Na+ and K+, although a specialized
pines. The superior colliculi also use GABAC receptors at some AMPA receptor subtype also alters Ca2+ permeability. NMDA
synapses. receptors carry slower integrative excitatory currents and gate
Together with GABA, glycine is a major inhibitory neurotrans- calcium ions in addition to sodium and potassium ions. The
mitter in the spinal cord and brainstem. Very closely related to the primary target for general anesthetic agents is the NMDA subtype,
GABAA receptors, glycine receptors (GlyRs) are hetero-oligomeric which is a heterotetramer consisting of an NR1 subunit combined
ligand-gated chloride channels and consist of three α and two β with one or more NR2 (A–D) subunits and, in some subtypes, an
subunits. Four α subunit genes (α1–α4) are expressed, and co- NR3 subunit. The NR1 subunit is obligatory. Two ligand recog-
expression of the β subunits is essential for targeting the receptor nition sites must be occupied for channel opening; one for
to the synapse. Strychnine is a major GlyR antagonist, whereas β- glutamate and one for glycine. The channel is blocked by Mg2+
alanine and taurine are full or partial agonists. Glycine and GABA ions. The Mg2+ block is removed by membrane depolarization.
are coreleased from interneuron terminals in the spinal cord and This property, together with the selective Ca2+ permeability of the
the brainstem.28–31 GlyRs may mediate some of the actions of channel, means that NMDA receptors can, in some contexts,
volatile anesthetic agents in the spinal cord and brainstem.5 Similar function as “coincidence detectors” used in the formation of
to GABAA receptors, GlyRs undergo developmental changes in memories. However, the slow integrative currents produced by
their expression. As with GABAA receptors, the activation of GlyRs NMDA receptor activation is also used in other types of circuits
in immature neurons induces the outflow of chloride ions, (e.g., those producing rhythm in breathing). Most inhalational
membrane depolarization, neuronal excitation, calcium influx, anesthetic agents variably inhibit NMDA receptors; ketamine is
and transmitter release. This is in contrast to the inhibitory effects an NMDA receptor antagonist, and the gases nitrous oxide and
these receptors have on mature neurons.32 The effect of anesthetic xenon inhibit NMDA receptor currents.5
agents on the GlyRs in the developing human brain is unclear. The intracellular C termini of the NMDA receptor subunits
The neurotransmitter acetylcholine exerts its pre- and postsy- couples the receptor to a huge complex of proteins termed the
naptic effects on muscarinic and nicotinic receptors. Neuronal postsynaptic density (PSD), a structure unique to glutamaterigic
nicotinic acetylcholine receptors (nAChRs) are principally ligand- synapses. The PSD comprises thousands of proteins, most of
operated cation channels (calcium, sodium, and potassium) and whose function is uncharacterized. Nevertheless, some proteins
modulate the activity of various transmitter systems. They are have been characterized. For example, the neuronal form of nitric
widely distributed in various regions of the brain potentially oxide synthase (nNOS or type I NOS) is coupled to the NMDA
relevant to general anesthesia. In the brain, the pentameric receptor via the PSD protein 95 (PSD 95), which allows tight
channels are formed from α (α2–α10) and β (β2–β4) subunits, regulation of calcium influx and regulation of type I NOS acti-
whereas the γ, δ, and ⑀ subunits are present in muscle. The α vity.36 The hippocampus is particularly rich in NMDA synapses
subunit contains the acetylcholine binding site. In addition to the and appears to play a central role in learning and memory.
acetylcholine binding site, nAChRs have associated modulatory Plasticity within the hippocampus is mediated in part through
sites for neurosteroids and acetylcholine esterase inhibitors. The changes in synaptic strength and revealed by long-term potentia-
predominant neuronal nAChRs are composed of the subunits tion and long-term depression. NMDA receptors are crucial for
(α4)2(β2)3 and (α7)5. Both receptor subtypes can be pre- or inducing these plastic changes, and blocking these receptors
postsynaptic. The α7 receptors are fast-inactivating nonselective reduces plasticity and impairs learning. Intravenous and volatile
cation channels with high Ca2+ permeability. The (α4)2(β2)3 anesthetic agents appear to impair long-term potentiation and
receptors are mainly permeable to Na+ and K+. The nAChRs may enhance long-term depression development.37 One of the down-
be involved in Parkinson and Alzheimer diseases and the stream effectors of the NMDA receptor is the second messenger
pathophysiology of schizophrenia. The main interest of nAChRs cGMP. General anesthetic agents interact with the receptor, cGMP
for the anesthesiologist is the potential as a target for analgesic formation, and degradation (Figure 5–6).
agents and neuropathic pain research. However, a narrow thera- cGMP has long been recognized as a secondary messenger, but
peutic window between analgesic efficacy and toxicity has hin- its importance in signal transduction was not been recognised
dered the development of nicotinic agonists as novel analgesics.33 until the identification of the “first messenger,” now identified as
An exciting new development is the potential neuroprotective nitric oxide (NO). Low intracellular concentrations of cGMP
effect of nicotine following spinal cord injury.34 when compared with cyclic adenosine monophosphate (cAMP)
Very closely related to the neuronal nicotinic receptors, further challenge investigations into its biologic role. cGMP is
the 5-HT3s are ligand-gated cation channels and targets for formed from GTP through the action of the enzyme guanylyl
commonly used antiemetics in anesthesia.35 The receptors are cyclase (GC), which exists in either soluble or particulate forms,
expressed throughout the brain, especially on GABAergic inter- with the soluble form being located within the cytosol and the
neurons. particulate form within the cell membrane. The particulate form
of GCs is activated through cell membrane–bound receptors such
Glutamate-Gated Ionotropic Receptors: as the natriuretic peptide receptors or intestinal peptide–binding
receptors. Binding of the ligand at the extracellular domain of
AMPA, Kainate, and NMDA these receptors results in the production of intracellular cGMP.
The glutamate receptor family mediates fast excitatory neurotrans- Soluble GC is the most abundant form in the CNS. It exists as a
mission at the majority of synapses in mammals. Glutamate heterodimer consisting of α and β subunits and is activated by the
receptors are widespread in the brain and are divided based on interaction with NO resulting in an up to 400-fold activation.
their pharmacology into three major subtypes: NMDA, AMPA, Clinically used activators of soluble GC are described as NO
and kainate. AMPA receptors are responsible for most fast exci- donors and include pharmacologic agents such as glycerol trinit-
tatory synaptic currents at glutamatergic synapses. AMPA recep- rate (nitroglycerin), sodium nitroprusside, or S-nitrosothiol
Figure 5-6. Simplified pathways of forma-

tion and degradation of cyclic guanosine
3⬘,5⬘- monophosphate (cGMP) within the
brain. Anesthetic agents have been shown
to interact with the process of the forma-
tion of cGMP, namely nitric oxide synthase
(NOS-1) and N-methyl-D-aspartic acid
(NMDA) receptors (NMDAr). GC-s =
soluble guanylyl cyclase; NO = nitric oxide;
PDE = phosphodiesterase; PSD95 =
postsynaptic density protein 95. Adapted
from reference 38.
agents. Methylene blue is a direct inhibitor of soluble GC but has ions. Nearly all AMPA receptors contain GluR2 subunits. AMPA
also been shown to inhibit NOS directly. receptors that do not contain GluR2 are permeable to Ca2+ in
The release of cGMP has effects at three levels by affecting addition to Na+ and K+. These specialized Ca2+ permeable AMPA
cGMP kinases (protein kinase G [PKG]), cGMP-regulated ion receptors are mostly found on GABAergic interneurons. AMPA
channels, and phosphodiesterase (PDE) activity. The duration of receptors show little anesthetic sensitivity.5
cyclic nucleotide signaling is dependent on the rate of cyclic nucle- The kainate receptor subtype consists of hetero-oligomers
otide formation and on its rate of breakdown. The cyclic nucleo- comprising the GluR5-7 and KA1 and KA2 subunits. The re-
tides, cAMP and cGMP, are hydrolyzed by PDE, of which 11 levance of the kainate receptor complex for general anesthesia is
isoforms are currently described. Clinically relevant human PDE unclear, but there is evidence for a presynaptic location in the
isoforms and their distributions are summarized in Table 5–1. hippocampus. Antagonists of kainate, NMDA, and AMPA recep-
Apart from the selective PDE inhibitors for PDE3 (milrinone), tors are thought to be of therapeutic benefit in stroke, head
PDE 4, (rolipram) and PDE 5 (sildenafil), there are several well- injuries, epilepsy, and pain.
known nonisoform specific inhibitors such as caffeine, theophyl-
line, and pentoxifylline. PDE isoforms 1, 2, and 3 utilize both
cyclic nucleotides as secondary messengers, whereas PDE5 and 6 Metabotropic Receptors
are specific for cGMP. PDE5 is cGMP-specific and is a well- α2-Adrenoreceptors are members of the G protein–coupled family
established and important regulator of cGMP function. The of membrane receptors and mediate the actions of the endogenous
activity of the PDE enzymes is regulated by cAMP and cGMP and catecholamines, epinephrine, and norepinephrine. Their distribu-
is subject to feedback activation and inhibition. tion is widespread, and they are located at pre- and postsynaptic
The AMPA receptor subtype is a hetero-oligomer formed from sites. Three α2-adrenoceptor proteins have been identified,
combinations of GluR1–4 subunits. When glutamate binds to the designated α2a, α2b, and α2c, with the α2a being responsible for most
receptor, the channels open to gate the movement of Na+ and K+ of the α2-adrenoceptor–mediated actions. The α2 adrenoreceptor
agonists exert their effects via coupled Gαi proteins by inhibiting
adenylyl cyclase and modifying K+/Ca2+ channel activity. α2-
TABLE 5-1. Human Phosphodiesterase Characteristics, Adrenoreceptor agonists such as clonidine and dexmedetomidine
Tissue Distribution, and Selective Inhibitors are used for the treatment of hypertension, sedation, and analgesia.
Family Main Characteristics Primary Tissue Distribution There are currently no in vitro selective agonists for the α2-
adrenoceptor subtypes.39
PDE 1 Calcium/calmodulin- Heart, brain, lung, smooth Serotonin (5-hydroxytryptamine [5-HT]) is a major neuro-
stimulated muscle transmitter in the CNS, being involved in wakefulness (see Role of
PDE 2 cGMP-stimulated Adrenal gland, heart, lung Neurotransmitters in Sleep-Awake States). 5-HT is synthesized
PDE 3 cGMP-inhibited, Heart, lung, liver, platelets from L-Tryptophan in serotonergic neurons and enterochromaffin
cAMP-selective cells. To date, 13 human subtypes of the serotonin receptor have
PDE 4 cAMP-specific, Sertoli cells, kidney, brain been identified and are subdivided into seven different classes (5-
cGMP-insensitive HT1 to 5-HT7). Serotonin transduces its effects via G protein–
PDE 5 cGMP-specific Lung, brain, smooth muscle coupled receptors, with 5-HT1 utilizing Gαi-mediated adenylyl
PDE 6 cGMP-specific Photoreceptors cyclase modulation and 5-HT2 signaling via Gαq and phospholi-
cAMP = cyclic adenosine monophosphate; cGMP = cyclic guanosine pase β (PLC-β). The 5-HT1A receptors are involved in depression
monophosphate. and anxiety, and selective serotonin re-uptake inhibitors (SSRIs)
are widely used, whereas the 5-HT1B/D receptors have emerged as

targets for migraine treatment (sumatriptan). 5-HT2 receptors may
present future targets for treatment of schizophrenia and obesity,
whereas 5-HT3 receptors are targets for the control of periopera-
tive nausea and vomiting.
DEVELOPMENTAL CONSIDERATIONS
The effects of general anesthesia on neuronal development in
humans are controversial. Some rodent animal studies have
suggested that prolonged exposure to anesthetic agents leads to
widespread apoptotic neurodegeneration in the developing brain,
deficits in hippocampal synaptic function, and persistent memory
and learning impairments.40,41 These studies need to be balanced
against evidence that withholding anesthesia during the peri-
operative period increases the incidence of intraoperative and
postoperative complications.42,43 The brain growth, synaptic dif-
ferentiation, and cellular proliferation period occurs at different Figure 5-7. Simplified illustration of the extrinsic apoptotic pathway.
times in different species. In humans, it is both a pre- and a The ligation or binding of CD95L (FasL) to its receptor CD95 (Fas)
leads to the recruitment of an adapter protein (Fas-associated death
postnatal phenomenon (from the 6th mo of gestation to 24 mo
domain [FADD]). The FADD recruits the procaspase-8, a death-
after birth), whereas in rats, mice, and other primates, it is mainly
inducing signaling complex (DISC). A high local concentration of
a postnatal phenomenon, thereby suggesting that application of active caspase 8 activates the main downstream effector, caspase 3.
the rodent model to human CNS development may not be ap- Caspase 3 triggers the characteristic cellular changes associated with
propriate.44 apoptosis. Courtesy of Dr. Morgan Blaylock.
Neuronal cell death occurs via two2 mechanisms: apoptosis
and necrosis. Apoptosis, programmed cell death or cellular suicide,
extrinsic pathway through specialized death surface receptors,
is a kinetic event that can be triggered by a variety of stimuli such
whereas in the intrinsic pathway, apoptosis is induced from within
as cytokines, hormones, viruses, and toxic neurologic insults.
the cell, mainly through mitochondrial activation in response to
Necrosis, in contrast to apoptosis, can affect a number of conti-
extracellular cues and internal insults such as DNA damage. The
guous cells and trigger an inflammatory reaction and/or death of
extrinsic pathway plays a fundamental role in the maintenance of
cellular structures in the surrounding tissue. Necrosis, which
tissue homeostasis, especially in the immune system. The extrinsic
typically occurs as a result of neuronal injury or cytotoxic expo-
signaling pathway initiates apoptosis by triggering a trans-
sure, is a pathologic or an accidental mode of cellular death. It is
membrane receptor–mediated interaction (Figure 5–7). The
characterized by irreversible swelling of the cytoplasm and the
intrinsic apoptosis pathway is induced from within the cell, mainly
mitochondria (Table 5–2).
through activation of mitochondria in response to extracellular
The mechanism of apoptosis is a highly complex network of
stimuli and internal insults such as DNA damage.47,48
energy-dependent cascades. Characteristic morphologic features
One of the first processes involved in the mitochondrial ap-
that define apoptosis are dependent on caspase activation and
optotic pathway is increased permeability of the outer mitochon-
cleavage of specific cellular proteins or the liberation of “death”
drial membrane releasing mitochondrial molecules, most
provoking substrates within the cell. Apoptosis is, therefore,
importantly cytochrome C, into the cytoplasm. The primary me-
considered a caspase-mediated form of cell death.45 There are
chanism of the increased permeability of the outer mitochondrial
two main pathways of caspase-mediated cell death: the extrinsic
membrane during apoptosis involves members of the Bcl-2 family
or death receptor–mediated pathway and the intrinsic or
of proteins such as Bax and Bid. Once released, cytochrome C binds
mitochondria-dependent pathway.46 Apoptosis is induced in the
to an adaptor molecule termed Apaf-1, which recruits procaspase-
9, then designated the apoptosome. This is required for the cleavage
TABLE 5-2. Comparison of Contrasting Morphologic and activation of caspase-3, the main effector caspase, by caspase-
Features of Apoptosis and Necrosis 9 (Figure 5–8). It remains to be determined whether general
Apoptosis Necrosis anesthesia demonstrates a preference to a particular pathway,
which may then influence the choice of general anesthetic agents.
Chromatin condensation Nuclear swelling
Cell shrinkage Cell swelling
Preservation of organelles Disruption of organelles FUTURE DEVELOPMENTS
and cell membranes The better understanding of the physiology of sleep and wakeful-
Rapid engulfment by Rupture of cell membrane and ness, neurotransmitters, and neuronal networks has led to new
neighbouring cells release of cellular contents insights into possible targets of general anesthesia.5 Further
preventing pericellular
research will undoubtedly lead to the development of anesthetic
inflammation
agents targeting specific neurotransmitter systems and potentially
Maintenance of integrity Inflammatory response
allow real-time monitoring of its effects. If the current concern
Ingested by phagocytes
regarding the impact of general anesthesia on neurodevelopment
Figure 5-8. Simplified illustration of the in-

trinsic apoptotic pathway. Cytochrome C is
released from the mitochondria as a result of
Bax or of caspase 2 activation. The released
cytochrome C binds to an adapter molecule
termed Apaf-1, which via oligomerization of
procaspase 9 forms the apoptosome, ultimately
leading to caspase 3 activation and apoptosis.
Courtesy of Dr. Morgan Blaylock.
is verified, it remains to be seen whether this will change the cur- 13. Kelz MB, Sun Y, Chen J, et al. An essential role for orexins in emer-
rent standard practice in pediatric anesthesiology. The integration gence from general anesthesia. Proc Natl Acad Sci U S A. 2008;105:
and translation of emerging evidence in basic neuroscience 1309–1314.
research into clinical studies will guarantee an exciting future for 14. Kohyama J, Shimohira M, Iwakawa Y. Maturation of motility and
motor inhibition in rapid-eye-movement sleep. J Pediatr. 1997;130:
basic research in the field of pediatric anesthesiology.
117–1122.
15. Iglowstein I, Jenni OG, Molinari L, Largo RH. Sleep duration from
infancy to adolescence: reference values and generational trends.
REFERENCES Pediatrics. 2003;111:302–307.
1. Meyer H. Welche Eigenschaft der Anaesthetica bedingt ihre narko- 16. Lu J, Sherman D, Devor M, Saper CB. A putative flip-flop switch for
tische Wirkung? Arch Exp Pathol Pharmakol (Nauyn-Schmiedeberg’s). control of REM sleep. Nature. 2006;441:589–594.
1899;42:109–118. 17. Von Economo C. Sleep as a problem of localization. J Nerv Ment Dis.
2. Overton CE. Studien über die Narkose zugleich ein Beitrag zur 1930;71:249–259.
allgemeinen Pharmakologie. Gustav Fischer, Jena, Germany. 1901 18. Szymusiak R, Gvilia I, McGinty D. Hypothalamic control of sleep.
3. Franks NP, Lieb WR Do general anesthetics act by competitive Sleep Med. 2007;8:291–301.
binding to specific receptors? Nature. 1984;310:599–601. 19. Saper CB, Chou TC, Scammell TE. The sleep switch: hypothalamic
4. Franks NP, Lieb WR. Volatile general anesthetics activate a novel control of sleep and wakefulness. Trends Neurosci. 2001;24:726–731.
neuronal K+ current. Nature. 1988;333:662–664. 20. Rudolph U, Antkowiak B. Molecular and neuronal substrates for
5. Franks NP. General anaesthesia: from molecular targets to neuronal general anaesthetics. Nat Rev Neurosci. 2004;5:709–720.
21. Wisden W, Laurie DJ, Monyer H, Seeburg PH. The distribution of 13
pathways of sleep and arousal. Nat Rev Neurosci. 2008;9:370–386.
GABAA receptor subunits in the rat brain. I. Telencephalon,
6. Nelson LE, Guo TZ, Lu J, et al. The sedative component of anesthesia
diencephalons, mesencephalon. J Neurosci. 1992;12:1040–1062.
is mediated by GABAA receptors in an endogenous sleep pathway.
22. Goetz T, Wulff P, Wisden W. GABAA receptors—molecular biology,
Nat Neurosci. 2002;5:979–984.
cell biology, and pharmacology. In: Squire LR, editor. Encyclopedia
7. McCarley RW. Mechanisms and models of REM sleep control. Arch
of Neuroscience. Oxford: Academic Press; June 2009.
Ital Biol. 2004;142:429–467. 23. Farrant M, Nusser Z. Variations on an inhibitory theme: phasic and
8. McCarley RW. Neurobiology of REM and NREM sleep. Sleep Med. tonic activation of GABAA receptors. Nat Rev Neurosci. 2005;6:
2007;8:302–330. 215–229.
9. Hallanger AE, Wainer BH. Ascending projections from the pedun- 24. Rudolph U, Mohler H. Analysis of GABAA receptor function and
culopontine tegmental nucleus and the adjacent mesopontine dissection of the pharmacology of benzodiazepines and general
tegmentum in the rat. J Comp Neurol. 1988;274:483–515. anesthetics through mouse genetics. Annu Rev Pharmacol Toxicol.
10. Alam MN, Gong H, Alam T, et al. Sleep-waking discharge patterns of 2004;44:475–498.
neurons recorded in the rat perifornical lateral hypothalamic area. 25. Chandra D, Jia F, Liang J, et al. GABAA receptor alpha 4 subunits
J Physiol. 2002;538:619–631. mediate extrasynaptic inhibition in thalamus and dentate gyrus and
11. Lee MG, Hassani OK, Jones BE. Discharge of identified orexin/ the action of gaboxadol. Proc Natl Acad Sci U S A. 2006;103:15230–
hypocretin neurons across the sleep-waking cycle. J Neurosci. 2005; 15235.
25:6716–6720. 26. Belelli D, Lambert JJ. Neurosteroids: endogenous regulators of the
12. Sonner JM, Antognini JF, Dutton RC, et al. Inhaled anesthetics and GABAA receptor. Nat Rev Neurosci. 2005;6:565–575.
immobility: mechanisms, mysteries, and minimum alveolar anes- 27. Mihic SJ, Ye Q, Wick MJ, et al. Sites of alcohol and volatile anaesthetic
thetic concentration. Anesth Analg. 2003;97:718–740. action on GABAA and glycine receptors. Nature. 1997;389:385–389.
28. Song W, Chattipakorn SC, McMahon LL. Glycine-gated chloride 39. Tobias JD. Dexmedetomidine: applications in pediatric critical care
channels depress synaptic transmission in rat hippocampus. and pediatric anesthesiology. Pediatr Crit Care Med. 2007;8:115–131.
J Neurophysiol. 2006;95:2366–2379. 40. Jevtovic-Todorovic V, Hartman RE, Izumi Y, et al. Early exposure to
29. Chéry N, de Koninck Y. Junctional versus extrajunctional glycine and common anesthetic agents causes widespread neurodegeneration in
GABA(A) receptor-mediated IPSCs in identified lamina I neurons the developing rat brain and persistent learning deficits. J Neurosci.
of the adult rat spinal cord. J Neurosci. 1999;19:7342–7355. 2003;23:876–882.
30. Jonas P, Bischofberger J, Sandkühler J. Corelease of two fast neuro- 41. Fredriksson A, Pontén E, Gordh T, Eriksson P. Neonatal exposure to
transmitters at a central synapse. Science. 1998;281:419–424. a combination of N-methyl-D-aspartate and gamma-aminobutyric
31. O’Brien JA, Berger AJ. Cotransmission of GABA and glycine to brain acid type A receptor anesthetic agents potentiates apoptotic neuro-
stem motoneurons. J Neurophysiol. 1999;82:1638–1641. degeneration and persistent behavioral deficits. Anesthesiology.
32. Ye JH. Regulation of excitation by glycine receptors. Results Probl Cell 2007;107:427–436.
Differ. 2008;44:123–143. 42. Anand KJ, Sippell WG, Aynesley-Green A. Randomised trial of
33. Vincler M. Neuronal nicotinic receptors as targets for novel anal- fentanyl anaesthesia in preterm babies undergoing surgery: effects
gesics. Expert Opin Investig Drugs. 2005;14:1191–1198. on the stress response. Lancet. 1987;1:62–66.
34. Garrido R, Springer JE, Hennig B, Toborek M. Apoptosis of spinal 43. Anand KJ, Sippell WG, Schofield NM, Aynsley-Green A. Does
cord neurons by preventing depletion nicotine attenuates arachidonic halothane anaesthesia decrease the metabolic and endocrine stress
acid-induced of neurotrophic factors. J Neurotrauma. 2003;20: responses of newborn infants undergoing operation? Br Med J (Clin
1201–1213. Res Ed). 1988;296:668–672.
35. Tramèr MR. [Postoperative nausea and vomiting] (German). Anaes- 44. Dobbing J, Sands J. Comparative aspects of the brain growth spurt.
thesist. 2007;56:679–685. Early Hum Dev. 1979;3:79–83.
36. Tao F, Johns RA. Effect of disrupting N-methyl-D-aspartate receptor– 45. Samali A, Zhivotovsky B, Jones D, et al. Apoptosis: cell death defined
postsynaptic density protein-95 interactions on the threshold for by caspase activation. Cell Death Differ. 1999;6:495–496.
halothane anesthesia in mice. Anesthesiology. 2008;108:882–887. 46. Hengartner MO. The biochemistry of apoptosis. Nature. 2000;407:
37. MacDonald JF, Jackson MF, Beazely MA. G protein–coupled recep- 770–776.
tors control NMDARs and metaplasticity in the hippocampus. 47. Li P, Nijhawan D, Budihardjo I, et al. Cytochrome c and dATP-
Biochim Biophys Acta. 2007;1768:941–951. dependent formation of Apaf-1/caspase-9 complex initiates an
38. Engelhardt T, Chan MK, McCheyne AJ, et al. The effect of varying apoptotic protease cascade. Cell. 1997;91:479–489.
continuous propofol infusions on plasma cyclic guanosine 3⬘,5⬘- 48. Zou H, Henzel WJ, Liu X, et al. Apaf-1, a human protein homologous
monophosphate concentrations in anesthetized children. Anesth to C. elegans CED-4, participates in cytochrome c–dependent activa-
Analg. 2007;105:616–619. tion of caspase-3. Cell. 1997;90:405–413.
Central Nervous System:

Anatomy and Physiology 6
Bruno Bissonnette C H A P T E R
INTRODUCTION development of the primitive streak and Hensen’s node. The

notochord extends rostrally from Hensen’s node (stage 7), and
It is important for anesthesiologists to understand the anatomic during the next 48 hours, fusion of the neural folds occurs at the
and psychological differences between an adult and a newborn, level of the third or fourth somite (of which there are six or seven
an infant, and a growing child.1 It is even more important when by this stage). The rhombencephalon or hindbrain corresponds
the brain is involved. Challenges in neuroanesthesia are most often to this area.6 By stage 11, neural folds extend to the level of the
the result of the lack of knowledge of the disturbances caused by colliculi. The terminal hole is distorted by the primordia of the
a pathologic process affecting the central nervous system (CNS). thalamus and the corpus striatum. The neuroectoderm is con-
These alterations can be significant in the anesthesia preparation nected to the amniotic cavity through the posterior neuropore at
and perioperative management. this stage.
The CNS does not reach maturity until the end of the first year
of life. Many pathologic processes result from abnormal neuro-
embryologic development, which may affect the physiology of the Later Stage
brain as a whole. The understanding of cerebral physiology is an After closure of the anterior neuropore (stage 11), an interval
important part of both neuroanesthesia and intensive care in order occurs before differentiation of the telencephalon or forebrain.
to reduce both the neuromorbidity and the mortality. It is essential Bilateral cerebral vesicles appear in stage 15; they connect later to
to know the embryology, anatomy, and physiology of this vital the neural tube, thus, creating the foramina of Monro. As these
system in order to provide good clinical care of the child with structures enlarge, areas that will later develop into the lobes of
intracranial or spinal pathology. the brain become identifiable: frontal and parietal areas (stage 17),
occipital area (stage 19), and temporal pole (stage 23). The main
differentiation of the cerebral cortex occurs during the third
NEUROEMBRYOLOGY trimester.7 However, even at this stage of development, the CNS
AND DEVELOPMENT bears no resemblance to its final anatomic configuration. As the
brain develops, the external appearance changes. The surface of
The three major processes by which the CNS develops are the brain begins to develop fissures and sulci. As gyri develop,
(1) neurulation, (2) canalization, and (3) retrogressive differen- most of the surface of the cortex becomes buried. During stage 22,
tiation (Table 6–1). a layer of neuroblasts derived from pyramidal cells migrates to the
marginal zone, forming the primordium of the cortical gray
Neurulation matter. During stage 23, the caudate nucleus is divided from the
putamen and globus pallidus by the progressive development of
Early Stage upper and lower fibers. The early development of the cerebellum
Neural tube development occurs in the first 56 to 60 days after occurs mainly about 1 month after the embryonic period begins
fertilization2–5 (see Table 6–1). During stage 6 (second wk of de- even though, at this stage, the paired cerebellar primordia have
velopment), the nervous system begins to appear with the not developed an identifiable pattern. The anlage of the cere-
bellum may be found when the pontine and cervical flexures begin
to form (stage 13). The cerebral nuclei derived from the dience-
TABLE 6-1. Phases and Stages of Neural Development phalon or midbrain appear at various stages, with the thalamic
During Gestation structure appearing at stage 15. As the embryo makes the transi-
tion to fetus, the CNS is still relatively primitive, with the
Phases Stages Age, d Outcome
development of the brain occurring during the later phases of
1. Neurulation 7 16–28 Brain, spinal cord gestation and into the postnatal period.
through L2–4
2. Canalization 13–20 30–52 Sacral, coccygeal
segments Canalization and Retrogressive
3. Retrogressive 18–Birth 46–after Filum terminale Differentiation
differentiation birth Canalization is the process of development of the neural tube
Modified from reference 6, with permission. caudal to that created by neurulation, which forms the lower
CHAPTER 6 ■ Central Nervous System: Anatomy and Physiology 81
lumbar, sacral, and coccygeal segments. During this process, a embryo develops, primordial endothelium-lined channels form a
secondary phase of caudal neural tube development occurs with a plexiform network from which arteries and veins develop (second
proliferation of cells in the wall of the neural tube. This leads to an period, stages 10–13). Thus, circulation to the CNS is established.
excess of segments. Retrogressive differentiation is the process by In the third period, direct connections between the arterial side
which these excess segments are remodeled to form the cauda and the primitive aorta and between the venous side and the
equina and the filum terminale.8 Eventually, the conus medullaris jugular system are formed. The arterial and venous systems are
is brought to its adult level opposite L1–2. divided in the fourth period (stage 19) and extend into fetal
development. The fifth and final stage extends into the postnatal
period and is characterized by late histologic changes in the vas-
Neural Tube Defects and Embryology cular walls as they become adult in form. Most vascular malforma-
Any defect in the development of the CNS may be referred to as a tions are believed to occur before the arterial walls thicken when
neural tube defect. These may be classified by the extent of the embryo is about 40 mm long and represents a structural defect
involvement of the CNS: (1) those involving the brain and spinal in the primitive arteriolar-capillary network.10
cord, (2) those involving the brain alone, and (3) those involving
the spinal cord alone. If both the brain and the spinal cord fail to
undergo complete neurulation, a condition of total dysraphism or NEUROANATOMY
craniorachischis occurs. Anencephaly results when the brain alone Gross Anatomy
fails to close. Many abnormalities associated with the later stages
of development of the nervous system may be of significance to In order to understand the complex nature of the CNS, it is
the pediatric neuroanesthetist. Migrational abnormalities are essential to have a working knowledge of its anatomy. The
associated with schizencephaly (clefts in the cerebral wall), neuroanesthetist should have a clear understanding of the
pachygyri (sparse, broad gyri), and polymicrogyria. Lissencephaly effects of trauma and other pathologic processes on the function
(smooth brain) may result from migrational abnormalities or of the brain and spinal cord in order to introduce manage-
earlier defects in development. Agenesis of the corpus callosum is ment strategies to minimize the disruption to the functioning of
often associated with migrational abnormalities, although it is not the CNS.
considered to be a migrational abnormality in itself. Myeloceles The CNS is protected by the calvarium and vertebral column.
result from caudally defective neurulation. If an enlarged sub- At birth, the calvarium is composed of ossified plates covering the
arachnoid space is present dorsally to the defective cord, the dura mater, separated by fibrous sutures and the fontanelles
condition of meningomyelocele is present. (Figure 6–1). Two fontanelles are present at birth. The posterior
fontanelle closes at 2 to 3 months, whereas the anterior fontanelle
closes between 10 to 18 months. This fibrous membrane will
The Ventricular and Cerebrospinal normally become ossified during adolescence.11 The single
Fluid Systems continuous space within the calvarium and the vertebral column
contains the brain parenchyma (neurons, glial tissue, and
During stage 12, the posterior neuropore closes and, at that point, interstitial fluid), cerebrospinal fluid (CSF; 10%), and the cerebral
the ventricular system is closed. It now consists of the systems blood volume (CBV). An increase in the volume of any of these
within the prosencephalon, diencephalon, mesencephalon, rhom- compartments results in compression and displacement of vital
bencephalon (metencephalon, nyencephalon), and central canal components of the CNS because of a lack of extensibility (e.g.,
of the spinal cord. The roof of the rhombencephalon thins during impedance) within the subdural space and low compliance of the
stage 14 and evaginations of the cerebral hemispheres develop system as a whole. Any process that causes an increase in the
(stage 15). The anlage of the lateral ventricles, third ventricle, and volume of the tissue compartments within the craniospinal system
the foramen of Monro become demarcated, and by stage 20, the (tumor growth, hydrocephalus, hemorrhage) may cause a rapid
cerebral hemispheres have overlapped the diencephalons, with the rise in intracranial pressure (ICP). It is essential to note that the
lateral ventricles becoming the largest of the ventricular system. ability to compensate for an acute rise in ICP even in presence of
The foramen of Magendie is created from a perforation in the roof an open fontanelle is virtually nonexistent because of the lack of
of the fourth ventricle. About 10 weeks later in the development of distensibility of the dura mater. The dura mater offers high resis-
the CNS, the foramina of Luschka develop. As the tectum and tance to a rapid rise in volume of any of the tissue compartments
tegmentum enlarge, the aqueduct of Sylvius narrows. The choroid enclosed within it.12 Conversely, a slow rise in ICP may allow a
plexuses differentiate and the brain mass increases, reducing the more progressive expansion of the nonfused fontanelles and
volume of the ventricular system. The ventricular system normally separation of the fibrous sutures.13 It is possible to use the anterior
terminates after birth at the level of the obex of the caudal floor of fontanelle to assess the ICP in the infant either by clinical
the fourth ventricle as the spinal canal is obliterated by cellular palpation or with the use of skin transducers.14,15
proliferation within the spinal cord. In the Arnold-Chiari malfor- At birth, the brain weighs about 335 g (10–15% of body weight)
mation complex, the embryologic development of the caudal cere- and grows rapidly throughout the first year of life, doubling
bellum is abnormal; the central canal remains enlarged, causing its weight by 6 months. At 1 year of age, the brain weighs 900 g;
hydrosyringomyelia. at 2 years, 1000 g; finally reaching its adult weight by 12 years
(1200–1400 g). At this point it makes up about 2 % of the body’s
weight.11 The intracranial space may be separated into two com-
Cerebrovascular Development partments by a layer of dura mater and the tentorium cerebelli.
There are five periods of development of the cerebral vasculature.9 These are the supratentorial compartment and the infratentorial
Initially (up to stage 8 or 9), there are no arteries or veins. As the compartment.
Figure 6-2. Midsagittal nuclear magnetic resonance imaging (MRI)

scan shows the supratentorial (A) and posterior fossa (B) structures.
The white arrow shows the tentoria cerebelli and the straight sinus.
structures. Obstruction of the anterior cerebral artery may lead to

ischemia. As the pressure within the supratentorial compartment
increases, the diencephalon, cerebral peduncle, oculomotor ner-
Figure 6-1. Three-dimensional image constructed from a computed ves, posterior communicating artery, and uncus of the temporal
tomography scan of a 7-month-old infant showing the craniofacial lobe, which sits in the middle cranial fossa adjacent to the incisura,
contours. The face is smaller than the cranium. The V shape downward will herniated, leading to contralateral hemiplegia, ipsilateral large
of the face helps us to understand why the mouth of the infant is small. irregular pupil, and abnormal posturing.
The open anterior fontanelle is easily seen. The coronal and metopic
sutures are also visualized.
The Infratentorial Compartment
The Supratentorial Compartment The infratentorial compartment, often described as the posterior
The supratentorial compartment is the larger compartment of the cranial fossa, comprises the cerebellum, the pons, and the medulla
craniospinal space and includes the anterior and middle cranial oblongata. It is delineated by the anterior and posterior occipital
fossae. It contains the cerebral hemispheres, which consist of three portions of the skull. The consequences of lesions in this area can
lobes (frontal, parietal, and parieto-occipital) and the dience- be very severe because of compression of many vital structures
phalon, which comprises the thalamus, hypothalamus, epithala- such as the reticular activating system, the cardiac and respiratory
mus, and subthalamus. The diencephalon (rostral end of the control centers, and the cranial nerves. The cerebellum, which is
brainstem) occupies the central part of the supratentorial com- the largest structure in the infratentorial compartment, is mainly
partment, the size of which is determined by the calvaria and associated with the regulation of posture, muscle tone, and coor-
tentorium cerebelli (Figure 6–2). The tentorium is a tent-shaped dination. Hence, lesions to the cerebellum may lead to an unsteady
dural septum forming a roof over the posterior cranial fossa gait, hypotonia, and tremor. Increased pressure within the poste-
between the supratentorial compartment and the cerebellum. It rior fossa may lead to a pressure differential across the foramen
has an oval opening (tentorial incisura) between the anteromedial magnum, the pressure cone phenomenon. This leads to herniation
aspects of the right and the left leafs through which the brainstem of the cerebellar tonsils (posteroinferior prolongations of the
passes from the middle to the posterior cranial fossa. The cerebral cerebellum) through the foramen magnum. This condition is
hemispheres are separated by the falx cerebri, a sickle-shaped commonly fatal and may be preceded by relatively subtle clinical
portion of dura in the longitudinal fissure separating the hemis- signs.
pheres. If there is a primary brain injury severe enough to cause
major hemorrhage or edema, both the inferior edge of the falx
cerebri and the tentoria incisura become important sites of
The Spinal Canal Compartment
secondary injury. A differential pressure may occur across the The spinal canal compartment contains the spinal cord and the
incisura, leading to herniation of the brainstem and other vital CSF. The spinal cord is the continuation of the medulla oblongata
Figure 6-3. Position of the distal end of the spinal cord in relation to the vertebral column and meninges according to
the age of development of the patient. The sacral nerve (S1) root must stretch upward significantly to accommodate the
upward change in position of the spinal cord. A: 24 Weeks. B: Newborn. C: 8-Year-old child. D: Adult.
and is a cylindrical object, flattened slightly anteriorly and The venous sinuses of the dura mater are the most important
posteriorly where the vascularization occurs. Following retrogres- components of the venous drainage of the brain. They are valveless
sive differentiation at birth, the spinal cord ends at the interver- channels between the dura mater and the cranial periosteum.
tebral level of L3–4, reaching the usual adult level of L1–2 at the Their endothelium is continuous with that of the veins draining
age of 8 (Figure 6–3). The adult spinal cord is 42 to 45 cm in length
and may actually terminate anywhere between T12 and L3. The
spinal cord occupies approximately 66% of the entire vertebral
space, the rest being occupied by the CSF. The intradural space
extends to the level of S2, and therefore, the segment of L2 to S2
consists of a reservoir of CSF. This may act as a mechanism to
compensate for increases in ICP. However, acute decompression of
the spinal compartment by lumbar puncture may lead to trans-
foraminal herniation, because the spinal compartment is larger
than the posterior fossa and has greater compliance secondary to
the slight distensibility of the spinal dura mater and the compres-
sibility of the venous plexuses.
Vascular Anatomy
Blood flow to the brain is supplied by two sets of paired arteries,
the internal carotid and the vertebral arteries. Each of these four
arteries contributes to the circle of Willis or circulus arteriosus
cerebri formed by the posterior cerebral artery, the posterior
communicating artery, the internal carotid siphon, the anterior
cerebral artery, and the anterior communicating artery (Figure
6–4). The circle of Willis prevents cerebral ischemia and infarction
in the event of failure of one of these blood supplies to the brain;
however, this protective mechanism is incomplete. In most cases
of occlusion to one of the vessels of the circle of Willis, insufficient Figure 6-4. The cerebral arterial circle of Willis and its principal
blood is supplied by the collateral routes. Up to 28% of individuals branches in a 9-month-old child. 1 = Basilar artery; 2 = posterior
lack at least one anastigmatic component of the arterial circle, the cerebral artery; 3 = posterior communicating artery; 4 = middle
most commonly absent part being the anterior communicating cerebral artery; and 5 = anterior cerebral artery. The black arrow
artery. shows the anterior communicating artery.
into them. There is no muscle in the sinus walls, and hence, tears Venous drainage from the spinal cord is via two systems, the
to the venous sinuses during surgery may lead to severe hemorrh- internal and the external venous plexuses, which communicate
age. The superior sagittal sinus, situated in the midline, is particu- with each other and with the segmental systemic veins and the
larly vulnerable during surgery for correction of craniosynostosis portal system.17 The internal venous plexus surrounds the dura
and during a morcellation craniectomy. Most commonly, this and the posterior longitudinal ligament in a weavelike pattern of
sinus ends by becoming the right transverse sinus, which runs thin-walled, valveless veins. At each segmental level, the plexus
above the tentorium cerebelli to the S-shaped sigmoid sinus receives veins from the cord plus a basivertebral vein from the
laterally. Most of the blood in the venous sinuses of the dura enters vertebral body. The occipital and basilar sinuses of the brain
the sigmoid sinuses and then into the venous enlargements or communicate with this system via the foramen magnum. Venous
superior bulbs of the internal jugular veins. The blood of the blood from the internal venous plexus drains into the interverte-
inferior petrosal sinuses enters the internal jugular veins directly. bral veins passing through the intervertebral and sacral foramina
The smallest sinus, the occipital sinus, communicates with the to the vertebral, intercostal, lumbar, and lateral sacral veins. Veins
internal vertebral plexus. The cavernous sinuses situated around draining vertebral bodies form the external venous plexuses,
the sella turcica join the inferior petrosal sinuses. which join to form the anterior vertebral plexus. Veins draining
the ligamentum flavum form the posterior venous plexus.
Vascular Anatomy of the Spinal Cord
Blood supply to the spinal cord is separated into anterior and NEUROPHYSIOLOGY
posterior circulations with no collateral flow between them. Both Cerebral Metabolism and Ionic Transport
circulations arise from the vertebral arteries, supplemented by the
intercostal and lumbar vessels from the descending aorta (Figure The physiologic structure and function of the human brain
6–5). A single anterior spinal artery supplies the ventral two thirds represent one of the most complex structures of all biologic
of the spinal cord, which includes the corticospinal tracts and the systems. A young adult has about 100 million neurons each
motor neurons. The dorsal one third is supplied by paired connected to other neurons through 100 to 1000 synapses. The
posterior spinal arteries that form a plexus on the surface of the two major elements involved in this complex system are the
cord.16 The ventral spinal cord is supplied by the anterior spinal innumerable synaptic connections and the presence of several
artery and, to a variable extent, by collateral flow from radicular intra- and intercellular messenger, the last ones acting as
arteries arising from the aorta. The anterior spinal artery may not interneuronal mediators.18 The energy required to maintain and
be continuous throughout its length. Its branches run circum- regulate these biologic systems is somewhat extensive. After
ferentially on the surface of the spinal cord or penetrate the 8 years of age, the human brain weighs only 2% of the total body
parenchyma and divide within the gray matter (sulcal branches). mass. However, it consumes more than 20% of all the adenosine
Radicular arteries arise from intercostal and lumbar arteries on triphosphate (ATP) produced by the entire body. Although
the left side of the aorta. Of the 62 radicular arteries present during metabolic activity is necessary to sustain the complex interactive
intrauterine life, only 5 to 8 are still present in the adult. Forty-five functions of the brain, it also renders the neuronal tissue
percent of the population has fewer than 5 radicular arteries (1–2 particularly vulnerable to any reduction of energetic reserve.
cervical, 2–3 thoracic, and 1–2 lumbar). Hence, there are certain Under normal physiologic conditions, the main substance used
watershed areas of the cord (upper thoracic and lumbar levels) to produce cerebral energy is D-glucose (2-deoxyglucose being the
that are very vulnerable to ischemia. The great radicular artery of only molecular form capable of crossing the blood-brain barrier
Adamkiewicz arising from the aorta between the eighth thoracic [BBB] in both directions).19 D-Glucose is the only source of
and the third lumbar roots provides up to 50% of the entire spinal metabolic energy used by the Krebs cycle to produce ATP. Any
cord blood flow and, therefore, is crucial to the blood supply to important decrease in the supply of glucose leads to coma and
the cord. It may be particularly vulnerable to damage during aortic possibly to cellular and cerebral death. It is interesting to note that
or spinal surgery and trauma. the brain, despite its enormous glucose requirement (6.8 mg
glucose/100 g/min in a child as opposed to 5.5 mg glucose/100 g/
min in an adult), does not store glucose and does not elaborate
any glycogen. The muscular and hepatic reserves of glycogen are,
respectively, 10 and 100 times that of the brain. Thus, with normal
consumption of ATP, the brain’s glucose reserve secures only
3 minutes of energy supply to maintain normal cerebral function.
The brain depends almost, if not entirely, on blood perfusion for
a daily glucose consumption of 120 g. D-Glucose comes from the
aerobic glucogenesis of the liver and muscles. A minimum
quantity is synthesized de novo through amino acids, glycerol, and
intermediate metabolites of the Krebs cycle. In infants and young
children, the use of ketones (also an important source of energy in
the adult after prolonged starvation) contributes to the supply of
energy to the brain. The use of these metabolic products such as
beta-hydrobutyrate and acetoacetate is normal in the child. The
ability of the CNS to use ketones as substrate to energy is essential
Figure 6-5. Arterial blood supply to the spinal cord. 1 = posterior when there is a drop in glucose supply. An adult requires a period
spinal artery; 2 = radicular artery; and 3 = anterior spinal artery. of 12 to 16 hours to increase ketone production and begins to
utilize them as energy substrate. More than 50% of all oxygen used Cerebral Blood Flow and CBV
by the brain during a period of starvation is used to oxidize ketone
bodies. However, ketones produce only enough energy to main- The cerebral blood flow (CBF) is one of the variables that can be
tain vital cellular functions but, do not, for example, allow recovery modified by the anesthesiologist. It is indirectly linked to the
from a hypoglycemic coma. intracerebral blood volume. Manipulation of the CBF helps to
D-Gglucose penetrates the brain through a transport mecha- control ICP. Although the presence of intracranial pathology may
nism assisted by a specific membrane transporter having saturabi- change or even paradoxically inverse the relationship between ICP
lity properties (first-order kinetics) and competitive affinity to the and CBF, in most cases, the use of an anesthetic technique to alter
receptor. Aerobic glycolysis and phosphorylative oxidation CBF remains an efficient and powerful tool for the anesthesio-
produce ATP, CO2, and H2O. Aerobic glycolysis in the internal logist.
membrane of the mitochondria creates 30 ATP directly whereas An adult brain weighs 1400 g on average and receives about
6 ATP come from 2 NADH (nicotinamide adenine dinucleotide, 20% of the cardiac output at rest. It controls its own O2 supply
reduced form) generated in the cytosol during glycolysis. Aerobic according to its metabolic requirement for O2 and glucose (meta-
mitochondrial oxidative metabolism produces 18 times more ATP bolism flow coupling). Current techniques used to measure CBF
per molecule of glucose than cytoplasmic anaerobic glycolysis in do not give a precise estimation of global CBF. The use of positron
which NADH cannot be retransformed into NAD (nicotinamide emission tomography (PET) confirmed that the mean CBF in
acid dehydrogenase) because of the lack of O2. In case of anaerobic the adult is 50 mL/100 g/min with a variability of 30 to 90 mL/
metabolism, NAD is regenerated by the transformation of pyru- 100g/min.23 In the pediatric population, CBF is 42 to 48 mL/min/
vate into lactate. Basic glucose consumption by the brain is 100 g in term neonates, 90 mL/100 g/min between the ages of 4
approximately 0.3 to 0.8 mmol/100 g/min, which is higher than and 6 months, peaks around 110 mL/min/100 g at 3 to 4 years to
that reported for the heart (6–9 mmol/min).20 The combustion of subsequently decrease to approximately 78 mL/min100 g at
1 glucose molecule requires 6 molecules of O2. In the presence of 9 years24–26 The global CBF of children from 6 months to 4 years
O2, 90 to 95% of all carbohydrates are consumed by the brain of age is twice than of the adult. An accelerated cerebral develop-
through the phosphor-oxidative pathway. The production of ment during this period explains the important increase in CBF.
cerebral lactate represents less than 4% of the glucose metabolized Nevertheless, it has been reported that CBF in children born
in presence of O2. prematurely is much lower than adults, varying significantly from
Of all human organs, the brain is the organ that consumes the 5 to 23 mL/min/100g in 26 to 28 weeks premature newborns to
second largest amount of O2, after the glomic cells of the carotid approximately 50 mL/100g/min at term.27,28 This reduction of CBF
body known as the ultimum moriens (the last cells to die). The is associated with the presence of decreased cerebral mass and
total O2 consumption of the brain or the cerebral metabolic rate metabolism as well as the significant absence of cerebral develop-
for oxygen (CMRO2) in a young man (average age, 21 y) is 3.5 mL ment in the first few weeks of life. The CBF of gray matter is higher
O2/100 g/min.21 It is almost the same in an elderly person (average than that of the corresponding white matter.29 The perfusion of
age, 71 y). However, children (average age, 6 y) have a significantly the cerebral white matter represents about one third of that of the
increased CMRO2 (5.5 mL O2/100 g/min). This increase in O2 gray matter, and this ratio remains constant during the entire
consumption is probably related to the energetic requirements of lifetime.30 This implies that the age-related reduction of cerebral
growth. The brain is the organ most sensitive to lack of O2. For metabolism and CBF is mainly because of a loss of synapses or a
this reason, it is capable of regulating the use of O2 according to its drop in their activity rather than to a neuronal anatomic loss.
needs. The interstitial cerebral compartment is maintained constant
O2 is necessary for the synthesis and maintenance of mitochon- by the presence of the astrocytes and the tight junctions (9 Å) that
drial ATP. The ATP produced by aerobic glycolysis is almost form the BBB (Figure 6–6). The BBB is impermeable to electroly-
entirely utilized for maintaining transmembrane electric functions tes and allows osmotic pressures to equilibrate by a water shift be-
and ionic gradients. It is also used to supply energy for the biosyn- tween the blood and the brain compartments. Therefore, normal
thesis, liberation, and capture of synaptic neurotransmitters. The brain volume is physiologically controlled by plasma osmotic
most costly energetic mechanism is undoubtedly the transmem- pressure. Brain cells are resistant to osmotic variation and possess
brane transport of ions. About 60% of ATP produced is used to powerful adaptation mechanisms that correct neuronal volume
maintain the ionic transmembrane potential, mainly the Na+/K+- within minutes. When cerebral injury occurs, the BBB can be
ATPase pump.22 Following a period of depolarization and libera- injured and water transfer across the BBB is dependent on hydros-
tion of synaptic neurotransmitters, much energy is required to tatic pressure gradients. The interstitial pressure is high with tight
ensure the neuronal recapture of K+ (repolarization) and neuro- cell junctions. This also prevents the flux of water toward the
transmitters. Consequently, even the basic neurologic activity interstitium.
requires a large O2 supply, which significantly increases during a
period of external stimulation (visual) or voluntary movement. In Cerebral Perfusion Pressure
the presence of ischemia or anoxia, any interruption of the ionic
pump will cause a loss of cellular regulation and intracellular acid- The arteriovenous pressure gradients that are observed are much
base balance. The anesthesiologist must try to maintain the energy more complex in the brain than in other organs because the brain
balance between cerebral supply and demand. Approximately 50% is confined in a closed cranial vault. The presence of a rigid “box”
of the CMRO2 is used by the astrocytes for the maintenance of brings about the formation of arteriovenous gradients that are
energy production (e.g., ATP-glutamate–dependent pumps) and directly dependent on the variation of ICP, which is normally
synthesis of neurotransmitters (the functional metabolism of the higher than the atmospheric pressure and central venous pressure
brain). The other 50% is used to maintain the structural characte- (CVP).30 Consequently, neither the CVP nor the venous pressure
ristics and functional metabolism of the brain cells.18 of the cerebral sinuses affect CBF. The relative absence of pressure
Figure 6-7. The effect of cerebral perfusion pressure (CPP) on cerebral

blood flow (CBF). CBF is autoregulated between 50 and 150 mmHg in
the adult. In the child aged 6 months to 12 years, CBF is maintained
constant to higher values than those in the adult, whereas for the prema-
ture baby and infant younger than 6 months of age, mean CBF is lower
Figure 6-6. Relevant anatomic characteristics of the brain vessel. The
and the inferior and superior limits of autoregulation are different.
neural vasculature differs from the peripheral systemic vessels by the
tight junctions, the presence of numerous mitochondria, and rare
pinocytic vesicles. Astrocyte feet surround the vessel and form the the myogenic response) takes from 30 seconds up to 3 minutes to
blood-brain barrier. respond. The myogenic mechanism is probably the most efficient
against severe and rapid changes in CPP, whereas the metabolic
inside the venous sinuses is a consequence of the very resistant control system is associated with slower changes caused by modi-
fibrous wall that protects them from most changes in ICP. The fication of the metabolic flow balance.34 The myogenic theory rests
hydrostatic pressure of the cerebral venous sinuses is determined on the concept that smooth endovascular muscles have an
almost entirely by the CVP. However, contrary to the venous intrinsic property capable of reacting to changes in CPP. The
sinuses, the pressure of the veins of the cerebral tissue is totally presence of stretching receptors capable of recognizing changes in
dependent on ICP. However, this should always be higher than transmural pressure rather than the locoregional variation of flow
ICP in order to avoid any extrinsic compression. Direct measure- has been confirmed (the Bayliss effect described in 1902).36 In
ment of their pressure has demonstrated this hypothesis. For that children, the myogenic response seems even faster than described
reason, cerebral perfusion pressure (CPP) is equal to the mean in adults. It is activated within the first 10 seconds after an abrupt
arterial pressure (MAP) less CVP or ICP (the greater of the two): change in CPP and completed under 2 minutes.34,37 The second
component of this cerebrovascular autoregulatory control is the
CPP = MAP – ICP (or CVP) fine-tuning response based on neurogenic and metabolic media-
tors. The control of CBF by direct innervation of the autonomous
Cerebral Autoregulation nervous system remains a complex phenomenon.35 Several neuro-
transmitters have been identified as having a direct contribution
The term autoregulation is used to describe the phenomenon by to the cerebral autoregulation mechanism. The presence of an
which the CBF is maintained constant despite important changes important sympathetic innervation, mainly noradrenergic, on the
in CPP (Figure 6–7). This control is limited in the adult to CPP major cranial vessels and the small arteries cannot be neglected,
range between 50 and 150 mmHg of CPP.31 The lower and higher α1-, α2-, and β-adrenergic receptors having been identified on
thresholds of cerebral autoregulation in the infant and the young the cortical microcirculation.38 Scientific evidence suggests that
child are not known. Animal models suggest that the lower and the microcirculation is mainly responsible for the fine-tuning of
higher limits of the autoregulation mechanism are lower than the cerebral autoregulation.
those observed in the adult, 40 to 90 mmHg, respectively.32,33 It The metabolic factors involved in this system are the levels of
has been shown in infants and young children undergoing balloon CO2, K+, and adenosine.35 CO2 is the most powerful vasodilator of
dilation of coarctation of the aorta that the cerebral autoregulation the cerebral vessels. An increase in CO2 produces cerebral vaso-
mechanism is present and capable of rapid response.34 However, dilatation and causes an increase in CBF and CBV. When CO2
the effect of systemic arterial hypotension on cerebral autoregula- doubles from 40 to 80 mmHg, CBF also doubles and is the same
tion of the newborn remains unknown. It is reasonable to think for a reduction in CO2, halving from 40 to 20 mmHg when CBF
that CBF is rather well maintained despite low perfusion pressures. is reduced by as much. In the adult, CBF varies in a linear way
CBF is matched to CMRO2. At rest, it is maintained at a with any change in PaCO2 (arterial pressure of carbon dioxide)
constant level of about 50 mL/min/100 g for a large range of MAP. between 20 and 80 mmHg (Figure 6–8). A 1-mmHg fall in PaCO2
With decreasing MAP, cerebral vasodilatation occurs and CBV results in a 4% decrease in CBF. As PaCO2 falls, CSF pH rises and
increases. With hypertension, vasoconstriction leads to a decrease periarteriolar changes in pH are reflected in vasoconstriction. The
in CBV and ICP. This autoregulation process is necessary to use of prolonged hyperventilation to control ICP is effective only
maintain local tissue PCO2 (carbon dioxide pressure) constant. for a period of 6 to 8 hours, after which, unless the CO2 has
Three mechanisms—myogenic, metabolic, and neurogenic—are dropped again, CBF will return to its prehyperventilation value.
involved in cerebral autoregulation.35 The rapid component (i.e., The clinical implication for this physiologic observation is that, if
Figure 6-8. Hypocapnia widens the autoregulation plateau, whereas

hypercapnia reduces it. Young WL. Clinical Neuroscience Lectures, Ca- Figure 6-9. Hypotension impairs CO2 reactivity of the cerebral vascu-
thenart Publishing, Munster, IN 1993. lature when compared with normotension. With permission from W. L.
Young, 1993, USA.
hyperventilation is maintained for a certain period and then
normoventilation and, thus, normocapnia are then restored adequate autoregulation, the global distribution of CBF is not
rapidly, the pH of the interstitial space will drop. This decrease in uniform, which implies the presence of a regional vascular regula-
pH will be linked to the increase in PaCO2 and CBF and CBV will tion linked to the regional CMRO2. Adults show no change in CBF
increase dramatically, which will cause an increase in ICP. Chronic until PaO2 (arterial oxygen pressure) falls below 50 mmHg, at
hyperventilation will result in slow movement of bicarbonate ions which time, CBF begins to increase exponentially. The CBF seems
out of the CSF with normalization of CSF pH and CBF within 24 to depend on the quantity of oxygen available for the mitochon-
hours.39 However, sudden increases in PaCO2 after chronic hyper- drial phosphorylative oxidation mechanisms. However, hyperoxia
ventilation of more than 24 hours can result in cerebral vasodila- does not modify CBF. Below a certain autoregulation limit, the
tation and increases in ICP.40 Previous studies have suggested that CBF varies in parallel with changes in CPP. When CPP is lower
the immature brain is relatively unresponsive to small changes in than the inferior limit of autoregulation, the regions most vulner-
PaCO2,41 but investigations on fetal rabbit brain have demonst- able to ischemia are the vascular transition zones between the gray
rated that CBF responds to changes in PaCO2.42 In the child, a and the white matters as well as the vital subcortical structures and
study using transcranial Doppler has shown that the mathematical the basal nuclei. When CPP is greater than the superior autore-
relationship, describing the relationship between CBF when CO2 gulation limit, CBF increases and the hydrostatic force transmitted
varies between 20 and 80 mmHg, is a logarithmic curve, which on the vasculature already dilated to a maximum could cause
suggests that the maximum vasodilatation effect of CO2 is rapidly edema, thrombotic occlusion, and/or intracerebral (mainly of the
reached at around 50 mmHg.43 germinal matrix) and intraventricular hemorrhage. Occlusive
Cerebrovascular reactivity to CO2 represents the first therapeu- thrombosis seems to result from fibrinoid necrosis of the vascular
tic line used by emergency physicians, anesthetists, and intensivists endothelium causing the formation of platelet aggregates.
to control ICP. However, the effect of CO2 on the cerebral vas- The controlled hypertension concept is based on intact cerebral
culature seems to be transient. A sustained modification in the autoregulation.45 In the case of brain injury, a decreased CPP leads
CO2 level for 6 to 8 hours causes a resetting of CBF to its initial to cerebral vasodilatation, increasing CBV and further increasing
value. This suggests that the cerebrovascular effect of CO2 is ICP. To counteract this process, increasing MAP leads to an in-
mediated via changes in H+ concentration in the extracellular creased CPP and reflex cerebral vasoconstriction. This vasocon-
space. The vascular effect of CO2 is about 6 hours because the striction decreases CBF and CBV, thus, further decreasing ICP and
extracellular HCO3– needs 6 to 8 hours to reset the acid-base increasing CPP. This therapeutic approach, by vasoconstriction in
balance and, thus, the extracellular pH. It is important to stress uninjured areas, leads to increased perfusion in injured areas
the importance of mild hypocapnia, which widens the autoregula- (Robin Hood effect).46,47 Clinically, it is achieved by expanding
tion plateau, whereas hypercapnia decreases this plateau (Figure plasma volume and the use of vasopressor agents if needed.
6–9). Hypotension (MAP decreases) impairs CO2 reactivity of the However, it must be stressed that controlled hypertension must be
cerebral vasculature, whereas normotension maintains its effect progressive to allow autoregulation to occur and must stay within
(see Figure 6–9). Blood viscosity may also have a major impact on the patient’s autoregulation range of 80 to 100 mmHg. Cerebral
cerebral autoregulation. A decrease in blood viscosity will cause a autoregulation can be impaired in the newborn, presenting a state
temporary increase in CBF, which will be rapidly corrected by of severe respiratory distress in the presence of an anoxic or a hy-
metabolic adjustment.44 poxic episode48 or simply during the administration of vasodilator
Cerebral O2 and glucose demands also directly influence cere- agents such as CO2, nitroprusside, or inhalational anesthetic
bral vasoreactivity and CBF. The cerebral vascular response to agents. Abrupt MAP changes will transiently lead to changes in
hypoxia is not well studied in children. Even in the presence of CBF. The autoregulation window ranges from a mean CPP of 50
to 150 mmHg in normal subjects and is shifted to higher values in Not surprisingly, medications such as acetazolamide and
hypertensive patients and to lower values in hypotensive patients furosemide, which can reduce the production of CSF, have a
or in the brain surrounding an arteriovenous malformation. minimal effect on ICP. Only patients with an marked decrease in
Several factors impair cerebral vasoregulation. The two of primary intracerebral compliance with a very high ICP may benefit from
concern are PaCO2 and volatile anesthetic agents. Intravenous this pharmacologic effect. In patients with ICP issues, it is
agents like thiopental, etomidate, and propofol are cerebral vaso- important to avoid using certain anesthetic agents such as
constrictors. When cerebral vasoreactivity is uneven, vasodilating enflurane, which can increase the secretion of CSF, or alfentanil,
agents can increase blood flow to uninjured areas, thus decreasing which can hinder its reabsorption. Finally, resorption rate depends
blood flow to injured areas (vascular steel effect), whereas vaso- on the CSF–to–venous pressure gradient and resorption resis-
constricting agents increase blood flow to injured areas (Robin tance. The pressure gradient between the CSF and the venous
Hood effect). compartment is called effective CSF pressure.
CSF Spinal Cord Blood Flow

The brain is highly sensitive to environmental changes, and any The use of the Doppler technology has simplified the noninvasive
change in the extracellular ionic concentration can modify its evaluation of CBF. In the child, it has opened up the study of the
activity. The CSF composition is controlled very strictly, which pathophysiology of the cerebral circulation and the circulation in
differentiates CSF from other fluids in the body (Table 6–2). The the spinal cord. Previously, almost all scientific data linked to the
brain is protected by two barriers, the BBB and the blood-CSF circulation of the spinal cord came from animal studies.51 Despite
barrier, which is responsible for maintaining ionic homeostasis the fact that blood flow is evaluated in velocity rather than in
between blood and CSF and, moreover, between blood and the milliliters per minute, the studies on blood flow in the spinal cord
respiratory control centers. The CSF is largely secreted by the cho- carried out on cats demonstrate an excellent statistical correlation
roidian plexi (80%), which are located in the cerebral ventricles. with the measurements obtained by Doppler velocimetry. Animal
The capillaries of the choroidian plexi are equipped with openings studies confirm that the physiology of the blood flow in the spinal
and intercellular spaces allowing the free passage of molecules cord is comparable with that of CBF. However, because the spinal
through this special endothelium that is responsible for the cord metabolism is proportionally lower than that of the brain,
secretion of CSF. The presence of an extrachoroidian site involved blood flow in the spinal cord is lower. Blood flow in the gray spinal
in the production of CSF has not been clearly identified. However, matter is 50% of blood flow at the level of the gray matter of the
it has been suggested that the surface of the ependyma as well as brain, whereas blood flow in the white matter represents only one
the cerebral parenchyma are potentially able to participate in the third of the perfusion of the white cerebral matter.
production of CSF. In the adult, normal CSF volume varies The equation of the perfusion pressure of the spinal cord
between 100 and 150 mL or 1.5 to 2.0 mL/kg. Under normal (PPSP) is: PPSP = MAP – extrinsic pressure. At the spinal cord
conditions, the production and reabsorption of CSF are balanced. level, it is the equivalent of the CPP at the brain level. This concept
The production of CSF in the adult is 0.35 mL/min or 500 mL/ is clinically useful because it highlights the factors influencing
day.49 In the child, it is slightly less or about 0.3 mL/min. Because blood flow at the spinal cord level. Extrinsic pressure can be the
the total CSF reserve is lower in the child, the effect on cerebral result of a tumor, hematoma, CSF, and/or epidural venous con-
compliance is more pronounced, and because the total quantity is gestion. The presence of autoregulation in the spinal cord secures
lower, the total CSF volume can be replaced entirely three to four a constant flow as occurs in the brain. Although the limit values
times a day. CSF is mainly formed by the passive transport of Na– are often described as 60 to 150 mmHg, an inferior limit of
, Cl–, and HCO–3, which follows a simple concentration gradient 45 mmHg and a superior limit of 180 mmHg have also been
with water passively following these ions, whereas active transport reported. It is most difficult to rely on monitoring to evaluate the
is necessary for glucose and amino acids. There are virtually no impact of an extrinsic compression on the spinal cord. It is, thus,
proteins in the CSF (see Table 6–2). Arachnoidian villi are recommended to maintain the PPSP above 50 mmHg by
responsible for the passive reabsorption process of CSF through maintaining a normal MAP.
their endovenous outgrowth. This reabsorption mechanism has Finally, vascular reactivity of the spinal cord to changes in
not yet been fully understood. A reduction of 35% in the PaCO2 and PaO2 is very comparable with that of the brain. Thus,
production of CSF causes a reduction of only 1.1 mmHg in ICP.50 a PaO2 higher than 60 mmHg does not affect spinal blood flow.
However, spinal cord blood flow significantly increases when PaO2
is lowered to below 60 mmHg. Studies suggest that PaCO2 affects
TABLE 6-2. Composition of the Human Cerebrospinal blood flow in a linear fashion between 20 and 80 mmHg, result-
Fluid and Plasma ing in absolute variation from 0.5 to 1.0 mL/100 g/min.52 It has
Constituants CSF Plasma been demonstrated that CBF in the adult changes from 1 to 2 mL/
100 g/min.31,53
Sodium (mEq/L ) –1
138.0 140.0
Potassium (mEq/L–1) 2.8 4.0
Calcium (mEq/L–1) 2.4 4.6 CONCLUSION
Magnesium (mEq/L–1) 2.7 1.8
Successful anesthesia for infants and children affected with a
Chloride (mEq/L–1) 124.0 99.0
neurologic disease depends on a good understanding of the ana-
Glucose (mg/dL–1) 60.0 99.0
tomy and physiology of the CNS.54 Application of basic principles
Protein (g/dL–1) 0.05 7.1
facilitates the clinical management of intracranial or spinal patho-
CSF = cerebrospinal fluid. logies during neurosurgical procedures. Ischemia and necrosis
represent the ultimate consequence of physiologic imbalance. 19. Bachelard HS: Specificity and kinetic properties of monosaccharide
Although the brain does no mechanical work, a substantial uptake into guinea pig cerebral cortex in vitro. J Neurochem. 1971;
amount of energy is needed to maintain its cellular integrity and 18:213–222.
biologic functions. Cerebral protection is possible only if one 20. Nishiki K, Erecinska M, Wilson DF: Effect of Amytal on metabolism
anticipates the physiologic changes triggered by a pathologic dis- of perfused rat heart: relationship between glycolysis and oxidative
phosphorylation. Am J Physiol. 1979;237:C221–C230.
turbance and applies fundamental concepts to restore the normal
21. Sokoloff L: Circulation and energy metabolism of the brain. In: Siegel
physiology as soon as possible.55 This clinical management is the G, Agranoff B, Albers R, Molinoff P, editors. Basic Neurochemistry:
exclusive domain of the anesthesiologist and the neurosurgeon Molecular, Cellular and Medical Aspects. New York: Raven Press; 1989.
and will be discussed in Chapters 93 and 92. pp. 565–591.
22. Erecinska M, Silver IA: ATP and brain function. J Cereb Blood Flow
Metab. 1989;9:2–19.
REFERENCES 23. Powers WJ, Grubb RJ, Darriet D, et al. Cerebral blood flow and
1. Kleinman S, Bissonnette B: Management of successful pediatric cerebral metabolic rate of oxygen requirements for cerebral function
neuroanesthesia. In: Bissonnette B, editor. Cerebral Protection, Res- and viability in humans. J Cereb Blood Flow Metab. 1985;5:600–608.
uscitation and Monitoring: A Look Into the Future of Neuroanesthesia. 24. Bucher HU, Edwards AD, Lipp AE, et al. Comparison between near
Philadelphia: WB Saunders; 1992. p. 537. infrared spectroscopy and 133Xenon clearance for estimation of
2. Streeter G: Developmental horizons in human embryos. Description cerebral blood flow in critically ill preterm infants. Pediatr Res. 1993;
of age group XIII, embryos about 4 or 5 millimeters long, and age 33:56–60.
group XIV, period of indentation of the lens vesicle. Contrib Embryol. 25. Edwards AD, Wyatt JS, Richardson C, et al. Cotside measurement of
1942;31:211. cerebral blood flow in ill newborn infants by near infrared spectros-
3. Streeter G: Developmental horizons in human embryos. Description copy. Lancet. 1988;2:770–771.
of age group XV, XVI, XVII and XVIII, being the third issue of a 26. Altman DI, Powers WJ, Perlman JM, et al. Cerebral blood flow
survey on the Carnegie collection. Contrib Embryol. 1948;32:133–167. requirement for brain viability in newborn infants is lower than in
4. Streeter G: Developmental horizons in human embryos (fourth adults. Ann Neurol. 1988;24:218–226.
issue). A review of the histogenesis of bone and cartilage. Contrib 27. Younkin DP, Reivich M, Jaggi J, et al. Noninvasive method of
Embryol. 1949;33:149–178. estimating human newborn regional cerebral blood flow. J Cereb
5. Streeter G: Developmental horizons in human embryos. Description Blood Flow Metab. 1982;2:415–420.
of age groups XIX, XX, XXi, XXII, XXIII, being the fifth issue of 28. Cross KW, Dear PR, Hathorn MK, et al. An estimation of intracranial
a survey of the Carnegie collection. Contrib Embryol. 1951;34: blood flow in the newborn infant. J Physiol (Lond). 1979;289:
165–198. 329–345.
6. Heuser C, Corner G: Development horizons in human embryos. Des- 29. Ogawa A, Sakurai Y, Kayama T, et al. Regional cerebral blood flow
cription of age group X, 4 to 12 somites. Contrib Embryol. 1975;36: with age: changes in rCBF in childhood. Neurol Res. 1989;11:
29–42. 173–176.
7. Lemire R, Loeser JD, (eds). Normal and Abnormal Development of 30. Farrar J, Roach M: The effects of increased intracranial pressure
the Normal Nervous System. New York, Harper & Row; 1975. p 421. on flow through major cerebral arteries in vitro. Stroke. 1973;4:
8. Streeter G: Factors involved in the formation of the filum terminale. 795–806.
Am J Anat. 1919;25:1–22. 31. Lassen NA, Christensen MS: Physiology of cerebral blood flow. Br J
9. Streeter G: The development of the human cerebrospinal fluid Anaesth. 1976;48:719.
pathway with particular references to the roof of the fourth ventricle. 32. Hernandez MJ, Brennan RW, Bowman GS: Autoregulation of cerebral
J Anat. 1918;105:467–481. blood flow in the newborn dog. Brain Res. 1980;184:199–202.
10. Padget D: The cranial venous system in man in reference to develop- 33. Purves MJ, James IM: Observations on the control of cerebral blood
ment, adult configuration and relation to the arteries. Am J Anat. flow in the sheep fetus and newborn lamb. Circ Res. 1969;25:651–667.
1956;98:307–319. 34. Bissonnette B, Benson L: Does balloon dilatation angioplasty for
11. Milhorat T: Circulation of the cerebrospinal fluid. In: McLaurin R, coarctation of the aorta affect cerebrovascular circulation in children?
Schut L, Venes J, Epstein F, editors. Pediatric Neurosurgery. Survey of Circulation. 1991;84:545–546.
the Developing Nervous System. Section of Pediatric Neurosurgery of 35. Baumbach GL, Heistad DD: Effects of sympathetic stimulation and
the American Society of Neurological Surgeons. Philadelphia: WB changes in arterial pressure on segmental resistance of cerebral vessels
Saunders; 1989. pp. 170–180. in rabbits and cats. Circ Res. 1983;52:527–533.
12. Harris M, Stone D: Anesthesia for increased intracranial pressure in 36. Sparks H: Effect of a quick stretch on isolated vascular smooth
pediatrics. Probl Anesth. 1980;4:67–88. muscle. Circ Res. 1973;20:1538–1544.
13. Loefgren J, Zwetnow NN: Cranial and spinal components of the 37. Symon L, Held K, Dorsch NW: A study of regional autoregulation in
cerebrospinal fluid pressure-volume curve. Acta Neurol Scand. 1973; the cerebral circulation to increased perfusion pressure in normo-
49:575–585. capnia and hypercapnia. Stroke. 1973;4:139–147.
14. Hill A, Volpe J: Measurement of intracranial pressure using the Ladd 38. Kobayashi H, Magnoni MS, Govoni S, et al. Neuronal control of brain
intracranial pressure monitor. J Paediatr. 1984;98:974–977. microvessel function. Experientia. 1985;41:427–434.
15. Hill A: Intracranial pressure measurements in the newborn. Clin 39. Rosomoff H, Holaday D: Cerebral blood flow and cerebral oxygen
Perinatol. 1985;12:161–178. consumption during hypothermia. Am J Physiol. 1954;179:85–97.
16. Ross RT: Spinal cord infarction in disease and surgery of the aorta. 40. Muizelaar JP, van, der, Poel, Hg, Li ZC, et al. Pial arteriolar vessel
Can J Neurol Sci. 1985;12:289–295. diameter and CO2 reactivity during prolonged hyperventilation in
17. Batson O: The vertebral vein system. AJR Am J Roentgenol. 1957;78: the rabbit. J Neurosurg. 1988;69:923–927.
195–207. 41. Hidaka A, Suzuki Y, Komatani M, et al. Influence of maternal
18. Bickler P: Energetics of cerebral metabolism and ion transport. In: hyperoxia or hypercarbia on the hemodynamics of the placenta and
Bissonnette B, editor. Cerebral Protection, Resuscitation and Moni- fetal brain. N Sanka Fuj Gak Zas. 1986;38:1754–1762.
toring: A Look Into the Future of Neuroanesthesia. Philadelphia: WB 42. Yamashita N, Kamiya K, Nagai H: CO2 reactivity and autoregulation
Saunders; 1992. pp. 563–575. in fetal brain. Childs Nerv Syst. 1991;7:327–331.
43. Pilato MA, Bissonnette B, Lerman J: Transcranial Doppler: response 49. Ruben RC, Henderson ES, Ommaya AK, et al. The production of
of cerebral blood-flow velocity to carbon dioxide in anaesthetized cerebrospinal fluid in man and its modification by acetazolamide.
children. Can J Anaesth. 1991;38:37–42. J Neurosurg. 1966;25:430–436.
44. Muizelaar JP, Wei EP, Kontos HA, et al. Cerebral blood flow is re- 50. Bissonnette B, Ravussin P. Biomechanics and intracranial hyper-
gulated by changes in blood pressure and in blood viscosity alone. tension. Ann Fr Anesth Reanim. 1997;16:389–394.
Stroke. 1986;17:44–48. 51. Goto T, Crosby G: Anesthesia and the spinal cord: In: Bissonnette B,
45. Rosner MJ, Daughton S: Cerebral perfusion pressure management in editor. Cerebral Protection, Resuscitation and Monitoring: A Look
head injury. J Trauma. 1990;30:933–940. Into the Future of Neuroanesthesia. Philadelphia: WB Saunders;
46. Drummond J, Oh Y, Cole D, et al. Phenylephrine-induced hyper- 1992. pp. 493–521.
tension reduces ischemia following middle cerebral artery occlusion 52. Sandler AN, Tator CH: Review of the measurement of normal spinal
in rats. Stroke. 1989;20:1538–1544. cord blood flow. Brain Res. 1976;118:181–198.
47. Andrews P: What is the optimal perfusion pressure after brain injury: 53. Lassen N: Cerebral and spinal cord blood flow. In: Cottrell J, editor.
a review of the evidence with emphasis on arterial pressure. Acta Anesthesia and Neurosurgery. St. Louis: CV Mosby; 1986. pp. 1–22.
Anaesthesiol Scand. 1995;39:112–114. 54. Bissonnette B. Specificities of neurosurgical anesthesia in the child.
48. Tweed A, Cote J, Lou H, et al. Impairment of cerebral blood flow Ann Fr Anesth Reanim. 2003:21:73–77
autoregulation in the newborn lamb by hypoxia. Pediatr Res. 1986;20: 55. Bissonnette B. Cerebral protection. Paediatr Anaesth. 2005,14:
516–519. 403–407.
Normal and Abnormal Development

of the Heart and the Circulation 7
Christian Apitz and Andrew N. Redington C H A P T E R
INTRODUCTION extending between the AV and the ventriculoarterial junctions. In

terms of its own intrinsic morphology, this ventricular mass can be
The development of the heart reflects a complex interaction of divided into (1) inlet portions surrounding the AV valves and
genes, environment, biomechanical events, and chance. Although extending to the attachments of their papillary muscles, (2) apical
the embryo is growing exponentially, the heart transforms from a trabecular components, and (3) outlet components supporting
muscle-wrapped tube without valves, septums, conduction sys- the arterial valves. The atrial and ventricular chambers and the
tem, or coronary circulation into a four-chambered structure that great arteries are paired structures. Each member of the pair is
will pump blood to the lungs and body 60 to 160 times/min for distinguishable by its morphologically right or morphologically
more than 80 years. In approximately 1% of pregnancies, this left characteristics. Congenitally malformed hearts can then
usually well-orchestrated process fails and congenital heart disease be analyzed in the way that these morphologically right and left
results. Even in the normal heart, important maturational changes components are arranged and connected or, in some cases, not
must be taken into account when caring for infants and children. connected.
In this chapter, we explore some of the important issues that are of
clinical relevance to those providing anesthesia care for the
pediatric population. The Atria
The part of the atrium most uniformly present and most distinc-
tive of rightness and leftness is the appendage. The morphologic-
THE SPECTRUM OF ally right appendage is triangular-shaped with a broad base at its
CONGENITAL HEART DISEASE junction with the smooth-walled atrium, whereas the morpholo-
AND ITS DESCRIPTION gically left appendage is a finger-like structure having a narrow
junction with the smooth-walled atrial component. The great
No matter what the cause, the ability to describe any structural veins cannot be used to distinguish accurately between a left and
cardiac abnormality in a cohesive and comprehensive manner a right atrium because an anomalous drainage of the great veins is
forms the basis of communication, management, and description not uncommon in complex congenital defects.
of outcomes. There have been two “schools” of, often hotly de-
bated, nomenclature: (1) the Van-Praaghian and (2) the Anderso-
The Ventricles
nian systems, which are eponymously named after their advocates.
Both have evolved and became more aligned since the early 1980s. The most characteristic pattern to distinguish morphologically
They are based on the description of the heart as a series of right and morphologically left ventricles is their trabecular com-
segments.1–4 Without wishing to enter the debate of superiority, ponents. Characteristically, the right ventricle has coarse apical
and in the interests of clarity, in this section, we describe the most trabeculations whereas the left ventricle typically has fine trabe-
widely used system, the Andersonian system of sequential culations. Additional morphologic criteria for the right ventricle
segmental analysis. Although it is beyond the scope of this chapter are the moderator band crossing the ventricular cavity (this is an
to explore all of this morphologic method in detail, what follows is especially useful feature for echocardiographic diagnosis) and the
a usable synopsis of the main concepts. presence of tendinous cords attaching the septal leaflet of the
tricuspid valve to the ventricular septum.
The Segments The Great Arteries

The basis of segmental analysis is the concept that all congenital The description of the arterial trunks is made on the basis
heart malformations can be readily analyzed in terms of three of patterns of branching. An aorta can be distinguished as an
basic segments: (1) the atria, (2) the ventricular mass, and (3) the arterial trunk giving rise to systemic and coronary arteries. A
great arteries. These segments have uniquely defining features and pulmonary trunk is one giving rise to pulmonary arteries. A
discrete anatomic boundaries. The atria are separated from the common arterial trunk is defined as a single arterial vessel from
ventricles by the fibrous tissue plane of the atrioventricular (AV) which systemic, pulmonary, and coronary arteries arise directly.
junction. The ventriculoarterial junction is marked by the attach- The second step of the segmental analysis is to describe the
ment of the arterial wall to the ventricular mass. The ventricular connections between the components of the different segments.
segment of the heart is, therefore, defined as the muscle mass Usually, we start with the description of the arrangement of the
Figure 7-1. Arrangement of the appendages.
heart. According to the classification of the bodily arrangements,

we distinguish four basic arrangements: (1) the usual arrangement
(situs solitus), (2) the mirror image (situs inversus), (3) right
isomerism, and (4) the left isomerism. Because the appendages
are the most constant component to distinguish between the right
and the left parts of segments, the arrangement of the heart is
defined by the arrangement of the appendages (Figure 7–1).
ARRANGEMENTS OF THE APPENDAGES: Usually, the morphologi- Figure 7-3. Single outlet of the heart with a common arterial trunk.
cally right atrium is right-sided and the morphologically left
atrium is left-sided (situs solitus = usual). In the mirror-image
arrangement (situs inversus), the morphologically right atrium is around the left ventricle in a fashion comparable with the
left-sided. There are two other atrial arrangements, right or left observer’s right hand being placed upon the morphologically right
isomerism of the atrial appendages, in which both appendages ventricular septal surface, with the palm against the septum, the
have morphologically right or morphologically left characteristics. thumb in the inlet, the fingers in the outlet, and the wrist in the
trabecular component. This pattern of ventricular topology can
THE AV JUNCTION: We have to distinguish the more common
be termed a right-hand pattern, and is also almost always seen in
biventricular AV connection, in which each atrium is connected
hearts with situs inversus and AV discordance. The complemen-
to its own ventricle, and the univentricular AV connections, in
tary left-handed pattern is usually found in hearts with either situs
which the atria are connected to only one ventricle (Figure 7–2).
inversus and AV concordance or AV discordance in situs solitus.
This could be seen as a double-inlet ventricle or one with absent
right AV connection or absent left AV connection. In this second THE VENTRICULOARTERIAL JUNCTION: There are four different
group of hearts, it is always necessary to describe the type and types of ventriculoarterial connection. The first two of these are
mode of AV connection together with the ventricular morphology ventriculoarterial concordance, in which the aorta is connected to
and the size of a rudimentary ventricle if present. a left ventricle and the pulmonary trunk to a right ventricle, and
ventriculoarterial discordance, in which there is the reverse con-
VENTRICULAR TOPOLOGY: In situs solitus with AV concordance,
nection (most commonly referred to as transposition). The other
the morphologically right ventricle almost always wraps itself
two connections describe arrangements that are neither concor-
dant nor discordant, including double-outlet ventricle, in which
both great arteries are connected to the same ventricular chamber,
and single outlet of the heart, either with the ventricles draining
via a common arterial trunk or with one ventriculoarterial con-
nection absent, either an atretic aortic or a pulmonary trunk
without connection to the ventricle (Figure 7–3).
CARDIOVASCULAR EMBRYOLOGY
Cardiovascular embryology offers the basis for understanding the
pathogenesis of many types of congenital heart defects and is
particularly relevant to the abnormal development of the cardiac
Figure 7-2. Biventricular (A) and univentricular (B) atrioventricular segments.5 However, as with sequential segmental analysis
junction with usual arrangement of the appendages. B: An absent right previously addressed in the section “The spectrum of congenital
atrioventricular connection (tricuspid atresia). heart disease and its description”, a detailed discussion of this
CHAPTER 7 ■ Normal and Abnormal Development of the Heart and the Circulation 93
complex area is beyond the scope of this chapter. Nonetheless, we coalesces to develop continuity with the dorsal aorta and the
provide a brief overview of the key elements of cardiovascular pulmonary trunk coalesces with six arch structures to form the
development in early fetal life. branch pulmonary arteries, supplying the lungs. Abnormal sep-
Although ultimately becoming a contiguous and integrated tation can lead to the development of a common arterial trunk
structure, the ventricular myocardium is now known to be derived (truncus arteriosus) and other abnormalities such as aortopul-
from several different embryologic origins. For example, even monary window, an anomalous origin of a branch pulmonary
though they ultimately come to share myofibers, elements of the artery from the ascending aorta.
right and left ventricles derive from separate heart fields in very
early embryogenesis. The vascular system of a human embryo
starts to develop in the second and third weeks of gestation. At ETIOLOGY OF CONGENITAL
this point, diffusion alone is not sufficient to provide oxygen and HEART DISEASE
other substrates to the developing organs. Consequently, angioge-
Fundamental to the understanding of the origin of cardiac defects
nic cell structures move toward the developing heart at the cranial
are the impressive advances in the understanding of develop-
end of the embryo, forming the endocardial tubes. These tubes
mental mechanisms of cardiac morphogenesis. In the following
form the dorsal aorta and the rudimentary venous system. As the
section, we address the most important factors contributing to
heart tube continues to develop, the dorsal aorta and the vitell-
maldevelopment of the heart.
oumbilical veins serve as anchors as the heart tube bulges and
loops. The looping of the heart tube serves to form the primordial
heart chambers with a sinus venosus, the paired primitive atria, Genetic Factors
the AV sulcus, the primitive ventricle, and its developing inter-
ventricular sulcus. On the outflow of the tube, the bulbous cordis Although there is increasing understanding of the role of genetic
is forming part of the right ventricle and its outflow tract. As the influences on early cardiac development, our understanding
heart tube forms its bulboventricular loop, a common atrium is remains incomplete. A substantial part of cardiovascular diseases
formed. Partitioning of the atrium, by the appearance of the is either directly caused by gene mutations (monogenic) or at least
septum primum, occurs by about the 28th day. The primum sep- modified by genetic variation (polygenic, multifactorial).6 Among
tum fuses with the endocardial cushions with superior perfora- infants born with associated noncardiac anomalies, chromosomal
tions that ultimately coalesce to form the ostium secundum. If anomalies and single-gene disorders are more frequently identi-
these perforations are too large, a secundum atrial septal defect fied, and conversely, cardiac anomalies are overrepresented in
will result. At the same time as atrial septation is occurring, the many definable genetic “syndromes.” For example, approximately
left atrium and pulmonary veins are becoming confluent with the 50% of children with trisomy 21 will have an associated cardiac
lung buds to allow pulmonary venous return to the left atrium. As anomaly.7 AV septal defect is the most frequent defect, followed
the atrial wall expands, the pulmonary veins become fully incor- in decreasing order by ventricular septal defect, atrial septal defect,
porated into the posterior wall of the left atrium. Failure of in- tetralogy of Fallot, and patent ductus arteriosus.8–10 Although less
corporation of the pulmonary veins will lead to forms of total frequently encountered than trisomy 21, almost all infants with
anomalous pulmonary venous connection (TAPVC) with drai- trisomy 18 will have a congenital cardiac defect. Among the sex
nage of the pulmonary veins to other structures. The most com- chromosome abnormalities, Turner’s syndrome is the most
mon form of TAPVC is supracardiac drainage (usually via frequent, with 10 to 40% of these patients having coarctation of
connection of the pulmonary veins to remnants of the left-sided the aorta and associated bicuspid aortic valve.11 It is likely that
cardinal venous system, which usually disappears during early many cardiac diseases will have more subtle genetic origins such
fetal life). Other forms of TAPVC include connection to the splan- as point mutations or microdeletions. The most frequent micro-
chnic veins below the diaphragm (infradiaphragmatic TAPVC), deletion syndrome associated with congenital heart disease is
to cardiac veins (TAPVC to coronary sinus), or mixed types. 22q11 syndrome. The syndrome has a population prevalence of
The formation of the ventricles initially occurs from separate approximately 1 in 2000 in the United States. It has drawn con-
heart fields, but ultimately develops as a looping of the newly siderable attention because a number of common psychiatric
formed heart tube. The interventricular sulcus grows to separate illnesses are phenotypic features including attention deficit dis-
the right and left ventricles, which continue to expand until the order, schizophrenia, and bipolar disorder.12,13 These children are
seventh week of gestation. The inlet of the ventricles develops from born with a spectrum of “conotruncal” abnormalities including
the AV canal, which gradually shifts to the right in order to allow tetralogy of Fallot, interrupted aortic arch, and common arterial
communication between the atrial mass and the developing right trunk.
ventricle. Fusion of the endocardial cushions is responsible for
completion of both the septation of the atrium and the ventricle
and is integral to the formation of the AV valves. A common AV
Environmental Factors
canal between the atria and the ventricles is present in the normal It has long been known that maternal factors can modify cardiac
heart as it develops, but may also persist as one of the most development. Maternal infection with rubella is rare in Western
common of all cardiac anomalies. Failure of ventricular septation populations, but it leads to severe abnormalities of the pulmonary
in the presence of normal separation of the AV junctions will arteries. Maternal viral illness in the third trimester is often asso-
account for the remainder of ventricular defects, which can be ciated with myocarditis in the newborn infant, coxsackie being
classified broadly as perimembranous, muscular, doubly committed, the most common viral agent. Ingested teratogens can be equally
and juxta-arterial. devastating. The potential risks caused by maternal drug intake
The outflow tract of the ventricle is gradually partitioned to were brought to light by the thalidomide tragedy. Exposure of
form a separate aorta and pulmonary trunk. The ascending aorta mothers who took thalidomide during pregnancy resulted in a
high risk of cardiac malformations, especially of the conotruncal Closure of the Foramen Ovale
type, tetralogy of Fallot, and truncus arteriosus.14 In addition,
various anticonvulsants used by mothers for the treatment of When the umbilical cord is clamped, the low-resistance placental
epilepsy such as barbiturates, valproic acid, or diphenylhydantoin circulation is lost and the systemic vascular resistance (SVR)
have been found to cause defects such as pulmonary stenosis and increases. With the initiation of respiration, the pulmonary vas-
tetralogy of Fallot. There are also more generic effects of maternal cular resistance (PVR) begins to decrease and the lungs begin to
disease. Maternal diabetes not only may lead to a specific form of be perfused with a greater amount of blood. With the increased
transient hypertrophic cardiomyopathy in the newborn15 but is flow to the lungs, blood return from the lungs to the left atrium
also associated with increased risk of structural heart disease via also increases. Clamping of the umbilical cord decreases return of
mechanisms yet to be fully elucidated.16 Maternal phenylketonuria systemic blood to the right atrium. These events represent the
may also be a cause of congenital heart disease in the offspring, in reverse of the situation that occurred in the fetus, when right atrial
which patent ductus arteriosus, coarctation of the aorta, and return from the placenta exceeded left atrial return. Now, with
tetralogy of Fallot are the most frequently reported lesions.17 increased pulmonary blood flow and increased left atrial pressure
Mothers with systemic lupus erythematosus, even if not obviously relative to right atrial pressure, the flap mechanism of the foramen
ill, have a risk of congenital complete heart block in the offspring ovale results in functional closure.
because of isoimmune damage of the fetal cardiac conduction
tissue.18 Closure of the Ductus Arteriosus
In normal term infants, the ductus arteriosus functionally closes
Abnormalities of Intracardiac Blood Flow within 24 hours after birth. One factor responsible for ductal
A group of human congenital cardiac malformations are asso- closure is the increase in oxygen tension related to conversion to
ciated with abnormal blood flow patterns in the fetus. The fetal the lung as the organ of respiration. Another may be the change in
levels of local circulating prostaglandins. Final anatomic closure of
flow hypothesis of congenital heart disease has long been debated,
the ductus ateriosus by way of muscle contraction, thrombosis,
because it is very difficult to separate “chicken from egg” (i.e., is it
and fibrosis usually occurs within the first few months of life.
a subtle structural abnormality that modifies flow or vice versa?).
Factors that can delay ductal closure include prematurity, hypoxe-
However, there does appear to be some evidence that primary
mia, and associated congenital heart disease.
abnormalities of flow can lead to structural defects. A good
example of this is the development of right ventricular outflow
tract abnormalities in the recipient of an in utero twin-to-twin Closure of the Ductus Venosus
transfusion.19 The flow hypothesis for the development of left
heart hypoplasia is less well defined. Although experimental The ductus venosus (which in utero is a conduit for oxygenated
preparations have shown that perturbations in left heart flow blood from the placenta to bypass the liver and go directly to the
such as closure of the foramen ovale in the developing fetus heart) functionally closes soon after birth, but there is evidence
can lead to the typical disease, the clinical pathogenesis is less that it may remain anatomically open for up to 20 days before
clear.20 Indeed, hypoplasia of the left ventricle may be present in a closing secondary to connective tissue proliferation that obliterates
variety of congenital heart defects.21,22 The severity of left the lumen. With clamping of the umbilical cord, venous return
ventricular hypoplasia may range from mild hypoplasia to its most in the inferior vena cava is composed only of blood returning from
severe form, hypoplastic left heart syndrome.23 Left ventricular the lower body and the abdominal organs. Reduction of flow
hypoplasia is not a distinct disorder, but rather represents the through the ductus venosus allows it to passively collapse and
common end point of a wide variety of different pathophysiolo- functionally close. Sphincter-like structures appearing at the
junction of the ductus venosus and the umbilical vein have also
gic mechanisms, all resulting in diminished flow through the
been proposed as mechanisms responsible for regulation of ductus
left ventricle in utero.24 Thus, diminution in flow may be the cause
venosus blood flow and for facilitation of ductus venosus closure.
or the consequence of anatomic obstruction (e.g., restrictive
The practical importance of this is that umbilical vein catheteriza-
foramen ovale, mitral or aortic stenosis), intrinsic left ventri-
tion is a convenient method of central catheter placement for the
cular disease (fibroelastosis), or extrinsic compression (congenital
administration of drugs and fluids in the newborn. In addition, it
diaphragmatic hernia), genetics, or a combination of several
allows a pathway through which balloon atrial septostomy can be
factors. performed via the umbilicus in the first day or two of life in infants
with transposition of the great arteries.
THE NORMAL CIRCULATION
AT BIRTH The Transitional Pulmonary Circulation
Even in the normal heart, important maturational changes must In early gestation, the PVR is very high. Therefore, the lungs
be taken into account when caring for children. At birth, a trans- receive only a small portion of the combined ventricular output.
formation must be made from having a parallel circulation, a During the last weeks of gestation, pulmonary blood flow begins
placenta as a respiratory organ, and a liquid environment in the to increase, reaching 8 to 10% of combined ventricular output by
lungs, to having a series circulation, a lung as a respiratory organ, term. This period of increased pulmonary blood flow coincides
and a gaseous environment. This requires that the shunt pathways, with a period of growth of the pulmonary vascular bed and with
which were necessary for the placenta to function as the organ of the beginning of release of surface active material. The immediate
respiration, abruptly cease to operate and that the lungs quickly postnatal decrease in PVR results from the independent effects of
begin their role as organs of gas exchange. mechanical expansion of the lungs and the increase in arterial
oxygen pressure (PaO2). In the normal state in the human neonate, All of the normal physiologic responses that occur immediately
the PVR is approximately one half that of the SVR at 24 hours following birth may themselves be modified by the presence of
of age and continues to decrease until it reaches adult values by congenital heart disease. The various shunt pathways present in
6 weeks of age.25 the fetus that allow a parallel circulation to exist also permit many
fetuses with congenital cardiac malformations to grow and
develop normally in utero. Problems arise at birth and during the
Persistent Pulmonary Hypertension
transitional period only when the shunt pathways begin to close.
of the Newborn For example, a newborn infant with hypoplastic left heart syn-
PVR will not fall at birth and persistent pulmonary hypertension drome does well during the transitional period until the ductus
will result if the pulmonary vascular bed has not demonstrated arteriosus closes, leaving the infant with no means for systemic
normal pharmacologic maturation or if some perinatal insult such cardiac output. In the following section we describe common
as hypoxia sustains the vasoconstricted state of the pulmonary physiologic variants of transition in the presence of congenital
vascular bed. Persistent pulmonary hypertension of the newborn heart disease.
may also result from structural abnormalities. For example,
following an intrauterine insult, peripheral, normally nonmus-
cular arteries may be muscularized and muscular arteries may CONGENITAL HEART DISEASE
show medial hypertrophy. In conditions causing pulmonary
hypoplasia such as diaphragmatic hernia, a severe reduction in the
Left-to-Right Shunts at the
number of alveoli and pulmonary vascular hypoplasia appear to be Ventricular and Arterial Level
the cause of pulmonary hypertension. As a consequence of persis- The physiologic alterations associated with left-to-right shunt
tent pulmonary hypertension in the newborn, the ductus arterio- lesions at the ventricular or great artery level are determined
sus and foramen ovale do not close after birth. This leads to principally by the size of the defect and the postnatal changes in
intracardiac or great arterial level shunting of blood away from SVR and PVR (Figure 7–4). During fetal life, a large defect at the
the lungs and severe hypoxemia unless the PVR can be reduced ventricular level has no major physiologic effect. This is due
relative to the SVR. mainly to the presence of a high PVR in the fetus, which limits
any shunting into the pulmonary circulation, and the low
The Abnormal Transitional Circulation resistance of the placental circuit. However, following birth, the
decrease in PVR at the same time that the SVR is increasing
Problems occur when fetal pathways that should close during the becomes the major determinant of left-to-right shunt flow. As
transitional period stay open or reopen, as in a premature baby discussed in the section on “The normal circulation at birth”, the
with a ductus arteriosus. Reopening of the duct, as a result of a normal decline in PVR to adult levels takes place within the first
hypoxic stimulus, may cause a large left-to-right shunt and pul- 6 weeks after birth. In the presence of a large communication, this
monary edema because of the relatively rapid fall in resistance in decline may be delayed by 1 to 3 months. Nonetheless, there is a
the poorly muscularized pulmonary arteries of the premature gradual increase in pulmonary blood flow with increasing
infant. Other potential shunt pathways may exist or remain open symptoms of congestive heart failure and failure to thrive. The
in the full-term newborn, but without causing apparent problems marked volume overload results in left atrial and pulmonary
in early life. This is because the PVR falls more slowly in these venous hypertension and dilatation of the left and right ventricles.
infants. Consequently, symptoms from left-to-right shunting The former contributes to the production of pulmonary edema,
through a ductus arteriosus or ventricular septal defect may not and the latter stimulates an increase in ventricular mass. The need
become evident for several weeks after birth. for intervention is governed by symptoms and/or the presence of
Figure 7-4. Examples of left-to-right shunts at the ventricular and arterial levels. Ventricular septal defect (A), aortopulmonary window (B), and
persistent ductus arteriosus (C).
pulmonary hypertension. For nonlimiting defects (large ventri-

cular septal defect, aortopulmonary window, large patent ductus
arteriosus), the risk of irreversible pulmonary hypertension
(pulmonary vascular disease) rises steeply after the first year of
life. Therefore, elective intervention is usually planned in the first
3 to 6 months of life. The onset of pulmonary vascular disease may
be accelerated in some, and there may be a lack of signs or
symptoms even when the defect is large. Important causes of
accelerated pulmonary hypertension include the coexistence of
pulmonary parenchymal disease or upper airway obstruction, the
latter of which is particularly common in infants with trisomy 21.
For that reason, it is recommended that all children with trisomy
21 undergo echocardiographic screening early in life.26 When
present, pulmonary hypertension with incipient pulmonary
vascular disease represents a risk factor for adverse outcomes after
surgery. The risk of overt pulmonary hypertensive crisis in the
postoperative period has receded with the trend toward earlier
surgical correction, but the degree of postoperative elevation of
PVR still predicts the rate of postoperative recovery.27
Left-to-Right Shunts at the Atrial Level

By contrast with left-to-right shunts at the ventricular or arterial
level, shunting at the atrial level appears to be determined princip- Figure 7-5. Transposition of the great arteries with intact ventri-
ally by the relative compliances of the right and left ventricles and cular septum. Mixing of blood occurs at the atrial level (arrow) and
not necessarily by the size of the defect, unless the communication is increased by maintaining patency of the ductus arteriosus.
is very small. The direction of blood flow through the defect is
determined by left and right atrial pressure differences during the
cardiac cycle. The latter, in turn, reflect the relative compliances of Single-Ventricle Physiology
the ventricles. In utero, atrial communications permit flow rela- Single-ventricle physiology is shared by several anatomic sub-
tions that mimic normal shunting across the foramen ovale. strates. The most common is the hypoplastic left heart syndrome
Because the right ventricle is relatively stiff and noncompliant, left- (in which the systemic ventricle is the right ventricle), but similar
to-right shunting is minimal early in life. As PVR falls and the physiology is seen in those with absent right AV connection
right ventricle becomes more compliant, the left-to-right shunt (“classic tricuspid atresia”), unbalanced AV septal defect (in which
increases gradually. The development of congestive heart failure either the left or the right ventricle is too small to support the
from increases in pulmonary blood flow secondary to atrial level circulation), and pulmonary atresia with intact ventricular sep-
shunts is relatively rare. Despite large communications, pulmonary tum. Although the details of the specific management of each of
artery pressures and resistances with few exceptions tend to be these conditions are beyond the scope of this chapter, some
low, hence, closure (nowadays, usually by transcatheter device) general rules are common to each of these conditions.
can be delayed for several years. Some of these lesions manifest ductal-dependent pulmonary
perfusion. In the setting of hypoplastic right heart lesions, the right
ventricle is essentially bypassed with right-to-left shunting at the
Transposition of the Great Arteries atrial level. In the case of tricuspid atresia, pulmonary blood flow
There appears to be little, if any, effect of transposition of the may take place via a ventricular septal defect to the pulmonary
great arteries on the fetal flow pathways or circulatory dynamics artery or via the ductus arteriosus. In the case of pulmonary atresia
(Figure 7–5). However, soon after birth, transposition of the with intact septum, pulmonary blood flow depends totally on
great arteries with limited mixing of pulmonary venous and patency of the ductus arteriosus. These lesions appear to have little
effect on fetal growth and development. Postnatally, the dominant
systemic venous streams is an acutely life-threatening condition
physiologic theme is hypoxemia except where there is un-
because of the sudden imposition of an extremely low level of
obstructed flow into the pulmonary circulation. Early treatment
systemic arterial oxygen saturation. Early treatment with pro-
includes prostaglandin E2 therapy to maintain patency of the duc-
staglandin E2 therapy to maintain ductal patency is life-saving, but
tus arteriosus and surgical creation of a systemic–to–pulmonary
is ineffective in the absence of an intracardiac shunt. Contrary to artery anastomosis usually during the first weeks of life. The long-
popular belief, the effect of ductal reopening has little to do with term palliative strategy is the creation of the so-called Fontan
mixing of desaturated and oxygenated blood at the level of the circulation (see Ductal-dependent systemic perfusion).
great arteries, but rather has its effects by increasing pulmonary
venous return, increasing left atrial pressure, and thereby
improving mixing at the atrial level. All of this will be further Ductal-Dependent Systemic Perfusion
improved by the performance of a balloon atrial septostomy, These defects include variations on the theme of hypoplastic
which is performed in most newborns with transposition before left heart syndrome including aortic atresia, interruption of the
surgical repair. aortic arch, and coarctation of the aorta (Figure 7–6A). During
Figure 7-6. Hypoplastic left heart syndrome

before (A) and after (B) Norwood palliation.
intrauterine development, systemic perfusion is not compromised, permissive hypercapnia may increase systemic blood flow and
being maintained by the ductal flow from right ventricle to aorta. lower total body oxygen consumption.32
Postnatally, systemic perfusion falls as the ductus arteriosus Further surgical intervention in patients with hypoplastic left
constricts. In the case of aortic atresia, the entire systemic cir- heart syndrome is necessary to avoid the chronic volume overload
culation depends on an open duct, whereas with interruption of state of the single ventricle. Following the Glenn procedure, the
the arch and coarctation of the aorta, lower body perfusion is superior vena cava venous return passes directly to and through
acutely curtailed. Although coarctation of the aorta and inter- the lungs, thereby increasing effective pulmonary blood flow and
ruption of the aortic arch can usually be surgically corrected reducing cardiac work. Thus, the pulmonary blood flow equals
so that the circulation is restored to near-normal during the the brachiocephalic arterial flow, which is typically approximately
first week of life, the classic hypoplastic left heart will be treated half of the total
. ventricular
. output. The pulmonary to systemic
by a series of palliative procedures extending over the first 2 or flow ratio (Q p:Q s) ratio is therefore approximately 0.5. This
3 years of life, starting with the so-called Norwood procedure (see typically results in a decrease in the ventricular volume load,
Figure 7–6B). Be it with the traditional or the new hybrid improved ventricular function, and improved AV valve function.
approach,28,29 the goals of the initial Norwood procedure include Patients with clinical signs of significantly elevated superior vena
providing unobstructed systemic blood flow, unobstructed pul- cava pressure may have obstruction at the anastomosis, distal
monary venous return to the single ventricle (usually via atrial pulmonary artery distortion, or marked elevations in PVR.
septectomy), and limitation of pulmonary blood flow. An accept- Excessive cyanosis (oxygen saturation < 75%) should be
able balance between the pulmonary and the systemic output investigated promptly. Etiologies include pulmonary or systemic
provides enough pulmonary flow for adequate oxygen delivery venous desaturation or decreased pulmonary blood flow because
to prevent acidosis without an excessive volume load to the of venous collaterals. Transient, or rarely permanent, sinus node
single ventricle or physiologic “steal” of blood away from the dysfunction is common and responds well to chronotropic agents
systemic circulation. Assuming a mixed venous oxygen saturation or temporary atrial pacing.33
of 65% and a pulmonary venous oxygen saturation of 95%, arterial The Glenn procedure is followed by the third state of the repair
oxygen saturation should be 80%. For the patient with either of total cavopulmonary anastomosis or the Fontan circulation,
excessive cyanosis (oxygen saturation < 75%) or relatively high whereby the inferior vena cava is connected to the pulmonary
(>85–88%) systemic oxygen saturations, the postoperative phy- artery (Figure 7–7). Postoperative management after the Fontan
siology must be carefully evaluated. Excessive cyanosis is caused operation must be specifically tailored to the preoperative anatomy
mainly by pulmonary issues such as pneumothorax or pleural and physiology as well as to the specific type of surgical procedure
effusion, and decreased pulmonary blood flow is caused by performed. In general, it is geared toward optimizing cardiac
a restrictive systemic–to–pulmonary artery shunt or elevated output at the lowest central venous pressure possible. Low cardiac
PVR. The patient who is too pink typically has low PVR and output may be caused by inadequate preload due to hypovolemia
pulmonary blood flow far in excess of systemic blood flow. This (low right atrial and left atrial pressures), elevated PVR (low left
may result in inadequate systemic perfusion, renal dysfunction, atrial and high right atrial pressures), or anatomic obstruction in
and an inability to wean the patient from mechanical ventilation. the systemic venous pathway. Alternatively, low cardiac output
The management of such neonates has considerably evolved since in the face of high left atrial pressure is an ominous sign and
the early 1990s, with a move away from ventilatory maneuvers to may be due to ventricular dysfunction, loss of AV synchrony, AV
increase PVR (breathing of subatmospheric concentrations of valve regurgitation, or ventricular outflow obstruction. Significant
oxygen or additional inhaled CO2) to pharmacologic therapy to arrhythmias (e.g., junctional ectopic tachycardia) are particularly
lower SVR (phenoxybenzamine or milrinone).30,31 Nonetheless, poorly tolerated in this patient population. Mechanical positive-
4. Anderson RH. Terminology. In: Anderson RH, Baker EJ, Macartney

FJ, et al., editors. Paediatric Cardiology. 2nd ed. London, Toronto:
Churchill Livingstone; 2002. pp. 19–36.
5. Wenink ACG. Embryology of the heart. In: Anderson RH, Baker EJ,
Macartney FJ, et al., editors. Paediatric Cardiology. 2nd ed. London,
Toronto: Churchill Livingstone; 2002. pp. 621–53.
6. Dahme T, Katus HA, Rottbauer W. Fishing for the genetic basis of
cardiovascular disease. Dis Model Mech. 2009;2:18–22.
7. American Academy of Pediatrics. Health supervision for children
with Down syndrome. Pediatrics. 2001;107:442–449.
8. Freeman SB, Bean LH, Allen EG, et al. Ethnicity, sex, and the
incidence of congenital heart defects: a report from the National
Down Syndrome Project. Genet Med. 2008;10:173–180.
9. Frid C, Drott P, Lundell B, et al. Mortality in Down’s syndrome in
relation to congenital malformations. J Intellect Disabil Res. 1999;
43:234–241.
10. Vis JC, Duffels MG, Winter MM, et al. Down syndrome: a cardio-
vascular perspective. J Intellect Disabil Res. 2009;53:419–425. [Epub
2009;February 18.]
11. Sachdev V, Matura LA, Sidenko S, et al. Aortic valve disease in Turner
syndrome. J Am Coll Cardiol. 2008;51:1904–1909.
12. Bassett AS, Chow EWC, Husted J, et al. Clinical features of 78
Figure 7-7. Hypoplastic left heart syndrome after establishment of a
adults with 22q11 deletion syndrome. Am J Med Genet. 2005;138:
total cavopulmonary anastomosis.
307–313.
13. Bassett AS, Chow EWC. Schizophrenia and 22q11.2 deletion
pressure ventilation with increased mean airway pressures may syndrome. Curr Psychiatr Rep. 2008;10:148–157.
adversely affect PVR and ventricular filling. Early institution of 14. Pexieder T. Teratogens. In: Pierpont ME, Moller JM, editors. The
spontaneous ventilation may improve hemodynamic function in Genetics of Cardiovascular Disease. Boston: Martinus-Nijhoff; 1986.
the awake state. The duration and frequency of pleural and peri- pp. 25–68.
cardial effusions, typically the most frequent postoperative pro- 15. Gutgesell HP, Speer ME, Rosenberg HS. Characterization of the
blem requiring prolonged hospitalization, have been reduced with cardiomyopathy in infants of diabetic mothers. Circulation. 1980;61:
the use of baffle fenestrations and the “adjustable atrial septal 441–456.
defect.”34 16. Ferencz C, Rubin JD, McCarter RJ, Clark EB. Maternal diabetes and
cardiovascular malformation: predominance of double outlet right
ventricle and truncus arteriosus. Teratology. 1990;14:313–326.
SUMMARY 17. Rouse B, Azen C, Koch R, et al. Maternal Phenylketonuria Collabora-
tive Study (MPKUCS) offspring: facial anomalies, malformations,
The wide spectrum of diseases, resulting physiologic responses, and early neurological sequelae. Am J Med Genet. 1997;69:89–95.
and modes of treatment make the care of infants with congenital 18. Lee LA. The clinical spectrum of neonatal lupus. Arch Dermatol Res.
heart disease particularly challenging. The relationship between 2009;301:107–110.
pulmonary physiology, ventilation, and cardiac physiology is 19. Lougheed J, Sinclair BG, Fung Kee Fung K, et al. Acquired right
almost ubiquitous and must be taken into account when assessing ventricular outflow tract obstruction in the recipient twin in twin-
twin transfusion syndrome. J Am Coll Cardiol. 2001;38:1533–1538.
and managing these patients. Those providing anesthetic care for
20. Schall SA, Dalldorf FG. Premature closure of the foramen ovale and
patients with congenital heart disease may be called upon to hypoplasia of the left heart. Int J Cardiol. 1984;5(1):103–107.
provide anesthetic care for surgical correction or palliation directly 21. Tchervenkov CI, Jacobs ML, Tahta SA. Congenital Heart Surgery
related to the congenital heart disease, during diagnostic and Nomenclature and Database Project: hypoplastic left heart syndrome.
therapeutic cardiac catheterization, or for surgical procedures Ann Thorac Surg. 2000;69:S170–S179.
unrelated to the congenital heart disease. Given the frequent 22. Corno AF. Borderline left ventricle. Eur J Cardiothorac Surg. 2005;
occurrence of multiple congenital anomalies, these patients 27:67–73.
frequently require anesthetic care at various stages of their lives 23. Tchervenkov CI, Jacobs JP, Weinberg PM, et al. The nomenclature,
for procedures outside of the cardiovascular system. The care of definition and classification of hypoplastic left heart syndrome.
children with complex abnormalities should be in specialized Cardiol Young. 2006;16:339–368.
units staffed by subspecialty experts, at all levels, in the mana- 24. Cohen MS, Rychik J. The small left ventricle: how small is too small
gement of children with congenital heart disease. for biventricular repair? Semin Thorac Cardiovasc Surg Pediatr Card
Surg Annu. 1999;2:189–202.
25. Rudolph AM. Fetal and neonatal pulmonary circulation. Am Rev
Respir Dis. 1977;115:11–18.
REFERENCES 26. Wren C, Richmond S, Donaldson L. Presentation of congenital heart
1. Van Praagh R. The segmental approach to diagnosis in congenital disease in infancy: implications for routine examination. Arch Dis
heart disease. The cardiovascular system. Birth Defects Orig Artic Ser. Child Fetal Neonatal Ed. 1999;80:F49–F53.
1972;8:4–23. 27. Schulze-Neick I, Li J, Penny DJ, Redington AN. Pulmonary vascular
2. Van Praagh R. Terminology of congenital heart disease: glossary and resistance after cardiopulmonary bypass in infants: effect on post-
commentary. Circulation. 1977;56:139–143. operative recovery. J Thorac Cardiovasc Surg. 2001;121:1033–1039.
3. Anderson RH, Tynan M. Sequential chamber localization. In: Hamer 28. Calderone CA, Benson L, Holtby H, et al. Initial experience with
J, Rowlands DJ, editors. Recent Advances in Cardiology. Vol. 8. hybrid palliation for neonates with single-ventricle physiology. Ann
Edinburgh: Churchill Livingstone; 1981. pp. 265–285. Thorac Surg. 2007;84:1294–1300.
29. Akinturk H, Michel-Behnke I, Valeske K, et al. Hybrid transcatheter- 32. Li J, Zhang G, Holtby H, et al. Carbon dioxide—a complex gas in a
surgical palliation: basis for univentricular or biventricular repair: complex circulation: its effects on systemic hemodynamics and oxy-
the Giessen experience. Pediatr Cardiol. 2007;28:79–87. gen transport, cerebral, and splanchnic circulation in neonates after the
30. De Oliveira NC, Ashburn DA, Khalid F, et al. Prevention of early Norwood procedure. J Thorac Cardiovasc Surg. 2008;136:1207–1214.
sudden circulatory collapse after the Norwood operation. Circulation. 33. Cohen MI, Wernovsky G, Vetter VL, et alA. Sinus node function after
2004;110(11 Suppl 1):II133–II138. a systematically staged Fontan procedure. Circulation. 1998;98
31. Guzzetta NA. Phenoxybenzamine in the treatment of hypo- (19 Suppl):II352–II358.
plastic left heart syndrome: a core review. Anesth Analg. 2007;105: 34. Mott AR, Spray TL, Gaynor JW, et al. Improved early results with
312–315. cavopulmonary connections. Cardiol Young. 2001;11:3–11.
Airway Development 8
Pierre Fayoux and Bruno Marciniak C H A P T E R
INTRODUCTION first on either side of the midline are marked local thickenings
resulting from the rapid proliferation of mesenchymal tissue. Until
During the course of development, the upper airway undergoes these thickenings have extended from either side to merge in the
significant anatomic restructuring from the neonatal period to midline, a conspicuous midline notch remains. With their merger,
adulthood. Anatomic restructuring—including changes in size the arch of the lower jaw is completed.1 The primitive mouth
and shape and the anatomic relationship between the various (stomodeum) appears as a slight depression in the surface ecto-
components—is particularly prominent during the first few years derm separated by the oropharyngeal membrane. This membrane
of life. Many of the specific anatomic variations and differences of ruptures at 24 to 26 days of gestation. With rupture of the mem-
the newborn and premature airway are important to outline and brane, the primitive gut communicates with the amniotic cavity.2
consider because of their implications for airway management. At 28 days of gestation, the face begins to show its eventual
This chapter separates the discussion of airway development into relationship to the five primordia from which it is derived: the
three parts: the face and the nasal chamber, the oropharynx in- frontonasal prominence (the cranial boundary of the stomodeum
cluding the tongue, and the laryngotracheal lumen. For each part, or primitive mouth); the paired maxillary prominences (first
the embryologic development and the morphologic modification branchial arch); and the paired mandibular prominences (also
during the fetal period, infancy, and childhood are detailed. derived from the first branchial arch). The mandibular promi-
nences grow medially and begin to merge with each other by the
THE FACE end of the fourth week of gestation, forming the lower lip, the chin,
and the mandible.2 The midface is formed through the prolifera-
Embryologic Considerations tion of the facial primordial tissue between 4 and 8 weeks of
gestation. The nasomedial prominence expands and displaces the
The development of the skull can be divided into two major parts:
forebrain prominence from the forming mouth by merging in the
the development of the neurocranium, which forms the cranial
midline. The nasomedial prominences also fuse with the rapidly
vault and skull base, and the viscerocranium, which forms the
elongating maxillary processes to complete the formation of the
skeletal part of the face. Most of the structures of the face and neck
originate from the first two branchial (pharyngeal) arches, tissues that constitute the upper jaw and lip. The segment of the
consisting of an outer layer of ectodermal tissue and an inner layer upper jaw, which is of medial nasal origin, gives rise externally to
of epithelium of endodermal origin. Both of these enclose the core the upper lip in the region of the philtrum. A deeper triangular
of mesenchymal tissue. The mesenchyma for the formation of the portion of the fused nasomedial prominence becomes the pre-
cranial structures is from the para-axial and lateral plate meso- maxillary portion of the dental arch as well as the median (pri-
derm, together with a substantial part from neural crest cells. mary) part of the palate. The intermaxillary segment in the central
These neural crest cells of the developing 3- to 4-week embryo, portion of the upper lip area consists of three parts: the labial com-
composed of ectoderm, are found at the junction of the neural ponent, forming the philtrum; a maxillary component associated
plate and surface ectoderm. Neural crest cells migrate to the with the four upper central incisor teeth; and a palatal component,
branchial arch mesoderm. The face develops as a result of this which becomes the primary palate. The upper lip is formed by the
massive cell migration and their interactions with differentiating merging of the maxillary prominences with the nasomedial
cells of mesodermal origin, which contribute to the skeletal prominences.
components of the face. During the second month of gestation, the development of the
The dorsal portion of the viscerocranium, originating from the palate separates the nasomaxillary complex from the oral cavity.
first pharyngeal arch, forms the maxillary process. This process The premaxilla forms from the fusion of the globular processes of
extends forward and forms the premaxilla, maxilla, zygomatic the nasomedian process forming a small triangular median
bone, and part of the temporal bone. The anterior part also forms portion of the palate (primary palate). The main part of the palate
the mandibular process and gives rise to the mandible. The dorsal (secondary palate) is derived from the maxillary process. It
part of the mandibular process, together with the structures origi- develops in a medial direction, fusing in the midline, and unites
nating from the second pharyngeal arch, forms the ossicles of the with the premaxilla and the developing nasal septum. The soft
middle ear. palate forms from continued growth of the posterior edge of these
The caudal boundary of the oral cavity is less complex, consist- palatal processes, ending with the formation and fusion of the two
ing of the paired primordium of the mandibular arch. Appearing halves of the uvula.
CHAPTER 8 ■ Airway Development 101
The nose originates in the cranial ectoderm, which subse-

quently develops into the frontonasal prominence, with the forma-
tion of nasal placodes during the third week of development. The
superior portion of the nose is formed from the nasolateral pro-
cesses, whereas the inferior portion of the nasal cavity is incom-
plete until the paired maxillary processes of the first branchial arch
grow anteriorly and medially to fuse with the nasomedial pro-
cesses. The nasomedial processes merge on the midline to form
the upper lip and the septum of the nose, which serves to separate
the two nasal chambers. The nasal chambers extend posteriorly
during development under the influence of the posteriorly dir-
ected fusion of the palatal processes. As this occurs, the membrane
that separates the two nasal chambers from the oral cavity thins.
By the 38th day of development, the two-layer oronasal mem-
brane, consisting of nasal and oral epithelium, ruptures, forming
the choanae. The principal stages of craniofacial and nasopharyn-
geal development are illustrated in Figure 8–1.
Morphologic Considerations
The development of the face is influenced by the development of
the system of paranasal sinuses. Originally, because the sinuses are
absent, the facial structures are small compared with the neuro-
cranium. The first signs of the development of the maxillary sinus
are evident at approximately the 10th week of gestation as a pouch
in the lateral wall of the ethmoidal infundibulum. The other
paranasal sinuses also begin their formation during the fetal
period as diverticuli of the lateral nasal wall and gradually dif-
ferentiate inside the cranial bones to form the ethmoid, frontal,
and sphenoid sinuses. The sinuses develop postnatally. Their
maturation is not complete until adolescence or early adulthood.
The maxillary and ethmoidal sinuses are present at birth, whereas
the frontal and sphenoidal sinuses are not clinically detectable at
birth. Development begins around 2 years of age. Frontal sinuses
can usually not be detected radiographically until about 7 years of
age. The paranasal sinuses will not reach their final shape and size
until the end of puberty, giving the final appearance to the face.3–5
The skull base grows rapidly until 6 years of age, with relatively
slower growth thereafter.6 In addition, the cranial base flexes
postnatally during the rapid growth trajectory that is complete by
2 years of age. Modification of this angulation can occur as a result
of growth within the sphenooccipital, midsphenoidal, and sphe-
noethmoid synchondroses as well as from differential drift and
rotation of the components of the basioccipital, sphenoid, and
ethmoid relative to each other.7 The depth of the nasopharynx
increases because of remodeling of the palate as well as changes
in the angulation of the skull base.2 The soft tissues of the pharyn-
geal structures surrounding the upper airway grow proportionally
to the skeletal structures during the chilhood.8 Postnatally, the
dimensions of the nasal cavity increase very quickly. During the
first year of life, the total minimal cross-sectional area increases Figure 8-1. Embryologic development of the upper airway. The
by 67%, and the volume of the nasal airways increases by 36% principal stages of airway development during the embryologic period
when measured by acoustic rhinometry.9 Choanal diameter also are shown. Right column, Craniofacial development. Left column,
undergoes rapid growth until 2 years of age and does not reach Nasopharyngolaryngeal development.
its maximum size until 14 years of age.10 The volume of the
newborn oral cavity is proportionally less than that of an adult,
owing to the significantly shorter mandibular rami. The volume of OROPHARYNX AND TONGUE
the oral cavity increases during the first 12 months of life because Embryologic Considerations
of rapid growth in the height of the mandibular rami and eruption
of the dentition, which leads to enlargement of the lower face The primordial areas involved in forming the covering of the
(Figure 8–2).11 tongue appear early during the second month of development.1
With all of the shiftings of the components that occur as the

tongue develops, a small pit known as the foramen cecum deli-
neates the border between the parts of the tongue that are formed
from the first and second branchial arches. The foramen cecum
is a vestige of the invagination from the floor of the pharynx that
gives rise to the thyroid primordium.
Compared with the adult tongue, the neonatal tongue12 contains
considerably less fat and soft tissue, a relatively enlarged extrinsic
musculature, and a less-developed superior longitudinal muscle,
resulting in a flatter dorsal surface and a larger tongue than that of
the adult configuration. Attachments between the extrinsic mus-
cles and the transverse muscle, present only in the neonatal
tongue, may explain the poor lateral mobility of this structure.
LARYNX AND TRACHEA

Embryologic Considerations
The larynx is developed embryologically from ectodermal,
endodermal, and mesodermal tissues that are derived from the
third, fourth, and sixth branchial arches and pouches.1,3,4,13 The
laryngeal cartilages and muscles form from the mesenchyma of
the fourth and sixth pharyngeal arches. Cartilaginous tissues from
these pharyngeal arches fuse to form the cartilaginous structures
of the airway including the arytenoid, thyroid, cricoid, corniculate,
and cuneiform cartilages. The hyoid bone is derived from the
second branchial arch (lesser horn and superior portion of the
body) and the third branchial arch (greater horn and inferior part
of the body). During the fourth week of embryonic life, a ventral
and midline diverticulum arises from the foregut, referred to as
the respiratory primordium. As this primordium deepens, it
becomes the laryngotracheal tube. The laryngotracheal groove
fuses from the caudal to the cephalic end, forming a tracheoeso-
phageal septum that separates the laryngotracheal groove from
the esophagus. In the fifth to sixth embryologic week, three masses
of tissue appear around the primordial glottic slit at the base of
the third and fourth branchial arches.13 At approximately 6 weeks
of embryonic age, with the rapid proliferation of the mesenchyma
Figure 8-2. Maturation of craniofacial and mandibular structures, at the end of the laryngotracheal tube into the arytenoid promi-
based on three-dimensional reconstructions of images from a com- nences, the laryngeal entrance develops from a simple slit to a
puted tomography (CT) scanner (Osirix software). The volume of the T-shaped opening located directly below the epiglottal swelling.
newborn oral cavity is proportionally lower than that of the adult The epiglottis itself develops from the caudal part of the eminentia
because of the significantly shorter mandibular ramus. The volume of hypobranchialis (anterior parts of the third and fourth pharyngeal
the oral cavity increases significantly during the first 12 months of life arches). Between the arytenoid prominences is the epithelial
because of rapid growth in the height of the mandibular ramus and lamina, limited cephalad by the vestibulotracheal canal and
eruption of the dentition, which lead to enlargement of the lower face. caudad by the pharyngotracheal canal. The rapid proliferation of
the laryngeal epithelium leads to temporary occlusion of the
The tongue surface arises primarily from the mesenchyma of the lumen (Figure 8–3). After recanalization of the lumen at about
first arch, with significant contributions from the third and fourth 10 weeks of gestation, a pair of lateral recesses (laryngeal ven-
arches. In 5-week-old embryos, paired lateral thickenings, the tricles) remains. Around the lateral recesses, the true and false
lateral lingual swellings, arise as a result of the rapid proliferation vocal cords can be recognized as mesenchymal bands. During the
of the mesenchyma beneath the overlying epithelium. These next 6 weeks, the larynx develops almost to its definitive ap-
structures border a posterior small median elevation known as the pearance with the formation of thyroid, cricoid, and arytenoid
tuberculum impar. Behind the tuberculum impar, the copula, cartilages from the mesenchyma and further differentiation of the
another median elevation, unites the second and third second epiglottis.5 At the end of the embryologic period, the larynx
arches into a midventral prominence. The copula extends in a structures are macroscopically differentiated. The fetal period is
cephalocaudad direction from the tuberculum impar to the characterized by the maturation of laryngeal ultrastructures,
primordial swelling that marks the beginning of the epiglottis. particularly at the glottic level.14
Neonatal laryngeal morphology differs significantly from that of
the adult and major postnatal changes occur during the first year
of life. The larynx has a conical shape in infants and children,
wider at the supraglottic level and narrower at the subglottic level.
The adult larynx has more of a symmetrical cylindrical shape
(Figure 8–4).15,16 The neonatal supraglottic area has larger ventri-
cular bands, larger arytenoids, and a shorter epiglottis, the latter
frequently configured in a U or an Ω (omega) shape (Figure 8–5).
The angle between the epiglottis and the glottic plane is more
acute than in the adult. Neonatal vocal cords are shorter than those
of the adult, representing only the anterior half of the glottis, the
posterior half being covered by vocal process of arytenoids (Figure
8–6).17 The maturational descent of the larynx, considered as an
essential event in the transition from an obligate nasal to oral
breather, results in the further separation of the epiglottis from the
soft palate.
At 23 to 25 weeks of embryonic life, the fetal hyoid and larynx
are high relative to the cervical vertebrae, with the larynx extend-
ing from the basioccipital level to the level of the third and fourth
cervical vertebrae (C3–4).18,19 In the neonate, the hyoid lies op-
posite the junction between C2 and C3, just inferior to the man-
dible, with the larynx extending down to C3 to C4.18,20 By 2 years of
age, the hyoid and larynx have attained their adult position relative
to the cervical vertebrae, with the superior margin of the hyoid
body opposite the junction between C3 and C4 (Figure 8–7).21,22
During the majority of postnatal growth, the hyolaryngeal com-
plex descends relative to the face and cranial base, but not relative
to the vertebral column.11 However, the hyoid descends relative to
the palatal plane during the first year of life, presumably because
of rapid growth in the height of the mandibular ramus. The
maturational position of the tip of the epiglottis relative to the
vertebral level is controversial, with a biphasic pattern according
to Sasaki23 and Westhorpe22 or a gradual linear descent according
to Schwartz and Keller.24 Schwartz and Keller reported that the tip
Figure 8-3. Median cross-section through the neck of a human em- of the epiglottis is opposite the middle of the body of C2 in
bryo at 8 weeks. The laryngeal cartilages can be identified. The epithelial children 1 day to 24 months of age, at the inferior end of the plate
lamina is limited cephalad by the vestibulotracheal canal and caudad by of C2 in children 25 months to 10 years of age, and at the C2–3
the pharyngotracheal canal. At this stage, the glottic lumen is occluded. intervertebral disk in adolescents.24 The hyolaryngeal descent
Figure 8-4. Evolution of

laryngeal lumen morphology.
The neonatal larynx has a
conical shape, wider at the
supraglottic level and nar-
rower in the subglottic level.
The larynx of an older infant
or adult larynx has a symmet-
rical cylindrical shape. The
hyolaryngeal descent leads to
a decrease in the pharyngo-
laryngotracheal angle.
Figure 8-5. Morphologic changes of the supraglottic structures

Endoscopic views of the supraglottic larynx. The supraglottic area
of a neonate has larger ventricular bands, larger arytenoids, and a Figure 8-7. Maturational descent of the larynx. The maturational
shorter epiglottis, which is frequently U or Ω (omega) shaped. descent of the larynx is shown on parasagittal CT images. In the
newborn, the hyoid lies opposite the junction between C2 and C3, and
the glottis lies opposite the junction between C3 and C4. After 2 years
relative to the craniovertebral structures leads to a decrease in the
of age, the hyoid and larynx have attained their adult position relative
orolaryngopharyngeal angle25 and the laryngotracheal angle (see
to the cervical vertebrae, as illustrated by this 13-year-old patient. The
Figure 8–4). hyoid body projects opposite the junction between C3 and C4 and the
Laryngotracheal measurements grow in a quasilinear fashion glottis is opposite C5.
during the fetal period, with a linear relationship observed be-
tween the laryngotracheal measurements and either body weight
or height.26–28 The exception is the glottis, which has a curvilinear during airway management in the premature and neonatal po-
growth pattern.26,28 The cricoid lumen is significantly less than the pulation. The management of the neonatal pediatric airway is
tracheal and glottic lumens during perinatal period, thereby discussed in detail in chapters 43 and 72. However, the specific
implications of some of the anatomic and morphologic differences
representing the narrowest section of the airway.17,28 Sasaki23 and
are reviewed.
Wailoo and Emery29 suggested that there were three phases of
The development of the mandibulofacial skeleton and modifi-
laryngotracheal lumen growth (fetal period, birth to prepubertal
cations of the relationship between the soft palate and the tongue
period, and postpubertal period), with the greatest growth oc-
make classic predictive tools of intubation such as the Mallampati
curring during the earliest period and decreasing thereafter.
score inappropriate in pediatric population. The high position of
Litman and colleagues30 and Arens and associates8 reported a
the neonatal larynx leads to a more anterior location of the glottis
linear growth pattern of the laryngotracheal lumen during child-
during laryngoscopy. Because of the supraglottic morphology,
hood. The evolution of cricoid and tracheal luminal dimensions high position of the larynx, and acute glottoepiglottic angle, the
during childhood reported is outlined in Table 8–1.10,23,26–34 direct visualization of the glottic plane is more difficult in neo-
nates. As such, the Cormak classification is also not applicable.
Consequences of Anatomic Differences in Moreover, the frequency of laryngomalacia in this age group may
further decrease the visualization of the glottis. In this case, the
Pediatric Airway Management most effective landmark for placement of an endotracheal tube is
Anatomic differences of the neonatal airway suggest the need for the triangle formed by the arytenoid cartilages and the epiglottis.
the consideration of modifications of technique and equipment The more acute laryngotracheal angle, related to the high position
TABLE 8-1. Development of Laryngotracheal Lumen*

Laryngeal Diameter, Tracheal Diameter,
Age mm mm
<28 GA 2.2–3.1 2.5–5
28–34 GA 2.9–3.5 2.7–5.5
34–38 GA 2.7–5.5 3–6
38–41 GA 3.7–6.4 3.7–6.5
1y 4.5–10 5.2–7.8
3y 6–12 6.3–9
5y 7–12 8–10
10 y 7–16 12
*
The growth of the laryngotracheal lumen according to anatomic and radiologic
Figure 8-6. Evolution of the glottis. The vocal cords of a neonate make studies reported from the literature. See references 10, 23, 26–34. The mean
up only the anterior half of the glottis whereas the posterior half makes diameters reported in studies of Wailoo and Emery29 and Eckel and coworkers17
up the vocal process of the arytenoids. This is compared with the glottis were recalculated based on the results expressed, respectively, in perimeter and
of a 12-year-old in which the vocal cords make up two thirds of the surface area of the subglottic cross-section.
glottis. GA = gestational age in weeks.
of the neonatal larynx, not only is associated with a higher 15. Cotton RT. Management and prevention of subglottic stenosis in
incidence of difficulties during endotracheal intubation but also infants and children. In: Bluestone CD, Stool SE, Kenna MA, editors.
results in a higher risk of anterior laryngotracheal injury such as Pediatric Otolaryngology. 3rd ed. Philadelphia: WB Saunders; 1996.
cricotracheal or cricothyroid dislocation. pp. 1373–1389.
The laryngeal structures have some degree of elasticity before 16. Hudgins PA, Siegel J, Jacobs I, Abramowsky CR. The normal pedi-
atric larynx on CT and MR. AJNR Am J Neuroradiol. 1997;2:
36 weeks of gestation, thereby permitting placement of an
239–245.
endotracheal tube (ETT) that is larger than that predicted by direct 17. Eckel HE, Koebke J, Sittel C, et al. Morphology of the human larynx
anatomic measurement.35 Therefore, in the premature population, during the first five years of life studied on whole organ serial
the risk of injury is greatest to the posterior glottic region. This sections. Ann Otol Rhinol Laryngol. 1999;3:232–238.
elasticity disappears around term, and the site of injury is then 18. Bosma JF (ed). Anatomy of the infant head. 1st edn. Johns Hopkins
predominantly in the subglottic area. The traumatic risk is cor- University Press, Baltimore, 1986. pp 462.
related to the outer diameter (OD) of the ETT. Therefore, guide- 19. Magriples U, Laitman JT. Developmental change in the position of
lines regarding sizing of the ETT should focus on the OD and not the fetal human larynx. Am J Phys Anthropol. 1987;4:463–472.
the inner diameter (ID). The relationship between the OD and the 20. Laitman JT, Heimbuch RC, Crelin ES. Developmental change in a
ID is different according to different manufacturers because of basicranial line and its relationship to the upper respiratory system in
living primates. Am J Anat. 1978;4:467–482.
differences in the thickness of the wall of the ETT. For similar ODs
21. Roche AF, Barkla DH. The level of the larynx during childhood. Ann
of various ETTs, the ID may vary up to 1 mm. This is important Otol Rhinol Laryngol. 1965;3:645–654.
when considering the risk of airway trauma related to the OD of 22. Westhorpe RN. The position of the larynx in children and its relation-
the ETT and the respiratory resistance during spontaneous ship to the ease of intubation. Anaesth Intensive Care. 1987;4:
ventilation, which is dependent on the ID of the ETT. 384–388.
23. Sasaki CT. Development of laryngeal function: etiologic significance
in the sudden infant death syndrome. Laryngoscope. 1979;12:
REFERENCES 1964–1982.
1. Carlson BM. Development of head, neck, and lymphoid system. In: 24. Schwartz DS, Keller MS. Maturational descent of the epiglottis. Arch
Patten’s Foundations of Embryology. 6th ed. New York: McGraw-Hill; Otolaryngol Head Neck Surg. 1997;6:627–628.
1996. pp. 513–715. 25. Vorperian HK, Kent RD, Gentry LR, Yandell BS. Magnetic resonance
2. Holzman RS. Anatomy and embryology of the pediatric airway. imaging procedures to study the concurrent anatomic development
Anesthesiol Clin North Am. 1998;4:707–727. of vocal tract structures: preliminary results. Int J Pediatr Otorhi-
3. Sadler TW. Langman’s Medical Embryology. 7th ed. Baltimore: nolaryngol. 1999;3:197–206.
Williams & Wilkins; 1995; pp. 1–460. 26. Schild JA. Relationship of laryngeal dimensions to body size and
4. Moore KL, Persaud TVN. The Developing Human: Clinically Oriented gestational age in premature neonates and small infants. Laryn-
Embryology. 6th ed. Philadelphia: WB Saunders; 1998. pp. 1–563. goscope.1984;94:1284–1291.
5. Pohunek P. Development, structure and function of the upper 27. Kalache KD, Franz M, Chaoui R, Bollmann R. Ultrasound measure-
airways. Paediatr Respir Rev. 2004;1:2–8. ments of the diameter of the fetal trachea, larynx and pharynx
6. Myer CM 3rd. Growth of the pediatric skull base: assessment using throughout gestation and applicability to prenatal diagnosis of
magnetic resonance imaging. Laryngoscope. 1995;105(9 Pt 2 Suppl obstructive anomalies of the upper respiratory-digestive tract. Prenat
75):1–10. Diagn. 1999;19:211–218.
7. Lieberman DE, McCarthy RC. The ontogeny of cranial base angula- 28. Fayoux P, Marciniak B, Devisme L, Storme L. Prenatal and early
tion in humans and chimpanzees and its implications for reconstruct- postnatal morphogenesis and growth of human laryngotracheal
ing pharyngeal dimensions. J Hum Evol. 1999;5:487–517. structures. J Anat. 2008;213:86–92.
8. Arens R, McDonough JM, Corbin AM, et al. Linear dimensions of the 29. Wailoo MP, Emery JL. Normal growth and development of the
upper airway structure during development: assessment by magnetic trachea. Thorax. 1982;8:584–587.
resonance imaging. Am J Respir Crit Care Med. 2002;1:117–122. 30. Litman RS, Weissend EE, Shibata D, Westesson PL. Developmental
9. Djupesland PG, Lyholm B. Changes in nasal airway dimensions in changes of laryngeal dimensions in unparalyzed, sedated children.
infancy. Acta Otolaryngol. 1998;6:852–858. Anesthesiology. 2003;98:41–45.
10. Violaris NS, Pahor AL, Chavda S. Objective assessment of posterior 31. Too-Chung MA, Green JR. The rate of growth of the cricoid cartilage.
choanae and subglottis. Rhinology. 1994;3:148–150. J Laryngol Otol. 1974;88:65–70.
11. Lieberman DE, McCarthy RC, Hiiemae KM, Palmer JB. Ontogeny of 32. Tucker GF, Tucker JA, Vidic B. Anatomy and development of the
postnatal hyoid and larynx descent in humans. Arch Oral Biol. cricoid. Serial section whole organ study of perinatal larynges. Ann
2001;2:117–128. Otol Rhinol Laryngol. 1977;86:766–769.
12. Iskander A, Sanders I. Morphological comparison between neonatal 33. Fishman RA, Pashley NRT. A study of the premature neonatal airway.
and adult human tongues. Ann Otol Rhinol Laryngol. 2003;9:768–776. Otolaryngol Head Neck Surg. 1981;89:604–607.
13. Tucker HM. The Larynx. New York: Thieme Medical Publishers; 34. Sellars I, Keen EN. Laryngeal growth in infancy. J Laryngol Otol.
1987. pp. 18–19. 1990;104:622–625.
14. Fayoux P, Devisme L, Merrot O, et al. Histologic structure and 35. Fayoux P, Devisme L, Merrot O, Marciniak B. Determination of
development of the laryngeal macula flava. Ann Otol Rhinol Laryngol. endotracheal tube size in a perinatal population. An anatomical and
2004;6:498–504. experimental study. Anesthesiology. 2006;104:954–960.
Respiratory Physiology 9
Etsuro K. Motoyama C H A P T E R
INTRODUCTION DEVELOPMENT OF THE

Pediatric anesthesia involves perioperative and critical care of RESPIRATORY SYSTEM
patients of all sizes between preterm infants weighing less than Prenatal Development of the Lung
1 kg and teenagers weighing well over 100 times that of small
infants. Physiologic differences between the two extremes of The morphologic development of the human lung is seen as early
pediatric patients may even be more significant than their as several weeks into the embryonic period and continues well into
differences in body size. In order for an infant to survive in the the first decade and beyond of the postnatal life (Figure 9–1).1 The
extrauterine environment, the circulatory and respiratory systems entire endodermal structure of the lung arises from the primitive
must undergo the most drastic changes during the first few foregut as a ventral pouch in the third week of embryonic
minutes of life. The neonate must exercise the effective neural development when the fetus is only 3 mm in length. The outgrowth
drive and respiratory muscles to displace the fluids filling the of the endodermal cavity together with surrounding mesenchymal
airways and pulmonary alveoli and introduce sufficient air into tissue projects into the pleuroperitoneal cavity to form lung buds.
the lungs against the surface tension to establish sufficient alveolar The future airway and alveolar membranes including mucous
surface for pulmonary gas exchange. In response to rapid increases glands are derived from the endoderm; whereas the smooth
in blood O2 tensions, pulmonary vascular beds must dilate rapidly muscle, cartilage, connective tissues, lymph, and blood vessels
and increase pulmonary blood flow so as to establish regional originate from the mesenchymal elements surrounding the lung
buds.2 During the pseudoglandular period, which extends into the
alveolar ventilation-pulmonary perfusion balance and maintain
17th week of gestation, the budding of bronchi and the growth of
adequate pulmonary gas exchange. Simultaneously, the pattern of
lung tissues progress rapidly. At the end of this period, preacinar
circulation must change from fetal placental circulation—in which
branching of the future airways down to the terminal bronchioles
the right and left heart outputs function in parallel, perfusing the
are all but completed.3 Any disturbance of the free expansion of the
lower and upper portions of the body, respectively—to the adult-
developing lung in this period, as seen in congenital diaphragmatic
type circulation with the circulation of blood through the right
hernia, results in hypoplasia of the lung and airway branching.4
and left sides of the heart in series.
The canalicular period, which extends into the 24th week of ges-
Neonatal adaptation of the medullary respiratory control and
tation, is characterized by airway branching into future respiratory
lung mechanics evolves much more slowly than circulatory bronchioles, as the relative amount of the connective tissues
adaptation, which takes at least several weeks. Even beyond this diminishes. At the same time, there is increased secretory gland
period of adaptation, the maturation of the infant’s lungs and the and capillary formation around the airways.2
chest wall, which support the stability of lung inflation, continues At approximately the 24th week of gestation, at the beginning
during the first year and beyond. These different cardiorespiratory of the terminal sac (alveolar) period, clusters of terminal air sacs
characteristics in infants and young children make anesthetic appear with flattened epithelia.5 These terminal air sacs (saccules)
management quite different and extremely challenging for are larger with relatively thicker walls with fewer capillaries than
pediatric anesthesiologists. future alveoli.6 Type II pneumocytes, which produce pulmonary
In this chapter, we first review the prenatal development of the surfactant, appear at 24 to 26 weeks of gestation but occasionally
lungs and neonatal adaptation. We then review the postnatal as early as the 20th week.7 At 26 to 28 weeks of gestation, the
development and growth of the lung and thorax. We also discuss proliferation of the capillaries surrounding the saccules becomes
some essential and practical aspects of respiratory physiology in sufficient for pulmonary gas exchange.8 These morphologic and
infants and children that have direct and indirect relevance to biochemical developments may occur earlier in some extremely
pediatric anesthesiology. Such information is indispensable for a premature infants born before the 25th week of gestation who
better understanding of the complexity of neonatal physiology and survive with neonatal intensive care.
for the proper care of infants and young children during the From the 28th week of gestation onward, the wall thickness of
perioperative period. the saccules decreases rapidly with increasing septal capillary
CHAPTER 9 ■ Respiratory Physiology 107
Figure 9-1. Stages of human lung development and their timing. Note overlapping between stages, particularly be-
tween the alveolar stage and the stage of microvascular maturation. Open-ended bars indicate uncertainty as to exact
timing. From Zeltner TB, Burri PH. The postnatal development and growth of the human lung. II. Morphology. Respir
Physiol. 1987;67:269, with permission.
networks. There is further lengthening of terminal air sacs with study that demonstrated an acceleration of lung maturation in the
the possible additional development of air spaces. The formation fetus after the administration of corticosteroids to mothers 24
of alveoli from the terminal saccules occurs in some human fetuses to 48 hours before the delivery of premature infants. Prenatal
as early as the 32nd week of gestation. By the 36th week of glucocorticoid therapy has been used routinely since the 1980s to
gestation, alveoli are consistently present,9 although the majority induce lung maturation and surfactant synthesis in mothers at risk
of the terminal air sacs are primarily saccules at the time of birth of premature delivery.
with further growth of alveoli during the postnatal period.
The lung produces a large quantity of liquid, which expands the
airways while the larynx is closed. This expansion helps to stimulate Perinatal Adaptation
lung growth and development. The lung fluid is periodically At birth, the infant must overcome the high surface tension within
expelled into the uterine cavity, contributing approximately one the alveoli with its first several breaths to introduce air into the
third of the total amniotic fluid. During the 1990s, prenatal ligation liquid-filled lung. Even a normal full-term infant with sufficient
or occlusion of the trachea was thought to be a potential treatment surfactant available must exert a large negative pleural pressure
of the fetus with congenital diaphragmatic hernia (CDH).10 This (≤–80 cmH2O) to overcome the surface force/tension (Figure
treatment causes the expansion of the fetal airways and results in 9–2).16 The fluid in the trachea and the rest of the airways is
accelerated growth of the otherwise hypoplastic lung. Fetal surgery expelled quickly through the upper airways, whereas residual fluid
for the repair of CDH was eventually abandoned.11 leaves the lung more slowly through the lymphatic system and the
Idiopathic respiratory distress syndrome (IRDS) or hyaline pulmonary circulation. With the expansion of the lung, arterial
membrane disease (HMD) occurring in prematurely born infants oxygen tension (PaO2) increases, dramatically reducing pulmo-
is the most common cause of neonatal maladaptation and is caused nary vascular resistance. The resultant large increase in pulmonary
by the immaturity of the lung, with its insufficient pulmonary blood flow and the increase in left atrial pressure and the decrease
surfactant production and inactivation. Experimental studies in in right atrial pressure reverse the pressure gradient across the
animals have shown that certain hormones, such as cortisone12,13 atria and functionally close the foramen ovale. The accelerated
and thyroxine,14 enhance lung maturation, as evidenced by the production of pulmonary surfactant and its abundant presence on
earlier appearance of type II pneumocytes and surfactant the alveolar surface is essential for the smooth transition from the
production. In 1972, Liggins and Howie15 reported the first clinical fetal to the neonatal state.
Figure 9-2. A: A pressure-volume curve of expansion of a gas-free lung. A–B represents the initial expansion. In the example,
approximately 13 cmH2O pressure will be necessary to overcome surface forces. C represents deflation to zero pressure with
gas trapping. B: Pressure-volume relationships during the first breath of a newborn weighing 4.3 kg. Here, 60 to 70 cm H2O
pressure was necessary to overcome the surface forces. A and B: From reference 16, with permission.
Postnatal Development of adolescents and adults, and flow resistance in absolute terms is
the Lung and Thorax higher. However, when normalized for per unit lung volume or
body size, infants’ airway size as well as airway resistance is
The development and growth of the lung and surrounding thorax generally lower than in adults.22,23 For example, the upper airway
continue with amazing speed during the first year of life; the caliber of a 3.5-kg neonate (3.5 mm endotracheal [ET] tube size)
morphologic development of the lungs, however, continues is relatively larger than that of a 70-kg adult (8–9 mm ET tube).
throughout the first decade of life. Although the formation of the These findings do not necessarily conflict with the clinical
airway system, down to the terminal bronchioles, is completed by evidence that infants and toddlers are more prone to severe
the 16th week of gestation,3 alveolar formation in human fetuses obstruction of upper and lower airways. The absolute (not relative)
begins only at about the 36th week of gestation. At birth, the airway diameters in infants are much smaller than those in
number of terminal air sacs (most of which are saccules) is adults, and young children develop upper airway obstruction
between 20 and 50 million, less than one tenth that of adults. The more often and more severely than do adults. Given the smaller
postnatal development of alveoli from primitive saccules occurs cross-sectional area of the pediatric airway, relatively mild
more rapidly than previously assumed and is essentially completed airway inflammation, edema, or secretions can lead to far-greater
by 18 months of age.9 degrees of obstruction in the subglottic (croup) to bronchiolar
During the early postnatal period, the lung volume of infants is (bronchiolitis) airways in infants than in adults.
disproportionately small in relation to body size. In addition,
because of higher metabolic rates in infants (O2 consumption per
unit body weight is twice as high as that of adults), the ventilatory CONTROL OF BREATHING
requirement per unit of lung volume in infants is markedly
increased. Thus, infants have much less reserve of lung surface area
Prenatal Development
for gas exchange. This is an important reason why infants and Respiratory rhythmogenesis occurs long before parturition.
young children develop rapid O2 desaturation with hypoventilation In 1970, Dawes and coworkers24 were the first to demonstrate
or apnea of a relatively short duration. “breathing” activities with rhythmic diaphragmatic contractions in
In the neonate, static (elastic) recoil pressure of the lung is very fetal lambs. Rhythmic movement of the human fetal thorax was
low (i.e., compliance is high), not unlike that of geriatric or recorded soon afterward by means of ultrasound techniques.25
emphysematous lungs with diminished elastic recoil, because the More recent studies have demonstrated that breathing activities
development of elastic fibers does not occur until the postnatal in human fetuses occur regularly during the last trimester of
period.17–19 Perhaps more important clinically, the elastic recoil pregnancy. Fetal breathing activities naturally occur only during
pressure of the thorax (chest wall) is extremely low because of the REM (rapid eye movement) sleep and are most active with
infant’s very compliant cartilaginous rib cage with its limited increased levels of maternal blood sugar a few hours after a
thoracic muscle mass (see Control of Breathing). These unique maternal meal.26
characteristics make infants more prone to lung collapse and Hypoxia depresses, rather than stimulates, fetal respiratory
respiratory insufficiency, especially under general anesthesia (see movement. This suppression may be related to decreased REM
Anesthetic Effect on Respiratory Muscles). Throughout infancy sleep with hypoxia.27 Normally, low fetal arterial PaO2 (carotid
and childhood, static recoil pressure of the lung steadily increases PaO2, 19–25 mmHg) may be a physiologic mechanism that
(compliance, normalized for size, decreases) toward normal values suppresses fetal breathing activities.28 Severe hypoxia induces
for young adults.20,21 gasping, which is independent of the peripheral chemoreceptors
The actual size of the airway from the larynx to the bronchioles and is unrelated to rhythmic fetal breathing. The near-term fetus
in infants and children, of course, is much smaller than that in is relatively insensitive to arterial carbon dioxide tension (PaCO2)
changes. In the fetal lamb, however, extreme hypercapnia (PaCO2 4. Continuous rhythmicity is independent of PaCO2; it is
> 60 mmHg) can induce rhythmic breathing movement that is unaffected by carotid denervation.
preceded by a sudden activation of inspiratory muscle tone with 5. Hypoxia depresses or abolishes, rather than stimulates,
expansion of the thorax and inward movement (inhalation) of continuous breathing.
amniotic fluid in amounts of up to 30 to 40 mL/kg (an apparent
increase in functional residual capacity [FRC]) (Motoyama,
unpublished observation). When PaCO2 was reduced, breathing Control of Breathing in Neonates
activities ceased, followed by a reversal of the sequence of events and Infants
noted above (i.e., relaxation of the thorax and outward flow of Response to Hypoxemia
amniotic fluid).
During the first several weeks of life, both full-term and preterm
neonates respond to moderate hypoxemia (15% inhaled O2) with
Perinatal Adaptation a transient (a few minutes) increase in breathing followed by
sustained respiratory depression33 (Figure 9–3). However, in cold
Before the 1980s, the traditional view of the mechanism that environments, the initial period of transient hyperventilation is
triggers the onset of breathing at birth was that transient fetal abolished in neonates born between 32 and 37 weeks of gestation,
asphyxia during labor and delivery stimulates fetal gasping indicating the importance of maintaining a neutral thermal
followed by rhythmic breathing that is maintained by tactile, environment.34,35 By contrast, when 100% O2 is given, a transient
auditory, thermal, and other sensory stimuli. However the onset of decrease in ventilation is followed by sustained hyperventilation in
breathing activity occurs weeks before parturition and the onset of neonates. This ventilatory response to hyperoxia, similar to that of
air breathing. It is not clear why and how the fetus must “breathe” the fetus, is distinctly different from that of the adult, in whom
in utero when respiratory gas exchange is handled by the placenta. ventilation continues to be decreased. 36 By 3 weeks after birth,
One reason may be prenatal practice or exercise of the respiratory hypoxemia induces a sustained increase in ventilation, as is seen
muscles by the fetus suggested by Dawes.29 Another reason is that in older children and adults.33
the stretching of the airways and lung parenchyma is an important The biphasic depression of ventilation in hypoxemic neonates
stimulus for lung development. Experimental blockade of fetal has been attributed to central depression, rather than to the
breathing with bilateral phrenic nerve sections in the fetal lamb depression of the peripheral chemoreceptors.37 Conversely, in the
results in hypoplasia of the lung.30 study of newborn monkeys under hypoxemia, both tracheal
The current concept of the mechanism of continuous neonatal occlusion pressure (an index of central neuronal drive) and
breathing may be summarized as follows31,32:
diaphragmatic electromyogram (EMG) studies increased above
1. Neonatal breathing is but a continuation of breathing activity, the control levels, during both the initial increase in ventilation
which is present weeks before parturition. and the subsequent sustained ventilatory depression.38 These
2. The clamping of the umbilical cord is an important factor findings imply that the biphasic ventilatory response to hypoxemia
initiating or “restarting” rhythmic breathing. in the neonate results from changes in the mechanics of the
3. Relative “hyperoxia” (PaO2 > 40–60 mmHg) with air breathing respiratory system (such as increased stiffness or fatigue of the
compared with the low fetal PaO2 (20–30 mmHg) augments thoracic muscles or upper airway obstruction), rather than
and maintains rhythmicity. neuronal depression, as has been assumed.39
Figure 9-3. Effect on breathing 14% O2 (hypoxemia)

from room air and then 100% O2 (hyperoxia) in
three newborn infants. Ventilation (mean ± standard
error of the mean [sem]) is plotted against time.
During acute hypoxia, there was a transient increase
in ventilation followed by depression. Hyperoxia
increased ventilation. Modified from reference 101.
at 10 to 12 months of age.41,43 An addition of 2 to 4% CO2 to the

inspired gas mixture abolishes periodic breathing, probably
because of respiratory stimulation.44
Central apnea of infancy is the cessation of breathing activity
lasting longer than 15 to 20 seconds or a shorter period of apnea
associated with bradycardia (heart rate < 100 beats/min), cyanosis,
or pallor.45 The mechanism of apnea in preterm infants is not well
understood but is related to an immature respiratory control
mechanism.46 Central apnea is relatively rare in full-term neonates
but occurs in the majority of premature infants.41,42 In a more
recent study with data on home monitoring involving more than
1000 infants with sudden infant death syndrome (SIDS), their
siblings, and controls who were monitored consecutively for 180
days (Collaborative Home Infant Monitoring Evaluation or
CHME Study), prolonged central apnea among full-term infants
was shown to be less common than was previously thought. Two
to 3% of healthy full-term infants developed central, obstructive,
or mixed apnea lasting more than 30 seconds during sleep. In
addition, prolonged obstructive sleep apnea (OSA) was observed
in a few normal-term infants with a simple upper respiratory
infection (URI), whereas 15 to 30% of preterm infants developed
prolonged apnea and severe desaturation with a URI.47
Figure 9-4. Mean steady-state CO2 response curves at different in-
spired oxygen concentrations in eight preterm infants. The slope of Postoperative Apnea in Premature Infants
the CO2 response curve decreases with decreasing oxygen. The slope in-
creases with increasing oxygen. From Rigatto H, De La Torre Verduzco
With advances in neonatal intensive care and improved survival
R, Cates DB: Effects of O2 on the ventilatory response to CO2 in of prematurely born infants since the early 1980s, postoperative
preterm infants. J Appl Physiol. 1975;39:896–9. apnea has become an important clinical issue in pediatric
anesthesia. There have been controversies regarding the age
at which these ex–premature infants can be safely discharged
Response to CO2 from the hospital after simple surgical procedures such as inguinal
Both full-term and preterm neonates respond to increased PaCO2 herniorrhaphy. The classic paper by Liu and colleagues and a
by increasing ventilation, but to lesser extents than in older infants. number of subsequent studies have shown that prematurely
The slope of the CO2 response curve is less in preterm than in born infants less than 44 weeks postconception, especially those
full-term neonates. The CO2 response (“slope”) increases with with a history of apnea, are at a high risk (20–40%) of developing
postnatal age, independent of postconceptional age.32,40 Although postoperative apnea.48 Apnea occurs mostly within 12 hours
this increase in CO2 sensitivity may represent an increase in postoperatively.49 Conversely, Kurth and associates reported
chemosensitivity, it may also be due to the improved mechanics of that postoperative apnea could occur as late as 56 weeks post-
the respiratory system. In adults, the CO2 response curve increases conception.50
in slope as well as shifts to the left with the severity of hypoxemia. More recent studies indicate that a number of compounding
By contrast, in neonates breathing a hypoxic mixture, the CO2 factors are associated with the development of postoperative
response curve is shifted to the right and the slope decreased. apnea, such as the extent of surgery, anesthetic techniques, anemia,
Furthermore, hyperoxia (breathing 100% O2) shifts the curve to and postoperative hypoxemia.51 It appears that the probability of
the left and increases the slope (Figure 9–4).33 postoperative apnea between 44 and 60 weeks postconception is
less than 5%.52,53 The only important exception is the anemic infant
Periodic Breathing and Central Apnea (hematocrit ≤ 30%) in whom the risk of developing apnea remains
Full-term neonates sleep most of the time and spend 50% of their high regardless of the postconceptional age.51,53
sleep time in active (REM) sleep, compared with the 20% of REM Most of the patients in these reports of postoperative apnea in
sleep of adults. Premature neonates stay in REM sleep most of preterm infants were anesthetized with halothane and isoflurane,
the time.28,32 Both full-term and premature neonates breathe agents with relatively high lipid solubility that remain in the
irregularly. Periodic breathing, in which rhythmic breathing is body tissues for a prolonged period of time. In the era of newer
interposed with a series of short apneic spells lasting less than anesthetic agents with a much lower lipid solubility (sevoflurane
10 seconds without cyanosis or bradycardia, occurs during both and desflurane), increased use of total intravenous anesthesia, as
active and quiet (non-REM) sleep and even during wakefulness. well as the use of regional block, the incidence of postoperative
Although breathing is more irregular in REM sleep than in non- apnea in preterm infants seems to have decreased.54 Indeed,
REM sleep, periodic breathing occurs mostly during quiet sleep.41 postoperative apnea is reported to be significantly lower with
The incidence of periodic breathing in full-term neonates is about sevoflurane or desflurane anesthesia than with other inhalational
80%, whereas it is nearly 100% in premature neonates.41,42 The anesthetic agents.55
frequency of periodic breathing diminishes after 44 weeks Both theophylline and caffeine have been known to be effective
postconception and thereafter with maturation during the first in reducing the incidence of apnea in premature infants.42,56
year of life. It is still present at sometime in nearly 30% of infants Caffeine is especially useful for prematurely born infants for the
prevention of postoperative apnea.57 In addition, xanthine

derivatives, including theophylline and caffeine, are known to
strengthen muscle contractility and prevent fatigue.58 Therefore,
respiratory stimulation in the premature infants may occur by
both central and peripheral mechanisms. It is important to note
that hypoxemia or hypoxia induced by upper airway obstruction
(OSA) can trigger central apnea, because cerebral hypoxia is a
potent respiratory depressant. Indeed, many apneic episodes are
found to be mixed apnea and are often triggered by upper airway
obstruction.47
Postoperative Apnea in Children

Postoperative apnea is not limited to ex–premature infants. Apnea
or hypoventilation can occur in infants and children of all ages as
well as adults who are predisposed to upper airway obstruction
(OSA), not related to neuronal or central apnea. Surgical
correction of upper airway obstruction caused by obstructive
lesions such as micrognathia, macroglossia, adenotonsillar
hypertrophy, and nasal polyps can improve OSA. Children with
Down syndrome (trisomy 21) have an increased incidence of OSA,
which is often exaggerated during the perioperative period
because of the residual depressant effect of anesthetic agents,
opioids, or sedatives.39 With increasing obesity among adolescents
and even among younger children since the later 1990s, especially Figure 9-5. Schematic representation of the respiratory neurons on the
in the United States, perioperative OSA has become a more dorsal surface of the brainstem. Cross-hatched areas contain predomi-
frequent and important clinical entity for pediatric anesthe- nantly inspiratory neurons, blank areas contain predominantly expira-
siologists.59 tory neurons, and dashed areas contain both inspiratory and expiratory
neurons. Böt C = Bötzinger complex; C1 = first cervical spinal nerve;
CP = cerebellar peduncle; DRG = dorsal respiratory group; 4th Vent =
Neural Control of Breathing fourth ventricle; IC = inferior colliculus; NA = nucleus ambiguus; NPA
= nucleus para-ambigualis; NPBL = nucleus parabrachialis lateralis;
The mechanism that regulates and maintains pulmonary gas
NPBM = nucleus parabrachialis medialis; NRA = nucleus retroam-
exchange is remarkably efficient in healthy individuals in whom bigualis; PRG = pontine rerspiratory group; VRG = ventral respiratory
PaCO2 is kept within a very narrow range (40 ± 2 mmHg), whereas group. Courtesy of Dr. M. Tabatabai.
O2 consumption and CO2 production vary greatly between states
of rest and exercise. Breathing is achieved by the coordinated
action of a large number of inspiratory and expiratory muscles. of neurons is located in the ventrolateral medulla. It consists of
Inspiration is produced mainly by the contraction of the both inspiratory and expiratory neurons61 (Figure 9–5).
diaphragm and, to a lesser extent, the external intercostal muscles The respiratory rhythm or cycle generated by the respiratory
and other thoracic muscles, which generate negative pleural neurons is composed of three phases: inspiration, postinspiration
pressure and draw air through the airways to the lung. Expiration (or early expiration), and late expiration. During the inspiration
is primarily produced by the elastic recoil of the lung and phase, inspiratory neurons, which are premotor to the phrenic and
the thorax while the sustained contraction (with diminishing intercostal motor nuclei, display an augmented discharge.60 At the
intensity) of the diaphragm and the upper airway muscles end of the inspiratory phase, inspiratory neurons receive a
(expiratory braking) impedes and smoothens the expiratory transient inhibition (off-switch) that terminates the increase of
inspiratory neuronal activity.61 Afferent inputs to the inspiratory
phase of breathing. Rhythmic contraction and relaxation of the
neurons, especially those from the pulmonary stretch receptors,
respiratory muscles are governed by the respiratory centers in
which are highly concentrated in the upper trachea, affect the
the brainstem and are tightly regulated with multiple feedback
timing of the off-switch. The larger the airway inflation or tidal
systems that match the level of alveolar ventilation to the
volume (VT), the shorter the duration of inspiration62. During the
metabolic needs. These feedback mechanisms include central and postinspiration (or early expiration) phase, the inspiratory
peripheral chemoreceptors, stretch receptors in the airways and neurons receive both excitatory and inhibitory impulses associated
lung parenchyma with vagal afferenta, and segmental reflexes in with active braking of expiratory airflow as the contraction of the
the spinal cord regulated by muscle spindles.60 diaphragm gradually diminishes.60 After the postinspiration phase
Respiratory neurons in the medulla have inherent rhythmicity of the respiratory cycle, lung volume decreases passively to the
even without the rostral brain or sensory afferents. Respiratory preinspiratory level or to FRC. Under certain conditions, such as
neurons are concentrated in two bilaterally symmetrical areas during exercise or during the administration of inhalational
(dorsal and ventral groups) near the level of the obex in the anesthetic agents, expiratory muscles may undergo active contrac-
medulla. The dorsal respiratory group (DRG) of respiratory tions. In this phase of the respiratory cycle, inspiratory neurons
neurons is located in the dorsomedial medulla and contains receive inhibitory postsynaptic potentials in an augmented
mostly inspiratory neurons. The ventral respiratory group (VRG) pattern. Throughout the expiratory phase of the respiratory cycle,
decreasing inhibitions of the onset of subsequent inspiration exist. neurons and the DRG and VRG neurons in the medulla. Electrical
In addition, various afferent inputs affect the onset of inspiration stimulation of the PRG produces rapid shallow breathing, whereas
or prolong the duration of expiration. More specifically, respira- transection of the brainstem at a level caudal to the PRG results
tory neurons are grouped together as follows: in prolonged inspiratory time (TI) or apnea with sustained
inspiration (apneusis).63 The PRG probably plays a secondary role
DRG of Neurons in modifying the inspiratory off-switch mechanism.69
The DRG is spatially associated with the tractus solitarius, the
principal tract for the 9th and 10th cranial nerves. These nerves Respiratory Rhythm Generation
carry afferent fibers from the airways and lungs, heart, and Rhythmic breathing can be maintained without the brain rostral
peripheral arterial chemoreceptors. The DRG functions as an to the pons and in the absence of feedback from peripheral
important primary and possibly secondary relay site for visceral chemoreceptors. Thus, respiratory rhythmogenesis apparently
sensory inputs via the glossopharyngeal and vagal afferent fibers. takes place in the brain stem. The PRG, DRG, and VRG have all
Furthermore, because many of the inspiratory neurons in the DRG been considered as possible sites of the central respiratory
project to the ipsilateral and contralateral spinal cord and make pacemaker or pattern generator.70,71 The prevailing view is that
excitatory connections with phrenic motor neurons, the DRG rhythmicity is a property of the synaptic interactions among the
serves as a source of inspiratory drive to phrenic and possibly various groups of respiratory, motor, and sensory neurons in the
external intercostal motor neurons.63 network.60,72 Studies in neonatal and fetal rats have indicated that
respiratory rhythm is generated in the small cluster of pacemaker
neurons in the ventrolateral medulla near the Boetzinger (pre-
VRG of Neurons Boetzinger) complex.73,74 Such respiratory rhythmogenesis may be
The VRG extends from the rostral to the caudal end of the medulla uniquely needed for the fetus to initiate and maintain breathing
and has three subdivisions (see Figure 9–5). The Botzinger activities when there is little or no feedback from chemoreceptors
complex, located in the most rostral part of the medulla in the to the medulla.
vicinity of the retrofacial nucleus, contains mostly expiratory
neurons. These neurons send inhibitory signals to DRG and
VRG neurons and project into the phrenic motor neurons in the Pulmonary and Thoracic Receptors
spinal cord, causing inhibition and contributing to the “inspiratory
The respiratory tract (the upper airways, trachea, and bronchi),
off-switch” mechanism.64,65 The middle portion of the VRG is
lung, and chest wall have a number of sensory receptors that
occupied by the nucleus ambiguus (NA) and nucleus para-
respond to mechanical and chemical stimuli. These receptors affect
ambigualis (NPA), which are located side by side. Axons of the not only ventilation but also circulatory and other nonrespiratory
motor neurons originating at the NA project along with other functions.
vagal nerve fibers and innervate laryngeal abductor (inspiratory)
and adductor (expiratory) muscles via the recurrent laryngeal
nerve.66 The NPA contains mostly inspiratory neurons, which Upper Airway Receptors
respond to lung inflation. The axons of these neurons project to The major role of the receptors in the pharynx is associated with
both the phrenic and the external intercostal motor neurons in the swallowing function. It involves the inhibition of breathing,
the spinal cord. The nucleus retroambigualis occupies the caudal closure of the larynx, and coordinated contractions of the
portion of the VRG and contains expiratory neurons whose axons pharyngeal muscles.75 The larynx has a rich concentration of
project into the spinal motor neuron pools of the internal various receptors. Activation of these receptors can cause apnea,
intercostal and abdominal expiratory muscles.67 The inspiratory coughing, closure of the glottis, laryngospasm, and changes in the
neurons of the DRG send collateral fibers to the inspiratory ventilatory pattern.76 These reflexes, which affect the patency of
neurons of the NPA in the VRG. These connections may provide the upper airway, respond to transmural pressure or airflow
ipsilateral synchronization of the inspiratory activity between the changes. Three types of receptors stimulate the superior laryngeal
neurons in the DRG and those in the VRG. Furthermore, the nerve: pressure receptors, drive (irritant) receptors, and flow
neurons in the NPA send collateral fibers to the contralateral NPA, (or cold) receptors.77 The laryngeal flow receptors produce
and vice versa.65 These connections may be responsible for the inspiratory modulation while breathing room air, but become
bilateral synchronization of the medullary inspiratory motor silent when inspired air is warmed and fully saturated. The activity
neuron output. of pressure receptors increases markedly with upper airway
obstruction.77,78
Pontine Respiratory Group of Neurons Newborn animals are particularly sensitive to the stimulation
An additional group of inspiratory and expiratory neurons exists of the superior laryngeal nerve either directly or through the
in the dorsolateral portion of the rostral pons, although their receptors, which results in ventilatory depression or apnea. In
function appears to be secondary or ancillary to DRG and VRG of puppies anesthetized with pentobarbital, water in the laryngeal
the medulla. Inspiratory neurons are concentrated ventrolaterally lumen produced apnea whereas normal saline with neutral pH did
in the region of the nucleus parabrachialis lateralis, whereas the not. The principal stimulus for the apneic reflex was reduced or
expiratory neurons are located more medially in the vicinity of the absent chloride ion concentrations.79 The strong inhibitory
nucleus parabrachialis medialis.68 These respiratory neurons are responses of various upper airway receptors in the newborn have
referred to as the pontine respiratory group (PRG), which, in the been attributed to immaturity of the central nervous system.79
past, was called the pneumotaxic center, a term now considered Infants, particularly premature neonates, exhibit a clinically
obsolete. There are reciprocal projections between the PRG important airway protective reflex response to fluid at the entrance
to the larynx.80,81 This reflex seems to trigger prolonged breath- SARs

holding and apnea in neonates and young children during SARs are mechanoreceptors that lie within the submucosa of
inhalation induction of anesthesia. When a small quantity of smooth muscles in the membranous posterior wall of the trachea
warmed saline solution is dripped into the nasopharynx in and major bronchi.85 SARs are stimulated by the distention of the
sleeping neonates, it pools in the piriform fossa and then overflows airways during inspiration (periodic lung inflation). They inhibit
into the interarytenoid space at the entrance to the larynx. This inspiratory activity (Hering-Breuer inflation reflex) and show little
area is densely populated with various nerve endings and response to steady levels of lung inflation. Although SARs are
receptors. The most common response to fluid accumulation is predominantly mechanoreceptors, hypocapnia stimulates and
swallowing. These neonates also respond by central apnea, with hypercapnia inhibits their discharge.86
the glottis either open or gently closed. Coughing or awakening The inflation reflex is important in human newborn infants
may also occur, but these are infrequent. An apneic response is as well as in cats in adjusting the pattern of breathing.62,87 In
more prominent with water than with normal saline solution.80 anesthetized cats, TI is decreased with increasing VT with
These findings appear clinically relevant and particularly hypercapnia, indicating the presence of the inflation reflex in the
important in pediatric anesthesia. During inhalation induction, normal VT range. Vagotomy abolishes this reflex and TI is
pharyngeal reflexes (swallowing) are abolished while laryngeal prolonged (Figure 9–6). In the human adult, TI is independent
reflexes remain intact.82 Secretions would, therefore, accumulate in of VT until the latter increases to about twice the normal VT, when
the hypopharynx without swallowing, which would cause breath- the inflation reflex appears. Apnea that is often observed in adult
holding or central apnea. Positive-pressure breathing with a mask patients during the emergence from general anesthesia with the
and bag, in an attempt to support ventilation, instead of suctioning endotracheal tube cuff inflated may be related to the inflation
the secretions in the larynx, would push secretions further down reflex, because deflation of the cuff often establishes rhythmic
into the larynx, stimulating the superior laryngeal nerve and breathing. The upper trachea has a high concentration of stretch
triggering true laryngospasm.39 receptors.
The upper airway protective mechanism involves both the
pharynx and the larynx and includes sneezing, swallowing, RARs
coughing, and laryngeal closure. Laryngospasm is a sustained tight
RARs are located within the airway epithelial cells and are most
closure of the vocal cords caused by contraction of the adductor
concentrated in the regions of the carina and large bronchi.88 RARs
(cricothyroid) muscles that persists beyond the removal of the
react to both mechanical and chemical stimuli and, unlike SARs,
initial stimulus triggering the glottic closure. In puppies, it is
respond rapidly to large inflation, deflation, and distortion of
elicited by repetitive stimulation of the superior laryngeal nerve.83
the lung. In addition, RARs are stimulated by cigarette smoke,
By contrast, hyperventilation and hypocapnia as well as light
anesthesia increase the activity of adductor neurons and reduce
the mean threshold of the adductor reflex.75 Hyperthermia and
decreased lung volume also facilitate laryngospasm elicited by
the stimulation of the superior laryngeal nerve.83 By contrast,
hypoventilation and hypercapnia, positive intrathoracic pressure,
and deep anesthesia depress excitatory adductor after-discharge
activity and increase the threshold of the reflex that precipitates
laryngospasm.84 It is interesting to note that hypoxia (PaO2 <
50 mmHg) also increases the threshold for laryngospasm. These
findings are consistent with clinical impressions that laryngos-
pasm occurs most frequently under light anesthesia and that it can
be broken by deepening anesthesia or by awakening the patient. In
addition, laryngospasm can also be broken when the patient
becomes severely hypoxemic, suggesting a fail-safe mechanism by
which asphyxia tends to prevent sustained laryngospasm.39
Furthermore, in puppies, positive upper airway pressure inhibits
the glottic closure reflex and laryngospasm. This finding also
supports the clinical observation that, during emergence from
anesthesia in infants and young children, the maintenance of
positive end-expiratory pressure (PEEP) and inflation of the lung
at the time of extubation seem to reduce both the incidence and
the severity of laryngospasm.39
Tracheobronchial and Pulmonary Receptors Figure 9-6. Relation between tidal volume (VT) and inspiratory time
(TI) as ventilation is increased in response to respiratory stimuli. Note
There are three types of major receptors: slowly adapting (pulmo- that in region I, VT increases without changes in TI. Also shown as
nary stretch) receptors (SARs) and rapidly adapting (irritant) dashed lines are the VT trajectories for three different tidal volumes
receptors (RARs), both of which are innervated by myelinated in region II. From Berger AJ: Control of breathing. In: Murray JF,
vagal afferents, and unmyelinated C fiber endings or J (juxta- Nadel JA, editors. Textbook of Respiratory Medicine. Philadelphia:
alveolar) receptors. WB Saunders; 1988, with permission.
ammonia, and other irritant gases, including inhaled anesthetics, of isolated upper airways to halothane resulted in depression
with considerable interindividual variability. RARs are more of respiratory-modulated pressure receptors, whereas irritant
consistently stimulated by histamine, prostaglandins, and leuko- receptors and cold (flow) receptors were consistently stimulated in
trienes, suggesting their role in response to pathologic states, a dose-dependent manner.75 Laryngeal pressure receptors may be
such as bronchial asthma.63 The stimulation of RARs in the large a part of the feedback mechanism that maintains the patency of
airways may be responsible for reflexes such as coughing, bron- the upper airways. The depression of this feedback mechanism,
chospasm, and tracheal mucus secretion. Activation of RARs in together with the activation of irritant receptors, may play an
the periphery of the airways may produce hyperpnea. important role in the collapse of the upper airways during the
When the vagal afferents are partially blocked by cold temper- induction of inhalational anesthesia.
ature, inflation of the lung produces a sustained contraction of the
diaphragm and prolonged inflation of the lung (the paradoxical
reflex of Head). This reflex is most likely mediated by RARs. It may Chemical Control of Breathing
also be related to the sigh mechanism, which may be triggered by Regulation of alveolar ventilation and maintenance of normal
the collapse of some parts of the lung with quiet breathing and PaCO2 within a very narrow range are the principal functions of
increasing surface force. In the neonate, mechanical inflation of the central (medullary) and peripheral (carotid) chemoreceptors.
the lung initiates a deep, gasping breath, which may be related
to the paradoxical reflex, and helps expand unaerated portions of
the lung.89 Central Chemoreceptors
The central or medullary chemoreceptors, located near the surface
C Fiber Endings (J Receptors) of the ventrolateral medulla, are spatially separated from the
medullary respiratory centers. The central chemoreceptors
Most afferent axons arising from the lung, heart, and abdominal respond primarily to changes in hydrogen ion concentration in
viscera are slow-conducting unmyelinated vagal fibers. Studies by the adjacent interstitial fluid and cerebrospinal fluid (CSF), rather
Paintal90 have suggested the presence of such receptors located near than to changes in PaCO2.93 Because CO2 rapidly passes through
the pulmonary or capillary wall (juxtapulmonary or J receptors). the blood-brain barrier into the CSF, which has a poor buffering
C fiber endings are stimulated by pulmonary congestion, edema, capacity, central chemoreceptors are readily stimulated by
or microemboli as well as irritant gases, including inhalational increases in PaCO2. By contrast, ventilatory responses to acute
anesthetic agents. Such stimulation of J receptors causes apnea
metabolic acidosis and alkalosis are limited because changes in
followed by rapid shallow breathing as well as bronchoconstriction,
hydrogen ion concentration are not rapidly transmitted to CSF.
hypersecretion, hypotension, and bradycardia. In addition, stimu-
In chronic acid-base disturbances, the pH of CSF surrounding
lation of C fiber endings can provoke severe reflex contraction of
the chemoreceptors is generally maintained close to the normal
the laryngeal muscles, which may be partially responsible for the
value of approximately 7.3, regardless of arterial pH.94 Under these
laryngospasm observed during inhalational induction with iso-
circumstances (patients with chronic obstructive pulmonary
flurane or desflurane. Inhalation of irritant gases or particles causes
disease or high altitude dwellers), the maintenance of alveolar
a sensation of tightness of the chest, or dyspnea, probably by
activation of pulmonary receptors. Bilateral vagal blockade in some ventilation becomes more dependent on the hypoxic stimulation of
patients with lung disease abolishes dyspneic sensation and the peripheral chemoreceptors (see Peripheral Chemoreceptors).
increases breath-holding time.91
Peripheral Chemoreceptors
Chest Wall Receptors The primary site of peripheral chemoreceptors affecting venti-
The chest wall muscles, especially intercostal muscles (and, to a lation is in the carotid bodies, located at the bifurcation of the
lesser extent, the diaphragm), contain various types of mechano- common carotid artery. Peripheral chemoreceptors react rapidly
receptors that can produce respiratory reflexes.92 The two types of to changes in PaCO2 and pH. Their contribution to the ventilatory
receptors most extensively studied are muscle spindles, which lie drive has been estimated to be about 15% of resting ventilation,
parallel to the extrafusal muscle fibers, and the Golgi tendon but may be much larger when ventilation is increased.95 The
organs, which lie in series with the muscle fibers.63 The muscle carotid body has three types of neural components: type I
spindles are slowly adapting mechanoreceptors and are innervated (glomus) cells, type II (sheath) cells, and sensory nerve fiber
by motor neurons that excite intrafusal fibers of the spindle. The endings.96 Sensory nerve fibers originate at the terminals in
arrangement of muscle spindles is appropriate for the respiratory apposition to the glomus cells and travel through the carotid
muscle load-compensation mechanism.63 The Golgi tendon nerve, which enters the glossopharyngeal nerve. The sheath cells
organs are located at the point of insertion of the muscle fiber into envelope both the glomus cells and the sensory nerve terminals.63
its tendon and are also a slowly adapting mechanoreceptor. The carotid bodies are perfused with an extremely high level of
blood flow through a very short artery arising directly from the
internal carotid artery. They rapidly respond to an oscillating
Anesthetic Effects on the Upper Airway Receptors PaCO2, rather than to a constant PaCO2. This mechanism may, in
Inhalation induction of anesthesia in children is often associated part, be responsible for exercise-induced hyperventilation.97
with reflex responses such as breath-holding and laryngospasm. The primary and unique role of peripheral chemoreceptors,
Studies in animals have demonstrated that inhaled anesthetic however, is their response to decreases in PaO2. Moderate-to-
agents stimulate upper airway receptors directly and affect severe hypoxemia (PaO2 < 60 mmHg) results in significant in-
breathing. In dogs under urethane-chloralose anesthesia and creases in ventilation in a dose-dependent fashion.98 Ventilatory
breathing spontaneously through a tracheostomy, the exposure stimulation, however, is absent in certain hypoxemic or hypoxic
states, such as moderate-to-severe anemia and carbon monoxide

poisoning. Under these conditions, as PaO2 is kept near normal,
the chemoreceptors are not stimulated despite decreased arterial
O2 content and possible tissue hypoxia. In neonates during the
first several weeks of age, ventilation is depressed, rather than
stimulated, by hypoxemia caused by direct hypoxic suppression or
depression of medullary respiratory centers, although peripheral
chemoreceptor activities are present (see Central Chemoreceptors).
In acute hypoxemia, the ventilatory response via the carotid
chemoreceptors is partially opposed by the effect of hypocapnia
and respiratory alkalosis, which suppresses the central chemo-
receptors. Acidification of the CSF by means of medication, such
as acetazolamide, restores hyperventilation (the method used for
acute ascent to high altitude by mountain rescuers). When a
hypoxic environment persists for more than several days or
weeks, for example, during a sojourn to high altitude, ventilation
increases further as CSF bicarbonate decreases and pH returns
toward normal despite continuous hypocapnia.99 In chronic
hypoxemia lasting for years, the carotid bodies gradually lose their
hypoxic response. In high-altitude-dwelling natives of the Andes
and Himalayas, the blunted response of carotid chemoreceptors
to hypoxemia takes 10 to 15 years to develop and is sustained for
a long time.100,101 In cyanotic heart disease in children, the hypoxic
response is lost within a few years, but returns after surgical
correction of right-to-left shunts and restoration of normoxia.102
In patients with chronic respiratory insufficiency and hyper-
capnia, hypoxemic stimulation of carotid chemoreceptors pro-
vides the primary stimulation of the medullary respiratory
centers. If these patients are given O2 and PaO2 increases rapidly,
as in the immediate postoperative period, stimulus by hypoxemia
is removed, ventilation may decrease or cease, and PaCO2
increases further. This is particularly the case in patients with
chronic hypercapnia. These patients may become comatose with
extremely high PaCO2 values (CO2 narcosis), and cardiorespira-
tory catastrophe may follow. Instead of O2 therapy alone, these
patients need their ventilation improved artificially with or with-
out added O2.
Figure 9-7. Effect of acute hypoxemia on the ventilatory response to
steady-state arterial carbon dioxide pressure (PaCO2) in one subject.
Assessment of Respiratory Control Inspired oxygen was adjusted in each experiment to keep arterial oxy-
gen pressure (PaO2) constant at the level as indicated. From reference
CO2 Response Curve 98, with permission.
The graphic presentation of the relationship
. between
. arterial or
end-tidal PCO2 and minute ventilation (VI or VE) is commonly Depression or a shift to right of the CO2 response curve occurs
known as the CO2 response curve. This curve normally reflects the in patients whose carotid bodies have been removed.104 This may
response or sensitivity of the medullary respiratory centers to also occur in patients with lung disease in whom increases in
PCO2. The CO2 response curve is a useful and practical means for intact neural stimulation cannot be translated into increased
evaluating the chemical control of breathing, provided that the ventilation. Under these circumstances, it had long been difficult
mechanical properties of the respiratory system, including to separate out neural components from mechanical failure of
neuromuscular transmission, the respiratory muscles, chest wall the respiratory apparatus.105 In 1975, Whitelaw and coworkers
and lungs, and airways, are intact. Normally, ventilation increases demonstrated that negative mouth pressure generated against
linearly with increasing PCO2, up to 10% or so, when ventilation occlusion (occlusion pressure) at 0.1 s (P0.1) correlates well with
starts to decrease (CO2 narcosis). Under hypoxemic conditions, neural (phrenic) impulse and is unaffected by the mechanical
the CO2 response is potentiated, primarily by the stimulation of properties of the respiratory system.106 Milic-Emili and Grunstein
carotid chemoreceptors, resulting in the shift to the left of the proposed that the ventilatory response to CO2 be analyzed not as
curve (Figure 9–7).98 An exception is during the newborn period the product of tidal volume (VT) and respiratory rate (f) but rather
in terms of the product of mean inspiratory flow rate (VT/TI,
when hypoxemia causes respiratory depression and the rightward
where TI is inspiratory time), as an indication of neural drive, and
shift of the curve (see Figure 9–3).40 By contrast, inhalational
the duty cycle of breathing (TI/TTOT, where TTOT is the respiratory
anesthetic agents, opioids, and sedatives in general depress the
cycle duration) as follows107:
medullary respiratory centers and result in the rightward shift of .
the CO2 response curve (Figure 9–8).103 VI = VT × f = VT/TI × TI/T TOT
Anesthetic Effect on Respiratory Muscles

Under normal circumstances, inspiration of air into the lung is
produced by coordinated contractions of inspiratory muscles and
exhalation is accomplished passively by the elastic recoil of the
lung and chest wall. General anesthesia affects ventilation by
decreasing the intensity of motor neuron impulses to inspiratory
muscles, but with different degrees of depression. Three groups
of muscles coordinate the inspiratory phase of breathing: the
diaphragm, the external intarcostal muscles (pump muscles), and
the upper airway muscles, which maintain the patency of the
pharynx and larynx during inspiration. In quiet breathing, the
contraction of the diaphragm is the primary force producing tidal
ventilation, whereas the intercostal muscles stiffen the chest wall
and resist negative intrathoracic pressure from sucking the thorax
inward, which would result in thoracoabdominal asynchrony, as
seen in the neonate with labored breathing with or without upper
airway obstruction. By contrast, an increase in ventilation during
exercise or hypercapnia is accomplished primarily by increased
intercostal activity.
Sensitivity to anesthetics differs among various inspiratory
muscles and their neurons. Froese and Bryan were the first to
compare the depressant effects of anesthesia on the diaphragm
and intercostal muscles in children and adults.110 Using two-
dimensional magnetometers to measure chest wall and abdominal
circumferences, they demonstrated that light halothane anesthesia
depressed intercostal muscle activities disproportionately more
than it did the diaphragm. Subsequently, Ochiai and colleagues,
in their electromyographic studies in cats, demonstrated that the
phasic inspiratory activity of the genioglossus muscle (which
Figure 9-8. CO2 response curve with halothane. Family of steady-
state CO2 response curves in one subject awake and at three levels of moves the tongue anteriorly and maintains the patency of the
halothane anesthesia. Note progressive decrease in ventilatory response pharyngeal airway) was most sensitive to the depressant effect of
to PaCO2 with increasing anesthetic depth (minimum alveolar concen- halothane at a given concentration.111 The diaphragm was most
tration [MAC]). The ventilatory response in awake state was measured resistant or least sensitive whereas the sensitivity of the intercostal
in response to end-tidal carbon dioxide pressure (PCO2). Courtesy of muscles to halothane was intermediate (Figure 9–9). Furthermore,
Dr. Edwin S. Munson; data based on reference 103. the same group of investigators found that, in kittens, phasic
activity of the genioglossus was more readily depressed than in
The distinct advantage of analyzing the ventilatory response in adult cats.112
this way is that VT/TI is an index of the inspiratory drive, Unlike the laryngeal airway, the pharyngeal airway is not
independent of the timing element. Conversely, VT is time supported by a rigid cartilaginous or bony structure. Its wall
dependent, because VT = VT/TI × TI. The second parameter, consists of soft tissues surrounded by the upper airway muscles
TI/TTOT, is a dimensionless index of effective timing (respiratory and is kept patent with sustained and cyclic contractions of the
duty cycle) that is determined by the vagal afferent and central pharyngeal dilator muscles (the genioglossus, geniohyoid, tensor
inspiratory off-switch mechanism.108 It is apparent from this palatine, and others).39,113 Anesthesia-induced depression of these
equation that a reduction in ventilation in a patient under general pharyngeal dilator muscles seems responsible for upper airway
anesthesia or with lung disease is caused either by changes in the obstruction that is often seen in infants and young children.
drive (VT/TI) or the timing component (TI/TTOT) or both. The work of breathing increases significantly in anesthetized
children breathing spontaneously without an oral airway when
compared with those with an oral airway or laryngeal mask air-
Anesthetic Effects on Respiratory Control way in place, thereby indicating the presence of partial upper
airway obstruction. The addition of low continuous positive
Anesthetic Effect on the CO2 Response Curve airway pressure (CPAP of 5–6 cmH2O) further decreases the work
Most anesthetic agents, opioids, and sedatives depress ventilation, of breathing even in those with an oral airway or laryngeal mask
either by themselves or in combination . with other agents. They airway.114
invariably affect minute ventilation (V I) and its components, VT, In healthy awake patients, exhalation of VT is produced
frequency, VT/TI, TI/T TOT, or their combinations. All inhaled passively by elastic recoil of the lung and chest wall. Under
anesthetics (perhaps with the exception of diethyl ether, which has halothane anesthesia, however, there have been reports of active
not been in clinical use since the 1970s) depress ventilation contractions of abdominal expiratory muscles.115 If this active
profoundly in a dose-dependent fashion (see Figure 9–8). This expiration occurs in anesthetized, spontaneously breathing
subject has been extensively studied in adults.109 Information on patients, it would further contribute to the reduction of FRC at
the effects of anesthetic agents on the CO2 response in infants and end-expiration, airway closure, and possibly, increased venous
children, however, has been limited. admixture.
Figure 9-10. Total lung capacity (TLC) and lung volume subdivisions.
ERV = expiratory reserve volume; FRC = functional residual capacity;
IC = inspiratory capacity; IRV = inspiratory reserve volume; RV =
residual volume; VC = vital capacity; VT = tidal volume.
Figure 9-9. Decrease in phasic inspiratory muscle activity, expressed
as peak height of moving time average (MTA), in percent change from TLC measured with the tracer gas washout technique
control (1% halothane), during halothane anesthesia in adult cats. Values was reported to be relatively small (~60 mL/kg) in infants,
are mean ± sem. *P < .05 compared with the diaphragm (DI); **P <.05 although air spaces in the lung might not have been fully
compared with the genioglossus muscle (GG). From reference 111. recruited (the lung inflated with relatively low pressure of 20–25
cmH2O).117 TLC in children who are older than 18 months
LUNG VOLUMES AND (measured with an adequate inflation pressure of 35–40 cmH2O)
increases with growth until 5 years of age, when it reaches
MECHANICS OF BREATHING 90 mL/kg, the value for older children and adults.117 In normal
Lung Volumes children and adolescents, lung volume is correlated well with body
size, especially height.39
Total lung capacity (TLC) is the maximum lung volume during
inspiration with maximal contraction of inspiratory muscles. TLC
is subdivided into inspiratory capacity (IC) and FRC. IC and FRC Elastic Properties
are further subdivided as shown in Figure 9–10. FRC is the lung
volume at the end of normal expiration when inspiratory muscles Compliance of the Lung, Thorax,
are totally relaxed. It is normally about 50% of TLC (FRC/TLC and Respiratory System
ratio, 0.5) in the upright position and 40% of TLC in the supine In order to expand the lung and achieve tidal ventilation by
position. Residual volume (RV) is the amount of air remaining in contraction of the inspiratory muscles (or with positive pressure
the lung after maximum expiration and is roughly 25% of TLC applied to the airway system), one has to overcome the elastic
(RV/TLC ratio, 0.25). FRC is determined by the balance between recoil of the lung and thoracic structures, which resist the
the outward recoil (expansion) of the thorax and the inward expansion. This elastic recoil pressure is fairly constant over the
recoil of the lung. The two opposing forces result in a negative range of normal V T, but it increases at the extremes of lung
interpleural pressure of approximately –5 cmH2O in older children inflation or deflation. The elastic recoil pressures of the lung, chest
and adults. In infants, interpleural pressure is at or slightly below wall, or respiratory system (lung and thorax) are expressed
the atmospheric pressure. as compliance of the lung (CL), thorax or chest wall (CW), or
In infants, the chest wall is extremely compliant (outward recoil respiratory system (CRS) and are expressed in units of lung volume
is low) whereas the inward recoil of the lung is only mildly lower per units of pressure change as follows:
than that of adults.19,116 Consequently, FRC or relaxation volume
CL = ▲V/▲
▲P
(VR) of young infants at complete relaxation (such as central
apnea, general anesthesia, or the use of neuromuscular blocking where ▲ V is usually the VT and ▲ P is the transpulmonary
agents) decreases to a mere 10 to 15% of TLC.116 This low VR is pressure (pressure difference between the airway and the
substantially below the closing capacity (CC) and results in small interpleural pressure). In the case of CW, ▲ P is the pressure
airway closure, atelectasis, ventilation/perfusion imbalance, and difference across the chest wall (interpleural and atmospheric
hemoglobin desaturation. pressures) and for CRS, the pressure difference between the airway
and the atmospheric pressures. The reciprocal of compliance is elastic fibers (Figure 9–13). At both extremes of human life (e.g.,
elastance (E = 1/C) and E can be added as follows: neonatal and geriatric), the lung is prone to premature airway
closure.18 Elastic recoil pressure of the lung at 60% of TLC increases
ERS = EL + EW
from approximately 1 cmH2O to 7 cmH2O at 7 years and as high
1/CRS = 1/CL + 1/CW as 9 cmH2O during the latter half of the teenage years.119,120
The measurement of compliance is usually made at the extreme
of tidal breath where there is no airflow (static compliance, CST(L), Developmental Changes in Compliance
CST(W), and CST(RS)). Even without any inherent changes in of the Lung and Thorax
the pressure-volume characteristics of the lung, compliance of In infants, outward recoil of the thorax is extremely low (com-
the lung (CL) (or that of the respiratory system, CRS) decreases as pliance, high)116 because of the soft cartilagenous rib cage and
the end-expiratory volume increases from the midpoint of TLC poorly developed thoracic musculature. In comparison, inward
(as with air-trapping or with excessive levels of PEEP). CL also recoil of the lung is only mildly diminished compared with that
decreases when FRC decreases to below normal at the midpoint of in adults. In the neonate, the CW is three to six times higher than
TLC (as with general anesthesia or administration of neuro- CL. Consequently, static balance of these opposing forces would
muscular blocking agents, see Effects of Anesthesia on Respiratory shift and decrease FRC to very low levels. This decrease in FRC
Mechanics). Therefore, the measurement of the pressure-volume would make parenchymal airways unstable and prone to collapse.
relationship over the entire range of TLC provides a more accurate This situation does occur under general anesthesia or muscle
description of the elastic properties of the lung and respiratory paralysis and, to a lesser extent, during apnea and active (REM)
system39 (Figure 9–11). sleep when inspiratory muscles are relaxed.117,121,122
In normal lungs, compliance measured during the respiratory When does the chest wall of infants become stiffer and
cycle (dynamic compliance [CDYN]) is approximately the same as CW decrease to the level of CL? Papastamelos and associates
static compliance. Conversely, when there is airway obstruction have shown that the development of the chest wall occurs much
with an increased pressure swing during tidal ventilation, CDYN sooner than was previously believed.123 In their study, both CL
is relatively decreased, whereas static compliance is relatively and CW were very high in young infants and CW was two to three
unaffected. This difference between static compliance and CDYN times higher than CL. However, the chest wall developed rapidly
increases with increasing respiratory frequency (frequency with increasing rigidity and, by 9 to 12 months of age, CW
dependence of compliance) and is a sign of airway obstruction.118 decreased to the level of CL. Both CW and CL continued to
After several days of postnatal adaptation with the concomitant decrease (elastic recoil, increase) thereafter for the entire study
removal of lung fluid, lung compliance of the neonate is extremely period of 3 years. This rapid development of the chest wall (with
high (elastic recoil, low),21 because of poorly developed elastic resultant stiffening and a decrease in CW) in young infants was
fibers119 (Figure 9–12). These functional characteristics of pressure- attributed to the shift from the horizontal to the upright posture
volume relationships are not too dissimilar to those of geriatric in early infancy, which presumably requires stronger thoracic
patients with pulmonary emphysema with the loss of functioning musculature.123
Figure 9-11. Schematic representation of the pres-

sure volume (P-V) curve and compliance of the res-
piratory system. At the midpoint of the P-V curve
(indicated as FRC awake), the slope and compliance
(Crs = ▲P/▲ ▲V) is the highest. When functional
residual capacity (FRC) is decreased to the lower,
flatter portion of the P-V curve under general anes-
thesia or paralysis (indicated as FRC anesthetized),
Crs decreases even without changes in the mechanics
of the lung.
Figure 9-12. Pressure-volume curves obtained from excised lungs at autopsy. Data are grouped by postnatal
ages as shown by symbols. It is evident that elastic recoil pressure (horizontal distance between nil distending
pressure and the curve at a given distending volume) increases with postnatal development of the lungs.
Based on data from references 17 and 119, with permission.
Figure 9-13. Static pressure-volume curves (deflation limbs) of the lungs in various conditions as
indicated. From Bates DV, editor: Respiratory Function in Disease: An Introduction to the Integrated
Studies. 3rd ed. Philadelphia: WB Saunders; 1989. p. 558.
The breathing pattern of infants younger than 6 months of age airways, the tissue viscoelastic resistance or the resistance of
is predominantly diaphragmatic (abdominal) and the intercostal the lung and thoracic tissues themselves to deformation, and
(rib cage) contribution to VT is relatively less than that in adults. inertial resistance (inertance) resulting from the movement of
After 9 months of age, the rib cage portion of V T increases to gas molecules within the airways, especially at high velocities.
approximately 50%, the level seen in older children and adults, By contrast to compliance (or elastance), which is measured at
This increase in the thoracic portions of VT is brought about by points of no flow, flow resistance is present only when the lung is
changes in the shape of the rib cage (from a “horizontal” to a “V” in motion.
shape) and the maturation of the thoracic musculature.124
Airway Resistance
Maintenance of FRC in Infants The pressure required to overcome frictional resistance and
In spite of an excessively compliant chest wall and the tendency produce flow between the airway opening (Pao) at the mouth and
for static FRC (VR) to fall, dynamic FRC in awake, spontaneously alveoli (PALV) is proportional to flow rate.132 Airway resistance
breathing infants is well maintained near the values seen in older (Raw) is expressed as pressure gradient across the airways:
children and adults because of a number of mechanisms that .
(P = Pao – PALV) per unit flow (V):
prevent FRC from collapsing. These mechanisms include .
Raw = P/V (cmH2O/L/s)
1. “Breaking” of expiration with continual (although diminish-
ing) diaphragmatic activity in the early expiratory phase. If the respiratory system is assumed to have a single
2. Tachypnea with short expiratory time and the initiation of compartment with a constant elastance or compliance (E = 1/C)
inspiration before the end of passive expiration. The resultant and a constant resistance (R), the equation of forces acting on the
intrinsic PEEP (PEEPi) maintains dynamic FRC higher than respiratory system can be expressed:
relaxed FRC or VR. . . .
P = EV + RV + IV
3. Sustained tonic activities of the inspiratory muscles throughout
the respiratory cycle (especially external intercostal muscles). where inertance (I) is very small in tidal breathing and can be
ignored. During normal tidal breathing, approximately 90% of the
How long does dynamic FRC continue postnatally? A study by pressure gradient required is needed to overcome the elastic forces
Colin and coworkers has demonstrated that the transition from and the remaining 10% of the pressure is expended to counter the
dynamic to relaxed FRC in infants occurs between 6 and 12 months flow resistance.133
of age.125 By 1 year of age, the breathing pattern is predominantly Flow resistance is related to the length (l), the radius of the tube
that of relaxed end-expiratory volume, as in older children and (r), and the viscosity of the gas (η) as follows:
adults. Perhaps the most important of all these mechanisms that
sustain FRC is the tonic activity of the external intercostal muscles, r = 8lη/πr4
the diaphragm, and other inspiratory muscles,126 the diaphragm, Assuming a laminar flow (as seen in small or peripheral
and other inspiratory muscles. This mechanism effectively stiffens airways), it is apparent from this equation (Poiseuille’s law) that
the chest wall and maintains higher levels of FRC at end-expiration. the most important factor affecting flow resistance is the change
in the radius of the tube (airways), because resistance is inversely
Anesthetic Effect on FRC proportional to the fourth power of the radius. When the flow is
turbulent, as occurs in large airways, the flow resistance increases
General anesthesia with or without muscle relaxants markedly approximately with r5. Therefore, R aw in infants with smaller
diminishes or abolishes inspiratory muscle tone and results in airway diameters is much higher, in absolute terms, than Raw in
a reduction in FRC. In healthy young adults, a reduction in older children and adults. In terms of body size, however, the
FRC following the induction of anesthesia has been reported caliber of airways in general is wider and Raw is lower in infants
to be between 9 and 25%.127,128 In older individuals, the average and children than in adults.21,23
reduction in FRC is greater (30%), probably due to decreased
elastic recoil of the lung.129 The effect on FRC of general anesthesia
is more pronounced in infants and young children because their Upper Airway Resistance
thorax is more compliant,130 as discussed in more detail in the The airway system extends from the airway opening at the naris or
section “Effects of Anesthesia on Respiratory System Mechanics.” the mouth to the alveolar duct at the periphery of the lung.
A reduction in FRC is not limited to general anesthesia or muscle Functionally, the airway system can be subdivided into the upper
paralysis alone.131 Henderson-Smart and Read have reported a (extrathoraic) and lower (intrathoracic) airways. During quiet
30% reduction in thoracic gas volume (FRC measured with body breathing, airflow resistance through the nasal passages accounts
plethysmograph) in infants when their sleep pattern changed from for approximately 65% of total Raw in adults.134 Stocks and Godfrey
quiet (non-REM) to active (REM) sleep with the relaxation of found that nasal resistance accounted for approximately 49%
respiratory muscles.129 of the total Raw in European infants, whereas it was significantly
less in infants of African origin (31%).135 Overall, upper R aw is
approximately two thirds of the total Raw.
Dynamic Properties Except when crying, newborn infants are obligatory nasal
Breathing involves cyclic contractions of respiratory muscles and breathers. The cephalad position of the epiglottis and the close
the generation of force, which must overcome resistive and elastic approximation of the soft palate to the tongue and epiglottis in
properties of the lung and chest wall. The resistive properties of the neonates may be a reason why mouth breathing is more difficult
respiratory system include the resistance to airflow within the than nasal breathing.136 When the nasal airway is occluded, some
infants, especially during REM sleep, do not respond sufficiently were disproportionately small and Raw high, compared with
to initiate adequate mouth breathing and OSA ensues. In infants, adults.140 They postulated that the diameters of peripheral air-
insertion of a nasogastric tube significantly increases total ways of the same generation were disproportionately smaller
resistance by as much as 50% and may compromise breathing.137 in infants than in older children and adults. However, Motoy-
If the upper airway is narrowed by either compression, increased ama has demonstrated in healthy infants and children under
wall thickness (inflammation), or luminal obstruction (secre- general anesthesia that the conductance of the upstream segment,
tions),or their combinations, the resultant increase in Raw would normalized for lung volume, is disproportionately high (paren-
be far greater in infants than in adults. Life-threatening upper chymal Raw, low) in infants and decreases with age.21 This study,
airway obstruction, such as croup (laryngotracheobronchitis) based on the measurements of maximum expiratory flow-volume
and epiglottitis (supraglottitis), are seen almost exclusively in curves, indicated that lower Raw toward the periphery of the lung
infants. parenchyma is relatively lower in infants during the early postnatal
years than in adults. A later study in children has also confirmed
Lower Raw these findings.141
Between the trachea and the alveolar duct, there are an average of
23 airway generations138 (Figure 9–14). As gas molecules move Tissue Viscoelastic Resistance
from the trachea toward the terminal airways during inspiration, It has been assumed for a long time that the majority of the forces
the radius of the successive generations of airways becomes necessary to overcome the total respiratory system resistance
smaller and, therefore, the resistance to flow is expected to during breathing were expended by airway (frictional) resistance.
increase. In reality, however, the total cross-sectional area of the The pressure needed to overcome tissue viscous resistance during
airway segments increases dramatically toward the periphery, inspiration was estimated to be about 35% in adults and 28% in
although the diameter of successive single airways decreases. children.19 However, studies since the mid-1980s on mechanical
This is because the number of airways increases markedly ventilation, in both animals and humans, have indicated that
and, consequently, the resistance to flow of the airways decreases viscoelastic resistance, or the energy required to counter the lung
toward the periphery138 (see Figure 9–14). Indeed, using a retro- and chest wall tissues’ hysteresis or viscoelasticity, contributed a
grade catheter technique, Macklem and Mead demonstrated that significantly greater proportion of the total resistance than
the peripheral airways, less than about 1 mm in diameter (around previously assumed.142 Furthermore, flow and volume dependence
the 14th generation), contribute less than 10% of the lower Raw or of viscoelastic resistance (Rvis or ▲R) behaves very differently and
3% of the total Raw.139 is opposite that of flow resistance. Raw increases with increasing
On the basis of physiologic studies of the lungs using the flow because of higher turbulence, whereas Raw decreases with
retrograde technique at autopsy, Hogg and colleagues reported increasing lung volume because airway caliber also increases with
that peripheral airways in children younger than 6 years of age volume. The traditional view has been that the total resistance
Figure 9-14. A: Diagrammatic representation of the sequence of elements in the conductive, transitory, and respiratory zones
of the airways. AD = alveolar ducts; AS = alveolar sacs; BL = bronchioles; BR = bronchi; RBL = respiratory bronchioles; T = ter-
minal generation; TBL = terminal bronchioles; z = order of generation of branching. B: Total airway cross-sectional area, A(z),
in each generation, z. A and B: From reference 138, with permission.
Figure 9-15. Flow and volume dependence

of respiratory system resistance (Rrs) and its
subdivisions, resistive component (Rint or airway
resistance [Raw]) and viscoelastic component
▲Rrs) (Rrs = Rint + ▲Rrs). IA: Average relation-
(▲
ship of Rrs and Rint with increasing inspiratory
flow at a constant inspiratory volume (0.47 L)
in 16 anesthetized and paralyzed adult subjects.
IB: Similar relationship between ▲Rrs with vari-
able inspiratory flow. IIA: Average relationship
of Rrs and Rint with variable inspiratory volume
at a constant inspiratory flow (0.56 L/s–1) in same
subjects as IA. IIB: Similar relationship in terms
of ▲Rrs. Bars, 1 standard deviation (sd). Modified
from D'Angelo E, Calderini G, Torri F, et al.
Respiratory mechanics in anesthetized paralyzed
humans: effects of flow, volume, and time. J Appl
Physiol. 1989;67:2556–64.
followed the same direction of flow and volume dependence. markedly in patients breathing through an ET tube under general
Paradoxically, Rvis decreases with increasing flow while the volume anesthesia.
is kept constant, and while the flow rate is kept constant, Rvis
increases with increasing lung volume143 (Figure 9–15). Further-
more, the direction of changes in total resistance followed that Effects of Anesthesia on Respiratory Mechanics
of Rvis, but not Raw. A study in anesthetized and ventilated children General anesthesia significantly affects respiratory mechanics
has shown the same flow and volume dependence of Rvis as in and alters pulmonary gas exchange. The single most important
adults; that is, opposite the direction of changes in Raw122,144 (Figure mechanism causing a cascade of changes in respiratory mechanics
9–16). This new evidence on the behavior of Rvis has important in anesthetized infants and children appears to be the relaxation of
clinical implications. Traditionally, the patient with airway inspiratory muscles by anesthetics. This muscle relaxation, in turn,
obstruction has been treated with large VTs and a slow respiratory results in a reduction in FRC, cephalad displacement of the
rate, to allow complete exhalation in order to avoid PEEPi and air diaphragm, airway closure and atelectasis of dependent lung seg-
trapping. With the new understanding, it makes more sense to ments, ventilation-perfusion imbalance, and eventually, increases
breathe with smaller VT and higher respiratory rate in order to in venous admixture.146,147
minimize both Rvis and total respiratory system resistance and
decrease the work of breathing.145
Anesthetic Effects on FRC
In awake adults, FRC is maintained with the rigid thorax and
Time Constant of the Respiratory System sustained inspiratory muscle tone throughout the respiratory
When the lung is allowed to empty passively from end-inspiration cycle. Sustained inspiratory muscle tone is especially important in
to FRC, the speed of lung deflation is determined by the product infants because of the extremely compliant cartilaginous thoracic
of respiratory system resistance and compliance (R × C or R/E), cage with poorly developed thoracic muscles. Turning from the
which is a unit of time (time constant, τ). If the respiratory system upright to the supine position alone reduces FRC about 10% of
is considered as a single compartment with a constant resistance TLC (0.7–0.8 L in adults) even in awake individuals. Anesthesia
and compliance within the VT range of breathing (which is a with or without muscle paralysis reduces FRC further by aboli-
reasonable assumption in healthy individuals): shing the inspiratory muscle tone (the diaphragm and inter-
τ = RC costals). FRC under general anesthesia (called relaxation volume,
VR) is decreased 9 to 25% in healthy young adults, bringing FRC
Under these conditions, the volume-time profile can be closer to the level of RV in the awake state.127,128 In older patients,
represented by an exponential decay and at 1 time constant (1 × τ), the average reduction in FRC was reported to be greater (30%),
VT is reduced by 63%. In healthy children and adults, τ is 0.4 to 0.5 probably because of decreased elastic recoil of the lung and airway
s, whereas it is considerably shorter in neonates (0.2–0.3 s).19 In closure.148
patients with obstructive lung disease, such as bronchial asthma, The effect of general anesthesia on FRC is more pronounced
τ is increased because of an increase in Raw. It is also increased in infants and young children because of their thorax is more
Figure 9-16. Flow and volume dependence of respiratory system resistance (Rrs) and its subdivisions, resistive component (Rint or Raw) and vis-
coelastic component (▲ ▲R or Rvisc) (Rrs = Rint + ▲R), in eight healthy children (2–5 y of age). A: Average relationship of Rrs, Rint, and ▲R with in-
.
creasing inspiratory flow (VI) at a constant inspiratory volume (VT, 12 mL/kg–1). Rint tended to increase, whereas ▲R and Rrs decreased significantly
with increasing flow. These changes
. are similar to those in adults. B: Average relationship of Rrs, Rint, and ▲R with increasing volume while inspira-
tory flow was kept constant (VI, 15 mL/s–1/kg–1) in the same subjects as A. As in adults, Rint decreased significantly with increasing volume, whereas
.
▲R increased significantly with increasing volume. Unlike in adults, the total resistance (Rrs ) did not change with volume. Bars, 1 sem; VI, inspira-
tory flow; Vr, relaxation volume (or FRC under anesthesia and paralysis). A and B: Data from reference 122.
compliant and more vulnerable to collapse when general anes-

thesia decreases or abolishes thoracic inspiratory muscle tone. In
children (6–18 y of age), there was a 35% reduction in FRC under
general anesthesia and paralysis from awake controls. When
evaluating only those children who were 12 years of age or youn-
ger, the average reduction in FRC was 46%.149 Fletcher and asso-
ciates reported a 35% decrease in respiratory system compliance
in children under general anesthesia,150 reflecting airway closure
or atelectasis.151,152 The reduction in FRC also occurs in children
breathing spontaneously under both inhaled and intravenous
anesthesia.151,152
In a classic study in healthy adults, general anesthesia (thio-
pental) was associated with a reduction of FRC by 25%.128 The
addition of muscle paralysis tended to decrease FRC further, but
the difference was not statistically significant.128 In a recent study
in infants and children receiving propofol anesthesia and
mechanical ventilation, the addition of a muscle relaxant de-
creased FRC even greater in infants 0 to 6 months of age compared
with children 2 to 6 years of age.153 FRC decreased from 21.3 to
12.2 mL/kg (–43%) in infants versus from 25.6 to 23.0 mL/kg (–
10%) in children.153
Anesthetic Effects on the

Position of the Diaphragm
Using cineradiography, Froese and Bryan were the first to report
the cephalad displacement of the diaphragm in the supine posi-
tion in children under general anesthesia that contributes to the
reduction in FRC.110 The cephalad displacement was more
pronounced in the posterior, dependent portion of the dia-
phragm during either spontaneous breathing or paralysis with
mechanical ventilation. This finding was explained by the loss
of inspiratory muscle tone, which allowed the abdominal viscera Figure 9-17. Top: Transverse computed tomography (CT) scan of the
to push the diaphragm cephalad. Cyclic displacement of the thorax during anesthesia (5 min after induction) without positive end-
diaphragm by mechanical ventilation under muscle paralysis expiratory pressure (PEEP). Note the appearance of atelectasis in the
was predominantly anterior and was far less in the posterior, dependent regions of both lungs. Bottom: Transverse CT scan of the
dependent portion of the diaphragm. The cephalad displace- thorax during anesthesia with a PEEP of 5 cmH2O, showing the disap-
ment of the diaphragm was far less when the patients were pearance of atelectasis in dependent regions of both lungs. From refer-
ence 156, with permission.
not paralyzed.151
Anesthetic Effects on Airway indicates that the likely cause of the observed density is compres-
Closure and Atelectasis sion of the lung (gravity-dependent atelectasis), rather than
resorption of the gas following the airway closure.147 Conversely,
The reduction of FRC to values at or below RV and CC makes the atelectasis does not develop rapidly if the lungs are ventilated with
airways vulnerable to premature closure during tidal exhalation 30 to 40% O2 in nitrogen, indicating that absorption of O2 from the
and increases venous admixture.152 CC is the volume at which alveolar space is also an important factor for the development of
airways in the dependent portion of the lung start to collapse. atelactasis.157 (The effect of anesthesia on FRC and the effect of
Using computed tomography (CT) scanning, increased density, PEEP on FRC under general anesthesia are discussed more in
representing airway closure and/or atelectasis, has been reported detail in the section on “Effect of Anesthesia on Respiratory
immediately following the induction of anesthesia and muscle Mechanics.”)
paralysis in adults154 as well as in infants and children155,156 (Figure
9–17). Atelectasis occurs in most patients and is localized to
the posterior, dependent portions of the lungs bilaterally. Serafini Effect of PEEP on FRC Under General Anesthesia
and coworkers also reported that the addition of low PEEP The addition of PEEP is important and effective in preventing
(5 cmH2O) prevented the development of increased density on anesthesia-induced reductions in FRC and resultant airway
CT scans in children ventilated with an O2-N2O mixture.156 In closure and atelectasis.132 Thorsteinsson and colleagues have
adults, although PEEP of 10 cmH2O consistently reopens portions shown that FRC, or more accurately, end-expiratory volume under
of collapsed lungs, the lung collapse returns immediately after general anesthesia and paralysis (VR) is situated in the lower, flatter
the removal of the PEEP.157 The rapid onset of airway closure or portion of the pressure-volume curve and is much lower than
atelectasis (as evidenced by increased density on the CT scan) normal FRC in the steep midportion of the pressure-volume
soon after induction of anesthesia or the removal of PEEP curve.117 The mean PEEP that was needed to restore FRC to the
Figure 9-18. Compliance of respi-

ratory system (Crs) under general
anesthesia in infants and children
and the effect of positive end-
expiratory pressure (PEEP). An
addition of PEEP (5–6 cmH2O)
improves (restores) Crs signifi-
cantly in all age groups studied.
The beneficial effect of PEEP, how-
ever, was most dramatic in infants
younger than 8 months of age (see
text). From reference 132.
normal, midportion of the pressure-volume curve (with optimum Anesthetic Effects on Compliance
compliance) was 6 cmH2O in infants younger than 6 months of of the Respiratory System
age and 12 cmH2O in children. A more recent study in children It has been known that respiratory system compliance decreases
(2–6 y) under general anesthesia also showed that PEEP as high as soon after the induction of general anesthesia. Westbrook and
17 cmH2O was needed to raise FRC to the midpoint of the associates found a 25% reduction in FRC shortly after the induction
inspiratory pressure-volume curve of the respiratory system with- of anesthesia along with a marked rightward shift and decrease in
out previous recruitment maneuvers.122 Clinically, a lower level the slope of the pressure-volume curve of the lung128 (Figure 9–19).
of PEEP (5–6 cmH2O), preceded by deep sighs (TLC maneuvers), There was also a small reduction in CW. The mechanism and
appears sufficient to maintain respiratory system compliance the sequence of events leading to these changes were not well
without higher PEEP, which may have deleterious hemodynamic understood at that time, although a reduction in muscle tone with
effects. A study has shown that, in infants younger than 6 months anesthesia and the resultant reduction in FRC were considered as
of age, the addition of PEEP (6 cmH2O), preceded by deep sighs possible causes. This puzzle was solved by De Troyer and Bastenier-
or recruitment (TLC) maneuvers, increased the CRS an average Geens in their study on healthy volunteers with partial muscle
of 75%, indicating a large volume of lung recruitment. By contrast, paralysis, as described earlier in the section on the Anesthetic
in older infants and toddlers (9 mo–2.5 y of age), the increase effects on FRC.126 These authors postulated that, in the awake state,
in CRS with PEEP was 22%. The change in CRS with PEEP in inspiratory muscles (external intercostals and the diaphragm) have
older children (2.5–6.0 y) was 9%, the level one would expect in intrinsic tone that maintains outward recoil and rigidity of the chest
adults132 (Figure 9–18). Thus, physiologic PEEP is clinically im- wall. The sequence of events leading to reduced CL and CW are as
portant for infants and young children younger than 3 years follows: anesthesia or paralysis abolishes inspiratory muscle tone,
whereas PEEP is essential, if not mandatory, for infants younger thereby reducing the outward recoil and CW. This reduction in the
than 9 months undergoing general anesthesia with controlled outward recoil of the chest wall, in turn, reduces FRC and finally
ventilation. decreases CL with the shift in the position of the pressure-volume
It has been a common practice in clinical anesthesia for many curve with or without airway closure. As previously discussed in
years that, toward the end of inhalation anesthesia before the section on Elastic Properties, with more compliant chest walls,
extubation, the patient be “preoxygenated” by turning off all the infants and young children would be more vulnerable for decreases
inhaled anesthetics and turning up the flow of 100% O2 to wash in FRC and resultant airway closure and atelectasis.
out the inhalational anesthetic agents from the lungs and cir-
culation. This maneuver has also been suggested to fill the
lungs with pure O2 to ensure better oxygenation of the patient Anesthetic Effects on Resistance
during the immediate postoperative period. The patient’s trachea of the Respiratory System
is then extubated, when ready, with or without positive airway Although studies on pressure-flow relationships during anesthesia
pressure.158,159 Benoit and associates found significant areas of are relatively limited compared with the abundant information on
atelectasis remaining in the lung with moderate O2 desaturation pressure-volume relationships, most available studies show
(mean PaO2 < 80 mmHg) after preoxygenation with 100% O2 even considerable increases in Raw and total respiratory system resist-
after proper recruitment (TLC or VC) maneuvers with deep ance even after the resistance to gas flow through the ET tube is
sighs.159 By contrast, in the same study, after the VC maneuvers subtracted.127 Clinically, however, the presence of an ETl tube adds
were performed with 40% O2 instead of 100% O2, atelectasis was the most significant frictional resistance, equaling or surpassing
significantly reduced and PaO2 was significantly higher (~95 the total Raw before intubation. These changes are related to the
mmHg) than in those with preoxygenation with 100% O2. These smaller diameter of the ET tube compared with that of the upper
findings emphasize the importance of lung recruitment maneu- airway dimensions.147 In patients who are anesthetized and
vers using an inert gas (nitrogen) and PEEP to stent open the breathing spontaneously without an ET tube, increased Raw results
terminal airways and prevent atelectasis. from the relaxation of pharyngeal and laryngeal muscles and the
Figure 9-19. A–C: Pressure-volume curves

of the total respiratory system (left panel),
the lung (middle panel), and the chest wall
(right panel) awake and during anesthesia
without and with muscle paralysis. Note the
right shift and flatter slope of the curves of
the total system and of the lung (reduced
compliance) during anesthesia and the minor
effect of adding muscle paralysis. The
pressure-volume curve of the chest wall
remains much the same awake and anes-
thetized. Pao = airway opening (mouth)
pressure; Pes = esophageal pressure; Ptp =
transpulmonary (Pao – Pes) pressure.
From reference 128, with permission.
resultant partial obstruction of the upper airways, as previously Dead Space and Alveolar Ventilation
discussed in the section on Upper Airway Resistance.
The part of minute volume that contributes
. to pulmonary
gas exchange is alveolar ventilation (VA). The remainder of air
VENTILATION AND moves in and out of respiratory
. dead space (VD) and does not
PULMONARY CIRCULATION participate in gas exchange. VA can be expressed in terms of CO2
in arterial blood:
Ventilation is achieved by the movement of air in and out of the . .
VA = (PB – 47) x VCO2/PaCO2
lung. The diaphragm is the most important muscle producing .
normal breathing, whereas the intercostal and accessory respir- where VCO2 is the CO2 production per minute, PaCO2 is arterial
atory muscles are mobilized when increased ventilation is needed. CO2 tension, and (PB – 47) is the barometric pressure minus
Normally, exhalation is accomplished passively by the elastic recoil water vapor pressure at 37°C. .Thus, assuming that the CO2
of the lung and thorax. Exhalation by the neonate, however, production remains constant, if VA is halved, PaCO2 will double
appears active even when resting or asleep. Similar active expira- and vice versa.
tory activities have been observed in healthy individuals under In normal individuals, anatomic dead space (VDanat), the
general inhalation anesthesia.115 The mechanisms have not been amount of air in the respiratory system from the airway opening
elucidated. Forced exhalation is accomplished with the contraction to the terminal bronchioles proximal to the gas-exchanging
segments of the lung, can be estimated as 1 mL/lb or 2 mL/kg of
of abdominal muscles together with the spinal flexors and internal
body weight.162 In children and young adults, a more accurate
intercostal muscles. . estimate can be obtained based on body height.163 In reality, VD
Minute volume or ventilation (VE) is the amount of air breathed varies significantly from VDanat and is dependent upon the
in or out per minute and is the product of V T and respiratory distribution of ventilation and pulmonary blood flow.
frequency (f), as follows: The
. . difference
. between minute volume and alveolar ventila-
VE = VT × f tion VE or VA is the wasted or dead space ventilation due to
physiologic dead space (VDphys). The VDphys can be calculated from
The respiratory rate or frequency (f) of quiet breathing is high the PCO2 between the arterial blood and the mixed expired gas
in young infants with frequencies up to 30 to 40 breaths/min. (PECO2) and is normally expressed as a fraction of the VT:
Respiratory rate decreases with age down to 8 to 12 breaths/min
in the young adult. The exact basis for this change is not known, VD/ VT = (PaCO2 – PECO2)/PaCO2
.
but may be related to the work of breathing. It appears that, in VA is considerably higher per unit of lung volume in normal
humans, respiratory rate and V T are adjusted to accomplish infants than in adults. This is because of the relatively higher
breathing with the least amount of work. The relatively high rate metabolic rate and O2 consumption of infants whose lung volume
in neonates compared with that in adults is consistent with this is also relatively smaller than that of adults.
minimum work concept.160 Conversely, Mead has proposed that,
in the normal resting state, breathing is adjusted so that the
minimum average force of the respiratory muscles is needed.161 Distribution of Ventilation
He further postulated that the principal site of the sensory end of Distribution of ventilation is affected by gravitational force. In the
the control mechanism is in the lung. upright position, the interpleural pressure surrounding the apex of
the lung is more negative than at the base. Consequently, the lung.167 In paralyzed and ventilated adults, tidal ventilation is
transmural distending pressure and the regional FRC at the apex preferentially shifted to the uppermost part of the lung, presu-
are greater than the regional distending pressure and the regional mably by a similar mechanism with decreased FRC and air-
FRC at the base (Figure 9–20A). With tidal inspiration, a greater way closure.
fraction of air is distributed to the base, where regional FRC is at In infants and young children, with the use of CT imaging,
the steepest portion of the pressure-volume curve, as long as the increased density (airway closure or atelectasis) has been consis-
airways to this segment remain open (see Figure 9–20A, B). tently observed immediately after the induction of anesthesia.156
Similarly, in the lateral decubitus position in adults, the lower lung The addition of low PEEP cleared the density in the dependent
receives a larger share of VT than the upper lung.164 lung, preventing atelectasis. Similarly, in infants and young child-
In infants, however, the opposite seems to be the case. In the ren, especially those younger than 8 months with an exceptionally
lateral decubitus position in infants with unilateral lung disease, compliant chest wall, respiratory system compliance was reduced
oxygenation improves when the healthy lung is up165 (Figure markedly under general anesthesia and paralysis. The addition of
9–21). Using a krypton-81m ventilation scan, Davies and cowor- PEEP (5–6 cmH2O) restored the compliance and O2 saturation.132
kers have demonstrated that, in infants and young children up to These findings demonstrate the presence of airway closure and
2 years of age with or without lung disease, tidal ventilation is maldistribution of ventilation under general anesthesia, parti-
preferentially distributed to the uppermost part of the lung and cularly in young infants and children.
diminished in the dependent lung.166 This paradoxical distribution
of ventilation in young children under sedation may be explained
by premature airway closure in the dependent lung. Because the
Distribution of Pulmonary Perfusion
infants’ chest wall is exceptionally compliant, the interpleural As with regional ventilation, gravity affects pulmonary blood flow
pressure is near atmospheric. This condition resembles that of and results in the uneven distribution of pulmonary perfusion.
adults breathing at extremely low lung volumes near RV (see West and colleagues divided the characteristics of upright lung
Figure 9–20B). Under these circumstances, airway closure occurs perfusion into three zones, which they later modified into four
and ventilation is preferentially shifted to the upper part of the zones.168,169 Perfusion of lung tissues depends on the interrelation
Figure 9-20. Effect of vertical gradient of pleural surface pressure on distribution of tidal ventilation. A: At the beginning of
lung inflation from functional residual capacity (FRC), the lower regions are operating on the steeper part of the compliance
curve of the lungs than the upper regions. Accordingly, during slow inspiration from FRC, ventilation is greater in the lower
lung regions (arrows). B: At residual volume (RV), the pleural surface pressure at the lung base is positive (+4.8 cmH2O) and
the lower airways are closed. Consequently, at the beginning of slow inspiration from RV, the lower lung regions are not ven-
tilated and the uppermost part of the lung is preferentially ventilated (arrows). A and B: From Milic-Emili J. Pulmonary stat-
ics. In: Widdicomb JG, editor: Respiratory Physiology. MTP International Review of Science. Series 1, vol. 2, Borough Green
Kent, UK: Butterworth; 1974; and Baltimore: University Park Press; 1974. p. 105, with permission.
peak pulsatile pressure and flow. Ventilation in zone I, therefore,

is mostly wasted for gas exchange. Excessive PEEP would widen
zone I and increase alveolar dead space; by contrast, increases in
pulmonary perfusion pressure as seen in exercise or hypoxemia
(high altitude) decreases or abolishes zone I. In zone II (also
known as the waterfall zone) below zone I, Pa becomes higher than
PA as the vertical distance above the right ventricle decreases,
whereas PV remains lower than PA. The driving pressure in zone
II is the difference between pulmonary arterial and airway
pressures (Pa – PA), which determines regional pulmonary blood
flow independent of downstream venous pressure (waterfall
phenomenon). Regional blood flow increases toward the base
of the lung as the driving pressure increases, until Pv equals PA.
In zone III, both Pa and PV are higher than PA. Throughout this
zone, the driving pressure of the blood flow is the difference
between Pa and PV. However, the blood flow is greater toward the
base of the lung, presumably because both the Pa and PV are
Figure 9-21. Posterior krypton-81m ventilation lung scan in a healthy greater and the pulmonary vessels are distended. The relationship
31-year-old man and in a 2-month-old girl after repair of a right con- among the Pa, PV, and PA in these three zones can be summarized
genital diaphragmatic hernia. In the adult, ventilation is preferentially as follows:
distributed to the dependent lung; in the infant, the reverse is seen, with
ventilation greater in the uppermost lung. For all scans, the distribution
Zone I: PA > Pa > PV
of ventilation to each lung is expressed as a percentage of the total to Zone II: Pa > PA > PV
both lungs. From reference 165, with permission.
Zone III: Pa > PV > PA
among three pressures, namely, airway pressure (PA), pulmonary In zone IV, pulmonary blood flow is progressively decreased
arterial pressure (Pa), and pulmonary venous pressure (PV) toward the base of the lung, presumably because of increased
(Figure 9–22). Because normal pulmonary circulation is a low- interstitial pressure surrounding the extra-alveolar vessels. This
pressure system, regional pulmonary perfusion pressure varies zone increases in size with reductions in lung volume toward RV
from the top to the bottom of the lung, barely overcoming the and with increasing interstitial fluid volume, such as interstitial
hydrostatic pressure to reach the apex of the upright lung, pulmonary edema.169
especially in tall adults. Both pulmonary perfusion pressure and In the supine position, the vertical distance between the top
flow are increased toward the base of the lung.169 and the bottom of the lung is diminished and zone I disappears.
In apical zone I, PA is higher than both Pa and PV. Alveolar Zone II also decreases as PV increases throughout the lung. The
capillary blood flow is absent or occurs only intermittently with effect of gravity in infants and young children, who have a smaller
Figure 9-22. Four zones of lung perfusion. Zone

I has no flow because alveolar pressure exceeds
pulmonary arterial pressure, thereby collapsing
alveolar vessels. Zone II is present when pulmonary
arterial pressure exceeds alveolar pressure and both
are greater than pulmonary venous pressure. This is
termed the vascular waterfall, because flow is unaf-
fected by downstream (pulmonary venous) pres-
sure. Zone III is characterized by a constant driving
force, the difference between pulmonary arterial
and venous pressure. Both are greater than alveolar
pressure. Flow increases throughout zone III, even
though driving pressure is constant because the ab-
solute pressures lower in the lung distend the ves-
sels to a greater extent, thereby lowering resistance.
Zone IV has less flow per unit lung volume, proba-
bly because of the increased parenchymal pressure
surrounding pulmonary vessels. From reference
168, with permission.

. .
hydrostatic gradient, especially in the supine position, would be pulmonary flow due to left-to-right shunt, the VA/Q ratio is
minimal. In addition, PA is elevated during the first months of life, decreased.
as the transition from the fetal to the extrauterine circulatory The lung
. has
. an intrinsic regulatory mechanism that preserves
pattern is being completed. This further diminishes the gravita- a. normal
. VA /Q ratio. In the lung segment with a relatively high
tional effect on pulmonary circulation. VA/Q ratio, a low regional PCO2 constricts small airways and, at
the same
. . time, dilates pulmonary vasculature. In the area with a
low VA/Q ratio, in addition to the PCO2 effects as just discussed,
Ventilation–Pulmonary Perfusion Relations hypoxic pulmonary vasoconstriction . (HPV)
. tends to decrease
In order to maintain normal gas exchange in the lung, it is essential regional blood flow and steers the VA/Q ratio toward normali-
that regional distribution of ventilation and blood flow be well zation. Administration of vasoactive agents, such as β-adrenergic
agonists, theophylline, sodium nitroprusside, and nitroglycerin,
balanced.
. . The overall ratio of ventilation and pulmonary perfusion
. . diminishes or abolishes HPV and increases venous admixture.171
(VA/Q) is approximately 0.8. Because both components of VA/Q
In children with severe reactive airway disease, such as status
are influenced by gravity, they are both affected by the individual’s
asthmaticus, administration of a β-adrenergic agonist is often
body position. When the patient is in the upright posture, associated with a substantial decrease in PaO2 concomitant
both the ventilation and the pulmonary. blood . flow are less in the with significant decreases in RAW. Inhaled anesthetics decrease
apex than in the base of the lung. The VA/Q ratio is highest at the HPV in vitro,172,173 but their effect on HPV in vivo has not been
apex and decreases toward the base because the difference in conclusively demonstrated.174,175
pulmonary blood flow between the apex and the base of the lung
is greater relative to the changes in ventilation170 (Figure 9–23). In
hypotensive and hypovolemic patients, gravitational effects may O2 TRANSPORT
be exaggerated with positive-pressure breathing. In the supine or
For the maintenance of body metabolism, O2 must be transported
lateral decubitus position, similar gravitational effects exist but are
continuously to all body tissues and CO2 must be eliminated.
less pronounced. During exercise, both ventilation and pulmonary Changes in metabolic demand are met by the integrated response
blood flow are increased and more evenly distributed as the of three major components of the gas transport systems: alveolar
gravitational effect is diminished. In awake infants and young ventilation, cardiac output, and hemoglobin concentration and
children, distribution of pulmonary perfusion is more even than characteristics. With acute increases in O2 demand, such as severe
in adults because of relatively higher blood pressure and less exercise, high fever, or hypoxemia, O2 transport is increased
gravitational effect. . . primarily by increases in cardiac output, together with increased
In abnormal or diseased lungs, the VA/Q ratio may be in- pulmonary ventilation for the maintenance of alveolar PO2 and
creased or decreased as the result of uneven distribution of PCO2 levels. Chronic hypoxemia, as occurs in cardiopulmonary
ventilation,
. uneven
. pulmonary perfusion, or both. The most disease or during a sojourn to a high altitude, results in increased
extreme VA/Q mismatches are seen in children with congenital hemoglobin and erythrocyte mass, produced by increased
heart disease. In patients with decreased pulmonary blood flow erythropoietin activities. This adaptation, however, is a relatively
with right-to-left
. . intracardiac shunt, such as in the tetralogy of slow process and takes several weeks to accomplish.176 Hemo-
Fallot, the VA/Q ratio is increased; whereas in those with increased globin concentrations greater than the upper normal level of
Figure 9-23. Effect of vertical height (expressed as

the level of the anterior ends of the ribs) on ventila-
tion and pulmonary blood flow (left-hand ordinate)
and the ventilation-perfusion ratio (right-hand or-
dinate). From West JB: Ventilation/Blood Flow and
Gas Exchange. 2nd ed. Oxford: Blackwell Scientific;
15 to 16 g/dL (and especially a hematocrit > 60%) increase 97%. Because the dissociation curve is increasingly flat at the high
viscosity and interfere with microcirculation. end of the curve, further increases in PO2 result in only a small
O2 is transported in blood in two ways: combined with increase in saturation, reaching 100% saturation between 130 and
hemoglobin as oxyhemoglobin or dissolved in plasma. The 160 mmHg. As blood circulates through the tissues, O2 is taken
amount of O2 carried by the plasma depends on the PaO2 and its up from the capillaries and both the PO2 and the oxygen saturation
solubility. Under most statues, this amount is small, approximately of hemoglobin (SaO2) decrease.
0.31 mL/100 mmHg at 37°C (Bunsen coefficient). Conversely, The blood of healthy adults has an SaO2 of 50% when the PO2
each molecule of hemoglobin combines loosely with four is approximately 27 mmHg at 37°C and pH 7.4. The P50 (PO2 of
molecules of O2 (1.34 mL O2/g hemoglobin). In normal air whole blood at 50% O2 saturation) is an indicator of the affinity of
breathing, as much as 98% of O2 is carried by hemoglobin. The hemoglobin for O2. An increase in blood pH (both respiratory
amount of O2 dissolved in plasma, however, becomes clinically and metabolic alkalosis) increases the O2 affinity of hemoglobin
important for O2 transport when the patients with severe anemia (Bohr effect) and decreases P50. Similarly, a decrease in tempe-
or carbon monoxide poisoning are given 100% O2 to breathe or rature shifts the dissociation curve to the left with a decrease in
when hyperbaric O2 treatment is administered. Because it is highly the P50. A decrease in pH or an increase in temperature has the
lipid soluble, CO2 diffuses freely through cell membranes and is opposite effect.177
transported more readily in the blood than O2. CO2 is primarily
transported in blood as bicarbonate ions (as much as 70%). A
smaller, but substantial, fraction (15–30%) is combined with Effect of Organic Phosphates on
hemoglobin (to form carbaminohemoglobin) whereas the rest is O2 Affinity of Hemoglobin
dissolved in plasma and erythrocytes (10%).
In addition to temperature and the Bohr effect, the O2 affinity
of hemoglobin is decreased by an addition of organic phos-
O2 Dissociation Curve phates, particularly 2,3-diphosphoglycerate (2,3-DPG) and aden-
osine triphosphate (ATP), which bind to deoxyhemoglobin but
The O2 dissociation curve of hemoglobin reflects the affinity of not to oxyhemoglobin.178 Human erythrocytes contain unusually
hemoglobin for O2 (Figure 9–24). As mixed venous blood in the high concentrations of 2,3-DPG compared with ATP and other
pulmonary artery in healthy subjects circulates through the organic phosphates.179 An increase in erythrocyte 2,3-DPG
pulmonary capillary network, PO2 increases from approximately decreases O2 affinity, shifts the O2 dissociation curve to the right,
40 to 100 mm Hg in arterialized blood with hemoglobin in and increases the unloading of O2 molecules at the tissue level.
pulmonary venous blood becoming saturated with O2 to about The level of 2,3-DPG is increased in chronic hypoxemia, such as
seen in patients with cyanotic heart disease and those living at
high altitudes.
Developmental Changes in
O2 Affinity of Hemoglobin
In the neonate, 70 to 80% of hemoglobin is fetal hemoglobin or
hemoglobin F that contains gamma polypeptide chains (α2γ2), as
opposed to beta chains in adult type hemoglobin A (α2β2). Fetal
hemoglobin reacts poorly with 2,3-DPG. Consequently, red cell
O2 affinity is very high (P50 of 18–20 mmHg) and O2 delivery at the
tissue level decreased despite an increased red cell mass and
hemoglobin levels (hemoglobin ≥ 18 g/dL). During early infancy,
the total hemoglobin level decreases rapidly as red cells containing
fetal hemoglobin diminish, reaching the lowest level (11 ± 1 g/dL)
at 2 to 3 months of age (physiologic anemia of infancy). During the
same time period, the O2 affinity of hemoglobin decreases and P50
increases rapidly. By 3 to 6 months of age, P50 is increased to that
of the adult (27 mmHg) and continues to increase so that
at 9 months of age, O2 affinity reaches its highest value of 29 to
30 mmHg.180,181
In spite of a large swing in hemoglobin levels throughout
infancy and childhood, O2 unloading at the tissue level steadily
Figure 9-24. Schematic representation of oxygen dissociation curve increases during this period (Table 9–1). The O2 affinity of
and factors that affect blood oxygen affinity. Oxygen partial pressure hemoglobin continues to be relatively low throughout childhood
at 50% blood oxygen saturation (P50) is a convenient index of oxygen (and most likely through adolescence) before it attains the adult
affinity. P50 of adult blood (at 37°C; pH, 7.40; PCO2, 40 mmHg) is level. This high P50, associated with increased levels of ATP and
roughly 27 mmHg and is influenced by a number of factors. 2,3 DPG = 2,3-DPG, is probably related to the general growth and develop-
2,3-diphosphoglycerate; H+ = hydrogen ion concentration; PaO2 = arte- ment of the body and the high plasma levels of inorganic
rial oxygen tension; SaO2 = arterial oxygen saturation; T° = blood tem- phosphate.182 It can be speculated that, with increased O2 unload-
perature (see text). ing capacity, children do not require the higher levels of hemo-
TABLE 9-1. Changes in P50, Hemoglobin, and Oxygen Unloading With Age
Percent Saturation at Venous Oxygen Unloaded,a
Age P50, mmHg Oxygen Tension of 40 mmHg Hemoglobin, g/100 mL mL/100 mL
1d 19.4 87 17.2 1.84
3 wk 22.7 80 13.0 2.61
6–9 wk 24.4 77 11.0 2.65
3–4 mo 26.5 73 10.5 3.10
6 mo 27.8 69 11.3 3.94
8–11 mo 30.0 65 11.8 4.74
5–8 y 29.0b 67 12.6 4.73
9–12 y 27.9b 69 13.4 4.67
Adult 27.0 71 15.0 4.92
P50 = arterial oxygen pressure at 50% hemoglobin saturation.
a
Assume arterial oxygen saturation of 95%.
b
Derived from data of Card RT and Brain MC; remainder of P50 as previously reported.
From reference 180.
globin present in adults (physiologic “anemia” of childhood; for infants and children have not yet emerged. A hemoglobin level
hemoglobin levels, 11–12 g/dL). of 8.0 g/dL (hematocrit, 24%) may be adequate for an otherwise
These findings have important clinical implications for pedi- healthy child for a simple surgical procedure. Conversely, posto-
atric anesthesiologists. Until the 1980s, children with a hemoglo- perative hypoxemia is common even among healthy infants and
bin level less than 10 g/dL were considered anemic and were not children undergoing simple elective procedures, such as inguinal
acceptable for general anesthesia and surgery. This level of hemo- herniorrhaphy and myringotomies and ear tube insertions.184
globin was used arbitrarily without the realization that the charac- Children with a borderline anemia should be given O2 by mask
teristics of O2 affinity of hemoglobin and tissue O2 unloading are during and after the transfer to the postoperative care unit and
quite different in children, especially during the first year of life. their SaO2 monitored with pulse oximetry (SpO2). The lowest
We can see from Table 9–2 that, for an infant older than 3 months acceptable level of hemoglobin for infants younger than 2 months
(P50 = 30 mmHg), a hemoglobin level of 8.2 g/dL is equivalent to has not been established, although a hemoglobin level of 12 to 13
10 g/dL in adults (P50 = 27 mmHg), in terms of tissue O2 delivery. g/dL (equivalent to 89 g/dL in adults) or a hematocrit of 36 to 40%
Conversely, for a 2-month-old premature infant (P50 = 24 mmHg), is desirable for sick infants.
a hemoglobin level of 10 g/dL is equivalent to only 6.8 g/dL in The availability and the routine use of pulse oximetry since the
adults and less than 5.5 g/dL in older infants. This level is not late 1980s, as dictated by the American Society of Anesthesiolo-
acceptable for anesthesia and surgery for sick infants with limited gists and others, have dramatically improved the quality of
lung function and cardiac output.39 monitoring and safety of patients undergoing general anesthesia
A graphic comparison of O2 unloading at the tissue level among and surgery by maintaining proper oxygenation of patients.185
neonates, older infants, and adults is illustrated in Figure 9–25. In addition, in premature infants, the maintenance of a proper
Assuming that the SaO2 is 100% and the mixed venous PO2 is 40 range of oxygenation is especially important for the prevention
mmHg, approximately 25% of O2 content in adult arterial blood of hyperoxia and the resultant retinopathy of prematurity.186
(P50 = 27 mmHg) is unloaded at the tissue level. In older infants In premature infants with a birthweight of less than 1300 g, the
(P50 = 30 mmHg), O2 unloading is increased to approximately 35% incidence of retinopathy increases markedly with the exposure to
because of the low O2 affinity of hemoglobin. By contrast, in a PaO2 exceeding 80 mmHg for 12 hours or more.12 Thus, SaO2
newborn infants with a high O2 affinity (P50 = 20 mmHg), less than must be maintained carefully so as to maintain PaO2 within the
15% of O2 content can be unloaded at the tissue level unless mixed normal rage of 60 to 80 mmHg. Because O2 affinity of red blood
venous PO2 decreases or cardiac output and ventilation increase.39 cells is very high at birth and decreases rapidly during the first
With the spread of HIV in epidemic proportions in many 6 months of age, the estimated PaO2 should be adjusted according
parts of the world, including the industrialized nations, and the to age, as shown in Table 9–3. In the neonate with a P50 of 18 to 20
resultant anxiety among the medical profession and lay public mmHg, the range of SaO2 required to maintain adequate PaO2
about blood transfusion, the criteria for transfusion have changed (60–80 mmHg) is 97 to 98%, whereas in the adult (P50, 27 mmHg),
dramatically since the early 1980s. Although this problem has it is 91 to 96%. In the neonate, conversely, an SaO2 of 91%
been discussed extensively for adult patients,183 useful guidelines corresponds to a PaO2 of only 41 mmHg. Although the values in
TABLE 9-2. Hemoglobin Requirement for Equivalent Tissue Oxygen Delivery

P50, mmHg Hb for Equivalent O2 Delivery, g/dL
Adult 27 7 8 9 10 11 12 13
Infant > 3 mo 30 5.7 6.5 7.3 8.2 9.0 9.8 10.6
Neonate < 2 mo 24 10.3 11.7 13.2 14.7 16.1 17.6 19.1
Hb = hemoglobin; P50 = arterial oxygen pressure at 50% hemoglobin saturation.
Figure 9-25. Schematic representation of oxygen-

hemoglobin dissociation curves with different oxygen affinities.
In infants older than 3 months of age with high P50 (nearly 30
mmHg vs 27 in adults), tissue oxygen delivery per gram of he-
moglobin is increased. In neonates with a lower P50 (20 mmHg)
and a higher oxygen affinity, tissue oxygen unloading at the same
tissue PO2 is reduced.
Table 9–3 are estimated on the basis of Severinghaus’ nomogram mmHg is required to fully saturate hemoglobin thereby resulting
for the Bohr effect, published data comparing PaO2 and corre- in an SaO2 reading of 100%, this value cannot be reached in room
sponding SaO2 seem to agree well with values in the nomogram.39 air at sea level. The pulse oximeter by Nellcor, a brand widely used
Another factor compounds the confusion that is clinically too in the United States, reads an SpO2 that is 2 to 3% higher than the
important to ignore. The accuracy of pulse oximeter readings true SaO2 in the 90 to 100% range. The original unit by Ohmeda,
differs among manufacturers. Although a PaO2 above 130 to 160 which was more commonly used in Europe, conversely, tended
TABLE 9-3. Estimated PO2 at Different P50 of Red Blood Cellsa

Age
1D 2 Wk 6–9 Wk 6 Mo–6 Y Adult
P50, mmHgb 19 22 24 29 27
SO2, % Estimated PO2 (mm Hg) at neutral pH (7.40)
99 108 130 143 171 156
98 77 92 101 122 111
97 64 77 84 101 92
96 56 68 74 89 82
95 52 62 68 82 74
94 48 58 63 76 69
93 45 55 60 72 66
92 43 52 57 68 62
91 41 50 55 66 60
90 40 48 53 63 58
88 37 45 49 59 54
86 35 42 47 56 51
84 34 40 44 53 49
82 32 39 42 51 47
80 31 37 41 49 45
78 30 36 39 47 43
76 29 34 38 45 41
74 28 33 36 44 40
72 27 32 35 42 39
70 26 31 34 41 37
P50 = arterial oxygen pressure at 50% hermoglobin saturation; PO2 = oxygen pressure; SO2 = oxygen saturation.
a
Calculated from Severinghaus JW. Blood gas calculator. J Appl Physiol 1966;21:1108 assuming that the shift in oxygen
dissociation curve of hemoglobin due to changes in its oxygen affinity at neutral pH (7.40) is the same as the shift due
to the Bohr effect.
b
PO2 at which oxygen saturation of hemoglobin (SO2) is 50%.
to read about 2% lower than actual SaO2.187,188 Unfortunately,

the newer and perhaps more advanced pulse oximeter manu-
factured by Masimo, which is being increasingly used in the
United States and elsewhere, had to add a similar fudge factor to
be comparable with the other pulse oximeter outputs (Motoyama,
EK, personal communication). In view of these findings, the range
of SpO2 of 93 to 95% (or even lowerw), often recommended as
the desirable maintenance level for neonates and premature
infants, corresponds only to a PaO2 of 40 to 50 mmHg, which
seems much too low for adequate tissue oxygenation, particularly
for sick infants. In addition, respiratory alkalosis, often resulting
from controlled mechanical ventilation, would shift the O2
dissociation curve further to the left (P50, even lower) and further
decrease PaO2 and tissue O2 delivery. In clinical practice, therefore,
SpO2 values of 95 to 97% (corresponding to a PaO2 of 50 to
70 mmHg in the neonate and 60 to 80 mmHg in infants 1–2 mo
old) should be considered for adequate oxygenation without
O2 toxicity.
SURFACE ACTIVITY AND

PULMONARY SURFACTANT
The surface of the alveoli and small airways are lined with a
specific phospholipid-protein complex that possesses a unique
surface activity and stabilizes the gas-liquid interface of small
air spaces. These materials are collectively called pulmonary
surfactant and are essential for pulmonary gas exchange and, thus,
for human survival.
Surfactant and Lung Mechanics

The relationship among pressure (P), surface tension (T), and
radius (r) of a small sphere, such as a soap bubble or pulmonary
alveolus, is expressed by the LaPlace equation: Figure 9-26. Schematic drawing of stable alveoli of different sizes
(see text).
P = n T/r
where n = 1 for a cylindrical airway, n = 2 in case of the spaces afforded by the presence of pulmonary surfactant. Surface
alveolus, and n = 4 for a soap bubble. It can be seen from this tension accounts for more than 65% of elastic recoil pressure, even
equation that, if the surface tension is constant (as is the case with in lungs with normal surfactant activity. Elastic recoil pressure is
most liquid substances, such as water or detergents) in multiple essential to keep the small airways extended via the interdepen-
spheres that are connected to a common tube, the sphere with the dence of airways and the lung parenchyma. Conversely, when
smallest radius would have the highest pressure. Thus, the smaller the alveolar surface area is not expanded periodically (sighs),
spheres would empty their gas content into the larger ones minimum surface tension would gradually rise and the alveoli
and collapse. If this concept were applied to a lung, the lung unit start to collapse, especially in the dependent portions of the lung
would be unstable, with most alveoli collapsing into several large with lower regional lung volumes. These changes occur even in
terminal air spaces, as seen in premature infants with IRDS or normal lungs under general anesthesia, resulting in scattered
HMD with insufficient or inadequate surfactant activity.39 Such airway closures and microatelectasis. This condition can be
alveolar instability, fortunately, does not occur in normal lungs. prevented by the addition of a moderate level of PEEP (5–7
As Clements and associates initially demonstrated, saline extract cmH2O). Once the alveoli or small airways collapse, it will require
of minced normal lung tissues exhibits an extremely low surface a high sustained airway pressure (30–40 cmH2O, 10–15 s) to
tension (0–5 dynes/cm compared with 72 dynes/cm with saline overcome surface tension and reopen the airspace.
alone) during dynamic compression of the surface area on a
Wilhelmy balance.189 When the surface area is expanded, surface
Cell Biology and Biochemistry
tension increases sharply (30–50 dynes/cm). These findings
indicate that, in normal lungs, the surface tension decreases as the
of Pulmonary Surfactant
alveolar radius decreases during expiration and vice versa. Thus, Pulmonary surfactant is produced in the cuboidal type 2 alveolar
the stability of small air spaces is maintained, regardless of the size pneumocytes, which are found on the alveolar surface, between
of each alveolus (Figure 9–26). the flat type 1 pneumocytes that cover most of the alveolar surface
Surface tension plays an important role in normal lung area. Surfactant is formed in the lamellar bodies within type 2
physiology and gas exchange beyond the stability of terminal air pneumocytes, which start to appear at approximately the 27th
week of gestation. The contents of mature lamellar bodies are host defense in the lung. By contrast, SP-B and SP-C are small,
expelled into the alveolar surface by exocytosis.190 The alveolar hydrophobic proteins and play critical roles in enhancing the
lining layer harvested by lung lavage contains 80 to 90% stability of surfactant phospholipids on the alveolar lining.193
phospholipids and 10% lipoproteins. The largest fraction of The synthesis of pulmonary surfactant is tightly regulated
phospholipids (70–80%) is lecithin or phosphatidylcholine (PC), during both fetal and postnatal development.194 Synthesis of both
of which the majority is disaturated PC (DPPC) and is highly surfactant phospholipids and proteins increases markedly during
surface-active. Another important surface-active phospholipid is late gestation and the levels of surfactant protein mRNA are
phosphatidylglycerol (PG), which accounts for 5 to 10% of the increased during the perinatal period in association with increased
phospholipids within the alveoli.191 Other phospholipid fractions surfactant production and secretion for neonatal respiratory
include phosphatidyl-ethanolamine (PE), phosphatidylserine (PS), adaptation.
and sphingomyelin (S), which are also surface-active. In the fetal Pulmonary surfactant phospholipids and proteins are taken up
lung, surfactant is secreted into alveolar or lung fluid that rapidly, mostly by type 2 alveolar penumocytes and are recycled
eventually constitutes approximately one third of the amniotic (Figure 9–27). In adult rabbits, approximately 10% of the alveolar
fluids. The quantity of PC increases rapidly toward the term. The pool of PC (10–15 mg/kg body weight) is recycled every hour.
ratio of PC (lecithin) to sphingomyelin (L/S ratio) is correlated In newborn rabbits, the turnover time of the alveolar PC is
with the degree of lung maturation in premature newborn 10 hours.195 Although alveolar macrophages contribute 10 to 15%
infants.192 of surfactant uptake, this pathway appears important in the control
Four surfactant-specific proteins have been isolated and of steady-state surfactant homeostasis.
characterized with the locations of their genes in specific chro-
mosomes identified. Surfactant protein A, B, C, and D (SP-A,
SP-B, SP-C, SP-D), named in the order of discovery, are primarily Acceleration of Surfactant Biosynthesis
produced in type 2 pneumocytes. Surfactant proteins, with the In the early 1970s, deLemos and coworkers12 and Motoyama and
exception of SP-C, are also produced in Clara cells in the respi- colleagues13 demonstrated that surfactant biosynthesis in the fetal
ratory bronchioles. These proteins play specific roles in surfactant lung is accelerated by glucocorticoids. Subsequently, a variety of
homeostasis and host defense.193 Surfactant proteins can be pharmacologic agents was also shown to enhance lung maturation
classified into two distinct groups based on their characteristic or surfactant secretion including thyroxine,14 heroin,196 cyclic
structure and function. SP-A and SP-D are relatively abundant adenosine monophosphate (cAMP), epidermal growth factor
hydrophilic proteins that belong to the calcium-dependent lectin (EGF), tumor necrosis factor-␣ (TNF-α), and transforming
family of proteins. They have relatively weak surface-active growth factor-β (TGF-β).193 In 1972, Liggins and Howie reported
qualities, but are able to bind complex carbohydrates on the accelerated human fetal lung maturation after the administration
surface of microorganisms and likely play important roles in of corticosteroids to pregnant women 24 to 48 hours before
Figure 9-27. Life cycle of pulmonary

surfactant. Surfactant protein A (SP-A),
SP-B, SP-C, and lipids are packaged in
lamellar bodies and secreted by type II
alveolar epithelial cells into the air
space. Lamellar bodies unfold into tu-
bular myelin, which gives rise to the
lipid/protein film at the air-liquid inter-
face. Used surfactant lipids are released
from the film as small vesicles, which
are taken up and recycled or degraded
by type II cells. Alveolar macrophages
also take up surfactant and degrade it.
From Whitsett JA, Horowitz AD: Sur-
factant and associated proteins. In:
Fishman AP, editor. Fishman’s Pul-
monary Diseases and Disorders. 3rd ed.
New York: McGraw-Hill; 1998. Chapter
7, p. 123.
the delivery of premature babies.15 Prenatal steroid therapy has muscle tone and abolishes other mechanisms that maintain
been widely and successfully practiced ever since, with minimal thoracic stability in the awake state. Consequently, anesthesia in
side effects. infants results in airway closure and atelectasis of dependent lung
segments. The loss of pharyngeal muscle tone results in partial
Surfactant Replacement Therapy upper airway obstruction even when the child is breathing
spontaneously. Chest wall stability develops by 12 months of age,
The intratracheal instillation of bovine or synthetic surfactant in
although increases in the outward recoil of the chest wall and the
premature infants born with surfactant deficiency, originally
inward recoil of the lung continue for several more years. The
described by Fujiwara and associates in 1980 has been established
addition of moderate PEEP prevents the airways from prema-
as an important and essential form of treatment for surfactant
deficiency with the demonstration of marked improvements in ture closure and maintains ventilation/perfusion stability under
morbidity and mortality in infants born prematurely.197 Surfactant general anesthesia.
replacement with preparations containing surfactant phospho- O2 affinity of hemoglobin changes dramatically during the first
lipids and SP-B and SP-C rapidly increases lung volume and months of life because of the characteristics of fetal hemoglobin
compliance and decreases the requirement for positive-pressure with a high O2 affinity (low P50) and a low tissue O2 unloading
ventilation as well as O2 requirements. Synthetic surfactant with- capability. Consequently, the relationship between PaO2 and SaO2
out surfactant proteins is less effective and its efficacy is generally in young infants is quite different from that of the adult. Beyond
delayed. More recently, surfactant replacement therapy has been this period, the P50 increases, because of increased 2,3-DPG, and
extended to treat other clinical conditions including neonates with tissue O2 delivery of hemoglobin surpasses that of the adult. These
persistent pulmonary hypertension (PPHN), congenital diaphrag- changes are important for the evaluation of anemia and criteria
matic hernia, and meconium aspiration syndrome as well as for blood transfusion during anesthesia, surgery, and intensive
infants and children with acute lung injury or acute respiratory care of neonates and young infants.
distress syndrome (ARDS) in whom surfactant production by
type 2 pneumocytes is diminished or surfactant inactivated by
protein leakage into the alveolar spaces.198 Measurements of
REFERENCES
surfactant activity and surfactant components in bronchoalveolar 1. Burri PH. The postnatal growth of the rat lung. III. Morphology. Anat
lavage can be used for the diagnosis of surfactant deficiency in Rec. 1974;178:711.
patients with ARDS caused by a variety of etiologies including 2. Emery JL. The Anatomy of the Developing Lung. London: Heinemann
neonates with homozygous SP-B deficiency.199,200 This latter Medical Books; 1969 p 223.
disorder is characterized by atelectasis and respiratory failure in 3. Reid L. The embryology of the lung. In: DeReuck AVS, Porter R,
editors. Development of the Lung. Ciba Foundation Symposium.
full-term neonates and is uniformly fatal within several months
London: Churchill Livingstone; 1967. p. 109.
of life unless treated with lung transplantation. 4. Areechon W, Reid L. Hypoplasia of lung with congenital
diaphragmatic hernia. Br Med J. 1963;1:230.
5. Hislop A, Reid L. Development of the acinus in the human lung.
CONCLUSION Thorax. 1974;29:90.
It is evident that an infant or a young child is not a small adult on 6. Boyden EA. The pattern of the terminal air spaces in a premature
infant of 30–32 weeks that lived nineteen and a quarter hours. Am J
the basis of respiratory physiology and, consequently, should
Anat. 1969;126:31.
not be treated as such for anesthetic management. Neonatal 7. Spear GS, Vaeusorn O, Avery ME, et al. Inclusions in terminal air
adaptation seems to take approximately 1 month for a full-term spaces of fetal and neonatal human lung. Biol Neonate. 1969;14:344.
neonate or 44 weeks postconception for a premature infant. This 8. Gilbert-Barness E, Kapur RP, Oligny LL, et al., (eds) Potter’s Pathology
is particularly true in terms of respiratory control. Hypoxic of the Fetus, Infant and Child. 2nd Ed. St-Louis: Mosby Inc. 2007. p 2445
stimulation of breathing is not sustainable in the neonate, and the 9. Langston C, Kida K, Reed M, et al. Human lung growth in late
incidence of postanesthetic apnea is not uncommon in the gestation and in the neonate. Am Rev Respir Dis. 1984;129:607.
prematurely born infant during this period. During the perinatal 10. Harrison MR, Adizick NS, Flake AW, et al. Correction of congenital
and neonatal periods, the production of pulmonary surfactant is diaphragmatic hernia in utero. VI. Hard-earned lessons. J Pediatr
markedly increased to accommodate the aeration and stabilization Surg. 1993;28:1411.
11. Harrison MR, Keller RL, Hagwood SB, et al. A randomized trial of
of previously fluid-filled air spaces. Beyond the period of neonatal fetal endoscopic tracheal occlusion for severe fetal congenital
adaptation, the development and growth of the lung continues at diaphragmatic hernia. N Engl J Med. 2003;349:1916–1924.
an accelerated pace. The formation of the alveoli begins late in 12. deLemos RA, Shermeta DW, Knelson JH, et al. Acceleration of ap-
gestation and is essentially completed by 18 months of age with pearance of pulmonary surfactant in the fetal lamb by administration
the number of alveoli increasing 10-fold in this short time period. of corticosteroids. Am Rev Respir Dis. 1970;102:459.
As lung parenchymal maturation and growth continue, elastic 13. Motoyama EK, Orzalesi MM, Kikkawa Y, et al. Effect of cortisol on
fibers, which are nearly absent at birth, increase rapidly in the the development of fetal rabbit lungs. Pediatrics. 1971;48:547.
lung. As a result, the elastic recoil pressure increases and lung 14. Wu B, Kikkawa Y, Orzalesi MM, et al. The effect of thyroxine on the
compliance decreases toward normal adult levels throughout the maturation of fetal rabbit lungs. Biol Neonate. 1973;22:161.
first decade of life. Collagen fibers, in which development takes 15. Liggins GC, Howie RN. A controlled trial of antepartum glucocor-
ticoid treatment for prevention of the respiratory distress syndrome
longer than that of elastic fibers, add strength and stability to
in premature infants. Pediatrics. 1972;50:515.
pulmonary membranes, preventing damage from hyperdistention. 16. Karlberg P, Cherry RB, Escardo FE, et al. Respiratory studies in
The chest wall is very compliant at birth and is incapable of newborn infants. II. Pulmonary ventilation and mechanics of brea-
maintaining FRC against elastic recoil of the lung when general thing in the first minutes of life, including the onset of respiration.
anesthesia removes the normally present sustained inspiratory Acta Paediatr Scand. 1962;51:121.
17. Fagan DG. Post-mortem studies of the semistatic volume-pressure 40. Rigatto H, Brady JP, Chir B, et al. Chemoreceptor reflexes in preterm
characteristics of infants’ lungs. Thorax. 1976;31:534. infants. II. The effect of gestational and postnatal age on the
18. Mansell A, Bryan C, Levison H. Airway closure in children. J Appl ventilatory response to inhaled carbon dioxide. Pediatrics. 1975;
Physiol. 1972;33:711. 55:614.
19. Bryan AC, Wohl ME. Respiratory mechanics in children. In: Geiger 41. Kelly DH, Stellwagen LM, Kaitz E, et al. Apnea and periodic breathing
SR, Macklem PT, Mead J, Fishman AP, editors. Handbook of in normal full-term infants during the first twelve months. Pediatr
Physiology. Section 3. The Respiratory System. Vol. 3. Mechanics of Pulmonol. 1985;1:215.
Breathing. Part 1. Bethesda, Md: American Physiological Society; 42. Glotzbach SF, Tansey PA, Baldwin RB, et al. Periodic breathing in
1986. p. 179. preterm infants. Influence of bronchopulmonary dysplasia and
20. Zapletal A, Motoyama EK, Gibson LE, et al. Pulmonary mechanics in theophylline. Pediatr Pulmonol. 1989;7:78.
asthma and cystic fibrosis. Pediatrics. 1971;48:64. 43. Fenner A, Schalk U, Hoenicke H, et al. Periodic breathing in prema-
21. Motoyama EK. Pulmonary mechanics during early postnatal years. ture and neonatal babies. incidence, breathing pattern, respiratory
Pediatr Res. 1977;11:220. gas tensions, response to changes in the composition of ambient air.
22. Polgar G. Opposing forces to breathing in newborn infants. Biol Pediatr Res. 1973;7:174.
Neonate. 1967;11:1. 44. Chernick V, Heldrich F, Avery ME. Periodic breathing of premature
23. Stocks J, Godfrey S. Specific airway conductance in relation to infants. J Pediatr. 1964;64:330.
postconceptional age during infancy. J Appl Physiol. 1977;43:144. 45. Brooks JG. Apnea of infancy and sudden infant death syndrome. Am
24. Dawes GS, Fox HE, Leduc MB, et al. Respiratory movements and J Dis Child. 1982;136:1012.
paradoxical sleep in the foetal lamb. J Physiol (Lond). 1970;210:47P. 46. Jansen AH, Chernick V. Development of respiratory control. Physiol
25. Boddy K, Robinson JS. External method for detection of fetal Rev. 1983;63:437.
breathing in utero. Lancet. 1971;2:1231. 47. Ramanathan R, Corwin MJ, Hunt CE, et al. Cardiorespiratory events
26. Patrick J, Campbell K, Carmichael L, et al. Patterns of human fetal recorded in the home. Comparison of healthy infants with those at
breathing during the last 10 weeks of pregnancy. Obstet Gynecol. increased risk for SIDS. JAMA. 2001;17:2199–2207.
1980;56:24. 48. Liu LMP, Coté CJ, Goudsouzian NG, et al. Life-threatening apnea in
27. Boddy K, Dawes GS, Fisher R, et al. Foetal respiratory movements, infants recovering from anesthesia. Anesthesiology. 1983;59:506.
electrocortical and cardiovascular responses to hypoxaemia and 49. Steward DJ. Preterm infants are more prone to complications
hypercapnia in sheep. J Physiol (Lond). 1974;243:599. following minor surgery than are term infants. Anesthesiology. 1982;
28. Rigatto H, Kalapesi Z, Leahy FN, et al. Ventilatory response to 100% 56:304.
and 15% O2 during wakefulness and sleep in preterm infants. Early 50. Kurth CD, Spitzer AR, Broennle AM, et al. Postoperative apnea in
Hum Dev. 1982;7:1. preterm infants. Anesthesiology. 1987;66:483.
29. Dawes GS. Breathing before birth in animals and man. An essay in 51. Welborn LG, Hannallah RS, Luban NL, et al. Anemia and postoperative
developmental medicine. N Engl J Med. 1974;290:557. apnea in former preterm infants. Anesthesiology. 1991;74:1003.
30. Alcorn D, Adamson DT, Maloney JE, et al. Morphological effects of 52. Malviya S, Swartz J, Lerman J. Are all preterm infants younger than
chronic bilateral phrenectomy or vagotomy in the fetal lamb lung. 60 weeks postconceptual age at risk for postanesthetic apnea?
J Anat. 1980;130:683. Anesthesiology. 1993;78:1076.
31. Baier RJ, Hasan SU, Cates DB, et al. Effects of various concentrations 53. Coté CJ, Zaslavsky A, Downes JJ, et al. Postoperative apnea in former
of O2 and umbilical cord occlusion on fetal breathing and behavior. preterm infants after inguinal herniorrhaphy. A combined analysis.
J Appl Physiol. 1990;68:1597. Anesthesiology. 1995;82:809.
32. Rigatto H. Maturation of breathing control in the fetus and newborn 54. Kim J, Thornton J, Eipe N. Spinal anesthesia for the premature
infant. In: Beckerman RC, Brouillette RT, Hunt CE, editors. infants. is this really the answer to avoid postoperative apnea? Pediatr
Respiratory Control Disorders in Infants and Children. Baltimore: Anesth. 2009;19:56–58.
Williams & Wilkins; 1992. p. 61. 55. Murphy JJ, Swanson T, Ansermino M, Milner R. The frequency of
33. Rigatto H, Brady JP, de La Torre Verduzco R. Chemoreceptor reflexes apnea in premature infants after inguinal hernia repair. do they need
in preterm infants. I. The effect of gestational and postnatal age on overnight monitoring in the intensive care unit? J Pediatr Surg.
the ventilatory response to inhalation of 100% and 15% oxygen. 2008;43:865–868.
Pediatrics. 1975;55:604. 56. Aranda JV, Trumen T. Methylxanthines in apnea of prematurity. Clin
34. Cross KW, Oppe TE. The effect of inhalation of high and low Perinatol. 1979;6:87.
concentrations of oxygen on the respiration on the respiration of the 57. Welborn LG, DeSoto H, Hannallah RS, et al. The use of caffeine in the
premature infant. J Physiol (Lond). 1952;117:38. control of post-anesthetic apnea in former premature infants.
35. Perlstein PH, Edward NK, Sutherland JM. Apnea in premature Anesthesiology. 1988;68:796.
infants and incubator-air-temperature changes. N Engl J Med. 1970; 58. Aubier M, DeTroyer A, Sampson M, et al. Aminophylline improves
282:461. diaphragmatic contractility. N Engl J Med. 1981;305:249.
36. Dripps RD, Comroe JH Jr. The respiratory and circulatory response 59. Landsman IS, Werkhaven JA, Motoyama EK. Anesthesia for pediatric
of normal man to inhalation of 7.6 and 10.4 percent CO2 with a otorhynolaryngologic surgery. In: Motoyama EK, Davis PJ, editors.
comparison of the maximal ventilation produced by severe muscular Smith’s Anesthesia for Infants and Children. 7th ed. Philadelphia:
exercise, inhalation of CO2 and maximal voluntary hyperventilation. Mosby-Elsevier; 2006. pp. 789–822.
Am J Physiol. 1947;149:43. 60. Cherniack NS, Pack AI. Control of ventilation. In: Fishman AP,
37. Albersheim S, Boychuk R, Seshia MMK, et al. Effects of CO2 on editor. Fishman’s Pulmonary Diseases and Disorders. 3rd ed. New
immediate ventilatory response to O2 in preterm infants. J Appl Physiol. York: McGraw-Hill; 1998. p. 164.
1976;41:609. 61. von Euler C. Brain stem mechanisms for generation and control of
38. LaFramboise WA, Woodrum DE. Elevated diaphragm electromyo- breathing pattern. In: Cherniack NS, Widdicombe JG, editors.
gram during neonatal hypoxic ventilatory depression. J Appl Physiol. Handbook of Physiology. Section 3. The Respiratory System. Vol. 2.
1985;59:1040. Control of Breathing. Part 1. Bethesda, Md: American Physiology
39. Motoyama EK. Respiratory physiology in infants and children. In: Society; 1986. p. 1.
Motoyama EK, Davis PJ, editors. Smith’s Anesthesia for Infants and 62. Clark FJ, von Euler C. On the regulation of depth and rate of
Children. 7th ed. St. Louis: 2006 Mosby. p. 12–69. breathing. J Physiol (Lond). 1972;222:267.
63. Berger AJ. Control of breathing. In: Murray JF, Nadel JA, editors. Breathing. Hering-Breuer Centenary Symposium. London:
Textbook of Respiratory Medicine. Philadelphia: WB Saunders; Churchill Livingstone; 1970. p. 233.
1994. p. 149. 92. Duron B. Intercostal and diaphragmatic muscle endings and
64. Berger AJ. Phrenic motoneurons in the cat. Subpopulations and afferents. In: Hornbein TF, editor. Regulation of Breathing. Part 1.
nature of respiratory drive potentials. J Neurophysiol. 1979;42:76. New York: Marcel Dekker; 1981. p. 473.
65. Merrill EG, Lipski J, Kubin L. Origin of the expiratory inhibition of 93. Pappenheimer JR, Fenci V, Heisey SR, et al. Role of cerebral fluids
nucleus tractus solitarius inspiratory neurons. Brain Res. 1983;263:43. in control of respiration as studied in unanesthetized goats. Am J
66. Bastel HL, Lines AJ. Neural mechanisms of sneeze. Am J Physiol. Physiol. 1965;208:436.
1975;229:770. 94. Mitchell RA, Carman CT, Severinghaus JW, et al. Stability of
67. Miller AD, Erure K, Suzuki I. Control of abdominal muscles by brain cerebrospinal fluid pH in chronic acid-base disturbances in blood.
stem respiratory neurons in the cat. J Neurophysiol. 1985;54:155. J Appl Physiol. 1965;20:443.
68. Mitchell RA, Berger AJ. Neurol regulation of respiration. In: 95. Severinghaus JW. Hypoxic respiratory drive and its loss during
Hornbein TF, editor. Regulation of Breathing. Part I. New York: Marcel chronic hypoxia. Clin Physiol. 1972;2:57.
Dekker; 1981. p. 541. 96. McDonald DM. Peripheral chemoreceptors. structure-function
69. von Euler C, Trippenbach T. Cyclic excitability changes of the relationships of the carotid body. In: Hornbein TF, editor. Regulation
inspiratory “off switch” mechanism. Acta Physiol Scand. 1975;93:560. of Breathing. Part 1. New York: Marcel Dekker; 1981. p. 105.
70. Cohen MI. Central determinants of respiratory rhythm. Annu Rev 97. Fenner A, Jansson EH, Avery ME. Enhancement of the ventilatory
Physiol. 1981;43:91 response to carbon dioxide by tube breathing. Respir Physiol.
71. von Euler C. On the central pattern generator for the basic breathing 1968;4:91.
rhythmicity. J Appl Physiol. 1983;55:1647. 98. Nielsen M, Smith H. Studies on the regulation of respiration in acute
72. Feldman JL, Ellenberger HH. Central coordination of respiratory and hypoxia. Acta Physiol Scand. 1951;24:293.
cardiovascular control in mammals. Ann Rev Physiol. 1988;50:593. 99. Severinghaus JW, Mitchell RA, Richardson BW, et al. Respiratory
73. Smith JC, Ellenberger HH, Ballanyi K, et al. Pre-Boetzinger complex. control of high altitude suggesting active transport regulation of CSF
A brain stem region that may generate respiratory rhythm in pH. J Appl Physiol. 1963;18:1155.
mammals. Science. 1991;254:726. 100. Sorensen SC, Severinghaus JW. Irreversible respiratory insensitivity
74. Johnson SM, Smith JC, Funk GD, Feldman JL. Pacemaker behavior to acute hypoxia in man born at high altitude. J Appl Physiol.
of respiratory neurons in medullary slices from neonatal rat. 1968;25:217.
J Neurophysiol. 1994;72:2598. 101. Lahiri S, Brody JS, Motoyama EK, et al. Regulation of breathing in
75. Nishino T. Swallowing as a protective reflex for the upper respiratory newborns in high altitude. J Appl Physiol. 1978;44:673.
tract. Anesthesiology. 1993;79:588. 102. Edelman NH, Lahiri S, Brando L, et al. The blunted ventilatory
76. Widdicombe JG. Reflexes from the upper respiratory tract. In: response to hypoxia in cyanotic congenital heart disease. N Engl J
Cherniak NS, Widdicombe JG, editors. Handbook of Physiology. Med. 1970;282:405.
Section 3. The Respiratory System. Vol. II. Control of Breathing. 103. Munson ES, Larson CP, Babad AA, et al. The effects of halothane,
Part 1. Bethesda, Md: American Physiological Society; 1985. p. 363. fluroxene and cyclopropane on ventilation. A comparative study in
77. Sant’Ambrogio G, Mathew OP, Fisher JT, et al. Laryngeal receptors man. Anesthesiology. 1966;27:716.
responding to transmural pressure, airflow and local muscle activity. 104. Wade JG, Larson CP Jr, Hickey RF, et al. Effect of carotid endar-
Respir Physiol. 1983;54:317. terectomy on carotid chemoreceptor and baroreceptor function
78. Sant’Ambrogio G, Mathew OP, Sant’Ambrogio FB, et al. Laryngeal in man. N Engl J Med. 1970;282:823.
cold receptors. Respir Physiol. 1985;59:35. 105. Guz A, Noble MIM, Eisel JH, et al. The role of vagal inflation
79. Boggs DF, Bartlett D. Chemical specificity of a laryngeal apneic reflex reflexes in man and other animals. In: Porter R, editor. Breathing.
in puppies. J Appl Physiol. 1982;53:455. Hering-Breuer Centenary Symposium. London: Churchill Livings-
80. Davies AM, Koening JS, Thach BT. Upper airway chemoreflex tone; 1970. p. 17.
responses to saline and water in preterm infants. J Appl Physiol. 106. Whitelaw WA, Derenne JP, Milic-Emili J. Occlusion pressure as a
1988;64:1412. measure of respiratory center output in conscious man. Respir
81. Pickens DL, Schefft GL, Thach BT. Pharyngeal fluid clearance and Physiol. 1975;23:181.
aspiration preventive mechanisms in sleeping infants. J Appl Physiol. 107. Milic-Emili J, Grunstein MM. Drive and timing components of
1989;66:1164. ventilation. Chest. 1975; 70(Suppl):181.
82. Guedel A. Inhalation Anesthesia. New York: MacMillan. 1937. 108. Bradley GW, von Euler C, Marttila I, et al. A model of the central
83. Suzuki M, Sasaki CT. Laryngeal spasm. a neurophysiologic and reflex inhibition of inspiration in the cat. Biol Cybern.
redefinition. Ann Otol Rhinol Laryngol. 1977;86:150. 1975;19:105.
84. Ikari T, Sasaki CT. Glottic closure reflex. control mechanisms. Ann 109. Pavlin EG, Hornbein TF. Anesthesia and control of ventilation. In:
Otol Rhinol Laryngol. 1980;89:220. Fishman AP, Cherniack NS, Widdicombe JG, editors. Handbook of
85. Bartlett D Jr, Jeffrey P, Sant’Ambrogio G, et al. Location of stretch Physiology. Section 3. The Respiratory System. Vol. II. Control of
receptors in the trachea and bronchi of the dog. J Physiol (Lond). Breathing. Bethesda, Md: American Physiological Society; 1986.
1976;258:409. p. 793.
86. Pack AI. Sensory inputs to the medulla. Annu Rev Physiol. 1981;43:73. 110. Froese AB, Bryan AC. Effects of anesthesia and paralysis on
87. Olinsky A, Bryan MH, Bryan AC. Influence of lung inflation on diaphragmatic mechanics in man. Anesthesiology. 1974;41:242.
respiratory control in neonates. J Appl Physiol. 1974;36:426. 111. Ochiai R, Guthrie RD, Motoyama EK. Effects of varying concen-
88. Sant’Ambrogio G. Information arising from the tracheobronchial tree trations of halothane on the activity of the genioglossus, intercostals,
of mammals. Physiol Rev. 1982;62:531. and diaphragm in cats. an electromyographic study. Anesthesiology.
89. Cross KW, Klaus M, Tooley WH, et al. The response of the newborn 1989;70:812.
baby to inflation of the lungs. J Physiol (Lond). 1960;151:551. 112. Ochiai R, Guthrie R, Motoyama EK. Differential sensitivity
90. Paintal AS. Vagal sensory receptors and their reflex effects. Physiol of halothane anesthesia on the geniolglossus, intercostals, and
Rev. 1973;53:159. diaphragm in kittens. Anesth Analg. 1992;74:338.
91. Noble MIM, Eisele JH, Trenchard D, et al. Effect of selective 113. Isono S. Developmental changes of pharyngeal airway patency.
peripheral nerve blocks on respiratory sensations. In: Porter R, editor. Implications for pediatric anesthesia. Pediatr Anesth. 2006;16:109–112.
114. Fine GF, Keidan I, Kagawa T, et al. Work of breathing during 137. Stocks J. Effect of nasogastric tubes on nasal resistance during
spontaneous breathing in anesthetized children. A comparison infancy. Arch Dis Child. 1980;55:17.
among the face mask, laryngeal mask airway and endotracheal tube. 138. Weibel ER. Morphometry of the Human Lung. New York: Academic
Anesthesiology. 1998;89–3A:A1291. Press; 1963.
115. Freund F, Roos A, Dood RB. Expiratory activity of the abdominal 139. Macklem PT, Mead J. Resistance of central and peripheral airways
muscles in man during general anesthesia. J Appl Physiol. 1964; measured by a retrograde catheter. J Appl Physiol. 1967;22:395.
19:963. 140. Hogg JC, Williams J, Richardson JB, et al. Age as a factor in the
116. Agostoni E. Volume-pressure relationships of the thorax and lung in distribution of lower airway conductance and in the pathologic
the newborn. J Appl Physiol. 1959;14:909. anatomy of obstructive lung disease. N Engl J Med. 1970;282:1283.
117. Thorsteinsson A, Larsson A, Jonmarker C, et al. Pressure-volume 141. Taussig LM, Landau LI, Godfrey S, et al. Determinants of forced
relations of the respiratory system in healthy children. Am J Respir expiratory flows in newborn infants. J Appl Physiol. 1982;53:1220.
Crit Care Med. 1994;150:421. 142. Milic-Emili J, Robatto FM, Bates JH. Respiratory mechanics in
118. Woolcock AJ, Vincent NJ, Macklem PT. Frequency dependence of anaesthesia. Br J Anaesth. 1990;65:4.
compliance as a test for obstruction in small airways. J Clin Invest. 143. D’ Angelo E, Calderini G, Torri FM, et al. Respiratory mechanics in
1969;48:1097. anesthetized paralyzed humans. Effects of flow, volume and time.
119. Fagan DG. Shape changes in static V-P loops for children’s lungs J Appl Physiol. 1989;67:2556.
related to growth. Thorax. 1977;32:198. 144. Kaditis AG, Motoyama EK, Seki I, et al. Flow and volume depen-
120. Zapletal A, Samanek M, Paul T. Lung Function in Children and dence of respiratory mechanics in anesthetized children. Pediatr Res.
Adolescents. Methods, Reference Values. New York: Karger; 1987. 1999;46:419.
121. Henderson-Smart DJ, Read DJC. Reduced lung volume during 145. Kaditis AG, Venkataraman ST, Zin WA, et al. Partitioning of respi-
behavioral active sleep in the newborn. J Appl Physiol. 1979;46:1081. ratory system resistance in children with respiratory insufficiency.
122. Kaditis AG, Motoyama EK, Zin W, et al. Effect of lung expansion Am J Respir Crit Care Med. 1999;159:389.
and PEEP on respiratory mechanics in anesthetized children. Anesth 146. Don H. The mechanical properties of the respiratory system during
Analg. 2008;106:775–785. anesthesia. Int Anesthesiol Clin. 1977;15:113.
123. Papastamelos C, Panitch HB, England SE, et al. Developmental 147. Hedenstierna G. Effects of anaesthesia on respiratory mechanics.
changes in chest wall compliance in infancy and early childhood. In Milic-Emili J, Lucangelo U, Pesenti A, et al., editors. Basics of
J Appl Physiol. 1995;78:179. Respiratory Mechanics and Artificial Ventilation. Milan: Springer-
124. Hershenson MB, Colin AA, Wohl MEB, et al. Changes in contri- Verlag; 1999. p. 223.
bution of the rib cage to tidal breathing during infancy. Am Rev 148. Bergman NA. Distribution of inspired gas during anesthesia and
Respir Dis. 1990;141:992. artificial ventilation. J Appl Physiol. 1963;18:1085.
125. Colin AA, Wohl MEB, Mead J, et al. Transition from dynamically 149. Dobbinson TL, Nisbet HIA, Pelton DA. Functional residual capacity
maintained to relaxed end-respiratory volume in human infants. (FRC) and compliance in anaesthetized paralysed children. Part I.
J Appl Physiol. 1989;67:2107. In vitro tests with the helium dilution method of measuring FRC.
126. De Troyer A, Bastenier-Geens J. Effects of neuromuscular blockade Can Anaesth Soc J. 1973;20:310.
on respiratory mechanics in conscious man. J Appl Physiol. 1979; 150. Fletcher M, Ewert M, Stark C, et al. Influence of tidal volume on
47:1162. respiratory compliance in anesthetized infants and young children.
127. Rehder K, Marsh MH. Respiratory mechanics during anesthesia and J Appl Physiol. 1990;68:1127.
mechanical ventilation. In: Fishman AP, Macklem PT, Geiger SR, 151. Reber A, Nylund U, Hedenstierna G. Position and shape of the
et al., editors. Handbook of Physiology. Section. 3. The Respiratory diaphragm. Implications for atelectasis formation. Anaesthesia.
System. Vol. III. Mechanics of Breathing, Part 2. Bethesda, Md: 1998;53:1054.
American Physiological Society; 1986. p. 727. 152. Dueck R Prutow RJ, Davies NJ, et al. The lung volume at which
128. Westbrook PR, Stubbs SE, Sessler AD, et al. Effects of anesthesia and shunting occurs with inhalation anesthesia. Anesthesiology. 1988;
muscle paralysis on respiratory mechanics in normal man. J Appl 69:854.
Physiol. 1973;34:81. 153. von Ungern-Sternberg BS, Hammer J. Schibler A et al. Decrease of
129. Henderson-Smart DJ, Read DJC. Reduced lung volume during functional residual capacity and ventilation homogeneity after
behavior active sleep in the newborn. J Appl Physiol. 1979;46:1081. neuromuscular blockade in anesthetized young infants and pre-
130. Dobbinson TL, Nisbet HIA, Pelton DA. Functional residual capacity school children. Anesthesiology. 2007;105:670–675.
(FRC) and compliance in anaesthetized paralysed children. Part I. 154. Brismar B, Hedenstierna G, Lundquist H, et al. Pulmonary densities
In vitro tests with the helium dilution method of measuring FRC. during anesthesia with muscular relaxation. a proposal of atelectasis.
Can Anaesth Soc J. 1973;20:310. Anesthesiology. 1985;62:422.
131. Fletcher M, Ewert M, Stark C, et al. Influence of tidal volume on 155. Damgaard Pedersen K, Qvist T. Pediatric pulmonary CT-scanning
respiratory compliance in anesthetized infants and young children. anaesthesia-induced changes. Pediatr Radiol. 1980;9:145.
J Appl Physiol. 1990;68:1127. 156. Serafini G, Cornara G, Cavalloro F, et al. Pulmonary atelectasis
132. Motoyama, EK. Effects of positive end-expiratory pressure (PEEP) during paediatric anaesthesia. CT scan evaluation and effect of pos-
on respiratory mechanics and oxygen saturation (SpO 2) in infants itive end-expiratory pressure (PEEP). Paediatr Anaesth. 1999;9:225.
and children under general anesthesia. Anesthesiology. 1996;85: 157. Rothen HU, Sporre B, Engberg G, et al. Prevention of atelectasis
A1099. during general anaesthesia. Lancet. 1995;345:1387.
133. Sly PD, Hayden MJ. Applied clinical respiratory physiology. In 158. Tusman G, Boehm SH, Tempra A, et al. Effects of recruitment
Taussig LM, Landau LI, editors. Pediatric Respiratory Medicine. maneuvers on atelectasis in anesthetized children. Anesthesiology.
St. Louis: Mosby; 1998. p. 95. 2003;98:14–22.
134. Ferris BG, Mead J, Opie LH. Partitioning of respiratory flow 159. Benoit Z, Wicky S, Fischer J-F, et al. The effect of increased FIO2
resistance in man. J Appl Physiol. 1964;19:653. before tracheal extubtion on postoperative atelectasis. Anesth Analg.
135. Stocks J, Godfrey S. Nasal resistance during infancy. Respir Physiol. 2002;95:1777–1781.
1978;34:233. 160. Cook CD, Sutherland JM, Segal S, et al. Studies of respiratory
136. Sasaki CT. Development of laryngeal function. etiologic significance physiology in the newborn infant. III. Measurements of mechanics
in the sudden infant death syndrome. Laryngoscope. 1979;89:1964. of respiration. J Clin Invest. 1957;36:440.
161. Mead J. Control of respiratory frequency. J Appl Physiol. 1960; 181. Oski FA. The unique fetal red cell and its function. Pediatrics.
15:325. 1973;51:494.
162. Radford EP Jr, Ferris BJ Jr, Kriet BC. Clinical use of nomogram to 182. Card RT, Brain MC. The “anemia” of childhood: evidence for
estimate proper ventilation during artificial respiration. N Engl J a physiologic response to hyperphosphatemia. N Engl J Med.
Med 1954;251:877. 1973;288:388.
163. Hart MC, Orzalesi MM, Cook CD. Relation between anatomic 183. Consensus Conference. Perioperaative red blood cell transfusion.
respiratory dead space and body size and lung volume. J Appl JAMA. 1988;260:2700.
Physiol. 1963;18:519. 184. Motoyama EK, Glazener CH. Hypoxemia after general anesthesia
164. Kaneko K, Milic-Emili J, Dolovich MB, et al. Regional distribution in children. Anesth Analg. 1986;65:267.
of ventilation and perfusion as a function of body position. J Appl 185. Coté CJ, Rolf N, Liu LMP, et al. A single-blind study of pulse
Physiol. 1966;21:767. oximetry and caprnography in children. Anesthesiology. 1991;
165. Heaf DP, Helms P, Gordon I, et al. Postural effects on gas exchange 74:984.
in infants. N Engl J Med. 1983;308:1505. 186. Flynn JT, Bancalari E, Snyder ES, et al. A cohort study of trans-
166. Davies H, Kitchman R, Gordon I, et al. Regional ventilation in cutaneous oxygen tension and the incidence and severity of
infancy. reversal of adult pattern. N Engl J Med. 1985;313:1626. retinopathy of prematurity. N Engl J Med. 1992;326:1050.
167. Milic-Emili J, Henderson JAM, Dolovich MB, et al. Regional 187. Jennis MS, Peabody JL. Pulse oximetry. An alternative method for
distribution of gas in the lung. J Appl Physiol. 1966;21:749. the assessment of oxygenation in newborn infants. Pediatrics.
168. Hughes JMB, Glazier JB, Maloney JE, et al. Effect of lung volume on 1987;79:524.
the distribution of pulmonary blood flow in man. Respir Physiol. 188. Bucher HU, Fanconi S, Baeckert P, et al. Hyperoxemia in newborn
1968;4:58. infants. Detection by pulse oximetry. Pediatrics. 1989;84:226.
169. West JB. Ventilation, blood flow, and gas exchange. In: Murray JF, 189. Clements JA, Brown ES, Johnson RP. Pulmonary surface tension
Nadel JA, editors. Textbook of Respiratory Medicine. 2d ed. and mucus lining of the lungs; some theoretical considerations.
Philadelphia: WB Saunders; 1994. p. 47. J Appl Physiol. 1958;12:262.
170. Wagner PD. Ventilation, pulmonary blood flow, and ventilation- 190. Kikkawa Y, Motoyama EK, Cook CD. Ultrastructure of lungs of
perfusion relationships. In: Fishman AP, editor. Fishman’s Pulmonary lambs: the relation of osmiophilic inclusions and alveolar lining
Diseases and Disorders. 3d ed. New York: McGraw-Hill; 1998. p. 177. layer to fetal maturation and experimentally produced respiratory
171. Benumof JL. Respiratory physiology and respiratory function distress. Am J Pathol. 1965;47:877.
during anesthesia. In: Miller RD, editor. Anesthesia. 4h ed. New 191. Rooney SA, Canavan PM, Motoyama EK. The identification of
York: Churchill Livingstone; 1994. p. 552–77. phosphatidylglycerol in the rat, rabbit, monkey and human lung.
172. Sykes MK, Loh L, Seed RF, et al. The effect of inhalational Biochim Biophys Acta. 1974;360:56–67.
anesthetics on hypoxic pulmonary vasoconstriction and pulmo- 192. Kulovich MV, Hallman M, Gluck L. The lung profile. I. Normal
nary vascular resistance in the perfused lungs of the dog and cat. pregnancy. Am J Obstet Gynecol. 1979;135:57.
Br J Anaesth. 1972;44:776. 193. Whitsett JA, Horowitz AD. Surfactant and associated proteins. In:
173. Bjertnaes LJ. Hypoxia-induced pulmonary vasoconstriction in man. Fishman AP, editor. Fishman’s Pulmonary Diseases and Disorders.
Inhibition because of diethyl ether and halothane anesthesia. Acta 3rd ed. New York: McGraw-Hill; 1998. p. 119.
Anaesthesiol Scand. 1978;22:570. 194. Mendelson CR, Boggaram V. Hormonal control of the surfactant
174. Marshall BE, Marshall C. Anesthesia and pulmonary circulation. system in fetal lung. Annu Rev Physiol. 1991;53:415.
In Covino BJ, Fozzard HA, Rehder K, et al., editors. Effects of 195. Jobe H, Rider EO. Catabolism and recycling of surfactant. In:
Anesthesia. Bethesda, Md: American Physiological Society; 1985. Robertson B, van Golde LMG, Batenburg JJ, editors. Pulmonary
p. 121. Surfactant. From Molecular Biology to Clinical Practice. Amsterdam:
175. Pavlin EG, Su JY. Cardiopulmonary pharmacology. In, Miller RD, Elsevier; 1992. p. 313.
editor. Anesthesia. 4th ed. New York: Churchill Livingstone; 1994. 196. Tauesch HW Jr, Carson SH, Wang NS, et al. Heroin induction of
p.. 125. lung maturation and growth retardation in fetal rabbits. J Pediatr.
176. Finch CA, Lenfant C. Oxygen transport in man. N Engl J Med. 1973;82:869.
1972;286:407. 197. Fijiwara T, Maeta H, Chida S, et al. Artificial surfactant therapy in
177. Comroe JH. Physiology of Respiration. 2nd ed. Chicago: Year Book hyaline membrane disease. Lancet. 1980;1:55.
Medical; 1974. p. 328 198. Jobe AH. Pulmonary surfactant therapy. N Engl J Med. 1993;
178. Benesch R, Benesch RE. The effect of organic phosphates from the 328:861.
human erythrocytes on the allosteric properties of hemoglobin. 199. Haslam PL, Postle AD, Reymondos K, Barker CS. Measurement of
Biochem Biophys Res Commun. 1967;26:162. pulmonary surfactant components and function in bronchoalveolar
179. Oski FA, Delivoria-Papadopoulos M. The red cell, 2,3-diphos- lavage fluid. Eur Respir Rev. 1999;9:66.
phoglycerate, and tissue oxygen release. J Pediatr. 1970;77:941. 200. Nogee LM, deMello DE, Dehner LP. Brief report. Deficiency of
180. Oski FA. Designation of anemia on a functional basis. J Pediatr. pulmonary surfactant protein B in congenital alveolar proteinosis.
1973;83:353. New Engl J Med. 1993;328:406.
Renal Function, Acid-Base,

and Electrolyte Homeostasis 10
John Chandler and Robert Plant C H A P T E R
INTRODUCTION cells (capillary endothelium and Bowman’s capsular epithelium),

which are tightly adherent to a common basement membrane.
Despite the efficiency with which the body’s various homeostatic There are relatively large fenestrations between the endothelial
mechanisms work to maintain the internal milieu within tight cells. The epithelial cells interdigitate tightly, thereby providing a
limits, the system has its limitations. Fluid, electrolytes, and acid- filtration barrier to large molecules and blood components, but
base disturbances are extremely common in the perioperative not to water and small molecules.
period. Such disturbances are of particular concern to the The two main determinants of filterability (in descending order
pediatric anesthesiologist because the corrective mechanisms in of importance) are molecular size and charge. The cut-off size is
children are more easily overwhelmed than those in adults. not absolute. Resistance to filtration begins at a molecular radius
Cardiovascular, neurologic, and neuromuscular function can be of approximately 2 nm. Substances of molecular radius larger
significantly disturbed by major fluid and electrolyte disturbances. than 4 nm are not filtered at all. The glomerular membranes are
The kidneys regulate the volume and composition of the body’s negatively charged; consequently, positively charged molecules are
fluids. Maintaining a physiologic pH is vital to the body’s filtered at a greater molecular size than those negatively charged.1
biochemical and enzymatic reactions. Changes in ventilation and Urine formation begins with the production of an ultrafiltrate of
perfusion, common during anesthesia and surgery, can rapidly plasma by the glomerulus. This activity is dependent upon a large
alter acid-base balance. It is essential that the anesthesiologist be renal blood flow (RBF). The volume of ultrafiltrate produced per
familiar with the many disturbances of acid-base and fluid- minute is referred to as the glomerular filtration rate (GFR). RBF
electrolyte states that may affect the pediatric patient. This chapter and GFR share an interdependent relationship because GFR relies
examines the important physiology of the kidney, with particular on RBF for its preservation and GFR influences RBF via a feedback
attention to fluid and electrolyte handling and acid-base balance, mechanism.
and provides a structured approach to the anticipation, diagnosis,
and perioperative management of the specific physiologic distur- Glomerular Filtration
bances in these areas.
Approximately 900 L of plasma pass through the adult kidneys
each day. Of this 900 L, the proportion that passes across the
RENAL PHYSIOLOGY glomeruli (the filtration fraction) is about 20%. This equates to
roughly 180 L/day or a GFR of 125 mL/min. Glomerular filtration
The functional unit of the kidney is the nephron, with each kidney differs from transcapillary exchange, which occurs in other tissues,
containing over 1 million of them. They consist of a hollow, single- by virtue of the much greater proportion of water and small solutes
cell–walled, tortuous tube. The nephron can be conveniently that cross the capillary wall and by the near-complete exclusion
divided into six functional and anatomic divisions, a basic of plasma proteins from the ultrafiltrate. GFR is affected by
understanding of which is crucial to a proper understanding four factors:
of acid-base balance and fluid and electrolyte handling. These
divisions are 1. Glomerular hydrostatic pressure (PG), which promotes
filtration, depends on the relative vascular tone of the afferent
1. The glomerular capillaries and Bowman’s capsule. and efferent arterioles and on RBF.
2. The proximal convoluted tubule (PCT). 2. Bowman’s capsular hydrostatic pressure (PB), which opposes
3. The loop of Henle (LOH). filtration, is generally a minor determinant of GFR; however, it
4. The distal convoluted tubule. may increase significantly with obstructive process of the
5. The collecting tubule. urinary collecting system.
6. The juxtaglomerular apparatus. 3. πG, which opposes filtration, is primarily determined by plasma
albumin concentration.
4. πB, which promotes filtration, is generally zero in the normal
Renal Blood Flow and Glomerular Filtration state because of the lack of proteins in the glomerular filtrate.
The glomerulus is formed by a cluster of capillary loops projecting
Because πB is considered to be zero because of the almost
into an invagination of the proximal end of the nephron lined by
complete lack of proteins in filtrate, the GFR can be expressed as
a single layer of epithelial cells, commonly referred to as Bowman’s
capsule. The barrier to filtration is formed by these two layers of GFR = KF (PG – PB – πG)
CHAPTER 10 ■ Renal Function, Acid-Base, and Electrolyte Homeostasis 141
where KF is the filtration constant. GFR is an excellent measure is 20 to 25% of adult levels at term. RBF and GFR both increase
of the excretory function of the kidney. It is the best estimate of rapidly in the postnatal period because of both an increase in
functioning renal mass in patients with chronic renal disease, and cardiac output and a decrease in renal vascular resistance, doubling
decline in GFR is the principal indicator of ongoing progression of by 2 weeks and reaching adult levels (120 mL/min/70kg) by 2 years
disease. of age.3
Both GFR and RBF can be measured using the clearance
concept. The renal clearance of a substance X (Cx) is the amount
Renal Blood Flow
of plasma from which all of the substance is removed and excreted
Between 20 and 25% of cardiac output perfuses the kidneys. RBF into the urine per unit time. It is described by the equation:
is determined by the following relationship:
Cx = (Ux × V)/Px
Renal artery pressure – renal vein pressure
(renal perfusion pressure) where Ux and Px are urine and plasma concentrations of X, and
RBF = V is the volume of urine generated per unit time.
renal vascular resistance (RVR) Ideally, calculation of RBF would require a marker that is
Renal perfusion pressure approximates mean arterial pressure, completely cleared from plasma on its passage through the
whereas RVR is primarily determined by afferent and efferent kidneys. Para-aminohippuric acid (PAH) clearance is commonly
arteriolar tone. RBF is not distributed equally to all parts of the used to estimate RBF. The accuracy of this technique is good
kidney. Blood flow to the cortex greatly exceeds that to the medulla (within 10% of the true value) in adults, but less (within 65% of the
(98% vs 2%). RBF is controlled by both intrinsic and extrinsic true value) in infants under 3 to 5 months of age.4
mechanisms with short-lived changes in blood pressure being The clearance of a substance that is freely filtered but neither
counteracted by autoregulation. This autoregulation is capable of reabsorbed nor secreted by the tubules is used to calculate
preserving RBF and GFR over a range of mean arterial pressures GFR. Exogenous or endogenous markers may be used. The “gold
from approximately 75 to 150 mmHg. This is accomplished standard” of GFR measurement employs an inulin (a poly-
through two processes including (1) a myogenic reflex, which saccharide) infusion to achieve a steady-state plasma concen-
involves the contractile response of the afferent arteriolar smooth tration. However, this assay is inconvenient to perform and assays
muscle to increases in hydrostatic pressure, and (2) a tubuloglo- of plasma and urine inulin concentration are problematic. In
merular feedback, which regulates afferent arteriolar resistance to clinical practice, the concentration of creatinine, an endogenous
ensure constant sodium chloride (NaCl) delivery to the macula metabolite produced at a relatively constant rate and eliminated
densa of the juxtaglomerular apparatus (JGA). mainly by filtration, is used to estimate GFR. This is achieved
The JGA is a specialized area of each nephron that consists of a using one of a number of equations calculated from large
segment of the afferent arteriole, containing the juxtaglomerular observational studies. The Modification of Diet in Renal Disease
cells in its wall, and the end of the thick ascending cortical segment (MDRD) equation is used most often in adults5 and the Schwartz
of the LOH, the macula densa. Increased RBF and GFR increase equation6 is commonly utilized for children and adolescents.
NaCl delivery to the distal tubule, stimulating the macula densa of There are two main problems with creatinine-based calculations.
the JGA. This causes constriction of the afferent arteriole by a First, with declining GFR (down to 60% of normal), tubular
paracrine effect and a consequent decrease in GFR and NaCl secretion assists in creatinine elimination producing a “creatinine-
delivery. A decrease in GFR or RBF causes diminished NaCl, a blind” range of reduced GFR. Second, there is a large variability in
consequent dilation of the afferent arteriole, renin release resulting creatinine production between individuals and at different times
in an increased GFR, and NaCl delivery to the macula densa. Renin in the same individual. Children have especially inconsistent
released into the bloodstream acts on angiotensinogen to form plasma creatinine concentrations and the Schwartz equation
angiotensin I, which is converted in the lungs by angiotensin- underestimates GFR in muscular children and overestimates GFR
converting enzyme (ACE) to angiotensin II. Angiotensin II is a in anorexic or chronically ill children.7
potent vasoconstrictor in the renal and systemic vasculature. Its Recent research has focused on a low molecular protein,
effect is to constrict the efferent arterioles preferentially resulting in cystatin C. It is produced at a constant rate by all nucleated cells,
a decrease in RBF; however, there is a preservation of GFR because freely filtered by the glomerulus, and completely catabolized in,
of an increase in the filtration fraction. Although the effects of the and not secreted by, the tubular cells. Reference ranges in children
prostaglandins (PGE2 and PGI2) do not contribute greatly to the reach adult levels in the second year of life and are unaffected by
regulation of RBF during the normal state, they oppose vaso- nutritional status or muscle mass. Cystatin C has been shown to be
constrictive effects during times of stress or hypovolemia, thereby elevated in the creatinine-blind range of GFR from 60 to 90
maintaining RBF. mL/min/70 kg. A recent meta-analysis examining calculation of
Extrinsic mechanisms of RBF control are classified as neural, GFR from cystatin C concentrations showed improved diagnostic
hormonal, and autacoidal. These influence the balance between accuracy compared with creatinine-based estimates.8
afferent and efferent arteriolar tone. Sympathetic fibers innervate
all parts of both the renal vasculature and the nephron. Direct
effects on RBF are mediated via vascular ␣1-adrenergic receptors Tubular Function
that trigger vasoconstriction of both the afferent and the efferent
arterioles and a decrease in RBF and GFR.2 Following filtration, glomerular filtrate travels through the
four main parts of the nephron: the proximal tubule, LOH, distal
tubule, and collecting duct.9 The filtrate is modified by reab-
Developmental aspects of RBF and GFR sorption and secretion to arrive at the end of the nephron as urine.
Nephrogenesis is complete by 36 weeks of gestation. RBF and GFR These modifications are the processes whereby the body regulates
are both low in neonates and correlate with gestational age. GFR electrolyte and water balance and acid-base status and excretes
unwanted metabolites and foreign substances. The three deter-

minants of urine composition are glomerular filtration, tubular
reabsorption, and tubular secretion.
The two types of solute transfer across the membrane of tubular
cells are
1. Passive transport, which is subdivided into
a. Simple diffusion.
b. Facilitated diffusion.
2. Active transport, which may be described as
c. Primary.
d. Secondary.
e. Tertiary.
f. Pinocytosis.
Simple diffusion is the movement of solutes down an electrical
or a chemical gradient. Although facilitated diffusion also occurs
down a concentration gradient, it is dependent upon a specific
carrier protein. Conversely, active transport moves solute against
a concentration gradient and, as a result, consumes energy.
Primary active transport mechanisms use energy directly derived
from adenosine triphosphate (ATP) such as the Na+/K+-ATPase
pump. Secondary active transport mechanisms couple the
movement of sodium to the cotransport or exchange of another
molecule such as the Na+-K+-2Cl– cotransporter. Tertiary active
transport systems are associated with secondary active transport
mechanisms such as the ␣-ketoglutarate cotransporter. Na+/K+-
ATPase is a basolateral membrane transport protein that is critical Figure 10-1. Major transport proteins in the proximal tubular cells.
to the operation of all of the passive and most of the active ATP = adenosine triphosphate. Adapted from Johnson and Freehally (9)
transport processes of the renal tubule. It accounts for the high
renal oxygen consumption (and energy necessary for normal renal Sodium is actively pumped across the basolateral membranes
function). Approximately 70% of the oxygen consumption of the generating the gradient from lumen to interstitium for sodium
kidney is used for the turnover of Na+/K+-ATPase. Three Na+ ions reabsorption with water following passively. As a result, fluid
are exchanged for two K+ ions for every ATP molecule that is leaving the proximal tubule is iso-osmolar with plasma. At normal
hydrolyzed. This has two consequences. First, it maintains a very plasma concentrations, glucose is almost completely reabsorbed
low concentration of Na+ intracellularly, and second, it maintains from the proximal tubular fluid with Na+ ions, via a cotransporter.
an electrical gradient of (70mV across the cell membrane. These The glucose transport system is remarkably efficient up to the
gradients act to increase the reabsorptive force for sodium across “tubular maximum,” with little glucose excretion. Beyond this, the
the luminal membrane. Na+/K+-ATPase activity is affected by transporters are overwhelmed and the excess glucose is excreted.
many factors. It is increased by norepinephrine via ␣-adrenergic The plasma glucose concentration at which this occurs is the
receptors and angiotensin II, and it is decreased by dopamine, threshold for glucose.
atrial natriuretic factor, and endothelin. Because of the depen-
dence of so many transport systems on sodium gradients, changes
LOH
in the activity of Na+/K+-ATPase affect the excretion of many
substances. The LOH has two main functions: the reabsorption of water and
ions, and the establishment and maintenance of a hypertonic
medullary interstitium, which enables the distal segments of the
Proximal Tubule nephron to concentrate urine. The LOH contains three distinct
In addition to its primary role of bulk reabsorption, the proximal parts: two thin limbs (descending and ascending) that are
segment of the nephron has three other functions: secretion of metabolically inactive and a thick ascending limb (TAL) that is
organic molecules (e.g., creatinine), hydroxylation of vitamin D, metabolically active. The descending limb passes from the cortex
and formation of ammonia to regulate acid-base balance. into the medulla and is permeable to water but relatively
Morphologically, the proximal tubular cells are well adapted to impermeable to sodium chloride. By contrast, the TAL passes back
their functions. To increase surface area, their luminal membranes to the cortex and is impermeable to water but permeable to NaCl.
have an abundance of microvilli and the basolateral membranes These LOHs are accompanied by capillaries (vasa recta).
have many in-foldings. To provide the energy for transport, Between 20 and 30% of the filtered sodium, chloride, and
tubular cells contain many mitochondria. potassium is reabsorbed in the LOH accompanied by approxi-
Proportionally, the PCT reabsorbs more than half of the filtered mately 20% filtered water. The TAL is the primary site of ion
sodium, potassium, chloride, calcium, urea, and water and almost removal from the filtrate. A unique carrier protein, the Na+/K+/2Cl –
all of the filtered bicarbonate (HCO3), phosphate, glucose, amino cotransporter (NKCC) is responsible for most ion movement
acids, and low-molecular-weight proteins. These processes are across the luminal membrane. This is the site of action of loop
largely dependent upon sodium gradients (Figure 10–1). diuretics (Figure 10–2). In common with most other transport
cortical collecting duct, and the medullary collecting duct. These

three segments are responsible for reabsorption of approximately
8% of filtered sodium, reabsorption of a variable amount of water
(8-17% of that filtered), and secretion of variable amounts of
K+ and H+ ions.
The first section of the distal tubule (early distal tubule), which
forms part of the JGA, is also functionally similar to the TAL of
the LOH. It continues the process of dilution of tubular fluid
by ion reabsorption although it is impermeable to water. A
thiazide diuretic–sensitive, luminal membrane sodium chloride
cotransporter powered by the basolateral Na+/K+-ATPase is the
major ion transporter. Parathyroid hormone (PTH)–sensitive
calcium reabsorption also occurs in this section accompanied by
magnesium.
The late distal tubule–cortical collecting duct is made up of two
types of cells: principal cells and intercalated cells. Principal cells are
primarily responsible for aldosterone-mediated sodium reabsorp-
tion and potassium secretion. These functions are predictably
reliant upon basolateral Na+/K+-ATPase to create a concentration
gradient down which sodium and potassium flow in opposite
directions via carrier proteins across the luminal membrane
(Figure 10–3). Aldosterone has two main effects on principal cells:
(1) it increases the number of Na+/K+-ATPase carriers in the
basolateral membrane and (2) it increases the number of carrier
proteins in the luminal membrane. The net effect of aldosterone is
Figure 10-2. Ion channels in the loop of Henle. to retain sodium and secrete potassium. Increased delivery of Na+
to this segment (i.e., the upstream effects of natriuretics such as
loop and thiazide diuretics) will enhance kaliuresis.
proteins in the nephron, it relies upon the sodium gradient created The two subtypes of intercalated cells (alpha and beta) are
by basolateral Na+/K+-ATPase. Because of the low concentration of responsible for secretion of H+ and HCO3 ions, respectively.
potassium in the tubular fluid, a recycling system pumps ions back H+ ion secretion in a intercalated cells is partly under the control
into the lumen to allow continued function of the NKCC. The of aldosterone. These cells are also important in potassium
removal of two negative charges for each positive charge leaves the
luminal fluid with a positive charge relative to the interstitium.
This electrical gradient facilitates the movement of calcium and Lumen Cell Interstitium
magnesium via the intercellular pathways to the interstitium.
Countercurrent multiplication creates the hypertonic environ-
ment of the medullary interstitium and countercurrent exchange
helps maintain it. Countercurrent multiplication comprises two
elements. First, the TAL is impermeable to water, and therefore,
the tubular fluid becomes progressively hypotonic as NaCl is
pumped into the interstitium. The resulting increased interstitial Ald
osmolarity equilibrates with the descending limb tubular fluid,
leaving it hypertonic. This hypertonic fluid then enters the TAL, 3Na
which again produces hypotonic tubular fluid by removing NaCl, Na ATP
but a greater amount of salt needs to be removed than in the 2K
previous circuit. This creates a more hypertonic interstitium,
which produces a still more hypertonic descending limb fluid and
so on until the maximum reabsorptive capacity of the TAL is
reached. The result of this multiplication leaves a maximum K+ K+
interstitial osmolarity of approximately 1200 mOsm/L. The second
part of the countercurrent exchange is due to the capillary loops of
the vasa recta. In order to prevent the solutes in the interstitium
from being “washed out” by blood flow, ions and water are
exchanged in opposite directions between vessels traveling to and
from the medulla, thereby protecting the hyperosmolar inter-
stitium created by countercurrent multiplication.
Distal Tubule and Collecting Duct

The distal tubule and collecting duct have three functionally Figure 10-3. The principal cell of the distal tubule/collecting duct.
different segments: the early distal tubule, the late distal tubule– Ald = aldolase; ATP = adenosine triphosphate.
reabsorption via a H+ ion transport system. These cells are

discussed further in the “Acid-Base Balance” section.
The cells of the medullary collecting duct are modified
principal cells. It is here that the final volume and osmolarity of
excreted urine are determined. The cells are permeable to sodium
via a luminal carrier that can be inhibited by atrial natriuretic
peptide. Water permeability of the medullary collecting duct cells
is determined by antidiuretic hormone (ADH). ADH is the
primary determinant of urine volume and osmolarity. It is secreted
by the posterior lobe of the pituitary gland in response to increased
plasma osmolarity and decreases in systemic blood pressure.
The basolateral membrane of these cells is permanently highly
permeable to water owing to fixed water-carrying proteins
called aquaporins (types 3 and 4). The luminal membrane is
impermeable to water in the absence of ADH. In the presence of
ADH, aquaporin (type 2)-containing vesicles are inserted into
the luminal membrane allowing water to enter the cell and then
move to the interstitium across the water-permeable basolateral
membrane10 (Figure 10–4). Water reabsorption in the medullary
collecting duct is therefore reliant upon two variables: (1) the
presence of ADH-induced luminal aquaporins to allow water to
cross epithelial cells and (2) the hypertonic interstitium created by
the LOH to provide a gradient down which water moves.11 This
results in a hypertonic urine and electrolyte-free water retention.
The difference between urine osmolarity in the presence and the
absence of ADH can be seen in Figure 10–5. Figure 10-5. The effect of antidiuretic hormone (ADH) on the
osmolarity and volume of tubular fluid. Adapted from Guyton A,
Hall J. The kidneys and body fluids. In: Textbook of Medical Physiology.
Developmental Aspects of Tubular Function Philadelphia: Elsevier Saunders; 2006.
Differences between adult and neonatal tubular function can
be categorized into morphologic, functional, and regulatory
expression is similarly decreased at birth and develops to adult
categories. The reabsorptive area offered by the PCT increases
levels during the first year of life.3
greatly during the first 2 years of life. This results from an increase
Hormone effects on the kidney in infants are somewhat
in its length and the development of in-folding of both the luminal
different than those in adults.12 The renin-angiotensin system in
and the basolateral membranes. The number and function of
the very young cannot be maximally inhibited, which decreases
the powerhouse of tubular reabsorption, the Na+/K+-ATPase
the kidneys’ ability to deal with large NaCl loads. The implications
transporter, are reduced at birth. Na+/K+-ATPase activity increases
of these differences between adult and immature kidneys on
5- to 10-fold during the postnatal period. Because of the decreased
neonatal renal function are
activity of Na+/K+-ATPase in early life, all transporters reliant on
the Na+ gradient, which it provides, are also reduced in function. 1. Neonates are obligate salt losers.
For example, PCT’s maximum capacity for glucose reabsorption in 2. Neonates cannot excrete a large salt load.
premature babies is 10 times less than that in adults. Aquaporin 3. Neonates cannot concentrate urine effectively.
4. Processes linked to sodium gradients work inefficiently (e.g.,
glucose reabsorption, potassium secretion).
ACID-BASE BALANCE
Physiology
Acid-Base Chemistry
The concentration of H+ ions in both the extracellular fluid (ECF)
and the intracellular fluid (ICF) is aggressively maintained by the
body. Almost all cellular and organ functions are sensitive to
changes in (H+) concentrations, and consequently, large deviations
are incompatible with life. Normal ECF (H+) concentrations are
very low, in the order of 40 nmol/L, which is 3 to 4 million times
less than that of sodium. In order to express these concentrations
more conveniently, the negative log (p) of (H+) or pH is used.
Thus, normal pH of the ECF is 7.4. Because this is a logarithmic
Figure 10-4. Effect of antidiuretic hormone (ADH) on the medullary scale, an increase in one unit of the pH scale is equivalent to a 10-
collecting duct cells. fold increase in concentration.
An acid is any substance that releases a proton (H+) in solution that is,
and a base is any substance that accepts a proton (H+) in solution.
Strong acids are those that readily give up H+ ions, thereby
decreasing the pH of a solution. Conversely, strong bases are those
( )
pH = pK – log (HA)
(A⫺)
that avidly take up H+ ions and increase pH. In an acidic solution, This equation is known as the Henderson-Hasselbach equa-
a weak acid (e.g., the phosphate group of a nucleic acid) will tend tion, from which it is apparent that the pH of a solution is related
to hold onto its H+ ion (i.e., remain largely unionized), whereas a to the ratio of the dissociated anion to the undissociated acid.
weak base will take up protons (i.e., ionize). The reverse is true for Buffer system power is maximized under two conditions: (1) when
a basic solution in which a weak acid will give up protons (and the concentrations of the conjugate pairs are equal: (A–) = (HA),
ionize) and a weak base will remain un-ionized or only partially that is, when pH = pK, and (2) when the absolute concentrations
ionized. A buffer is a mixture of a weak acid and its conjugate base of the conjugate pairs are high.
or a weak base and its conjugate acid. A buffer will resist change
in (H+) in a solution by readily accepting or donating H+. THE HCO3 BUFFER: The conjugate pairs of the HCO3 buffer sys-
The body at rest continuously produces two types of acid: tem is H2CO3 and HCO3⫺ (i.e., H2CO3 ↔ HCO3⫺ + H+). However,
(1) volatile and (2) nonvolatile. Volatile acid is produced by tissue CO2 can be substituted for H2CO3 because H2O + CO2 ↔ H2CO3.
respiration and excreted by the lungs as CO2. As a result, this Therefore, the result of adding acid to the HCO3 buffer is the pro-
metabolically derived CO2 has no impact on acid-base balance. duction of CO2 and water, which are readily excreted by the lungs
Nonvolatile acids are independent of CO2 production. They and kidneys, respectively. If the solubility coefficient of CO2 (0.03
include either (1) organic acids produced by muscle, liver, and mmol/L) and the pKa (6.1) for HCO3 are substituted, the Hen-
adipose tissue (e.g., lactic acid, hydroxybutyric acid, and derson-Hasselbach equation applied to HCO3 can be written as
acetoacetic acid) or (2) fixed acids produced by the metabolism
of sulfur-containing amino acids and organic phosphates
(e.g., sulfuric and phosphoric acids). These nonvolatile acids (
pH = 6.1 + log (HCO3)
0.03 PaCO2 )
accumulate at the rate of approximately 1 mEq/kg/day and are From this equation, the pH of plasma can be calculated if the
excreted by the kidneys.13 The regulation of acid-base balance is of arterial carbon dioxide pressure (PaCO2) and (HCO3⫺) are known.
particular importance during the provision of anesthetic care. The fact that the pKa of 6.1 is not close to physiologic pH
Anesthesia and surgery, through their effects on tissue perfusion suggests that HCO3 might not be an efficient buffer because at pH
and ventilation, can alter acid-base balance. Conversely, altered of 7.4, (HCO3⫺) greatly exceeds (H2CO3). The HCO3 buffer system
states of acid-base balance can alter the patient’s response to has two important advantages: (1) the concentrations of CO2 and
anesthesia. The rates at which these effects occur are greater in HCO3⫺ can be altered by the lungs and the kidneys, respectively,
children than in adults. and (2) HCO3⫺ is present in plasma in relatively large concen-
trations. The implication of the fact that the pKa for HCO3 is less
Protection against (H+) Changes than normal plasma pH is that HCO3 buffers change more
Three levels of protection against (H+) changes are effectively if they are tending to decrease pH than if they are
tending to increase pH.
1. Immediate chemical buffering.
2. Respiratory compensation. THE PHOSPHATE BUFFER: This buffer system is important both
3. Renal compensation. intracellularly and in renal tubules where its concentration reaches
useful levels. The conjugate pair is
Chemical buffering is provided by various body fluid buffer HPO42– + H+ ↔ H2PO4– (pKa = 6.8)
systems including (1) the main extracellular buffer—HCO3; This system is suited to working in the ICF and tubular fluid
(2) the two main urinary buffers—phosphate and ammonia; and for two reasons: (1) phosphate is concentrated in these fluids and
(3) the three main intracellular buffers—protein, hemoglobin, and (2) the pH of these fluids is less than that of plasma and, thus,
phosphate. We present a brief overview of chemical buffer closer to the pKa of the phosphate buffer system.
function followed by a discussion of the individual buffers. Where
HA is a weak acid in solution, it will dissociate as follows: HA ↔ HEMOGLOBIN: Hemoglobin (Hb) is the principal nonbicarbonate
H+ + A–. HA can act as an acid by donating H+ and A– can act as blood buffer. The Hb molecule has many buffering sites,
a base by taking up H+. Therefore, A– is the conjugate base of the principally histidine moieties with a pK of 6.8. Unlike HCO3, Hb
acid HA. The equivalent reaction for a base B is B + H+ ↔ BH+ can effectively buffer volatile (CO2) and nonvolatile acids by acting
where BH+ is the conjugate acid of the base B. as a weak acid and as a potassium salt:
For the first reaction outlined previously, a dissociation H+ + KHb ↔ HHb + K+
constant K can be defined:
CO2 + H2O + KHb ↔ HHb + HCO3⫺ + K+
K = H⫺)(A–
(
(HA) ) PROTEIN BUFFERS: Proteins are important in intracellular
buffering because, in addition to their high ICF concentrations,
and
many protein buffer pairs have a pKa at or near 7.4. Protein amino
(H+) = K(HA) acids have –COOH groups that can release H+ and –NH2 groups
(A–) that can accept H+ ions. Therefore, they act as weak acids or bases
The negative log of this reaction is depending on the pH of the solution.
–log(H+) = pK – log (HA)
( )
(A–)
RESPIRATORY COMPENSATION: Medullary chemoreceptors that
respond to changes in cerebrospinal fluid (CSF) pH modulate the
respiratory response to changes in the acid-base state. The lungs

are responsible for eliminating the 15,000 mmol of CO2 produced
daily by metabolism and for compensation for metabolic varia-
tions. A decrease in pH stimulates the medullary chemoceptors,
causing increased ventilation and a prompt decrease in PaCO2,
restoring pH toward normal. An increase in pH inhibits the
medullary chemoceptors, causing a prompt increase in PaCO2,
which restores pH toward normal. Both of these corrections are
incomplete. The response to alkalosis is limited by progressive
hypoxia, secondary to hypoventilation. In general, PaCO2 does not
tend to increase to greater than 55 mmHg in response to metabolic
alkalosis
RENAL COMPENSATION: Under normal conditions, the kidneys
excrete the same amount of nonvolatile acid as are produced by
metabolism each day (1 mEq/kg/day). Compensation for acid-
base changes entails four mechanisms:
1. Filtered HCO3 reabsorption.
2. H+ secretion.
3. HCO3 regeneration by titratable acid excretion.
4. HCO3 secretion.
Although all parts of the nephron contribute to HCO3 Figure 10-7. Active H+ secretion in the collecting tubule.
reabsorption, the proximal tubular cells perform 85% of this task. ATP = adenosine triphosphate; CA = carbonic anhydrase.
For each mmol of HCO3 reabsorbed, 1 mmol of H+ is secreted into
the tubular fluid. This is achieved by the Na+/H+ secondary active tubular generation of HCO3 into the blood. The net effect is Na+
transport protein and is limited by the sodium gradient so that the reabsorption and HCO3⫺ reabsorption. For every mole of HCO3⫺
minimal tubular pH achievable is 6.7. The secreted H+ ions that is neutralized in the tubular fluid, a mole enters the blood,
combine with filtered HCO3– forming H2CO3 and ultimately H2O although it is not the same mole.
and CO2. CO2 enters tubular cells and freely combines there with Active secretion of H+ ions occurs in the alpha-intercalated cells
water in a reaction catalyzed by carbonic anhydrase to form of the late distal and collecting tubules. This process is achieved by
carbonic acid. This in turn, dissociates into H+ and HCO3⫺. The primary active transport and allows a much greater gradient (≤900
HCO3⫺ enters the bloodstream via the basolateral Na+/HCO3⫺ times) across the luminal membrane to be achieved than in the
cotransporter and the H+ is resecreted into the tubule (Figure proximal tubule. A pH of 4.4 is the minimum possible for tubular
10–6). Thus, filtered HCO3 is neutralized with the concomitant fluid. Carbonic anhydrase is the source of the H+ ions and the
HCO3 produced is cycled back to the interstitium via a basolateral
Cl⫺/HCO3⫺ exchanger (Figure 10–7).
The amount of H+ excreted in the urine is limited by the ability
of tubular cells to produce a concentration gradient across
the luminal membrane. As we have seen, this is limited at a
pH of approximately 4.4. At this pH, the (H+) is only 0.1 mEq/L.
Given the requirement to excrete 1 mEq/L/day of acid,
a mechanism of excreting much more H+ is necessary. To limit the
(H+) in the filtrate, two buffers (called titratable acids) bind H+,
limiting its concentration and thereby allowing much more to
be excreted. The first buffer is the phosphate system, which has
been previously mentioned. HPO42– is concentrated in the renal
tubules and accepts an H+, forming H2PO4–. Once this phosphate
buffer has been exhausted and all filtered HCO3 reabsorbed,
ammonia becomes the most important buffer. Ammonia (NH3)
is produced in the tubular cells, largely from the deamination
of glutamine. It diffuses into the lumen where it combines
with H+ to form ammonium ions (NH4+). NH4+ and H2PO4– are
not reabsorbed, resulting in loss of H+ and, consequently,
generation of HCO3 from the disassociation of carbonic acid
(Figure 10–8).
In the presence of alkalosis, the amount of HCO3 that is filtered
normally allows the kidneys to excrete large quantities if necessary.
Figure 10-6. Cellular mechanisms for bicarbonate reabsorption in The beta-intercalated cells of the cortical collecting tubule are
the proximal tubule. ATP = adenosine triphosphate; CA = carbonic capable of actively secreting HCO3⫺ in response to an alkaline
anhydrase. load, but only if there is sufficient luminal Cl– for exchange,
Developmental Aspects of Acid-Base Balance

In utero, the fetus maintains a mild respiratory acidosis, with a
similar plasma HCO3 concentration, but a greater PaCO2 than its
mother. Following birth, infants have a reduced plasma HCO3
concentration and PaCO2 than older children and adults. They
have a comparatively greater basal acid production and are less
able to respond to an acid load. Endogenous acid production in
small children is somewhat between 50 and 100% greater per
kilogram than in adults. This is primarily because of the deposi-
tion of Ca2+ in bone, a process that produces 0.5-1 mEq/L of
acid/day. HCO3 absorption from the gastrointestinal (GI) tract is
an important source of base to neutralize this nonvolatile acid and,
in part explains the tendency of infants to become profoundly
acidotic when suffering from gastroenteritis.
Both HCO3 reabsorption and acid excretion are poorly
developed in infants. The HCO3 tubular threshold (the plasma
level above which HCO3 appears in the urine) is less for two
reasons: (1) the immaturity of Na+/ K+-ATPase and its inability to
produce a sufficient sodium gradient and (2) decreased carbonic
anhydrase activity. Acid secretion is also impaired by two pro-
cesses: (1) decreased H+-ATPase activity in the collecting ducts
impairs the ability of the kidney to produce an acid urine (minimal
pH, ~6.5) and (2) titratable acid excretion is less because of the
limited availability of tubular phosphate and ammonia. The net
result is that the infant or small child is living near its limit of acid
Figure 10-8. Titratable acid excretion. ATP = adenosine triphosphate; compensation and is, therefore, prone to develop acidosis during
CA = carbonic anhydrase; DA = deamination. the course of an acute illness or starvation.
because the luminal channel that allows HCO3⫺ excretion is one

that exchanges it one-to-one for Cl⫺. This fact is key to the under- Pathophysiology of Acid-Base Disturbances
standing of metabolic alkalosis (Figure 10–9). Metabolic Acidosis
Although frequently used to describe a situation in which there is
a decrease in the pH, the term acidosis more correctly describes a
situation that, if unopposed, would tend to cause a fall in pH.
The term acidemia more accurately describes the situation in
which there has been an actual fall in pH. For example, a person
may have a chronic respiratory acidosis but, because of renal
compensation, may have a normal pH and, therefore, not in fact
be acidemic. Various pathologic conditions may result in acidosis
(Table 10–1).
The clinical manifestations of acid include a combination
of sympathoadrenal stimulation and direct depressant effects.
With a pH less than 7.2, the depressant effects predominate.
Cardiovascular effects include direct myocardial and smooth
muscle depression, which results in vasodilatation, leading to
progressive hypotension. There is also decreased response to
endogenous or exogenous catecholamines and an increased risk of
ventricular fibrillation (decreased fibrillation threshold). There is
a rightward shift in the oxyhemoglobin dissociation curve. Central
nervous system (CNS) depression occurs to a greater extent
during respiratory than during metabolic acidosis, because H+
ions do not readily cross the blood-brain barrier whereas CO2
does. Additional CNS effects include increased intracranial
pressure because of increased cerebral blood flow and intracellular
acidosis, which may be partially responsible for “CO2 narcosis.”
Progressive hyperkalemia may develop because of the exchange
of intracellular K+ for H+ (an ~0.6 mEq/L potassium increase per
Figure 10-9. Bicarbonate secretion at the β-intercalated cells of the 0.1 decrease in pH).
collecting tubule ATP = adenosine triphosphate; CA = carbonic The CNS and cardiovascular depressant effects of most
anhydrase. sedatives, volatile inhalational anesthetic agents, and intravenous
TABLE 10-1. Causes of Acidosis The normal anion gap is 8 to 16 mmol/L. In reality, a true anion
gap does not exist because all anions and cations maintain
Causes of Metabolic Causes of Respiratory electroneutrality. The “anion gap” represents the difference
Acidosis Acidosis between the unmeasured anions and the unmeasured cations,
High Anion Gap Alveolar Hypoventilation defined as
Increased production of acid CNS depression Anion gap = (Unmeasured anions) – (Unmeasured cations)
Inborn errors of metabolism Depressant drugs
Lactic acidosis CNS ischemia/trauma “Unmeasured anions” include phosphates, sulfates, and organic
Ketoacidosis Neuromuscular disorders anions, such as plasma proteins. “Unmeasured cations” include
Failure to excrete acid Myopathies Ca2+ and Mg2+. Any process involving increased (endogenous or
Renal failure Neuropathies ingested) nonvolatile acid will result in a “high anion gap” acidosis.
Ingestion of toxins/acid Parenchymal lung disorders Normal anion gap acidosis is typified by hyperchloremia.
Salicylate Pneumonia Another quick and useful test in the evaluation of metabolic
Ethanol Pulmonary edema acidosis is the urine pH. In the presence of a significant metabolic
Ethylene glycol/methanol Cystic fibrosis acidosis, intact functioning of the distal tubule is evidenced by the
Airway obstruction ability to generate a urinary pH less than 5.5 in all ages and less
Normal Anion Gap than 5.0 in older children. In certain patients, it may be necessary
Foreign body
GI tract bicarbonate wastage to render the patient more academic, using one of the acid load
Laryngospasm
Severe diarrhea protocols in order to obtain this diagnostic information.
Bronchospasm
Enterocutaneous fistula The urine anion gap can also be calculated. It may provide
Tumor
Ileostomy additional information in the case of hyperchloremic, normal
Chest wall/pleura
Renal bicarbonate wastage anion gap acidosis.
Kyphoscoliosis
Proximal RTA
Flail chest Urine anion gap = (Na+ + K+ + NH4+) – (Cl– + HCO3–).
Impaired H+ excretion
Pneumothorax
Hypokalemic distal RTA The capacity of the distal tubule to generate NH4+ in response
Hyperkalemic distal RTA Increased CO2 Production to acidosis is greater than its ability to generate free H+; thus,
Dilutional Malignant hyperthermia measurement of (NH4+) would be a more sensitive indicator of
Large carbohydrate load urinary acidification ability. However, NH4+ is not easily measured,
(enteral or parenteral but it can be estimated from the urine anion gap as the difference
carbohydrate load)
between (Na+) + (K+) and (Cl–). In reality, (HCO3–) can be
Shivering
excluded from this calculation because it will not be present in a
Seizure
metabolic acidosis and such the urine anion gap is calculated as
Thyrotoxicosis
Neuroleptic malignant (Na+ + K+) – Cl–.
syndrome
The result of this calculation is generally negative in a metabolic
CNS = central nervous system; GI = gastrointestinal; RTA = renal tubular acidosis. acidosis, thereby confirming NH4+ formation. A positive result
suggests failure to acidify urine.
anesthetic agents are enhanced by acidemia. In addition, any HIGH ANION GAP ACIDOSIS: High anion gap acidosis results
anesthetic agent that inhibits sympathetic tone will allow un- from increased endogenous or exogenous nonvolatile acid by
opposed cardiovascular depression. The arrhythmogenic effects of either:
halothane are greater in acidemia. If acidemia is present, the use of
1. Increased production of acid.
suxamethonium may cause a dangerous increase in plasma potas-
2. Failure to excrete acid.
sium. Respiratory, but not metabolic, acidosis can prolong the effect
3. Ingestion of toxins/acid.
of nondepolarizing neuromuscular blocking agents. Most opioids
are weak bases, and therefore, acidosis increases the nonionized Various pathologic conditions can result in increased
drug fraction, increasing CNS penetration and drug effect. production of acid. Inborn errors of metabolism are a group of
Metabolic acidosis is, by definition, a primary reduction in inherited disorders that present in the newborn period or early
(HCO3–) and can be caused by three processes: childhood. They may be disorders of amino acid metabolism (e.g.,
maple syrup urine disease) or organic acid metabolism (e.g.,
1. HCO3 wastage. methylmalonic or propionic acidemia). Inherited disorders of
2. Excessive acid load. carbohydrate metabolism may also cause severe lactic acidosis
3. Rapid dilution of the ECF with HCO3 free fluid. (e.g., glycogen storage disease type 1). Lactic acidosis is more
Occasionally, the cause of the metabolic acidosis is not obvious commonly a result of severe tissue hypoxia, as a result of
(e.g., toxins, renal tubular acidosis [RTA], and inborn errors of hypoxemia, hypoperfusion, or the inability to use oxygen as in
metabolism). Useful diagnostic information obtained from simple cyanide poisoning. Less commonly, decreased hepatic and renal
tests includes the plasma anion gap. This is defined as the lactate utilization and metabolism can lead to accumulation.
difference between the major measured cations and the major Causes include hypoperfusion, hepatic disease, and alcoholism.
measured anions. The anion gap is calculated as Accumulation of D-lactic acid, not recognized by routine assay,
can occur in the short bowel syndrome, causing acidosis.
Anion gap = (Na+ + K+) – (Cl– + HCO3–) Ketoacidosis, with accumulation of beta-hydroxybutyric acid and
acetoacetic acid, can result from a relative or absolute lack of type 4) is most frequently observed in children with hypoaldo-
insulin. It is also seen following starvation. steronism or pseudohypoaldosteronism (aldosterone resistance),
Failure to excrete the endogenous acid load can also result in either occurring as an isolated problem or associated with chronic
metabolic acidosis. Endogenously produced acids are normally renal parenchymal damage. Acidosis in these patients is only a
excreted by the kidneys in the urine. Renal failure typically causes part of a spectrum of metabolic and biochemical abnormalities
progressive metabolic acidosis from accumulation of these acids. caused by the impaired aldosterone effect. Hyperkalemia asso-
Finally, ingestions of toxins or acids may result in acidosis. The ciated with the aldosterone defect impairs H+ excretion via a
presence of a severe metabolic acidosis in an otherwise healthy number of mechanisms including the effect of increased ICF (K+)
child should suggest ingestion of drugs or toxins. Salicylate in the principal cells of the collecting tubule causing lower
ingestion is the classic example in childhood. Salicylates dis- intracellular (H+). After an acid load, the urine can be acidified,
rupt the Krebs cycle and oxidative phosphorylation, leading but the net acid excretion remains subnormal owing to low NH4+
to lactate accumulation and metabolic acidosis. The typical production. There is no wastage of HCO3.
concomitant respiratory alkalosis seen in adults with salicylate Dilutional acidosis will also produce a normal anion gap
overdose is much less evident in children. Ethanol inhibits hepatic acidosis. Rapid expansion of the extracellular space with non-
gluconeogenesis and causes hepatic underutilization of lactate, bicarbonate-containing fluid, such as large volumes of normal
leading to metabolic acidosis, which can be severe in children, saline, commonly produces an acidosis. This has been explained
especially those with underlying liver disease. Ethylene glycol and by the increase in the volume of distribution of existing HCO3
methyl alcohol breakdown products also precipitate lactic acidosis effecting a decrease in HCO3 concentration. In addition, volume
because of interference with mitochondrial function by a direct expansion may increase the filtrate volume and sodium load
toxic effect. passing the PCT and leading to reduced absorption of HCO3–.
NORMAL ANION GAP METABOLIC ACIDOSIS: Normal anion gap More recently, it has become apparent that “dilutional” acidosis is
acidosis is most commonly caused by HCO3 wastage through the more commonly a function of the chloride load and that it can
GI tract. GI HCO3 wastage can be profound when one considers occur in the absence of plasma expansion. The use of buffered
that small bowel, biliary, and pancreatic secretions contain solutions with a lower chloride concentration, such as Ringer’s
approximately five times as much HCO3 as plasma. Any condition lactate, are associated with less chloride load and acidosis.14
leading to severe diarrhea, artificial drainage, and/or fistulation The expanded theory of acid-base balance15 would explain such
will rapidly lead to profound HCO3 wastage, with a compensatory acidosis on the basis of decreasing strong ion difference (SID). The
hyperchloremia maintaining a normal anion gap. With the SID is the difference between strong cations (Na+, K+, Ca2+, Mg2+)
exception of congenital chloride diarrhea, which does not cause and strong anions (Cl–, unidentified anions). To maintain electro-
HCO3 loss, acute diarrheal disease is the most common cause of neutrality, a decrease in SID must be balanced by an increase in the
hyperchloremic acidosis. Urine in contact with the colon will balancing (H+).16 Dilutional acidosis is important to the anes-
cause HCO3 wastage by exchange of HCO3 for chloride, a problem thesiologist because confusion may arise over whether an intrao-
that declined with the advent of direct cutaneous diversion of the perative acidosis represents poor tissue perfusion or hypovolemia
ureters. Recent use of bowel augmentation cystoplasty makes this that might trigger administration of normal saline.17 Obviously,
a more common phenomenon again, although significant acid- this would worsen the situation if the acidosis was in fact sec-
base disturbance is seen in only a minority of patients. ondary to excess chloride load.
Renal wastage of HCO3 occurs in proximal (formerly type 2) TREATMENT OF METABOLIC ACIDOSIS: In treating a metabolic
RTA. This condition is characterized by low renal HCO3 threshold acidosis, any respiratory component contributing to the acidosis
and impairment of proximal generation of HCO3. Distal mech- should be corrected. If HCO3 therapy is instituted, it may
anisms to excrete H+ remain intact; therefore, severe acidemia is transiently increase PaCO2 as HCO3 is consumed by acid,
unusual. Although it may occur as an isolated defect, it is generally emphasizing the need to control ventilation in severe acidemia.
part of a generalized tubular defect as in Fanconi’s syndrome with Specific measures are dependent on treating the underlying cause
additional urinary wastage of amino acids, glucose, phosphate, of the acidosis. In the case of the inborn errors of amino acid
and other organic and inorganic substances handled by the metabolism discussed under “High Anion Gap Acidosis,” dietary
proximal tubules. protein should be restricted and adequate calories provided by
Normal anion gap acidosis with a positive urine anion gap (i.e., lipid and carbohydrate until a definitive diagnosis is made by
distal tubules not producing NH4+) is suggestive of a renal inability plasma and urine organic acid analysis. The relevant metabolite
to acidify urine, typical of distal RTA. A variety of conditions have can then be removed if necessary by dialysis or rendered harmless
as a common link an inability of the distal renal tubules to acidify by intracellular transport using a dextrose/insulin infusion. Lactic
urine. These are grouped under the heading distal tubular acidoses acidosis, caused by hypoxia or hypoperfusion, is treated primarily
and can be usefully divided into hypo- and hyperkalemic types. by measures aimed at reversing the tissue oxygen deprivation. The
Hypokalemic distal RTA (formerly type 1) is characterized by an question of the use of HCO3 is discussed later in this section.
inability to decrease urinary pH below 5.3 even in the presence of Specific therapy for diabetic ketoacidosis consists of fluid resusci-
severe acidemia. Although proximal re-absorption of HCO3 is tation, insulin, potassium, phosphate, and magnesium. Acidosis
normal, the elevated urine pH causes a certain amount of filtered related to renal failure is treated primarily by addressing the cause
HCO3 to escape re-absorption. Up to 50% of patients suffer from of the renal failure and reversing it if possible. Alkalinization of
nephrocalcinosis and urolithiasis, caused by a combination of the urine with sodium HCO3 to a pH greater than 7.0 enhances the
hypercalciuria and hypocitraturia. In children, distal RTA is elimination of salicylate following salicylate poisoning. For eth-
mainly caused by genetic defect in the H+ pump, whereas in adults, ylene glycol or methanol intoxication, ethanol infusion is indi-
it is usually multifactorial. Hyperkalemic distal RTA (formerly cated. Ethanol competes with ethylene glycol or methanol for
alcohol dehydrogenase and slows the formation of formic acid or to a degree by the ability of acidosis to stimulate catecholamine
oxalic acid, respectively. More recently, specific pharmacologic release. Acidosis causes vasodilatation, whereas correction with
therapy with fomepizole, an agent that inhibit alcohol dehydro- HCO3 causes vasoconstriction. This may lead to persistence
genase, has largely replaced the need for ethanol infusions. When of anaerobic metabolism in a critically ill patient. Also, acidosis
significant acidosis or visual or mental disturbances are present, may have a role in protecting from cell death in clinical shock.
consideration should be given to hemodialysis. With proximal Sodium HCO3 solution has the potential to cause volume
hypokalemic RTA, the most common clinical problems are failure overload, hyperosmolality, and hypernatremia. One of its principal
to thrive, vomiting, and stunted growth. The mainstay of treat- disadvantages is its ability to generate CO2. This can result in
ment is correction as required of Na+, K+, and Ca2+ deficits and intracellular hypercarbia and a paradoxical worsening of the
possibly also vitamin D supplementation. Severe acidemia is intracellular pH.
uncommon, and hence, the achievement of normal serum HCO3
concentration is neither necessary nor practicable (the low renal Respiratory Acidosis
threshold for HCO3 means massive doses would be necessary to
achieve this). Distal hypokalemic RTA requires sodium and Respiratory acidosis is defined as a primary increase in PaCO2.
potassium citrate or HCO3 in the region of 1 to 2 mmol/kg/day to This drives the equation H2O + CO2 ↔ H2CO3 ↔ H+ + HCO3– to
restore normal thriving. However, in this condition, long-term the right, leading to an increase in (H+) and a fall in pH. PaCO2
renal function is principally threatened by nephrocalcinosis. The represents the balance between production of CO2 from
appropriate alkali supplementation should be titrated to achieve carbohydrate and fat metabolism and its elimination through
normal HCO3 levels and normalization of renal calcium excretion. the lungs. Although increased muscle activity, body temperature,
Hyperkalemic distal RTA (hypo- or pseudohypoaldosteronism) and thyroid hormone can all increase CO2 production, in general,
rarely requires treatment of acidosis; however, hyperkalemia may production varies little under normal circumstances and respir-
be a problem that is best treated by an adequate urine output, atory acidosis is the result of alveolar hypoventilation. In a patient
dietary sodium supplementation, and avoidance of medications with limited ability to increase alveolar ventilation, an increase in
that further increase serum K+ values. CO2 production can precipitate respiratory acidosis.
The primary goal of therapy in metabolic acidosis is correction The physiologic response to respiratory acidosis can be
or reversal of the underlying cause. Empirical alkali therapy aimed divided into acute and chronic phases. The acute (6–12 h)
at preventing severe acidemia (pH < 7.2) is often recommended, response to respiratory acidosis is limited. Buffering is primarily
but is of questionable benefit. The most urgent concern associated by hemoglobin and the exchange of extracellular H+ for Na+ and
with acidosis is the risk of impaired myocardial contraction and K+ from bone and intracellular fluid. The renal response acutely is
decreased myocardial and vascular response to endogenous or limited, such that plasma (HCO3–) increases only about 1 mmol/L
exogenous catecholamines. for each 10 mmHg increase in PaCO2 above 40 mmHg. The
Various formulas exist for calculation of HCO3 dose: chronic response is characterized by renal compensation. This
is appreciable only after 12 to 24 hours and may be incomplete for
HCO3 deficit (mEq) = 0.6 × Wt (kg) ×
up to 3 to 5 days. During chronic respiratory acidosis, plasma
(desired (HCO3–) – measured (HCO3–)
(HCO3–) increases approximately 4 mmol/L for each 10 mmHg
where 0.6 represents the apparent HCO3 space (a reflection of increase in PaCO2 above 40 mmHg.
total body buffering capacity), which is 60% of body weight in mild
TREATMENT OF RESPIRATORY ACIDOSIS: The treatment of
to moderate acidosis (apparent HCO3 space varies from ~25%
respiratory acidosis is to reverse the imbalance between production
at normal pH to 100% at a pH of 7.0) and where a (HCO3–) of
of CO2 and alveolar ventilation. In specific instances, measures
15 mEq/L is considered adequate to maintain pH in a safe
to reduce CO2 production are appropriate (e.g., dantrolene in
range in the absence of any respiratory acidosis. An alternative
formula is malignant hyperthermia, antithyroid medication, or reduction in
carbohydrate intake). Temporizing measures aimed at improving
HCO3 deficit (mEq) = Base excess × Wt (kg) × 30% alveolar ventilation may include bronchodilation, reversal of
narcosis, or respiratory stimulant administration (doxapram,
For the latter formula, half of the estimated dose is given and
caffeine). In a patient with moderate to severe acidosis (pH < 7.20),
another blood gas measured subsequently.
In lactic acidosis, the restoration of tissue perfusion will result CO2 narcosis, or respiratory fatigue, ventilatory support is
in metabolism of lactate by the heart, liver, and kidneys and indicated. In a patient with chronic respiratory acidosis who is
regeneration of HCO3, which will return to normal levels. In this accustomed to a higher than normal PaCO2, the aim should be to
situation, administration of HCO3 can give rise to an overshoot return PaCO2 to the “patient’s normal: level, because lowering it to
alkalosis. This is by contrast to some other organic acidoses (e.g., “normal” levels will result in a metabolic alkalosis.
diabetic ketoacidosis) in which a variety of organic acids with
different renal thresholds are produced. In some circumstances, Alkalosis
these acids may be excreted by the kidneys in the early stages of the The word alkalosis is best used to describe a situation tending to
disorder. Although this is helpful as a homeostatic response in the cause a rise in pH. An alkalemia is the correct term for a situation
short term, it can result in depletion of HCO3 substrate and a in which there has actually been a rise in pH. Alkalosis has a
persistence of metabolic acidosis when the shock and metabolic
number of clinically important effects related to its biochemical
disturbance have been corrected. In this particular circumstance,
and vascular effects. Alkalosis
the administration of HCO3 may be appropriate. However, the
disadvantages of HCO3 therapy are its unproven benefits and the 1. Increases peripheral vascular resistance and may precipitate
associated risks. The negative inotropic effects of acidosis are offset coronary vasospasm.
2. Shifts the oxyhemoglobin curve to the left, increasing If the cause of a metabolic alkalosis is unclear, a random urine
hemoglobin’s affinity for oxygen and potentially reducing chloride concentration can help identify possible sources. In
oxygen delivery to the tissues. chloride-sensitive alkalosis, the urinary chloride is typically less
3. Decreases cerebral blood flow. than 15 mmol/L, whereas in chloride resistant alkalosis, it is
4. Increases bronchial smooth muscle tone, but relaxes typically greater than 20 mmol/L.
pulmonary vascular resistance. Chloride-sensitive alkalosis is caused by chloride depletion
5. Results in hypokalemia caused by K+ movement into cells in resulting from loss by a number of routes including the GI tract,
exchange for H+. the kidney, or the skin (sweat). The mechanism whereby metabolic
6. Decreases ionized (Ca2+) because alkalosis increases the alkalosis develops is common to all. Normal tubular Na+ re-
number of plasma protein binding sites for Ca2+.
absorption is through the NKCC channel. This does not occur in
Alkalosis has implications for anesthesia related both to its the absence of luminal Cl–. Therefore, there is enhanced re-
direct effects and to the often concomitant hypokalemia. Alkalosis absorption of Na+ through exchange for K+ and H+ distally, leading
may prolong opioid-induced respiratory depression owing to inexorably toward metabolic alkalosis (and often hypokalemia).
enhanced protein binding. Augmentation of nondepolarizing GI loss of Cl– occurs through vomiting, nasogastric suction,
neuromuscular block is reported, and this may be an indirect villous adenoma, and the rare chloride diarrhea. In the case of
effect related to hypokalemia. Respiratory alkalosis can cause pyloric stenosis, there is loss of H+, Na+, and K+ in addition to Cl–
decreased cerebral blood flow especially in the presence of and ECF depletion. The kidney responds by avid absorption of
systemic hypotension. The combination of alkalemia and
tubular Na+, which can be done only at an accelerated rate of
hypokalemia is particularly arrhythmogenic and can produce
supraventricular and ventricular arrhythmias. exchange with H+, and K+ in the distal tubule, leading inexorably
to metabolic hypokalemic alkalosis. Congenital chloride diarrhea
METABOLIC ALKALOSIS: Metabolic alkalosis is by definition a is a rare, autosomal recessive condition characterized by an
primary elevation of plasma (HCO3–) with a tendency to an inability to transport chloride against an electrochemical gradient.
increase in pH. Metabolic alkalosis has the capacity to be self- Thus, chloride in the gut is unabsorbed, leading to a severe
sustaining after the inciting event resolves. This is attributable to osmotic diarrhea. There is typically a history of polyhydramnios
a chloride depletion, which impairs HCO3 excretion as explained
and prematurity. Symptoms of abdominal distention and watery
in the section on Metabolic Acidosis. It is precipitated by three
basic processes (Table 10–2): diarrhea begin in the first 2 weeks of life. Renal loss of Na+, K+,
and Cl– in response to diuretic therapy can precipitate a metabolic
1. Chloride depletion (“chloride-sensitive” alkalosis). alkalosis. In the initial stages, urinary chloride concentration will
2. H+ loss with enhanced mineralocorticoid effect (“chloride- be increased but subsequently decreased. If there is inadequate
resistant” alkalosis). dietary intake of chloride (e.g., an infant being fed formula
3. Excessive intake of alkali. containing Na+ but no Cl–), a metabolic alkalosis readily develops
because increased H+ or K+ secretion must accompany tubular
TABLE 10-2. Causes of Alkalosis reabsorption of Na+. Children with cystic fibrosis lose excessive
amounts of Na+ and Cl– in their sweat and can become Cl–- and
Causes of Metabolic Causes of Respiratory
volume-depleted in hot weather, leading to metabolic alkalosis.
Alkalosis Alkalosis
Chloride-resistant metabolic alkalosis includes a number of
Chloride-Sensitive Central Stimulation conditions in which there is increased renal excretion of H+ for
GI tract chloride loss Pain Na+ re-absorption as a primary event. Mineralocorticoid activity
Vomiting Anxiety enhances distal tubular Na+ absorption and K+ and H+ loss and,
Nasogastric suction Infection thus, promotes urinary acidification. This can be a primary event
Villous adenoma Fever independent of plasma rennin, as is the case with primary
Chloride diarrhea Drugs (e.g., salicylates) hyperaldosteronism, Cushing’s syndrome, and some types of
Renal chloride loss congenital adrenal hyperplasia. Alternatively, it may be due to
Peripheral Stimulation
Diuretic therapy increased plasma renin activity because of ECF depletion, renal
Hypoxemia
Renal response to respiratory artery stenosis, or Bartter’s syndrome. Bartter’s syndrome is an
High altitude
acidosis autosomal recessive syndrome caused by disturbed tubular
Severe anemia
Sweat chloride re-absorption. Except for severe hypokalemia and
Pulmonary disease
Chloride-Resistant Bartter’s syndrome, all of these are associated with ECF expansion
Iatrogenic and hypertension. It is frequently observed that hypokalemia and
Enhanced mineralocorticoideffect
Overventilation metabolic alkalosis occur together because many conditions
Primary hyperaldosteronism
Cushing’s syndrome precipitate both (e.g., chronic vomiting).
Congenital adrenal hypoplasia “Milk-alkali” syndrome, with excess alkali ingestion leading to
Increased plasma renin activity metabolic alkalosis, occurs less commonly in children than in
ECF depletion adults. Healthy kidneys are generally well able to cope with excess
Renal artery stenosis HCO3. When the renal threshold is exceeded, HCO3 leaks into the
Bartter’s syndrome urine and normal pH is restored (assuming the presence of
luminal Cl– to allow for HCO3– excretion). Nonabsorbable anions
Excessive Alkali Intake (e.g., carbenicillin) will cause continued HCO3– generation by the
“Milk-alkali” syndrome tubular epithelial cells as they bind to the H+ secreted into the
ECF = extracellular fluid; GI = gastrointestinal. luminal fluid, thus generating a metabolic alkalosis.
TREATMENT OF METABOLIC ALKALOSIS: As with metabolic TABLE 10-3. Age-Related Changes in Total Body Water
acidosis, the primary aim in the treatment of metabolic alkalosis
is correction of the underlying cause. Severe metabolic alkalosis Preterm Term 1–3 Y Adult
with (HCO3–) greater than 50 mmol/L is a rare occurrence, usually TBW, % of wt 85 80 65 65
seen only when there is prolonged loss of gastric juice, diuretic ECF, % of wt 55 45 25 25
therapy, or hyperadrenalism. In the case of chloride-sensitive ICF, % of wt 30 35 40 40
alkalosis, the treatment of choice is intravenous fluid replacement
with normal saline and potassium replacement with KCl. The ECF = extracellular fluid; ICF = intracellular fluid; TBW = total body water;
wt = weight.
amount of saline required is often calculated on the basis of a
From reference 16.
“chloride deficit”. In practice, the required amount of saline is that
volume that restores circulating volume and increases urinary
In the fetus during the first trimester, TBW accounts for more
chloride excretion to greater than 20 mmol/L. KCl is not an
appropriate fluid for total Cl– replacement because the rate of than 90% of weight, the greatest portion of this being in the ECF.
administration is limited to 3 mmol/kg/day. Metabolic alkalosis At term, approximately 56% of TBW is in the ECF. With increasing
associated with primary increases in mineralocorticoid activity is age, TBW decreases and the proportion of TBW as ECF decreases,
responsive to the aldosterone antagonist spironolactone or to so that by 3 years of age adult proportions are reached. The
direct inhibition of the aldosterone-mediated renal tubular Na+ movement of water between these compartments is dependent on
channel with amiloride. the concentration of osmotically active particles in each. This
movement occurs by osmosis. Osmosis is the movement of water
RESPIRATORY ALKALOSIS: Respiratory alkalosis is by definition across a semipermeable membrane because of a difference in the
a primary decrease in PaCO2. The mechanism is generally an concentrations of nondiffusible solutes on either side. The osmotic
inappropriate increase in alveolar ventilation relative to CO2 pressure is the pressure that must be applied to the side with more
production. The distinction between acute and chronic respiratory solute to prevent net movement of water. Osmotic pressure is
alkalosis is less obvious because the change in (HCO3–) is variable. dependent only on the number and not the nature of the particles.
Plasma (HCO3–) decreases 2 to 5 mmol/L for each 10 mmHg One mole of a substance is that amount that contains 6 × 1023
decrease in PaCO2 below 40 mmHg. Causes of respiratory alkalosis (Avogadro’s number) molecules of that substance. The weight of
include (1) central stimulation due to pain, anxiety, infection, fever, 1 mole of a substance in grams is that substance’s molecular
or drugs (salicylates); (2) peripheral stimulation of chemoreceptors weight. One osmole is the amount that will release that number of
from hypoxemia, high altitude, severe anemia, or pulmonary osmotically active particles in solution, which equals the
disease; and (3) iatrogenic from excessive mechanical ventilation. molecular weight divided by the number of active particles
TREATMENT OF RESPIRATORY ALKALOSIS: The treatment of produced, that is, 1 mole of NaCl produces 2 osmoles in solution.
respiratory alkalosis is essentially the treatment of the underlying A difference of 1 mOsm/L between two solutions will produce an
disorder. Severe alkalemia (pH > 7.6) has been treated with osmotic pressure of 19.3 mmHg across an intervening semi-
intravenous hydrochloride or ammonium chloride. permeable membrane. The osmolarity of a solution is the number
of osmotically active particles per liter of solvent, whereas the
osmolality of the same solution is the number of osmotically active
FLUID AND ELECTROLYTES particles per kilogram of solvent. In humans, the solvent is
essentially water with a density of 1 kg/L, which is why osmolality
Physiology and osmolarity are sometimes used interchangeably.
Despite large variations in daily intake of fluids and electrolytes,
the concentrations of these are maintained nearly constant by the
Regulation of Compartments
body. This fluid and electrolyte homeostasis is an essential
requirement for normal cellular and organ function. Fluid and Diffusion between the ECF and the ICF takes place across the cell
electrolyte disturbances are very common in the perioperative membrane by one of three methods: (1) diffusion directly through
period. Intravenous fluid therapy is often required to correct fluid the lipid bilayer of the cell membrane (e.g., O2, CO2, H2O, and
deficits and losses associated with surgery. The anesthesia provider lipid-soluble molecules); (2) movement through protein channels
should be familiar with the physiology of fluid and electrolyte (e.g., Na+, K+, and Ca2+); and (3) facilitated diffusion through
homeostasis, along with the management of the common abnor- transmembrane carrier proteins (e.g., glucose and amino acids).
malities. This is especially in the field of pediatric anesthesiology Fluid exchange between the ECF and the ICF is governed by the
where the physiologic capacity for coping with inappropriate fluid osmotic forces generated by the differences in nondiffusible solute
and electrolyte therapy is more limited. concentrations between the compartments. A relative change in
osmolality will result in movement of water from the hypo-
osmolar to the hyperosmolar compartment. If serum osmolality
Definition of Compartments
increases, as in diabetes insipidus, water will move from the ICF
The body is composed of 50 to 70% water by weight. The variation to the ECF to equalize osmolalities. Similarly, if the ECF osmolality
depends on the proportion of adipose tissue, which contains only decreases, as in the syndrome of inappropriate antidiuretic
10% water whereas muscle contains 75% water. Total body water hormone secretion (SIADH), water will move from the ECF to the
(TBW) varies inversely with age, and females have a lower TBW ICF. In this regard, potassium is the major determinant of ICF
than males. TBW is composed of ICF and ECF. The latter in turn osmolality and sodium is the major determinant of ECF
is composed of the interstitial space (ISS) and intravascular space
osmolality:
(IVS) fluid, separated by the capillary membrane. The age-related
changes in TBW and its distribution are shown in Table 10–3. (K+)ICF = ~140 mmol/L and (Na+) = approximately 140 mmol/L
Diffusion within the ECF, between the ISS and the IVS, takes TABLE 10-5. Factors Regulating the Secretion of
place across the capillary membrane. This can occur directly Antidiuretic Hormone
through the endothelial cell, as is the case for O2, CO2, H2O, and
lipid-soluble molecules, or through the 6- to 7-nm-wide inter- Stimulatory Inhibitory
cellular clefts, as is the case for low-molecular-weight molecules Narcotics Phenytoin
such as Na+, K+, Cl–, and glucose. Because proteins cross the Nicotine Alcohol
intercellular clefts poorly under normal circumstances, they are β-Adrenergic agents Narcotic antagonists
the osmotically active solutes involved in osmotic movement Anesthetic agents α-Adrenergic agents
across the capillary membrane. By contrast to the situation across Hypoxia
the cell membrane, the movement of water between the ISS and Hypercapnia Potentiate ADH Action
the IVS across the capillary membrane is governed by hydrostatic Vincristine Chlorpropamide
in addition to osmotic forces. There is generally a hydrostatic force Cyclophosphamide Aspirin
tending to force water out of the IVS at the arterial side of a Clofibrate
capillary bed and the opposite at the venous side. The normal Carbamazepine
functioning of this system is also dependant on the structural Barbiturates
integrity of the capillary membrane and the effective removal of
protein from the ISS by the lymphatic system. ADH = antidiuretic hormone.
From reference 11.
Regulation of Osmolality and Fluid Balance

than 1 pg/mL. At a plasma osmolality of 295 mOsm/kg water or
There is an intimate association between sodium and water greater, the plasma ADH concentration is maximal at greater than
balance that is important in the understanding of ECF osmolality
5 pg/mL. There are a variety of nonosmotic stimuli for ADH
and volume homeostasis. In essence, the body controls ECF
secretion including
volume by controlling the excretion of its dominant cation—
sodium—and controls osmolality (mainly (Na+)) by controlling 1. Hemodynamic causes such as hypovolemia and hypotension,
water intake and excretion. These two complementary mech- which are mediated through low-pressure atrial baroreceptors
anisms are summarized in Table 10–4 and dealt with in more and high-pressure carotid baroreceptors.
detail in the following sections. 2. Perioperative causes such as nausea, pain, anxiety, and
administration of opiate drugs.
OSMOREGULATION: Plasma osmolality is closely regulated by
3. Drugs (Table 10–5).
specialized neurones in the supraoptic and paraventricular nuclei
4. Pulmonary stimuli including pneumonia, bronchiectasis, and
of the hypothalamus. These osmoreceptors control the release of
mechanical ventilation.
ADH and the thirst mechanism. When the ECF osmolality
5. Febrile illnesses.
increases, these cells shrink and release ADH, which increases
6. CNS disturbances including head injury and infections.
water re-absorption at the renal collecting ducts, tending to reduce
7. Endocrine disturbances (e.g., hypoaldosteronism, hypo-
ECF osmolality. At a plasma osmolality of 280 mOsm/kg water or
thyroidism).
less, plasma ADH concentration is maximally suppressed to less
Neurons in the lateral preoptic area of the hypothalamus are
also very sensitive to changes in ECF osmolality, and activation of
TABLE 10-4. Regulation of Fluid Balance (Volume) these neurons by increased osmolality causes thirst. Because it
and Osmolality is the only mechanism that increases water intake, thirst is the
main protective mechanism against hyperosmolality and hyper-
Volume Regulation Osmoregulation
natremia. The thirst mechanism is operative only in those who are
Purpose Control ECF volume Control ECF able to increase their water intake, which is often not the case with
osmolality sick patients, especially in the pediatric age group.
Mechanism Vary renal Na+ excretion Vary water intake ECF volume and sodium concentration are regulated by a
Vary water excretion number of sensor and effector mechanisms. Although they are not
Sensors Afferent renal arterioles Hypothalamic generally regarded as such, the principal volume receptors in the
Carotid baroreceptors osmoreceptors body are in fact baroreceptors. Because blood pressure is the
Atrial stretch receptors product of cardiac output and systemic vascular resistance, signi-
Effectors Renin-angiotensin- Thirst ficant changes of intravascular volume (preload) also transiently
aldosterone Antidiuretic hormone affect blood pressure. Changes in pressure at the carotid barore-
Sympathetic nervous ceptors, as mentioned previously in the section on Regulation of
system Osmolality and Fluid Balance, modulate nonosmotic ADH release
Tuberoglomerular and, in addition, sympathetic nervous activity. Changes at the
balance afferent renal arteriole and macula densa modulate the renin-
Renal pressure angiotensin-aldosterone system. Changes at the atrial stretch
natriuresis receptors also modulate nonosmotic ADH release and atrial
Atrial natriuretic peptide natriuretic peptide release.
Antidiuretic hormone EFFECT OF ADH: In the face of disorders that threaten to cause
ECF = extracellular fluid. hyponatremia and cellular overhydration, the kidney will excrete
From reference 17. solute-free water and, conversely, will conserve solute-free water
when hypernatremia is threatened. In the proximal tubule, and adjusting this value depending on clinical circumstances and
water is reabsorbed primarily with solute absorption through the variables mentioned previously in this section. Until the
aquaporin-1 water channels. Some re-absorption of solute-free postnatal diuresis occurs, administration of salt-free dextrose
water takes place in the thin ascending limb of the LOH in solutions aiming to deliver 7 mg/kg/min of glucose to meet meta-
response to medullary hypertonicity. The TAL permits active bolic needs is recommended.12
solute absorption through the NKCC cotransporter, but is
INFANTS AND OLDER CHILDREN: Fluid therapy in children can be
impermeable to water. This process is vital because it is the basis
categorized as: maintenance, deficit, and replacement of losses
for the “diluting” segment of the nephron, and in addition, the
(please refer to the section on Deficits and Losses later in this
transport of solute from the medullary thick ascending limb of the
chapter). The quantity and type of maintenence intravenous fluids
loop of Henle (MTALH) generates the hypertonic medullary
prescribed for children has been the subject of some contro-
interstitium. This creates the osmotic gradient for absorption of versy.18–20 Traditionally, maintenance fluid requirements have
solute-free water. The maintenance of the hypertonic medulla been calculated with reference to the energy expenditure of the
is dependent on the delivery of Na+ and Cl– to the MTALH child. Heat loss is directly related to IWL and indirectly to the
and, in addition, the delivery of sufficient urea to allow the requirement for excretion of waste products in urine. For healthy
“countercurrent multiplier” to operate. children, Holliday and Segar calculated the relationships of calorie
ADH acts on the collecting duct via the V2 receptor, leading to expenditure to body weight and calorie expenditure to water
insertion of the aquaporin-2 water channel across the membrane requirement.21 Their calculation rendered the following estimates
of what is otherwise a water-impermeable section of the nephron. of energy expenditure: 100 cal/kg up to 10 kg; 50 cal/kg for each
Solute-free water re-absorption is thus permitted by the action of kilogram between 10 and 20 kg; and 20 cal/kg for each kilogram
ADH, driven by the medullary osmotic gradient. over 20 kg. Given that fluid requirement is roughly 100 mL/100 cal
expended, simple math leads approximately to the familiar “4:2:1:
or Oxford formula:
Fluid Management
4 mL/kg/h for the first 10 kg
Basic Fluid Requirements 2 mL/kg/h for the next 10 kg
NEONATES: Fluid homeostasis in newborn babies differs from that 1 mL/kg/h for each subsequent kilogram
in older children and adults because both fluid requirements
For example, a 15-kg child would require (4 mL × 10 kg ×
and excretion are substantially different in neonates. Fluid
24 h) + (2 mL × 5 kg × 24 h) = 1200 mL of fluid/day.
requirements in both term and premature babies are much greater
In addition to the fluid requirements, Holliday and Segar also
than those in older children owing to greater metabolism and
recommended electrolyte requirements based upon the electrolyte
growth and greater insensible water loss (IWL). IWL is greater in
constituents of cow’s and breast milk, arriving at a figure of 2 to
neonates because of the larger relative body surface area and as a
3 mEq/100 kcal/day of sodium and potassium, while acknowledg-
result of greater transepithelial water loss (TEWL) from the
ing that much greater loads could be readily handled by the
immature skin, which is deficient in stratum corneum, and from kidney.21 Given these calculations, 0.18% saline in dextrose
the immature respiratory tract. TEWL is increased by radiant became adopted as the maintenance fluid of choice for children
heaters and phototherapy units and decreased by adequate because using the “4:2:1” volumes, it delivers approximately the
humidification of incubators and inspired gases. Despite the recommended amount of sodium and enough glucose to prevent
inability of the immature kidney to concentrate urine, healthy ketosis. This approach works very well for healthy children. In sick
infants are able to maintain an adequate water balance over a wide children, however, there are many nonosmotic stimuli of ADH
range of intake once their insensible and obligatory urinary losses release, and especially so during the perioperative period. These
are covered. As discussed earlier in the section on the Definition patients retain electrolyte free water at the expense of excreting a
of Compartments, neonates have relatively greater ECF and TBW concentrated urine with a large sodium content.22,23 This becomes
volumes. As a result, newborns undergo a diuresis and natruresis dangerous when these patients have a source of electrolyte-free
in the first postnatal days.12 This is mediated by atrial natriuretic water continually added (80% of the volume of 0.18% is effectively
peptide and is part of the normal physiologic response that results electrolyte-free water). In the presence of this inappropriate ADH,
in the contraction of the ECF volume. The result of this is a nega- ECF sodium concentration gradually declines. Children can
tive sodium balance during these immediate postnatal days. become profoundly hyponatremic and continue to produce
A large number of complicated tables describe neonatal fluid hypertonic urine and retain free water owing to nonosmotic ADH
requirements as a function of weight and gestational age. Because secretion.24 This leads to our current recognition that the number
of the large number of variables that affect neonatal fluid balance, one cause of postoperative seizures is hyponatremia and the
a more physiologic approach seems sensible. The most useful number one cause of postoperative hyponatremia is the inappro-
parameters to monitor fluid balance in newborn babies are priate administration of hypotonic fluids.
weight, serum sodium concentrations, and urine output. Weight Hyponatremia principally affects the CNS because of
accurately reflects changes in water balance of neonates. Ideally, movement of water across the blood-brain barrier from the
weights should be monitored twice daily. Changes in serum plasma to brain neurons, glia, and interstitium, causing cerebral
sodium concentrations during the first days of life are sensitive edema. This is manifested clinically as a progression from con-
markers of dehydration and overhydration, respectively. Urine fusion and agitation to a reduced level of consciousness, seizures,
production should be monitored, with a target of 0.5 to 1 mL/kg/h. coma, and ultimately, herniation of vital brain structures and death
Adequate humidification of incubators and inspired gases is as plasma sodium concentration decreases. Children are especially
important. A reasonable approach to fluid administration in at risk from hyponatremia because they have larger numbers of
infants would entail the administration of 40 mL/kg/day initially brain cells per volume of cranium and they have proportionately
less skeletal muscle mass (in which ≤ 50% of body water is state or surgical problem likely to affect fluid status (e.g., bowel
located) than adults (see “Alternations in Serum Sodium Concen- obstruction, peritonitis, dialysis). Preoperative fasting can cause
tration,” later). significant dehydration and even hypoglycemia in children.
Many case reports have described morbidity and mortality in Assuming that a healthy child is in fluid and electrolyte balance
children related to maintenance fluid in the form of hypotonic at the onset of fasting, then the deficit incurred is that child’s
solutions at appropriate rates.19,25 Observational studies have calculated hourly requirement multiplied by the number of hours
shown that as many as 10% of general pediatric hospital admis- fasting. This is generally replaced, along with hourly maintenance
sions develop in-hospital hyponatremia, with the majority of these fluid, as one half during the first hour and one half over the next
due to electrolyte-free water administration in the setting of 2 hours.
increased ADH.26 Administration of isotonic saline is associated Data are conflicting about the need for glucose in the
with a more rapid normalization of plasma ADH levels in sick perioperative period. Early work has shown that hypoglycemia
children than hypotonic fluids.27 Three randomized, controlled may occur in children younger than 4 years who are fasted for
trials have compared the administration of hypotonic and isotonic 6 hours.32 Others have failed to show hypoglycemia in children
fluids for maintenance in children.27–29 Children undergoing fasted for 6 to 8 hours.33,34 Preterm infants, conversley, should be
surgery tend to exhibit a decrease in serum sodium concentration monitored for hyperglycemia because their kidneys are less well
in the first 24 hours postoperatively. Those given hypotonic saline able to hyperfiltrate glucose in hyperglycemia.35,36
decrease their serum sodium concentration substantially more (an Children who are permitted to drink clear fluids until 2 to
average 4.5 mmol/L) than children who received isotonic fluids. A 3 hours before elective anesthesia have residual gastric volumes
systematic review of six studies has demonstrated both the and pH similar to those fasted for longer periods. The shorter
tendency of hypotonic fluid administration to produce hypo- fasting periods are advantageous in that children are less thirsty,
natremia and the safety of isotonic saline in medical and surgical have a better perioperative experience, and have improved
pediatric populations.30 No cases of hypernatremia in children compliance.36–38 Clinical practice has changed to incorporate
treated with isotonic saline were reported, confirming the ability shorter pediatric fasting guidelines.39
of the pediatric kidney to maintain sodium homeostasis. As a Whereas the estimation of fluid deficit on the basis of fasting
result of these articles, it has been suggested that hypotonic fluids time and hourly requirement may be sufficient in elective cases, an
be abandoned in the acutely ill or perioperative pediatric patient assessment of hydration status is usually required in the case of
to be replaced by isotonic saline solutions with or without any disease process associated with increased fluid requirements
glucose.19,31 or losses (e.g., vomiting, diarrhea, pyrexia). Some of these may
It has been suggested that children at risk for nonosmotic also merit specific assessment of electrolyte status, which is dealt
secretion of ADH should be prescribed intravenous fluids at with further in the section on Deficits.
decreased infusion rates. In the presence of ADH, the kidneys Assessment of hydration is largely on the basis of clinical signs
retain water, and hence, requirements are reduced. However, with laboratory measurements as indicated in Table 10–6.
when compared with traditional infusion regimens, this approach In children, it is important to note that the compensatory
does not appear to influence serum sodium concentration, and response to hypovolemia is largely through increased heart
therefore, such fluid restriction is not necessary, especially in the rate because the ability to increase stroke volume as a means to
postoperative setting.29 increase cardiac output is a later development. Peripheral vasocon-
Further adjustments must be made to maintenance fluid striction generally maintains blood pressure within a normal range
requirements in children according to the clinical context. For except until severe hypovolemia is present. Hence, hypotension is
example, an increase in free-water requirement is necessary in the a late and ominous sign of hypovolemia, suggesting imminent
following circumstances: decompensation and requiring immediate treatment.
1. Pyrexia, which increases requirements by 12% per degree
centigrade above 37.5°C. Losses
2. Sweating, which increases requirements by 10 to 25%. INTRAOPERATIVE THIRD SPACE LOSS: Intraoperative losses are
3. Hypermetabolic states (e.g., hyperthyroidism, salicylism, and subdivided into third space loss and blood loss. Surgical trauma,
burns) in which requirements increase by 25 to 75%. blunt trauma, infection, burns, and many of the surgical condi-
4. Radiant heat or phototherapy, which increases requirements tions that bring the pediatric patient to operation are associated
increase by 25%. with the isotonic transfer of fluid from the ECF to a nonfunctional
interstitial compartment. This is called third space loss. If such
A decrease in water requirements is necessary in the following sequestration of fluid continues without replacement, the plasma
circumstances: volume will become depleted. Third space loss is impossible to
1. Hypothermia, in which requirements decrease 12% per degree measure, and therefore, it must be estimated by the extent of the
centigrade below 37.5 °C. surgery and the clinical response to appropriate fluid replacement.
2. Edematous and antidiuretic states. The magnitude of third space loss is usually highest in infants
undergoing intra-abdominal procedures and least in those under-
going superficial surgery or neurosurgery. Approximate ranges are
Deficits shown in Table 10–7. Because replacement of sequestered plasma
In addition to providing for maintenance requirements, peri- volume is the aim, Ringer’s lactate, normal saline, or some other
operative fluid therapy needs to address any preexisting deficits isotonic fluid is an appropriate replacement fluid. The clinical
in water and electrolytes. The preoperative assessment must response to appropriate replacement is a sustained and adequate
include a history of the duration of fasting; presence and duration blood pressure and heart rate, adequate tissue perfusion, and a
of fever, vomiting, diarrhea, sweating; and the particular disease urine output of 1 to 2 mL/kg/h.
TABLE 10-6. Signs and Symptoms of Varying Degrees of Dehydration

Signs and Symptoms Mild Moderate Severe
Weight loss, % 5 10 15
Deficit, mL/kg 50 100 150
Vital signs
Pulse Normal ↑, Weak ↑↑, Feeble
Blood pressure Normal Normal/low Reduced, orthostatic
Respiration Normal Deep Deep and rapid
Appearance Thirsty, restless, alert Thirsty, restless, or lethargic but Drowsy to comatose, limp, cold sweaty,
rousable, pale gray/cyanosed
Skin turgor Normal ↓ ↓↓
Anterior fontanelle Normal Sunken Markedly depressed
Mucous membranes Moist Dry Very dry
Urine
Flow (mL/kg/h) <2 <1 <0.5
Specific gravity 1.020 1.0202–1.030 >1.030
INTRAOPERATIVE BLOOD LOSS REPLACEMENT: Pediatric patients TABLE 10-8. Estimated Blood Volume in Pediatric Patients
undergoing major surgery including organ transplantation, cardiac
surgery, trauma surgery, or major burn surgery invariably require Age EBV, mL/kg
blood volume replacement. The indications for when replacement Premature neonate 90–100
with blood components is necessary are not always clear or Term neonate 80–90
well-defined. It is imperative that the anesthesia provider has a 3 mo–1 y 75–80
preoperative plan regarding blood loss replacement, based on the 3–6y 70–75
patient’s preoperative condition, preoperative hematocrit, and >6 y 65–70
nature of the surgery. The concept of an allowable blood loss (ABL)
EBV = estimated blood volume.
is a useful approach to planning when blood products are indicated.
Blood loss is typically replaced with a nonglucose-containing
crystalloid such as Ringer’s lactate with 3 mL administered for every about to be exceeded. Subsequently, ongoing losses in excess of
1 mL of blood lost. This is done to achieve, in effect, normovole- ABL must be appropriately replaced with blood to maintain the
mic hemodilution to a predetermined hematocrit. The lowest desired hematocrit. Because the hematocrit of the red cell
hematocrit that is acceptable has not been defined. It clearly varies concentrate (RCC) is approximately 60 to 75% depending on the
with the patient’s preoperative medical state and the anticipated anticoagulant that is used, 0.5 mL/1 mL blood loss is generally
postoperative course. Generally, a hematocrit of 28 to 30% is adequate. Concurrent crystalloid or colloid administration is
acceptable, although in the case of neonates, a value of 40% is more necessary to maintain intravascular volume. This may include
appropriate and lower values down to a hematocrit of 18% may be either colloid, 0.5 mL/mL RCC, or crystalloid, 1.5 mL/mL RCC.
acceptable in some patients. In determining ABL, an estimate of As a rule of thumb, 1 mL/kg of RCC will raise the hematocrit by
blood volume (EBV) must first be made (Table 10–8). Using EBV approximately 1.5%. The management of major transfusion and
and the patient’s original hematocrit (Ho), the ABL can be calculated blood component therapy is dealt with in chapter 53 and 54.
from the following formula:
ABL = Wt × EBV × (Ho – Hl)/Ha. Electrolyte and Fluid Disorders:
where Hl is the lowest acceptable hematocrit and Ha is the Pathophysiology and Management
average of H1 and Ho ((Ho + Hl)/2). Alterations in serum sodium concentration
Intraoperative blood loss is replaced with isotonic crystalloid
such as Hartmann’s solution or Ringer’s lactate at a rate of 3 mL/1 As previously discussed in the section on Fluid and Electrolytes,
mL blood loss, or a milliliter for milliliter volume of isotonic the regulation of plasma volume and plasma osmolality are linked
colloid solution such as 5% albumin, until the ABL is exceeded or in such a way that it is generally more appropriate to view altera-
tions of serum sodium as disorders of water balance rather than of
sodium balance. Disturbances of both water and sodium homeo-
TABLE 10-7. Estimation of Third Space Losses stasis are common in pediatric practice. Pure sodium deficiency is
in Pediatric Patients rare, the occurrence in association with a water deficit being the
Estimated Third Space norm. With sodium deficiency, the ECF is invariably depleted with
Procedure Loss, mL/kg/h appropriate signs and symptoms of same, as outlined in the section
on Regulation of Compartments.
Intra-abdominal surgery 6–10
Intrathoracic surgery 4–7
HYPONATREMIA: Hypo-osmolality is usually associated with
hyponatremia, but in some situations, hyponatremia does not
Eye surgery/neurosurgery/ 1–2
necessarily reflect hypo-osmolality, which must be considered in
superficial surgery
the approach to a patient with a “low serum sodium” (Figure 10–10).
Figure 10-10. Etiology and pathology

of plasma hypo-osmolality. ECF =
extracellular fluid; SIADH = syndrome
of inappropriate secretion of antidiuretic
hormone.
In the evaluation of the patient with hyponatremia, various false osmolality. In the case of extrarenal losses, the renal response is
causes of a low serum sodium must be ruled out. With factitious production of a concentrated urine with low urinary (Na+).
hyponatremia, a fluid shift occurs between ICF and ECF as a result Sources of extrarenal loss include (1) GI loss (diarrhea, vomiting,
of an increase in ECF osmolality by impermeate solutes such as fistulae, nasogastric aspirate, or ileostomy output; (2) third space
glucose or, mannitol or toxins such as alcohol, methanol, or loss (ileus, ascites, burns, peritonitis); or (3) skin (excessive
ethylene glycol. In factitious hyponatremia, the plasma osmolality sweating).
is high and is the difference between measured osmolality In the some salt-losing states, hypovolemia will develop but the
and calculated osmolality (2 × ([(Na+) + (Urea) + (Glucose)]) > normal renal conservation of sodium will not occur, with urine
10 mOsm/kg) except in the setting of hyperglycemia.40 (Na+) remaining high. In addition, urine volume will be main-
Pseudohyponatremia results from an increase in the non- tained for relatively longer, allowing the potential development of
aqueous portion of plasma. This may occur in hyperlipidemia, profound salt and water deficit. These situations include diuretics,
hyperproteinemia, or glycine absorption in transurethral surgery. mannitol, glucosuria, RTAs, salt-losing nephropathies, mineralo-
In these cases, the sodium concentration expressed as millimoles corticoid deficiency, postobstructive dieresis, and the diuretic
per liter of plasma (as opposed to millimoles per liter of plasma phase of acute tubular necrosis (ATN).
water) will be low. In such pseudohyponatremias, the measured
HYPONATREMIA WITH NORMAL TOTAL BODY SODIUM: Hypo-
osmolality is usually normal, but there is again a discrepancy
natremia without the features of either ECF depletion or excess is
between the measured and the calculated osmolality of greater
seen in situations in which the primary disorder is mainly water
than 10 mOsm/kg.40
retention in the absence of sodium retention, with the excess water
In true hyponatremia, plasma osmolality will be low (<285
being distributed equally between the ECF and the ICF. It may be
mOsm/kg), due to either a loss of salt in excess of water or a gain
seen with glucocorticoid insufficiency, hypothyroidism, drug
in water in excess of salt. An assessment of ECF volume status will
therapy, reset osmostat, and the SIADH. SIADH is the most
differentiate the causal groups.
common euvolemic hypotonic condition and is defined as the
HYPONATREMIA WITH LOW TOTAL BODY SODIUM: Progressive presence of hyponatremia and hypo-osmolality in normotensive,
loss of both salt and water will lead to symptoms and signs of ECF normovolemic, nonedematous patients without renal, hepatic,
depletion. As intravascular deficit reaches 5 to 10%, nonosmotic adrenal, thyroid, or cardiac dysfunction. The levels of ADH
ADH release is triggered and takes precedence over any (arginine vasopressin) are inappropriately high for the osmolality
hyponatremia-induced suppression of ADH because preservation of the blood and are not suppressed by further hydration and
of intravascular volume takes place at the expense of plasma dilution of body fluids. The urine is not maximally dilute despite
Increase in ADH
Positive balance of Relative increase

solute-free water in urine osmolality
Increase in TBW and Hyponatraemia,

ECF reduced plasma
osmolality, and
increased ICF
Reduced plasma Increased GFR Reduced urea and

aldosterone creatinine Figure 10-11. Sequence of events of
the mechanism of the syndrome of
inappropriate antidiuretic hormone
secretion (SIADH). ADH = antidiuretic
hormone; ECF = extracellular fluid;
GFR = glomerular filtration rate;
Increased urinary
sodium excretion ICF = intracellular fluid; TBW =
total body water.
plasma hypo-osmolality. A sequence of events for the mechanism total body sodium. When the increase in water is greater than that
of SIADH is shown in Figure 10–11. of sodium, hyponatremia will result. In hypoproteinemic states,
Causes of SIADH in children may be divided into CNS, pul- such as the nephrotic syndrome or chronic malnutrition, the
monary, and malignant etiologies. CNS causes include infection reduced plasma oncotic pressure permits movement of fluid from
(encephalitis, meningitis, or intracranial abscess), hypoxia or the IVS to the interstitial space ISS. This reduction in effective
ischemia, cerebral vascular accidents, primary or secondary CNS circulating volume results in enhanced renal tubular re-absorption
malignancy, Guillain-Barré syndrome, and cerebral malforma- of sodium and water in an attempt to correct the hypovolemia, but
tions. Pulmonary causes include infection (abscess, pneumonia, because of the reduced oncotic pressure, the retained water and
tuberculosis, aspergillosis), positive-pressure ventilation, atele- sodium continue to expand the ISS. Cardiac insufficiency or
ctasis or pneumothorax in the newborn, hyaline membrane hepatic insufficiency with ascites will also create the situation of a
disease, and cystic fibrosis. Malignant causes include Hodgkin’s reduced effective circulating volume with retention of sodium and
disease, lymphosarcoma, thymoma, GI tract carcinoma, leukemia, water. All of these conditions produce hyponatremia by similar
and lung carcinoma. mechanisms with decreased “effective arterial volume” leading to
Hyponatremia due to SIADH is uncommon in premature and decreased GFR with increased proximal tubular fluid absorption,
term infants younger than 6 weeks because of factors that limit further enhanced by increased renal sympathetic tone. There is
the urinary concentrating ability to less than 600 mOsm/kg. These decreased filtrate delivery to the MTALH-diluting segment. The
include low dietary sodium intake, low ADH levels, and reduced
apparent decrease in effective arterial volume is also a potent
tubular sensitivity to ADH.41–43 Antidiuretic drugs can induce
nonosmotic stimulant of ADH release. All of these derangements
hyponatremia by causing inappropriate ADH release, potentiating
impair the ability to excrete solute-free water. The renal response
its action, or by impairing solute-free water excretion independent
of ADH. For example chlorpropamide increases ADH release and will be to produce small volumes of concentrated urine with
enhances its effect on the renal tubule; carbamazepine increases urinary (Na+) less than 20 mmol/L.
ADH release without a direct tubular effect; and oxytocin mimics In the case of acute or chronic renal failure, a hypo-osmolar
ADH in its effect on the renal tubule. intake will result in hyponatremia. There will be expansion of the
Reset osmostat refers to a state of chronic asymptomatic ECF with edema and hypervolemia. Urine volume is usually
hyponatremia that may be seen in malnutrition or chronic illness. reduced with urinary (Na+) greater than 20 mmol/L. Urine and
In these states, the level of osmolality that triggers ADH release is plasma osmolality are similar, with plasma osmolality maintained
lowered below 285 mOsm/kg.44 Normal response to fluid or by increased urea despite hyponatremia.
sodium load is retained. CLINICAL MANIFESTATIONS OF HYPONATREMIA: Apart from
Compulsive water drinking with chronic water excess as a symptoms relating to the volume disturbance associated with
cause of hyponatremia is rare in childhood, but may occur some of the causes of hyponatremia just outlined, the symptoms
in adolescents as part of a behavioral disorder or psychiatric relating to the hyponatremia itself are largely confined to the CNS
condition. It is similar to SIADH in that the water excess is
and result from increased intracellular water. The severity of
distributed between ECF and ICF so that signs of volume overload
symptoms is related to the severity of the hyponatremia and the
are rarely seen.
rapidity of the change in serum sodium. Children with mild to
HYPONATREMIA WITH INCREASED TOTAL BODY SODIUM: moderate hyponatremia, (Na+) greater than 125 mmol/L, are fre-
Edematous disorders are characterized by an increase in TBW and quently asymptomatic. Early symptoms are generally nonspecific
including irritability, headache, anorexia, weakness, and depressed (12 mL/kg/h) until (Na+) is greater than 125 mmol/L, followed by
tendon reflexes. Serious manifestations are associated with (Na+) slower correction with normal saline over 24 to 48 hours.
less than 120 mmol/L. These include progressive cerebral edema Alternatively, a single bolus dose of 3% saline (3 mL/kg) can be
leading to confusion, lethargy, seizures, coma, and death. Slowly administered over 5 to 10 minutes for patients with symptomatic
developing or chronic hyponatremia is generally less symptomatic, hyponatremia (seizures). There is some concern that overrapid
because a progressive compensatory loss of intracellular solutes correction of hyponatremia can lead to neurologic deterioration
(Na+, K+, and amino acids) restores cell volume to normal. through development of central pontine myelinolysis and
demyelination of extrapontine myelinated neurons, which is the
ANESTHETIC IMPLICATIONS OF HYPONATREMIA: Hyponatremia rationale for slower correction of hyponatremia once a level of a
is often a manifestation of a serious underlying problem and, as serum sodium concentration above 125 mmol/L has been
such, merits careful preoperative assessment. Levels of (Na+) achieved.
greater than 130mmol/L–1 are generally considered safe for general
anesthesia; for elective procedures, the sodium level should be HYPERNATREMIA AND HYPEROSMOLALITY: Hypernatremia is by
corrected to at least this level. Lower levels may result in cerebral definition a plasma (Na+) greater than 150 mmol/L. It reflects a
edema that could manifest intraoperatively as a decrease in relative excess of salt relative to water but, importantly, does not
minimum alveolar concentration (MAC) or postoperatively as reflect total body sodium thath may be normal, high, or low.
agitation, confusion, or drowsiness. Hypernatremia is nearly always the result of either loss of water
in excess of sodium or, less commonly, retention of sodium.
TREATMENT OF HYPONATREMIA: The management of
Generally, even when renal concentrating ability is impaired, the
hyponatremia is dependent on the severity, rapidity of onset, and thirst mechanism is highly effective in preventing hypernatremia,
duration of the hyponatremic state. Although a detailed disease- but in the case of infants or debilitated children, this may not be
specific description of therapies is beyond the scope of this functional or the patients may not be able to gain access to water.
chapter, a summary of the basic approach to the correction of Hypernatremia will cause hyperosmolality of the ECF so that the
hyponatremia relating to these disease categories follows. volume of this compartment is well maintained at the expense of
In hyponatremia with reduced total body sodium, as in extra- the ICF, which bears the brunt of the fluid deficit. Relative
renal losses of salt and water and renal or extrarenal salt-losing preservation of the ECF volume will also, to some degree, mask
states, an ECF volume deficit needs to be replaced and a sodium the classic signs of dehydration and hypovolemia.
deficit. The sodium deficit may be calculated as: Premature infants and neonates have an inability to excrete a
Na+ deficit (mmol) = TBW × (Desired (Na+) – Present (Na+) sodium load45,46 because of reduced GFR and a tubular inability
to increase fractional excretion of sodium (FENa). Although several
If dehydration is significant, an initial resuscitation phase is conditions cause hypernatremia, the two primary mechanisms are
frequently required. Isotonic fluid such as normal saline is either (1) loss of water in excess of sodium or (2) gain of sodium
appropriate, at rates of 5 to 10 mL/kg/30–60 min until hemo- in excess of water. The assessment of hypernatremia is shown
dynamic parameters indicate adequate resuscitation. More rapid in Figure 10–12. Loss of water in excess of sodium may occur
administration is indicated if there is end-organ evidence of because of (1) extrarenal losses (diarrhea, vomiting, hyperventi-
hypoperfusion. The fluid deficit should then be replaced with lation, or pyrexia); (2) inadequate intake; or (3) renal losses
normal saline, with appropriate maintenance fluids additionally, (diabetes insipidus, hyperglycemia, or an osmotic diuresis).
aiming to correct the fluid and sodium deficit over a 24-h period.
Hyponatremia with excess total body sodium, as in the EXTRARENAL WATER LOSS: In pediatric practice, the most
edematous conditions just discussed, is treated primarily by salt common presentation of hypernatremia is as hypernatremic
and water restriction with diuretic therapy. In hypoproteinemic dehydration, typically from viral gastroenteritis. Although the
states, the infusion of a 25% albumin solution in addition to the water loss may be greater than isotonic or hypertonic losses, the
diuretic therapy may help preserve the intravascular volume, signs of dehydration may be less, as explained previously in the
increase intravascular colloid osmotic pressure, increase the section of Fluid and Electrolytes. The situation may be exacerbated
efficacy of the diuretic therapy, and hasten the resolution of the by concomitant poor free water intake and inappropriate high-
edema. solute feeding. Less commonly, the same situation may arise as a
In euvolemic hyponatremic states, the decision as to how to result of insensible respiratory tract losses with respiratory tract
correct the sodium level is based on the clinical symptoms and the infection or insensible skin losses in pyrexia.
rapidity with which the disorder developed. It is desirable to INADEQUATE INTAKE: The thirst mechanism is, under normal
prevent symptoms by bringing the sodium concentration above circumstances, a potent line of defense against hypernatremia. In
125 mmol/L. In general, hyponatremia with a serum sodium infants who are unable to get water for themselves, comatose or
concentration above 125 mmol/L should be corrected in the same debilitated patients, or those with hypodypsia because of a lesion
amount of time as it took to develop. In SIADH, the basis of affecting the thirst center, hypernatremic dehydration develops.
treatment is the creation of a negative water balance at the same An appropriate renal response is seen, with small volumes of
time as treating the underlying cause. Asymptomatic or mildly
concentrated urine.
symptomatic patients should be treated by water restriction to
between one half and two thirds of maintenance requirements. If RENAL WATER LOSS: Increased loss of solute-free water due to
water restriction does not hasten the correction of hyponatremia, impaired urinary concentrating ability occurs in the setting of an
intravenous loop diuretics may be added to increase free water inadequate response to appropriate ADH levels or an inadequate
clearance. Urinary sodium and potassium losses should be secretion of ADH. In both of these instances, there is an
monitored and replaced. For severe symptoms of water inappropriately low urine osmolality in the face of increased
intoxication, 3% saline may be given at a rate of 6 mmol/kg/h plasma osmolality and hypernatremia. Central diabetes insipidus
Figure 10-12. Assessment of hyper-

natremia
encompasses a number of disorders in which there is decreased of response to exogenous ADH in the form of 1-deamino-(8-D-
central release of ADH (Table 10–9). Nephrogenic diabetes arginine) vasopressin (DDAVP), and to water deprivation. A water
insipidus includes a number of clinical situations characterized by deprivation test is not without risk and is contraindicated in the
an impaired tubular response to ADH (see Table 10–9). setting of hypernatremia. DDAVP in a dose of 2 μg/m2
Polyuria is the hallmark of these disorders. In the older child, intravenously or 20 μg/m2 intranasally should produce an increase
polyuria may manifest as nocturia, nocturnal enuresis, thirst, or in urine osmolality to greater than 800 mOsm/L after 4 hours, if
polydipsia. However, in an infant, polyuria may go unnoticed. the renal response to ADH is intact. In a normally hydrated
These patients are at greater risk than older patients for hyper- normonatremic patient, a water deprivation test may be per-
natremic dehydration. Typical presentation includes nonspecific formed. The aim is to measure urine and plasma osmolality during
signs such as failure to thrive, developmental delay, irritability, 6 to 8 hours of water deprivation or until 3% body weight loss is
frequent feeding requirements, constipation, and unexplained lost. The test is abandoned if a normal urine osmolality response
pyrexia. of greater than 800 mOsm/L is found. If this does not occur,
When diabetes insipidus is suspected, normal renal function, DDAVP is administered at the end of the deprivation period. In
normal plasma calcium and potassium, and normal urinary tract central diabetes insipidus, the urine osmolality will subsequently
ultrasound should first be confirmed. The diagnosis is on the basis rise to greater than 800 mOsm/L, whereas in nephrogenic diabetes
insipidus, the urine osmolality will remain unchanged.
Hyperglycemia associated with diabetic ketoacidosis or exces-
TABLE 10-9. Etiology of Diabetes Insipidus sive glucose administration can cause hypotonic fluid loss by
Central Nephrogenic osmotic diuresis. In diabetic ketoacidosis, there may be unre-
cognized hypernatremia contributing to the hyperosmolality
Head trauma Congenital caused by hyperglycemia, because an increase in the blood glucose
Intracranial tumor Hypocalcemia of 5 mmol/L should lower the measured sodium concentration by
Intracranial hemorrhage Hypokalemia 2.5 mmol/L owing to fluid shift into the ECF. Calculation of
CNS infection Reflux nephropathy corrected (Na+) is by the following formula47:
Idiopathic Obstructive nephropathy
Postneurosurgical procedure Fanconi’s syndrome (Na+)corrected = (Na+)measured + (2.5 mmol/L
Sickle cell nephropathy for each 5 mmol/L glucose over normal)
Polycystic nephropathy Hypernatremia in the absence of a fluid deficit is unusual. It
Chronic renal failure can be iatrogenic in the case of inappropriate intravenous fluid
Drugs (lithium/rifampin) therapy (hypertonic saline or sodium HCO3 or incorrect reconsti-
CNS = central nervous system. tution of feed). Sea water ingestion can also cause hypernatremia.
Disorders associated with mineralocorticoid excess such as nocturnal nasogastric fluid for infants, are the first line of therapy.
Cushing’s or Conn’s syndrome may result in hypernatremia Measures to reduce the daily urinary volumes include dietary
and edema. measures such as a low-sodium and -protein diet,and medications
Neurologic symptoms predominate in patients with hyper- such as hydrochlorthiazide and indomethacin.
natremia, with any fluid deficit being less evident. Restlessness,
lethargy, and hyperreflexia can progress to seizures, coma, and Alterations in Serum Potassium Concentration
ultimately, death. Neurologic manifestations develop by two main
methods. First, symptoms are thought to relate to cellular Potassium in the body plays a major role in the electrophysiology
dehydration and the severity correlates more closely with the rate of cell membranes as well as carbohydrate and protein synthesis.
of movement of water out of brain cells than with the absolute level The resting membrane potential of all cell membranes is depen-
of sodium. Focal intracerebral hemorrhage or subarachnoid dent on the ratio of intracellular to extracellular potassium
hemorrhage may develop when the osmolar gradient develops concentration. Intracellular potassium concentration is approxi-
rapidly.48 Second, neurologic manifestations may be precipitated mately 140 mmol/L, whereas extracellular potassium is approxi-
by treatment. This is because of the development of idiogenic mately 4 mmol/L. Changes in ECF (K+) can be mediated by
“osmoles,” notably the amino acid taurine, during prolonged alterations in intake, loss of potassium, or changes in ECF/ICF
hypernatremia. These idiogenic osmoles have a protective effect distribution. The intracellular/extracellular (K+) ratio is dependent
and return brain water to normal.49 Thus, during rehydration of on the activity of the membrane Na+/K+-ATPase, which is affected
chronic hypernatremic dehydration and the return of serum by H+ balance, plasma tonicity, plasma insulin, epinephrine, and
sodium to normal values, there is a slower decline in the intra- aldosterone concentrations. The kidney is the major excretory
cellular decline of these idiogenic osmoles and, therefore, a organ for potassium. Urinary potassium is predominantly derived
marked brain avidity for water with the potential development of from distal tubular secretion because over 90% of proximally
cerebral edema. Other clinical features of hypernatremia include filtered K+ is re-absorbed. Secretion occurs in the principal cells of
hypocalcemia and hyperglycemia, the etiology of which is obscure. the middle and late distal tubule and the cortical collecting duct.
In animal studies, hypernatremia increases the MAC for Potassium secretion is enhanced by increased distal tubular
volatile anesthetic agents, but in clinical practice, the associated sodium delivery, reduced distal chloride delivery, mineralo-
fluid deficits are more likely to be of significance. Any hypo- corticoid activity, and alkalosis. A useful determination is the
volemia will accentuate the hypotensive effects of the vasodilation urinary Na+/K+ ratio, which is normally between 1 and 4, the
or cardiac depression of anesthetic agents. Similarly, the volume of higher figure being seen in premature infants. In pediatric prac-
distribution for intravenous drugs will be reduced, necessitating tice, it is important to be aware of the age-related changes in
dose reductions. Elective surgery should be postponed in patients plasma (K+) (Table 10–10).
with (Na+) greater than 150mmol/L until a cause is established and HYPOKALEMIA: Hypokalemia is defined as a plasma (K+) less than
both isotonic and water deficits replaced. 3.5 mmol/L. It is produced by either (1) total body potassium
The approach to the treatment of hyponatremia is based on deficiency (inadequate intake, extrarenal loss, renal loss) or
determining the etiology and addressing this as well as correcting (2) redistribution (alkalosis, familial periodic paralysis, insulin
the fluid deficit. Regardless of the etiology, in the presence of a administration, drugs, toxins). Pseudohypokalemia is a situa-
circulatory deficit, initial management must be resuscitation with tion that has been described when blood samples from leuke-
isotonic saline to restore vital signs and urine output. Restoration mic patients with exceedingly high white blood cell counts
of normal hydration and sodium concentration should then take (=100,000/mm3) are not promptly separated into plasma and
place over at least 48 hours. This should be extended to 72 hours cellular components before estimation of plasma (K+). In such
with (Na+) greater than 170 mmol/L. Coexisting potassium deficit circumstances, the ongoing uptake of K+ by the white blood cells
or metabolic acidosis should also be addressed. During therapy, when samples are left standing at room temperature gives a
plasma sodium levels should be closely monitored so that serum spurious impression of hypokalemia.50
sodium is not allowed to fall faster than 0.5 mmol/L/h. Oliguria on
the initial assessment, in the absence of circulatory impairment, HYPOKALEMIA ASSOCIATED WITH TOTAL BODY POTASSIUM DE-
should prompt determination of urinary (Na+) to confirm that the FICIENCY: Because of the kidney’s ability to decrease urinary (K+)
oliguria is purely volume related, in which case, the urine (Na+) to as low as 5 to 20 mmol/L and potassium’s ubiquitous presence
will be less than 20 mmol/L. Other features consistent with pre- in foods, a deficient diet alone seldom causes symptomatic
renal oliguria may also present. A fluid challenge is then appro- hypokalemia. However, inadequate intake in association with
priate in such patients to reverse intravascular dehydration. obligatory physiologic renal and GI tract losses, accentuated by a
Persistent oliguria is suggestive of possible renal vein thrombosis,
a complication of hypernatremia often associated with hematuria,
thrombocytopenia, and renal enlargement. TABLE 10-10. Age-Related Changes in Potassium
Central diabetes insipidus is treated by aerosolized DDAVP Age Plasma K+ concentration, mmol/L
administered nasally along with regulated water intake to prevent
hypernatremia. In patients with proven central diabetes insipidus, 30–32 wk 6.5 ± 0.5
administration of aerosolized DDAVP at a dose of approximately 33–35 wk 5.6 ± 0.2
20 μg/m2 will correct the urinary concentration defect. Dose and 36–38 wk 5.3 ± 0.3
water intake need to be individualized to avoid hyponatremia. The 39–41 wk 5.1 ± 0.2
management of nephrogenic diabetes insipidus aims to prevent 1–12 mo 5.0 ± 0.5
dehydration and hypernatremia while reducing the fluid intake to 2–20 y 4.3 ± 0.4
tolerable levels. Freely offered fluids as dictated by thirst, with From reference 16.
high sodium intake, may cause a relative deficit. Such a deficit may mediated activation of the Na+/K+-ATPase. This is mediated
be symptomatic in a patient maintained on potassium-free through β2 receptors in most tissues except the heart in which β1
intravenous fluid, in protein-calorie malnutrition, or in infants fed receptors mediate K+ uptake. Conversely, α-adrenergic receptor
inappropriate formulas. activation increases (K+) by reducing muscle uptake and pro-
In children and infants, the most common cause of hypo- moting hepatic release. Toxicity from barium salts, theophylline,
kalemia is secondary to acute or chronic GI tract losses. Diarrheal and toluene also cause intracellular K+ shift with hypokalemia.
potassium losses may be marked, as may upper or lower GI Hypokalemic periodic paralysis is a rare, autosomal dominant
fistula/stoma losses and losses from ureterosigmoidostomies. In disorder with episodic bouts of profound muscle weakness and
the case of vomiting, hypokalemia does not result directly from severe hypokalemia. It generally presents within the first or second
GI tract potassium loss, but rather from the kaliuretic effect of the decade of life. High carbohydrate intake, low potassium intake,
metabolic alkalosis on the renal tubules. Diarrhea results in direct exercise, infection, and alcohol are known precipitants of attacks.
potassium loss and very often a metabolic acidosis. Volume deple- A similar syndrome has been described in thyrotoxicosis, espe-
tion from any of these may cause secondary hyperaldosteronism cially amongst Asian patients.
and enhance urinary potassium losses. Excessive sweating or
CLINICAL MANIFESTATION OF HYPOKALEMIA: Hypokalemia
heatstroke may cause hypokalemia through a combination of
is generally asymptomatic until levels fall below 3.0 mmol/L.
exocrine gland loss and secondary hyperaldosteronism due to ECF
Symptoms are the result of the effect of hypokalemia on skeletal,
contraction. This is a particular risk to cystic fibrosis patients.
cardiac, and smooth muscle, renal function, and hormonal and
Renal wastage of potassium occurs by five different mech-
metabolic effects. Skeletal manifestations are the earliest signs
anisms. Increased distal tubular Na+/K+ exchange will occur in with weakness, cramps, paralysis, and rhabdomyolysis. Cardiac
response to increased circulating mineralocorticoid concen- manifestations include electrocardiographic (ECG) abnormalities,
trations, glucocorticoids, or foods and drugs that mimic/enhance arrhythmias, decreased contractility, and labile blood pressure
mineralocorticoid effects. Thus, Cushing’s syndrome, Conn’s owing to autonomic dysfunction. ECG changes are due to delayed
syndrome, non–salt-losing congenital hyperplasia, and high-dose ventricular repolarization and include flattening and inversion
corticosteroid therapy may be associated with hypokalemia. of the T-wave, an increasingly prominent U-wave, ST-segment
Licorice contains glycyrrhizic acid, whose structure resembles the depression, and prolongation of the PR interval. Increased
cyclopentenophenanthrene steroid molecule and thereby behaves myocardial automaticity and delayed repolarization promote both
like aldosterone. If ingested in excess, it can cause hypokalemia. atrial and ventricular arrhythmias. Paralytic ileus is the typical
Increased delivery of Na+ to the distal tubule will result in smooth muscle response to hypokalemia. Renal dysfunction is
increased Na+/K+ exchange and potassium wastage. This occurs also common including both structural and functional changes.
with proximal tubulopathies such as proximal RTA and Fanconi’s Decreased RBF and GFR, renal hypertrophy, tubuloepithelial
syndrome. Similarly, the use of thiazide and loop diuretics dilation, vacuolization, and sclerosis may be caused by hypo-
enhances distal Na+ delivery and potassium wastage. This effect is kalemia.51 Functional defects include impaired concentrating
enhanced by concomitant chloride deficiency and contraction ability (tubular ADH resistance), sodium retention, HCO3 re-
alkalosis. The presence in the distal tubular lumen of a non- absorption often resulting in alkalosis, and impaired urinary
absorbable anion increases the electronegativity of the luminal acidification. Hormonal effects of hypokalemia include decreased
fluid, thus enhancing K+ and H+ excretion. This is the basis for the insulin, growth hormone, and aldosterone release. Altered protein
kaliuretic effect of carbenicillin and large doses of penicillins. metabolism in chronic hypokalemia can result in a negative
Congenital disorders associated with K+ wastage cause hypo- nitrogen balance. Increased ammonia production secondary
kalemia. The major example is Bartter’s syndrome, which involves to hypokalemia can precipitate encephalopathy in patients with
an inherited defect in either the NKCC cotransporter or the liver disease.
inwardly rectifying potassium channel (ROMK) in the MTALH.
The resulting biochemical defect is a hypokalemic alkalosis with ANESTHETIC IMPLICATIONS OF HYPOKALEMIA: Although mild
hypercalciuria. Clinical symptoms include failure to thrive, rickets, chronic hypokalemia (>3.0 mmol/L) does not appear to be a
polyuria, polydipsia, hypotonia, and tetany. Lastly, direct renal significant risk for anesthesia, the anesthesiologist needs to
epithelial damage may precipitate kaliuresis and hypokalemia. consider the rate at which the hypokalemia developed and the
Renal toxins such as amphotericin B, polymixin, and aminogly- likelihood of these causes being responsible, because these
cosides and interstitial nephritides such as pyelonephritis produce conditions may in themselves be of more significance to the
hypokalemia by such a mechanism. planned anesthetic than the absolute value of the plasma (K+). In
addition, the anesthesiologist needs to be aware that the use of
HYPOKALEMIA ASSOCIATED WITH POTASSIUM REDISTRIBUTION:
glucose-containing solutions or hyperventilation may result in a
Although hypokalemia is usually associated with total body significant drop in the serum (K+). Digoxin toxicity is more likely
potassium depletion, hypokalemia can be caused by intracellular in the setting of hypokalemia. In patients receiving the drug, a
shifts in K+ without depletion. Alkalosis, of respiratory or meta- plasma (K+) above 4.0 mmol/L is preferable. The effects of
bolic origin, causes an intracellular shift of K+. This effect is more neuromuscular blocking agents may be enhanced by hypokalemia,
marked for metabolic alkalosis with a decrease of plasma (K+) by necessitating a reduction in dose and careful attention to nerve
approximately 0.3 mmol/L for each 0.1 unit increase in pH as stimulator testing of degree of paralysis and adequacy of reversal.
opposed to about 0.25 mmol/L fall per 0.1 pH unit increase in
respiratory alkalosis. Insulin, by a direct effect on the membrane TREATMENT OF HYPOKALEMIA: The treatment of hypokalemia
Na+/K+-ATPase increases Na+ efflux and K+ influx, thereby involves addressing the underlying cause as well as restoring
lowering plasma (K+). β-Adrenergic agonists promote cellular normal plasma (K+). Mild to moderate hypokalemia can be treated
uptake of K+ by cyclic adenosine monophosphate (cAMP)– with either supplementation of the diet with potassium-rich foods
or oral potassium supplements. In patients with cardiac or neuro- sodium channel deactivation. It presents with episodic paralysis
muscular manifestations of hypokalemia, intravenous replacement and hyperkalemia, lasting from minutes to hours.
is appropriate. The rate of cellular potassium uptake, even in a
INCREASED POTASSIUM INTAKE: Increased intake of potassium
depleted state, is limited, and therefore, slow replacement and
rarely causes hyperkalemia unless given rapidly and intravenously.
ECG monitoring is required when intravenous potassium is
An intake of 50 mmol K+ (<2% normal daily intake) orally by
administered. Intravenous potassium administration should be no
an adult can cause a transient rise in the serum (K+) of 0.5 to
faster than 0.25 mmol/kg/h. Concentrations of up to 40 mmol/L
1.0 mmol/Lr, which is dealt with by intracellular sequestration and
of potassium in the replacement fluid may be given peripherally,
subsequent excretion over 15 to 30 minutes. Thus, with normal
but higher concentrations should be given via central access
renal function, large amounts of oral potassium are tolerated well.
because of the risk of thrombophlebitis. Concentrations of greater
The intravenous administration of K+ at greater than 0.5 mmol/
than 60 mmol/L are not recommended. Administration of potas-
kg/h can rapidly cause dangerous hyperkalemia. Other sources of
sium supplementation may be required in redistributive hypo-
a large intravenous load of K+ include the transfusion of old
kalemia, even though there is no total body deficit. However, there
banked blood (15–30 mmol/L (K+]), irradiated blood, and
is the potential for plasma (K+) to increase as the underlying cause
potassium penicillins.
is treated.
DECREASED RENAL POTASSIUM EXCRETION: Decreased GFR
HYPERKALEMIA: Hyperkalemia is defined as a plasma (K+) above
inevitably leads to hyperkalemia. In chronic renal failure (CRF),
5.5 mmol/L. Because the kidney’s capacity to excrete potassium is
hyperkalemia is slow to develop in the absence of endogenous or
tremendous, hyperkalemia is, with a few exceptions, usually
exogenous K+ loads. In CRF, there is increased fractional excretion
associated with impaired renal excretion. The causes of hyper-
of potassium per surviving nephron, increased colonic potassium
kalemia can be grouped into three categories: (1) redistribution
excretion, and increased intracellular distribution. In acute renal
hyperkalemia, (2) increased potassium intake, and (3) decreased
failure (ARF), there is obviously less time for these compensatory
renal potassium excretion. Pseudohyperkalemia is an artifactual
mechanisms to develop and the resultant hyperkalemia may be of
elevation in the measured plasma (K+). Spurious elevations of
more rapid onset and severe degree. In addition, associated
plasma (K+) measurement may occur when there is red cell acidosis impairs the intracellular redistribution of the retained
hemolysis (e.g., from prolonged application of a tourniquet while potassium. The daily increase in serum (K+) averages 0.3 to
obtaining a specimen). In vitro release of K+ from platelets or 0.5 mmol/L in oliguric ARF under optimal conditions, but can
white cells can elevate the measured plasma (K+) in the setting exceed 0.7 mmol/L/day when there is concomitant increased
of thrombocytosis or leukocytosis, respectively (platelet count catabolism or trauma.
> 1000 × 109/L or white cell count > 70 × 109/L). Aldosterone promotes distal tubular Na+ absorption and K+
REDISTRIBUTION HYPERKALEMIA: A number of conditions cause loss. Therefore, aldosterone deficiency, as in primary hypo-
a shift in K+ from the ICF to the ECF, thereby elevating the plasma aldosteronism and pseudohypoaldosteronism, causes hyper-
(K+) without an increase in total body potassium. Acidosis causes kalemia. In addition, adrenal insufficiency and Addison’s disease
an extracellular shift of K+ as K+ and H+ are exchanged to buffer are characterized by salt wastage and hyperkalemia. Hyporeni-
the falling pH. As with hypokalemia, the effects of metabolic nemic hypoaldosteronism is a syndrome characterized by a degree
acidosis are greater than those of respiratory acidosis. Metabolic of hyperkalemia that is inappropriate to the degree of reduction of
acidosis causes an increase of the plasma (K+) of approximately GFR. It occurs in the setting of interstitial nephritis, obstructive
0.6 mmol/L for every 0.1 unit decrease of the pH as opposed to a uropathy, and sickle cell disease. Drugs that interfere with the
0.1 mmol/L decrease in plasma (K+) for every 0.1 pH decrease in renin-angiotensin-aldosterone system have the potential to cause
respiratory acidosis. Hypertonicity, as occurs in hyperglycemia hyperkalemia, especially if there is any additional renal impair-
with poorly controlled diabetes, causes extrusion of K+ from cells, ment. Non-steroidal anti-inflammatory drugs (NSAIDs) interfere
a situation compounded by the lack of insulin, which would have with prostaglandin-mediated renin release; ACE inhibitors
the reverse effect. Conversely, hyperglycemia in a nondiabetic interfere with angiotensin-mediated aldosterone release; heparin
patient will induce hypokalemia because of the increase in insulin in large doses can interfere with aldosterone release; and spirono-
release that is stimulated by the hyperglycemia and the resultant lactone, the potassium-sparing diuretic, directly antagonizes
intracellular movement of K+. Tissue damage will cause direct aldosterone’s distal tubular action.
release of K+. This occurs in trauma, burns, rhabdomyolysis, CLINICAL FEATURES OF HYPERKALEMIA: The most important
major hemolysis, tumor lysis with chemotherapy, and acute graft effects of hyperkalemia are on skeletal muscle and cardiac muscle.
rejection. Succinylcholine increases muscle cell K+ permeability The first signs are ECG changes, primarily because of delayed
during depolarization, causing an acute rise in plasma (K+). This depolarization, occurring when the plasma (K+) reaches 7.0
effect is augmented in patients with renal failure, high body stores mmol/Lr with prolongation of the PR-interval and tenting of the
of potassium, or when there are increased extrajunctional acety- T-wave. Shortening of the QT-interval, QRS widening, and ST-
choline receptors, as in the case of spinal cord injuries, lower segment depression occur when the plasma (K+) is 8.0 mmol/Lr.
motor neuron lesions, certain myopathies such as Duchenne’s, and With a further increase in the plasma (K+), there is loss of the P-
following major trauma and burns. β-Adrenergic blockade wave, loss of the R-wave, and progressive widening of the QRS
accentuates the plasma (K+) increase that occurs with exercise. The complex. This results in an electrocardiogram that resembles a
basis for the adrenergic effect on ECF/ICF K+ is detailed under sine wave until ventricular fibrillation occurs at a plasma (K+) level
“Hypokalemia,” earlier. Digoxin, by blocking Na+/K+-ATPase, can of 9.0 mmol/L or greater. These changes are augmented by hypoxia
in overdose cause hyperkalemia. Hyperkalemic periodic paralysis and acidosis. Arrhythmias may occur at lower levels in these
is a rare, autosomal dominant disorder because of a defect in contexts. Skeletal muscle weakness is not seen until plasma (K+) is
above 8.0 mmol/L. The weakness is due to sustained spontaneous Calcium is vital to the body because of its obvious importance
depolarization and inactivation of muscle membrane Na+ in bone metabolism and also for the stability it provides to
channels, resulting in an ascending paralysis. excitable cell membranes, regulation of neuromuscular function,
blood coagulation, cellular transport, secretory function, and as
ANESTHETIC IMPLICATIONS OF HYPERKALEMIA: Hyperkalemia is
an intracellular “second messenger.” Normal plasma calcium
a medical emergency whose management takes precedence over concentration is 2.1 to 2.6 mmol/L. Forty percent is protein-
elective surgery. The management of the hyperkalemic emergency bound, 50% is in the free ionized form, and 10% is bound to
surgical patient is directed at both lowering the plasma potassium anions such as citrate and amino acids. The free ionized calcium
and avoiding further increases. The use of succinylcholine is concentration (Ca2+) is physiologically most important. It is
contraindicated in hyperkalemia, as are any potassium-containing normally 1.1 to 1.25 mmol/L or 2.2 to 2.5 mEq/L. Changes in
intravenous fluids including lactated Ringer’s. Avoidance of respi- plasma albumin concentration will affect the total, but not the
ratory or metabolic acidosis is essential to avoid further increases ionized calcium concentration. An approximate correction for
in the plasma (K+). Therefore, ventilation should be controlled plasma calcium is to add (or subtract) 0.02 mmol/L for each gram
under general anesthesia; mild hyperventilation may even be by which the plasma albumin lies below (or above) a standard
desirable. Neuromuscular function must be closely monitored figure, normally 40 g/L. Changes in pH directly affect the degree
because hyperkalemia can exaggerate the effects of nondepo- of protein binding and, thus, the ionized (Ca2+). Ionized (Ca2+)
larizing neuromuscular blocking agents. increases approximately 0.03 mmol/L for each decrease of 0.1 unit
TREATMENT OF HYPERKALEMIA: Because of its lethal potential, in pH and decreases by the same amount for a similar pH increase.
hyperkalemia greater than 6.0 mmol/L should receive emergency Calcium enters the ECF by either absorption from the GI tract
treatment with cardiac monitoring and resuscitation facilities or resorption from bone and leaves the ECF by deposition into
readily to hand. The treatment of hyperkalemia can be thought of bone, urinary excretion, secretion into the GI tract, and sweat
as having four components: (1) reducing the potassium load; formation. Three hormones (PTH, vitamin D, and calcitonin)
(2) reversing the membrane effects of hyperkalemia; (3) increasing regulate ECF (Ca2+), acting primarily on bone, small bowel, and
intracellular K+ shift; and (4) removing potassium. Reducing the the distal tubules of the kidney. GI tract absorption of calcium is
potassium load can be accomplished by decreasing dietary potas- by vitamin D–dependent, saturable, energy-dependent absorption
sium, discontinuing K+-containing fluids, prescribing medica- and by vitamin D–dependent, nonsaturable, passive absorption.
tions, and removing the conditions that favor hyperkalemia such Calcium absorption is enhanced by dietary sugars (e.g., lactose)
as acidosis or sodium restriction. These measures may be suffi- in the absence of vitamin D, which may explain higher calcium
cient in mild hyperkalemia, but more rapid measures are required levels in infants. Up to 80% of the total daily intake is lost in the
when ECG changes or neuromuscular signs are evident. Antago- feces. The kidneys are responsible for calcium excretion. Normally,
90% of filtered calcium is absorbed. Proximal tubular absorption
nizing the membrane effects of hyperkalemia with calcium is the
parallels sodium absorption. In the MTALH, calcium and
fastest means of reversing cardiotoxicity. Intravenous calcium
magnesium absorption takes place through a paracellular route as
gluconate at 100 to 200 mg/kg/dose is an effective measure, even
a result of the electropositive gradient. Therefore, loop diuretics,
in the absence of hypocalcemia. Calcium decreases the threshold
which interfere with the generation of this gradient, increase
potential of excitable tissue, thus stabilizing the myocardial cell
urinary excretion. In the distal convoluted tubule/collecting
membrane. The intracellular shift of potassium is stimulated by
segment, calcium reabsorption is accomplished by an apical
insulin, alkalosis, and β-adrenergic stimulation. Dextrose (0.5 g/
calcium channel, a basolateral sodium-calcium exchanger, and
kg) as a 10% solution, with insulin added at a ratio of 1 unit/5 g of
calcium ATPase pump and is regulated by PTH. Therefore,
dextrose will rapidly reduce the plasma (K+) within minutes. thiazide diuretics, which decrease intracellular (Na+) and therefore
Equally effective is sodium HCO3 (1–2 mmol/kg/dose) intraven- increase basolateral Na+/Ca2+ exchange, will increase Ca2+ re-
ously. These are effective irrespective of acid-base or insulin status. absorption. PTH is the most important regulator of ECF (Ca2+).
An inhaled β-adrenergic agonist, such as salbutamol (albuterol), Decreases in (Ca2+) stimulate PTH secretion, and increases inhibit
will also reduce the plasma (K+) by a further 0.1 to 0.3 mmol/L. PTH secretion. The calcemic effect of PTH is due to mobilization
Hyperventilation (and, thus, respiratory alkalosis) increases of Ca2+ from bone, indirect increased small bowel absorption via
intracellular shift to a lesser extent, but also increases urinary enhanced vitamin D formation, and enhanced renal tubular
excretion of K+ for up to 24 hours. Removal of potassium from the reabsorption.
body may be accomplished by polystyrene sulfonate resins, which Vitamin D is the product of the conversion of cholecalciferol
act as ion exchangers in the GI tract. However, the onset of action first by the liver to 25-cholecalciferol and then by the kidneys to
is slow. Loop diuretics (furosemide) may be used to increase 1,25-dihydroxycholecalciferol. The latter process is enhanced by
urinary K+ losses. If hyperkalemia remains severe, especially with PTH and hypophosphatemia. Vitamin D augments intestinal
more severe ECG changes and renal impairment, dialysis therapy calcium absorption, facilitates the action of PTH on bone, and
is necessary. augments the renal tubular effect of PTH. Calcitonin is a
polypeptide hormone secreted by the parafollicular cells of the
Disorders of Calcium Homeostasis thyroid, in response to hypocalcemia. Calcitonin secretion is
inhibited by hypercalcemia. The effects of calcitonin include the
CALCIUM METABOLISM AND REGULATION: Regulation of
inhibition of bone re-absorption and the augmentation of urinary
calcium, phosphorus, and magnesium within narrow limits is
calcium excretion.
dependent on the action of PTH, calcitonin, and 1,25 dihydroxy-
cholecalciferol (vitamin D) on the GI tract, bone, and renal HYPOCALCEMIA: Hypocalcemia should be diagnosed only on the
tubules. Additional influences include acid-base status and ECF basis of a plasma ionized (Ca2+). If not available, the plasma (Ca2+)
volume status. should be corrected for albumin concentration. A plasma (Ca2+)
TABLE 10-11. Etiology of Hypocalcemia pedal spasm (Trousseau’s sign). Cardiac manifestations include a
prolonged QT-interval, decreased cardiac contractility, dysrhy-
1. Failure of appropriate PTH secretion: thmias, and decreased responsiveness to digitalis and β-adrenergic
Neonatal hypocalcemia: agonists. Laryngospasm, bronchospasm, and a high-pitched cry
Early hypocalcemia-calcitonin-PTH imbalance are seen in older infants.
Delayed postfeeding hypocalcemia (transient physiologic
hypoparathyroidism) ANESTHETIC IMPLICATIONS OF HYPOCALCEMIA: Hypocalcemia
Congenital hypoplasia of the parathyroid glands: should be corrected preoperatively and efforts made to avoid
Aplasia or hypoplasia further decreases in ionized calcium concentration including
Pseudoidiopathic hypoparathyroidism avoidance of alkalosis and frequent monitoring of plasma ionized
Acquired hypoparathyroidism: (Ca2+) during transfusion or albumin infusion. In hypocalcemia,
Idiopathic hypoparathyroidism the potentiation of the negative inotropic effects of anesthetic
Genetic autoimmune hypoparathyroidism agents should be expected, whereas the response to neuro-
Surgical hypoparathyroidism muscular blocker agents may be enhanced.
2. Inadequate responsiveness of tissues to PTH TREATMENT OF HYPOCALCEMIA: Symptomatic hypocalcemia is
Vitamin D deficiency: a medical emergency requiring administration of intravenous
Primary deficiency calcium. Calcium is available as a chloride, gluconate, or gluceptate
Defect in production of active 1,25- solution. Of the commonly used solutions of either calcium
dihydroxycholecalciferol chloride (10%) or calcium gluconate (10%), calcium chloride
Pseudohypoparathyroidism type 1 and 2 provides three times the elemental calcium of calcium gluconate
Magnesium deficiency on a milligram-for-milligram basis (27.2 mg/mL of elemental
Hypernatremia, hypokalemia, infections. calcium in calcium chloride vs 9 mg/mL of elemental calcium in
3. Hyperphosphatemia calcium gluconate). Calcium chloride is most commonly used in
4. Precipitation of calcium critically ill children.56,57 If calcium gluconate is used, three times
Pancreatitis as much is required to result in a similar increase in the plasma
Rhabdomyolysis ionized (Ca2+) when compared with calcium chloride. The recom-
Fat embolism mended dose of 5 to 7 mg/kg of elemental calcium can be given as
5. Chelation of calcium 0.2 to 0.25 mL/kg of calcium chloride 10% infused over 10 minutes
Multiple transfusions and repeated once if required.58 The danger of cardiac dysfunction
Rapid infusion of large amount of albumin with too-rapid infusion and soft tissue necrosis with extravasation
must be recognized. The potential for concurrent hypomag-
PTH = parathyroid hormone.
nesemia must be considered and treated simultaneously, as
outlined in the section on Hypomagnesemia later in this chapter.
less than 1.0 mmol/L or a corrected total calcium concentration
less than 2.0 mmol/L is indicative of true hypocalcemia. The HYPERCALCEMIA: Hypercalcemia may occur by a number of
potential causes of hypocalcemia in the pediatric-aged patient are mechanisms listed in Table 10–12, but because its features are
outlined in Table 10–11.52 nonspecific, it is less easy to diagnose. Primary hyperparathy-
Early neonatal hypocalcemia develops within 48 hours after
birth in about 33% of premature neonates, born at 37 weeks of
gestation or less, 50% of infants of insulin-dependent diabetics, TABLE 10-12. Etiology of Hypercalemia
and 30% of infants with birth asphyxia. Elevated calcitonin levels, 1. Hyperparathyroidism
as opposed to lowered PTH levels, are suggested as the cause.53,54 Primary
Delayed hypocalcemia occurring 5 to 7 days after birth, is often Tertiary
associated with cow’s milk ingestion. Maternal vitamin D levels 2. Malignancy
may play a role in late neonatal hypocalcemia.55 CRF causes hypo- Bony destruction
calcemia by a number of mechanisms including (1) hyperpho- PTH-like mediator release
sphatemia leading to soft tissue calcification; (2) increased sulfate Neoplastic vitamin D production
and phosphate complex formation; (3) defective 1,25-dihydroxy- 3. Increased intestinal calcium absorption
cholecalciferol synthesis with impaired calcium absorption; and Hypervitaminosis D
(4) PTH resistance. In pancreatitis, precipitation of calcium with Granulomatous disease (sarcoidosis/Ttuberculosis)
fats (soaps) occurs following the release of lipolytic enzymes and Milk-alkali syndrome
fat necrosis. A similar mechanism is likely in fat embolism. Large- 4. Increased bony reabsorption
volume transfusion may produce calcium chelation with the Chronic immobilization
citrate ions in the blood preservative. A transient reduction Paget’s disease
in plasma (Ca2+) may follow large-volume rapid infusions of 5. Thyrotoxicosis
albumin. 6. Drug-induced
CLINICAL FEATURES OF HYPOCALCEMIA: Increased neuro- Thiazide diuretics
muscular excitability forms the basis for the typical symptoms of Lithium
hypocalcemia. Central features include irritability, anxiety, jitteri- 7. Familial hypocalciuric hypercalcemia
ness, twitching, and seizures. There may be perioral, finger, and Idiopathic infantile hypercalcemia (Williams’ syndrome)
toe paraesthesias, masseter spasm (Chvostek’s sign), and carpo- PTH = parathyroid hormone.
roidism is rare in childhood, occurring as part of the multiple phorus excretion depends on both intake and plasma level. PTH
endocrine adenoma syndrome with hypercalcemia, hyper- inhibits proximal tubular re-absorption of filtered phosphorus,
calciuria, and nephrolithiasis. Infantile hyperparathyroidism is a enhancing urinary phosphorus excretion. In the absence of PTH,
life-threatening surgical emergency, characterized by plasma the re-absorption of phosphorus is complete.
(Ca2+) of 3.7 to 7.2 mmol/L, unexplained anemia, hepatospleno- Plasma phosphorus exists in both organic and inorganic forms.
megaly, skeletal demineralization, and nephrocalcinosis. Secon- Organic phosphorus is in the form of phospholipids. Inorganic
dary hyperparathyroidism is the elevation of PTH levels secondary phosphorus exists as H2PO4– and HPO42– in a ratio of 1:4. Of
to chronic hypocalcemia. Tertiary hyperparathyroidism occurs inorganic phosphorus, 80% is filterable in the kidney and
when prolonged secondary hyperparathyroidism gives rise to 20% is protein bound. Normal plasma level is 2.5 to 4.5 mg/dL
autonomous PTH secretion leading to hypercalcemia. Neoplasia (0.8-1.5 mmol/L) in adults and up to 6 mg/dL in children.
can give rise to hypercalcemia even without bony metastases Hypophosphatemia increases vitamin D production, whereas
through the release of PTH-like mediators or neoplastic produc- hyperphosphatemia decreases it.
tion of 1,25-dihydroxy vitamin D. Increased intestinal absorption
of calcium is seen in hypervitaminosis D and in granulomatous
HYPOPHOSPHATEMIA: Causes of hypophosphatemia include
those associated with a total body depletion of phosphorus and/or
disease in which there is enhanced sensitivity to vitamin D.
an intracellular shift of ECF phosphorus (Table 10–13).11
CLINICAL FEATURES OF HYPERCALCEMIA: The symptoms of
CLINICAL MANIFESTATIONS OF HYPOPHOSPHATEMIA: Mild to
hypercalcemia are relatively nonspecific with typical features
moderate hypophosphatemia (1.5–2.5 mg/dL) is generally asym-
including anorexia, nausea, vomiting, weakness, drowsiness, con-
ptomatic. By contrast, severe hypophosphatemia (<1.0 mg/dL) is
fusion, and ultimately, coma. Typical ECG changes are a shortened
associated with widespread organ dysfunction. The features of
QT-interval and ST-segment. Hypertension is often seen before severe hypophosphatemia are largely neuromuscular and hema-
hypovolemia develops. The renal effects of hypercalcemia include tologic. Neurologic and neuromuscular features include ence-
polyuria due to a nephrogenic diabetes insipidus (insensitivity to phalopathy, coma, and seizures as well as skeletal myopathy and
the tubular effect of ADH), decreased GFR, nephrolithiasis, and rhabdomyolysis. Hematologic features include impaired oxygen
nephrocalcinosis. Pancreatitis, peptic ulceration, and renal failure delivery (decreased 2,3,-diphosphoglycerate [2,3-DPG] levels),
may complicate hypercalcemia. hemolysis (because of reduced intracellular ATP), impaired leuko-
ANESTHETIC IMPLICATIONS OF HYPERCALCEMIA: Hypercalcemia cyte function, and platelet dysfunction. Cardiomyopathy, respira-
is a medical emergency that should, if possible, be corrected tory failure, skeletal demineralization, and hepatic dysfunction
before any general anesthetic is administered. Saline diuresis, may occur with severe hypophosphatemia.
as explained below in Treatment of Hypercalcemia, should be ANESTHETIC IMPLICATIONS OF HYPOPHOSPHATEMIA: Anesthetic
continued intraoperatively, taking care to avoid hypovolemia, management of the hypophosphatemic patient requires familiarity
hypokalemia, or hypomagnesemia. Acidosis should be avoided to with the potential complications outlined in the clinical manifes-
prevent an increase in the plasma ionized (Ca2+). tation of hypophosphatemia above, along with avoidance of meas-
TREATMENT OF HYPERCALCEMIA: The most effective treatment ures likely to further decrease plasma phosphorus concentration,
of hypercalcemia is establishment of a brisk diuresis. This is done
by a saline infusion at 20 mL/kg/h for 4 hours and furosemide TABLE 10-13. Etiology of Hypophosphatemia
(1 mg/kg/dose), which augments urinary calcium excretion.
Gastrointestinal
During saline diuresis, hypokalemia or hypomagnesemia may
Inadequate intake (e.g., during enteral nutrition)
develop. Frequent monitoring of plasma levels is required with
Refeeding syndrome
replacement when necessary. For plasma ionized (Ca2+) greater
Chronic antacid administration (intraluminal binding of
than 3.7 mmol/L, mithramycin, administered intravenously in a
phosphorus)
dose of 25 μg/kg over 4 to 8 hours, will produce a fall in plasma
Vitamin D deficiency
ionized (Ca2+) within 1 day. Calcitonin, 4 IU/kg subcutaneously
Renal
every 12 hours, will produce a more moderate fall in plasma
Fanconi’s syndrome
ionized (Ca2+) that is usually not sustained. In the presence of renal Recovery phase of acute tubular necrosis
or cardiac failure, emergency dialysis may be required. Post–renal transplant dysfunction
Postobstructive diuresis
Disorders of Phosphorous Homeostasis Vitamin D–resistant rickets
PHOSPHOROUS METABOLISM AND REGULATION: Phosphorus is Idiopathic hypocalciuria
an important intracellular constituent, required for the synthesis Excess PTH
of phospholipids and phosphoproteins in cell membranes and Diuretic therapy
intracellular organelles as well as phosphonucleotides involved in Hypomagnesemia
protein synthesis and reproduction. In addition, it is a key Hyperglycemia
constituent of ATP used for the storage of energy. Approximately Salicylate poisoning
0.1% of total body phosphorus is in ECF, 85% is in bone, and 15% Intracellular shift
is intracellular. Fifty to 60% of dietary phosphorus is absorbed in Respiratory alkalosis (effect greater than metabolic alkalosis)
the small intestine. Vitamin D increases intestinal absorption. The Carbohydrate ingestion
kidneys are the major route for phosphorus excretion and are Insulin ingestion
responsible for regulating total body phosphorus. Urinary phos- PTH = parathyroid hormone.
such as hyperglycemia and respiratory alkalosis. Neuromuscular HYPOMAGNESEMIA: Hypomagnesemia is a common and often
function should be closely monitored and severe hypophos- overlooked problem, especially in the critically ill. It is frequently
phatemia may make postoperative ventilatory support necessary. associated with other electrolyte abnormalities such as hypo-
TREATMENT OF HYPOPHOSPHATEMIA: Oral phosphorus is
calcemia or hypokalemia. Hypomagnesemia is generally the result
generally preferable to intravenous phosphorus administration, of either inadequate intake or absorption or increased renal
which may result in hypocalcemia and metastatic calcification. In excretion. Inadequate intake may result from prolonged fasting or
severe, symptomatic hypophosphatemia, intravenous phosphorus inadequate supplementation during enteral or parenteral feeding.
can be given over 6 to 12 hours in a dose of 2 to 5 mg/kg of Inadequate absorption may result from several different types of
elemental phosphorus as the potassium or sodium phosphate. pathology in the GI tract including malabsorption syndromes,
When potassium phosphate is used, the potential clinical impact small bowel or biliary fistulas, prolonged nasogastric suctioning,
of the potassium dose must also be considered. severe diarrhea, and short gut syndrome. Increased losses may
occur through the kidney because of increased sodium load,
HYPERPHOSPHATEMIA: Hyperphosphatemia is seen with increased hyperglycemia, the use of diuretics (loop or osmotic), hyper-
intake, decreased excretion, or cellular release of phosphorus. calciuria, hyperparathyroidism, hyperaldosteronism, damage
Increased intake may occur with phosphate enemas and laxatives to the renal tubules related to various medications (cisplatin,
or high-phosphorus diets (e.g., cows’ milk in infants). Decreased aminoglycoside antibiotics, amphotericin B, and alcohol), or
excretion may result from renal failure, hypoparathyroidism, and during the postobstructive phase of ATN or GI obstruction.
pseudohypoparathyroidism. The cellular release of potassium
occurs with hemolysis, rhabdomyolysis, and tumor lysis (e.g., post CLINICAL MANIFESTATIONS OF HYPOMAGNESEMIA: Many patients
chemotherapy for lymphoma/leukemia). with hypomagnesemia are asymptomatic, but cardiovascular,
neurologic, and neuromuscular manifestations may be seen.
CLINICAL MANIFESTATIONS OF HYPERPHOSPHATEMIA: The Cardiovascular effects include electrical irritability and poten-
clinical manifestations of hyperphosphatemia are largely as a
tiation of digitalis toxicity, both of which are exaggerated by
result of its effect of decreasing plasma ionized (Ca2+). Thus, the
concomitant hypokalemia. ECG changes include prolongation of
symptoms of hyperphosphatemia are those of hypocalcemia
the PR- and QT-intervals, often reflecting concomitant hypocal-
(see Hypocalcemia). In addition, hyperphosphatemia may con-
cemia. Anorexia, weakness, fasciculations, paraesthesia, confusion,
tribute to the genesis of ARF in rhabdomyolysis, tumor lysis
ataxia, and seizures may also be seen.
syndrome, and hemolysis. Hyperphosphatemia may lead to
calcium-phosphorus precipitation and deposition in brain, lungs, ANESTHETIC IMPLICATIONS OF HYPOMAGNESEMIA: Isolated
kidneys, pancreas, corneas, and blood vessels. hypomagnesemia should be corrected before elective procedures
because of its potential to cause arrhythmias. In addition, co-
ANESTHETIC IMPLICATIONS OF HYPERPHOSPHATEMIA: The
existent electrolyte disorders involving calcium, potassium, and
anesthetic implications of hyperphosphatemia relate primarily to
phosphorus should be sought and corrected as appropriate.
the associated hypocalcemia (see Hypocalcemia).
TREATMENT OF HYPOMAGNESEMIA: Asymptomatic hypomag-
TREATMENT OF HYPERPHOSPHATEMIA: The treatment of
nesemia should be treated with oral supplementation or intramus-
hyperphosphatemia is through the decrease of dietary intake of
cular magnesium. Serious manifestations such as seizures should
phosphorus and the use of phosphate-binding antacids such as
be treated with intravenous magnesium sulfate. The intravenous
aluminum hydroxide or carbonate. In severe cases, hemodialysis
dose is 25 to 50 mg/kg every 4 to 6 hours.52 Intravenous magne-
may be necessary.
sium should be administered over 20 or 30 minutes and repeated
plasma magnesium levels checked to avoid overtreatment and the
Disorders of Magnesium Homeostasis adverse effects of hypermagnesemia (see Hypermagnesemia).
MAGNESIUM METABOLISM AND REGULATION: Magnesium is an HYPERMAGNESEMIA: Increases in plasma magnesium are almost
important intracellular cation that functions as a cofactor in many
always due to excessive intake, renal impairment, or a combination
enzyme pathways. Approximately 1 to 2% is in the ECF, 67% is in
of the two (e.g., the use of magnesium-containing antacids or
bone, and 31% is intracellular. Dietary absorption occurs primarily
laxatives in the setting of renal failure). Iatrogenic hypermag-
in the distal small bowel, and renal excretion is the primary route
nesemia may also occur in the newborn fetus of a mother treated
of elimination. Re-absorption of 95% of the filtered load occurs
with magnesium for preeclampsia. Less common causes include
primarily in the LOH and less so in the proximal and distal
adrenal insufficiency, hypothyroidism, rhabdomyolysis, and
tubules. Re-absorption occurs by a paracellular route down
lithium administration.
an electrochemical gradient. Factors known to increase renal
magnesium re-absorption include hypomagnesemia, PTH, CLINICAL MANIFESTATIONS OF HYPERMAGNESEMIA: Features
hypocalcemia, ECF depletion, and metabolic alkalosis. Factors of hypermagnesemia include neurologic, neuromuscular, and
known to decrease renal magnesium re-absorption include cardiac effects. Signs of hypermagnesemia appear at plasma levels
hypermagnesemia, acute volume expansion, hyperaldosteronism, of 4 mmol/L or greater. Initial signs are ECG changes with pro-
hypercalcemia, ketoacidosis, diuretics, phosphate depletion, and longation of the PR-interval and QRS-complex widening.
alcohol consumption. Plasma magnesium levels are closely Hyporeflexia, weakness, and sedation are characteristic. Mag-
maintained between 1.5 and 2.1 mEq/L (0.7–1.0 mmol/L or 1.7– nesium impairs the release of acetylcholine and decreases endplate
2.4 mg/dL). The exact mechanisms are unclear but involve the sensitivity to acetylcholine at the neuromuscular junction. At
interaction of the GI tract absorption, bone storage, and renal levels of 10 mmol/L or greater, vasodilation, bradycardia, heart
excretion. block, and myocardial depression can lead to hypotension.
ANESTHETIC IMPLICATIONS OF HYPERMAGNESEMIA: Hyper- 11. Dabbagh S, Ellis D. Regulation of fluids and electrolytes. In:
magnesemia necessitates close monitoring of the electrocardio- Motoyama E, Davis P, editors. Anesthesia for Infants and Children.
gram, blood pressure, and neuromuscular function. Potentiation St. Louis: Mosby; 1990.
of the vasodilating and negative inotropic effects of anesthetic 12. Hartnoll G. Basic principles and practical steps in the management of
fluid balance in the newborn. Semin Neonatol. 2003;8:307–313.
agents is to be expected. The effect of nondepolarizing neuro-
13. Guyton A, Hall J. The kidneys and body fluids. In: Textbook of
muscular blocking agents may be enhanced. Medical Physiology. Philadelphia: Elsevier Saunders; 2006.
TREATMENT OF HYPERMAGNESEMIA: The effects of hypermag- 14. Waters JH, Miller LR, Clack S, et al. Cause of metabolic acidosis in
nesemia mentioned earlier in the section on Clinical Manifestations prolonged surgery. Crit Care Med. 1999;27:2142–2146.
of Hypermagnesemia can largely all be reversed transiently, but 15. Stewart PA. Modern quantitative acid-base chemistry. Can J Physiol
Pharmacol. 1983;61:1444–1461.
rapidly, by the administration of intravenous calcium. Further ther-
16. Beattie T. Disturbances in fluid and electrolyte balance. In: Webb N,
apy includes cessation of exogenous administration and potentia- Postlethwaite R, editors. Clinical Pediatric Nephrology. 3rd ed. New
tion of renal excretion. A loop diuretic along with infusion of normal York: Oxford; 2003.
saline enhances urinary magnesium excretion. Use of a normal 17. Morgan GE Jr, Mikhail MS, Murray MJ, (eds). Clinical Anesthesiology.
saline diuresis may also result in hypocalcemia, which will further McGraw-Hill/Appleton & Lange; 3rd edition 2001. p. 644–59.
accentuate the effects of hypermagnesemia. If there is renal impair- 18. Holliday MA, Friedman AL, Segar WE, et al. Acute hospital-induced
ment and hypermagnesemia, emergency dialysis may be required. hyponatremia in children: a physiologic approach. J Pediatr.
2004;145:584–587.
19. Moritz ML, Ayus JC. Prevention of hospital-acquired hyponatremia:
CONCLUSION a case for using isotonic saline. Pediatrics. 2003;111:227–230.
20. Shafiee MA, Bohn D, Hoorn EJ, et al. How to select optimal
Although no review of this length could claim to be exhaustive, maintenance intravenous fluid therapy. QJM. 2003;96:601–610.
the information presented here should provide an overview of the 21. Holliday MA, Segar WE. The maintenance need for water in
common and important perioperative disturbances of fluid and parenteral fluid therapy. Pediatrics. 1957;19:823–832.
electrolyte homeostasis likely to be encountered by the pediatric 22. Bozkurt P, Kaya G, Yeker Y, et al. Effects of systemic and epidural
anesthesiologist. Fluid, electrolytes, and acid-base disturbances morphine on antidiuretic hormone levels in children. Paediatr
are extremely common in the perioperative period. Such dis- Anaesth. 2003;13:508–514.
turbances are of particular concern to the pediatric anesthesio- 23. Sharples PM, Seckl JR, Human D, et al. Plasma and cerebrospinal
logist because the corrective mechanisms in children are more fluid arginine vasopressin in patients with and without fever. Arch
easily overwhelmed than in adults. Given the role that the kidneys Dis Child. 1992;67:998–1002.
24. Halberthal M, Halperin ML, Bohn D. Lesson of the week: acute
play in these homeostatic processes, a fundamental knowledge of
hyponatraemia in children admitted to hospital: retrospective
renal physiology is mandatory for the provision of anesthesia in analysis of factors contributing to its development and resolution.
infants and children. BMJ. 2001;322:780–782.
25. Arieff AI, Ayus JC, Fraser CL. Hyponatraemia and death or per-
manent brain damage in healthy children. BMJ. 1992;304:1218–1822.
REFERENCES 26. Hoorn EJ, Geary D, Robb M, et al. Acute hyponatremia related to
1. Deen WM, Lazzara MJ, Myers BD. Structural determinants of intravenous fluid administration in hospitalized children: an
glomerular permeability. Am J Physiol Renal Physiol. 2001;281: observational study. Pediatrics. 2004;113:1279–1284.
F579–F596. 27. Gerigk M, Gnehm HE, Rascher W. Arginine vasopressin and renin in
2. DiBona GF. Neural control of the kidney: past, present, and future. acutely ill children: implication for fluid therapy. Acta Paediatr.
Hypertension. 2003;41:621–624. 1996;85:550–553.
3. Kon V, Ichikawa I. Glomerular function. In: Barratt M, Avner E, 28. Neville KA, Verge CF, Rosenberg AR, et al. Isotonic is better than
Niaudet P, editors. Pediatric Nephrology. 5th ed. Philadelphia: hypotonic saline for intravenous rehydration of children with
Lippincott Williams & Wilkins; 2004. gastroenteritis: a prospective randomised study. Arch Dis Child.
4. Calcagno PL, Rubin MI. Renal extraction of para-aminohippurate in 2006;91:226–232.
infants and children. J Clin Invest. 1963;42:1632–1639. 29. Yung M, Keeley S. Randomised controlled trial of intravenous
5. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to maintenance fluids. J Paediatr Child Health. 2009;45:9–14.
estimate glomerular filtration rate from serum creatinine: a new 30. Choong K, Kho ME, Menon K, et al. Hypotonic versus isotonic saline
prediction equation. Modification of Diet in Renal Disease Study in hospitalised children: a systematic review. Arch Dis Child.
Group. Ann Intern Med. 1999;16;130:461–470. 2006;91:828–835.
6. Schwartz GJ, Haycock GB, Edelmann CM, Jr, et al. A simple estimate 31. Duke T, Molyneux EM. Intravenous fluids for seriously ill children:
of glomerular filtration rate in children derived from body length and time to reconsider. Lancet. 2003;362:1320–1323.
plasma creatinine. Pediatrics. 1976;58:259–263. 32. Thomas DK. Hypoglycaemia in children before operation: its
7. Herget-Rosenthal S, Bokenkamp A, Hofmann W. How to estimate incidence and prevention. Br J Anaesth. 1974;46:66–68.
GFR—serum creatinine, serum cystatin C or equations? Clin 33. Aun CS, Panesar NS. Paediatric glucose homeostasis during
Biochem. 2007;40:153–161. anaesthesia. Br J Anaesth. 1990;64:413–418.
8. Roos JF, Doust J, Tett SE, et al. Diagnostic accuracy of cystatin C 34. Nilsson K, Larsson LE, Andreasson S, et al. Blood-glucose
compared to serum creatinine for the estimation of renal dysfunction in concentrations during anaesthesia in children. Effects of starvation
adults and children—a meta-analysis. Clin Biochem. 2007;40:383–391. and perioperative fluid therapy. Br J Anaesth. 1984;56:375–379.
9. Shirley DG, Capasso G, Unwin RJ. Renal physiology. In: Freehally J, 35. Brodehl J, Franken A, Gellissen K. Maximal tubular reabsorption
Floege J, Johnson RJ, editors. Comprehensive Clinical Nephrology. 3rd of glucose in infants and children. Acta Paediatr Scand. 1972;61:
ed. St. Louis: Mosby; 2007. p. 13–26. 413–420.
10. Nielsen S, Frøkiaer J, Marples D, et al. Aquaporins in the kidney: from 36. Phillips S, Daborn AK, Hatch DJ. Preoperative fasting for paediatric
molecules to medicine. Physiol Rev. 2002;82:205–244. anaesthesia. Br J Anaesth. 1994;73:529–536.
37. Nicolson SC, Dorsey AT, Schreiner MS. Shortened preanesthetic 49. Trachtman H, Barbour R, Sturman JA, et al. Taurine and osmore-
fasting interval in pediatric cardiac surgical patients. Anesth Analg. gulation: taurine is a cerebral osmoprotective molecule in chronic
1992;74:694–697. hypernatremic dehydration. Pediatr Res. 1988;23:35–39.
38. Schreiner MS, Triebwasser A, Keon TP. Ingestion of liquids compared 50. Adams PC, Woodhouse KW, Adela M, et al. Exaggerated hypo-
with preoperative fasting in pediatric outpatients. Anesthesiology. kalaemia in acute myeloid leukaemia. Br Med J (Clin Res Ed). 1981;
1990;72:593–597. 282:1034–1035.
39. Emerson BM, Wrigley SR, Newton M. Pre-operative fasting for 51. Relman AS, Schwartz WB. The nephropathy of potassium depletion:
paediatric anaesthesia. A survey of current practice. Anaesthesia. a clinical and pathological entity. N Engl J Med. 1956;255:195–203.
1998;53:326–330. 52. Banasiak K, Carpenter T. Disorders of calcium, magnesium and
40. Gennari FJ. Current concepts. Serum osmolality. Uses and limita- phosphorus homeostasis In: Nichols D, editor. Rogers Textbook of
tions. N Engl J Med. 1984;310:102–105. Pediatric Intensive Care. 4th ed. Philadelphia: Lippincott Williams &
41. Edelmann CM, Barnett HL, Troupkou V. Renal concentrating Wilkins; 2008.
mechanisms in newborn infants. Effect of dietary protein and water 53. Hillman LS, Rojanasathit S, Slatopolsky E, et al. Serial measurements
content, role of urea, and responsiveness to antidiuretic hormone. of serum calcium, magnesium, parathyroid hormone, calcitonin, and
J Clin Invest. 1960;39:1062–1069. 25-hydroxy-vitamin D in premature and term infants during the first
42. Svenningsen NW, Aronson AS. Postnatal development of renal week of life. Pediatr Res. 1977;11:739–744.
concentration capacity as estimated by DDAVP-test in normal and 54. Venkataraman PS, Tsang RC, Chen IW, et al. Pathogenesis of early
asphyxiated neonates. Biol Neonate. 1974;25:230–241. neonatal hypocalcemia: studies of serum calcitonin, gastrin, and
43. Godard C, Geering JM, Geering K, et al. Plasma renin activity related plasma glucagon. J Pediatr. 1987;110:599–603.
to sodium balance, renal function and urinary vasopressin in the 55. Cockburn F, Belton NR, Purvis RJ, et al. Maternal vitamin D intake
newborn infant. Pediatr Res. 1979;13:742–745. and mineral metabolism in mothers and their newborn infants.
44. Goldberg M. Hyponatremia. Med Clin North Am. 1981;65: Br Med J. 1980;281:11–14.
251–269. 56. Broner CW, Stidham GL, Westenkirchner DF, et al. A prospective,
45. Aperia A, Broberger O, Herin P, et al. A comparative study of the randomized, double-blind comparison of calcium chloride and
response to an oral NaCl and NaHCO3 load in newborn preterm and calcium gluconate therapies for hypocalcemia in critically ill children.
full term infants. Pediatr Res. 1977;11:1109–11. J Pediatr. 1990;117:986–989.
46. Aperia A, Broberger O, Thodenius K, et al. Development of renal 57. White RD, Goldsmith RS, Rodriguez R, et al. Plasma ionic calcium
control of salt and fluid homeostasis during the first year of life. Acta levels following injection of chloride, gluconate, and gluceptate salts
Paediatr Scand. 1975;64:393–398. of calcium. J Thorac Cardiovasc Surg. 1976;71:609–613.
47. Harris GD, Fiordalisi I, Finberg L. Safe management of diabetic 58. 2005 American Heart Association (AHA) guidelines for cardio-
ketoacidemia. J Pediatr. 1988;113:65–68. pulmonary resuscitation (CPR) and emergency cardiovascular care
48. Finberg L. Hypernatremic (hypertonic) dehydration in infants. (ECC) of pediatric and neonatal patients: pediatric advanced life
N Engl J Med. 1973;289:196–198. support. Pediatrics. 2006;117:e1005–e1028.
Digestive System, Metabolic

Functions, and Nutrition 11
Bénédicte Ringuier, Jean-Louis Giniès, and Jean-Claude Granry C H A P T E R
INTRODUCTION lipase as well as gastrin, are present as early as the 14th week of
gestation.1–3 The production of gastric acid is in the order of
Throughout the course of the intrauterine life, a parallelism exists 1 mL/kg/h for the newborn at term as well as the premature infant,
between the development of intestinal structures and digestive aged 32 weeks. Acid secretion exists in the premature infant
functions. The presence of the sucrase-isomaltase complex is evidenced by the finding of a pH less than 4 from the first day of
contemporary to the formation of the brush border. However, a life.4–8 When expressed as mEq/kg/h, acid secretion is minimal in
number of functions, in particular pancreatic enzymes, the the premature infant (32 wk old), on the order of 0.01 mEq/kg/h.
secretion of gastric acid, and the synthesis of bile acids are not For the newborn at term, acid secretion on the first day of life is
mature at birth. This is likely to affect the capacity of the digestion approximately 0.02 mEq/kg/h. The maximum H+ ion secretion,
and the absorption of nutrients in the newborn and, particularly, especially in response to a stimulation triggered by histamine or
the premature infant. This chapter discusses the development of pentagastrin, is not different from the basal secretion until 2 to 3
the intrauterine digestive, gastric, intestinal, pancreatic, and biliary months of age. At that time, it is half of the value of the adult (0.2–
functions and their consequences on the intestinal digestive 0.4 mEq/kg/h). Adult values for acid secretion are achieved at 1 year
capacities and the absorption of the nutrients. of life.4,9 This very weak response of parietal cells to stimulation is
The metabolic status of the patient helps to determine the pro- even more paradoxical because the plasma levels of gastrin are very
per nutritional support. It must be adapted to improve physiologic high at birth, even higher in premature infants than in newborns at
stability, which can improve the outcome of hospitalized child- term. This neonatal hypergastrinemia demonstrates a lesser
ren.1,2 This challenge is significant because a quarter of the sensitivity of the parietal cells to gastrin in the neonatal period.4,9
children admitted to the intensive care unit are malnourished.
This malnutrition has a tendency to worsen the course of hospi-
talization.3 In this context, malnutrition is associated with an Intrinsic Factor Secretion
increased risk of infection, a prolongation of the duration of
assisted ventilation, and a delay of healing.2,4,5 It has been demon- The maturation of the secretion of the intrinsic factor comes from
strated that a Pediatric Risk of Mortality (PRISM) score greater the same cells producing the hydrochloric acid and is carried out
than 10, a C-reactive protein (CRP) greater than 50 mg/L, and much more quickly. It is present in the newborn at term and can
fluid restriction are independent factors responsible for the delay be measured even in the premature infants at birth. By the age of
in providing proper caloric support.6 Overnutrition is also 3 months, it is already equal to half of what is normally observed
deleterious, leading to a risk of hepatic steatosis (fatty liver) and a in the adult. Therefore, the newborn is able to absorb a dose of
prolongation of the need for assisted ventilation and hospitali- vitamin B12 immediately after birth and as effectively as the adult.6,9
zation.4,5 Because of the consequences of these nutritional issues,
The American Society of Parenteral and Enteral Nutrition has
made the following recommendations among children hospita-
Pepsin and Lipase Secretion
lized in the intensive care unit7 : Already measurable at the 15th week of gestation, the secretion of
pepsin increases starting at the 28th week of gestation.7 Never-
1. Assess the nutritional status. theless, it remains very low at birth until 3 months of age. By
2. Evaluate the energy expenditure (EE) by indirect calorimetry 18 months of age, it achieves values comparable with those of the
or the use of standardized equations to avoid overnutrition. adult.10,11 In addition, because of the lack of acid secretion, the
3. Encourage the use of enteral nutrition (EN) rather than gastric pH exceeds the optimum pH of pepsin, which results,
parenteral nutrition (PN). particularly among premature infants, in a lack of gastric digestion
of proteins during the first weeks of life. That could promote the
transfer in the neonatal period of intact proteins into the
GAASTROINTESTINAL TRACT circulation. This consideration is also important for consideration
SECRETORY FUNCTION of the fasting guidelines in this age group.
Similar maturation of lipase production and secretion occur
Acid Production during in the fetus and neonate. Present from the 11th week of
The parietal gastric cells, which produce hydrochloric acid and the gestation, lipase secretion at birth is half that of the adult. Levels
intrinsic factor, are individualized as early as the 11th week of observed in the adult population are achieved by 3 months of
gestation. The principal cells, which produce pepsin and gastric age.7,10,12
CHAPTER 11 ■ Digestive System, Metabolic Functions, and Nutrition 171
INTESTINAL MORPHOGENESIS
AND MATURATION OF THE
BRUSH BORDER
Intestinal Morphogenesis
The anatomic structures and functions of the intestine develop
early during gestation and, for all practical purposes, are com-
pleted by the sixth month of gestation. The intestine lengthens a
thousand times from the fifth week of gestation until birth. This
grow is linear until the second week of gestation and then
progresses more quickly with intestinal length doubling during
the last weeks of gestation. The small intestine measures approxi-
mately 100 cm after the 20th week, 170 cm by the 31st week, and
200 to 250 cm in the term newborn. During the same period, the
length of the colon increases from 25 to 50 cm.13 The volume
involved in the rapid development of the intestinal structure
combined with that of the liver results in the primitive intestinal
herniating into the umbilical cord as early as the sixth week of
gestation. The primitive gastrointestinal (GI) tract is, therefore,
transiently in a sac communicating freely with the abdominal
cavity before it returns to the abdominal cavity by the 10th week. Figure 11-2. Development of the sucrase activity during fetal life and
The differentiation of the GI tract begins during that period. It the neonatal period in human. Modified from reference 52.
proceeds from the proximal end to the caudal end. The villi appear
at the level of the duodenum during the eighth week, the jejunum
by the 10th week, and the distal ileum at the 14th week of gesta- organization of the brush border (from the seventh to the eighth
tion. The epithelium is multistratified until the eighth week, at week at the level of the proximal intestine). It increases until the
which time it becomes monostratified, allowing the development 14th week of gestation, at which time it is similar in function to
of the villi. At 12 weeks of gestation, the mucosa of the GI tract is that of the adult system15,16 (Figure 11–2).
no longer constituted by a single layer of cells, but gradually The emergence of the neutral β-galactosidase (lactase) system,
develops into mature cylindrical cells with microvillus membrane responsible for the digestion of both lactose and the thermoresis-
of normal length (Figure 11–1).14 tant maltases, occurs much later.15,17 It appears after the sucrase-
isomaltase complex is developed and occurs toward the ninth
week of gestation (Figure 11–3). However, its activity remains very
Hydrolytic Enzymes low until the 12th week, after which time it increases significantly
to reach adult values after the 35th week of gestation.16,17 The
Hydrolytic enzymes include three different protein complexes: peptidases involved in the terminal peptides digestion appear at
1. The sucrase-isomaltase complex. the same time as the individualization of the brush border.18
2. The lactase-maltase complex.
3. The peptidase and enterokinase complex.
The emergence of the sucrase-isomaltase complex, which
covers the totality of the saccharase-dextrokinase activity and
three quarters of the maltase activity, is contemporary to the
Figure 11-1. Jejunal enterocyte maturation sequence during human Figure 11-3. Development of the lactase activity during the fetal life
fetal life. and the neonatal period in human. Modified from reference 52.
Transfer Systems NEWBORN AND PREMATURE

The development of transmembrane transport systems also occurs INFANT DIGESTION AND
very early in the development of the intestinal structures. Glucose INTESTINAL ABSORPTION
uptake, measured by a technique of inversed concentration bags
The capacity of digestion and intestinal absorption of food and
and increased transmural potentials, can be identified at the level
nutrients in the newborn at term are associated with the develop-
of the jejunum as early as the 19th week.19 These findings imply ment of the intestinal structures, the production of the digestive
that the carrier of glucose facilitating its cellular entry coupled enzymes, and the functionality of the transfer systems. It is also
with sodium in the intestinal cell is well developed. The active dependent on the nature of carbohydrates, proteins, and fats
transportation system of sodium (the Na-K-ATPase–dependent), presented to the infant.
which allows the accumulation of glucose against a transmural
difference in concentration, is already functional at this stage. At
the level of the ileum, we must wait until the 15th week of gestation Digestion and Absorption of Carbohydrates
for glucose to demonstrate an increase in transmural potentials
The newborn and the premature infant are sufficiently mature at
difference. At this stage, glucose uptake is four to five times higher
birth to digest and absorb carbohydrates. This requires hydrolysis
in the jejunum than it is by the age of 11 or 12 weeks. At 21 weeks
at the level of the microvillus membrane (trace and disaccharides)
of gestation, the values are substantially equal to the level
or direct transfer into the circulation (monosaccharides). Lactose
measured in the jejunum and the ileum, but they still are three provided by the mother’s milk is responsible for 40% of the energy
fifths and at birth two thirds of those observed in the adult.20 and is one of the main nutrients that the intestine of the newborn
must digest and absorb immediately after birth. The activity of
Pancreatic Functions lactase is the limiting factor in the absorption of lactose. It reaches
its maximum values near term. The digestive tolerance of lactose
The development of the anatomic structures of the pancreas has often been questioned in the neonatal period and in the
occurs later than those of the intestine. The first acinar cells appear premature infant. It may indeed be insufficient in the premature
during the 12th week of intrauterine life, and the first pancreatic infant during the first week of life, leading to malabsorption and
lobules begin to form in the course of the 14th week of gestation.21 fermentation by the colon.28 Nevertheless, the ability to digest
The lobular and lobar architecture of the pancreas, the acini, and lactose appears to be satisfactory within a few days after birth in
the channels of the gland are well individualized in the embryo by the most newborn and premature infants.17,29,30
the age of 16 weeks. However, the pancreatic functions are not In spite of the very low activity of pancreatic amylase, the infant
mature at birth. The activity of the α-amylase is usually absent is perfectly capable of digesting a quantity of starch as high as 100
until birth. It remains extremely low during the first weeks of life. g/m2 as early as 1 month of age.31 The significant activity of pan-
Its concentration is, at the age of 6 months, three to four times creatic amylase at birth, which is comparable with that of adults, is
lower than that of older children and does not reach adult values more than 10 times higher than what is required to hydrolyze the
until 2 to 3 years of age.22,23 It is the only enzyme whose concentra- quantity of starch that is normally ingested. The intestinal glucoa-
tion in pancreatic secretions increases significantly in the years mylase complex contributes in part to these digestive capabilities in
following birth.24 term and premature infants.32,33 However, the ␣-amylase present in
Trypsin appears earlier than amylase. At 7 months of gestation, the mother’s milk and the salivary glands’ ␣-amylase also play an
its concentration is half of what it will be at birth.22,23 However, essential role in the digestion of these nutrients. The concentration
trypsin concentration is still low at birth. Even after stimulation, of ␣-amylase found in the mother’s milk is identical to the ␣-
it is only 10% of that which occurs in children older than 1 year. amylase activity present in the salivary glands. Its activity is maxi-
The values are even lower in premature infants, particularly in the mum in the colostrum and tends to decrease during lactation.34,35
days immediately following birth. The trypsin activity reaches,
within the first month of life, approximately those values observed
in a 2- to 6-year-old child24,25 and its ability to digest casein is not
Digestion and Absorption of Proteins
very different in infants than in adults (1.6 g/kg/h). Finally, a lipase The secretion of the proteolytic enzymes by the pancreas, although
activity begins after the fifth month of gestation. At birth, it is only incompletely developed until 2 to 3 years of age, is generally
25% of the values observed among children older than 1 year.22,23 sufficient from birth. No significant difference in the digestion of
Its activity is even lower among premature infants, but it grows proteins between premature and term infants or between young
rapidly. infants and older children has been identified.36,37 A 5-month-old
infant can digest in 1 hour the quantity of protein contained in
250 mL of cow’s milk.38 It is clear that the capacity of digestion and
Bile Salt Synthesis and Function absorption of protein is functionally sufficient in the newborn.
Bile is present in the fetal gallbladder as early as the 22nd week of However, the amount of proteins that can be given to a neonate is
intrauterine life, but the total bile salts concentration in the limited because of the immaturity of renal function and not
vesicular bile is still three times lower among infants younger than because of the digestive apparatus.
1 year than that observed among children older than 1 year.26 In
the term newborn, a biliary secretion inadequacy is present during Digestion and Absorption of Fats
the initial 2 to 3 weeks of life.27 This deficiency is linked to low
synthesis, which is two times less in the newborn at term and six
(Breast Milk vs Cow’s Milk)
times lower in the premature infant when compared with the Digestion and absorption of triglycerides, which constitutes 98%
levels observed in the adult. of fat ingested by the infant, depend on many factors including
1. Total lipase activity, primarily pancreatic, but also that of gas- mately half of lipids without significant variation after the seventh
tric origin whose activity is present at birth. and ninth months of gestation. When compared with the fat
2. The intraluminal concentration of bile salts, which are indi- present in breast milk, the malabsorption of cow’s milk fat is the
spensable to the micelle solubilization of products of lipolysis, consequence of the inadequacy of biliary secretion during the
3. The structure of triglycerides present in the milk ingested. neonatal period. Among newborns prematurely fed on cow’s milk
or industrial formula, there is a close correlation between the
For the newborn at term, the absorption coefficient of fats is
90 to 95% during the first weeks of life and at least 96% at 11/2 degree of the fat malabsorption and the intraluminal bile salts
months of age. The absorption of the fat present in the mother’s concentration. This correlation is not found when the child is fed
milk if it is pasteurized or lyophilized is less optimal. It has been breast milk.43,44 The chemical structure of the triglycerides present
measured at 80% during the first days of life, increasing to 93% in the mother’s milk (i.e., less stearic acid on the external position
between 1 and 2 months of age. It is more than 95% only after and palmitic acid, especially in the internal position on the
2 months of age.37,39 This better absorption of the fat present in glycerol molecule) is indeed much more favorable to the micelle
fresh breast milk emphasizes the physiologic importance of the solubilization than that of the triglycerides in the cow’s milk,
gastric lipase. This lipase is produced in a stable quantity all which contains a higher concentration of stearic and palmitic
through the lactation period. This lipase resists gastric acidity and acids, especially in the external position on the glycerol molecule.
pancreatic proteolysis because of the bile salts. Its function is In addition, the high concentration of calcium in the cow’s milk,
complementary to the pancreatic lipase at an age at which the approximately three times higher than that of breast milk, leads
activity of the latter is still low. Its role during the newborn period to the development of insoluble and nonabsorbable calcium stea-
is, therefore, important. It is responsible for a significant part, up rate, which is the result of a reaction between the calcium and the
to 50%, of the hydrolysis of the triglycerides in the milk.40 Its stearic acid released by pancreatic lipase. Because this malabsorp-
importance in the neonatal period is illustrated by the fact that the tion results in a loss of 15 to 20% of energy produced by the
absorption coefficient of fats in premature infants fed by stomach calories consumed, formulations containing medium-chain trigly-
tube decreases when intragastric lipolysis is bypassed by the use of cerides, whose absorption is independent of bile salts, have been
a nasojujenal tube.41 By contrast, its role appears negligible in the developed for the feeding of premature infants.45
infant after a few months of life.42
The malabsorption of the fat included in cow’s milk is much
greater than the 1% of breast milk because the newborn at term
METABOLIC FUNCTIONS,
has an absorption coefficient of cow’s milk fats estimated at 60% ENERGETICS, AND
during the first week of life, 80% at 15 days, and 85% between NUTRITIONAL STATUS
2 and 3 months of age.43 In the premature infant, malabsorption of
fats is even more significant (Figure 11–4).41 It affects approxi-
Assessment of the Nutritional Status
Nutritional assessment is based on the acquisition of data evaluat-
ing the anthropometric and biologic conditions. The develop-
mental information is summarized in Table 11–1. The analysis of
the growth is based on static and dynamic parameters.
Static Parameters
Static parameters include weight, size, and head circumference,
which are collected and compared with average values provided by
tables or growth curves used as reference. These tables and charts
can express the variations using the Z-score (i.e., deviation from
the median). The ratios of weight-to-age (weight–to–ideal weight
TABLE 11-1. Information About Nutritional Evaluation

Personal and Family History
Associated pathologies
Previous therapies
Family, psychological, and social context
Weight and size of the parents
Food Custom Investigation
Quantity of food rations
Quality of the alimentation:
● Deficit or excess of nutrients
● Eccentric or monotonous regime
Figure 11-4. Distribution of fat absorption coefficients in 18 premature Quality of the appetite
infants fed with milk obtained from a woman or from a cow. Modified
Presence of vomiting or diarrhea
from reference 82.
TABLE 11-2. Classification of Malnutritiona TABLE 11-3. Calculation of the Total Fat Mass and the Lean
Body Mass Obtained from the Measurement of Skin Folds
Normal Minor Moderate Severe
Report Malnutrition Malnutrition Malnutrition 1. Determine the weight (kg) and the age (y) of the patient.
2. Obtain the thickness (ply of cutaneous tissue in millimeters)
Size/ 95 90–95 85–90 85
from four areas; bicipital, tricipital, subscapular, and suprailiac.
age, %
3. Calculate the sum of all plies obtained from the four areas
Weight/ 90 80–90 70–80 70
(millimeters).
age, %
4. Apply the following equations according to the age and sex
a
The decrease in the ratio size-to-age suggests a chronic malnutrition (stunting) and calculate the body density (D):
whereas the ratio weight-to-age defines an acute malnutrition (wasting).
From reference 46. Brook’s equation (1–11 y)15:
D (boys) = 1.1690 – 0.0788 × log sum of the 4 plies (mm)
for age) and size-to-age (size–to–ideal size for age) suggest the D (girls) = 1.2063 – 0.0999 × log sum of the 4 plies (mm)
acute (wasting) or chronic (stunting) nature of malnutrition and
assess its severity according to the criteria defined by Waterlow46 Durnin and Rahaman’s equation (12–16 y)16:
(Table 11–2). D (boys) = 1.1533 – 0.0643 × log sum of the 4 plies (mm)
The ratio of weight-to-size (weight–to–ideal weight for the size) D (girls) = 1.1369 – 0.0598 × log sum of the 4 plies (mm)
serves as a diagnostic criterion of malnutrition when it is less than
90% (undernutrition is severe if the ratio < 80%). Two indices are 1. Calculate the fat mass = body weight (kg) × 4.95/D – 4.5
used: 2. Calculate the lean body mass = body weight (kg) – fat mass (kg)
From references 51 and 52.
1. The body mass index (weight/size2) or BMI.
2. The ratio of waist size/size (waist-to-height ratio).47
is less than 3.2 mg/dL. The utility of its assay is limited by the
The curve of references of the BMI for children of 5 to 19 years prolonged half-life (20 d), which explains why it cannot be used in
of age revised in 2006 by the World Health Organization (WHO) the early screening of malnutrition. Furthermore, it has a lack of
and a recent editorial by Greer are recommended for additional specificity for nutritional status because decreases of albumin
reading.48,49 These curves help to define: overweight above +1 plasma concentration may be seen in other pathologic states such
standard deviation (sd), obesity above +2 sd, paucity (thinness) as hepatocellular failure, excessive digestive losses, or hemodilu-
below –2 sd, and severe paucity (severe thinness) below –3 sd. tion. In addition, it has been demonstrated that, for 50% of
Dynamic Parameters TABLE 11-4. Nutritional Protein: Normal Plasma Level

The curves developed to assess the speed of growth were esta- and Variation Factors
blished in 1991.50 They enable the practitioner to date the Normal
beginning of nutritional impact of a pathologic condition and to Protein Plasma Level Variation Factors
verify the effectiveness of nutritional intervention.
Albumin 36–45 g/L Malnutrition
Insuffisance hepato cellulaire:
Anthropometry
hepatocellular insufficiency
Anthropometry corresponds to the study of the body compart- Pertes digestives, urinaires ou
ments. It provides information on the state of energy reserves or cutanées: Digestives, urinary
fat mass and the lean body mass. The fat mass can be evaluated and cutaneous losses
using the measurement of skin folds, whereas the lean body mass Hepatic disorders
is calculated from the fat mass (Table 11–3).51,52 In children with Infections prolongées:
edema or ascites, the study of the fat mass and of the lean body Prolonged infections
mass allows one to quantify the malnutrition status, even though Thyroxin- 0.32–0.35 g/L Malnutrition
the weight is falsely increased, thereby negating the value of the binding Hepatic disorders
classic ratios. During renutrition, the use of anthropometry mea- prealbumin Hyperthyroidism
surements help to provide information on the changes to the com- Inflammation
partments. It has been demonstrated that malnourished children Retinol- 44–76 mg/L Malnutrition
reconstituted preferentially their lean body mass by proliferation binding Inflammation
of their active cell mass.53 protein Vitamin A deficiency, zinc
deficiency
Biologic Evaluation of the Nutritional Status Hepatic disorders
The concentrations of certain plasma proteins reflect the synthetic Glomerular nephropathy
Transferrin 2–4 g/L Glomerular nephropathy
functions of the body and are regarded as markers of the nutri-
tional status.54 None of these proteins is a specific marker of Enteropathy
malnutrition, and their sensitivities vary according to their half- Hepatic disorders
lives (Table 11–4). Serum albumin is a classic marker of protein Inflammation
status and, therefore, malnutrition. The pathologic threshold value Iron deficiency
children with hypoalbuminemia at admission, there was no cor- EE using the weight, 92% use the age, and 30% use the predictive
relation between this anomaly and the clinical outcome (e.g., equations, whereas only 17% use indirect calorimetry.58
duration of assisted ventilation and hospitalization).55
The interest of the assay of thyroxin-binding prealbumin is
based on its short half-life (2 ds), which makes it an interesting Estimation of EE by the Use
early and sensitive marker of malnutrition. It shows a rapid and of Predictive Equations
measurable increase within 5 days following renutrition. It is an The three predictive equations used most commonly are outlined
effective marker that can be used as a parameter to monitor the in Table 11–5.58–62 The equations of Harris and Benedict published
therapy. However, two potential limits to its specificity should be in 1919 were established from basal metabolic measurements
noted. An increase in the serum concentration can be observed obtained among 239 subjects, ranging in age from 15 to 73 years.60
in the case of chronic renal failure or hyperthyroidism and a For healthy children, two other equations have been developed
decrease occurs in the presence of a zinc or retinol deficiency.
Transferrin, with an intermediate half-life (8 d), is a very
sensitive marker of malnutrition, but its specificity is poor. Varia- TABLE 11-5. Equations for Calculating Resting Energy
tions in plasma concentration may occur related to liver function, Expenditure and Basal Metabolic Rate
the presence of an inflammatory syndrome, or anemia. Retinol- A. Infants (0–3 Y)
binding protein (RBP) has a short half-life (12 h), but also lacks
specificity. Insulin-like growth factor-1 (IGF-1) has a plasma con- WHO Male REE = 60.9 W – 54
centration that varies according to the age and the pubertal stage Female REE = 61 W – 51
of the patient, but its rapid normalization occurs after a few days Schofield (W) Male BMR = 59.48 W – 30.33
of renutrition, which makes it an efficient marker of nutrition. Female BMR = 58.29 W – 31.05
Table 11–4 outlines the plasma concentrations of the proteins Schofield Male BMR = 0.167 W + 1517.4 H –
used as markers of nutritional status and their modifications in (W and H) 617.6
the event of an inflammatory syndrome. Some authors have Female BMR = 16.25 W + 1023.2 H –
proposed different scores that integrate the values of nutritional 413.5
protein weighted by the values of proteins during inflammation. Harris- Male REE = 66.47 + 13.75 W + 5 H –
The prognostic inflammatory and nutritional index (PINI) was Benedict 6.76 A
established in 1985.56 The PINI is a simple scoring system of the Female REE = 655.10 + 9.56 W + 1.85 H –
overall health that integrates blood markers of inflammation and 4.68 A
nutritional status (albumin and transthyretin). The formula is B. Children (3–10 Y)
PINI = orosomucoid (mg/L) × CRP (mg/L)/ WHO Male REE = 22.7 W + 495
albumin (g/L) × complement (mg/L) Female REE = 22.4 W + 499
It is a reliable indicator of nutritional status and a prognostic Schofield (W) Male BMR = 22.7 W + 505
indicator in the case of trauma, burns. or infectious syndromes Female BMR = 20.3 W + 486
(i.e., with high risk of comorbidity if the PINI > 21). It has been Schofield (W Male BMR = 19.6 W + 130.3 H + 414.9
modified in pediatric resuscitation to57 and H) Female BMR = 16.97 W + 161.8 H +371.2
Harris- Male REE = 66.47 + 13.75 W + 5 H –
PINI modified = fibrinogen (mg/dL) × CRP (mg/dL)/ Benedict 6.76 A
transferrin (mg/dL) × prealbumin(mg/dl). Female REE = 655.10 + 9.56 W + 1.85 H –
It has been reported that, in 71 intubated and ventilated 4.68 A
children, the PINI correlated best with the amount of protein C. Teenagers (10–18 Y)
provided. The score decreased after 5 days of EN.
WHO Male REE = 12.2 W + 746
Female REE = 17.5 W + 651
ESTIMATION OF ENERGY Schofield (W) Male BMR = 13.4 W + 693
METABOLISM AND Female BMR = 17.7 W + 659
Schofield (W Male BMR = 16.25 W + 137.2 H + 515.5
NUTRITIONAL NEEDS and H) Female BMR = 8.365 W + 465 H + 200
In the accurate assessment of the energy metabolism of the child, Harris- Male REE = 66.47 + 13.75 W + 5 H –
it is important to adapt the energy inputs to expenditures, to avoid Benedict 6.76 A
under- or overnutrition, and to allow normal growth. The total Female REE = 655.10 + 9.56 W + 1.85 H –
EE is the sum of EE related to basal metabolism (basal metabolic 4.68 A
rate), to the metabolism of growth, to the physical activity, and to
D. White’s Equation for Critically Ill Children
the diet-induced thermogenesis. The EE can be measured by
direct or indirect calorimetry or estimated by means of equations EE = (17 × (A, mo) + 48 × (W) + 292 ×
predictive of the nutritional status and established by population (body temperature, °C) – 9677) × 0.239
norms. The pediatric resuscitation guidelines advocate the esti- A = age, y; BMR = basal metabolic rate, kcal/day; EE = energy expenditure;
mation of the daily energy needs by using the weight of the patient H = height, m; REE = resting energy expenditure; W = weight, kg; WHO =
or by referring to weighted predictive equations or measures of World Health Organization.
EEs.58 In Europe, 83% of pediatric resuscitation teams estimate the Data from references 59–63.
since 1985. The accuracy of these equations for patients undergo- precisely by one or two measures of EE using indirect calorimetry
ing critical care resuscitation are controversial, with conflicting as long as the leak around the endotracheal tube is less than 10%
data in regards to under- or overevaluation of the EE.63–66 Three of the expired volume and that the fractional concentration of
studies have suggested that the estimation of the EEs provided by oxygen in inspired gas (FIO2) is less than 0.6.66,69,70 The respiratory
the equation of Schofield were not significantly different from quotient can also be used as a marker of adequate feeding. A
direct measurements.65–68 respiratory quotient greater than 0.85 eliminates the possibility of
In order to limit the inaccuracies that are present in critically ill undernutrition (specificity, 89%; negative predictive value, 90%),
children, White and coworkers have proposed an equation whereas a respiratory quotient greater than 1 indicates overnutri-
predictive of the EE at rest for children ventilated in the critical tion (specificity, 97%; positive predictive value, 93%).72
care unit (see Table 11–5).63 This equation includes the tempera-
ture of the body based on the observation made by Joosten and
colleagues, who reported that any variation of a mere 1°C in- NUTRITION OF THE CHILD
creased the EE by an average of 6%.69 Unfortunately, the accuracy IN CRITICAL CARE
of the equation developed by White and coworker has not been
Nutritional support should be considered for all patients who may
validated.68 In order to take into account the hypermetabolic
not resume normal enteral feeding (full oral diet) within 3 days.62,66,73
response to stress, it is classically recommended to multiply the
estimated values obtained in healthy children by various factors:
1.1 in postoperative patients, 1.4 in patients with congenital heart Enteral Nutrition
disease or severe sepsis, and 2.1 in case of burns or severe
trauma.62,70,71 A recent study demonstrated that the hypermeta- The superiority of the enteral approach in comparison to the
bolic response (defined as > 110% of the estimated value) in parenteral access has been well demonstrated in the adult popula-
resuscitation occurs in only 15 to 35% of children and that 22 to tion. However, the pediatric literature lacks formal proof for this
42% of children are hypometabolic (EE measured at < 90% of the commonly accepted practice. It is generally accepted that the
calculated EE).68 Faced with all these inaccuracies, Skillman and enteral approach is preferred among all children, with the
Wischmeyer have proposed in 2008 to estimate the EE by exception of those whose digestive tract must remain unusable for
averaging the results of two different equations.66 a prolonged period of time.66,74 The early use of EN promotes the
preservation of the mechanical and immunologic functions of
the digestive system, which stimulates the trophic activity of the
Measurement of EE by Calorimetry intestine and reduces the risk of bacterial translocation, thereby
reducing the incidence of sepsis and multivisceral failures.75,76
The oxidation of nutrients allows the production of energy, and
In adults, the early use of enteral nutrition (in the first 24–48 h)
the energy produced corresponds to the EE. There is a link
is recommended by the European Conference Consensus as grade
between heat released, oxygen consumption (VO2), and carbon
C evidence.73 The most recent recommendations also suggest the
dioxide produced (VCO2). Equation 1 shows that the oxidation of
same approach for children.66,77 In pediatric resuscitation, the
a molecule of glucose produces 673 kcal:
advantages of EN begin within the first 12 hours and include
Equation 1: C6H12O6 + 6 O2 → 6 CO2 + 6 H2O – 673 kcal
1. An immediate improvement in the nutritional status, which
The lower respiratory quotient of this reaction is equal to 1 can be assessed by the concentrations of complement and
because VO2 is equal to VCO2. In application of this equation, the transferrin.57
energy released by the oxidation of a known quantity of glucose 2. Rapid calorie intake in conformation to the estimated EE,
can be obtained by which has been demonstrated to improve intensive care unit
outcome.57
1. Direct calorimetry: estimated directly if the amount of heat
3. A significant reduction in the number of digestive compli-
produced is measured.
cations, such as abdominal distention, diarrhea, necrotizing
2. Indirect calorimetry: estimated by the measurement of VO2
enterocolitis, and hemorrhage.78,79
and VCO2.
Although EN may be administered by a nasogastric tube, in
Similar equations are available for other nutrients: palmitate
critically ill children, alterations in GI motility including gastro-
(Equation 2) and amino acid (Equation 3):
paresis may lead to intolerance of nasogastric nutrition. The
Equation 2: C16H32O2 + 23 O2 → 16 CO2 + 16 H2O – 239 recovery of satisfactory peristalsis occurs earlier in the duodenum
kcal RQ = 0.7 and jejunum than in the stomach. Also, the protective role of the
pylorus favors the use of postpyloric EN because it may be safer
Equation 3: 1 AA + 5.1 O2 → 4.1 CO2 + 0.7 urea + 2.8 H2O – 475
and lower the risk of regurgitation and pneumonitis. However,
kcal RQ = 0.8
these potential risks remain controversial in the literature.66,74,80,81
where AA is amino acid and RQ is The placement of a feeding tube throughout the pylorus may be
Direct calorimetry consists of placing a subject in an insulated difficult, especially in critically ill infants and children. Several
and thermally isolated room and measuring the heat generated. It techniques have been described to facilitate this procedure. The
is a very accurate, but complex, method to implement. Use of this intragastric insufflation of air (10 mL/kg) or the administration
technique is generally limited to research or validation of the other of an intravenous prokinetic agent such as erythromycin (3 mg/kg)
methods. Indirect calorimetry is feasible at the bedside, even in or metoclopramide (0.15 mg/kg) have been suggested. However,
children hospitalized in the critical care unit.63–73 In ventilated the efficacy of these methods has been received with varying
children, the total daily measurement of the EE can be assessed results.78,81
EN should be initiated at rates of 0.5 to 1 mL/kg/h with an in- TABLE 11-6. Amino Acids, Lipids, and Fluid and
crease of 0.5 to 1 mL/kg/h every 3 to 4 hours if the gastric residues Electrolytes Requirement During Parenteral Nutrition
are lower than 25% of the volume administered within the previous
3 to 4 hours and there is no abdominal distention. The objective is Amino acids 1st mo of life 1.5–3
to obtain normal caloric intake for the patient within 36 to (g/kg/d) 1st mo–3 y 1–2.5
48 hours. Although generally well tolerated, the literature suggests 3–5 y 1–2 (3 for critically ill
that patients with certain comorbid diseases may be somewhat patients)
intolerant of enteral feedings. In children with acute renal failure, 6–12 y 1–2 (3 for critically ill
the use of duodenal EN is possible in 90% of the cases but is patients)
associated with an increased rate of digestive complications.82 In Adolescent 1–2
critically ill children, for instance, those with shock, although the Lipids Infants with 3–4 (0.13–0.17 g/kg/h)
enteral route may provide better caloric intake, there may be a (g/kg/d) linoleic acid 0.1
significant increase in digestive complications (30.7% vs 9.1%).80 Children with 2–3 (0.08–0.13 g/kg/h)
Several studies have reported significant interest in the potential linoleic acid 0.1
impact of the administration of immunonutrition, especially in Na+ Infants 2–3
patients in the critical care setting. Immunonutrition consists of a (mmol/kg/d) Children 1–3
mixture of arginine, glutamine, omega-3 polyunsaturated fatty K+ Infants 1–3
acid, antioxidants, beta-carotene, vitamin E, zinc, selenium, and (mmol/kg/d) Children 1–3
copper. In children with septic shock, immunonutrition modifies Fluid Infants 120–150 (maximum, 180)
the production of cytokine without affecting its regulation. Fur- (mL/kg/d) 1–2 y 80–120 (maximum, 150)
thermore, it does not have a significant impact on the incidence of 3–5 y 80–100
complications.83,84 In children with serious traumatic brain injury, 6–12 y 60–80
the use of immunonutrition reduces the rate of interleukin-8 (IL- 13–18 y 50–70
8) production and the degree of gastric colonization on the fifth Modified from reference 62.
day without influencing the number of nosocomial infections, the
duration of assisted ventilation or hospitalization time, and the
are outlined in Tables 11–6 and 11–7.62 Three elements must be
survival rate.85 The outcome of critically ill adults hospitalized is
taken into account when PN is begun:
improved by supplementation of glutamine. In children, the
available data are rare, but the most recent recommendations pro- 1. PN must allow a gain in weight consistent with the reference
pose the use of supplementation for children with serious condi- curves.
tions, especially if they are victims of thermal injury or severe 2. The nutrients administered (carbohydrates, amino acids, and
trauma.66 The catabolism and oxidation of the arginine are in- lipids) must be in accordance with the recommendations in
creased in the case of burns or severe sepsis in children, but the terms of quantity and distribution.
data are insufficient to recommend supplementation.66 3. The tolerance of the PN must be monitored for hyperglycemia,
The positive effects of probiotics on the immune system and elevated triglyceride values, and cholestasis.
the prevention of diarrhea after antibiotic therapy have been
established in children. However, in the critical care situation, a Lipids (see Table 11–6) can provide a significant intake of
randomized probiotic study (Lactobacillus rhamnosus) versus calories in a small volume (2.0 kcal/mL for 20% emulsions) with
placebo had to be interrupted because of an increased number of a low osmolarity. They contain the essential fatty acids and should
nosocomial infections in the probiotic group.86 represent 25- to 40% of the nonprotein calories in the case of
exclusive PN. Classically, although the lipid intake is increased
gradually, no benefit of this practice has been demonstrated.62,66
Complications and Disadvantages Carbohydrates (see Table 11–7) should contribute 60 to 75% of
of Enteral Nutrition the nonprotein calories. The contribution of essential amino acids
The median energy intake can be significantly lower with EN than (histidine, isoleucine, leucine, lysine, methionine, phenylalanine,
with PN or combined techniques. Interruptions are much more threonine, tryptophan, and valine) is vital because they cannot be
frequent than with PN. These may occur during invasive pro- synthesized by the body. As with lipids, the advantage of a gradual
cedures or examinations, because of the need for free water increase in intake is not demonstrated.66 Even in premature
restriction, and the occurrence of digestive intolerance.87 Digestive
intolerance occurs in up to 50% of cases including significant
residuals (26–31%), vomiting (3–50%), abdominal distention (3.5– TABLE 11-7. Carbohydrates Requirement in Parenteral
15%), diarrhea (2.4–20%), enterocolitis (0.4–3.7%), duodenal Nutrition, g/kg/d
perforation (1.5–1.9%), and hemorrhage (0.3%).78,80,82,85,87 However, Weight, kg Day 1 Day 2 Day 3 Day 4
intolerance rarely requires the total suspension of EN (1.1% of the
children in the critical care unit), except when there is a state of <3 10 14 16 18
shock in which interruption is needed in almost 19% of cases.78,80 3–10 8 12 14 16–18
10–15 6 8 10 12–14
15–20 4 6 8 10–12
Parenteral Nutrition 20–30 4 6 8 ⬍12
PN should be started within 3 to 5 days if the use of EN is not >30 3 5 8 ⬍10
possible, or if it is poorly tolerated.62,66 The main recommendations Modified from reference 62.
infants, the immediate administration of essential amino acids ac- to have normal digestive capabilities of fats and carbohydrates.
cording to the recommended doses has been shown to be effective Regardless of the scenario, if nutrition is adapted to the metabolic
and well tolerated.88 To ensure that the use of the amino acids by condition of the child, it can significantly improve the prognosis
the body is optimal, although not for the purpose of energy of critically ill patients. It is essential to incorporate this goal in the
support, the ratio of calorie-to-nitrogen should be maintained at management of children, especially those confronted with dysfunc-
30 to 40 kcal/g of amino acid.62 tional metabolic and nutritional status caused by critical medical or
surgical conditions. Although the pediatric literature still lacks
evidence for many of the specific recommendations on this subject,
Monitoring and Complications
it is clear that the basic principles in the management of these
Monitoring of the tolerance to the lipid administration requires patients must be maintained. Clinical research in this field must
the daily determination of the triglyceride level. It has been be encouraged in order to answer many additional questions in this
demonstrated that hypertriglyceridemia in children is associated field.
with an increase of the duration of mechanical ventilation and
hospitalization.55 The intake should be reduced if the plasma
concentration of triglycerides exceeds 250 mg/dL in infants and REFERENCES
400 mg/dL in children.62 Close surveillance of patients with sepsis,
1. Deren JJ. Development of structure and function in the fetal and
newborns with hyperbilirubinemia, and patients with thrombo- newborn stomach. Am J Clin Nutr. 1971;24:144–159.
cytopenia or coagulation disturbances is mandatory because high 2. Dubois PM, Paulin C, Chayvialle JA. Identification of gastrin-
triglyceride levels may exacerbate these conditions. Hepatic secreting cells and cholecystokinin-secreting cells in the gastroin-
enzymes should be regularly determined and lipid intake de- testinal tract of the human fetus and adult man. Cell Tissue Res.
creased or interrupted in the presence of cholestasis. Supple- 1976;175:351–356.
mentation with omega-3 polyunsaturated fatty acids may hasten 3. Kelly EJ, Brownlee KG, Newell SJ. Gastric secretory function in the
the regression of cholestasis induced by PN in infants.89 The developing human stomach. Early Hum Dev. 1992;31:163–166.
tolerance to carbohydrate intake is assessed by monitoring plasma 4. Euler AR, Byrne WJ, Meis PJ, et al. Basal and pentagastrin-stimulated
acid secretion in newborn human infants. Pediatr Res. 1979;13:36–37.
levels of glucose and glycosuria. Various potentially detrimental 5. Hyman PE, Clarke DD, Everett SL, et al. Gastric acid secretory
effects of hyperglycemia have been reported in the literature, and function in preterm infants. J Pediatr. 1985;106:467–471.
its presence may be correlated with an increased risk of morbidity 6. Kelly EJ, Newell SJ, Brownlee KG, et al. Gastric acid secretion in
and even mortality, especially in patients with traumatic brain preterm infants. Early Hum Dev. 1993;35:215–220.
injury. It is associated with an increased in duration of stay, 7. Ménard D, Monfils S, Tremblay E. Ontogeny of human gastric lipase
increased duration of assisted ventilation, and increased risk of and pepsin activities. Gastroenterology. 1995;108:1650–1656.
death in postoperative cardiac surgery patients.90,91 The mecha- 8. Marino LR, Bacon BR, Hines JD, et al. Parietal cell function of full-
nisms to explain this hyperglycemia and its consequences vary. In term and premature infants: unstimulated gastric acid and intrinsic
case of systemic infection, van Waardenburg and associates have factor secretion. Pediatr Gastroenterol Nutr. 1984;3:23–27
9. Euler AR, Byrne WJ, Cousins LM, et al. Increased serum gastrin
reported that hyperglycemia was secondary to insulin resistance in concentrations and gastric acid hyposecretion in the immediate
children without shock and to a low plasma concentration of newborn period. Gastroenterology. 1977;72:1271–1273.
insulin in the case of septic shock.92 In the adult population, strict 10. DiPalma J, Kirk CL, Hamosh M, et al. Lipase and pepsin activity in
control of the glucose level improves the clinical prognosis and the gastric mucosa of infants, children, and adults. Gastroenterology.
outcome.93 Although definitive data are lacking in the pediatric 1991;101:116–121.
population, pending further data, it appears reasonable to suggest 11. Kely EJ, Brownlee KG. When is the fetus first capable of gastric acid,
maintaining the plasma glucose concentration between 140 and intrinsic factor and gastrin secretion? Biol Neonate. 1993;63:153–156.
180 mg/dL.66 However, if insulin administration is started to 12. Sarles J, Moreau H, Verger R. Human gastric lipase: ontogeny and
variations in children. Acta Paediatr. 1992;81:511–513.
maintain normoglycemia, frequent monitoring of blood glucose is
13. Weaver LT, Austin S, Cole TJ. Small intestinal length: a factor essential
mandatory, given the devastating consequences of hypoglycemia for gut adaptation. Gut. 1991;32:1321–1323.
in infants and children. Excessive glucose intake may also be 14. Moxey PC, Trier JS. Development of villus absorptive cells in the
responsible for the emergence of liver steatosis often accompanied human fetal small intestine: a morphological and morphometric
by the increased production of hepatic very low density lipopro- study. Anat Rec. 1979;195:463–482.
tein (VLDL) caused by the diversion of substrates to lipogenesis.62 15. Antonowicz I, Lebenthal E. Developmental pattern of small intestinal
enterokinase and disaccharidase activities in the human fetus.
Gastroenterology. 1977;72:1299–1303.
CONCLUSION 16. Lacroix B, Kedinger M, Simon-Assmann P, et al. Early organogenesis
of human small intestine: scanning electron microscopy and brush
The maturation of the digestive functions and intestinal absorption border enzymology. Gut. 1984;25:925–930.
in humans is remarkable, especially considering its developmental 17. Auricchio S, Rubino A, Muerset G. Intestinal glycosidase activities in
precocity during intrauterine and neonatal life. Immediately after the human embryo, fetus, and newborn. Pediatrics. 1965;35:944–954.
birth, the newborn’s GI function is such that it is capable of absorb- 18. Auricchio S, Stellato A, De Vizia B. Development of brush border
ing all the necessary nutrients for growth and development. These peptidases in human and rat small intestine during fetal and neonatal
include secretion of lipase and amylase by the pancreas and bile life. Pediatr Res. 1981;15:991–995.
19. Koldovsky O, Heringova A, Jirsova V, et al. Transport of glucose
salts from the liver. Although bile salts are present at birth, they are
against a concentration gradient I everted sacs of jejunum and ileum
least developed. Therefore, breast milk is essential for the neonate’s of human fetuses. Gastroenterology. 1965;48:185–187.
nutrition because of its enzymatic components and also because of 20. Levin RJ, Koldovský O, Hosková J, et al. Electrical activity across
the triglyceride structure, which is better adapted to this degree of human foetal small intestine associated with absorption processes.
intestinal immaturity. The intake of breast milk allows the newborn Gut. 1968;9:206–213.
21. Laitio M, Lev R, Orlic D. The developing human fetal pancreas: an 45. Okamoto E, Muttart CR, Zucker CL, et al. Use of medium-chain
ultrastructural and histochemical study with special reference to triglycerides in feeding the low-birth-weight infant. Am J Dis Child.
exocrine cells. J Anat. 1974;117:619–634. 1982;1361:428–431
22. Track NS, Creutzfeldt C, Bokermann M. Enzymatic, functional and 46. Waterlow JC: Classification and definition of protein-calorie mal-
ultrastructural development of the exocrine pancreas—II. The human nutrition. Br Med J. 1972; 3:566–569.
pancreas. Comp Biochem Physiol A Comp Physiol. 1975;51:95–100. 47. Nambiar S, Truby H, Abbott RA, et al. Validating the waist-height
23. Zoppi G, Andreotti G, Pajno-Ferrara F, et al. Exocrine pancreas func- ratio and developing centiles for use amongst children and adoles-
tion in premature and full term neonates. Pediatr Res. 1972;6: cents. Acta Paediatr. 2009;98:148–152.
880–886. 48. Greer FR. Time to step up to the plate: adopting the WHO 2006
24. Zoppi G, Andreotti G, Pajno-Ferrara F, et al. The development of growth curves for US infants. J Pediatr. 2008;153:622–628.
specific responses of the exocrine pancreas to pancreozymin and 49. de Onis M, Onyango AW, Borghi E, et al. World Health Organization.
secretin stimulation in newborn infants. Pediatr Res. 1973;7:198–203. Development of a WHO growth reference for school-aged children
25. Boehm G, Bierbach U, DelSanto A, et al. Activities of trypsin and and adolescents. Bull World Health Organ. 2007;85:660–667.
lipase in duodenal aspirates of healthy preterm infants: effects of 50. Guo SM, Roche AF, Fomon SJ, et al. Reference data on gains in weight
gestational and postnatal age. Biol Neonate. 1995;67:248–253. and length during the first two years of life. J Pediatr. 1991;119:
26. Halpern Z, Vinograd Z, Laufer H, et al. Characteristics of gallbladder 355–362.
bile of infants and children. J Pediatr Gastroenterol Nutr. 1996;23: 51. Brook CG. Determination of body composition of children from
147–150. skinfold measurements. Arch Dis Child. 1971;46:182–184.
27. Watkins JB, Ingall D, Szczepanik P, et al. Bile-salt metabolism in the 52. Durnin JV, Rahaman MM. The assessment of the amount of fat in
newborn. Measurement of pool size and synthesis by stable isotope the human body from measurements of skinfold thickness. Br J Nutr.
technic. N Engl J Med. 1973;288:431–434. 1967;21:681–689.
28. MacLean WC Jr, Fink BB. Lactose malabsorption by premature 53. Moukarzel A, Goulet O, Salas J, et al. Catch-up growth and energy
infants: magnitude and clinical significance. J Pediatr. 1980;97: metabolism on total parenteral nutrition (TPN): paradoxical features
383–388. of extremely marasmic infants. Clin Nutr. 1989;8:83.
29. Fosbrooke AD, Wharton BA. “Added lactose” and “added sucrose” 54. Yoder MC, Anderson DC, Gopalakrishna GS, et al. Comparison of
cow’s milk formulae in nutrition of low birth weight babies. Arch Dis serum fibronectin, prealbumin, and albumin concentrations during
Child. 1975;50:409–418. nutritional repletion in protein-calorie malnourished infants. J
30. Mayne AJ, Brown GA, Sule D, et al. Postnatal development of Pediatr Gastroenterol Nutr. 1987;6:84–88.
disaccharidase activities in jejunal fluid of preterm neonates. Gut. 55. Hulst JM, van Goudoever JB, Zimmermann LJ, et al. The role of
1986;27:1357–1361. initial monitoring of routine biochemical nutritional markers in
31. De Vizia B, Ciccimarra F, De Cicco N, et al. Digestibility of starches critically ill children. J Nutr Biochem. 2006;17:57–62.
in infants and children. J Pediatr. 1975;86:50–55. 56. Ingenbleek Y, Carpentier YA. A prognostic inflammatory and
32. Lebenthal E, Lee PC, Heitlinger LA. Impact of development of the nutritional index scoring critically ill patients. Int J Vitam Nutr Res.
gastrointestinal tract on infant feeding. J Pediatr. 1983;102:1–9. 1985;55:91–101.
33. Shulman RJ, Feste A, Ou C. Absorption of lactose, glucose polymers, 57. Briassoulis G, Zavras N, Hatzis T. Malnutrition, nutritional indices,
or combination in premature infants. J Pediatr. 1995;127:626–631. and early enteral feeding in critically ill children. Nutrition. 2001;17:
34. Dewit O, Dibba B, Prentice A. Breast-milk amylase activity in English 548–557.
and Gambian mothers: effects of prolonged lactation, maternal parity, 58. van der Kuip M, Oosterveld MJ, van Bokhorst DE, et al. Nutritional
and individual variations. Pediatr Res. 1990;28:502–506. support in 111 pediatric intensive care units: a European survey.
35. Murray RD, Boutton TW, Klein PD, et al. Comparative absorption of Intensive Care Med. 2004;30:1807–1813.
[13C]glucose and [13C]lactose by premature infants. Am J Clin Nutr. 59. Schofield WN. Predicting basal metabolic rate, new standards and
1990;51:59–66. review of previous work. Hum Nutr. 1985;39C:5–41.
36. Senterre J. Net absorption of starch in low birthweight infants. Acta 60. Harris JA, Benedict FG. A Biometric Study of Basal Metabolism in
Paediatr Scand. 1980;69:653–657. Man. Washington, DC: Carnegie Institute; 1919.
37. Williamson S, Finucane E, Ellis H, et al. Effect of heat treatment of 61. World Health Organization. Energy and Protein Requirements. Report
human milk on absorption of nitrogen, fat, sodium, calcium, and of a Joint FAO/WHO/UNU Expert Consultation. Geneva: WHO;
phosphorus by preterm infants. Arch Dis Child. 1978;53:555–6338. 1985.
38. Lindberg T. Proteolytic activity in duodenal juice in infants, children, 62. Koletzko B, Goulet O, Hunt J, et al. Guidelines on paediatric paren-
and adults. Acta Paediatr Scand. 1974;63:805–808. teral nutrition of the European Society of Paediatric Gastroen-
39. Fomon SJ, Ziegler EE, Thomas LN, et al. Excretion of fat by normal terology, Hepatology and Nutrition (ESPGHAN) and the European
full-term infants fed various milks and formulas. Am J Clin Nutr. Society for Clinical Nutrition and Metabolism (ESPEN). J Pediatr
1970;23:1299–1313. Gastroenterol Nutr. 2005;41:S1–87.
40. Hernell O, Bläckberg L, Chen Q, et al. Does the bile salt-stimulated 63. White MS, Shepherd RW, McEniery JA. Energy expenditure in
lipase of human milk have a role in the use of the milk long-chain 100 ventilated, critically ill children: improving the accuracy of
polyunsaturated fatty acids? J Pediatr Gastroenterol Nutr. 1993;16: predictive equations. Crit Care Med. 2000;28:2307–2312.
426–431. 64. Briassoulis G, Venkataraman S, Thompson AE. Energy expenditure
41. Roy RN, Pollnitz RB, Hamilton JR, et al. Impaired assimilation of in critically ill children. Crit Care Med. 2000;28:1166–1172.
nasojejunal feeds in healthy low-birth-weight newborn infants. J 65. Sy J, Gourishankar A, Gordon WE, et al. Bicarbonate kinetics and
Pediatr. 1977;90:431–434. predicted energy expenditure in critically ill children. Am J Clin Nutr.
42. McClean P, Harding M, Coward WA, et al. Bile salt-stimulated lipase 2008;88:340–347.
and digestion of non-breast milk fat. J Pediatr Gastroenterol Nutr. 66. Skillman HE, Wischmeyer PE. Nutrition therapy in critically ill
1998;26:39–42. infants and children. J Parenter Enteral Nutr. 2008;32:520–534.
43. Signer E, Murphy GM, Edkins S, et al. Role of bile salts in fat mala- 67. van der Kuip M, de Meer K, Westerterp KR, et al. Physical activity as
bsorption of premature infants. Arch Dis Child. 1974;49:174–180. a determinant of total energy expenditure in critically ill children.
44. Järvenpää AL. Feeding the low-birth-weight infant. IV. Fat absorption Clin Nutr. 2007;26:744–751.
as a function of diet and duodenal bile acids. Pediatrics. 1983;72: 68. Framson CM, LeLeiko NS, Dallal GE, et al. Energy expenditure in
684–689. critically ill children. Pediatr Crit Care Med. 2007;8:264–267.
69. Joosten KF, Verhoeven JJ, Hop WC, et al. Indirect calorimetry in 82. Lopez-Herce J, Sanchez C, Carrillo A, et al. Transpyloric enteral
mechanically ventilated infants and children: accuracy of total daily nutrition in the critically ill child with renal failure. Intensive Care
energy expenditure with 2 hour measurements. Clin Nutr. 1999; Med. 2006;32:1599–1605.
18:149–152. 83. Briassoulis G, Filippou O, Hatzi E, et al. Early enteral administra-
70. de Klerk G, Hop WC, de Hoog M, et al. Serial measurements of tion of immunonutrition in critically ill children: results of a
energy expenditure in critically ill children: useful in optimizing blinded randomized controlled clinical trial. Nutrition. 2005;21:
nutritional therapy? Intensive Care Med. 2002;28:1781–1785. 799–807.
71. Seashore JH: Nutritional support of children in the intensive care 84. Briassoulis G, Filippou O, Kanariou M, et al. Comparative effects of
unit. Yale J Biol Med. 1984;57:111–134. early randomized immune- or non–immune-enhancing enteral
72. Hulst JM, van Goudoever JB, Zimmermann LJ, et al. Adequate nutrition on cytokine production in children with septic shock.
feeding and the usefulness of the respiratory quotient in critically ill Intensive Care Med. 2005;31:851–858.
children. Nutrition. 2005;21:192–198. 85. Briassoulis G, Filippou O, Kanariou M, et al. Temporal nutritional
73. Ebner C, Hartl W, Heymann C, et al. ESPEN (European Society for and inflammatory changes in children with severe head injury fed a
Parenteral and Enteral Nutrition). ESPEN guidelines on enteral regular or an immune-enhancing diet: A randomized, controlled
nutrition: intensive care. Clin Nutr. 2006;25:210–223. trial. Pediatr Crit Care Med. 2006;7:56–62
74. Major K, Lefor AT, Wilson M. Route of nutrition support. Nutrition. 86. Honeycutt TC, El Khashab M, Wardrop RM 3rd, et al. Probiotic
2002;18:445–446. administration and the incidence of nosocomial infection in pediatric
75. Hadfield RJ, Sinclair DG, Houldswoth PE, et al. Effects of enteral and intensive care: a randomized placebo-controlled trial. Pediatr Crit
parenteral nutrition on gut mucosal permeability in the critically ill. Care Med. 2007;8:452–458
Am J Respir Crit Care Med. 1995;152:1545–1548. 87. Rogers EJ, Gilbertson HR, Heine RG, et al. Barriers to adequate
76. Heyland D, Cook DJ, Winder B, et al. Enteral nutrition in the critic- nutrition in critically ill children. Nutrition. 2003;19:865–868.
ally ill patients: a prospective survey. Crit Care Med. 1995;23: 88. Thureen PJ, Melara D, Fennessey PV, et al. Effect of low versus high
1055–1060. intravenous amino acid intake on very low birth weight infants in the
77. Hulst JM, Joosten KF, Tibboel D, et al. Causes and consequences of early neonatal period. Pediatr Res. 2003;53:24–32.
inadequate substrate supply to pediatric ICU patients. Curr Opin Clin 89. Gura KM, Lee S, Valim C, et al. Safety and efficacy of a fish-oil–based
Nutr Metab Care. 2006;9:297–303. fat emulsion in the treatment of parenteral nutrition-associated liver
78. Sanchez C, Lopez-Herce J, Carrillo A, et al. Early transpyloric enteral disease. Pediatrics. 2008;121:e678–86.
nutrition in critically ill children. Nutrition. 2007;23:16–22. 90. Klein GW, Hojsak JM, Rapaport R, et al. Hyperglycemia in the
79. Gottschlich MM. The 2002 Clinical Research Award: an evaluation of pediatric intensive care unit. Curr Opin Clin Nutr Metab Care. 2007;
the safety of early vs delayed enteral support and effects on clinical, 10:187–192.
nutritional, and endocrine outcomes after severe burns. J Burn Care 91. Yates AR, Dyke PC II, Taeed R, et al. Hyperglycemia is a marker for
Rehabil. 2002;23:401–415. poor outcome in the postoperative pediatric cardiac patients. Pediatr
80. López-Herce J, Mencía S, Sánchez C, et al. Postpyloric enteral nutri- Crit Care Med. 2006;7:351–355.
tion in the critically ill child with shock: a prospective observational 92. van Waardenburg DA, Jansen TC, Vos GD, et al. Hyperglycemia in
study. Nutr J. 2008;7:6. children with meningococcal sepsis and septic shock: the relation
81. Phipps LM, Weber MD, Ginder BR, et al. A randomized controlled between plasma levels of insulin and inflammatory mediators. J Clin
trial comparing three different techniques of nasojejunal feeding tube Endocrinol Metab. 2006;91:3916–3921.
placement in critically ill children. JPEN J Parenter Enteral Nutr. 93. Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin
2005;29:420–424. therapy in the medical ICU. N Engl J Med. 2006;354:449–461.
Endocrine System 12
Carlos Hervás Puyal, Manuel García Górriz, and Rosario Nuño Sanz C H A P T E R
INTRODUCTION the form of prohormones, which must be modified after synthesis

to give rise to biologically active hormones. The steroid hormones
Growth and development are genetically determined and are are synthesized from cholesterol. The body does not usually
modulated by a number of factors that either facilitate or hinder contain significant deposits of hormones because synthesis is
the expression of that genetic code and may in turn be subdivided generally followed by a quick metabolic turnover. Hormones can
into regulating, permissive, and effecting factors. The regulating be stored within secretory granules, bound to the cell membrane
factors, which are responsible for the transcription of gene-coded in the case of protein hormone–secreting cells or in the precursor
instructions into the adult individual phenotype, will be high- form (cholesterol) in cells that secrete steroid hormones. Because
lighted. Their mechanism of action involves the induction of of their limited storage capacity, the majority of hormones are
enzyme, hormone, and structural protein synthesis. At the initial released into the plasma at a rhythm that reflects their rate of
stages of embryonic development, this regulation depends exclu- synthesis. Diurnal rhythm, sleep, development, and nervous
sively on an autocrine or a paracrine mechanism. Later during system factors can influence the release of some hormones.
fetal life, some tissues differentiate into endocrine glands and Hormones are generally transported by the blood. The majority
secrete several hormones with specific metabolic actions that will of the peptide hormones circulate freely, with the exception of
become the main regulators of postnatal growth. insulin-like growth factors (IGFs) and growth hormone (GH).
Hormones that are not soluble in water require the presence of
carrier proteins. Albumin and prealbumin are the general carrier
BASIC CONCEPTS IN proteins, but some are hormone-specific such as thyroglobulin
ENDOCRINOLOGY (Tg) and sex hormone–binding globulin (SHBG). These binding
Concept of the Neuroendocrine System proteins act as reservoirs in such a way that the protein carrier–
bound hormone is in a dynamic equilibrium with the free fraction
Multicellular organisms require mechanisms by which the indi- in the plasma. Hormones must bind to specific sites on the target
vidual cells can intercommunicate. In humans, this intercommu- cells, receptors, to perform their function. Hormone-receptor
nication is achieved by means of the endocrine, nervous, and binding is noncovalent and reversible. Hormonal function is
immune systems.1–2 These systems regulate growth, development, centered on various physiologic processes including reproduction;
reproduction, homeostasis, and the response to environmental growth; development; maintenance of homeostasis; regulation of
stimuli. These interactions lead to the concept of the neuroen- cardiovascular function; and production, use, and storage of
docrine system, which integrates and coordinates the metabolic energy. The principal regulating mechanism that controls hor-
activities of the organism.3–4 The central regulator of this system is mone synthesis and secretion is a humoral process by which the
the hypothalamus. The hypothalamus receives and modulates a hormone concentration itself determines the need to increase or
large number of signals that arrive from the higher brain centers. decrease production. This regulation is carried out through
In turn, it transmits this information in the form of hormonal various feedback circuits, which can be altered by nonhormonal
stimuli, which regulate the activity of the cells in the anterior factors.
pituitary.
HYPOTHALAMIC-
Classification and Mode ADENOHYPOPHYSEAL SYSTEM
of Action of Hormone
Endocrinology is the discipline that studies the internal secretory
Overview
glands and their products, termed hormones. Hormones can be The hypothalamus and the hypophysis (pituitary gland) constitute
classified according to their chemical structure (peptide, steroid, a functional unit that controls several important functions in the
and amine) and their mechanism of action through either intra- organism.5 The specific actions of this unit are exerted by means
cellular receptors (group 1) or cell membrane receptors (group 2). of its hormonal secretions. Hypothalamic regulation of the hypo-
Hormone synthesis takes place mainly in the endocrine glands, physis is carried out by a neural route in the posterior hypophysis
although there is some activity in other tissues (e.g., brain, diges- (neurohypophysis) and through a vascular transport system in the
tive tract). The majority of protein hormones are synthesized in anterior hypophysis (adenohypophysis).4 The neuroendocrine
The neurons of the hypothalamic nuclei receive the innervation of

fibers proceeding from neurons that synthesize monoamines.
These are extensively distributed through the mesencephalon and
lower brainstem. The biologic amines (dopamine, adrenaline,
noradrenaline, and serotonin) play an important role in the neuro-
endocrine regulation of the adenohypophysis.
Regulation of Adenohypophyseal Secretion

The regulation of adenohypophyseal function is carried out by
coordinated neuronal and humoral mechanisms. The hypophy-
siotropic hypothalamic neurons are, in themselves, able to sustain
a certain autonomic function.3,5 However, to achieve complete
function, other stimulating and inhibiting impulses from various
brain regions or the hypothalamus itself are needed. Several
important brain structures, such as the septum, hippocampus, and
amygdale, contribute information to the hypothalamus through an
interaction of afferent and efferent pathways. The hypothalamus
contains specialized neurons that possess receptors sensitive to
changes in hormone levels, temperature, glucose levels, and
Figure 12-1. Feedback loops. osmolality. This information has an influence on the activity of the
hypophysiotropic and neurophysiotropic hypothalamic neurons.
cells of the hypothalamus synthesize and release neurosecretory The hypothalamic peptidergic neurons are, in turn, controlled by
substances. These substances are deposited in the posterior lobe of neurotransmitter-synthesizing neurons and other substances.6
the hypophysis or used to control the synthesis and release of the The hypothalamic peptidergic neurons are, in turn, controlled
adenohypophyseal hormones (hypophysiotropic hypothalamic by neurotransmitter-synthesizing neurons and other substances.
hormones), reaching the anterior hypophysis by means of the hy- An example of these is a series of small peptides found within the
pophyseal portal system. Hormone secretion in the hypothalamic- central nervous system (CNS) neurons that function as neuro-
hypophyseal axis is regulated by two systems that maintain transmitters, acting directly on the hypothalamic neurons or the
hormone levels within narrow margins. The first is based on the adenohypophysis (Figure 12–2). The primitive hypothalamic-
secretion of each of the hormones according to an intrinsic, spe- pituitary complex differentiates and synthesizes hypothalamic
cific rhythm, and the second is a feedback control mechanism. hypohysiotropic factors and pituitary hormones early in gestation,
This last system acts in both the hypothalamus and the hypophysis whereas the maturation of neuroendocrine control of hormonal
and is divided into three types (Figure 12–1): secretion by the fetal pituitary gland does not occur until late
1. Long loop: Peripheral concentrations of the hormone inhibit

or stimulate the synthesis or secretion of its corresponding
hypophyseal hormone through the hypothalamus.
2. Short loop: The hypophyseal hormones act upon the hypo-
thalamus.
3. Ultrashort loop: The hypothalamic and hypophyseal hormones
can modulate their own secretion.
Anatomic Data
The hypothalamus is located at the base of the brain, superior
to the pituitary gland and superior and posterior to the optic
chiasma, at the floor of the third ventricle. It is posteriorly related
to the mammillary tubercula. Its lower part, the tuber cinereum,
has a central projection that forms the base of the third ventricle,
the median eminence. This eminence is surrounded by the pars
tuberalis of the adenohypophysis. The anterior portion extends to
a frontal plane that includes the anterior commissure and the optic
tract. It is in dorsal relation with the cerebral thalamus. The
median eminence is a specialized region of the floor of the third
ventricle, which gives rise to the pituitary stalk. It has an important
vital function, being the area of contact between the tuberoin-
fundibular nerve terminals and the capillaries of the hypophyseal
portal circulation, by which the stimulating and inhibiting hypo-
thalamic factors that regulate hypophyseal function are transfer-
red. It is a highly vascularized area with considerable blood flow. Figure 12-2. Hypothalamic-hypophyseal functional unit.
CHAPTER 12 ■ Endocrine System 183
gestation or during the postnatal period. The growth and develop- TABLE 12-1. Anterior Pituitary, Hypophysiotropic
ment of the target tissues are affected in utero by the relative Hormones, and Their Target Organs
deficient secretion of adrenocorticotropic hormone (ACTH),
thyroid-stimulating hormone (TSH), follicle-stimulating hormone Hypophysiotropic Pituitary Target
(FSH), luteinizing hormone (LH), and growth factors.7–8 Vascular Hormones Hormones Organ Hormone
connection between the brain and the hypophysis is not estab- TRH TSH Thyroid T3 and T4
lished until midgestation.9 Thereafter, hypothalamic neurotrans- LH-RH LH Gonads E2 and testosterone
mitters and peptidergic hormones directly enter the pituitary to FSH Gonads Inhibin, E2,
regulate the synthesis and release of the hormonal products.9 testosterone
Dysfunction of the hypothalamic-hypophyseal system leads to GH-RH GH Multiple IGF-1
a deficient output of hypophysiotropic hormones or, less fre- Somatostatin GH Multiple IGF-1
quently, to an excess in their secretion. The most common cause CRH ACTH Suprarenal Cortisol
of panhypopituitarism in childhood is compression of the hypo- ADH ACTH Suprarenal Cortisol
physeal gland by a craniopharyngioma. Less frequent causes are Dopamine Prolactin Breast ?
hypothalamic tumors, tuberculosis, sarcoidosis, toxoplasmosis,
and some aneurysms. Treatment consists of specific hormone ACTH = adrenocorticotropic hormone; ADH = antidiuretic hormone; CRH =
corticotrophin-releasing hormone; E2 = estradiol; FSH = follicle-stimulating
replacement, which includes gonadotropins, cortisol, and thyro- hormone; GH = growth hormone; GH-RH = growth hormone–releasing
xin. In those patients scheduled for surgery, preoperative assess- hormone; IGF-1 = insulin-like growth factor-1; LH = luteinizing hormone; LH-
ment should be performed, taking into account the presence of RH = luteinizing hormone–releasing hormone; T3 = triiodothyronine; T4 =
any endocrine dysfunction as well as the possibility of intracranial thyroxine; TRH = thyrotropin-releasing hormone; TSH = thyroid-stimulating
hypertension or decreased compliance associated with tumors. In hormone.
those patients undergoing operations on the hypothalamic-hypo-
physeal system, the potential occurrence of diabetes insipidus, median eminence. TRH reaches the hypophysis from the median
hormonal deficiencies, reduced insulin requirements in the pre- eminence through the hypophyseal portal system and acts on the
sence of diabetes mellitus, hyperpyrexia, and cerebrospinal fluid thyrotrope cells. Prostaglandins and calcium seem to be implicated
losses should be considered. The effects on hypothalamic hor- in the release of TSH by TRH. The intravenous administration of
monal release induced by the different anesthetic agents are largely TRH produces a rapid dose-dependent release of hypophyseal TSH
hypothetical. Opiate receptor occupation by morphine derivatives that reaches a peak concentration at 20 minutes. In addition to
develops a negative-feedback control on endorphin secretion by stimulating TSH release, a second phase provokes an increase in
their precursors. This effect remains throughout the entire surgical TSH synthesis and increases thyroidal cell growth. Somatostatin
procedure whenever strongly active morphine-like agents (fen- and high doses of glucocorticoids reduce the response of TSH to
tanyl) are used at high doses and it disappears upon awakening. TRH. The main hypothalamic control over TSH is stimulatory. The
Halogenated anesthetic agents and neuroleptic agents induce an thyroid hormones exercise a negative-feedback regulation. Small
increase in plasma GH, whereas morphine-like agents increase increases in T3 (triiodothyronine) and T4 (thyroxine) levels de-
prolactin (PRL) levels. Droperidol antagonizes actions of dopa- crease the release of TSH in response to TRH. Inversely, small
mine on hypophyseal D2 receptors. decreases in circulating thyroid hormone levels increase TSH
release in response to TRH. The hypothalamus modulates the
sensitivity of the thyroidal cells to the negative-feedback mecha-
Hypophysiotropic-Hypothalamic Hormones nism of the thyroid hormones. TRH also stimulates the release of
Synthesis of the adenohypophyseal hormones is regulated by PRL, and in certain pathologic conditions (acromegaly, renal
neurosecretions originating in the peptidergic neurons of the failure, hepatic failure, anorexia), it induces the release of GH.
hypothalamic nuclei (Table 12–1). Finally, TRH has a series of nonendocrine effects. As a neurotrans-
mitter, it tends to produce excitatory consequences including
increased motor activity, trembling, and peripheral neural
Thyrotropin-Releasing Hormone
sympathetic activity with shivering, hypertension, tachycardia,
Thyrotropin-releasing hormone (TRH) can be detected in the fetal diaphoresis, and nausea. An abnormality anywhere in the
hypothalamus by midgestation.10 The precise profile of the hypothalamic-pituitary-thyroid axis can result in deficient thyroid
ontogeny of TRH secretion and function in the fetus is undefined hormone secretion and hypothyroidism. It is classified as tertiary
at this time. During the early phase of development, the thyroid when the defect is one of hypothalamic function, secondary for
gland will develop in the absence of TRH and TSH. The fetus abnormalities of TSH synthesis and release, and primary for
progresses from a state of both primary (thyroid) and tertiary diseases that impair thyroid hormone secretion or action. The
(hypothalamic) hypothyroidism in midgestation through a state of anesthetic care of the symptomatic patient requires caution when
mild tertiary hypothyroidism during the final weeks of pregnancy any depressant medications are given. Prolonged effects may result
to fully matured thyroid function in the perinatal period.10 Thyroid from decreased drug metabolism. Invasive monitoring may be
hormones affect important developmental processes including indicated when significant blood loss or fluid shifts are expected to
growth, thermogenesis, and development. Early treatment of occur. Care should be taken to minimize heat loss intraoperatively.
congenital hypothyroidism in the neonate prevents mental retar-
dation, suggesting that the period of thyroid dependency of the
human brain begins in the postnatal period. Norepinephrine Luteinizing Hormone–Releasing Hormone
directly stimulates TRH secretion in the paraventricular nucleus Development of the neuroendocrine system responsible for the
neurons, whereas dopamine inhibits its secretion at the level of the regulation of gonadotropin secretion, including FSH and LH,
begins during the final half of gestation.3 Luteinizing hormone– Somatostatin reduces splanchnic blood flow by 30% and inhibits
releasing hormone (LH-RH) content increases until midgestation gastric and duodenal motility. Finally, it inhibits galactose and
and then decrease steadily throughout the last half of gestation.10 lactose absorption in the small intestine, gluconeogenesis stimu-
The prepubertal reproductive system is characterized by FSH and lated by glucagon, and hepatic glycogenolysis.
LH secretion with a high ratio of FSH to LH and an enhanced
sensitivity to the negative-feedback effects of sex steroids. The
Growth Hormone–Releasing Factor
release of LH-RH is pulsatile in nature. LH-RH pulse frequency is
lower in prepubertal children than during early puberty. LH-RH Growth hormone–releasing factor (GH-RF) secretion is regulated
stimulates the release of LH and FSH. Epinephrine and norepine- by the action of dopamine upon the hypothalamic factors and by
phrine stimulate the secretion of LH-RH while modulating other complex interactions among many neurotransmitters and pep-
factors (opioid peptides and gamma-aminobutyric acid [GABA]) tides. Secretion is pulsatile, and prolonged administration does
modulate gonadotropin secretion. The biologic activity of LH-RH not seem to provoke desensitization of its hypophyseal effects.
depends on the form of administration. Pulsatile administration GH-RF stimulates the synthesis and release of GH in a time- and
results in the ongoing release of gonadotropins, whereas conti- dose-dependent manner, without affecting the secretion of other
nuous administration produces transitory stimulation followed by hypophyseal hormones. The response of GH to GH-RF is greater
in young individuals and decreases after the fourth decade of life.
desensitization and inhibition of secretion. Cell function can be
The capacity of the hypophysis to respond to GH-RF is exhausted
modified by changes in the receptor density. The number of recep-
by repeated administration of the peptide.
tors increases with estrogens and decreases with the androgens.
The intravenous administration of LH-RH to a normal adult
produces a dose-dependent release of LH and FSH, the former Corticotropin-Releasing Factor
being more pronounced. Complex interactions, important for Corticotropin-releasing factor (CRF) secretion is controlled by at
control of LH and FSH release, are established between the steroid least two types of stimuli including stress and the biologic clock
sex hormones and LH-RH. The differences in the secretion of LH responsible for the circadian rhythm of the hypophyseal-adrenal
and FSH seem to be due to variations in the sensitivity to LH-RH axis. The circadian rhythm is independent of plasma cortisol
and to the effects of steroid and peptide hormone feedback. FSH levels. The secretory neurons receive multiple stimuli from dif-
is more sensitive than LH to the inhibitory effects of the estrogens. ferent parts of the brain, regulating their function. It stimulates
Supraphysiologic doses of testosterone suppress basal gonadotro- the hypophyseal release of ACTH and beta-lipoprotein from pro-
pin levels and decrease their response to LH-RH. Regulation of opiomelanocortin. CRF plays an important role in regulation of
gonadotropin secretion is complex, with simulating and inhibit- the autonomous nervous system, stimulating the sympathetic and
ing effects at different levels of the hypothalamic-hypophyseal- inhibiting the parasympathetic nervous system. It influences
gonadal system, and interactions among several feedback effects. behavior and learning capacity and stimulates the production of
somatostatin by the cortical and hypothalamic cells.
Growth Hormone Release–Inhibiting
Factor or Somatostatin Hypothalamic Prolactin–Inhibiting Factor
Somatostatin is a tetradecapeptide found within the body of the PRL is secreted under inhibitory tonic control. A break in the
neuron and in the nerve terminals. It is widely distributed hypothalamic-adenohypophyseal connection by pituitary stalk
throughout the CNS and is considered to be a neurohormone both section or destructive hypothalamic lesions results in PRL hyper-
in the hypothalamus and in the hypophysis. In the pancreatic secretion. The hormone that inhibits PRL has not as yet been
islets, somatostatin can be located in the D and A cells. It may act conclusively identified. According to some authors, dopamine
as a local regulator of function in the islets of Langerhans, with is implicated, whereas others have proposed neuropeptides as
the peptide being released to the intercellular space and acting well. High concentrations of dopamine are found in the median
directly on the endocrine cells of the pancreas. Somatostatin seems eminence. Concentrations in portal blood are high enough to
to interfere with the release of various hormones but does not inhibit PRL release.
affect their synthesis. Its exact mechanism of action is still
unknown. Somatostatin’s effects on the pituitary include blockade Hypothalamic Prolactin–Releasing Factor
of GH release in response to exercise, insulin-induced hypoglyce-
The structure of prolactin-releasing factor (PRF) is not known; it
mia, arginine, L-dopa and inhibition of the secretory waves of GH may correspond to that of TRH. It is believed that the vasoactive
produced during sleep and in situations of stress. Basal secretion intestinal polypeptide present in the hypothalamus and in pitui-
continues despite suppression of the GH response. Endovenous tary stalk blood can act as a physiologic stimulator of PRL
perfusion of this peptide inhibits TSH release by TRH and secretion. GABA and prostaglandins (PG2) may also have a role.
suppresses the nocturnal increase of basal TSH levels. It does not Some studies have demonstrated a release of PRL by serotonin and
alter ACTH secretion in normal individuals, but it is inhibitory in an inhibition by antiserotoninergic agents.
cases of ACTH hypersecretion. Extrahypophyseal actions include
inhibition of the release of insulin, glucagon, and other peptide
hormones from the gastroenterohepatic system. Somatostatin Other Substances Isolated
controls secretion of insulin and glucagon in the islets of Langer- From the Hypothalamus
hans, either through a paracrine effect, by direct membrane con-
tact, or through a local vascular system. An elevated blood glucose Substance P
stimulates the release of glucagon, provoking somatostatin secre- Substance P is an 11-amino acid peptide. In the hypothalamus, it
tion, which in turn exerts an inhibitory control on glucagon. has been isolated from the neuron bodies of the dorsomedial and
ventromedial nuclei and in the anterior hypothalamic nucleus, but believed to inhibit the feeding centers. Thus, when in-
not in the external layer of the median eminence.11 Substance P hibition fails because of destruction of the ventromedial
has also been found in various structures outside the hypothala- area, hyperpyrexia and obesity often appear.
mus. It acts mainly upon the smooth muscle. At the vascular level, 2. Regulation of body water metabolism.
it produces vasodilation and hypotension, whereas in the intestine, 3. Regulation of the secretion of several adenohypophyseal hor-
it causes contraction of the smooth muscle of the intestinal wall. mones.
It stimulates salivary secretion and has analgesic effects that are
antagonized by naloxone. Substance P plays an important role in
the dorsal horn of the spinal cord where it modulates sensitivity to HYPOPHYSIS
pain by activating the neurokinin-1 (NK-1) receptor.11 The dis- Anatomic Data
tribution of nerve endings with a high content in substance P is
closely related to the distribution of enkephalin and opiate recep- The hypophysis (pituitary) is a gland located in the sella turca of
tors within the CNS. Substance P seems to act as both a neuro- the sphenoid bone and is covered with a layer of dura mater, called
transmitter and a neuromodulator, causing either hyperalgesia or the sellar diaphragm, which is traversed by the pituitary stalk. It is
analgesia, depending on its site of action.11 It has interactions with connected to the tuber cinereum region through the pituitary stalk
other neurochemical substances including opioids, resulting in below the base of the brain. The lateral walls of the sella turca are
enhancement or blunting of their effects. It seems to behave as a in contact with the cavernous sinus, which contains the internal
neurotransmitter of the exciting type. carotid artery and cranial nerves III, IV, V, and VI. Its size is vari-
able, increasing during pregnancy and decreasing with age. The
hypophysis can be divided into two morphologically and functio-
Neurotensin nally different units: the neurohypophysis and the adenohypo-
Neurotensin is a tridecapeptide with a single amino acid sequence. physis. The adenohypophysis does not possess direct innervation,
It is distributed throughout the CNS, with highest concentrations except for a small number of sympathetic fibers that penetrate the
in the hypothalamus. It is also found in the intestine. Endovenous anterior lobe next to the blood vessels. These nerve fibers can
administration produces hypotension, a painful sensation, and modify blood flow but not hormone secretion. The hypothalamus
hyperglycemia. Neurotensin increases PRL, ACTH, GH, LH, and has a neurohumoral regulating function. The cells of the adeno-
FSH production. Intraventricular administration increases the hypophysis group to form “nests” or acinus-like structures sur-
effects of barbiturates, produces hypothermia, and results in rounded by a network of sinusoidal capillaries. Different cell types
analgesic effects. exist for each hormone synthesized (Table 12–2). The adenohy-
pophyseal cytology changes in parallel to the functional alterations
Vasoactive Intestinal Peptide of the gland.
Vasoactive intestinal peptide (VIP) is a polypeptide with a short
half-life. At the level of the CNS, it is distributed in the hypothala- Adenohypophyseal Hormones
mus, median eminence, and the hypophyseal portal blood. It is
concentrated within the vesicles of the synaptic terminals of the Overview and Assessment
nerves, together with other neurotransmitters such as dopamine The anterior hypophysis can regulate several organs by the inte-
and noradrenaline. The peripheral effects of VIP include vasodila- gration of specific signals from the brain and by the intermittent
tion, stimulation of cardiac contractility, bronchodilation, gly- production of releasing factors that stimulate the selective release
cogenolysis, lipolysis, insulin secretion, gastric inhibition, and of hormones from a specific gland (Table 12–3). All of the adeno-
pancreatic secretion flow. It also stimulates activation of the hypophyseal hormones are governed by pulsatile secretion. The
adenylate cyclase system of the suprarenal cortex cells, resulting in adenohypophyseal hormones are classified into three families
steroidogenesis among other effects. VIP is believed to act as a according to their structure and activity: (1) corticotropin hor-
paracrine secretion or local hormone at the peripheral level, mone family and related peptide hormones. Within this group are
whereas in the CNS, it functions as a neurotransmitter or neuro- included ACTH, beta-lipoprotein, and the opioid peptides
modulator. (encephalins, endorphins) as well as the hormone that stimulates
the melanocytes of the intermediate lobe of certain animals. All
of these are derived from a large-molecule common precursor; (2)
Other Functions of the Hypothalamus glycoprotein hormone family, which includes FSH, LH, chorionic
The endocrine-metabolic aspects of hypothalamic function can
be classified into TABLE 12-2. Classification of Anterior Pituitary Cell Types
1. Regulation of energy metabolism and control of sleep, body Cell Type Hormone
temperature, weight, and appetite.
a. Sleep rhythms are regulated by the centers located within Somatotropic GH
the lateral hypothalamus. Lactotropic PRL
b. Body temperature is maintained constant by the activity of Thyrotropic Thyrotropin
the thermoregulating centers located in the tuber cinereum. Gonadotropic LH
These centers control both heat loss and production. FSH
c. Appetite and body weight are thought to be regulated Corticotropic ACTH
by the lateral areas (feeding) and the ventromedial areas ACTH = adrenocorticotropic hormone; FSH = follicle-stimulating hormone;
(regulating centers). Stimuli from the regulating centers are GH = growth hormone; LH = luteinizing hormone; PRL = prolactin.
TABLE 12-3. Adrenohypophyseal Hormones extremely high. GH stimulates the metabolism of nucleic acids
and proteins mainly in the liver (production of IGF-1), adipose
Pituitary Hormone Target Organ Hormone tissue (lipolysis), and the muscles (insulin antagonism). Its action
TSH Thyroid T4, T3 can be described as anabolic, lipolytic, and diabetogenic. GH
LH Gonads Estradiol administration in children produces a positive nitrogen balance,
Testosterone decreases in urea production, a redistribution of body fat, and a
FSH Gonads Inhibin reduction in the use of carbohydrates. Although prolonged admi-
Activin nistration produces insulin resistance and the appearance of
Follistatin hyperglycemia, it has no effect on the development of diabetes
ACTH Adrenal gland Cortisol androgens mellitus. GH and GH-RF levels increase during puberty, a
GH IGF-1 phenomenon modulated by the amplitude and not the frequency
PRL Breast, gonads ? of the secretory episodes. Significant increases in plasma IGF-1
and growth factor–transporting protein levels are produced at this
ACTH = adrenocorticotropic hormone; FSH = follicle-stimulating hormone; time. The increases in circulating IGF-1 explain the rapid growth
GH = growth hormone; LH = luteinizing hormone; PRL = prolactin; TSH =
thyroid-stimulating hormone;
seen during puberty.
gonadotropin, and TSH. With a 15 to 30% carbohydrate content Adrenocorticotropic Hormone

and proceeding from a primitive common molecule, they are all ACTH is synthesized from a large precursor molecule, pro-
composed of two amino acid chains, called alpha and beta. The opiomelanocortin (POMC). POMC is cleaved in the hypophysis,
structure of the alpha chain is very similar or identical in all of giving rise to ACTH, beta-lipoprotein, and an N-terminal precur-
them, whereas their biologic specificity resides in the beta chains; sor. ACTH receptors are located not only in the hypophysis but
and (3) somatotropin family, which includes GH, PRL, and also in the mononuclear leukocytes and in the cells of the spleen.
placental lactogen. The structure of the hormones in this group is The most important biologic action of ACTH is maintenance of
very similar. adrenal function. In addition to its trophic effect on this gland,
ACTH stimulates the synthesis of corticosteroids, mineralocor-
Growth Hormone ticoids, and androgens from the adrenal gland. Its main action is
related to control of cortisol secretion; it has a weak action on the
GH is a nonglycosylated protein, with a single polypeptide chain, mineralocorticoids and a principal control on the renin-angio-
secreted by the adenohypophyseal somatotrope cells. The tensin system. It also stimulates the melanocytes, probably by the
secretion of GH is pulsatile; its plasma concentrations are widely action of alpha- or beta-lipoprotein, which structurally have
variable, indicating the great number of factors involved in its sequences similar to those of melanocyte-stimulating hormone
secretion. GH is regulated by at least two hypothalamic hormones, (MSH). ACTH acts as a powerful steroidogenic stimulus on the
one stimulating and one inhibiting. The physiologic stimuli that adrenal glands of the human fetus and can have relevant functions
influence its secretion to the greatest degree include exercise, in adrenal gland growth over the fetal life. The fetal levels of
stress, and certain metabolic states, such as fasting and food ACTH seem to originate in the fetus; there is no correlation be-
ingestion. GH inhibits its own secretion through a short-loop tween maternal levels and fetal levels at birth, and the transmission
mechanism. In like manner, its secretion is modified by various of maternal ACTH seems very limited. Three mechanisms of
hormones and neurotransmitters. GH-containing adenohypophy- ACTH secretion are recognized: circadian rhythm related to the
seal cells are detected from the sixth week of intrauterine life. The phases of sleep and activity, inhibition of ACTH secretion by
levels of GH increase gradually with gestational age. Although circulating glucocorticoids, and quick release in response to stress.
changes can barely be seen during the first year of life, there is an ACTH itself can inhibit corticotropin-releasing hormone (CRH)
almost 10-fold increase during puberty. The levels of circulating secretion by a short-loop, negative-feedback mechanism. ACTH
GH at the moment of birth, which approach those that may occur secretion is episodic. The number and duration of the episodes
with acromegaly, are significantly higher than those of the mother. are greatest 3 or 4 hours before getting up in the morning and
These levels decrease until, at 3 months after birth, they reach gradually decrease during the day, with little activity in the final
concentrations similar to those of prepubertal subjects. hours of the night. These changes, initiated by pulsatile release of
The principal action of GH is to favor growth. This activity is hypothalamic CRF, produce the classic circadian rhythm of ACTH
not carried out directly, but instead through the induction of and cortisol. The rhythm disappears in Cushing’s disease patients,
certain plasma components called somatomedins. The structure of in patients with altered consciousness, and in subjects who receive
these components is very similar to that of proinsulin, and for this exogenous corticosteroids (chronic administration suppresses the
reason, they are also called insulin-like growth factors (IGF) and hypothalamic-hypophyseal-adrenal system). Cortisol and the
include IGF-1 or somatomedin C and IGF-2. IGF-1 and -2 can be glucocorticoids inhibit ACTH secretion through a negative-
synthesized by various tissues, but the liver synthesizes the feedback system that acts on the hypothalamus (inhibits CRF
majority of them together with their carrier proteins and releases release) and on the hypophysis (reduces hypophyseal response).
them to the circulation. The agents stimulate protein synthesis. This negative-feedback mechanism has two components: an
Somatomedin C does not show appreciable daily variations, but it immediate component that initiates its effect minutes after in-
does show changes with age. Before 6 years of age, levels are very creases in plasma glucocorticoid concentrations and a delayed
low; they increase significantly with puberty and then decrease component that appears much later when glucocorticoid concen-
once again to adult levels. Somatomedin C levels are very low in trations are high, decreasing, or low.
cases of GH deficit, fasting states, caloric and protein malnutrition, Hormonal responses after surgery are characterized by in-
and hepatic diseases. In acromegaly and gigantism, the levels are creased hypothalamic-pituitary-adrenal (HPA) axis hormones.
Stress produces ACTH release, and the common mediator in all on the Leydig or interstitial cells in men, stimulating testosterone
cases is hypothalamic CRF. Other stimuli such as cold, insulin hy- synthesis, and on the interstitial cells in women, stimulating steroi-
poglycemia, hemorrhage, and serious infections are also ACTH- dogenesis and favoring development of the luteal body. The
releasing factors. Norepinephrine increases plasma ACTH gonadotropins bind to membrane receptors and induce cyclic
concentrations, whereas propanolol increases the ACTH response adenosine monophosphate (cAMP) synthesis. In men, FSH acts
to the hypoglycemic stimulus. Serotonin stimulates ACTH release. upon the Sertolí cells, stimulating the development of the semi-
Stressful circumstances, as can be generated by a surgical or an niferous tubules and promoting spermatogenesis. Moreover, FSH
anesthetic procedure, stimulate ACTH release, partly because of increases the number of LH receptors and stimulates aromatiza-
an increase in CRF. However, ACTH secretion is greater than that tion of the androgens to estradiol. In women, it acts by binding to
obtained with maximal stimulation by CRF. The immunologic the granular cells of the follicles and stimulates growth and
system bears a close relationship with the HPA axis. Glucocor- maturation of the follicles, acting synergistically with the estrogens
ticoids inhibit the immune response, and some immunologic and LH. Changes in sensitivity to the feedback mechanisms are
mediators are strong stimulators of ACTH secretion. These media- related not only to gender but also to age. Gonadotropin secretion
tors may account, to some extent, for the connection between is pulsatile, with rapidly appearing waves or peaks that are
stress and activation of the HPA axis, with the resulting increased superimposed on a continuous basal secretion. The hypothalamus
cortisol levels modulating the immune response. Most of the controls the synthesis and release of LH and FSH through LH-RH.
inhaled anesthetic agents elicit an increase in plasma cortisol levels The gonadal steroid hormones establish a system of negative
feedback with the gonadotropins and the hypothalamic hormones.
(two- to threefold of its initial values within 2 h of their adminis-
From the beginning of puberty to the end of maturity, there is an
tration) except for isoflurane, which has a lesser effect.
increase in gonadotropin secretion, first of FSH and later of FSH
and LH, because of a decrease in sensitivity of the negative-
Thyroid-Stimulating Hormone feedback mechanisms. With puberty, a characteristic nocturnal
TSH is a glycoprotein hormone formed by an alpha subunit pulsatile release that is minimal during the day appears. At the end
common to LH and FSH and a beta subunit that gives it specificity. of puberty, secretion is pulsatile over 24 hours. The pulsatile
Its main biologic action is regulation of the synthesis, storage, and secretion is controlled by cyclic neuronal centers that act through
release of the thyroid hormones and determination of the size of LH-RH. The action of the sex steroids (estrogens, androgens, and
the thyroid gland. TSH possesses extrathyroidal actions, such as gestagens) on FSH secretion is carried out by the hypophysis,
stimulation of lipolysis in the adipocytes and an action favoring which would probably stimulate secretion, whereas testicular and
production of exophthalmos in certain experimental animals. ovarian inhibin would suppress secretion. The androgens appear
to suppress LH synthesis and release at the level of the hypophysis
TSH appears in the fetus at 10 days of gestation. In 10% of normal
and the hypothalamus. The estrogens would have a stimulating
individuals, its concentration in plasma may be undetectable (0.5–
effect on the hypophysis, which would partially explain the
5.0 mU/L). TSH secretion is pulsatile and presents a circadian
increase in sensitivity to LH-RH with the ovulatory peak, showing
variation with maximum secretion between 4:00 AM and 6:00 AM
greater LH and FSH response. By contrast, they would have an
with minimum secretion at 3:00 PM. TRH is the most important inhibitory effect in the hypothalamus.
hypothalamic factor for TSH secretion. It has also been observed
at the extrahypophyseal level. The thyroid hormones, T3 and T4,
inhibit TSH production by a direct hypophyseal mechanism. The Prolactin
affinity of T3 for the hypophyseal receptors is much greater than PRL is a polypeptide hormone whose single demonstrated activity
that of T4, whereas exogenous administration of T4 inhibits TSH consists of stimulation and maintenance of lactation. Some of the
release to a greater degree than T3. Half of intrahypophyseal T3 actions attributed to PRL are produced in synergism with the
results from a conversion of T4. In humans, the effect of T3 and T4 gonadal and suprarenal steroid hormones. The increase in
on the hypothalamus is not known. Somatostatin inhibits basal estrogen production during pregnancy stimulates growth and
TSH release, the response of TSH to TRH, and the nocturnal TSH replication of the hypophyseal lactotrope cells. The hypophysis
peak. Dopamine and glucocorticoids reduce TSH concentrations doubles in size during pregnancy and returns to normal after the
and the response of TSH to TRH. TSH concentrations can be infant’s birth. PRL-containing cells can be detected in the fetal
interpreted correctly only when serum levels of the thyroid hypophysis after the 10th week of gestation. Circulating PRL levels
hormones are known. The latter are increased in hyperthyroidism, follow a similar process, showing a great increase during the third
inhibiting TSH release with associated TSH suppression and abo- trimester and a gradual decrease after birth. PRL acts through
lition of the TSH response to TRH. TSH-induced hyperthyroidism specific receptors in several tissues (e.g., mammary, testicular, and
is rare. Plasma concentrations of TSH remain constant throughout ovarian) and the liver. PRL initiates and maintains the process of
life except in the newborn period in which there are increases in lactation. It is inhibited during gestation by the estrogen and
the first 24 hours after birth. As a consequence of surgical trauma, progesterone concentrations. PRL concentrations increase from
there is a decrease in T3 and T4 levels with normal TSH. Thio- the beginning of pregnancy. This is a gradual process and is
pental has an antithyroid action because it diminishes hormonal probably due to increases in the estrogens. Suckling at the nipple
synthesis. This effect is immediate and goes on for several days. produces an immediate PRL release reflex. Other factors, such as
Halothane promotes TSH secretion and T4 release. stress situations, surgery, anesthesia, insulin hypoglycemia, and
arginine, produce PRL release. PRL release with stress is blocked
by opioid antagonism and is probably mediated by endogenous
Gonadotropins (LH and FSH) opioids. The hypothalamus exerts an inhibitory tonic control over
LH and FSH are glycoprotein substances formed by two peptide PRL secretion through a still-unidentified factor. TRH stimulates
chains, alpha and beta. Structurally, they are similar to hypophy- PRL secretion. Dopamine inhibits PRL secretion, whereas sero-
seal TSH and to human chorionic gonadotropin (hCG). LH acts tonin stimulates it through hypothalamic PRF.
Neurohypophyseal Hormones cause an intense vasoconstriction. Hypothalamic neurotransmit-

ters and neuropeptides intervene in the regulation and modulation
Antidiuretic Hormone or Vasopressin of ADH release. Catecholamines influence endogenous ADH
A part of the antidiuretic hormone (ADH) produced is released to release by activation of the alpha and beta receptors. Angiotensin
the CSF and a part enters the anterior hypophysis through the II is a potent stimulator of ADH release in situations of hypovole-
portal system. ADH acts in the tissues through binding to specific mia. Acetylcholine stimulates ADH release by its nicotinic effect
receptors coupled with protein G. There are two types of receptors: on the supraoptic neurons. Although the importance of these
activation of V1 stimulates hydrolysis of phosphatidylinositol and neurotransmitters and peptides has not been completely defined,
mobilization of intracellular calcium. Two subunits, V1a and V1b, the antidiuretic action produced by stress, vomiting, and pain
have been described. V1a, found in the liver and kidney, has a indicates that there could be an influence of the higher neural
potent vasoconstricting effect, whereas stimulation of V1b located centers on ADH release. The pharmacologic agents that stimulate
in the anterior hypophysis, triggers corticotropin secretion. V 2 ADH secretion are nicotine, morphine, barbiturates, vincristine,
activation produces the antidiuretic and vasodilatory effects of cyclophosphamide, clofibrate, chlorpropamide, and some tricyclic
ADH, as well as its ability to increase the release of coagulation anticonvulsants and antidepressants. Ethanol inhibits neurohy-
Factor VIII. ADH does not cross the placental barrier and is pophyseal function under several conditions. Some narcotic anta-
present in the neurohypophysis after the 11th week of gestation.12 gonists also inhibit ADH release. The hormones of the suprarenal
One of its functions during fetal life may be to contribute to cortex and the posterior hypophysis possess an antagonistic effect
circulatory adjustment, facilitating the movement of water across on water excretion. Cortisol elevates the osmotic threshold for
the placenta from the mother to the fetus.12 ADH release. It also acts directly on the renal tubules, decreasing
ADH conserves water, increasing urinary concentration. At the the permeability to water and increasing the free water in the
collecting tubule, it enhances the hydro-osmotic flow of water absence of ADH.
from the tubule lumen to the medullary interstitium and con-
tributes to maintaining constant the osmolality and volume of the Oxytocin
body fluids. Occupation of 2.5% of the V2 receptors by ADH pro-
duces a complete antidiuretic effect. The release of ADH depends Oxytocin is a nonapeptide, synthesized in the paraventricular and
on several stimuli. The hypothalamus, the neurohypophysis, and supraoptic nuclei of the hypothalamus. It is transported in
the kidneys form an interrelated system that is in charge of body neurosecretory granules via neuronal axons to the neurohypo-
fluid homeostasis. The angiotensin-renin axis, which regulates physis, where it is stored together with an oxytocin-specific
sodium balance, is also connected with the hypothalamic-ADH- neurophysin. The release of oxytocin is stimulated by nerve
kidney system. The thirst center regulates the intake of water, impulses originating in the hypothalamus, which cause depolari-
whereas the kidney regulates water excretion. The effective os- zation of the neurosecretory terminals of the posterior lobe of the
molality of the intracellular liquid is the main regulator of thirst hypophysis. The subsequent release of oxytocin is a calcium-
and of ADH release. dependent process. The estrogens stimulate the release of oxytocin
and neurophysin. Oxytocin acts on the membranes of myoepi-
Effective osmolality = mean osmolality – (urea + glucose – 7.5) thelial and myometrial cells, increasing their force of contraction.
The osmoreceptor cells, located in the anterior hypothalamus, The sensitivity of the myometrium to oxytocin increases during
change their volume through the flow of water across their cell pregnancy. Hypophyseal concentrations of oxytocin similar to
membrane in response to changes in osmolality. In this way, there those in women are also found in men, though their function
is stimulation of the neurons that transmit nerve impulses to the is not known. Oxytocin is metabolized in the liver and kidney. The
supraoptic and paraventricular nuclei, provoking ADH release, and uterus and mammary gland also contribute to its elimination. It
to the cortex to detect the sensation of thirst. The blood pressure is used clinically to induce labor, to control hemorrhage after
and volume of the blood are secondary determinants of ADH incomplete abortion, and to treat altered milk flow. Its antidiuretic
secretion and of thirst. The receptors related to volume are located action is maximum after the administration of 40 to 50 mU/min.
in the carotid sinus and the aortic arch (high-pressure barorecep-
tors) and in the left auricle and lung (low-pressure receptors). PINEAL GLAND OR EPIPHYSIS
Decreases in plasma volume stimulate ADH release by reducing
the tonic inhibitory impulses sent by the vagus and glossopharygeal The pineal gland or epiphysis is a single, pinecone-shaped organ
cranial nerves (after multiple synapses in the brainstem) from the located on the roof of the third ventricle, close to the choroid
left atrium toward the hypothalamus. This process is a consequence plexuses and in front of the anterior quadrigeminal tubercles. It is
of the effect on the distention receptors of this structure and the innervated exclusively by postganglionar sympathetic fibers
pulmonary veins. Positive-pressure ventilation, quiet standing, and proceeding from the superior cervical ganglia. The pineal is
vasodilatation also act upon this mechanism, which permits derived from the ependymal cells of the third ventricle and is
restoration of plasma volume, even, at times, surpassing osmotic formed of parenchymatous cells (pinealocytes), sustained by a
inhibition. Sensitivity is lower than that of the osmoreceptors network of neuroglia. The pinealocytes have β-adrenergic recep-
because a decrease of 10 to 15% of circulation volume is required tors acted upon by norepinephrine, which is released by the
to produce a significant release of ADH. Once this point is reached, sympathetic nerve terminals and controls melatonin synthesis
ADH concentrations can increase up to 10-fold the values induced from serotonin. It also receives fibers from the CNS system
by hypertonicity. Increased plasma volume inhibits ADH release. through the pineal stalk. The neurotransmitters of the pineal gland
Activation of the carotid and aortic baroreceptors by hypotension are peptides or acetylcholine whose neuronal bodies are localized
produces a release of ADH. High concentrations of ADH may in several brain nuclei.
The physiologic significance of the pineal gland is not known, arising from the cervical ganglia and the vagus nerve, respectively.
although it is recognized that the pinealocytes have neurosecretory This innervation regulates the vasomotor system and, thus, the
ability. A wide range of biogenic amines are found within the blood flow of the gland. A fine network of adrenergic fibers
pineal gland including serotonin, norepinephrine, histamine, terminates at the thyroid cells, connecting with them through
dopamine, melatonin, GABA, and vasotocin. It also contains specific receptors, thereby demonstrating a direct function of this
hypothalamic peptides such as TRH and GH-inhibiting factor or system in the regulation of thyroid function.
somatostatin. Melatonin is a pineal gland hormone synthesized The anatomic relation of the thyroid to the recurrent nerves
from tryptophan and serotonin. One of the most important factors and to the parathyroid glands is important. The recurrent
that regulate melatonin secretion is the light-dark cycle. Stimu- laryngeal nerves arise from the vagus nerve on both sides. The
lation by light inhibits secretion and prolonged darkness increases right recurrent laryngeal nerve originates where the vagus nerve
it. Nocturnal levels are 10-fold higher than diurnal levels. The light crosses the first portion of the subclavian artery. It passes behind
information reaches the pineal gland by means of a multisynaptic this artery and descends 1 to 2 cm from the trachea next to the
nervous pathway connected with the retina. Increases in sym- thyroid where it penetrates the posterior larynx at the cricothyroid
pathetic activity, intense hypoglycemia, stress, and l-dopa admi- articulation. The left recurrent arises from the vagus where it
nistration stimulate its secretion. The β-adrenergic inhibitors crosses the aortic arch, passes behind the arch, and ascends next
decrease its synthesis and secretion. Melatonin inhibits gonadal to the thyroid within 1 to 2 cm of the trachea until it reaches the
function by decreasing gonadotropin secretion. This effect seems laryngeal muscles. Although their exact location varies, the two
to take place in the hypophyseal-hypothalamic system and, pairs of parathyroid glands usually lie on the posterior surface of
perhaps, directly in the gland itself. The function of melatonin in the thyroid lobes. The thyroid gland has a unique histologic
the brain is the induction of sleep. structure within the endocrine system, being formed by groups of
follicles of varying size (15–500 mm in diameter). The follicle is
formed by a layer of cylindrical epithelial cells filled with a mainly
THYROID GLAND colloidal substance and is the functional unit of the gland.
The thyroid hormones, T4 and T3 exert important actions during
fetal development participating in the growth, differentiation, and
maturation of the CNS. After birth and throughout life, the
Physiology
thyroid hormones participate in the regulation of several basic Iodine is an essential trace element for all vertebrates, being re-
metabolic processes, such as oxygen consumption and the meta- quired for the biosynthesis of the thyroid hormones. The body
bolism of the energy substrates and proteins. All organ systems obtains iodine by ingestion, and the requirements for this
require minimum levels of these hormones for normal func- substance increase with age. The range in children is 90 μg/kg/d
tioning. in the breast-fed infant to 120 μg/kg/d in children 10 years old.
Adult requirements are approximately 150 μg/kg/d.14 During
pregnancy and lactation, it increases to up to 200 μg/kg/d. Iodine
Anatomy is absorbed in the proximal small intestine in both the organic and
The thyroid is the first gland to appear during embryonic de- the inorganic forms. The inorganic form makes for the majority,
velopment and can be identified at 16 to 17 days of gestation. Of after hydrolysis of the organic compounds produced in the
endodermal origin, the thyroid arises from a proliferation of the gastrointestinal tract. The release of iodide after enzymatic
pharyngeal epithelium, migrating caudally at 40 to 50 days of hydrolysis is later completed in the liver and kidney. In this way,
gestation to attain its definitive position.13 It remains joined to its iodide forms part of the extracellular fluid iodide pool, which in
primitive origin by the thyroglossal duct, which later disappears. iodine-rich conditions, reaches concentrations of 1 to 1.5 mg/
The distal part of this duct persists in the adult and can undergo dL/min. As it passes through the circulation, this iodide is taken
hyperplasia, giving rise to a contiguous structure called the up by the kidneys, thyroid gland, gastric parietal cells, and salivary
pyramidal lobe. The ability of the thyroid to concentrate iodine glands. Iodide uptake by the parietal cells and the salivary glands
appears in the second embryonic trimester and hormone pro- is re-absorbed and recovered by the iodide pool; thus, there is
duction begins at 20 to 24 weeks of gestation. The thyroid is an competition only between the kidney and the thyroid. Renal
unpaired gland located in the anterior region of the neck in front iodide clearance is 30 to 40 mL/min and is not related to humoral
of the cricoid cartilages. It has two symmetrical lobes on either factors or iodide concentrations. For this reason, the thyroid is
side of the trachea and larynx. These lobes are joined by a part of subjected to a degree of competition unrelated to its necessities.
the glandular structure located above the trachea, called the Thyroid iodide clearance varies according to the functional state
isthmus. If the pyramidal lobe is present, it is attached to the of the gland. The intrathyroid iodine pool is, by far, the largest in
isthmus. The thyroid is large, weighing 1 to 3 g in the newborn the organism. When the availability of iodine is abundant, this
and 20 g in an adult. It is richly vascularized by the superior pool reaches 8000 mg, the majority in the form of iodinated amino
thyroid arteries, arising from the external carotids, and by the acids. Iodine elimination is carried out mainly by the kidneys.
inferior thyroid arteries, which arise from the subclavian artery. With a daily ingestion of 500 mg, for example, 488 mg is excreted
The amount of blood that reaches this gland (4–6 mL/min/g) is mainly by the kidney as iodide, and the remaining 12 mg is
greater than the flow to a highly vascular organ such as the kidney eliminated in the feces, essentially in the form of organic iodine.
(3 mL/min/g). With increases in size and hyperfunctioning of the The main function of the thyroid gland is to generate and
gland, vascularization increases accordingly, at times surpassing release the thyroid hormones, T4 and T3, produced in the thyroid
1 L/min, giving rise to a thrill and a thyroid murmur. The thyroid follicles.15,16 The complex process of thyroid hormone biosynthesis
is innervated by adrenergic and cholinergic systems, with branches can be summarized as follows: (1) uptake of plasma iodine by
means of the iodine pump in the thyroid cell, resulting in an iodine tal development, serious alterations of the CNS are produced and
concentration 40 times greater than plasma levels; (2) organization when a deficit occurs before growth is complete. The mechanism
of iodine by the peroxidases; (3) iodination of the tyrosyl of action of the thyroid hormones in the peripheral tissues (Figure
components of thyroglobulin (glycoprotein previously formed by 12–3) has not yet been clearly defined. They exert their action after
the thyroid cell and principal component of follicular colloid) for they are introduced in the cell, but by contrast to the steroid
the elaboration of monoiodotyrosine (MIT) and diiodotyrosine hormones, they do not require binding to cytosolic receptors to
(DIT); (4) coupling of the iodotyrosines by means of peroxidase penetrate the cell nucleus. The nuclear receptors of the thyroid
action to form T3 and tetraiodothyronine or T4; and (4) thyroid hormones have been recognized for some time, but recently, two
cell uptake of colloid droplets by pinocytosis or endocytosis, and types of receptors (TRa and TRb) have been identified and cloned.
after proteolytic cleavage of the thyroglobulin–thyroid hormone The binding of T3 to these nuclear receptors gives rise to the T3-TR
bonds, release of the hormone to the circulation. complex, which in turn functions by binding to specific DNA
The thyroid gland forms a part of the hypothalamic- sequences or response elements (TRE, thyroid hormone response
adenohypophyseal–dependent endocrine system. Its principal element) found in the regulating regions of the genes that respond
mechanism of functional regulation is TSH negative feedback. The to thyroid hormones. There are different types of TREs because
thyroid is also governed by a system of autoregulation, separate T3 controls the expression of numerous genes. This is the main
from TSH secretion, and closely related to the amount of iodine in mechanism of action of the thyroid hormones through which the
the organism.17 The more iodine there is in the diet, the less is synthesis of various proteins is regulated. Besides this central
taken up by the thyroid and vice versa. The rapid administration mechanism, the thyroid hormones activate mitochondria, through
of considerable amounts of iodine notably reduces the organi- the action of a specific mitochondrial protein and also a primary
fication of iodide, a phenomenon known as the Wolff-Chaikoff effect on the cytoplasmic membrane regulating the transcellular
effect. The effect is transitory; if the supply continues, the gland flow of substrates and cations. Through these highly complex
adapts to the situation, and “escape” occurs, in which thyroid mechanisms, the thyroid hormones activate energy metabolism
function may even rise above normal. Nearly the total amount of by increasing calorie consumption and regulate the growth and
circulating T4 is strongly bound to various proteins, mainly a maturation of tissues and the turnover of numerous substrates,
globulin, thyroxine-binding globulin (TBG); a prealbumin, vitamins, and hormones in the body. The biologic activity of T3 is
thyroxine-binding prealbumin; and albumin, which carry 70 to several times greater than that of T4 and its metabolic effects are
75%, 15 to 29%, and 5 to 10% of the transporting function, res- more rapid. T3 metabolism is also faster, with a turnover three or
pectively. T3 transport is carried out by TBG and, to a small degree, four times greater than that of T4. These data demonstrate the
by albumin. Only the free fraction is responsible for biologic importance of T3 in determining the metabolic state of the person
actions in the peripheral tissues. Only 0.03% of the total amount and cast doubt on the intrinsic activity of T4. It may be that all the
of T4circulates freely. The percentage of free T3 is much greater, actions of T4 are produced after its peripheral transformation into
reaching 0.3% of the total hormone. Thus, although the total T3. This metabolic process constitutes a significant extraglandular
concentrations of the two hormones are very different, the levels regulation mechanism of thyroid function. Various clinical situa-
of biologically active free fractions are more similar. Normal tions are characterized by decreased peripheral conversion of T4
serum concentrations of the thyroid hormones in pediatric patient into T3, which is almost always accompanied by increases in rT3.
are listed in Table 12–4. The daily secretion of T4 is approximately Thyroid gland dysfunction, with overproduction or underpro-
80 mg. Approximately 35% of this production is converted in the duction of T3 or T4, may result in adverse patient responses during
periphery into T3, constituting 80% of the circulating T3. Likewise, the perioperative period. The overproduction of thyroid hor-
35% of the T4 produced is transformed into reverse T3 (rT3), which mones results in an exaggerated response to surgical stimulation
has no known metabolic effects. and potentiates the administration of medications that stimulate
The effect of the thyroid hormones extends to all the organs the sympathetic nervous system. Modified drug metabolism can
and tissues. These hormones participate in morphogenesis, produce organ toxicity under anesthesia (hepatic toxicity with
growth differentiation, and development by regulating numerous volatile anesthetic drugs and nephrotoxicity with enflurane).18,19
metabolic processes such as oxygen consumption, thermogenesis, Controlled studies in hyperthyroid patients have not demonst-
mineral balance, and the synthesis and breakdown of proteins, rated an increased requirement for anesthetic agents, despite the
carbohydrates, and lipids. Deficiencies of the thyroid hormones clinical impression to the contrary, but the elevations in body
produce several effects depending on age. During fetal and neona- temperature in these patients can alter drug metabolism as well as
TABLE 12-4. Normal Serum Concentrations in Pediatric Patient (mean ± 2 de)

Age T4, mg/dL T3, ng/dL TBG, mg/dL TSH, mU/mL
Umbilical cord 10.2 (7.4–13) 45 (15–75) 5.6 9 (<2.5–17.4)
1–3 d 17.2 (11.8–22.6) 124 (32–216) 5.0 8 (<2.5–13.3)
2–4 wk 11 (7–15) 190 (160–240) — 4 (0.6–10)
4–12 mo 11 (7.8–16.5) 176 (110–280) 4.4 2.1 (0.6–6.3)
1–5 y 10.5 (7.3–15) 168 (105–269) 4.2 2 (0.6–6.3)
5–10 y 9.3 (6.4–13.3) 150 (94–241) 3.8 2 (0.6–6.3)
10–15 y 8.1 (5.6–11.7) 113 (83–213) 3.3 1.9 (0.6–6.3)
de = dose equivalent; T3 = triiodothyronine; T4 = thyroxine; TBG = thyroxine-binding globulin; TSH = thyroid-stimulating hormone.
Physiology of Calcium
and Phosphorus Metabolism
PTH, together with 1,25-(OH)2-D3 (active metabolite of vitamin
D) and calcitonin, forms a complex endocrine system that controls
the metabolism of calcium and phosphorus in all vertebrates.
Other factors (diet, physical agents), hormones (GH, thyroxine,
gonadal hormones, cortisol, somatomedins), and some incom-
pletely characterized substances also play roles in various aspects
of the regulation and modulation of effector organ response to
these hormones. Calcium, a bivalent metal, is the most abundant
cation of the organism accounting for 2.24% of lean body weight
in adults. It is found in the musculoskeletal system and participates
in numerous biologic processes that require a constant, precise
level of calcium. It is essential for enzymatic system function,
blood coagulation, hormonal action, nerve and muscle excitability,
and muscle contractility. Ninety-nine percent is found in the bone,
Figure 12-3. Mechanism of action of the thyroid hormones.
forming insoluble and relatively inaccessible hydroxyapatite crys-
tals. The remainder is found mainly in muscle and the extra-
hemodynamic and ventilatory needs. Neuromuscular blocking cellular fluid. From 0.5 to 1% of the body’s calcium is rapidly
agents need to be carefully selected with avoidance of agents such exchangeable with plasma. The normal serum calcium con-
as pancuronium which may induce tachycardia, and those that centration is 8.5 to 10.5 mg/dL. Regulation is precise and varia-
may result in histamine release. In the reversal of nondepolarizing tions do not exceed 1.5 mg/dL. Total serum calcium is composed
neuromuscular blockade, glycopyrrolate is a logical choice because of three fractions. The ionized fraction (47%) is biologically active
it has less chronotropic effect than atropine. The underproduction and directly regulated by the hormones. The ionized fraction
of thyroid hormones cause a hypodynamic cardiovascular state together with the complex fraction (6%), which is bound to
with bradycardia, decreased cardiac output and stroke volume, as phosphates, citrates, and bicarbonate, constitutes the diffusible
well as exaggerated sensitivity to depressant drugs, decreased fraction. The protein-bound fraction (47%) is nondiffusible. Four
intravascular volume with increased systemic vascular resistance, fifths of the total circulating protein-bound calcium is bound to
and unresponsive baroreceptor reflexes. There may be reduced albumin and the remainder to globulin.
metabolism of anesthetic drugs, particularly opioids. Reduced Under normal conditions, 30 to 40% of dietary calcium (600–
adrenal cortical function often accompanies hypothyroidism. 1000 mg) is absorbed in the small intestine. The nonabsorbed
calcium plus the content of the secreted digestive juices (200 mg/d)
make up the fecal excretion. This process is influenced by the
PARATHYROID GLANDS calcium content in the diet and other components of the diet with
various factors increasing absorption (lactose, fatty acids) or
Anatomy decreasing absorption (phosphates, phytates). The net calcium
The parathyroid glands are paired organs that originate in the absorption is generally equivalent to urinary excretion. Calcium
endodermis of the third (inferior parathyroids) and fourth excretion to the intestinal lumen is a nonregulated constant
(superior parathyroids) branchial pouches. There are normally process, whereas net absorption is regulated by 1,25-(OH)2-D3.
four parathyroids in humans, although in 2 to 5.5% of the Daily adult calcium requirements are 500 to 600 mg/d, but given
population, six to eight are present. The parathyroids are small, the variability of the daily dietary ingestion, 800 mg/d is recom-
weighing 30 to 50 mg each (somewhat more in women). They mended.22 An additional 200 mg is required during growth, lacta-
migrate with the thyroid isthmus, a fact that determines a variable tion, and pregnancy and in persons older than 60 years. The
ectopic localization, anywhere from the angle of the mandible to calcium requirement in children aged 1 to 10 years is at least 800
the pericardium. The parathyroids may be located in the thyroid mg/d.22
gland capsule or embedded in the thyroid tissue but are always Calcium is absorbed in the intestine by two processes, passive
individualized by a capsule of conjunctive tissue, through which diffusion and active transport by carrier proteins, whose synthesis
vascular and nervous elements penetrate to the interior. The is induced by 1,25-(OH)2-D3. Passive diffusion is produced when
parathyroid glands are composed of three main cell types: chief, calcium concentrations in the lumen are very high, generating a
oxyphil, and clear cells. The chief cells are the most abundant and positive concentration gradient. The bone is the main reservoir of
are responsible for secretion of parathyroid hormone (PTH) and calcium, but exchange between bone and plasma is low. The
a carrier protein (SP-I) whose function has not been clearly mobilization of calcium from the bone is subject to cell control
defined.20 During fetal life, these cells produce PTH-related and contragradient transport. Calcitonin decreases the mobiliza-
peptide (PTHrP), which is involved in fetal bone metabolism and tion of calcium and PTH increases it. Calcium is filtered by the
transplacental transport of calcium.21 The oxyphilic cells comprise renal glomeruli. There is 99% tubular re-absorption of the filtrate,
less than 5% of the cells of the parathyroid gland. They are dis- of which only 10% is regulated by PTH and 1,25-(OH)2-D3 in the
persed among the chief cells and their function is unknown. The distal tubule. The capacity of the kidneys to eliminate calcium
clear cells are larger cells that do not seem to have secretory func- is limited. Thus, in conditions of increased bone resorption or
tion. They are prominent in some cases of glandular hyperplasia. greater intestinal absorption, the excretory function can be
overwhelmed, producing hypercalcemia. Likewise, in hypocalce- to PTH, a single-chain polypeptide containing 84 amino acids.
mia, the kidney’s capacity to decrease calcium excretion (~100 PTH is found within the free chief cells or stored in secretory
mg/d) is clearly limited. The physiologic response to calcium granules for later release. The intact hormone goes through at least
overload includes by a fast mechanism that inhibits PTH secretion one more cleavage in the secretory granules to generate inactive
and its effects in bone and kidney and a slow mechanism that carboxy-terminal fragments that can be released with the intact
decreases 1,25-(OH)2-D3 synthesis and its intestinal effects. hormone to the circulation. The precursors (prepro-PTH and pro-
The phosphorus content in the body is approximately 700 g, of PTH) do not have known biologic activity and are not detected in
which 85% is in the skeleton and 15% in soft tissue and body fluid. the circulation. The main regulator of PTH secretion and storage
Osseous phosphorus is intimately associated with calcium, form- is plasma ionized calcium through a negative-feedback mecha-
ing crystals of hydroxyapatite (amorphous calcium phosphate). nism. When plasma ionized calcium reaches high levels, a PTH
Extraosseous phosphorus is essentially intracellular. Very little is breakdown pathway is quickly activated within the chief cells,
inorganic, because the majority is bound to carbohydrates, lipids, provoking PTH proteolysis without affecting the hormonal
and proteins. Phosphorus is necessary for cell function and precursors. Low levels of calcium ion inhibit this process. A
organic metabolic processes because it regulates a number of nonsuppressible basal PTH secretion in proportion to the mass of
enzymes. It plays an important role in providing oxygen to the chief cells in the gland is independent of extracellular calcium. The
tissues as well as regulating the levels of 2,3-diphosphoglycerate extracellular magnesium concentration also participates in regula-
and adenosine monophosphate (ATP) in the red blood cells. It tion of PTH secretion. Thus, important deficits of magnesium
forms a part of the urine and plasma buffer systems and is involved would produce decreases in hormone production with resistance
in the energy-storing processes of the organism. An adult ingests to its effects in the peripheral target cells.
approximately 1400 mg/d of phosphorus, 60% of which is PTH metabolism occurs in the liver, kidney, and to a lesser
absorbed by passive diffusion and active transport (similar to that degree, bone. In the liver and kidney, intact PTH is cleaved to form
of calcium) mediated by an 1,25-(OH)2-D3-stimulated carrier inactive carboxy-terminal and active amino-terminal fragments.
protein. Intestinal absorption is concentrated in the duodenum The carboxy-terminal fragments, together with a small proportion
and ileum. There is a linear relationship between net absorption of the amino-terminal fragments and intact PTH, are eliminated
and dietary phosphorus intake. Under normal conditions, the mainly by glomerular filtration. Re-uptake of the amino-terminal
amount of phosphorus excreted in the urine is equal to the net fragments occurs in the tubules. In parathyroid gland venous
digestive absorption. Normal plasma phosphorus varies from 2.2 blood, intact PTH makes up 80% of secretion and the fragments
to 4.4 mg/dL in adults. Although levels are higher in children, they 20%, whereas at the peripheral level, the contribution of carboxy-
decrease after puberty to reach normal adult levels. Ninety percent terminal fragments is 80% and PTH is reduced to 10%. The
of inorganic phosphorus circulates in a free form or bound to amino-terminals are biologically active, but have a short circulat-
monovalent and divalent anions and 10% is bound to proteins. Of ing half-life, similar to that of intact PTH (~20 min), whereas the
the 7000 mg of phosphorus that is filtered daily by the kidneys, carboxy-terminals are inactive and have a longer half-life (40 min).
6100 mg is re-absorbed in the proximal tubule by a sodium- PTH plays a pivotal role in the homeostasis of extracellular
dependent, saturable process (maximum tubular transport) and calcium and is essential for protecting the organism against
900 mg is excreted in urine. PTH is the main regulator, inhibiting hypocalcemia by regulating mineral mobilization from the bone,
renal re-absorption of phosphorus, whereas calcitonin and 1,25- kidney, and intestine (Figure 12–4). In the kidney, PTH produces
(OH)2-D3 are less important. Phosphorus regulation in hyper- a rapid and dramatic increase in urinary phosphate excretion,
phosphatemic and hypophosphatemic states involves both independent of changes in glomerular filtration. This is carried
immediate and delayed mechanisms. Decreases in serum phos- out by decreases in proximal tubule re-absorption of this ion. PTH
phorus produce initial stimulation of 1,25-(OH)2-D3 synthesis in induces increased tubular re-absorption of calcium and magne-
the kidney, greater mobilization of calcium and bone phosphorus, sium and urinary excretion of bicarbonate by inhibiting its pro-
and efficient adaptation of renal tubule re-absorptive capacity. The ximal tubule re-absorption. Hypercalciuria can predominate in
1,25-(OH)2-D3 stimulates intestinal absorption of calcium and situations of chronic hypercalcemia despite elevated PTH levels.
phosphorus and enhances mobilization of these ions from the This is explained by the fact that PTH in the distal tubule affects
bone. This cascade of events inhibits release of PTH, which in turn only 10% of the calcium that is re-absorbed. Ninety percent of the
increases renal phosphorus re-absorption with a tendency to filtered load of calcium is re-absorbed by a nonsaturable PTH-
restore normal phosphorus levels. In hyperphosphatemia, there is independent process and is linked to sodium transport in the
a decrease in ionized calcium which stimulates PTH release, thus proximal tubule and Henle’s loop. cAMP is involved in the PTH-
provoking phosphaturia and restoring serum phosphorus to induced phosphaturia mechanism. PTH is bound to a receptor on
normal. The delayed defense mechanism of the organism to the basal tubular cell, activating the adenyl cyclase system and
prolonged variations in phosphorus levels depends mainly on the increasing cAMP in the target cells.23 In the skeleton, PTH initially
re-absorptive capacity of the renal tubule, which increases or stimulates osteocyte osteolysis and bone resorption by preexisting
decreases according to phosphorus secretion. This mechanism is osteoclasts, generates new osteoclasts, and depresses osteoblast
largely PTH-independent, and an interval of more than 48 hours function. The final effect of these processes is increased calcium
is required to reach the maximum effect. and phosphate release to the blood. In the long term, PTH
stimulates generation of coupling factors for bone remodeling and
can even override direct inhibition of the osteoblasts and provoke
Parathyroid Hormone or Parathormone differentiation of cells with osteoblast function and formation of
Pro-PTH, a 90-amino acid fragment, is obtained from prepro- new bone.24 Because the osteoblasts, but not the osteoclasts, have
PTH, a 115-amino acid precursor, in the smooth endoplasmic PTH receptors, it is possible that a part of the effects of this
reticulum. Cleavage of another hexapeptide results in conversion hormone on the osteoclasts is mediated by the former. It has been
Figure 12-4. Biologic activity of parathormone (PTH).
demonstrated that PTH is less effective in promoting bone

resorption in the absence of 1,25-(OH)2-D3. PTH induces renal
synthesis of 1,25-(OH)2-D3, which stimulates intestinal absorption
of calcium and phosphorus.
Vitamin D
Vitamin D and its metabolites form a group of steroid compounds
that also play an active role in the regulation of calcium and
phosphorus metabolism. Vitamin D3 (cholecalciferol) and vitamin Figure 12-5. Vitamin D, metabolism, and biologic activity.
D2 (ergocalciferol) are absorbed from food by passive diffusion in
the presence of biliary salts in the gastrointestinal tract. These
compounds, bound to chylomicrons, pass through the lymphatic tion seems to be influenced by the concentration of substrate
system to the general circulation, where they circulate bound to a (vitamin D3). Calcium, phosphorus, and PTH have no influence
carrier protein (alpha globulin). Under normal conditions, on the activity of this enzyme, although 1,25-(OH)2-D3 and
vitamin D is mainly produced in the skin (granular stratum of the anticonvulsant medications depress it by incompletely defined
epidermal cells). Here, the ultraviolet rays of the sun transform mechanisms. The 25-(OH)-D3 is the most abundant vitamin D
the provitamin 7-dehyrocholesterol into previtamin D3 by non- metabolite in the blood and is 100 times less powerful in
enzymatic photochemical conversion (Figure 12–5).25 Previtamin stimulating intestinal calcium absorption than 1,25-(OH)2-D3. In
D3 then slowly converts to vitamin D3 at body temperature. It the mitochondria of the proximal tubules of the kidney, 25-(OH)-
circulates bound to alpha globulin, a carrier protein common to all D3 is hydroxylized in position 1 to produce 1,25-(OH)2-D3 the
the vitamin D metabolites, but with an affinity 200 times greater most active and biologically potent metabolite of vitamin D for
than for vitamin D3. This protein is no more than 3% bound with inducing bone resorption and intestinal absorption of calcium and
vitamin D3 in physiologic conditions, and thus, it is a large phosphorus. It circulates at very low concentrations (~30 pg/mL)
potential reservoir. Endogenous levels of vitamin D3 are tightly and has a half-life of 2 to 4 hours. A second hydroxylation takes
controlled because, despite prolonged exposure to sunlight, place in the kidney and, through 24R-hydroxylase, gives rise to
increases are minimum. This control is probably through the 24,25-(OH)2-D3. With a half-life of 6 hours, this compound is
regulation of vitamin D release in the skin and not by inhibition present in higher quantities in plasma (1–5 ng/mL) and has a
of hepatic 25-hydroxylase. The adipose and muscle tissues contain regulation contrary to that of 1,25-(OH)2-D3. It has little biologic
the largest deposits of vitamin D in the organism. activity, similar to that of 25-(OH)-D3.
Synthesis of the active form of vitamin D is carried out by PTH secretion is stimulated in hypocalcemia and this, in
successive hydroxylations. The first hydroxylation results in 25- turn, stimulates renal 1-hydroxylase, which results in greater
(OH)-D3 production and takes place primarily in the liver, with synthesis of 1,25-(OH)2-D3. This process tends to restore normal
90% occurring in the microsomal system. This initial hydroxyla- calcium concentrations and at the same time suppresses 24-
tion also occurs in the kidney and intestine. Although there is no hydroxylation. The gradual increases in calcium produces a
retroactive inhibition of 25-(OH)-D3 on 25-hydroxylase, regula- reduction in 1,25-(OH)2-D3 synthesis and parathyroid gland
activity. Type 1-hydroxylase activity is also present in the bone, calcium, although its main effect is vasodilatation. This peptide is
intestine, and platelets, and type 24-hydroxylase activity is present also produced by certain tumors and, thus, can be used as a tumor
in the intestine, cartilage, and bone. Hypophosphatemia increases marker. In patients with medullary carcinoma of the thyroids and
1,25-(OH)2-D3 levels and decreases production of 24,25-(OH)2- other neoplasms (bronchial carcinoma), 32-amino acid calcitonin
D3. Similar to the effects of calcium, increased serum phosphorus can coexist with circulating forms of high-molecular-weight
inhibits the production of 1,25-(OH)2-D3 and stimulates synthesis immunoreactive calcitonin. The sequences of calcitonin have been
of 24,25-(OH)2-D3. There are approximately 20 metabolites of deciphered in different species (human, pig, sheep, cattle, salmon,
vitamin D, with biologically inert calcitroic acid being the main and rat) and have shown to have in common nine amino acids and
metabolite of 1,25-(OH)2-D3. Excretion of vitamin D metabolites a carboxy-terminal proline amide. All are active in humans,
takes place mainly through the bile, and there is evidence of although their potencies are different. Salmon calcitonin is 10
enterohepatic circulation for 25-(OH)-D3 and 1,25-(OH)2-D3. times more powerful than human calcitonin, being more resistant
Vitamin D regulates the intestinal absorption of calcium and to breakdown and having a higher affinity for receptors in the
phosphorus. Ionized calcium is absorbed by the intestinal tract by bone and kidney.26
an active transport process (65% in the ileum and 17% in the Calcitonin is secreted in response to increases in plasma
jejunum) and by passive diffusion (only 15%). The active transport calcium concentrations. When calcium concentrations exceed
is vitamin D–dependent and is characterized by the entrance of 9 mg/dL, there is a positive correlation between serum calcium
calcium through the microvilli of the intestinal cells against the concentration and calcitonin levels. There is also an unidentified
concentration gradient and by active expulsion of the ion into the relationship between calcitonin production and gastrointestinal
blood through the lateral basement membrane. Neither calcitonin hormones (gastrin, cholecystokinin, glucagon), β-adrenergic
nor PTH directly affects this absorption. The process is regulated catecholamines, estrogens, and vitamin D. Calcitonin intervenes in
by 1,25-(OH)2-D3, which traverses the basolateral border of the calcium metabolism at different levels, particularly in bone, where
intestinal mucosa cell and interacts with a specific receptor. The it inhibits osteoclast bone resorption and the activity of certain
1,25-(OH)2-D3 receptor complex enters the nucleus, inducing the enzymes that increase with PTH (Figure 12–6). This effect in the
production of calcium and phosphorus carrier protein mRNAs. bone is greater in situations of increased in bone remodeling (e.g.,
Two other enzymes related to intestinal calcium absorption, growth, Paget’s disease) or with previous vitamin D or PTH
alkaline phosphatase and calcium-dependent ATPase, have been stimulation. With prolonged administration, its physiologic effects
isolated. After migrating from the luminal pole to the basolateral decrease (“escape”). The hormonal action requires the activation
border of the intestinal cell, calcium passes into the blood together and participation of adenyl cyclase. The inhibitory action on bone
with phosphorus. This process requires a high sodium gradient. resorption does not accompany changes in serum calcium in
The role of vitamin D in regulation of the passive diffusion process normal conditions. In the intestine, calcitonin facilitates calcium
is not known. In the bone, 1,25-(OH)2-D3 promotes bone absorption, and in the presence of calcium in the intestine, various
resorption, which in conjunction with its stimulating action on gastrointestinal hormones that stimulate calcitonin secretion
the net calcium absorption in the intestine favors a mineral-rich (gastrin, cholecystokinin) are produced. Calcitonin administration
environment in the areas of bone remodeling, making possible transiently increases urinary excretion of calcium, phosphorus,
mineralization of new bone matrix. It has been provend that 1,25- sodium, potassium, and magnesium. The phosphaturic effects are
(OH)2-D3 stimulates differentiation of the osteoclast progenitors to not mediated by PTH. Calcitonin binds to specific renal receptors
mature cells, an effect that is enhanced by PTH. In the kidney, with adenyl cyclase activation. In Paget’s disease, calcitonin
1,25-(OH)2-D3 increases tubular re-absorption of calcium and administration has analgesic effects, which seem to be mediated
phosphorus. through a beta endorphin. This fact, together with the presence
of calcitonin-like peptides in the CNS, indicates its possible role as
a central neurotransmitter or modulator. The physiologic function
Calcitonin
Calcitonin is a hormonal, 32-amino acid polypeptide that is
secreted by the parafollicular C cells of the thyroid gland in
response to hypercalcemia. Its primary physiologic effect is the
inhibition of bone resorption. The C cells originate in the fetal
neural crest, migrate caudally, and subsequently localize in the last
brachial pouch. They later reach their definitive site in the thyroid
gland and, to a lesser degree, in the thymus and parathyroid
glands. They are mainly found in the internal and medial part of
the thyroid lobes. The gene responsible for calcitonin’s complex
biosynthesis is located on chromosome 11. The hormone is
formed from a precursor molecule, preprocalcitonin, which
cleaves to become procalcitonin. This large polypeptide gives rise
to calcitonin at its median region and to 21-amino acid katacalcin
from its extreme amino-terminal. Katacalcin has effects that serve
to lower serum calcium values. It is secreted simultaneously with
calcitonin in pathologic states including medullary carcinoma of
the thyroid.
The calcitonin gene codifies a protein, calcitonin gene–related
peptide (CGRP), which has a weak action of lowering serum Figure 12-6. Calcitonin, physiologic effects.
and importance of calcitonin are still not well established because hypoparathyroid state further predisposing these patients to
calcitonin deficiency does not produce a defined clinical process. hypocalcemia.30 In rare circumstances, DiGeorge’s syndrome,
characterized by hypoplasia or aplasia of the parathyroid and
thymus gland, congenital heart disease, and abnormalities of
Anesthetic Implications chromosome 22, may present as neonatal hypocalcemia. These
of Calcium Disorders patients also have associated defects in cellular immunity.31
The evaluation of disturbances in calcium homeostasis must be
made by measurement of ionized calcium concentrations because
this is the physiologically active form of calcium. The ionized
SUPRARENAL GLANDS
calcium plasma concentration is dependent on the arterial pH The suprarenal (adrenal) glands are paired structures located
(increased by acidosis and decreased by alkalosis). at the upper pole of the kidney. They perform the functions of
two distinct and well-differentiated endocrine glands. The cortex
Hypercalcemia of the suprarenal glands is of mesodermal origin. It synthe-
sizes steroid hormones, which are classified according to their
Potential causes of hypercalcemia in the pediatric population in- predominant biologic effects into glucocorticoids, mineralocor-
clude primary hyperparathyroidism, vitamin A and D intoxica- ticoids, and androgens. The suprarenal medulla, located in the
tion, immobilization, malignancies, sarcoidosis, and milk-alkali interior of the gland, is of ectodermal origin and forms a part of
syndrome. The perioperative management is based on the main- the sympathetic-adrenal system, which belongs to the autonomic
tenance of hydration and urine output to facilitate calcium ex- or visceral system. The medulla synthesizes, stores, and secretes
cretion, avoidance of nephrotoxic medications, recognition of the catecholamines.
physical signs and symptoms of hypercalcemia, and continuous
monitoring of the electrocardiogram. However, there is evidence
that QT intervals may not be reliable indices of changes in plasma Suprarenal Cortex and Steroid Hormones
calcium levels. There is no evidence that specific anesthetic tech-
The suprarenal glands are small, weighing 4 to 5 g at birth, reduced
niques or medications are better in such patients. The response to
to less than 1 g in normal infants aged 1 year, and have an adult
neuromuscular blocking agents may be unpredictable, and
weight of 4 to 6 g. The cortex contains 90% of their mass. They
therefore, use of short-acting agents, reduction of the initial dose,
are highly vascularized glands. Arterial blood enters by the
and monitoring with a peripheral nerve stimulator are suggested.27
capsular plexus through branches of the inferior diaphragmatic
arteries, aorta, and renal branches. Venous blood drains through
Hypocalcemia a central vein to the renal vein on the left side and the inferior cava
A low plasma albumin concentration remains the most common on the right. Three zones having different cell types are recognized
cause of a low total serum calcium concentration; however, the in the suprarenal cortex, including the zona glomerulosa consist-
ionized calcium may be normal. In infants and children, common ing of small cells; the zona fasiculata, the largest zone, formed of
causes of a low ionized calcium concentration include hypopara- clear cells with lipid inclusions; and the internal zona reticularis,
thyroidism, acute pancreatitis, vitamin D deficiencies, hyperphos- formed of eosinophilic and lipofuscin granules. The suprarenal
phatemia, and renal failure. The rapid infusion of calcium cortex forms in the sixth week of gestation by condensation of
chelators (edetate and citrate in same radiographic contrast media mesodermal tissues adjacent to the coelomic epithelium. In this
phase, the internal fetal zone, where dehydroepiandrosterone
or citrate in blood-stored transfusion), or their slow metabolism
sulfate (DHEA-S) synthesis predominates over cortisol, and the
or elimination owing to hypothermia or hepatic/renal dysfunc-
external definitive zone, which gives rise to the definitive cortex,
tion, can also reduce plasma calcium concentrations. Alkalosis
can be distinguished. After birth, the fetal zone progressively
caused by hyperventilation or the intravenous administration of
disappears and is substituted by the definitive zone at 6 months.
sodium bicarbonate can alter calcium binding to proteins and
Ten percent of premature and newborn babies have accessory
result in low ionized calcium concentrations.28 During the suprarenal glands consisting only of cortical cells. The majority of
perioperative period, the prompt recognition of hypocalcemia is these disappear during childhood.
necessary because of the potential deleterious physiologic effects The steroid hormones are derived from a common precursor,
on the cardiovascular system. Typical electrocardiographic chan- cholesterol, which is obtained from dietary ingestion or syn-
ges (prolonged QT) or, more frequently, exaggerated hypotension, thesized in the cell. Eighty percent of the cholesterol used for
secondary to anesthetic drug administration, are signs of the steroidogenesis in the suprarenal cortex cells comes from plasma
decreased plasma ionized calcium concentration. The monitoring low-density lipoproteins (LDL). These are taken up by membrane
of the electrocardiogram, arterial blood gases, arterial pH, plasma receptors and internalized. Cholesterol esters are hydrolyzed in
albumin, and plasma ionized calcium concentrations should be the lysosomes by cholesterol esterases and cholesterol is released.
part of the intraoperative management. The effect of nondepola- The remaining 20% is synthesized by the cells from acetate and
rizing neuromuscular blocking agents may be potentiated by coenzyme A (acetyl CoA). ACTH increases the number of LDL
hypocalcemia. Preterm neonates, neonates of diabetic mothers, receptors and cholesterol sterase activity, increasing the amount
and neonates with birth asphyxia are particularly prone to of free intracellular cholesterol. In the structure of all the steroid
neonatal hypocalcemia.29 In the preterm neonates, the immaturity hormones, there is a common cyclopentanoperhydrophenan-
of the renal system results in the decreased renal excretion of threne nucleus. The 18-carbon atom derivatives (C-18) are known
phosphate and a resulting high plasma concentration that inhibits as estranes, the C-19 derivatives as androstanes, and the C-21
calcium resorption. In addition, the kidney shows a relatively as pregnanes. Conversion of cholesterol into the various steroids
refractory response to PTH, and there is a relative and transient is carried out by the action of an enzyme system containing
cytochrome P450, which requires NADPH (nicotinamide adenine regulated by a hypothalamic-hypophyseal system through a
dinucleotide phosphate, reduced form) and molecular oxygen, CRF-ACTH-cortisol negative-feedback mechanism. ACTH is a
located in the mitochondria or the endoplasmic reticulum hypophyseal peptide that acts by binding to specific receptors and
(microsomes). acting through the cAMP system in the presence of calcium.
Conversion of cholesterol to pregnenolone occurs in the mito- ACTH has immediate effects on steroidogenesis. Within minutes,
chondria and is regulated by ACTH, angiotensin II, and potas- it increases the transformation of cholesterol into pregnenolone
sium. In the smooth endoplasmic reticulum, under the action of by activation of the enzyme required for this conversion. Chronic
steroid 3-β-dehydrogenase, pregnenolone undergoes various ACTH secretion increases protein and DNA synthesis in the sup-
transformations. Pregnenolone is transformed to progesterone in rarenal cortex cells, provoking their hypertrophy and hyperplasia.
the zona glomerulosa. In the zona fasiculata and zona reticularis, The glucocorticoids inhibit the secretion and synthesis of CRF,
conversion of pregnenolone to 17-α-hydroxypregnenolone pre- ACTH, and arginine-vasopressin.33
dominates. In the zona glomerulosa, progesterone follows the The principal regulator of aldosterone production, angiotensin
pathway of aldosterone synthesis and 17-α-hydroxyprogesterone II, acts by binding to high-affinity membrane receptors associated
follows that of cortisol. By means of hydroxylations in position 21 with guanosine diphosphate (GTP)–dependent proteins. Angio-
and the action of a P450-specific cytochrome, deoxycorticosterone tensin II is produced under the proteolytic action of renin on
and 11-deoxycortisol, respectively, are formed. These steroids pass circulating plasma angiotensinogen (globulin of hepatic origin) to
to the mitochondria, where an 11-β-hydroxylation-specific P450 form the decapeptide angiotensin I, which has a weak vasocon-
cytochrome catalyzes their transformation into corticosterone and strictor effect. Angiotensin I passes into the circulation and, by the
cortisol. All three zones of the suprarenal cortex are active. There action of angiotensin-converting enzyme (ACE), which is present
is a “functional compartmentation” because of the distribution of in numerous tissues (particularly the lung), is converted into
the enzymes involved in steroidogenesis. Thus, aldosterone is angiotensin II. Besides inhibiting renin release, this octapeptide
produced only in the zona glomerulosa, the most external part, has a potent direct vasoconstrictor effect and is the suprarenal
whereas cortisol and the androgens are synthesized exclusively in stimulant of aldosterone synthesis. Angiotensin II has a short half-
the zona fasiculata and the zona reticularis.32 The suprarenal life (1–2 min) and is converted into other peptides by the action
glands also synthesize androgens, 19-carbon atom steroids, of an aminopeptidase. One of these peptides, angiotensin III, a
which result from the removal of the lateral C-17 chain of 17-α- 7-amino acid peptide, is also biologically active in the suprarenal
hydroxypregnenolone. Secretion of androgens with weak glands, although it is less potent than angiotensin II.
androgenic activity, dihydroepiandrosterone (DHEA), DHEA-S, Renin is an enzyme synthesized by the cells of the renal
and androstenedione predominates. In the peripheral tissues, juxtaglomerular apparatus, which is located in the walls of the
these are transformed into potent androgens. The suprarenals also afferent arterioles near the macula densa of the distal tubule.
secrete small quantities of testosterone and estradiol. The Secretion of renin is regulated by a system of baroreceptors in the
biosynthesis of steroid hormone is summarized in Figure 12–7. arteries adjacent to the juxtaglomerular cells. Increases in cir-
Secretion of glucocorticoids and androgens is mainly regulated by culating aldosterone cause augmented sodium and water retention
hypothalamic and hypophyseal factors. Aldosterone production and an increase in blood pressure, which inhibit renin produc-
is controlled by a multifactorial system whose most important tion. A decrease in the sodium concentration stimulates its release.
components are the renin-angiotensin system and the extracellular The sympathetic nervous system augments renin release through
concentration of potassium. Suprarenal cortisol secretion is the effects of norepinephrine via the ␤-adrenergic system.
Figure 12-7. Steroid hormone biosynthesis.

glycoprotein of hepatic origin, also transports corticosterone, pro-

gesterone, deoxycorticosterone (DOCA), prednisolone, and other
synthesized corticosteroids. Free cortisol is the physiologically
active fraction, and with changes in the fixed cortisol concentra-
tion, the free fraction is maintained constant. Cortisol has a half-
life of 60 to 80 minutes. As occurs with all the steroids, its
metabolism is mainly hepatic with the production of hydrocortisol
and tetrahydrocortisone. Ninety percent is eliminated by the
kidneys in the urine, and the remainder is eliminated in the bile.
ACE The majority of circulating aldosterone, the principal plasma
mineralocorticoid, is bound to albumin (50–60%). Binding with
CBG is only 10% that of cortisol. Free aldosterone concentrations
in plasma are greater than those of DOCA, 90% of which is
protein-bound. Aldosterone has a half-life of 45 minutes and is
metabolized in the liver. The suprarenal androgens, androsten-
dione and DHEA, have a higher affinity to the carrier protein, SH-
BG, than to CBG, but their affinity is lower than that of the
peripheral androgens, testosterone and dehydrotestosterone. They
Figure 12-8. Renin-angiotensin-aldosterone system.
are partially metabolized by the liver, but there is substantial
peripheral metabolism in the gonads, skin, and adipose tissue,
where they are interconverted into various sex steroids.
A diagrammatic representation of the renin-angiotensin- All of the steroid hormones have a common mechanism of
aldosterone system is presented in Figure 12–8. An acute increase action. The steroid separates from its carrier protein and diffuses
in the plasma potassium concentration causes a reduction in the through the membrane, binding to specific intracellular protein
release of renin and directly stimulates aldosterone production by receptors. There are two types of receptors: type I receptors are
the zona glomerulosa. A chronically elevated potassium confound in low concentrations and have a high affinity for both
centration exerts a trophic effect on this area. The mechanism of mineralocorticoids and glucocorticoids and type II receptors,
action of this process is the depolarization of the cell membrane which are more abundant, have a decreased affinity to mineralo-
with activation of the calcium channels and a resultant increase in corticoids, acting mainly as glucocorticoid receptors. It is possible
intracellular calcium. There is also a small increase in cAMP.34 that the specificity of the hormonal action in the mineralocorti-
Other factors that intervene in the regulation of aldosterone coid target tissues depends on the presence of the enzyme, P450-
synthesis are ACTH, which stimulates aldosterone release, and C11, which converts cortisol to cortisone. Cortisone has a low
atrial natriuretic factor, which blocks it. Reductions in sodium affinity for type I receptors. In tissues in which this enzyme is
concentration increase the release of renin and, consequently, of absent, the glucocorticoids bind to the type I receptor to exert their
aldosterone. Dopaminergic agents can inhibit aldosterone release. biologic actions.35 The activated steroid receptor complex acquires
Secretion of DHEA and androstenodione is controlled by ACTH. the capacity to bind to DNA at the level of specific regulating
The gonadotropins do not appear to have any control in the sequences called, in the case of glucocorticoids, the glucocorticoid
process. In addition, there seems to be an ACTH-independent response element (GRE). The interaction with DNA increases or
regulation that is dependent on a proposed hypophyseal factor inhibits the capacity to stimulate gene expression and transcrip-
that controls androgen secretion, particularly during puberty tion of new mRNA.
(adrenarche). The predominant actions of the glucocorticoids are on inter-
Many pharmacologic agents inhibit steroid biosynthesis. mediary metabolism. They influence electrolyte and water meta-
Metyrapone is an inhibitor of 11-hydroxylation, but also 17-, 18-, bolism and affect almost all organs and tissues of the organism.
and 21-hydroxylation, reducing cortisol production. Aminoglu- In carbohydrate metabolism, cortisol is a contraregulating hor-
tethimide inhibits the conversion of cholesterol to pregnenolone, mone with anti-insulin activity, decreasing insulin-receptor
blocking the production of cortisol and aldosterone. Mitotane binding and blunting tissue glucose uptake except in the liver,
affects suprarenal synthesis by blockade of the mitochondrial and heart, brain, and red blood cells. In the liver, it induces glucose
extrasuprarenal cortisol metabolism. It also produces intense synthesis by stimulating gluconeogenesis and increasing glycogen
atrophy of the zona fasiculata and reticularis and, to a lesser degree, deposits, and it indirectly stimulates gluconeogenesis by inducing
the zona glomerulosa by cytolysis. Trilostane inhibits 3-dehy- the release of glucagon. In addition to inhibiting amino acid
drogenase-isomerase hydroxysteroid. Ketoconazole inhibits the uptake and protein synthesis, it stimulates their mobilization by
P450 cytochrome enzymes, 11-hydroxylase, and 17,20-lyase among catabolism of muscle and bone. It also mobilizes fatty acids,
others. Another substitute imidazole derivative, etomidate, used as facilitating the activation of cellular lipase by the catecholamines
an anesthetic induction agent, inhibits 11-hydroxylase and des- and the hypophyseal peptides. By itself, cortisol inhibits lipolysis
molase and reduces cortisol synthesis in a dose-dependent manner. and blocks lipogenesis. The glucocorticoids are released mainly in
Cortisol is the main circulating glucocorticoid, with 95% situations of stress and subsequently act to block the production
bound to plasma proteins. Seventy percent is bound to a high- and release of many hormones and neurotransmitters including
affinity, low-capacity globulin, transcortin or cortisol-binding catecholamines, prostaglandins, and kinins. In the absence of this
globulin (CBG), 10 to 15% is bound to a low-affinity, high- control, these products can lead to shock. Cortisol maintains the
capacity protein, albumin, and less than 5% is bound to other arterial smooth muscle capacity to respond to the vasopressor
proteins or circulates in free form. To a lesser degree, CBG, a stimuli and participates in the maintenance of arterial blood
pressure, cardiac output, and renal blood flow. The glucocorticoids of postganglionic sympathetic neurons without axons that pro-
have a great influence on the distribution and excretion of body duce, store, and release catecholamines. The predominant cate-
water. Cortisol affects renal water excretion by decreasing secre- cholamine is epinephrine. Catecholamines are released directly to
tion of ADH while augmenting the rate of glomerular secretion the blood, as with the endocrine organs.
and the permeability of the tubular cells, thereby enhancing free
water clearance. High concentrations of cortisol decrease intestinal
calcium absorption and increase its renal excretion, contributing SEX DIFFERENTIATION
to the development of osteopenia. It also induces the production Human beings are differentiated into two sexes, male and female,
of a factor that is essential for the maturation of the fetal lung. The through a process that has different phases throughout life.
absence of this factor in premature neonates contributes to the Genetic sex, gonadal sex, and genital sex are determined during
development of the infantile respiratory distress syndrome due to the fetal period. Phenotypic sex and psychosocial sex are
surfactant deficiency. determined during infancy and, particularly, in puberty and
In the digestive tract, the glucocorticoids inhibit DNA synthesis
adulthood.39 Sex differentiation during the fetal period requires a
and increase stomach secretion, an effect that can favor the for-
series of steps that are established and regulated, in part, by genetic
mation of gastroduodenal ulcers. High glucocorticoid concentra-
and endocrine factors (Figure 12–9). Genetic sex is determined at
tions can have an anti-inflammatory activity. They modify cell
the moment the ovum is fertilized by the sperm. According to the
immunity and can inhibit the formation of antibodies at high
X or Y sex chromosome contained in the fertilizing sperm,
doses. They also have complex effects in the brain. Pharmacologic
feminine (46 XX) or masculine (46 XY) genetic sex is established.
doses of these hormones tend to produce euphoria. Depressive
Gonadal sex is determined early in the life of the embryo and
states are common in Cushing’s syndrome and have also been
depends on genetic sex. Starting from the blueprint of the undif-
described, although less often, in patients with suprarenal insuffi-
ciency. Glucocorticoids suppress ACTH secretion, tend to de- ferentiated primitive gonads, ovarian differentiation in females
crease ADH release, and augment insulin and PTH. takes place during the eighth week of gestation and testicular
Painful stimuli results in an immediate physiologic, humoral, differentiation in males occurs during the seventh week. This
and inmune response. The stress response is a catabolic reaction process terminates in the 28th week of fetal life. In the absence of
with a significant increase of cortisol, catecholamines, aldosterone, the Y chromosome, the primitive gonad differentiates into the
glucagons, and other steroid hormones.36 This pituitary-adrenal ovary. However, for complete differentiation of the ovary, as well
response is present in the neonate and can be prolonged in pre- as its maintenance, a double X chromosome is required. Dif-
term neonates.37 Several studies have demonstrated a correlation ferentiation of the primitive gonad into the testes depends on the
between an increase of serum cortisol concentration after surgery presence of a testes-determining factor (TDF) coded by a gene on
and the degree of arousal and distress during the operation.38 The the short limb of the Y chromosome, corresponding to the gene
harmful effects of the surgical stimuli can be reduced by a suitable known as the sex-determining region, Y chromz (SRY). Other
perioperative analgesia.37 Following major surgical procedures, genes, both autosomal and X-linked, are also required for the
neonates receiving potent analgesic and anesthesia agents have complete differentiation of the testes.
been shown to have decreased morbidity and also decreased To determine masculine genital sex, the fetal testes must
mortality.36 produce hormonal products including müllerian duct–inhibiting
The mineralocorticoids regulate electrolyte transport across the factor (MIF) in the Sertoli cells and testosterone in the Leydig
various epithelial tissues. Aldosterone is the principal endogenous cells. Secretion of MIF is initiated during the eighth week
hormone in this group, whereas corticosterone and desoxycorti- of gestation. Its stimulation depends on hypophyseal FSH,
costerone are secreted in small amounts. Aldosterone acts being greatest around the middle of gestation, chronologically
primarily upon the kidney, but also on the intestine, the salivary parallel to the disappearance of the müllerian ducts. The
glands, and the sweat glands, increasing sodium uptake and development and maintenance of the wolffian ducts is regulated
potassium excretion. Aldosterone also increases the secretion of by testosterone. Maturation of the testosterone-producing Leydig
hydrogen ions in the medullary collecting tubules of the kidneys. cells is initially induced by hCG, although in the first trimester of
Their secretion and synthesis are regulated by the renin-angio- fetal life, hypophyseal LH also plays a role. The action of
tensin system and plasma concentrations of potassium. Primary testosterone on the wolffian ducts is regulated through specific
mineralocorticoid–related diseases are rare in children. Hyperal- receptors. In the absence of MIF, the müllerian ducts develop to
dosteronism may occur in association with various forms of form the uterus, Fallopian tubes, and the upper two thirds of the
congenital adrenal hyperplasia. Secondary hyperaldosteronism vagina. In the absence of testosterone, the blueprint of the
with low total body sodium and accumulation of potassium is wolffian ducts does not develop. Finally, the absence of
present in congestive heart failure, cirrhosis of the liver, and testosterone and its metabolites, which act upon the tubercles and
nephrotic syndrome. The excess of mineralocorticoids results in the urogenital sinus, allows differentiation of the external
increased sodium retention with hypertension (typically with high feminine genital sex (lower third of the vagina, labia major, and
diastolic blood pressures) and hypocalemia with metabolic clitoris).
alkalosis, hypocalemic nephropathy, and possible tetany with Psychosocial sex refers to a complex and progressive dif-
normal serum calcium. ferentiation that leads to different types of identity. Several
basic mechanisms, such as learning and education, are impli-
cated in this differentiation, reinforced by correct pubertal
Suprarenal Medulla development. Studies investigating the presence of anatomic or
The suprarenal medulla is embryologically and functionally a part functional differentiating factors in the CNS are under way.
of the sympathetic nervous system. It is considered to be a group Additional efforts are focused on determining whether the sex
Figure 12-9. Genetic, gonadal, and genital sex differentiation in the human fetus.
hormones (androgens) have a role in the differentiation of certain physical and psychic changes, with rapid growth and important
attitudes.40 developmental phenomena, coinciding with sexual maturity.
GROWTH Growth Regulation

Growth is a complex biologic process by which living beings Growth is determined genetically and environmental factors can
progressively increase in mass, mature morphologically, and reach facilitate or obstruct expression of the genetic pattern. Genetic
full functional capacity. It is a continuous process that is initiated control is carried out through a polygenic mechanism, in which
with fertilization of the ovum and terminates at the end of ado- the various genes show their maximum expression in different
lescence. Growth is determined genetically and is modulated by a periods of life. Among the environmental factors, nutrition is of
variety of extragenetic factors. The interaction of these elements capital importance, but others such as climate, psychosocial
produces the growth pattern. Growth after the embryonic stages elements, and family also play a part.42–44 Growth is regulated
in humans is controlled and regulated by an intricate system in mainly by local mechanisms and systemic or hormonal
which systemic and endocrine mechanisms intervene together mechanisms (Figure 12–10). The hormones directly implicated in
with local factors.41 the growth process include hypophyseal GH, thyroid hormones,
cortisol, suprarenal androgens, testosterone, active metabolites
of vitamin D, and insulin. GH is the main regulator of extrauterine
Growth Pattern growth and, together with the somatomedins or IGFs, it forms
The human species has a growth curve characterized by two an efficient system for adaptation of growth to the environmental
periods of rapid development separated by a period of stable and metabolic situation. The thyroid hormones, essentially T3,
growth.42 The first period of rapid growth corresponds to the fetal regulate maturation of the CNS and GH production, with-
period and the first months of life, and the second occurs during out affecting cell proliferation. The androgens participate in
puberty. Between these phases, there is an interval of uniform sexual differentiation and maturation, stimulating GH production
growth with slight acceleration around 7 to 10 years of age coin- and cell maturation at puberty. At low doses, the estrogens have
ciding with the adrenarche. In utero, growth is regulated by auto- an action similar to that of the androgens, but at high doses,
crine and paracrine mechanisms during which the transplacental they limit growth by accelerating epiphyseal closure. Because
passage of nutrients is crucial for modulating insulin secretion, of its role in cell metabolism, insulin is almost a fundamental
stimulating synthesis of both IGF-1 and IGF-2, as well as modu- factor in prenatal growth. Physiologic doses of glucocorticoids
lating their activity. In the postnatal period, the rapid growth facilitate GH secretion and collagen synthesis. Vitamin D and
decelerates, and at 6 months of age, endocrine regulation is PTH regulate bone growth. Local growth factors are produced
initiated by GH. From 3 years of age to the pubertal growth spurt, in a variety of tissues, acting upon the cells that produce them or
there is a period of slow uniform growth with a small transitory the surrounding cells by intracrine, autocrine, and paracrine
acceleration at 7 to 10 years of age. Puberty is a period of great mechanisms.45
TABLE 12-5. Basal and Peak Serum Concentrations of

Luteinizing Hormone and Follicle-Stimulating Hormone
in Normal Pediatric Populationsa
Males
AGE, Y FSH LH
Basal Peak Basal Peak
1–3 1.0 4.3 0.9 3.6
4–9 0.8 3.0 0.8 2.6
10–13 1.1 3.1 0.7 3.4
11–15 1.5 3.0 1.0 6.9
13–18 2.0 3.5 1.3 10
Adult 2.3 5.2 2.0 15
Females
AGE, Y FSH LH
Basal Peak Basal Peak
Figure 12-10. Main factors in growth regulation.
1–3 1.5 14 0.7 4.0
4–9 1.2 8.3 0.9 2.7
PUBERTY 10–13 1.7 6.4 0.9 2.9
Puberty can be considered a critical stage in the process of deve- 11–15 2.0 6.6 1.0 5.0
lopment in which the child becomes an adult. It is characterized by 13–18 3’1 7.0 1.8 13
a phase of intense changes regulated by substantial hormonal mo- Adult
difications and the fundamental reactivation of the hypothala- Menstruating 3.3 6.6 2.4 18
mic-hypophyseal gonadal axis. This activation coincides with Follicular phase 3.8 7.6 2.5 13
activation of growth (hypothalamic-hypophyseal-somatomedin Luteal phase 2.0 5.0 1.4 17
axis) and is preceded by maturation of the suprarenal and thyroid FSH = follicle-stimulating hormone; LH = luteinizing hormone.
glands. These endocrine glands affect the gonads and secondary aMedium values in U/L.
sex characteristics, resulting in the acquisition of reproductive From reference 46.

capacity, the phenotype resulting in a rapid growth phase, the end
of growth, and acquisition of sex phenotype, and the psychological pediatric population (medium values in units per liter) are dis-
maturity of the person. However, the neuroendocrine mechanisms played in Table 12–5.46
responsible for puberty begin much earlier, in four recognized Two key events take place over the course of puberty. The
phases. The first phase begins during fetal life and extends to intrinsic inhibiting CNS mechanism over gonadotropin secretion is
infancy. In this phase, the reproductive system is very active with progressively reduced, and the sensitivity of the hypothalamic-
gonadal hormone levels similar to those found at the beginning hypophyseal system to the negative feedback of the gonadal hor-
of puberty and with elevated gonadotropin levels. Maturation of mones also decreases progressively.47 A new mechanism of positive
the CNS limits LH-RH secretion by an unknown intrinsic feedback between estrogens and gonadotropins, responsible for the
mechanism independent of the gonadal steroids and decreases secretory peak of LH and FSH preceding ovulation, appears in girls.
gonadotropin production. The second or prepubertal phase ex- In this phase, gonadal hormones similar to those in an adult are
reached, and LH-RH administration produces a definitive release of
tends from early infancy to the end of the first decade of life and
LH and smaller release of FSH. The capacity to secrete LH-RH at
is characterized by decreased gonadotropin secretion (particularly
correct frequency and amplitude is acquired during this phase and
LH) with a high FSH/LH ratio, low LH response to LH-RH
is absolutely necessary to attain normal reproductive function.
administration, low gonadotropin levels, and a hypothalamic-
During puberty, the concentration of IGF increases in parallel to
hypophyseal system that is highly sensitive to the negative the increases in sex steroids. Concentrations above adult values can
feedback of the gonadal steroids. In this phase, LH-RH and the persist for months or years after having reached the peak of pubertal
gonadotropins exhibit a very short pulsatile release with slight development. The values later decrease and reach normal adult
nocturnal increases. The third stage or pubertal phase begins at values. The initial increase of suprarenal androgens (adrenarche)
the end of the first decade of life and is characterized by a sharp has a fundamental role in the physiology of puberty in both sexes.
amplification of pulsatile nocturnal LH secretion, which is depen- This increase is related to body weight and is responsible for growth
dent on episodic LH-RH release. The rhythmicity and duration of acceleration and bone development as well as changes in the
the LH-RH release are critical to attaining normal sexual maturity. hypothalamic-hypophyseal system. The first signs of sexual matu-
As pubertal maturation follows its course, gonadal hormone rity are the appearance of the mammary buds in girls and enlarge-
secretion increases and the differences between diurnal and ment of the scrotum/testes in boys.48 The development of the sex
nocturnal LH secretions become progressively smaller until the characteristics culminates with maturation of reproductive capacity
fourth stage or sexual maturity is reached, in which they disappear. with menarche in women and formation of mature spermatozoids
Basal and peak serum concentrations of LH and FSH in normal with fertilizing capacity in men.
CONCLUSION 16. Fisher DA. The thyroid. In: Kaplan SA, editor. Clinical Pediatric
Endocrinology. Philadelphia: WB Saunders; 1990. p. 87.
The endocrine system is necessary for the body’s homeostatic 17. Gruters A. Congenital hypothyroidism. Pediatr Ann. 1992;21:15–28.
regulation, growth and development, and the physiologic response 18. Seino H, Dohi S, Aiyoshi Y, et al. Postoperative hepatic dysfunction
to stress. An understanding of endocrine physiology and patho- after halothane or enflurane anesthesia in patients with hyper-
physiology is essential for the anesthetic management of pediatric tiroidism. Anesthesiology. 1986;64:122–125.
19. Berman ML, Kuhnert L, Phythyon JM, et al. Isoflurane- and
patients. Although pediatric endocrine diseases are a relatively
enflurane-induced hepatic necrosis in triiodythyronine-pretreated
uncommon indication for a surgical procedure, abnormalities of rats. Anesthesiology. 1974;58:1–5.
endocrine function may be present in any surgical pediatric 20. Gorr S, Dean W, Radley T, Cohn D. Calcium-binding and aggrega-
patient. Alterations in any of the endocrine systems may occur tion properties of parathyroid secretory protein-I (chromogranin A).
with either the over- or the underproduction of the hormonal Bone Miner. 1988;4:17–25.
components of these glands. These pathologic processes may be 21. Mallette L. The parathyroid polyhormones: new concepts in the spec-
related to destructive processes of the endocrine glands, enzymatic trum of polypeptide hormone action. Endocr Rev. 1991;12:110–117.
deficiencies in the synthesis of the endocrine products (congenital 22. Committee on Dietary Allowances, Food and Nutrition Board. Na-
adrenal hyperplasia), autoimmune diseases, or paraneoplastic tional Research Council. Recommended Dietary Allowances. 10th
edition. Washington, DC: The National Academies Press; 1989.
syndromes. More importantly, the exogenous administration of 23. Coleman DT, Fitzpatrick LA, Bilezikian JP. Biochemical mechanism
pharmacologic doses of corticosteroids may be required in the of parathyroid hormone action. In: Bilezikian JP, Levine MA, Marcus
treatment of various nonendocrine disorders and may secondarily R, editors. The Parathyroids. New York: Raven Press; 1994. p. 239.
result in suppression of the HPA axis with the need for peri- 24. Canalis E, Centrella M, Burch W. Insulin-like growth factor I
operative supplementation. mediates selective anabolic effects of parathyroid hormone in bone
cultures. J Clin Invest. 1989;83:60–65.
25. Webb A, Holick M. The role of sunlight in the cutaneous production
REFERENCES of vitamin D3. Annu Rev Nutr. 1988;8:375–399.
26. Wolfe HJ. Calcitonin: perspectives in current concepts. J Endocr
1. Fox M, Marañon A, Vilardel E. Endocrinologia. In: Farreras P, Invest. 1982;5:423–432.
Rozman C, editors. Medicina Interna. Vol. I. Barcelona, Spain: 27. Al-Mohaya S, Naguib M, Abdelatif M, Farag H. Abnormal responses
Ediciones Doyma; 1988. pp. 11793–11835. to muscle relaxants in a patient with primary hyperpathyroidism.
2. Wilson J, Daniels G, Martin J. Endocrinologia y metabolismo. In: Anesthesiology. 1986;65:554–556.
Isselbacher K, Braunwald E, Wilson J, et al., editors. Principios de 28. Zaloga GP, Chernow B. Hypocalcemia in critical illness. JAMA.
Medicina Interna. Vol II. Madrid: McGraw-Hill-Interamericana de 1986;256:1924–1929.
Espana; 1994. pp. 2171–2225. 29. David L, Anast C. Calcium metabolism in newborn infants. J Clin
3. Webb BM. Neuroendocrinology. In Argente J, Carrascosa A, Gracia Invest. 1974;54:187–189.
R, Rodriguez F, editors. Tratado de Endocrinología Pediátrica y de la 30. Tsang RC, Chen IW, Friedman MA, et al. Parathyroid function in
Adolescencia. Madrid : Editores Médicos SA ; 1995. pp 423–445. infants of diabetic mothers. J Pediatr. 1975;86:399–441.
4. Felig P, Baxter J, Frohman L, editors. Endocrinology and Metabolism. 31. Flashburg MH, Dunbar BS, August G, Watson D. Anesthesia for
3rd ed. New York: McGraw-Hill, Health Professions Division; 1995. surgery in an infant with DiGeorge syndrome. Anesthesiology.
pp. 3–313. 1983;58:479–481.
5. Robertson G. The endocrine brain and pituitary gland. In: Becker K, 32. Fraser R. Biosynthesis of adrenocortical steroids. In: James VHT, edi-
editor. Principles and Practice of Endocrinology and Metabolism. 2nd tor. The Adrenal Gland. New York: Raven Press; 1992. pp. 117–130.
ed. Philadelphia: JB Lippincott; 1995. pp. 84–265. 33. Saffran M, Schally AV. Release of corticotrophin by anterior pituitary
6. Kappy M, Blizzard R, Migeon C, (Eds). The Diagnosis and Treatment tissue in vitro. Can J Biochem Physiol. 1955;33:408–415.
of Endocrine Disorders in Childhood and Adolescence. 4th ed. 34. Quinn 53, Williams OH. Regulation of aldosterone secretion. Annu
Springfield, Ill: Charles C. Thomas; 1994. pp. 42–94. Rev Physiol. 1988;50:409–426.
7. DeGroot L, editor. Endocrinology. 3rd ed. Philadelphia: WB Saunders; 35. Barrihat K, Mellon PL. The orphan nuclear receptor, steroidogenic
1995. pp. 151–186. factor-1, regulates the glycoprotein hormone-subunit gene in
8. Martin J, Reichlik S, editors. Clinical Neuroendocrinology. 2nd ed. pituitary gonadotropes. Mol Endocrinol. 1994;8:878–885.
Philadelphia: FA Davis; 1987. pp. 11–17. 36. Anand KJS, Hickey PR. Pain and its effects in the human neonate and
9. Bertrand J, Rappaport R, Sizonenko P, editors. Endocrinology. Phy- fetus. N Engl J Med. 1987;317:1321.
siology, Pathophysiology, and Clinical Aspects. 2nd ed. Baltimore: 37. Anand KJS, Aynley-Green A. Metabolic and endocrine effects of
Williams & Wilkins; 1993. pp. 19–78. surgical ligation of PDA in the human preterm infant: are there
10. Cowett RM, (ed). Principles of perinatal-neonatal metabolism. New implications for further improvement of postoperative outcome? Mod
York: Springer-Verlag; 1998; p. 1275. Probl Pediatr. 1985;23:143.
11. Miranda A, editor. Dolor Postoperatorio, Estudio, Valoración y Trata- 38. Gunnar MR, Fisch RO, Korsvik S, Donhowe JM. The effects of cir-
miento. Barcelona, Spain: Editorial JIMS; 1992. pp. 105–167. cumcision on serum cortisol and behavior. Psychoneuroendocri-
12. Styne DM. Endocrine factors affecting neonatal growth. In: Polin P, nology. 1981;6:269.
Fox B, (eds). Fetal and Neonatal Physiology. Philadelphia: WB Saun- 39. Bergadá C, Coco R, Chemes H. Assymetric Gonadal Differentiation.
ders; 1992. p. 266–75. In: Martinez Mora J, (ed). Intersexual States. Disorders of Sex Dif-
13. Fisher DA, Polk DH. Development of the thyroid gland. Baillieres ferentiation. Barcelona, Spain: Doyma; 1994; p. 283–9.
Clin Fndocrinol Metab. 1989; 3:627–657. 40. Breedlove SM. Sexual differentiation of the human nervous system.
14. Delange F. Recommendations on iodine nutrition for mothers and Annu Rev Psychol. 1994;45:389–418.
infants in Europe. In: Delange F, Dunn JT, Glinoer D, (eds). Iodine 41. Blizzard RM. Control of growth: a review of the physiology and
Disorders in Europe: A Continuing Concern. New York: Plenum interrelationships of growth hormone (GH), OH-releasing hormone
Press; 1993. pp. 471. (OHRH), insulin-like growth factor (IOF-Y), estrogens and andro-
15. Burrow ON, Oppenheimer JR, Volpe R, editors. Thyroid Function gens. In: Taner JM, editor. Auxology 88. Perspectives in the Science of
and Disease. Philadelphia: WB Saunders; 1990. p. 335. Growth and Development. London: Srnith-Oordon; 1989. p. 283.
42. Tanner JM, (ed). Fetus into Man. Physical Growth From Conception 46. Roger M, Lahlou N, Lidner D, Chaussain JL, Exploración de la
to Maturity. 2nd ed. Cambridge, Mass: Harvard University Press; hormona liberadora de gonadotropinas en pediatría. In: Ranke MB,
1989. p. 271. editor. Diagnóstico Endocrinológico Funcional en Niños y Adolescentes.
43. Waterlow JC, (ed). Linear Growth Retardation in Less Developed Madrid : Diaz de Santos; 1993. pp. 259–278.
Countries. New York: Raven Press; 1988. p. 295. 47. Cuttler L, Rosenfield RL, Ehrmann DA, et al. Maturation of gona-
44. Bizzar RM. Psychosocial short stature. In: Lifshitz F, editor. Pediatric dotropin and sex steroid responses to gonadotropin releasing hor-
Endocrinology. New York: Marcel Dekker; 1990. p. 77. mone agonist in males. J Clin Endocrinol Metab. 1993;76:26–31.
45. Underwood LE, Van Wyk JJ. Normal and aberrant growth. In: Wilson 48. Rosenfield RL. Normal and almost normal precocious variations in
JD, Foster DW, editors. Williams Textbook of Endocrinology. 8th ed. pubertal development, premature pubarche and premature thelarche
Philadelphia: WB Saunders; 1992. p. 1079. revisited. Horm Res. 1994;41(Suppl 2):7–13.
Principles of Hematopoiesis,
Immunity, and Coagulation 13
Chaim Kaplinsky, Raz Somech, and Gili Kenet C H A P T E R
INTRODUCTION particular microenvironment (niche) is critical for hematopoiesis.

Several studies have demonstrated that osteoblasts are also crucial
The anesthesiologist is facing an ever-increasing amount of regulatory cellular elements of the HSC microenvironment. Their
complex information that has risen beyond the empirical and function and fate are controlled by ligand-mediated signaling
descriptive era and now requires an understanding of processes at pathways.3,4 In addition to soluble factors, matrix components and
the molecular level. This chapter presents a review of the anatomy the extracellular matrix contribute to the in vivo microenviron-
and physiology of normal coagulation, hematopoiesis, and ment of HSCs.
immune system from the neonatal period through childhood to The colonization of the hematopoietic organs is a multistep
adolescence. The developmental aspects of these systems as well as process that begins with primitive cells emerging from the aorta-
the consequences of deranged differentiation and maturation gonad-mesonephros region. These primitive cells travel to the fetal
leading to hematologic and immunologic abnormalities are briefly liver where they proliferate before their movement to their final
described. Unfortunately, it is not possible, within the confines of sites in the bone marrow and spleen. These processes are under
a chapter, to provide a comprehensive and detailed review of the the control of stromal cell–derived factors (SDF) such as SDF-1.5
total knowledge concerning hematopoiesis, blood components, All blood cells are derived from embryonic connective tissue. They
and the immune system. The chapter focuses on clinically relevant can be first detected by the 14th day of gestation. The first blood
aspects, aiming at turning theoretical knowledge into practice and cells produced by the embryo are red cells that have megaloblastic
translating this information from the bench to the bedside. features. By the ninth to 10th week of gestation, they acquire a
normoblastic appearance. By the fifth to sixth week of gestation,
the fetal liver is the major site for erythropoiesis and remains the
HEMATOPOIESIS principal organ of hemopoiesis until the sixth fetal month.
Overview Myelopoiesis begins at the fourth to fifth fetal month. At birth,
most of the hematopoietic activity is in the bone marrow, with
The marrow cavity can be visualized as a maze composed of a only minor residual activity in the liver and spleen. The amount of
network of vascular channels, arterial vessels, small arterioles, and the marrow continues to grow and expand following birth by
capillaries that drain into sinusoids through veins. It is held increased and rapid turnover of cells.
together by reticular fibroblastoid cells, energy-rich fat cells, and The clonal nature of hematopoiesis and the concept that a
macrophages. The sinusoidal wall consists of a single layer of single pluripotent stem cell exhibits the capacity to repopulate the
endothelial cells and is devoid of supporting cells. The lack of a entire hematopoietic system was first demonstrated by Till and
regular vessel wall in the sinusoids results in a high level of McCulloch.6 The fact that a stem cell can differentiate to form
permeability. The hematopoietic cells are found between the progenitor cells for all lineages of the cellular components of the
interlacing network of vascular sinuses. The stromal cells support blood was demonstrated in disease states like chronic myeloid
attachment and subsequent growth, which is enhanced by specific leukemia7 and polycythema vera8 in which clonality of each of the
chemokines. The concept of the hematopoietic stem cell (HSC) abnormal erythroid, granulocytic, and megakaryocytic precursor
was first proposed by Schofield in 1978, who suggested that stem was evident. Moore and Metcalf demonstrated the presence of
cells are fixed tissue cells that are prevented from differentiation HSCs in the yolk sac and the murine fetal liver,9 and Micklem and
and continue to proliferate within the functionally and spatially Ross showed that these HSCs have a proliferative capacity of six
characterized “niche.”1 Within this niche, the microenvironment generations when serially transplanted into the spleen of an
supports and instructs these stem cells.1 It has been shown that irradiated recipient.10 Murine models, particularly short- and
HSCs and hematopoietic precursors are not randomly distributed long-term transplant studies, have provided a number of insights
in the bone marrow, but rather are localized close to the endo- into the biology of HSCs and their progenitors. The results of these
steum of the bone and around blood vessels within the endosteal studies have demonstrated that HSCs are able to generate every
zone, which provides the appropriate environment for the HSCs to lineage found in the hematopoietic system including red blood
perform their role in hematopoiesis. The centrally located vascular cells, platelets, and a variety of lymphoid and myeloid cells.11,12
niche serves as the location that allows differentiation and, HSCs are rare, constituting only 1/10,000 to 1/1,000,000 of the
ultimately, mobilization of the cellular elements of the blood to cells in the bone marrow depending on the species, age, and
the peripheral circulation.2 The interaction of HSCs with their technical aspects of the model. Although HSCs are primarily
found in the bone marrow, they are present in a variety of other (c-kit ligand), and insulin-like growth factor (IGF-1). EPO
tissues including the peripheral and umbilical cord blood. They expression is up-regulated in response to hypoxia, which results in
are also found, albeit in lower numbers, in the liver, spleen, and the production of a surplus of CFU-Es and a large fraction of EPO-
several other solid organs. These HSCs may have somewhat dependent progenitors remaining “on call” in the marrow sinuses.
different properties than those found in the bone marrow, but they Within 12 hours, the rate of erythropoiesis increases by as much
retain the ability to generate all of the different blood lineages in as threefold as a wave of pluripotent stem cells is stimulated into
large numbers for a prolonged period of time. A single pluripotent active cell cycles. EPO is essential for the terminal maturation of
stem cell is capable of giving rise to many committed progenitor erythroid cells.24 The erythroid progenitor cells undergo timed
cells, which are destined to form differentiated recognizable morphologic changes manifested by gradual loss of nuclear
precursors of the specific cellular components of the blood.13 material (denucleation). The end product of erythropoiesis, the
However, any cell at any specific stage of development has only enucleated red cell, is a transport cell that functions as a carrier of
one differentiation option and can produce only one specified pair oxygen to and from the tissues.
of daughter cells.14
Currently, the specific phenotype of human HSCs and pro-
genitors has not been completely defined. Most studies suggest that Myelopoiesis, Granulocytes,
human HSCs and progenitors are small quiescent cells that express and Neutrophil Function
the surface glycoprotein CD34.15,16 In addition, the cells express high Neutrophil precursors are first detected in the yolk sac and then in
levels of multidrug resistant (MDR) activity, lack expression of the liver, spleen, and bone marrow. Mature neutrophils are first
lineage commitment markers, and express low levels of thymus cell detected by the 14th to 16th weeks of gestation. Up until the 22nd
antigen-1 (Thy-1). Human CD34+ cells that express high levels of to 24th weeks of gestation, neutrophils constitute less than 10%
CD34 with low or absent levels of a variety of other cell surface of circulating leucocytes, increasing to 50 to 60% at term.25 The
markers including CD33, CD38, thy-1, and CD71 appear to be ability of the human neonate to increase neutrophil production in
enriched for primitive progenitor and HSC activity, whereas more response to infection is limited. The most clearly defined deficits
mature progenitors express one or more of these markers. in neonatal neutrophil function are adherence and migration in
These cells are parents to precursor cells known as colony- response to chemotactic stimuli. Monocytes from term neonates
forming units (CFUs). When cultured in semisolid media, cells are normal in number and as competent as adult monocytes in
supplemented with appropriate growth factors are capable of phagocytic and microbicidal activity.26,27 Neutrophils, eosinophils,
yielding progeny of granulocyte-macrophage–colony forming and basophils are formed in the marrow from a unipotential CFU,
units (CFU-GMs), erythroid colony–forming units (CFU-Es), and following synchronized stimulation by interleukin-3 (IL-3) and
megakaryocyte colony–forming units (CFU-Megs), or combi- specific colony-stimulating factors.28 These cells arise through
nations of multilineage colonies (CFU-GEMM). A coordinated similar cytokinetic patterns of proliferation, differentiation, and
hierarchy of growth factors that are elaborated by marrow stromal maturation. Volume and nuclear changes accompany maturation
cells, fibroblasts, and endothelium govern the proliferation of and division of proliferating myeloid cells.
hematopoietic cells in vivo.17,18 By morphologic criteria, six stages of myeloid maturation are
Hematopoiesis is a complex process of interplay between conventionally recognized including three early stages, including
several components including HSCs, progenitors, and the bone myeloblasts, promyelocytes, and myelocytes, and the three later
marrow microenvironment, as well as a balance between matu- myeloid stages, including metamyelocytes, band forms, and
ration, proliferation, and programmed cell death. It involves stim- segmented neutrophils.29 The production of neutrophils is highly
ulation and regulation by cytokines,19 chemokines, extracellular compartmentalized into the circulating granulocyte pool and the
matrix components,20–22 and a number of intrinsic genes including marginating granulocyte pool. The transit times within each
the Rb family, the E2Fs, cyclins, SCL, and Hox that regulate compartment are relatively long, lasting up to 14 days from the
proliferation and self-renewal of early hematopoietic cells.23 The stem cell compartment to release into the circulating granulocyte
classic model for hematopoiesis is that committed HSCs give rise pool. In certain disease states, these transit times shorten in order
to two lineages: (1) a common lymphoid progenitor capable of to increase the production and supply of granulocytes. Once
producing lymphocytes and (2) a common myeloid progenitor released into the blood stream, neutrophils have a half-life of 6 to
with developmental potential restricted to myeloid, macrophage, 10 hours. However, once in the tissues, they may live another day
eosinophil, erythroid, and megakaryocyte lineages. Erythroid and or two before disintegrating by apoptosis.30 Neutrophils are the
megakaryocyte lineages arise from a common megakaryocyte- infantry of the host defenses because their primary function is to
erythroid progenitor (MEP) derived from the common myeloid move rapidly into tissue sites to destroy invading microbes and
progenitor. However, progenitors that have surface markers clear inflammatory debris.
similar to those of HSCs, but have become Flt3-positive, after During infections, activated macrophages release cytokines
further differentiation into lymphoid and myeloid lineages, do such as IL-2, IL-6, and tumor necrosis factor, which activate
not produce megakaryocytes or erythrocytes in vitro or in vivo stromal cells and T lymphocytes to produce more colony-
(Figure 13–1).23 stimulating factors and increase myeloid cell production. To
respond to inflammatory stimuli, the neutrophil is equipped with
an array of cell surface receptors for adhesive ligands, chemo-
Erythropoiesis attractants, and cytokines. Neutrophils are attracted to inflam-
The regulation of erythroid differentiation, proliferation, and matory sites by plasma chemotactic factors generated by the
maturation results from the coordinated and sequential interplay interaction of immunoglobulins and complement with antigens
of three essential cytokines: erythropoietin (EPO), stem cell factor or pathogens. This process is commonly known as chemotaxis.
CHAPTER 13 ■ Principles of Hematopoiesis, Immunity, and Coagulation 205
Figure 13-1. Hierarchy of hematopoiesis from the earliest hematopoietic stem cell (HSC). CLP =
common lymphoid progenitor; CMP = common myeloid progenitor; GMP = granulocyte mono-
cyte progenitor; LT-HSC = long-term HSC; MEP = megakaryocyte-erythroid progenitor; ST-HSC =
short-term HSC.
Through this process, neutrophils are recruited from the flowing chemotactic cytokines that operate in sequence to recruit only the
blood within the vascular system and adhere to vascular endothe- specific circulating subsets with the appropriate receptors for these
lium. Neutrophils are capable of locomotion, phagocytosis, and signals (Figure 13–2).
secretory functions. Circulating hematopoietic progenitors must Mature eosinophils make up 0.3% of the nucleated bone
exit blood vessels near specific areas of injury, inflammation, or marrow cells and 5 to 10% of peripheral granulocytes. They arise
tissue repair. The vessel wall at these sites displays a specific from a progenitor CFU-Eos (eosinophil colony-forming unit),
combination of signals in the form of adhesion molecules and committed to terminal differentiation into eosinophils. The
Figure 13-2. Current view on the possible role of shear in integrin outside-in
signaling promoting transendothelial migration. The leading edge of leukocytes
positioned at endothelial junctions rearranges under shear forces to trigger protusions
and gap formation between underlying endothelial cells. Reproduced with permission
of Prof. Ronen Alon, The Linda Jacobs Chair in Immune and Stem Cell Research,
Weizmann Institute, Rehovot, Israel.
Figure 13-3. Selectins, chemoattractants (chemokines), and integrins coordinate in capturing a

circulating leukocyte to the vessel wall at specific sites. Further leukocyte exposure to apical endothelial
chemokines and shear flow triggers their potential to undergo transendothelial migration without
disrupting the integrity of the endothelial barrier. Reproduced with permission from Prof. Ronen Alon,
The Linda Jacobs Chair in Immune and Stem Cell Research, Weizmann Institute, Rehovot, Israel.
majority of mature eosinophils reside in tissues. The number of single, large, multilobulated, polyploid nucleus. Eventually, each
circulating eosinophils has a circadian nature, being highest at megakaryocyte releases approximately 104 platelets. Unlike other
night. The granules of the eosinophils contain major basic protein cells, megakaryocytes undergo an endomitotic cell cycle during
(dense core), peroxidase, eosinophil-derived neurotoxin, arginine- which they replicate DNA, but do not undergo anaphase (mitosis)
rich cationic proteins, acid phosphatase, and other hydrolytic or cytokinesis. As a result, they acquire a DNA content of up to
enzymes. Eosinophils are armed with receptors for the epitopes 256N/cell.
of the Fc region of immunoglobulins of the IgG and IgE classes as Megakaryopoiesis is first noted in the embryonic yolk sac,
well as receptors for complement. The functions of eosinophils although studies of animals with severe quantitative and quali-
include anaphylactic reactions, IgG production, bacterial killing, tative platelet deficiencies, such as NF-E2–/– mice, have demon-
and early antigen recognition. The two major functions of strated that platelets are not critical for prenatal survival.33
eosinophils are defense against helminths and modulation of the Megakaryopoiesis is regulated by multiple transcription factors
immediate hypersensitivity response. The first of these functions that control the survival and proliferation of increasingly
is carried out by binding of the eosinophils to the helminth committed progenitors including the GATA-1/FOG-1 complex,
followed by peroxidation of the larval surface with damage from Fli-1 and TEL, NF-E2, RUNX1. Chemokines involved in these
the release of major basic proteins and hydrolytic enzymes processes include thrombopoietin (TPO) (Mpl), IL-3, IL-6; IL-11,
(Figure13–3). The capacity of eosinophils to restrain the self- IL-12, granulocyte macrophage colony–stimulating factor (GM-
destructive hypersensitivity and inflammatory reactions is CSF), SDF1/CXCR4, and PF4 (Figure 13–4). Mpl ligand or TPO,
mediated by amino-oxidases and histaminase that neutralize a more potent and relatively specific megakaryocyte/platelet
histamine. Prostaglandins E1 (PGE1) and E2 (PGE2) also serve a cytokine, has been shown to markedly stimulate megakar-
role because they inhibit degranulation of mast cells and basophils. yocyte production. The TPO:Mpl axis appears to be important for
hematopoiesis in general and megakaryopoiesis specifically.34,35
Megakaryocyte Biology
THE IMMUNE SYSTEM
Although erythroid and megakaryocyte lineages are believed
to share a common MEP, the signals that regulate the final separa- Overview and General Mechanism Involved
tion of these lineages are not well understood. Erythroid and The two components of the immune system, namely, innate
megakaryocytic precursors express both common and unique immunity and adaptive immunity, interact synergistically to
hematopoietic transcription factors. The first cells fully committed provide protection against microbials and infectious agents while
to the megakaryocyte lineage, termed CFU-Meg, are characterized maintaining tolerance to self-antigens. The primary host response
by a unique cell surface phenotype and form a small cluster of is mediated by the innate immunity (natural immunity) through
pure megakaryocytes in culture.31 CFU-Meg cells give rise to 2N natural physical and chemical barriers, phagocytic cells, and
megakaryocytes, which, in turn, undergo endomitosis and various blood proteins or excreted cytokines. The immune
cytoplasmic differentiation, resulting in a pool of mature megakar- response carried out by these mediators is rapid, is nonspecific,
yocytes recognized by their large size and characteristic mor- and confers short-lasting protective immunity to the host.36 By
phology.32 The hallmark of megakaryocyte development is the contrast, the adaptive immune system is characterized by a late
formation of a large cell (50–100 μm in diameter) containing a response, specificity, an ability to mount a memory response, and
Figure 13-4. Regulation of megakaryopoiesis by cytokines, chemokines, and transcription factors. BFU-EM = burst-forming
units—erythrocyte, megakaryocyte; CFU-EM = colony-forming units—erythrocyte, megakaryocyte; CFU-GEMM = colony-
forming units—granulocyte, erythrocyte, macrophage, megakaryocyte; CFU-Meg = colony-forming units—megakaryocyte;
HSC = hematopoietic stem cell. Modified from reference 31.
an ability to discriminate between self and nonself. This highly programmed cell death.38 Inherited defects in one or more compo-
evolved system is constructed mainly of lymphocytes and includes nents of the immune system result in primary immunodefi-
two major arms: (1) humoral immunity mediated by soluble ciencies. These diseases provide valuable insight into the immune
proteins (antibodies) and (2) cellular immunity mediated by system, notably in vivo immune responses to microorganisms as
circulating cells. Antibodies produced by B lymphocytes are the based on the variable vulnerability to pathogens and opportunistic
primary component of and responsible for the humoral system. agents in these patient populations.39
These antibodies recognize specific antigens of microbial
pathogens and provide a principal response in defense against
encapsulated microbial organisms and microbial toxins through Embryogenesis of the Immune System
neutralization, opsonization, and activation of the complement The ontogeny of the host defense system begins during the first
pathway. Five different types of antibodies are involved in humoral month of gestation with hematopoietic stem cells located within
immunity: IgM, IgD, IgG, IgE, and IgA. Each antibody has an the blood islands of the yolk sac. These pluripotential stem cells
antigen-binding site, a hinge region, and a region that determines will further differentiate into all of the cellular components
its class or subclass. Cellular immunity is mediated by the T cell of blood including granulocytes, monocytes, and lymphocytes,
receptor (TCR) complex. Two major types of T cells are involved megakaryocytes, and erythrocytes. Hematopoiesis occurs
including CD4+ (helper) and CD8+ (cytotoxic) T cells. These two predominantly in the liver during the first 3 months of fetal life
subsets of T cells comprise approximately 60 to 65% and 30 to 35% until the skeletal elements are formed, after which time they
of circulating T cells, respectively. By contrast to the recognition of become the major site of hematopoiesis. T, B, and NK lymphocytes
whole antigens by B cells, most T cells cannot bind free antigen. are derived from lymphoid stem cells. Precursors of T and B
They recognize antigens only when they are bound to and lymphocytes can be detected by 7 to 8 weeks of gestation.
presented by major histocompatibility complex (MHC) molecules. Lymphocytes destined to become T cells emerge from the bone
The adaptive immune system eliminates pathogenic challenges marrow and travel to the developing thymus for further mat-
through clonal selection, which ensures diversity and an unlimited uration. The maturation of B lymphocytes occurs in the bone
repertoire of both cell types.37 A third subset of lympocytes in marrow under the influence of the stromal reticular cells. The
addition to the T and B cells is the natural killer (NK) cells. These basic cellular elements of the immune system such as the
cells are considered cytotoxic lymphocytes and are a component TCR/CD3 complex can be found in peripheral lymphoid organs at
of innate immunity. They play a major role in the rejection of 13 to 15 weeks of gestation, whereas the ability to respond to
tumors and virus-infected cells in a manner unrestricted by MHC polyclonal stimuli such as PHA (phytohemagglutinin) is detected
antigens because they do not require antigenic presentation. The at 15 to 16 weeks of gestation. Nevertheless, the system is
NK cells kill by releasing small cytoplasmic granules of proteins functionally immature at birth and requires antigen selection to
called perforin and granzyme that cause the target cell to die by achieve full maturation during infancy.40
The Development of the T Cell Lineage repair genes is critical for the development of different TCR
through rearrangement of the VDJ segments. Those cells with
The thymus, which is the main organ for T cell development and nonproductive TCR rearrangements are destined for programmed
maturation, develops from the third and fourth pharyngeal cell death. Successful rearrangement of the beta chain of the TCR
pouches. This multilobed organ is composed of cortical and stimulates expression of CD4 and CD8 and rearrangement of
medullary areas surrounded by a capsule. It contains MHC- the alpha chain. At this step, cells are called double-positive T cells
expressing thymic epithelial cells, dendritic cells, and macro- (expressing both CD4 and CD8). Subsequently, interaction of
phages. Progenitor T cells migrate from the circulation into the MHC molecules on thymic epithelial cells through a process
thymus following the expression and elaboration of specific che- termed negative and positive selection further commits and
mokine receptors, chemokines, and adhesion molecules. Thymic differentiates the surviving T cells. By negative selection, clones
education occurs during the movement of progenitor cells from bearing TCRs that have a “phigh” affinity for self-MHC or self-
the cortex toward the medulla (Figure 13–5). It is a mandatory antigens are deleted (self-antigen means peptides from self-
process for the selection of T cells that have the ability to respond proteins bound to MHC molecules). Positive selection is unique to
to several exogenous antigens presented in the context of self- T cells. It appears that cells are selected for a “moderate” affinity for
MHC molecules. TCRs that are expressed on the surface of T cells self-MHC–peptide complexes. Only about 2% of all double-
are composed mostly of heterodimeric proteins composed of positive T cells survive the dual positive and negative selection
either alpha/beta (>95%) or gamma/delta chains. These protein processes. Interaction with MHC class II molecules generates
chains have variable (V), diverse (D), joining (J), and constant (C) CD3+/CD4+/CD8– T cells, whereas interaction with MHC class
segments (beta and delta chains) or V, J, and C regions (alpha and I molecules generates CD3+/CD8+/CD4– T cells. These single-
gamma chains) encoded by noncontinuous gene segments. Pre-T positive (either for CD4 or for CD8) functional T cells are released
cells first attempt to undergo rearrangement of their TCR genes from the thymus to the peripheral blood41 (see Figure 13–5).
while expressing the CD3 complex (Figure 13–6). At that time, During the rearrangement process in the thymus, unused and
they do not express either CD4 or CD8 and are therefore called excised DNA segments form the TCR excision from circular
double-negative T cells. An accurate machinery involving recombi- complexes (TRECs). The presence of these extrachromosomal
nation, activating, DNA recognition, damage, and subsequent DNA circles, which are not replicated during peripheral T cell
Figure 13-5. Development of T and B lymphocytes

Figure 13-6. Gene structure of immunoglobulin chains and T cell receptor chains
division, serve to identify newly thymus-derived T cells. of cellular and humoral immunity, and in some cases, decreased B
Quantifying TRECs has recently emerged as another tool to assess and NK cell number and function. Deleterious mutations in more
thymic activity. Indeed, a reduced number of TREC copies has than 10 different genes including components of cytokine
been found in patients with severe combined immunodeficiency receptors (IL-2RG, Jak3, and IL-7Rα), components essential for
(SCID) and HIV and was proposed as a potential tool to follow T antigen receptor gene rearrangement (RAG1, RAG2, and Artemis),
cell reconstitution after stem cell transplantation (Figure 13–7). components of the T cell antigen receptor (CD3δ, CD3e, CD3z),
A profound defect in either T cell differentiation or function toxic accumulations of metabolites that affect immune stem cells
may cause SCIDs. Typically, patients have T cell lymphopenia, lack (adenosine deaminase [ADA] deficiency), and a deficiency of
Figure 13-7. Development of T cell

receptor excision circles (TRECs). A:
The alpha and delta loci. B: Deletion
of the delta locus. C: Complete
recombination of the alpha locus.
CD45, a key protein involved in pre-TCR and/or TCR signaling at T lymphocyte– and antigen-independent process that results in
the positive selection stage may cause human SCID. These the expression of membrane IgM and IgD molecules and a specific
genotypes result in near absence of circulating mature CD3+ T antigen-binding site of the B cell receptor. The B cell receptor is
cells and variable degree of absent of B or NK cells.42 composed of one heavy chain and one light chain (kappa or
In the periphery, CD4+ helper T cells may be classified into lambda chains). During B cell development, a progenitor cell
Th1, Th2, or Th3 (regulatory cells) subsets based on the predo- (pro-B cell), carrying Ig gene segments is assembled by DNA
minant patterns of cytokine secretion and functional attributes. rearrangements involving the joining of V, D, and J (heavy-chain)
A Th1 response is important for cell-mediated immunity and and V and J (light-chains) elements into a contiguous sequence
interferon (INF)-γ. IL-2, and tumor necrosis (TNF)-α are the upstream of the IgM (and IgD) constant region (see Figure 13–6).
predominant cytokines produced. A Th2 response is critical in The first identifiable cell within the B cell lineage is the pro-B cell
humoral immunity and hypersensitivity. IL-4, IL-5, and IL-13 are that expresses precursor proteins that allow the recombination of
the main cytokines released. Th3 cytokines are transform- gene segments at the heavy-chain locus and the expression of a
ing growth factor (TGF)-β and IL-10, which are important in surrogate light chain. Expression of this pre-B cell is essential for
regulating the Th1/Th2 balance. In order to explain the increasing allelic exclusion of a nonused heavy-chain locus. Interactions of
prevalence of allergy noted in many Westernized populations, a the developing B cells with bone marrow stromal cells and several
shift from Th1 to Th2 response or inability to suppress Th2 cytokines such as IL-2 and IL-7 result in the maturation of the pre-
response during infancy has been suggested (“hygiene hypo- B cell into a mature B cell with the replacement of the surrogate
thesis”).43 A recent modification of the hygiene theory suggests light chain by a fully rearranged light chain. A mature B cell has
induction of Th3 cytokines that controls both Th1 and Th2 the ability to respond to antigen; however, these IgM (IgD is
responses (Figure 13–8). spliced) antibodies are of low avidity. Shaping of the secondary
antibody repertoire is generated by two modifications. Class-
switch recombination (CSR) replaces IgM with other isotypes
The Development of the B Cell Lineage (IgG, IgE, IgA), thus allowing a change in antibody effector
Antibody-mediated immune responses play a critical role in the function. The second modification is somatic hypermutation
defense against extracellular pathogens and many viruses. The (SHM), which allows production of high-affinity antibodies by
primary development of the B cell lineage occurs in the fetal introduction of point mutations at a high rate in the V regions of
liver and in the bone marrow (see Figure 13–5). This is a the Ig genes, allowing the selection of high-affinity antigen-
Figure 13-8. Hygiene hypothesis. A link

between the Th1/Th2 paradigm, Th3 cytokines
response, and the risk of developing allergic
diseases in Westernized countries. Th = helper
T cell.
specific antibodies. These secondary antibody repertoire processes in foreign antigens, the newborn needs a complex set of immu-
are generated in the peripheral lymphoid organs and are antigen- nologic functions involving both innate and adaptive immunity.
dependent and T cell–dependent. The main cross-talk between The neonate should be able to maintain and control protection
T and B cells is through the interaction between CD40L (CD154) against infection and primary colonization of the skin and intes-
expressed by activated T cells and CD40 expressed by B cells. Both tinal tract as well as to avoid potentially harmful proinflammatory/
CSR and SHM require transcription through target switch and T helper responses that can induce alloimmune reactions between
V regions on V(D)J exons and DNA editing, which requires two mother and fetus. However, several important differences between
crucial enzymes expressed by germinal center B cells, AID, and the neonatal and the adult immune systems remain. Some com-
UNG.44 A defect of CSR or SHM is associated with hyper-IgM ponents function less well in neonates compared with adults,
syndrome. The study of these patients has allowed us to recognize giving rise to the concept of an “immunodeficiency of imma-
that both T and B cell interactions (resulting in CD40-mediated turity.” One particularly clear example that shows the weakness of
signaling) and intrinsic B cell mechanisms involving AID and the neonatal immune system is infection with HIV. In the absence
UNG genes are important for CSR and SHM. of retroviral therapy, there is a more rapid progression from initial
Inherited defects in several genes are known to cause reduced infection to disease presentation in pediatric patients than in
or absent immunoglobulin levels. Common variable immuno- adults after the primary infection. In addition, the neonate may
deficiency (CVID) is the most frequent symptomatic primary be at risk for graft-versus-host disease following the adminis-
immune deficiency. CVID is characterized by the sequelae of an tration of allogeneic blood even in the absence of a specific
antibody deficiency syndrome with impaired terminal B cell immunodeficiency state. Differences between neonatal and adult
differentiation, hypogammaglobulinemia, and susceptibility to immune systems include a reduction in the available bone marrow
recurrent infections.45 By contrast, defects in early B cell develop- reserve of granulocyte precursors, the decreased production
ment can result in agammaglobulinemia. Approximately 85% of of proinflammatory cytokines from the components of innate
patients with defects in early B cell development have X-linked immunity, a reduction in serum complement activity, decreased
agammaglobulinemia, a disorder caused by mutations in the cyto- ability to produce antibodies against bacterial polysaccharide
plasmic Bruton’s tyrosine kinase (BTK). This kinase is the most antigens, and increased percentage of T lymphocytes bearing
critical signal transduction pathway initiated by the pre-B cell and an antigenically “naïve” cell surface phenotype. Although T cell
B cell antigen receptor complex. An additional 5 to 7% of patients immunity is relatively intact at birth, the ability to respond with
with defects in early B cell development have mutations in the antibody production to specific antigens develops chronologically.
components of the pre-B cell and B cell antigen receptor complex.46 The neonate receives passive protection through the placental
transfer of maternal IgG during the third trimester of pregnancy.
Chronology of Immune Defense Ig concentrations similar to or higher than maternal concentra-
tions are achieved after 34 weeks of gestation. The maternal IgG
Mechanisms in Infants and Children disappears by the age of 9 months, by which time endogenous
In order to survive after transition from a sterile intrauterine synthesis of IgG is well established. The IgM and IgA of the
environment to a nonsterile ex utero environment, which is rich neonate are entirely endogenously synthesized because maternal
IgM and IgA do not cross the placenta. Human milk contains transplantation procedure.48 Absence of constitutive and inducible
bacterial and viral antibodies, including relatively high concen- expression of MHC class I or II determinants on immune cells
tration of secreted IgA antibodies, that are passively transferred to result in the bare lymphocyte syndrome. MHC class II deficiency
the neonate. This passive transfer of antibodies serves to augment is characterized by an SCID phenotype.49
the immune system. The limited capacity of naive neonatal T cells The variability in HLA phenotypes is of considerable interest
to produce certain lymphokines with immature humoral immu- given its association with susceptibility to certain human diseases.
nity may contribute to the poor response to polysaccharide A few examples of this include autoimmune diseases, infectious
vaccines (which is a T cell–independent response) and to diseases, primary immunodeficiencies, and malignancies. The
encapsulated bacteria such as group B streptococci. In addition, strongest linkage for the association of an HLA phenotype and a
neonatal B cells require a competent signal by an activating T cell specific disease is for ankylosing spondylitis and the B27 pheno-
and a higher concentration of IL-2, IL-4, and IL-6 than do adult type, with a relative risk of disease estimated at 90%. Examples for
B cells. Neonatal T cells produce sufficient IL-2 to drive T cell other associations between HLA markers and various autoim-
proliferation but not enough for optimal B cell differentiation. mune diseases include Goodpasture’s syndrome and DR2,
By contrast, the neonatal response to protein antigens ap- rheumatoid arthritis and DR4, diabetes mellitus type 1 and HLA-
pears relatively intact because this immune response is T cell– DR3, and myasthenia gravis and HLA-DQ.
dependent, and a mature T cell immunity ensures an adequate
response. Limitations in isotype expression by B cells after
immunization with T cell–dependent antigens appear primarily
Immune Tolerance
to reflect limitations in T cell help rather an intrinsic limitation Tolerance is the term used to describe the process that eliminates
of B cells.40,47 or neutralizes autoreactive cells. Knowing the mechanism of
tolerance is important in understanding the pathophysiology of
autoimmune diseases. Both central and peripheral mechanisms
The MHC are involved in the establishment and maintenance of immune
Antibodies and TCRs are highly specific in their ability to tolerance. Deletion of self-reactive T cells in the thymus through
recognize a foreign antigen and display tolerance to self-antigens. negative and positive selection (of clones with high or moderate
The specificity of the receptor is mainly carried out by a set of MHC/T cell affinity, respectively) is the central mechanism
for tolerance. Peripheral T cell tolerance is achieved through
molecules known as MHC, displayed on the cell surface. MHC
ignorance (expression of low level of antigen or physical barriers),
molecules provide the basis for discriminatory self from nonself,
anergy (absence of costimulation signals), and peripheral deletion
the ability to elicit graft rejection, and the governing of the
(activation of apoptotic pathway) and regulation. The latter is
intrathymic selection of T cells. The MHC is encoded by several
carried out through CD4+ T cells specializing in suppression of
genes located on human chromosome 6 (Figure 13–9). They are the immune response. These regulatory T cells (TREG) express
inherited in haplotypic fashion from each parent and are CD4 and CD25 and actively suppress pathologic and physiologic
codominantly expressed. Class I molecules are encoded by the immune responses, contributing to the maintenance of immu-
BCA region and are therefore called human leukocyte antigen nologic self-tolerance and immune homeostasis mainly by secre-
(HLA)-A, HLA-B, and HLA-C, whereas class II molecules are tion of TGF-β and IL-10 (Figure 13–10). The discovery of FOXP3
encoded by the D region and are therefore called HLA-DR, as an essential transcription factor not only for differentiation and
HLA-DQ, and HLA-DP. A region between these two areas on function of TREG cells but also for the regulation of intracellular
chromosome 6 encodes class III molecules including some molecules related to effector T cell responses has provided new
components of the complement system. The major role of class II insights into the pathogenesis of immune-mediated diseases.50
MHC molecules is in antigen presentation to T cells and in graft Indeed, a rare X-linked disorder known as immune dysregulation,
rejection. Therefore, providing a graft that is highly matched polyendocrinopathy, enteropathy, X-linked (IPEX) caused by
to the recipient in the HLA-A, HLA-B, HLA-C, HLA-DR, and mutations of the FOXP3 gene, has provided important new
HLA-DQ molecules is important to ensure success after a insights into the essential role of TREGs in maintaining tolerance
Figure 13-9. Scheme of the human leukocyte antigen (HLA) locus on chromosome 6.
Figure 13-10. Development of naturally occurring and

adaptive T regulatory cells (TREG) in the thymus and in
peripheral blood.
to self-antigens.51 B -cell tolerance is achieved e by elimination of down the active process of coagulation by proteolysis of Factors
ither immature B cells or autoreactive clones in the bone marrow Va and VIIIa.
or in the T cell zones of the spleen or lymph nodes. It is predo- Coincident with platelet aggregation is the formation of
minantly dependent on interactions with T cells. thrombin via the intrinsic and extrinsic coagulation cascades.
Thrombin formation is the final step of the common coagulation
pathway (see Figure 13–12). Thrombin then results in the
COAGULATION formation of fibrin strands from fibrinogen. Further assembly and
Hemostasis is the complex and dynamic process leading to clot polymerization of fibrin occurs in the presence of Factor XIII or
formation and cessation of hemorrhage at the site of vascular fibrin-stabilizing factor, which cross-links the fibrin strands.56–58
injury. It involves the interplay of endothelial cells, platelets, As clot is formed, the fibrinolytic system is activated to control the
coagulation factors, and the fibrinolytic system, which ensures the coagulation system and maintain patency of the blood vessel. 59
sealing of injured blood vessels as well as maintenance of their The delicate equilibrium between coagulation and fibrinolysis is
patency once clots have been created. The following section deals further maintained by the presence of circulating coagulation
with some of the more commonly encountered congenital and inhibitors. Thrombi are composed of fibrin and blood cells;
acquired bleeding disorders as well as thrombotic disorders the relative proportion of these influence the types of thrombi.
affecting children. White thrombi, composed mainly of platelets and fibrins strands,
form under high-shear/-flow conditions at sites of rupture or
atherosclerotic plaques of the arterial wall. Mural thrombi may
Physiology of the Coagulation Process give rise to emboli, causing distal ischemia. Venous thrombi
forming in areas of slow flow are the classic “red thrombi,”
The endothelium of the intact vessel wall serves as a barrier
composed of red blood cells with fibrin and relatively fewer
between the blood components and the thrombogenic sub-
endothelium. It synthesizes endothelin, prostacyclin (PGI2) and
NO, which control vessel vasoconstriction and vasodilatation.
The endothelium also inhibits surface clot formation by the
secretion of thrombomodulin and heparan sulfate and modulates
fibrinolysis via synthesis of tissue plasminogen activator (TPA)
and plasminogen activator inhibitors (PAIs).52–55
The initial event in hemostasis is platelet adhesion to exposed
vascular subendothelium after injury, which is mediated by the
binding of von Willebrand’s factor (vWf) to platelet integrin or
glycoprotein Ib (GPIb). Following adhesion, the platelets are acti-
vated, change shape, degranulate, and release active mediators
from storage granules. The next step is platelet aggregation
mediated by binding of fibrinogen to the platelet GpIIb-IIIa
complex. Coincident with this binding, platelets enable the tenase
(Xase) complex (Factors IXa, VIIIa, and X) and the prothrom-
binase complex (Factors Xa, Va, and prothrombin) to assemble on
the surface, resulting in thrombin formation (Figures 13–11 and
13–12). Thrombin is essential for clot formation as well as for
clot inhibition. Once thrombin is formed, it is inhibited by the
fibrinolytic enzyme, antithrombin (AT). Thrombin also binds
to thrombomodulin and activates proteins C and S to slow Figure 13-11. General overview of the coagulation process.
Neonatal Hemostasis: Developmental

Aspects and Laboratory Evaluation
Hemostasis is a dynamic process that begins in utero. Coagulation
factors are synthesized starting at 10 weeks of gestational age.
Their concentrations gradually increase, being physiologically
lower in premature infants than in full-term infants or healthy
children.65–68 The absolute values of reference ranges for coagu-
lation assays in neonates and children vary with analyzer and
reagent systems. All laboratory measures confirm the concept of
developmental hemostasis by showing that physiologic concen-
trations of coagulation proteins gradually increase and are lower
in premature infants than in full-term infants or healthy
children.65–69 A study of 125 premature infants suggested a correla-
tion between coagulation Factors II, V, VII, and X with gestational
age and also with perinatal events. Extreme prematurity, perinatal
asphyxia, and lower birthweight were associated with poorer
coagulation status and potentially higher susceptibility to perinatal
Figure 13-12. The coagulation cascade. hemorrhagic complications.70
The activation of platelets71,72 and coagulation proteins73 and
platelets. In areas of moderate blood flow, thrombi are a mixture release of TPA74 usually occur during the birth process and
of platelets, fibrin, and red cells.60–63 probably represent a developmental, nonpathologic phenomenon.
Nevertheless, any complications of delivery, resulting in birth
asphyxia, may play an important role in the pathogenesis of
Bleeding Tendency consumptive coagulopathy and promote the risk for significant
An increased bleeding tendency may result from alterations of bleeding. In the neonate, plasma concentrations of vitamin
blood vessel integrity and its collagen-fibril structure, changes in K–dependent coagulation factors (II, VII, IX, X) and contact
platelet number or function, and altered levels of the coagulation factors (XI, XII, prekallikrien, and high-molecular-weight
factors. A careful history (including family history) can provide a kininogen) are at about 50% of adult values.68 The postnatal gain
valuable screening measure for the detection of a bleeding in coagulation factor concentrations in infancy is greatest among
tendency. In addition, the following symptoms may indicate the premature infants with the lowest gestational age at birth.75
presence of a bleeding disorder and lead to its perinatal diagnosis: The capacity of newborns to generate thrombin, which is
bleeding into the scalp forming cephalohematomas, injury-related directly dependent on plasma concentrations of procoagulants,
bleeding following relatively minor invasive procedures (e.g., is reduced.76,77 Thrombin generation shows age dependency with
circumcision), hematoma formation following intramuscular endogenous thrombin potential at 30 to 60% in cord plasma
injections, and bleeding into the skin at sites of peripheral compared with adult plasma. However, newborn plasma shows
venipunctures. Facial purpura following birth is usually associated more rapid thrombin formation and enhanced sensitivity to
with severe platelet dysfunction or thrombocytopenia. Oral activated protein C (APC) and a lower concentration of tissue
mucous membrane bleeding is common in thrombocytopenic factor.78–80 After activation with low-dose tissue factor, higher
infants; however, gum bleeding and epistaxis are rarely present in amounts of anticoagulants are required to suppress cord plasma
neonates. Joint hemarthroses, typical for severe hemophilia, rarely thrombin generation compared with adult plasma.81 This may
occur before the onset of ambulation. Persistent oozing from the stem from the fact that the theoretically increased risk of bleeding
umbilical stump is typical for infants with defective fibrinogen is balanced by the protective effects of physiologic deficiencies of
production or function and Factor XIII deficiency. Bleeding the inhibitors of coagulation as well as by the decreased capacity
isolated to a single organ is more likely to occur because of a of the fibrinolytic system in infants.68,82,83
local cause (trauma) rather than a hemostatic abnormality. Hemo-
ptysis, hematemesis, gastrointestinal tract bleeding, or hematuria Laboratory Screening Tests for
is rarely the presenting symptom of a bleeding disorder. Bleeding Neonates
By contrast, hematuria in neonates may be the presenting symp-
tom of renal vein thrombosis. A small proportion of infants Diagnostic problems of special concern are the need to adapt all
with severe coagulation factor deficiencies present with intra- coagulation assays for small amounts of blood and the age-related
cranial hemorrhage (ICH) as the first manifestation of their interpretation required for test results. The initial set of laboratory
bleeding tendency.64 Nevertheless, hemostatic abnormalities such tests, which may provide important information regarding the
as disseminated intravascular coagulation (DIC), liver failure, or possible etiologies of hemorrhagic disorders, include a platelet
vitamin K deficiency may exacerbate those symptoms in critically count, a prothrombin time (PT) and an activated thromboplastin
ill infants and children. Although vitamin K deficiency has time (aPTT). Fibrinogen levels, thrombin clotting time (TCT),
become exceedingly rare with the routine perinatal administration and bleeding time (BT) may be added in some cases, followed by
of vitamin K, disastrous consequences may occur when vitamin specific factor assays, as required.
K is omitted for any reason. In such cases, a careful history The normally prolonged aPTT in neonates reflects de-
regarding the administration of vitamin K is paramount in making creased plasma concentrations of the contact factors, whereas
the appropriate diagnosis. the prolonged PT reflects decreased plasma levels of vitamin
K–dependent factors.66–68 The interpretation of coagulation factor nonimmune thrombocytopenia in neonates and infants include
assay results should consider the fact that, in neonates and infants, asphyxia, perinatal aspiration, necrotizing enterocolitis, heman-
the lower normal boundary for the assays of Factors II, X, and XI giomas, respiratory distress syndrome, and DIC. In the neonatal
may overlap with values typically seen in adults who are period, septicemia and DIC, both of which are associated with
heterozygous for factor deficiencies.66–69 The levels of other factors increased consumption, are the most common causes of throm-
including VIII, V, and XIII correlate well with the normal values bocytopenia.89 In older children, DIC, giant hemangiomas, in-
seen in the adult population, and therefore, the diagnoses of dwelling catheters, hypersplenism, and hypothermia are more
hemophilia A, Factor V, and Factor XIII deficiencies can be common. Congenital and hereditary thrombocytopenia, because
established. Plasma concentrations of fibrinogen may be skewed of impaired or ineffective production, are uncommon and
upward, despite the fact that TCT may be prolonged, because generally do not manifest early in life. Bone marrow replacement
of the normal and expected presence of “fetal” fibrinogen.84 BT, disorders such as congenital leukemia, neuroblastoma, histocy-
the test that measures platelets and vessel wall interaction and tosis, and osteopetrosis are likewise relatively uncommon during
function, is shorter in healthy neonates than in adults. This the neonatal period but should always be kept in the differential
phenomenon probably is the result of a higher hematocrit and the diagnosis when more common causes are excluded. The quali-
presence of large red cells as well as increased concentrations and tative abnormalities associated with either platelet structure-
enhanced function of vWf and large vWf multimers.66–69,85 It has function relationships or congenital metabolic defects are very
also been shown that premature infants exhibit lower levels of rare. A severe form of the various types of thrombasthenia may
vWF-cleaving protease (ADAMTS13) than term infants, poten- manifest itself in the neonatal period (see the slide presentation
tially promoting the risk for intravascular platelet aggregation and for demonstration of a typical platelet aggregation test in a patient
focal cerebral ischemia in these neonates.86 with Glanzmann’s thrombasthenia, a quality platelet defect).
In general, if the initial laboratory test results reveal abnor- Review of the peripheral blood smear and a bone marrow aspirate
malities when compared with age-related values, a stepwise may provide diagnostic information enabling detection of some
diagnostic approach should follow to characterize specific defects. platelet disorders. Evaluation of thrombocytopenia when other
This may include specific factor assays to pinpoint the acquired screening tests are normal may be simplified and based on the
or congenital bleeding diathesis. In the bleeding neonate that has mean platelet volume (Figure 13–13).
no laboratory abnormality, Factor XIII activity should be assessed Evaluation of qualitative platelet function disorders, especially
by direct measurement or using a simple test, based on dissolving in neonates, is troublesome and requires a significant amount of
a fibrin clot in 5-molar urea. In addition, when primary hemo- blood drawn in order to obtain platelet-rich plasma for classic
static defects are suspected, platelet function should be evaluated. testing of aggregation with specific agonists. Some studies have
reported that neonatal platelets are normally hyporeactive. This
Platelet Disorders: Clinical and may result from decreased receptor numbers, deficient throm-
boxane synthesis, and impaired signal transduction,71,72,90,91 as well
Laboratory Diagnosis as from perinatal platelet activation.74 Some studies have also
By far, the most common hemostatic abnormality in neonates and revealed increased platelet deposition on subendothelial surfaces
children is thrombocytopenia.87,88 The etiology of thrombocy- in neonates, probably because of the higher concentration of vWf
topenia is variable and caused by increased destruction, decreased and its large multimers that are present in neonatal plasma.92
production, dilution from massive blood transfusion, or seques- Whole blood shear and flow-based platelet assays have demon-
tration in the spleen (Table 13–1). Conditions associated with strated that the platelet function of neonates correlates with
TABLE 13-1. Diagnostic Approach to the Bleeding Child

Conditions Differential Diagnosis Tests
Plt ↓ DIC Thrombin time. FSP.
PT ↑ Factor V assay.
PTT ↑ Red cell fragmentation.
Plt normal Vitamin K deficiency. Factor II, V, VII, X assays.
PT ↑ Hepatocellular damage. Excessive heparin. Liver function tests.
PTT ↑ Congenital factor VIII, IX, XI deficiency. Response to vitamin K.
Plt normal vWD. Factor VIII, IX, XII assay.
PT normal Heparin administration.
PTT ↑
Plt normal Congenital factor VII deficiency.
PT ↑ Factor VII assay.
PTT normal
All screening tests normal Platelet dysfunction Platelet aggregation tests.
(vWD). Thrombin time.
Factor XIII deficiency. Factor XIII assay
DIC = disseminated intravascular coagulation; FSP = fibrin split products; Plt = platelet; PT = prothrombin time; PTT = partial thromboplastin time; vWD = von
Willebrand’s disease;
a process occurring secondary to a variety of underlying

insults.96,97 In the neonatal period, sepsis, asphyxia, preeclampsia
and maternal toxemia, respiratory distress syndrome, necrotizing
enterocolitis, and hypothermia may initiate DIC. In infants and
children, bacterial sepsis, leukemia, and severe intracranial
injuries are the more common causes of DIC. The diagnosis of
DIC is based on the presence of thrombocytopenia, prolonged PT,
aPPT, decreased fibrinogen levels, elevated fibrinogen split
products, and the presence of microangiopathic hemolytic
anemia. Recently, more sensitive markers for endogenous throm-
bin and plasmin generation have become available and may soon
have some clinical utility in securing the diagnosis. In practice,
no single laboratory test can be used exclusively to confirm or
Figure 13-13. Evaluation of thrombocytopenia with normal exclude DIC. The cornerstone of the management of DIC is
screening tests. treatment of the underlying disorder while supportive therapy is
applied to correct the hemostatic abnormalities. The practical
approach for diagnosis of the bleeding pediatric patient is
gestational age.93 However, apart from conditions with severe summarized in Table 13–1.
congenital platelet dysfunction, the clinical correlation and the
predictive value of platelet function testing in neonates under
various conditions remains to be elucidated. Therapy of Bleeding Disorders
in Neonates and Children
Congenital Factor Deficiencies: Therapeutic options for treatment of the various bleeding disor-
Symptoms and Diagnosis ders include routine vitamin K for neonatal prophylaxis to avoid
vitamin K deficiency bleeding (VKDB) and fresh frozen plasma
The clinical presentation of a severe factor deficiency is (FFP) or specific factor concentrates for the treatment of VKDB or
spontaneous bleeding or excessive bleeding following minor specific factor deficiencies. Such therapy may include recombinant
trauma in otherwise healthy infants. ICH may be the presenting or plasma-derived Factor VIII or Factor IX to treat hemophilia A
symptom.64 The majority of newborns with congenital coagulation or B; prothrombin complex concentrates or fibrogamin for Factor
factor deficiencies do not bleed in the perinatal period unless XIII deficiency; recombinant activated Factor VII for hemophilia
traumatized or when a hemostatic challenge is present. The patients with inhibitors, Factor VII deficiency, or Glanzmann’s
correct diagnostic assays and appropriate management vary thrombasthenia; cryoprecipitate for hemophilia A, vWD, and
according to the underlying basic disorder. Patients with Factors fibrinogen disorders; platelet transfusions for platelet function
VIII and IX deficiencies (hemophilia A and B) generally have disorders; and adjunct antifibrinolytic therapy for all infants with
limited problems during the first year of life if they are not bleeding disorders during acute bleeding episodes or surgical
traumatized during or immediately after delivery. Excessive procedures.98 For diseases such as hemophilia, the progress of gene
bruising may be noted, but bleeding into the joints is uncommon. therapy trials may yield the best therapeutic answer within a few
During the toddler years when the child is learning to walk and years. Prenatal diagnosis of most congenital severe factor deficien-
frequently falling, bleeding episodes are more common and acute cies is currently possible in families with a history of inherited
hemorrhages, spontaneous or post-traumatic, usually occur. coagulation factor deficiency.64
Although von Willebrand’s disease (vWD) is the most common
congenital bleeding disorder, patients rarely present during the
neonatal period. The most common variant, type I vWD, accounts Thrombotic Disorders
for about 70% of patients and is associated with mild bleeding. Thrombosis occurs when the usual balance between protective
However, type 3 vWD, which is associated with low or mechanisms and thrombogenic factors is disrupted. This may be
undetectable levels of vWf, manifests as a severe bleeding disorder, caused by exposure of the subendothelium following vascular
often similar to severe hemophilia.94,95 injury, activation of platelets and coagulation factors without
sufficient neutralization by coagulation inhibitors, stasis or im-
paired fibrinolysis of blood clots. In cases of acute severe arterial
Acquired Coagulation Disorders and or venous thromboembolism, thrombolytic therapy can be
Associated Abnormalities considered. Within the pediatric population, such therapy is more
The most common of the acquired coagulation disorders are often recommended in neonates and premature babies, given their
liver disease, vitamin K deficiency, anticoagulant therapy, and DIC low capacity for spontaneous fibrinolysis.
with consumption of coagulation factors. The liver is the site of The incidence of thromboembolic events among children is
synthesis of the majority of the coagulation factors. It is also much lower than among adults.99–101 Among children, neonates
involved in the clearance from the circulation of activated exhibit the highest risk with a reported incidence of 0.24 to 0.51
coagulation factors and activators of fibrinolysis. Hepatocellular per 10,000 births for venous thrombosis.101–103 The pathogenesis
damage is frequently associated with excessive bleeding owing to of any vascular thrombosis stems from acquired as well as
subnormal or deficient levels of coagulating factors. The hemo- inherited causes, the latter defined as inherited thrombophilia.104
static abnormalities in liver disease may be similar to those found The most common genetic thrombophilias include the substitu-
in DIC. DIC should not be considered a disease in itself, but rather tion of arginine by glutamine at amino acid residue 506 in
coagulation Factor V (Factor V Leyden) 105 and a guanine to Anesthesia and Coagulation Disorders
arginine transition at position 20210 of the 3’ untranslated region
of the Factor II gene (FIIG20210A) otherwise known as the The evaluation of a pediatric patient before surgery varies from
prothrombin mutation.106 These changes make these molecules that of the adult in many aspects including coagulation problems.
resistant to the endogenous fibrinolytic cascade. In addition, the Routine preoperative evaluation is not necessary unless there is
homozygous state with amino acid alterations in the enzyme enough concern to suggest congenital or familial problems such as
bleeding disorders, hypercoagulable states, and anemias or a
methyl-tetrahydrofolate reductase may be associated with vascular
history of drug exposure (anticoagulants). These are generally
disease, possibly because of increased plasma homocysteine
identified during the taking of the preoperative history. Specific
levels.107 Genetic prothrombotic risk factors play an important role
hematologic and oncologic conditions that may affect the anes-
in the pathogenesis of infantile thrombosis.99–103 As already
thetic plan are outlined in Table 13–2. Significant coagulation
mentioned in the section on “Neonatal Hemostatis: Development
abnormalities may be encountered during obstetric interventions,
aspects and laboratory evaluation”, plasma concentrations of cardiac surgery with cardiopulmonary bypass, and liver trans-
coagulation inhibitors differ among newborns and adults. The plantation, in which both the coagulation and the fibrinolytic
values of protein C, protein S, AT-III, and heparin cofactor II are systems have been triggered and vigorously activated. Continuous
low at birth. Protein C levels reach adult values in early childhood. monitoring of coagulation studies and subsequent replacement
Plasminogen levels are also low in neonates, reaching normal therapy with appropriate clotting factors or anticoagulants may be
adults levels at 6 months of age. The etiologies of classic thrombo- indicated. DIC is the most dreaded outcome of serious medical
philia are mostly caused by decreased or absent inhibitors of conditions such as sepsis, acidosis, shock, electric shock, and many
coagulation. Homozygous patients with prothrombotic disorders other situations may also trigger its appearance. Therapy should be
such as protein C and protein S deficiencies rarely present during started promptly, but the outcome depends on the successful
the neonatal period or infancy. All of the reported cases have pretreatment of the primary disease.
sented with life-threatening or lethal conditions, such as purpura Replacement of blood products and correction of coagulation
fulminans, large vessel thrombosis, hemorrhagic necrosis of the function may be necessary before surgery. Patients with factor
skin, and secondary DIC. The homozygous state for AT-III defi- deficiencies should have their PT/PTT (partial thrombolasin time)
ciency is incompatible with life. Patients who are heterozygous for corrected before surgery by either specific factor concentrates
prothrombotic disorders rarely have thromboembolic events in (VIII or IX) or FFP. Additional therapy may include the use
infancy. Problems generally arise when there is an additional insult of topical agents such as fibrin adhesives or the perioperative
such as immobilization, infection, or surgery that unmasks the administration of antifibrinolytic agents such as aminocaproic
basic problem. A prothrombotic state may also be associated with acid or tranexamic acid. Patients who require chronic anticoagu-
acquired thrombophilic risk factors such as the presence of anti- lation because of previous thromboembolism or valve replace-
phospholipid antibodies.108 In these patients, thrombosis is also ment should stop their warfarin treatment 3 to 5 days before
often triggered by additional predisposing factors such as sepsis, surgery, if possible, with a switch to heparin or low-molecular-
cancer, or the presence of central lines.109–111 weight heparin (LMWH) therapy. LMWH should be stopped
TABLE 13-2. Preoperative Hematologic Considerations

Conditions Definition Comments
Anemia Hemoglobin < No specific transfusion trigger—based on patients’ comorbid conditions.
7–10 g/dL RBC transfusion (10–15 mL/kg).
For elective surgery, erythropoietin may be considered to avoid
transfusions.
Thrombocytopenia Platelet count < Platelet replacement (one unit of random donor platelets/10 kg or 10–15
50,000/mm3 mL/kg of pheresed platelets). If no increment in previous transfusion,
use single donor or HLA-matched.
Premedication if previous allergic or anaphylactic reaction.
Antiaggregants: aspirin Withhold for 5 d before surgery.
Restart immediately postoperatively.
If intraoperative bleeding occurs, platelet transfusion.
Anticoagulation: Coumadin INR > 1.8 Withhold for 3–5 d preoperatively with parallel heparin or LMWH
replacement. If 1.8 < INR < 2.5, institute therapy for 1 d
and restart postoperatively.
In emergency situation, intravenous vitamin K.
If overt bleeding: FFP or off-label use of rFVIIa.
Heparin Maintenance Stop 4–6 h preoperatively.
Restart 6–24 h postoperatively.
LMWH Maintenance Withhold one dose at night and one at morning preoperatively.
Restart that same evening.
HLA = human leukocyte antigen; INR = International Normalized Ratio; LMWH = low-molecular-weight heparin; RBC = red blood cell; rFVIIa = recombinant
activated factor VII.
12 to 24 hours before surgery and heparin should be stopped 4 to Broxmeyer HE. Regulation of hematopoiesis by chemokine family
6 hours before surgery. In emergency situations, vitamin K and members. Int J Hematol. 2001;74:9–17.
22. Majka M, Janowska-Wieczorek A, Ratajczak J, et al. Numerous growth
FFP should be given to allow the procedure to proceed. Once factors, cytokines, and chemokines are secreted by human CD34(+) cells,
the bleeding risk has subsided, preoperative anticoagulation myeloblasts, erythroblasts, and megakaryoblasts and regulate normal
medications should be resumed with the intention of achieving hematopoiesis in an autocrine/paracrine manner. Blood. 2001;97:
therapeutic levels of PTT and the International Normalized 3075–3085.
Ratio (INR). 23. Blank U, Karlson G, Karlson S. Signaling pathways governing stem cell
fate. Blood. 2008;111:492–503.
24. Sieff CA, Emerson SG, Mufson A, et al. Dependence of highly enriched
human bone marrow progenitors on hemopoietic growth factors and
CONCLUSION their response to recombinant erythropoietin. J Clin Invest. 1986;77:
74–81.
It has been long conceptualized that a child is not a miniature 25. Manroe BL, Weinberg AG, Rosenfeld CR, et al. The neonatal blood count
reflection of an adult. The abnormalities encountered in neonates, in health and disease. I. Reference values for neutrophilic cells. J Pediatr.
infants, and later, in children and adolescents, are age-, develop- 1979;95:89–98.
ment-, and maturation-dependent. Anatomic malformations, 26. R.I Walker, R. Willemze. Neutrophil kinetics and the regulation of
genetic aberrations, and exogenous factors may all contribute to granulopoiesis. Rev Infect Dis. 2(1980):282– .
27. Christensen RD, Rothstein G. Exhaustion of mature marrow neutrophils
the disruption of the normal hematopoietic process, formation in neonates with sepsis. J Pediatr. 1980;96:316–318.
of cellular and humoral blood components, and function of 28. Nicola NA, Johnson GR. The production of committed hemopoietic
the immune system. These factors may affect not only on the colony forming cells from multipotential precursor cells in vivo. Blood.
intraoperative care of the patients but also the entire continuum 1982;60:1019–1029.
of their perioperative care. 29. Vincent PC. The measurement of granulocyte kinetics. Br J Haematol.
1977;36:1–4.
30. Squier, MKT Seher AJ, Cohen JJ. Apoptosis in leukocytes. J Leukol Biol.
1955;57:2–10.
REFERENCES 31. Pang L, Weiss MJ, Poncz. M. Megakaryocyte biology and related
1. Schofield R. The relationship between the spleen colony-forming cells disorders. J Clin Invest. 2005;115:3332–3338.
and the haematopoietic stem cell. Blood Cells. 1978;4:7–25. 32. Jackson CW, Gosslee DG. Maturation of rat megakaryocytes studied by
2. Wilson A, Trumpp A. Bone marrow hematopoietic stem cell niches. microspectrophotometric measurement of DNA. Proc Soc Exp Biol Med
Nat Rev Immunol. 2006;6:93–106. 1965;119:1194–1199.
3. Nilsson SK, Johnston HM, Coverdale JA. Spatial localization of 33. Shivdasani RA, Rosenblatt MF, Zucker-Franklin D, et al. Transcription
transplanted hematopoietic teem cells. inferences for the localization of factor NF-E2 is required for platelet formation independent of the actions
stem cell niches. Blood. 2001;97:2293–2299. of thrombopoietin/MGDF in megakaryocyte development. Cell. 1995;
4. Arai F, Hirao A, Ohmura M, et al. Tie2/angiopoietin-1 signaling regulates 81:695–704.
hematopoietic stem cell quiescence in the bone marrow niche. Cell. 34. Kaushansky K. The molecular mechanisms that control thrombopoiesis.
2004;118:149–61. J. Clin. Invest. 2005;115:3339–3347.
5. Nagasawa T. A chemokine, SDF-1/PBSF, and its receptor, CXC chemokine 35. Kaushansky K, Lok S, Holly RD, et al. Promotion of megakaryocyte
4, as mediator of hematopouesis. Int J Hematol. 2000;72:408–411. progenitor expansion and differentiation by the c-Mpl ligand thrombo-
6. Till JE, McCulloch EA. A direct measurement of the radiation sensitivity poietin. Nature. 1994;369:568–571.
of normal mouse bone marrow cells. Radiat Res. 1961;14:213–222. 36. Medzhitov R, Janeway C Jr. Innate immunity. N Engl J Med. 2000;
7. Fauser AA, Kanz L, Bross KJ, Löhr GW. T cells and probably B cells arise 343:338–344.
from the malignant clone in chronic myelogenous leukemia. J Clin Invest. 37. Delves PJ, Roitt IM. The immune system. First of two parts. N Engl J Med.
1985;75:1080–1082. 2000;343:37–49.
8. Adamson JW, Fialkow PJ, Murphy Set al. Polycythemia vera: stem cell 38. Delves PJ, Roitt IM. The immune system. Second of two parts. N Engl J
and probable clonal origin of the disease. N Engl J Med. 1976;295:913– Med. 2000;343:108–117.
916. 39. Fischer A. Human primary immunodeficiency diseases. Immunity.
9. Moore MAS, Metcalf DI. Ontogeny of the hematopoietic system. Yolk sac 2007;27:835–845.
origin of in-vivo and in-vitro colony-forming cells in the developing 40. Levy O. Innate immunity of the newborn: basic mechanisms and clinical
mouse embryo. Br J Haematol. 1970;18:279–296. correlates. Nat Rev Immunol. 2007;7:379–390.
10. Micklem HS, Ross E. Heterogeneity and aging of hematopoietic stem 41. Huston DP. The biology of the immune system. JAMA. 1997;278:
cells. Ann Immunol. 1978;129:367–376. 1804–1814.
11. Eaves C, Miller C, Cashman J, et al. Hematopoietic stem cells: inferences 42. Kalman L, Lindegren ML, Kobrynski L, et al. Mutations in genes required
from in vivo assays. Stem Cells. 1997;15(Suppl 1):1–5. for T-cell development: IL7R, CD45, IL2RG, JAK3, RAG1, RAG2,
12. Jones RJ, Collector MI, Barber JP, et al. Characterization of mouse ARTEMIS, and ADA and severe combined immunodeficiency: HuGE
lymphohematopoietic stem cells lacking spleen colony-forming activity. review. Genet Med. 2004;6:16–26.
Blood. 1996;88:487–491. 43. Romagnani S. Coming back to a missing immune deviation as the main
13. Keller G, Snodgrass R. Life spans of multipotential hematopoietic stem explanatory mechanism for the hygiene hypothesis. J Allergy Clin
cells in vivo. J Exp Med. 1990;117:1407–1418. Immunol. 2007;119:1511–1513.
14. Novak LP, Stewart CC. Stochastic versus deterministic in hematopoiesis: 44. Notarangelo LD, Lanzi G, Peron S, Durandy A. Defects of class-switch
what is what? Br J Haematol. 1991;78:149–154. recombination. J Allergy Clin Immunol. 12006;17:855–864.
15. Berenson RJ, Andrews RG, Bensinger WI, et al. Antigen CD34+ marrow 45. Salzer U, Grimbacher B. Common variable immunodeficiency: the power
cells engraft lethally irradiated baboons. J Clin Invest. 1988;81:951–955. of co-stimulation. Semin Immunol. 2006;18:337–346
16. Civin CI, Trischmann T, Kadan NS, et al. Highly purified CD34-positive 46. Conley, ME Broides A, Hernandez-Trujillo V, et al. Genetic analysis of
cells reconstitute hematopoiesis. J Clin Oncol. 1996;14:2224–2233. patients with defects in early B-cell development. Immunol Rev. 2005;
17. Nicola NA. Hemopoietic cells growth factors and their receptors. Annu 203:216–234.
Rev Chem. 1989;58:45–77. 47. Adkins B, Leclerc C, Marshall-Clarke S. Neonatal adaptive immunity
18. Sachs. L The molecular control of blood cell development. Science. comes of age. Nat Rev Immunol. 2004;4:553–564.
1987;238:1374–1379. 48. Klein J, Sato A. The HLA system. First of two parts. N Engl J Med. 2000;
19. Metcalf D. Hematopoietic cytokines. Blood. 12008;11:485–491. 343:702–709.
20. Zhu J, Emerson SG. Hematopoietic cytokines, transcription factors and 49. Nekrep N, Fontes JD, Geyer M, Peterlin BM. When the lymphocyte loses
lineage commitment. Oncogene. 2002;21:3295–3313. its clothes. Immunity. 12003;8:453–457.
50. Bacchetta R, Gambineri E, Roncarolo MG. Role of regulatory T cells and 77. Haidi H, Cimenti C, Leschnik B, et al. Age dependency of thrombin
FOXP3 in human diseases. J Allergy Clin Immunol. 2007;120:227–235. generation measured by means of calibrated automated thrombography.
51. Torgerson TR, Ochs HD. Immune dysregulation, polyendocrinopathy, Thromb Haemost. 2006;95:772–775.
enteropathy, X-linked: forkhead box protein 3 mutations and lack of 78. Cvirm G, Gallistl S, Leschnik B, Muntean W. Low tissue factor pathway
regulatory T cells. J Allergy Clin Immunol. 2007;120:744–750. inhibitor together with low antithrombin allows sufficient thrombin
52. Weksler BB, Marcus AS, Jaffe EA: Synthesis of prostaglandin I2 generation in neonataes. J Thromb Haemost. 2003;1:263–268.
(prostacyclin) by a cultured human and bovine endothelial cells. Proc Natl 79. Cvirm G, Gallistl S, Rehak T, et al. Elevated thrombin-forming capacity
Acad Sci U S A. 1977;74:3922. of tissue factor activated cord compared with adult plasma. J Thromb
53. Teien AN, Abildgaard U, Hook M. The anticoagulant effect of heparan Haemost. 2003;1:1785–1790.
sulfate and dermatan sulfate. Thromb Res. 1976;8:859–867. 80. Hyytiainen S, Wartiovaara Kautto U, Ulander VM, et al. The procoa-
54. Heeb MH, Espana F, Geiger M, et al. Protein C inhibitor and plasminogen gulant effects of factor V Leiden may be balanced against decreased levels
activator inhibitor-3. J Biol Chem. 1987;262:15813. of factor V and do not reflect in-vivo thrombin formation in newborns.
55. Warner TD, Mitchell, JA deNucci G, et al. Endothelin-1 and endothelin- Thromb Haemost. 2006;95:434–440.
3 release EDRF from isolated perfused arterial vessels of the rat and rabbit. 81. Baier K, Cvirm G, Fritsch P, et al. Higher concentrations of heparin and
J Cardiovasc Pharm. 1989;13:85. hirudin are required to inhibit thrombin generation in tissue-factor
56. Downing, MR Butkowski RJ, Clark MMM, et al. Human prothrombin activated cord plasmathan in adult plasma. Pediatr Res. 2005;57:685–689.
activation. J Biol Chem. 1975;250:8897. 82. Parmer N, Albisetti M, Berry LR Chan AK. The fibrinolytic system in
57. Esmon CT. The roles of protein C and thrombomodulin in the regulation newborns and children. Clin Lab. 2006;52:115–124.
of blood coagulation. J Biol Chem. 1989;264:4743. 83. Parmer N, Mitchell LG, Berry LR, et al. The influence of age on in-vitro
58. Tracy PB, Eide LL, Mann KG. Haman prothrombinase complex assembly plasmin generation in the presence of fibrin monomer. Acta Hematol.
and function on isolated peripheral blood cell populations. J Biol Chem. 2006;115:141–151.
1985;260:2119. 84. Witt I, Muller H, Kunter LJ. Evidence for the existence of fetal
59. Erickson LA, Scleef RR, Ny T, Loskutoff DJ. The fibrinolytic system of fibrinogen. Thromb Diath Haemorrh. 1969;22:101–109.
the vascular wall. Clin Hematol. 1985;14:513. 85. Katz JA, Moake JL, McPherson PD, et al. Relationship between human
60. Freiman DG. The structure of thrombi. In: Colman RW, Hirsh J, Marder development and disappearance of unusually large von Willebrand
VJ, Salzman EW, editors. Hemostasis and Thrombosis: Basic Principles and factor multimers from plasma. Blood. 1989;73:1851–1858.
Clinical Practice. Philadelphia: JB Lippincott; 1987. 86. Hellstrom-Westas L, Ley D, Berg AC, et al. VWF-cleaving proteas
61. Chandler AB. The anatomy of a thrombus. In: Sherry S, Brinkhous KM, (ADAMTS 13) in premature infants. Acta Paediatr. 2005;94:205–210.
Genton E, Stengle JM, editors. Thrombosis. Washington, DC: National 87. Pearson HA, McIntosh S. Neonatal thrombocytopenia. Clin Hematol.
Academy of Sciences; 1969. 1978;7:111.
62. Jorgensen L. Experimental platelet and coagulation thrombi: a histological 88. Pearson, HA Shulman NR, Marder VJ, Cone TE Jr. Isoimmune neonatal
study of arterial and venous thrombi of varying age in untreated and thrombocytopenic purpura. Clinical and therapeutic considerations.
heparinized rabbits. Acta Pathol Microbiol Scand (A). 1964;62:189. Blood. 1964;23:154–177.
63. Baumgartner HR. The role of blood flow in platelet adhesion, fibrin 89. Castle V, Andrew M, Kelton J, et al. Frequency and mechanism of
deposition and formation of mural thrombi. Microvasc Res. 1973;5: neonatal thrombocytopenia. J Pediatr. 1986;108:749–755.
167. 90. Rajasekar D, Bernard M, Francis J, Bednarek F. Platelet hyporeactivity in
64. Kulkarni R, Ponder KP, James AH, et al. Unresolved issues in diagnosis very low birth weight neonates. Thromb Haemost. 1997;77:1002–1007.
and management of inherited bleeding disorders in the perinatal period: 91. Israels SJ, Odaibo FS, Robertson C, et al. Deficient thromboxane
a White Paper of the Perinatal Task Force of the Medical and Scientific synthesis and response in platelets from premature infants. Pediatr Res.
Advisory Council of the National Hemophilia Foundation, USA. 1997;41:218–223.
Haemophilia. 2006;12:205–211. 92. Linder N, Shenkman B, Levin E, et al. Deposition of whole blood platelet
65. Reverdiau-Moalic P, Delahousse B, Bardos GBP, et al. Evolution of blood on extracellular matrix under flow conditions in preterm infants. Arch
coagulation activators and inhibitors in the healthy human fetus. Blood. Dis Child. 2002;86:127–130.
1996;88:900–906. 93. Levy-Shraga Y, Maayan-Metzger A, Lubetsky A, et al. Platelet function
66. Andrew M, Payes B, Milner R, et al. Development of the human coagu- of newborns as tested by cone and plate(let) analyzer correlates with
lation system in the healthy premature infant. Blood. 1988;72:1651–1657. gestational age. Acta Hematol. 2006;115:152–156.
67. Andrew M, Paes B, Johnston M. Development of the hemostatic system 94. Werner EJ, Broxson EH, Tucker EL, et al. Prevalence of von Willebrand
in the neonate and young infant. Am J Pediatr Hematol Oncol. 1990;12: disease in children: a multiethnic study. J Pediatr. 1993;123:893.
95–104. 95. Nichols WC, Ginsburg D. Von Willebrand disease. Medicine. 1997;76:1.
68. Andrew M, Vegh P, Johnston M, et al. Maturation of the hemostatic 96. Hataway W, Mull M, Pechet G. Disseminated intravascular coagulation
system during childhood. Blood. 1992;80:1998–2005. in newborn. Pediatrics. 1969;43:233.
69. Monagle P, Barnes C, Ignjatovic V, et al. Developmental hemostasis— 97. Corrigan J. Activation of coagulation and disseminated intravas-
impact for clinical hemostasis laboratories. Thromb Haemost. 2006; cular coagulation in the newborn. Am J Pediatr Hematol Oncol. 1979;
95:362–372. 1:245.
70. Salonvaara M, Riikonen P, Kekomäki R, et al. Effects of gestational age 98. Brettlet D, Levine P. Clinical manifestations and therapy of inherited
and prenatal and perinatal events on the coagulation status in premature coagulation factor deficiencies. In: Colman RW, Hirsh J, Marder VJ,
infants. Arch Dis Child Fetal Neonatal Ed. 2003;88:F319–F323. Salzman EW, editors. Hemostasis and Thrombosis: Basic Principles and
71. Israels S, Daniels M, McMillan E. Deficient collagen-induced activation Clinical Practice. 3rd ed. Philadelphia: JB Lippincott; 1999. pp. 169–183.
in the newborn platelet. Pediatr Res. 1990;27:337–343. 99. Andrew M. Developmental hemostasis: relevance to thromboembolic
72. Wasiluk A. Antigen density of P-selectin on the platelets of healthy term complications in pediatric patients. Thromb Haemost. 1995;74:415–425.
newborns. Platelets. 2004;15:459–461. 100. Andrew M, David M, Adams M, et al. Venous thromboembolic (VTE)
73. Suarez CR, Menendez CE, Welenga JM, Fareed J. Neonatal and maternal complications in children: first analyses of the Canadian registry of VTE.
hemostasis. Value of molecular markers in the assesment of hemostatic Blood. 1994;83:1252–1257.
status. Semin Thromb Hemost. 1984;10:280–284. 101. Heleen Van-Omen C, Heijboer BH, Buller HR, et al. Venous throm-
74. Runnebaum IB, Maurer SM, Daly L, Bonnar J. Inhibitors and activators boembolism in childhood: a prospective two-year registry in the
of fibrinolysis during and after childbirth in maternal and cord blood. Netherlands. J Pediatr. 2001;139:676–681.
J Perinat Med. 1989;17:113–119. 102. Schmidt B, Andrew M. Neonatal thrombosis: report of a prospective
75. Salonvaara M, Riikonen P, Vahtera E, et al. Development of selected Canadian and international registry. Pediatrics. 1995;96:939–943.
coagulation factors and anticoagulants in preterm infants by the age of 103. Nowak-Gottl U, Von-Kries R, Gobel U. Neonatal symptomatic throm-
six months. Thromb Haemost. 2004;92:688–696. boembolism in Germany: two year survey. Arch Dis Child Fetal Neonatal.
76. Andrew M, Schmidt B, Mitchell L, et al. Thrombin generation in newborn 1997;76:F163–F167.
plasma is critically dependent on the concentration of prothrombin. 104. Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis.
Thromb Haemost. 1990;63:27–30. N Engl J Med. 2001;344:1222–1231.
105. Dalback B. New molecular insights of thrombophilia: resistance to 108. Berkun Y, Padeh S, Barash J, et al. Antiphospholipid syndrome in
activated protein C caused by Arg506 to Gln. Mutation in factor V as children and recurrent thrombosis. Arthritis Rheum. 2006;55:850–855.
pathogenetic risk factor for venous thrombosis. Thromb Haemost. 109. Heller C, Schobess R, Kurnik K, et al. Abdominal thrombosis in neonates
1995;74:139–148. and infants: role of prothrombotic risk factors—a multicenter case-
106. Poort, SR Rosendal FR, Rewifman PH, Bertina RM. A common genetic control study. Br J Haematol. 2000;111:534–539.
variation in the 3’ untranslated region of the prothrombin gene is 110. Lanari M, Lazzarotto T, Papa I, et al. Neonatal aortic arch thrombosis
associated with elevated plasma prothrombin levels and an increase in as a result of congenital cytomegalovirus infection. Pediatrics. 2001;
venous thrombosis. Blood. 1996;88:3698–3703. 108:E114
107. Frosst P, Bloom HJ, Milos R, et al. A candidate genetic risk factor for 111. Nowak-Göttl U, Wermes C, Junker R, et al. Prospective evaluation of the
vascular disease: a common mutation in methylene-tetrahydrofolate thrombotic risk in children with acute lymphoblastic leukemia carrying
reductase. Nat Genet. 1995;10:111–113. the MTHFR TT 677 genotype, the prothrombin 20210G>A variant, and
further prothrombotic risk factors. Blood. 1999;93:1595–1599.
Temperature Regulation:
Physiology and Pharmacology 14
Igor Luginbuehl C H A P T E R
INTRODUCTION been measured in degrees Celsius or Fahrenheit. A temperature

of zero Kelvin equals approximately 273.15°C or approximately
Maintaining central body temperature within narrow limits is a 459.67°F. A body temperature of 37.0°C is equal to 98.6°F; the
prerequisite for the survival of homeothermic organisms and following formulas allow for easy conversion among Celsius,
requires a complex feedback system. Despite changes in the Fahrenheit, and Kelvin:
ambient temperature, a homeothermic organism has the ability to
maintain central or core body temperature constant. In humans, °Celsius = (°Fahrenheit – 32) × 0.56
core body temperature refers to the temperature of the vessel-rich °Fahrenheit = (1.8 × °Celsius) + 32
Kelvin = °Celsius + 273.15
group organs (i.e., brain, heart, lungs, liver, and kidneys). Under
normal conditions, this temperature is maintained within ± 0.2°C In order to detect perioperative changes in temperature,
of its normal value of 37.0°C. This so-called interthreshold range appropriate measures to assess temperature need to be in place.
represents the minimal deviation tolerated by the body under Guidelines of the American Society of Anesthesiologists and
normal circumstances. Within this range, no thermoregulatory numerous other national anesthesia societies require or at least
effector responses are triggered and the human organism behaves recommend that one method for measuring body temperature
poikilothermic. Not many other physiologic parameters are as during anesthesia be available.3–7 Although standard for clinical
tightly and effectively controlled as central body temperature. purposes in earlier times, mercury-in-glass thermometers have
Measuring body temperature in almost 25,000 patients and now been mostly replaced by thermocouples and thermistors.
acquiring a total of more than 1 million measurements at the A thermocouple consists of two different metals, commonly
University Hospital of Leipzig, the German physician, Karl copper and constantan (a copper-nickel-manganese-iron alloy).
Reinhold August Wunderlich (1815–1877), was the first to The principle is based on the Seebeck effect, named after the
systematically measure axillary body temperature under various Estonian physicist Thomas Johann Seebeck (1770–1831) who, in
conditions, to widely use thermometers in clinical practice, and 1821, discovered the temperature-measuring properties of this
to define the normal body temperature of 37.0°C with a range of setup. The Seebeck effect states that a small electrical potential
36.2 to 37.5°C.1 He also realized that body temperature oscillates is produced at any junction between two different metals from
not only in sick but also in healthy subjects. Given the fact that the thermoelectric series. The magnitude of this current is
thermometers at that time were rather bulky and slow and that temperature-dependent and can, therefore, be used to measure
temperature.
computers were not available for data analysis, even by today’s
The American inventor, Samuel Ruben (1900–1988), dis-
standards, Wunderlich’s work should be regarded as a most
covered in 1930 that electrical resistance changes exponentially
impressive achievement. However, the calibration and accuracy of
with temperature. This formed the basic principle of the therm-
the thermometers that he used are not known and the same
istor type of thermometer, a semiconductor resistor that consists
applies to his statistical methods for data analysis. A systematic of a tiny blob of metal (copper, cobalt, nickel, or manganese). The
review of the literature defined the normal for axillary temperature change in resistance is used to measure temperature, which is also
in adult men and women as ranging between 35.5 and 37.0°C (the reflected in the name thermistor, a combination of the words
oral, rectal, and tympanic temperature ranges were 33.2–38.2°C, “thermal” and “resistor.” Both thermocouples and thermistors
34.4–37.8°C, and 35.4–37.8°C, respectively). The authors con- are fairly inexpensive, are easily available, and have a reasonably
cluded that the range of normal body temperature, particularly its fast response time. For clinical purposes, both are considered
lower limit, needs to be adjusted.2 sufficiently accurate, although thermistors in general are more
precise (up to ± 0.1°C).
Temperature-sensitive liquid crystals have been used to mea-
TEMPERATURE MONITORING sure skin temperature. Although safe, easy, convenient to handle,
Temperature is one of the seven base quantities in the Interna- and with a theoretical accuracy in the range of ± 0.5°C, these
tional System of Units (SI) and its unit is Kelvin (symbol K). By devices generally do not meet the accuracy criteria required for
definition, 1 Kelvin is the fraction 1/273.15 of the thermodynamic clinical use because the measurement can easily be influenced by
temperature of the triple point of Vienna Standard Mean Ocean changes other than body temperature and skin blood flow.8,9 To
Water (i.e., despite the name, the reference is pure water). How- compensate for this error, it has been suggested to simply add a
ever, in medicine (and daily life), temperature has traditionally correction factor to an arbitrary skin temperature measurement,
but this does not provide a reliable estimate of central temperature However, most monitoring sites have specific limitations, which
and is, therefore, neither recommended nor widely used in may result in different temperature readings, and it is useful to
anesthesia practice.8,10 However, at least one study has reported know the physiologic and clinical significance of such differences.
that forehead temperature assessed by liquid crystal thermometry Because of its wide variability depending on the site of
correlates better with esophageal temperature than axillary or monitoring, skin temperature is not an acceptable site for the
rectal temperature during rapid rewarming after cardiopulmonary estimation of core temperature.32,33 Several investigators have
bypass (CPB) surgery.11 suggested that skin monitoring can be used with the monitoring
Although less suitable for continuous temperature monitoring of 4 to 15 cutaneous sites and the use of both weighted and un-
under anesthesia, infrared thermometers (thermopiles) are widely weighted formulas to accurately describe mean skin tempera-
used in clinical practice (e.g., in postanesthesia care units). Their ture30,34–36 However, to be of clinical value, skin temperature would
function is based on the fact that any object with a temperature have to accurately reflect central temperature in the perioperative
above absolute zero (i.e., ~273.15°C) emits blackbody radiation period and during hypothermia or malignant hyperthermia.
with a characteristic temperature-dependent wavelength. These For example, it is unlikely that skin temperature closely correlates
probes consist of a small lens that allows the infrared radiation with central temperature during the early stages of malignant
from an object to be focused onto a detector that then converts hyperthermia, because skin perfusion will be significantly altered
the infrared energy into an electrical signal with a corresponding by circulating catecholamine levels that are up to 20 times higher
temperature readout. The two main advantages of this type of than normal.37
thermometer are that they have a quick response time (typically No physiologic evidence exists that hypothalamic temperature
< 1 s) and that they do not need to be in direct contact with the precisely represents central temperature. Benzinger, nevertheless,
object to be measured, which makes them theoretically ideal for suggested that central temperature is the temperature of the
tympanic (and, to a lesser degree, skin) temperature assessment. hypothalamus and that tympanic membrane temperature probes
However, the medical literature is, at best, inconclusive about the reliably reflect central temperature.38 A pulmonary artery catheter
clinical benefits and accuracy of these thermometers.12–26 with a distal-tip thermistor is the gold standard for assessing
Handheld infrared scanners (noninvasive temporal artery central body temperature, providing the reference temperature
thermometers) have recently been developed to assess central against which all other sites are compared. However, because of
temperature via skin temperature measurement. By contrast to its invasive nature, its use is limited to special situations, namely,
liquid crystal thermometers, these devices theoretically detect the critically ill children.
highest temperature in the temporal or forehead region, which Tympanic membrane temperature has been suggested to be
normally is the skin area in closest proximity to the temporal the most ideal temperature-monitoring site to determine core
artery. Unlike liquid crystal thermometers, the device compensates body temperature. However, the accuracy of infrared tympanic
for ambient temperature with a built-in proprietary algorithm. thermometers is controversial. In order to accurately reflect
However, in both adult and pediatric patients, the accuracy of tympanic temperature, even noninfrared temperature probes are
the device has not been considered sufficient to meet clinical not required to be in direct contact with the tympanic membrane
purposes.26–29 as long as the probe seals the external auditory canal, allowing the
air column trapped between the probe and the tympanic mem-
brane to reach a steady state. However, it has been demonstrated
Sites for Temperature Monitoring that tympanic temperature does not correlate well with brain
Within the body, temperature is neither constant nor uniform and temperature in the initial postoperative period in infants and
its regulation involves several organs and systems. Because of the children after cardiac surgery and, therefore, does not provide an
high perfusion rate, core tissues maintain their temperature accurate estimate of central body temperature.39,40 Mainly because
relatively constant and tightly regulated within the superimposed of the difficulty related to obtaining appropriate-sized thermistors,
circadian changes in central temperature. By contrast, peripheral but also because of concerns regarding tympanic membrane
tissues demonstrate a much wider and far less uniform tem- perforation, their clinical use has been discouraged.41,42
perature range, which may differ by several degrees within a short Nasopharyngeal temperature probes can accurately reflect core
distance from each other.30 This is explained by the fact that temperature if properly positioned, that is, placing the tip of the
the peripheral compartment acts as a highly dynamic buffer probe in the posterior nasopharynx in close proximity to the
between the central and the shell compartment. Depending on the soft palate. This provides a good estimate of the hypothalamic
requirements and the environment, it acts as a source of heat gain temperature. However, an uncuffed endotracheal tube with a
or heat loss. moderate to large air leak may create enough leak flow to result
Body temperature can be monitored at basically any anatomic in falsely low temperature readings. Further limitations include
site. However, the accuracy of measurements depends on the slight, but usually self-limiting, bleeding from the nose or
chosen site, with each site having its advantages and disadvan- nasopharynx (particularly in children with large adenoids) and
tages.31,32 The ideal site of temperature monitoring should reflect impracticality during mask anesthesia. Nevertheless, in clinical
core temperature and be associated with no (or only negligible) practice, this site is an often used, is easy accessible, and remains
morbidity. Because core temperature is the key player in the- a fairly reliable site for temperature measurement. Oral tempera-
rmoregulation, it has attracted the most clinical attention. Core ture has been reported to reliably reflect central temperature
temperature measuring sites available for clinical use include the in orally intubated adult patients in the critical care unit.18,43
tympanic membrane, nasopharynx, distal esophagus, pulmonary Limitations include impracticality and potential inaccuracy with
artery, and with some limitations, bladder and rectum. Under ideal mask anesthesia because a moderate to large leak around the
conditions, all of these sites provide similar readings in awake as endotracheal tube or an open mouth during anesthesia can result
well as in anesthetized humans undergoing noncardiac surgery.31 in falsely low readings.
CHAPTER 14 ■ Temperature Regulation: Physiology and Pharmacology 223
Esophageal temperature probes are often combined with simultaneously at multiple sites (e.g., rectum, bladder, esophagus,
an esophageal stethoscope, which makes this site particularly nasopharynx, tympanic membrane). For nonintubated pediatric
attractive for the pediatric population. However, in infants and patients undergoing a short operative or diagnostic procedure, the
children as well as in cachetic patients, the thermal insulation is author uses either a rectal or, with its limitations in mind, an
minimal between the tracheobronchial tree and the esophagus. axillary temperature probe. If the child’s trachea is intubated, other
The inspiratory gas flow may, therefore, depending on its tem- preferred sites include the distal esophagus (combined with
perature, result in erroneous temperature readings, particularly esophageal stethoscope) or the nasopharynx.
when minute ventilation is high and the gas temperature is sig-
nificantly different from body temperature.32 Central temperature
is measured only if the tip of the probe is positioned in the distal THERMOREGULATION
third of the esophagus at the point at which the heart sounds are The French obstetricians, Etienne Stéphane Tarnier (1828–1897),
the loudest.32,44 However, in patients with endotracheal intubation, and his student, Pierre Constant Budin (1846–1907), both now
esophageal temperature is more reliable than rectal temperature considered fathers of modern perinatology, were the first to
and more practical than tympanic temperature. The optimal depth detect that, although the survival rate of neonates with a rectal
of a nasally inserted esophageal temperature probe in adults has temperature between 32.5 and 33.5°C was a shocking and dismal
been determined as:45 10%, it could be dramatically increased to 77% when the infants
were warmed to a rectal temperature of 36 to 37°C.52 No other
body height (cm) medical intervention can claim an equally profound impact on
Insertion depth [cm] = – 4 cm
4 neonatal survival rates. In addition, this is a great example to
highlight the power and limits of thermoregulation.
Malpositioning of the axillary temperature probe is the most Tarnier was also the inventor of the first incubator for
common reason for its notoriously low reliability in reflecting premature and small–for–gestational age neonates. The idea for
central temperature. Nevertheless, it is the most commonly used an incubator occurred to him while visiting the Paris zoo in 1880,
and convenient site for temperature monitoring during the where he saw eggs of exotic birds being hatched in a “couveuse”
administration of general anesthesia. Axillary temperature has (incubator). He immediately recognized the potential of such a
been reported to be as accurate in measuring central temperature device and had one custom built for his hospital. In 1881, this
as tympanic membrane, esophageal, and rectal temperature sites, resulted in the first closed incubator used in a hospital.53 The
but this requires the tip of the thermometer to be carefully placed incubator had space for four babies and used an oil flame to heat
over the axillary artery and the arm to be closely adducted.32 In a large tank of water underneath the bed. Other investigators later
small children, high flow rates of intravenous solutions at less than confirmed Tarnier and Budin’s findings regarding the importance
body temperature on the arm of the thermometer may result in of thermal stability for neonatal adaptation and further eluci-
falsely low temperature reading, which explains why the axillary dated the mechanisms by which infants and children behave as
temperature probe should not be placed on the same side as the homeotherms.54–57
infusion. In terms of thermoregulation, the body can be treated as a
The accuracy of rectal temperature monitoring can be affected three-compartment model with central, peripheral, and shell com-
by problems of probe insulation by feces, cooler blood returning partments (Figure 14–1). The vessel-rich group organs represent
from the legs, the influence of an open abdominal cavity for sur- the majority of the central compartment; the musculoskeletal
gery, or irrigation of the abdomen or bladder with fluids of a system makes up the greater part of the peripheral compartment
and acts as a dynamic buffer in the thermoregulatory system
temperature different from the rectal temperature. A significant
between the core and the shell, which is represented by the skin
lag in the response time may occur in situations with rapid
and functions as a barrier to the environment.
changes in central temperature (e.g., cooling and rewarming on
Circadian rhythms ensure optimal function of a biologic
CPB).46–48 With these limitations in mind, the rectal site usually
system, maximizing its performance and efficiency while
provides an easy and fairly reliable way to monitor central tem- maintaining an appropriate comfort level.58 It appears that the
perature and is associated with minimal morbidity.32 If possible, circadian changes in core body temperature are generated by
rectal temperature should not be used in patients with inflamma- a rhythmic input from the central pacemaker located in the
tory bowel disease (risk of perforation), bleeding disorders, suprachiasmatic nuclei (hypothalamus) acting upon impulses
thrombocytopenia or neutropenia, perirectal disease such as from neighboring hypothalamic thermoregulatory centers, which
hemorrhoids (risk of bleeding), or in patients whose abdomen, may not only alter the thresholds for thermoregulatory effectors
bowel, or bladder is to be irrigated (inaccurate reading). Bladder (e.g., cutaneous vasodilatation or sweating) but also modulate the
temperature is also considered an appropriate site for core tem- set point of body temperature.59,60
perature measuring.49,50 In adults, it has been demonstrated that Despite the fact that the central body temperature is under very
as long as urinary output is maintained at approximately 250 mL/ tight control, it shows circadian variations. The circadian rhythm
h, bladder temperature closely reflects pulmonary artery tempera- of body temperature is generally closely related to the sleep-wake
ture.49,51 However, when urinary output is normal or decreased, cycle. However, under specific circumstances, it may also occur
this site becomes a less accurate representation of central tem- independently of it, dependent on pineal melatonin secretion and
perature. the circadian pacemaker’s response to light.61–63 In the evening,
The choice of the temperature monitoring site is often influ- when ambient light and physical activity usually decrease, the
enced by the operative procedure. In patients undergoing cardiac secretion of melatonin increases, which results in cutaneous
surgery, temperatures from different body sites convey useful vasodilatation and eventually a drop in body temperature and
information explaining why temperature is usually measured the induction of sleep (heat loss mode).64 Because of supine
Figure 14-1. Central and peripheral compartment during anesthesia. Depiction of the anesthesia-induced changes in the
sizes of the central and peripheral compartments. A: In the awake child, the core and peripheral compartment show a normal
relationship. B: Following 1 hour of anesthesia, internal redistribution of heat from expansion of the core and shrinkage of the
peripheral compartment results in a rapid decrease in core temperature associated with an increase in peripheral compartment
and skin temperature. C: After approximately 2 hours of anesthesia, thermoregulatory vasoconstriction becomes effective and
the central compartment shrinks again in favor of the peripheral compartment. This pronounced peripheral vasoconstriction
leads to a marked decrease in skin temperature. A–C: Adapted from reference 505.
positioning in bed, sympathetic tone and stress on the cardio- phase of the menstrual cycle).73 A delicate and sophisticated
vascular system are reduced, further supporting the decrease in control system is responsible for effectively balancing heat
body temperature. The observed changes in the evening are production and heat loss to maintain body temperature within
reversed in the morning, when the internal clock and brighter its tight limits. Despite this powerful regulatory system with the
ambient light reduce melatonin secretion, which in turn causes ability of the body to dissipate or generate heat by regulating
increased physical activity and distal cutaneous vasoconstriction skin blood flow, sweat production, minute ventilation, and metab-
that reduce heat loss and result in higher central, but lower olism, it can easily be overwhelmed by external factors. Anesthesia
peripheral, temperature signaling the organism to wake up (heat and surgery may have a significant impact on thermoregulation,
gain mode).65–67 In an individual with a “constant daily routine,” and minor changes in body temperature may result in cellular and
the phasic changes in central body temperature cause a plateau tissue dysfunction. This explains the need not only for a tight
between 2:00 PM and 10:00 PM, with a maximum at 5:00 PM and a regulation system but also for perioperative temperature moni-
minimum at around 5:00 AM.58 toring and management. Without appropriate prevention, inad-
These circadian changes in body temperature are age- vertent hypothermia is an almost certain occurrence in patients
dependent and, when compared with young adults, are less of any age undergoing anesthesia and surgery. Unfortunately, this
developed in neonates and older people.68 Circadian swings in fact has led to a widespread acceptance of hypothermia as an
body temperature rhythms are already present in the first days of inevitable consequence of anesthesia, leading Pickering half a
life, although the phase variability is increased and the amplitude century ago to his famous statement: “The practical difficulty in
diminished.61,69,70 In approximately 50% of preterm infants (28– cooling men is to break through the defenses of the body; the most
34 wk of gestational age), the circadian pattern in body tem- effective means is to give an anesthetic, which … has been shown
perature can even be detected.71 Other circadian rhythms that to interrupt at some point or points the reflex arcs which protect
control body temperature may still be absent or weak (e.g., against cooling, particularly by shivering.”74
changes between rest and activity), although the suprachiasmatic
nuclei (the location of the central pacemaker) and its melatonin
receptors are developed by 18 weeks of gestation. This most likely
Physiology of Thermal Regulation
implies that the functional pacemaker does not have a mature Survival from a body temperature as low as 13.7°C has been
effector system at this point of development.72 reported,75 whereas death, resulting most likely from protein
Body temperature also follows a monthly rhythm in fertile denaturation, occurs within 7°C from normothermia at approxi-
women (owing to a higher set-point temperature in the luteal mately 44°C and irreversible neuronal changes may occur at core
temperatures around 40°C.76,77 This demonstrates that the more direct connection from the spinal cord to the brain via
tolerance to cold is more than three times higher than to heat, spinohypothalamic pathways.86–88 Thermosensitivity of peripheral
which explains why the system to dissipate heat has to be much thermosensors most likely is associated with changes in the
more effective than the cold defense system. Similar to other resting membrane potential. Their activity increases significantly
regulatory systems in the body, temperature is controlled by a during temperature changes but normalizes quickly again once
sophisticated network of sensors (afferent input), a central the temperature has stabilized.83 Peripheral thermoreceptors,
controller (hypothalamus), and effectors (efferent output). The including skin warm and cold sensors, express several different
thermoregulatory system uses negative-feedback mechanisms types of transient receptor potential (TRP) channels, which are
to keep variations from normal values as minimal as possible.78 part of a mammalian TRP superfamily consisting of approximately
The most important center for integration of afferent thermal 30 different channel types divided into six subfamilies.83 Each of
information and triggering of autonomic thermoeffector re- these channels is sensitive to a narrow temperature range only, but
sponses is the preoptic anterior part of the hypothalamus (POAH). combined, they cover a wide temperature range.89 The so-called
This is where afferent signals from temperature-sensitive cells thermo-TRP channels consist of the heat-sensitive channels
from various tissues converge, including other parts of the brain TRPV1–V4, M2, M4, and M5, whereas TRPM8 and A1 channels
(e.g., pons, medulla oblongata, midbrain), spinal cord, vessel-rich are cold-sensitive.90,91 Activation of these channels at the peripheral
group organs, respiratory and gastrointestinal tract, and the skin terminals of cutaneous or visceral warm fibers triggers a cation
surface. The processing of thermoregulatory information occurs influx with subsequent depolarization of neurons in the dorsal
in three stages: (1) afferent thermal sensing, (2) central integration root ganglion projecting to thermosensitive neurons in lamina I of
and regulation, and (3) efferent response. the dorsal horn.92 From here, their axons decussate to ascend
within the spinothalamic tract and to send off collateral branches
to the parabrachial nucleus in the pons, where projections to the
Afferent Thermal Sensing POAH then activate warm-sensitive neurons and/or inhibit cold-
In the periphery of the body, anatomically distinct warm and sensitive neurons.89 The vagal nerve may also convey afferent
cold receptors sense the ambient temperature. The skin con- thermal information and be involved in the induction of fever and
tains approximately 10 times more cold than warm receptors, nutritional and/or metabolic information signaled to the brain,
underlining the important function of the skin in detecting which may influence metabolism and body temperature. However,
cold.79 These cold receptors are located in the epidermis and the its role in thermoregulation is still largely unknown.93
subcutaneous tissue and convey their information by thin, mye-
linated A-delta fibers. Unmyelinated C fibers transfer information
Central Regulation
collected by warm receptors, which are located in the deeper layers
of the skin. However, the speed of transmission depends more on The primary thermosensitive area and most important center in
the intensity of the stimulus than on the type of nerve fiber. In the control of autonomic thermoeffector responses in the central
addition, the rate of a skin temperature change affects its impact nervous system is located in the POAH. However, other parts of
on central thermoregulation. A rapid change contributes about the brain, such as the dorsomedial hypothalamus, periaqueductal
five times as much as the same change made slowly,80 although gray matter, and nucleus raphe pallidus in the medulla oblongata,
it seems that only CPB is capable of inducing temperature also play a crucial role in thermoregulation. These centers are
changes fast enough to substantially alter the provoked regulatory responsible not only for the integration of afferent thermal infor-
response. Afferent thermal signals from cold and warm receptors mation but also for the reception and processing of nonthermic
potent enough to trigger a thermoregulatory response converge afferent information, which is important in controlling adaptive
at the level of lamina I neurons, from which they reach the brain mechanisms and thermoregulatory behavior.94 The threshold
via a spinoreticulohypothalamic pathway and project to the in this system represents the central temperature at which a
reticular formation.81 This form of convergence may occur at particular regulatory effect is initiated, whereas the gain quantifies
several levels along the signal pathway and enables the body to the intensity of the response. Approximately 70% of the POAH
collect thermal information from a larger body area.82 Finally, the neurons are temperature-insensitive, although slightly more
tertiary neurons of this afferent pathway terminate in the than 20% are warm-sensitive.95 Using chemical and/or thermal
hypothalamus (mainly the POAH area). Peripheral, deep body stimulation in the POAH, it can be demonstrated that both heat
thermosensitive receptors measure core temperature and are loss and heat generation are mainly controlled by these warm-
found in close proximity to the great vessels, the viscera, the abdo- sensitive neurons.96,97 Increased activity on their part owing to
minal wall, and the spinal cord.83 These primary thermosensitive increased input from warm-sensitive thermoreceptors triggers
receptors are bipolar neurons whose cell bodies are located in the heat loss (i.e., cutaneous vasodilatation and sweating) and, at the
dorsal root ganglia, from which their central axon projects to the same time, inhibits heat generation by tonic inhibition of cold-
lamina I of the spinal dorsal horn. From there, lamina I neurons sensitive neurons in the hypothalamus and brainstem. By contrast,
transmit their information via a spinothalamocortical pathway decreased activity of the warm-sensitive POAH neurons initiates
to the insular cortex either with a relay in the posterior part of heat gain mechanisms (i.e., cutaneous vasoconstriction and shiv-
the ventromedial nucleus of the thalamus or with two relays in the ering and nonshivering thermogenesis) and inhibits heat loss
parabrachial nucleus and the basal ventromedial nucleus of the mechanisms.83,92,98 Because these warm-sensitive neurons in the
thalamus. However, the significance of this pathway lies more in POAH show spontaneous membrane depolarizations (owing to
the thermoregulatory interaction, behavior, and decision-making inhibition of a transient outward hyperpolarizing potassium
related to the environment than in actual thermoregulation current), they are considered to be pacemakers with warming
itself.84,85 There are indications that some peripheral thermo- significantly accelerating their depolarization rate.91,98,99 Accord-
receptors have the option to convey their information through a ingly (and unlike peripheral thermoreceptors), the cellular
mechanism responsible for neuronal warm sensitivity lies in the Efferent Responses
thermosensitive elements of the depolarizing current. Warm- The importance of skin temperature in thermoregulation lies in
insensitive neurons use mainly inhibitory (and, less commonly, its ability to trigger behavioral changes such as seeking shade in
excitatory) postsynaptic potentials to modulate the activation and hot weather or bundling up in cold weather. However, in regards
sensitivity of warm-sensitive neurons.98 Electrophysiologic studies to the autonomic thermoregulatory response, it accounts for only
have demonstrated that some midbrain reticulospinal neurons (for about 20% of the effector response.107–109 The main determinant
shivering) and premotor neurons in the medulla oblongata (for of the autonomic thermoregulatory response depends on afferent
skin vasomotor control) have direct projections to the spinal cord thermal information from central core tissues, which include the
level to elicit thermoregulatory effector control.93 brain (areas other than the POAH), the spinal cord, and deep
The difference between the lowest temperature triggering warm thoracic and abdominal tissues, with each of them contributing
responses and the highest temperature triggering cold responses approximately 20% to the central thermoregulatory control.110–113
defines the thermal sensitivity of the system. The concept of Although highly sophisticated and efficient, our thermoregulatory
thermoregulation described in the section on Thermoregulation system is easily overwhelmed by environmental challenges outside
forms the basis of the “set-point” model originally described by the thermoneutral temperature range (i.e., ~28°C for an unclothed
Hammel, in which the body defends a certain temperature (or, adult). Behavioral responses are, therefore, paramount and the
more precisely, a temperature range, normally 37.0 ± 0.2 °C) set most important thermoregulatory effector in humans. When
by the organism.100 A central temperature above and below this appropriate, they easily surpass the efficiency of all the autonomic
range triggers heat loss and heat gain mechanisms, respectively. It responses combined.
should be emphasized that this set-point model has more recently Digital skin blood flow can be divided into nutritional
been reviewed, questioned, criticized, and defended.98,101–104 The (capillaries) and thermoregulatory (arteriovenous shunts) com-
set-point theory in thermoregulation has been borrowed from ponents. Thermoregulatory cutaneous vasoconstriction is the first
engineering models to serve as a convenient analogy and to and most consistent thermoregulatory response to hypothermia.
provide a method to improve our understanding of how body Cold-mediated decreases in cutaneous blood flow are most
temperature is regulated through the control of heat production pronounced in arteriovenous shunts of the hands, feet, ears, lips,
and heat loss. This model uses the assumption that the body and nose. Thermoregulatory vasoconstriction can decrease the
compares its core temperature against a set reference temperature blood flow in these locations by up to 99% of the flow at neutral
in a unified control system to create an error signal that then temperature.114 These thermoregulatory arteriovenous shunts
triggers a correcting effector response. Although such a model may typically have a diameter of approximately 100 μm, which means
be ideal for teaching purposes, it may not accurately reflect the true that one can divert 10,000 times as much blood as a capillary
concept of thermoregulation. There is no question that peripheral with a 10-μm diameter under otherwise unchanged conditions
temperature sensors, as well as afferent and efferent pathways, exist (given pressure gradient, length and blood viscosity remain
in the body; however, the correlate for the reference signal and how constant).115 A combination of neural mechanisms and local,
it is established in the thermoregulatory system has not been direct temperature effects on the skin vessels lead to thermo-
determined yet.105 regulatory cutaneous vasodilatation during heat and vasocon-
The critical review of the set-point model originated when striction during cold exposure. However, in terms of neuronal
Kobayashi proposed a new and different approach to thermoregulation of cutaneous arteriovenous shunts, one has to
distinguish between nonglabrous (hairy) and glabrous (nonhairy)
regulation.106 In short, he proposed that peripheral and central
skin areas (i.e., palms, soles, lips). In glabrous skin, blood flow is
thermoreceptors synapse via several neurons to a thermoregu-
controlled solely by vasoconstrictive impulses mediated by
latory effector cell. Once the temperature reaches the range for
norepinephrine binding to peripheral, postsynaptic α1- and
which the sensory neuron is sensitive, this neuron significantly
α2-receptors. In nonglabrous skin regions, blood flow is controlled
increases its firing rate and hence triggers, independent of a central
by dual sympathetic opposing mechanisms, which include both
controller, a response in the effector cell. If a sufficient number of noradrenergic-mediated vasoconstriction and cholinergic-
neurons in the same sensitivity range fire simultaneously, a mediated vasodilatation. It is unknown whether this cholinergic
thermoeffector response will be elicited. In this model, no central vasodilatation is triggered by the same nerves that trigger sweat-
network for integration of afferent information is required; ing. However, two observations would support this assumption:
thermoregulation happens almost “automatically” by the tem- (1) sweating and active thermoregulatory vasodilatation usually
perature discriminating sensory neurons. The thermoregu- begin simultaneously and (2) patients suffering from anhidrotic
latory effectors work by adjusting their own threshold and gain ectodermal dysplasia (an inherited disease with congenital lack
according to the physiologic needs. They do so by selecting the of sweat glands) are unable not only to sweat but also to actively
order of responses and by regulating the intensities. In terms of vasodilate their cutaneous arterioles in response to heat.116–120
set point, with Kobayashi’s model, which is increasingly, but not It has also been demonstrated that nitric oxide contributes up
unanimously, favored among physiologists, there is no single to 30% of this heat stress–related active vasodilatation, which
controller and no unified temperature to which the body tries to may also require the release of histamine (H1 receptor action),
adhere. The central body temperature is the averaged result of all vasoactive intestinal peptide (VIP), and additional, as yet
these individual and independent thermoeffector loops. Despite unknown, neurotransmitter(s) for complete vasodilatation.121–125
these limitations and perhaps inaccuracies, the set-point model Vasoconstriction in response to local cooling is triggered by
has a long tradition in thermoregulation, has made the concept of local activation of adrenergic nerves and is independent of central
thermoregulation easier to understand, and even if proved to be nervous system input.126 In the case of localized heat exposure,
incorrect at some point in the future, will most likely be difficult cutaneous vasodilatation occurs in response to local capsaicin
to eliminate for quite some time. release, which activates TRPV1 channels in afferent C fibers,
triggering antidromic calcitonin gene–related peptide (CGRP), means as early as the 36th or 37th week of gestation. Because sweat-
neurokinin A, and substance P,127 although TRP channels are ing on the palms and soles occurs independently of thermal
thermosensitive themselves. sweating, it is known as emotional or mental sweating because it is
Skin blood flow at rest during normothermia accounts for triggered independent of temperature by stress and other
approximately 5% (or 250 mL/min) of cardiac output, which emotions.142 By contrast, thermoregulatory sweating depends
translates to approximately 80 to 100 W of heat dissipation more on the postnatal age in a way that almost every neonate,
per hour in an adult. This roughly equals the metabolic heat independent of the gestational age, is able to sweat in response to
production at rest. During extreme heat stress with maximal high ambient temperatures after 2 weeks of life.143 Babies born at
vasodilatation, up to 60% (or 6–8 L/min) of the cardiac output can 36 weeks or older are even capable of thermoregulatory sweating
be directed to the skin.118,128 This results in a drastically increased from day 1 of life. Thermoregulatory sweating in neonates occurs
heat transfer from the core to the periphery of the body, from first and most pronounced on the forehead.143 However, the
which the heat dissipates by means of convection and radiation. intensity and extent of the sweat response depend on gestational
Most likely, sweating is also profuse in this scenario, which further age. Although the extent of the sweat response increases rapidly
increases heat loss and at the same time provides cooling of the with postnatal age, sweat intensity increases only slowly and the
blood, which upon return to the core, also helps cooling the ambient temperature required to induce sweating are higher in
body.128–130 By contrast, profound vasoconstriction during marked immature babies. Despite the ability of thermoregulatory sweating,
hypothermia drops skin blood flow to almost zero, thereby its efficiency is initially is very limited.143 Full-term neonates begin
reducing heat loss to the environment and, in case of shivering, to sweat when the rectal temperature reaches 37.5° to 37.9°C and
allows the generated heat from the muscles to be transported to ambient temperature exceeds 35°C. The onset of sweat production
the core instead of being dissipated through the skin. Such in infants who are small for gestational age is slower than in full-
profound changes in the distribution of cardiac output need to term infants, but their maximal sweating rates are comparable.144
be regulated carefully, which explains why both sympathetic Premature infants with a gestational age of less than 30 weeks show
cutaneous vasoconstriction and vasodilatation participate in no response because their sweat glands are not yet fully developed.
arterial blood pressure regulation via the baroreflex.116,131–134 The The total number of sweat glands varies between 2.5 and
decrease in cutaneous perfusion secondary to thermoregulatory 5 million. The density is approximately 10 times higher on the
vasoconstriction results in an impressive heat loss reduction from palms and soles than on the back (~600 vs 60 glands/cm2). The
hands and feet by 50%, but by only 17% from the trunk, which amount of sweat produced is regulated through a combination of
reduces overall heat loss by approximately 25%.135 the number of activated sweat cells (responsible for the initial
The ability of the body to dissipate heat from heat stress or increase in sweat rate) and the amount of sweat production per
metabolic processes is vital to the human body, but the potential gland (responsible for a further rise in sweat rate).145,146 The
of active vasodilatation of skin vessels for heat loss is limited and, absolute number of sweat glands recruited increases in a linear
therefore, sweating is required. The latent heat of vaporization of manner with rising rectal temperature during exercise, with sweat
sweat, which is 2.5 × 106 J/kg, defines the energy required for the gland recruitment on the limbs being proportionally greater than
evaporation of 1 kg of sweat. This demonstrates the extraordinary on the trunk.147
power of sweating as a means of heat loss, particularly when Children have a smaller body surface area, but already
considered that an extremely athletic adult can produce 2 to 3 L of the complete number of sweat glands. This means that their
sweat per hour, although these rates cannot be maintained for a sweat gland density is up to six times higher than in adults.148
prolonged period of time.136,137 The human body has apocrine Nevertheless, because of a lower sweat production per gland, the
and eccrine sweat glands, but only the latter are involved in overall sweating rate in children is lower than in adults, which is
sweat production. Sweating is primarily controlled by core body explained by the smaller sweat gland size (which is directly related
temperature, but is secondarily affected by skin temperature, to sweating rate and to cholinergic and adrenergic sensitivity
which has the power to influence the rate of sweating through of the sweat gland), a lower sensitivity of the sweating mechanism
central mechanisms. In addition, localized warming of sweat to thermal stimuli, and possibly, a lower sweat gland metabolic
glands directly activates sweating, whereas cooling inhibits capacity.149–151 During exercise in the heat, adults started to
sweating.138,139 Sweating is the only effective mechanism for heat sweat after a rise in rectal temperature of 0.2°C, whereas children
loss in an environment with air temperatures equal to or above required a rise of 0.7°C to reach the sweating threshold. Further-
skin temperature. Under these circumstances, anything that limits more, the sweat production per degree temperature increase in
evaporation, such as impermeable or tight clothes or high ambient children was lower than in adults.152 With their larger body surface
humidity, restricts the efficiency of sweating and may lead to area–to–mass ratio, children have an advantage over adults in
hyperthermia or heat stroke with potentially fatal outcome. a thermoneutral or warm environment when metabolic heat
Sweat gland development starts from the epidermal ridge as an dissipation can depend on convection, radiation, and conduction
epithelial cell cord at about 14 to 16 weeks of gestation. It begins only. This same large body surface area–to–mass ratio is the factor
first on the palms and soles, then in the axillae at approximately responsible for increased heat loss in the cold as well as increased
20 weeks of gestation, and finally on the remainder of the skin heat absorption in a hot climate.
3 to 4 weeks later.140,141 Although the lumen of the sweat glands Sweat is initially secreted as an isotonic precursor fluid into
starts to develop as early as 16 weeks of gestation, it widens only the secretory coil. As it is transported out through the glandular
in the last 8 weeks of gestation and the myoepithelial cells become duct in the direction of the skin surface, sodium, chloride,
identifiable no earlier than the last weeks of pregnancy. At birth, and bicarbonate are re-absorbed leaving sweat hypotonic in
the sweat glands on the palms and soles are functional and comparison with plasma and slightly acidic. However, at high
morphologically identical to those in adults. Sweat production on sweating rates, the re-absorptive mechanism can be overwhelmed
the palms and soles is already functional on day 1 of life, which by the high flow rates and electrolyte losses may increase,
explaining the fact that sodium concentration of sweat depends The formula for mean body temperature was originally designed
on the sweating rate.149 Increased sweating occurs through a in 1935162:
combination of an increased number of activated sweat glands
Tmean body = 0.65 × Tcore + 0.35 × Tskin mean
and increased amount of sweat released per gland.145 The exact
neurologic pathways responsible for sweating are only partially where Tskin mean refers to mean skin temperature calculated
known. It is known from animal studies that efferent fibers from from the skin temperatures of trunk, lower leg, and forearm.
the POAH traveling via the pons and the medullary raphe regions Although its accuracy has been confirmed by some investi-
project to the intermediolateral cell column of the spinal cord and gators,162,163 other studies found it to be unreliable and suggested
on through the white ramus communicans to synapse in the that a more sophisticated approach was needed.164,165
sympathetic ganglia. Postganglionic, nonmyelinated C fibers then The thermoregulatory responses and their corresponding
join peripheral nerves to reach the sweat glands153,154 Cholinergic threshold temperatures in the awake state and under anesthesia
innervation clearly outnumbers adrenergic terminals. Sympathetic in adults, children, and infants are depicted in Figure 14–2.
cholinergic nerve endings mainly surround the secretory coil
of the sweat gland, but a few projections also extend to the
sweat duct.149 Binding of acetylcholine to muscarinic sweat gland Heat Loss Mechanisms
receptors increases the intracellular calcium concentration, In order to be homeothermic (maintain a constant core tem-
resulting in increased permeability for potassium and chloride perature independent of the ambient temperature), the organism
ions, which then triggers the secretion of sweat from the secretory must be capable of both regulated and active heat dissipation and
cells.155 By contrast, β adrenergic–mediated sweat secretion relies heat generation. Controlled heat dissipation is fundamental to
exclusively on activation of a cyclic adenosine monophosphate homeotherms and accomplished in two steps, both of which are
(cAMP)–dependent cystic fibrosis transmembrane conductance mediated by radiation, convection, conduction, and evaporation
regulator (CFTR, the ion channel defective in cystic fibrosis), and governed by the physical laws described in the second law of
leading to increased chloride, but not potassium, ion conductance. thermodynamics. The latter states that spontaneous heat flow can
Compared with cholinergic secretion, β adrenergic secretory occur only from an object of higher temperature (higher energy)
response is smaller.156,157 to an object of lower temperature (lower energy).
The CFTR mutation in cystic fibrosis results in reduced sodium In the first step of heat loss during anesthesia (see Figure
re-absorption from the isotonic sweat precursor fluid from the 14–1), heat is transferred from the core to the peripheral compart-
glandular duct and, hence, sweat with higher concentration of ment and the skin surface, referred to as internal redistribution of
sodium and chloride. Acetylcholine is also involved in the heat. As the name implies, this process does not, despite the now
contraction of myoepithelial cells located in the basal membrane lower core temperature, result in significant heat loss. In the
of the sweat gland duct. It had been suggested that the high- second step, heat is now dissipated from the skin surface to the
frequency, pulsatile secretion of sweat (at 12–21 Hz) is caused by environment and physiologic adaptations of regional blood flow
pulsatile myoepithelial contraction158; however, a later study failed (thermoregulatory vasodilatation) as well as changes in the ther-
to confirm these findings.159 The main function of the myoepi- mal conductance properties of the insulation tissue can influence
thelial cells lies most likely in the provision of structural support the degree of heat loss. A study in naked adult men in an ambient
for the secretory epithelium, so that it can easily develop and temperature of 27°C quantified the relative contributions of
withstand high intraluminal hydrostatic pressures to overcome radiation, convection, and evaporation to total heat loss as 58%,
difficulties in transporting sweat onto the skin surface under 15%, and 27%, respectively.166 A similar study in newborns kept in
conditions such as sweat pore occlusion.159 This could potentially a thermoneutral environment determined the contribution of
occur when the skin becomes wet (e.g., during sweating) and skin radiation, convection, evaporation, and conduction to total heat
cells swell enough to partially obstruct sweat secretion. This loss to be 39%, 34%, 24%, and 3%, respectively.167 However, any
and the fact that sweating is a vital process may explain why change in ambient temperature, air draft, or relative humidity can
intraluminal pressure in the sweat gland has been reported to be change not only the overall magnitude of heat loss but also the
as high as 500 mmHg.160 relative contribution of each of these four physical components.
Skin temperature varies considerably throughout the body. Simply changing the ambient temperature to 22°C changed the
Mean skin temperature refers to a physiologically weighted, contribution of radiant, evaporative, and convective heat loss in
averaged skin temperature. Several different formulas exist to healthy women to over 70%, 15%, and 10 to 15% of total heat loss,
calculate it and they can be divided into four categories: area- respectively.168
weighted formulas, derived regression formulas, physiologic Although not often viewed as a major priority during intrao-
formulas, and modifications.34–36,161 For anesthetized children perative care, the maintenance of normothermia can have
younger than 10 years, mean skin temperature can be calculated significant effects during both the intraoperative and the
as follows: postoperative periods. Although generally counterproductive
during anesthesia, the ongoing heat loss serves an important
Tskin mean = 0.5 × Tchest + 0.2 × purpose in the unanesthetized person. Without any heat loss to
Tupper arm + 0.1 × Tthigh + 0.2 × Tleg.36 the environment, the body temperature would increase by
Similarly, mean body temperature describes a physiologically approximately 1°C/h at rest. The importance of heat loss becomes
weighted, averaged body temperature, which was created in even more obvious considering that in athletes, metabolic heat
generation can increase 20-fold during strenuous exercise.169
an attempt to accurately reflect the thermoregulatory importance
The resulting increase in body temperature has been calculated
of various tissues, in particular the central compartment. Mean
by the formula:
body temperature is now often used instead of or together
with the core temperature to define the thresholds for sweating. HSR = m␬ dTB/dt
Figure 14-2. Threshold temperatures. Graphic depiction of the expansion of the interthreshold range under
general anesthesia compared with the awake state. The temperature indicated on the thermometer represents
the body temperature at which the corresponding thermoregulatory mechanism is triggered. The range between
the first cold response (thermoregulatory vasoconstriction) and the first warm response (thermoregulatory
vasodilatation) defines the interthreshold range and is an indicator of the sensitivity of the thermoregulatory
system. Adapted from reference 504.
where HSR = heat storage rate (W); m = the body mass (kg); surface area in direct contact with the object (A), and the
␬ = the specific heat coefficient of the human body (3.5.103 J/kg conductive heat transfer coefficients (hk) of the two materials.
°C)162; dTB = the change in body temperature (°C); and dt = the Conductive heat transfer can be calculated using the formula:
time interval (s). For clinical purposes, metabolic heat production C = hk A (T1 – T2).
at rest is estimated to be approximately 4.2 kJ/kg/h (or 1 kcal/
kg/h). The conductive heat transfer coefficient, hk, is a property of
the material or interface between the two objects and determines
the rate of heat transferred per unit area and unit temperature
Conduction difference (W/m2 × °C). Ideally, the patient should be well shielded
Conduction refers to heat transfer from a warmer to a cooler object from cold objects (bolsters and/or unwarmed blankets in the case
when they are in direct physical contact with each other (Figure of the operating room table) or, even better, lying on a warming
14–3). In humans, the amount of heat transferred by conduction blanket or a forced-air warming device. These simple steps should
(C) depends on the temperature gradient (T1 – T2) between the keep conductive heat losses to a minimum during surgery.
skin and the object with which it is in direct contact, the skin However, large amounts of cold intravenous or irrigation fluids
of 4.1 to 5.8 N × m/s × m2 × °C.170 Thus, heat transfer by radiation

depends primarily on the temperature and the surface area of the
two surfaces concerned. As previously stated, newborns and
infants have a large surface area–to–volume ratio; thus, radiant
heat loss is proportionally greater the smaller the infant. Radiation
is the major heat loss mechanism in the awake and the anes-
thetized infant under normal conditions. Radiant heat loss in the
operating room is caused by a temperature gradient between the
patient and the surrounding objects (e.g., operating room walls,
anesthesia cart and machine). As long as such a gradient exists,
the patient (warmer “object” ) will continue to transfer heat to the
cooler objects around him or her, thus losing energy to the
environment. Because heat loss by radiation is directly related to
the temperature gradient, warming up the operating room before
the arrival of the patient reduces this temperature gradient and,
thus, radiation heat loss. However, this must be done a sufficient
Figure 14-3. Heat loss mechanisms. The four major heat loss mecha- time before the patient arrives to allow for warming of the walls
nisms are illustrated in the top predator of Antarctica, the leopard seal, and other objects in the environment. A thin, single covering layer
who, like most animals, is a true expert in thermoregulation. Lying on (e.g., a hospital gown providing minimal insulation) can help to
the ice results in conductive heat loss, the wet fur leads to evaporation,
significantly reduce heat losses by convection and radiation and,
the warm body temperature in comparison with the cold ambient air
favors convective heat loss, whereas on the one hand, radiation warms
thus, to increase thermal comfort.
the body (sun), and on the other hand, the warm body loses thermal
energy, heating up the environment by radiation. Convection
The transfer of heat to moving molecules (e.g., air or liquid)
can quickly result in significant conductive heat losses and should is called convection (see Figure 14–3). The rate and direction
be avoided. of convective heat loss in a human exposed to air depend on
the velocity of the air draft, the size of the skin surface area
exposed, and the temperature difference between the surface
Radiation of the skin or other membrane and the surrounding fluid (i.e.,
Radiation heat transfer describes heat exchange by electromagnetic gas or liquid). Changes in lung minute ventilation and body
waves between two objects of different temperatures not in direct posture may affect convective heat loss, but under normal
contact with each other (see Figure 14–3). Radiation does not circumstances, the contribution of convection to total heat loss is
require a medium for heat transfer between the two objects. It can minor. The following formula can be used to calculate convective
be transmitted through a vacuum (e.g., the sun warms the earth by heat loss:
radiation). Obeying the second law of thermodynamics, radiation
Q = hc A (Tsk – Ta)
causes the warmer object to cool and the cooler object to warm.
This heat transfer occurs predominantly in the infrared light where Q = heat exchange by convection (W); A = surface area
spectrum at a wavelength in the range of 0.75 to 1000 mm. exposed (m2); hc = convective heat transfer coefficient (W/m2 ×
Radiation heat transfer depends upon the difference of the fourth °C); Tsk = mean skin temperature (°C); and Ta = ambient
power of the absolute temperatures of the two objects and the temperature (°C). The convective heat exchange coefficient
surface area available for radiation but also on factors like depends on the physical properties of the medium (i.e., gas or
emissivity (a number between 0 and 1, with 1 meaning that a body fluid), air draft (or fluid current) velocity, and body shape. Its value
emits all of its thermal radiation and absorbs all the thermal for the human body when immersed in still water at neutral
radiation striking it), surface reflectivity, and other variables temperature and in cold water is approximately 43 and 53 W/m2
describing the object’s surface characteristics: × °C, respectively.171 The “wind chill factor” is probably the best-
known example of convective heat loss.
R = e s A (Tsk4 – Tr4)
where R = heat transfer by radiation (W); e = emissivity; s = Stefan Evaporation
Boltzmann constant (5.67 × 10–8 J/s × m2 × K4); A = surface area Evaporation describes the transition of molecules from the liquid
of the object (m2); Tsk = skin temperature; and Tr = temperature (sweat) into the gaseous state (sweat vapor) (see Figure 14–3). In
of the second object (both in K). The exact calculation of radiation order to reach the gaseous phase, the molecules must obtain a
heat transfer is rather complicated. Because of the small dif- certain kinetic energy to overcome the intermolecular forces of
ferences, it has been accepted for clinical purposes to use the the liquid phase. This is an energy-dependent process, energy is
simple difference between the two temperatures. Emissivity and drained from the body in the form of heat. Under conditions of
the Stefan Boltzmann constant can be integrated into the radiation thermal neutrality, evaporation accounts for 15 to 25% of total heat
coefficient hr (N × m/s × m2 × °C), simplifying the formula to R loss. Physical determinants of evaporative heat loss include relative
= hr A (Tsk – Tr). The value of the radiation coefficient (hr) humidity of the ambient air, air draft velocity, and lung minute
depends on the temperatures of the two surfaces, emissivity, and ventilation. The driving force for evaporation is the vapor pressure
several other factors. For a clothed human, its value is in the range difference between the body surface and the environment. The
higher the ambient humidity the less effective sweating will be. Voluntary Muscle Activity
Evaporative heat loss in the operating room consists of three The mechanical efficiency of muscle contractions—the ratio
components: (1) sweat (sensible water loss), (2) (nonthermoregu- between power output and the sum of the caloric equivalent
latory) water loss from the skin, respiratory tract, and open of oxygen consumption and power output—can initially reach
surgical wounds (insensible water loss), and (3) evaporation of up to 50% for short exercises (seconds), but quickly decreases
liquids applied to the skin such as antimicrobial solutions for skin to levels in the range of 25 to 35% for sustained, steady-state
disinfection. The energy required to evaporate 1 kg of a certain exercise (e.g., cycling).175,176 This forms the basis of heat generation
fluid is known as the latent heat of vaporization (2.5 ×106 J/kg by voluntary muscle activity, because most of the difference
for sweat). Evaporative heat loss can be calculated with the follow- between energy input and mechanical energy output is con-
ing formula: verted into heat. However, during anesthesia, this form of heat
E = he Awet (Psk – Pa) generation is, similar to thermoregulatory behavioral changes,
either absent or only minimal and does not significantly con-
where E = evaporative heat loss (W); he = evaporative heat transfer tribute to thermoregulation.
coefficient (W/m2 × kPa); Awet = wet skin area (m2); Psk = water
vapor pressure on the skin surface; and Pa = ambient water vapor
pressure (both in kPa). The coefficient for evaporative heat Shivering Thermogenesis
transfer (he) integrates the latent heat of vaporization of water and Shivering refers to involuntary, irregular muscular activity
the essential effect of air draft on evaporation. For clinical triggered by hypothermia (although strong emotions like fear or
purposes, he can be calculated using the formula: pain can also act as triggers) that commonly begins in the muscles
he = 124 V0.5 (W/m2 × kPa) of the upper body (e.g., masseter). Before the onset of overt shiver-
ing, tonic motor neuron activity increases resulting in elevated
where V denotes air draft velocity (m/s). Humidification of dry muscle tone throughout the body with a concomitant rise in
inspired respiratory gases causes a small amount of heat loss by metabolic heat generation.177 Only when this tone has risen above
evaporation of water from the tracheobronchial epithelium. a certain threshold level does shivering become visible. Mild
Respiratory losses in adults during anesthesia account for only 5 shivering can be voluntarily suppressed to some extent with
to 10% of total heat loss.172 Alveolar ventilation on a per-kilogram breath-holding or distraction techniques.178 The shivering inten-
basis is significantly higher in infants and children than in adults, sity is higher in central muscles where it can reach up to about
which explains why respiratory losses can account for up to one 16% of maximal voluntary muscle contraction, whereas this is
third of total heat loss in that age group. Breathing cool and dry air limited to about 4% in peripheral muscles.179 In awake, young, and
(by contrast to warm and humidified air) increases evaporative healthy adults, shivering can increase the metabolic rate by almost
and convective heat loss from the respiratory tract.32,173 Heat loss 500% for very short periods of time.180–186 This number is often
from evaporation inside a large surgical incision may equal cited to sensitize anesthesiologists to the adverse effects of shiver-
all other sources of intraoperative heat loss combined.174 ing, but fortunately, the incidence and intensity of shivering,
Evaporation of fluids from the exposed (and unprotected) particularly when sustained and in older patients, are reduced in
bowel may eventually result in a bowel temperature that is well the postoperative period, mainly because of appropriate analgesic
below the temperature of the rest of the body. Returning this cold therapy, slower spontaneous rewarming, and a less active ther-
bowel back into the abdominal cavity can precipitate a brisk moregulatory response.187–190 The average increase in oxygen
drop in body temperature owing to conductive heat loss.174 This consumption in the elderly, who have the highest risk for adverse
can be avoided by either covering the exposed bowel in a plastic perioperative cardiac events, was found to be only 38% higher in
envelope or irrigating the abdominal cavity with warm saline shivering than in nonshivering patients,190 although other studies
solution immediately after the bowel has been returned into the
reported postoperative increases in oxygen consumption of up to
abdomen.
130%.180 For an otherwise healthy patient, the increased oxygen
consumption associated with shivering is compensated by an
Heat Production increase in cardiac output without adverse effects. However, for
patients with already limited cardiac or pulmonary reserves, the
Except for evaporation, the other three physical mechanisms that increased oxygen requirements could potentially result in
are usually responsible for heat loss (i.e., radiation, conduction, decreased tissue oxygenation and a potential risk for ischemia,
and convection) can, depending solely on the temperature although shivering per se was not associated with a higher risk
gradient, also be used to transfer heat to the patient. Beside these of myocardial infarction.180,187 Shivering can lead to increased
passive ways of increasing the body heat content, homeothermic intraocular and intracranial pressure, wound dehiscence, and
organisms have the ability to actively increase their metabolic rate, damage to the teeth.191,192 Along with nausea and vomiting and dry
which increases not only oxygen consumption but also heat mouth, postanesthetic shivering is one of the leading causes of
production and represents an important and efficient part of
discomfort in patients recovering from general anesthesia.193 An
thermoregulation. In addition to the heat generated from basic
inverse correlation between intraoperative temperature and
metabolism, the body can actively increase metabolic heat
postoperative oxygen consumption has been demonstrated.194
production in four different ways:
Despite the incidence of postoperative shivering being inversely
1. Voluntary muscle activity. related to core temperature, shivering also occurred in patients
2. Involuntary muscle activity (shivering thermogenesis). kept strictly normothermic during anesthesia with isoflurane or
3. Nonshivering thermogenesis. desflurane, indicating that a significant component of posto-
4. Dietary thermogenesis. perative shivering is nonthermoregulatory, with pain being a
potential trigger.195,196 One study in more than 1500 children 1. Recruitment of different metabolic pathways within the same
undergoing general anesthesia found a surprisingly low shiver- muscle fiber.
ing incidence of 3.5%.197 Risk factors for postoperative shivering 2. Recruitment of specific subpopulations of muscle fibers within
in this study included the use of intravenous induction agents the same muscle.
(thiopental vs sevoflurane), patient older than 6 years, and pro- 3. Recruitment of muscles varying in fiber composition.
longed duration of surgery (over 40 min). A smaller study Changing the type of muscle fibers (type I or II) activated also
reported a higher incidence of 14.4% shivering in children and, in changes the fuel mixture. However, in humans, the fiber
addition, found atropine administration and lower intraoperative composition varies significantly not only between muscles but
temperature to be risk factors.198 A large study in adults reported also between individuals.208 In adults, hypoglycemia below ap-
a shivering incidence of 6.3%, and risk factors identified included proximately 2.5 mmol/L can result in limitation or complete
male gender, orthopedic surgery, anticholinergic premedication, inhibition of shivering, an effect that, first, seems to be related to
and use of neuromuscular blocking agents, whereas intraoperative inhibition of hypothalamic neurons rather than a general lack of
use of alfentanil or morphine seemed to have a protective effect.199 substrate and, second, is easily and almost immediately reversible
Two different electromyographic (EMG) patterns can be identified by administration of intravenous dextrose.209
during shivering including a basal, continuous low-intensity Animal research indicates that the motor center for shivering
shivering with a rate of 4 to 8 Hz associated with a low shivering is located in the dorsomedial part of the posterior hypothalamus
threshold and type I muscle fibers or superimposed bursts of high- adjacent to the wall of the third ventricle, but neurons from the
intensity shivering at a much lower frequency of 0.1 to 0.2 Hz rostral raphe pallidus may also be involved.210–212 Impulses from
associated with a high-shivering threshold and type II muscle peripheral cold receptors and from the spinal cord itself ascend
fibers, creating the typical “waxing and waning” picture in the through the lateral spinothalamic tract and relay in the medulla
EMG pattern.200,201 The shivering intensity depends on the (nucleus raphe magnus) and the pons (locus subcoeruleus) before
duration of cold exposure, the ambient temperature, and anatomic they impinge at the POAH. Electrostimulation or cold stimulation
characteristics (e.g., fat content and surface area of the body).186 of the posterior hypothalamus triggers shivering.212–215 In the
The time course and the relationship between shivering and absence of cold sensation or hypothermia, it is assumed that this
nonshivering thermogenesis in infants have been examined, center is inhibited by impulses from the heat-sensitive area (i.e.,
but the exact time sequence and factors involved in the transi- the center that triggers heat loss) in the POAH.
tion from nonshivering thermogenesis to shivering thermo- The efferent impulses leave the dorsomedial region of the
genesis remain to be elucidated. Although the importance of posterior hypothalamus and descend through the midbrain area,
nonshivering thermogenesis rapidly decreases after the first dorsolaterally to the red nucleus, and then on through pons and
year of life, shivering thermogenesis assumes a more important medulla oblongata to the lateral columns of the spinal cord. In
role in thermoregulation. However, it has been demonstrated that addition, selective stimulation and inhibition of reticulospinal
shivering occurs only when all the other mechanisms such as neurons, located in the reticular formation dorsolateral to the red
behavioral responses, nonshivering thermogenesis (both of which nucleus, demonstrated that in fact their signals control shivering.82
are ineffective under anesthesia), and maximal thermoregulatory However, it is not known whether these neurons receive synaptic
vasoconstriction have failed to maintain body temperature within input from the preoptic or posterior hypothalamus.93 Shivering
the interthreshold range.202 can also be induced at the spinal level by local cooling, which
It is generally accepted that newborns and small infants are not means that the basic mechanisms for shivering are located in the
able to shiver, presumably because of a combination of general spinal cord and that the higher centers may act more to control
immaturity of the musculoskeletal system and limited muscle rather than to initiate the response. The recruitment of motor
mass, which renders muscle activity rather ineffective in terms of neurons and their associated muscles form the final pathway for
heat production. However, a few case reports and occasional shivering. Motor neurons seem to be recruited in the order of their
observations exist describing shivering in neonates, which size, with the smaller ones being activated first, followed by the
occurred in some cases at a rectal temperature between 35.0 and small tonic, and finally the larger, phasic motor neurons.216
35.3°C.203,204 It is debatable, if this was indeed thermoregulatory Various treatment options exist for shivering. Prevention of
shivering or if other factors (e.g., drugs) were involved, because hypothermia is certainly a good start to avoid the development of
reported temperatures were not always extremely low. With shivering, however as mentioned in the section on Voluntary
respect to thermoregulation, it is generally safe to assume that Muscle Activity, not all shivering is thermoregulatory in nature.
neonates and small infants are not able to shiver, and even if they Facial warming has been shown to reduce shivering in actively
were, the effect on temperature would be negligible. cooled, unanesthetized, healthy adult volunteers almost com-
Although carbohydrates account for only 1% of energy stores pletely and within seconds.217 Pharmaceutical treatment options
(lipids 95% and proteins 4%) in healthy adults, carbohydrate for shivering have included meperidine (pethidine), clonidine,
oxidation may provide up to 60% of the total heat generated dexmedetomidine, ondansetron, and physostigmine.218–220 Meper-
during cold exposure.205 In the presence of artificially elevated idine is probably the drug most commonly used in the treatment
carbohydrate storages (carbohydrate-rich diet) this percentage of shivering. Inhibition of shivering with meperidine significantly
may increase to 65 to 80%. Conversely, if glycogen reserves are amplifies and prolongs core temperature afterdrop and the re-
depleted, the body utilizes lipid and (to a lesser extent) protein warming rate in unanesthetized, actively cooled volunteers.221
oxidation as a source of energy.206 Glycogen depletion does not,
therefore, compromise heat production from shivering. The rate
of glycogen oxidation is independent of plasma glucose levels. Fuel Nonshivering Thermogenesis
selection for shivering (between carbohydrates, lipids, and Nonshivering thermogenesis refers to an increase in metabolic heat
proteins) can be modified in three ways207: production in excess of the basal metabolism that is not associated
with muscle activity. Heat produced by basal metabolism is oxidative phosphorylation, but it also induces BAT cell prolif-
also known as obligatory thermogenesis, whereas nonshivering eration, lipase activity in the BAT cells, mitochondriogenesis, and
thermogenesis is part of the adaptive thermogenesis that also increased expression and activation of UCP-1.227,238 Precursor cells
includes shivering thermogenesis and voluntary muscle activity. of BAT express β1-adrenergic receptors, which are important for
This heat generation originates mainly from metabolism of brown BAT cell proliferation, whereas β3-receptors are involved in BAT
adipose tissue (BAT), but to a lesser degree also from skeletal cell differentiation.239 Mature brown adipocytes mainly express
muscle, liver, brain, and white fat. Nonshivering thermogenesis is α1- and β3-receptors, with the latter being the most important in
the main source of thermoregulatory heat generation in newborns terms of nonshivering thermogenesis.227
and small infants, whereas in adults, shivering is the most impor- The majority of the heat produced by nonshivering thermo-
tant source of heat production. genesis is mainly a byproduct of fatty acid metabolism, but a
Differentiation of BAT begins between 20 and 30 weeks of minor part can also originate from glucose metabolism. The
gestation in the human fetus.222 It accounts for approximately activation of nonshivering thermogenesis results in an increased
1 to 6% of the total body weight (depending on nutrition and proportion of cardiac output being diverted through the brown
activation status) and can be detected in six main locations. This fat, which may reach up to 25% of the cardiac output, thus
includes large deposits between the scapulae and in the axillae; in facilitating the direct warming of the blood. Nonshivering
medium-size deposits in the mediastinum, around the internal thermogenesis can be inhibited pharmacologically with ganglionic
mammary vessels, the aorta, and the kidneys or adrenal glands; and β adrenergic receptor blockade,240 inhalational anesthetic
and in smaller amounts around the blood vessels of the neck. agents,241–243 and surgically by sympathectomy.244 In vitro, halo-
A significant percentage of venous vessels exiting from the inter- thane has been shown to inhibit nonshivering thermogenesis
scapular BAT drain into the spinal canal surrounding the spinal in BAT cells from hamsters within 5 minutes of the onset of
cord like a heat exchanger.223 Because functional mitochondria can exposure. Within 15 minutes after discontinuation of halothane,
absorb99m Technetium-tetrofosmin, the use of gamma-camera nonshivering thermogenesis recovers to approximately 50%.241
imaging with this radioactive tracer in infants and children allows Similar findings have also been reported from in vivo animal
the visualization of the interscapular BAT. Activity has been shown studies.243 Nonshivering thermogenesis has also been shown to be
to be higher in winter than in summer with peak activity detected inhibited in infants younger than 9 months of age anesthetized
in infants younger than 2 years of age.224 with fentanyl and propofol.245 However, an in vitro study on BAT
Brown fat is a highly specialized tissue whose brown color is cells from hamsters concluded that inhibition of nonshivering
due to the abundance of large mitochondria in the cytoplasm of thermogenesis is caused by volatile anesthetic agents (halothane
these multiloculated, triglyceride-containing fat cells. The mito- was the only vapor tested that is still clinically used), but not with
chondria are densely packed with cristae and have an increased nonvolatile anesthetic agents including pentobarbital, propofol,
content of respiratory chain components and uncoupling protein- or ketamine. Therefore, a distinction between thermogenesis
1 (UCP-1 or thermogenin) located on the inner mitochondrial inhibitors and thermogenesis noninhibitors has been suggested.246
membrane.225,226 Because of UPC-1, these mitochondria have the Analysis of oxygen consumption and plasma concentrations of
unique ability to uncouple oxidative phosphorylation resulting in free fatty acids and glycerol in newborns between 6 and 30 hours
heat production instead of generating adenosine triphosphate of age with a gestational age of 32 to 40 weeks demonstrated that,
(ATP). The proton motive force across the inner mitochondrial within 20 minutes of cold exposure (ambient temperature of 25–
membrane is normally used by ATP synthase for the generation of 26°C), oxygen consumption doubled and the plasma concen-
ATP from adenosine diphosphate (ADP). Activation of UCP-1 tration of glycerol significantly increased.247 The authors also
increases proton leakage across the inner mitochondrial mem- noted that the nape of the neck was the warmest skin area (i.e., in
brane in brown adipocytes and allows the proton motive force to close proximity to interscapular BAT) on the babies exposed to
be dissipated as heat instead of being used for ATP synthesis.227 cold. This study further demonstrates that term and preterm
Besides UPC-1, glucocorticoids, leptin (an adipocyte-derived neonates are capable of nonshivering thermogenesis shortly after
hormone that acts on the ventromedial nucleus of the hypo- birth. Premature infants, full-term neonates, and infants are easily
thalamus to signal satiety and regulate body weight), and thyroid able to double their metabolic heat production during cold
hormones have the potential to significantly modulate BAT exposure.247–249 Clinically significant nonshivering thermogenesis
thermogenesis.228–231 In fact, one of the deiodinases (type II or is possible within minutes after birth and may persist up to the
brown adipose tissue iodothyronine 5’monodeiodinase) is present age of 2 years.250 Although powerful and efficient, it should be kept
in BAT, and it has been estimated that BAT is responsible for about in mind that the effect of nonshivering thermogenesis is limited
50% of total systemic conversion of thyroxine (T4) to triiodo- and cannot compensate for the increased risk of hypothermia in
thyronine (T3).232,233 Cold acclimation may lead to a 10-fold neonates and infants.
increase in the release of T3 from BAT, whereas starvation inhibits Nonshivering thermogenesis appears not to be functional
it.234 The lack of this deiodinase has profound, negative effects on or clinically significant in adults.251 This is supported by the fact
BAT function.235 that oxygen consumption does not increase significantly when
Despite their name, the homologous proteins UCP-2, UCP-3, patients are vasoconstricted.247,248 However, there seems to be a
UPC-4, and UPC-5 do not have the ability to uncouple oxida- wide interindividual variability that depends on gender, body
tive phosphorylation, although their exact role remains to be composition, age, cold acclimation, and most likely, genetic
determined.236,237 factors.251 In addition, under certain pathologic conditions,
Brown fat tissue has a very high density of blood vessels and humans have the potential to regenerate BAT, for example, in the
sympathetic nerve endings. Cold exposure activates the sympa- presence of a pheochromocytoma (caused by high and sustained
thetic nervous system, and the release of norepinephrine not only sympathetic stimulation),252,253 Chagas’ disease,254 or a hibernoma
results in the activation of ␤-receptor–mediated uncoupling of (a rare, benign brown fat tumor originating from BAT remnants).
Marked cold acclimation enables winter swimmers to survive acids seem to increase core temperature, at least in part, by
significantly greater temperature gradients between body and increasing the set-point temperature.266
environment than non–cold-adapted subjects, which has been in
part attributed to increased nonshivering thermogenesis.255
However, there is no proof that the nonshivering thermogenesis Thermal Regulation in the Newborn
in these swimmers originates from BAT. In adults, alternative Premature and infants small for gestational age but also full-term
mechanisms of metabolic heat generation exist, and it has been neonates have a significantly higher skin surface area–to–body
demonstrated that the (noncontractile) contribution of skeletal mass ratio than that in adults. The normal ratio in a term neonate
muscles can account for approximately 40% of thermogenesis is approximately 0.07 (0.2 m2/3.0 kg) vs 0.023 in an adult (1.72
induced by local epinephrine infusion.256 Hydrolysis of ATP by m2/75 kg), which leaves the neonate with a ratio almost three times
Ca2+-ATPase of the skeletal muscle sarcoplasmic reticulum may higher than the adult. Compared with adults, children, therefore,
represent another important source of heat.251 Further study in lose proportionally more heat in a cold environment but, at the
cold-acclimated adults has demonstrated increased nonshivering same time, also absorb more heat when it is hot. As such, the
thermogenesis that can be inhibited by propranolol.257 neonatal thermoregulatory system may be compromised and
easily overwhelmed by external factors. This fact is amplified, on
the one hand, by increased thermal conductance in children
Dietary Thermogenesis secondary to a thinner layer of subcutaneous fat and, on the other
Total daily energy expenditure consists of three primary compo- hand, by increased evaporative heat loss owing to a lower keratin
nents including resting metabolic rate, activity thermogenesis, and content in the infant’s skin.267,268 Infants and children, therefore,
diet-induced thermogenesis.258 The thermogenic response to the not only cool faster but also rewarm two to three times faster than
ingestion or infusion of certain nutrients (e.g., amino acids and adults after hypothermia.269
proteins) has been described as dietary thermogenesis and is In his 1961 classical paper, Brück demonstrated that neonates
commonly measured as the increase in energy expenditure above are able to actively regulate and defend their body temperature.56
the basal metabolic rate. It consists of two separate components: an Until then, most clinicians considered neonates too immature
obligatory and a regulatory component. The former is due to the to respond to differences in ambient temperature. Even more
energy requirements for digestion, absorption, and conversion surprising is the fact that many clinicians, despite Budin’s work
of the nutrients into their respective storage forms, whereas the half a century earlier,52 believed that it was safe to keep the rectal
latter describes a mechanism for energy dissipation.259 In healthy temperature of preterm neonates in the range of 33 to 35°C during
individuals, a diet high in protein and carbohydrate content the first week of life and some even used medications to achieve
this state of hibernation.270,271 This practice derived from the idea
induces a greater thermogenic response than a high-fat diet.260
that lower body temperature should equal lower oxygen con-
Except for a difference in time course, the thermogenic effects of
sumption (van’t Hoff-Arrhenius effect, see explanation below in
intravenous amino acid administration and oral protein intake are
this section). However, because core temperature is maintained
basically identical. An intraoperative infusion of small amounts
mainly by metabolic heat generation (nonshivering thermogen-
of amino acids in adults can increase their heat generation by up
esis), at that age with lower body temperatures, oxygen consump-
to 500% during general anesthesia when compared with the awake
tion is actually significantly higher.272 The neonate, even when
state.261 The clinical effect of this phenomenon is demonstrated by
born prematurely, is capable of active thermoregulation. When
a study showing that adults patients receiving pre- and intrao- subjected to a cool environment, the metabolic rate increases in
perative amino acid infusions maintained their core temperature an attempt to compensate for increased heat loss. Conversely, in a
at 36.5 ± 0.1 °C, whereas the temperature in the control group was hot environment, the baby becomes restless, vasodilates the skin
35.7 ± 0.1°C.262 A similar thermogenic response can also be vessels, and sweats to increase heat loss. The narrow temperature
elicited during spinal anesthesia.263 The synthesis and breakdown range in between these thresholds for ambient temperature is
of proteins in extrasplanchnic tissues and stimulation of cellular known as the thermoneutral zone.
amino acid oxidation seem to play a crucial role in dietary Neutral temperature, or more accurately the thermoneutral
thermogenesis, although the exact physiology remains to be zone, is defined as the ambient temperature range in which the
elucidated. Approximately half of the heat generated from the oxygen demand (as a reflection of metabolic heat production) is
oxidation of infused amino acids originates from the splanchnic minimal and temperature regulation is achieved by noneva-
region and results in an overall increase in cardiac output of almost porative physical processes alone such as cutaneous vasodilation
20% with significantly increased blood flow to extrasplanchnic, or vasoconstriction.273 The lower limit of the thermoneutral zone
but not splanchnic, tissues.264 In the same study, splanchnic oxygen defines the lower critical temperature and refers to the ambient
uptake during the first postprandial hour increased by 50%, temperature below which the rate of metabolic heat production of
accounting for almost two thirds of the increase in whole-body a resting thermoregulating organism increases by shivering and/or
oxygen consumption. In the second postprandial hour, oxygen nonshivering thermogenic processes to maintain thermal balance.
uptake increased in extrasplanchnic tissues, but no further in The upper critical temperature refers to the upper limit of the
splanchnic tissues. During general anesthesia, thermoregulation thermoneutral zone and describes the ambient temperature above
is attenuated and, therefore, amino acid triggered thermogenesis which evaporative heat losses are triggered to maintain body
potentially exaggerated. However, dietary thermogenesis can be temperature within the normal range.273
powerful enough to cause hyperthermia even in the awake patient The thermal environment depends on ambient air temperature,
with intact thermoregulation or in a cold environment with ample air flow velocity, relative humidity, and radiant heat exchange. All
potential for heat dissipation.265 Leading to a synchronous increase of these factors can be conveniently controlled or eliminated in an
in the autonomic thermoregulatory defense thresholds, amino incubator (isolette). The mean temperature required to provide
thermal neutrality to a healthy baby nursed naked in a draft-free ing visceral surfaces (e.g., abdomen and thorax), resulting in
environment with uniform temperature and moderate humidity significant evaporative heat losses. Many premature babies require
depends on the baby’s birthweight. For a birthweight of 1.0 kg, phototherapy, which increases not only skin blood flow but also
1.5 kg, 2.0 kg, and more than 2.5 kg, these temperatures are 35°C evaporative heat loss.278,279
(for the first 10 days of life), 34°C (for the first 10 days of life), Despite the risks of hypothermia, maintaining a core
34°C (for the first 2 days of life), and 33°C (for the first 2 days of temperature at or above 37.8°C in infants weighing less than 2 kg
life), respectively.270 In comparison, the neutral temperature for an is associated with a higher mortality.280 In part, this may be
unclothed adult is about 28°C. Clothing the babies and putting explained by the van’t Hoff-Arrhenius law (or Q10 effect), which
them in an incubator obviously allows the use of slightly reduced basically states that for every 10°C increase in temperature, the
temperatures. Metabolic heat production increases in both term rate of a chemical reaction increases on average by a factor of 1.5
and preterm infants in response to cold exposure, but the meta- to 2.5. This in turn can increase the neonate’s metabolic heat
bolic rise is greater among term babies during the first 10 days of production to a point at which their heat loss mechanisms become
life.56 The lower temperature limit of thermal regulation—that is., overwhelmed. Despite the higher risk for hypothermia of neonates
the lowest ambient temperature in which thermal balance can and small babies because of physical circumstances (e.g., size,
be maintained for a limited time period and at which metabolic cold environment), this age group may react to an infection with
hypothermia instead of fever.
rate reaches its peak—is 0°C in adults compared with 22°C in
newborns.273 Maintaining core temperature in a cool environment
results in increased oxygen consumption and may lead to Thermoregulation and Anesthesia
metabolic acidosis. Neonatal cold exposure can lead to a vicious
circle starting with a drop in body temperature that triggers All anesthetic agents, inhalational or intravenous, inhibit
nonshivering thermogenesis. If the cold exposure persists, thermoregulation at the peripheral and central level to variable
depletion of the BAT will ensue and eventually result in failing degrees in a linear or nonlinear and often dose-dependent
heat generation and, thus, a further drop in body temperature with fashion.44,281,282 The interthreshold range for thermoregulation in
lethargy and finally death.274 an awake, healthy adult is controlled within the set point of
A normal rectal temperature in a neonate does not necessarily 37°C by 0.4°C in either direction. The shift of the threshold
temperatures for triggering a thermoregulatory response under
indicate minimal oxygen consumption, because the baby may
anesthesia may result in an expansion of the interthreshold range
use all of its defense mechanisms to maintain normothermia
by a factor of more than 10. This expansion is significantly greater
and, thus, have a high oxygen consumption. It has been demon-
on the hypothermic than on the hyperthermic side (~2.5°C vs
strated that neonatal oxygen consumption is directly related to
1.3°C, respectively).283,284 The mechanism by which the body
the temperature gradient between the skin surface and the
determines the absolute threshold temperatures is not known, but
environment. It can easily double and, in some cases, even triple
it appears that the thresholds are influenced by multiple factors
even during the first hours of life in response to cold stress.203 Of
such as sodium, calcium, thyroid hormones, tryptophan, general
particular concern regarding thermoregulation in the newborn anesthetic agents and other medications, circadian rhythms,
and small infants is the head, which accounts for approximately exercise, pyrogens, food intake, as well as cold and warm accli-
20% of the total skin surface area at that age and which also has the mation. The anesthesia-induced changes result in a wider temper-
highest regional heat flux ability.275,276 In neonates and infants, the ature range over which active thermoregulatory responses are
head is the site for the production and loss of up to 40% and 85% absent or diminished and the body behaves in a poikilothermic
of body heat, respectively. This phenomenon results to the thin manner with passive temperature changes proportional to the
skull bones and the frequently sparse scalp hair.277 Although this difference between heat gained from metabolic production and
setup is beneficial in a clothed or covered baby with intact heat lost to the environment. General anesthesia eliminates
thermoregulation to avoid hyperthermia, it is less advantageous not only the behavioral aspect of thermoregulation but also
in anesthetized infants who are at high risk of hypothermia. In shivering thermogenesis, because most patients are paralyzed
addition, cold exposure of the face significantly increases the or immobilized. Nonshivering thermogenesis and peripheral
metabolic rate in term and preterm neonates with oxygen vasoconstriction (although both occurring at lower tempera-
requirements increasing by as much as 23% and 36%, respec- tures only) are, therefore, the only defense mechanisms against
tively.274 These factors emphasize the need for protecting the baby’s hypothermia that are active in anesthetized neonates and small
head from heat loss during surgery.248 infants. Older children and adults are left only with peripheral
Thermoregulatory vasoconstriction and vasodilatation are vasoconstriction.
generally present on the first day of life and can occur in both the Unfortunately, the definition of hypothermia is not unanimous,
premature and the full-term infant.56,198 The even greater increased but the subdivisions into mild (core temperature 34.0–35.9°C),
skin surface area–to–body mass ratio and thermal transfer moderate (32.0–33.9°C), and severe hypothermia (<32.0°C)
coefficients put the premature and small–for–gestational age appear reasonable for clinical purposes.285 Patients with mild
newborn at the highest risk for accidental hypothermia with the intraoperative hypothermia demonstrate profound peripheral
narrowest temperature range in which thermoregulatory stability vasoconstriction that can easily be measured using skin surface
can be maintained. The slightly lower skin surface area–to–body temperature gradients (e.g., forearm vs finger tip skin temper-
mass ratio and increased motor tone in small–for–gestational-age ature), laser Doppler blood flow measurements, volume plethys-
infants offer a slight advantage in the protection against hypother- mography, or other techniques.201,283,284 Although the maximal
mia when compared with the premature infant in terms of heat intensity of peripheral vasoconstriction and its gain (i.e., the
loss or transfer. In addition to these physical limitations, surgery incremental increase in its intensity with progressing core
further increases heat loss and fluid requirements by expos- hypothermia) are preserved under anesthesia, there is a significant
shift of its threshold temperature toward hypothermia when temperature reaching 33.6 ± 0.4°C. The reason for this profound
compared with awake, unanesthetized patients. The one exception inhibition of thermoregulation in children anesthetized with
seems to be desflurane, which not only lowers the threshold tem- enflurane is unknown, but it was concluded that the risk of
perature but also decreases the gain of peripheral arteriovenous hypothermia in this age group with enflurane is significantly
shunt vasoconstriction.286 The threshold temperatures at which higher when compared with isoflurane or halothane.291 Of note,
vasoconstriction and nonshivering thermogenesis occur define because there are no studies done determining the MAC equiv-
the corresponding lower thermoregulatory threshold for an alent of enflurane in children, end-tidal gas concentrations may
anesthetic agent at any given concentration. not have been equipotent. By contrast, enflurane administered to
healthy adult volunteers at an end-tidal concentration of 1.3%
Thermoregulation and Inhalational (0.77 MAC) triggered thermoregulatory vasoconstriction at
Anesthetic Agents 35.1 ± 0.6°C in the absence of painful stimuli. The addition of
painful electrical stimulation raised the threshold temperature
The decrease in thermoregulatory threshold temperature for to 35.5 ± 0.8°C, demonstrating a mild, although clinically insig-
vasoconstriction in adults under isoflurane anesthesia is inversely nificant, effect of nociception on anesthesia-induced thermo-
correlated to the isoflurane concentration with the threshold regulatory inhibition.292 In a concentration of 1 MAC in adult
temperature dropping by approximately 3°C for every 1% increase women, enflurane increased the sweating threshold only slightly
in end-tidal isoflurane concentration.44 The same group of more than previously reported for isoflurane, although the gain
investigators later found that isoflurane reduces the threshold and maximum intensity of the sweating response were well
temperature disproportionately more at higher anesthetic con- preserved.293
centrations, revealing a nonlinear dose-response relationship.282,287 In healthy adults immersed in cold water, the administration of
In adults anesthetized with 0.7% isoflurane, the shivering tem- 10 to 25% nitrous oxide in a normoxic mixture reduced shivering
perature threshold and the peak intensity of shivering were thermogenesis in a dose-independent manner.107 Similar results
decreased. However, isoflurane produces a clonic muscular were reported for 30% nitrous oxide in oxygen,294,295 whereas the
activity that is different from normal shivering and superimposed sweating threshold was unaffected.295 When compared with
on normal thermoregulatory shivering. During progressive sevoflurane or isoflurane anesthesia at 1 MAC, the mixture of
hypothermia, these marked changes in the shivering pattern from 0.5 MAC nitrous oxide and 0.5 MAC sevoflurane or isoflurane
a linear increase to an unusual sawtooth pattern may help to resulted in a significantly higher threshold temperature for
increase the gain of shivering.288 thermoregulatory vasoconstriction.296 In adults undergoing
The rapid heat loss to the environment in small infants and orthopedic or open abdominal surgery, anesthesia with either
children is favored by their high surface area–to–mass ratio, but sevoflurane or isoflurane in 70% nitrous oxide resulted in a similar
is partially offset by their increased metabolic rate and well- decrease in the threshold temperature for vasoconstriction;
developed thermoregulatory vasoconstriction, which under however, the decrease in body temperature was significantly
isoflurane anesthesia showed basically the same changes as slower in the sevoflurane group (0.5 ± 0.2°C/h vs 1.0 ± 0.3°C/h
those reported in adults. Central temperature thresholds under with isoflurane).297 Studies using various 1 MAC combinations
isoflurane anesthesia do not, therefore, appear to be a function of of xenon, nitrous oxide, and isoflurane demonstrated that the
weight or age.289 However, because of the physical characteristics of calculated reduction of the vasoconstriction threshold tem-
infants and children, the speed of cooling is higher than in adults. perature was most pronounced with xenon (34.6 ± 0.8°C),
Halothane administered to adults in a concentration of intermediate with isoflurane (35.1 ± 0.6°C), and lowest with
0.86 to 1.01% decreased the threshold for thermoregulatory nitrous oxide (35.7 ± 0.6°C).298
vasoconstriction to 34.4 ± 0.2°C.284 Halothane in a concentration Desflurane significantly increases the sweating threshold
of 0.6% combined with a caudal epidural block with bupivacaine temperature in adults in a dose-dependent and linear fashion.
lowered the threshold temperature for vasoconstriction in infants However, the threshold temperatures for vasoconstriction and
and children to 35.7°C.290 The higher halothane concentration shivering are reduced nonlinearly. Although the decrease in the
used for adults may explain the lower threshold temperature threshold temperatures for vasoconstriction and shivering at 0.8
in that group. Neither the omission of the caudal block nor a MAC seem to be in a similar range compared with other inhala-
higher end-tidal halothane concentration (0.9%) resulted in a tional anesthetic agents, the vasoconstriction threshold was higher
significantly altered threshold temperature when compared with than expected at 0.5 MAC, thereby supporting the assumption
the children receiving the lower halothane concentration in that desflurane may trigger a nonlinear concentration-response
combination with a caudal block.290 However, despite thermo- relationship with regards to thermoregulatory vasoconstriction.299
regulatory vasoconstriction, central temperature in children As mentioned earlier in this section on Thermoregulation and
weighing more than 30 kg continued to drop, whereas the tem- Anesthetic Agents, by contrast to other inhalational anesthetic
perature reached a plateau in patients weighing less than 30 kg. medications, the gain of thermoregulatory vasoconstriction with
The exact reasons for this finding are unknown, but nonshivering desflurane in adults is markedly decreased even at relatively low
thermogenesis may play a role. It appears that thermoregulatory desflurane concentrations (0.4 MAC).
defense mechanisms in small, anesthetized children are more Hypothermia affects not only the physical characteristics of
effective than in the older age group including adults. Comparing inhalational anesthetic agents but also the pharmacokinetics and
halothane, enflurane, and isoflurane at an end-tidal concentration pharmacodynamics of intravenous agents. In the temperature
of 1.0 minimum alveolar concentration (MAC) in combination range of 28 to 32°C, the decrease in MAC with lower temperatures
with a caudal epidural block in children confirmed the previous parallels the increase in lipid solubility of the anesthetic gas.300–304
findings for isoflurane and halothane. However, all but one child For isoflurane, there is a linear reduction in the MAC of 5.1%/°C
in the enflurane group failed to vasoconstrict despite their core temperature decrease.302 Thus, for any inspired concentration of
an inhalational anesthetic agent in a hypothermic patient, an is similar to the reduction seen during halothane anesthesia
increased amount of anesthetic agent will be delivered to the (34.4 ± 0.2°C).283 When propofol was administered to healthy adult
tissues at a time when the anesthetic requirements are decreased. volunteers, who also had a lumbar epidural anesthesia, there was
The mechanism by which hypothermia reduces the MAC is a slight increase in the threshold temperature for sweating with a
unknown. According to the Meyer-Overton rule, the MAC of a significant and linear decrease in the threshold temperatures for
volatile anesthetic agent is inversely proportional to its lipid vasoconstriction and shivering.311 Furthermore, the vasoconstriction-
solubility (i.e., its oil-to-gas partition coefficient) whereas the to-shivering range increased only slightly during propofol anes-
product of anesthetic gas partial pressure (i.e., MAC) and its lipid thesia.109
solubility is constant. Because hypothermia increases the lipid Small infants (<1 y of age), undergoing abdominal surgery
solubility of the volatile anesthetic agents, the MAC has to be lower and anesthetized with propofol and fentanyl, demonstrated
to keep the product constant. However, it seems that the increased vasoconstricted by the time core temperature reached 36°C.
solubility of the inhaled anesthetic agents in the lipid phase of the However, reducing core temperature further to 34.0 to 34.5°C
central nervous system does not fully explain the MAC reduction did not result in increased oxygen consumption. Instead, oxygen
associated with hypothermia. consumption decreased linearly and hypothermia failed to
increase plasma catecholamine concentrations. Even when lower-
Thermoregulation and Intravenous ing the core temperature approximately 2°C below the vasocon-
Anesthetic Agents striction threshold, no evidence of nonshivering thermogenesis
could be identified. Infants thus appear similar to adults in their
Opioids are a large and variable group of drugs in respect to both
inability to increase their metabolic rate in response to mild
their opioid receptor affinity and their chemistry. Therefore, not
intraoperative hypothermia.245 When comparing general anes-
unexpectedly, their effects on thermoregulation are not uniform.
thesia in adults induced with a single intravenous dose of pro-
Both μ-receptor and combined μ and ␬ receptor agonists impair
pofol (2.5 mg/kg) followed by maintenance anesthesia with
thermoregulation. In the clinically relevant plasma concentration
sevoflurane in 60% nitrous oxide and oxygen versus induction
range, the pure μ receptor agonist alfentanil leads to a mild, dose-
with sevoflurane followed by the same maintenance, core tem-
dependent and linear increase in the sweating threshold and a
perature in the propofol group was significantly lower than in the
marked, but also linear and dose-dependent decrease in the
sevoflurane group (35.5 ± 0.3°C vs 36.2 ± 0.2°C).312 The brief
thresholds for vasoconstriction and shivering. Similar to general
propofol-induced vasodilation is thought to be responsible for
anesthesia, the vasoconstriction-to-shivering range remains
facilitating core-to-peripheral redistribution of body heat leading
normal.305 The combined μ and κ receptor agonist meperidine
to nonrecoverable heat loss to the environment and hypothermia
(pethidine) also results in a slight increase in the threshold
persisting throughout surgery.
temperature for sweating and a reduction in the threshold
Midazolam produces only a slight decrease in the threshold
temperature for vasoconstriction. However, the meperidine-
temperature for sweating, with a more profound reduction in the
induced reduction of the shivering threshold is twice as great as
the one for vasoconstriction. This significant increase in the threshold temperature for vasoconstriction. This results in a
vasoconstriction-to-shivering range with meperidine is, at least in threefold expansion of the interthreshold range, which is similar
part, due to its κ receptor activity and clinically used to effectively to the findings with central neuraxial nerve blockade (see Section
treat shivering.305 However, neither alfentanil nor meperidine on Thermoregulation and Regional Anesthesia), but contrasts
reduce the maximum intensity or the gain of shivering. with the effects of inhaled anesthetic agents, propofol, or opioids,
When given to awake, healthy adults, tramadol, which has in which the interthreshold range can expand by a factor of more
a weak affinity for μ receptors and monoaminergic actions than 10.313 Intramuscular premedication in healthy adults with
(serotonin and noradrenaline re-uptake inhibition), results in a midazolam produces a dose-dependent temperature decrease after
linear and concentration-dependent decrease in the threshold 30 minutes because of impaired thermoregulatory vasoconstric-
temperature for sweating (approximately –1.03 ± 0.67°C), whereas tion, which allows heat to be redistributed from the core to the
the decrease in the threshold temperatures for vasoconstriction and peripheral compartment.314 This hypothermic effect of midazolam
shivering are more pronounced (–3.0 ± 4.0°C and –4.2 ± 4.0°C, can be neutralized by simultaneous administration of atropine.315
respectively). Because the vasoconstriction threshold temperature In adults, core hypothermia during the first hour of anesthesia
decreases more than the one for sweating, the interthreshold range is less after induction of anesthesia with ketamine than with
doubles, which, in regards to thermoregulatory inhibition, is propofol, even when anesthesia was maintained with sevoflurane
considered mild. The effects of tramadol are thought to reduce the and 60% nitrous oxide in oxygen in both groups. The finding is
thermoregulatory set point rather than generally impair ther- postulated to be caused by the preserved arteriovenous shunt
moregulation.306 Tramadol has also been used successfully to stop vasoconstriction during induction of anesthesia with ketamine
postanesthetic shivering.307 The pharmacokinetics of barbiturates versus propofol, which reduces the extent of redistribution hypo-
and opioids are also affected by hypothermia, which may further thermia.316 In a prospective, randomized trial, children younger
affect their thermoregulatory effects.308,309 Surprisingly little than 8 years of age undergoing anesthesia for herniorrhaphy
research has been done regarding the thermoregulatory effects of received either ketamine or halothane/nitrous oxide in oxygen
sufentanil, fentanyl, and morphine when given as the sole drug to after intramuscular premedication with scopolamine.317 Children
humans. Sufentanil linearly reduces the shivering threshold in the halothane group had a greater decrease in temperature than
temperature and has been used successfully in the treatment of children in the ketamine group. In children older than 24 months
postoperative shivering.310 Sufentanyl in combination with 70% of age, body temperature in the ketamine group increased slightly
nitrous oxide in oxygen lowers the threshold for thermoregulatory after the induction of anesthesia. However, independent of the
vasoconstriction by approximately 2.5°C to 34.2 ± 0.5°C, which anesthetic technique used, hypothermia during general anesthesia
was greatest in children with the highest surface area–to–body (e.g., phenylephrine infusion) can limit the size of the peripheral
weight ratio.317 compartment and, hence, the magnitude of hypothermia caused
In healthy adult volunteers, dexmedetomidine reduces the by redistribution.325
threshold temperatures for vasoconstriction and shivering in a During lumbar epidural anesthesia in adult volunteers, internal
linear and dose-dependent manner and, thus, expands the redistribution contributed 89% to the initial temperature decrease
interthreshold range despite the fact that the sweating threshold in the first hour. During the subsequent 2 hours of epidural
remains unchanged.318 The co-administration of meperidine has anesthesia, redistribution still accounted for 62% of core
an additive effect on the reduction of the shivering threshold, temperature reduction. In the first 3 hours of epidural anesthesia,
making this combination an effective treatment option for redistribution was responsible for 80% of the overall temper-
postoperative shivering.319 Premedication with 150 μg of oral ature drop, and even after 3 hours of anesthesia, redistribution
clonidine in adults neither affects redistribution hypothermia nor remained the main culprit of core hypothermia. Despite the
worsens hypothermia during general anesthesia.320 Clonidine greater fractional contribution of redistribution during epidural
given as a bolus dose (either 2 or 4 μg/kg) followed by an infusion anesthesia, core temperature decreased only half as much as
of either 2 or 4 μg/kg/h resulted in a dose-independent increase in during general anesthesia because the metabolic heat generation
the threshold temperature for sweating, but its gain remained could be maintained and thermoregulatory vasoconstriction in
unchanged.321 By contrast to other sedatives and anesthetic agents, the upper (nonanesthetized) body part was unaffected.326 The
clonidine seems to reach an early ceiling effect beyond which the degree of core hypothermia during central neuraxial anesthesia
administration of additional doses fails to further enhance its depends on the amount of internal heat redistribution because of
effects on thermoregulation, suggesting that the thermoregu- a lack of thermoregulatory vasoconstriction in the anesthetized
latory inhibition of clonidine is limited. The thermoregu- body part and, thus, is directly related to the number of der-
latory changes induced by clonidine resemble those of volatile matomes blocked rather than to a centrally mediated inhibition
anesthetic agents, opioids, and propofol. The antishivering effect of thermoregulation.327,328 Similar to general anesthesia, advanced
of clonidine appears to result from central thermoregulatory age is also associated with more severe hypothermia during spinal
inhibition rather than a specific peripheral action on thermogenic anesthesia.328 Epidural and spinal anesthesia commonly affect a
muscular activity.321 major part of the body mass, and therefore, hypothermia can be
Atropine blocks sympathetic, cholinergic-mediated sweating, quite pronounced. Regional anesthesia affects metabolic heat
increases the threshold temperatures for sweating, and may generation only minimally.329 However, by contrast with general
therefore lead to hyperthermia in children.322 Systemic admin- anesthesia, central neuraxial anesthesia abolishes thermoregu-
istration of atropine leads to marked (regional) cutaneous vaso- latory peripheral vasoconstriction in the anesthetized body parts,
dilation at the same core temperature with the skin temperature and hence, patients may fail to reach a steady state between heat
following passively. The effect of systemic atropine in stimulating loss and heat generation. Despite maximal vasoconstriction in
cutaneous vasodilation has been suggested to be the result of the body part not affected by regional anesthesia, progressive
a combination of central and local responses, which may be and serious hypothermia may not be preventable because the
mediated by the release of vasoactive substances.323 nonanesthetized body mass is usually comparably small. At a
normal leg skin temperature of approximately 33°C, the cutaneous
cold sensors are more active than the warm sensors. Blocking
Thermoregulation and Regional Anesthesia these afferent pathways by central neuraxial anesthesia techniques
The central integration of afferent and efferent thermal impulses could potentially be interpreted as relative leg warming by the
remains fully functional during regional anesthesia and protects hypothalamus. In addition, this blockade seems to be responsible
against either hypothermia or hyperthermia. However, the for the low intensity of shivering, and in some individuals its
problem with regional anesthesia in terms of thermoregulation is delayed onset, further increasing the risk for hypothermia.329–331
the blockade of afferent and efferent signals from and to the Mainly because of the failure of the upper body muscles to
anesthetized body part. Intraoperative hypothermia secondary to compensate for lower body paralysis, the gain of shivering during
regional anesthesia is caused by a combination of lost regional epidural anesthesia is reduced by more than 60%.332 When com-
thermal sensation, inhibition of thermoregulatory vasocon- paring epidural with general anesthesia in adults undergoing
striction and shivering, and increased internal redistribution radical prostatectomy, intraoperative and postoperative core
of heat to the anesthetized body part with increased heat loss to temperature profiles were virtually identical in the two groups.
the environment. The factors responsible for intraoperative Epidural anesthesia was associated with less intraoperative upper
hypothermia during general anesthesia principally also apply for body thermoregulatory impairment but greater and persistent
central neuraxial anesthesia. In the first 30 minutes after the postoperative lower body impairment. Although the age-related
induction of neuraxial anesthesia, the central core temperature in differences were minimal in the general anesthesia group, younger
healthy adult volunteers decreased by approximately 0.5 to 1.5°C, patients appeared to maintain thermoregulation better than older
accounting for 81% of the core temperature decrease in the first patients with neuraxial anesthesia.190 Inhibition of thermoregu-
hour of anesthesia. Decreased metabolic heat generation and lation during regional anesthesia is reflected as significant
increased heat loss to the environment were responsible for the expansion of the interthreshold range. Comparable changes in
residual part in temperature drop. The impact of redistribution the threshold temperatures for sweating, vasoconstriction, and
of heat on the temperature drop decreased to 43% during shivering during epidural and spinal anesthesia with a doubl-
the second and third hour of anesthesia. This redistribution ing of the interthreshold range suggest that thermoregulatory
accounted for a total of 65% of temperature reduction during the processing is similarly affected during both types of regional
first 3 hours of anesthesia, making it the major cause of hypo- anesthesia.331 The thermoregulatory inhibition described for
thermia.324 Accordingly, the administration of a vasoconstrictor regional anesthesia is unlikely the result of the systemic absorption
of local anesthetic agents because similar local anesthetic agent equally important as it is during general anesthesia, only a third of
plasma concentrations without regional anesthesia fail to clinicians monitor temperature during regional anesthesia and less
reproduce these thermoregulatory changes.333 Regional anesthesia than 15% use reliable core temperature monitoring techniques.337
for large surgical incisions may be associated with profound and It is likely that significant hypothermia, although common, goes
even more severe hypothermia than with general anesthesia, and undetected and, therefore, untreated in these patients.
the recovery time to normal body temperature may be prolonged.
By contrast, regional anesthesia reduces the risk of hypothermia Anesthesia and Hypothermia
when the incision is small and the patient is kept well insulated.334
The combination of general anesthesia with isoflurane and General anesthesia leads to an expansion of the interthreshold
epidural anesthesia in adults further reduces the threshold temper- range, both by increasing the threshold temperature for sweating
ature for thermoregulatory vasoconstriction thereby significantly and by decreasing the threshold temperature for vasoconstriction
exacerbating hypothermia when compared with general anes- and shivering. As a result, hypothermia is common, although most
thesia alone.335 During combined enflurane (1 MAC) and epidural often mild (≥ 34°C). Its etiology remains multifactorial including
anesthesia in healthy female volunteers, the sweating threshold 1. Anesthesia-induced inhibition of central thermoregulation.338
was 1.4 ± 0.7°C higher than during epidural anesthesia alone.293 2. Internal redistribution of heat from the central to the periph-
Diabetic patients with autonomic neuropathy receiving a general eral compartment.329
anesthesia had delayed thermoregulatory vasoconstriction result- 3. Linear reduction in metabolic heat production as a function of
ing in lower core temperatures after 2 hours of anesthesia than mean and core body temperatures (4–8%/°C).339
diabetic patients without autonomic dysfunction.336 4. Increased exposure to the environment (up to 90% of heat loss
By contrast, the combination of halothane anesthesia with a occurs via skin mainly by radiation and convection).
caudal epidural block in children undergoing hypospadias repair
Anesthesia-induced hypothermia has a typical temperature
failed to significantly alter the threshold temperature for vasocon-
profile and develops in three distinct phases (Figure 14–4):
striction when compared with children receiving halothane
anesthesia and a penile block (35.9°C with caudal block vs 35.7°C 1. Internal redistribution of heat.
with penile block).290 Although these data would demonstrate 2. Thermal imbalance.
that temperature monitoring during regional anesthesia is 3. Thermal steady state (plateau or rewarming).
Figure 14-4. Intraoperative course of changes in body temperature. Graphic representation of the
three typical phases of intraoperative hypothermia in relation to the duration of anesthesia. The first
phase relates to internal redistribution with a drop in core temperature secondary to the expansion
of the central core volume induced by peripheral vasodilatation (the same heat content is now dis-
tributed in a larger volume). The second phase is characterized by actual heat loss to the environ-
ment resulting in further reduction in body temperature until the threshold temperatures of defense
mechanisms are reached. The third phase, thermal steady state in adults and rewarming phase in in-
fants and children, is due to the active thermoregulatory defense mechanisms including peripheral
vasoconstriction, shivering, and nonshivering thermogenesis becoming effective. Adapted from ref-
erence 504.
INTERNAL REDISTRIBUTION OF HEAT: In order to understand the reduction in heat loss of 26%, which was deemed rather small
concept of internal redistribution of heat, it is helpful to remember when compared with the reduction in metabolic heat pro-
the thermoregulatory division of the body into central, peripheral, duction during anesthesia and the amount of heat lost by
and skin (or “shell” ) compartments. The core temperature des- evaporation from a large surgical incision.341 The limited effect
cribes the temperature of the central compartment, which in an of thermoregulatory vasoconstriction may be related to the fact
awake adult at rest, accounts for approximately 66% of the body that overall heat loss from the skin is determined predominantly
mass. This increases to about 71% during general anesthesia.340 by capillary blood flow in large skin areas covering the limbs and
The central compartment contains the vessel-rich group organs the trunk. However, these capillaries are unable to vasoconstrict to
that make up approximately 10% of the total body weight in adults the same degree as the arteriovenous shunts and also markedly
and 22% in neonates, but receive 75% of the total cardiac output. outnumber them. Despite these limitations, it seems possible
The peripheral compartment makes up the remainder of the body that limiting the size of the peripheral compartment in relation
mass and acts as a dynamic buffer with a capacity in the adult of to the central compartment by peripheral vasoconstriction
more than 600 kJ between the core and the shell compartment, reduces the amount of heat dissipated and thereby contributes
thereby allowing the body by means of vasodilation or vasocon- to establishing the thermal plateau.339 Even more important in the
striction to maintain core temperature constant with a minimal achievement of the thermal plateau is the evolving constraint of
amount of energy expenditure for thermoregulation despite the metabolic heat generated for a core that is now becoming
absorption or dissipation of significant amounts of heat. The shell smaller again, approaching its original awake size. This is basically
(or skin) compartment is almost virtual and defines the barrier a reversal of the internal redistribution.339 This concept is
between the body and the environment. supported by the finding that the use of unilateral or bilateral
Shortly after the induction of general anesthesia, peripheral leg tourniquets in small children anesthetized with halothane in
vasodilation increases the size of the central compartment, nitrous oxide and oxygen resulted in core hyperthermia, which
resulting in the distribution of its heat content to a larger volume. was more pronounced with bilateral tourniquets.342 Similar results
At the same time, the anesthesia-induced reduction in metabolic have also been demonstrated in adults.343 Most likely, hyper-
heat generation makes it almost impossible for the body to thermia induced with a tourniquet results from the limited
compensate for the expansion of the central compartment. As the expansion of the central compartment, thereby containing the
name implies, heat is mainly redistributed, with only a fraction metabolic heat within a smaller central compartment. This is
being lost, to the peripheral compartment, resulting in a decreased further supported by the fact that deflation of the tourniquet(s)
core temperature and increased peripheral and skin compartment leads to a drop in central temperature.343–345 Despite reaching
temperature. This can be demonstrated by a forearm-fingertip or a thermal plateau, mean body temperature and body heat content
calf-toe temperature gradient that may exceed 8°C and is caused continue to decrease, although at a much slower rate (i.e.,
by a more than fourfold increase in the perfusion of forearms and 0.2°C/h). That is, vasoconstriction reestablishes the normal core–
legs after the induction of anesthesia.324 to–peripheral temperature gradient by preventing metabolic heat,
which is largely generated in the core, from escaping to peripheral
THERMAL IMBALANCE: The second phase of anesthesia- tissues.339
induced hypothermia, also known as thermal imbalance, results The assessment of the contribution of nonshivering thermo-
from a combination of decreased metabolic heat generation genesis in adult volunteers under anesthesia has demonstrated that
and increased heat loss to the environment. This phase lasts it has little effect on the thermal plateau.346 Even in small children
approximately 2 to 3 hours and causes a linear decrease in mean anesthetized with propofol and fentanyl, there is a failure to trigger
body temperature of typically 0.5 to 1.0°C/h. Heat generation nonshivering thermogenesis at core temperatures approximately
during anesthesia is reduced not only by inhibition of metabolism 2°C below the vasoconstriction threshold. Similar to adults,
but also by very limited or absent muscular activity (e.g., absent or infants and children are unable to increase their metabolic rate in
reduced work of breathing).44,292 All of the heat loss mechanisms response to anesthesia-induced hypothermia.245 However, by
(i.e., radiation, convection, evaporation, and conduction) contri- contrast to adults, the third stage of the response to anesthesia-
bute in variable degrees to heat loss from the patient to the
induced hypothermia in infants and children is a rewarming
environment during anesthesia and surgery. Heat loss mainly
rather than just a plateau phase. With muscular activity and
becomes a function of the temperature difference between the
nonshivering thermogenesis inhibited and metabolic heat
patient’s body surface and the environment. Therefore, heat loss
production reduced during anesthesia, the only possible expla-
decreases passively as the body temperature decreases toward
nation for this rewarming phase is peripheral vasconstriction,
room temperature (i.e, the temperature gradient shrinks).
which seems to be more efficient in this age group than in adults.
THERMAL STEADY STATE (PLATEAU OR REWARMING PHASE): A clinical study in children undergoing general anesthesia for
In the third stage of the response to anesthesia-induced hypo- surgery found a twofold increase in oxygen consumption during
thermia, the body almost reaches an equilibrium between internal mild hypothermia, which was attributed to a higher metabolic
heat production and heat dissipation to the environment, resulting heat generation.347,348 This increased oxygen demand to maintain
in a core temperature that reaches a plateau and, hence, remains normal core temperature may create or exacerbate pre-existing
fairly constant. This temperature plateau usually occurs between cardiopulmonary insufficiency intraoperatively and even more so
34.5 and 35.5°C and is also termed the thermal steady-state phase. in the postoperative period. Norepinephrine released to trigger
In order to achieve this steady state, the patient must increase vasoconstriction may contribute to the development of acidosis,
metabolic heat production and/or reduce heat loss. In adult tissue hypoxia, and increased right-to-left pulmonary shunting.349
volunteers anesthetized with isoflurane at an end-tidal concen- Sustained pulmonary artery hypertension and right-to-left
tration of 1%, thermoregulatory vasoconstriction occurred at a pulmonary shunting may lead to the formation of a vicious circle
core temperature of 34.6 ± 0.4°C and resulted in a maximal with ongoing pulmonary hypertension and vasopasm.
Anesthesia and Hyperthermia anatomic and physiologic characteristics of an infant or child, we

Similar to hypothermia using thresholds and gain, hyperthermia can control many of these other factors. Several preventive and
triggers important physiologic thermoregulatory responses. The effective measures exist so that hypothermia must no longer be
defense mechanisms to fight core hyperthermia are preserved viewed as an accepted and inevitable sequelae of anesthesia and
during general anesthesia; however, the thresholds triggering them surgery. Although hypothermia has been shown in several studies
are shifted toward higher temperatures. Volatile anesthetic agents to be beneficial, mainly for patients with any type of ischemia or
significantly expand the interthreshold range but change the gain traumatic brain injury,354,355 the vast majority of patients under-
and maximum intensity of the response only minimally.293 The going anesthesia do not suffer from these comorbid processes, and
interthreshold range expansion during anesthesia is not sym- therefore, the adverse effects of hypothermia generally outweigh
metrical and differs for hypothermia and hyperthermia. Although the benefits. Studies providing evidence for the adverse effects
the reduction in the threshold temperature (thermoregulatory of intraoperative and postoperative hypothermia have been
vasoconstriction) for hypothermia in an anesthetized patient may performed only the adult population. However, there are no
be as great as 3.5°C, the increase in the threshold temperature for reasons to believe that these findings do not apply to infants and
thermoregulatory vasodilatation may be as little as 1.0°C.293 children.
This observation suggests that the human body is significantly Hypothermia inhibits chemotaxis and phagocytosis of granu-
more sensitive to hyperthermia than to hypothermia. Therefore, locytes, natural killer cell cytotoxicity, macrophage migration,
it may be that hyperthermia represents a more dangerous threat to and T cell–mediated antibody production.356–360 Intraoperative
the organism than a similar degree of hypothermia.293 production of reactive oxygen species (i.e., hydroxyl ions, active
The efferent responses to hyperthermia are limited to active aldehydes, hypohalites, and lipid peroxides) by polymorpho-
vasodilatation and sweating. Thermoregulatory vasodilatation nuclear leukocytes has been shown to be linearly related to core
triggered by warm stress is not simply the absence of vasocon- temperature in patients undergoing colorectal surgery.356 In a
striction, but rather an active peripheral vasodilatation resulting in randomized, double-blind study in 200 adult patients undergoing
increased dissipation of heat.118,120,145,149,350 In fact, it has been open colorectal surgery, patients were assigned either to routine
demonstrated in adult volunteers that α-adrenergic vasocon- warming measures (hypothermic group with a temperature of
striction induced by high intravenous doses of norepinephrine 34.7 ± 0.6 °C at the end of surgery) or to additional warming
during local (forearm) or whole-body warming cannot fully ablate measures (normothermic group with a core temperature of 36.6 ±
the heat-induced vasodilatation.351 During normothermia, skin 0.5 °C at the end of surgery).361 The incidence of surgical wound
infections was three times higher in the hypothermia group and
blood flow is controlled by tonic adrenergic stimulation. With
the time to suture removal and hospital discharge was prolonged
increasing core temperature, skin blood flow initially increases by
by 1 and 2.6 days, respectively. It has been hypothesized by these
reducing the tonic vasoconstriction. For glabrous or non–hair-
and other investigators that the increased rate of wound infections
containing skin (palmar and plantar surfaces and lips), aside from
and delayed wound healing may be a direct consequence of
the direct vasodilating effects of heat itself, this mechanism is the hypothermia-induced vasoconstriction, which results in dimin-
only way to adjust local blood flow. However, once the threshold ished tissue oxygen partial pressures.361,362 The induction of
temperature has been reached in nonglabrous skin areas (hair- thermogenesis with an amino acid infusion during general
containing skin), active cutaneous vasodilatation is initiated by a anesthesia has been shown not only to prevent postopera-
combination of sympathetic cholinergic impulses and release of tive hypothermia and shivering but also to result in a shorter
vasoactive substances including histamine, VIP, nitric oxide, and hospital stay.262
perhaps other neurotransmitter(s).121–124 Normally, coagulation tests are performed at 37°C, which results
It has also been demonstrated that men sweat more than in the effects of hypothermia being masked.363,364 However, if the
women. Compared with men, heat loss in women depends more tests are done at the actual body temperature of the patient, it has
on cutaneous vasodilatation than on sweating, irrespective of been shown that the enzymatic reactions of the coagulation cascade
the phase of the menstrual cycle. However, the menstrual cycle are inhibited by hypothermia, which is reflected by a prolongation
modifies the threshold temperature for vasodilatation and of partial thromboplastin and prothrombin time, although the
sweating in women. The differences are more pronounced during clinical significance of these findings remain debatable.365–367
the luteal than during the follicular phase.352 The threshold In vitro experiments during moderate to profound hypothermia
temperatures in women for hyperthermia defense are significantly
(33 and 22°C) reveal an increase in platelet α-granule release, in
higher than in men. However, the later onset of sweating in
platelet binding of PAC-1 and P-selectin antibodies, and in platelet
women does not result in a significant increase in rectal tem-
aggregation and binding to fibrinogen (via activation of glycopro-
perature, which is probably caused by a complex interaction
tein [GP] IIb/IIIa receptors). Upon rewarming, the aggregation
between sweating, increased skin blood flow, and reduced
response of previously cooled platelets fully normalizes.368 The
metabolic rate.353
authors concluded that, because hypothermia appears to result in
ADVERSE EFFECTS OF HYPOTHERMIA: In both adults and platelet activation, hypothermia-induced coagulopathy is unlikely
children, hypothermia during anesthesia is common. In infants to be caused by an intrinsic defect in platelet function. A study in
and children, it is usually more pronounced, mainly because of mice confirmed these results.369 However, these findings are in stark
their anatomic disadvantages in terms of thermoregulation, which contrast to other reports. Coagulation and platelet function were
have been previously discussed in the section on Physiology of analyzed in 16 otherwise healthy adult patients scheduled for
Thermal Regulation. The exposure of open body cavities to low elective intracranial surgery at a core temperature of 32°C.367 Both
humidity and operating room temperatures, infusion of large prothrombin time and platelet count decreased slightly during
amounts of cold fluids, and ventilation with cold and dry gases all hypothermia. Thrombelastography showed normal clot strength
increase risk of hypothermia. Although we cannot change the in temperature-adjusted measurements; however, clot formation
was delayed. No changes were detectable if the test was performed Although oxygen consumption in the postoperative period is
at 37°C. This was interpreted as an indicator for reduced plasmatic often increased, particularly in the presence of shivering, studies
coagulation and platelet reactivity during hypothermia. The com- examining the effects of shivering have concluded that shivering
parison of results obtained from thrombelastography performed itself is not a significant risk factor for perioperative myocardial
at 37°C and at the actual body temperature of the patient demon- ischemia.180,187 Instead, the hypothermia-induced sympathetic
strated prolonged reaction and coagulation time as well as a nervous system activation results in higher norepinephrine (by
reduced clot formation rate in the presence of hypothermia.370 251%) and epinephrine (by 120%) plasma concentrations, a
Increased bleeding during hypothermia in humans has been shown greater degree of peripheral vasoconstriction, higher arterial blood
to be the result of a platelet adhesion defect and not reduced pressure, and a risk of ventricular arrhythmias in the early
enzyme activity or platelet activation. Reduced platelet function postoperative period.380–382 The sympathetic activation is asso-
and enzyme activity likely contributed to coagulopathy at tem- ciated with increased cardiac work that can be inhibited by
peratures below 33°C.371 By contrast, moderate hypothermia to a β adrenoreceptor blockers.382 In addition, general anesthesia
mean body temperature of 32.5 ± 0.4°C accomplished in the first combined with hypothermia (33.9 ± 0.5°C) in healthy volunteers
hour after induction of anesthesia and maintained during surgery resulted in significantly greater suppression of the baroreceptor
for subarachnoid aneurysms in 359 adult patients appeared to be reflex–mediated heart rate control, both intraoperatively and
safe and not associated with a higher rate of perioperative compli- postoperatively.383 High-risk cardiovascular patients undergoing
cations such as hemodynamic instability, coagulation abnorma- major surgery have been shown to have a threefold increased
lities, or infections.372 risk of perioperative cardiac complications (i.e., unstable angina/
Although these conflicting results demonstrate that not all of ischemia, cardiac arrest, myocardial infarction, or ventricular
the effects of hypothermia on coagulation and platelet function tachycardia) in the presence of postoperative hypothermia (35.4 ±
have been fully elucidated, from a clinical point of view, it seems 0.1°C) when compared with normothermic patients (36.7 ±
reasonable to assume that, independent of the exact patho- 0.1°C). Again, hypothermia was found to be an independent risk
physiologic causes, blood loss is increased during hypothermia. factor, and maintaining normothermia resulted in a 55% risk
This has been confirmed in a recent meta-analysis of 24 studies reduction for adverse cardiac events.384
demonstrating that even mild hypothermia (a decrease of 1°C) Hypothermia increases the cardiac action potential duration
significantly increased surgical blood loss by approximately 16% and refractory period significantly even at temperature changes
as well as the relative risk for transfusion by approximately 22%.373 of as little as 1 to 2°C. This is explained by delayed repolarization,
Similar findings were reported from an adult study that included which is reflected by prolongation of the QT interval in the
patients undergoing unilateral total hip arthroplasty in which electrocardiogram, thereby increasing the risk of arrhythmias.
intraoperative and postoperative blood loss were significantly Furthermore, nonuniform cooling or rewarming of the heart may
greater in the group with mild hypothermia (35 ± 0.5°C).374 Thirty cause significant dispersion of conduction, action potential
minutes of prewarming before induction of anesthesia in adults duration, and refractoriness in the myocardium. This dispersion
scheduled for major abdominal surgery resulted not only in may cause a unidirectional block and create a substrate for reentry
less hypothermia but also in a reduction of blood loss, length of atrial and ventricular arrhythmias.385
Hypothermia inhibits drug metabolism and may lead to
hospital stay, and total anesthetic costs.375 Decreased platelet
prolonged drug activity. Intraoperative hypothermia in adults has
function with prolonged bleeding time during hypothermia has
been shown to result in delayed recovery from anesthesia.386,387
also demonstrated in adult volunteers and appears to be secondary
However, in a study of 87 children, there was no difference in
to changes in platelet surface proteins with diminished platelet
recovery between normothermic and hypothermic patients.388 The
aggregation and thromboxane B2 (the stable metabolite of throm-
effects of hypothermia on neuromuscular blocking agents includes
boxane A2) generation.376
a reduction of the requirements caused by increased sensitivity
Myocardial infarction is one of the main determinants
of the neuromuscular junction as well as diminished hepatic
of perioperative morbidity and mortality in adults. In adults
clearance because of reduced affinity of the drug substrate for
scheduled for vascular reconstruction of the lower extremities, microsomal enzymes and decreased renal drug elimination.386,389–
electrocardiographic signs and symptoms (angina) of myocardial 392
In the case of vecuronium, mild hypothermia (core temperature
ischemia in the first 24 hours after surgery were significantly 34.5°C) resulted in a more than twofold increase in the duration
more frequent in the hypothermic (<35.0°C) than in the nor- of the spontaneous train-of-four (TOF) ratio recovery to 10% and
mothermic group (>35.0°C).377 After subgroup and multivariate from 75% when compared with normothermic individuals (core
analyses, body temperature remained an independent predictor temperature > 36.5°C). However, the neostigmine-induced TOF
of myocardial ischemia. In addition, the incidence of arterial ratio recovery time was not significantly different in the two
oxygen pressure (PaO2) values below 80 mmHg was greater in the groups.386 Another volunteer study confirmed these findings and
hypothermic than in the normothermic group. The need for determined that the vecuronium plasma clearance diminishes
prolonged mechanical ventilation, increased length of stay in the by approximately 11%/°C temperature reduction and that a
intensive care unit, a higher rate of red blood cell transfusions, and decreased rate constant for drug equilibration between plasma
increased postoperative mortality in hypothermic group patients and effect site increases the slope of the concentration-response
were noted in a retrospective study in 5701 patients after <X> relationship.393 In healthy volunteers anesthetized with a propofol
coronary artery bypass grafting (CABG) surgery with CPB.378 A infusion and paralyzed with a single bolus dose of atracurium, the
decreased incidence of ischemia and myocardial injury, assessed time required for spontaneous TOF ratio recovery to 10% was
with serum troponin I levels, has been noted in patients who were prolonged by more than 50% in the hypothermia group, whereas
kept normothermic throughout the non-CPB phases of CABG the time required for the TOF ratio recovery from 25 to 75% was
surgery.379 similar in the hypothermia and the normothermia groups.394
In addition, propofol blood concentrations at hypothermia were term and 29°C for premature neonates.397 For adults, 21°C has
approximately 28% higher than in normothermia. By contrast, been determined to be the critical ambient temperature in order
hypothermia in adult neurosurgical patients did not affect the time to maintain normothermia.398–400 As a rule of thumb, an increase
to respond to commands after propofol anesthesia, and it was in the operating room temperature of 1°C results in a heat loss
concluded that propofol dosing does not require adjustment reduction of approximately 10%.
during mild hypothermia.395 Decreased clearance of other Convective heat loss is best controlled by keeping the patient
pharmacologic agents including verapamil and propanolol have covered, because the air flow produced by the air conditioning
been demonstrated in the presence of hypothermia.396 system in the operating room has to adhere to certain hygienic
Unfortunately, most of these adverse effects of hypothermia are standards (i.e., the air exchange rate should equal ~15 times the
derived from adult studies. However, until similar studies exist operating room volume/h for systems solely using outdoor air and
specifically for the pediatric population, it seems reasonable to 25 times for systems relying on recirculated air).401 These
assume that the same negative consequences related to hypo- requirements result in a mandatory constant air draft responsible
thermia will also occur in children. Avoiding hypothermia for the convective heat losses.
therefore is crucial not only in the adult patient but also (or Evaporative heat loss occurs from the respiratory tract and
most likely even more so) in the pediatric patient. Applying our accounts for only 5 to 10% of total heat loss during anesthesia.
knowledge from thermal physiology and thermoregulation Evaporation also results from surgical field preparation and
combined with meticulous and proactive anesthetic care will thereafter from skin incision and open wounds, particularly from
provide a means for maintaining normothermia in the vast large open body cavities (i.e., chest and abdomen) from which heat
majority of our patients. One should keep in mind that it is easier loss can be significant. Relative operating room humidity should
to keep patients warm from the start of anesthesia than to rewarm be kept in a range of 40 and 60%. Conductive heat loss should be
them later on. The vicious circle of hypothermia and its main minimal during surgery because the patient should not come in
adverse effects are presented in Figures 14–5 and 14–6, respectively. direct contact with cold objects. Maintaining the operating room
PREVENTING HYPOTHERMIA: OPERATING ROOM TEMPERATURE: temperature at a higher level is, therefore, a crucial step in the
The main mechanisms of heat loss during anesthesia are radi- prevention of hypothermia, particularly when the type of surgery
ation and convection. As mentioned in the section on Heat Loss requires the majority of the body surface to be exposed.
Mechanisms, radiant heat loss is a function of the temperature PREWARMING: Intensive skin-surface warming before the
difference between the patient and the surrounding objects. induction of anesthesia with a forced-air warming device will
Warming the operating room reduces the temperature gradient induce peripheral vasodilatation and equilibrate peripheral and
between the patient and the environment, thereby decreasing heat central compartment temperatures. This minimizes redistribution
loss via radiation. The efficiency of higher operating room tem- hypothermia and is an effective strategy to maintain intraop-
peratures to control the body temperature of newborns during erative normothermia.402–406 Although an effective and otherwise
surgery was demonstrated many years ago.397 Ideally, operating affordable technique to avoid hypothermia, in most cases, this
room temperatures should be kept at a minimum of 27°C for full- technique will require additional logistic organization and
Figure 14-5. Adverse effects of hypothermia in neonates. Hypothermia in neonates triggers norepinephrine secretion that results in
pulmonary and peripheral vasoconstriction, but also in activation of brown adipose tissue (BAT) for the generation of metabolic heat.
This cascade eventually results in a vicious circle that, if left untreated, may result in mortality in the infant.
Figure 14-6. Adverse effects of hypothermia. The cascade of events triggered by hypothermia that eventually may lead to an
increased rate of wound infections and delayed wound healing. Adapted from reference 506.
operating room personnel. An adult volunteer study found that in premature babies can increase significantly (up to 150%) when
neither sweating nor thermal discomfort limited heat transfer nursed under the radiant heater, although this should rarely be
during the first hour of prewarming and that half an hour of relevant in the anesthetic setting, in which the time exposed to the
forced-air warming enhanced peripheral tissue heat content (i.e., radiant heater is generally limited.408,409 In order to avoid skin
in arms and legs) by more than the amount of heat normally burns, the manufacturer recommended that minimal distance
redistributed during the first hour of anesthesia.405 However, from the patient’s skin must be respected.
although shivering may double the heat production, sweating may
dissipate more than 10 times the amount of normal basal heat REFLECTIVE BLANKETS: The effect of reflective blankets (i.e., an
production. Therefore, if the patient is sweaty after prewarming aluminized plastic foil designed to reflect ~80% of body heat) has
and her or his body surface is exposed to ambient air, significant produced conflicting results in adults, whereas data in the
evaporative heat losses may occur and eliminate the benefits of pediatric population are limited. However, it has been reported
prewarming. The prewarming technique could prove beneficial that normothermia can be maintained with reflective blankets if
for certain peripheral plastic reconstructive surgeries because 60% or more of the patient’s body surface area is covered.410 This
forearm capillary blood flow doubled or even tripled, depending device may have a place in the out-of-hospital trauma setting
on the settings on the forced-air warming device. In addition, (particularly in combination with other warming measures), but
thermoregulatory vasodilatation on the lower extremities resulted once in the hospital, other significantly more effective treatment
in significantly increased capillary blood flow in the calf and options are available to achieve or maintain normothermia.411–414
toes.405 Despite the active transfer of heat through the patient’s skin Drawbacks, mainly in the context of out-of-hospital care, included
via convection and radiation, central temperature remained the fact that a clothed body radiates only a small amount of heat
relatively constant or even slightly decreased in these patients.402– and the impermeability of the plastic foil to both water and water
406
This can be explained by the fact that these volunteers were vapor allows condensation to be formed on the blanket’s interior
awake (i.e., nonanesthetized), young, and healthy with fully within less than 20 minutes (especially when the ambient
functional thermoregulation. temperature is low). This condensation can potentially lead to wet
clothing with rapid conduction of heat away from the body. Once
RADIANT HEATERS: Radiant heaters are most commonly used the clothes are wet enough, the aluminum component becomes
during the induction of anesthesia when insertion of central effective and conducts heat about 10,000 times better than air
venous lines, arterial cannulae, and/or regional anesthesia (thermal conductivity 250 W/m × K for aluminum vs 0.024 W/m
catheters is planned. Extreme differences in radiant warmer × K for air).415
performances and energy transfer to the mattress surface can be In infants and children, nonevaporative cutaneous heat loss
found, which depend on heater-element composition, reflector can be reduced by almost 30% by simply covering the body
design, and heater-to-mattress distance.407 Insensible water losses with disposable surgical drapes.275 Therefore, the significance of
hypothermia prevention by covering the body should not be resulting in significant heat loss. This can best be avoided by using
underestimated. In general, the percentage of skin surface area self-adhesive plastic foils to cover the surgical field and the
covered is more important than the choice of insulating material surrounding drapes. That way, fluids are directed away from the
or the skin region covered.416 Even one layer of plastic over patient and the patient stays dry.
otherwise exposed body areas helps to limit radiant, conductive, WARMING OF FLUIDS: It is well established that the rapid infusion
and evaporative heat losses.417 Covering very low birthweight of large amounts of cold fluids can be used to induce hypothermia.
infants with a thin plastic layer reduces the requirement for The peripheral infusion of 2 L of normal saline solution at 4°C
radiant heat, oxygen consumption, and insensible water loss.418 over 20 to 30 minutes in cardiac arrest survivors assigned to the
By contrast, facial cooling has been shown to increase oxygen hypothermia treatment group resulted in a quick and reliable core
requirements by 23% and 36% in term and premature newborns, temperature drop of 1.4°C.429 Central venous infusion of 40 mL/kg
respectively.274 The particular importance of the head in regards to of normal saline at 4°C over 30 minutes to anesthetized and
thermoregulation in small infants has been discussed earlier in the paralyzed volunteers resulted in a temperature drop of 2.5°C, and
section on Thermal Regulation in the Newborn and is highlighted the researchers concluded that central venous infusion is more
by the fact that the head accounts for approximately 20% of the effective than peripheral injection.430 Similar results have been
total skin surface area in neonates and represents the area with the reported from a cardiac arrest survivor study for whom the
highest regional heat flux.275 administration of 30 mL/kg of lactated Ringer’s solution at 4°C
SKIN-WARMING DEVICES: A wide selection of passive and active was used to induce a rapid fall in temperature of 1.7°C.431
skin-surface warmers is available including circulating hot water Therefore, it is apparent that in order to maintain normothermia,
blankets, infrared radiant heaters, convective forced-air heaters, all intravenous fluids (including blood products) must be warmed,
and water-warming garments (WWGs). The forced-air warmers at least when infused rapidly and in large amounts.
use a disposable under- and/or overbody blanket blowing warm Various devices are available to prewarm infusions to the
air toward or over the patient’s skin, thereby raising the effective desired degree including specialized warmers combining fluid
ambient temperature immediately surrounding the patient.402 warming with a rapid infusion pump system that is able to manage
Newer versions using the same principle offer customizable, very high flow rates in excess of 1000 mL/min. However, to take
whole-body suits instead of blankets to maximize skin surface full advantage of the warming capabilities of these devices, heated
coverage. A different approach has been adopted for WWGs, or short extension tubing should be used because otherwise
which are based on the liquid-cooled space suits used by significant heat loss of the infusate during transit from the warm-
astronauts.419 With this system, the body is covered by a special ing device to the intravenous cannula may occur.432,433 At an ambi-
garment designed to allow maximal body surface coverage with- ent temperature of 20°C and warming of the intravenous fluid to
out impinging on the surgical field. Underneath this garment, 37°C, flow rates of at least 750 mL/h were required to keep the in-
warm water is circulated adjacent to the skin surface. The system fusate temperature above 32°C more than 25 cm from the warmer.
is computer-controlled using temperature probes for afferent At lower and more appropriate infusion rates for pediatric patients,
feedback algorithms to achieve a preset body temperature. This heat exchange with the environment is further aggravated.433
seems to be the most efficient system and its safety has also been A study in patients aged 1 to 3 years demonstrated that con-
demonstrated in children.420–422 The main advantage of the WWG servative fluid management (keeping the patients slightly hypo-
over a forced-air warming device seems to derive from the fact volemic preoperatively and intraoperatively) for minor surgical
that the WWG allows a larger body surface area to be covered and procedures could avoid core hypothermia (core temperature
37.1°C vs 36.4°C in patients who received more aggressive fluid
warmed (i.e., the part of the body the patient is lying on).422
therapy. In both groups, the fluid infusion temperature was
However, it seems that so far the favorable cost-efficiency ratio
37°C.434 However, despite this slight temperature advantage, this
and the ease of use of forced-air warming devices has limited the
should not preclude pediatric patients from appropriate fluid
widespread use of WWGs. In most cases, both these devices allow
resuscitation because other and more effective measures to
not only the maintenance of normothermia but also an effective
maintain normothermia are usually easily available.
means of rewarming a hypothermic patient.402,423–425 Although
Both the chest and the abdomen make up a large, well-perfused
the potential heat transfer rate is higher for circulating water
surface area and, therefore, allow for significant heat exchange
mattresses, they are less effective than forced-air warmers because
during intraoperative lavage of these cavities. To avoid profound
significant heat loss still occurs from the anterior body surface.402
and precipitous hypothermia, all irrigation fluids should be
They are an ideal supplement to a forced-air warming blanket, but warmed to body temperature before use.
used alone for long and major procedures, they often fail to
maintain normothermia. The author most often uses forced-air HUMIDIFYING AND HEATING AIRWAY GASES: High-efficiency
underbody blankets. To get the maximal benefit, one has to make particulate air filters (HEPA) commonly are made from glass
sure before skin incision that air is freely circulating in the blanket fibers suspended in a rigid frame and pleated to increase the
and that no body parts are in close proximity to the warm air inlet surface area and hence efficiency without significantly increasing
to avoid skin burns (particularly in infants and neonates).426–428 the resistance to air flow. Larger particles (>0.3 μm) are filtered by
In patients with low cardiac output, peripheral vascular artery inertial impaction and interception, whereas smaller particles are
disease, or otherwise compromised vascular circulation (e.g., captured by brownian diffusion.435 Particles with a diameter of
cross-clamping of the aorta for coarctation repair or vasocon- 0.3 μm (the typical diameter of bacteria) are the most likely to
strictor therapy), the device must be used only with extreme be deposited in the lungs if inhaled and are also the most difficult
caution and the “high” temperature setting should not be used for size to eliminate by filtration because at this size the effects of
a prolonged period of time. Another problem can be pooling of inertial impaction, interception, and brownian motion are least
fluids from the surgical field between the patient and the blanket effective.435
Heat and moisture exchangers (HMEs) usually contain a advantages of these devices on the humidification and tempera-
hydrophilic material (e.g., cellulose) and HME filters (HME with ture of inspired gases,173,450–454 but other studies have failed to
an antimicrobial filter [HMEF]) also contain a single pleated sheet demonstrate significant benefits in terms of maintaining body
of hydrophobic resin-bonded and electrostatically charged temperature, especially when high fresh gas flow rates were
ceramic filaments to eliminate microorganisms.436 In clinical used.455–457 In order to avoid thermal injury to the tracheobronchial
practice, the terms HME and HMEF are often used interchange- mucosa, active humidifiers should heat inspiratory gases to
ably. The HMEs/HMEFs are designed to retain moisture exhaled normal body temperature only. It has been known for decades that
by the patient, but they can contribute to airway humidification dry inspiratory gases cause a significant reduction in mucociliary
only if they are placed in the circuit in a way that bidirectional gas clearance and, hence, tracheal mucus flow and, therefore, may
flow occurs (i.e., at the Y piece or distal to it). Otherwise, the result in tracheobronchial injury.458–461 Humidification not only
HMEs/HMEFs may even facilitate drying of the absorber and prevents these adverse effects461,462 but also reduces respiratory
thereby increase the risk of carbon monoxide poisoning. heat losses.438,463 The in vivo performance of different HMEs/
In spontaneously breathing patients, the tracheobronchial tree HMEFs is variable and often does not correspond to the in vitro
acts as a natural heat and moist exchanger, ensuring that the air specifications declared by the manufacturers.464,465
reaching the alveoli is fully saturated with water vapor and has Fully saturated air at 37°C contains 43 to 44 g of water vapor/m3
body temperature. The warming of the air and its humidification air.466 Evidence demonstrates that a relative humidity of at least
in adults results in a heat loss reduction of approximately 5 to 50% is required to maintain normal mucociliary function and
10 W/h, which is rather small in perspective to the overall heat prevent bronchospasm and tracheobronchial injury.461,462,467 This
loss under anesthesia of about 70 to 80 W/h.437 Endotracheal latter value is easily achieved with heat- and moisture-exchanging
intubation significantly reduces the surface area of the respiratory filters. Although it would seem reasonable to strive to achieve the
tract available for heat and moisture exchange and renders same values as a spontaneously breathing person does (i.e.,
the system insufficient. Artificial heating and humidification inspiratory gas temperature of 37°C with 100% relative humidity),
of inspiratory gases is therefore required to minimize these recommendations for anesthesia fail to provide an evidence-based
convective (warming the air from ambient to body temperature) minimal absolute humidity with values varying from 14 to
and evaporative (humidification of the air) heat losses from the 44 g/m3.468–470 Other sources suggest a relative humidity above
respiratory tract and provide airway humidification at the same 50%, but more recent research advocates for values closer to 75 to
time.438 Humidity of an air-water mixture can be described as 100% with a temperature above 34°C for inspired gases to avoid
absolute humidity (the mass of vaporized water in 1 m3 of air, mucociliary dysfunction and/or tracheobronchial injury.471 This
usually expressed in grams per cubic meter [g/m3]) or relative level of humidification and temperature is currently not achieved
humidity (defined as the percentage of the partial pressure of by HMEs/HMEFs, especially not with high fresh gas flows. Using
water vapor in the air-water mixture compared with the saturated a low fresh gas flow of 0.6 L/min increased the absolute humidity
vapor pressure of water at a specific temperature). The exothermic of inspired gases more than fourfold (22.8 ± 2.4 g/m3 vs 5.6 ± 3.4
reaction of carbon dioxide with the absorber in anesthesia circuits g/m3) when compared with a high fresh gas flow of 6 L/min,
results in the condensation of water in the air exiting the absorber whereas the changes in body and inspired gas temperature were
canister. However, the addition of dry, fresh gases quickly not significantly different between the two groups.472 In adults, the
decreases the humidity of the inspired air, explaining the need for heating and humidification of inspiratory gases to 37°C and 100%
other means of humidification, particularly when using a fresh gas relative humidity not only maintained normothermia but also
flow that exceeds the upper flow limit for prevention drying of the reversed hypothermia during general surgery.
CO2 absorber (i.e., ~0.5–1.0 L/min).439–441 For HMEs/HMEFs to The higher minute ventilation per kilogram body weight in the
maintain a humidity of greater than 20 mg/L, the fresh gas flow pediatric population makes humidification and warming of
has to be below 2 to 3 L/min.442,443 inspiratory gases not only more important but also more effective
Humidification can be either active (i.e., a heated device filled than in adults.173,473 Heat loss in newborns during general anes-
with water is used to create vaporized or nebulized water) or thesia is reduced significantly when heated, humidified gases
passive (i.e., with a so-called HMEF, or “artificial nose” ). An are used instead of dry anesthetic gases.474 By design, all HMEs/
interesting hybrid device has been described based on an HME HMEFs increase apparatus deadspace (although neonatal humid-
with computer-controlled addition of water to the filter resulting ifiers [HMEs] are now available with a deadspace of < 2 mL,
in 100% relative humidity444; however, the combination of active whereas for HMEFs with an antimicrobial filter are available
humidification and HME may result in filter obstruction.445,446 with a deadspace of 12–15 mL). These may result in the under-
Producing water vapor by directing air over (pass-over humidifier) estimation of arterial CO2 partial pressure when relying on end-
or through (bubble-through humidifier) heated water are the tidal CO2 measurement, particularly in small children breathing
physical principles behind vaporizers, whereas nebulizers produce spontaneously. They may also require an increase in the venti-
tiny droplets of water either by ultrasound (droplet diameter lation parameters settings.475–477 A typical HME/HMEF creates an
1–10 mm) or by a high-velocity gas jet through water entrained additional pressure gradient of approximately 1.0 to 2.0 cmH2O
with the Bernoulli effect (droplet diameter 5––30 mm). The size at a fresh gas flow of 30 to 60 L/min leading to a slight increase in
of the water droplets determines how deep they will penetrate into airway resistance, which is less of an issue during mechanical
the airway. Droplets between 1 and 3 mm in diameter are small ventilation, but becomes more important with spontaneous venti-
enough to reach the bronchioles and are considered an ideal lation such as may occur when weaning infants from mechanical
size.447 Active humidifiers require proper care and sterilization to ventilation or during the emergence from anesthesia.478–480 With a
avoid infections. In general, the active humidifiers achieve better Mapleson F system, this resistance increase may result in up to
humidification than HMEs,173,448 although the differences are not 50% of the fresh gas flow being forced into the expiratory limb
always clinically significant.449 Several studies have confirmed the thereby prolonging inhalational induction.481,482
Despite the overall better efficiency of active humidifiers, SUMMARY

HMEs/HMEFs have replaced them in the majority of hospitals
mainly because of their simplicity in handling, acceptable effec- In order to maintain central body temperature within its narrow
tiveness, active bacterial filtration capabilities, and reduced normal range of 37.0 ± 0.2°C, a highly sophisticated and efficient
workload and costs.461,483,484 Additional advantages of HMEs/ regulation system is in place. It utilizes peripheral vasoconstriction
HMFEs include eliminating the risks of airway burns and and shivering and nonshivering thermogenesis to preserve and/
overhumidification with overhydration.485,486 However, despite or generate body heat, whereas peripheral vasodilatation and
their simplicity, HMEs/HMEFs are not without adverse effects and sweating are triggered to result in heat loss. Except for shivering
risks. The addition of a HME/HMEF introduces more connection thermogenesis, all these mechanisms are already functional in
sites in the breathing circuit and, therefore, poses the increased neonates. However, because of anatomic differences, small infants
risk for disconnection. The connection between the endotracheal and children are at a higher risk for temperature disturbances than
tube and the HME/HMEF seems to be a common site of discon- older patients both in and out of the operating room. Anesthesia
nection, which has resulted in a number of incidents, some of alters thermoregulation and results in significant widening of the
them fatal.487,488 As mentioned in the section on Humidifying and interthreshold range (the temperature range within which no
Heating Airway Gases, if positioned in the expiratory limb of the compensatory thermoregulatory actions are triggered). Without
circuit, HMEs/HMEFs may facilitate drying of the CO2-absorber preventive measures, heat loss during anesthesia exceeds met-
resulting in increased carbon monoxide generation and delayed abolic heat generation, which may result in hypothermia and
inhalational induction, because it has been demonstrated that a the myriad of potential adverse effects associated with it. In
dry absorber increases not only the absorption of inhalational modern anesthesia practice, several options compensate for the
anesthetics but also the amount of their degradation that may increased thermal losses in order to maintain perioperative
result in an overall reduced concentration of volatile agent normothermia. This chapter has reviewed the physiology and
delivered to the patient.489,490 pathophysiology of thermoregulation, heat loss mechanisms, and
A HME with an antimicrobial filter (i.e., a HMEF) has the options to avoid or reduce them. Furthermore, the specific effects
potential to block the passage of microorganisms and its efficiency of anesthetic agents on thermoregulation in relation to the patient’s
is described by the percentage of particles being able to penetrate age as well as the adverse effects of temperature disturbances have
the filter and potentially reach the patients airway (some been presented.
manufacturers give separate numbers for viral and bacterial
particles). In other words, an efficiency of 99.9997% translates into
three particles out of a million being able to pass beyond the filter. REFERENCES
Although this represents an impressive barrier, it seems not to be 1. Wunderlich KRA. The course of temperature in disease: a guide to
enough to protect the circuit from contamination, and most groups clinical thermometry. Am J Med Sci. 1869;57:425–447.
advocate to changing the circuit and HMEF after each patient.491,492 2. Sund-Levander M, Forsberg C, Wahren LK. Normal oral, rectal,
Other investigators consider HMEFs to be efficient enough that the tympanic and axillary body temperature in adult men and women: a
circuit can be reused at least twice.493,494 Beside their antimicrobial systematic literature review. Scand J Caring Sci. 2002;16:122–128.
characteristics, HMEs/HMEFs also efficiently filter latex particles.495 3. American Society of Anesthesiologists. Standards for Basic Anesthetic
Severe or complete obstruction of HMEs/HMEFs with dif- Monitoring. 2005. Available at: www.asahq.org/publicationsAnd
ficulties or even the inability to ventilate can result from copious Services/standards/02.pdf Accessed June 2, 2010.
secretions in patients with chronic obstructive pulmonary disease 4. Australian and New Zealand College of Anaesthetists. Recom-
mendations on Monitoring During Anaesthesia. 2006. Available
or mucoviscidosis, pulmonary edema, the use of nebulized
at: http://www.anzca.edu.au/resources/professional-documents/
medications (e.g., albuterol), simultaneous administration of
professional-standards/ps18.html Accessed June 2, 2010.
humidified air (e.g., by an active humidifier), or HME/HMEF 5. La Société Française d’Anesthésie et de Réanimation. Recomman-
manufacturing problems (e.g., retained foreign body in dations Concernant la Surveillance des Patients en Cours d’Anesthésie.
HME).445,446,488,496–501 In at least two cases, a blocked HME/HMEF 1994. Available at: http://www.sfar.org/recomperop.html Accessed
caused bilateral pneumothoraces.502,503 It has, therefore, been June 2, 2010.
recommended that HMEs/HMEFs should not be used in 6. Canadian Anesthesiologists’ Society. 2007. Available at: http://www.
combination with active humidifiers and only with extreme cas.ca/members/sign_in/guidelines/practice_of_anesthesia/default.as
caution in patients with one of these conditions. In addition, it is p?load=patient_monitoring Accessed June 2, 2010.
recommended that easy access and visibility of the HME/HMEF 7. Schweizerische Gesellschaft für Anästhesiologie und Reanimation.
be ensured throughout the procedure.435 SGAR: Standards und Empfehlungen. 2002. Available at: http://www.
sgar-ssar.ch/Standards-und-Empfehlungen.90.html?&0= Accessed
PATIENT TRANSPORT: Although we have focused on the intra- June 2, 2010.
operative care of patients, measures to prevent hypothermia are 8. Leon JE, Bissonnette B, Lerman J. Liquid crystalline temperature
equally important during patient transport. Patients should be monitoring: does it estimate core temperature in anaesthetized
appropriately covered during any transport. For older children paediatric patients? Can J Anaesth. 1990;37:S98.
and adults, a warm blanket may be sufficient; however, neonates 9. MacKenzie R, Asbury AJ. Clinical evaluation of liquid crystal skin
thermometers. Br J Anaesth. 1994;72:246–249.
and particularly premature babies should, whenever possible,
10. Burgess GE 3rd, Cooper JR, Marino RJ, et al. Continuous monitoring
be transported in a prewarmed incubator. If an incubator is of skin temperature using a liquid-crystal thermometer during
not available, chemical heating pads can be used to maintain anesthesia. South Med J. 1978;71:516–518.
normothermia or even rewarm a small patient. Even a short in- 11. Allen GC, Horrow JC, Rosenberg H. Does forehead liquid crystal
hospital transport may be all it takes to ruin all of the successful temperature accurately reflect “core” temperature? Can J Anaesth.
intraoperative efforts to maintain normothermia. 1990;37:659–662.
12. Leon C, Rodriguez A, Fernandez A, et al. Infrared ear thermometry 36. Puhakka K, Anttonen H, Niskanen J, et al. Calculation of mean skin
in the critically ill patient. J Crit Care. 2005;20:106–110. temperature and changes in body heat content during paediatric
13. Heusch AI, McCarthy PW. The patient: a novel source of error in anaesthesia. Br J Anaesth. 1994;72:548–553.
clinical temperature measurement using infrared aural thermometry. 37. Sessler DI. Malignant hyperthermia. J Pediatr. 1986;109:9–14.
J Altern Complement Med. 2005;11:473–476. 38. Benzinger M. Tympanic thermometry in surgery and anesthesia.
14. Bock M, Hohlfeld U, von Engeln K, et al. The accuracy of a new JAMA. 1969;209:1207–1211.
infrared ear thermometer in patients undergoing cardiac surgery. 39. Bissonnette B, Holtby HM, Davis AJ, et al. Cerebral hyperthermia in
Can J Anaesth. 2005;52:1083–1087. children after cardiopulmonary bypass. Anesthesiology. 2000;93:
15. Dodd SR, Lancaster GA, Craig JV, et al. In a systematic review, 611–618.
infrared ear thermometry for fever diagnosis in children finds poor 40. Muma BK, Treloar DJ, Wurmlinger K, et al. Comparison of rectal,
sensitivity. J Clin Epidemiol. 2006;59:354–357. axillary, and tympanic membrane temperatures in infants and young
16. El-Radhi AS, Patel S. An evaluation of tympanic thermometry in a children. Ann Emerg Med. 1991;20:41–44.
paediatric emergency department. Emerg Med J. 2006;23:40–41. 41. Tabor MW, Blaho DM, Schriver WR. Tympanic membrane per-
17. Hissink Muller PC, van Berkel LH, de Beaufort AJ. Axillary and rectal foration: complication of tympanic thermometry during general
temperature measurements poorly agree in newborn infants. anesthesia. Oral Surg Oral Med Oral Pathol. 1981;51:581–583.
Neonatology. 2008;94:31–34. 42. Wallace CT, Marks WE Jr, Adkins WY, et al. Perforation of the
18. Lawson L, Bridges EJ, Ballou I, et al. Accuracy and precision of tympanic membrane: a complication of tympanic thermometry
noninvasive temperature measurement in adult intensive care during anesthesia. Anesthesiology. 1974;41:290–291.
patients. Am J Crit Care. 2007;16:485–496. 43. Giuliano KK, Scott SS, Elliot S, et al. Temperature measurement in
19. Moran JL, Peter JV, Solomon PJ, et al. Tympanic temperature critically ill orally intubated adults: a comparison of pulmonary artery
measurements: are they reliable in the critically ill? A clinical study of core, tympanic, and oral methods. Crit Care Med. 1999;27:2188–
measures of agreement. Crit Care Med. 2007;35:155–164. 2193.
20. Amoateng-Adjepong Y, Del Mundo J, Manthous CA. Accuracy of an 44. Stoen R, Sessler DI. The thermoregulatory threshold is inversely
infrared tympanic thermometer. Chest. 1999;115:1002–1005. proportional to isoflurane concentration. Anesthesiology. 1990;72:
21. Childs C, Harrison R, Hodkinson C. Tympanic membrane temperature 822–827.
as a measure of core temperature. Arch Dis Child. 1999;80:262–266. 45. Mekjavic IB, Rempel ME. Determination of esophageal probe
22. M. Imamura, T. Matsukawa, M. Ozaki, et al. The accuracy and insertion length based on standing and sitting height. J Appl Physiol.
precision of four infrared aural canal thermometers during cardiac 1990;69:376–379.
surgery. Acta Anaesthesiol Scand. 1998;42:1222–1226. 46. Maxton FJ, Justin L, Gillies D. Estimating core temperature in infants
23. Craig JV, Lancaster GA, Taylor S, et al. Infrared ear thermometry and children after cardiac surgery: a comparison of six methods.
compared with rectal thermometry in children: a systematic review. J Adv Nurs. 2004;45:214–222.
Lancet. 2002;360:603–609. 47. Ash CJ, Cook JR, McMurry TA, et al. The use of rectal temperature
24. Jensen BN, Jensen FS, Madsen SN, et al. Accuracy of digital tympanic, to monitor heat stroke. Mo Med. 1992;89:283–288.
oral, axillary, and rectal thermometers compared with standard rectal 48. Greenes DS, Fleisher GR. When body temperature changes, does
mercury thermometers. Eur J Surg. 2000;166:848–851. rectal temperature lag? J Pediatr. 2004;144:824–826.
25. Siberry GK, Diener-West M, Schappell E, et al. Comparison of temple 49. Brauer A, Martin JD, Schuhmann MU, et al. accuracy of intraoperative
temperatures with rectal temperatures in children under two years urinary bladder temperature monitoring during intra-abdominal
of age. Clin Pediatr (Phila). 2002;41:405–414. operations. Anasthesiol Intensivmed Notfallmed Schmerzther. 2000;35:
26. Suleman MI, Doufas AG, Akca O, et al. Insufficiency in a new 435–439.
temporal-artery thermometer for adult and pediatric patients. Anesth 50. Schuhmann MU, Suhr DF, von Gosseln HH, et al. Local brain surface
Analg. 2002;95:67–71, table of contents. temperature compared to temperatures measured at standard
27. Greenes DS, Fleisher GR. Accuracy of a noninvasive temporal artery extracranial monitoring sites during posterior fossa surgery.
thermometer for use in infants. Arch Pediatr Adolesc Med. 2001; J Neurosurg Anesthesiol. 1999;11:90–95.
155:376–381. 51. Horrow JC, Rosenberg H. Does urinary catheter temperature reflect
28. Hebbar K, Fortenberry JD, Rogers K, et al. Comparison of temporal core temperature during cardiac surgery? Anesthesiology. 1988;69:
artery thermometer to standard temperature measurements in 986–989.
pediatric intensive care unit patients. Pediatr Crit Care Med. 2005; 52. Budin P. The nursling. (1907).
6:557–561. 53. Dunn PM. Stephane Tarnier (1828–1897), the architect of peri-
29. Myny D, De Waele J, Defloor T, et al. Temporal scanner thermometry: natology in France. Arch Dis Child Fetal Neonatal Ed. 2002;86:
a new method of core temperature estimation in ICU patients. Scott F137–9.
Med J. 50 (2005), 15–8. 54. Silverman W, Blanc W. Effects of humidity on survival of newly born
30. Colin J, Timbal J, Boutelier C. experimental determination of the premature infants. Pediatrics. 1957;22:477–486.
equation permitting the calculation of the mean body temperature 55. Silverman W, Fertig J, Bergen A. Influence of thermal environment
in neutral and hot environment. J Physiol (Paris). 1971;63:229–231. upon survival of newly born premature infants. Pediatrics. 1958;
31. Cork RC, Vaughan RW, Humphrey LS. Precision and accuracy of 22:876.
intraoperative temperature monitoring. Anesth Analg. 1983;62: 56. Brück K. Temperature regulation in the newborn infant. Biol Neonate.
(211–4). 1961;3:65.
32. Bissonnette B, Sessler DI, LaFlamme P. Intraoperative temperature 57. Cross KW, Tizard JP, Trythall DA. The gaseous metabolism of the
monitoring sites in infants and children and the effect of inspired gas newborn infant breathing 15% oxygen. Acta Paediatr. 1958;47:217–
warming on esophageal temperature. Anesth Analg. 1989;69:192–196. 237.
33. Lacoumenta S, Hall GM. Liquid crystal thermometry during 58. Weinert D, Waterhouse J. The circadian rhythm of core temperature:
anaesthesia. Anaesthesia. 1984;39:54–56. effects of physical activity and aging. Physiol Behav. 2007;90:246–256.
34. Ramanathan NL. A new weighting system for mean surface 59. Refinetti R, Menaker M. The circadian rhythm of body temperature.
temperature of the human body. J Appl Physiol. 1964;19:531–533. Physiol Behav. 1992;51:613–637.
35. Shanks CA. Mean skin temperature during anaesthesia: an 60. Aizawa S, Cabanac M. The influence of temporary semi-supine and
assessment of formulae in the supine surgical patient. Br J Anaesth. supine postures on temperature regulation in humans. J Therm Biol.
1975;47:871–875. 2002;27:109–114.
61. Sitka U, Weinert D, Berle K, et al. Investigations of the rhythmic 87. Griffin JD, Saper CB, Boulant JA. Synaptic and morphological cha-
function of heart rate, blood pressure and temperature in neonates. racteristics of temperature-sensitive and -insensitive rat hypothala-
Eur J Pediatr. 1994;153:117–122. mic neurones. J Physiol. 2001;537:521–535.
62. Weinert D, Sitka S, Minors DS, et al. The development of circadian 88. Newman HM, Stevens RT, Apkarian AV. Direct spinal projections to
rhythmicity in neonates. Early Hum Dev. 1994;36:117–126. limbic and striatal areas: anterograde transport studies from the
63. Van Someren EJ. More than a marker: interaction between the upper cervical spinal cord and the cervical enlargement in squirrel
circadian regulation of temperature and sleep, age-related changes, monkey and rat. J Comp Neurol. 1996;365:640–658.
and treatment possibilities. Chronobiol Int. 2000;17:313–354. 89. Caterina MJ. Transient receptor potential ion channels as
64. Van Someren EJ. Thermoregulation as a sleep signaling system. Sleep participants in thermosensation and thermoregulation. Am J Physiol
Med Rev. 2004;8:327; author reply 327–8. Regul Integr Comp Physiol. 2007;292:R64-76.
65. Raymann RJ, Swaab DF, Van Someren EJ. Cutaneous warming 90. Ni D, Gu Q, Hu HZ, et al. Thermal sensitivity of isolated vagal
promotes sleep onset. Am J Physiol Regul Integr Comp Physiol. pulmonary sensory neurons: role of transient receptor potential
2005;288:R1589–97. vanilloid receptors. Am J Physiol Regul Integr Comp Physiol.
66. Waterhouse J, Folkard S, Van Dongen H, et al. Temperature profiles, 2006;291:R541–50.
and the effect of sleep on them, in relation to morningness- 91. Wechselberger M, Wright CL, Bishop GA, et al. Ionic channels and
eveningness in healthy female subjects. Chronobiol Int. 2001;18: conductance-based models for hypothalamic neuronal thermo-
227–247. sensitivity. Am J Physiol Regul Integr Comp Physiol. 2006;291:
67. Waterhouse J, Weinert D, Minors D, et al. The effect of activity on R518–29.
the waking temperature rhythm in humans. Chronobiol Int. 1999; 92. Benarroch EE. Thermoregulation: recent concepts and remaining
16:343–357. questions. Neurology. 2007;69:1293–1297.
68. Weinert D. Age-dependent changes of the circadian system. 93. Nagashima K, Nakai S, Tanaka M, et al. Neuronal circuitries
Chronobiol Int. 2000;17:261–283. involved in thermoregulation. Auton Neurosci. 2000;85:18–25.
69. Mirmiran M, Kok JH. Circadian rhythms in early human 94. Hori T, Katafuchi T. Cell biology and the functions of thermo-
development. Early Hum Dev. 1991;26:121–128. sensitive neurons in the brain. Prog Brain Res. 1998;115:9–23.
70. Brown PJ, Dove DA, Tuffnell CS, et al. Oscillations of body 95. Nakayama T, Hammel HT, Hardy JD, et al. Thermal stimulation of
temperature at night. Arch Dis Child. 1992;67:1255–1258. electrical activity of single units of the preoptic region. Am J Physiol.
71. Mirmiran M, Kok JK, de Kleine MJ, et al. Circadian rhythms in 1963;204:1122–1126.
preterm infants: a preliminary study. Early Hum Dev. 1990;23:139–146. 96. Chen XM, Hosono T, Yoda T, et al. Efferent projection from the
72. Reppert SM, Weaver DR, Rivkees SA, et al. Putative melatonin preoptic area for the control of non-shivering thermogenesis in rats.
receptors in a human biological clock. Science. 1988;242:78–81. J Physiol. 1998;512:883–892.
73. Hardy JD. Physiology of temperature regulation. Physiol Rev. 97. Zhang YH, Yanase-Fujiwara M, Hosono T, et al. Warm and cold
1961;41:521–606. signals from the preoptic area: which contribute more to the control
74. ickering G. Regulation of body temperature in health and disease. of shivering in rats? J Physiol. 1995;485:195–202.
Lancet. 1958;1:59–64. 98. Boulant JA. Neuronal basis of Hammel’s model for set-point
75. Gilbert M, Busund R, Skagseth A, et al. Resuscitation from accidental thermoregulation. J Appl Physiol. 2006;100:1347–1354.
hypothermia of 13.7 degrees C with circulatory arrest. Lancet. 99. Zhao Y, Boulant JA. Temperature effects on neuronal membrane
2000;355:375–376. potentials and inward currents in rat hypothalamic tissue slices.
76. Lepock JR. Cellular effects of hyperthermia: relevance to the J Physiol. 2005;564:245–257.
minimum dose for thermal damage. Int J Hyperthermia. 2003;19: 100. Hammel HT. In: Yamamoto WS, Brobeck JR, editors. Physiological
252–266. Controls and Regulations. Philadelphia: WB Saunders; 1965. pp.
77. Iwagami Y. Changes in the ultrastructure of human cells related to 71–97.
certain biological responses under hyperthermic culture conditions. 101. Cabanac M. Adjustable set point: To honor Harold T. Hammel.
Hum Cell. 1996;9:353–366. J Appl Physiol. 2006;100:1338–1346.
78. Shanks CA. Heat balance during surgery involving body cavities. 102. Caputa M. Comments on Do fever and anapyrexia exist? Analysis of
Anaesth Intensive Care. 1975;3:114–117. set point–based definitions. Am J Physiol Regul Integr Comp Physiol.
79. Poulos DA. Central processing of cutaneous temperature informa- 2005;289:R281; author reply R281–2.
tion. Fed Proc. 1981;40:2825–2829. 103. Romanovsky AA. Do fever and anapyrexia exist? Analysis of set
80. Wyss CR, Brengelmann GL, Johnson JM, et al. Altered control of skin point–based definitions. Am J Physiol Regul Integr Comp Physiol.
blood flow at high skin and core temperatures. J Appl Physiol. 1975; 2004;287:R992–5.
38:839–845. 104. Romanovsky AA. Vioxx, celebrex, bextra…do we have a new target
81. Nomoto S, Shibata M, Iriki M, et al. Role of afferent pathways of heat for anti-inflammatory and antipyretic therapy? Am J Physiol Regul
and cold in body temperature regulation. Int J Biometeorol. 2004; Integr Comp Physiol. 2005;288:R1098–9.
49:67–85. 105. Mekjavic IB, Eiken O. Contribution of thermal and nonthermal
82. Asami T, Hori T, Kiyohara T, et al. Convergence of thermal signals on factors to the regulation of body temperature in humans. J Appl
the reticulospinal neurons in the midbrain, pons and medulla Physiol. 2006;100:2065–2072.
oblongata. Brain Res Bull. 1988;20:581–596. 106. Kobayashi S. Temperature-sensitive neurons in the hypothalamus:
83. Romanovsky AA. Thermoregulation: some concepts have changed. A new hypothesis that they act as thermostats, not as transducers.
Functional architecture of the thermoregulatory system. Am J Physiol Prog Neurobiol. 32 (1989), 103–35.
Regul Integr Comp Physiol. 2007;292:R37–46. 107. Cheung SS, Mekjavic IB. Human temperature regulation during
84. Craig AD. How do you feel? Interoception: the sense of the subanesthetic levels of nitrous oxide-induced narcosis. J Appl
physiological condition of the body. Nat Rev Neurosci. 2002;3: Physiol. 1995;78:2301–2308.
655–666. 108. Lenhardt R, Greif R, Sessler DI, et al. Relative contribution of skin
85. Craig AD. Interoception: the sense of the physiological condition of and core temperatures to vasoconstriction and shivering thresholds
the body. Curr Opin Neurobiol. 2003;13:500–505. during isoflurane anesthesia. Anesthesiology. 1999;91:422–429.
86. Cliffer KD, Burstein R, Giesler GJ Jr. Distributions of spinothalamic, 109. Matsukawa T, Kurz A, Sessler DI, et al. Propofol linearly reduces the
spinohypothalamic, and spinotelencephalic fibers revealed by vasoconstriction and shivering thresholds. Anesthesiology. 1995;
anterograde transport of pha-l in rats. J Neurosci. 1991;11:852–868. 82:1169–1180.
110. Jessen C, Feistkorn G. Some characteristics of core temperature 134. Tripathi A, Nadel ER. Forearm skin and muscle vasoconstriction
signals in the conscious goat. Am J Physiol. 1984;247:R456–64. during lower body negative pressure. J Appl Physiol. 1986;60:1535–
111. Jessen C, Mayer ET. Spinal cord and hypothalamus as core sensors 1541.
of temperature in the conscious dog. I. Equivalence of responses. 135. Sessler DI, McGuire J, Moayeri A, et al. Isoflurane-induced
Pflugers Arch. 1971;324:189–204. vasodilation minimally increases cutaneous heat loss. Anesthesiology.
112. Mercer JB, Jessen C. Central thermosensitivity in conscious goats: 1991;74:226–232.
hypothalamus and spinal cord versus residual inner body. Pflugers 136. Armstrong LE, Hubbard RW, Jones BH, et al. Preparing Alberto
Arch. 1978;374:179–186. Salazar for the heat of the 1984 Olympic marathon. Phys Sportsmed.
113. Simon E. Temperature regulation: the spinal cord as a site of 14 (1986), 73– 81.
extrahypothalamic thermoregulatory functions. Rev Physiol Biochem 137. Godek SF, Bartolozzi AR, Burkholder R, et al. Sweat rates and fluid
Pharmacol. 1974;71:1–76. turnover in professional football players: A comparison of national
114. Hillman PE, Scott NR, van Tienhoven A. Vasomotion in chicken football league linemen and backs. J Athl Train. 2008;43:184–189.
foot: dual innervation of arteriovenous anastomoses. Am J Physiol. 138. Smiles KA, Elizondo RS, Barney CC. Sweating responses during
1982;242:R582–90. changes of hypothalamic temperature in the rhesus monkey. J Appl
115. Hales JRS. In: Johansen K, Burggren W, editors. Cardiovascular Physiol. 1976;40:653–657.
Shunts: Phylogenetic, Ontogenetic and Clinical Aspects. Copenhagen: 139. Vanbeaumont W, Bullard RW. Sweating: direct influence of skin
Munksgaard; 1985. pp. 433–51. temperature. Science. 1965;147:1465–1467.
116. Johnson JM. Nonthermoregulatory control of human skin blood 140. Li J, Fu X, Sun X, et al. The interaction between epidermal growth
flow. J Appl Physiol. 1986;61:1613–1622. factor and matrix metalloproteinases induces the development of
117. Brengelmann GL, Freund PR, Rowell LB, et al. Absence of active sweat glands in human fetal skin. J Surg Res. 2002;106:258–263.
cutaneous vasodilation associated with congenital absence of sweat 141. Fu X, Li J, Sun X, et al. Epidermal stem cells are the source of sweat
glands in humans. Am J Physiol. 1981;240:H571–5. glands in human fetal skin: evidence of synergetic development of
118. Kellogg DL Jr. In vivo mechanisms of cutaneous vasodilation and stem cells, sweat glands, growth factors, and matrix metallopro-
vasoconstriction in humans during thermoregulatory challenges. teinases. Wound Repair Regen. 2005;13:102–108.
J Appl Physiol. 2006;100:1709–1718. 142. Harpin VA, Rutter N. Development of emotional sweating in the
119. Kamijo Y, Lee K, Mack GW. Active cutaneous vasodilation in resting newborn infant. Arch Dis Child. 1982;57:691–695.
humans during mild heat stress. J Appl Physiol. 2005;98:829–837. 143. Harpin VA, Rutter N. Sweating in preterm babies. J Pediatr.
120. Sugenoya J, Ogawa T, Jmai K, et al. Cutaneous vasodilatation 1982;100:614–619.
responses synchronize with sweat expulsions. Eur J Appl Physiol 144. Sulyok E, Jequier E, Prod’hom LS. Thermal balance of the newborn
Occup Physiol. 1995;71:33–40. infant in a heat-gaining environment. Pediatr Res. 1973;7:888–900.
121. Kellogg DL Jr, Crandall CG, Liu Y, et al. Nitric oxide and cutaneous 145. Kondo N, Shibasaki M, Aoki K, et al. Function of human eccrine
active vasodilation during heat stress in humans. J Appl Physiol. sweat glands during dynamic exercise and passive heat stress. J Appl
1998;85:824–829. Physiol. 2001;90:1877–1881.
122. Wilkins BW, Chung LH, Tublitz NJ, et al. Mechanisms of vasoactive 146. Randall WC. Quantitation and regional distribution of sweat glands
intestinal peptide–mediated vasodilation in human skin. J Appl in man. J Clin Invest. 1946;25:761–767.
Physiol. 2004;97:1291–1298. 147. Buono MJ. Limb vs trunk sweat gland recruitment patterns during
123. Bennett LA, Johnson JM, Stephens DP, et al. Evidence for a role for exercise in humans. J Therm Biol. 2000;25:263–266.
vasoactive intestinal peptide in active vasodilatation in the 148. Foster KG, Hey EN, Katz G. The response of the sweat glands of the
cutaneous vasculature of humans. J Physiol. 2003;552:223–232. newborn baby to thermal stimuli and to intradermal acetylcholine.
124. Wong BJ, Wilkins BW, Minson CT. H1 but not H2 histamine J Physiol. 1969;203:13–29.
receptor activation contributes to the rise in skin blood flow 149. Shibasaki M, Wilson TE, Crandall CG. Neural control and
during whole body heating in humans. J Physiol. 2004;560: mechanisms of eccrine sweating during heat stress and exercise.
941–948. J Appl Physiol. 2006;100:1692–1701.
125. Shastry S, Minson CT, Wilson SA, et al. Effects of atropine and 150. Falk B, Bar-Or O, Calvert R, et al. Sweat gland response to exercise
L-name on cutaneous blood flow during body heating in humans. in the heat among pre-, mid-, and late-pubertal boys. Med Sci Sports
J Appl Physiol. 2000;88:467–472. Exerc. 1992;24:313–319.
126. Pergola PE, Kellogg DL Jr, Johnson JM, et al. Role of sympathetic 151. Sato K, Sato F. Individual variations in structure and function of
nerves in the vascular effects of local temperature in human forearm human eccrine sweat gland. Am J Physiol. 1983;245:R203–8.
skin. Am J Physiol. 1993;265:H785–92. 152. Araki T, Toda Y, Matsushita M, et al. Age differences in sweating
127. Holzer P. Neurogenic vasodilatation and plasma leakage in the skin. during muscular exercise. Jpn J Fitness Sports Med. 1979;28:239–248.
Gen Pharmacol. 1998;30:5–11. 153. Low PA. Evaluation of sudomotor function. Clin Neurophysiol.
128. Rowell LB. Human cardiovascular adjustments to exercise and 2004;115:1506–1513.
thermal stress. Physiol Rev. 1974;54:75–159. 154. Nakamura K, Matsumura K, Hubschle T, et al. Identification
129. Johnson JM, Brengelmann GL, Hales JR, et al. Regulation of the of sympathetic premotor neurons in medullary raphe regions
cutaneous circulation. Fed Proc. 1986;45:2841–2850. mediating fever and other thermoregulatory functions. J Neurosci.
130. Johnson JM, O’Leary DS, Taylor WF, et al. Effect of local warming 2004;24:5370–5380.
on forearm reactive hyperaemia. Clin Physiol. 1986;6:337–346. 155. Sato K, Kang WH, Saga K, et al. Biology of sweat glands and their
131. Crandall CG, Johnson JM, Kosiba WA, et al. Baroreceptor control of disorders. I. Normal sweat gland function. J Am Acad Dermatol.
the cutaneous active vasodilator system. J Appl Physiol. 1996;81: 1989;20:537–563.
2192–2198. 156. Reddy MM, Bell CL. Distinct cellular mechanisms of cholinergic
132. Kellogg DL Jr, Johnson JM, Kosiba WA. Baroreflex control of the and beta-adrenergic sweat secretion. Am J Physiol. 1996;271:
cutaneous active vasodilator system in humans. Circ Res. 1990;66: C486–94.
1420–1426. 157. Shamsuddin AK, Reddy MM, Quinton PM. Iontophoretic (beta)-
133. Rowell LB, Wyss CR, Brengelmann GL. Sustained human skin and adrenergic stimulation of human sweat glands: possible assay for
muscle vasoconstriction with reduced baroreceptor activity. J Appl cystic fibrosis transmembrane conductance regulator activity in
Physiol. 1973;34:639–643. vivo. Exp Physiol. 2008;93:969–981.
158. Nicolaidis S, Sivadjian J. High-frequency pulsatile discharge of 183. Pflug AE, Aasheim GM, Foster C, et al. Prevention of post-
human sweat glands: myoepithelial mechanism. J Appl Physiol. anaesthesia shivering. Can Anaesth Soc J. 1978;25:43–49.
1972;32:86–90. 184. Ciofolo MJ, Clergue F, Devilliers C, et al. Changes in ventilation,
159. Sato K, Nishiyama A, Kobayashi M. Mechanical properties and oxygen uptake, and carbon dioxide output during recovery from
functions of the myoepithelium in the eccrine sweat gland. Am J isoflurane anesthesia. Anesthesiology. 1989;70:737–741.
Physiol. 1979;237:C177–84. 185. Horvath SM, Spurr GB, Hutt BK, et al. Metabolic cost of shivering.
160. Schulz IJ. Micropuncture studies of the sweat formation in cystic J Appl Physiol. 1956;8:595–602.
fibrosis patients. J Clin Invest. 1969;48:1470–1477. 186. Eyolfson DA, Tikuisis P, Xu X, et al. Measurement and prediction
161. Nadel ER, Bullard RW, Stolwijk JA. Importance of skin temperature of peak shivering intensity in humans. Eur J Appl Physiol. 2001;84:
in the regulation of sweating. J Appl Physiol. 1971;31:80–87. 100–106.
162. Burton AC. The average temperature of the tissues of the body. 187. Frank SM, Fleisher LA, Olson KF, et al. Multivariate determinants
J Nutr. 1935;9:261–280. of early postoperative oxygen consumption in elderly patients.
163. Lenhardt R, Sessler DIL. Estimation of mean body temperature Effects of shivering, body temperature, and gender. Anesthesiology.
from mean skin and core temperature. Anesthesiology. 2006;105: 1995;83:241–249.
1117–1121. 188. Pauca AL, Dripps RD. Clinical experience with isoflurane (forane):
164. Snellen JW. An improved estimation of mean body temperature preliminary communication. Br J Anaesth. 1973;45:697–703.
using combined direct calorimetry and thermometry. Eur J Appl 189. Kurz A, Plattner O, Sessler DI, et al. The threshold for thermoregu-
Physiol. 2000;82:188–196. latory vasoconstriction during nitrous oxide/isoflurane anesthesia
165. Jay O, Reardon FD, Webb P, et al. Estimating changes in mean body is lower in elderly than in young patients. Anesthesiology. 1993;79:
temperature for humans during exercise using core and skin 465–469.
temperatures is inaccurate even with a correction factor. J Appl 190. Frank SM, Shir Y, Raja SN, et al. Core hypothermia and skin-surface
Physiol. 2007;103:443–451. temperature gradients. Epidural versus general anesthesia and the
166. Hardy JD, Dubois EF. The technique of measuring radiation and effects of age. Anesthesiology. 1994;80:502–508.
convection. J Nutr. 1938;15:461–475. 191. Rosa G, Pinto G, Orsi P, et al. Control of post anaesthetic shivering
167. Hey E. In: Austin CR, editor. The Mammalian Fetus in Vitro. with nefopam hydrochloride in mildly hypothermic patients after
London: Chapman and Hall; 1973. p. 251. neurosurgery. Acta Anaesthesiol Scand. 1995;39:90–95.
168. Hardy JD, Milhorat AT, Dubois EF. Basal metabolism and heat loss 192. Mahajan RP, Grover VK, Sharma SL, et al. Intraocular pressure
of young women at temperatures from 22°C to 35°C. J Nutr. changes during muscular hyperactivity after general anesthesia.
1941;21:383–404. Anesthesiology. 1987;66:419–421.
169. Maughan R, Shirreffs S. Exercise in the heat: challenges and 193. Alfonsi P. Postanaesthetic shivering: epidemiology, pathophysiology,
opportunities. J Sports Sci. 2004;22:917–927. and approaches to prevention and management. Drugs. 2001;61:
170. Goldman RF. In: Folinsbee LJ, Wagner JA, Borgia JF, et al., editors. 2193–2205.
Environmental Stress: Individual Human Adaptations. New York: 194. Roe CF, Santulli TV, Blair CS. Heat loss in infants during general
Academic Press; 1978. pp. anesthesia and operations. J Pediatr Surg. 1966;1:266–274.
171. Boutelier C, Bougues L, Timbal J. Experimental study of convective 195. Horn EP, Schroeder F, Wilhelm S, et al. Postoperative pain facil-
heat transfer coefficient for the human body in water. J Appl Physiol. itates nonthermoregulatory tremor. Anesthesiology. 1999;91:
1977;42:93–100. 979–984.
172. Bickler PE, Sessler DI. Efficiency of airway heat and moisture 196. Horn EP, Sessler DI, Standl T, et al. Non-thermoregulatory shivering
exchangers in anesthetized humans. Anesth Analg. 1990;71:415–418. in patients recovering from isoflurane or desflurane anesthesia.
173. Bissonnette B, Sessler DI. Passive or active inspired gas humidi- Anesthesiology. 1998;89:878–886.
fication increases thermal steady-state temperatures in anesthetized 197. Akin A, Esmaoglu A, Boyaci A. Postoperative shivering in children
infants. Anesth Analg. 1989;69:783–787. and causative factors. Paediatr Anaesth. 2005;15:1089–1093.
174. Roe CF. Effect of bowel exposure on body temperature during 198. Lyons B, Taylor A, Power C, et al. Postanaesthetic shivering in
surgical operations. Am J Surg. 122 (1971), 13–5. children. Anaesthesia. 1996;51:442–445.
175. Krustrup P, Gonzalez-Alonso J, Quistorff B, et al. Muscle heat 199. Crossley AW. Six months of shivering in a district general hospital.
production and anaerobic energy turnover during repeated intense Anaesthesia. 1992;47:845–848.
dynamic exercise in humans. J Physiol. 2001;536:947–956. 200. Haman F, Legault SR, Weber JM. Fuel selection during intense
176. Gonzalez-Alonso J, Quistorff B, Krustrup P, et al. Heat production shivering in humans: EMG pattern reflects carbohydrate oxidation.
in human skeletal muscle at the onset of intense dynamic exercise. J Physiol. 2004;556:305–313.
J Physiol. 2000;524:603–615. 201. Stuart D, Ott K, Ishikawa K, et al. The rhythm of shivering.
177. Meigal AY, Oksa J, Gerasimova LI, et al. Force control of isometric 3. Central contributions. Am J Phys Med. 1966;45:91–104.
elbow flexion with visual feedback in cold with and without 202. Hemingway A. Shivering. Physiol Rev. 1963;43:397–422.
shivering. Aviat Space Environ Med. 2003;74:816–821. 203. Adamson SK Jr, Gandy GM, James LS. The influence of thermal
178. Israel DJ, Wittmers LE, Hoffman RG, et al. Suppression of shivering factors upon oxygen consumption of the newborn human infant.
by breath holding, relaxation, mental arithmetic, and warm water J Pediatr. 1965;66:495–508.
ingestion. Aviat Space Environ Med. 1993;64:1108–1112. 204. Petrikovsky B, Silverstein M, Schneider EP. Neonatal shivering and
179. Bell DG, Tikuisis P, Jacobs I. Relative intensity of muscular hypothermia after intrapartum amnioinfusion. Lancet. 1997;350:
contraction during shivering. J Appl Physiol. 1992;72:2336–2342. 1366–1367.
180. Bay J, Nunn JF, Prys-Roberts C. Factors influencing arterial PO2 205. Haman F, Peronnet F, Kenny GP, et al. Effect of cold exposure on
during recovery from anaesthesia. Br J Anaesth. 1968;40:398–407. fuel utilization in humans: plasma glucose, muscle glycogen, and
181. Sessler DI, Israel D, Pozos RS, et al. Spontaneous post-anesthetic lipids. J Appl Physiol. 2002;93:77–84.
tremor does not resemble thermoregulatory shivering. Anesthesio- 206. Haman F, Peronnet F, Kenny GP, et al. Effects of carbohydrate
logy. 1988;68:843–850. availability on sustained shivering. I. Oxidation of plasma glucose,
182. Pauca AL, Savage RT, Simpson S, et al. Effect of pethidine, fentanyl muscle glycogen, and proteins. J Appl Physiol. 2004;96:32–40.
and morphine on post-operative shivering in man. Acta Anaesthesiol 207. Haman F. Shivering in the cold: from mechanisms of fuel selection
Scand. 1984;28:138–143. to survival. J Appl Physiol. 2006;100:1702–1708.
208. Simoneau JA, Bouchard C. Human variation in skeletal muscle 232. Polk DH. Thyroid hormone effects on neonatal thermogenesis.
fiber–type proportion and enzyme activities. Am J Physiol. 1989;257: Semin Perinatol. 1988;12:151–156.
E567–72. 233. Silva JE, Larsen PR. Potential of brown adipose tissue type II
209. Gale EA, Bennett T, Green JH, et al. Hypoglycaemia, hypothermia thyroxine 5⬘-deiodinase as a local and systemic source of
and shivering in man. Clin Sci (Lond). 1981;61:463–469. triiodothyronine in rats. J Clin Invest. 1985;76:2296–2305.
210. Dimicco JA, Zaretsky DV. The dorsomedial hypothalamus: a new 234. Fernandez JA, Mampel T, Villarroya F, et al. Direct assessment of
player in thermoregulation. Am J Physiol Regul Integr Comp Physiol. brown adipose tissue as a site of systemic tri-iodothyronine
2007;292:R47–63. production in the rat. Biochem J. 1987;243:(281–4).
211. Tanaka M, Owens NC, Nagashima K, et al. Reflex activation of rat 235. de Jesus LA, Carvalho SD, Ribeiro MO, et al. The type 2 iodo-
fusimotor neurons by body surface cooling, and its dependence on thyronine deiodinase is essential for adaptive thermogenesis in
the medullary raphe. J Physiol. 2006;572:569–583. brown adipose tissue. J Clin Invest. 2001;108:1379–1385.
212. Tanaka M, Tonouchi M, Hosono T, et al. Hypothalamic region 236. Nedergaard J, Golozoubova V, Matthias A, et al. Ucp1: the only
facilitating shivering in rats. Jpn J Physiol. 2001;51:625–629. protein able to mediate adaptive non-shivering thermogenesis
213. Thornhill JA, Halvorson I. Electrical stimulation of the posterior and metabolic inefficiency. Biochim Biophys Acta. 2001;1504:
and ventromedial hypothalamic nuclei causes specific activation 82–106.
of shivering and nonshivering thermogenesis. Can J Physiol 237. Erlanson-Albertsson C. The role of uncoupling proteins in the
Pharmacol. 1994;72:89–96. regulation of metabolism. Acta Physiol Scand. 2003;178:405–412.
214. Hammel HT, Hardy JD, Fusco MM. Thermoregulatory responses 238. Schiff D, Stern L, Leduc J. Chemical thermogenesis in newborn
to hypothalamic cooling in unanesthetized dogs. Am J Physiol. infants: catecholamine excretion and the plasma non-esterified fatty
1960;198:481–486. acid response to cold exposure. Pediatrics. 1966;37:577–582.
215. Halvorson I, Thornhill J. Posterior hypothalamic stimulation of 239. Cannon B, Nedergaard J. Brown adipose tissue: function and
anesthetized normothermic and hypothermic rats evokes shivering physiological significance. Physiol Rev. 2004;84:277–359.
thermogenesis. Brain Res. 1993;610:208–215. 240. Silverman WA, Zamelis A, Sinclair JC, et al. Warm nap of the
216. Henneman E, Somjen G, Carpenter DO. Functional significance of newborn. Pediatrics. 1964;33:984–987.
cell size in spinal motoneurons. J Neurophysiol. 1965;28:560–580. 241. Ohlson KB, Mohell N, Cannon B, et al. Thermogenesis in brown
217. Iaizzo PA, Jeon YM, Sigg DC. Facial warming increases the adipocytes is inhibited by volatile anesthetic agents. A factor
threshold for shivering. J Neurosurg Anesthesiol. 1999;11:231–239. contributing to hypothermia in infants? Anesthesiology. 1994;81:
218. Horn EP, Standl T, Sessler DI, et al. Physostigmine prevents pos- 176–183.
tanesthetic shivering as does meperidine or clonidine. Anesthesiology. 242. Lindahl SGE, Grigsby EJ, Meyer DM, et al. Thermogenetic response
1998;88:108–113. to mild hypothermia in anaesthetized infants and children. Paediatr
219. Blaine Easley R, Brady KM, Tobias JD. Dexmedetomidine for the Anaesth. 1992;2:23–29.
treatment of postanesthesia shivering in children. Paediatr Anaesth. 243. Dicker A, Ohlson KB, Johnson L, et al. Halothane selectively inhibits
2007;17:341–346. nonshivering thermogenesis. Possible implications for thermo-
220. Kranke P, Eberhart LH, Roewer N, et al. Postoperative shivering in regulation during anesthesia of infants. Anesthesiology. 1995;82:
children: a review on pharmacologic prevention and treatment. 491–501.
Paediatr Drugs. 2003;5:373–383. 244. Stern L, Lees MH, Leduc J. Environmental temperature, oxygen
221. Giesbrecht GG, Goheen MS, Johnston CE, et al. Inhibition of consumption, and catecholamine excretion in newborn infants.
shivering increases core temperature afterdrop and attenuates Pediatrics. 1965;36:367–373.
rewarming in hypothermic humans. J Appl Physiol. 1997;83:1630– 245. Plattner O, Semsroth M, Sessler DI, et al. Lack of nonshivering
1634. thermogenesis in infants anesthetized with fentanyl and propofol.
222. Lean ME, James WP, Jennings G, et al. Brown adipose tissue Anesthesiology. 1997;86:772–777.
uncoupling protein content in human infants, children and adults. 246. Ohlson KB, Lindahl SG, Cannon B, et al. Thermogenesis inhibition
Clin Sci (Lond). 1986;71:291–297. in brown adipocytes is a specific property of volatile anesthetics.
223. Aherne W, Hull D. The site of heat production in the newborn Anesthesiology. 2003;98:437–448.
infant. Proc R Soc Med. 1964;57:1172–1173. 247. Dawkins MJ, Scopes JW. Non-shivering thermogenesis and brown
224. Fukuchi K, Ono Y, Nakahata Y, et al. Visualization of interscapular adipose tissue in the human new-born infant. Nature. 1965;206:
brown adipose tissue using (99m)Tc-tetrofosmin in pediatric 201–202.
patients. J Nucl Med. 2003;44:1582–1585. 248. Mestyan J, Bata G, Jarai I, et al. The significance of facial skin
225. Ricquier D, Kader JC. Mitochondrial protein alteration in active temperature in the chemical heat regulation of premature infants.
brown fat: a sodium dodecyl sulfate-polyacrylamide gel electro- Biol Neonat. 1964;7:243–254.
phoretic study. Biochem Biophys Res Commun. 1976;73:577–583. 249. Hey EN, Katz G. Temporary loss of a metabolic response to cold
226. Himms-Hagen J. Cellular thermogenesis. Annu Rev Physiol. stress in infants of low birthweight. Arch Dis Child. 1969;44:323–
1976;38:315–351. 330.
227. Sell H, Deshaies Y, Richard D. The brown adipocyte: update on its 250. Oya A, Asakura H, Koshino T, et al. Thermographic demonstration
metabolic role. Int J Biochem Cell Biol. 2004;36:2098–2104. of nonshivering thermogenesis in human newborns after birth: its
228. Commins SP, Watson PM, Padgett MA, et al. Induction of relation to umbilical gases. J Perinat Med. 1997;25:447–454.
uncoupling protein expression in brown and white adipose tissue 251. van Marken Lichtenbelt WD, Daanen HA. Cold-induced
by leptin. Endocrinology. 1999;140:292–300. metabolism. Curr Opin Clin Nutr Metab Care. 2003;6:469–475.
229. Jessen K. The cortisol fluctuations in plasma in relation to human 252. Lean ME, James WP, Jennings G, et al. Brown adipose tissue in
regulatory nonshivering thermogenesis. Acta Anaesthesiol Scand. patients with phaeochromocytoma. Int J Obes. 1986;10:219–227.
1980;24:151–154. 253. Garruti G, Ricquier D. Analysis of uncoupling protein and its
230. Jessen K. The relation between thyroid function and human mRNA in adipose tissue deposits of adult humans. Int J Obes.
regulatory nonshivering thermogenesis. Acta Anaesthesiol Scand. 1992;16:383–390.
1980;24:144–150. 254. Soares FA, Silveira TC. Accumulation of brown adipose tissue in
231. Gale CC. Neuroendocrine aspects of thermoregulation. Annu Rev patients with Chagas heart disease. Trans R Soc Trop Med Hyg.
Physiol. 1973;35:391–430. 1991;85:605–607.
255. Vybiral S, Lesna I, Jansky L, et al. Thermoregulation in winter 280. Yashiro K, Adams FH, Emmanouilides GC, et al. Preliminary
swimmers and physiological significance of human catecholamine studies on the thermal environment of low-birth-weight infants. J
thermogenesis. Exp Physiol. 2000;85:321–326. Pediatr. 1973;82:991–994.
256. Simonsen L, Bulow J, Madsen J, et al. Thermogenic response to 281. Washington DE, Sessler DI, Moayeri A, et al. Thermoregulatory
epinephrine in the forearm and abdominal subcutaneous adipose responses to hyperthermia during isoflurane anesthesia in humans.
tissue. Am J Physiol. 1992;263:E850–5. J Appl Physiol. 1993;74:82–87.
257. Paolone VJ, Paolone AM. Thermogenesis during rest and exercise in 282. Kurz A, Xiong J, Sessler DI, et al. Isoflurane produces marked and
cold air. Can J Physiol Pharmacol. 1995;73:1149–1153. nonlinear decreases in the vasoconstriction and shivering
258. Donahoo WT, Levine JA, Melanson EL. Variability in energy thresholds. Ann N Y Acad Sci. 1997;813:778–785.
expenditure and its components. Curr Opin Clin Nutr Metab Care. 283. Sessler DI, Olofsson CI, Rubinstein EH. The thermoregulatory
2004;7:599–605. threshold in humans during nitrous oxide–fentanyl anesthesia.
259. Jequier E. Thermogenic responses induced by nutrients in man: Anesthesiology. 1988;69:357–364.
their importance in energy balance regulation. Experientia Suppl. 284. Sessler DI, Olofsson CI, Rubinstein EH, et al. The thermoregulatory
1983;44:26–44. threshold in humans during halothane anesthesia. Anesthesiology.
260. Westerterp KR, Wilson SA, Rolland V. Diet induced thermogenesis 1988;68:836–842.
measured over 24h in a respiration chamber: effect of diet 285. Brux A, Girbes AR, Polderman KH. controlled mild-to-moderate
composition. Int J Obes. 1999;23:287–292. hypothermia in the intensive care unit. Anaesthesist. 2005;54:
261. Sellden E, Brundin T, Wahren J. Augmented thermic effect of amino 225–244.
acids under general anaesthesia: a mechanism useful for prevention 286. Kurz A, Xiong J, Sessler DI, et al. Desflurane reduces the gain of
of anaesthesia-induced hypothermia. Clin Sci (Lond). 1994;86: thermoregulatory arteriovenous shunt vasoconstriction in humans.
611–618. Anesthesiology. 1995;83:1212–1219.
262. Sellden E, Lindahl SG. Amino acid-induced thermogenesis reduces 287. Xiong J, Kurz A, Sessler DI, et al. Isoflurane produces marked and
hypothermia during anesthesia and shortens hospital stay. Anesth nonlinear decreases in the vasoconstriction and shivering thre-
Analg. 1999;89:1551–1556. sholds. Anesthesiology. 1996;85:240–245.
263. Kasai T, Nakajima Y, Matsukawa T, et al. Effect of preoperative 288. Ikeda T, Kim JS, Sessler DI, et al. Isoflurane alters shivering patterns
amino acid infusion on thermoregulatory response during spinal and reduces maximum shivering intensity. Anesthesiology.
anaesthesia. Br J Anaesth. 2003;90:58–61. 1998;88:866–873.
264. Brundin T, Wahren J. Effects of I.V. amino acids on human 289. Bissonnette B, Sessler DI. The thermoregulatory threshold in infants
splanchnic and whole body oxygen consumption, blood flow, and and children anesthetized with isoflurane and caudal bupivacaine.
blood temperatures. Am J Physiol. 1994;266:E396–402. Anesthesiology. 1990;73:1114–1118.
265. Sellden E. Peri-operative amino acid administration and the 290. Bissonnette B, Sessler DI. Thermoregulatory thresholds for
metabolic response to surgery. Proc Nutr Soc. 2002;61:337–343. vasoconstriction in pediatric patients anesthetized with halothane
266. Nakajima Y, Takamata A, Matsukawa T, et al. Effect of amino acid or halothane and caudal bupivacaine. Anesthesiology. 1992;76:
infusion on central thermoregulatory control in humans. 387–392.
Anesthesiology. 2004;100:634–639. 291. Nebbia SP, Bissonnette B, Sessler DI. Enflurane decreases the
267. Fanaroff AA, Wald M, Gruber HS, et al. Insensible water loss in low threshold for vasoconstriction more than isoflurane or halothane.
birth weight infants. Pediatrics. 1972;50:236–245. Anesth Analg. 1996;83:595–599.
268. Sedin G, Hammarlund K, Stromberg B. Transepidermal water loss 292. Washington DE, Sessler DI, McGuire J, et al. Painful stimulation
in full-term and pre-term infants. Acta Paediatr Scand Suppl. minimally increases the thermoregulatory threshold for
1983;305:27–31. vasoconstriction during enflurane anesthesia in humans.
269. Szmuk P, Rabb MF, Baumgartner JE, et al. Body morphology Anesthesiology. 1992;77:286–290.
and the speed of cutaneous rewarming. Anesthesiology. 2001;95: 293. Lopez M, Ozaki M, Sessler DI, et al. Physiologic responses to hyper-
18–21. thermia during epidural anesthesia and combined epidural/
270. Hey E. Thermal neutrality. Br Med Bull. 1975;31:69–74. enflurane anesthesia in women. Anesthesiology. 1993;78:1046–1054.
271. Lacomme M, Chabrun J, Boreau T, et al. application of the so-called 294. Passias TC, Mekjavic IB, Eiken O. The effect of 30% nitrous oxide on
artificial hibernation method to neonatal pathology. Etudes thermoregulatory responses in humans during hypothermia.
Neonatales. 1954;3:3–29. Anesthesiology. 1992;76:550–559.
272. Baumgart S. Iatrogenic hyperthermia and hypothermia in the 295. Mekjavic IB, Sundberg CJ. Human temperature regulation during
neonate. Clin Perinatol. 2008;35:183–197, ix–x. narcosis induced by inhalation of 30% nitrous oxide. J Appl Physiol.
273. Bligh J, Johnson KG. Glossary of terms for thermal physiology. J 1992;73:2246–2254.
Appl Physiol. 1973;35:941–961. 296. Ozaki M, Sessler DI, Suzuki H, et al. Nitrous oxide decreases the
274. Sinclair JC. Thermal control in premature infants. Annu Rev Med. threshold for vasoconstriction less than sevoflurane or isoflurane.
1972;23:129–148. Anesth Analg. 1995;80:1212–1216.
275. Anttonen H, Puhakka K, Niskanen J, et al. Cutaneous heat loss in 297. Saito T. A comparison of the body temperature during sevoflurane
children during anaesthesia. Br J Anaesth. 1995;74:306–310. anesthesia and isoflurane anesthesia. Ann N Y Acad Sci. 1997;
276. Simbruner G, Weninger M, Popow C, et al. Regional heat loss in 813:786–788.
newborn infants. Part I. Heat loss in healthy newborns at various 298. Goto T, Matsukawa T, Sessler DI, et al. Thermoregulatory thresholds
environmental temperatures. S Afr Med J. 1985;68:940–944. for vasoconstriction in patients anesthetized with various 1-
277. Fleming PJ, Azaz Y, Wigfield R. Development of thermoregulation minimum alveolar concentration combinations of xenon, nitrous
in infancy: possible implications for SIDS. J Clin Pathol. 1992;45: oxide, and isoflurane. Anesthesiology. 1999;91:626–632.
17–19. 299. Annadata R, Sessler DI, Tayefeh F, et al. Desflurane slightly increases
278. Oh W, Yao AC, Hanson JS, et al. Peripheral circulatory response to the sweating threshold but produces marked, nonlinear decreases
phototherapy in newborn infants. Acta Paediatr Scand. 1973;62:49– in the vasoconstriction and shivering thresholds. Anesthesiology.
54. 1995;83:1205–1211.
279. Oh W, Karecki H. Phototherapy and insensible water loss in the 300. Antognini JF. Hypothermia eliminates isoflurane requirements at
newborn infant. Am J Dis Child. 1972;124:230–232. 20 degrees C. Anesthesiology. 1993;78:1152–1156.
301. Eger EI 2nd, Johnson BH. MAC of I-653 in rats, including a test of 323. Kolka MA, Stephenson LA. Cutaneous blood flow and local sweat-
the effect of body temperature and anesthetic duration. Anesth ing after systemic atropine administration. Pflugers Arch. 1987;410:
Analg. 1987;66:974–976. 524–529.
302. Liu M, Hu X, Liu J. The effect of hypothermia on isoflurane MAC 324. Matsukawa T, Sessler DI, Sessler AM, et al. Heat flow and dis-
in children. Anesthesiology. 2001;94:429–432. tribution during induction of general anesthesia. Anesthesiology.
303. Antognini JF, Lewis BK, Reitan JA. Hypothermia minimally de- 1995;82:662–673.
creases nitrous oxide anesthetic requirements. Anesth Analg. 325. Ikeda T, Ozaki M, Sessler DI, et al. Intraoperative phenylephrine
1994;79:980–982. infusion decreases the magnitude of redistribution hypothermia.
304. Kushikata T, Hirota K, Kotani N, et al. Isoflurane increases nore- Anesth Analg. 1999;89:462–465.
pinephrine release in the rat preoptic area and the posterior 326. Matsukawa T, Sessler DI, Christensen R, et al. Heat flow and
hypothalamus in vivo and in vitro: relevance to thermoregulation distribution during epidural anesthesia. Anesthesiology. 1995;83:
during anesthesia. Neuroscience. 2005;131:79–86. 961–967.
305. Ikeda T, Kurz A, Sessler DI, et al. The effect of opioids on 327. Leslie K, Sessler DI. Reduction in the shivering threshold is
thermoregulatory responses in humans and the special antishivering proportional to spinal block height. Anesthesiology. 1996;84:
action of meperidine. Ann N Y Acad Sci. 1997;813:792–798. 1327–1331.
306. De Witte JL, Kim JS, Sessler DI, et al. Tramadol reduces the 328. Frank SM, El-Rahmany HK, Cattaneo CG, et al. Predictors of hypo-
sweating, vasoconstriction, and shivering thresholds. Anesth Analg. thermia during spinal anesthesia. Anesthesiology. 2000;92:1330–
1998;87:173–179. 1334.
307. De Witte J, Rietman GW, Vandenbroucke G, et al. Post-operative 329. Hynson JM, Sessler DI, Glosten B, et al. Thermal balance and tremor
effects of tramadol administered at wound closure. Eur J patterns during epidural anesthesia. Anesthesiology. 1991;74:
Anaesthesiol. 1998;15:190–195. 680–690.
308. Kadar D, Tang BK, Conn AW. The fate of phenobarbitone in 330. Kurz A, Sessler DI, Schroeder M, et al. Thermoregulatory response
children in hypothermia and at normal body temperature. Can thresholds during spinal anesthesia. Anesth Analg. 1993;77:721–726.
Anaesth Soc J. 1982;29:16–23. 331. Ozaki M, Kurz A, Sessler DI, et al. Thermoregulatory thresholds
309. Koren G, Barker C, Goresky G, et al. The influence of hypothermia during epidural and spinal anesthesia. Anesthesiology. 1994;81:282–
on the disposition of fentanyl—human and animal studies. Eur J 288.
Clin Pharmacol. 1987;32:373–376. 332. Kim JS, Ikeda T, Sessler DI, et al. Epidural anesthesia reduces the
310. Alfonsi P, Sessler DI, Du Manoir B, et al. The effects of meperidine gain and maximum intensity of shivering. Anesthesiology. 1998;88:
and sufentanil on the shivering threshold in postoperative patients. 851–857.
Anesthesiology. 1998;89:43–48. 333. Glosten B, Sessler DI, Ostman LG, et al. Intravenous lidocaine does
311. Leslie K, Sessler DI, Bjorksten AR, et al. Propofol causes a dose- not cause shivering-like tremor or alter thermoregulation. Reg
dependent decrease in the thermoregulatory threshold for Anesth. 1991;16:218–222.
vasoconstriction but has little effect on sweating. Anesthesiology. 334. Cattaneo CG, Frank SM, Hesel TW, et al. The accuracy and
1994;81:353–360. precision of body temperature monitoring methods during regional
312. Ikeda T, Sessler DI, Kikura M, et al. Less core hypothermia when and general anesthesia. Anesth Analg. 2000;90:938–945.
anesthesia is induced with inhaled sevoflurane than with 335. Joris J, Ozaki M, Sessler DI, et al. Epidural anesthesia impairs both
intravenous propofol. Anesth Analg. 1999;88:921–924. central and peripheral thermoregulatory control during general
313. Kurz A, Sessler DI, Annadata R, et al. Midazolam minimally impairs anesthesia. Anesthesiology. 1994;80:268–277.
thermoregulatory control. Anesth Analg. 1995;81:393–398. 336. Kitamura A, Hoshino T, Kon T, et al. Patients with diabetic
314. Matsukawa T, Hanagata K, Ozaki M, et al. I.M. Midazolam as neuropathy are at risk of a greater intraoperative reduction in core
premedication produces a concentration-dependent decrease in temperature. Anesthesiology. 2000;92:1311–1318.
core temperature in male volunteers. Br J Anaesth. 1997;78:396–399. 337. Frank SM, Nguyen JM, Garcia CM, et al. Temperature monitoring
315. Matsukawa T, Ozaki M, Nishiyama T, et al. Atropine prevents practices during regional anesthesia. Anesth Analg. 1999;88:
midazolam-induced core hypothermia in elderly patients. J Clin 373–377.
Anesth. 2001;13:504–508. 338. Sessler DI. Central thermoregulatory inhibition by general
316. Ikeda T, Kazama T, Sessler DI, et al. Induction of anesthesia with anesthesia. Anesthesiology. 1991;75:557–559.
ketamine reduces the magnitude of redistribution hypothermia. 339. Kurz A, Sessler DI, Christensen R, et al. Heat balance and
Anesth Analg. 2001;93:934–938. distribution during the core-temperature plateau in anesthetized
317. Engelman DR, Lockhart CH. Comparisons between temperature humans. Anesthesiology. 1995;83:491–499.
effects of ketamine and halothane anesthesia in children. Anesth 340. Deakin CD. Changes in core temperature compartment size on
Analg. 1972;51:98–101. induction of general anaesthesia. Br J Anaesth. 1998;81:861–864.
318. Talke P, Tayefeh F, Sessler DI, et al. Dexmedetomidine does not alter 341. Sessler DI, McGuire J, Hynson J, et al. Thermoregulatory vaso-
the sweating threshold, but comparably and linearly decreases the constriction during isoflurane anesthesia minimally decreases
vasoconstriction and shivering thresholds. Anesthesiology. cutaneous heat loss. Anesthesiology. 1992;76:670–675.
1997;87:835–841. 342. Bloch EC, Ginsberg B, Binner RA Jr, et al. Limb tourniquets and
319. Doufas AG, Lin CM, Suleman MI, et al. Dexmedetomidine and central temperature in anesthetized children. Anesth Analg.
meperidine additively reduce the shivering threshold in humans. 1992;74:486–489.
Stroke. 2003;34:1218–1223. 343. Estebe JP, Le Naoures A, Malledant A, et al. Use of a pneumatic
320. Bernard JM, Fulgencio JP, Delaunay L, et al. Clonidine does not tourniquet induces changes in central temperature. Br J Anaesth.
impair redistribution hypothermia after the induction of anesthesia. 1996;77:786–788.
Anesth Analg. 1998;87:168–172. 344. Akata T, Kanna T, Izumi K, et al. Changes in body temperature
321. Delaunay L, Herail T, Sessler DI, et al. Clonidine increases the following deflation of limb pneumatic tourniquet. J Clin Anesth.
sweating threshold, but does not reduce the gain of sweating. Anesth 1998;10:17–22.
Analg. 1996;83:844–848. 345. Sanders BJ, D’Alessio JG, Jernigan JR. Intraoperative hypothermia
322. Fraser JG. Iatrogenic benign hyperthermia in children. Anesthe- associated with lower extremity tourniquet deflation. J Clin Anesth.
siology. 1978;48:375. 1996;8:504–507.
346. J. M. Hynson, D. I. Sessler, A. Moayeri, et al. Absence of non- 368. Faraday N, Rosenfeld BA. In vitro hypothermia enhances platelet
shivering thermogenesis in anesthetized adult humans. Anesthesio- GPIIb-IIIa activation and P-selectin expression. Anesthesiology.
logy. 79 (1993), 695–703. 1998;88:1579–1585.
347. Ryan JF. In: Cooperman L, Orkin F, editors. Complications in 369. Lindenblatt N, Menger MD, Klar E, et al. Sustained hypothermia
Anesthesiology. Philadelphia: JB Lippincott; 1982. p. 284. accelerates microvascular thrombus formation in mice. Am J Physiol
348. McHoney MC, Corizia L, Eaton S, et al. Laparoscopic surgery in Heart Circ Physiol. 2005;289:H2680–7.
children is associated with an intraoperative hypermetabolic 370. Douning LK, Ramsay MA, Swygert TH, et al. Temperature corrected
response. Surg Endosc. 2006;20:452–457. thrombelastography in hypothermic patients. Anesth Analg. 1995;
349. Kanto WP Jr, Calvert LJ. Thermoregulation of the newborn. Am 81:608–611.
Fam Physician. 1977;16:157–163. 371. Wolberg AS, Meng ZH, Monroe DM 3rd, et al. A systematic
350. Detry JM, Brengelmann GL, Rowell LB, et al. Skin and muscle evaluation of the effect of temperature on coagulation enzyme
components of forearm blood flow in directly heated resting man. activity and platelet function. J Trauma. 2004;56:1221–1228.
J Appl Physiol. 1972;32:506–511. 372. Kimme P, Fridrikssen S, Engdahl O, et al. Moderate hypothermia
351. Wilson TE, Cui J, Crandall CG. Effect of whole-body and local for 359 operations to clip cerebral aneurysms. Br J Anaesth.
heating on cutaneous vasoconstrictor responses in humans. Auton 2004;93:343–347.
Neurosci. 2002;97:122–128. 373. Rajagopalan S, Mascha E, Na J, et al. The effects of mild peri-
352. Inoue Y, Tanaka Y, Omori K, et al. Sex- and menstrual cycle– operative hypothermia on blood loss and transfusion requirement.
related differences in sweating and cutaneous blood flow in Anesthesiology. 2008;108:71–77.
response to passive heat exposure. Eur J Appl Physiol. 2005;94: 374. Schmied H, Kurz A, Sessler DI, et al. Mild hypothermia increases
323–332. blood loss and transfusion requirements during total hip
353. Grucza R, Lecroart JL, Hauser JJ, et al. Dynamics of sweating in men arthroplasty. Lancet. 1996;347:289–292.
and women during passive heating. Eur J Appl Physiol Occup Physiol. 375. Bock M, Muller J, Bach A, et al. Effects of preinduction and intra-
1985;54:309–314. operative warming during major laparotomy. Br J Anaesth. 1998;
354. Hypothermia after Cardiac Arrest Study Group. Mild therapeutic 80:159–163.
hypothermia to improve the neurologic outcome after cardiac arrest. 376. Michelson AD, MacGregor H, Barnard MR, et al. Reversible
N Engl J Med. 2002;346:549–556. inhibition of human platelet activation by hypothermia in vivo and
355. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose in vitro. Thromb Haemost. 1994;71:633–640.
survivors of out-of-hospital cardiac arrest with induced hypo- 377. Frank SM, Beattie C, Christopherson R, et al. Unintentional hypo-
thermia. N Engl J Med. 2002;346:557–563. thermia is associated with postoperative myocardial ischemia. The
356. Wenisch C, Narzt E, Sessler DI, et al. Mild intraoperative hypother- Perioperative Ischemia Randomized Anesthesia Trial Study Group.
mia reduces production of reactive oxygen intermediates by Anesthesiology. 1993;78:468–476.
polymorphonuclear leukocytes. Anesth Analg. 1996;82:810–816. 378. Insler SR, O’Connor MS, Leventhal MJ, et al. Association between
357. Beilin B, Shavit Y, Razumovsky J, et al. Effects of mild perioperative postoperative hypothermia and adverse outcome after coronary
hypothermia on cellular immune responses. Anesthesiology. artery bypass surgery. Ann Thorac Surg. 2000;70:175–181.
1998;89:1133–1140. 379. Nesher N, Zisman E, Wolf T, et al. Strict thermoregulation atte-
358. Biggar WD, Bohn DJ, G. Kent G, et al. Neutrophil migration in nuates myocardial injury during coronary artery bypass graft
vitro and in vivo during hypothermia. Infect Immun. 1984;46: surgery as reflected by reduced levels of cardiac-specific troponin I.
857–859. Anesth Analg. 2003;96:328–335, table of contents.
359. Bardosi L, Tekeres M. Impaired metabolic activity of phagocytic 380. Frank SM, Higgins MS, Breslow MJ, et al. The catecholamine,
cells after anaesthesia and surgery. Br J Anaesth. 1985;57:(520–3. cortisol, and hemodynamic responses to mild perioperative
360. van Oss CJ, Absolom DR, Moore LL, et al. Effect of temperature on hypothermia. A randomized clinical trial. Anesthesiology. 1995;82:
the chemotaxis, phagocytic engulfment, digestion and O2 consump- 83–93.
tion of human polymorphonuclear leukocytes. J Reticuloendothel 381. Frank SM, el-Gamal N, Raja SN, et al. Alpha-adrenoceptor
Soc. 1980;27:561–565. mechanisms of thermoregulation during cold challenge in humans.
361. Kurz A, Sessler DI, Lenhardt R. Perioperative normothermia to Clin Sci (Lond). 1996;91:627–631.
reduce the incidence of surgical-wound infection and shorten 382. Frank SM, Satitpunwaycha P, Bruce SR, et al. Increased myocar-
hospitalization. Study of wound infection and temperature group. N dial perfusion and sympathoadrenal activation during mild
Engl J Med. 1996;334:1209–1215. core hypothermia in awake humans. Clin Sci (Lond). 2003;104:
362. Jonsson K, Jensen JA, Goodson WA 3rd, et al. Tissue oxygenation, 503–508.
anemia, and perfusion in relation to wound healing in surgical 383. Tanaka M, Nagasaki G, Nishikawa T. Moderate hypothermia
patients. Ann Surg. 1991;214:605–613. depresses arterial baroreflex control of heart rate during, and delays
363. Bunker JP, Goldstein R. Coagulation during hypothermia in man. its recovery after, general anesthesia in humans. Anesthesiology.
Proc Soc Exp Biol Med. 1958;97:199–202. 2001;95:51–55.
364. Shimokawa M, Kitaguchi K, Kawaguchi M, et al. The influence of 384. Frank SM, Fleisher LA, Breslow MJ, et al. Perioperative maintenance
induced hypothermia for hemostatic function on temperature- of normothermia reduces the incidence of morbid cardiac events. A
adjusted measurements in rabbits. Anesth Analg. 2003;96:1209– randomized clinical trial. JAMA. 1997;277:1127–1134.
1213, table of contents. 385. Bjornstad H, Tande PM, Refsum H. Cardiac electrophysiology
365. Rohrer MJ, Natale AM. Effect of hypothermia on the coagulation during hypothermia. Implications for medical treatment. Arctic Med
cascade. Crit Care Med. 1992;20:1402–1405. Res. 1991;50:71–75.
366. Felfernig M, Blaicher A, Kettner SC, et al. Effects of temperature on 386. Heier T, Caldwell JE, Sessler DI, et al. Mild intraoperative hypo-
partial thromboplastin time in heparinized plasma in vitro. Eur J thermia increases duration of action and spontaneous recovery of
Anaesthesiol. 2001;18:467–470. vecuronium blockade during nitrous oxide-isoflurane anesthesia in
367. Kettner SC, Sitzwohl C, Zimpfer M, et al. The effect of graded humans. Anesthesiology. 1991;74:815–819.
hypothermia (36 degrees C-32 degrees C) on hemostasis in 387. Lenhardt R, Marker E, Goll V, et al. Mild intraoperative hypo-
anesthetized patients without surgical trauma. Anesth Analg. thermia prolongs postanesthetic recovery. Anesthesiology. 1997;87:
2003;96:1772–1776, table of contents. 1318–1323.
388. Bissonnette B, Sessler DI. Mild hypothermia does not impair 411. Bridges E, Schmelz J, Evers K. Efficacy of the blizzard blanket or
postanesthetic recovery in infants and children. Anesth Analg. blizzard blanket plus thermal angel in preventing hypothermia
1993;76:168–172. in a hemorrhagic shock victim (sus scrofa) under operational
389. Heier T, Caldwell JE, Sessler DI, et al. The relationship between conditions. Mil Med. 2007;172:17–23.
adductor pollicis twitch tension and core, skin, and muscle tem- 412. Cohen S, Hayes JS, Tordella T, et al. Thermal efficiency of pre-
perature during nitrous oxide–isoflurane anesthesia in humans. warmed cotton, reflective, and forced-warm-air inflatable blankets
Anesthesiology. 1989;71:381–384. in trauma patients. Int J Trauma Nurs. 8 (2002), 4–8.
390. Ham J, Miller RD, Benet LZ, et al. Pharmacokinetics and phar- 413. Schmelz JO, Bridges EJ, Wallace CM, et al. Comparison of three
macodynamics of D-tubocurarine during hypothermia in the cat. strategies for preventing hypothermia in critically injured casualties
Anesthesiology. 1978;49:324–329. during aeromedical evacuation. Mil Med. 2007;172:322–326.
391. Miller RD, Agoston S, van der Pol F, et al. Hypothermia and the 414. Watts DD, Roche M, Tricarico R, et al. The utility of traditional
pharmacokinetics and pharmacodynamics of pancuronium in the prehospital interventions in maintaining thermostasis. Prehosp
cat. J Pharmacol Exp Ther. 1978;207:532–538. Emerg Care. 1999;3:115–122.
392. Khuenl-Brady KS, Spar H. Clinical pharmacokinetics of 415. Renstrom B. Space or rescue blanket—a bluff? Arctic Med Res.
rocuronium bromide. Clin Pharmacokinet. 1996;31:174–183. 1992;51:212–213.
393. Caldwell JE, Heier T, Wright PM, et al. Temperature-dependent 416. Sessler DI, McGuire J, Sessler AM. Perioperative thermal insulation.
pharmacokinetics and pharmacodynamics of vecuronium. Anesthe- Anesthesiology. 1991;74:875–879.
siology. 2000;92:84–93. 417. Belghazi K, Tourneux P, Elabbassi EB, et al. Effect of posture on the
394. Leslie K, Sessler DI, Bjorksten AR, et al. Mild hypothermia alters thermal efficiency of a plastic bag wrapping in neonate: assessment
propofol pharmacokinetics and increases the duration of action of using a thermal “sweating” mannequin. Med Phys. 2006;33:637–644.
atracurium. Anesth Analg. 1995;80:1007–1014. 418. Baumgart S. Reduction of oxygen consumption, insensible water
395. Leslie K, Bjorksten AR, Ugoni A, et al. Mild core hypothermia and loss, and radiant heat demand with use of a plastic blanket for low-
anesthetic requirement for loss of responsiveness during propofol birth-weight infants under radiant warmers. Pediatrics. 1984;74:
anesthesia for craniotomy. Anesth Analg. 2002;94:1298–1303, table 1022–1028.
of contents. 419. Kuznetz LH. Automatic control of human thermal comfort by a
396. McAllister RG Jr, Tan TG. Effect of hypothermia on drug meta- liquid-cooled garment. J Biomech Eng. 1980;102:155–161.
bolism. In vitro studies with propranolol and verapamil. 420. Nesher N, Wolf T, Uretzky G, et al. A novel thermoregulatory system
Pharmacology. 1980;20:95–100. maintains perioperative normothermia in children undergoing
397. Bennett EJ, Patel KP, Grundy EM. Neonatal temperature and elective surgery. Paediatr Anaesth. 2001;11:555–560.
surgery. Anesthesiology. 1977;46:303–304. 421. Janicki PM, Higgins MS, Janssen J, et al. Comparison of two dif-
398. Morris RH. Influence of ambient temperature on patient tempera- ferent temperature maintenance strategies during open abdominal
ture during intra-abdominal surgery. Ann Surg. 1971;173:230–233. surgery: upper body forced-air warming versus whole body water
399. Morris RH. Operating room temperature and the anesthetized, garment. Anesthesiology. 2001;95:868–874.
paralyzed patient. Arch Surg. 1971;102:95–97. 422. Taguchi A, Ratnaraj J, Kabon B, et al. Effects of a circulating-water
400. Morris RH, Wilkey BR. The effects of ambient temperature on garment and forced-air warming on body heat content and core
patient temperature during surgery not involving body cavities. temperature. Anesthesiology. 2004;100:1058–1064.
Anesthesiology. 1970;32:102–107. 423. Kurz A, Kurz M, Poeschl G, et al. Forced-air warming maintains
401. Memarzadeh F, Manning AP. Comparison of operating room intraoperative normothermia better than circulating-water
ventilation systems in the protection of the surgical site. ASHRAE mattresses. Anesth Analg. 1993;77:89–95.
Trans. 2002;108:1–13. 424. Karayan J, Thomas D, Lacoste L, et al. Delayed forced air warming
402. Sessler DI, Moayeri A. Skin-surface warming: heat flux and central prevents hypothermia during abdominal aortic surgery. Br J Anaesth.
temperature. Anesthesiology. 1990;73:218–224. 1996;76:459–460.
403. Hynson JM, Sessler DI, Moayeri A, et al. The effects of preinduction 425. Ciufo D, Dice S, Coles C. Rewarming hypothermic postanes-
warming on temperature and blood pressure during propofol/ thesia patients: a comparison between a water coil warming blanket
nitrous oxide anesthesia. Anesthesiology. 1993;79:219–228, discus- and a forced-air warming blanket. J Post Anesth Nurs. 1995;10:
sion 21A-22A. 155–158.
404. Glosten B, Hynson J, Sessler DI, et al. Preanesthetic skin-surface 426. Truell KD, Bakerman PR, Teodori MF, et al. Third-degree burns due
warming reduces redistribution hypothermia caused by epidural to intraoperative use of a Bair hugger warming device. Ann Thorac
block. Anesth Analg. 1993;77:488–493. Surg. 2000;69:1933–1934.
405. Sessler DI, Schroeder M, Merrifield B, et al. Optimal duration and 427. Azzam FJ, Krock JL. Thermal burns in two infants associated with
temperature of prewarming. Anesthesiology. 1995;82:674–681. a forced air warming system. Anesth Analg. 1995;81:661.
406. Just B, Trevien V, Delva E, et al. Prevention of intraoperative 428. Siddik-Sayyid SM, Abdallah FW, Dahrouj GB. Thermal burns in
hypothermia by preoperative skin-surface warming. Anesthesiology. three neonates associated with intraoperative use of Bair hugger
1993;79:214–218. warming devices. Paediatr Anaesth. 2008;18:337–339.
407. Simenauer R, Spencer T. Dynamic thermal responses of five com- 429. Kim F, Olsufka M, Carlbom D, et al. Pilot study of rapid infusion of
mercially available infant radiant warmer systems. Biomed Instrum 2 l of 4 degrees C normal saline for induction of mild hypothermia
Technol. 2000;34:203–211. in hospitalized, comatose survivors of out-of-hospital cardiac arrest.
408. Marks KH, Gunther RC, Rossi JA, et al. Oxygen consumption and Circulation. 2005;112:715–719.
insensible water loss in premature infants under radiant heaters. 430. Rajek A, Greif R, Sessler DI, et al. Core cooling by central venous
Pediatrics. 1980;66:228–232. infusion of ice-cold (4 degrees C and 20 degrees C) fluid: isolation
409. Jones RW, Rochefort MJ, Baum JD. Increased insensible water loss of core and peripheral thermal compartments. Anesthesiology.
in newborn infants nursed under radiant heaters. Br Med J. 2000;93:629–637.
1976;2:1347–1350. 431. Bernard S, Buist M, Monteiro O, et al. Induced hypothermia using
410. Bourke DL, Wurm H, Rosenberg M, et al. Intraoperative heat large volume, ice-cold intravenous fluid in comatose survivors of
conservation using a reflective blanket. Anesthesiology. 1984;60: out-of-hospital cardiac arrest: a preliminary report. Resuscitation.
151–154. 2003;56:9–13.
432. Bissonnette B, Paut O. Active warming of saline or blood is 455. Yamashita K, Yokoyama T, Abe H, et al. Efficacy of a heat and
ineffective when standard infusion tubing is used: an experimental moisture exchanger in inhalation anesthesia at two different flow
study. Can J Anaesth. 2002;49:270–275. rates. J Anesth. 2007;21:55–58.
433. Faries G, Johnston C, Pruitt KM, et al. Temperature relationship to 456. Linko K, Honkavaara P, Nieminen MT. Heated humidification in
distance and flow rate of warmed I.V. Fluids. Ann Emerg Med. major abdominal surgery. Eur J Anaesthesiol. 1984;1:285–291.
1991;20:1198–1200. 457. Gregorini P, Cangini D. Control of body temperature during
434. Ezri T, Szmuk P, Weisenberg M, et al. The effects of hydration on abdominal aortic surgery. Acta Anaesthesiol Scand. 1996;40:187–190.
core temperature in pediatric surgical patients. Anesthesiology. 458. Toremalm NG. Air-flow patterns and ciliary activity in the trachea
2003;98:838–841. after tracheotomy. A method of determination in vitro of the rate of
435. Lawes EG. Hidden hazards and dangers associated with the use of ciliary beat in a tracheal model. Acta Otolaryngol. 1961;53:442–454.
HME/filters in breathing circuits. Their effect on toxic metabolite 459. Marfatia S, Donahoe PK, Hendren WH. Effect of dry and
production, pulse oximetry and airway resistance. Br J Anaesth. humidified gases on the respiratory epithelium in rabbits. J Pediatr
2003;91:249–264. Surg. 1975;10:583–592.
436. Williams DJ, Stacey MR. Rapid and complete occlusion of a heat 460. Burton JD. Effects of dry anaesthetic gases on the respiratory
and moisture exchange filter by pulmonary edema (clinical report). mucous membrane. Lancet. 1962;1:235–238.
Can J Anaesth. 2002;49:126–131. 461. Chalon J, Ali M, Ramanathan S, et al. The humidification of
437. Baumgarten RK. Humidifiers are unjustified in adult anesthesia. anaesthetic gases: its importance and control. Can Anaesth Soc J.
Anesth Analg. 1985;64:1224–1225. 1979;26:361–366.
438. Dery R. Water balance of the respiratory tract during ventilation 462. Forbes AR. Temperature, humidity and mucus flow in the intubated
with a gas mixture saturated at body temperature. Can Anaesth Soc trachea. Br J Anaesth. 1974;46:29–34.
J. 1973;20:719–727. 463. Berry FA Jr, Hughes-Davies DI, DiFazio CA. A system for mini-
439. Fang ZX, Eger EI 2nd, Laster MJ, et al. Carbon monoxide pro- mizing respiratory heat loss in infants during operation. Anesth
duction from degradation of desflurane, enflurane, isoflurane, Analg. 1973;52:170–175.
halothane, and sevoflurane by soda lime and baralyme. Anesth 464. Thiery G, Boyer A, Pigne A, et al. Heat and moisture exchangers in
Analg. 1995;80:1187–1193. mechanically ventilated intensive care unit patients: a plea for an
440. Baum J, Sachs G, C. vd Driesch C, et al. Carbon monoxide generation independent assessment of their performance. Crit Care Med.
in carbon dioxide absorbents. Anesth Analg. 1995;81:144–146. 32003;1:699–704.
441. Baxter AD. Low and minimal flow inhalational anaesthesia. 465. Lemmens HJ, Brock-Utne G. Heat and moisture exchange devices:
Can J Anaesth. 1997;44:643–652; quiz 652–3. are they doing what they are supposed to do? Anesth Analg.
442. Barra Bisinotto FM, Braz JR, Martins RH, et al. Tracheobronchial 2004;98:382–385, table of contents.
consequences of the use of heat and moisture exchangers in dogs. 466. McFadden ER Jr, Pichurko BM, Bowman HF, et al. Thermal
Can J Anaesth. 1999;46:897–903. mapping of the airways in humans. J Appl Physiol. 1985;58:564–570.
443. Kleemann PP. Humidity of anaesthetic gases with respect to low 467. Mercke U. The influence of varying air humidity on mucociliary
flow anaesthesia. Anaesth Intensive Care. 1994;22:396–408. activity. Acta Otolaryngol. 1975;79:133–139.
444. Larsson A, Gustafsson A, Svanborg L. A new device for 100 per cent 468. Cigada M, Elena A, Solca M, et al. The efficiency of 12 heat and
humidification of inspired air. Crit Care. 2000;4:54–60. moisture exchangers: an in vitro evaluation. Intens Care World.
445. Barnes SD, Normoyle DA. Failure of ventilation in an infant due to 1990;7:98–101.
increased resistance of a disposable heat and moisture exchanger. 469. Epstein RA. Humidification during positive-pressure ventilation of
Anesth Analg. 1996;83:193. infants. Anesthesiology. 1971;35:532–536.
446. Buckley PM. Increase in resistance of in-line breathing filters in 470. Bengtson JP, Bengtson A, Sonander H, et al. Humidity of the Bain
humidified air. Br J Anaesth. 1984;56:637–643. and circle systems reassessed. Anesth Analg. 1989;69:83–86.
447. Tayyab MA, Ambiavagar M, Chalon J. Water nebulization in a non- 471. Kilgour E, Rankin N, Ryan S, et al. Mucociliary function deteriorates
rebreathing system during anaesthesia. Can Anaesth Soc J. 1973; in the clinical range of inspired air temperature and humidity.
20:728–735. Intensive Care Med. 2004;30:1491–1494.
448. Cohen IL, Weinberg PF, Fein IA, et al. Endotracheal tube occlusion 472. Igarashi M, Watanabe H, Iwasaki H, et al. Clinical evaluation of low-
associated with the use of heat and moisture exchangers in the flow sevoflurane anaesthesia for paediatric patients. Acta Anaesthesiol
intensive care unit. Crit Care Med. 1988;16:277–279. Scand. 1999;43:19–23.
449. Schiffmann H, Rathgeber J, Singer D, et al. Airway humidification 473. Bissonnette B, Sessler DI, LaFlamme P. Passive and active inspired
in mechanically ventilated neonates and infants: a comparative study gas humidification in infants and children. Anesthesiology.
of a heat and moisture exchanger vs. a heated humidifier using a 1989;71:350–354.
new fast-response capacitive humidity sensor. Crit Care Med. 474. Fonkalsrud EW, Calmes S, Barcliff LT, et al. Reduction of operative
1997;25:1755–1760. heat loss and pulmonary secretions in neonates by use of heated and
450. Tausk HC, Miller R, Roberts RB. Maintenance of body temperature humidified anesthetic gases. J Thorac Cardiovasc Surg. 1980;80:
by heated humidification. Anesth Analg. 1976;55:719–723. 718–723.
451. Lu CC, Ho ST, Liaw WJ, et al. The effect of heat-moisture exchanger 475. Hardman JG, Mahajan RP, Curran J. The influence of breathing
and closed-circuit technique on airway climate during desflurane system filters on paediatric capnography. Paediatr Anaesth.
anesthesia. J Anesth. 2008;22:7–12. 1999;9:35–38.
452. Henriksson BA, Sundling J, Hellman A. The effect of a heat and 476. Chau A, Kobe J, Kalyanaraman R, et al. Beware the airway filter:
moisture exchanger on humidity in a low-flow anaesthesia system. deadspace effect in children under 2 years. Paediatr Anaesth.
Anaesthesia. 1997;52:144–149. 2006;16:932–938.
453. Poopalalingam R, Goh MH, Chan YW. The effect of heat and 477. Pelosi P, Solca M, Ravagnan I, et al. Effects of heat and moisture
moisture exchanger and gas flow on humidity and temperature in a exchangers on minute ventilation, ventilatory drive, and work of
circle anaesthetic system. Singapore Med J. 2002;43:563–565. breathing during pressure-support ventilation in acute respiratory
454. Johansson A, Lundberg D, Luttropp HH. The effect of heat and failure. Crit Care Med. 1996;24:1184–1188.
moisture exchanger on humidity and body temperature in a low- 478. Le Bourdelles G, Mier L, Fiquet B, et al. Comparison of the effects
flow anaesthesia system. Acta Anaesthesiol Scand. 2003;47:564–568. of heat and moisture exchangers and heated humidifiers on
ventilation and gas exchange during weaning trials from mechanical 492. Neft MW, Goodman JR, Hlavnicka JP, et al. To reuse your circuit: the
ventilation. Chest. 1996;110:1294–1298. HME debate. AANA J. 1999;67:433–439.
479. Iotti GA, Olivei MC, Palo A, et al. Unfavorable mechanical effects of 493. Body SC, Philip JH. Gram-negative rod contamination of an
heat and moisture exchangers in ventilated patients. Intensive Care ohmeda anesthesia machine. Anesthesiology. 2000;92:911.
Med. 1997;23:399–405. 494. Daggan R, Zefeiridis A, Steinberg D, et al. High-quality filtration
480. Wilkinson KA, Cranston A, Hatch DJ, et al. Assessment of a hygro- allows reuse of anesthesia breathing circuits resulting in cost savings
scopic heat and moisture exchanger for paediatric use. Anaesthesia. and reduced medical waste. J Clin Anesth. 1999;11:536–539.
1991;46:296–299. 495. Barbara J, Chabane MH, Leynadier F, et al. Retention of airborne
481. Goddard JM, Bennett HR. Filters and Ayre’s t-piece. Anaesthesia. latex particles by a bacterial and viral filter used in anaesthesia
1996;51:605. apparatus. Anaesthesia. 2001;56:231–234.
482. Da Fonseca JM, Wheeler DW, Pook JA. The effect of a heat 496. Stacey MR, Asai T, Wilkes A, et al. Obstruction of a breathing
and moisture exchanger on gas flow in a Mapleson F breathing system filter. Can J Anaesth. 1996;43:1276.
system during inhalational induction. Anaesthesia. 2000;55: 497. Barton RM. Detection of expiratory antibacterial filter occlusion.
571–573. Anesth Analg. 1993;77:197.
483. Luchetti M, Pigna A, Gentili A, et al. Evaluation of the efficiency of 498. Prasad KK, Chen L. Complications related to the use of a heat and
heat and moisture exchangers during paediatric anaesthesia. moisture exchanger. Anesthesiology. 1990;72:958.
Paediatr Anaesth. 1999;9:39–45. 499. Prados W. A dangerous defect in a heat and moisture exchanger.
484. Wilmshurst JM, Rahman MA, Shah V, et al. The heat moisture Anesthesiology. 1989;71:804.
500. Walton JS, Fears R, Burt N, et al. Intraoperative breathing circuit
exchange device (HME) in neonatal ventilation. Am J Perinatol.
obstruction caused by albuterol nebulization. Anesth Analg. 1999;
1999;16:13–16.
89:650–651.
485. Smith HS, Allen R. Another hazard of heated water humidifiers.
501. Aarhus D, Soreide E, Holst-Larsen H. Mechanical obstruction in
Anaesthesia. 1986;41:215–216.
the anaesthesia delivery-system mimicking severe bronchospasm.
486. Shroff PK, Skerman JH. Humidifier malfunction—a cause of Anaesthesia. 1997;52:992–994.
anesthesia circuit occlusion. Anesth Analg. 1988;67:710–711. 502. McEwan AI, Dowell L, Karis JH. Bilateral tension pneumothorax
487. Adams AP. Breathing system disconnections. Br J Anaesth. 1994; caused by a blocked bacterial filter in an anesthesia breathing circuit.
73:46–54. Anesth Analg. 1993;76:440–442.
488. Caplan RA, Vistica MF, Posner KL, et al. Adverse anesthetic 503. Smith CE, Otworth JR, Kaluszyk P. Bilateral tension pneumothorax
outcomes arising from gas delivery equipment: a closed claims due to a defective anesthesia breathing circuit filter. J Clin Anesth.
analysis. Anesthesiology. 1997;87:741–748. 1991;3:229–234.
489. Funk W, Gruber M, Wild K, et al. Dry soda lime markedly degrades 504. Bissonnette B. Thermoregulation and paediatric anaesthesia. Curr
sevoflurane during simulated inhalation induction. Br J Anaesth. Opin Anesthesiol. 1993;6:537–542.
1999;82:193–198. 505. Gurtner C, Paut O, Bissonnette B. Temperature regulation: phy-
490. Janshon GP, Dudziak R. interactions of dry soda lime with enflurane siology and pharmacology. In: Bissonnette B, Dalens B, editors.
and sevoflurane. Clinical report on two unusual anesthesias. Pediatric Anesthesia—Principles and Practice. 1st ed. New York:
Anaesthesist. 1997;46:1050–1053. McGraw-Hill; 2002. p. 180.
491. Lloyd G, Howells J, Liddle C, et al. Barriers to hepatitis c trans- 506. Luginbuehl I, Bissonnette B, Davis PJ. Thermoregulation? Physiology
mission within breathing systems: efficacy of a pleated hydrophobic and Perioperative Disturbances. In: Motoyama E, Davis PJ, editors.
filter. Anaesth Intensive Care. 1997;25:235–238. Smith’s Anesthesia for Infants and Children. Philadelphia: Mosby
Elsevier; 2006. p. 170.
Development and Evaluation

of Pain and the Stress Response 15
R. Blaine Easley, Kenneth M. Brady, Andrew R. Wolf, C H A P T E R
Kanwaljeet J. S. Anand, and Joseph D. Tobias
INTRODUCTION developed.6 Given the nonverbal nature of neonates and infants,

they are incapable of reporting and describing the subjective
Although withholding analgesia during surgical stimulus is cruel phenomenon of pain. Therefore, it was concluded that these age
for patients of any age, providing anesthesia and analgesia to groups were also incapable of nociception.
neonates undergoing surgery is a relatively new practice. Our Nociception begins with the sensation of the stimulus at the
understanding of the neonatal experience of pain and the effects level of the peripheral nervous system.7 Unlike the specific
of nociception has root in this practice revolution. Today, it is sensations of touch, pressure, heat, or cold, there are no specific
accepted without question that neonates require the treatment of pain sensors. Rather, pain is sensed by free nerve endings. Rapidly
pain and that the provision of general anesthesia is mandatory for adapting pressure receptors are the first to appear during fetal life,
any surgical procedure. With these beliefs supported by the followed by the development of slowly adapting pressure receptors,
literature, surgical practice without neonatal analgesia will be a and then rapidly adapting mechanoceptors. The depolarization
distant memory. However, the erroneous assumptions that created responses of these receptors to mechanical injury, chemical
the aversion to pain control in the neonate and the methods used irritants, and inflammatory mediators are similar to those of adult
to refute those assumptions are instructive. receptors.8 Cutaneous sensory receptors appear in the perioral area
The neonate’s responses to pain includes decorticate reflexes, at 7 weeks postconceptual age (PCA), spread to the hands and feet
and early descriptions of these responses led to the conclusion that by 11 weeks PCA, and are present at all cutaneous and mucous
the lack of localization indicated a lack of conscious perception of surfaces by 20 weeks PCA. Fetal sensory receptors are located
the stimuli.1 This counterintuitive concept was supported with on or close to the skin surface soon after development and, with
anatomic descriptions of the fetal brain showing a lack of the development of the stratum corneum, gradually become
myelination2 and the apparent inability of the human infant to subepidermal. Reflexes to cutaneous sensory stimulation from the
retain memory.3 Pain was also strictly defined as an emotional perioral area of the human fetus occur as early as 7 weeks PCA;
experience, and infants lacked the ability to communicate their from the rest of the face, the palms of the hands, and the soles of
emotional experience. Therefore, demonstrating the need for the feet by 11 weeks PCA; from the trunk and proximal parts of
neonatal analgesia to a skeptical audience required a shift in focus the arms and legs by 15 weeks PCA; and from all cutaneous and
from pain to nociception and from memory to neuroplasticity. mucosal surfaces by 20 weeks PCA.9,10 The development of these
Landmark studies that came from this effort demonstrated a sensory reflexes is preceded by synaptogenesis between afferent
profound stress response with deleterious effects on outcome fibers and sensory neurons in the dorsal horn of the spinal cord.
caused by untreated nociception in the preterm infant4 as well as The sensation of pain is mediated via free nerve endings of A-delta
evidence for long-term hyperalgesia as a neuroplastic consequence and C fibers. These fibers do not demonstrate fatigue; rather,
of untreated neonatal pain.5 Data from these and similar studies repeated or continuous stimulation increases the ease of trans-
forced a change in the practice of neonatal medicine and created mission of the impulse. Histologic studies show that the density
the culture of pediatric and neonatal anesthesia that we now of nociceptive nerve endings in the newborn skin is similar to that
presuppose. In this chapter, we review, from a developmental of adult skin.11 More importantly, the neurophysiologic properties
perspective, the anatomy and physiology of nociception in of the earliest nociceptors are also similar to those of adults.
developing infants and children. Further, we describe the impact Myelinated fibers are the first to grow into the developing spinal
of the physiologic stress response on both the biochemical and the cord and form connections with deeper layers of the dorsal horn,
behavioral acute pain response. Finally, we review commonly used with collaterals to neurons in the substantia gelatinosa. With the
pediatric pain assessment tools and how they are utilized to ingrowth of C fibers (unmyelinated fibers) and synaptogenesis
recognize perioperative pain in the nonverbal infant and child. with superficial dorsal horn neurons, these collaterals undergo
developmental degeneration. Nociceptive stimuli in fetal life (and
in the extremely premature neonate) are transmitted by myeli-
NEUROANATOMY nated A fibers until the maturation of C fiber connections.12
Nociceptive systems develop during the second and third The first-order neuron, whose cell body lies in the paraver-
trimesters of gestation, with further maturational changes tebral ganglion, carries the nociceptive input into the dorsal horn
occurring during the first 2 years of life. Part of the reluctance to of the spinal cord. The first-order neuron synapses with a second-
aggressively treat pain during the neonatal period and infancy was order neuron in the dorsal horn of the spinal cord. The second-
rooted in the belief that the pain system was not yet fully order neuron then crosses the midline and ascends in various
A B
Figure 15-1. A: Pain perception pathway: The spinothalamic tract. first-order and second-order neurons, spinal interneuron, and
descending inhibitory neurons. Later in development, a noxious stimulus will result in (1) activation of the peripheral nerve that will
synapse to a second-order neuron, (2) the second-order neuron (spinothalamic tract) will transmit the response up the spinal cord
to the thalamus, (3) From the thalamus, thalamocortical connections to cortical and subcortical regions result in pain perception.
B: Development of neurotransmitters. At 8 to 10 weeks postconcetpual age, first-order neurons develop to the periphery and this
correlates with the presence of neurotransmitters substance P, calcium gene–related protein (CGRP), and somatostatin. At 12 to
16 weeks postconceptual age, additional transmitters and receptors become available in both the peripheral nerves (glutamate,
vasoactive intestinal peptide, and neuropeptide Y) and the spinal interneurons (met-enkephalin) of the fetus. At 34 to 38 weeks
postconceptual age, descending inhibitory pathways become active and demonstrate increased dopamine and norepinepherine
neurotransmitter activity with serotonin becoming active following birth.
pathways, including the spinothalamic tract, synapsing in the of this nociceptive transmission occurs by the release of met-
thalamus with a third-order neuron, which projects to the sensory enkephalin from local interneurons and norepinephrine, dopa-
cortex.13 In the dorsal horn of the spinal cord, nociceptive input is mine, and serotonin from descending inhibitory axons. These
modified (amplified and inhibited) by descending fibers from the descending inhibitory axons originate in supraspinal centers and
central nervous system and interneurons within the dorsal horn. terminate at all levels of the spinal cord and brainstem. During the
This modulation is mediated via various chemical compounds first and second trimesters up until the latter half of the third
(substance P, adrenergic agents, serotonin, and endogenous trimester, an imbalance exists between the mechanisms that
opioids), which bind to the first- or second-order neuron via facilitate and inhibit nociceptive input, with the former being
specific receptor systems (Figure 15–1A). favored. Of the nociceptive neurotransmitters, substance P,
In the first trimester of pregnancy, development of the spinal calcitonin gene–related peptide, and somatostatin are expressed
cord and central nervous system begins with the closure of the in the dorsal horn by 8 to 10 weeks PCA. Glutamate, VIP, and
neural canal. At this time, the dorsal horn begins to appear. neuropeptide Y appear at 12 to 16 weeks PCA. Modulation of
Electron microscopic and immunochemical studies demonstrate incoming noxious stimuli in extremely premature infants may
that the development of the various neuronal cell types in the occur through the local release of met-enkephalin, which is first
dorsal horn with their laminar arrangement, interneuronal expressed at 12 to 16 weeks PCA. However, this mechanism is
connections, and the expression of their specific neurotransmitters unlikely to be effective in diminishing the transmission of
and receptors begins before 13 weeks of gestation and is completed intensive painful stimuli. In the latter half of the third trimester,
by 30 to 32 weeks PCA. Initially, the receptive fields of dorsal horn with the maturation of the descending inhibitory pathways from
neurons are very large, with an extensive overlap between the supraspinal centers, inhibition of incoming sensory stimuli can
receptive fields of adjacent neurons. As maturation occurs, the occur with the release of dopamine and norepinephrine in the
receptive fields of individual dorsal horn cells progressively dorsal horn of the spinal cord. These neurotransmitters are first
decrease and can be more precisely defined.14 On a cellular level, expressed at 34 to 38 weeks of human gestation, followed by
the transmission of nociceptive impulses through the dorsal horn serotonin, which develops during the postneonatal period.15,16
of the spinal cord is mediated and modulated via the release of Conduction of nociceptive impulses to the supraspinal centers
excitatory neurotransmitters (see Figure 15–1B), such as substance occurs via the spinothalamic, spinoreticular, and spinomesence-
P, glutamate, calcitonin gene–related peptide, vasoactive intestinal phalic tracts located primarily in the anterolateral and lateral white
polypeptide (VIP), neuropeptide Y, and somatostatin. Modulation matter tracts of the spinal cord. Lack of, or decreased, myelination
CHAPTER 15 ■ Development and Evaluation of Pain and the Stress Response 261
in these tracts was previously proposed as an index of immaturity those in the adult, but even at this stage, different classes of afferent
of the neonatal central nervous system and was used to support responses to noxious stimuli can be demonstrated. Initially,
the argument that neonates cannot feel pain or do not react to stimulation of cutaneous afferents fail to produce suprathreshold
it in the same manner as adults. This argument was widely excitation in dorsal horn cells, but by birth, depolarization can be
supported despite the common knowledge that incomplete produced from light touch alone.22 However, whereas the synaptic
myelination does not imply lack of function but merely imposes a linkage remains weak at birth, suprathreshold stimulation provo-
slower conduction velocity in the central nerve tracts of neonates. kes a long-lasting hyperexcitable state in the dorsal horn cells.24
In addition, any slowing in the central conduction velocity would Polymodal nociceptors, which pass to the dorsal horn via
be completely offset by the shorter interneuronal distances that C fibers, show fully mature responses to pinch, heat, and chemical
must be traveled by the impulse when comparing an infant with stimulation by birth.25 However, despite their observed anatomic
the much larger (and longer) adult.17 The nociceptive tracts to the connections, these C fiber afferents fail to evoke activity in the
brainstem and thalamus are completely myelinated by 30 weeks dorsal horn cells until a week after birth. Thus, whereas the C fiber
of human gestation, and the thalamocortical pain fibers are fully connections remain immature at birth and fail to directly transmit
myelinated by 37 weeks. The timing of the thalamocortical their nociceptive input, they may greatly increase the response to
connection is of crucial importance for cortical perception, other noxious (A fibers) and non-noxious inputs. This, together
because most sensory pathways to the neocortex have synapses in with the large receptive fields observed in dorsal root ganglion
the thalamus. In the primate fetus, thalamic neurons produce cells, may increase the likelihood of a central response from the
axons that arrive in the cerebrum before midgestation. These relatively immature nervous system. The lack of functional des-
fibers remain just below the neocortex until migration and cending inhibitory pathways from higher centers also contributes
dendritic arborization of cortical neurons are complete and finally to the potentially excitable and poorly damped responses to
establish synaptic connections at 20 to 24 weeks PCA.17 afferent inputs.
The functional maturity of the cerebral cortex is suggested
by the presence of fetal and neonatal electroencephalographic
(EEG) patterns and by the behavioral development of neonates. Central Integration of Afferent Inputs
Intermittent EEG bursts in both cerebral hemispheres, first seen at In the human, complex central integration of afferent sensory and
20 weeks PCA, become sustained at 22 weeks and are bilaterally nociceptive input is present at 30 weeks of gestation. Visual- and
synchronous at 26 to 27 weeks PCA. By 30 weeks, the distinction auditory-evoked potentials are present,18 and a complex EEG
between wakefulness and sleep can be made on the basis of EEG pattern reactive to external influences is seen at this time.19 Klimach
patterns.18,19 Cortical components of somatosensory-, auditory-, and Cooke have demonstrated the presence of somatosensory-
and visual-evoked potentials have been recorded in preterm babies evoked responses (SERs) in the preterm neonate.20 In fact, SERs
before 26 weeks PCA.20 Several forms of behavior imply cortical have been measured in infants as young as 28 weeks of gestation.
function during fetal life. Well-defined periods of quiet sleep, These investigators also demonstrated that the velocity of both
active sleep, and wakefulness occur even in utero, beginning at peripheral nerve conduction and central conduction increased
28 weeks PCA. In addition to specific behavioral responses to with gestational age. However, they observed considerable vari-
pain, neonates have various cognitive, coordinative, and associa- ability in peripheral velocity and central processing in younger
tive capabilities in response to visual and auditory stimuli, attesting infants, suggesting that large individual differences exist in
to the presence of cortical function and intact processing of maturation rates. SERs continue to mature during infancy.26
nociceptive input. Several lines of evidence suggest that the Subarachnoid injections of lidocaine in the ex–premature infant
complete nervous system is active during prenatal development cause rapid loss of the SERs that correspond to the onset of motor
and that detrimental or developmental changes in any part can and sensory blockade. The offset of the block can be monitored
affect the entire system.13 with the return of SERs and shortening of the latency back to the
baseline.27 Positron-emission tomography scans in the infant have
shown that glucose utilization is maximal in the sensory areas of
NEUROPHYSIOLOGY the cerebral cortex, implying a high level of activity.28
OF NOCICEPTION Recent evidence also suggests that cortical activation occurs
after painful stimuli in preterm neonates.29 Bartocci and cowor-
Development of the Response kers, using near-infrared spectroscopy in preterm infants at 28 to
to Pain Stimulation 36 weeks PCA, demonstrated increased blood flow in the soma-
The human fetus is capable of spontaneous movements and tosensory cortex but not in the occipital cortex after venipunc-
complex responses early in gestation. Reflex movement in ture.30 In a similar study, Slater and colleagues recorded cortical
response to direct stimulation begins at 7.5 weeks PCA, initially activation after heel sticks in 18 infants between 25 and 45 weeks
localized to the head and neck region.21 Sensitivity develops in PCA.31 No cortical response was noted after tactile stimulation,
a craniocaudal direction, with the lower limbs responding by even when this stimulation was accompanied by reflex limb
14 weeks PCA. Data from the immature rat and other animals withdrawal. Taken together, these studies provide additional
show that responses to stimulation are initially inconsistent, evidence that the conscious sensory perception of painful stimuli
nonspecific, and poorly localized.22 However, if a response is is present even in preterm newborns.
achieved, it can be extremely exaggerated and long-lasting.23 These
observations tie in well with neurophysiologic data in animals and Interneuronal Connections
clinical work with preterm human infants. Single-cell studies from
the dorsal root ganglion of the rat show that cutaneous receptive Given the data presented in the section on Development of the
fields are present in the hindlimb as soon as innervation to the Response to Pain Stimulation, it is now well established that even
skin has occurred.24 The firing rates and durations are lower than premature human newborns have the functional components of a
pain system and are capable of pain perception. In fact, the

development of a pain system suggests that the pain threshold may
be decreased in preterm neonates compared with term neonates or
older infants. The cutaneous flexor reflex has a lower threshold in
preterm neonates than in term neonates or adults.32 Thresholds
for the flexor withdrawal reflex are decreased (sensitized) after
repeated stimulation or local tissue injury in preterm neonates.
This prolonged hypersensitivity is abolished if topical analgesia is
applied before the injury.33 Sensitization of this reflex may result
from immature segmental or descending inhibition in the spinal
cord, the immaturity of other spinal or supraspinal mechanisms,
or factors associated with the intensive care environment and
critical illness (e.g., noise).
Human studies are necessarily less invasive than animal work,
but developments in minimally invasive monitoring and studies
Figure 15-2. The effect of increasing postconceptional age
that compare nociceptive reflexes with animal models provide
(PCA) and site of stimulus on cutaneous withdrawal threshold
additional valuable information. The cutaneous withdrawal reflex,
in the neonate. Below 30 weeks PCA, the thresholds within the
previously termed the “nociceptive flexor reflex,” occurs when the
receptive field are uniform at all sites tested (sole, ankle, leg).
limb withdraws in response to a stimulus of sufficient intensity. In
adult humans, it is elicited by a specific nociceptive stimulus to After 30 weeks, a gradient of thresholds is observed, increasing
the limb, with a threshold similar to the pain threshold, whereas progressively from the sole of the foot toward the knee. A and
in neonates, it can be elicited simply by touching the limb34; hence, B: Adapted from reference 34.
the change in terminology. The reflex is observed even in the most
premature infants, but the responses change considerably with early in gestation, their concentrations are usually very low, and
maturation.34 Fitzgerald used von Frey hairs to give a graded they may not always be found at sites that suggest a functional
intensity of stimulus and obtained a control threshold for role.38 By contrast, receptors are often seen in higher densities and
withdrawal of the foot.33 The cutaneous withdrawal reflex was have a more widespread distribution than in adult life, which may
compared between infants whose feet had received regular heel facilitate responses at a time when only low levels of transmitter
lancing with or without application of a topical anesthetic cream. are available.7 The transient appearance of receptor populations
Heel lancing caused hypersensitivity or wind-up of the reflex but that have ceased to be expressed by birth39 remains puzzling and
only in the heel-lanced foot. The application of a topical anesthetic demonstrates the large gap that exists between what we know of in
cream could prevent development of the hypersensitivity. vitro cytochemical findings and our observations and under-
Contralateral stimulation of the other foot at the time of testing standing of in vivo nociception. Opioid receptors change both in
suppressed the withdrawal response, a centrally mediated pheno- numbers and in receptor type during development. Pasternak and
mena seen in adult humans and the rat pup. A more detailed study associates demonstrated that, in newborn rats, high-affinity
followed that confirmed that the youngest infants had the lowest binding sites for a triated encephalin ligand increased by up to
threshold for the response and that the threshold for the reflex
threefold in the first 2 weeks of life, whereas during this period, a
increased with postconceptual age.35 The receptive field for the
large rise in analgesic response to morphine occurred.40 The level
reflex was also much larger in preterm infants and could be elicited
of high-affinity binding correlated with the median effective dose
not only from the foot but also from the leg (Figure 15–2).
(ED50) values for morphine analgesia. By contrast, the effects of
The impression that emerges is that even the very preterm
infant has complex interneuronal connections capable of inte- morphine on ventilatory drive during this period (2–14 d after
grated responses to tactile or nociceptive input. These infants also birth) were constant. Other studies have confirmed the increase in
show inconsistent responses to external stimuli, which may reflect the number of opioid receptors and changes in their binding
the late functional connections of sensory afferents (particularly C affinities during development.41 Opioid receptor expression is
fibers) within the spinal cord. However, the combination of larger dynamic even during intrauterine development.42
receptive fields, recruitment of non-nociceptive afferents, and
reduced inhibitory controls results in “underdampened” responses
(long-lasting, exaggerated, and poorly localized) once afferent
Gene and Protein Expression
stimuli have achieved central activation above a threshold level. During normal brain development, whether animal or human,
Inconsistency of response to more complex noxious stimuli may significant expansion and growth of specific neurons and synapses
also reflect the profound effects that conscious state36 and other occur, known as synaptogenesis. Most important, this crucial
external responses37 have on behavior. period of neuronal expansion is guided by targeted deletion of
other cells (apoptosis). These processes are under the control of
genetic, environmental, cellular, hormonal, and other factors (such
CYTOCHEMISTRY as stressful stimuli and anesthetic agents). Depending upon the
Receptors Involved in Pain Perception age and brain region, as many as half of the synaptic connections
made in the first year of life will be gone a few years later. The
Studies of developmental cytochemistry in animal models have nociceptive response to stress and pain becomes important to the
focused on substance P, opioid peptides and receptors, N-methyl- dynamic molecular and cellular processes that simultaneously
D-aspartic acid (NMDA) receptors, and the expression of the C-fos signal the death, or “pruning,” of certain neurons and the
gene. Although transmitters can be demonstrated to be present reinforcement and growth of others.43
The ability to evaluate and analyze gene and protein expression NOCICEPTION AND PAIN
on cellular and tissue levels has led to a more systems-based
approach to the adaptation to nociceptive triggers, resulting in
PERCEPTION IN THE INFANT,
new insights into the physiologic responses to painful stimulus. CHILD, AND ADOLESCENT
The implication of such varied responses in rodent models allows General Considerations
us to assess the earliest alterations in gene expression within
peripheral nerves, the spinal cord, and brain in both acute and Based on the previous review of the anatomy, physiology, and
chronic pain response models.44 molecular mechanisms of nociception, it is clear that nociception
Analysis of the brain, spine, and peripheral nerves using and, perhaps, pain perception are present during gestation. In
genomic microarray techniques in mature and fetal animal models addition, the systems are dynamic, changing during both the
of nociception has informed our understanding of the dynamic, intrauterine and the extrauterine periods. Having discussed the
diverse, and variable molecular responses of neural pathways to sensory (afferent) mechanisms, we now examine the effects
pain. Because these integrative techniques are rapidly evolving, (efferent responses) that painful stimuli have on the developing
high-throughput techniques combined with bioinformatics have infant and child. The International Association for the Study of
enabled the first system-wide gene-expression analysis, termed Pain (IASP) has defined pain as “an unpleasant sensory and
genomics. These approaches have been applied to protein analysis, emotional experience associated with actual or potential tissue
termed proteomics, and have resulted in the identification of damage, or described in terms of such damage. Pain is always
previously unrecognized alterations in actual transcribed and subjective; each individual learns the application of the word
activated proteins from within a specific cell line and/or specific through experiences related to injury in early life.”56 The “sensory
tissues.15,45 experience” of pain serves to alert the individual to potential or
Neurotransmitters mentioned in the section on Neuroanatomy actual bodily damage and puts in place protective responses
provide excellent examples of the utility of these techniques. First, that may vary from withdrawing the threatened limb (noxious
studies have localized the expression of early inducible genes external stimulus) to immobilizing the limb to prevent further
(EIGs) with the Fos protein in the specific areas of the dorsal horn pain (bone fracture). The “emotional experience” of pain leads to
associated with primary afferent termination.46 In this rodent an expression of pain as a behavioral language that has some
model, precursor C-fos gene and protein expression can be instinctive properties (e.g., crying) and other learned responses
demonstrated after formalin or capsaicin injection, but it does not that are modulated by experience, social development, and other
occur after application of mustard oil, which is a specific stimulus factors. Clearly, the neonatal nociceptive responses are initially
for C fiber afferents.47 This observation correlates well with the purely instinctive and serve to protect the infant, but does this
neurophysiologic data on the later development of central C fiber imply that the noxious stimulus does not induce emotional
connections.25 These integrative techniques have also resulted in distress? Although the IASP definition implies that pain is learned
the identification of genetic variations in the opioid receptor. through experience, others have maintained that pain is an
Following the studies of Pasternak and associates,40 these tech- inherent quality of life itself and that the neonate does not require
niques have identified within animal and human populations previous experience to sense emotional distress.57
gene-splice variants and single-nucleotide polymorphisms that As the infant develops, behavioral responses to painful stimuli
can better explain the clinical variability in analgesia seen between change because of maturation of nociceptive pathways and their
drugs that bind to altered opioid receptors differently.48 Future integration at higher centers as well as the development of
directions in molecular pain research will develop molecular cognitive and emotional skills. Older infants develop anticipatory
signatures of neuronal and receptor responses that correlate with responses to pain by 6 months of age, and distraction can be used
our phenotypic definitions of acute and chronic nociception and in this age group to reduce the duration and magnitude of
will lead to more personalized pain treatments based on these responses to painful stimuli.58 The neonate responds to a heelstick
molecular characterizations (pharmacogenomics).49 with a facial response of pure pain, but it has been suggested that
by 18 months of age the facial expression has changed to pain
mixed with anger. Groaning, flinching, muscle rigidity, and
Substance P and Opioid Peptides resistance to handling develop later as a learned response in the
In the human fetus, substance P appears in the dorsal horn at 8 to older infant and child.59,60 Fewer data are available on age-related
10 weeks PCA50 followed by enkephalin at 12 to 14 weeks.51 changes in nociception in the older child and adolescent. Pain
Endorphinergic cells appear early in fetal life in the anterior lobes thresholds appear to increase with age, and adolescents rate lower
of the pituitary gland and, by 20 weeks PCA, are responding to levels of pain on both behavioral and self-reporting scales for
stimulation by corticotrophin-releasing factor.52 Human data similar noxious stimuli than do younger children.61 It is unclear
confirm the changing profile of opioid receptors with develop- as to whether these changes represent improved self-control and
ment. A study that compared opioid binding sites in the human learned coping strategies or that pain perception itself changes
cerebellum reported more opioid-specific binding sites in the with age. Even within similar age groups, differences in behavioral
developing cerebellum than in the mature cerebellum, and the responses to pain occur, representing both intrinsic personality
ontogenic profile of opioid receptor subtypes differed in that differences in pain response and other learned cultural responses.
increased Δ and κ receptors were found in infant tissue at birth Infants who are judged to have a better general mood in everyday
compared with the adult, whereas mu receptor–binding affinity life have shorter pain responses to blood-sampling procedures
and capacity fell dramatically in neonatal life.53 Again, this than infants with more unhappy dispositions.62 Boys respond
provides a potential explanation for the variable responses to more quickly to painful stimuli than do girls, and responses to
different opioid drugs and the development of extreme tolerance noxious stimuli are dependent on pre-existing medical conditions
observed in some critically ill infants and children.54,55 and the state of arousal at the time of the stimulus.4,63
Effects of Nociception handling phase rather than during the actual procedure. This was
in contrast to the older infants, who displayed maximum response
The initial effects of nociception can be categorized under during the procedure itself. Measurement of ventilatory frequency
physiologic responses, behavioral responses, and stress responses, and RR interval on the electrocardiogram has shown that vagal
and these have been used either individually or together to form tone is significantly reduced during painful procedures in the
the basis of measurement of the severity of the noxious stimulus. neonate and that the reduction is related to the intensity of the
These responses can be elicited by noxious stimuli from the surgical stimulus.70
preterm neonate onward, but age-related differences do exist. Other physiologic responses that have been investigated in the
context of nociception are transcutaneous oxygen tension,
Physiologic Responses ventilatory patterns, and sweating. Large variations in oxygen
saturation have been described as a response to surgical stimu-
Hemodynamic responses to fetal surgery occur at as early as 18
lation,71 but the changes are inconsistent. Neonates undergoing
weeks PCA (Table 15–1).64 Middle cerebral artery pulsatility index
circumcision or heelstick can respond with a fall in transcutaneous
(MCA PI) was measured in fetuses undergoing therapeutic
oxygen tension.72 However, some neonates have no changes73 or
procedures that involved puncture of the fetal trunk, and results
were compared with a matched group that had umbilical cord even an increase in response to a noxious stimulus.74 Noxious
puncture. MCA PI fell significantly in the fetuses undergoing stimulation usually produces a rise in ventilatory rate; however,
invasive procedures, indicating a significant fall in cerebrovascular breath-holding and apnea can occur and result in a fall in oxygen
resistance during the noxious input. Heart rate and blood pressure saturation. Ventilated preterm neonates frequently “fight the
have both been extensively studied as potential indicators of infant ventilator” when subjected to surgical procedures with inadequate
pain. A rise in heart rate occurs from activity, sepsis, pyrexia, analgesia, producing significant changes in oxygen saturation and
drugs, and both noxious and non-noxious stimulation, making it raised intrathoracic pressure that can precipitate pneumothorax.
a relatively poor measure of nociception. The average increase of Water loss from the palm increases 200% to 300% after a
heart rate during heelstick in a group of neonates has been heelstick.75 The effect is dramatic, taking only a minute to develop
reported to be 49 ± 27.5 beats/min, indicating the large inter- and returning to the baseline within 5 minutes. The response is
individual variation in response.65 Surprisingly, circumcision, graded according to the intensity of painful stimulus but is also
which represents a much greater noxious stimulus, does not affected by crying and level of arousal.76
produce a larger rise in heart rate,66 although others have reported Fluctuations in arterial oxygen content and blood pressure may
that heart rate changes in the neonate are related to the magnitude have particularly important consequences for clinical and sub-
and duration of the stimulus.67 These same studies have observed clinical neurologic compromise in the preterm infant. Alterations
that the postcircumcision heart rate returns to baseline within 10 in cerebral blood flow related to nursery care and procedures have
minutes of the procedure despite the painful nature of the wound. been demonstrated,77,78 Noninvasive measurements of cerebral
Systemic blood pressure may be a better measurement of oxygenation using near-infrared spectroscopy have demonstrated
nociception than heart rate. It varies according to state of arousal, decrements of 20 to 50% in cerebral oxygenation, lasting up to 60
drugs, and other external factors but is much less sensitive than seconds during routine nursery care.79 Further, Slater and collea-
heart rate to these effects. Blood pressure and intracranial pressure gues demonstrated a relative increase in ipsilateral cortical blood
responses to heelstick, surgery, and endotracheal intubation can be volume compared with the contralateral side during a painful
extreme. Neonates undergoing awake nasotracheal intubation stimulus in the infant.31 Volpe reported that normal arterial blood
were reported to have a rise in mean arterial pressure of 57% and pressure can shift close to the upper autoregulatory limit, render-
a similar rise in intracranial pressure during the procedure.68 It is ing the infant at risk of hemorrhage during nociceptive stimula-
now unusual to observe such large rises in blood pressure during tion.80 Decrements in cerebral blood flow may preferentially affect
invasive procedures because of the more appropriate use of cerebral white matter. Immature autoregulation of cerebral blood
anesthesia and analgesia. Age-related differences in cardiovascular flow in the preterm infant may render these infants vulnerable to
responses to noxious stimuli have been reported.69 In a study on various neurologic events (such as intraventricular hemorrhage) as
lumbar puncture in preterm infants, infants younger than 32 well as a wide range of subclinical brain alterations that may be
weeks PCA showed the greatest rise in blood pressure during the associated with less severe, but pervasive, learning and behavior
problems associated with the long-term neurologic impairments
TABLE 15-1. Main Physiologic Responses to Pain associated with prematurity.81
Function Effect of Pain Stimulation
Behavioral Responses
Middle cerebral artery Decrease
From laboratory evidence, we know that the central nociceptive
pulsatility index
connections remain immature in the preterm neonate (Table 15–
Intracranial pressure Increase
2). However, the larger receptive fields, the immaturity of the
Systemic blood pressure Increase
descending inhibitory pathways, and the ability of non-C fibers to
Heart rate Increase (inconstant in neonates)
transmit nociceptive inputs into the dorsal horn facilitated by
Transcutaneous oxygen Decrease
subthreshold C fiber effects result in an underdamped, poorly
tension
discriminative system with a potential for very exaggerated
Vagal tone (amplitude of Decrease
responses. This model is borne out in Andrews and Fitzgerald’s
sinus arrhythmia)
observations on the cutaneous withdrawal reflex34 and other
Palmar sweating Increase
studies that have shown that newborn reactions to painful stimuli
Cerebral oximetry Decrease
can be diffuse, unlocalized, or sometimes completely absent.82 This
TABLE 15-2. Nonverbal Behaviors Associated With Pain coworkers have studied changes in cortisol and beta-endorphin
concentrations in response to intrauterine needling.92 Fetal blood
Facial expression Grunting samples taken from the intra-abdominal portion of the umbilical
Vocalizations Restlessness vein via the fetal abdominal wall were associated with a time-
Body movements Protective body movement dependent increase in cortisol and beta-endorphin concen-
Social interaction Muscle tension trations, whereas samples obtained from the placental cord were
Clenched teeth Immobility not associated with similar increases in these hormones. The
Wrinkled forehead Pacing neonatal stress responses to surgical trauma are present from birth
Biting lips Rhythmic movements and appear to be greater in magnitude93 and to cause significantly
Scowling Silence greater postoperative catabolic changes when compared with older
Closing eyes tightly Withdrawn children.94
Widely opened eyes or mouth Reduced attention span Given the fragility of neonatal homeostasis and the reduced
Crying Avoidance of painful metabolic and cardiovascular reserves in this age group, an
Moaning situations excessive stress response is potentially more harmful. Although it
Gasping Focus on pain relief is unclear whether more complete suppression of the stress
Groaning measures response results in improved postoperative recovery for most
children and adults undergoing elective surgery,95 the sick patient
at the limits of survival may be an exception. Adult and pediatric
failure to respond consistently to a standard noxious stimulus clinical studies both suggest that critically ill patients may benefit
such as circumcision can confound any attempt to quantify pain from techniques that reduce the stress response. Anand and
using behavioral measurement. By contrast, careful studies on colleagues have further demonstrated this observation in a series
behavioral responses to heelstick have shown that specific of studies evaluating anesthetic management and the stress
expressions such as eye squeezing, brow contraction, nasolabial response of the neonate93,96—perhaps best illustrated in their study
furrowing, taut tongue, and mouth opening are specific for this of very preterm infants undergoing patent ductus arteriosus
type of painful stimuli.36 Other studies of heelstick have shown (PDA) ligation, in which neonates with inadequate analgesia had
that, in addition to facial movements, other body movements can large rises in catecholamines, glucagon, glucocorticoid hormones,
be specific and graded according to the stimulus.83,.84 glucose, and gluconeogenic substrates.4 The metabolic stress
Spectrographic analysis of the sounds made by a crying infant response was mitigated in neonates receiving 10 μg/kg of fentanyl
in response to a noxious stimulus suggests that they are distinct before surgery. Further clinical studies from the same investigators
from those resulting from other causes such as hunger or fear.85 have suggested that control of the stress response in infants
Moreover, the latency and duration of the first cry can be cor-
undergoing cardiac surgery decreases circulatory, ventilatory, and
related with the intensity of the stimulus.86 However, cry
metabolic complications. The stress responses and outcomes were
characteristics do not appear to be entirely specific for pain. They
evaluated in neonates undergoing cardiac surgery under “deep
appear to indicate a more general level of distress that is modified
anesthesia” with high doses of sufentanil and were compared with
by the interaction between the infant and the observer. Therefore,
those receiving a halothane-based anesthetic. The authors
with the exception of immediate responses to point pain
reported no deaths out of 30 patients in the sufentanil group
(heelstick), the quality of an infant’s cry is not a reliable measure
compared with 4 out of 15 in the control group. A reduced
for pain intensity. However, the presence of a cry and the ability to
incidence of sepsis, metabolic acidosis, and disseminated
modify this behavior by comfort or distraction have been used
intravascular coagulation was also seen in the high-dose opioid
effectively as part of a multidimensional approach in the evalua-
group.97 The findings of these studies suggest an important
tion of postoperative pain.87,88
correlation between reduction in the stress response and reduced
Painful stimuli have profound effects on infant sleeping
postoperative morbidity and mortality.
patterns. Normally, the newborn spends approximately 50% of its
sleeping time in rapid eye movement (REM) sleep.89 Painful These studies provide evidence that the release of catabolic
stimuli result in disruption of the normal sleep pattern with the stress hormones leads to a breakdown of fats, proteins and
selective loss of REM sleep for up to a day after surgery.90 Less is carbohydrate stores at any age. The latter may be particularly
known about long-term effects of disturbance of the sleep-wake detrimental in neonates, who have limited stores. Further, stress
cycle caused by repeated painful stimuli, but data on behavioral hormone interference with immune function may delay wound
outcome in preterm neonates are worrisome, given that healing and increases the risk of sepsis. Studies regarding the
preservation of REM sleep is essential for the ability to cope with long-term effects of these neurohumoral responses suggest that
stress and the maintenance of psychological well-being.91 Not only the developing infant is vulnerable and that these changes may
do painful stimuli alter sleep patterns, but sleep patterns also alter result in increased neurologic morbidity.98 High concentrations
responses to painful stimuli. Studies on behavioral responses to of glucocorticoids in animals are associated with hippocampal
heel lancing show that the facial response and cry varied with the damage and exacerbation of hypoxic-ischemic neuronal
alertness of the infant at the time of the stimulus.36 damage.99,100 Similar effects of hippocampal volume loss have been
observed in adult humans with Cushing’s syndrome,101 and a
higher incidence of cerebral atrophy and dementia has been noted
Stress Response in victims subjected to torture.102
Trauma to the body induces local changes (the inflammatory By contrast, complete elimination of the stress response may
response) and systemic hormonal and metabolic changes (the also be undesirable. Suppression of the pituitary adrenocortical
stress response). Stress responses can be elicited by noxious system in critically ill patients has been reported to have
stimuli, even during fetal development. Giannakoulopoulos and lethal consequences,103 and high-dose opioids can adversely affect
cardiovascular and ventilatory function to the point that hemo- SECONDARY EFFECTS
dynamic (inotropic and chronotrophic) and ventilatory support
may be required. Opioids have also been shown to have a
OF NOCICEPTION
dose-dependent and time-dependent effect on cell-mediated Although newborn infants often have short-lived behavioral and
immunity,104 which is disturbing in the context of a critically ill stress responses to noxious stimuli, evidence suggests that surgical
patient in an intensive care unit. Therefore, a technique that trauma or injury at this age can have long-term consequences for
reduces the stress response should not be necessarily regarded as sensory and pain behavior in infancy. Studies of neonates exposed
better based solely on a measurable biochemical difference105 but to repeated noxious stimuli have demonstrated the development
should be considered within an individualized context. Infant data of hypersensitivity to further stimulation.33 Circumcision with-
suggest that doses of opioids much lower than previously recom- out adequate analgesia can cause behavioral changes such as
mended can be used to adequately suppress responses to major irritability, reduced attentiveness, and poor orientation that may
surgery.106 Fentanyl doses of 25 μg/kg appear quite adequate continue for several days, long after the expected duration of
without causing significant cardiovascular depression. Regional pain.114 More recently, it has been shown that awake circumcision
anesthetic techniques with either epidural or spinal analgesia can can have behavioral effects that can last for months after the
been used to provide analgesia and stress reduction without procedure.5 During a study on infant pain responses to routine
ventilatory depression.16,107 inoculations, Taddio and associates observed that male patients
Markers commonly used to measure the stress response had a greater response than females and that males circumcised at
include catecholamines, cortisol, adrenocorticotropic hormone birth appeared to have a greater response to the vaccination
(ACTH), beta-endorphin, and serum glucose concentration. injection at 4 to 6 months of age than uncircumcised patients.115
Catecholamines have very short half-lives and reflect an instan- This interesting observation was followed up by a prospective trial
taneous picture, with wide variations in plasma levels from minute of 87 males who had either no circumcision, neonatal circum-
to minute. Measurement cannot be taken at the bedside. By cision with topical EMLA (eutectic mixture of local anesthetics)
contrast, whole blood glucose can be measured immediately and cream, or circumcision without any analgesia.5 Patients were
accurately. Blood glucose concentrations are tightly controlled in videotaped during their vaccination procedure at 4 months and
patients who are not receiving intravenous glucose and who are analyzed for pain response and duration of cry. The results
not stressed. A rise in blood glucose may be used to give an confirmed that patients undergoing neonatal circumcision
accurate picture of stress responses in both the pituitary-adrenal without analgesia had altered behavioral response to pain even
and the pituitary-cortical axes and can be measured in real time, 6 months later and that the application of topical EMLA cream
even in infants.108 at circumcision could partially prevent this hypersensitivity
The harmful effects of the stress response are evident, and
(Figure 15–3).
various agents are effective at achieving adequate anesthesia and
Early pain experience may also alter a child’s perception of
analgesia. However, increasing evidence in developing animal
a noxious stimulus,116 and long-term postoperative behavioral
models suggests that many routine anesthetic agents may be
differences during normal activity have been suggested from twin
harmful to the developing brain (see Chapter 3). The possibility,
studies.117 Alleviation of pain and distress are, therefore, especially
as suggested by animal models, of anesthesia-induced neuronal
cell loss during an otherwise uneventful procedure has sparked important in this age group. Comforting strategies that reduce
vigorous discussions among anesthesiologists about the safety of the stress of interventional procedures in preterm infants are
various anesthetic practices in human newborns and infants. associated with improved developmental and clinical outcomes.118
Interestingly, the most commonly used anesthetics that have been By contrast, opioids need to be used with caution in the manage-
investigated for their neurodegenerative properties (e.g., benzo- ment of pain in neonates. Administering opioids to animals during
diazepines, ketamine, propofol, nitrous oxide, and isoflurane) the perinatal period increases their pain sensitivity into adult
have indeed been shown to exacerbate neuronal cell death or life.119 Human data have suggested that previous opioid exposure
apoptosis.109,110 Whether this is acceleration of the normal ap- may increase subsequent pain sensitivity120 and may be associated
optotic process or pathologic cell death remains unclear.111 with increased self-destructive behavior in adolescence.121
Regardless, the anesthesiologist caring for a newborn is faced with Certainly ex–premature infants that have been previously sub-
the conundrum that no analgesia is harmful and yet the very jected to opioid infusions can be difficult to manage in the
anesthetics administered to the developing brain may also cause pediatric intensive care unit even years later owing to an apparent
long-term harm. Contrary to the growing literature that anes- sensitivity to noxious stimuli that does not appear to be well
thetics cause harm to the developing rodent brain, a recent study controlled with usual doses of opioids.
in an infant rat model found that neurodegenerative effects and
behavioral impairment after repetitive painful stimulation were
ameliorated by a low-dose of ketamine (5 mg/kg).112 Notably, this EVALUATION OF PAIN
study differed from the others in both the modest dose of Factors Affecting the Evaluation of Pain
anesthetic given (ketamine at 5 mg/kg vs 20 mg/kg), and the
presence of a painful stimuli. This finding offers an alternative The evaluation of pain in children cannot be reduced to a
argument that nociceptive stimulation during surgical anesthesia standardized reproducible variable because of the highly
may protect the brain from anesthesia-induced neurodegenera- individual and diverse nature of the experience. The older child
tion, whereas anesthetics administered during noxious surgical has the ability to communicate directly with an assessor through
stimulation protect the brain from the deleterious effects of speech, but the infant (from the Latin infans meaning incapable of
unopposed painful insults.113 At this time, no evidence exists that speech) does not. Moreover, pain evaluation is a broader term than
either opioids or α2 agonists contribute to apoptotic processes pain measurement, because it encompasses cognitive, physiologic,
within the developing brain. sensory, behavioral, affective, sociocultural, and environmental
factors.122 Such issues must clearly be taken into account when

interpreting the “score” obtained from a pain measurement. Most
currently used pain assessment tools concentrate on behavioral,
physiologic, and sensory aspects of pain to provide quantitative
measurements. However, the modulating influence of cognitive,
affective, sociocultural, and environmental factors in the quanti-
tative measurement of pain can be significant, particularly in the
adolescent. Well-motivated young adults who have been raised in
a sociocultural group that is not given to expansive expressions of
distress are likely to provide lower pain scores for the same
stimulus than are others. Even in the newborn, general disposition
and mood can affect behavioral aspects of pain,62 resulting in
a varied pain response that must be regarded as inherent to
the individual. Children with cognitive difficulties represent a
special problem, because their responses are not equivalent
to those of other children of comparable age. Pain assessment
must be highly individualized for these children in close coopera-
tion with their parents, because conventional tools may be of
limited value.
Assessing pain based on physiologic measurements is proble-
matic, because variables such as blood pressure, heart rate,
and oxygen saturation change in response to many events other
than pain. Even behavioral responses can be modified consi-
derably by pacifying measures, state of arousal, and distraction.
One of the most interesting phenomena to be described is the
effect of oral sucrose in modifying neonatal pain responses. Oral
sucrose given to an infant immediately before heelstick can reduce
overall crying time and heart rate in a dose-dependent fashion.123
The effect has been postulated to result from the release of
endogenous opioids during non-nutritive sucking. Further
evidence for this mechanism is that the effect has been reported to
be eliminated by the administration of opioid antagonists such as
naloxone. Although it has been claimed that this phenomenon
represents true “analgesia,” other studies have shown that oral
pacifiers do not alter cardiovascular or stress responses to circum-
cision pain.124 However, many of these studies did not include the
use of sucrose solutions, which seem to play a key role in the
provision of this type of analgesia. It has, therefore, been suggested
that nonpharmacologic techniques such as massage, auditory and
tactile stimuli, and oral sucrose must be regarded as important
coping strategies that can modulate “pain experience” and “pain
measurement,” but should not be regarded as an “analgesic.”125
As with any type of treatment or therapy, a method of assessing
response is the first step in achieving success. Such is also the case
with pain management in infants and children, because a means
of assessing pain helps to determine both the severity of pain and
the child’s response to therapy. These tools range from simple,
bedside checklists with four or five components that require only
5 to 10 seconds to complete to lengthy, involved surveys that are
cumbersome and time-consuming in a busy office practice or
Figure 15-3. Infant pain responses to vaccination after neonatal hospital setting. Early tools to assess pain in adult patients, which
circumcision (circle), neonatal circumcision with additional relied on self-reporting, were difficult if not impossible to apply
local anaesthetic (square), and uncircumcised males (triangle) to preverbal patients such as neonates and infants as well as to
in terms of facial action score, duration of cry, and visual ana- cognitively impaired children and adolescents. Although tools
logue scale (VAS). Assessments were conducted by blinded have been developed to assess pain in these populations,126–128 in
observers. Patients in the circumcised group had significantly most clinical scenarios, the routine and standardized assessment
greater responses than the uncircumcised group. The use of of pain in pediatric patients remains inconsistent at best. The use
local anesthesia at the time of neonatal circumcision appeared of pain scales and compliance with these processes are aided by
to have a modifying effect on the subsequent response at the mandate of various hospital credentialing boards and auditing
infant vaccination. *Values are shown as mean (95% confidence agencies, which frequently evaluate pain management protocols
interval [CI]). From reference 5, with permission. as benchmark criteria.
Suitable Criteria and Tools complex verbal descriptors such as “mild,” “moderate,” “severe,” or
“excruciating” should not be used in children younger than 13
Efforts to develop valid tools for the measurement of pain in years.133 Pain in older children carries a strong affective com-
infants and children are made more difficult by the rapid ponent with anxiety, anger, or depression, and these need to be
maturation of behavioral pain responses in infancy and childhood. taken into account in the assessment of longer-term pain. In this
Most of the early studies on infant pain measurement were based age group, sociocultural, environmental, and affective factors exert
on a single painful stimulus such as a heelstick, which is a useful a very large and variable effect on an individual’s experience and
model because it provides a relatively consistent stimulus from external expression of pain. Pain may become a symptom to avoid
which to identify and grade responses. However, the applicability situations or to gain advantage. All factors pertaining to the
of these data to postoperative pain in infants is limited because individual’s “pain experience” must be considered holistically to
longer-lasting pain in this age group does not produce the easily allow an appropriate analgesic plan to be formed in cooperation
identifiable and gross responses associated with an immediate, with the individual.
self-limited nociceptive stimulus such as a pinprick.129 The variety Observational tools rely on an observer’s assessment of stereo-
of pain assessment tools available to the clinician reflect the child’s typic patterns of behavior that may suggest pain, including the
increasing ability to communicate with the trained pain assessor patient’s facial features, body positioning, and the presence or
who can integrate these measurements with the myriad of con- absence of crying. Younger children are best managed with both
founding factors described previously. Techniques to measure self-reporting and observational pain tools. By 3 years of age,
postoperative pain require assessment tools that are specific to children may be able to self-report the intensity of pain using
patient age and the nature of the pain. Further, the pain measure- modified visual analogue scales such as FACES127 or OUCHER134
ment tool must be validated for both interobserver agreement and scales or other tests that let a child quantitatively describe his
social validation (determining whether a measurement of or her level of pain, such as with the poker chip tool.135 One
behavior is measuring the construct for which it is intended). advantage of the FACES scale is that it can be used with various
Much emphasis has been placed on evaluations repeated at regular ethnic groups and across language barriers between providers and
intervals that can identify changes in quality of analgesia over time patients. Although the FACES scale was designed as a self-report
rather than relying on a single measurement.130 scoring system, some centers have modified its use into an
Pain assessment tools can be categorized into five broad cate- observational tool. In this circumstance, the health care provider
gories, including self-report, observational (or behavioral), physio- assesses the child and selects the facial expression (and hence the
logic, neurophysiologic, and hormonal-metabolic (changes in degree of pain) that she or he believes the patient is manifesting.
stress hormones such as epinephrine, norepinephrine, or cortisol). In the pediatric population, acute illnesses, cognitive states, or
Pain assessment in the verbal child most commonly relies on a age may preclude the use of self-report scales. Observational
self-reported visual analogue score (VAS), as is routinely done in assessment tools have been described and validated for various
the adult population. These scales ask the patient to identify where patient populations, including neonates,115,136 preterm infants,137–
their pain falls on a straight line from 0 (no pain) to 10 (worst 140
and patients with cognitive impairment. The latter group of
imaginable pain) and rely on the patient’s ability to assess and patients represents a growing subpopulation of the pediatric-aged
report their own pain. Various scales have been designed to be patient and, therefore has received significant attention since the
more user-friendly and applicable in younger children (down to early 2000s. For patients with cognitive impairment, different
5–7 y of age); they include poker chips, a ladder, colored crayons, assessment tools may be helpful in the assessment of their
or pictures of children in varying degrees of distress. With the pain. The Non-Communicating Children’s Pain Checklist—
poker chip scale, the child expresses pain as a certain number Postoperative Version (NCCPC-PV) was developed specifically
of red poker chips (1–4). Mild pain would be one poker chip, for use in this population.141 It includes the grading of several
whereas four chips are “the most hurt” the child could have. The specific behaviors, such as vocalization, socialization, facial
pain ladder is a picture of a ladder with nine steps or rungs.131 At expression, activity, body and limb positioning, and physiologic
the bottom of the ladder is “no hurt,” and at the top of the ladder signs that have been shown to be indicative of pain in children
is “hurt as bad as it could be.” The child is then asked to point at with cognitive impairment. Alternatively, scales such as the Face,
the appropriate place on the ladder to indicate the amount of pain Legs, Activity, Cry, and Consolability (FLACC) scoring system,
that she or he is experiencing. The severity of pain can also be which is used for preverbal children, can be modified for cog-
expressed by selecting a colored crayon, with red indicating severe nitively impaired children by the addition of specific descriptors
pain and blue indicating little or no pain. However, reporting and parent-identified behaviors for each individual patient.139
accuracy when using colors to express pain may have some Recently, the clinical utility of these scales was studied, and a
variability, because the association of blue with calm or no pain comparison of their application found the revised FLACC to have
and red with pain does not cross all ethnic groups. Self-reporting distinct advantages that may allow a more effective adaptation to
scores correlate well with behavioral responses and adult ratings clinical practice.142 These tools have been shown to have excellent
but tend to have less reliability until 5 years of age. Children interobserver reliability and are quick and easy to use, even in a
younger than 5 years tend to chose extremes from the scales and busy clinical practice (Table 15–3).
are confused by the meaning of the scale, choosing the painful Physiologic parameters used in pain scales may include heart
faces to express their unhappiness rather than their lack of rate, blood pressure, respiratory rate, oxygen saturation, palmar
analgesia. Children older than 7 years can generally use VAS or sweating, alterations in heart rate variability, or changes in
color analogue scales, and in this age group, the memory for pain pupillary size. However, factors other than pain may alter these
is quite accurate over time. This population can accurately recall physiologic parameters or alter responses to the painful stimulus.
pain intensities a week later, independent of their anxiety and A frequent scenario is the critically ill infant or child in an
general memory abilities.132 However, it is recommended that intensive care unit whose blood pressure is low because of a
TABLE 15-3. Characteristics of Observational Pain Assessment Tools in Nonverbal Children

Tool Categories Items Scored Score Range/Interpretation Age Range, y
Revised FLACC Facial expression 5 items, each with a score Range: 0–10; >3 = moderate 4–19
Leg position of 0–2 to severe pain
Activity
Cry/vocalization
Consolability
NCCPC-PV Vocal 27 items, each with a score Range: 0–81; >10 = moderate 3–18
Social of 0–3 to severe pain
Facial
Activity
Body and limbs
Physiologic
FLACC = Face, Leg Position, Activity, Cry, Consolability; NCCPC-PV = Non-Communicating Children’s Pain Checklist—Postoperative Version.
comorbid disease process, thereby negating the ability to use an has been modified for different age groups.87 The CRIES score is
elevated blood pressure as an indicator of pain. a simple neonatal tool that uses both physiologic and behavioral
Neonatal pain assessments use observational scoring (facial measurement. However, the use of oxygen saturation is question-
expression, body position, crying, and movements) often com- able in that pain is not always associated with reduction in oxygen
bined with physiologic measurement such as blood pressure or saturation.144 The COMFORT score has no less than eight vari-
oxygen saturation. Studies in this age group demonstrate that ables, including separate scoring for blood pressure and heart rate.
single behaviors are unreliable in the assessment of pain and that This tool suffers from the extensive crossover in scoring of the
the interobserver correlation and specificity can be improved by a separate components (i.e., agitation and alertness, blood pressure,
multidimensional approach that may also include physiologic and heart rate).143
measurements.129 Tools commonly used include the Objective Another pediatric pain assessment tool that combines
Pain Scale (OPS),88 Children’s Hospital of Eastern Ontario Pain observational and physiologic data is the CHEOPS developed by
Score (CHEOPS),128 crying, requires oxygenation, increased vital McGrath and colleagues.128 This scale assigns a score of 0 to 2 for
signs, expression and sleepless (CRIES),136 and alertness, calmness/ six categories, including cry, facial expression, verbal complaints
agitation, respiratory response, physical movement, blood of pain, position of the torso, whether the child is touching the
pressure, heart rate, muscle tone, facial tension (COMFORT) wound, and position of the legs. The CHEOPS pain assessment
scales.143 The descriptors for these pain scales are compared in tool was one of the first to be validated. It describes each criterion
Table 15–4. Although facial expression alone has proved useful in in subtle detail, which may make it more discriminatory at the
the evaluation of the instantaneous pain associated with heelstick, expense of making it cumbersome for everyday clinical practice.
suctioning, or other invasive procedures, these pain assessment The final pain assessment tools use neurophysiologic and
tools attempt to quantify pain with different multidimensional hormonal-metabolic changes. Both are generally restricted to
approaches. None of these individual tools can be regarded as the research protocols and have limited applicability for the every-
ideal. The OPS score has a physiologic measurement (blood day practice of pediatric pain management. Neurophysiologic
pressure) as well as behavioral assessments, but most of the other monitoring is the least well known and least well studied of the
descriptors overlap, so that pain scores tend to be either very low pain assessment tools. Potential tools include EEG monitoring and
(no pain) or very high (major pain), with little gradation. However, waveform analysis, pupillary responses, brainstem-evoked res-
this scoring system is one of the simplest and practical to use and ponses, galvanic skin changes, and perhaps even changes in the
TABLE 15-4. Comparison of Commonly Used Infant Pain Assessment Tools

OPS CHEOPS CRIES COMFORT
Heart rate/BP X — X XX for BP + heart rate
Cry X X X —
Facial expression — X X X
Verbal expression X X — —
Position (torso)/movement XX for posture + movement X — XX for muscle tone + movement
Position (legs)/movement — X — —
Position (hands)/movement — X — —
Agitation/calmness X — X X
Oxygen saturation — — X —
Ventilatory responses — — — X
Alertness — — — X
Total criteria 6 6 5 8
BP = blood pressure; CHEOPS = Children’s Hospital Eastern Ontario Pain Scale; COMFORT = alertness, calmness/agitation, respiratory response, physical movement,
blood pressure, heart rate, muscle tone, facial tension; CRIES = crying, requires oxygenation, increased vital signs, expression and sleepless; OPS = Objective Pain Scale.
subcortical areas of the brain and brainstem. Hormonal-metabolic 9. Clancy B, Cauller LJ. Widespread projections from subgriseal neurons
changes such as alterations in plasma levels of stress hormones, (layer VII) to layer I in adult rat cortex. J Comp Neurol. 1999;407:
275–286.
including epinephrine and cortisol, have been used to study pain 10. Clancy B, Darlington RB, Finlay BL. Translating developmental time
management regimens for patients with acute illnesses or those across mammalian species. Neuroscience. 2001;105:7–17.
undergoing major surgical procedures.32,145,146 To date, these tools 11. Ulfig N, Setzer M, Neudorfer F, Saretzki U. Changing distribution patterns
are limited to the research arena and tend to be too cumbersome, of synaptophysin-immunoreactive structures in the human dorsal
too expensive, or unvalidated, thereby limiting their application striatum of the fetal brain. Anat Rec. 2000;258:198–209.
12. Judas M, Rasin MR, Kruslin B, et al. Dendritic overgrowth and alterations
to our current clinical practice. in laminar phenotypes of neocortical neurons in the newborn with
semilobar holoprosencephaly. Brain Dev. 2003;25:32–39.
13. Fitzgerald M. The development of nociceptive circuits. Nat Rev Neurosci.
CONCLUSIONS 2005;6:507–520.
14. Laughlin SB, Sejnowski TJ. Communication in neuronal networks.
Pain is a complex phenomenon, representing a neurophysio- Science. 2003;301:1870–1874.
logic nociceptive response combined with a psychobehavioral 15. Carpenter KJ, Dickenson AH. Molecular aspects of pain research.
component that is present throughout life. During the in utero Pharmacogenomics J. 2002;2:87–95.
course of neurobehavioral development of the fetus to the mature 16. Wolf AR. Pain, nociception and the developing infant. Paediatr Anaesth.
1999;9:7–17.
infant, it remains unclear at what stage pain pathway transmission 17. Craig AD. Pain mechanisms: labeled lines versus convergence in central
becomes pain sensation. This issue will continue to be debated processing. Annu Rev Neurosci. 2003;26:1–30.
emotionally and philosophically. Nevertheless, it is important to be 18. Henderson G. Electrophysiological analysis of opioid action in the central
aware of the consequences of noxious stimuli and bodily injury, nervous system. Br Med Bull. 1983;39:59–64.
including hemodynamic, inflammatory, and stress responses. 19. Torres F, Anderson C. The normal EEG of the human newborn. J Clin
Neurophysiol. 1985;2:89–103.
Ongoing evidence continues to demonstrate the deleterious 20. Klimach VJ, Cooke RW. Maturation of the neonatal somatosensory
physiologic effects of pain in children and the beneficial results of evoked response in preterm infants. Dev Med Child Neurol. 1988;30:
effective postoperative analgesia. This growing body of clinical 208–214.
knowledge has coincided with the growing public awareness of 21. Bradley PB, Briggs I. Actions of serotonin and related substances on
the importance of effective pain management to the well-being of single neurons in the brain. Adv Biochem Psychopharmacol. 1974;10:
infants and children. Although the long-term effects are unclear, 159–166.
22. Fitzgerald M. A physiological study of the prenatal development of
the use of analgesic drugs in all pediatric patients (from preterm cutaneous sensory inputs to dorsal horn cells in the rat. J Physiol.
infants to adolescents) remains a necessity. The effects of these 1991;432:473–482.
medications and their pharmacokinetics and dynamics need to 23. Guy ER, Abbott FV. The behavioral response to formalin in preweanling
be carefully studied to ensure that the drugs themselves do not rats. Pain. 1992;51:81–90.
cause additional problems. In older infants and children, several 24. Fitzgerald M. The post-natal development of cutaneous afferent fibre
input and receptive field organization in the rat dorsal horn. J Physiol.
validated pain assessment tools can help to identify pain in infants 1985;364:1–18.
and children. Each practitioner must work to integrate these 25. Fitzgerald M, King AE, Thompson SW, Woolf CJ. The postnatal
tools and develop hospital-wide systems for the application of development of the ventral root reflex in the rat: a comparative in vivo
appropriate pain monitoring and treatment techniques. Pain, like and in vitro study. Neurosci Lett. 1987;78:41–45.
hunger, is a non-negotiable experience for children. Either they 26. Cracco JB, Cracco RQ, Graziani LJ. The spinal evoked response in infants
and children. Neurology. 1975;25:31–36.
are free of pain and are well or they have pain and are suffering. 27. Harnik EV, Hoy GR, Potolicchio S, et al. Spinal anesthesia in premature
The latter requires our immediate attention. The recognition and infants recovering from respiratory distress syndrome. Anesthesiology.
treatment of both medical and surgical pain in children has 1986;64:95–99.
improved but continues to lag behind adult pain management. 28. Chugani HT, Phelps ME. Maturational changes in cerebral function in
Further work is essential to refine and develop techniques to infants determined by 18FDG positron emission tomography. Science.
1986;231:840–843.
promptly identify the onset of pain in pediatric patients and to
29. Anand KJ. Pharmacological approaches to the management of pain in the
develop and implement more effective pediatric pain treatments. neonatal intensive care unit. J Perinatol. 2007;27(Suppl 1):S4–S11.
30. Bartocci M, Bergqvist LL, Lagercrantz H, Anand KJ. Pain activates cortical
areas in the preterm newborn brain. Pain. 2006;122:109–117.
REFERENCES 31. Slater R, Boyd S, Meek J, Fitzgerald M. Cortical pain responses in the
infant brain. Pain. 2006;123:332; author reply 332–334.
1. McGraw M. Neural maturation as exemplified in the changing reactions 32. Whitfield MF, Grunau RE. Behavior, pain perception, and the extremely
of the infant to pinprick. Child Dev. 1941;12:31–42.
low-birth weight survivor. Clin Perinatol. 2000;27:363–379.
2. Tilney FAK. Behavior in its relation to the development of the brain. Bull
33. Fitzgerald M, Millard C, McIntosh N. Cutaneous hypersensitivity
Neurol Inst N Y. 1931;1:229–313.
3. Merskey H. On the development of pain. Headache. 1970;10:116–123. following peripheral tissue damage in newborn infants and its reversal
4. Anand KJ, Sippell WG, Aynsley-Green A. Randomised trial of fentanyl with topical anaesthesia. Pain. 1989;39:31–36.
anaesthesia in preterm babies undergoing surgery: effects on the stress 34. Andrews K, Fitzgerald M. The cutaneous withdrawal reflex in human
response. Lancet. 1987;1:62–66. neonates: sensitization, receptive fields, and the effects of contralateral
5. Taddio A, Katz J, Ilersich AL, Koren G. Effect of neonatal circumcision on stimulation. Pain. 1994;56:95–101.
pain response during subsequent routine vaccination. Lancet. 1997;349: 35. Fitzgerald M, Walker S. Infant pain traces. Pain. 2006;125:204–205.
599–603. 36. Grunau RV, Craig KD. Pain expression in neonates: facial action and cry.
6. Lee SJ, Ralston HJ, Drey EA, et al. Fetal pain: a systematic multidisci- Pain. 1987;28:395–410.
plinary review of the evidence. JAMA. 2005;294:947–954. 37. Taddio A, Katz J. The effects of early pain experience in neonates on pain
7. Lowery CL, Hardman MP, Manning N, et al. Neurodevelopmental responses in infancy and childhood. Paediatr Drugs. 2005;7:245–257.
changes of fetal pain. Semin Perinatol. 2007;31:275–282. 38. Marti M, Stocchi S, Paganini F, et al. Pharmacological profiles of
8. Kostovic I, Judas M. Correlation between the sequential ingrowth of presynaptic nociceptin/orphanin FQ receptors modulating 5-
afferents and transient patterns of cortical lamination in preterm infants. hydroxytryptamine and noradrenaline release in the rat neocortex. Br J
Anat Rec. 2002;267:1–6. Pharmacol. 2003;138:91–98.
39. Tribollet E, Goumaz M, Raggenbass M, et al. Early appearance and 63. Yamada J, Stevens B, de Silva N, et al. Hair cortisol as a potential biologic
transient expression of vasopressin receptors in the brain of rat fetus and marker of chronic stress in hospitalized neonates. Neonatology.
infant. An autoradiographical and electrophysiological study. Brain Res 2007;92:42–49.
Dev Brain Res. 1991;58:13–24. 64. Teixeira J, Fogliani R, Giannakoulopoulos X, et al. Fetal haemodynamic
40. Pasternak GW, Zhang A, Tecott L. Developmental differences between stress response to invasive procedures. Lancet. 1996;347:624.
high and low affinity opiate binding sites: their relationship to analgesia 65. Owens ME, Todt EH. Pain in infancy: neonatal reaction to a heel lance.
and respiratory depression. Life Sci. 1980;27:1185–1190. Pain. 1984;20:77–86.
41. Barg J, Rius RA, Bem WT, et al. Differential development of beta- 66. Williamson PS, Williamson ML. Physiologic stress reduction by a local
endorphin and mu opioid binding sites in mouse brain. Brain Res Dev anesthetic during newborn circumcision. Pediatrics. 1983;71:36–40.
Brain Res. 1992;66:71–76. 67. Clifton RK, Graham FK, Hatton HM. Newborn heart-rate response and
42. Zhang Y, Wang YH, Zhang XH, et al. Proteomic analysis of differential response habituation as a function of stimulus duration. J Exp Child
proteins related to the neuropathic pain and neuroprotection in the dorsal Psychol. 1968;6:265–278.
root ganglion following its chronic compression in rats. Exp Brain Res. 68. Kelly MA, Finer NN. Nasotracheal intubation in the neonate: physiologic
2008;189:199–209. responses and effects of atropine and pancuronium. J Pediatr. 1984;105:
43. Wang C, Slikker W. Strategies and experimental models for evaluating 303–309.
anesthetics: effects on the developing nervous system. Anesth Analg. 69. Porter FL, Miller JP, Cole FS, Marshall RE. A controlled clinical trial of
2008;106:1643–1658. local anesthesia for lumbar punctures in newborns. Pediatrics. 1991;88:
44. Komori N, Takemori N, Kim HK, et al. Proteomics study of neuropathic 663–669.
and nonneuropathic dorsal root ganglia: altered protein regulation 70. Porter FL, Porges SW, Marshall RE. Newborn pain cries and vagal tone:
following segmental spinal nerve ligation injury. Physiol Genomics. parallel changes in response to circumcision. Child Dev. 1988;59:495–505.
2007;29:215–230. 71. Venus B, Patel KC, Pratap KS, et al. Transcutaneous PO2 monitoring
45. Julius D, Basbaum AI. Molecular mechanisms of nociception. Nature. during pediatric surgery. Crit Care Med. 1981;9:714–716.
2001;413:203–210. 72. Rawlings DJ, Miller PA, Engel RR. The effect of circumcision on
46. Munglani R, Hunt SP. Molecular biology of pain. Br J Anaesth. 1995; transcutaneous PO2 in term infants. Am J Dis Child. 1980;134:676–678.
75:186–192. 73. Norris S, Campbell LA, Brenkert S. Nursing procedures and alterations in
47. Williams S, Evan G, Hunt SP. Spinal c-fos induction by sensory transcutaneous oxygen tension in premature infants. Nurs Res. 1982;
stimulation in neonatal rats. Neurosci Lett. 1990;109:309–314. 31:330–336.
48. Uhl GR, Sora I, Wang Z. The mu opiate receptor as a candidate gene for 74. Brown L. Physiologic responses to cutaneous pain in neonates. Neonatal
pain: polymorphisms, variations in expression, nociception, and opiate Netw. 1987;6:18–22.
responses. Proc Natl Acad Sci U S A. 1999;96:7752–7755. 75. Harpin VA, Rutter N. Development of emotional sweating in the newborn
49. Chou WY, Wang CH, Liu PH, et al. Human opioid receptor A118G infant. Arch Dis Child. 1982;57:691–695.
polymorphism affects intravenous patient-controlled analgesia morphine 76. Harpin VA, Rutter N. Making heel pricks less painful. Arch Dis Child.
consumption after total abdominal hysterectomy. Anesthesiology. 2006; 1983;58:226–228.
105:334–337. 77. Soul JS, Hammer PE, Tsuji M, et al. Fluctuating pressure-passivity is
50. Charnay Y, Paulin C, Chayvialle JA, Dubois PM. Distribution of substance common in the cerebral circulation of sick premature infants. Pediatr Res.
P–like immunoreactivity in the spinal cord and dorsal root ganglia of the 2007;61:467–473.
human foetus and infant. Neuroscience. 1983;10:41–55. 78. Tsuji M, Saul JP, du Plessis A, et al. Cerebral intravascular oxygenation
51. Charnay Y, Paulin C, Dray F, Dubois PM. Distribution of enkephalin in correlates with mean arterial pressure in critically ill premature infants.
human fetus and infant spinal cord: an immunofluorescence study. Pediatrics. 2000;106:625–632.
J Comp Neurol. 1984;223:415–423. 79. Gagnon RE, Leung A, Macnab AJ. Variations in regional cerebral blood
52. Gibbs DM, Stewart RD, Liu JH, et al. Effects of synthetic corticotropin- volume in neonates associated with nursery care events. Am J Perinatol.
releasing factor and dopamine on the release of immunoreactive beta- 1999;16:7–11.
endorphin/beta-lipotropin and alpha-melanocyte-stimulating hormone 80. Volpe JJ. Brain injury in the premature infant. Neuropathology, clinical
from human fetal pituitaries in vitro. J Clin Endocrinol Metab. 1982;55: aspects, pathogenesis, and prevention. Clin Perinatol. 1997;24:567–587.
1149–1152. 81. Porter FL, Wolf CM, Miller JP. Procedural pain in newborn infants: the
53. Zagon IS, Gibo DM, McLaughlin PJ. Adult and developing human influence of intensity and development. Pediatrics. 1999;104:e13.
cerebella exhibit different profiles of opioid binding sites. Brain Res. 82. Burton IF, Derbyshire AJ. Sleeping fit caused by excruciating pain in an
1990;523:62–68. infant. AMA J Dis Child. 1958;95:258–260.
54. Yaster M. Pain and sedation management in the critically ill. In Nichols 83. Rich EC, Marshall RE, Volpe JJ. The normal neonatal response to pin-
DG, Ackerman AD, Carcillo JA, et al. (eds). Rogers’s Textbook of Pediatric prick. Dev Med Child Neurol. 1974;16:432–434.
Intensive Care. 4th ed. Wolters Kluwer Health/Lippincott Williams & 84. Franck LS. A new method to quantitatively describe pain behavior in
Wilkins. Philadelphia, PA, USA 2008. pp. 1725–1758. infants. Nurs Res. 1986;35:28–31.
55. Easley RB, Nichols DG. Withdrawal assessment in the pediatric intensive 85. Levine JD, Gordon NC. Pain in prelingual children and its evaluation by
care unit: quantifying a morbidity of pain and sedation management in pain-induced vocalization. Pain. 1982;14:85–93.
the critically ill child. Crit Care Med. 2008;36:2479–2480. 86. Grunau RV, Johnston CC, Craig KD. Neonatal facial and cry responses
56. Merskey H, Trimble M. Personality, sexual adjustment, and brain lesions to invasive and non-invasive procedures. Pain. 1990;42:295–305.
in patients with conversion symptoms. Am J Psychiatry. 1979;136:179–182. 87. Norden J, Hannallah R, Getson P, et al. Concurrent validation of an
57. Kassowitz KE. Psychodynamic reactions of children to the use of objective pain scale for infants and children. Anesth Analg. 1991;72:S199.
hypodermic needles: a study in the contrast of uncontrolled and self- 88. Norden J, Hannallah R, Getson P, et al. Concurrent validation of an
controlled emotions. AMA J Dis Child. 1958;95:253–257. objective pain scale for infants and children. Anesthesiology. 1992;75:
58. Izard CE, Hembree EA, Dougherty LM, et al. Changes in facial expression A934.
of 2 to 19 month old infants following acute pain. Dev Psychol. 1983;19: 89. Rosen I. The physiological basis for continuous electroencephalogram
418–426. monitoring in the neonate. Clin Perinatol. 2006;33:593–611, v.
59. Lavigne JV, Schulein MJ, Hahn YS. Psychological aspects of painful medi- 90. Aynsley-Green A. Pain and stress in infancy and childhood—where to
cal conditions in children. II. Personality factors, family characteristics now? Paediatr Anaesth. 1996;6:167–172.
and treatment. Pain. 1986;27:147–169. 91. Oliveira AJ, Nunes ML, Fojo-Olmos A, et al. Clinical correlates of periodic
60. Lavigne JV, Schulein MJ, Hahn YS. Psychological aspects of painful breathing in neonatal polysomnography. Clin Neurophysiol. 2004;115:
medical conditions in children. I. Developmental aspects and assessment. 2247–2251.
Pain. 1986;27:133–146. 92. Giannakoulopoulos X, Teixeira J, Fisk N, Glover V. Human fetal and
61. Haslam DR. Individual differences in pain threshold and level of arousal. maternal noradrenaline responses to invasive procedures. Pediatr Res.
Br J Psychol. 1967;58:139–142. 1999;45:494–499.
62. Axia G, Bonichini S, Benini F. Pain in infancy: individual differences. 93. Anand KJ, Hansen DD, Hickey PR. Hormonal-metabolic stress responses
Percept Mot Skills. 1995;81:142. in neonates undergoing cardiac surgery. Anesthesiology. 1990;73:661–670.
94. Grewal RS, Mampilly J, Misra TR. Postoperative protein metabolism and pain after neonatal and pediatric cardiac surgery. Pediatr Nurs. 1997;
electrolyte changes in pediatric surgery. Int Surg. 1969;51:142–148. 23:263–271.
95. Chumbley GM, Hall GM. Recovery after major surgery: does the 121. Jacobson B, Eklund G, Hamberger L, et al. Perinatal origin of adult self-
anaesthetic make any difference? Br J Anaesth. 1997;78:347–349. destructive behavior. Acta Psychiatr Scand. 1987;76:364–371.
96. Anand KJ. Neonatal stress responses to anesthesia and surgery. Clin 122. Morton NS. Pain assessment in children. Paediatr Anaesth. 1997;7:
Perinatol. 1990;17:207–214. 267–272.
97. Anand KJ, Hickey PR. Halothane-morphine compared with high-dose 123. Haouari N, Wood C, Griffiths G, Levene M. The analgesic effect of
sufentanil for anesthesia and postoperative analgesia in neonatal cardiac sucrose in full term infants: a randomised controlled trial. BMJ.
surgery. N Engl J Med. 1992;326:1–9. 1995;310(6993):1498–500.
98. Volpe JJ. Cerebral white matter injury of the premature infant—more 124. Cignacco E, Hamers JP, Stoffel L, et al. The efficacy of non-
common than you think. Pediatrics. 2003;112:176–180. pharmacological interventions in the management of procedural pain
99. Sapolsky RM, Pulsinelli WA. Glucocorticoids potentiate ischemic injury in preterm and term neonates. A systematic literature review. Eur J Pain.
to neurons: therapeutic implications. Science. 1985;229:1397–400. 2007;11:139–152.
100. Sapolsky RM, Uno H, Rebert CS, Finch CE. Hippocampal damage 125. Leslie A, Marlow N. Non-pharmacological pain relief. Semin Fetal
associated with prolonged glucocorticoid exposure in primates. J Neonatal Med. 2006;11:246–250.
Neurosci. 1990;10:2897–2902. 126. Beyer JE, Wells N. The assessment of pain in children. Pediatr Clin North
101. Jensen TS, Smith DF. Monoaminergic mechanisms in stress-induced Am. 1989;36:837–854.
analgesia. J Neural Transm. 1982;53:247–255. 127. Bieri D, Reeve RA, Champion GD, et al. The Faces Pain Scale for the
102. Starkman MN, Gebarski SS, Berent S, Schteingart DE. Hippocampal self-assessment of the severity of pain experienced by children:
formation volume, memory dysfunction, and cortisol levels in patients development, initial validation, and preliminary investigation for ratio
with Cushing’s syndrome. Biol Psychiatry. 1992;32:756–765. scale properties. Pain. 1990;41:139–150.
103. Ledingham IM, Watt I. Influence of sedation on mortality in critically ill 128. McGrath P, Vair C, McGrath MJ, et al. Pediatric nurses’ perception of
multiple trauma patients. Lancet. 1983;1:1270. pain experienced by children and adults. Nurs Pap. 1985;16:34–40.
104. Belin BM, Ball DJ, Langer JC, et al. The effect of age on peripheral motor 129. Johnston CC, Strada ME. Acute pain response in infants: a multidi-
nerve function after crush injury in the rat. J Trauma. 1996;40:775–777. mensional description. Pain. 1986;24:373–382.
105. Quinn M, Carraccio C, Sacchetti A. Pain, punctures, and pediatricians. 130. Lloyd-Thomas A. Assessment and control of pain in children.
Pediatr Emerg Care. 1993;9:12–14. Anaesthesia. 1995;50:753–755.
106. Duncan HP, Cloote A, Weir PM, et al. Reducing stress responses in 131. Houck CS, Tobias JD, Tresgallo ME, et al. The treatment of pain in
the pre-bypass phase of open heart surgery in infants and young neonatal and pediatric patients. In: Cousins MJ, Carr DB, Horlocker TT,
children: a comparison of different fentanyl doses. Br J Anaesth. 2000; et al. (eds). Neural blockade in Clinical Anesthesia and Pain Medicine.
84:556–564. 4th edition. Wolters Kluwer Health/Lippincott Williams & Wilkins.
107. Wolfe JM, Lein DY, Lenkoski K, Smithline HA. Analgesic administration Philadelphia, PA, USA 2008. pp. 1169–1199.
to patients with an acute abdomen: a survey of emergency medicine 132. Zonneveld LN, McGrath PJ, Reid GJ, Sorbi MJ. Accuracy of children’s
physicians. Am J Emerg Med. 2000;18:250–253. pain memories. Pain. 1997;71:297–302.
108. Piper HG, Alexander JL, Shukla A, et al. Real-time continuous glucose 133. McGrath PJ, Beyer J, Cleeland C, et al. American Academy of Pediatrics
monitoring in pediatric patients during and after cardiac surgery. Report of the Subcommittee on Assessment and Methodologic Issues
Pediatrics. 2006;118:1176–1184. in the Management of Pain in Childhood Cancer. Pediatrics. 1990;86:
109. Olney JW, Young C, Wozniak DF, et al. Anesthesia-induced develop- 814–817.
mental neuroapoptosis. Does it happen in humans? Anesthesiology. 134. Beyer JE, Denyes MJ, Villarruel AM. The creation, validation, and
2004;101:273–275. continuing development of the Oucher: a measure of pain intensity in
110. Johnson SA, Young C, Olney JW. Isoflurane-induced neuroapoptosis in children. J Pediatr Nurs. 1992;7:335–346.
the developing brain of nonhypoglycemic mice. J Neurosurg Anesthesiol. 135. Hester NO. Pain in children. Annu Rev Nurs Res. 1993;11:105–142.
2008;20:21–28. 136. Krechel SW, Bildner J. CRIES: a new neonatal postoperative pain
111. Anand KJ, Hall RW. Controversies in neonatal pain: an introduction. measurement score. Initial testing of validity and reliability. Paediatr
Semin Perinatol. 2007;31:273–274. Anaesth. 1995;5:53–61.
112. Anand KJ, Garg S, Rovnaghi CR, et al. Ketamine reduces the cell death 137. Stevens B, Johnston C, Petryshen P, Taddio A. Premature Infant Pain
following inflammatory pain in newborn rat brain. Pediatr Res. Profile: development and initial validation. Clin J Pain. 1996;12:13–22.
2007;62:283–290. 138. Breau LM, McGrath PJ, Stevens B, et al. Healthcare professionals’
113. Loepke AW, McGowan FX, Soriano SG. CON: the toxic effects of perceptions of pain in infants at risk for neurological impairment. BMC
anesthetics in the developing brain: the clinical perspective. Anesth Pediatr. 2004;4:23.
Analg. 2008;106:1664–1669. 139. Malviya S, Voepel-Lewis T, Tait AR. A comparison of observational and
114. Dixon S, Snyder J, Holve R, Bromberger P. Behavioral effects of objective measures to differentiate depth of sedation in children from
circumcision with and without anesthesia. J Dev Behav Pediatr. 1984; birth to 18 years of age. Anesth Analg. 2006;102:389–394.
5:246–250. 140. McGrath PJ, Rosmus C, Canfield C, et al. Behaviours caregivers use to
115. Taddio A, Goldbach M, Ipp M, et al. Effect of neonatal circumcision on determine pain in non-verbal, cognitively impaired individuals. Dev
pain responses during vaccination in boys. Lancet. 1995;345:291–292. Med Child Neurol. 1998;40:340–343.
116. Grunau RE, Holsti L, Peters JW. Long-term consequences of pain in 141. Breau LM, Finley GA, McGrath PJ, Camfield CS. Validation of the Non-
human neonates. Semin Fetal Neonatal Med. 2006;11:268–275. communicating Children’s Pain Checklist—Postoperative Version.
117. Stevenson J, Batten N, Cherner M. Fears and fearfulness in children and Anesthesiology. 2002;96:528–535.
adolescents: a genetic analysis of twin data. J Child Psychol Psychiatry. 142. Voepel-Lewis T, Malviya S, Tait AR, et al. A comparison of the clinical
1992;33:977–985. utility of pain assessment tools for children with cognitive impairment.
118. Als H, Lawhon G, Brown E, et al. Individualized behavioral and Anesth Analg. 2008;106:72–78, table of contents.
environmental care for the very low birth weight preterm infant at high 143. Bear LA, Ward-Smith P. Interrater reliability of the COMFORT Scale.
risk for bronchopulmonary dysplasia: neonatal intensive care unit and Pediatr Nurs. 2006;32:427–434.
developmental outcome. Pediatrics. 1986;78:1123–1132. 144. Suraseranivongse S, Kaosaard R, Intakong P, et al. A comparison of
119. Zadina JE, Kastin AJ. Neonatal peptides affect developing rats: beta- postoperative pain scales in neonates. Br J Anaesth. 2006;97:540–544.
endorphin alters nociception and opiate receptors, corticotropin- 145. Anand KJ. Effects of perinatal pain and stress. Prog Brain Res.
releasing factor alters corticosterone. Brain Res. 1986;394:21–29. 2000;122:117–129.
120. McRae ME, Rourke DA, Imperial-Perez FA, et al. Development of a 146. Fitzgerald M, Beggs S. The neurobiology of pain: developmental aspects.
research-based standard for assessment, intervention, and evaluation of Neuroscientist. 2001;7:246–257.
Chronic and Recurrent Pain

in the Pediatric Patient 16
Stephen C. Brown and Patricia A. McGrath C H A P T E R
INTRODUCTION other people. Children’s perceptions of pain are defined by their

age and cognitive level; their previous pain experiences against
Pain control is an integral component of pediatric clinical care. which they evaluate each new pain; the relevance of the pain or
Children may experience many different types of pain related to disease causing pain; their expectations for obtaining eventual
invasive procedures, the cumulative effects of toxic therapies, recovery and pain relief; and their ability to control the pain
progressive disease, or psychological factors. The pain is often themselves. Although plasticity and complexity are critical features
complex with multiple sources, composed of nociceptive and for all pain perception, plasticity seems an even more important
neuropathic components. In addition, several situational factors feature for controlling children’s pain.
usually contribute to children’s pain, distress, and disability. Thus, Much research has been conducted to identify the critical
to adequately treat pain in children, we must evaluate the primary factors responsible for the plasticity of pain perception.2 Animal
pain sources and ascertain which situational factors are relevant behavior studies, in which the physiologic responses activated by
for which children and families. Treatment emphasis should shift a noxious stimulus are directly recorded, have demonstrated that
accordingly from an exclusive disease-centered framework to a certain factors such as the primate’s attention, the predictability of
more child-centered focus. a painful stimulus, and the relevance of the stimulus can directly
In this chapter, we describe a child-centered framework for modify the intensity of the physiologic responses evoked by a
understanding and controlling pain in children. Pain control constant noxious stimulus. Parallel psychophysical studies, in
should include regular pain assessments, appropriate analgesics which adults rate the painfulness of constant noxious stimuli in
administered at regular dosing intervals, adjunctive drug therapy different contexts, have demonstrated that these same factors can
for symptom and side effects control, and nondrug interventions modify the perceived intensity and unpleasantness of the
to modify the situational factors that can exacerbate pain and consequent pain sensations. Psychologically mediated modulation
suffering. Basic information on the pathophysiology, pharma- of pain can occur at the earliest levels of pain processing as well as
cology, and physical interventions will not be repeated in this at its highest levels. Both positron emission tomography (PET)
chapter because they are presented elsewhere in this textbook. and functional magnetic resonance imaging (MRI) studies have
This chapter provides a complementary focus to these other demonstrated that painful stimulation activates different cortical
contributions by describing the unique nature of children’s pain regions, depending on an individual’s expectations and attention.3
including the primary factors that affect their pain and quality of Human studies evaluating the impact of environmental and
life, presenting guidelines for selecting and administering drug psychological factors on the perception of experimentally induced
therapy in accordance with the nociceptive and neuropathic pain have been conducted primarily in adults. However, results
components, and recommending practical nondrug therapies for from laboratory studies conducted with children are consistent
integration within a home or hospital setting. with those from adult studies.4,5 In addition, significant amount
of compelling evidence about the powerful mediating role of
psychological factors in children’s pain has been derived from
THE NATURE OF CHILDREN’S PAIN clinical studies of acute, recurrent, and chronic pain. These studies
Since the early 2000s, we have gained an increasing appreciation highlight the need to recognize and evaluate the mediating impact
for the plasticity and complexity of children’s pain. As with adults, of these factors in order to optimally control children’s pain.
children’s pain is often initiated by tissue damage caused by The model illustrated in Figure 16–1 provides a framework for
noxious stimulation, but the consequent pain is neither simply assessing these factors, based on our knowledge of the plasticity
nor directly related to the amount of tissue damage. Perhaps even and complexity of children’s pain. Some factors, such as gender,
more than in adults, differing pain responses to the same tissue temperament, and cultural background, are relatively stable for a
damage are noted. The eventual pain evoked by a relatively child, whereas other factors, such as age, cognitive level, previous
constant noxious stimulus can be different depending on children’s pain experience, and family learning, change progressively (listed
expectations, perceived control, or the significance that they attach in the open box in the figure). These child characteristics shape
to the pain.1 Children do not sustain tissue damage in an isolated how children generally interpret and experience the various
manner, devoid of a particular context, but actively interpret the sensations caused by tissue damage. By contrast, the cognitive,
strength and quality of any pain sensation, determine the behavioral, and emotional factors (listed in the shaded boxes) are
relevance of any hurting, and learn how to interpret the pain by not stable. They represent a unique interaction between the child
observing the general environment, especially the behavior of and the situation in which the pain is experienced.1,6 These
Figure 16-1. A model depicting the situational factors that modify children’s pain perception.
situational factors can vary dynamically throughout the course of encompass parents’ and children’s wider behaviors in response to
a child’s illness, depending on the specific circumstances in which a chronic or recurrent pain problem or progressive illness.
children experience pain. For example, a child receiving treatment Common behavioral factors include children’s distress or coping
for cancer will have repeated injections, central venous catheter reactions (e.g., crying, using a pain control strategy) and parent’s
access attempts, and lumbar punctures, all of which may cause and health staff ’s subsequent reactions to them (e.g., displaying
some pain depending on the analgesics, anesthetics, or sedatives frustration, calmly providing encouragement for children to use
that are used. Even though the tissue damage from these pro- pain control strategies, engaging them in conversation and
cedures is the same each time, the particular set of situational activities).4 They also include the extent to which children
factors for each treatment is unique for a child, depending on a are physically restrained during invasive or aversive treatments
child’s (and parent’s) expectations, a child’s (and parent’s and and the broader physical and social restrictions on children’s and
staff ’s) behaviors, and on a child’s (and family’s) emotional state. family’s lives if children become sicker. Distress behaviors and
Although the causal relationship between an injury and a conse- some altered behavioral patterns may initiate, exacerbate, or
quent pain seems direct and obvious, what children understand, maintain children’s pain. In general, as children’s mental or
what they do, and how they feel all affect their pain. Certain factors physical activity increases, as children use coping and pain control
can intensify pain, exacerbate suffering, or adversely affect a child’s methods, as their distress and disability behaviors decrease, and
quality of life.4 Although parents and health care providers may as staff and parental responses become more consistent in
be unable to change the more stable child characteristics, they encouraging the child to use pain control methods, their pain
can modify situational factors and dramatically improve children’s should lessen. Children seem to report less pain, feel less distressed
pain and lives. by pain, and have a higher quality of life when families and
staff encourage them to remain engaged in life and live as fully
as possible.
THE IMPACT OF SITUATIONAL Emotional factors include parents’ and children’s feelings in
response to pain, to the daily effects of the underlying illness or
FACTORS ON CHILDREN’S PAIN condition, and to the subsequent impact of the children’s disease
Cognitive factors include children’s understanding about the pain on the family. Children’s emotions affect their ability to under-
source, their ability to control what will happen, their expectations stand what is happening, their ability to cope positively, their
regarding the quality and strength of pain sensations that they will behaviors, and ultimately, their pain. Children’s immediate
experience, their primary focus of attention (i.e., distracted away emotional reactions to pain may vary from a relatively neutral
from or focused primarily on the pain), and their knowledge of acceptance to annoyance, anxiety, fear, frustration, anger, or
pain control strategies. In general, children’s pain can be lessened sadness. The specific emotions depend on the nature of the pain
by providing accurate age-appropriate information about pain, for including its type, cause, intensity, and duration as well as its
example, emphasizing the specific sensations that children will impact on their lives. In general, the more emotionally distressed
experience (such as the stinging quality of an injection, rather than children are, the stronger or more unpleasant their pain. When
the general hurting aspects), by increasing their control and children do not understand what is happening, when they lack
choices, by explaining the rationale for what can be done to reduce control and do not know independent pain control strategies, their
pain, and by teaching them some independent pain-reducing emotional distress increases and their pain intensifies. Similarly,
strategies.1,7,8 For children with chronic and recurrent pain, key when children’s behaviors are restricted, when they are physically
cognitive factors also include the relevance or meaning of their restrained during medical procedures, or when their usual daily
illness, particularly if there is a life-threatening potential, and their activities and social interactions are disrupted, their emotional
understanding of the significance of their lives. distress and pain can intensify. Children with life-threatening
Behavioral factors refer to the specific behaviors of children, conditions may not understand what they are feeling or may be
parents, and staff when children experience pain and also unable to verbalize their fears and anxieties. Even very subtle
CHAPTER 16 ■ Chronic and Recurrent Pain in the Pediatric Patient 275
behavioral cues can still evoke fear, uncertainty, apprehension, or TABLE 16-1. Situational Factors in Pediatric Palliative Care
depression depending on children’s ages and what they understand
about their disease and separation. Thus, an essential component Cognitive Factors
of pain control should be evaluating whether these emotions are Meaning of life
exacerbating children’s pain and distress and impairing the quality Inaccurate understanding of:
of their lives. ?Impact of situational factors on pain and quality of life
?Course of disease
?Goals of therapy
SITUATIONAL FACTORS IN Little independent control over pain
CHRONIC AND RECURRENT PAIN Limited choices
Cognitive and emotional factors are the most salient situational Expectation for continuing pain and suffering
Misunderstanding of drug therapy:
factors that affect pain in children. Children sometimes have
?Narcotics, non-narcotics, adjuvant analgesics
already endured a prolonged period of intermittent pain, physical
?Dosing and administration
disability, and multiple aversive treatments. Children undergoing
?Criteria for evaluating effectiveness
active and often changing therapies are more focused on the future
consequences of their disease. Their thoughts, behaviors, and Behavioral Factors
feelings change as their condition begins to improve or deteriorate. Social withdrawal
Naturally, the type of support, information, and guidance children Physical inactivity, physical therapy
require also changes. Although the impact is profound for all Passive approach to pain control
children and families, each child and family is unique with respect Secondary gains:
to their specific psychological, medical, social, and spiritual needs. ?Stress reduction
All families experience anguish and grief, but they may also ?Emotional denial
experience denial, anxiety, anger, guilt, frustration, and depression. ?Parent or staff attention
It is essential that health professionals listen attentively and Inappropriate drug management:
observe carefully not only to ensure that all the needs of both the ?Choice or mode of drug administration
child and the family are met but also to resolve the myriad factors ?Failure to aggressively treat medication side effects
that can exacerbate children’s pain and suffering. The primary Failure to evaluate pain sources and document pain level
situational factors for chronic and recurrent pain are listed in Table Failure to use effective nondrug therapies
16–1. To many of our patients and families, we often summarize Emotional
these factors as the three Ps including pharmacologic, psycho- Anxiety about:
logical, and physical factors. This summary has evolved from our ?Pain
treatment of children referred to our pain clinic. Child and family ?Suffering
factors are listed in italics; the factors that are relevant for health ?Meaning of life
staff as well as families are listed in roman type. Fear of:
The care of children with chronic and recurrent pain may at ?Separation
times involve the care of children for palliative care. The shift in ?Inadequate pain control
care from curative to palliative therapies may signify to some ?Increasing adverse symptoms
children and families that health professionals are giving up on ?Impact on family
the child. Children and families must understand that stopping Anger
ineffective therapies is not giving up, but represents a rational Sadness or depression
decision based on children’s best interests. Pain control is also an Distancing by staff and friends
essential component of palliative care.9–15 Children and parents
should not fear that health professionals have given up on
controlling pain and aversive symptoms. As with chronic and on an already distressed child and family and can create a situation
recurrent pain, all symptoms must be treated aggressively from in which children’s pain and disability intensifies. The reader is
the dual perspective of targeting the primary source of tissue referred to references 13 and 16 through 21 for a comprehensive
damage and modifying the secondary contributing factors. care of the dying child.
Although most families receive accurate information about their Children’s physical activity can be progressively restricted
disease and required treatments, few children or their parents because of the disability caused by their condition. Parents who
receive concrete information about their pain, the factors that can encourage children to adopt passive patient roles, to behave
attenuate or exacerbate it, a rationale for the interventions they differently from other children, and to depend primarily on others
receive, and training in effective nondrug pain control methods. for pain control will undoubtedly create a situation in which
The latter may be particularly important for children in palliative children’s pain is maximized. It is possible to create some “normal
care, who have diminishing control in their lives. Children and environment” in which children can participate and actively
their parents often do not understand that pain control therapies involve themselves. One cannot overemphasize the importance of
may vary in efficacy because of changing disease, the effects of one of the three 3Ps, that being physical activity.
other drugs, and situational factors. Thus, their confidence in Children who experienced adverse physical effects from
certain pain control therapies can decrease, even though these medication, such as weight gain, may have become acutely self-
therapies would effectively alleviate pain at another time. The fear conscious about their appearance. As a result, these children may
of inadequate pain control places an enormous emotional burden have progressively withdrawn from social interactions with their
peers because they anticipated negative reactions. Children TABLE 16-2. Primary Components of Pain Assessment
become more distant from the people and activities that they
had enjoyed. Moreover, many children may lose the opportunity Sensory Characteristics
to be regarded as unique individuals by the friends and classmates Onset
they value. Instead, they are regarded increasingly as sick or Location
different. Their peers and their daily accomplishments (social, Intensity
academic, or athletic) provide special meaning about a child’s Quality
unique value in the world. Although families emphasize children’s Duration
value to them and to the world, children often lose the objective Spread to other sites (consistent with neurologic pattern)
feedback they had routinely received. The increased withdrawal Radiation
and social isolation can exacerbate their pain and emotional Temporal pattern
distress. Although important for children and families, the Accompanying symptoms
exclusive focus on the family increases a child’s social isolation and
Medical/Surgical
may cause more anxiety for some children. Inadvertently, the
Investigations conducted
family may prevent children from interacting both with peers,
who can lessen their anxiety through play and conversation, Radiologic and laboratory results
and with health professionals, who can help them to resolve Consult results
their anxiety. As can be often quoted from consultations in our Analgesic and adjuvant medications (type, dose, frequency,
clinic, “A child not in school is a child whose pain is far more route, length of medication trial)
difficult to treat.” Clinical Factors
Children fear separation and abandonment; some children Environmental features
may fear that their illness is a punishment. Children may feel Roles of medical and associated health professionals
frightened, isolated, and guilty unless they are able to openly Nature of interventions
express and resolve their concerns. It is essential to acknowledge Complementary and alternative therapy
and resolve their fears. Children should receive accurate infor- Documentation of pain
mation, consistent with their beliefs, presented in a calm, Criteria for determining analgesic effectiveness
reassuring manner. Unresolved emotions add anguish and may Cognitive Factors
intensify their pain. Understanding of pain source
Understanding of diagnosis, treatment, and prognosis
Expectations
OPTIMAL PAIN CONTROL Perceived control
FOR CHILDREN Relevance of disease or painful treatments
Pain control is an intrinsic component of pediatric care. Because Knowledge of pain control
children may experience complex pains because of myriad Behavioral Factors
physical and psychological factors, pain control must be child- General coping style
centered rather than disease-centered. Health care providers must Learned pain behaviors
carefully evaluate the varied causes and contributing factors to Overt distress level
select the most effective therapies for each child’s pain. Onset, Parent’s behaviors
location, intensity, quality, duration (or frequency, if recurring), Physical activities and limitations
spatial extent, temporal pattern, and accompanying physical Social activities and limitations
symptoms are the key pain characteristics for assessment (Table Emotional Factors
16–2). All of these characteristics should be evaluated as part of Frustration
the initial clinical examination with pain intensity and any other Anxiety
characteristics that are clinically relevant for children monitored Fear
regularly. Children’s descriptions about the nature of their pain Denial
(when self-report is available) complete the information obtained Sadness
through radiologic and laboratory investigations. Because several Anger
situational factors usually contribute to children’s pain, distress, Depression
and disability, health care providers should evaluate the extent to
which these may be relevant for a child, building on their
knowledge of the child’s and family’s previous experiences nondrug therapies (cognitive, physical, and behavioral techniques)
throughout the child’s life and their observations of the current are equally essential. As we monitor the child’s improvement in
situation. response to the therapies initiated, we refine our pain diagnosis
The differential diagnosis of a child’s pain is a dynamic process and treatment plan accordingly. Pain control is practically
that guides our clinical management. We should select specific achieved by adjusting both drug and nondrug therapies in a
therapies to target the responsible central and peripheral mecha- rational child-centered manner based on the assessment process
nisms and to mitigate the pain-exacerbating impact of situational as outlined by the treatment algorithm in Figure 16–2. (The
factors, recognizing that the multiple causes and contributing different therapies are described later in the chapter.) Controlling
factors will vary over time. Drug therapies (analgesics, analgesic- children’s pain requires an integrated approach because many
adjuvants, and anesthetics) are essential for pain control, but factors are responsible, no matter how seemingly clear-cut the
Misconceptions About the Risk of Addiction

Some health care providers and parents believe that opioid anal-
gesics should be administered only as a last resort, to avoid drug
addiction. They have not understood that Tolerance + Physical
Dependence = Addiction. As a result, children have not always
received the potent analgesics required to relieve severe pain.
Moreover, they may not understand that opioid-related side effects
should be treated aggressively so that the potential efficacy of these
drugs for controlling pain is not compromised by adverse side
effects.
Misconceptions About the Efficacy

of Nondrug Therapies
Many health professionals do not realize that relatively simple
nondrug strategies can lessen children’s pain. As a result, they have
not taught children or their parents how to use practical cognitive,
physical, and behavioral strategies that are effective for reducing
pain, distress, and pain-related disability. Similarly, they have not
taught parents the importance of evaluating and modifying
situational and familial factors to lessen children’s pain.
Misconceptions About Comprehensive Pain Control

Many health care providers believe that drug therapies are both
necessary and sufficient to control children’s pain. They have not
prescribed nondrug therapies to supplement or complement
Figure 16-2. A treatment algorithm for controlling children’s pain. analgesics, even when situational factors are impeding analgesic
efficacy.
etiology. Adequate analgesic prescriptions, administered at regular Misconceptions About Pain Assessment
dosing intervals, must be complemented by a practical cognitive- Many health care providers do not know how to routinely assess
behavioral approach to ensure optimal pain relief. children’s pain levels or the factors that intensify their pain and
distress. As a result, it may be difficult to evaluate the effectiveness
Misconceptions Regarding of changes in drug therapy, complementary therapies, and
situational factors.
Pain Control in Children
Several misconceptions have led to inadequate pain control Misconceptions About Who Is
in children (revised from reference 1). in Charge of Pain Control
One individual should assume primary responsibility for ensuring
Misconceptions About Children’s Pain Systems that a child’s pain is controlled adequately. Diffusion of res-
Many health care providers continue to treat children’s pain from ponsibility among various health care providers leads to gaps in
an erroneous disease model perspective wherein pain is always recognizing a child’s pain and treating pain appropriately.
proportional to the extent and severity of tissue damage. As a
result of misconceptions about the plasticity and complexity of Misconceptions About the Importance
children’s nociceptive systems, they focus on the primary source of of Consistent Pain Control
noxious stimulation, but not on all the causative and contributing The medical specialties, which provide care to children through-
factors that affect nociceptive processing. As a result of mis- out their illness, do not always adopt a consistent approach to pain
conceptions about nociceptive and neuropathic components of assessment and pain control, similar to their consistent approach
pain, they fail to use the wide range of analgesic and analgesic- to disease diagnosis and medical treatment. The failure to regard
adjuvants available to control pain. pain control as important throughout a child’s treatment can lead
to difficulties for children, especially if previous experiences with
inadequate pain management create undue stress and anxiety for
Misconceptions About the Pharmacodynamics them and their parents.
and Pharmacokinetics of Opioid Analgesica
As a result of misconceptions about the pharmacodynamics and
pharmacokinetics of opioid analgesics, health professionals do not GUIDELINES FOR PAIN ASSESSMENT
always select the most appropriate drugs, doses, dosing intervals, Pain assessment is an integral component in the diagnosis and
or administration routes. treatment of children’s pain. A thorough medical history, physical
examination, and assessment of pain characteristics and con- change throughout the course of their illness. At present, health
tributing factors are necessary to establish a correct clinical dia- care providers must use their content expertise and consult with
gnosis. Subsequent assessments of pain intensity enable us to parents to carefully consider which behavior or behaviors are the
determine when treatments are effective and to identify those most relevant indices of pain for a particular child. They can chart
children for whom they are most effective. Health care providers the presence and intensity of these behaviors (it is likely that these
need pain measures that are convenient to administer and whose will be more subtle indices than on current standardized scales)
resulting pain scores provide meaningful information about and interpret them as an indirect measure of pain.
children’s pain experiences. An extensive array of pain measures Psychological or self-report pain scales directly capture an
have been developed and validated for use with infants, children, individual’s subjective experience of pain. Interviews, ques-
and adolescents.22–24 tionnaires, adjective checklists, and numerous pain intensity scales
Like adult pain measures, children’s pain measures are classified are available for children, each with some evidence of validity and
as physiologic, behavioral, and psychological, depending on what reliability.22,28 Clinical interviews are ideally suited for learning
is monitored, physical parameters (e.g., heart rate, sweat index, about the sensory characteristics of pain, the aversive component,
blood pressure, cortisol level), distress behaviors (e.g., grimaces, and contributing cognitive, behavioral, and emotional factors.
cries, protective guarding gestures), or children’s own descriptions Interviews should also include a simple rating scale to document
of what they are experiencing (e.g., words, drawings, numerical pain strength. Children choose a level on the scale that best
ratings). Physiologic and behavioral measures provide indirect matches the strength of their own pain (i.e., a level on a number
estimates of pain because health care providers must infer the or thermometer scale, a number of objects, a mark on a visual
location and strength of a child’s pain solely from his or her res- analogue scale, a face from a series of faces varying in emotional
ponses. By contrast, psychological measures can provide direct in- expression, or a particular word from adjective lists). Pain intensity
formation about the location, strength, quality, duration, and affect. scales are easy to administer, requiring only a few seconds once
The criteria for an accurate pain measure are similar to those children understand how to use them. Many of these scales yield
required for any measuring instrument. A pain measure must be pain scores on a 0 to 10 scale. Visual and colored analogue scales
valid in that it measures a specific aspect of pain so that changes are versatile for use with acute, chronic, and recurrent pain and
in pain ratings reflect meaningful differences in a child’s pain provide a convenient and flexible pain measure for use in hospital,
experience. The measure must be reliable in that it provides office, and at home.
consistent and trustworthy pain ratings regardless of the time of Health care providers must consider the age and cognitive
testing, the clinical setting, or who is administering the measure. ability of a child when selecting a pain scale. Most toddlers (~2 y
The measure must be relatively free from bias in that children of age) can communicate the presence of pain using words learned
should be able to use it similarly, regardless of differences in how from their parents to describe the sensations they feel when they
they may wish to please adults. The pain measure should be hurt themselves. They use concrete analogies to describe their
practical and versatile for assessing different types of pain (e.g., perceptions. Gradually children learn to differentiate and describe
disease-related, procedural pain) in many different children three levels of pain intensity: “a little,” “some or medium,” and “a
(according to age, cognitive level, cultural background), and it lot.” By the age of 5, most children can differentiate a wider range
should be applicable in diverse clinical and home settings. of pain intensities and many can use simple pain intensity scales.
Although physiologic parameters can provide valuable infor- Children’s understanding and descriptions of pain naturally
mation about a child’s distress state, more research is required to depend on their age, cognitive level, and previous pain experience.
develop a sensitive system for interpreting how these para- Children begin to understand pain through their own hurting
meters reflect pain strength. At present, there are no valid experiences; they learn to describe the different characteristics of
physiologic pain scales for children. Most behavioral pain scales their pains (intensity, quality, duration, and location) in the same
are checklists of the different distress behaviors that children way that they learn specific words to describe different sounds,
exhibit when they experience a certain type of pain.22,25,26 To tastes, smells, and colors. Most children can communicate
develop these scales, trained health care providers carefully observe meaningful information about their pain. Gradually, they develop
children when they are in pain (e.g., after surgery) and document an increasing ability to describe specific pain features such as the
behaviors that seem to be caused by the pain. They then list these quality (aching, burning, pounding, sharp), intensity (mild to
“presumed pain” behaviors (e.g., crying, facial expression, limb severe), duration and frequency (a few seconds to years), location
rigidity) on an itemized checklist. Parents complete the pain scale (from a diffuse location on their skin to more precise inter-
by checking which of the listed behaviors they see when children nal localization), and unpleasantness (mild annoyance to an
are ill. On many scales, parents also rate the intensity of the intolerable discomfort). Children’s understanding of pain and the
behaviors. The intensity scores for each of the observed behaviors language that they use to describe pain come from the words and
are summed to produce a composite pain score. Although most expressions used by their families and peers and from characters
behavioral scales measure acute pain reliably in most patients, depicted in books, television, videos, and movies. For a more
there remains a need to develop more sensitive measures for extensive review of developmental factors in children’s pain, the
children who are cognitively or physically impaired.27 The reader is referred to references 1, 6, and 29 through 33. Physicians
complexity of a child’s disease or health condition, concomitant should always ask children directly about their pain. Pain onset,
drug therapy, and the other distress sources in the health care location, frequency (if recurring), quality, intensity, accompanying
environment may limit children’s ability to behave, thereby making physical symptoms, and pain-related disability should be assessed
the behavioral pain score unreliable. Their pain behaviors may be as part of children’s clinical examination. Health care providers
very different from those of the children studied to develop the should also assess relevant situational factors in order to modify
original scales. Moreover, the most salient pain behavior may be their pain-exacerbating impact, especially the factors listed in
very child-dependent and vary widely among different children or Table 16–1.
ANALGESIC SELECTION in children,42–44 we still await published studies to support this

wider use in children, both in general and specifically in palliative
AND ADMINISTRATION care.45 Similar pediatric studies are also required for the recently
Pain control should include regular pain assessments, appropriate proposed indications for the use of pregabalin, a pharmacologic
analgesics with adjuvant analgesics administered at regular dosing analogue of gabapentin, in chronic pain conditions.
intervals, adjunctive drug therapy for symptom and side effect NSAIDs are similar in potency to aspirin. NSAIDs are used
control, and nondrug therapies to modify the situational factors primarily to treat inflammatory disorders and to lessen mild to
that can exacerbate pain and suffering. Analgesics include aceta- moderate acute pain. They should be used with caution in patients
minophen, non-steroidal anti-inflammatory drugs (NSAIDs), and with hepatic or renal impairment, compromised cardiac function,
opioids. Adjuvant analgesics include a variety of drugs with hypertension (because they may cause fluid retention), and those
analgesic properties, such as anticonvulsants and antidepressants, with a history of gastrointestinal bleeding or ulcers. NSAIDs may
that were initially developed to treat other health problems. The also inhibit platelet aggregation and, thus, must be monitored
use of adjuvant analgesics has become a cornerstone of pain con- closely in patients with prolonged bleeding times. Although
trol in pediatric care. They are especially crucial when pain has a acetaminophen should be considered the routine nonopioid
neuropathic component. analgesic for children, NSAIDs are often more effective for
The guiding principles of analgesic administration are “by the patients with bony lesions causing chronic and recurrent pain.
ladder,” “by the clock,” “by the child,”, and “by the mouth.” “By the Tramadol was launched in the area of pain practice in the late
ladder” refers to a three-step approach for selecting drugs 1970s in Germany. It has more recently been released in Canada
according to their analgesic potency based on the child’s pain level: in a long-acting oral preparation (Zytram XL) and as a com-
acetaminophen to control mild pain, codeine to control moderate bination drug with acetaminophen (Tramacet). Its use has been
pain, and morphine for strong pain.34 The ladder approach was welcomed as an additional analgesic in our drug armamentarium
based on our scientific understanding of how analgesics affect pain with a potency compatible with level two agents of the WHO
of nociceptive origins. If pain persists despite starting with the analgesic ladder. Tramadol is a synthetic, 4-phenyl-piperidine
appropriate drug, recommended doses, and dosing schedule, analogue of codeine that is marketed as a racemic mixture of (+)
move up the ladder and administer the next more potent analgesic. and (–) enantiomers. The opioid activity of tramadol results from
Even when children require opioid analgesics, they should low-affinity binding of the (+) enantiomer to μ opioid receptors.
continue to receive acetaminophen (and NSAIDs, if appropriate) The (+) enantiomer inhibits serotonin uptake and has a direct
as supplemental analgesics. The analgesic ladder approach is based serotonin-releasing action, whereas the (–) enantiomer is a more
on the premise that acetaminophen, codeine, and morphine effective inhibitor of norepinephrine uptake.46 The analgesic
should be available in all countries and that doctors and health potency of tramadol is considered to be medium, having one tenth
care providers can relieve pain in the majority of children with a the potency of morphine. Its advantages over opioids are mainly
few drugs. The World Health Organization (WHO) model of (1) the lower incidence of side- effects such as respiratory depression,
appropriate policies, (2) adequate drug availability, (3) education nausea, vomiting, constipation, sedation and a low potential for
of the health care workers, policymakers and the public, and (4) dependence or abuse. Rose and coworkers reported that, in 113
implementation has been shown to provide an effective strategy to children, aged 7 to 16 years, oral tramadol at 1 mg/kg every 4 to 6
establish pediatric pain control.35,36 Oral morphine in either hours for various painful conditions provided effective analgesia
immediate-release or sustained-release form remains the analgesic and was well tolerated.47 Tramadol may prove particularly useful in
of choice for moderate or severe pain.37,38 The accelerated use of patients with poor cardiopulmonary, renal, or hepatic function and
narcotics and sedatives (when required) takes place when end of in those whom NSAIDs are not recommended or need to be used
life care (EOLC) discussions have been implemented.39 with caution.48 A growing number of studies and case reports have
Increasing attention is focusing on “thinking beyond the demonstrated the safety and efficacy of tramadol in the pediatric
ladder” in accordance with our improved understanding of pain population.49,50 Although it continues to be prescribed routinely in
of neuropathic origins.40,41 Children should receive adjuvant Europe and North America, its clinical use is not recommended
analgesics to more specifically target neuropathic mechanisms. in the pediatric population in some countries because of limited
Regrettably, two of the main classes of adjuvant analgesics, prospective studies in patients younger than 18 years.
antidepressants and anticonvulsants, have unfortunate names. Although the specific drugs and doses are determined by the
Proper education of health care providers, parents, and children needs of each child, general guidelines for drug therapies to
should lead to a wider acceptance and use of these medications control pain for children with chronic and recurrent pain are few.
for pain management. For example, amitriptyline may require 4 to Guidelines have been developed through a Consensus Conference
6 weeks to affect depression, but often requires only 1 to 2 weeks on the Management of Pain in Childhood Cancer, published as a
to affect pain. The newer classes of antidepressants, the selective supplement to Pediatrics51; in a monograph from the WHO
serotonin re-uptake inhibitors (SSRIs), may be beneficial to treat entitled, “Cancer Pain Relief and Palliative Care for Children”15;
depression in a child with pain, but have not been shown to be and in clinical practice guidelines.52–54 The drugs listed in this
beneficial for pain management. The other main class of adjuvant chapter are based primarily on these sources, from the abundance
analgesics is the anticonvulsants. The two principal medications of literature on pain management for children with cancer or those
used for this purpose in pediatric patients are carbamazepine and receiving palliative care, and from guidelines from our insti-
gabapentin. With gabapentin, the main dose-limiting side effect is tution.55 Recommended starting doses for analgesic medications
sedation so that a slow titration to maximal dose is required. to control children’s disease-related pain are listed in Tables 16–3
Because of its greater number of significant side effects, the use of and 16–4. Starting doses for adjuvant analgesic medications to
carbamazepine has decreased and the use of gabapentin has control pain, drug-related side effects, and other symptoms
increased. Although some reports support the use of gabapentin are listed in Table 16–5. For further review of analgesics and
TABLE 16-3. Nonopioid Medications for Relieving Pain in Children

Drug Dosage Comments
Acetaminophen 10–15 mg/kg p.o., q4–6h Lacks gastrointestinal and hematologic side effects; lacks anti-
inflammatory effects; may mask infection-associated fever. Dose
limit of 65 mg/kg/d or 4 g/d, whichever is less.
Ibuprofen 5–10 mg/kg p.o., q6–8h Anti-inflammatory activity. Use with caution in patients with
hepatic or renal impairment, compromised cardiac function or
hypertension (may cause fluid retention or edema), history of GI
bleeding or ulcers. Inhibits platelet aggregation. Dose limit of 40
mg/kg/d (maximum dose 2400 mg/d).
Naproxen 10–20 mg/kg/d p.o., divided q12h Anti-inflammatory activity. Use with caution and monitor closely
in patients with impaired renal function. Avoid in patients with
severe renal impairment. Dose limit of 1 g/d.
Diclofenac 1 mg/kg p.o., q8-12h Anti-inflammatory activity. Similar GI, renal, and hepatic
precautions as noted for ibuprofen and naproxen. Dose limit of
50 mg/dose.
GI = gastrointestinal.
Note: Increasing the dose of nonopioids beyond the recommended therapeutic level produces a “ceiling effect” in that there is no additional analgesia, but there are
major increases in toxicity and side effects.
adjuvant analgesics in children, the reader is referred to references preoccupied with their symptoms. Thus, it is essential to establish
41 and 56 through 63. and maintain a therapeutic window of pain relief for children.
Analgesic doses should be adjusted “by the child.” No one dose
will be appropriate for all children with pain. The goal is to select
Principles of Opioid Administration a dose that prevents children from experiencing pain before they
1. If pain relief is inadequate and there is no toxicity at peak onset receive the next dose. It is essential to monitor the child’s pain
of opioid action, increase the dose in 50% increments. regularly and adjust analgesic doses as necessary to control the
2. Avoid intramuscular administration. pain. The effective opioid dose to relieve pain varies widely among
3. Whenever using continuous infusion, plan for hourly rescue different children or even at different times in the same child.
doses with short-onset opioids if needed. The rescue dose is Some children require massive opioid doses at frequent intervals
usually 50 to 200% of the continuous hourly dose. If greater to control their pain. If such large doses are necessary for effective
than six rescues are necessary in a 24-hour period, increase the pain control, and the side effects can be managed by adjunctive
daily infusion total by the total amount of rescue doses for medication so that children are comfortable, the doses are
the previous 24 hours. An alternative is to increase infusion appropriate. Children receiving opioids may develop altered sleep
by 50%. patterns so that they are awake at night, fearful and complaining
4. If changing between opioids with a short duration of action, about pain, and then sleep intermittently throughout the day. They
start the new opioid at 50% of the equianalgesic dose. Titrate to should receive adequate analgesics at night with antidepressants or
effect. If changing between opioids from short to long duration hypnotics as necessary to enable them to sleep throughout the
of action (i.e., morphine to methadone), start at 25% of the night. To relieve severe ongoing pain, opioid doses should be
equianalgesic dose and titrate to effect. These adjustments are increased steadily until comfort is achieved, unless the child
needed because of incomplete cross-tolerance between opioids. experiences unacceptable side effects such as somnolence or
5. To taper opioids (anyone on opioids over 1 wk must be tapered respiratory depression (Table 16–6).
Medications should be administered to children by the simplest
to avoid withdrawal): taper by 50% for 2 days, and then
and most effective route, usually by mouth. Because children are
decrease by 25% every 2 days. When the dose is equianalgesic
afraid of painful injections, they may deny that they have pain or
to an oral morphine dose of 0.6 mg/kg/d, the dose may be
they may not request medications. When possible, children should
stopped. Some patients on opioids for prolonged periods may
receive medications through routes that do not cause additional
require much slower weaning.
pain. Although optimal analgesic administration for children
Children should receive analgesics at regular times, “by the requires flexibility in selecting routes according to children’s needs,
clock,” to provide consistent pain relief and prevent breakthrough parenteral administration is often the most efficient route for
pain. The specific drug schedule (every 4 or 6 h) is based on the providing direct and rapid pain relief. Because intravenous,
drug’s duration of action and the child’s pain severity. Although intramuscular, and subcutaneous routes cause additional pain for
breakthrough pain episodes have been recognized as a problem children, serious efforts have been expended on developing more
in adult pain control, they may represent an even more serious pain-free modes of administration that still provide relatively
problem for children. Unlike adults, who generally realize that direct and rapid analgesia. Attention has focused on improving
they can demand more potent analgesic medications or more the effectiveness of oral routes. As an example, oral transmucosal
frequent dosing intervals, children have little control, little fentanyl citrate (OTFC) has previously been shown to provide the
awareness of alternatives, and fear that their pain cannot be rapid onset of analgesia via a pleasant route for children
controlled. They may become progressively frightened, upset, and undergoing painful medical procedures. OTFC produces effective
TABLE 16-4. Opioid Medications: Usual Starting Doses for Analgesia in Pediatric Patients
Equianalgesic Dose IV:p.o. Starting Dose Duration of
Drug (parenteral) Starting Dose IV Ratio p.o./Transdermal Action
Morphine 10 mg Bolus dose: 0.05–0.1 mg/kg 1:3 0.15–0.3 mg/kg/dose q4h 3–4 h
q2–4 h; Continuous
infusion: 0.01–0.04
mg/kg/h
Hydromorphone 1.5 mg 0.015–0.02 mg/kg q4h 1:5 0.06 mg/kg q3–4h 2–4 h
Codeine 120 mg Not recommended 1.0 mg/kg q4h 3–4 h
(maximum 1.5
mg/kg/dose)
Oxycodone 5–10 mg Not recommended 0.1–0.2 mg/kg q3–4h 3–4 h
Meperidinea 75 mg 0.5–1.0 mg/kg q3–4h 1:4 1.0–2.0 mg/kg q3–4h 1–3 h
(dose limit 150 mg)
Fentanylb 100 μg Bolus dose: 1–2 μg/kg; 25 μg transdermal patch 15–20 min
continuous infusion: (IV); 72 h
1–2 μg/kg/h (patch)
Controlled-release 0.6 mg/kg q8h or
morphinec,d 0.9 mg/kg q12h
Controlled-release 0.18 mg/kg q12h
hydromorphoned
Controlled- 3 mg/kg q12h
release codeined
Controlled-release 0.6 mg/kg q12h
oxycodoned
Methadone 10 mg 0.1 mg/kg q4–8h 1: 2 0.2 mg/kg q4–8 h 12–50 h
Tramadol 100 mg 2.0 mg/kg q4–6h 1 mg/kg 4–6 h
q4-6h (dose limit
400 mg/d)
Note: Doses are for opioid-naive patients. For infants younger than 6 mo, start at one quarter to one third the suggested dose and titrate to effect.
a
Avoid use in renal impairment as metabolite may cause seizures.
b
Potentially highly toxic. Not for use in acute pain control.
c
Use may be hampered by child’s difficulty in swallowing large tablets.
d
The widely equianalgesic doses in adults are used as guidelines in pediatric practice, but have not been substantiated in children.
plasma concentrations within 15 to 20 minutes.64 Children aged 2 continue to receive “rescue doses” to control breakthrough pain,
to 14 years have shown good cooperation and sedation when given as necessary. As outlined in Table 16–4, the rescue doses should
OTFC as a premedication prior to anesthetic induction.65,66 OTFC be 50 to 200% of the continuous hourly infusion dose. If children
produced safe and effective analgesia for outpatient wound care experience repeated breakthrough pain, the basal rate can be
in children and the taste was preferred to oral oxycodone.67 increased by 50% or by the total amount of opioid administered
Many hospitals have restricted the use of intramuscular through the rescue doses over a 24-hour period (divided by
injections because they are painful and drug absorption is not 24 h).
reliable. They advocate the use of the intravenous route so that Patient-controlled analgesia (PCA) enables children to
medications can be administered directly without causing further administer analgesic doses according to their pain level. PCA
pain. Topical anesthetic creams should also be applied prior to the provides children with a continuum of analgesia that is prompt,
insertion of intravenous lines in children. The use of Port-Aa-Cath economical, not nurse-dependent, and results in a lower overall
or some type of chronic indwelling central venous access has use of opioids.68–73 PCA has a high degree of safety, allows for wide
become the gold standard in pediatrics, particularly for children variability between patients, and avoids delays in analgesic
who require the administration of multiple drugs at frequent administration. The reader is referred to reference 49 for a full
intervals. A continuous infusion has several advantages over review of PCA. It can now be regarded as a standard for the
intermittent subcutaneous, intramuscular, or intravenous admi- delivery of analgesia in children older than 5 years of age.74
nistration. This method circumvents repetitive injections, prevents However, there are opposing views about the use of background
delays in analgesic drug administration, and provides continuous infusions with PCA. Although they may improve efficacy, they
levels of pain control while avoiding adverse effects that occur with may increase the occurrence of adverse effects such as nausea,
peak levels and pain breakthroughs at trough levels. Continuous vomiting, sedation, and respiratory depression. In a comparison of
infusion should be considered when children have pain for which PCA with and without a background infusion for children having
oral and intermittent parenteral opioids do not provide satis- lower extremity surgery, the total morphine requirements were
factory pain control or when intractable vomiting prevents oral reduced in the PCA-only group and the background infusion
medications. Children receiving a continuous infusion should offered no advantage.75 In another study comparing background
TABLE 16-5. Adjuvant Analgesic Drugs

Drug Category Drug, Dosage Indications Comments
Antidepressants Amitryptyline: Neuropathic pain (i.e., Usually results in improved sleep
0.2–0.5 mg/kg p.o. Titrate upward by 0.25 vincristine-induced, and pain relief within 3–5 d.
mg/kg q2–3d. Maintenance dose: 0.2–3.0 radiation plexopathy, May result in insomnia.
mg/kg. Alternatives: nortriptyline, tumour invasion, Anticholinergic side effects are
doxepin, imipramine, venlafaxine. CRPS-1). dose-limiting. Use with caution
for children with increased risk
for cardiac dysfunction.
Anticonvulsants Carbamazepine: Initial dose of 10 mg/kg/d Neuropathic pain, Monitor for hematologic,
p.o. divided OD or BID. Maintenance especially pain with hepatic, and allergic reactions.
dose: up to 20–30 mg/kg/d p.o. divided shooting or stabbing Side effects may include
q8h. Increase dose gradually over 2–4 wk. qualities. gastrointestinal upset, ataxia,
Alternatives: phenytoin, clonazepam. dizziness, disorientation,
Gabapentin: 5 mg/kg/d p.o. Titrate up somnolence.
over 3–7 d. Maintenance dose: 15–50
mg/kg/d p.o. divided TID
Sedatives, hypnotics, Diazepam: 0.025–0.2 mg/kg p.o. q6h. Acute anxiety or muscle Sedative effect may limit opioid
anxiolytics spasms. use. Other side effects include
depression and dependence
with prolonged use.
Lorazepam: 0.05 mg/kg/dose SL. Premedication for
Midazolam: 0.5 mg/kg/dose p.o. admi- painful procedures.
nistered 15–30 min prior to procedure; Sedative side effects maybe
0.05 mg/kg/dose IV for sedation. helpful.
Antihistamines Hydroxyzine: 0.5 mg/kg p.o. q6h. Opioid-induced pruritus, Side effects include agitation,
Diphenhydramine: 0.5–1.0 mg/kg p.o./IV anxiety, nausea. sleep disturbance, and
q6h. anorexia. Administer second
Psychostimulants Dextroamphetamine or methylpheni- Opioid-induced somno- dose in afternoon to avoid
date: 0.1–0.2 mg/kg BID. Escalate to 0.3– lence. Potentiation of sleep disturbances.
0.5 mg/kg as needed opioid analgesia.
Corticosteroids Prednisone, prednisolone, and Headache from increased Side effects include edema,
dexamethasone: dose depends on clinical intracranial pressure, dyspeptic symptoms, and
situation. Dexamethasone: initial dose of spinal, or nerve com- occasional gastrointestinal
0.2 mg/kg IV to a maximum of 10 mg. pression; widespread bleeding. Burning and pain
Subsequent dose of 0.3 mg/kg/d IV metastatic disease. with peripheral IV
divided q6h. administration.
CRPS-1 = complex regional pain syndrome type 1; SL = sublingual.
infusion and PCA, children between 9 and 15 years of age is a potent synthetic opioid, which like morphine binds to
achieved better pain relief with PCA, whereas children between μ receptors. However, fentanyl is 75 to 100 times more potent than
5 and 8 years of age showed no difference.76 Our current standard morphine. The intravenous preparation of fentanyl has been used
is to add a background infusion to the PCA if the pain is not extensively in children. A transdermal preparation of fentanyl was
controlled adequately with PCA alone (bolus-only mode). The introduced in 1991 for use with chronic pain. This route provides
selection of opioid used in PCA is perhaps less critical than the a noninvasive but continuously controlled delivery system.
appropriate selection of parameters such as bolus dose, lockout, Although limited data are available regarding transdermal fentanyl
and background infusion rate. The opioid choice may be based on (TF) in children, its use is increasing for children with stable and
adverse effect profile rather than efficacy. Clearly, PCA offers chronic pain. Noyes and Irving demonstrated that TF was well
special advantages to children who have little control and who are tolerated, provided effective pain relief in 11 of 13 children, and
extremely frightened about uncontrolled pain. PCA is as it states, suggested that it was the ideal approach for children in whom
patient-controlled analgesia. When special circumstances require compliance with oral analgesics was problematic.77 In the palliative
that alternate people administer the medication, we do allow both care setting, children were converted from oral morphine to TF.78
nurse- and parent-controlled analgesia. Under these circum- The investigators noted diminished side effects and improved
stances, parents require our nurse educators to fully educate them convenience with TF. The majority of parents and investigators
on the use of PCA. considered TF to be better than previous treatment. No serious
Alternatives to the intravenous for pain management are still adverse events were attributed to fentanyl, suggesting that TF was
being investigated, especially in the pediatric population. Fentanyl both effective and acceptable for children and their families.
TABLE 16-6. Opioid-Related Adverse Effects

Side Effect Management Strategy
Respiratory depression Reduce opioid dose by 50%, gradual dose titration to maintain pain relief without
respiratory depression.
Respiratory arrest Control of airway, breathing and circulation as needed. Naloxone, titrated to effect with
0.01 mg/kg/dose IV/ETT repeated as needed. Even smaller frequent doses of diluted
naloxone or naloxone drip are preferable for patients on chronic opioid therapy to
avoid severe, painful withdrawal syndrome. Repeated doses often required until
opioid side effect subsides given short half-life of naloxone.
Drowsiness and sedation Frequently subsides after a few days without dosage reduction. Methylphenidate or
dextroamphetamine (0.1 mg/kg administered BID in the morning and midday so as
not to interfere with nighttime sleep). The dose can be escalated in increments of
0.05–0.1 mg/kg to a maximum of 10 mg/dose for dextroamphetamine and 20
mg/dose for methylphenidate.
Constipation Increased fluids and bulk, prophylactic laxatives as indicated.
Nausea and vomiting Administer an antiemetic (e.g., ondansetron, 0.1–0.15 mg/kg IV/p.o./transmucosal q8h.
Antihistamines (e.g., dimenhydrinate 0.5 mg/kg/dose 4–6 h IV/p.o.) may also be
used. Prechemotherapy, nabilone 0.5–1.0 mg p.o. and then q12h may also be used.
Confusion, nightmares, hallucinations Reassurance only with mild symptoms. A reduced dose of opioid or a change to a
different opioid. Addition of a neuroleptic agent (e.g., haloperidol 0.1 mg/kg p.o./IV
q8h to a maximum of 30 mg/d).
Multifocal myoclonus, seizures Generally occur only during extremely high-dose therapy. Reduction in opioid dose
indicated if possible. Addition of a benzodiazepine (e.g., clonazepam 0.05 mg/kg/d
divided BID or TID increasing by 0.05 mg/kg/d q3d as needed up to 0.2 mg/kg/d to a
maximum of 20 mg/d).
Urinary retention Rule out bladder outlet obstruction, neurogenic bladder, and other precipitating
medications (e.g., tricyclic antidepressant). Particularly common with epidural
opioids. Change of opioid, route of administration, and dose may relieve symptom.
Bethanechol or catheter may be required.
ETT = endotracheal tube.
Similarly, no adverse effects were noted in a study of TF for scores, and sedation scores. A complete set of intravenous and
children with pain caused by sickle cell crisis.79 This study showed epidural monitoring guidelines have been included in Table 16–7.
a significant relationship between TF dose and fentanyl con-
centration. Pain control with TF was improved in 7 of 10 patients Dosing Considerations for
in comparison with PCA alone. In a multicenter crossover study Neonates and Infants
in adults, TF resulted in significantly less constipation and less
daytime drowsiness than morphine, but a greater incidence of Research on controlling pain in neonates has led to improved and
sleep disturbance and shorter sleep duration.80 Of those patients rational therapeutic regimens to provide safe and effective
able to express a preference, significantly more preferred TF. As analgesia while minimizing adverse effects.84–91 Neonates and
with all opioids, fatal adult complications have been noted infants require the same three categories of analgesic drugs as
with the use of multiple transdermal patches.81 Zernikow and older children. However, the differences in pharmacokinetics and
colleagues provide a thorough summary in a recently published pharmacodynamics among neonates, preterm infants, and full-
review of TF in childhood and adolescence.82 term infants warrant special dosing considerations for infants and
The use of regional techniques (epidural and spinal) for the close monitoring when they receive opioids. Acetaminophen can
administration of local anesthetic agents and analgesics for child- be safely administered to neonates and infants with limited
ren continues to be an integral part of pain control.83 Experience concern for hepatotoxicity, when given for short courses at the
from many centers suggests that these techniques can be extremely recommended dose (10–15 mg/kg p.o.). The rate of absorption is
useful for children with advanced disease with resulting pain that slower in neonates and the plasma half-life is prolonged. Peak
may be difficult to control by more conventional means. It is also serum concentrations are reached at approximately 60 minutes
feasible for children to receive epidural and spinal infusions at after an oral dose and subsequent doses may be required at 6-
home on an extended basis. rather than 4-hour intervals. Acetaminophen does not cause
When one undertakes the administration of potent analgesics respiratory depression and does not produce tolerance.
and anesthetics, whether by intravenous or a regional anaesthetic Opioid analgesics are the mainstay of treatment for controlling
technique such as an epidural or spinal approach, appropriate severe pain in neonates. When compared as in Table 16–4, the
monitoring remains paramount to ensuring the safety of our starting doses for opioid analgesics in infants younger than 6
patients. This involves the education and training of staff, the months of age are one quarter to one third the recommended
immediate availability of resuscitative drugs and equipment, and doses for older patients. As with children, the dosage and mode of
an accurate and timely pain record consisting of vital signs, pain administration of opioids need to be titrated to achieve the degree
TABLE 16-7. Analgesia Monitoring Guidelines factors including immaturity of the blood-brain barrier and
increased sensitivity owing to the immaturity of ventilatory
Baseline Assessment responses to hypoxemia and hypercarbia. Therefore, opioids
Obtain RR, HR, BP, O2 saturation, sedation score, and pain score should be used more cautiously in infants younger than 6 months
before administering a single or intermittent dose or initiating of age and only with appropriate monitoring or cardiovascular and
continuous infusion. respiratory function. Proper dosing and careful monitoring will
Intermittent Intravenous Administration help minimize adverse effects. Tolerance has significance only as
RR, HR, BP, and sedation score q5min × 4, then q30min × 2, a signal of receptor function or a potential indicator of withdrawal
and then as per child’s condition/pre-existing orders. when therapy is discontinued.
Pain score q20–30 min. Neonates who have pain severe enough to require opioids
Continuously monitor O2 saturation only for children whose usually have an intravenous line in place. If a limited number of
underlying condition predisposes them to respiratory doses are needed and if intravenous access is not available,
depression. intramuscular or subcutaneous routes are still used occasionally in
Intravenous additive (to run over 15–20 min) full-term neonates. However, these routes are painful and not
RR, HR, BP, and sedation score q10min × 2, then every 30 min suitable for preterm neonates because of their sparse muscle mass
× 2, and then as per child’s condition. and delicate skin. They are also not suitable for long-term pain
Pain score at completion of the flush, then q30min × 2, and then management in term neonates because plasma levels and clinical
as per child’s condition or pre-existing orders. effects are less controlled and difficult to titrate, especially with
Continuously monitor O2 saturation only for children whose intramuscular administrations. Intravenous bolus dosing may
underlying condition predisposes them to respiratory produce high peak concentrations resulting in depressed mental
depression. status and respiratory depression followed by a rapid decline in
Continuous IV Infusion/PCA plasma levels causing alternating periods of pain and analgesia.
RR, HR, BP, pain score, and sedation score q1h × 4, then RR and Thus, a continuous intravenous infusion of opioids, producing
sedation score q1h, and then HR, BP, and pain score q4h. constant blood levels and minimal fluctuations in analgesia, is the
Continuously monitor O2 saturation and document reading q1h. most effective route. The use of peripherally inserted central
catheters (PICCs) has become standard practice for the neonate
Intermittent Epidural Administration with difficult venous access or for the patient that may require
RR, HR, and BP q5min for the first 20 min following a bolus access for a prolonged period. For morphine dosing, Anand and
dose, and then RR and sedation score q1h. associates have recommended an initial loading dose of 50 μg/kg
HR, BP, pain score, and motor block score q4h. followed by a continuous infusion at 10 to 20 μg/kg/h.85 Further
Continuously monitor only for children whose underlying increases in the infusion rate may be required to titrate to clinical
condition predisposes them to respiratory depression. effect or with the development of tolerance. However, infants must
Continuous Epidural infusiona,b be monitored carefully because most opioids have a prolonged
RR, HR, BP, sedation score, pain score, and motor block score duration of action in neonates, so that continuous infusions can
q1h × 4 h, then RR and sedation score q1h, and HR, BP, pain result in slow accumulation of the drug over time with high blood
score, and motor block score with sensory level q4h. levels that may not be detected immediately.
Continuously monitor O2 saturation and document reading q1h. The principal and potentially life-threatening side effect of all
opioid drugs is the dose-dependent respiratory depression leading
BP = blood pressure; ECG = electrocardiographic; HR = heart rate; PCA =
to apnea, which may be observed in infants and neonates at
patient-controlled analgesia; RR = respiratory rate.
a
Opioids used with bupivacaine. relatively low doses. This may be advantageous in ventilated
b
After any change in drug dose, infusion rate or if transferred between patient patients, but obviously poses considerable challenges when using
care areas, return to assessments q1h for 4 h. Continuous RR or apnea opioids in spontaneously breathing newborns. Opioid-induced
monitoring may provide additional benefits for certain children who are respiratory depression can be reversed with naloxone, but the
receiving continuous opioid infusions by alerting the nurse to a decreasing RR. effect of the drug diminishes within 30 minutes so that repeated
RR monitoring is not a substitute for frequent patient observation and vital sign naloxone dosing may be required. If apnea does occur, stimulation
monitoring. ECG monitoring is not routinely required, but may be ordered if the
of the baby will usually elicit some respiratory effort temporarily
child’s underlying condition predisposes them to ECG abnormalities.
Adapted from 2001–2002 Drug Formulary, The Hospital for Sick Children,
while emergency arrangements are made to provide respiratory
Toronto. support and administer naloxone. Naloxone should be titrated to
effect in increments of 10 μg/kg until the desired effect is obtained
or up to a total dose of 100 μg/kg. High doses of naloxone may
of analgesia required and a reasonable level of sedation. The drug produce a massive stress response from sudden nociception and
clearance and the analgesic effects of morphine, fentanyl, withdrawal or may result in undesirable fluid shifts. Following an
sufentanil, and methadone for infants older than 6 months and effective dose of naloxone, the neonate should be monitored
children are similar to those for young adults. Thus, the general closely for at least 24 hours. In fact, because plasma concentrations
clinical impression is that morphine and other opioids have a of morphine can increase in some neonates even after an opioid
reasonable margin of safety and excellent efficacy for most infusion is discontinued, neonates require close monitoring for at
children older than 6 months of age. However, premature and least 24 hours after morphine administration is discontinued.
term newborns show reduced clearance of most opioids. The Young infants, especially premature babies or those who have
widely observed sensitivity of newborns to morphine is probably neurologic abnormalities or pulmonary disease, are more sus-
because of pharmacokinetic factors including a smaller volume of ceptible to apnea and respiratory depression when systemic
distribution and diminished clearance as well as physiologic opioids are used. An infant’s metabolism is altered because of the
immaturity of the hepatic microsomal enzymes so that the who have complex health care difficulties because there may be
elimination half-life of opioids is longer and there may be multiple sources of noxious stimulation caused by disease and the
increased entry of the opioid into the brain owing to immaturity effects of prescribed therapies. Yet, children’s pain must be
of the blood-brain barrier. Both factors result in young infants controlled, even when the specific etiology has not yet been
having a higher concentration of opioids in the brain for a given determined. Otherwise, children become increasingly anxious,
dose than mature infants or adults. Thus, nonventilated infants fearful, and distressed, thereby beginning a cycle of increasing pain
who are younger than 1 year of age should be monitored closely that will be more difficult to alleviate.
when they receive opioids because extreme sedation and Parents are often anxious about opioids for their children,
decreased respiratory effort may be difficult to assess. Institutions particularly when children require increased dose increments.
in which neonates and infants are treated should train personnel Staff must educate parents that physical dependence and tolerance
in the safe and effective administration of analgesia and provide are very different from addiction. Parents will then understand
appropriate technologies for monitoring. Monitoring should that physical dependence and tolerance are normal drug effects;
include respiratory rate, heart rate, blood pressure, sedation score, they do not mean that their children with pain have become
and pain score at regular intervals, as outlined in Table 16–7. addicted. Physical drug dependence is well recognized. When
Epidural analgesia is now widely used for infants with opioids are suddenly withdrawn, infants and children may
postoperative pain. The hemodynamic effects of major regional suffer from irritability, anxiety, insomnia, diaphoresis, rhinorrhea,
analgesia in infants with postoperative pain appear minimal. For nausea, vomiting, abdominal cramps, and diarrhea. These
pediatric epidural infusions, the standard local anesthetic that we withdrawal symptoms can be prevented by the gradual tapering
use is bupivacaine at an infusion rate of 0.2 to 0.4 mg/kg/h. of an opioid. Even though children with severe pain require
Epidural infusions that exceed the recommended rate may lead to progressively higher and more frequent opioid doses because of
convulsions. In addition even at constant infusion rates, bupiva- drug tolerance, they should receive the doses they need to relieve
their pain. However, children who require increased opioids to
caine levels may continue to increase after 48 hours. Epidural
relieve previously controlled pain should be assessed carefully to
opioids such as morphine and fentanyl have been used success-
determine whether the disease has progressed because pain may
fully, even for very young infants. The proper use of infusions or
be the first sign of advancing disease.
intermittent doses of epidural opioids or local anesthetics requires
Therapists can use familiar analogies to explain depen-
expertise and appropriate monitoring, as outlined in Table 16–7.
dence, tolerance, and addiction. For example, parents are often
accustomed to drinking coffee in the morning. They know that
PHYSICAL DEPENDENCE, they will experience some noticeable effects without their usual
caffeine intake, but they also know that they can withdraw from
TOLERANCE, AND ADDICTION coffee by gradually lowering their daily consumption. The fact that
Physical dependence is defined as a state of adaptation that often their body is used to a certain amount of caffeine at certain times
includes tolerance and is manifested by a drug class–specific of the day means that they are dependent. Similarly, many people
withdrawal syndrome that can be produced by abrupt cessation, become accustomed to a certain level of salt for a food to taste
rapid dose reduction, decrease in the blood level of the drug, or the “salty.” After a while, they may need to increase their salt intake if
administration of an antagonist. Tolerance is a state of adaptation they want foods to taste the same, because their bodies have
in which exposure to a drug induces changes that result in a adjusted to or now tolerate the previous amount of salt so that it
diminution of one or more of the drug’s effects over time. no longer has the same effect. In the same way, their children can
Addiction is a primary, chronic, neurobiologic disease, with become tolerant to a morphine dose so that they require a slightly
genetic, psychosocial, and environmental factors influencing its higher dose to achieve the same pain reduction. These benign
development and manifestations. It is characterized by behaviors examples of a body’s normal responses to substances often help
that include one or more of the following four Cs: impaired control parents understand that when opioids are prescribed for their
over drug use, compulsive use, continued use despite harm children, the effects of those drugs are well known, are well
(consequences), and craving.92 The fear of opioid addiction in understood, and will not lead to adverse effects including
children has been greatly exaggerated. Although physical depen- addiction.
dence is common, gradual tapering protocols can control the
withdrawal syndromes caused by an abrupt cessation of the
medication. Physical dependence may develop in as short a period
Opioid-Related Adverse Effects
as 5 to 7 days. Tolerance is also an expected change to be seen and The safe, rational use of opioid analgesics requires an under-
should be anticipated in children. There is no empirical evidence standing of their clinical pharmacology. The potent opioids that
that children receiving opioid analgesics for pain control are at we use to treat children for pain control have no fixed upper dose
risk for addiction. By contrast, children who do not receive limit. The dose can be increased as necessary to maximize pain
appropriate analgesic medications are probably more at risk for control, as long as children do not experience dose-limiting side
“pseudoaddiction” by becoming excessively concerned about effects (i.e., vomiting, respiratory depression). The goal should be
receiving their next medication dose in the hope that they might titrating medication either up or down for maximum clinical
eventually relieve their suffering. effect. Side effects must be anticipated and treated aggressively.
Parents, and occasionally staff, may have misconceptions about Because opioids produce physical dependence and tolerance,
the use of potent opioids. Although the sensory characteristics of doses must be increased over time to control pain. Doses must be
children’s pain should be consistent with the known pattern from adjusted according to the child’s need depending on pain severity,
the presumed source of tissue injury, the source is not easily prior analgesic medication use, and the bioavailability and drug
identified for all children. This is particularly true for children distribution of the medication.
All opioids have a similar spectrum of side effects. These well- In addition, health care providers can teach children how to
known problems should be anticipated and treated whenever use a few pain control methods to lessen pain and guide families
opioids are administered, so that children can receive pain control to recognize the particular circumstances that exacerbate pain and
without suffering untoward effects. Children may not report all distress. These methods provide children with some independent
side effects (e.g., constipation, dysphoria) voluntarily, so they strategies, either to relieve mild pain or to complement the
should be asked specifically about these problems. Some side medication needed to relieve strong pain. Children should begin
effects may resolve within the first 1 or 2 weeks of initiating therapy by learning a few basic methods. As they acquire confidence in
as the child develops tolerance to them (e.g., nausea, vomiting, and using these methods, they seem to naturally adapt them to fit their
drowsiness). The clinician must educate the patient about these personality or invent new equally effective methods. A therapist
problems and encourage them to give the medication an adequate guides them throughout this process. Children should be
trial. Slow titration may minimize this problem. Other side effects interested and motivated in learning some independent pain
may require aggressive treatment. If they persist despite appropriate control methods. They seem more adept than adults at using
interventions, conversion to an alternate opioid may be indicated. nondrug therapies, presumably because they are usually less
There is generally incomplete cross-tolerance between opioids, so biased than adults about their potential efficacy.
that a general guideline for converting from one opioid to another Distraction is a simple and effective pain control method.
is to begin the new opioid at the lower dosing range and titrate When children intently attend to something other than their pain,
upward. When used in therapeutic doses, opioids have not been they can lessen its intensity and unpleasantness. Distraction is
demonstrated to cause long-term permanent organ toxicity. This often incorrectly perceived as a simple diversionary tactic with
makes them a safe choice for use in infants and children. There is the implication is that the pain is still there, but the child is
evidence that untreated severe chronic pain may cause cognitive momentarily focused elsewhere. However, when children’s
impairment, which is improved with opioid therapy. The treatment attention is fully absorbed in some engaging topic or activity,
of opioid side effects is summarized in Table 16–6. distraction is a very active process that can reduce the neuronal
responses to a noxious stimulus. Children do not simply ignore
their pain, but are actually reducing it. The essential feature for
Nondrug Therapies achieving pain relief is a child’s ability to attend fully to and
Cognitive and Behavioral Approaches concentrate on something else besides the pain. Therefore, the
choice of a distraction is crucial and varies according to children’s
An extensive array of nondrug therapies are available to treat age and interests. Young children usually need to be actively
children’s pain, including counseling, guided imagery, hypnosis, involved with their parents or peers, whereas older children and
biofeedback, behavior management, acupuncture, massage, home- adolescents can distract themselves more independently. Children
opathic remedies, naturopathic approaches, and herbal medicines. should work with their parents or a therapist to choose distracting
Nondrug therapies are generally regarded as safe with few activities that can be practically incorporated into their lives.
contraindications to their use in otherwise healthy children. How- Guided imagery is a specific method of distraction and attention.
ever, almost no pediatric research has been conducted on many A health care provider guides children to concentrate fully on the
of the therapies regarded as complementary to traditional medical image of an experience or situation. Children recall and vividly
approaches. Thus, the efficacy of complementary therapies describe what they experienced including the colors, sounds,
for treating children’s pain is unknown, even though children tastes, and feel of the situation. Children are guided to become as
are increasingly using complementary therapies.93 By contrast, immersed in their image as if it were occurring in the present
the evidence base supporting the efficacy of cognitive and situation.
behavioral approaches is strong.4,5,15,94–105 These methods can There is considerable overlap among the interventions of
mitigate some of the factors that intensify pain, distress, and attention/distraction, guided imagery, and hypnosis. Hypnosis
disability for children. usually begins with an induction procedure in which a child’s full
The primary cognitive and behavioral therapies are listed in attention is focused gradually on the therapist and their
Table 16–8. Cognitive therapies are directed at a child’s beliefs, suggestions. The therapist guides the child into a very relaxed
expectations, and coping abilities. They encompass a wide range physical and mental state, an altered level of consciousness, which
of approaches from basic patient education to formal psycho- is distinct from an alert or sleep state. The induction procedure
therapy. Most children and families benefit from supportive typically includes guided imagery for children and progressive
counseling. Accurate information about what will happen and muscle relaxation for adolescents. The induction can be very
what children may feel should improve children’s understanding, simple for young children. They can be guided into a hypnotic
increase their control, lessen their distress, and reduce their pain. state as they vividly imagine their favorite television shows,
movies, books, or cartoon characters.106–108 As they imagine an
TABLE 16-8. Cognitive and Behavioral Therapies activity, scene, or character, they gradually receive suggestions for
relaxation, reduced anxiety, increased control, and pain reduction.
Cognitive Behavioral The therapist provides consistent positive suggestions, rather than
Information Simple exercise authoritative commands. The emphasis is on the child’s own
Choices and control Participation in activities natural abilities, as in “Notice that your back, legs (painful body
Counseling Desensitization training areas) feel lighter, the heaviness and pain are starting to lessen. It
Stress management Relaxation training seems as if your back doesn’t hurt as much as before. You are doing
well at turning down the pain switch.” During a hypnotic state,
Attention and distraction Biofeedback
individuals become extremely susceptible to suggestions including
Guided imagery Behavioral modification
suggestions for pain relief. Children become so involved in
Hypnosis
thoughts or ideas that they dissociate from a “reality orien-
tation.”107 Hypnosis enables children to redirect attention from the they should understand that these practical methods relieve pain
painful sensation or to reinterpret the sensation as something because they change the factors that usually increase pain and they
more pleasant, less aversive, or less bothersome.108 Like adults, help to restore normal sensory input.
children differ in their ability to be hypnotized. Children’s ability All children should learn that pain from some procedures is
to use their imagination is the key component in determining their generally less when they are able to choose the site and rub the
hypnotic susceptibility. area before and after the injection or fingerstick. They should learn
Behavior therapy is often used in combination with cognitive that pain is less when they are very relaxed. Progressive muscle
therapy. The goals are to lessen the specific behaviors amongst the relaxation uses simple exercises in which they tense and relax their
child, family, and staff that may increase pain, distress, or disability body limbs, whereas using biofeedback can help to show them that
while concomitantly increasing healthy behaviors that engage any type of pain can be intensified if the muscles are always
children in living as fully as possible. Relaxation training is a tightened. Children should learn that fear and anxiety can make
common method used for children with chronic pain. Therapists them tense and increase pain. They need practical tools to alleviate
train children how to achieve a state of mental and physical their fear or their anxiety toward necessary treatments. Children
relaxation so that children can eventually relax independently and families must learn that what they think, how they behave,
when they experience pain or feel stressed and fearful about their and how they feel affect their children’s pain. Then they can begin
condition. Therapists may use guided imagery, hypnosis, deep to work independently and with staff to create additional nondrug
breathing, or progressive relaxation exercises to train children. pain control methods based on the child’s interest, the cultural
Biofeedback is a useful tool for teaching children to recognize setting, and the availability of resources. Specific interventions
when their bodies are relaxed. Surface electrodes, attached to the should be selected and administered to children as part of a
skin or specific muscle groups, transform the electrical activity of comprehensive pain program, in the same manner as the most
the body into easily observable signals. appropriate analgesics are selected and administered in adequate
doses, at regular dosing intervals, through the most efficient
Pain Control Methods routes.
Health professionals and parents can relieve children’s pain, not
only by administering analgesic drugs but also by increasing their
understanding and control, decreasing their emotional distress, SUMMARY
and teaching them some simple methods to reduce their pain and Optimal pain control for children with chronic and recurrent pain
anxiety. In addition to providing support and reassurance, parents requires an integrated treatment plan with both drug and nondrug
can help children to understand what will happen, make choices, therapies. However, the specific interventions must be selected
gain whatever control is possible within the setting, and inde- after determination of the primary and secondary sources of
pendently use pain-reducing methods. Thus, the family as well as noxious stimulation and after a thorough assessment of the unique
health professionals share a fundamental role in managing the situational, behavioral, emotional, and familial factors that affect
children’s pain. The key concept underlying the use of all analgesic a child’s pain. It is impossible to adequately relieve children’s pain
and nonanalgesic therapies for children is “by the child.” from a unidimensional perspective, in which pain is considered
Specific pain control methods that require the child to as synonymous with the nature and extent of tissue damage.
concentrate and focus attention should always be used for children Childhood pain must be viewed from a multidimensional
with pain. Beales noted critical differences between adults and perspective because multiple sensory, environmental, and
children in their perceptions of pain.109 Children’s pain seemed emotional factors are responsible for the pain, no matter how
even less positively correlated with pathology than adults’ pain. seemingly clear-cut the etiology may be. Treatment begins with a
Beales suggested that some of the psychological mechanisms
thorough assessment of these multiple factors using structured
involved in pain perception may be manipulated more easily in
interviews and standardized measures. Pharmacologic, physical,
children than in adults, consistent with our clinical observations
and psychological strategies must be incorporated into a flexible
that children’s pain is more plastic than that of adults.1,102 Children
intervention program for children, in which parents and siblings
seem to possess an enhanced ability to absorb themselves com-
pletely in a task, game, or imagined event and, thus, might be more form an essential component of treatment.
able than adults to trigger endogenous pain-inhibitory mech- Like adults, children’s pain affects the entire family and must
anisms. Even very young children can easily learn to use a variety be viewed within a broader context. Effective pain control is
of practical pain control methods. The goals of therapy are to possible when the goals are to reduce or block nociceptive activity
enable children to understand what is happening and to have by attenuating responses in peripheral afferents and central
something that they can actively do to lessen their anxiety, distress, pathways, activate endogenous pain inhibitory systems, and
and pain. modify situational factors that exacerbate pain. Thus, the choice
The specific methods selected depend on the age of the child, for pain control is not merely “drug versus nondrug therapy,” but
the type of pain experienced, and the resources available. Simple rather a therapy that mitigates both the causative and the
methods such as deep breathing, blowing bubbles, alternately contributing factors for pain. Pain management is a continuous
tightening and relaxing their fists, squeezing their mother’s hand, dynamic process, because the disease state and factors that
listening to stories or music, and imagining that they are in a influence pain are not static. Different combinations of drug and
pleasant setting can be very effective for reducing procedure- nondrug therapies will be required at different times. Thus, health
related pain, when used with appropriate analgesics. When professionals must continually assume as much responsibility for
possible, children should learn a few basic methods to reduce their monitoring and relieving children’s pain as for medically
pain and distress. They should not be encouraged to develop a managing their diseases. Children should not suffer. We have the
false reliance on the magical benefits of any one method. Instead, knowledge to ensure that children receive adequate pain control.
REFERENCES Recommendations. Royal College of Nursing Institute, London, UK.

2002, p. 43.
1. McGrath PA, (ed). Pain in Children: Nature, Assessment and 25. McGrath PJ. Behavioral measures of pain. In: Finley GA, McGrath
Treatment. New York: Guilford Publications; 1990. p. 1–455. PJ, editors. Measurement of Pain in Infants and Children. Seattle: IASP
2. Price DD (ed). Psychological Mechanisms of Pain and Analgesia. Press; 1998. pp. 83–102.
Seattle: IASP Press; 1999. p. 1–250. 26. Sweet SD, McGrath PJ. Physiological measures of pain. In: Finley G,
3. Casey K, Bushnell ME, (eds). Pain Imaging. Seattle: IASP Press; 2000. McGrath PJ, editors. Measurement of Pain in Infants and Children.
p. 1–248. Seattle: IASP Press; 1998. pp. 59–81.
4. McGrath PA, Hillier LM. Modifying the psychological factors that 27. Hunt AM. Identification of pain cues of children with severe
intensify children’s pain and prolong disability. In: Schechter NL, Berde neurological impairment. In: Proceedings of the 9th World Congress on
CB, Yaster M, editors. Pain in Infants, Children, and Adolescents. 2nd Pain. Abstract 84. Seattle: IASP Press; 1999.
ed. Philadelphia: Lippincott Williams & Wilkins; 2003. pp. 85–104. 28. Champion GD, Goodenough B, von Baeyer CL, et al. Measurement
5. Bernstein BA, Patcher LM. Cultural considerations in children’s pain. of pain by self-report. In: Finley GA, McGrath PJ, editors.
In: Schechter N, Berde C, Yaster M (Eds). Pain in Infants, Children Measurement of Pain in Infants and Children. Seattle: IASP Press;
and Adolescents, 2nd ed. Lippincott, Williams and Wilkins, Philadel- 1998. pp. 123–160.
phia, PA, 2003, pp. 142–6. 29. Bush JP Harkins SW, (eds). Children in Pain: Clinical and Research
6. Ross DM, Ross SA. Childhood Pain: Current Issues, Research and Issues from a Developmental Perspective. New York: Springer-Verlag;
Management. In: Fields HL, Dubner R, Cervero F, (Eds). Advances in 1991. p. 1–476.
Pain Research and Therapy. Urban and Schwarzenberg, Baltimore, 30. Gaffney A, McGrath PJ, Dick B. Measuring pain in children:
MD. 1988; p. 384–8. developmental and instrumental issues. In: Schechter NL, Berde CB,
7. McGrath PA, de Veber LL. The management of acute pain evoked by Yaster M, editors. Pain in Infants, Children and Adolescents. 2nd ed.
medical procedures in children with cancer. J Pain Symptom Manage. Philadelphia: Lippincott Williams & Wilkins; 2003. pp. 128–142.
1986;1:145–150. 31. McGrath PJ, Unruh AM. Pain in children and adolescents. In:
8. Poltorak DY, Benore E. Cognitive-behavioral interventions for McGrath PJ. Pain Research and Clinical Management. Amsterdam:
physical symptom management in pediatric palliative medicine. Elsevier; 1988; p. 351.
Child Adolesc Psychiatr Clin N Am. 2006;15:683–691. 32. Peterson L, Harbeck C, Farmer J, et al. Developmental contributions
9. Goldman A, (ed). Care of the Dying Child. 2nd ed. London and New to the assessment of children’s pain: conceptual and methodological
York: Oxford University Press; 1994. p. 1–224. implications. In: Bush JP, Harkins SW, editors. Children in Pain:
10. Goldman A, Frager G, Pomietto M. Pain and palliative care. In: Clinical and Research Issues from a Developmental Perspective. New
Schechter NL, Berde CB, Yaster M, editors. Pain in Infants, Children, York: Springer-Verlag; 1991. pp. 33–58.
and Adolescents. Philadelphia: Lippincott Williams & Wilkins; 2003. 33. Gauvain-Piquart A, Pichard-Leandri E. (eds). La douleur chez l’en-
p. 539–62. fant. Paris: MEDSI McGraw Hill, 1989. p. 1–183.
11. Chaffee S. Pediatric palliative care. Prim Care. 2001;28:365–390. 34. World Health Organization. Cancer Pain Relief and Palliative Care
12. American Academy of Pediatrics, Committee on Bioethics and (Technical Report Series 804). Geneva, Switzerland, WHO 1990.
Committee on Hospital Care. Palliative care for children. Pediatrics. 35. Stjernsward J. Palliative care: the public health strategy. J Public Health
2000;106:351–357. Policy. 2007;28:42–55.
13. Goldman A. ABC of palliative care. Special problems of children. 36. Monteiro Caran EM, Dias CG, Seber A, et al. Clinical aspects and
BMJ. 1998;316:49–52. treatment of pain in children and adolescents with cancer. Pediatr
14. Frager G. Palliative care and terminal care of children. Child Adolesc Blood Cancer. 2005;45:925–932.
Psychiatr Clin N Am. 1997;6:889–900. 37. Wiffen PJ, Edwards JE, Barden J, et al. Oral morphine for cancer pain.
15. World Health Organization. Cancer Pain Relief and Palliative Care in Cochrane Database Syst Rev. 2003;4:CD003868.
Children. Geneva: World Health Organization; 1998. pp. ix, 76. 38. Hain RD, Miser A, Devins M, et al. Strong opioids in pediatric
16. Stevens M. Care of the dying child and adolescent: family adjustment palliative medicine. Paediatr Drugs. 2005;7:1–9.
and support. In: Doyle D, Hanks G, MacDonald N, editors. Oxford 39. Tan GH, Totapally BR, Torbati D, et al. End-of-life decisions and
Textbook of Palliative Medicine. Oxford: Oxford University Press; palliative care in a children’s hospital. J Palliat Med. 2006;9:332–342.
2004. pp. 806–822. 40. Staats PS. Cancer pain: beyond the ladder. J Back Musculoskeletal
17. Stevens M. Psychological adaptation of the dying child. In: Doyle D, Rehabil. 1998;10:69–80.
Hanks G, MacDonald N, editors. Oxford Textbook of Palliative 41. Galloway KS, Yaster M. Pain and symptom control in terminally ill
Medicine. Oxford: Oxford University Press; 2004. pp. 798–806. children. Pediatr Clin North Am. 2000;47:711–746.
18. Howell D, Martinson L. Management of the dying child. In: Pizzo P, 42. Hauer JM, Wical BS, Charnas L. Gabapentin successfully manages
Poplack D, editors. Principles and Practice of Pediatric Oncology. chronic unexplained irritability in children with severe neurologic
Philadelphia: JB Lippincott; 1993. pp. 1115–1124. impairment. Pediatrics. 2007;119:e519–e522.
19. Davies B, Howell D. Special services for children. In: Doyle D, Hanks 43. Butkovic D, Toljan S, Mihovilovic-Novak B. Experience with
G, MacDonald N, editors. Oxford Textbook of Palliative Medicine. gabapentin for neuropathic pain in adolescents: report of five cases.
Oxford: Oxford University Press; 1998. pp. 1078–1084. Paediatr Anaesth. 2006;16:325–329.
20. Sourkes BM. The broken heart: anticipatory grief in the child facing 44. Lauder GR, White MC. Neuropathic pain following multilevel
death. J Palliat Care. 1996;12:56–59. surgery in children with cerebral palsy: a case series and review.
21. Collins JJ. Palliative care and the child with cancer. Hematol Oncol Paediatr Anaesth. 2005;15:412–420.
Clin North Am. 2002;16:657–670. 45. Klepstad P, Kaasa S, Cherny N, et al. Pain and pain treatments in
22. McGrath PA, Gillespie J. Pain assessment in children and adolescents. European palliative care units. A cross sectional survey from the
In: Turk D, Melzack R, editors. Handbook of Pain Assessment. 2nd ed. European Association for Palliative Care Research Network. Palliat
New York: Guilford Press; 2001. pp. 97–118. Med. 2005;19:477–484.
23. Finley GA, McGrath PJ. Measurement of pain in infants and children. 46. Bozkurt, P. Use of tramadol in children. Paediatr Anaesth.
In: Progress in Pain Research and Management. Vol. 10. Seattle: IASP 2005;15:1041–1047.
Press; 1998. pp. ix, 210. 47. Rose JB, Finkel JC, Arquedas-Mohs A, et al. Oral tramadol for the
24. Morrell C, Woodfield T, Nelstrop L. Clinical Practice Guidelines. treatment of pain of 7–30 days’ duration in children. Anesth Analg.
The Recognition and Assessment of Acute Pain in Children: 2003;96:78–81, table of contents.
48. Scott LJ, Perry CM. Tramadol: a review of its use in perioperative 69. Hill HF, Chapman CR, Kornell JA, et al. Self-administration of
pain. Drugs. 2000;60:139–176. morphine in bone marrow transplant patients reduces drug
49. Hullett BJ, Chambers NA, Pascoe EM, et al. Tramadol vs morphine requirement. Pain. 1990;40:121–129.
during adenotonsillectomy for obstructive sleep apnea in children. 70. Rodgers BM, Webb CJ, Stergios D, et al. Patient-controlled analgesia
Paediatr Anaesth. 2006;16:648–653. in pediatric surgery. J Pediatr Surg. 1988;23:259–262.
50. Brown SC, Stinson J. Treatment of pediatric chronic pain with 71. Shapiro B, Cohen D, Howe C. Use of patient-controlled analgesia for
tramadol hydrochloride: siblings with Ehlers-Danlos syndrome— patients with sickle cell disease. J Pain Symptom Manage. 1991;6:176.
hypermobility type. Pain Res Manag. 2004;9:209–211. 72. Tahmooressi J, Schmalzle S, Tobin J. Patient-controlled analgesia in
51. Schechter NL, Altman A, Weisman S. Report of the Consensus Con- the adolescent undergoing Cotrel-Dubosset rod. J Pain Symptom
ference on the Management of Pain in Childhood Cancer. Pediatrics Manage. 1991;6:160.
1990;86:813–7. 73. Webb C, Paarlberg J, Sussman M. The use of a PCA device by parents
52. Acute Pain Management Guideline Panel. Acute pain management in or nurses for postoperative pain in children with cerebral palsy. J Pain
infants, children and adolescents: Operative or medical procedures Symptom Manage. 1991;6:160.
and trauma. Clinical practice guidelines. Agency for Health Care Pol- 74. McDonald AJ, Cooper MG. Patient-controlled analgesia: an appropriate
icy and Research, Public Health Service, U.S. Department of Health method of pain control in children. Paediatr Drugs. 2001;3:273–284.
and Human Research. Rockville, MD, 1992. 75. McNeely JK, Trentadue NC. Comparison of patient-controlled
53. Consensus Panel, T. Pediatric Pain and Symptom Algorithms for Pal- analgesia with and without nighttime morphine infusion following
liative Care. Children’s Hospital, Seattle, WA, 1999. lower extremity surgery in children. J Pain Symptom Manage. 1997;
54. Jacox A, Carr D, Payne R, et al. New Clinical-Practice Guidelines for 13:268–273.
the Management of Pain in Patients with Cancer. NEJM 1994; 76. Bray RJ, Woodhams AM, Vallis CJ, et al. A double-blind comparison
330:651–55. of morphine infusion and patient controlled analgesia in children.
55. Drug Information Services. Drug Handbook and Formulary 2007- Paediatr Anaesth. 1996;6:121–127.
2008. The Hospital for Sick Children. Toronto, Canada, 2007. 77. Noyes M, Irving H. The use of transdermal fentanyl in pediatric
56. Houlahan KE, Branowicki PA, Mack JW, et al. Can end of life care oncology palliative care. Am J Hosp Palliat Care. 2001;18:411–416.
for the pediatric patient suffering with escalating and intractable 78. Hunt A, Goldman A, Devine T, et al. Transdermal fentanyl for pain relief
symptoms be improved? J Pediatr Oncol Nurs. 2006;23:45–51. in a paediatric palliative care population. Palliat Med. 2001;15:405–412.
57. Collins JJ, Weisman SJ. Management of pain in childhood cancer. In:
79. Christensen ML, Wang WC, Harris S, et al. Transdermal fentanyl
Schechter N, Berde C, Yaster M (Eds). Pain in Infants, Children and
administration in children and adolescents with sickle cell pain crisis.
Adolescents, 2nd ed. Lippincott, Williams and Wilkins, Philadelphia,
J Pediatr Hematol Oncol. 1996;18:372–376.
PA, 2003, pp. 517–538.
80. Ahmedzai S, Brooks D. Transdermal fentanyl versus sustained-release
58. Krane EJ, Leong MS, Golianu B, et al. Treatment of Pediatric Pain
oral morphine in cancer pain: preference, efficacy, and quality of life.
with Nonconventional Analgesics. In: Schechter NL, Berde CB, Yaster
The TTS-Fentanyl Comparative Trial Group. J Pain Symptom Manage.
M, (Eds). Pain in Infants, Children, and Adolescents. 2nd ed. Lip-
1997;13:254–261.
pincott Williams & Wilkins; Philadelphia, PA, 2003. p. 225–241.
81. Edinboro LE, Poklis A, Trautman D, et al. Fatal fentanyl intoxication
59. Maunuksela EL, Olkkola KT. Nonsteroidal anti-inflammatory drugs
following excessive transdermal application. J Forensic Sci. 1997;42:
in pediatric pain management. In: Schechter NL, Berde CB, Yaster
741–743.
M, editors. Pain in Infants, Children, and Adolescents. 2nd ed.
82. Zernikow B, Michel E, Anderson B. Transdermal fentanyl in child-
Philadelphia: Lippincott Williams & Wilkins; 2003. pp. 171–181.
hood and adolescence: a comprehensive literature review. J Pain.
60. Yaster M, Kost-Byerly S, Maxwell LG. Opioid agonists and
2007;8:187–207.
antagonists. In: Schechter NL, Berde CB, Yaster M, editors. Pain in
83. Wilder RT. Regional anesthetic techniques for chronic pain
Infants, Children, and Adolescents. 2nd ed. Philadelphia: Lippincott
management in children. In: Schechter NL, Berde CB, Yaster M, editors.
Williams & Wilkins; 2003. pp. 181–225.
61. Yaster M, Tobin JR, Kost-Byerly S. Local anesthetics. In: Schechter Pain in Infants, Children, and Adolescents. 2nd ed. Philadelphia:
NL, Berde CB, Yaster M, editors. Pain in Infants, Children, and Lippincott Williams & Wilkins; 2003. pp. 396–416.
Adolescents. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 84. Stevens BJ, Johnston CC, Gibbins S. Pain assessment in neonates. In:
2003. pp. 241–265. Anand K, Stevens B, McGrath P, (Eds). Pain in neonates. Amsterdam:
62. Mercadante S. Cancer pain management in children. Palliat Med. Elsevier; 2000. p. 101–34.
2004;18:654–662. 85. Anand K, Shapiro B, Berde CB. Pharmacotherapy with systemic
63. Gregoire MC, Frager G. Ensuring pain relief for children at the end analgesics. In: Anand K, McGrath P, editors. Pain in Neonates. New
of life. Pain Res Manag. 2006;11:163–171. York: Elsevier; 1993. pp. 155–198.
64. Schutzman SA, Liebelt E, Wisk M, et al. Comparison of oral 86. Fitzgerald M, Howard R. The neurobiological basis of pediatric pain.
transmucosal fentanyl citrate and intramuscular meperidine, In: Schechter N, Berde C, Yaster (Eds). Pain in Children and Adoles-
promethazine, and chlorpromazine for conscious sedation of children cents, 2nd ed. Lippincott Williams & Wilkins; Philadelphia, PA, 2003.
undergoing laceration repair. Ann Emerg Med. 1996;28:385–390. p. 19–43.
65. Dsida RM, Wheeler M, Birmingham PK, et al. Premedication of 87. Franck L, Gregory G. Clinical evaluation and treatment of infant pain
pediatric tonsillectomy patients with oral transmucosal fentanyl in the neonatal intensive care unit. In: Schechter NL, Berde CB, Yaster
citrate. Anesth Analg. 1998;86:66–70. M, editors. Pain in Infants, Children, and Adolescents. Baltimore:
66. Malviya S, Voepel-Lewis T, Huntington J, et al. Effects of anesthetic Lippincott Williams & Wilkins; 1993. pp. 519–536.
technique on side effects associated with fentanyl Oralet premedi- 88. Greeley W, Boyd J, Kern F. Pharmacokinetics of analgesic drugs. In:
cation. J Clin Anesth. 1997;9:374–378. Anand K, McGrath P, editors. Pain in Neonates. New York: Elsevier;
67. Sharar SR, Carrougher GJ, Selzer K, et al. A comparison of oral 1993. pp. 107–154.
transmucosal fentanyl citrate and oral oxycodone for pediatric 89. Koren G, Butt G, Chinyanga H, et al. Postoperative morphine
outpatient wound care. J Burn Care Rehabil. 2002;23:27–31. infusion in newborn infants: assessment of disposition characteristics
68. Gaukroger, P. Patient-controlled analgesia in children. In: Schechter and safety. J Pediatr. 1985;107:963–967.
NL, Berde CB, Yaster M, editors. Pain in Infants, Children, and 90. Collins C, Koren G, Crean P, et al. Fentanyl pharmacokinetics and
Adolescents. Baltimore: Lippincott Williams & Wilkins; 1993. hemodynamic effects in preterm infants during ligation of patent
pp. 203–212. ductus arteriosus. Anesth Analg. 1985;64:1078–1080.
91. Lynn S, Slattery J. Morphine pharmacokinetics in early infancy. 100. Katz ER, Kellerman J, Ellenberg L. Hypnosis in the reduction of
Anesthesiology. 1987;66:136–139. acute pain and distress in children with cancer. J Pediatr Psychol.
92. Gallagher R. Opioid Therapy for Cancer Pain. In: Gallagher R, (ed). 1987;12:379–394.
Managing Cancer Pain: The Canadian Health Care Professional’s Ref- 101. LaBaw W, Holton C, Tewell K, et al. The use of self-hypnosis by
erence. Healthcare & Financial Publishing, Rogers Media, Toronto, children with cancer. Am J Clin Hypn. 1975;17:233–238.
ON. 2005; p. 29–41. 102. McGrath PA, HL. A practical cognitive-behavioral approach for
controlling children’s pain. In: Gatchel R, Turk DC, editors.
93. Spigelblatt L, Laîné-Ammara G, Pless IB, et al. The use of alternative
Psychological Approaches to Pain Management. A Practitioner’s
medicine by children. Pediatrics. 1994;94:811–814.
Handbook. New York: Guilford Press; 1996, pp. 33–52.
94. Dahlquist LM, Gil KM, Armstrong FD, et al. Behavioral management 103. Olness K. Imagery (self-hypnosis) as adjunct therapy in childhood
of children’s distress during chemotherapy. J Behav Ther Exp cancer: clinical experience with 25 patients. Am J Pediatr Hematol
Psychiatry. 1985;16:325–329. Oncol. 1981;3:313–321.
95. Dash J. Hypnosis for symptom amelioration. In: Kellerman J, editor. 104. Olness K. Hypnosis in pediatric practice. Curr Probl Pediatr.
Psychologic Aspects of Childhood Cancer. Springfield, Ill: CC Thomas; 1981;12:1–47.
1980. pp. 215–230. 105. Zeltzer L, LeBaron S. Hypnosis and nonhypnotic techniques for
96. Hartman GA. Hypnosis as an adjuvant in the treatment of childhood reduction of pain and anxiety during painful procedures in children
cancer. In: Deasy-Spinetta P, editor. Living with Childhood Cancer. St. and adolescents with cancer. J Pediatr. 1982;101:1032–1035.
Louis: Mosby; 1981. pp. 143–152. 106. Hall H. Hypnosis and pediatrics. In: Tennes R, editor. Medical
97. Hilgard JR, LeBaron S. Relief of anxiety and pain in children and Hypnosis: An Introduction and Clinical Guide. New York: Churchill
Livingstone; 1999. pp. 79–93.
adolescents with cancer: quantitative measures and clinical
107. LeBaron S, Zeltzer L. Children in pain. In: Barber J, editor. Hypnosis
observations. Int J Clin Exp Hypn. 1982;30:417–442.
and Suggestion in the Treatment of Pain: A Clinical Guide. New York:
98. Hilgard JR, Frankel FH, LeBaron S, (eds). Hypnotherapy of Pain in WW Norton; 1996. pp. 305–340.
Children with Cancer. William Kaufman Inc, Los Altos, California. 108. Olness K, Kohen DP, editors. Hypnosis and Hypnotherapy with
1984; pp. 250. Children. 3rd ed. New York: Guilford Press; 1996. pp. xiv, 457.
99. Jay SM, Ozolins L, Elliott CH, et al. Behavioral management of 109. Beales J. Pain in children with cancer. In: Bonica J, Ventafridda V,
children’s distress during painful medical procedures. Behav Res Ther. (Eds). Advances in Pain Research and Therapy. Raven Press; New
1985;23:513–520. York, NY. 1979; p. 387–393.
Pharmacology II
P A R T
An Introduction to the Intricacies

17 of Pharmacology in Pediatrics
C H A P T E R Brian J. Anderson
INTRODUCTION generally more rapid in infants and children than in adults.10 The
greater fraction of the cardiac output distributed to the vessel-rich
Children have been labeled “therapeutic orphans” in the past.1 They tissue group (i.e., a clearance factor) and the lower tissue/blood
were involved in all of the major therapeutic catastrophes that have solubility (i.e., a volume factor) also affect the more rapid wash-in
shaped modern drug development,2,3 and as a consequence, of inhalational anesthetics in the younger age group.11 Solubility
pharmacokinetic (PK) and pharmacodynamic (PD) studies were determines volume of distribution. An inhalational agent with
not performed in children for many years because it was considered a greater volume of distribution will take longer to reach a steady-
unethical. Unmonitored off-label use of medicines in children, state concentration when delivered at a constant rate. The
extrapolated from adult data, has resulted in significant morbidity solubilities in blood of halothane, isoflurane, enflurane, and
that could have been avoided or minimized by appropriate testing methoxyflurane are 18% less in neonates than in adults.12 Infants,
in children.4–7 This morbidity extended to the practice of pediatric with their decreased solubility, would be expected to have a shorter
anesthesia; neonates and infants given continuous-infusion epidu- time to reach a predetermined FE/FI (fraction of expired gas–to–
ral analgesia suffered seizures attributable to high serum bupiva- fraction of inspired gas) ratio because of a smaller volume of
caine concentrations, and these high concentrations were a direct distribution. Decreased solubility (i.e., smaller volume of dis-
consequence of a failure to appreciate reduced clearance in the tribution) and size factors (i.e., faster physiologic processes)
neonatal age group.5 Licensing laws that encourage pediatric increase speed of onset. The increased minimum alveolar con-
studies,8,9 improvements in drug assay techniques that allow small- centration (MAC; i.e., a pharmacodynamic difference) and a rate-
volume samples, and population modeling have dramatically dependent cardiac output set the scene for a relative overdose with
altered the scene for pediatric pharmacologic studies. halothane. A lack of awareness of what constitutes bradycardia in
neonates and infants completes the recipe. Age has little effect on
the solubility of the less-soluble agents nitrous oxide and sevo-
PEDIATRIC DIFFERENCES flurane.13 Reduced solubility and the reduced cardiac effects of
Subsequent chapters detail current knowledge of pediatric sevoflurane guaranteed its superiority over halothane for many
anesthetic pharmacology. A recurring theme is the impact growth indications.
and development has on PK and PD in children. Disease type, The rate at which most drugs are absorbed when given by the
presentation, and progression are different from those in adults. oral route is slower in neonates and young infants than in older
Pediatric anesthesiologists have always sought detailed insight of children because gastric emptying is delayed; normal adult rates
the drugs they use and have been at the forefront of such research may not be reached until 6 to 8 months.14–17 The larger relative
in order to best serve their patients. The effect of some of these skin surface area, increased cutaneous perfusion, and thinner
differences is highlighted in this chapter. stratum corneum in neonates increase absorption and exposure
of topically applied drugs (corticosteroids, local anesthetic creams,
antiseptics). Neonates have a tendency to form methemoglobin
Pharmacokinetic Considerations because they have reduced levels of methemoglobin reductase and
fetal hemoglobin is more readily oxidized than adult hemoglobin.
Absorption This, combined with increased absorption through the neonatal
The majority of drugs used in anesthesia are administered either epidermis, resulted in reluctance to use lidocaine-prilocaine cream
intravenously or through the lungs. Pulmonary absorption is for repeat use in this age group.18,19
292 PART 2 ■ Pharmacology
Distribution HEPATIC ELIMINATION: The mixed function oxidases (phase I)

are reduced. Some appear to be switched on by birth, whereas in
BODY COMPOSITION: Total body water and extracellular fluid others, birth is necessary but not sufficient for the onset of ex-
(ECF)20 decrease dramatically in the first year of life. Polar drugs pression.23,24 Cytochrome P (CYP) 2E1 activity surges after birth,25
such as aminoglycosides and nondepolarizing neuromuscular CYP2D6 becomes detectable soon thereafter, the CYP3A4 and
blocking drugs (NMBDs) distribute rapidly into the ECF, but enter CYP2C families appear during the first week, whereas CYP1A2 is
cells more slowly. The initial dose of such drugs is consequently the last to appear.26 Neonates are dependent on the immature
higher in the infant than in older children and adults. The 90% CYP3A4 for levobupivacaine clearance and CYP1A2 for ropiva-
effective dose (ED90) of succinylcholine (mg/kg) is greater in caine clearance, dictating reduced epidural infusion rates in this
infants than in children and adults. age group.5,27,28
Body fat, protein mass, and relative body proportions change If a drug has a high extraction ratio, then intrinsic clearance
dramatically over the first few years of life and similarly affect may be very much greater than liver blood flow, and in these
volumes of distribution of drugs. These volumes will affect initial situations, hepatic clearance is primarily determined by liver blood
dose estimates. Reduction of propofol concentrations after induc- flow characteristics. Fentanyl clearance (CYP3A4) is 70 to 80% of
tion is attributable to redistribution. Neonates have low body fat adult values in term neonates and, standardized to a 70-kg person,
and muscle content and, therefore, less propofol is apportioned to reaches adult values within the first few weeks of life. Omphalo-
these tissues. Delayed awakening occurs because central nervous coele repair may be associated with raised intra-abdominal pres-
system concentration remains higher than that observed in older sure (a covariate effect), resulting in reduced fentanyl clearance
children as a consequence of reduced redistribution and reduced attributable to both decreased hepatic blood flow and reduced
clearance. hepatic function (decreased fentanyl extraction).
Some phase II pathways are mature in term neonates at
PLASMA PROTEINS: Albumen and α1-acid glycoprotein (AAG) birth (sulfate conjugation), whereas others are not (acetylation,
concentrations are reduced in neonates but are similar to those in glycination, glucuronidation).29 Covariate effects contribute to
adults by 6 months. Other endogenous compounds (e.g., biliru- clearance variability. Maturation of clearance (UGT2B7) occurs
bin) also compete with drugs for binding sites. AAG is an acute- more quickly in infants undergoing noncardiac surgery than in
phase reactant that increases after surgical stress. This causes an those receiving morphine after cardiac surgery.30 Similarly,
increase in total plasma concentrations for low to intermediate clearance of propofol (UGT, CYP2B6, CYP2C9, CYP2A6) was
extraction drugs such as bupivacaine.21 The unbound concentra- reduced after cardiac surgery in children admitted to a pediatric
tion, however, will not change because clearance of the unbound intensive care unit.31
drug is affected only by the intrinsic metabolizing capacity of the RENAL ELIMINATION: Drugs and their metabolites are excreted
liver. Any increase in unbound concentrations observed during by the kidneys by two processes—glomerular filtration and
long-term epidural administration is attributable to reduced tubular secretion. Glomerular filtration rate (GFR) is only 10%
clearance rather than AAG concentration.22 that of mature value at 25 weeks, 35% at term, and 90% of the adult
Total bupivacaine concentrations increase in the first 24 hours GFR at 1 year of age.32 Aminoglycosides are almost exclusively
after surgery in neonates given analgesia by continuous epidural cleared by renal elimination, and the maintenance dose is
infusion. This increase is attributable to an increase of AAG, which predicted by postmenstrual age because it predicts the time course
is an acute-phase reactant. This increase, combined with reports of development of renal function.33
of seizures in infants given epidural bupivacaine infusion, has led Immaturity of clearance pathways can be used to our advantage
to recommendations to stop epidural infusion at 24 hours. when managing apnea after anesthesia in the premature nursery
However, it is the unbound bupivacaine that is responsible for the graduate. N7-Methylation of theophylline in the newborn to
effect and this unbound concentration may not change, implying produce caffeine is well developed, whereas oxidative demethyla-
that the infusion could be run for a longer duration. Clearance is tion (CYP1A2) responsible for caffeine metabolism is deficient
the key parameter. Unfortunately, clearance is associated with a and develops over the ensuing months. Theophylline is effective
large between-subject variability, meaning that unbound bupiva- for the management of postoperative apnea in the premature
caine concentrations may continue to rise in those individuals neonate, partly because it is a prodrug of caffeine, which is effec-
with very low clearance. Infusion rates for continuous amide local tive in controlling apnea, in this age group and caffeine can be only
anesthetic regional blockade may be safely predicted based on slowly cleared by the immature kidney.
clearance and its variability estimates and these infusions may be EXTRAHEPATIC ELIMINATION: Many drugs are metabolized at
run for longer than 24 hours. extrahepatic sites. Remifentanil (and atracurium to some extent)
are rapidly broken down by nonspecific esterase in tissue and
Drug Metabolism erythrocytes. Clearance (L/h/kg) is increased in the younger
children,34–38 but this may be attributable to size. The half-life of
The main routes by which drugs and their metabolites leave the
formation of paracetamol by plasma esterase hydrolysis has been
body are the hepatobiliary system, the kidneys, and the lungs. The
investigated.39 Hydrolysis half-life was the same in all age groups
liver is the primary organ for clearance of most drugs. Nonpolar, when standardized for size using allometry.
lipid-soluble drugs are converted to more-polar and water-soluble
compounds. Water-soluble drugs are excreted unchanged in the
kidneys by glomerular filtration and/or renal tubular secretion. Metabolites
Many of these processes are immature in the neonate and mature Many drugs have active metabolites that contribute to effect. Ex-
within the first year of life. amples include norketamine from ketamine,40 4⬘-hydroxydiclofenac
CHAPTER 17 ■ An Introduction to the Intricacies of Pharmacology in Pediatrics 293
from diclofenac,41 O-demethyl tramadol from tramadol,42 and therapy, and disease have impact, and allele prevalence varies
morphine 6-glucuronide (M6G) from morphine.43 among ethnic groups. The situation in children is more complex.
Contributions to both the desired effect (analgesia) and the Allelic variants may remain unchanged throughout life, but trans-
undesired effects (nausea, respiratory depression) of M6G are the criptomonic, proteomic, and metobonomic data in children are
subject of clinical controversy.44 M6G PD has been explored in continuously changing throughout development.
adults using pupil size as a measure of central opioid effect, but
results are confusing. Effect compartment modeling suggested that
M6G was apparently 22 times less potent than morphine.45,46 Pharmacodynamic Considerations
Contrarily, other authors have suggested that M6G was four times Children’s responses to drugs have much in common with the
more potent than morphine in producing meiosis,47 half as potent responses in adults.63 The perception that drug effects differ in
as an analgesic,48 and with reduced respiratory depressive effects.49 children arises because the drugs have not been adequately studied
in pediatric populations who have size- and age-related effects as
Stereoisomerism well as different diseases.
There are, however, situations in which age-related PD changes
Some drugs commonly used in anesthetic practice are racemic have been described. Classic examples are MAC age-related
compounds, and activity may reside in only one isomer. There is changes of anesthetic inhalation agents and NMBD effects. Cal-
increasing interest in these isomers (e.g., levobupivacaine, S(+) cium is an effective inotrope in neonates because cardiac calcium
ketamine) because they may have a greater potency or safety stores in the endoplasmic reticulum are reduced. Amide local
profile.50,51 Interpretation of the pharmacokinetics of racemic anesthetic agents induce shorter block duration and require a larger
compounds may not be straightforward because clearance of one weight-scaled dose to achieve similar dermatomal levels when
enantiomer may be greater than that of the other, whereas thera- given by subarachnoid block to infants. This may be caused, in part,
peutic activity resides only in one enantiomer (e.g., ibuprofen).52 by myelination, spacing of nodes of Ranvier, and length of nerve
Enantiomeric PK differences are best explained by stereoselective exposed as well as size factors. Inhibitory gamma-aminobutyric
plasma protein binding and metabolism.53 acid (GABA) receptors, which may not reach maturity until 10
years of age, influence the response seen after benzodiazepines in
Pharmacogenomics children. The coagulation cascade is immature at birth, influencing
anticoagulant effect. There is an age-dependent expression of intes-
Pharmacogenomics (PG) is the investigation of variations of DNA tinal motilin receptors and the modulation of antral contractions in
and RNA characteristics as related to drug response that incor- neonates. Prokinetic agents may not be useful in very preterm
porates both PK and PD. There is large between-individual PK infants, partially useful in older preterm infants, and useful in full-
variability that is contributed to by polymorphisms of the genes term infants. Catecholamine release and response to vasoactive
encoding for metabolic enzymes.54 Genetic variability influencing drugs vary with age.
plasma cholinesterase activity and its influence on succinylcholine
is a well-known example. Another example is the CYP2D6 single
nuclear polymorphism (SNP) that is inherited as an autosomal STATE OF THE ART
recessive trait. Homozygous individuals are deficient in the meta-
bolism of a variety of important groups of drugs—β adrenorecep-
Improving the Pharmacopoeia
tor blocking agents, antidepressants, neurolept agents, and opioids. The introduction of a new drug onto the market is extremely
Poor metabolizers have reduced morphine production from costly for the pharmaceutical industry. Despite this cost, drugs of
codeine.55,56 Tramadol is also metabolized by O-demethylation in value to pediatric anesthesia continue to materialize. Improved
the liver (CYP2D6) to O-desmethyl tramadol (M1) and the M1 licensing regulations in both Europe and the United States ensure
metabolite has a μ-opioid affinity approximately 200 times greater that these compounds are investigated in children. Our manage-
than that of tramadol. ment of the neuromuscular junction, for example, will improve
A SNP is important only if it contributes greater than 50% with the introduction of sugammadex.
metabolism and has an active metabolite, a steep dose-response The benefits of pure compounds are recognized. The S(+)
relationship, and a narrow therapeutic index. These polymor- isomer of ketamine is now widely used and single-isomer non-
phisms may have little impact during the neonatal period when steroidal anti-inflammatory drugs (NSAIDs) are appearing for the
metabolism is developmentally limited.42,57–59 treatment of acute pain that may have fewer adverse effects than
PG differences also have an impact on PD. Candidate genes traditional NSAIDs. Nitroxyparacetamol (nitroacetaminophen) is
involved in pain perception, pain processing, and pain manage- a new nitric oxide–releasing version of paracetamol with analgesic
ment like opioid receptors, transporters, and other targets of phar- and anti-inflammatory properties. Potency is enhanced, and ani-
macotherapy are under investigation. These genetic differences mal models suggest reduced liver damage in overdose situations.
(G118 allele) may explain why some patients need higher opioid Xenon continues to be investigated as an anesthetic agent.
doses and the adverse effects profile may be modified by these Dexmedetomidine, licensed only for adult sedation in the inten-
mutations.60 Some genes (e.g., fetal hemoglobin) are expressed sive care unit, has found a niche with pediatric sedation. Investi-
much more in early life than in adults, and gene switching may gations in children by clinical anesthesiologists may result in
mean a drug is effective at one age and not another. broadening of the original narrow indication. Old therapies have
In adults, gene testing may prove invaluable for reducing found new roles. Intralipid is now used for the management of
adverse drug effects.61,62 However, most drug responses involve local anesthetic toxicity. Exploration of the PK and PD of old drugs
a large number of proteins regulated by multiple genes. Genotype such as ketamine should refine clinical use. Drug combinations
does not equate with phenotype; environment, concomitant often improve the effect seen from one drug alone.
Defining the Required Effect that the forces driving innovation and change are not always
predictable. The most popular analgesics in children, paracetamol
This target concentration strategy is a powerful tool for deter- and the NSAIDs, were derived almost by accident. Although
mining clinical dose.64 Anesthesia lends itself to this strategy in salicylic acid was used by ancient Egyptians, attempts to revive its
which we have clearly defined target effects and monitoring of use in the 18th century failed. Marketing by Bayer took off only
adverse effects. The key to this approach be able to measure such because of surreptitious use by local dentists after aspirin charac-
effects. We excel in the fields of neuromuscular, evoked potentials, terization. Paracetamol and indomethacin were byproducts of coal
anesthesia depth, and cardiovascular monitoring. These tools tar, the substrate that supported the German dye industry, esta-
continue to be refined and adapted for even the premature neo- blished Prussian economic power, and caused the loss of Great
nate. Measurement of target concentration in which effect is more Britain’s jewel in the crown, India.74
crudely measured is routine for inhalational agents. Anesthesia Future anesthetic benefits for children will come from incen-
has advanced from observing Guedel’s stages65 and a finger on the tives for drug development and investigation (regulatory climate),
pulse. The assessment and measurement of pain and its many PKPD understanding,75 target concentration approaches,76 stereoi-
subtleties, however, continue to be a barrier to effective analgesia, somer and circadian rhythm investigations,50–52,77 and understand-
although advances are progressive.66 ing of metabolites. Investigation of covariate effects influencing
PK (e.g., pharmacogenetics78) and PD (e.g., disease processes,
Population Modeling maturation) will reduce variability and allow tailoring of drugs to
individual need. Refinement of current or future effect measures
Pediatric anesthetists have embraced the population approach for will allow greater delivery finesse and reduce complication rates.
investigating PK and PD. This approach is achieved through Improvements in delivery systems with feedback systems must go
nonlinear mixed effects models. They provide a means to study hand in hand with effect measure improvements. Education
variability in drug responses among individuals representative of remains a major barrier, and it is hoped that subsequent chapters
those in whom the drug will be used clinically. Traditional will overcome a part of that barrier.
approaches to interpretation of time-concentration profiles (e.g.,
naive and standard two-stage approaches) relied on “rich” data
from a small group of subjects. By contrast, mixed effects models REFERENCES
can be used to analyse “sparse” (two or three samples) data from 1. Shirkey H. Therapeutic orphans [editorial]. J Paediatr. 1968;72:119–120.
a large number of subjects. Sampling times are not crucial for 2. Taussig HB. A study of the German outbreak of phocomelia: the thalido-
population methods and can be fitted around clinical procedures mide syndrome. JAMA. 1962;180:1106–1114.
or outpatient appointments. However, optimal sampling schedules 3. Burns LE, Hodgman JE. Fatal circulatory collapse in premature infants
receiving chloramphenicol. N Engl J Med. 1959;261:1318.
can be determined through previous information and the Fisher 4. Kauffman RE. Fentanyl, fads, and folly: who will adopt the therapeutic
Information Matrix.67–69 Sampling time bands rather than exact orphans? J Pediatr. 1991;119:588–589.
times are equally effective70 and allow flexibility in children. 5. Berde C. Convulsions associated with pediatric regional anesthesia.
Mixed effects models are “mixed” because they describe the Anesth Analg. 1992;75:164–166.
6. Olkkola KT, Aranko K, Luurila H, et al. A potentially hazardous
data using a mixture of fixed and random effects. Fixed effects
interaction between erythromycin and midazolam. Clin Pharmacol Ther.
predict the average influence of a covariate such as weight as an 1993;53:298–305.
explanation of part of the between-subject variability in a para- 7. Borowitz DS, Grand RJ, Durie PR. Use of pancreatic enzyme supplements
meter like clearance. Random effects describe the remaining for patients with cystic fibrosis in the context of fibrosing colonopathy.
variability between subjects that is not predictable from the fixed Consensus Committee. J Pediatr. 1995;127:681–684.
8. Tett SE, Holford NHG, McLachlan AJ. Population pharmacokinetics and
effect average. Explanatory covariates (e.g., age, size, renal pharmacodynamics: an underutilised resource. DIA Journal. 1998;32:
function, sex, temperature) can be introduced that explain the 693–710.
predictable part of the between-individual variability. Nonlinear 9. Saint-Raymond A, Seigneuret N. Medicines for children: time for Europe
regression is performed by an iterative process to find the curve of to act. Paediatr Perinatal Drug Ther. 2005;6:142–146.
best fit by maximizing the likelihood.71,72 10. Salanitre E, Rackow H. The pulmonary exchange of nitrous oxide and
halothane in infants and children. Anesthesiology. 1969;30:388–394.
Interpretation of truncated individual sets of data or missing 11. Lerman J. Pharmacology of inhalational anaesthetics in infants and
data is also possible with this type of analysis, rendering it useful children. Paediatr Anaesth. 1992;2:191–203.
for pediatric studies. The appropriate number of patients for a 12. Lerman J, Schmitt Bantel BI, Gregory GA, et al. Effect of age on the
population study is difficult to determine and will depend on the solubility of volatile anesthetics in human tissues. Anesthesiology.
number of covariates under examination.73 Population modeling 1986;65:307–311.
13. Malviya S, Lerman J. The blood/gas solubilities of sevoflurane, isoflurane,
also allows pooling of data across studies to provide a single robust halothane, and serum constituent concentrations in neonates and adults.
PK analysis rather than comparing separate smaller studies that Anesthesiology. 1990;72:793–796.
are complicated by different methods and analyses. 14. Gupta M, Brans Y. Gastric retention in neonates. Pediatrics. 1978;62:
26–29.
15. Grand RJ, Watkins JB, Torti FM. Development of the human intestinal
FUTURE DIRECTIONS tract: a review. Gastroenterology. 1976;70:790–810.
16. Liang J, Co E, Zhang M, et al. Development of gastric slow waves in
It is not possible to predict the future. The Bell telephone was once preterm infants measured by electrogastrography. Am J Physiol. 1998;274:
considered such an advance that every town would eventually have G503–G508.
17. Carlos MA, Babyn PS, Marcon MA, Moore AM. Changes in gastric
one. Missiles were thought to be the future method of mail emptying in early postnatal life. J Pediatr. 1997;130:931–937.
delivery and the US Postal Service sent 3,000 letters via missile 18. Taddio A, Shennan AT, Stevens B, et al. Safety of lidocaine-prilocaine
from Virginia to Florida in 1959. Lessons from the past suggest cream in the treatment of preterm neonates. J Pediatr. 1995;127:1002–1005.
CHAPTER 17 ■ An Introduction to the Intricacies of Pharmacology in Pediatrics 295
19. Taddio A, Stevens B, Craig K, et al. Efficacy and safety of lidocaine- 44. Wittwer E, Kern SE. Role of morphine’s metabolites in analgesia: concepts
prilocaine cream for pain during circumcision. N Engl J Med. 1997; and controversies. AAPS J. 2006;8:E348–E352.
336:1197–1201. 45. Romberg R, Olofsen E, Sarton E, et al. Pharmacokinetic-pharmacodynamic
20. Friis-Hansen B. Body water compartments in children: changes during modeling of morphine-6-glucuronide–induced analgesia in healthy volun-
growth and related changes in body composition. Pediatrics. 1961;28:169– teers: absence of sex differences. Anesthesiology. 2004;100:120–133.
181. 46. Lotsch J, Skarke C, Schmidt H, et al. The transfer half-life of morphine-
21. Erichsen CJ, Sjovall J, Kehlet H, et al. Pharmacokinetics and analgesic 6-glucuronide from plasma to effect site assessed by pupil size measure-
effect of ropivacaine during continuous epidural infusion for post- ment in healthy volunteers. Anesthesiology. 2001;95:1329–1338.
operative pain relief. Anesthesiology. 1996;84:834–842. 47. Westerling D, Persson C, Hoglund P. Plasma concentrations of morphine,
22. Anderson BJ, McKee AD, Holford NH. Size, myths and the clinical morphine-3-glucuronide, and morphine-6-glucuronide after intravenous
pharmacokinetics of analgesia in paediatric patients. Clin Pharmacokinet. and oral administration to healthy volunteers: relationship to nonanal-
1997;33:313–327. gesic actions. Ther Drug Monit. 1995;17:287–301.
23. Hines RN, McCarver DG. The ontogeny of human drug-metabolizing 48. van Dorp EL, Romberg R, Sarton E, et al. Morphine-6-glucuronide: mor-
enzymes: phase I oxidative enzymes. J Pharmacol Exp Ther. 2002;300: phine’s successor for postoperative pain relief? Anesth Analg. 2006;102:
355–360. 1789–1797.
24. Koukouritaki SB, Manro JR, Marsh SA, et al. Developmental expression 49. Romberg R, Olofsen E, Sarton E, et al. Pharmacodynamic effect of
of human hepatic CYP2C9 and CYP2C19. J Pharmacol Exp Ther. morphine-6-glucuronide versus morphine on hypoxic and hypercapnic
2004;308:965–974. Epub 2003;November 21. breathing in healthy volunteers. Anesthesiology. 2003;99:788–798.
25. Johnsrud EK, Koukouritaki SB, Divakaran K, et al. Human hepatic 50. Gaitan G, Herrero JF. Subanalgesic doses of dexketoprofen and HCT-2037
CYP2E1 expression during development. J Pharmacol Exp Ther. 2003;307: (nitrodexketoprofen) enhance fentanyl antinociception in monoarthritic
402–407. rats. Pharmacol Biochem Behav. 2005;80:327–332.
26. Kearns GL, Abdel-Rahman SM, Alander SW, et al. Developmental 51. Jackson ID, Heidemann BH, Wilson J, et al. Double-blind, randomized,
pharmacology—drug disposition, action, and therapy in infants and placebo-controlled trial comparing rofecoxib with dexketoprofen tro-
children. N Engl J Med. 2003;349:1157–1167. metamol in surgical dentistry. Br J Anaesth. 2004;92:675–680.
27. Anderson BJ, Hansen TG. Getting the best from pediatric pharmacokine- 52. Gregoire N, Gualano V, Geneteau A, et al. Population pharmacokinetics
tic data. Paediatr Anaesth. 2004;14:713–715. of ibuprofen enantiomers in very premature neonates. J Clin Pharmacol.
28. Chalkiadis GA, Anderson BJ. Age and size are the major covariates for 2004;44:1114–1124.
prediction of levobupivacaine clearance in children. Paediatr Anaesth. 53. Kauffman RE, Lieh-Lai MW, Uy HG, Aravind MK. Enantiomer-selective
2006;16:275–282. pharmacokinetics and metabolism of ketorolac in children. Clin Phar-
29. McCarver DG, Hines RN. The ontogeny of human drug-metabolizing macol Ther. 1999;65:382–388.
enzymes: phase II conjugation enzymes and regulatory mechanisms. J 54. de Wildt SN, Kearns GL, Leeder JS, van den Anker JN. Cytochrome
Pharmacol Exp Ther. 2002;300:361–366. P450 3A: ontogeny and drug disposition. Clin Pharmacokinet. 1999;37:
30. Lynn A, Nespeca MK, Bratton SL, et al. Clearance of morphine in 485–505.
postoperative infants during intravenous infusion: the influence of age 55. Williams DG, Hatch DJ, Howard RF. Codeine phosphate in paediatric
and surgery. Anesth Analg. 1998;86:958–963. medicine. Br J Anaesth. 2001;86:413–421.
31. Rigby-Jones AE, Nolan JA, Priston MJ, et al. Pharmacokinetics of propofol 56. Fagerlund TH, Braaten O. No pain relief from codeine …? An introduc-
infusions in critically ill neonates, infants, and children in an intensive tion to pharmacogenomics. Acta Anaesthesiol Scand. 2001;45:140–149.
care unit. Anesthesiology. 2002;97:1393–1400. 57. Pariente-Khayat A, Rey E, Gendrel D, et al. Isoniazid acetylation meta-
32. Rhodin MM, Anderson BJ, Peters AM, et al. Human renal function bolic ratio during maturation in children. Clin Pharmacol Ther. 1997;62:
maturation: a quantitative description using weight and postmenstrual 377–383.
age. Pediatr Nephrol. 2008;24:67–76. 58. Kearns GL, Robinson PK, Wilson JT, et al. Cisapride disposition in neo-
33. Langhendries JP, Battisti O, Bertrand JM, et al. Adaptation in neonatology nates and infants: in vivo reflection of cytochrome P450 3A4 ontogeny.
of the once-daily concept of aminoglycoside administration: evaluation of Clin Pharmacol Ther. 2003;74:312–325.
a dosing chart for amikacin in an intensive care unit. Biol Neonate. 59. Carrier O, Pons G, Rey E, et al. Maturation of caffeine metabolic pathways
1998;74:351–362. in infancy. Clin Pharmacol Ther. 1988;44:145–151.
34. Rigby-Jones AE, Priston MJ, Thorne GC, et al. Population pharmacokine- 60. Lotsch J, Skarke C, Liefhold J, Geisslinger G. Genetic predictors of the
tics of remifentanil in critically ill post cardiac neonates, infants and clinical response to opioid analgesics: clinical utility and future perspec-
children. Br J Anaesth. 2005;95:578P–579P. tives. Clin Pharmacokinet. 2004;43:983–1013.
35. Minto CF, Schnider TW, Egan TD, et al. Influence of age and gender on 61. Phillips KA, Veenstra DL, Oren E, et al. Potential role of pharmacogeno-
the pharmacokinetics and pharmacodynamics of remifentanil. I. Model mics in reducing adverse drug reactions: a systematic review. JAMA. 2001;
development. Anesthesiology. 1997;86:10–23. 286:2270–2279.
36. Ross AK, Davis PJ, Dear Gd GL, et al. Pharmacokinetics of remifentanil 62. Ensom MH, Chang TK, Patel P. Pharmacogenetics: the therapeutic drug
in anesthetized pediatric patients undergoing elective surgery or diagnos- monitoring of the future? Clin Pharmacokinet. 2001;40:783–802.
tic procedures. Anesth Analg. 2001;93:1393–1401. 63. Stephenson T. How children’s responses to drugs differ from adults. Br J
37. Kan RE, Hughes SC, Rosen MA, et al. Intravenous remifentanil: placental Clin Pharmacol. 2005;59:670–673.
transfer, maternal and neonatal effects. Anesthesiology. 1998;88:1467– 64. Holford NH. Target concentration intervention: beyond Y2K. Br J Clin
1474. Pharmacol. 2001;52(Suppl 1):55S–59S.
38. Egan TD. Pharmacokinetics and pharmacodynamics of remifentanil: an 65. Guedel AE, editor. Inhalational Anaesthesia: A Fundamental Guide. New
update in the year 2000. Curr Opin Anaesthesiol. 2000;13:449–455. York: Macmillan; 1937.
39. Anderson BJ, Pons G, Autret-Leca E, et al. Pediatric intravenous parace- 66. Walker SM. Pain in children: recent advances and ongoing challenges.
tamol (propacetamol) pharmacokinetics: a population analysis. Paediatr Br J Anaesth. 2008;101:101–110.
Anaesth. 2005;15:282–292. 67. Retout S, Mentre F. Further developments of the Fisher information
40. Herd DW, Anderson BJ, Holford NH. Modeling the norketamine matrix in nonlinear mixed effects models with evaluation in population
metabolite in children and the implications for analgesia. Paediatr pharmacokinetics. J Biopharm Stat. 2003;13:209–227.
Anaesth. 2007;17:831–840. 68. D’Argenio DZ. Incorporating prior parameter uncertainty in the design
41. van der Marel CD, Anderson BJ, Romsing J, et al. Diclofenac and meta- of sampling schedules for pharmacokinetic parameter estimation experi-
bolite pharmacokinetics in children. Paediatr Anaesth. 2004;14:443–451. ments. Math Biosci. 1990;99:105–118.
42. Allegaert K, Anderson BJ, Verbesselt R, et al. Tramadol disposition in the 69. D’Argenio D, Schumitzky A. ADAPT II User’s Guide: Pharmacokinetic/
very young: an attempt to assess in vivo cytochrome P450 2D6 activity. Br Pharmacodynamic Systems Analysis Software. Los Angeles: Biomedical
J Anaesth. 2005:231–239. Simulations Resource; 1997.
43. Bouwmeester NJ, Anderson BJ, Tibboel D, Holford NH. Developmental 70. Duffull S, Waterhouse T, Eccleston J. Some considerations on the design
pharmacokinetics of morphine and its metabolites in neonates, infants of population pharmacokinetic studies. J Pharmacokinet Pharmacodyn.
and young children. Br J Anaesth. 2004;92:208–217. 2005;32:441–457.
71. Peck CC, Sheiner LB, Nichols AI. The problem of choosing weights in 75. Holford NH, Sheiner LB. Understanding the dose-effect relationship:
nonlinear regression analysis of pharmacokinetic data. Drug Metab Rev. clinical application of pharmacokinetic-pharmacodynamic models. Clin
1984;15:133–148. Pharmacokinet. 1981;6:429–453.
72. Peck CC, Beal SL, Sheiner LB, Nichols AI. Extended least squares nonli- 76. Holford NH. The target concentration approach to clinical drug
near regression: a possible solution to the “choice of weights” problem in development. Clin Pharmacokinet. 1995;29:287–291.
analysis of individual pharmacokinetic parameters. J Pharmacokinet 77. Gaitan G, Ahuir FJ, Herrero JF. Enhancement of fentanyl antinocicep-
Biopharm. 1984;12:545–557. tion by subeffective doses of nitroparacetamol (NCX-701) in acute
73. Ribbing J, Jonsson EN. Power, selection bias and predictive performance nociception and in carrageenan-induced monoarthritis. Life Sci. 2005;
of the Population Pharmacokinetic Covariate Model. J Pharmacokinet 77:85–95.
Pharmacodyn. 2004;31:109–134. 78. Krekels EH, van den Anker JN, Baiardi P, et al. Pharmacogenetics and
74. Fairbanks VF. Blue gods, blue oil, and blue people. Mayo Clin Proc. paediatric drug development: issues and consequences to labelling and
1994;69:889–892. dosing recommendations. Expert Opin Pharmacother. 2007;8:1787–1799.
Using Pharmacokinetics and

Pharmacodynamic Models to
Prevent Adverse Events in
18
C H A P T E R
Neonates, Infants, and Children

Brian J. Anderson
INTRODUCTION trials. Such trials often use a homogeneous population. The maxi-
mum safe dose is chosen to show clear difference from placebo;
Models describe systems in simple terms, although some models smaller doses would require greater patient numbers and exhibit
may be quite sophisticated. They are used to describe, predict, and more noise. A sense of the dose- or concentration-response is not
explain observations. Pharmacokinetics (PK) and pharmacodyna- achieved for either TE or adverse effects, and further comparative
mics (PD) models are used to improve pediatric anesthetic mana- dose studies are required to define a minimum effective dose.
gement. They quantify the exposure-response relationship, often This TE approacho is intrinsic to pediatric anesthetists using
providing clarity and insight into complex systems as well as a target-controlled infusion systems. These devices target a specific
mechanistic understanding of the drug effect. Dose selection can plasma concentration in a typical individual, and this concentra-
be rationalized. Models may enable extrapolation beyond obser- tion is assumed to have a typical TE. The TC is one that achieves
ved data. Modeling is a knowledge management tool; it captures target therapeutic effect (e.g., anesthesia) without excessive ad-
and integrates data from all studies. Models can also be used for verse effects (e.g., hypotension). Effect monitoring (e.g., bispectral
hypothesis testing and can drive decision-making during drug [BIS] index) can be used to refine the TE.
development.
This chapter explores common models used in pediatric phar-
macology and demonstrates their usefulness to determine the
PK MODELS
appropriate dose for neonates, infants, and children, with conse- Compartment Models
quent reduction of adverse effects.
Noncompartment methods (“moment analysis”) represent the
gold standard for parameter estimation, but compartment models
THE TARGET CONCENTRATION dominate anesthetic literature. Compartment models may com-
APPROACH prise one, two, or more compartments. Drug is administered into
and eliminated from a central compartment. This central com-
The goal of treatment is the target effect (TE). A PD model is used partment may be connected to peripheral compartments.
to predict the target concentration (TC) given a TE. Population
estimates for the PD model parameters and covariate information
are used to predict typical PD values in a specific patient. Popula-
tion estimates of PK model parameter estimates and covariate
information are then used to predict typical PK values in a specific
patient. This TC strategy is a powerful tool for determining clinical
dose.1 Monitoring of serum drug concentrations and bayesian
forecasting may be used to improve dosing in individual patients.
Defining theTE also requires knowledge of adverse event
relationships. The best TC in Figure 18–1 may not be the higher
concentration of 7 mg/L if adverse effects are troublesome. Fur-
ther, an effect measure of 8 may offer little advantage over an effect
measure of 6, achieved with the lower concentration of 2.5 mg/L.
Other factors may also enter into decision-making. For example,
age, weight, concomitant disease pharmacogenetics, or other Figure 18-1. The higher target concentration (TC) of 7 mg/L
drugs may alter the shape of the concentration-response curve. achieves a better effect, but at the expense of increased adverse
This approach to dose selection is quite different from that com- effects. The lower concentration of 2.5 mg/L may be satisfactory
monly taken in double-blind, randomized, placebo-controlled and have fewer adverse effects.
A single compartment is often insufficient to characterize the

time-concentration profile and further compartments are required
(mammillary models). Drug is administered into a central com-
partment (V1) and redistributes to peripheral compartments (e.g.,
V2, V3; Figure 18–2A). In a two-compartment model, transfer of
drug between the central and the peripheral compartment is
relatively fast compared with the rate of elimination. A plot of the
natural log of concentration after bolus reveals two distinct slopes
(rate constants, α and β; see Figure 18–2B). Consequently, the
time-concentration profile is commonly described using a
polyexponential function:
.
C(t) = A . e–α . t . + B . e–β t
These parameters have little connection with underlying
physiology and an alternative parameterization is to use a central
volume and three rate constants (k10, k12, k21) that describe drug
distribution between compartments. Another common method
is to use two volumes (V1, V2) and two clearances (CL, Q). Q is
the intercompartment clearance, and volume of distribution at
steady state (Vss) is the sum of V1 and V2.
Students are commonly taught to estimate compartment model
PK parameters through interpretation of graphs representing
time-concentration profiles. Conversion of concentration to a log
scale (CL) allows estimation of elimination constants and com-
partment volumes (see Figure 18–2C). Integration of the function
describing this profile yields an area under the curve (AUC), from
which CL can be determined
Dose
CL = AUC
Computers have made use of nonlinear regression to directly
estimate parameters through iterative techniques using least-
squares curve fitting. Models with two or more compartments are
now commonly solved using differential equations, for example,
for a two-compartment mammillary model
dC1 (ratein + C2 ⋅ Q) − C1 ⋅ (Q + CL)
=
dt V1
dC2 Q ⋅ (C1 − C2)
=
dt V2
These parameter estimates can be used to predict dose. A
loading dose raises concentration in the plasma to TC promptly
and may be desirable in anesthesia when rapid effect is required.
In a one-compartment model, the volume of distribution is the Figure 18-2. A: A mammillary two-compartment pharmacoki-
proportionality factor that relates total amount of drug in the body netic (PK) model. B: Time-concentration profile for a two-
to plasma concentration: compartment model. C: Conversion of concentration to a log
scale allows estimation of elimination constants and compart-
Loading dose = V . TC ment volumes.
This calculation may not be applicable to many anesthetic
drugs that are characterized using multicompartment models. The because V1 poorly reflects the required scaling factor. A new
use of V1 results in a loading dose too high; too high a dose may parameter, the volume of distribution at the time of peak effect-site
cause transient toxicity. concentration (Vpe), is used and is calculated as
An alternative technique is to use the TE dose. The time to peak
effect (Tpeak) is dependent on clearance and effect-site equilibra- V1
Vpe =
tion half-time (Teq or T / keo). At a submaximal dose, Tpeak is
1
⎛ Cpeak ⎞
⎜ C 0 ⎟⎠
2
independent of dose. At supramaximal doses, maximal effect will ⎝

occur earlier than Tpeak and persist for longer duration because
C0 is the theoretical plasma concentration at t = 0 after the
of the shape of the sigmoid Emax (maximum effect change) model
bolus dose, and Cpeak is the predicted effect-site concentration at
(see ‘The Sigmoid Emax Model). This is due to similar considera-
the time of peak effect. Loading dose can then be calculated as
tions described in time course of immediate effects. The Tpeak
concept has been used to calculate optimal initial bolus doses,2 LD = Cpeak . Vpe
CHAPTER 18 ■ Pharmacokinetics and Pharmacodynamic Models to Prevent Adverse Events in Neonates and Children 299
Clearance is the most important parameter when defining a be clinically relevant because the percentage decrease in concen-
rational steady-state dosage regimen. At steady state, tration required for recovery is not necessarily 50%.
Dosing rate = rate of elimination = CL . TC
ss ss
When a drug is given intermittently, Recirculatory Models

Maintenance dose = dosing rate × dosing interval Standard compartment models are unable to accurately describe
drug concentrations immediately after bolus administration of an
When a drug is given by constant infusion, anesthetic induction agent. Mixing in the central compartment is
Infusion ratess = dosing ratess not instantaneous, making it difficult to model the fast blood-to-
brain concentration equilibrium.5 Pulmonary uptake may also
Once the TC of a drug is defined, the infusion rate is deter- occur.6 Recirculatory models help explain these early phase PK.7
mined by CL. This equation is true at steady state, but many The pulmonary and peripheral intravascular and extravascular
anesthetic drugs distribute to peripheral compartments and steady systems, each consisting of volumes and time delays, are con-
state may not be achieved during the time that the patient is nected according to circulatory physiology.8 Parameters are estim-
anesthetized. Dose adjustment is required to achieve constant able by administering the drug under investigation as well as an
effect until steady-state conditions are reached. intravascular marker. Such models have proved valuable in deter-
Propofol PK is usually described using a three-compartment mining anesthetic induction doses9 and neuromuscular blocking
mammillary model. In order to achieve steady state of 3 μg/mL in drug (NMBD) PD.10
children 3 to 11 years, dosing changes are required, for example,
a loading dose of 2.5 mg/kg followed by an infusion rate of 15 mg/
kg/h for the first 15 minutes, 13 mg/kg/h from 15 to 30 minutes, Physiologically Based PK Modeling
11 mg/kg/h from 30 to 60 minutes, 10 mg/kg/h from 1 to 2 hours,
Organ maturation, body composition, and ontogeny of drug
and 9 mg/kg/h from 2 to 4 hours. Target-controlled infusion (TCI)
elimination pathways have marked effects on PK parameters in
pumps are capable of finer tuning by making adjustments at 10-
second intervals.3 the first few years of life. Clearance estimates from physiologically
The PK of drug disposition confined to a one-compartment based pharmacokinetic modeling (PBPK) use data on ontogeny
model is often expressed in terms of half-life. Half-life (T / ) is the
1
of individual clearance pathways, derived from measurements of
2
time required to change the amount of drug in a body compart- enzyme expression and activity in postmortem livers11,12 and from
ment by one half (either by decreasing during elimination or by in vivo data from drugs that are cleared by similar pathways.13
increasing during a constant infusion): Continued input of information concerning genetic, physiologic,
organ and tissue size and composition, protein binding, and
V demographic and clinical data into the library and algorithms for
T12 = ln(2) ⋅
CL PBPK programs has progressively improved their prediction
ability.14–19 These models have been used to assist with first-time
This half-life is related to the elimination rate constant (k), a
dosing in children. A general PBPK program for drug disposition
parameter representing the slope of the exponential decay curve:
in infants and children, covering the age range from birth to
CL adulthood, has been successfully evaluated using theophylline and
k= midazolam as model drugs.20 The introduction of population vari-
V
ability in enzyme abundance and activity, for example, contributes
Elimination half-life is of no value in characterizing disposition to between-individual variability estimates.
of intravenous anesthetic drugs during dosing periods relevant to
anesthesia. A more useful concept is that of the context-sensitive
half-time in which “context” refers to infusion duration. This is PD MODELS
the time required for the plasma drug concentration to decline by PK is what the body does to the drug, whereas PD is what the drug
50% after terminating infusion.4 The context-sensitive half-time is
does to the body. The precise boundary between these two pro-
the same as the elimination half-life for a one-compartment model
cesses is ill defined and often requires a link describing movement
and does not change with infusion duration. However, most drugs
of drug from the plasma to the biophase or effect site and its target.
in anesthesia conform to multiple-compartment models and the
Drugs may exert effect at nonspecific membrane sites, by inter-
context-sensitive half-times are markedly different from their
ference with transport mechanisms, by enzyme inhibition or
respective elimination half-lives.
induction, or by activation or inhibition of receptors.
Context-sensitive half-time may be independent of infusion
duration (e.g., remifentanil 2.5 min); moderately affected (pro-
pofol 12 min at 1 h, 38 min at 8 h); or display marked prolongation The Sigmoid Emax Model
(e.g., fentanyl 1 h at 24 min, 8 h at 280 min). This is caused by
return of drug to plasma from peripheral compartments after The relation between drug concentration and effect may be des-
ceasing infusion. Peripheral compartment size differs in children cribed by a sigmoid hyperbolic or Hill model, well known to anes-
from adults so that, at termination of infusion, more drug may thesiologists through the oxygen dissociation curve,21 according
remain in the body for any given plasma concentration than in to the equation
adults. The context-sensitive half-time for children given propofol,
for example, is longer.3 The context-sensitive half-time gives Effect = E0 +
( E max⋅ Ce )
N
insight into the PK of a hypnotic drug, but the parameter may not ( EC + Ce )
N
50
N
Figure 18-4. Estimation of minimum alveolar concentration

(MAC) using the “up and down” method. The nominal sample
size is six subjects and is the number of tests after and including
Figure 18-3. The sigmoid Emax (maximum effect change) the first pair of tests that have opposite results.
model for three drugs, each with a different Hill coefficient. The
median effective concentration (EC50) and efficacy are the same
but the EC80 is different for each drug. A higher concentration of This quantal effect model has application beyond that of esti-
the drug with the lower Hill coefficient will be required if an ef- mating MAC. Frawley and coworkers have used the model to
fect of 80% of maximal effect is desired. determine an effective spinal dose of levobupivacaine (1 mg/kg)
and of ropivacaine (1.08 mg/kg) in neonates.26,27
where E0 is the baseline response, Emax is the maximum effect
change, Ce is the concentration in the effect compartment, EC50 is Logistic Regression Model
the concentration producing 50% Emax, and N is the Hill coef-
ficient defining the steepness of the concentration-response curve When the pharmacologic effect is difficult to grade, it may be use-
(Figure 18–3).22 At low concentrations, the nonlinear relationship ful to estimate the probability of achieving the effect as a function
may approach linearity. of plasma concentration or MAC. Effect measures such as move-
Efficacy is the maximum response on a dose or concentration- ment/no movement or rousable/nonrousable are dichotomous.
response curve. EC50 can be considered a measure of potency Logistic regression is commonly used to analyze such data, and
relative to another drug provided N and Emax for the two drugs are the interpolated EC50 value refers to the probability of response.
the same. The μ opioid receptor agonists can be compared in this For example, an EC50 of 0.52 mg/L for arousal after ketamine
manner. The spectral edge frequency of the electroencephalogram sedation in children has been estimated (Figure 18–5) using this
(EEG) has been used as a PD measure to compare opioids. The technique.
steady-state serum concentration that caused one half of the
maximal EEG slowing was 6.9 standard deviation (sd) 1.5 μg/ LINKING PK WITH PD
L for fentanyl, compared with 520 sd 163 μg/L for alfentanil.23
Immediate Effects
Quantal Effect Model A simple situation in which drug effect is directly related to
concentration does not mean that drug effects parallel the time
The potency of anesthetic vapors may be expressed by minimum course of concentration. This occurs only when the concentration
alveolar concentration (MAC); this is the concentration at which
50% of subjects move in response to a standard surgical stimulus.
MAC appears at first sight to be similar to EC50, but is an expres-
sion of quantal response rather than magnitude of effect. There
are two methods of estimating MAC. Responses can be recorded
over the clinical dose range in a large number of subjects and
logistic regression applied to estimate the relationship between
dose and quantal effect; the MAC can then be interpolated. Large
numbers of subjects may not be available, and so an alternative is
often used. The “up and down” method described by Dixon
estimates only the MAC rather than the entire sigmoid curve.24,25
It involves a study of only one concentration in each subject and,
in a sequence of subjects, each receives a concentration depending
upon the response of the previous subject; the concentration is
either increased if the previous subject did not respond or
decreased if she or he did (Figure 18–4). The MAC is usually Figure 18-5. The probability of being aroused after ketamine
calculated either as the mean concentration of equal numbers of sedation determined using logistic regression. The EC50 was
responses and no responses or as the mean concentration of pairs 0.52 mg/L. Dichotomous data are shown as crosses. From
of “response/no response.” reference 61, with permission.
is low in relation to EC50. In this situation, the half-life of the drug

may correlate closely with the half-life of drug effect. Many drugs,
however, have a short half-life but a long duration of effect. This
may be attributable to induced physiologic changes (e.g., aspirin
and platelet function) or may be because of the shape of the Emax
model. If the initial concentration is very high in relation to the
EC50, then drug concentrations 5 half-lives later, when we might
expect minimal concentration, may still exert considerable effect.
Delayed Effects
Observed effects may not be directly related to serum concentra-
tion. There may be a delay because of transfer of the drug to effect
site (NMBD), a lag time (diuretics), physiologic response (antipy- Figure 18-8. Physiologic substance turnover model for
resis), active metabolite (propacetamol), or synthesis of physio- warfarin.
logic substances (warfarin).
Physiologic Substance Turnover Model
Delayed-Effect Compartment Model Many drug actions are mediated through synthesis or elimination
A plasma concentration-effect plot can form a clockwise hysteresis of a physiologic substance.30 The concentration at the site of drug
loop because of this delay in effect (Figure 18–6). Hull and collea- effect either stimulates or inhibits the rate of production or elimi-
gues28 and Sheiner and associates29 introduced the effect compart- nation of the physiologic substance (response variable). Warfarin,
ment concept for muscle relaxants. The effect compartment for example, inhibits the recycling of vitamin K epoxide to the
concentration is not the same as the blood or serum concentration active vitamin K form that is involved in the production of pro-
and is not a real measurable concentration (Figure 18–7). It has thrombin complex (Figure 18–8).
negligible volume and contains negligible blood. A single first- The time course of prothrombin complex activity (PCA(t)) is
order parameter (Teq or T / keo) describes the equilibration half-
1
determined by the solution to
2
time. This mathematical trick assumes concentration in the dPCA(t) = Rsyn . PD(W ) – Kp. PCA
central compartment is the same as that in the effect compartment dt (t)
at equilibration but that a time delay exists before drug reaches
the effect compartment. The concentration in the effect compart- where Rsyn is the PCA synthesis rate in the absence of war-
ment is used to describe the concentration-effect relationship.22 farin, Kp is the elimination rate constant for PCA, W(t) is the PK
model for warfarin, and PD(W) is the inhibitory effect of warfarin
on PCA synthesis. The IC50 is the warfarin concentration that
inhibits synthesis by 50%.31
Cumulative Effects
Many antineoplastic drugs have an effect that is a consequence of
cumulative exposure. The extent of binding of the drug to DNA is
proportionate to drug concentration and is irreversible. Response
may be predicted by measures of cumulative exposure to the drug
(e.g., AUC).
Figure 18-6. The clockwise hysteresis loop observed after an PEDIATRIC PK CONSIDERATIONS
orally administered drug
Growth and development are two major aspects of children not
readily apparent in adults. How these factors interact is not neces-
sarily easy to determine from observations because they are quite
highly correlated. Drug elimination clearance, for example, may
increase with weight, height, age, body surface area, and creatinine
clearance. One approach is to standardize for size before incor-
porating a factor for maturation and organ function.32
Size
Allometry
Allometry is a term used to describe the nonlinear relationship
between size and function. This nonlinear relationship is ex-
pressed as
Figure 18-7. The time-concentration profile for the effect com-
partment is delayed compared with that in the serum. y = a . BodyMassPWR
Figure 18-9. A comparison of the

temperature-standardized relation for
whole-organism metabolic rate as a
function of body mass. The “allomet-
ric 3/4 power model” fits for unicells,
poikilotherms, and homeotherms,
uncorrected for temperature, are also
shown. From reference 101, with
permission.
where y is the variable of interest (e.g., basal metabolic rate), a Instead of assuming a fixed value of Ffat in all cases, the idea of
is the allometric coefficient, and PWR is the allometric exponent. NFM is to estimate the value of Ffat that is most appropriate for
The value of PWR has been the subject of much debate. Basal the parameter being predicted. If Ffat is estimated to be zero, then
metabolic rate (BMR) is the most common variable investigated FFM alone is required to predict size.
and camps advocating for a PWR value of 2/3 (i.e., body surface Ffat has been estimated to be 0.21 to account for the fat mass
area) are at odds with those advocating a value of 3/4. contribution to size associated changes in glomerular filtration
In all species studied, including humans, the log of BMR plotted rate (GFR).37 Clearly, fat does not directly influence GFR but
against the log of body weight produces a straight line with a slope appears to be a component of total body size that indirectly drives
of 3/4 (Figure 18–9). Fractal geometry is used to mathematically the size of renal excretory capacity.
explain this phenomenon. The 3/4 power law for metabolic rates
was derived from a general model that describes how essential
materials are transported through space-filled fractal networks of Maturation
branching tubes.33 A great many physiologic-, structural-, and Remifentanil clearance in children aged 1 month to 9 years is
time-related variables scale predictably within and between species similar to adult rates when scaled using an allometric exponent of
with weight (W) exponents (PWR) of 3/4, 1, and 1/4, respectively.34 3 38
/4. Remifentanil is cleared by rapid hydrolysis by nonspecific
These exponents have applicability to PK parameters such as tissue and plasma esterases that do not appear to be influenced by
clearance (CL), volume (V), and half-time.34 The factor for size age after scaling for size. For most drugs, however, allometry alone
(Fsize) for total drug clearance may be expected to scale with a is insufficient to predict clearance in neonates and infants from
power of 3/4: adult estimates (Figure 18–10).39,40 The addition of a model des-
W /4
3
cribing maturation is required. The sigmoid hyperbolic has also
( )
Fsize ⫽ 70 been found useful for describing this maturation process (MF).
PMA Hill
Body Fat MF =
TM + PMA Hill
Hill
50
PK properties of some drugs are known to be changed in obesity.
Fat mass contributes to overall body size and may have an indirect The TM50 describes the maturation half-time, whereas the Hill
influence on both clearance and volume of distribution. Lean body coefficient relates to the slope of this maturation profile. It is
mass (LBM) or fat-free mass (FFM)35 may be inadequate descrip- possible that there is asymmetry about the point of inflection, and
tors of body size. These ideas have led to the proposal for different the addition of an extra parameter describing this asymmetry can
fractions of fat mass to explain how PK parameters vary with body be used to provide extra flexibility for this empirical function.41
composition. Maturation of clearance begins before birth, suggesting that
Normal fat mass (NFM) is an extension of the concept of postmenstrual age (PMA) would be a better predictor of drug
predicted normal weight36 that described the separate contribution elimination than postnatal age (PNA). The fetus is quite capable of
of FFM and NFM to prediction of drug clearance. The additional metabolizing some drugs from the second trimester, albeit at low
feature of NFM is a parameter (Ffat) that accounts for different rates.
contributions of fat mass (i.e., W – FFM)
NFM(kg) = FFM + Ffat . (W – FFM) Organ Function
Fsize = ( NFM
Wstd )
PWR
Only recently have changes associated with normal growth
and development been explicitly distinguished from pathologic
Figure 18-10. Age-related clearance changes for a hypothetical drug. All three models show an in-
crease in clearance over the first year of life because of maturation of metabolic pathways. Clearance
expressed using the per-kilogram model then decreases with age after 1 year to reach adult levels in
adolescence. This course is not evident with the allometric 3/4 power and surface area models. From
reference 90, with permission.
changes describing organ function (OF).32 Creatinine clearance, much faster than that of glucuronide conjugation.46 The matura-
for example, may be reduced in neonates, and this will affect tion profile of propofol supports this contention (see Figure
clearance of drugs eliminated through the renal system. The 18–11). Glucuronidation is the major metabolic pathway of pro-
contribution from maturation and organ dysfunction can be pofol metabolism and this pathway is immature in neonates,
difficult to distinguish. PK parameters (P) can be described in an although multiple cytochrome P450 isoenzymes, including
individual as the product of size (Fsize), maturation (MF), and CYP2B6, CYP2C9, or CYP2A6, also contribute to its metabolism
organ function (OF) influences in which Pstd is the value in a and cause a faster maturation profile than expected from
standard-size adult without pathologic changes in organ function: glucuronide conjugation alone.47
Creatinine clearance is commonly used as a measure of renal
P = Pstd . Fsize . MF . OF
organ function; it is used as a covariate to alter drug dose for ren-
ally excreted drugs. Serum unconjugated bilirubin concentration
is a crude marker of hepatic organ function, and elevated paraceta-
Application of PK Models mol concentrations were associated with reduced paracetamol
PK models that have used the modeling approach described earlier clearance in a neonatal cohort.48
in the section on PK models have clarified maturation of clearance
in the first year of life. Paracetamol,42 morphine,43 dexmedeto-
midine,44 propofol,45 and GFR37 clearance maturation have been PEDIATRIC PD CONSIDERATIONS
described. Current data suggest that GFR matures similar to Ontogeny of Drug Action
paracetamol or morphine clearance (Figure 18–11). Paracetamol
and morphine are cleared by individual isoforms of glucuronosyl Children’s responses to drugs have much in common with the
transferase (UGT1A6 and UGT2B7), and it has been suspected responses in adults.49 The perception that drug effects differ in
that these isoforms mature at different rates, consistent with children arises because the drugs have not been adequately studied
current estimated profiles. Further, paracetamol and morphine are in pediatric populations who have size- and age-related effects as
predominantly cleared by phase II conjugation processes that well as different diseases.
convert xenobiotics to water-soluble forms that can be eliminated There are, however, situations in which age-related PD changes
from the body through the renal system. It seems logical that GFR have been described, and many of these have application in anes-
matures before or at the same time as these phase II processes. thesia, for example, MAC age-related changes of anesthetic
Dexmedetomidine is cleared by both gluronidation and the renal inhalation agents. The proportion of type 1 fibers in the dia-
system. Unsurprisingly, maturation closely follows that of GFR. phragm that are more sensitive to NMBDs is also less in neonates,
Maturation of phase I metabolic processes have not been influencing an earlier return of diaphragmatic muscle activity.
described using the proposed size and maturation models. It is Calcium is an effective inotrope in neonates because cardiac
believed, however, that maturation the P450 enzyme systems are calcium stores in the endoplasmic reticulum are reduced. Amide
Figure 18-11. Clearance maturation, expressed as a percentage of mature clearance, of drugs in

which glucuronide conjugation (paracetamol, morphine, dexmedetomidine) plays a major role.
These profiles are closely aligned with glomerular filtration rate (GFR). By contrast, cytochrome
P450 isoenzymes also contribute to propofol metabolism and cause a faster maturation profile than
expected from glucuronide conjugation alone.
local anesthetic agents induce shorter block duration and require any true physiologic entity, they can be used as guides for anes-
a larger weight-scaled dose to achieve similar dermatomal levels thesia and, in so doing, have improved outcomes in adults. In older
when given by subarachnoid block to infants. This may be caused, children, the physiology, anatomy, and clinical observations
in part, by myelination, spacing of nodes of Ranvier, and length indicate the performance of the monitors may be similar to that in
of nerve exposed as well as size factors. Inhibitory gamma- adults, although the clinical relevance of outcomes may be diffe-
aminobutyric acid (GABA) receptors, which may not reach rent. In infants, their use cannot yet be supported in theory or in
maturity until 10 years of age, influence the response seen after practice.53,54 During anesthesia, the EEG in infants is funda-
benzodiazepines in children.50 The coagulation cascade is imma- mentally different from the EEG in older children; there remains
ture at birth, influencing anticoagulant effect.51 There is an age- a need for specific infant-derived algorithms if EEG-derived
dependent expression of intestinal motilin receptors and the anesthesia depth monitors are to be used in infants.55,56
modulation of antral contractions in neonates. Prokinetic agents The COMFORT pain scale has been used to model sedation in
may not be useful in very preterm infants, partially useful in older nonventilated infants after craniofacial surgery.57–59 The Wisconsin
preterm infants, and useful in full-term infants. Catecholamine sedation scale is a clinically used sedation score that is an integral
release and response to vasoactive drugs vary with age. Broncho- part of the structured model from American Academy of Pedi-
dilators have reduced effect in those infants younger than 1 year atrics/American Society of Anesthesiologists (AAP/ASA) sedation
because of immaturity of bronchial smooth muscle at this age. guidelines.60 The model is proposed to reduce risks during seda-
tion. This score has been used to model ketamine PD.61 However,
despite the use of such scales in procedural pain studies, few
Measures of Effect behavioral pain scales have been adequately validated in this
Outcome measures are more difficult to assess in children. Mea- setting.62,63 Observed or self-reported analgesic effect measures
surement techniques, disease and pathology differences, inhomo- vary between ages and even within one age group.64 Interobserver
geneous groups, recruitment issues, ethical considerations, and variability can be high.65
end point definition for establishing efficacy and safety confuse Electromyography response of the adductor pollicis is a con-
data interpretation.52 sistent effect measure for investigation of neuromuscular blockade
The common effects measured in anesthesia are anesthesia in both neonates and adults. Differences are minor, for example,
depth, pain and sedation, and neuromuscular blockade. A com- neonates do not tolerate repetitive stimulations as long as older
mon effect measure used to assess depth of anesthesia is the EEG children because of limited acetylcholine reserves. Early PKPD
or a modification of detected EEG signals (spectral edge fre- modeling in children involved D-tubocurarine (dTc).66 Clearance,
quency, BIS index, entropy). Physiologic studies in adults and standardized to a surface area model, is reduced in neonates and
children indicate that EEG-derived anesthesia depth monitors can infants compared with older children and adults. These age-
provide an imprecise and drug-dependent measure of arousal. related clearances resemble age-related changes in glomerular
Although the outputs from these monitors do not closely represent filtration. The T / keo, standardized for size, is high in neonates
1
2
and infants, reduced in children, and further reduced in adults. propofol, and alfentanil) tripled the duration of effect compared
The cause of this is uncertain, but it may be related to increased with propofol alone. Response surfaces can describe anesthetic
muscle bulk and concomitant increased muscle perfusion in older interactions, even those between agonists, partial agonists, com-
children and adults. petitive antagonists, and inverse agonists. Application of res-
In addition, covariate effects may be subtle and unaccounted ponse-surface methodology permits characterization of the full
for in many studies. The placebo effect contributed 50% of anal- concentration-response relation and, therefore, can be used to
gesia attributed to paracetamol a few hours after tonsillectomy.67 develop practical guidelines for optimal drug dosing.79
A circadian night rhythm effect was noted in an investigation of
infant propofol sedation after major craniofacial surgery.59 Severity
of illness may further influence the sedation PD of propofol.68 EXAMPLES OF PKPD MODEL USE
Defining TE or Side Effect
Measures of Adverse Effects Achievement of the TE is the aim of drug therapy. The dose may be
Neonates and young children may suffer permanent effects result- considered inappropriate and lead to adverse effects if the TE is
ing from a stimulus applied at a sensitive point in development. over- or undershot. Monitoring of anesthetic depth with modified
For example, congenital hypothyroidism, if untreated, causes EEG signal is increasingly popular during inhalational anesthesia
lifelong phenotypic changes. The incidence of vaginal carcinoma because adverse events caused by underdosing (awareness)80 or
is high in children of mothers treated with stilbesterol during overdosing (hypotension)81 are reduced. The use of MAC is helpful
pregnancy.69 There are concerns that neonatal exposure to some because it guides us with age-related changes in dose, but by itself,
anesthetic agents (e.g., ketamine, midazolam) may cause wide- it is unsatisfactory because 50% of subjects will move in response
spread neuronal apoptosis and long-term memory deficits.70,71 to a standard surgical stimulus at 1 MAC. A MAC value is
Anesthesia, however, generally involves examination of imme- associated with between-individual variability, and some patients
will require a greater concentration delivered. This between-subject
diate adverse effects such as Post-operative nausea and vomiting
variability is common for all drugs used in anesthesia.
(PONV), hypotension, or respiratory depression. A dose-response
A nighttime COMFORT score of 12 to 14 and a BIS index of
curve for intravenous morphine and vomiting was investigated in
70 to 75 were used as a TE for sedation in nonventilated children
children having day-stay tonsillectomy. Doses above 0.1 mg/kg
admitted to a pediatric intensive care unit. A dose of midazolam
were associated with a greater than 50% incidence of vomiting.72
1 mg/kg followed by an infusion of 0.5 mg/kg/h57 or a propofol
These data are similar to those in children undergoing inguinal
infusion of 30 mg/h59 in a 10-kg infant achieved this target. Large
herniorrhaphy,73 suggesting that lower doses of morphine are
interindividual variability warrants individual titration of sedative
associated with a decreased incidence of emesis after day-stay drugs.
surgery and encourage the use of alternative analgesic recipes. In chronically opioid-consuming patients, doses causing respi-
PKPD modeling has been used to define the relationship be- ratory depression and analgesia may differ from those in opioid-
tween remifentanil concentration and arterial carbon dioxide naive individuals. The dose-response relationship for analgesia
pressure (PaCO2). Simulations demonstrated that remifentanil and respiratory depression was defined by giving patients a
concentrations well tolerated in the steady state will cause a clini- fentanyl infusion of 2 μg/kg/min until the respiratory rate was
cally significant hypoventilation following bolus administration, lower than 5 breaths/min. It is assumed that adequate analgesia is
confirming the acute risk of bolus administration of fast-acting achieved at an effect-site concentration that is 30% that causing
opioids in spontaneously breathing patients.74 respiratory depression. PK simulations were used to estimate
effect-site concentration at the time of respiratory depression and
Drug Interactions to predict the patient-controlled analgesia settings that would
provide an effect-site fentanyl concentration that was 30% of the
An increase in the T / keo of dTc with increasing inspired halo-
1
2 concentration associated with respiratory depression.82
thane concentrations has been demonstrated.75 Halothane is a
negative inotrope76 and reduces skeletal muscle blood flow,77 so it
seems reasonable to interpret changes in T / keo as caused by
1
2
Defining TC
changes in blood flow. Inhalation anesthetic agents can also An effect-site TC has been estimated for many drugs used in
prolong duration of block; this effect is agent-specific. Sevoflurane anesthesia. For example, a propofol TC of 3 mg/L in a typical
potentiated vecuronium more than halothane; when compared patient can be achieved using preprogrammed TCI devices. A BIS
with balanced anesthesia, the dose requirements of vecuronium monitor can then be used to manually adjust infusion rate to
were reduced by approximately 60% and 40%, respectively.78 achieve a desired TE in the specific individual. Of note, the PDof
Anesthetic drug interactions traditionally have been charac- fentanyl and remifentanil in children (>1 y) were similar to those
terized using isobolographic analysis or multiple logistic regres- reported in adults.83 The luxury of such a feedback system is not
sion. Minto and coworkers have proposed a model based on available for most drugs. Instead, a concentration known to be
response-surface methodology.79 The combination of two or more associated with a quantified effect is targeted.
drugs is considered to act like a single drug with a concentration- A TC of 10 μg/L is used for morphine analgesia. Observations
response relationship. The properties of this virtual drug and the in children after cardiac surgery suggested that steady-state serum
parameters of its concentration-effect relationship are dependent concentrations higher than 20 mg/L resulted in hypercarbia
on the ratio of the concentrations of the two drugs. Computer (PaCO2 > 55 mmHg) and depressed CO2 response curve slopes.
simulations based on interactions at the effect site predicted that During washout, morphine concentrations more than 15 μg/L
the maximally synergistic three-drug combination (midazolam, resulted in hypercarbia in 46%, whereas concentrations less than
Figure 18-12. The median-concentration

profile and 95% confidence intervals for
1000 simulated children given intravenous
ketamine 1 mg/kg. Shading shows keta-
mine concentrations associated with
anaesthesia, arousal after anesthesia, and
analgesia in awake patients. From reference
15 μg/L were associated with hypercarbia in 13% of children. No Paracetamol dosing guidelines that achieve a TC of 10 mg/L from
age-related differences in respiratory effect were seen in these premature neonates through to adolescents have also been
studies at the same serum morphine concentration.84 Observation proposed.88
or self-reporting pain scales are used as part of the feedback loop A single dose of racemic ketamine 1.25 mg/kg for a typical
for dose incremental changes. 6-year-old child (20 kg) undergoing procedural sedation in the
Paracetamol is a mild analgesic. An effect-site concentration of emergency department may be inadequate for procedures that last
10 mg/L was associated with a pain reduction of 2.6 (Visual beyond 8 minutes. An understanding of the PKPD relationship
Analogue Score [VAS] 0–10) after tonsillectomy in children.85 This allows prediction of when a top-up dose (0.625 mg/kg) is required
concentration is achievable with standard dosing regimens in (Figure 18–13).89 This top-up dose could be timely if the child
children. Although increased dose may achieve greater pain relief, requires cast molding after initial reduction of a fractured limb.
the risk of hepatotoxicity limits dose and duration of therapy.
The TC may vary, depending on the desired TE. The TC for
ketamine analgesia (0.25 mg/L) is quite different from that of
The Delayed-Effect Link
anesthesia (2 mg/L) (Figure 18–12).86 The parameter (T / keo) describing the delay between observed
1
2
plasma concentration and effect is anticipated to be reduced in

children and related to size.90 The T / keo for paracetamol has been
1
Achieving TC 2
described using such size scaling.67 This parameter relating

PK parameter estimates (e.g., CL, V) and covariate information propofol concentration to effect (BIS) is reported as less than
(e.g., age, size) are used to predict dose. Morphine infusion, based adults in children91,92 and is related to age, with a smaller T / keo as
1
2
on clearance changes with age, has been predicted in children. A age decreases.83 Similar results are reported for sevoflurane.93
mean steady-state serum concentration of 10 μg/L can be achieved Effect observed will be dependent on the rate at which the drug is
in children after noncardiac surgery in an intensive care unit with infused along with other hypnotic drug interactions and the effect
a morphine hydrochloride infusion of 5 μg/h/kg at birth (term desired.94,95 Anxiety and catecholamine release may further
neonates), 8.5 μg/h/kg at 1 month, 13.5 μg/h/kg at 3 months, complicate this measure.94 Processing delays of EEG signals render
18 μg/h/kg at 1 year, and 16 μg/h/kg for 1- to 3-year-old children.87 T / keo monitor-specific. Failure to appreciate changing T / keo
1
2
1
2
Figure 18-13. Time concentration and sedation

profiles for a typical 6-year-old child (20 kg).
A target effect below 2 (arouses slowly to con-
sciousness, with sustained painful stimulus) for
15 min was achieved using bolus (1.25 mg/kg)
with a top-up dose (0.625 mg/kg) at 8 min.
From reference 89, with permission.
values with age will result in excessive dose in a young child if the 9. Krejcie TC, Avram MJ. What determines anesthetic induction dose? It’s
effect site is targeted and Tpeak is anticipated to be later than it the front-end kinetics, doctor! Anesth Analg. 1999;89:541–544.
10. Kuipers JA, Boer F, Olofsen E, et al. Recirculatory pharmacokinetics and
actually is because it was determined in a teenager or adult. pharmacodynamics of rocuronium in patients: the influence of cardiac
output. Anesthesiology. 2001;94:47–55.
11. Hines RN, McCarver DG. The ontogeny of human drug-metabolizing
Interactions Between Hypnotics enzymes: phase I oxidative enzymes. J Pharmacol Exp Ther. 2002;300:
and Analgesics 355–360.
12. McCarver DG, Hines RN. The ontogeny of human drug-metabolizing
Synergism between propofol and alfentanyl has been demonstrated enzymes: phase II conjugation enzymes and regulatory mechanisms. J
using response-surface methodology. Remifentanil alone had no Pharmacol Exp Ther. 2002;300:361–366.
appreciable effect on response to shaking and shouting or response 13. Johnson TN. Modelling approaches to dose estimation in children. Br J
Clin Pharmacol. 2005;59:663–669.
to laryngoscopy, whereas propofol could ablate both responses. 14. Edginton AN, Schmitt W, Voith B, Willmann S. A mechanistic approach
Modest remifentanil concentrations dramatically reduced the for the scaling of clearance in children. Clin Pharmacokinet. 2006;45:
concentrations of propofol required to ablate both responses.96 683–704.
When comparing the different combinations of midazolam, 15. Edginton AN, Schmitt W, Willmann S. Development and evaluation of a
propofol, and alfentanil, the responses varied markedly at each end generic physiologically based pharmacokinetic model for children. Clin
Pharmacokinet. 2006;45:1013–1034.
point assessed and could not be predicted from the responses of 16. Johnson TN, Tucker GT, Rostami-Hodjegan A. Development of CYP2D6
the individual agents.97 Similar response-surface methodology has and CYP3A4 in the first year of life. Clin Pharmacol Ther. 2008;83:
been taken for investigation of the combined administration of 670–671.
sevoflurane/alfentanil98 and remifentanil/propofol99 on ventilatory 17. Johnson TN, Rostami-Hodjegan A, Tucker GT. Prediction of the
control. These combinations have a strikingly synergistic effect on clearance of eleven drugs and associated variability in neonates, infants
and children. Clin Pharmacokinet. 2006;45:931–956.
respiration, resulting in severe respiratory depression in adults. 18. Bjorkman S. Prediction of cytochrome p450–mediated hepatic drug
These synergistic associations can be extended to pediatric sedation clearance in neonates, infants and children: how accurate are available
techniques. It is little wonder that the use of three or more sedating scaling methods? Clin Pharmacokinet. 2006;45:1–11.
medications compared with one or two medications was strongly 19. Jones HM, Parrott N, Jorga K, Lave T. A novel strategy for physiologically
associated with adverse outcomes.100 based predictions of human pharmacokinetics. Clin Pharmacokinet.
2006;45:511–542.
20. Bjorkman S. Prediction of drug disposition in infants and children by
means of physiologically based pharmacokinetic (PBPK) modelling:
CONCLUSIONS theophylline and midazolam as model drugs. Br J Clin Pharmacol. 2005;
59:691–704.
Achievement of a TE with minimal adverse effect is the key to 21. Hill AV. The possible effects of the aggregation of the molecules of
anesthetic drug use. PD models are useful tools to identify a TE haemoglobin on its dissociation curves. J Physiol. 1910;14:iv-vii.
and a TC at which that occurs. PK models, in turn, point to a dose 22. Holford NH, Sheiner LB. Understanding the dose-effect relationship:
that will achieve that YC. The population approach to modeling clinical application of pharmacokinetic-pharmacodynamic models. Clin
has proved beneficial to exploring PKPD differences in children. Pharmacokinet. 1981;6:429–453.
23. Scott JC, Ponganis KV, Stanski DR. EEG quantitation of narcotic effect:
Size, age, and organ function models have been used to explore the comparative pharmacodynamics of fentanyl and alfentanil. Anesthe-
PK. PD differences, particularly in neonates and infants, have been siology. 1985;62:234–241.
elucidated for common anesthetic vapors. The impact of other 24. Dixon WJ. Efficient analysis of experimental observations. Annu Rev
drugs, active metabolites, stereoisomer interactions, and pharma- Pharmacol Toxicol. 1980;20:441–462.
cogenomics on the concentration-response relationship remain 25. Dixon WJ. Staircase bioassay: the up-and-down method. Neurosci
Biobehav Rev. 1991;15:47–50.
undefined for many drugs. Lacking from our armamentarium are 26. Frawley G, Skinner A, Thomas J, Smith S. Ropivacaine spinal anesthesia
similar concentration-response relationships for adverse effects. in neonates: a dose range finding study. Paediatr Anaesth. 2007;17:
These must also be understood to define the TC. 126–132.
27. Frawley GP, Farrell T, Smith S. Levobupivacaine spinal anesthesia in
neonates: a dose range finding study. Paediatr Anaesth. 2004;14:838–844.
REFERENCES 28. Hull CJ, Van Beem HB, McLeod K, et al. A pharmacodynamic model for
pancuronium. Br J Anaesth. 1978;50:1113–1123.
1. Holford NH. The target concentration approach to clinical drug 29. Sheiner LB, Stanski DR, Vozeh S, et al. Simultaneous modeling of phar-
development. Clin Pharmacokinet. 1995;29:287–291. macokinetics and pharmacodynamics: application to D-tubocurarine.
2. Wada DR, Drover DR, Lemmens HJ. Determination of the distribution Clin Pharmacol Ther. 1979;25:358–371.
volume that can be used to calculate the intravenous loading dose. Clin 30. Holford NHG. Parametric models of the time course of drug action. In:
Pharmacokinet. 1998;35:1–7. Van Boxtel CJ, Holford NHG, Danhof M, editors. The In Vivo Study of
3. McFarlan CS, Anderson BJ, Short TG. The use of propofol infusions in Drug Action. Amsterdam: Elsevier; 1992. pp 61–69.
paediatric anaesthesia: a practical guide. Paediatr Anaesth. 1999;9:209–216. 31. Holford NH. Clinical pharmacokinetics and pharmacodynamics of
4. Hughes MA, Glass PS, Jacobs JR. Context-sensitive half-time in multi- warfarin. Understanding the dose-effect relationship. Clin Pharmacokinet.
compartment pharmacokinetic models for intravenous anesthetic drugs. 1986;11:483–504.
Anesthesiology. 1992;76:334–341. 32. Tod M, Jullien V, Pons G. Facilitation of drug evaluation in children
5. Hull CJ. How far can we go with compartmental models? Anesthesiology. by population methods and modelling. Clin Pharmacokinet. 2008;47:
1990;72:399–402. 231–243.
6. Boer F. Drug handling by the lungs. Br J Anaesth. 2003;91:50–60. 33. West GB, Brown JH, Enquist BJ. A general model for the origin of
7. Reekers M, Boer F, Vuyk J. Basic concepts of recirculatory pharmacokine- allometric scaling laws in biology. Science. 1997;276:122–126.
tic modelling. Adv Exp Med Biol. 2003;523:19–26. 34. Anderson BJ, Holford NH. Mechanism-based concepts of size and
8. Krejcie TC, Henthorn TK, Shanks CA, Avram MJ. A recirculatory phar- maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol. 2008;48:
macokinetic model describing the circulatory mixing, tissue distribution 303–332.
and elimination of antipyrine in dogs. J Pharmacol Exp Ther. 1994;269: 35. Janmahasatian S, Duffull SB, Ash S, et al. Quantification of lean body-
609–616. weight. Clin Pharmacokinet. 2005;44:1051–1065.
36. Duffull SB, Dooley MJ, Green B, et al. A standard weight descriptor for 62. Crellin D, Sullivan TP, Babl FE, et al. Analysis of the validation of existing
dose adjustment in the obese patient. Clin Pharmacokinet. 2004;43: behavioral pain and distress scales for use in the procedural setting.
1167–1178. Paediatr Anaesth. 2007;17:720–733.
37. Rhodin MM, Anderson BJ, Peters AM, et al. Human renal function 63. von Baeyer CL, Spagrud LJ. Systematic review of observational (beha-
maturation: a quantitative description using weight and postmenstrual vioral) measures of pain for children and adolescents aged 3 to 18 years.
age. Pediatr Nephrol. 2008;24:67–76. Pain. 2007;127:140–150.
38. Rigby-Jones AE, Priston MJ, Thorne GC, et al. Population pharma- 64. Bosenberg A, Thomas J, Lopez T, Kokinsky E, Larsson LE. Validation of
cokinetics of remifentanil in critically ill post cardiac neonates, infants a six-graded faces scale for evaluation of postoperative pain in children.
and children. Br J Anaesth. 2005;95:578P–579P. Paediatr Anaesth. 2003;13:708–713.
39. Johnson TN. The problems in scaling adult drug doses to children. Arch 65. Schade JG, Joyce BA, Gerkensmeyer J, Keck JF. Comparison of three
Dis Child. 2008;93:207–211. preverbal scales for postoperative pain assessment in a diverse pediatric
40. Edginton AN, Theil FP, Schmitt W, Willmann S. Whole body sample. J Pain Symptom Manage. 1996;12:348–359.
physiologically-based pharmacokinetic models: their use in clinical drug 66. Fisher DM, O’Keeffe C, Stanski DR, et al. Pharmacokinetics and
development. Expert Opin Drug Metab Toxicol. 2008;4:1143–1152. pharmacodynamics of D-tubocurarine in infants, children, and adults.
41. Richards FJ. A flexible growth function for empirical use. J Exp Bot. Anesthesiology. 1982;57:203–208.
1959;10:290–301. 67. Anderson BJ, Woollard GA, Holford NH. Acetaminophen analgesia in
42. Anderson BJ, Holford NH. Mechanistic basis of using body size and children: placebo effect and pain resolution after tonsillectomy. Eur J Clin
maturation to predict clearance in humans. Drug Metab Pharmacokinet. Pharmacol. 2001;57:559–569.
2009;24:25–36. 68. Peeters MY, Bras LJ, DeJongh J, et al. Disease severity is a major deter-
43. Anand KJ, Anderson BJ, Holford NH, et al. Morphine pharmacokinetics minant for the pharmacodynamics of propofol in critically ill patients.
and pharmacodynamics in preterm and term neonates: secondary results Clin Pharmacol Ther. 2008;83:443–451.
from the NEOPAIN trial. Br J Anaesth. 2008;101:680–689. 69. Linden G, Henderson BE. Genital-tract cancers in adolescents and young
44. Potts AL, Warman GR, Anderson BJ. Dexmedetomidine disposition in adults. N Engl J Med. 1972;286:760–761.
children: a population analysis. Paediatr Anaesth. 2008;18:722–730. 70. Fredriksson A, Archer T, Alm H, et al. Neurofunctional deficits and
45. Allegaert K, de Hoon J, Verbesselt R, et al. Maturational pharmacokinetics potentiated apoptosis by neonatal NMDA antagonist administration.
of single intravenous bolus of propofol. Paediatr Anaesth. 2007;17: Behav Brain Res. 2004;153:367–376.
1028–1034. 71. Wang C, Sadovova N, Fu X, et al. The role of the N-methyl-D-aspartate re-
46. Kearns GL, Abdel-Rahman SM, Alander SW, et al. Developmental ceptor in ketamine-induced apoptosis in rat forebrain culture. Neuro-
pharmacology—drug disposition, action, and therapy in infants and science. 2005;132:967–977.
children. N Engl J Med. 2003;349:1157–1167. 72. Anderson BJ, Ralph CJ, Stewart AW, et al. The dose-effect relationship for
47. Allegaert K, Peeters MY, Verbesselt R, et al. Inter-individual variability in morphine and vomiting after day-stay tonsillectomy in children. Anaesth
propofol pharmacokinetics in preterm and term neonates. Br J Anaesth. Intensive Care. 2000;28:155–160.
2007;99:864–870. 73. Weinstein MS, Nicolson SC, Schreiner MS. A single dose of morphine
48. Palmer GM, Atkins M, Anderson BJ, et al. I.V. acetaminophen pharma- sulfate increases the incidence of vomiting after outpatient inguinal
cokinetics in neonates after multiple doses. Br J Anaesth. 2008;101: surgery in children. Anesthesiology. 1994;81:572–577.
523–530. 74. Bouillon T, Bruhn J, Radu-Radulescu L, et al. A model of the ventilatory
49. Stephenson T. How children’s responses to drugs differ from adults. Br J depressant potency of remifentanil in the non-steady state. Anesthesiology.
Clin Pharmacol. 2005;59:670–673. 2003;99:779–787.
50. Marshall J, Rodarte A, Blumer J, et al. Pediatric pharmacodynamics of 75. Stanski DR, Ham J, Miller RD, Sheiner LB. Pharmacokinetics and
midazolam oral syrup. Pediatric Pharmacology Research Unit Network. pharmacodynamics of D-tubocurarine during nitrous oxide-narcotic and
J Clin Pharmacol. 2000;40:578–589. halothane anesthesia in man. Anesthesiology. 1979;51:235–241.
51. Takahashi H, Ishikawa S, Nomoto S, et al. Developmental changes in 76. Prys-Roberts C, Lloyd JW, Fisher A, et al. Deliberate profound hypo-
pharmacokinetics and pharmacodynamics of warfarin enantiomers in tension induced with halothane: studies of haemodynamics and
Japanese children. Clin Pharmacol Ther. 2000;68:541–555. pulmonary gas exchange. Br J Anaesth. 1974;46:105.
52. Baber NS. Tripartite meeting. Paediatric regulatory guidelines: do they 77. Pauca AL, Hopkins AM. Acute effects of halothane, nitrous oxide
help in optimizing dose selection for children? Br J Clin Pharmacol. and thiopentone on upper limb blood flow. Br J Anaesth. 1972;43:
2005;59:660–662. 326–333.
53. Davidson AJ. Measuring anesthesia in children using the EEG. Pediatr 78. Taivainen T, Meretoja OA. The neuromuscular blocking effects of vecuro-
Anesth. 2006;16:374–387. nium during sevoflurane, halothane and balanced anaesthesia in children.
54. Davidson AJ, Huang GH, Rebmann CS, Ellery C. Performance of entropy Anaesthesia. 1995;50:1046–1049.
and bispectral index as measures of anaesthesia effect in children of 79. Minto CF, Schnider TW, Short TG, et al. Response surface model for
different ages. Br J Anaesth. 2005;95:674–679. anesthetic drug interactions. Anesthesiology. 2000;92:1603–1616.
55. Davidson AJ, Sale SM, Wong C, et al. The electroencephalograph during 80. Myles PS, Leslie K, McNeil J, et al. Bispectral index monitoring to prevent
anesthesia and emergence in infants and children. Paediatr Anaesth. awareness during anaesthesia: the B-Aware randomised controlled trial.
2008;18:60–70. Lancet. 2004;363:1757–1763.
56. Jeleazcov C, Schmidt J, Schmitz B, et al. EEG variables as measures of 81. Keenan RL, Shapiro JH, Kane FR, Simpson PM. Bradycardia during anes-
arousal during propofol anaesthesia for general surgery in children: thesia in infants. An epidemiologic study. Anesthesiology. 1994;80:
rational selection and age dependence. Br J Anaesth. 2007;99:845–854. 976–982.
57. Peeters MY, Prins SA, Knibbe CA, et al. Pharmacokinetics and pharma- 82. Davis JJ, Swenson JD, Hall RH, et al. Preoperative “fentanyl challenge” as
codynamics of midazolam and metabolites in nonventilated infants after a tool to estimate postoperative opioid dosing in chronic opioid-
craniofacial surgery. Anesthesiology. 2006;105:1135–1146. consuming patients. Anesth Analg. 2005;101:389–395.
58. Prins SA, Peeters MY, Houmes RJ, et al. Propofol 6% as sedative in 83. Jeleazcov C, Ihmsen H, Schmidt J, et al. Pharmacodynamic modelling of
children under 2 years of age following major craniofacial surgery. Br J the bispectral index response to propofol-based anaesthesia during
Anaesth. 2005;94:630–635. general surgery in children. Br J Anaesth. 2008;100:509–516.
59. Peeters MY, Prins SA, Knibbe CA, et al. Propofol pharmacokinetics and 84. Lynn AM, Nespeca MK, Opheim KE, Slattery JT. Respiratory effects of
pharmacodynamics for depth of sedation in nonventilated infants after intravenous morphine infusions in neonates, infants, and children after
major craniofacial surgery. Anesthesiology. 2006;104:466–474. cardiac surgery. Anesth Analg. 1993;77:695–701.
60. Hoffman GM, Nowakowski R, Troshynski TJ, et al. Risk reduction in 85. Anderson B, Kanagasundarum S, Woollard G. Analgesic efficacy of
pediatric procedural sedation by application of an American Academy of paracetamol in children using tonsillectomy as a pain model. Anaesth
Pediatrics/American Society of Anesthesiologists process model. Pediat- Intensive Care. 1996;24:669–673.
rics. 2002;109:236–243. 86. Herd D, Anderson BJ. Ketamine disposition in children presenting for
61. Herd DW, Anderson BJ, Keene NA, Holford NH. Investigating the phar- procedural sedation and analgesia in a children’s emergency department.
macodynamics of ketamine in children. Paediatr Anaesth. 2008;18:36–42. Paediatr Anaesth. 2007;17:622–629.
87. Bouwmeester NJ, Anderson BJ, Tibboel D, Holford NH. Developmental 94. Sneyd JR, Rigby-Jones AE. Effect site: who needs it? Br J Anaesth. 2007;
pharmacokinetics of morphine and its metabolites in neonates, infants 98:701–704.
and young children. Br J Anaesth. 2004;92:208–217. 95. Rigby-Jones A, Sneyd JR. Cardiovascular changes after achieving cons-
88. Anderson BJ, van Lingen RA, Hansen TG, et al. Acetaminophen develop- tant effect site concentration of propofol. Anaesthesia. 2008;63:780.
mental pharmacokinetics in premature neonates and infants: a pooled 96. Bouillon TW, Bruhn J, Radulescu L, et al. Pharmacodynamic interaction
population analysis. Anesthesiology. 2002;96:1336–1345. between propofol and remifentanil regarding hypnosis, tolerance of
89. Dallimore D, Herd DW, Short T, Anderson BJ. Dosing ketamine for pedi- laryngoscopy, bispectral index, and electroencephalographic approxi-
atric procedural sedation in the emergency department. Pediatr Emerg mate entropy. Anesthesiology. 2004;100:1353–1372.
Care. 2008;24:529–533. 97. Short TG, Plummer JL, Chui PT. Hypnotic and anaesthetic interactions
90. Anderson BJ, Meakin GH. Scaling for size: some implications for between midazolam, propofol and alfentanil. Br J Anaesth. 1992;69:
paediatric anaesthesia dosing. Paediatr Anaesth. 2002;12:205–219. 162–167.
91. Munoz HR, Cortinez LI, Ibacache ME, Altermatt FR. Estimation of the 98. Dahan A, Nieuwenhuijs D, Olofsen E, et al. Response surface modeling
plasma effect site equilibration rate constant (KE0) of propofol in children of alfentanil-sevoflurane interaction on cardiorespiratory control and
using the time to peak effect: comparison with adults. Anesthesiology. bispectral index. Anesthesiology. 2001;94:982–991.
2004;101:1269–1274. 99. Nieuwenhuijs DJ, Olofsen E, Romberg RR, et al. Response surface
92. Munoz HR, Cortinez LI, Ibacache ME, Leon PJ. Effect site concentra- modeling of remifentanil-propofol interaction on cardiorespiratory
tions of propofol producing hypnosis in children and adults: com- control and bispectral index. Anesthesiology. 2003;98:312–322.
parison using the bispectral index. Acta Anaesthesiol Scand. 2006;50: 100. Cote CJ, Karl HW, Notterman DA, et al. Adverse sedation events in
882–887. pediatrics: analysis of medications used for sedation. Pediatrics.
93. Cortinez LI, Troconiz IF, Fuentes R, et al. The influence of age on the 2000;106:633–644.
dynamic relationship between end-tidal sevoflurane concentrations and 101. Gillooly JF, Brown JH, West GB, et al. Effects of size and temperature on
bispectral index. Anesth Analg. 2008;107:1566–1572. metabolic rate. Science. 2001;293:2248–2251.
Mechanisms of Action
19 of General Anesthetics
C H A P T E R Vincent P. Laudenbach, Souhayl Dahmani, Hawa Keïta-Meyer, and Jean Mantz
INTRODUCTION GENERALITIES ABOUT MOLECULAR

The common definition of the state of general anesthesia includes TARGETS OF ANESTHETIC AGENTS
different components—anxiolysis, amnesia, hypnosis (loss of con- Compelling data strongly suggest that clinically relevant concent-
sciousness and of neuronal synchronisation), sedation (reduced rations of anesthesia agents (from 1 μM to 1 mM) preferentially
awakeness), analgesia, blunting of the adrenergic response, immo- target ion channels coupled to neurotransmitter receptors.4,5
bility, and myorelaxation—all of which may vary in intensity. The Gamma-hydroxybutyric acid (GABA) receptors, subtype A, ap-
three main drug categories used in combination in order to obtain pear to be the best candidate given their wide distribution within
such a state include hypnotic drugs, opioids, and neuromuscular
the central nervous system, their physiologic role, and their high
blocking drugs.1 The present chapter excludes the two latter cate-
sensitivity to anesthetic agents.3,6 Of note, in the newborn rat hip-
gories.
pocampus (and in cultures derived from newborn neocortex), the
Ever since they became available in the field of clinical practice
endogenous GABA has a depolarizing activity, due in part to
and even after more than 100 years of research, the mechanisms of
action and sites of action of anesthetic agents remain incompletely differences in chloride concentration and conductance compared
deciphered. It remains difficult to explain how agents that differ with adults.7,8 Yet, whether this is clinically relevant, that is, un-
from a chemical point of view may induce that grossly similar state derlying some developmentally regulated, possibly “paradoxical”
of anesthesia.2 New investigation techniques such as patch-clamp, effects of anesthetics in human neonates, has still not been
targeted mutagenesis, transgenesis, or functional neuroimageing demonstrated.
have allowed tremendous insights into the precise comprehension Some anesthetic agents also act at the level of other receptors,
of such mechanisms. This is how multiple targets, anatomic sites, for example, glycine receptors (involved in the immobility pro-
and the prominent role of ion channels have been demonstrated.3 duced by general anesthesia at the level of spinal cord), nicotinic
The aim of this chapter is to review recent data concerning tar- acetylcholine receptors (nAChRs), serotonin-3 (5-HT3) receptors,
gets and sites of action of general anesthetic agents. We also dis- or glutamate receptors (α-amino-3-hydroxy-5-methyl-4-isoxazole
cuss anatomic and molecular locations for anesthetic effects of propionic acid [AMPA], kainite, and N-methyl-D-aspartate
immobility, sedation, hypnosis, and amnesia. Possible contribu- [NMDA]–sensitive receptors). Sodium, potassium, or calcium
tions to between-individual response attributable to genetics and voltage-gated channels have also been identified as important tar-
gender are reviewed. gets.4 Some recent data also highlight the particular contribution
of (1) 2P-K+ (two-pore domain “leak” K+) channels, which are
involved in the maintenance of the membrane potential, (2) HCN
PRINCIPAL INVESTIGATION channels (hyperpolarization-activated, cyclic nucleotide–gated),
TECHNIQUES THAT ALLOW FURTHER which belong to a family that give rise to “pacemaker” currents,
INSIGHTS INTO ANESTHETIC and (3) voltage-dependent Na+ channel expressed at the presynap-
MECHANISMS OF ACTION tic level.3
Finally, apart from mechanisms directly acting on neurotrans-
The patch-clamp: This technique allows the detection in real time mission systems, numerous anesthetic agents act via the modula-
of the activity of a single ion channel. tion of high-affinity uptake and release of neurotransmitors by
The targeted mutagenesis: This technique allows the targeted neuronal, but also non-neuronal, cells (i.e., astrocytosis).9–11
mutation of one or several amino acids of a given neurotransmitter
receptor, allowing analysis of the contribution of this amino acid
to the global properties of the receptor. MOLECULAR STRUCTURE OF
Transgenic animals, knock-out, and knock-in animals: These CHANNEL RECEPTORS AND
animals have been engineered at the molecular level in order to
invalidate a given gene (knock-out) or to introduce a mutant ver-
ACTION OF ANESTHETIC AGENTS
sion a given gene (transgenic or knock-in animals). The gene of in- GABAA, glycine, 5-HT3, and nAChRs belong to a common super-
terest may be, for instance, a subunit of a neurotransmitter receptor. family.10 All members of this family have five subunits constituting
Neuroimaging functional techniques: These techniques en- a ligand-gated channel. Each subsunit has a long extracellular N-
compass, for the main part, functional magnetic resonance imag- terminal domain, four transmembrane domains (TM1–TM4), an
ing and positron emission tomography scanning. intracellular loop between TM3 and TM4 (regulating domain of
CHAPTER 19 ■ Mechanisms of Action of General Anesthetics 311
Figure 19-2. Schematic drawing of ionotropic glutamate recep-

Figure 19-1. Schematic representation of one ionotropic receptors. The N-methyl-D-aspartate (NMDA)–sensitive receptor is
tor of the superfamily that includes gamma-aminobutyric acid coupled to a Ca2+-, K+-, and Na+-permeable channel. It also
A (GABAA), glycine, nicotinic, and serotoninergic receptors and possesses glycine, Zn2+, phencyclidine (PCP), and Mg2+ binding
of the five subunits forming the ion channel. Subunits have long sites that regulate function. Kainate-sensitive receptors are
N-terminal extracellular domains on which the ligand binds, coupled to a Na+- and K+-permeable channel. Alpha-amino-3-
four transmembrane domains (TM), an intracellular loop hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)–sensitive
between TM3 and TM4, and a short C-terminal domain. For receptors are also highly permeable to Na+ and K+ and harbor a
each receptor, the ion channel pore is made of the assembly of Zn2+ regulatory binding site.
the TM2 of the different subunits.
out the need for the endogenous neurotransmitter. Propofol also
delays the GABAA desensitization, a mechanism that plays an
the receptor, site of phosphorylation), and a short C-terminal
important role if inhibitory synapses are rapidly and repetitively
extracellular domain11 (Figure 19–1). Agonist binding sites are
activated.13
located on the extracellular domain. The intramembrane TM2
In addition to their predominant action on GABAA receptors,
domains constitute the ion channel itself (see Figure 19–1). At this
halogenated volatile anesthetics inhibit excitatory neurotransmis-
level, glutamate ligand-gated ion channel belong to a particular
sion at the presynaptic level, mainly by decreasing the release of
family. They have three transmembrane domains (M1, M3, and
glutamate.3 Conversely, nonhalogenated volatile anesthetics like
M4) plus a cytoplasmic re-entering loop (M2), which is the site of
the transmembrane ion channel. Here, the N-terminal domain
is extracellular, whereas the C-terminal domain is intracellular
(Figure 19–2). Glutamatergic ligand-gated ion channel are either
tetrameric or pentameric.11
It is now commonly admitted that most inhaled agents, among
which ethers (isoflurane, sevoflurane, desflurane, enflurane) as well
as some alkanes (e.g., halothane) act by enhancing the chloride
conductance of the GABAA receptor, thereby reinforcing inhibitory
synaptic and extrasynaptic transmission3,12 (Figure 19–3).
The majority of intravenous anesthetic agents, including
propofol and etomidate, selectively modulate the GABAA receptor
by reinforcing and lengthening the binding of GABA released by Figure 19-3. When applied to cultures of rat spinal ganglionic
presynaptic neurons.3 Thus, they increase the duration of the neurons, halothane (0.86 mM) potentiates by three- to fourfold
opening of the channel.3 Some intravenous anesthetics, at higher the GABAA channel receptor response to low concentrations
concentrations, may also elicit the GABAA channel opening with- (3.10–6 M) of GABA. From reference 64.
● The potentiation of the GABAA receptor by propofol is altered

by the mutation of specific amino acid located within theTM2
domain on the β subunit.26
● The sensitivity of NMDA receptors to ketamine is dependent
on arginine residues located at the level of the NR2B and
NR1 subunits. These arginines are part of the Mg2+ blockade–
sensitive site of the NMDA channel.25,27
These landmark works outline the high specificity of the inter-
actions between anesthetic agents and neurotransmitter receptors.
They demonstrate the complexity of such interactions because, for
example, two anesthetics modulating the activity of a given recep-
tor may act at different sites of this receptor.
ROLE OF 2P-K+ AND HCN CHANNELS

The activation of 2P-K+ ion channels by clinically relevant con-
centrations of volatile anesthetics was first observed in snail neural
cells, then in mammals. Such activation results in (1) an increase
in K+-mediated conductance and subsequent hyperpolarization,
(2) a reduction in postsynaptic excitatory potentials, and (3) a
disruption in neuronal synchronization. Mutant mice in which
the TREK-1 type 2P-K+ channel gene has been invalidated show a
reduction of the immobilizing effects of volatile anesthetics (by
7–37%) when compared with normal control mice.28 This is strong
Figure 19-4. Cellular currents measured by application of the
evidence supporting the involvement of this channel in the effects
patch-clamp technique, in “cell-attached” configuration, after
of some anesthetics.
applying 10 μM NMDA on hippocampal neurons. Currents
Halothane also depresses K+ currents mediated by HCN chan-
were measured on two different cells, with or without 0.1 μM
nels, resulting in a reduction of “pacemaker” potentials and in a
ketamine. Entering currents generate negative deflexions of the
reduction of the frequency of depolarization of some neurons
graph. From reference 4.
showing basal self-rhythmicity. Recently, it has been shown that
two clinically relevant concentrations of halothane depressed both
xenon,14 nitrous oxide,15 cyclopropane,16 as well as some intrave- HCN1 and HCN2.29 Among intravenous anesthetics, pentobarbi-
nous agents (i.e., ketamine)17 have little if any effect on the dif- tal inhibits K+ currents in thalamic neurons.30
ferent subtypes of GABAA receptors tested to date. Actually, they
mainly depress the excitatory neurotransmission at the postsyna-
ptic level by blunting the activation of NMDA receptors by gluta- ROLE OF VOLTAGE-DEPENDENT
mate (Figure 19–4). However, their action at the level of NMDA NA+ CHANNELS
channel receptors is somewhat different: whereas ketamine acts
by entering and blocking the channel itself in a noncompetitive Voltage-dependent Na+ channels are key actors of the propagation
manner,18 xenon inhibits the glycine co-activating site located on and integration of neuronal signals. In particular, they underlie
the NR1 NMDA subunit on its extracellular domain.19 Nitrous the initial step of depolarization when action potentials spread.
oxide blocks the glutamatergic transmission at both the pre- and Published works analyzing their contribution to the mechanisms
the postsynaptic level, but its precise site of action on NMDA of action of anesthetics have raised different conclusions.31–34 This
receptors has not been identified to date.20 Numerous volatile could be caused, in part, by their high level of structural vari-
anesthetics, as well as propofol, applied at subclinical concentra- ability.35 Indeed, depending on the kind of voltage-dependent Na+
tions, also inhibit nAChRs. This latter mechanism is likely to be channel analyzed, different pharmacologic effects of a given
involved in the antinociceptive, rather than the immobilizing, anesthetic can be observed, quantitatively as well as qualitatively.
effects of anesthetic agents.21,22 Moreover, the same neuron can bear different kinds of channels
Molecular genetic techniques (like targeted mutagenesis or the that may be more or less sensitive to an anesthetic agent.
engineering of chimeric receptors) have enabled the precise Different isoforms of voltage-dependent Na+ channels may
location of some regions and/or sites critical for the action of anes- have distinct cellular and subcellular locations.36 In mammals,
thetics. The current literature on this field is extremely important neuronal isoforms Nav1.2, Nav1.4, Nav1.5, and Nav1.6 are inhibited
and still growing. Some of the more important facts are by isoflurane and some other volatile agents. Contrarily, the Nav1.8
isoform is not sensitive to these agents.3 At clinically relevant
● Experiments conducted on the glycine receptor α1 subunit and concentrations, volatile anesthetics inhibit Na+ channels of spinal
on the α1, α2, β1, and ε1 subunits of the GABAA receptor have ganglionic neurons.3
identified some amino acid residues located between trans- Several lines of evidence strongly suggest that the inhibition of
membrane domains TM2 and TM3, which are mandatory for presynaptic Na+ channels is involved in the reduced release of
volatile anesthetics to potentiate these receptors in the presence excitatory neurotransmitters by volatile anesthetics.37,38 In primary
of their endogenous agonists.23–25 cultures of rat hypopituitary neurons, isoflurane inhibits Na+
currents on nerve endings, thus decreasing the amplitude of action cultures of cortical neurons.45 In mice bearing a mutant, etomidate-
potentials.39,40 On rat central neurons, the same agent reduces the insensitive β2 GABAA subunit, the loss of pedal withdrawal reflex
presynaptic vesicular exocytosis as well as the amplitude of post- and the burst suppression response in the electroencephalogram
synaptic excitatory potentials. In parallel, a small reduction of the after etomidate administration (which are thought to reflect the
amplitude of the presynaptic action potential is seen, with no hypnotic component of etomidate effects) are still observed,
observed direct action on Ca2+ currents.41 suggesting that these effects are mediated mainly via the β3 subunit
of cortical GABAA receptors.44 Cortical β3 subunit–containing
GABAA receptors also seem to play a pivotal role in propofol
WHICH ANATOMIC AND effects.45
MOLECULAR LOCATION FOR
WHICH ANESTHETIC PROPERTY? Sedation
Immobility Hentschke and coworkers have studied the effects of volatile
agents on spontaneous action potentials in the rat somatosensory
The blockade of movement, either spontaneous or evoked by a cortex, both in vivo and in vitro.46 In vivo, the mean rate of cortical
stimulus, seems mainly related to a depression of spinal reflex neurons firing were significantly reduced by concentrations much
pathways. This can be caused by a reinforcement of inhibitory lower than MACawake. At MACawake, spontaneous action potentials
neurotransmission or by a decrease in excitatory transmission by were blunted by about 50%. Isoflurane and enflurane had similar
spinal neurons. A large amount of data demonstrate that intra- efficiency on primary cultures of cortical neurons, that is, in the
venous agents (i.e., propofol) elicit immobility via the GABAA absence of subcortical structures. At concentrations equivalent to
receptor.42,43 In vivo studies have shown that the systemic adminis- MACawake, exposure of neuronal cultures to isoflurane and en-
tration of antagonists of the GABAA receptor prevents the inhibi- flurane elicited an increase in the inhibitory GABAergic synaptic
tory effects of propofol on spinal reflexes.43 At the molecular level, activity.46 Thus, cortical GABAA receptors seem to play a critical
only the α2, α3, β3, and γ2 subunits of the GABAA receptor are role in the sedative effects of halogenated agents. This was corro-
detected at the spinal level, whereas α1, β1, and γ2 subunits are borated by results of functional neuroimaging studies conducted
more abundant at the level of the cortex, hippocampus, and in the human. Subhypnotic, sedative concentrations of anesthetics
thalamus. Studies conducted on mutant mice have demonstrated reduce cortical metabolism by 30 to 50%, whereas the metabolism
that the immobilizing action of propofol and etomidate was of subcortical structures is not much altered.47
directly mediated by β3-containing GABAA receptors at the spinal Taken together, these different results suggest that the sedative
level.42,44 Similar studies have shown that the myorelaxant effect and hypnotic effects of general anesthetics largely involves cortical
of diazepam is mediated mainly by α2-containing spinal GABAA β2- and β3-containing GABAA receptors. The α1 subunit of GABAA
receptors.45 receptors plays an important role as well, notably in sedation and
As far as halogenated volatile anesthetics are concerned, some amnesia elicited by diazepam.48 It must be emphasized that, at the
studies show that the invalidation of the gene encoding the β3 protein level, β2 and α1 subunits of GABAA receptors are most
subunit of GABAA receptors results in the loss of the inhibition of frequently associated with γ2 subunits49 and that β2 subunit–
the paw withdraw reflex in the presence of halothane, enflurane, containing GABAA receptors are the most widely distributed
or isoflurane.42 Higher concentrations of anesthetic gases (15–24% isoforms in the central nervous system.
when compared with wild-type controls) are required to obtain the Finally, even though β2- and β3-containing GABAA receptors
same immobilizing effect.42 This strongly suggests the involvement are expressed in the thalamus, animal and human studies failed
of spinal β3-containing GABAA receptors in the immobilizing effect to demonstrate any effect of etomidate on thalamic functions.45
of these agents. Halogenated gas–induced immobilization also
involves K+ channels and glycine receptors.28
Finally, the inhibition of excitatory channel receptors also takes Amnesia
part in the immobilizing effects of halogenated volatile anesthetics. Amnesia is defined as a loss of memory. Memory is commonly
In mouse spinal cord slices, enflurane inhibits AMPA- and categorized as short (“active”) and long term. Notably, the process
NMDA-mediated currents. In vivo, intrathecal administration of of information by short-term memory involves the prefrontal and
NMDA receptor antagonists reduces isoflurane minimuml alveo- sensory cortex.50 Short-term memory has limited ability to stock
lar concentration (MAC) by about 30%.45 information, whereas the capacity of long-term memory is vir-
tually unlimited. Information processed by short-term memory is
subsequently transferred to long-term memory.
Sedation and Hypnosis Anesthesia-related amnesia most probably results from depres-
In humans, a possible definition of sedation is a state of reduced sion of hippocampus activity. Pyramidal hippocampal cells express
arousal with lengthened response times, reduced motor activity, predominantly extrasynaptic α5-containing GABAA receptors.
and difficulty producing clear speech. Hypnosis is most commonly These are extremely sensitive to volatile anesthetics.51 This could
defined as a complete lack of response to verbal orders. explain why low, subhypnotic concentrations of these agents alter
learning capability. However, animals invalidated for the α5-
GABAA subunit or bearing mutant α5-GABAA subunits with low
Hypnosis level of expression have better learning capability. Therefore, it
Etomidate is known to have high selectivity for β2 and β3 subunits– seems unlikely that amnesic properties of anesthetic agents are
containing GABAA receptors via a single asparagine residue.26 At related to a single selective action on the α5-GABAA subunit in the
hypnotic concentrations, it decreases the firing activity of primary hippocampus. Other anatomic structures like amygdala, a part of
Figure 19-5. Multiple sites and targets of anesthetic agents. Hypothetic mechanisms of volatile agents
(sevoflurane and isoflurane) and of intravenous anesthetics (propofol and etomidate) at clinically relevant
concentrations.
the limbic system, are also considered an important target for flurane, halothane, isoflurane, sevoflurane, and desflurane) and
anesthetics.52,53 Volatile anesthetics alter the process of information intravenous anesthetics (midazolam, thiopental, propofol) have
at this level, by interfering with both GABAergic and glutamater- been studied.55 These works suggest that differences in pharmaco-
gic transmission.54 kinetics related to gender may be counterbalanced by pharmacody-
In summary, as far as volatile anesthetics are concerned, seda- namics.55 In the clinical setting, differences in pharmacodynamics,
tion and hypnosis are induced at the level of the brain whereas metabolism, and/or clearance less than 20 to 30% between male
immobility is mainly related to an inhibition of spinal neurons. and female seem not to have any clinical relevance.55 Males are
Immobility from intravenous anesthetics results from both spinal more sensitive to propofol than females, with delayed awakening
and supraspinal actions. Effective concentrations required to after a single dose. Although the mechanisms underlying this
induce anesthesia differ notably between volatile and intravenous difference between male and female are not precisely deciphered,
anesthetics. For halogenated agents, a concentration of around a reduction of dose of about 30 to 40% has been proposed in men
1 mM is required, whereas for intravenous drugs, efficient concen- in order to obtain the same awakening time.55
trations are about three orders of magnitude lower. Moreover, Despite tremendous strides in the field of genetics since the
concentrations required for induction of sedation and hypnosis 2000s, pharmacogenetic knowledge of anesthetic drugs remains
are lower than those necessary for immobility. Ion channels sparse.56 This scope of research aims to determine the contribution
involved in sedation and hypnosis are members of the GABAA from genetic differences to between-individual differences in
receptor family. Sedation involves mainly β2-containing GABAA metabolism, efficiency, and adverse effects of a given drug. Such
receptors, whereas hypnosis involves mainly β3-containing differences may result from variations in genes involved in the
GABAA receptors (Figure 19–5). These generalizations are prob- pharmacokinetics or pharmacodynamics of anesthetic agents. To
ably true for intravenous as well as for volatile anesthetics. A major date, most studies conducted in humans have focused on benzo-
difference resides in the way those two categories of anesthetic diazepines.57–61 Most benzodiazepines are metabolized by hepatic
agents induce immobility. Volatile anesthetics reduce the excit- enzymes of the cytochrome P450 (CYP) family, metabolites being
ability of spinal neurons via multiple sites. On the contrary, the subsequently eliminated by the bile or the urine. Genetic poly-
spinal action of intravenous anesthetics is mediated almost ex- morphisms at the level of genes encoding these enzymes alter
clusively by GABAA receptors. These differences could explain the drugs metabolism. For example, diazepam’s elimination half-life is
higher efficiency of volatile anesthetics in inhibiting motor res- fourfold longer in individuals carrying two alleles of the A type of
ponses to noxious stimuli. Amnesia is mainly but not exclusively the cytochrome CYP2C19 G681A than individuals homozygous
linked to the action of anesthetic agents on hippocampal α5 for the G type allele.59 Consequently, these homozygous patients
subunit–containing GABAA receptors. have longer sedation and loss of consciousness.57 Contrary to
diazepam, pharmacogenetic studies focusing on midazolam have
found little variations depending on the genetic status, even
GENETIC AND GENDER-RELATED though midazolam clearance is reduced in patients bearing the
VARIABILITY IN RESPONSE CYP3A4 and CYP3A5 genes. This has little clinical consequences
because there are alternative pathways for the metabolism and
TO ANESTHETIC AGENTS excretion of this agent.57,58,60
The role of gender in pharmacokinetics and pharmacodynamics Genetic studies of inhaled volatile anesthetics have mainly
of various agents have been discussed.55 Volatile anesthetics (en- focused on the propensity to life-threatening adverse effects such
as malignant hyperthermia. About 50% of malignant hyperther- 17. Flood P, Krasowski MD. Intravenous anesthetics differentially modulate
mia cases have mutations within the gene encoding the ryanodine ligand-gated ion channels. Anesthesiology. 2000;92:1418–1425.
18. Akk G, Mennerick S, Steinbach JH. Actions of anesthetics on excitatory
receptor (RYR1).62,63 At least 23 different mutations of RYR1 have transmitter-gated channels. Handb Exp Pharmacol. 2008:53–84.
been shown to be linked to the malignant hyperthermia syn- 19. Dickinson R, Peterson BK, Banks P, et al. Competitive inhibition at the
drome.56 Conversely, there is little if any literature about the glycine site of the N-methyl-D-aspartate receptor by the anesthetics xenon
pharmacogenomics of inhaled anesthetics related to hypnosis in and isoflurane: evidence from molecular modeling and electrophysiology.
humans. Anesthesiology. 2007;107:756–767.
20. Ranft A, Kurz J, Becker K, et al. Nitrous oxide (N2O) pre- and post-
synaptically attenuates NMDA receptor–mediated neurotransmission in
the amygdala. Neuropharmacology. 2007;52:716–723.
CONCLUSION 21. Flood P, Ramirez-Latorre J, Role L. Alpha 4 beta 2 neuronal nicotinic
acetylcholine receptors in the central nervous system are inhibited by
The knowledge about cellular and molecular mechanisms of isoflurane and propofol but alpha 7-type nicotinic acetylcholine receptors
anesthesia, as well as its effects on neuronal circuits, has increased are unaffected. Anesthesiology. 1997;86:859–865.
significantly since the beginning of the 2000s. In summary, a large 22. Violet JM, Downie DL, Nakisa RC, et al. Differential sensitivities of
body of evidence establishes the major contribution of synaptic mammalian neuronal and muscle nicotinic acetylcholine receptors to
and extrasynaptic GABA and glutamate ion channel receptors to general anesthetics. Anesthesiology. 1997;86:866–874.
23. Koltchine VV, Finn SE, Jenkins E, et al. Agonist gating and isoflurane
the effects of anesthetic agents applied at clinically relevant potentiation in the human gamma-aminobutyric acid type A receptor
concentrations. Conversely, other ion channels as well as other determined by the volume of a second transmembrane domain residue.
receptors also intervene. Molecular engineered cells and animals, Mol Pharmacol. 1999;56:1087–1093.
as well as functional neuroimaging, are powerful tools for the 24. Krasowski MD, Koltchine VV, Rick CE, et al. Propofol and other intra-
understanding of phenomena associated to the state of anesthesia, venous anesthetics have sites of action on the gamma-aminobutyric acid
type A receptor distinct from that for isoflurane. Mol Pharmacol. 1998;53:
that is, amnesia, hypnosis, sedation, or immobility. Nonetheless,
530–538.
the pharmacogenomics of anesthetics remains only partially 25. Yamakura T, Shimoji K. Subunit- and site-specific pharmacology of the
explored and will probably provide additional useful information NMDA receptor channel. Prog Neurobiol. 1999;59:279–298.
for the design and safe use of new drugs in the future. 26. Pistis M, Belelli D, McGurk K, et al. Complementary regulation of anaes-
thetic activation of human (alpha6beta3gamma2L) and Drosophila
(RDL) GABA receptors by a single amino acid residue. J Physiol. 1999;
REFERENCES 515:3–18.
27. Yamakura T, Mori H, Masaki H, et al. Different sensitivities of NMDA
1. Rudolph U, Antkowiak B. Molecular and neuronal substrates for general receptor channel subtypes to non-competitive antagonists. Neuroreport.
anaesthetics. Nat Rev Neurosci. 2004;5:709–720. 1993;4:687–690.
2. Angel A. Central neuronal pathways and the process of anaesthesia. Br J 28. Heurteaux C, Guy N, Laigle C, et al. TREK-1 a K+ channel involved in
Anaesth. 1993;71:148–163. neuroprotection and general anesthesia. EMBO J. 2004;23:2684–2695.
3. Hemmings HC Jr, Akabas MH, Goldstein PA, et al. Emerging molecular 29. Chen X, Sirois JE, Lei Q, et al. HCN subunit-specific and cAMP-modu-
mechanisms of general anesthetic action. Trends Pharmacol Sci. 2005; lated effects of anesthetics on neuronal pacemaker currents. J Neurosci.
26:503–510. 2005;25:5803–5814.
4. Franks NP, Lieb WR. Molecular and cellular mechanisms of general 30. Wan X, Mathers DA, Puil E. Pentobarbital modulates intrinsic and
anaesthesia. Nature. 1994;367:607–614. GABA-receptor conductances in thalamocortical inhibition. Neuro-
5. Krasowski MD, Harrison NL. General anaesthetic actions on ligand-gated science. 2003;121:947–958.
ion channels. Cell Mol Life Sci. 1999;55:1278–1303. 31. Berg-Johnsen J, Langmoen IA. The effect of isoflurane on excitatory
6. Campagna JA, Miller KW, Forman SA. Mechanisms of actions of inhaled synaptic transmission in the rat hippocampus. Acta Anaesthesiol Scand.
anesthetics. N Engl J Med. 2003;348:2110–2124. 1992;36:350–355.
7. Rheims S, Minlebaev M, Ivanov A, et al. Excitatory GABA in rodent 32. Frenkel C, Duch DS, Urban BW. Effects of i.v. anaesthetics on human
developing neocortex in vitro. J Neurophysiol. 2008;100:609–619. brain sodium channels. Br J Anaesth. 1993;71:15–24.
8. Tyzio R, Minlebaev M, Rheims S, et al. Postnatal changes in somatic 33. Fujiwara N, Higashi H, Nishi S, et al. Changes in spontaneous firing
gamma-aminobutyric acid signalling in the rat hippocampus. Eur patterns of rat hippocampal neurones induced by volatile anaesthetics.
J Neurosci.. 2008;27:2515–2528. J Physiol. 1988;402:155–175.
9. Keita H, Henzel-Rouelle D, Dupont H, et al. Halothane and isoflurane 34. Urban BW. Differential effects of gaseous and volatile anaesthetics on
increase spontaneous but reduce the N-methyl-D-aspartate–evoked sodium and potassium channels. Br J Anaesth. 1993;71:25–38.
dopamine release in rat striatal slices: evidence for direct presynaptic 35. Catterall WA. Structure and function of voltage-gated ion channels. Annu
effects. Anesthesiology. 1999;91:1788–1797. Rev Biochem. 1995;64:493–531.
10. Ortells MO, Lunt GG. Evolutionary history of the ligand-gated ion- 36. Yu FH, Catterall WA. The VGL-chanome: a protein superfamily spe-
channel superfamily of receptors. Trends Neurosci. 1995;18:121–127. cialized for electrical signaling and ionic homeostasis. Sci STKE. 2004;
11. Dingledine R, Borges K, Bowie D, et al. The glutamate receptor ion 253:re15.
channels. Pharmacol Rev. 1999;51:7–61. 37. Schlame M, Hemmings HC Jr. Inhibition by volatile anesthetics of
12. Tomlin SL, Jenkins A, Lieb WR, et al. Stereoselective effects of etomidate endogenous glutamate release from synaptosomes by a presynaptic
optical isomers on gamma-aminobutyric acid type A receptors and mechanism. Anesthesiology. 1995;82:1406–1416.
animals. Anesthesiology. 1998;88:708–717. 38. Westphalen RI, Hemmings HC Jr. Selective depression by general
13. Bai D, Pennefather PS, MacDonald JF, et al. The general anesthetic anesthetics of glutamate versus GABA release from isolated cortical nerve
propofol slows deactivation and desensitization of GABA(A) receptors. terminals. J Pharmacol Exp Ther. 2003;304:1188–1196.
J Neurosci. 1999;19:10635–10646. 39. Ouyang W, Hemmings HC Jr. Depression by isoflurane of the action
14. Franks NP. Molecular targets underlying general anaesthesia. Br potential and underlying voltage-gated ion currents in isolated rat
J Pharmacol. 2006;147(Suppl 1):S72–S81. neurohypophysial nerve terminals. J Pharmacol Exp Ther. 2005;312:
15. Jevtovic-Todorovic V, Todorovic SM, Mennerick S, et al. Nitrous oxide 801–808.
(laughing gas) is an NMDA antagonist neuroprotectant and neurotoxin. 40. Ouyang W, Wang G, Hemmings HC Jr. Isoflurane and propofol inhibit
Nat Med. 1998;4:460–463. voltage-gated sodium channels in isolated rat neurohypophysial nerve
16. Raines DE, Claycomb RJ, Scheller M, et al. Nonhalogenated alkane terminals. Mol Pharmacol. 2003;64:373–381.
anesthetics fail to potentiate agonist actions on two ligand-gated ion 41. Wu XS, Sun JY, Evers AS, et al. Isoflurane inhibits transmitter release and
channels. Anesthesiology. 2001;95:470–477. the presynaptic action potential. Anesthesiology. 2004;100:663–670.
42. Jurd R, Arras M, Lambert S, et al. General anesthetic actions in vivo for inhibitory avoidance learning in rats. Anesthesiology. 2001;95:
strongly attenuated by a point mutation in the GABA(A) receptor beta3 708–715.
subunit. FASEB J. 2003;17:250–252. 54. Ranft A, Kurz J, Deuringer M, et al. Isoflurane modulates glutamatergic
43. Sonner JM, Zhang U, Stabernack C, et al. GABA(A) receptor blockade and GABAergic neurotransmission in the amygdala. Eur J Neurosci.
antagonizes the immobilizing action of propofol but not ketamine or 2004;20:1276–1280.
isoflurane in a dose-related manner. Anesth Analg. 2003;96:706–712. 55. Pleym H, Spigset O, Kharasch ED, et al. Gender differences in drug
44. Reynolds DS, Rosahl TW, Cirone J, et al. Sedation and anesthesia medi- effects: implications for anesthesiologists. Acta Anaesthesiol Scand. 2003;
ated by distinct GABA(A) receptor isoforms. J Neurosci. 2003;23:8608– 47:241–259.
8617. 56. Palmer SN, Giesecke NM, Body SC, et al. Pharmacogenetics of anesthetic
45. Grasshoff C, Rudolph U, Antkowiak B. Molecular and systemic mecha- and analgesic agents. Anesthesiology. 2005;102:663–671.
nisms of general anaesthesia: the “multi-site and multiple mechanisms” 57. Bertilsson L. Geographical/interracial differences in polymorphic drug
concept. Curr Opin Anaesthesiol. 2005;18:386–391. oxidation. Current state of knowledge of cytochromes P450 (CYP) 2D6
46. Hentschke H, Schwarz C, Antkowiak B. Neocortex is the major target of and 2C19. Clin Pharmacokinet. 1995;29:192–209.
sedative concentrations of volatile anaesthetics: strong depression of firing 58. Goh BC, Lee SC, Wang LZ, et al. Explaining interindividual variability of
rates and increase of GABAA receptor-mediated inhibition. Eur J docetaxel pharmacokinetics and pharmacodynamics in Asians through
Neurosci. 2005;21:93–102. phenotyping and genotyping strategies. J Clin Oncol. 2002;20:3683–3690.
47. Heinke W, Fiebach CJ, Schwarzbauer C, et al. Sequential effects of 59. Qin XP, Xie HG, Wang X, et al. Effect of the gene dosage of Cgamma
propofol on functional brain activation induced by auditory language P2C19 on diazepam metabolism in Chinese subjects. Clin Pharmacol
processing: an event-related functional magnetic resonance imaging Ther. 1999;66:642–646.
study. Br J Anaesth. 2004;92:641–650. 60. Shih PS, Huang JD. Pharmacokinetics of midazolam and 1⬘-hydroxy-
48. Rudolph U, Crestani F, Benke D, et al. Benzodiazepine actions mediated midazolam in Chinese with different CYP3A5 genotypes. Drug Metab
by specific gamma-aminobutyric acid(A) receptor subtypes. Nature. Dispos. 2002;30:1491–1496.
1999;401:796–800. 61. Wandel C, Witte JS, Hall JM, et al. CYP3A activity in African American
49. Mohler H, Fritschy JM, Rudolph U. A new benzodiazepine pharmacology. and European American men: population differences and functional
J Pharmacol Exp Ther. 2002;300:2–8. effect of the CYP3A4*1B5’-promoter region polymorphism. Clin Phar-
50. Pasternak T, Greenlee MW. Working memory in primate sensory systems. macol Ther. 2000;68:82–91.
Nat Rev Neurosci. 2005;6:97–107. 62. Girard T, Urwyler A, Censier K, et al. Genotype-phenotype comparison
51. Caraiscos VB, Newell JG, You-Ten KE, et al. Selective enhancement of of the Swiss malignant hyperthermia population. Hum Mutat. 2001;18:
tonic GABAergic inhibition in murine hippocampal neurons by low 357–358.
concentrations of the volatile anesthetic isoflurane. J Neurosci. 2004;24: 63. Stewart SL, Hogan K, Rosenberg H, et al. Identification of the Arg1086His
8454–8458. mutation in the alpha subunit of the voltage-dependent calcium channel
52. Alkire MT, Nathan SV. Does the amygdala mediate anesthetic-induced (CACNA1S) in a North American family with malignant hyperthermia.
amnesia? Basolateral amygdala lesions block sevoflurane-induced Clin Genet. 2001;59:178–184.
amnesia. Anesthesiology. 2005;102:754–760. 64. Nakahiro M, Yeh JZ, Brunner E, et al. General anesthetics modulate
53. Alkire MT, Vazdarjanova A, Dickinson-Anson H, et al. Lesions of GABA receptor channel complex in rat dorsal root ganglion neurons.
the basolateral amygdala complex block propofol-induced amnesia FASEB J. 1989;3:1850–1854.
Nitrous Oxide 20
Conor McDonnell C H A P T E R
INTRODUCTION PHYSICAL PROPERTIES OF N2O

Joseph Priestly first synthesized nitrous oxide (N2O) in 1772 while N2O is a sweet-smelling, colorless gas that is nonflammable
experimenting with a new device of his own invention that but supports combustion. Other properties are shown in Table
allowed him to collect gases over mercury; this in the same year he 20–1.
was elected to the French Academy of Sciences.1 The psychotropic
effects of N2O were first appreciated and publicized in 1799
by Humphrey Davy.2 His recommendations for private and N2O as an Anesthetic Agent
recreational use of N2O were immediately taken up by, among N2O, along with sevoflurane and isoflurane, remains one of the
others, Samuel Coleridge. However, his observation that “nitrous most widely used agents in pediatric anesthesia today. It has
oxide appears capable of destroying physical pain and it may a rapid onset and offset of action, but a low anesthetic potency
probably be used with advantage during surgical operations” went with a minimum alveolar partial pressure of 110 kPa (minimum
unheeded for some time. In 1844, the American dentist Horace alveolar concentration [MAC] of 104% at sea level). Therefore, as
Wells attended a lecture by Garner Colton on chemical pheno- well as the need to supply oxygen, it cannot be administered under
mena, and the next day, Wells inhaled N2O gas administered by atmospheric conditions as the sole agent to maintain anesthesia.
Colton and had an aching third molar tooth painlessly extracted. However, because of its analgesic properties and its ability to
This was the first operation performed under N2O inhalation decrease the required partial pressures of volatile inhaled agents
anesthesia. Although some public demonstrations around this (and, therefore, the cardiovascular depression that occurs with
time were unsuccessful, the use of N2O as a surgical analgesic took some volatile agents), N2O remains in common use as a “carrier
root with the advent of inhaled anesthesia and enjoyed a long and gas.” N2O is a low-cost agent and its use can further decrease costs
seemingly innocuous period of use until the mid to latter 20th associated with increased use of more potent volatile agents. N2O
century. The first clear association of N2O with morbidity came also speeds uptake of these more potent inhaled agents.
from a report in 1956 describing the development of aplastic The relative insolubility of N2O results in the expansion of gas-
anemia in patients treated for days with inhaled N2O.3 N2O still containing spaces because it is 34 times more soluble in blood
enjoys widespread use in anesthesia, dentistry, obstetrics, and (blood/gas partition coefficient of 0.47) than it is in nitrogen
emergency medicine. (blood/gas partition coefficient of 0.014). Previous work has
demonstrated that alveolar N2O concentrations increase faster in
infants and children than in adults.4 This property, in addition to
PRODUCTION AND STORAGE the fact that N2O usually composes a large fraction of the inspired
gas mixture, results in the rapid egress of N2O from alveoli to
N2O is produced commercially by heating ammonium nitrate at blood during induction of inhaled anesthesia (Figure 20–1). The
240°C. Water vapor and impurities, which include higher oxides resulting concentration of remaining alveolar gases increases the
of nitrogen, ammonia, and nitric acid, are subsequently removed
by passing through a series of scrubbers and washers. N2O is
stored in French-blue cylinders and pressurized to approximately TABLE 20-1. Physical and Anesthetic Properties
4400 kPa. N2O is usually stored below its critical temperature and of Nitrous Oxide
so is in simultaneous liquid and vapor phases. These cylinders Property Value
have a filling ratio of 0.75 in temperate countries and 0.67 in
tropical climates. Unlike cylinders filled with pressurized gas, Molecular weight 44
cylinder pressure remains effectively constant until all liquid N2O Melting point, °C –90.8
is vaporized. Most institutions use a pipeline supply of N2O Boiling point, °C –88.5
comprising a central bank of large cylinders, reserve banks, and a Critical remperature, °C 36.5
pipeline to appropriate sites within the hospital. In addition, all Blood/gas partition coefficent 0.47
modern anesthesia machines are equipped to supply N2O but Oil/gas partition coefficient 1.4
continue to hold reserve cylinders on the back of the machine MAC, % 105
should the central pipeline supply fail. MAC = minimum alveolar concentration.
Cardiovascular
N2O’s hemodynamic effects are inconsistent. Administered as a
40% mixture in oxygen, it can decrease cardiac output.13 When it
is added to halothane in healthy volunteers, N2O lowers cardiac
output but stimulates the sympathetic nervous system, therefore
resulting in increased arterial pressures because of increased
systemic vascular resistance.14 N2O administered to patients with
heart disease or compromised cardiac output (especially when
combined with opioids) can result in hypotension and decreased
cardiac output.15,16 Pulmonary vascular resistance is increased
because of constriction of the pulmonary vascular smooth muscle.
Figure 20-1. Nitrous oxide (N2O) equilibration curves. The This may lead to an increase in right atrial pressure, and as a
10% adult curve was taken from data reported by Salanitre et consequence, N2O is usually avoided in the setting of pulmonary
al.4; the 70% adult curve was obtained by recalculation of data hypertension. However, studies in infants have not demonstrated
from Severinghaus. Solid circles, infants 0–6 months, 60% N2O; additional increases in pulmonary vascular resistance when N2O
open circles, children 1–5 years, 60% N2O; solid squares, adults, is administered.17
10% N2O; open squares, adults, 70% N2O. FE = expired gas; FI = Increased vascular resistance results in decreased renal and
inspired gas. (source: Salanitre E, Rackow H. The pulmonary hepatic blood flow. The addition of N2O to halothane anesthesia
exchange of nitrous oxide and halothane in infants and children. can cause further splanchnic blood flow decreases.18
Anesthesiology 1969;30(4):388–94 with permission)
uptake of volatile agent into the blood, accelerating the onset of Central Nervous System
anesthesia. N2O increases cerebral blood flow, cerebral metabolic rate for
N2O has an affinity for many different receptor types.5 It has oxygen (CMRO2), and intracranial pressure.19 Likely, the increase
an inhibitory action on the N-methyl-D-aspartate (NMDA) re- in cerebral metabolism rather than any direct vasodilatory effect
ceptor and confers some neuroprotection from excessive NMDA accounts for the increase in cerebral blood flow. N2O added to
receptor activation and resulting glutamate release.6 N2O has isoflurane is a potent vasodilator, and this effect increases in a
demonstrated stimulatory activity at dopaminergic, α1 and α2 dose-dependent manner.20 Although sevoflurane at a MAC of 1.2
adrenergic, and opioid receptors.7–9 decreases cerebral blood flow velocity compared with awake
N2O is eliminated unchanged from the body almost entirely parameters, the addition of N2O increases flow toward the values
through the lungs, although a small amount diffuses through the obtained in the awake state.21 Cerebral blood flow velocity cor-
skin. A very small contribution is made to elimination through relates reasonably well with total cerebral blood flow and is
reductive metabolism by anaerobic bacteria in the gut. increased by N2O in awake subjects.22 Neither the addition nor the
removal of N2O in children receiving 1 age-adjusted MAC of
desflurane altered the cerebral blood flow velocity.23 N2O was even
THE EFFECTS OF N2O ON demonstrated to increase cerebral blood flow velocity and CMRO2
PHYSIOLOGIC SYSTEMS in the presence of electroencephalographic silence established by
propofol infusion.24 Addition of N2O to the inspired gas mixture
Respiratory after induction of hypocapnia reversed those decreases in cerebral
N2O causes a decrease in tidal volume and an increase in respira- blood flow associated with hyperventilation. This would suggest
tory rate, usually demonstrating maintenance of minute volume. that administration of N2O may offset the beneficial effects of
The increase in respiratory rate is caused by central nervous hyperventilation-induced hypocapnia in patients with intracranial
system activation. N2O-induced respiratory depression causes pathology.25
elevation of alveolar carbon dioxide in a dose-related manner.10,11 N2O may also exert direct effects on neural tissue. In rat
N2O also leads to reductions in the ventilation response to hypoxia hippocampal slices, exposure to N2O impaired electrophysiolo-
and hypercapnia. Although N2O is less of a ventilation depres- gic recovery after severe hypoxia.26 Although administration
sant than the potent volatile agents, it is not free of significant of isoflurane protected against microtubule-associated protein
effect. Inhalation of N2O also depresses tracheal mucociliary flow degradation during ischemic insult to the brain, N2O significantly
and neutrophil chemotaxis.12 At low concentrations, N2O has no decreased this protective effect, leading to a recommendation
effect on hypoxic pulmonary vasoconstriction; at higher N2O that N2O be discontinued should accidental cerebral ischemia
concentrations, hypoxic pulmonary vasoconstriction may be occur during anesthesia.27 The neurotoxic potential of N2O
impaired. was further described in another study that reported that these
The discontinuation of N2O at the end of anesthesia results in effects could be prevented by drugs that enhance GABAergic
a rapid outpouring of insoluble N2O from pulmonary arterial inhibition. The authors attributed the favorable safety record of
blood into the alveoli. This causes volume displacement of alveo- N2O to the low concentrations used and the fact that it is usually
lar gas, and high partial pressures of N2O can lower arterial combined with anesthetic agents that counteract its neurotoxic
oxygen pressures (PaO2). This is commonly referred to as diffusion potential.28
hypoxia but, in the absence of significant ventilation-perfusion Anesthesia that includes N2O administration trends toward
mismatch or shunting, is unlikely to be of important clinical increasing the voltage and decreasing the frequency of the electro-
relevance. encephalogram (EEG). N2O decreases the amplitude of brainstem
CHAPTER 20 ■ Nitrous Oxide 319
auditory-, cortical somatosensory-, and visual-evoked potentials amount of gas in the bowel. In the presence of obstruction, bowel
as well as increasing the latency of visual-evoked potentials. may contain many times more gas than normal (normal content
These factors should be considered when encountering not is ~100 mL). The greater the amount of gas contained in the bowel,
only patients for neurosurgical procedures but also for patients the greater the potential expansion and distention in the presence
with acute head injuries or the possibility of raised intracranial of N2O. (2) The duration of administration. At approximately 100
pressure present during nonneurosurgical procedures. minutes of N2O administration, bowel gas cavity will have
increased by 75 to 100%. (3) If the alveolar concentration of N2O
is 50%, the maximum possible increase in bowel gas is twofold. At
Analgesic and Sedative Effects an alveolar N2O concentration of 80%, maximum increase in
N2O demonstrates analgesic actions thought to be mediated by bowel gas approaches fivefold.
activation of opioid receptors in the periaqueductal gray matter The administration of N2O for a prolonged time during bowel
of the midbrain.5 This results in modulation of nociceptive or laparoscopic surgery results in operative difficulties for sur-
pathways through the release of norepinephrine and activation of geons and difficulties with abdominal closure. This may result in
α2 adrenoceptors in the dorsal horn of the spinal cord. This may more postoperative respiratory problems for the patient and likely
help explain the acute tolerance that develops to N2O as a con- results in prolonged hospitalization.30,35 In the patient with
sequence of central opioid peptide depletion. suspected bowel obstruction or compromised splanchnic perfu-
N2O provides excellent analgesia for acutely painful procedures sion, the higher gas content of the bowel accelerates the degree to
such as fracture manipulation and dressings or cast changes.29 N2O which N2O-induced expansion may occur. This can proceed to
may also have an expanding role in the emergency room or in the point of bowel ischemia, necrosis, and perforation.
preparation for positioning for radiologic procedures. N2O is also
used in the operating room as supplementation to regional or local Nausea and Vomiting
anesthetic techniques.
N2O was first used as an analgesic in the obstetric setting in Postoperative nausea and vomiting is a significant source of
1881 by Stanislaw Klikovich who administered premixed N2O patient discomfort and may result in unanticipated hospital
80% in oxygen. N2O can provide adequate labor analgesia for admission. The contribution of N2O has been extensively exami-
parturients, but coordination of administration with contractions ned and debated.36–43 The mechanism for any emetogenic potential
may prove difficult. Maternal side effects include nausea, dizzi- of N2O is not fully elucidated but is thought to be related to
ness, paraesthesia, and dry mouth. changes in middle ear pressures, bowel distention, decreased lower
esophageal sphincter pressure, and activation of dopaminergic
receptors. Although pediatric studies in the past have failed to
Adverse Effects demonstrate significant increases in the incidence of postoperative
nausea and vomiting associated with the use of N2O,36–38 more
Gas-Filled Spaces recent studies have refuted these findings and demonstrated an
N2O is 34 times more soluble in blood than nitrogen.30 Therefore, increased incidence.39,40 N2O may even reverse the antiemetic
N2O transported through the blood stream will enter gas- effects of continuous propofol infusion.40
containing cavities significantly faster than the nitrogen in those Adult evidence review concluded that 24 of 27 published
cavities can be removed. This results in pressure-volume changes studies demonstrate an increase in postoperative nausea and
that can result in significant patient discomfort and morbidity. vomiting attributable to the use of N2O.41 Possibly because post-
Expansion of the middle ear, especially during middle ear surgery, operative nausea and vomiting is such a multifactorial entity, the
can result in disruption of grafts and/or the ossicular chain.31 absolute effects of N2O differed per publication relative to the type
Tympanic membrane rupture during anesthesia with N2O has of surgery, patient population, and patient characteristics under
been reported.32 In certain ophthalmic surgeries, gas bubble review. A meta-analysis published that same year (1996) con-
tamponade is employed. Diffusion of N2O into this space results cluded that there was a 28% risk reduction to be observed by
in increased intraocular pressure, although the overall effects on omitting the use of N2O.42 This trend revealed a greater benefit in
outcome of surgery are not clear.33 the female population but a lesser effect in patients undergoing
More rapid and serious expansion can occur in the presence of abdominal surgery.
pneumothorax or lung bullae with resultant enlargement of If it were simply a choice between decreasing the incidence of
ventilation-perfusion inequality and development of hemodyna- postoperative nausea and vomiting by omitting N2O versus the
mic instability if the situation expands toward tension.30 potential risk for increased incidence of awareness, the decision
Certain surgeries carry an attendant risk of acute air embolism. on whether or not to employ N2O could not be equally applied to
Administration of N2O during such surgeries results in a more all patient populations or surgical procedures.43
rapid expansion of air emboli entering the circulation, and this
increases the risks and morbidity associated with such intraopera-
tive complications.34 Metabolic Derangements
N2O should be avoided in patients undergoing treatment for Prolonged administration of N2O results in inhibition of methio-
decompression sickness because rapid gas expansion of intra- nine synthetase.44 This results in megaloblastic changes, growth
vascular nitrogen containing bubbles will result in worsening of retardation, psychomotor retardation, and neurologic problems
symptoms and increased morbidity. similar to subacute combined degeneration of the spinal cord. It
The administration of N2O during bowel or laparoscopic sur- also interferes with DNA synthesis in both leukocytes and
gery can cause significant distention of the gas-containing bowel.30 erythrocytes.45 In 1956, it was reported that several patients se-
The amount of distention depends on three factors: (1) The dated with N2O for some days developed aplastic anemia.46 Having
isolated the use of N2O as the likely culprit, it was prospectively would likely be prudent to avoid N2O administration. With
examined by the authors in a 10-year-old boy. On the fourth day methylmalonic acidemia, patients can acutely develop severe
of 50% N2O administration, the boy developed granulocytopenia. metabolic acidosis, ketosis, and hyperammonemia at times of
N2O was discontinued but thrombocytopenia developed over increased protein catabolism. It has previously been demonstrated
subsequent days. Bone marrow biopsy demonstrated pernicious that 24 hours of exposure to N2O increases urinary methylmalonic
anemia with megaloblastic changes. Similar findings were re- acid levels threefold in healthy patients,53 and it would also seem
ported in cardiac surgical patients receiving 50% N2O for 24 hours prudent to avoid the use of N2O in patients with known methyl-
during and after surgery.47 malonic acidemia.
Inhibition of methionine synthetase by N2O was first demon- Case reports of sensory polyneuropathies resulting from
strated in rats. More recently, it has been demonstrated that recreational use and/or environmental exposure with N2O were
4 hours of exposure to 70% N2O in the equivalent of late middle- published in the 1970s.54,55 N2O irreversibly oxidizes the cobalt
aged (18-mo-old) rats produced lasting memory impairment that atom of vitamin B12, transferring it from the active to the inactive
was preceded by a reduction in cerebral cortical methionine state. A survey of 18,000 dentists and dental assistants demonst-
synthetase activity.48 Enzyme activity in patients with pre-existing rated that, with N2O exposure, there was a gender-independent
methionine synthetase deficiency is presumably not worsened by association of neurologic findings similar to those observed with
the administration of N2O; however, the resultant superimposed pernicious anemia.56 An 8-month-old baby developed bone mar-
inhibition of vitamin B12–mediated related metabolic pathways is row failure and severe neuropathy following 80 minutes of ex-
not yet known and the implications of brief exposures of clinically posure to N2O.57 It was subsequently discovered that the mother
relevant levels of N2O in children with methionine synthetase was vitamin B12–deficient and had been breast feeding the baby
deficiency remain unknown. with no other dietary supplementation. Similar nutritional-
Homocysteinuria is the second most common disease of amino induced vitamin B12 deficiencies have been described in reports
acid metabolism. In 2003, a case report described a fatal outcome of N2O-induced bone marrow failure and neuropathy.58
in a 3-month-old boy with type III homocysteinuria who had It would appear prudent at present to omit N2O when anes-
twice been exposed to N2O in a 4-day period.49 Death was pre- thetizing patients with known metabolic conditions, dietary
sumed to have resulted from N2O-induced methionine synthetase restrictions on vitamin B12 intake, or as an agent for prolonged
inhibition that led to methionine deficiency in the setting of sedation.
tetrahydrofolate reductase deficiency associated with the genetic
defect (Figure 20–2). Another type III patient developed myelo- Teratogenicity
pathy and macrocytic anemia after double exposure to N2O over There is strong evidence that prolonged exposure to N2O is tera-
a 10-week period.50 The inhibition of methionine synthase may togenic in mammalian models. Mechanism is likely multifactorial
also result in an increase in plasma homocysteine concentrations, rather than a simple consequence of impaired DNA synthesis. In
because the enzyme aids in the conversion of homocysteine to animal models, ␣1 adrenoceptor antagonists partially prevent N2O
methionine, and short-term exposure to N2O has demonstrated teratogenesis.59 Studies in pregnant patients receiving N2O early
significant increases in plasma homocysteine.51 Although hyper- in pregnancy have not demonstrated increased fetal loss or
homocysteinemia is an independent risk factor for coronary artery incidence of fetal abnormalities.60,61 However, exposure in the
and cerebrovascular disease, the significance of this observation in workplace is more controversial, and it is likely that workplace
the perioperative period is currently unknown.52 If it is known that exposure to N2O has an adverse effect on the outcome of pre-
a patient or family member has elevated homocysteine concentra- gnancy with an increased risk of spontaneous abortion among
tions in concert with decreased methionine concentrations, it women working with N2O for 3 or more hours per week in the
Figure 20-2. Metabolic pathways affected

by N2O. Hatched bars, points of inhibitio
by N2O; roman numerals, the three types
of homocysteinuria. MTHFR = methylene
tetrahydrofolate reductase. (Source:
Baum V. When nitrous oxide is no laughing
matter: nitrous oxide and pediatric anesthe-
sia. Pediatric Anesthesia 2007;17:824–30
with permission)
CHAPTER 20 ■ Nitrous Oxide 321
absence of scavenging equipment.62 Current wisdom states that, safer alternative options and to maintain a high profile in the
providing anesthetic gases are scavenged and the levels of ambient development of sedation protocols and guidelines designed for use
N2O are maintained below 100 ppm, the safety of those with outside the operating room.
long-term occupational exposure to N2O is not compromised. In
some patients undergoing resection of malignant tumors, blood
L-methionine concentration was lower and blood amino acid REFERENCES
significantly altered by the administration of N2O.63 Recommen- 1. Smith, W. D. A. (ed) Under the influence: a history of nitrous oxide and
dations from that publication were that consideration should be oxygen anaesthesia. London, Scientific and Medical Division, Macmillan
made for avoiding the use of N2O in patients with cancer. Publishers Ltd, 1982, pp. 188.
2. Rupani, G., de Wit, H., Zacny, J.P. Subjective and psychomotor effects of
nitrous oxide in healthy humans. In: Davy H (ed). Researches, chemical
and philosophical; chiefly concerning nitrous oxide, or dephlogisticated
RECREATIONAL USE nitrous air, and its respiration. London, Briggs and Cottle, 1800, p. 388–400.
N2O has remained a potential drug of abuse since its introduction 3. Lassen HCA, Henricksen E, Neukirch F, et al. Severe bone-marrow depres-
sion after prolonged nitrous-oxide anesthesia. Lancet. 1956;1:527–530.
to society in the early 1800s. When inhaled in high concentrations, 4. Salanitre E, Rackow H. The pulmonary exchange of nitrous oxide and
it produces an intense “high” with sensations of flying and floating. halothane in infants and children. Anesthesiology. 1969;30:388–394.
However, this practice has many adverse effects including suba- 5. Maze MJ, Fujinaga F. Recent advances in understanding the actions and
cute combined degeneration of the cord from chronic abuse, toxicity of nitrous oxide. Anaesthesia. 2000;55:311–314.
6. Jevtovi–Todorovi V, Todorovi SM, Mennerick S, et al. Nitrous oxide
hypoxic injury owing to self-administration of hypoxic mixtures, (laughing gas) is an NMDA antagonist, neuroprotectant and neurotoxin.
and frostbite of the vocal cords, which has been reported following Nat Med. 1998;4:460–463.
inhalation direct from N2O cylinders. 7. Ben-Ari Y, Kelly JS. Dopamine evoked inhibition of single cells of the
feline putamen and basolateral amygdala. J Physiol. 1976;256:1–21.
8. Orii R, Ohashi Y, Guo T, et al. Evidence for the involvement of spinal cord
ENVIRONMENTAL CONCERNS alpha1 adrenoceptors in nitrous oxide-induced antinociceptive effects in
Fischer rats. Anesthesiology. 2002;97:1458–1465.
Like carbon dioxide, methane, and perfluorocarbons, N2O is a 9. Fang F, Guo TZ, Davies MF, Maze M. Opiate receptors in the periaque-
greenhouse gas. N2O is approximately 300 times more effective ductal gray mediate analgesic effect of nitrous oxide in rats. Eur J
Pharmacol. 1997;336:137–141.
than carbon dioxide at trapping heat and contributes to global 10. Murat J, Saint-Maurice JP, Beydon L, et al. Respiratory effects of nitrous
warming. However, N2O accounts for less than 5% of total oxide during isoflurane anesthesia in children. Br J Anaesth. 1986;58:1122.
greenhouse gases. The vast majority of environmental N2O is 11. Wren W, Meeke R, Davenport J, et al. Effects of nitrous oxide on the
produced by the burning of fossil fuels, nitrogen-based fertilizers respiratory pattern of spontaneously breathing children during anaes-
in agricultural practice, and sewage management programs. The thesia. Br J Anaesth. 1984;56:881.
12. Hill GE, English JB, Stanley TH, et al. Nitrous oxide and neutrophil
contribution of anesthesia to the quantities of N2O in the atmos- chemotaxis in man. Br J Anaesth. 1978;50:555–558.
phere are likely ever-declining with the advent of scavenging, low- 13. Eisele J, Smith N. Cardiovascular effects of 40 percent nitrous oxide in
flow inhalational anesthesia, and total intravenous anesthesia. man. Anesth Analg. 1972;51:956.
14. Smith N, Eger E II, Stoelting R. The cardiovascular and sympathomimetic
responses to the addition of nitrous oxide to halothane in man. Anesthe-
EMERGING RESEARCH CONCERNS siology. 1970;32:410.
15. Moffitt E, Sethna D, Gary R, et al. Nitrous oxide added to halothane
As a weak anesthetic, N2O is often administered as a 70% or higher reduces coronary flow and myocardial oxygen consumption in patients
portion of the inspired gas mixture. This limits the inspired con- with coronary disease. Can Anaesthiol Soc J. 1983;30:5.
16. Reiz S. Nitrous oxide augments the systemic and coronary haemodynamic
centration of oxygen that can be delivered. In a recently published
effects of isoflurane in patients with ischemic heart disease. Acta Anaes-
study examining the effects of N2O in the adult postoperative thesiol Scand. 1983;77:464.
population, major postoperative complications including fever, 17. Hickey P, Hansen D, Stratford M, et al. Pulmonary and systemic hemo-
wound infection, pneumonia, pulmonary atelectasis, and severe dynamic effects of nitrous oxide in infants with normal and elevated
nausea and vomiting were significantly decreased if N2O was pulmonary vascular resistance. Anesthesiology. 1986;65:374.
omitted from the anaesthetic.64 This did not translate into de- 18. Seyde W, Ellis J, Longnecker D. The addition of nitrous oxide to halothane
decreases renal and splanchnic flow and increases cerebral flow in rats. Br
creased hospital stay for these patients, and the question remains J Anaesth. 1986;58:63.
whether it was the absence of N2O or the increase in inspired 19. Misfeldt BB, Jorgensen PB, Rishoj M. The effect of nitrous oxide and
oxygen that resulted in decreased postoperative complications. halothane upon the intracranial pressure in hypocapnic patients with
intracranial disorders. Br J Anaesth. 1974;46:853–858.
20. Strebel S, Kaufmann M, Anselmi L, Schaeffer HG. Nitrous oxide is a potent
CONCLUSIONS cerebrovasodilator in humans when added to isoflurane. A transcranial
Doppler study. Acta Anaesthesiol Scand. 1995;39:653–658.
N2O has maintained longevity as an anesthetic agent for nearly 21. Cho S, Fujigaki T, Uchiyama Y, et al. Effects of sevoflurane with and
200 years. However, the low toxicity of modern agents, the effects without nitrous oxide on human cerebral circulation. Transcranial
Doppler study. Anesthesiology. 1996;85:755–760.
of N2O on bowel distention, nausea and vomiting, methionine 22. Matthew RJ, Wilson WH, Humphreys D, Lowe JV. Effect of nitrous oxide
synthetase, and teratogenicity as well as emerging evidence exa- on cerebral blood velocity while reclining and standing. Biol Psychiatr.
mining the effects of N2O on the immature brain, homocysteine 1997;41:979–984.
concentrations, and major postoperative complications are fast 23. Karsli C, Luginbuehl IA, Bissonnette B. The effect of nitrous oxide on
making an argument against the continued widespread use of cerebral blood flow velocity in children anaesthetised with desflurane.
Anaesthesia. 2003;58:24–27.
N2O. As more health care professionals and specialties seek to 24. Matta BF, Lam AM. Nitrous oxide increases cerebral blood flow velocity
provide sedation without formal anesthesiology training or super- during pharmacologically induced EEG silence in humans.J Neurosurg
vision, it is our responsibility as anesthesiologists to investigate Anesthesiol. 1995;7:89–93.
25. Watts D, Luney SR, Lee D, Gelb AW. Effect of nitrous oxide on cerebral 44. Deacon R, Lumb M, Perry J, et al. Selective inactivation of vitamin B12 in
blood flow velocity after induction of hypocapnia. J Neurosurg Anesthesiol. rats by nitrous oxide. Lancet. 1978;2:1023–1024.
1998;10:142–145. 45. Maze MJ, Fujinaga M. Recent advances in understanding the actions and
26. Amorim P, Chambers G, Cottrell J, Kass IS. Nitrous oxide impairs toxicity of nitrous oxide. Anaesthesia. 2000;55:311–314.
electrophysiologic recovery after severe hypoxia in rat hippocampal slices. 46. Lassen HCA, Henricksen E, Neukirch F, et al. Treatment of tetanus. Severe
Anesthesiology. 1997;87:642–651. bone marrow depression after prolonged nitrous-oxide anaesthesia.
27. Sugaya T, Kitani Y. Nitrous oxide attenuates the protective effect of iso- Lancet. 1956;1:527–530.
flurane on microtubule-associated protein 2 degradation during forebrain 47. Amess JAL, Rees GM, Burman JF, et al. Megaloblastic haemopoiesis in
ischemia in the rat. Brain Res Bull. 1997;44:307–309. patients receiving nitrous oxide. Lancet. 1978;2:339–342.
28. Jevtovic-Todorovic V, Todorovic SM, Mennerick S, et al. Nitrous oxide is 48. Culley DJ, Raghavan SV, Yukhananov R, et al. Nitrous oxide decreases
an NMDA antagonist, neuroprotectant and neurotoxin. Nat Med. 1998; cortical methionine synthase and produces lasting memory impairment
4:460–463. in rats [abstract]. Anesthesiology. 2006;105:A1182.
29. Annequin D, Carbajal R, Chauvin P, et al. Fixed 50% nitrous oxide oxygen 49. Selzer RB, Rosenblatt DS, Laxova R, et al. Adverse effect of nitrous oxide
mixture for painful procedures: a French survey. Pediatrics. 2000;105:47. in a child with 5,10-methylenetetrahydrofolate reductase deficiency. N
30. Eger EL III, Saidman LJ. Hazards of nitrous oxide in bowel obstruction Engl J Med. 2003;349:45–50.
and pneumothorax. Anesthesiology. 1965;26:61. 50. Lacassie H, Nazar C, Yonish B, et al. Reversible nitrous oxide myelopathy
31. Karabiyik L, Bozkirli F, Celebi H, Goksu N. Effect of nitrous oxide on and a polymorphism in the gene encoding 5,10 methylenetetrahydro-
middle ear pressure: a comparison between inhalational anaesthesia with folate reductase deficiency. Br J Anaesth. 2006;96:222–225.
nitrous oxide and TIVA. Eur J Anaesthesiol. 1996;13:27–32. 51. Baum VC. When nitrous oxide is no laughing matter: nitrous oxide and
32. Ohryn M. Tympanic membrane rupture following general anesthesia with pediatric anesthesia. Pediatr Anesth. 1997;17:824–830.
nitrous oxide: a case report. AANA J. 1995;63:42–44. 52. Badner NH, Drader K, Freeman D, Spence JD. The use of intraoperative
33. Briggs M, Wong D, Groenewald C, et al. The effect of anaesthesia on the nitrous oxide leads to postoperative increases in plasma homocysteine.
intraocular volume of the C3F8 gas bubble. Eye. 1997;11:47–52. Anesth Analg. 1998;87:711–713.
34. Nyarwaya JB, Pierre S, Mazoit JX, et al. Effects of carbon dioxide 53. Rask H, Olesen AS, Mortensen JZ, et al. N2O and urine methylmalonic
embolism with nitrous oxide in the inspired gas in piglets. Br J Anaesth. acid in humans. Scand J Haematol. 1983;31:45–48.
1996;76:428–434. 54. Layzer RB, Fishman RA, Schafer JA. Neuropathy following abuse of
35. Scheinin B, Lindgren L, Scheinin TM. Peri-operative nitrous oxide delays nitrous oxide. Neurology. 1978;28:504–506.
bowel function after colonic surgery. Br J Anaesth. 1990;64:154. 55. Layzer RB. Myeloneuropathy after prolonged exposure to nitrous oxide.
36. Splinter WM, Komocar L. Nitrous oxide does not increase vomiting after Lancet. 1978;2:1227–1230.
dental restorations in children. Anesth Analg. 1997;84:506–508. 56. Brodsky JB, Cohen EN, Brown BW, et al. Exposure to nitrous oxide and
37. Splinter WM, Roberts DJ, Rhine EJ, et al. Nitrous oxide does not in- neurologic disease among dental professionals. Anesth Analg. 1981;60:
crease vomiting in children after myringotomy. Can J Anaesth. 1995;42: 297–301.
274–276. 57. Felmet K, Robins B, Tilford D, et al. Acute neurologic decompensation
38. Pandit UA, Malviya S, Lewis IH. Vomiting after outpatient tonsillectomy in an infant with cobalamin deficiency exposed to nitrous oxide. J Pediatr.
and adenoidectomy in children: the role of nitrous oxide. Anesth Analg. 2000;137:427–428.
1995;80:230–233. 58. .McNeely JK, Buczulinski B, Rosner DR. Severe neurological impairment
39. Bloomfield E, Porembka D, Grimes-Rice M. Avoidance of nitrous oxide in an infant after nitrous oxide anaesthesia. Anesthesiology. 2000;93:
and increased isoflurane during alfentanil based anesthesia decreases the 1549–1550.
incidence of postoperative nausea. Anesth Prog. 1997;44:27–31. 59. Ohara A, Mashimo T, Zhang P, et al. A comparative study of the
40. Crawford MW, Lerman J, Sloan MH, et al. Recovery characteristics of antinociceptive action of xenon and nitrous oxide in rats. Anesth Analg.
propofol anaesthesia, with and without nitrous oxide: a comparison with 1997;85:931–936.
halothane/nitrous oxide anaesthesia in children. Paediatr Anaesth. 1998; 60. Aldridge LM, Tunstall ME. Nitrous oxide and the fetus. A review and the
8:49–54. results of a retrospective study of 175 cases of anaesthesia for insertion of
41. Hartung J. Twenty-four of twenty-seven studies show a greater incidence shirodkar suture. Br J Anaesth. 1986;58:1348–1356.
of emesis associated with nitrous oxide than with alternative anesthetics. 61. Crawford JS, Lewis M. Nitrous oxide in early human pregnancy.
Anesth Analg. 1996;83:114–116. Anaesthesia. 1986;41:900–905.
42. Divatia JV, Vaidya JS, Badwe RA, Hawaldar RW. Omission of nitrous 62. Rowland AS, Baird DD, Shore DL, et al. Nitrous oxide and spontaneous
oxide during anaesthesia reduces the incidence of postoperative nausea abortion in female dental assistants. Am J Epidemiol. 1995;141:531–538.
and vomiting. A meta-analysis. Anesthesiology. 1996;85:1055–1062. 63. Crespo ML, Gimenez A, Bas T, et al. Effect of nitrous oxide and propofol
43. Tramer M, Moore A, McQuay H. Meta-analytic comparison of prophylac- on amino acid metabolism in neoplastic patients. Nutr Cancer. 1997;27:
tic antiemetic efficacy for postoperative nausea and vomiting: propofol 80–83.
anaesthesia vs omitting nitrous oxide vs total i.v. anaesthesia with 64. Myles PS, Leslie K, Chan MTV, et al. Avoidance of nitrous oxide for
propofol. Br J Anaesth. 1996;76:186–193. patients undergoing major surgery. Anesthesiology. 2007;107:221–231.
Volatile Anesthetics 21
George D. Politis C H A P T E R
INTRODUCTION pharmacology, clinical aspects, and potential detrimental effects of

these extraordinary agents.
Inhalational agents have been the centerpiece of pediatric anes-
thesia from the time of the earliest known pediatric anesthetics
described in 1848 in the case logs of John Snow.1 The advent of PHYSICOCHEMICAL PROPERTIES
the easily titratable short-acting intravenous anesthetics, propofol OF VOLATILE ANESTHETICS
and remifentanil, has offered pediatric anesthetists an attractive
option to volatile anesthesia. Nonetheless, volatile anesthetics will Commercially available modern potent inhalational agents, with
maintain center stage for the foreseeable future owing to their ease the exception of halothane, are based on either a methyl ethyl or
of use, low variability in response, lack of development of tole- a methyl isopropyl halogenated ether skeleton (Table 21–1).
rance, low frequency of organ toxicity, and rapid recovery profiles. Enflurane (CHF2-O-CF2-CHClF), isoflurane (CHF2-O-CHCl-
They allow induction without prior placement of an intravenous CF3), and desflurane (CHF2-O-CHF-CF3) are methyl ethyl ethers,
line, are easily titrated, and satisfy the basic requirements of and sevoflurane (CH2F-O-CH-(CF3)2) is a methyl isopropyl ether.
general anesthesia: provision of immobility, unconsciousness, Halothane is a polyhalogenated alkane (CH3CHBrCl).
amnesia, muscle relaxation, and blunting of autonomic reflexes. Numerous similarities exist in these molecules, as can readily
The two newest volatile anesthetics, sevoflurane and desflurane, be seen from the diagrams in Table 21–1. For example, isoflurane
have gained favor owing to several advantages over their predeces- and enflurane are stereoisomers, meaning that they share the same
sors, although only sevoflurane has achieved widespread popula- chemical formula and bond structure but the geometric posi-
rity in pediatric anesthesia. In fact, sevoflurane has now displaced tion of the atoms differs in space. In addition, desflurane and
halothane as the dominant anesthetic for children, after halothane isoflurane are identical molecules except for a difference of one
maintained that role for nearly a half a century.2 The key role of halogen atom on the alpha carbon; desflurane has a fluoride and
volatile anesthetics in pediatric anesthesia makes it imperative for isoflurane has a chloride in that position. These seemingly minor
the pediatric anesthetist to command a working knowledge of the molecular differences lead to substantial changes in the physical,
TABLE 21-1. Structures, Physical Properties, and Volatile Anesthetic Blood/Gas and Tissue/Blood Solubilities (λ)at 37°C
Halothane Enflurane Isoflurane Sevoflurane Desflurane
Chemical structure F H F F Cl F Cl F F CF3 F F F F
| | | | | | | | | | | | | |
F − C − C − Br H − C − O − C − C − H H − C − O − C − C − F F − C − O − C − C − F H − C − O − C − C − F
| | | | | | | | | | | | | |
F Cl F F F F H F H H F H H F
Molecular weight 197.4 184.5 184.5 200.1 168
Boiling point, °C 50.2 56.5 48.5 58.6 23.5
Vapor pressure, mmHg 244 172 240 185 664
Metabolized, % 20 2.4 0.2 5 0.02
λblood/gasadults 2.5 1.9 1.4 0.66a 0.42
λblood/gasneonates 2.1 1.8 1.2 0.66a —
λbrain/bloodadults 1.9 1.3 1.7 1.7 1.3
λbrain/bloodneonates 1.5 0.9 1.3 — —
λmuscle/bloodadults 2.3 1.6 2.1 3.1 2.0
λmuscle/bloodneonates 1.3 0.8 1.1 — —
λfat/bloodadults 67 46 56 48 27
Data for λblood/gas for sevoflurane comes from reference 19.
a
Metabolized percentages are from references 278 to 282.

All pediatric and adult (refers to middle-aged adults) solubility data for halothane, enflurane, and isoflurane come from reference 21.
All solubility data for sevoflurane and desfluranee are from reference 283 except where indicated.
pharmacokinetic, and pharmacodynamic properties of these

agents. For example, Table 21–1 shows that there are considerable
differences in lipid solubility, and anesthetic potency increases
with increasing lipid solubility.
Enflurane, halothane, desflurane, and isoflurane are chiral
molecules, meaning that they have an asymmetrical center, in
which a carbon atom is attached to four different substitution
groups. These agents are marketed as racemic mixtures of the
R and S enantiomeric mirror images. The S- form of isoflurane has
been shown to have as much as 53% increased potency over the
R- form.3 In addition, the R- form of halothane has been found to
have increased metabolism, leading to increased formation
of trifluoroacetylated proteins in the liver. Those proteins are
believed to form neo-antigens that are responsible for the immune-
mediated hepatic necrosis known as halothane hepatitis, which
is discussed in the section on Hepatic Toxicity Caused by Volatile
Anesthetic Metabolites.4 Whereas some believe that specific
clinical uses may develop for individual chiral volatile anesthetic
molecules based on selective potency and toxicity,5 others believe
that clinically significant advantages are not likely and that these
stereoselective actions are mainly of scientific interest.6
PHARMACOKINETICS OF
VOLATILE ANESTHETICS
The study of the human pharmacokinetics of volatile anesthetics Figure 21-1. The rate of rise of the ratio of end-tidal (alveolar)
examines the fate of those drugs over time when presented to to inspired volatile anesthetic concentrations in adult humans.
humans. A safe pediatric anesthetic can best be conducted when Adapted from reference 17.
one understands the pharmacokinetic principles that govern the
speed with which partial pressures of inhaled anesthetics rise in
body tissues (the “washin”), and how those principles differ for versus time (Figure 21–1). The relationship between these two
infants and children. In addition, understanding the factors that fractions is simple if one considers that when uptake removes four
govern the elimination of volatile agents (the “washout”) is impor- fifths of inspired anesthetic molecules, then the FA/FI ratio equals
tant to achieve proper timing of the termination of the anesthetic. 0.2; and if uptake removes one fifth of inspired molecules, then the
The next section examines factors affecting volatile anesthetic ratio equals 0.8. For the FA/FI ratio to increase toward 1.0, the rate
washin, namely, the alveolar anesthetic delivery, anesthetic uptake of delivery must exceed the rate of uptake. At equilibrium, once
from alveoli into pulmonary blood, and uptake from the arterial uptake is no longer operative, the FA/FI ratio would equal 1.0.
blood into tissues, and discusses ways in which these are inter- Salanitre and Rackow demonstrated that the rate of rise of
related. Anesthetic washout is also addressed. alveolar to inspired anesthetic partial pressures was greater for
children than for adults. Figure 21–2 shows their findings in
comparison with two prior adult studies.7 The inverse relationship
Volatile Anesthetic Washin between age and the rate of rise of FA/FI is reflected in the increased
speed of induction of the youngest pediatric patients and is caused
Anesthetics move along partial pressure and not concentration by several physiologic differences between children and adults.
gradients within and between fluids and tissues. In addition, the Those differences are listed in Table 21–2 and are expounded on in
partial pressure of the anesthetic, and not its concentration, is the next section on Alveolar Anesthetic Delivery: The Effect of the
responsible for the level of anesthesia achieved. Nonetheless, we Alveolar Ventilation–to–Functional Residual Capacity Ratio.
are more used to seeing amounts of anesthetics expressed in
percent rather than millimeters of mercury, and most manuscripts
use these terms interchangeably. That said, this chapter also inter- Alveolar Anesthetic Delivery: The Effect
changes those terms when appropriate. of the Alveolar Ventilation–to–Functional
The rate of increase of a volatile anesthetic’s partial pressure at Residual Capacity Ratio
the target tissue depends on multiple steps, and the relationship Anesthetic delivery to the alveoli is determined largely by alveolar
between the inspired and the alveolar partial pressures is critical. ventilation and functional residual capacity (FRC); larger alveolar
The alveolar anesthetic partial pressure (PA) and concentration are ventilation and smaller FRC lead to greater anesthetic delivery
referred to collectively as the alveolar anesthetic fraction (FA), and and, therefore, a more rapid rise of FA/FI. The most-soluble agents
the inspired anesthetic partial pressure (PI) and concentration are experience the greatest augmentation in rise of FA/FI because of
referred to as the inspired anesthetic fraction (FI). The alveolar this effect, as demonstrated in Figure 21–3. More soluble agents
anesthetic fraction rises toward FI at a rate determined by the are more dependent on alveolar ventilation to establish alveolar
balance between alveolar delivery and uptake. That relationship is concentration because of their greater uptake (see Alveolar
typically expressed graphically as the FA/FI ratio (or the PA/PI ratio) Anesthetic Uptake: Factors That Determine Uptake).
CHAPTER 21 ■ Volatile Anesthetics 325
Figure 21-2. The rate of rise of the ratio of end-tidal (alveolar)

to inspired halothane concentration for children 1 to 5 years old
(upper curve) versus adults (two lower curves). Adapted from Figure 21-3. The effect of alveolar ventilation on the rate of rise
reference 7. of alveolar to inspired anesthetic concentration for ether (solu-
ble), halothane (intermediate solubility) and N2O (insoluble).
The most prominent factor in the more rapid rise of FA/FI for An increase in alveolar ventilation speeds the rise most for the
more-soluble agents. Adapted from reference 11.
children than in adults (see Figure 21–2) is almost certainly the
increased alveolar ventilation in children, which leads to greater
anesthetic delivery. For children compared with adults, FA/FI rises infants and small children might be expected to have even greater
considerably more quickly for halothane,7 and if increased minute reductions in FRC than adults after initiation of anesthesia and
ventilation is a principle reason for that acceleration, then one muscle relaxation.8 Lower FRC in children compared with adults
might expect less difference for less-soluble agents such as sevo- increases alveolar anesthetic delivery and leads to a faster rise in
flurane. Although this author is unaware of such a comparison FA/FI.
using sevoflurane, a comparison using the even less soluble N2O
did demonstrate less of a difference, but maintained a moderately Alveolar Anesthetic Delivery: The Concentration
faster rise for children.7 In addition, infants tend to have smaller and Second Gas Effects
FRC than adults because they have similar lung compliance but
Anesthetic delivery may also be affected by the concentration of
considerably greater chest wall compliance; the balance of these
the anesthetic, with higher concentrations leading to greater
two determines FRC. In addition, the more compliant thoraces of
delivery and, therefore, a faster rise in FA/FI. This effect, known
as the concentration effect, is operative for N2O but not for volatile
TABLE 21-2. Factors That Increase the Rate of Rise of anesthetics administered in oxygen because their working
Alveolar to Inspired Volatile Anesthetic Partial Pressure concentrations are relatively low. Even desflurane with its higher
and the Mechanism Involved working concentrations does not demonstrate a concentration
effect.9 N2O is often administered at 50 to 70%, leading to a more
Mechanism of Effect rapid rise in FA/FI than when using low concentrations.9
Factor Increasing FA/FI on FA/FI The concentration effect is a complicated concept and has
usually been explained in an overly simplistic form to facilitate
↑Alveolar ventilationa ↑ Anesthetic delivery
understanding. An in-depth analysis of the concentration effect
↓ Functional residual capacitya ↑ Anesthetic delivery
and the “second gas effect” has been done by Korman and
↑ Inspired concentration of N2O ↑ Anesthetic delivery
↓ Cardiac output ↓ Anesthetic uptake Mapleson who described variations according to either a constant
↓ Blood/gas anesthetic solubilitya ↓ Anesthetic uptake inflow model in which the amount of gas coming into the lungs
↓ (PA – PV) caused by ↓ tissue/ ↓ Anesthetic uptake remains constant (and outflow decreases) or a constant outflow
blood solubility → ↑ tissue model in which case the amount of gas leaving the lungs remains
equilibrationa constant (and inflow increases).10 The model that applies depends
on whether the effect is experienced with spontaneous or mecha-
FA = alveolar anesthetic fraction; FI = inspired anesthetic fraction; PA = alveolar nical ventilation, and in fact, the truth may be somewhere in
anesthetic partial pressure; PV = venous anesthetic partial pressure.
(PA– PV) equals the alveolar–to–venous partial pressure difference.
between these two extremes. For our discussion of these two
a
Denotes factors that lead to a more rapid rise in FA/FI for neonates compared effects, we consider only the case of constant outflow, which
with adults. Decreased (PA– PV) in neonates is also augmented by an increased corresponds with the typical pediatric situation of spontaneous
percentage of blood flow going to the vessel-rich group. ventilation during an inhalational induction.
The concentration effect is caused by two elements, the first of

which is a concentrating effect and the second is an increase in
minute ventilation.11 The concentrating effect dictates that uptake
and removal of anesthetic gas from the lung will result in less of a
relative diminution of the lung’s anesthetic concentration when
administering an anesthetic gas in a high concentration. The
reason for less diminution is that replacement gas, coming from
the fresh gas flow, arrives in the lungs to replace anesthetic that
was taken up. Relative to anesthetics administered in low concen-
tration in which replacement gas volume is small compared with
lung volumes, high administered concentrations of N2O early in
the anesthetic lead to large replacement volumes. Consequently, a
large amount of fresh gas at the inspired anesthetic concentration
returns to the lung and the fall in concentration is small. The
second element of the concentration effect is related to the first in
that a high concentration of anesthetic gas leads initially to a large
volume of anesthetic taken up from the lungs. The gas that re-
places the uptake augments alveolar ventilation. The result is an
increase in alveolar anesthetic concentration beyond what which
would be expected from the concentrating effect alone. The
magnitude of the impact of the concentration effect on FA/FI can
best be understood by comparison with the impact of anesthetic
solubility on FA/FI. N2O administered at an inspired concentration
of 75% could be expected to have a similar rate of rise of FA/FI as
an anesthetic with one fourth the solubility administered at 1%.5
The quicker rise in FA/FI for N2O compared with desflurane (see
Figure 21–1) is caused by the concentration effect; they have
similar blood/gas partition coefficients. Figure 21-4. The magnitude of the second gas effect is demon-
The same two elements that cause the concentration effect, strated by showing the rate of rise of sevoflurane end-tidal
namely, concentration of residual gases and augmentation of (diamonds) and arterial (squares) partial pressures relative to
inspired ventilation, also influence concentrations of a second gas inspired partial pressures, administered both with (solid figures)
that is administered together with N2O. That effect, known as the and without (open figures) 70% N2O. Adapted from Figure 1 in
second gas effect, can lead to a more rapid rise in FA/FI of volatile reference 15.
anesthetics administered in low concentrations when they are
administered simultaneously with a high concentration of N2O.12
Uptake is minimal when any of the three factors in the numera-
Questions have been raised about the clinical applicability of the
tor approach zero, in which case the unopposed effects of ventila-
second gas effect13 and, in fact, regarding whether or not the
tion cause the FA/FI ratio to rise rapidly toward 1.0. The initial
second gas effect exists.14 However, the second gas effect was
steep rise in FA/FI for all agents is caused by low uptake because
recently shown to exist for sevoflurane15,16 and for desflurane,9 with alveolar partial pressure has not yet risen enough to mount a
a 10% faster rise in the FA/FI of 2% sevoflurane at 2 minutes when significant drive for anesthetic uptake, and the effect of anesthetic
using 67% N2O versus 100% oxygen.15 Peyton and coworkers delivery is therefore unopposed.
showed that the second gas effect of N2O on arterial partial
pressure of sevoflurane was two to three times greater than the
effect on end-expiratory partial pressure, as shown in Figure Alveolar Anesthetic Uptake: Blood/Gas
21–4. In addition, bispectral (BIS) index values (known to change Solubility of Volatile Anesthetics
minimally with N2O) decreased more rapidly during sevoflurane The blood/gas solubility of an anesthetic agent is expressed by its
administration with N2O.15 These data argue that the second gas blood-gas partition coefficient (λb/g), which describes the way in
effect does have clinical applicability. which that agent partitions itself between blood and alveolar gas
at equilibrium (equal partial pressures in blood and alveolar gas).
The partition coefficient reflects an agent’s affinity for two phases.
Alveolar Anesthetic Uptake: Factors For example, sevoflurane has a blood/gas partition coefficient
That Determine Uptake of 0.66, which indicates that, at equilibrium, the concentration
Alveolar anesthetic uptake into the pulmonary blood slows the of sevoflurane in blood is 0.66 times the concentration in the
rate of rise of alveolar to inspired anesthetic concentration. alveolar gas.
Anesthetic uptake from the lung is summarized by the following Blood/gas partition coefficients for inhaled anesthetics vary
formula11 and is directly related to the product of the blood/gas widely between agents and, in fact, vary between age groups
(see Table 21–1). Those with lower λb/g have less anesthetic uptake
solubility (λb/g), the cardiac output (Q), and the alveolar-to-venous
and, therefore, manifest a faster rise in the FA/FI. Consequently,
partial pressure difference (PA – PV):
the rate of rise of FA/FI for volatile anesthetics follows the order
Uptake = [(λb/g) × (Q) × (PA – PV)]/Barometric pressure desflurane > sevoflurane > isoflurane > enflurane > halothane (see
Figure 21–1).11,17 The blood/gas partition coefficients for halo- content and lower protein and lipid concentrations in neonates.21
thane and isoflurane are approximately 10% lower in children and The effect of that change in solubility can best be understood in
20% lower in neonates than in adults.18 Those same values for terms of time constants. The time constant (τ) describes the rate
preterm neonates do not differ according to gestational age and that a body compartment’s anesthetic partial pressure approaches
are similar to those for full-term neonates.19 In contrast, the λb/g for that of the blood and is the time required to achieve 63% equili-
sevoflurane does not differ according to age.19 The more rapid rise bration. Ninety-five percent equilibration is achieved by three time
in neonatal alveolar halothane and isoflurane partial pressures is constants. The time constant can be calculated by dividing the
to a small degree explained by this solubility difference.20 product of the compartment’s volume capacity and tissue/blood
solubility by the blood flow that is delivering anesthetic to the
compartment. The time constant for the VRG is reflected by the
Alveolar Anesthetic Uptake: Cardiac Output
equation:
Alveolar anesthetic uptake is directly proportional to cardiac
output.11 Greater cardiac output leads to greater anesthetic uptake, τvrg = Volume of the VRG (L) × λvr/b
which slows the rate of rise of FA/FI. Therefore, increased cardiac VRG blood flow (L/min)
output typically slows anesthetic induction. Conversely, lower The τ for the VRG for adults and infants can be estimated using
cardiac output decreases anesthetic uptake, speeds FA/FI, and known values for tissue volumes, cardiac output, and tissue/blood
typically speeds induction. Figure 21–5 shows that decreases in solubility.11,22 For a 70-kg adult with a cardiac output of 5 L/min
cardiac output cause the greatest augmentations of FA/FI for those and approximately 75% of that output going to the 6-L VRG
volatile anesthetics that are most soluble.11 Soluble anesthetics are volume, and an anesthetic agent with τvr/b equal to 2 (i.e., the
affected to a greater degree than insoluble ones because their approximate adult value for both halothane and sevoflurane), τvr/b
alveolar partial pressures rises are more dependent on anesthetic = (6 × 2)/3.75 ≈ 3.2 min, and 95% equilibration of VRG partial
uptake. pressure would occur by just under 10 minutes. For a 5-kg infant
with an approximate cardiac output of 1 L/min and 80% of that
Tissue Anesthetic Uptake and Its Effect going to approximately 1 L of VRG tissue, and with λvr/b for the
on Alveolar Uptake infant equal to 75% of the adult value (or in this case equal to 1.5),
The tissue/blood solubilities of volatile anesthetic agents are τvrg = (1 × 1.5)/0.8 ≈ 1.9 min. Ninety-five percent equilibration
critical in determining the speed with which tissue anesthetic con- would occur by 6 minutes. Therefore, the depressant effects of
centrations (and partial pressures) rise. The brain/blood solubility inhalational anesthetic agents on the brain and heart can be
for neonates is 20 to 30% lower than that for adults, with similar expected to occur faster for infants than for adults.
lower values for other vessel-rich group (VRG)/blood solubility The muscle group/blood solubility (λmg/b) of volatile agents
(λvr/b) values. The lower solubilities are due to increased water increases with age in a logarithmic linear fashion.21 The λmg/b for
neonates is approximately half that for adults, and therefore,
neonates have a considerably quicker equilibration of blood and
muscle group (MG) partial pressures than adults. Figure 21–6
shows the total anesthetic uptake and the individual tissue uptakes
(in adults) over time for N2O and halothane, which are similar in
Figure 21-6. Total and individual tissue group uptake (mL/min)

Figure 21-5. The effect of cardiac output on the rate of rise of of 1% halothane in adults, demonstrating the early uptake and
alveolar to inspired anesthetic concentration for ether (soluble), saturation by the vessel-rich group (VRG), followed by the
halothane (intermediate solubility), and N2O (insoluble). A muscle group (MG) and later by the fat group (FG). These curves
decrease in cardiac output speeds the rise most for the more- are identical in shape to curves for other volatile anesthetics.
soluble agents. Adapted from Figures 7 and 8 in reference 11. Adapted from Figures 3 and 4 in reference 11.
shape to other inhaled anesthetics.11 The VRG is the primary blood, and therefore, no change occurs in the rate of alveolar
tissue involved in anesthetic uptake during the initial 5 to 10 partial pressure rise. However, if cardiac output is not increased
minutes of an anesthetic, but by 10 minutes, uptake by the MG and peripheral perfusion is not maintained, there will be less
has surpassed the VRG. Those curves would be expected to be anesthetic uptake at the lung and a more rapid rise in alveolar
shifted to the left for neonates. anesthetic partial pressure but a slower rise in tissue partial
The neonate’s faster anesthetic equilibration of the VRG and pressure. The anesthetic effect is, therefore, delayed.
the MG leads to earlier decline in tissue anesthetic uptake. That
results in higher anesthetic partial pressures in the mixed venous
blood and lower alveolar–to–venous partial pressure differences. Volatile Anesthetic Elimination
The end result of the neonate’s faster rise in tissue anesthetic Many of the factors that dictate the washin and establishment of
partial pressures is a quicker fall in alveolar uptake, which speeds adequate brain partial pressure also dictate the washout and
the rise of FA/FI. As eluded to in the previous example, the diminution of that same partial pressure.11 For example, at the
neonate’s higher cardiac index (CI) and higher percentage of termination of anesthesia, FA falls relative to alveolar concentra-
cardiac output going to the VRG augments the speed of tissue tion just prior to cessation of anesthesia (FAO) at a rate that is
anesthetic equilibration. Although it may seem paradoxical that accelerated by increased ventilation and opposed by factors that
the higher CI of neonates would contribute to a faster induction increase anesthetic output from the blood to the alveoli. In ad-
(based on the discussion of cardiac output and anesthetic uptake dition, increasing alveolar ventilation hastens the fall in the ratio
just discussed), neonates appear to be an exception to the rule of of FA/FAO, with that effect being most pronounced for the most-
increasing cardiac output slowing induction. In this case, insoluble anesthetics. Similar to anesthetic uptake from the alveoli,
creased VRG blood flow and rapid VRG partial pressure equili- anesthetic output to the alveoli increases with increase in cardiac
bration hasten the fall in anesthetic uptake and speed induction.22 output, increase in λb/g, and increase in venous–to–alveolar
anesthetic partial pressure difference. The ratio of FA/FAO falls
Anesthetic Uptake: Effect of Ventilation-Perfusion rapidly for all volatile anesthetics during the first 1 or 2 minutes
Mismatches and Shunting at the Cardiac Level after discontinuation, as shown in Figure 21–7, owing to the initial
small venous–to–alveolar partial pressure gradient; output to the
An increase in the ratio of ventilation to perfusion (V̇/Q̇) occurs
lungs is minimal and the effect of alveolar ventilation is unop-
when there is ventilation of unperfused (deadspace ventilation) or
underperfused alveoli. Increases in V̇/Q̇ do not alter the rate of rise
of FA/FI as long as arterial CO2 remains normal because the overall
increase in ventilation necessary to maintain normocarbia also
maintains the ventilation of perfused alveoli at normal levels.
Conversely, decreases in V̇/Q̇ that occur with segmental pulmo-
nary disease such as atelectasis or pneumonia (pulmonary right-
to-left shunting) or with cardiac right-to-left shunting do have a
substantial effect on anesthetic partial pressure rise. Decreased
uptake of anesthetic leads to a faster rise in FA/FI. However, arterial
partial pressure rise is slower because the end mixture of blood
returning to the left heart is diminished by blood that had not
passed ventilated alveoli. The result is a gap between the alveolar
and the arterial partial pressures, which is indicative of right-to-
left shunting. A minor amount of right-to-left shunting and
mismatch is present in healthy individuals, and anesthesia has long
been known to exacerbate that mismatch.23 Larger mismatches are
pathologic and slow anesthetic induction. Slowing occurs to the
greatest extent with the least-soluble anesthetics, and the reason is
as follows. In order to maintain normocarbia in the face of a right-
to-left shunt, overall ventilation is increased, which increases ven-
tilation to areas of normally perfused lung. More-soluble volatile Figure 21-7. Alveolar anesthetic washout is portrayed for ether
anesthetics are most able to augment their rate of rise of FA/FI by (soluble), halothane (intermediate solubility), and N2O and
increasing alveolar ventilation, (see Alveolar Anesthetic Uptake: cyclopropane (insoluble). Washout is expressed by the ratio of
Blood/Gas Solubility of Volatile Anesthetics) and in this case, they alveolar anesthetic fraction (FA) to alveolar concentration at the
do so in the regions of the lung that are overventilated and normally time anesthesia is discontinued (FAO). The FA/FAO ratio initially
perfused. Therefore, more-soluble anesthetics maintain an end declines very rapidly because of the unopposed effect of ventila-
mixture of blood returning to the left heart that has an arterial tion prior to the establishment of anesthetic output to the lungs
anesthetic partial pressure close to that expected without shunting.11 (output occurs only after establishment of a venous–to–alveolar
Left-to-right shunts have different effects than right-to-left partial pressure difference). The first arrow shows where output
shunts. Normally, with left-to-right shunting, cardiac output is begins to balance ventilatory elimination and designates the be-
increased so that systemic tissue perfusion is maintained at normal ginning of a slower, but still rapid, fall owing to washout from
levels. In that case, the amount of mixed venous blood returning the VRG. The second arrow demonstrates slowing of alveolar
to the right heart ready for anesthetic uptake is normal. There is washout owing to slowing of VRG anesthetic elimination.
no effect on alveolar anesthetic uptake by the shunted saturated Adapted from reference 11.
posed. A subsequent less rapid but more sustained (10–15 min)

fall in FA/FAO occurs during washout of the anesthetic from the
VRG. During that phase, the fall remains relatively rapid because
the VRG partial pressure decrease leads to a rapid decline in mixed
venous partial pressure, a decline in the venous–to–alveolar pres-
sure gradient, and therefore, decreased output to the alveoli. The
subsequent slower decline in FA/FAO occurs because of slower
output of volatile agents from muscle and fat. As with anesthetic
washin, right-to-left shunting slows the anesthetic washout, and
does so to the greatest extent for the least-soluble volatile anes-
thetics.
Despite these similarities to the washin process, there are
considerable differences for anesthetic washout. For example, a
decrease in cardiac output will decrease anesthetic output from
blood to the alveoli and speed the fall in FA/FAO. One might expect
from lessons learned regarding washin that recovery would,
therefore, be faster. However, unless cerebral perfusion is maintai-
ned at normal levels, there is an opposing effect of the lower
cardiac output to slow the anesthetic time constant at the brain.
The overall effect is that brain partial pressure falls more slowly
with decreasing cardiac output.11 That effect is most pronounced
for the least-soluble anesthetics, but even halothane recovery is
slowed by decreased cardiac output. Also, hypothermia may be
present on emergence and can affect anesthetic elimination
because lower temperature increases blood and tissue solubility
and, therefore, slows the fall in both alveolar and tissue partial
pressures. Hypothermia may also alter the point at which patients
awaken (see “Anesthetic Potency,” later).
Another major difference between anesthetic washin and
washout is that, at termination of the anesthetic, tissues are vari- Figure 21-8. The 50%, 80%, and 90% decrement times
ably equilibrated with volatile agent and the degree of equilibration (shown in min as predicted according to a computer model)
depends on the duration of the anesthetic and the tissue time for desflurane, sevoflurane, isoflurane, and enflurane as a
constants. With shorter anesthetic duration, there is less opportu- function of anesthetic duration. The decrement times depict the
nity for transfer of anesthetic into muscle and fat, and the fall in predicted amount of time to achieve a particular percent drop
FA/FAO is rapid. The effect of anesthetic duration on the rate of in brain anesthetic partial pressure compared with the partial
fall of FA/FAO is more pronounced for more-soluble agents, but pressure at the time an anesthetic is discontinued. Adapted
from reference 24.
when anesthetic duration is brief, even halothane alveolar washout
is rapid.
Ultimately, the speed with which a patient awakens is deter- obtain that goal. In addition, with anesthetics lasting longer than
mined by how rapidly the brain anesthetic partial pressure falls. 11/2 hours, sevoflurane may not produce a rapid 90% decrement.
When anesthetic duration is short, muscle and fat groups are far Similar pediatric simulations have not yet been performed, but
from equilibration, and VRG washout occurs not only by redistri- one might expect that for neonates the lower tissue time constants,
bution to the alveoli but also by redistribution to muscle and fat. higher CI, and higher alveolar ventilation/FRC ratio would lead
When the depot of muscle and fat anesthetic is high (after prolon- to more rapid tissue washout than demonstrated in Figure 21–8.
ged anesthetic administration), washout is slower. The time- Whereas Bailey’s model is helpful for understanding the concept
sensitive nature of anesthetic washout has been demonstrated of time sensitivity for different agents and different decrements,
nicely by Bailey who designed a five-compartment computer the model does not consider the effects of changes in ventilation
model that used adult values for anesthetic solubility, ventilation, and perfusion. In reality, anesthetic washout is more complicated
and perfusion and showed that brain anesthetic partial pressure than portrayed by this model because ventilation and perfusion
falls at a rate that is influenced by anesthetic duration; the shorter are changing at the end of an anesthetic.
the duration, the faster the fall.24 He examined the fall of brain A final difference for anesthetic elimination is that some
partial pressure according to the amount of time to achieve a volatile anesthetics undergo hepatic metabolism (see Table 21–1).
sought-after degree of decrement (“decrement time”) from the Halothane is reported to undergo as much as 20 to 25% meta-
partial pressure at the time of anesthetic discontinuation.24 Figure bolism. However, the fraction of halothane removed by hepatic
21–8 shows that decrement times increase with increasing blood flow is inversely proportional to its partial pressure.25 At
anesthetic duration and do so most for the more-soluble anesthe- typical anesthetizing concentrations, hepatic halothane removal
tics. However, 50% decrements occur rapidly (<5 min) no matter is extremely small, and metabolism does not become a significant
what anesthetic or anesthetic duration has been employed. factor in the elimination process until the tail end of the recovery
However, when one seeks a decrement of 80% after a long anes- curve.11 Other volatile anesthetics are metabolized to considerably
thetic, only sevoflurane and desflurane can be expected to rapidly lesser degrees.
PHARMACODYNAMICS OF awake can be considered just as meaningful a measurement of

anesthetic potency as MAC. Intraoperative awareness in the
VOLATILE ANESTHETICS pediatric population has been found to be approximately six times
The study of pharmacodynamics of volatile anesthetics examines higher than in adults.36,37 Nonetheless, MAC-awake has received
the affect of those anesthetics on the body. In particular, the effects much less attention and has not been well defined across all
of volatile anesthetics on the central nervous system, the cardio- pediatric age groups, most likely owing to difficulty studying this
vascular system, and the respiratory system are most relevant. The end point in young children. Other types of MAC have been
following discussion examines those effects. Mechanisms of action defined, such as MAC for tracheal tube and laryngeal mask
of general anesthetics are discussed in chapter 19 and, therefore, placement and removal.38–45 These types of MAC values have
receive minimal attention here. One of hottest topics in pediatric limited utility for defining anesthetic potency and are largely
anesthesiology in decades is the potential of volatile and other outside the scope of this chapter. The following discussion of
anesthetic agents to cause neurotoxicity in the developing brain. anesthetic potency covers mainly MAC, but also what is known
Animal data for many species, including primates, have shown about MAC-awake in children, with all data referring to racemic
that anesthetic agents that antagonize N-methyl-D-aspartate mixtures of volatile agents (where applicable). The discussion also
receptors or agonize gamma-aminobenzoic acid-A receptors pro- covers how volatile anesthetic potency changes when volatile
duce neurodegenerative changes in the developing brain.26–30 anesthetics are combined with various adjuvants.
Epidemiologic data in a population-based cohort recently dem- Anesthetic potency varies with age (Table 21–3), such that
onstrated that the risk of developing a learning disorder was MAC for all volatile agents decreases with age in a predictable
increased in children who had received two or more general anes- manner for patients older than 1 year, decreasing 6 to 7% per
thetics prior to 4 years of age.31 The discussion of neurodegen- decade of life.35,46 Numerous studies demonstrate that MAC for all
erative changes following anesthetic exposure is the topic of agents remains relatively uniform between 1 and 12 years of age,
Chapter 3 and is, therefore, not discussed further here. with 10%t or less change during that period (see Table 21–3).47–50
MAC values reported for that age tend to be 15 to 40% higher than
values for young adults.35 Peak MAC values for all volatile
Anesthetic Effect of Volatile Agents anesthetics occur during the first year of life, and different agents
on the Central Nervous System: peak at different time points during that year (see Table 21–3). For
Volatile Anesthetic Potency example, the peak MAC value for desflurane occurs between 6 and
Hypnosis, derived from the Greek work for “sleep,” and immobility 12 months, whereas for isoflurane and sevoflurane MAC peaks
are the two most critical clinical end points of general anesthesia. earlier. No data exist for MAC of halothane for the 6- to 12-month
Minimum alveolar concentration (MAC) is the principal measure period, so that the highest known MAC of halothane is between
of anesthetic potency and is defined as the concentration of 1 and 6 months of age. For all agents except sevoflurane, MAC
volatile anesthetic required to prevent response to a noxious sti- during the first month of life is lower than later in infancy. That
mulus in 50% of a population (an ED50). Classically, the response relationship is most notable for halothane, for which the MAC
is extremity movement and the stimulus is a skin incision, and decreases by 28% for neonates, down to 0.87%, compared with
the term “MAC” is, therefore, used in reference to this classic 1.2% at 1 to 6 months of age.51 Sevoflurane MAC actually reaches
stimulus/response combination, unless otherwise specified. Vola- its highest value in the neonatal period with a value of 3.3%, which
tile anesthetics ablate movement to a skin incision largely through is where it remains until 6 months of age when it decreases and
action at the spinal level; perhaps through their effect on nocicep- remains at 2.5% until 12 years of age. The reasons for the decrease
tive transmission in reflex pathways,32 through action on the vent- in MAC with age and for these mentioned MAC variations during
ral spinal locomotor networks, or a combination.33 One additional the first year of life are unknown.
type of MAC worthy of discussion is the “MAC-awake” which Preterm neonates who were less than 37 weeks of gestational
measures the potency of a volatile anesthetic with respect to age at birth were found to have lower isoflurane MAC values than
hypnosis and delineates the concentration at which 50% of sub- those previously reported for full-term neonates.49,52 The MAC for
jects are able to follow a command.34,35 Hypnosis, with prevention isoflurane for preterm neonates born at less than 32 weeks of
of awareness, is at least as important as immobility, so that MAC- gestational age (mean of 30 wk postconceptual age [PCA] at time
TABLE 21-3. Age-Related MAC in % Concentration (±sd when available) According to Volatile Anesthetic Agent
0–1 mo 1–6 mo 6–12 mo 1–3 y 3–5 y 5–12 y
Halothane 0.87 (±0.03) 1.20 (±0.06) No data 0.97a 0.91b 0.87c
Isoflurane 1.6 (±0.01) 1.87 (±0.12) 1.8 (±0.01) 1.6 (±0.16) 1.6 (±0.06) No data
Sevoflurane 3.3 (±0.2) 3.2 (±0.1) 2.5 (±0.2) 2.6 (±0.3)d 2.5 (±0.2) 2.5 (±0.1)
Desflurane 9.16 (±0.02) 9.42 (±0.06) 9.92 (±0.44) 8.72 (±0.59) 8.62 (±0.45) 7.98 (±0.43)
MAC = minimum alveolar concentration; sd = standard deviation.
Data for isoflurane are from reference 49; for halothane, from references 48 and 51; for sevoflurane, from reference 50; and for desflurane, from reference 47.
When the age studied did not fit cleanly into this table’s age categories,a, b, and c note such an occurrence and the actual ages studied:
a
MAC value for 0.5–2.5 y.
b
MAC value for 2.5–7 y.
c
MAC value for 7–11 y.
d
MAC value 2.0 (±0.2) for sevoflurane when combined with 60% N2O.
e
MAC value was 7.5 (±0.1) for infants and 6.4 (±0.2) for 1–5 y when combined with 60% N2O according to reference 70.
of surgery) was 1.28%, which was lower than the value of 1.41% for with depth of anesthesia; BIS was lowest at 2 minutes from the
preterm neonates born at 32 to 37 weeks of gestational age (mean start of induction and then increased despite increasing depth of
of 35 wk PCA at time of surgery).52 Similar studies involving other anesthesia.62 Further concern regarding the BIS monitor’s ability to
volatile agents have not been performed. However, these isoflurane predict pediatric anesthetic depth during volatile anesthesia was
data suggest that the more immature the neonate, the lower the raised by Kim and associates in a study that demonstrated in-
anesthetic requirement and that even the most immature neonates creasing BIS values despite increasing end-tidal sevoflurane
do indeed require anesthesia. concentration from 3% up to 4%, a finding that spanned all ages
The MAC of halothane for children 4 to -18 years old who have studied (0.5- to 12-y-olds).63 A subsequent study did not produce
both cerebral palsy and mental retardation was shown to be that paradoxical BIS increase when a predicted effect site sevo-
approximately 25% lower than for healthy children.53 That study, flurane concentration of greater than 3% was compared with
which used tetanic stimulation instead of skin incision as the the BIS value, although a plateau effect was found. Lastly, BIS
stimulus, found halothane MAC to be 0.62% and 0.71% for those values at age-adjusted 1.0 MAC of desflurane and sevoflurane
impaired children who were on anticonvulsants and those who increase with decreasing age, making interpretation of BIS difficult
were not, respectively (a statistically insignificant difference), in younger children.61,64 These drawbacks suggest that BIS has
compared with 0.9% for healthy children. That finding was limited ability to predict pediatric anesthetic depth under volatile
consistent with animal data that showed no significant difference anesthesia.
in halothane MAC for dogs after 10 days of phenobarbital.54 One Volatile anesthetics combine with other drugs to produce
possible explanation for the lower anesthetic requirement in these immobility and hypnosis in either a synergistic, an additive, or an
children with mental retardation and cerebral palsy is an alteration infra-additive manner, implying that the effect of the anesthetic
in the balance of inhibitory/excitatory regulatory neurons within combinations exceed, equal, or are less than the sum of the
the brain and spinal cord. Although somatic responses to painful individual effects.65 The decrease in volatile anesthetic require-
stimuli appear to be mediated primarily at the spinal level, the ments due to co-administration of another drug is referred to as a
brain does appear to influence those responses.55 MAC reduction. Volatile anesthetics combine with one another in
A few other factors have been examined as potential influences an additive manner, so that administration of 0.5 MAC of two
on MAC. MAC appears to decrease with decreasing body tem- volatile anesthetics equals a total of 1 MAC. N2O combines ad-
perature. For isoflurane, the MAC of children 4 to 10 years old, ditively with all volatile anesthetics in adults, including sevoflurane
with left-to-right shunts, decreased 5.1%/°C decrease in tempera- and desflurane.66,67 Interestingly, in children, N2O is additive when
ture; isoflurane MAC was 1.69% at 37°C and decreased to 1.47% administered with either halothane68 or isoflurane69 but appears
at 34°C.56 Human MAC alteration by body temperature has yet to to be infra-additive with sevoflurane and desflurane.50,70 The MAC
be demonstrated for other volatile agents. The etiology of the effect reduction provided by 60% N2O was only 23% and 25% for
of temperature on MAC is poorly understood and cannot be children receiving sevoflurane and desflurane, respectively, instead
explained solely by increasing lipid solubility associated with lower of the 55% that would have been expected with additivity.50,70 The
body temperature.56 The impact of gender on the MAC of volatile infra-additive interaction of N2O with sevoflurane in children is
anesthetics has not been investigated in children; however, in further supported by a finding of only 40% reduction of MAC for
nonpregnant adults, there does not appear to be a gender effect.57 tracheal intubation when 66% N2O was added to sevoflurane.40
The second defining effect of volatile anesthetics is their ability Numerous noninhaled adjuvant medications combine with
to produce hypnosis and ablate recall. MAC-awake is close to the volatile agents to reduce anesthetic requirements, with the amount
anesthetic concentration that suppresses memory and learning of reduction dependent mainly on the class of adjuvant.65 All
and is known to decrease with increasing age in a manner that μ opioid receptor agonists interact synergistically with volatile
parallels the effect of age on MAC.35 The ratio of MAC-awake to agents with respect to prevention of movement to incision,
MAC remains constant across age groups, and for desflurane, producing a dose-dependent MAC reduction with a ceiling effect.
sevoflurane, and isoflurane is 0.34 (±0.02).35 Pediatric data Remifentanil in adults produced isoflurane MAC reductions of
regarding MAC-awake is sparse. Inomata found that sevoflurane approximately 70 to 80% when running infusion rates of 0.15 to
MAC-awake in 3 to 8 year olds was 0.81%, with a MAC-awake– 0.3 μg/kg/min.71 In children, Castanelli and coworkers found a
to–MAC ratio of 0.35.58 Davidson and colleagues reported lower sevoflurane MAC reduction of just over 60% with remifentanyl
MAC-awake values, 0.66% in 2 to 5 year olds and 0.43 to 45% in infused at 0.12 μg/kg/min, and they appeared destined to demon-
5 to 12 year olds, and noted that differences in MAC-awake values strate a greater than 80% MAC reduction for 0.25 μg/kg/min but
for children do not explain the higher incidence of awareness.34 truncated the study in that group when the up-down protocol de-
Depth-of-anesthesia monitors have been developed in an creased sevoflurane concentration to 0.29%.72 Fentanyl in adults
attempt to quantitate the hypnotic effect of general anesthetics. produced 61% and 74% MAC reductions at serum levels of
These monitors use complex adult-based algorithms to translate 3 ng/mL and 6 ng/mLl, respectively73 and produced similar MAC
multidimensional aspects of the raw electroencephalographic reductions and ceiling effects for desflurane and isoflurane (Figure
(EEG) into a single number. The bispectral index (BIS) monitor is 21–9).65,74,75 The reduction in MAC awake by fentanyl is not nearly
the most studied of these monitors and has been shown to have as pronounced as for MAC, with sevoflurane MAC-awake reduc-
several limitations in the pediatric population. Considerably tions of 24% and 15% in conjunction with serum levels 3 ng/mL76
higher BIS values (indicating less depth of anesthesia) were and 2 ng/mL,77 respectively. Evidence in children also indicates that
reported in children during halothane anesthesia, compared with opioids have minimal impact on production of hypnosis by volatile
sevoflurane, desflurane, and isoflurane anesthesia administered anesthetics.78
at the same age-adjusted MAC.59–61 However, the BIS values at Midazolam also combines in a synergistic manner with volatile
awakening were similar for both halothane and isoflurane. BIS agents and, in adults, produced a 40% halothane MAC reduction
values during sevoflurane induction in children did not correlate after a bolus dose of 0.1 mg/kg followed by an infusion designed
elevated intracranial pressure (ICP) because the brain is at

immediate risk of injury. The effects of volatile agents on cerebral
metabolism and cerebral blood flow (CBF) have been investigated
at length, including numerous pediatric studies. Volatile agents
produce dose-dependent decreases in the cerebral metabolic rate
for oxygen (CMRO2), and adult studies have shown that global
CBF and global CMRO2 remain coupled at 1 MAC of sevoflu-
rane.86 Volatile anesthetics in low concentrations produce vaso-
constriction of cerebral vessels because of their effect on CMRO2
but, with increasing concentrations, have a direct vasodilatory
effect on cerebral vasculature.87 Changes in CBF during volatile
anesthetic administration are agent-specific.
CBF in children has been studied mainly using transcranial
Doppler sonography measurements of middle cerebral artery
blood flow velocity. Cerebral blood flow velocity (CBFV) has been
shown to correlate well with changes in CBF.88 Fairgrieve and
colleagues demonstrated that sevoflurane at 0.5 to 1.5 MAC in
healthy children did not change CBFV despite significant decrease
Figure 21-9. Minimum alveolar concentration (MAC) for both in arterial pressure, suggesting that sevoflurane maintained cere-
isoflurane and desflurane at various fentanyl concentrations. bral autoregulation, and did not appear to increase CBF in that
Volatile anesthetic requirements are reduced greatly by the first anesthetic range.88 However, desflurane does appear to increase
few ng/mL. A ceiling effect is demonstrated (consistent with a CBF in that same MAC range, with maximal effect reached by 1.0
synergistic interaction), showing that escalating amounts of fen- MAC, and it has been suggested that desflurane should be used
tanyl do little to further reduce anesthetic requirements. with caution in patients with suspected elevation in ICP.89 How-
Adapted from reference 65. ever, when desflurane at 1.0 MAC replaced an age-adjusted
equipotent amount of isoflurane, there was no change in CBFV,
to maintain that postbolus serum concentration.79 Pediatric pre- though there was a large increase in CBFV when desflurane
anesthetic sedation with midazolam might be expected to produce replaced propofol.90 In children, N2O combined with 1.0 MAC of
a MAC reduction at the beginning of the case, and especially affect sevoflurane increases CBFV, but not when combined with 1.0
anesthetic requirements for tracheal intubation. Propofol interacts MAC of desflurane.91,92 The effect of N2O on CBF when used in
with sevoflurane in an additive manner, with respect both to combination with sevoflurane creates further doubt regarding
producing hypnosis and to prevention of movement.80 α2 Adrener- whether N2O has any role in pediatric neuroanesthesia.91
gic agonists reduce volatile anesthetic requirements, but the nature Manipulation of end-tidal carbon dioxide tension (ETCO2)
of their interaction has yet to be adequately classified.65,81 Two remains an important tool for manipulation of CBF and brain
studies in children demonstrate that oral clonidine 2 μg/kg as a volume, and therefore, maintenance of cerebrovascular CO2
premedication decreased sevoflurane MAC-awake by 50%, down reactivity during volatile anesthesia is important. In children,
to 0.37 to 0.40%,58,82 with only one of those studies showing greater CBFV remains responsive to changes in ETCO2 between 20 and
MAC-awake reduction at higher dosage. Preoperative oral 60 mmHg during anesthesia with 0.5 to 1 MAC of sevoflurane or
clonidine reduced sevoflurane MAC in children to a lesser degree isoflurane.93,94 The same is true for halothane for ETCO2 between
than it reduced sevoflurane MAC-awake; MAC reductions were 20 and 40 mmHg, and similar CBFV occurs with 0.5 to 1.0 MAC
22 to 28% and 42 to 44% for doses of 2 and 4 to 5 μg/kg, of halothane and isoflurane when the ETCO2 is the same.93
respectively.58,83 Pediatric data for combinations of dexmedeto- Cerebral perfusion pressure (CPP), ICP, and mean arterial
midine and volatile agents are not available, but in adults, dexme- pressure (MAP) alterations during the addition of sevoflurane,
detomidine has been shown to decrease isoflurane MAC by 31% desflurane, and isoflurane were measured in young children with
and 50%84 and sevoflurane MAC by 0% and 17%,81 with target suspected elevated ICP. When these volatile agents were added to
dexmedetomidine levels of 0.3 ng/mL and 0.6 ng/mL, respectively. a background of 60% N2O in amounts equal to non–age-adjusted
The reason for these discrepant results with isoflurane and partial pressures up to 1 MAC (70–80% of age-adjusted MAC for
sevoflurane is unknown. Lidocaine reduces MAC in dogs by 10 to that population), subjects experienced dose-dependent mild
28% when used in concentrations common in clinical practice.85 increases in ICP and larger decreases in MAP and CPP.95 Those
There does not appear to be any human data for volatile agent variables did not differ significantly among volatile agents. De-
MAC reduction by lidocaine. creases in CPP were largely the result of volatile agent–induced
decreases in MAP rather than increases in ICP, emphasizing the
importance of maintaining MAP in order to maintain cerebral
Effects of Volatile Anesthetics perfusion.
on Cerebrovasculature and on
Cortical Electrical Activity Effects of Volatile Anesthetics on Cortical
Cerebrovascular Effects Electrical Activity: EEG Changes, Epileptic
The effects of volatile anesthetic agents on the brain and the blood and Epileptiform Activity
flow to the brain are of enormous importance during the manage- EEG activity in children during volatile anesthesia is similar to
ment of patients with cerebral ischemia, cerebral edema, or that of adults and follows the general pattern of progression from
rapid alpha rhythms while awake to beta-type oscillations (13–30 flurane is epileptogenic and noted a distinct pattern of progression
Hz) seen during sedation, into global slowing with theta- and then of epileptiform activity prior to seizure activity. To my knowledge,
delta-type waves (0–4 Hz). Constant and associates monitored the no other study has been done that either corroborates that find-
electroencephalogram in children during induction with 8% ing or signifies that anesthesia-induced epileptiform activity is
sevoflurane and N2O and noted an increase in the total spectral detrimental. Nonetheless, Constant and associates put forth pedi-
power (TSP) of the EEG signal and a shift toward low-frequency atric guidelines that emphasize a need to avoid conditions that
spectral bands, with a maximal change at near 2 minutes into make epileptiform activity more likely to occur and suggested
induction. In the third minute of induction, fast oscillations of the avoiding hyperventilation and maintenance concentrations of
alpha- and beta-type increased at a point at which pupils had sevoflurane in excess of 1.5 MAC.96 They recommended consi-
returned to central position and anesthetic depth was increasing. deration of preanesthetic midazolam because their previous work
Burst suppression occurred in 20% as anesthesia deepened.96,97 suggested epileptiform activity did not occur after midazolam.98
Constant and associates also compared pediatric EEG patterns Data have been inconsistent regarding hyperventilation and
during halothane induction with those during sevoflurane in- epileptiform activity, with one author demonstrating suppression
duction and found an initial similar increase in TSP and shift of spikes with hyperventilation in children109 and another author
toward low-frequency bands. At loss of eyelash reflex, halothane failing to find an association.112 The one consistent finding has
induced a greater frequency of fast beta-type rhythms and less been that greater epileptiform activity is associated with higher
slow delta-type waves than sevoflurane, but at the time of central sevoflurane concentration.104,105,109,112 Further work needs to be
pupils, spectral components were similar. Five minutes after done to demonstrate whether there is a progression of epilepti-
intubation, halothane induced EEG changes composed of slow form discharges to frank seizures in children and whether this
waves with superimposed fast alpha- and beta-type rhythms, EEG pattern has any short- or long-term detrimental effects on
compared with mainly slow, sharp waves with sevoflurane.98 cognitive function.
Seizures during volatile anesthetic administration are rare,
though the incidence is unknown and mainly occur at the beginn-
ing and the end of anesthesia. Nonpurposeful movements occur Cardiovascular Effects of
around the second minute of sevoflurane induction with a fre- Volatile Anesthetics
quency of 42 to 60%, and coincide with a rapid increase in delta Volatile anesthetics affect the cardiovascular system in many ways,
wave EEG activity.97,98 There is no correlation with those involun- most notably through direct myocardial depression, by altering
tary movements and EEG seizure activity. Many case reports cardiac conduction, and by increasing the likelihood of cardiac
document seizure occurrence during volatile anesthesia, most dysrhythmias. Volatile anesthetics may cause peripheral vasodila-
notably with sevoflurane and enflurane, though few of those tion and alter the balance of the sympathetic and parasympathetic
reports have supporting EEG data.96,99 A single case report does nervous systems. These affects, which differ according the matura-
document EEG evidence of seizure activity in a child with no prior tion state of the cardiovascular system,113 lead to alterations in
history of seizures who was receiving sevoflurane.100 Reports of contractility, cardiac output, blood pressure (BP), heart rate (HR),
seizures induced by volatile agents in patients with a history of rhythmicity, and the electrocardiogram. These volatile anesthetic–
epilepsy are more common, and nonconvulsive seizures have been
induced alterations in cardiovascular parameters in infants and
documented.101 Volatile agents paradoxically appear to possess a
children are analyzed in the following sections.
proconvulsant activity, yet have been used to treat status epilep-
ticus because of their ability to produce electrical silence. Despite
this apparent rare proconvulsant activity of sevoflurane, there is Hemodynamic Effects
no contraindication to its use in patients with a history of epilepsy, All volatile anesthetics administered to children at typical working
though cautious use has been recommended.96,99 concentrations produce moderate decreases in BP and agent-
Considerable discussion has been given to the volatile dependent alterations in the HR. Age-dependent differences in
anesthetic–induced EEG pattern termed epileptiform activity, hemodynamic effects are best looked at by reviewing studies that
which is mainly associated with sevoflurane96,102–108 but has also examined these effects across the full spectrum of pediatric ages
been described with isoflurane109 and enflurane.110 Definitions of (such as those studies that determined age-related MAC values).
epileptiform activity vary among authors, emphasizing the dif- Lerman and coworkers reported hemodynamic responses to
ficulty in describing this phenomenon. The terminology is broken 1 MAC of sevoflurane and found systolic blood pressure (SBP)
down into categories according to the intensity and rhythmicity decreased 0 to 11% in children 1 to 12 years of age and 15 to 35%
of spikes and the background EEG at the time. The nomenclature in age groups younger than 1 year (compared with awake values).50
includes terms such as polyspikes, which imply occurrence of more They found a 30% or greater decrease in SBP in over 50% of infants
than two negative and positive deflections, rhythmic polyspikes, younger than 6 months, in 27% of infants 6 to 12 months, and in
which refers to polyspikes occurring at regular intervals,106 and 0 to 8% of children 1 to 12 years. HR was unchanged with sevo-
periodic epileptiform discharges (PED), which refer to periodic flurane for subjects younger than 3 years of age and increased
complexes occurring in a bilateral and synchronized manner.104 slightly for those 3 years and older. Taylor and colleagues per-
Epileptiform discharges occur in patients with and without formed a similar study with desflurane and found that 1.0 MAC
epilepsy and have been reported to occur with an incidence of up resulted in SBP decreases of 22 to 28% in children and in 25 to 34%
to 100%.104,111 One group of authors performed extended EEG in infants, with a 30% or greater decrease in SBP occurring in 42 to
recordings on eight young men receiving sevoflurane and reported 58% of infants and in 17 to 42% of children (no statistical dif-
epileptiform activity in seven of eight at 1.0 MAC and in all eight ference).47 HR decreased modestly with desflurane in the age range
at 2.0 MAC, with EEG seizure activity in three subjects (including of 6 months to 5 years but did not change from baseline in all other
one with clinical seizure correlate).111 They claimed that sevo- groups including neonates. In contrast to Taylor and colleagues’
data, others reported 15 to 20 beats/min increases in HR in caused greater myocardial depression than isoflurane. One study
children with desflurane concentrations of 1.0 MAC and only by Murray and colleagues corroborated more pronounced myo-
modest decreases in BP.89,95 Studies that determined age-related cardial depression with halothane than isoflurane,123 and two other
MAP of halothane and isoflurane did not evaluate hemodynamic reports by the same author (all three reports in infants and young
variables. However, Friesen and Wurl determined hemodynamic children) found those same agents produced statistically indistin-
consequences of age-adjusted 2.0 MAC of halothane for five age guishable decreases in SVI and ejection fraction, suggesting
groups (0–1 mo, 1–6 mo, 6–24 mo, 2–6 y, and 6–12 y) and found similar depression of myocardial function.124,125 Murray and asso-
a greater decrease in MAP and SBP for infants younger than ciates also found no difference in those variables when comparing
6 months (29–30 mmHg decrease) versus all older age groups neonates with older infants.125 A direct comparison of 1.0 and 1.5
(decreases of 13–18 mmHg).114 There was no difference in pressure MAC of halothane and sevoflurane in children found significant
alteration between neonates and infants 1 to 6 months. Also, there decrease in LVSF and VCFS and in load-independent measures of
was no significant difference in HR decreases across age groups, myocardial function with halothane but not with sevoflurane.
which decreased 10 to 22 beats/min. However, the clinical significance of those findings is questionable
The relative effects of different volatile agents on HR and BP because those same authors found no detectable difference be-
are best looked at in head-to-head comparisons. In children, tween agents with respect to SVI or CI.115 Another comparison of
comparisons of effects of 1.0 to 1.5 MAC of sevoflurane versus halothane and sevoflurane in children at 1.0 and 2.0 MAC found
halothane115,116 and isoflurane versus halothane117 found statistic- a statistically indistinguishable dose-dependent decrease in SVI
ally indistinguishable modest (7–21 mmHg) decreases in BP and, for both agents. CI tended to decreased for both agents and both
surprisingly, could find no statistical difference in HRs according concentrations, but those decreases were not statistically different
to volatile agent or from baseline awake values. Even in infants, a from baseline values or from one another.126 A comparison of
comparison of SBP and HR when anesthetized with 1.0 MAC of halothane and sevoflurane at 1.0 and 1.5 MAC in infants found
either sevoflurane or halothane found no anesthetic-related that both agents caused decreases in LVSF and VCFS and in load-
differences in those variables.118 Sponheim and associates com- independent measures of myocardial depression, but decreases
pared the effects of 1.0 MAC of sevoflurane, isoflurane, and were more pronounced with halothane. Sevoflurane decreased
desflurane in patients aged 0.5 to 5 years and found a 15 beats/min systemic vascular resistance (SVR) and did not alter CI at both
increase in HR compared with awake values with desflurane, a concentrations, whereas halothane did not alter SVR and
5 beats/min increase with isoflurane, and no change for sevo- decreased CI by approximately 30% at 1.0 MAC.127 In contrast, a
flurane. BP decreased a similar amount with all three agents, recent study in infants receiving 1 MAC of sevoflurane or halo-
dropping 9 to 15 mmHg.95 thane found nearly equivalent values for CI, LVSF, and VCFS
Although sevoflurane administration at maintenance concen- regardless of agent but did not compare those values with awake
trations of 1.0 to 1.5 MAC does not appear to affect HR, high baselines.118 A head-to-head comparison of anesthetic effects in
inspired sevoflurane concentrations during induction do tran- infants versus children with respect to ECHO or magnetic reson-
siently increase HR 20- to 40%.98,116,119 That effect, not observed ance imaging (MRI) obtained load-dependent or -independent
with similar halothane inductions, is thought to be caused by cardiac variables to my knowledge has not been performed.
sevoflurane-induced preferential withdrawal of parasympathetic Few studies have examined the hemodynamic effect of volatile
cardiac activity.98,120 Rapid increases in desflurane and isoflurane anesthetics in patients with congenital heart disease. Infants and
concentrations in adults transiently increase both HR and BP, with children with myriad types of congenital heart disease who re-
the increases being much more prominent with desflurane.121 ceived 1.0 and 1.5 MAC of halothane, sevoflurane, and isoflurane
Those increases were shown to be mediated by elevations in had decreased SVI, CI, and LVSF with halothane but no decrease
plasma epinephrine, norepinephrine, and vasopressin. Rapid in those variables with the other anesthetics.128 Cardiac MRI found
increases in desflurane concentration in children have been no difference in values for SVI, CI, and EF in patients with
associated with increases in HR and BP during induction122 and congenital heart disease who were receiving 1.0 MAC of either
increases in HR during maintenance,89 but it is unclear whether sevoflurane or isoflurane.129 Volatile anesthetics do not appear to
those increases were similar in nature than those reported in alter the ratio of pulmonary to systemic blood flow in infants and
adults. children with atrial or ventricular septal defects.130
Echocardiographic (ECHO) examinations may be better than Overall, existing data would suggest that all volatile agents
simple hemodynamic variables for demonstration of volatile produce moderate dose-dependent myocardial depression in
agent–induced differences in myocardial depression. Some ECHO infants and children and that halothane may cause slightly more
measurements of myocardial performance such as stroke volume depression than other agents, especially for infants and for patients
index (SVI), left ventricular shortening fraction (LVSF), and with congenital heart disease. Also, volatile anesthetic–induced
velocity of circumferential fiber shortening (VCFS) may be altered depression of baroreceptor response may leave infants more
independently or collectively by changes in HR, afterload, and vulnerable to myocardial depressant effects.131,132 Volatile anes-
preload.117 Other measurements are advantageous in that they are thetics are believed to depress myocardial function by decreasing
considered to be independent of load and HR.115,118 Several com- intracellular Ca2+ flux via action on calcium channels, ion ex-
parisons of ECHO variables have been performed in children change pumps, and sarcoplasmic reticulum.133,134 A summary of
during administration of different volatile anesthetics. Wolf and that literature, along with discussion of why infants may be more
coworkers found halothane and isoflurane administered to susceptible, has been provided in a detailed review by Baum and
children 2 to 7 years old did not alter preload or HR, but halothane Palmisano.113
decreased LVSF by 18% and 25% at 0.5 and 1.5 MAC, respec- Intravenous atropine has been found to restore decreased
tively.117 Isoflurane did not alter LVSF, suggesting that halothane cardiac output caused by halothane and sevoflurane, largely by
increasing HR and to a small degree by counteracting the volatile Respiratory System Effects
anesthetic–induced decrease in myocardial contractility.118,135,136 of Volatile Anesthetics
Volume expansion has been shown to ameliorate the myocardial
depressant effects of isoflurane but not halothane.124 Minimization Volatile anesthetics affect the pediatric respiratory system in a
of infants’ fasting time appears to lessen hypotension caused by variety of ways. They depress the respiratory center, depress
halothane.137 Reduction of volatile agent by substitution with N2O activity of chest wall and diaphragmatic musculature, alter upper
does not limit myocardial depression; equipotent (1.5 MAC) and lower airway dimensions, and diminish airway response to
mixtures of halothane or isoflurane in oxygen or in 60% N2O noxious stimuli. Those effects are examined individually in this
administered to infants and young children produced similar section.
levels of myocardial depression.123
Respiratory Depression and Effects
Effects on Cardiac Rhythm and on Airway Musculature
the Electrocardiogram Halothane, isoflurane, enflurane, desflurane, and sevoflurane all
All volatile anesthetics affect cardiac rhythm. Even in patients depress spontaneous respiration in children in a dose-dependent
without heart disease, halothane and sevoflurane are associated manner as evidenced by decreased tidal volume and minute
with bradycardia, nodal rhythms, minor as well as life-threatening ventilation and by either attenuated response to CO2 stimulus or
ventricular dysrhythmias, and asystole.138,139 Sevoflurane and other elevated partial pressure of CO2 during spontaneous ventila-
ethyl ethers promote dysrhythmias less than halothane. Kataria tion.152–157 Respiratory drive, measured with occlusion testing, was
and coworkers reported sevoflurane induced bradycardia in 2% lower in children breathing 1.5 MAC of halothane than 0.5 and
of infants and children as opposed to 12% with halothane.139 1.0 MAC.152 The degree of volatile anesthetic–induced respiratory
However, a different report noted nodal rhythm in 20% of infants depression varies with age; infants manifest greater decrease in
induced with sevoflurane.140 Second-degree heart block (Mobitz minute ventilation and greater increase in ETCO2 with increasing
type 1) has been reported in a patient receiving sevoflurane, halothane concentration than do children.158 Substitution of N2O
though evidence that sevoflurane was causative is lacking.141 for an equal MAC fraction of volatile agent may lead to slightly
Adult and pediatric studies show that sevoflurane, desflurane, less respiratory depression.159
and isoflurane all prolong the electrocardiographic QT interval, Differences in the amounts of respiratory depression caused
though results differ substantially from one report to another. An by halothane, sevoflurane, desflurane, and isoflurane in sponta-
investigation in infants younger than 6 months found that sevo- neously ventilating pediatric patients appear to be relatively small.
flurane caused prolongation while halothane did not,142 and Some evidence shows that sevoflurane relative to halothane
another study in children demonstrated that desflurane caused produces higher ETCO2 at 1.5 MAC,157 as well as lower minute
prolongation while sevoflurane did not.138 The mechanism of QT ventilation and respiratory rate, but no difference in respiratory
interval prolongation by sevoflurane has been described, and it drive at approximately 0.9 MAC volatile agent plus 66% N2O.154 A
has been noted that sevoflurane combines synergistically in an compensatory respiratory rate increase to counteract the decrease
animal model and in cloned human cardiac cells to dramatically in tidal volume occurs with halothane and, to a lesser degree, with
prolong repolarization when used in combination with class III sevoflurane and desflurane but does not seem to occur with
isoflurane.154–156 Despite compensatory respiratory rate increases
antiarrhythmic drugs.143 Torsades de pointes (Tdp) is associated
with some volatile anesthetics, minute ventilation decreases.
with prolongation of the QT interval, and numerous manuscripts
Respiratory rate decreases with enflurane, and extra caution
referenced here express concerns that volatile agent–induced
should be exercised when administering enflurane to sponta-
prolongation of repolarization may increase susceptibility. No
neously ventilating infants and children.155
report exists of a pediatric patient with a normal heart developing
Volatile anesthetics depress the intercostal muscles and dia-
Tdp because of volatile anesthetics, but one pediatric case report
phragm to varying degrees, changing the relative rib cage contribu-
noted that Tdp occurred in a patient with congenitally prolonged
tion to tidal volume. Halothane depresses inspiratory intercostal
QT interval caused by sevoflurane and suggested use of propofol
function with relative diaphragm sparing, resulting in paradoxical
in that setting.144 Others doubt that volatile anesthetics promote
respiration.152 That effect, which is more pronounced in infants
Tdp and argue that QT interval prolongation is neither necessary than in children, is lessened when a laryngeal mask is used as
nor sufficient for Tdp to occur, whereas transmural dispersion of opposed to an endotracheal tube.160 Sevoflurane and desflurane
repolarization is necessary and sufficient and is not affected by cause less paradoxical respiration than halothane because they act
sevoflurane.145,146 The clinical significance of QT prolongation by more on the diaphragm than on intercostals muscles.154,156
volatile anesthetics is unknown and will most likely remain a topic
of debate.
Halothane sensitizes the myocardium to epinephrine-induced Effects on Upper Airway Dimensions
ventricular dysrhythmias.147–149 Ethyl ether anesthetics may also Upper airway narrowing occurs in a dose-dependent manner as a
sensitize the myocardium, but to a lesser extent.149–151 The pediatric result of administration of sevoflurane to spontaneously breathing
population appears to be much less susceptible to this pheno- children. Sevoflurane at 1 MAC caused 13 to 18% reduction in
menon, and it has been suggested that up to 10 μg/kg of upper airway cross-sectional area of children accessed by MRI,
epinephrine can be given safely to pediatric patients without heart and at 1.5 MAC caused 28 to 34% reduction, with the majority of
disease who are receiving halothane.148 Maintenance of a normal narrowing occurring in the anteroposterior dimension.161 That
magnesium level lessens sensitization,147 as does administration effect is believed to be caused mainly by inhibition of upper airway
of epinephrine in lidocaine.149 musculature, but other mechanisms have been proposed.161,162
Isoflurane has a similar effect, but narrowing has not been shown
to be dose-dependent. Continuous positive airway pressure
(CPAP) has been shown to completely reverse anesthesia-induced
upper airway narrowing in infants.163 In order to avoid upper
airway narrowing and obstruction, it is prudent to routinely
implemented CPAP shortly after commencing inhalational
induction of anesthesia in infants and children.
Effects on the Lower Airway

Volatile anesthetics predominantly relax airway smooth muscle
and increase airway dimension and, therefore, lower airway re-
sistance. Halothane, isoflurane, and desflurane all produced
airway smooth muscle relaxation in a human in vitro model, with
the amount of relaxation dependent on the airway caliber, the
airway precontraction level, and the volatile agent.164 The bron-
chodilatory effect of volatile agents has led to their occasional use
in the treatment of children with refractory status asthmaticus. Figure 21-10. Airway resistance is shown to increase during
Sevoflurane, isoflurane, and halothane transiently attenuated desflurane anesthesia, but not during sevoflurane, in patients
severe allergy-induced bronchospasm in animal models, whereas with “airway susceptibility” owing to either asthma or an upper
desflurane led to exacerbation.165,166 Both desflurane and halothane respiratory tract infection in the prior 2 weeks. Airway resist-
produced bronchodilation in a dog model of acetylcholine- ance was measured after various time intervals of 1.0 MAC of
induced bronchospasm.167 Although some evidence indicates that each volatile anesthetic. During desflurane, resistance increases
desflurane has a bronchodilatory effect, a preponderance of data rapidly and to a similar degree for both causes of increased
indicates that other volatile agents would be preferable in a patient airway susceptibility, whereas during sevoflurane, the resistance
with an active bronchospastic event. remains similar to resistance during propofol. Adapted from
Sevoflurane was shown to have a slightly favorable effect on reference 168.
lower airway respiratory mechanics in healthy children and in
those with reactive airways, whereas desflurane produced a remains poorly understood. The effect site is thought to be
deleterious effect in both groups.168 Von Ungern-Sternberg and postjunctional at the neuromuscular junction.180 Isoflurane and
colleagues demonstrated that, relative to measurements made enflurane produced equivalent potentiation of curare blockade,
during propofol anesthesia, 1.0 MAC of desflurane led to an 18% which was greater than potentiation by halothane.175 Sevoflurane
increase in airway resistance in healthy children and a 54% potentiates rocuronium blockade more than isoflurane; 1.0 MAC
increase in children with “airway susceptibility” defined as either of sevoflurane reduced by 50% the amount of rocuronium needed
a history of reactive airways or an upper respiratory infection in to produce 90 to 99% twitch depression.176 Recovery from neuro-
the previous 2 weeks. Figure 21–10 shows that the degree of muscular blockade is also slower during sevoflurane anesthesia
resistance increase was independent of the cause of airway sus- than with isoflurane.177
ceptibility, and the increase reached maximal effect within
3 minutes of desflurane administration. Adult data for sevoflurane
and desflurane have shown similar findings,169 although one study Effects Caused by Volatile
found that desflurane had a bronchodilatory effect at 1.0 MAC but Anesthetic Metabolites
increased airway resistance at 2.0 MAC.170 Smoking increases
bronchoconstriction associated with desflurane,169 and the ques- Toxic metabolites of volatile anesthetics were considerably more
tion of whether secondhand smoke has a similar effect has yet to important with methoxyflurane and halothane than with the more
be addressed. recently introduced agents. The development of modern volatile
Volatile anesthetics appear to exert a protective effect against anesthetics has been carved with a vigilant eye toward prevention
induction of bronchospasm by chemical or noxious stimuli. of metabolite-induced kidney and liver injury. Understanding the
Animal studies show that, at 1.0 MAC, sevoflurane, desflurane, nature of these toxic metabolites is important for historic reasons
isoflurane, and halothane protect against bronchoconstriction but also because the possibility of injury from toxic metabolites
induced by methacholine and by histamine.171,172 Sevoflurane at has not been completely eliminated.
1.6 MAC has been shown to completely blunt the broncho-
constrictive response to endotracheal tube placement occurring Inorganic Fluoride Metabolite and Renal Toxicity
in children with a history of asthma.173
In vivo metabolism of volatile anesthetics, through action of the
cytochrome P450 (CYP450) isozyme system, occurs to a minimal
Volatile Anesthetic Effect on Skeletal Muscles extent for most modern volatile anesthetics. Hepatic metabolism
of the ether anesthetics occurs principally through the CYP450
Effect on Muscle Relaxation 2E1 (CYP450 2E1) microsomal enzyme, which leads to release of
Volatile anesthetics potentiate the relaxant effect of nondepolariz- inorganic fluoride and production of organic fluoride moieties
ing neuromuscular blockers174–178 and, at high concentrations, that are conjugated and excreted in the urine.181,182 The rank order
decrease neuromuscular transmission.179 The potentiation effect of metabolism as judged by fluoride concentrations at saturating
has been recognized for many decades, yet the mechanism substrate concentrations is methoxyflurane > sevoflurane >
enflurane > isoflurane > desflurane > 0.183 Halothane metabolism metabolites, including a common reversible subclinical form that
does not result in appreciable levels of inorganic fluoride. When results in mild transaminase elevations194–196 and a severe fulmi-
using methoxyflurane, inorganic fluoride plasma concentrations nant hepatic necrosis commonly referred to as halothane hepatitis
that exceeded 50 μM/L were associated with subclinical nephro- that often results in death. Halothane hepatitis has been shown to
toxicity, and concentrations greater than 90 μM/L produced frank result from a hypersensitivity reaction to an oxidative metabolite
renal tubular injury in humans.184 Because of that association, of halothane.197 The same CYP450 2E1 is largely responsible for
methoxyflurane fell into disuse. The cause of metabolite-induced conversion of halothane into trifluoroacetyl chloride, which binds
renal injury was assumed to be circulating serum inorganic to liver proteins. In susceptible individuals, this neoantigen
fluoride acting alone. The concentration of 50 μM/L associated stimulates formation of antibodies such that re-exposure to
with methoxyfluorane-induced subclinical nephrotoxicity was halothane (or, rarely, to other volatile anesthetics) causes massive
adopted as a threshold level to be avoided for all volatile agents. immune-mediated hepatic necrosis. Fatal hepatic necrosis occurs
Peak inorganic fluoride plasma concentrations for sevoflurane overall in between 6000 and 35,000 halothane anesthetics,181 but it
used at typical working concentration and duration are typically occurs much less frequently in children than adults. The entity is
well below 50 μM/L,50 but prolonged use results in concentrations considerably rarer with enflurane, isoflurane, or desflurane and
over 100 μM/L. Interestingly, sevoflurane, enflurane, and iso- has never been reported with sevoflurane (presumably because
flurane may all induce inorganic fluoride plasma concentrations in it does not undergo metabolism that results in formation of
this toxic range but have not produced renal toxicity even after trifluoroacetylated liver proteins). A pediatric case of presumed
prolonged exposure.181 That fact led to further investigation of the desflurane-induced severe hepatic dysfunction occurred in a
cause-effect relationship being ascribed to plasma concentrations 15-month-old with Moebius syndrome previously exposed to
of inorganic fluoride. Kharash and associates demonstrated that isoflurane. That patient developed elevated liver enzymes and
volatile anesthetic–induced nephrotoxicity appeared to depend coagulopathy associated with gastrointestinal bleeding but
not only on metabolism by hepatic P450 isozymes but also on eventually had resolution of symptoms.193
renal metabolism. They found that renal isozymes catalyzed
defluorination of methoxyflurane 3 to 10 times faster than for
sevoflurane.185 The same lead author recently demonstrated that VOLATILE ANESTHETIC
a second metabolite of methoxyflurane, dichloroacetic acid, DEGRADATION WITH
enhanced toxicity produced by inorganic fluoride.186 Those find- CO2 ABSORBENTS
ings work together to explain why renal injury has not been
reported to occur with other methyl ethyl ethers capable of pro- Degradation of volatile anesthetics by CO2 absorbents that incor-
ducing elevated plasma inorganic fluoride concentrations. Even porate strong bases such as potassium hydroxide (KOH) and
in patients with pre-existing renal insufficiency, sevoflurane does sodium hydroxide (NaOH) can result in formation of carbon
not appear to cause deterioration of renal function.187 None of the monoxide (CO) and haloalkenes such as 2-fluoromethyl-2-
volatile anesthetics in current clinical use causes a clinically signi- difluoro-1-(trifluoro-methyl) vinyl ether (known as compound
ficant effect on renal function, but it is possible that we have not A). The preferential binding of CO over oxygen to hemoglobin
yet seen the last chapter of this saga. leads to the neurotoxic and cardiotoxic effects of CO poisoning.198
Compound A is nephrotoxic in rats and causes measurable labo-
ratory changes in humans, but it has not been shown to lead to
Hepatic Toxicity Caused by Volatile clinically significant human renal injury. The composition of the
Anesthetic Metabolites most commonly used absorbents are listed in Table 21–4 and
Halothane, isoflurane, enflurane, and desflurane have all been demonstrate that soda lime and Baralyme (barium hydroxide
implicated as causative of postoperative liver dysfunction,188–193 lime), which have been popular for decades, contain considerable
though halothane is most notorious for that complication. Meta- amounts of the strong bases KOH and NaOH. Novel absorbents,
bolic byproducts are implicated in volatile anesthetic–induced the first of which was Amsorb, have been developed to minimize
hepatotoxicity. Halothane is metabolized to a much greater extent anesthetic degradation to toxic byproducts. Amsorb does not
than the ether anesthetics, with 20 to 25% metabolized. The degree contain KOH or NaOH, maintains moisture with a calcium chlo-
of metabolism depends on age; metabolism increases during the ride (CaCl2) humectant rather than depending on hygroscopic
first 2 years of life, reaching adult levels by the age of 2 years. Two properties of NaOH and KOH, is unreactive with modern volatile
types of adverse hepatic effects are associated with halothane anesthetics, and yet maintains adequate CO2 absorption.199,200
TABLE 21-4. Percent Base Composition of Commonly Used Carbon Dioxide Absorbents
Absorbent Name Ca(OH)2 KOH NaOH Ba(OH)2 CaCl2 LiOH H2O
Baralyme 72 5.3 0 10.5 0 0 12.2
Carbolime 83.2 0 3 0 0 0 13.8
Soda lime 79.8 0 3 0 0 0 17.2
Sodasorb II 76.5 2.3 2.3 0 0 0 18.9
Dragersorb Free 74–82 0 <2 0 3–5 0 14–18
Amsorb >75 0 0 0 0.7 0 14.5
LiOH 0 0 0 0 0 99 1
Data derived from references 201 and 199 with listed values for Amsorb Plus identical to those for Amsorb.
Lithium hydroxide is also unreactive with volatile agents, but cost Compound A is formed through a complex dehydrofluori-
and the corrosive quality remain an issue.201 Once novel absor- nation process and then undergoes glutathione-dependent
bents are universally available and affordable, concerns over metabolism that can lead to formation of reactive and toxic
volatile anesthetic degradation products are likely to become intermediates.203 Humans experience less metabolic toxification
nonexistent. Until then, the following discussions of each of the of compound A than rats and have proximal tubular cells that
problematic consequences of degradation remain quite relevant. are more resistant to compound A cytotoxicity.181 Considerable
debate has taken place over the potential nephrotoxic effects of
compound A, and some investigations have found mild dose-
CO Production dependent effects of sevoflurane anesthesia on variables such as
Volatile anesthetics can react with desiccated soda lime or urinary albumen and serum creatinine.210 However, investigations
Baralyme to form CO.202,203 Although the production of a clinically to date have found no clinically significant effects from compound
significant amount of CO is rare, such a degree of CO can appear A in humans undergoing sevoflurane anesthesia.181,203,211 To date,
in the anesthesia circuit given the right conditions.204 Volatile no human case of compound A–induced renal injury has been
anesthetics with a difluoromethyl group (desflurane, enflurane, reported since the early 1990s and over 100 million anesthetic with
and isoflurane) are most prone to this type of degradation.203 The sevoflurane.
tendency to degrade to CO follows the order: desflurane >
enflurane > isoflurane >> sevoflurane = halothane.205 Despite the
lower tendency for sevoflurane breakdown to produce CO, it has
Severe Exothermic Reactions and Explosions
been associated with clinically significant carboxyhemoglobin Associated With Sevoflurane Degradation
levels in children205 and in an adult who had a CO level of 29% Degradation of volatile anesthetics is an exothermic process.
(see section on “Sevoflurane Degradation,” later).206 CO formation Sevoflurane degradation by desiccated absorbents that contain
is more likely with Baralyme than with soda lime as the CO2 strong bases can lead to excessive heat production causing com-
absorbent.202 CO generation increases with increasing desiccation bustion and even explosions.206,212–214 Sevoflurane degradation is
of the absorbent.207,208 Reduction of absorbent water content to 5% complex, and there may be two sets of degradation processes
or less is associated with clinically significant CO formation, and taking place: an initial reaction that generates compound A but
that degree of desiccation requires 24 hours or longer of 10 L/min not CO and a second reaction that occurs at higher temperatures
flows through the absorbent canister.208 Other factors may play a and does produce substantial CO.205 One case report of an adult
role in desiccation, including infrequent use of an anesthesia patient noted that this degradation process occurred approxi-
machine. mately 2 hours into maintenance with sevoflurane, which resulted
Prevention is the solution to this problem. When CO2 absor- in the melting of the absorbent canister, the generation of fumes,
bents with strong bases are being used, several simple rules can be high carboxyhemoglobin, and the development of acute respira-
implemented that will help avoid this potentially catastrophic tory distress syndrome.206 Two other case reports noted that
problem. The most important rule is to turn off all fresh gas flow explosions occurred during, or in close proximity to, pediatric
in between cases and, certainly, at the end of the day. Additional inhalational inductions with 8% sevoflurane.213,214
safeguards have been suggested, including disconnecting fresh gas Sevoflurane reacts with desiccated absorbents that contain a
hoses to the absorbent canister and leaving the circuit reservoir strong base (particularly KOH), and this reaction can reach tem-
bag attached to the canister to decrease potential gas flow through peratures in excess of 100°C during laboratory experiments.205,212
the canister, should one forget to turn off the gas flow. Vigilance Extreme heat generation and explosions have taken place in both
should always be exercised at the beginning of the day to identify laboratory and clinical settings when high concentrations of
gas flow that has remained on overnight. When soda lime or sevoflurane, along with high gas flows, and desiccated Baralyme
Baralyme desiccation is suspected, the absorbent should be are used.206,213,214 Sevoflurane degradation produces heat, and heat
replaced. increases sevoflurane degradation, so that this reaction feeds on
itself. Production of methanol and formaldehyde may contribute
to the explosive nature of this reaction.212
Compound A Production A lack of rising inspired sevoflurane concentration despite
Sevoflurane undergoes Baralyme- and soda lime–dependent deg- a high dialed concentration on the vaporizer should prompt
radation in the absorbent canister to compound A, a haloalkene investigation of CO2 absorbent temperature and may be a harbin-
that is known to cause renal tubular necrosis in rats.181,203 Pro- ger that this dangerous degradation process is occurring. However,
duction of compound A is increased with increasing sevoflurane one case of a sevoflurane explosion is reported to have occurred
concentration, increasing temperature (as occurs with lower fresh without an unexpectedly low inspired sevoflurane concentration
gas flow), and desiccation of absorbent. Absorbents containing prior to the sudden explosion.213 CO production can be signifi-
KOH are more prone to this problem than those containing cant just prior to and after combustion and explosion, and
NaOH; compound A production is more pronounced with therefore, CO should be measured by co-oximetry whenever
Baralyme than with soda lime.209 Compound A does not form to this reaction has occurred in a circuit connected to a patient.
any appreciable extent when using Amsorb CO2 absorbent or the Vigilance in detection of this type of degradation is critical, but
more recently manufactured Amsorb Plus or Dragersorb Free, as with other degradation processes, prevention is paramount.
even when using 2% sevoflurane at a flow rate of 1 L/min for All measures avoiding absorbent desiccation and disposal of
prolonged time periods.199,200 Whereas Amsorb has slightly de- suspected desiccated absorbent should be taken (see CO pro-
creased absorptive capacity than Baralyme and soda lime, Amsorb duction). Soda lime is less likely than Baralyme to degrade sevo-
Plus and Dragersorb Free have comparable activity. flurane in this manner, and absorbents that are nonreactive with
sevoflurane, such as Amsorb, eliminate the possibility of this type The addition of N2O may smooth sevoflurane induction in
of reaction. children by substantially decreasing excitation.233,243 Addition of
50% N2O has also been shown to speed sevoflurane induction.243
In this author’s opinion, N2O has a role in inhalational induction
MALIGNANT HYPERTHERMIA of children and older infants, but should be omitted for infants
Malignant hyperthermia (MH) is a hypermetabolic life- younger than 6 months old because their induction is extremely
threatening condition that occurs in susceptible individuals after rapid with volatile agent alone, and they may benefit from addi-
receiving specific triggering agents. All modern volatile anes- tional oxygen owing to the rapid speed with which their oxygen
thetics have triggered MH.215–224 MH occurs in all races and age saturation typically declines.
groups and has an overall incidence of between 1:5,000 and Incremental increases in inhaled anesthetic concentration at
1:100,000 patients. It is most frequent in the pediatric population; induction, rather than immediate increase to maximum, is be-
52% of cases occur in patients younger than 15 years of age.225 lieved by some to provide a smoother, albeit a slower, induction.
Although MH has been reported in a newborn, the youngest con- Studies have demonstrated that incremental increases of sevo-
firmed case is in a 6-month-old. The average number of anesthetic flurane during induction slowed induction, did not improve mask
exposures prior to developing MH is three, but MH may develop acceptance, and did not decrease coughing, compared with
on the first exposure.225 Patients who are susceptible to MH, such immediate administration of 7 or 8% sevoflurane.243,244 Incremen-
as those with central core disease, multi-minicore disease, King tal increase of halothane has been common practice, despite a lack
Denborough syndrome, hypokalemic periodic paralysis, myotonia of evidence of benefits with that technique.
fluctuans, and those with a positive family history of MH should The single-breath vital capacity induction technique is a parti-
receive anesthetics that are free of triggering agents such as cularly useful method for inducing anesthesia in older children.
succinylcholine or volatile anesthetics. Patients with dystrophino- Agnor and coworkers demonstrated that the time to loss of eyelash
pathies, such as Duchenne’s muscular dystrophy, have not been reflex was only 33 seconds when children aged 5 to 12 years took
demonstrated to have a predisposition to MH, but they should and held a single vital capacity breath of 8% sevoflurane in oxygen,
also have a trigger-free anesthetic in order to avoid the possibility and speed of induction did not change when N2O was added.245
of rhabdomyolysis with associated hyperkalemic arrest.226 The ability to cooperate with this type of induction is only 10% in
Studies in MH-susceptible swine have found that MH onset is patients aged 4 to 5 years and approaches 50% by 8 years.246
faster with halothane than with isoflurane and faster with iso- Compared with the standard tidal volume technique, the single-
flurane than with desflurane.227 Two cases of suspected MH during breath method produced slightly shorter time to loss of eyelash
desflurane had initiation of symptoms at 3 and 7 hours after the reflex, was equally well tolerated, and produced better patient
initiation of desflurane.218,219 Caffeine-induced contractures are satisfaction.247 Lack of airway irritability when using the single-
augmented to a greater degree by halothane than by isoflurane or breath technique draws into question any purported benefit of
enflurane,228 but there is no clinical evidence showing a volatile incremental anesthetic increases during induction.
anesthetic–specific difference in MH incidence or severity.
Onset of Anesthesia in Clinical Practice:
VOLATILE ANESTHETICS IN Anesthetic Induction and the
CLINICAL PRACTICE Overpressure Technique
Induction with sevoflurane could be expected to be more rapid
Volatile Anesthetic Inhalational Induction: than with halothane owing to sevoflurane’s lower solubility.
Choice of Agents and Techniques However, speed of induction is determined not only by the washin
Inhalational induction is by far the most common technique of characteristics of an anesthetic but also by the maximum inspired
anesthetic induction for children in the United States229 and is a anesthetic partial pressure administered and the rapidity with
heavily utilized technique internationally. Halothane had been for which that maximum partial pressure is dialed in. Halothane
decades the principal volatile anesthetic used for inhalational vaporizers typically deliver a maximum of 5%, which equates to
induction, but sevoflurane has proved to be at least as good an four to six times the MAC for halothane. Sevoflurane vaporizers
induction agent, with just as low incidences of breath holding, typically deliver a maximum of 8% sevoflurane, which equals
coughing, laryngospasm, and oxygen desaturation as halo- approximately three to four times MAC. Overpressure of an
thane.50,230–234 The other ether anesthetics, desflurane, isoflurane, anesthetic refers to using an inhaled partial pressure above the
and enflurane, have proved to be unsuitable for inhalational induc- anesthetic partial pressure one desires in the VRG, in order to
tion owing to their high incidences of respiratory complica- obtain the desired VRG pressure more quickly. Vaporizers for
tions.122,235–239 The incidence of laryngospasm during desflurane sevoflurane and halothane are typically turned to maximum
induction was reported to be 49% and with isoflurane was concentration rapidly, if not immediately, at the start of induction.
23%.122,235 A few studies have claimed similar induction conditions The ability to apply greater overpressure when using halothane
for isoflurane and either sevoflurane or halothane in infants and compensates for its lower solubility compared with sevoflurane.
children,240,241 but a preponderance of evidence implies that the In fact, the speed of induction with halothane dialed immediately
only two suitable volatile anesthetics for inhalational induction to 4% is similar to that when using immediate 8% sevoflurane.234
are sevoflurane and halothane. Sevoflurane may be a better choice Interestingly, the similarity in speed and induction characteristics
in children with congenital heart disease owing to lesser hemo- of these two agents is noted by the fact that anesthesiologists who
dynamic effects and a lower incidence of dysrhythmias (see were blinded to whether they were using sevoflurane or halothane
Cardiovascular Effects of Volatile Anesthetics).128,242 during induction could not tell the difference.248 In a similar study,
blinded observers were able to guess the anesthetic, despite iden- In studies with that type of design, early emergence after des-
tical induction times, most likely because sevoflurane induction flurane or sevoflurane is generally quicker than after halo-
was associated with tachycardia.234 thane.250,252 Emergence from desflurane is faster than emergence
The ability to overpressure with both sevoflurane and halo- from either sevoflurane or isoflurane.252,253 In clinical practice,
thane is critical to achieve necessary rapidity of inhalational anesthesia is adjusted during the case and weaned at the end, and
induction, especially for older children in whom washin occurs at pediatric studies that have used a design that allows anesthetic
a slower rate than infants. The advantage of the overpressure titration have shown less differences in time to emergence, but
technique, however, comes with the inherent peril that the patient have still demonstrated faster early emergence when comparing
may receive an anesthetic overdose, especially when using halo- desflurane or sevoflurane with halothane.254,255 One comparison
thane. Two in vivo feedback mechanisms act to modulate the of isoflurane plus N2O versus sevoflurane plus N2O found no
speed with which one might approach the extremely high inspired difference in emergence times in children when 1.2 MAC (age-
concentration during overpressure of anesthesia. The first is a adjusted) total was continued until the end of surgery (average of
negative-feedback mechanism, which leads to a protective effect 135 min).256 That model may have given isoflurane an unfair
for the patient. This negative-feedback loop results from the advantage in that it took into consideration that N2O seems to
inhaled anesthetic lowering the minute ventilation of sponta- reduce pediatric MAC for isoflurane more than for sevoflurane,
neously ventilating patients. The lower minute ventilation leads so that the starting volatile agent MAC fraction for isoflurane was
to a slowing of the rise of alveolar to inspired partial pressure, less than for sevoflurane. Similar studies in adults have found
which acts to slow the rising VRG partial pressure. If controlled slightly quicker early emergence for sevoflurane plus N2O over
ventilation is employed during inhaled induction while using the isoflurane plus N2O.257,258 All of the studies that did demonstrate
overpressure technique, this protective negative-feedback mecha- quicker early emergence were unable to show a difference in time
nism is bypassed, and alveolar partial pressure will rise much more to discharge from the recovery room.250,252,254,255 However, Nord-
rapidly.11 Dogs that were administered 4% halothane using man and colleagues did find that children older than 4 years did
controlled ventilation had nearly 50% higher alveolar–to–inspired leave the recovery room 8 minutes earlier after desflurane than
partial pressures at 10 minutes, compared with when they brea- those who received isoflurane.253 That author also found that
thed the same concentration spontaneously, and nearly all dogs increasing anesthetic duration increased emergence time after
that received 4% by controlled ventilation went on to cardio- isoflurane but not after desflurane, as might be predicted by
vascular collapse compared with none that breathed 4% sponta- Bailey’s computer models as shown in Figure 21–8.
neously.249 Recall from the “Pharmacokinetic” section, earlier, that
halothane partial pressure rise will be most affected by augmen-
tation of ventilation because it is more soluble than sevoflurane. Emergence in Clinical Practice:
Controlled ventilation should be avoided when using halothane Emergence Delirium
overpressure inductions; if controlled ventilation becomes neces-
Emergence delirium (ED; also known as “severe emergence
sary, the inhaled halothane concentration should be substantially
agitation”) has been a major focus in pediatric anesthesia since the
decreased. The same precautionary measure should be considered
early 2000, but it is by no means a new phenomenon. Patients
during sevoflurane overpressure induction of infants. Children
with ED typically cry uncontrollably, make no eye contact or have
receiving 8% sevoflurane induction appear more resistant to
their eyes shut, do not recognize familiar persons or objects, and
cardiovascular depression; 8% sevoflurane used in conjunction
exhibit nonpurposeful thrashing movements. Severe agitation on
with rapid control of ventilation and administered up to the time
emergence puts patients at risk of self-injury, dislodging intra-
of tracheal intubation did not cause appreciable cardiovascular
venous lines or drains, or damaging their surgical site, and they
depression in patients 1 to 8 years of age.119
may require increased nursing support. Studies of ED had been
The second feedback mechanism results in a dangerous
hampered by lack of a uniform validated definition, but Sikich and
positive-feedback loop. As VRG anesthetic partial pressure rises,
Lerman validated and published an ED scoring system that should
cardiac output falls, leading to a faster rise in alveolar and VRG
solve that problem.259
partial pressures, which causes further fall in cardiac output. This
The incidence of ED depends on the volatile anesthetic used
downward spiral caused by this positive-feedback mechanism but also on which of the myriad definitions of ED were used. The
demands that overpressure of inhaled agents is carried out with reported incidence of ED is as high as 80%, and in general, the
extraordinary care, especially in infants who already have a more incidence follows the order: desflurane > sevoflurane > halo-
rapid anesthetic washin and who may be more sensitive to the thane.250,252,260–263 The increased interest in ED has largely been
cardiovascular depression of volatile agents. Again, this feedback because of the increased incidence when using desflurane or
loop would be expected to be more prominent with halothane sevoflurane. Whereas differences in the incidence of ED between
than with sevoflurane because rates of rise of partial pressures of those two agents and halothane are apparent, differences with
more-soluble agents are affected more by cardiac output changes. isoflurane are less apparent. Voepel-Lewis and associates found
that sevoflurane induction combined with isoflurane maintenance
Emergence in Clinical Practice: increased the incidence of ED twofold compared with all other
anesthetic combinations.264 However, some have found no differ-
Speed of Emergence ence in the incidence of ED after sevoflurane or isoflurane,265 and
One might predict that the least-soluble agents would lead to others have found less ED after isoflurane.266
considerably more rapid emergence than the more-soluble agents. The etiology of pediatric ED remains an enigma, though
Pediatric studies that have administered a set MAC multiple until pain, when not adequately controlled, is a contributing factor.267
the end of surgery, and then measured time to awaken, have However, emergence agitation (EA) does occur in a large percen-
demonstrated quicker emergence for the least-soluble agents.250–253 tage of children who undergo anesthesia for imaging studies and,
therefore, have no surgical pain.260,262,268 Some believe that ED arises 16. Hendrickx JF, Carette R, Lemmens HJ, De Wolf AM. Large volume N2O
from a direct effect of volatile anesthetics on the central nervous uptake alone does not explain the second gas effect of N2O on sevoflurane
during constant inspired ventilation. Br J Anaesth. 2006;96:391–395.
system. Preschool age, preoperative anxiety, and otolaryngologic 17. Yasuda N, Lockhart SH, Eger EI 2nd, et al. Comparison of kinetics of
procedures appear to put children at higher risk of ED.264,269–271 sevoflurane and isoflurane in humans. Anesth Analg. 1991;72:316–324.
Numerous agents have been shown to prevent ED, and given 18. Lerman J, Gregory GA, Eger EI 2nd. Hematocrit and the solubility of
the high incidence of ED after sevoflurane, isoflurane, or des- volatile anesthetics in blood. Anesth Analg. 1984;63:911–914.
flurane, one should consider prophylaxis. Dexmedetomidine, 19. Malviya S, Lerman J. The blood/gas solubilities of sevoflurane, isoflurane,
halothane, and serum constituent concentrations in neonates and adults.
clonidine, fentanyl, propofol, ketamine, and nalbuphene have all Anesthesiology. 1990;72:793–796.
been shown to decrease the incidence of ED, with numbers needed 20. Lerman J, Gregory GA, Willis MM, Eger EI 2nd. Age and solubility of
to treat in the 2.5 to 5 range.260,268,272–277 Strategies for treatment volatile anesthetics in blood. Anesthesiology. 1984;61:139–143.
of ED are non–evidence-based, but commonly used treatments 21. Lerman J, Schmitt-Bantel BI, Gregory GA, et al. Effect of age on the solu-
include small doses of fentanyl, propofol, midazolam, and dexme- bility of volatile anesthetics in human tissues. Anesthesiology. 1986;65:
307–311.
detomidine. 22. Brandom BW, Brandom RB, Cook DR. Uptake and distribution of
halothane in infants: in vivo measurements and computer simulations.
Anesth Analg. 1983;62:404–410.
CONCLUSIONS 23. Hulands GH, Greene R, Iliff LD, Nunn JF. Influence of anaesthesia on the
regional distribution of perfusion and ventilation in the lung. Clin Sci.
Volatile anesthetics are likely to remain the dominant tool of the 1970;38:451–460.
pediatric anesthesiologist for years to come. Increased under- 24. Bailey JM. Context-sensitive half-times and other decrement times of
standing of the consequences of metabolites and degradation inhaled anesthetics. Anesth Analg. 1997;85:681–686.
products has allayed some fears of negative consequences of the 25. Sawyer DC, Eger EI 2nd, Bahlman SH, et al. Concentration dependence
of hepatic halothane metabolism. Anesthesiology. 1971;34:230–235.
newer anesthetic agents. However, the potential for volatile 26. Loepke AW, Soriano SG. An assessment of the effects of general
anesthetic–induced life-threatening events has not vanished, and anesthetics on developing brain structure and neurocognitive function.
those who administer these agents must maintain a thorough Anesth Analg. 2008;106:1681–1707.
working knowledge of all the possibilities that may occur. Under- 27. Loepke AW, McGowan FX Jr, Soriano SG. CON: The toxic effects of
anesthetics in the developing brain: the clinical perspective. Anesth Analg.
standing the nuances of the washin and washout of these anes- 2008;106:1664–1669.
thetics, their age-related potency, how they interact with other 28. Jevtovic-Todorovic V, Olney JW. PRO: Anesthesia-induced developmen-
agents, and their effects on key organ systems will help the tal neuroapoptosis: status of the evidence. Anesth Analg. 2008;106:
practitioner administer an efficient and safe anesthetic. 1659–1663.
29. Mellon RD, Simone AF, Rappaport BA. Use of anesthetic agents in
neonates and young children. Anesth Analg. 2007;104:509–520.
30. Soriano SG, Anand KJ, Rovnaghi CR, Hickey PR. Of mice and men:
REFERENCES should we extrapolate rodent experimental data to the care of human
1. Ellis RH (ed). The Case Books of John Snow. London: Wellcome Institute neonates? Anesthesiology. 2005;102:866–868; author reply 8–9.
for the History of Medicine; 1994. 31. Wilder RT, Flick RP, Sprung J, et al. Early exposure to anesthesia and
2. Lerman J. Inhalational anesthetics. Paediatr Anaesth. 2004;14:380–383. learning disabilities in a population-based birth cohort. Anesthesiology.
3. Lysko GS, Robinson JL, Casto R, Ferrone RA. The stereospecific effects of 2009;110:796–804.
isoflurane isomers in vivo. Eur J Pharmacol. 1994;263:25–29. 32. Barter LS, Mark LO, Jinks SL, et al. Immobilizing doses of halothane,
4. Martin JL, Meinwald J, Radford P, et al. Stereoselective metabolism of isoflurane or propofol, do not preferentially depress noxious heat-evoked
halothane enantiomers to trifluoroacetylated liver proteins. Drug Metab responses of rat lumbar dorsal horn neurons with ascending projections.
Rev. 1995;27:179–189. Anesth Analg. 2008;106:985–990, table of contents.
5. Martin JL,Njoku DB. Metabolism and toxicity of modern inhaled 33. Jinks SL, Bravo M, Hayes SG. Volatile anesthetic effects on midbrain-
anesthetics. In: Miller RD (ed) Miller’s Anesthesia. 6th ed. Philadephia: elicited locomotion suggest that the locomotor network in the ventral
Elservier Churchil Livingstone; 2005. pp. 231–272. spinal cord is the primary site for immobility. Anesthesiology. 2008;108:
6. Nau C, Strichartz GR. Drug chirality in anesthesia. Anesthesiology. 1016–1024.
2002;97:497–502. 34. Davidson AJ, Wong A, Knottenbelt G, et al. MAC-awake of sevoflurane
7. Salanitre E, Rackow H. The pulmonary exchange of nitrous oxide and in children. Paediatr Anaesth. 2008;18:702–707.
halothane in infants and children. Anesthesiology. 1969;30:388–394. 35. Eger EI 2nd. Age, minimum alveolar anesthetic concentration, and
8. Hoffman JE. The respiratory system. In: Rudolph CD, Rudolph AM, minimum alveolar anesthetic concentration-awake. Anesth Analg. 2001;
Hostteter MT, et al. (eds) Rudolph’s Pediatrics. 21st ed. McGraw-Hill 93:947–953.
Medical Publishing Divison. New York, USA, 2005, p. 1905–2007. 36. Andrade J, Deeprose C, Barker I. Awareness and memory function during
9. Taheri S, Eger EI 2nd. A demonstration of the concentration and second paediatric Anaesthesia. Br J Anaesth. 2008;100:389–396.
gas effects in humans anesthetized with nitrous oxide and desflurane. 37. Davidson AJ, Huang GH, Czarnecki C, et al. Awareness during anesthesia
Anesth Analg. 1999;89:774–780. in children: a prospective cohort study. Anesth Analg. 2005;100:653–661,
10. Korman B, Mapleson WW. Concentration and second gas effects: can the table of contents.
accepted explanation be improved? Br J Anaesth. 1997;78:618–625. 38. Higuchi H, Ura T, Taoda M, et al. Minimum alveolar concentration of
11. Eger EI 2nd. Anesthetic Uptake and Action. Baltimore: Williams & sevoflurane for tracheal extubation in children. Acta Anaesthesiol Scand.
Wilkins; 1974. 1997;41:911–913.
12. Epstein RM, Rackow H, Salanitre E, Wolf GL. Influence of the 39. Neelakanta G, Miller J. Minimum alveolar concentration of isoflurane for
concentration effect on the uptake of anesthetic mixtures: the second gas tracheal extubation in deeply anesthetized children. Anesthesiology.
effect. Anesthesiology. 1964;25:364–371. 1994;80:811–813.
13. Mapleson WW, Korman B. The second gas effect is a valid concept. 40. Swan HD, Crawford MW, Pua HL, et al. Additive contribution of nitrous
Anesth Analg. 1999;89:1326. oxide to sevoflurane minimum alveolar concentration for tracheal
14. Sun XG, Su F, Shi YQ, Lee C. The “second gas effect” is not a valid concept. intubation in children. Anesthesiology. 1999;91:667–671.
Anesth Analg. 1999;88:188–192. 41. Yakaitis RW, Blitt CD, Angiulo JP. End-tidal halothane concentration for
15. Peyton PJ, Horriat M, Robinson GJ, et al. Magnitude of the second gas endotracheal intubation. Anesthesiology. 1977;47:386–388.
effect on arterial sevoflurane partial pressure. Anesthesiology. 2008;108: 42. Yakaitis RW, Blitt CD, Angiulo JP. End-tidal enflurane concentration for
381–387. endotracheal intubation. Anesthesiology. 1979;50:59–61.
43. Taguchi M, Watanabe S, Asakura N, Inomata S. End-tidal sevoflurane 70. Fisher DM, Zwass MS. MAC of desflurane in 60% nitrous oxide in infants
concentrations for laryngeal mask airway insertion and for tracheal and children. Anesthesiology. 1992;76:354–356.
intubation in children. Anesthesiology. 1994;81:628–631. 71. Lang E, Kapila A, Shlugman D, et al. Reduction of isoflurane minimal
44. Nishina K, Mikawe K, Shiga M, et al. Oral clonidine premedication alveolar concentration by remifentanil. Anesthesiology. 1996;85:721–728.
reduces minimum alveolar concentration of sevoflurane for tracheal 72. Castanelli DJ, Splinter WM, Clavel NA. Remifentanil decreases sevo-
intubation in children. Anesthesiology. 1997;87:1324–1327. flurane requirements in children. Can J Anaesth. 2005;52:1064–1070.
45. Cranfield KA, Bromley LM. Minimum alveolar concentration of des- 73. Katoh T, Kobayashi S, Suzuki A, et al. The effect of fentanyl on sevoflurane
flurane for tracheal extubation in deeply anaesthetized, unpremedicated requirements for somatic and sympathetic responses to surgical incision.
children. Br J Anaesth. 1997;78:370–371. Anesthesiology. 1999;90:398–405.
46. Mapleson WW. Effect of age on MAC in humans: a meta-analysis. Br J 74. McEwan AI, Smith C, Dyar O, et al. Isoflurane minimum alveolar
Anaesth. 1996;76:179–185. concentration reduction by fentanyl. Anesthesiology. 1993;78:864–869.
47. Taylor RH, Lerman J. Minimum alveolar concentration of desflurane and 75. Sebel PS, Glass PS, Fletcher JE, et al. Reduction of the MAC of desflurane
hemodynamic responses in neonates, infants, and children. Anesthesio- with fentanyl. Anesthesiology. 1992;76:52–59.
logy. 1991;75:975–979. 76. Katoh T, Ikeda K. The effects of fentanyl on sevoflurane requirements for
48. Gregory GA, Eger EI 2nd, Munson ES. The relationship between age and loss of consciousness and skin incision. Anesthesiology. 1998;88:18–24.
halothane requirement in man. Anesthesiology. 1969;30:488–491. 77. Katoh T, Uchiyama T, Ikeda K. Effect of fentanyl on awakening con-
49. Cameron CB, Robinson S, Gregory GA. The minimum anesthetic concentration of sevoflurane. Br J Anaesth. 1994;73:322–325.
centration of isoflurane in children. Anesth Analg. 1984;63:418–420. 78. Watcha MF, Lagueruela RG, White PF. Effect of intraoperative analgesic
50. Lerman J, Sikich N, Kleinman S, Yentis S. The pharmacology of sevo- therapy on end-expired concentrations of halothane associated with
flurane in infants and children. Anesthesiology. 1994;80:814–824. spontaneous eye opening in children. Anesth Analg. 1991;72:190–193.
51. Lerman J, Robinson S, Willis MM, Gregory GA. Anesthetic requirements 79. Inagaki Y, Sumikawa K, Yoshiya I. Anesthetic interaction between midaz-
for halothane in young children 0–1 month and 1–6 months of age. Anes- olam and halothane in humans. Anesth Analg. 1993;76:613–617.
thesiology. 1983;59:421–424. 80. Harris RS, Lazar O, Johansen JW, Sebel PS. Interaction of propofol and
52. LeDez KM, Lerman J. The minimum alveolar concentration (MAC) of sevoflurane on loss of consciousness and movement to skin incision
isoflurane in preterm neonates. Anesthesiology. 1987;67:301–307. during general anesthesia. Anesthesiology. 2006;104:1170–1175.
53. Frei FJ, Haemmerle MH, Brunner R, Kern C. Minimum alveolar con- 81. Fragen RJ, Fitzgerald PC. Effect of dexmedetomidine on the minimum
centration for halothane in children with cerebral palsy and severe mental alveolar concentration (MAC) of sevoflurane in adults age 55 to 70 years.
retardation. Anaesthesia. 1997;52:1056–1060. J Clin Anesth. 1999;11:466–470.
54. Viegas O, Stoelting RK. Halothane MAC in dogs unchanged by phenobar- 82. Kihara S, Inomata S, Yaguchi Y, et al. The awakening concentration of
bital. Anesth Analg. 1976;55:677–679. sevoflurane in children. Anesth Analg. 2000;91:305–308.
55. Borges M, Antognini JF. Does the brain influence somatic responses to 83. Inomata S, Kihara S, Yaguchi Y, et al. Reduction in standard MAC and
noxious stimuli during isoflurane anesthesia? Anesthesiology. 1994;81: MAC for intubation after clonidine premedication in children. Br J
1511–1515. Anaesth. 2000;85:700–704.
56. Liu M, Hu X, Liu J. The effect of hypothermia on isoflurane MAC in 84. Khan ZP, Munday IT, Jones RM, et al. Effects of dexmedetomidine on
children. Anesthesiology. 2001;94:429–432. isoflurane requirements in healthy volunteers. 1: pharmacodynamic and
57. Wadhwa A, Durrani J, Sengupta P, et al Women have the same desflurane pharmacokinetic interactions. Br J Anaesth. 1999;83:372–380.
minimum alveolar concentration as men: a prospective study. Anesthe- 85. Himes RS Jr, DiFazio CA, Burney RG. Effects of lidocaine on the
siology. 2003;99:1062–1065. anesthetic requirements for nitrous oxide and halothane. Anesthesiology.
58. Inomata S, Kihara S, Miyabe M, et al. The hypnotic and analgesic effects 1977;47:437–440.
of oral clonidine during sevoflurane anesthesia in children: a dose- 86. Mielck F, Stephan H, Weyland A, Sonntag H. Effects of one minimum
response study. Anesth Analg. 2002;94:1479–1483, table of contents. alveolar anesthetic concentration sevoflurane on cerebral metabolism,
59. Edwards JJ, Soto RG, Bedford RF. Bispectral index values are higher blood flow, and CO2 reactivity in cardiac patients. Anesth Analg. 1999;
during halothane vs. sevoflurane anesthesia in children, but not in infants. 89:364–369.
Acta Anaesthesiol Scand. 2005;49:1084–1087. 87. Engelhard K, Werner C. Inhalational or intravenous anesthetics for
60. Davidson AJ, Czarnecki C. The bispectral index in children: comparing craniotomies? Pro inhalational. Curr Opin Anaesthesiol. 2006;19:504–508.
isoflurane and halothane. Br J Anaesth. 2004;92:14–17. 88. Fairgrieve R, Rowney DA, Karsli C, Bissonnette B. The effect of sevo-
61. Tirel O, Wodey E, Harris R, et al. The impact of age on bispectral index flurane on cerebral blood flow velocity in children. Acta Anaesthesiol
values and EEG bispectrum during anaesthesia with desflurane and Scand. 2003;47:1226–1230.
halothane in children. Br J Anaesth. 2006;96:480–485. 89. Luginbuehl IA, Fredrickson MJ, Karsli C, Bissonnette B. Cerebral blood
62. Constant I, Leport Y, Richard P, et al. Agitation and changes of bispectral flow velocity in children anaesthetized with desflurane. Paediatr Anaesth.
index and electroencephalographic-derived variables during sevoflurane 2003;13:496–500.
induction in children: clonidine premedication reduces agitation com- 90. Smith JH, Karsli C, Lagace A, et al. Cerebral blood flow velocity increases
pared with midazolam. Br J Anaesth. 2004;92:504–511. when propofol is changed to desflurane, but not when isoflurane is
63. Kim HS, Oh AY, Kim CS, et al. Correlation of bispectral index with end- changed to desflurane in children. Acta Anaesthesiol Scand. 2005;49:
tidal sevoflurane concentration and age in infants and children. Br J 23–27.
Anaesth. 2005;95:362–366. 91. Rowney DA, Fairgrieve R, Bissonnette B. The effect of nitrous oxide on
64. Wodey E, Tirel O, Bansard JY, et al. Impact of age on both BIS values and cerebral blood flow velocity in children anaesthetised with sevoflurane.
EEG bispectrum during anaesthesia with sevoflurane in children. Br J Anaesthesia. 2004;59:10–14.
Anaesth. 2005;94:810–820. 92. Karsli C, Luginbuehl IA, Bissonnette B. The effect of nitrous oxide on
65. Hendrickx JF, Eger EI 2nd, Sonner JM, Shafer SL. Is synergy the rule? A cerebral blood flow velocity in children anaesthetised with desflurane.
review of anesthetic interactions producing hypnosis and immobility. Anaesthesia. 2003;58:24–27.
Anesth Analg. 2008;107:494–506. 93. Leon JE, Bissonnette B. Cerebrovascular responses to carbon dioxide in
66. Fragen RJ, Dunn KL. The minimum alveolar concentration (MAC) of children anaesthetized with halothane and isoflurane. Can J Anaesth.
sevoflurane with and without nitrous oxide in elderly versus young adults. 1991;38:817–825.
J Clin Anesth. 1996;8:352–356. 94. Rowney DA, Fairgrieve R, Bissonnette B. Cerebrovascular carbon dioxide
67. Katoh T, Ikeda K. The minimum alveolar concentration (MAC) of reactivity in children anaesthetized with sevoflurane. Br J Anaesth.
sevoflurane in humans. Anesthesiology. 1987;66:301–303. 2002;88:357–361.
68. Murray DJ, Mehta MP, Forbes RB, Dull DL. Additive contribution of 95. Sponheim S, Skraastad O, Helseth E, et al. Effects of 0.5 and 1.0 MAC
nitrous oxide to halothane MAC in infants and children. Anesth Analg. isoflurane, sevoflurane and desflurane on intracranial and cerebral
1990;71:120–124. perfusion pressures in children. Acta Anaesthesiol Scand. 2003;47:
69. Murray DJ, Mehta MP, Forbes RB. The additive contribution of nitrous 932–938.
oxide to isoflurane MAC in infants and children. Anesthesiology. 1991;75: 96. Constant I, Seeman R, Murat I. Sevoflurane and epileptiform EEG
186–190. changes. Paediatr Anaesth. 2005;15:266–274.
97. Constant I. BIS use in pediatric anesthesia: where are we? Can J Anaesth. 122. Zwass MS, Fisher DM, Welborn LG, et al. Induction and maintenance
2004;51:411–416. characteristics of anesthesia with desflurane and nitrous oxide in infants
98. Constant I, Dubois MC, Piat V, et al. Changes in electroencephalogram and children. Anesthesiology. 1992;76:373–378.
and autonomic cardiovascular activity during induction of anesthesia 123. Murray D, Forbes R, Murphy K, Mahoney L. Nitrous oxide: cardio-
with sevoflurane compared with halothane in children. Anesthesiology. vascular effects in infants and small children during halothane and
1999;91:1604–1615. isoflurane anesthesia. Anesth Analg. 1988;67:1059–1064.
99. Voss LJ, Sleigh JW, Barnard JP, Kirsch HE. The howling cortex: seizures 124. Murray D, Vandewalker G, Matherne GP, Mahoney LT. Pulsed Doppler
and general anesthetic drugs. Anesth Analg. 2008;107:1689–1703. and two-dimensional echocardiography: comparison of halothane and
100. Woodforth IJ, Hicks RG, Crawford MR, et al. Electroencephalographic isoflurane on cardiac function in infants and small children. Anesthesio-
evidence of seizure activity under deep sevoflurane anesthesia in a logy. 1987;67:211–217.
nonepileptic patient. Anesthesiology. 1997;87:1579–1582. 125. Murray DJ, Forbes RB, Mahoney LT. Comparative hemodynamic de-
101. Komatsu H, Taie S, Endo S, et al. Electrical seizures during sevoflurane pression of halothane versus isoflurane in neonates and infants: an
anesthesia in two pediatric patients with epilepsy. Anesthesiology. echocardiographic study. Anesth Analg. 1992;74:329–337.
1994;81:1535–1537. 126. Kawana S, Wachi J, Nakayama M, Namiki A. Comparison of haemo-
102. Vakkuri AP, Seitsonen ER, Jantti VH, et al. A rapid increase in the dynamic changes induced by sevoflurane and halothane in paediatric
inspired concentration of desflurane is not associated with epileptiform patients. Can J Anaesth. 1995;42:603–607.
encephalogram. Anesth Analg. 2005;101:396–400, table of contents. 127. Wodey E, Pladys P, Copin C, et al. Comparative hemodynamic depres-
103. Sarkela MO, Ermes MJ, van Gils MJ, et al. Quantification of epileptiform sion of sevoflurane versus halothane in infants: an echocardiographic
electroencephalographic activity during sevoflurane mask induction. study. Anesthesiology. 1997;87:795–800.
Anesthesiology. 2007;107:928–938. 128. Rivenes SM, Lewin MB, Stayer SA, et al. Cardiovascular effects
104. Vakkuri A, Yli-Hankala A, Sarkela M, et al. Sevoflurane mask induction of sevoflurane, isoflurane, halothane, and fentanyl-midazolam in
of anaesthesia is associated with epileptiform EEG in children. Acta children with congenital heart disease: an echocardiographic study of
Anaesthesiol Scand. 2001;45:805–811. myocardial contractility and hemodynamics. Anesthesiology. 2001;94:
105. Vakkuri A, Jantti V, Sarkela M, et al. Epileptiform EEG during sevo- 223–229.
flurane mask induction: effect of delaying the onset of hyperventilation. 129. Dalal PG, Corner A, Chin C, et al. Comparison of the cardiovascular
Acta Anaesthesiol Scand. 2000;44:713–719. effects of isoflurane and sevoflurane as measured by magnetic resonance
106. Yli-Hankala A, Vakkuri A, Sarkela M, et al. Epileptiform electroence- imaging in children with congenital heart disease. J Clin Anesth. 2008;20:
phalogram during mask induction of anesthesia with sevoflurane. 40–44.
Anesthesiology. 1999;91:1596–1603. 130. Laird TH, Stayer SA, Rivenes SM, et al. Pulmonary-to-systemic blood
107. Jantti V, Yli-Hankala A, Vakkuri A. The epileptogenic property of flow ratio effects of sevoflurane, isoflurane, halothane, and fentanyl/
sevoflurane and in patients without epilepsy. Anesth Analg. 2001;92:1359. midazolam with 100% oxygen in children with congenital heart disease.
108. Kaisti KK, Jaaskelainen SK, Rinne JO, et al. Epileptiform discharges Anesth Analg. 2002;95:1200–1206, table of contents.
during 2 MAC sevoflurane anesthesia in two healthy volunteers. 131. Murat I, Lapeyre G, Saint-Maurice C. Isoflurane attenuates baroreflex
Anesthesiology. 1999;91:1952–1955. control of heart rate in human neonates. Anesthesiology. 1989;70:
109. Iijima T, Nakamura Z, Iwao Y, Sankawa H. The epileptogenic properties 395–400.
of the volatile anesthetics sevoflurane and isoflurane in patients with 132. Gregory GA. The baroresponses of preterm infants during halothane
epilepsy. Anesth Analg. 2000;91:989–995. anaesthesia. Can Anaesth Soc J. 1982;29:105–107.
110. Niejadlik K, Galindo A. Electrocorticographic seizure activity during 133. Baum VC, Wetzel GT. Sodium-calcium exchange in neonatal myocar-
enflurane anesthesia. Anesth Analg. 1975;54:722–724. dium: reversible inhibition by halothane. Anesth Analg. 1994;78:
111. Jaaskelainen SK, Kaisti K, Suni L, et al. Sevoflurane is epileptogenic 1105–1109.
in healthy subjects at surgical levels of anesthesia. Neurology. 2003;61: 134. Schmidt U, Schwinger RH, Bohm S, et al. Evidence for an interaction of
1073–1078. halothane with the L-type Ca2+channel in human myocardium.
112. Julliac B, Guehl D, Chopin F, et al. Risk factors for the occurrence of Anesthesiology. 1993;79:332–339.
electroencephalogram abnormalities during induction of anesthesia 135. Barash PG, Glanz S, Katz JD, et al. Ventricular function in children
with sevoflurane in nonepileptic patients. Anesthesiology. 2007;106:243– during halothane anesthesia: an echocardiographic evaluation. Anesthe-
251. siology. 1978;49:79–85.
113. Baum VC, Palmisano BW. The immature heart and Anesthesia. Anesthe- 136. Friesen RH, Lichtor JL. Cardiovascular depression during halothane
siology. 1997;87:1529–1548. anesthesia in infants: study of three induction techniques. Anesth Analg.
114. Friesen RH, Wurl JL, Charlton GA. Haemodynamic depression by 1982;61:42–45.
halothane is age-related in paediatric patients. Paediatr Anaesth. 2000;10: 137. Friesen RH, Wurl JL, Friesen RM. Duration of preoperative fast cor-
267–272. relates with arterial blood pressure response to halothane in infants.
115. Holzman RS, van der Velde ME, Kaus SJ, et al. Sevoflurane depresses Anesth Analg. 2002;95:1572–1576, table of contents.
myocardial contractility less than halothane during induction of 138. Aypar E, Karagoz AH, Ozer S, et al. The effects of sevoflurane and
anesthesia in children. Anesthesiology. 1996;85:1260–1267. desflurane anesthesia on QTc interval and cardiac rhythm in children.
116. Piat V, Dubois MC, Johanet S, Murat I. Induction and recovery charac- Paediatr Anaesth. 2007;17:563–567.
teristics and hemodynamic responses to sevoflurane and halothane in 139. Kataria B, Epstein R, Bailey A, et al. A comparison of sevoflurance to
children. Anesth Analg. 1994;79:840–844. halothane in paediatric surgical patients: results of a multicentre
117. Wolf WJ, Neal MB, Peterson MD. The hemodynamic and cardiovascular international study. Paediatr Anaesth. 1996;6:283–292.
effects of isoflurane and halothane anesthesia in children. Anesthesiology. 140. Green DH, Townsend P, Bagshaw O, Stokes MA. Nodal rhythm and
1986;64:328–333. bradycardia during inhalation induction with sevoflurane in infants: a
118. Saudan S, Beghetti M, Spahr-Schopfer I, et al. Cardiac rhythm and left comparison of incremental and high-concentration techniques. Br J
ventricular function of infants at 1 MAC sevoflurane and halothane. Anaesth. 2000;85:368–370.
Paediatr Anaesth. 2007;17:540–546. 141. Shirley PJ, Johnston G. Sevoflurane induced atrioventricular block.
119. Politis GD, Frankland MJ, James RL, et al. Factors associated with Paediatr Anaesth. 2001;11:125–126.
successful tracheal intubation of children with sevoflurane and no 142. Loeckinger A, Kleinsasser A, Maier S, et al. Sustained prolongation of the
muscle relaxant. Pediatr Anesthesia. 2002;95:615–620. QTc interval after anesthesia with sevoflurane in infants during the first
120. Wodey E, Senhadji L, Pladys P, et al. The relationship between expired 6 months of life. Anesthesiology. 2003;98:639–642.
concentration of sevoflurane and sympathovagal tone in children. 143. Kang J, Reynolds WP, Chen XL, et al. Mechanisms underlying the QT
Anesth Analg. 2003;97:377–382, table of contents. interval-prolonging effects of sevoflurane and its interactions with other
121. Weiskopf RB, Moore MA, Eger EI 2nd, et al. Rapid increase in desflurane QT-prolonging drugs. Anesthesiology. 2006;104:1015–1022.
concentration is associated with greater transient cardiovascular stimula- 144. Saussine M, Massad I, Raczka F, et al. Torsade de pointes during
tion than with rapid increase in isoflurane concentration in humans. sevoflurane anesthesia in a child with congenital long QT syndrome.
Anesthesiology. 1994;80:1035–1045. Paediatr Anaesth. 2006;16:63–65.
145. Gurkan Y, Canatay H, Agacdiken A, et al. Effects of halothane and 170. Dikmen Y, Eminoglu E, Salihoglu Z, Demiroluk S. Pulmonary mecha-
sevoflurane on QT dispersion in paediatric patients. Paediatr Anaesth. nics during isoflurane, sevoflurane and desflurane anaesthesia. Anaes-
2003;13:223–227. thesia. 2003;58:745–748.
146. Whyte SD, Sanatani S, Booker PD. Torsades de pointes with sevoflurane. 171. Habre W, Petak F, Sly PD, et al. Protective effects of volatile agents against
Paediatr Anaesth. 2006;16:1199–1201; author reply 201. methacholine-induced bronchoconstriction in rats. Anesthesiology.
147. Crawford MW, Ho DS, Shams M, Gow R. Magnesium deficiency alters 2001;94:348–353.
the threshold for epinephrine-induced arrhythmias during halothane or 172. Katoh T, Ikeda K. A comparison of sevoflurane with halothane, en-
sevoflurane anesthesia in the rat. J Cardiothorac Vasc Anesth. 2004;18: flurane, and isoflurane on bronchoconstriction caused by histamine.
313–316. Can J Anaesth. 1994;41:1214–1219.
148. Karl HW, Swedlow DB, Lee KW, Downes JJ. Epinephrine-halothane 173. Habre W, Scalfaro P, Sims C, Tiller K, Sly PD. Respiratory mechanics
interactions in children. Anesthesiology. 1983;58:142–145. during sevoflurane anesthesia in children with and without asthma.
149. Johnston RR, Eger EI 2nd, Wilson C. A comparative interaction of Anesth Analg. 1999;89:1177–1181.
epinephrine with enflurane, isoflurane, and halothane in man. Anesth 174. Chapple DJ, Clark JS, Hughes R. Interaction between atracurium and
Analg. 1976;55:709–712. drugs used in Anaesthesia. Br J Anaesth. 1983;55 Suppl 1:17S–22S.
150. Weiskopf RB, Eger EI 2nd, Holmes MA, et al. Epinephrine-induced 175. Ali HH, Savarese JJ. Monitoring of neuromuscular function. Anesthesio-
premature ventricular contractions and changes in arterial blood logy. 1976;45:216–249.
pressure and heart rate during I-653, isoflurane, and halothane anes- 176. Woloszczuk-Gebicka B, Lapczynski T, Wierzejski W. The influence of
thesia in swine. Anesthesiology. 1989;70:293–298. halothane, isoflurane and sevoflurane on rocuronium infusion in
151. Hikasa Y, Okabe C, Takase K, Ogasawara S. Ventricular arrhythmogenic children. Acta Anaesthesiol Scand. 2001;45:73–77.
dose of adrenaline during sevoflurane, isoflurane, and halothane anaes- 177. Lowry DW, Mirakhur RK, McCarthy GJ, et al. Neuromuscular effects of
thesia either with or without ketamine or thiopentone in cats. Res Vet rocuronium during sevoflurane, isoflurane, and intravenous anesthesia.
Sci. 1996;60:134–137. Anesth Analg. 1998;87:936–940.
152. Lindahl SG, Yates AP, Hatch DJ. Respiratory depression in children 178. Rupp SM, Miller RD, Gencarelli PJ. Vecuronium-induced neuromus-
at different end tidal halothane concentrations. Anaesthesia. 1987;42: cular blockade during enflurane, isoflurane, and halothane anesthesia
1267–1275. in humans. Anesthesiology. 1984;60:102–105.
153. Murat I, Chaussain M, Hamza J, Saint-Maurice C. The respiratory effects 179. Caldwell JE, Laster MJ, Magorian T, et al. The neuromuscular effects of
of isoflurane, enflurane and halothane in spontaneously breathing desflurane, alone and combined with pancuronium or succinylcholine
children. Anaesthesia. 1987;42:711–718. in humans. Anesthesiology. 1991;74:412–418.
154. Brown K, Aun C, Stocks J, et al. A comparison of the respiratory effects 180. Kobayashi O, Ohta Y, Kosaka F. Interaction of sevoflurane, isoflurane,
of sevoflurane and halothane in infants and young children. Anesthe- enflurane and halothane with non-depolarizing muscle relaxants and
siology. 1998;89:86–92. their prejunctional effects at the neuromuscular junction. Acta Med
155. Wren WS, Allen P, Synnott A, et al. Effects of halothane, isoflurane and Okayama. 1990;44:209–215.
enflurane on ventilation in children. Br J Anaesth. 1987;59:399–409. 181. Kharasch ED. Adverse drug reactions with halogenated anesthetics. Clin
156. Behforouz N, Dubousset AM, Jamali S, Ecoffey C. Respiratory effects of Pharmacol Ther. 2008;84:158–162.
desflurane anesthesia on spontaneous ventilation in infants and children. 182. Hatch DJ. New inhalation agents in paediatric anaesthesia. Br J Anaesth.
Anesth Analg. 1998;87:1052–1055. 1999;83:42–49.
157. Yamakage M, Tamiya K, Horikawa D. Effects of halothane and sevo- 183. Kharasch ED, Thummel KE. Identification of cytochrome P450 2E1 as
flurane on the paediatric respiratory pattern. Paediatr Anaesth. 1994; the predominant enzyme catalyzing human liver microsomal defluori-
6:95–102. nation of sevoflurane, isoflurane, and methoxyflurane. Anesthesiology.
158. Brown KA, Reich O, Bates JH. Ventilatory depression by halothane in 1993;79:795–807.
infants and children. Can J Anaesth. 1995;42:588–596. 184. Cousins MJ, Mazze RI. Methoxyflurane nephrotoxicity. A study of dose
159. Murat I, Saint-Maurice JP, Beydon L, MacGee K. Respiratory effects of response in man. JAMA. 1973;225:1611–1616.
nitrous oxide during isoflurane anaesthesia in children. Br J Anaesth. 185. Kharasch ED, Hankins DC, Thummel KE. Human kidney methoxy-
1986;58:1122–1129. flurane and sevoflurane metabolism. Intrarenal fluoride production as a
160. Reignier J, Ben Ameur M, Ecoffey C. Spontaneous ventilation with possible mechanism of methoxyflurane nephrotoxicity. Anesthesiology.
halothane in children. A comparative study between endotracheal tube 1995;82:689–699.
and laryngeal mask airway. Anesthesiology. 1995;83:674–678. 186. Kharasch ED, Schroeder JL, Liggitt HD, et al. New insights into the
161. Crawford MW, Arrica M, Macgowan CK, Yoo SJ. Extent and localization mechanism of methoxyflurane nephrotoxicity and implications for
of changes in upper airway caliber with varying concentrations of anesthetic development (part 2): identification of nephrotoxic meta-
sevoflurane in children. Anesthesiology. 2006;105:1147–1152; discus- bolites. Anesthesiology. 2006;105:737–745.
sion 5A. 187. Higuchi H, Adachi Y, Wada H, et al. The effects of low-flow sevo-
162. Eastwood PR, Szollosi I, Platt PR, Hillman DR. Collapsibility of the flurane and isoflurane anesthesia on renal function in patients
upper airway during anesthesia with isoflurane. Anesthesiology. 2002; with stable moderate renal insufficiency. Anesth Analg. 2001;92:
97:786–793. 650–655.
163. Crawford MW, Rohan D, Macgowan CK, et al. Effect of propofol 188. Carney FM, Van Dyke RA. Halothane hepatitis: a critical review. Anesth
anesthesia and continuous positive airway pressure on upper airway size Analg. 1972;51:135–160.
and configuration in infants. Anesthesiology. 2006;105:45–50. 189. Lewis JH, Zimmerman HJ, Ishak KG, Mullick FG. Enflurane hepato-
164. Mercier FJ, Naline E, Bardou M, et al. Relaxation of proximal and distal toxicity. A clinicopathologic study of 24 cases. Ann Intern Med. 1983;98:
isolated human bronchi by halothane, isoflurane and desflurane. Eur 984–992.
Respir J. 2002;20:286–292. 190. Carrigan TW, Straughen WJ. A report of hepatic necrosis and death
165. Mitsuhata H, Saitoh J, Shimizu R, et al. Sevoflurane and isoflurane protect following isoflurane anesthesia. Anesthesiology. 1987;67:581–583.
against bronchospasm in dogs. Anesthesiology. 1994;81:1230–1234. 191. Martin JL, Plevak DJ, Flannery KD, et al. Hepatotoxicity after desflurane
166. Schutz N, Petak F, Barazzone-Argiroffo C, et al. Effects of volatile anesthesia. Anesthesiology. 1995;83:1125–1129.
anaesthetic agents on enhanced airway tone in sensitized guinea pigs. 192. Jang Y, Kim I. Severe hepatotoxicity after sevoflurane anesthesia
Br J Anaesth. 2004;92:254–260. in a child with mild renal dysfunction. Paediatr Anaesth. 2005;15:
167. Mazzeo AJ, Cheng EY, Bosnjak ZJ, et al. Differential effects of desflurane 1140–1144.
and halothane on peripheral airway smooth muscle. Br J Anaesth. 193. Cote G, Bouchard S. Hepatotoxicity after desflurane anesthesia in a 15-
1996;76:841–846. month-old child with Mobius syndrome after previous exposure to
168. von Ungern-Sternberg BS, Saudan S, Petak F, et al. Desflurane but not isoflurane. Anesthesiology. 2007;107:843–845.
sevoflurane impairs airway and respiratory tissue mechanics in children 194. Wright R, Eade OE, Chisholm M, et al. Controlled prospective study of
with susceptible airways. Anesthesiology. 2008;108:216–224. the effect on liver function of multiple exposures to halothane. Lancet.
169. Goff MJ, Arain SR, Ficke DJ, et al. Absence of bronchodilation during 1975;1:817–820.
desflurane anesthesia: a comparison to sevoflurane and thiopental. 195. Ray DC, Drummond GB. Halothane hepatitis. Br J Anaesth. 1991;67:
Anesthesiology. 2000;93:404–408. 84–99.
196. Kharasch ED, Hankins DC, Fenstamaker K, Cox K. Human halothane 221. Plurad D, Blaschke G, Jones S, Pfeiffer J. A case of malignant hyper-
metabolism, lipid peroxidation, and cytochromes P2A6 and P3A4. Eur thermia in a child encountered during a humanitarian assistance
J Clin Pharmacol. 2000;55:853–859. mission to the Philippines. Mil Med. 2008;173:805–808.
197. Pohl LR, Satoh H, Christ DD, Kenna JG. The immunologic and meta- 222. Pan TH, Wollack AR, DeMarco JA. Malignant hyperthermia associated
bolic basis of drug hypersensitivities. Annu Rev Pharmacol Toxicol. with enflurane anesthesia: a case report. Anesth Analg. 1975;54:47–49.
1988;28:367–387. 223. Otsuka H, Komura Y, Mayumi T, et al. Malignant hyperthermia during
198. Stewart RD. Proceedings: the effect of carbon monoxide on humans. J sevoflurane anesthesia in a child with central core disease. Anesthesio-
Occup Med. 1976;18:304–309. logy. 1991;75:699–701.
199. Kobayashi S, Bito H, Morita K, et al. Amsorb Plus and Dragersorb Free, 224. Ducart A, Adnet P, Renaud B, et al. Malignant hyperthermia during
two new-generation carbon dioxide absorbents that produce a low sevoflurane administration. Anesth Analg. 1995;80:609–611.
compound A concentration while providing sufficient CO2 absorption 225. Rosenberg H, Davis M, James D, et al. Malignant hyperthermia.
capacity in simulated sevoflurane anesthesia. J Anesth. 2004;18:277–281. Orphanet J Rare Dis. 2007;2:21.
200. Murray JM, Renfrew CW, Bedi A, et al. Amsorb: a new carbon dioxide 226. Yemen TA, McClain C. Muscular dystrophy, anesthesia and the safety of
absorbent for use in anesthetic breathing systems. Anesthesiology. 1999; inhalational agents revisited; again. Paediatr Anaesth. 2006;16:105–108.
91:1342–1348. 227. Wedel DJ, Gammel SA, Milde JH, Iaizzo PA. Delayed onset of malignant
201. Stabernack CR, Brown R, Laster MJ, et al. Absorbents differ enormously hyperthermia induced by isoflurane and desflurane compared with
in their capacity to produce compound A and carbon monoxide. Anesth halothane in susceptible swine. Anesthesiology. 1993;78:1138–1144.
Analg. 2000;90:1428–1435. 228. Britt BA, Endrenyi L, Frodis W, et al. Comparison of effects of several
202. Fang ZX, Eger EI 2nd, Laster MJ, et al. Carbon monoxide production from inhalation anaesthetics on caffeine-induced contractures of normal and
degradation of desflurane, enflurane, isoflurane, halothane, and sevo- malignant hyperthermic skeletal muscle. Can Anaesth Soc J. 1980;27:
flurane by soda lime and Baralyme. Anesth Analg. 1995;80:1187–1193. 12–15.
203. Anders MW. Formation and toxicity of anesthetic degradation products. 229. Politis GD, Tobin JR, Morell RC, Cantwell MF. Tracheal intubation of
Annu Rev Pharmacol Toxicol. 2005;45:147–176. healthy pediatric patients without muscle relaxant: A survey of technique
204. Berry PD, Sessler DI, Larson MD. Severe carbon monoxide poisoning utilization and perceptions of safety. Anesth Analg. 1999;99:737–741.
during desflurane anesthesia. Anesthesiology. 1999;90:613–616. 230. Katoh T, Ikeda K. Minimum alveolar concentration of sevoflurane in
205. Wissing H, Kuhn I, Warnken U, Dudziak R. Carbon monoxide pro- children. Br J Anaesth. 1992;68:139–141.
duction from desflurane, enflurane, halothane, isoflurane, and sevo- 231. Black A, Sury MR, Hemington L, et al. A comparison of the induction
flurane with dry soda lime. Anesthesiology. 2001;95:1205–1212. characteristics of sevoflurane and halothane in children. Anaesthesia.
206. Fatheree RS, Leighton BL. Acute respiratory distress syndrome after an 1996;51:539–542.
exothermic Baralyme-sevoflurane reaction. Anesthesiology. 2004;101: 232. Lerman J, Davis PJ, Welborn LG, et al. Induction, recovery, and safety
531–533. characteristics of sevoflurane in children undergoing ambulatory sur-
207. Baxter PJ, Kharasch ED. Rehydration of desiccated Baralyme prevents gery. Anesthesiology. 1996;84:1332–1340.
carbon monoxide formation from desflurane in an anesthesia machine. 233. Sarner JB, Levine M, Davis PJ, et al. Clinical characteristics of sevo-
Anesthesiology. 1997;86:1061–1065. flurane in children. A comparison with halothane. Anesthesiology. 1995;
208. Woehlck HJ, Dunning M 3rd, Raza T, et al. Physical factors affecting the 82:38–46.
production of carbon monoxide from anesthetic breakdown. Anesthe- 234. Morimoto Y, Mayhew JF, Knox SL, Zornow MH. Rapid induction of
siology. 2001;94:453–456. anesthesia with high concentrations of halothane or sevoflurane in
209. Yamakage M, Yamada S, Chen X, et al. Carbon dioxide absorbents children. J Clin Anesth. 2000;12:184–188.
containing potassium hydroxide produce much larger concentrations of 235. Fisher DM, Robinson S, Brett CM, et al. Comparison of enflurane,
compound A from sevoflurane in clinical practice. Anesth Analg. halothane, and isoflurane for diagnostic and therapeutic procedures in
2000;91:220–224. children with malignancies. Anesthesiology. 1985;63:647–650.
210. Eger EI 2nd, Gong D, Koblin DD, et al. Dose-related biochemical 236. McAteer PM, Carter JA, Cooper GM, Prys-Roberts C. Comparison of
markers of renal injury after sevoflurane versus desflurane anesthesia in isoflurane and halothane in outpatient paediatric dental anaesthesia.
volunteers. Anesth Analg. 1997;85:1154–1163. Br J Anaesth. 1986;58:390–393.
211. Mazze RI, Callan CM, Galvez ST, et al. The effects of sevoflurane on 237. Cattermole RW, Verghese C, Blair IJ, et al. Isoflurane and halothane for
serum creatinine and blood urea nitrogen concentrations: a retrospec- outpatient dental anaesthesia in children. Br J Anaesth. 1986;58:385–389.
tive, twenty-two-center, comparative evaluation of renal function in 238. Phillips AJ, Brimacombe JR, Simpson DL. Anaesthetic induction with
adult surgical patients. Anesth Analg. 2000;90:683–688. isoflurane or halothane. Oxygen saturation during induction with
212. Holak EJ, Mei DA, Dunning MB 3rd, et al. Carbon monoxide produc- isoflurane or halothane in unpremedicated children. Anaesthesia. 1988;
tion from sevoflurane breakdown: modeling of exposures under clinical 43:927–929.
conditions. Anesth Analg. 2003;96:757–764, table of contents. 239. Lindgren L, Randell T, Saarnivaara L. Comparison of inhalation
213. Castro BA, Freedman LA, Craig WL, Lynch C 3rd. Explosion within an induction with isoflurane or halothane in children. Eur J Anaesthesiol.
anesthesia machine: Baralyme, high fresh gas flows and sevoflurane 1991;8:33–37.
concentration. Anesthesiology. 2004;101:537–539. 240. Wren WS, McShane AJ, McCarthy JG, et al. Isoflurane in paediatric
214. Wu J, Previte JP, Adler E, et al. Spontaneous ignition, explosion, and fire anaesthesia. Induction and recovery from anaesthesia. Anaesthesia.
with sevoflurane and barium hydroxide lime. Anesthesiology. 2004;101: 1985;40:315–323.
534–537. 241. Bagshaw ON, Stack CG. A comparison of halothane and isoflurane for
215. Joseph MM, Shah K, Viljoen JF. Malignant hyperthermia associated with gaseous induction of anaesthesia in infants. Paediatr Anaesth. 1999;9:
isoflurane anesthesia. Anesth Analg. 1982;61:711–712. 25–29.
216. Garrido S, Fraga M, Martin MJ, Belda J. Malignant hyperthermia during 242. Girotra S, Singh A. Comparison of sevoflurane and halothane for
desflurane-succinylcholine anesthesia for orthopedic surgery. Anesthe- induction and intubation in pediatric cardiac surgical patients. Anesth
siology. 1999;90:1208–1209. Analg. 1999;88:SCA61.
217. Fu ES, Scharf JE, Mangar D, Miller WD. Malignant hyperthermia 243. Dubois MC, Piat V, Constant I, et al. Comparison of three techniques
involving the administration of desflurane. Can J Anaesth. 1996;43: for induction of anaesthesia with sevoflurane in children. Paediatr
687–690. Anaesth. 1999;9:19–23.
218. Uskova AA, Matusic BP, Brandom BW. Desflurane, malignant hyper- 244. Baum VC, Yemen TA, Baum LD. Immediate 8% sevoflurane induction
thermia, and release of compartment syndrome. Anesth Analg. in children: a comparison with incremental sevoflurane and incremental
2005;100:1357–1360, table of contents. halothane. Anesth Analg. 1997;85:313–316.
219. Lane JE, Brooks AG, Logan MS, eet al. An unusual case of malignant 245. Agnor RC, Sikich N, Lerman J. Single-breath vital capacity rapid
hyperthermia during desflurane anesthesia in an African-American inhalation induction in children: 8% sevoflurane versus 5% halothane.
patient. Anesth Analg. 2000;91:1032–1034, table of contents. Anesthesiology. 1998;89:379–384.
220. Girard T, Suhner M, Levano S, et al. A fulminant malignant hyper- 246. Fernandez M, Lejus C, Rivault O, et al. Single-breath vital capacity rapid
thermia episode in a patient with ryanodine receptor gene mutation inhalation induction with sevoflurane: feasibility in children. Paediatr
p.Tyr522Ser. Anesth Analg. 2008;107:1953–1955. Anaesth. 2005;15:307–313.
247. Lejus C, Bazin V, Fernandez M, et al. Inhalation induction using 266. Bortone L, Ingelmo P, Grossi S, et al. Emergence agitation in preschool
sevoflurane in children: the single-breath vital capacity technique children: double-blind, randomized, controlled trial comparing sevo-
compared to the tidal volume technique. Anaesthesia. 2006;61:535–540. flurane and isoflurane anesthesia. Paediatr Anaesth. 2006;16:1138–1143.
248. Bacher A, Burton AW, Uchida T, Zornow MH. Sevoflurane or halothane 267. Davis PJ, Greenberg JA, Gendelman M, Fertal K. Recovery characteris-
anesthesia: can we tell the difference? Anesth Analg. 1997;85:1203–1206. tics of sevoflurane and halothane in preschool-aged children undergoing
249. Gibbons RT, Steffey EP, Eger EI 2nd. The effect of spontaneous versus bilateral myringotomy and pressure equalization tube insertion. Anesth
controlled ventilation on the rate of rise of alveolar halothane con- Analg. 1999;88:34–38.
centration in dogs. Anesth Analg. 1977;56:32–34. 268. Isik B, Arslan M, Tunga AD, Kurtipek O. Dexmedetomidine decreases
250. Davis PJ, Cohen IT, McGowan FX, Latta K. Recovery characteristics of emergence agitation in pediatric patients after sevoflurane anesthesia
desflurane versus halothane for maintenance of anesthesia in pediatric without surgery. Paediatr Anaesth. 2006;16:748–753.
ambulatory patients. Anesthesiology. 1994;80:298–302. 269. Aono J, Mamiya K, Manabe M. Preoperative anxiety is associated with
251. O’Brien K, Robinson DN, Morton NS. Induction and emergence in a high incidence of problematic behavior on emergence after halothane
infants less than 60 weeks post-conceptual age: comparison of thiopen- anesthesia in boys. Acta Anaesthesiol Scand. 1999;43:542–544.
tal, halothane, sevoflurane and desflurane. Br J Anaesth. 1998;80: 270. Aono J, Ueda W, Mamiya K, et al. Greater incidence of delirium during
456–459. recovery from sevoflurane anesthesia in preschool boys. Anesthesiology.
252. Welborn LG, Hannallah RS, Norden JM. Comparison of emergence and 1997;87:1298–1300.
recovery characteristics of halothane in pediatric ambulatory patients. 271. Kain ZN, Caldwell-Andrews AA, Maranets I, et al. Preoperative anxiety
Anesth Analg. 1996;83:917–920. and emergence delirium and postoperative maladaptive behaviors.
253. Nordmann GR, Read JA, Sale SM, et al. Emergence and recovery in Anesth Analg. 2004;99:1648–1654, table of contents.
children after desflurane and isoflurane anaesthesia: effect of anaesthetic 272. Ibacache ME, Munoz HR, Brandes V, Morales AL. Single-dose dexme-
duration. Br J Anaesth. 2006;96:779–785. detomidine reduces agitation after sevoflurane anesthesia in children.
254. Welborn LG, Hannallah RS, McGill WA, et al. Induction and recovery Anesth Analg. 2004;98:60–63, table of contents.
characteristics of desflurane and halothane anaesthesia in paediatric 273. Tesoro S, Mezzetti D, Marchesini L, Peduto VA. Clonidine treatment for
outpatients. Paediatr Anaesth. 1994;4:359–364. agitation in children after sevoflurane anesthesia. Anesth Analg. 2005;
255. Viitanen H, Baer G, Annila P. Recovery characteristics of sevoflurane or 101:1619–1622.
halothane for day-case anaesthesia in children aged 1–3 years. Acta 274. Abu-Shahwan I, Chowdary K. Ketamine is effective in decreasing the
Anaesthesiol Scand. 2000;44:101–106. incidence of emergence agitation in children undergoing dental repair
256. Le Berre P-Y, Wodey E, Joly A, et al. Comparison of recovery after under sevoflurane general anesthesia. Paediatr Anaesth. 2007;17:
intermediate duration of anaesthesia with sevoflurane and isoflurane. 846–850.
Paediatr Anaesth. 2001;11:443–448. 275. Dalens BJ, Pinard AM, Letourneau DR, et al. Prevention of emergence
257. Ebert TJ, Robinson BJ, Uhrich TD, et al. Recovery from sevoflurane agitation after sevoflurane anesthesia for pediatric cerebral magnetic
anesthesia: a comparison to isoflurane and propofol anesthesia. Anes- resonance imaging by small doses of ketamine or nalbuphine adminis-
thesiology. 1998;89:1524–1531. tered just before discontinuing anesthesia. Anesth Analg. 2006;102:
258. Gauthier A, Girard F, Boudreault D, et al. Sevoflurane provides faster 1056–1061.
recovery and postoperative neurological assessment than isoflurane in 276. Abu-Shahwan I. Effect of propofol on emergence behavior in children
long-duration neurosurgical cases. Anesth Analg. 2002;95:1384–1388. after sevoflurane general anesthesia. Paediatr Anaesth. 2008;18:55–59.
259. Sikich N, Lerman J. Development and psychometric evaluation of the 277. Aouad MT, Yazbeck-Karam VG, Nasr VG, et al. A single dose of pro-
pediatric anesthesia emergence delirium scale. Anesthesiology. 2004;100: pofol at the end of surgery for the prevention of emergence agitation in
1138–1145. children undergoing strabismus surgery during sevoflurane anesthesia.
260. Cravero JP, Beach M, Thyr B, Whalen K. The effect of small dose Anesthesiology. 2007;107:733–738.
fentanyl on the emergence characteristics of pediatric patients after 278. Morio M, Fujii K, Satoh N, et al. Reaction of sevoflurane and its degra-
sevoflurane anesthesia without surgery. Anesth Analg. 2003;97:364–367, dation products with soda lime. Toxicity of the byproducts. Anesthesio-
table of contents. logy. 1992;77:1155–1164.
261. Cravero JP, Beach M, Dodge CP, Whalen K. Emergence characteristics 279. Liu J, Laster MJ, Eger EI 2nd, Taheri S. Absorption and degradation of
of sevoflurane compared to halothane in pediatric patients undergoing sevoflurane and isoflurane in a conventional anesthetic circuit. Anesth
bilateral pressure equalization tube insertion. J Clin Anesth. 2000;12: Analg. 1991;72:785–789.
397–401. 280. Ebert TJ, Frink EJ Jr, Kharasch ED. Absence of biochemical evidence for
262. Cravero J, Surgenor S, Whalen K. Emergence agitation in paediatric renal and hepatic dysfunction after 8 hours of 1.25 minimum alveolar
patients after sevoflurane anaesthesia and no surgery: a comparison with concentration sevoflurane anesthesia in volunteers. Anesthesiology.
halothane. Paediatr Anaesth. 2000;10:419–424. 1998;88:601–610.
263. Cole JW, Murray DJ, McAllister JD, Hirshberg GE. Emergence behaviour 281. Ebert TJ, Messana LD, Uhrich TD, Staacke TS. Absence of renal and
in children: defining the incidence of excitement and agitation following hepatic toxicity after four hours of 1.25 minimum alveolar anesthetic
anaesthesia. Paediatr Anaesth. 2002;12:442–447. concentration sevoflurane anesthesia in volunteers. Anesth Analg. 1998;
264. Voepel-Lewis T, Malviya S, Tait AR. A prospective cohort study of 86:662–667.
emergence agitation in the pediatric postanesthesia care unit. Anesth 282. Higuchi H, Sumikura H, Sumita S, et al. Renal function in patients with
Analg. 2003;96:1625–1630, table of contents. high serum fluoride concentrations after prolonged sevoflurane
265. Meyer RR, Munster P, Werner C, Brambrink AM. Isoflurane is anesthesia. Anesthesiology. 1995;83:449–458.
associated with a similar incidence of emergence agitation/delirium as 283. Yasuda N, Targ AG, Eger EI 2nd. Solubility of I-653, sevoflurane,
sevoflurane in young children—a randomized controlled study. Paediatr isoflurane, and halothane in human tissues. Anesth Analg. 1989;69:
Anaesth. 2007;17:56–60. 370–373.
Xenon and Anesthesia:

Pharmacology 22
Peter H. Tonner C H A P T E R
INTRODUCTION HISTORY
The biologic activity of noble gases was first described in the 1950s Xenon was discovered in 1898 by Ramsay and Travers after eva-
when their anesthetic properties were discovered.1,2 Noble gases poration of liquid air components. In 1962, it was categorized as
have been subdivided into three groups according to their a noble gas together with helium, neon, argon, krypton, and
anesthetic effect. Xenon belongs to the first group, revealing an radon, all of them found in the troposphere in minute amounts.
anesthetic effect under normal atmospheric pressure when mixed Compared with the other noble gases, xenon is the heaviest stable
with oxygen at a ratio of 70 to 30%. Compared with xenon, argon compound with a molecular weight of 131.3 (Table 22–2). With a
and krypton belong into the second group, which exerts an relative concentration of 0.0000087 vol%, it is rather rare. After
anesthetic effect only in the hyperbaric environment. The third the demonstration of its analgesic effects in mice in 1946,2 the first
group includes helium, neon, and radon; these are completely use of xenon as an anesthetic in humans can be traced back to
without an anesthetic effect3 (Table 22–1). Since its first reported 1951, reported by Cullen and Gross.4 They described a rapid loss
use in humans, xenon was accompanied by the belief that it was of consciousness and a quick recovery using the gas at an 80 vol%
the closest candidate for an ideal anesthetic gas.4 Although the concentration (Figure 22–1).
anesthetic use of xenon was not followed up rigorously, through
the following years, sporadic reports continued to support the CHEMICAL REACTIVITY
superior properties of this gas compared with the available inhala-
tional and intravenous anesthetics. Thus, xenon was demonstrated Because of its unique electron structure, xenon is chemically
in studies in animals and humans to exert superior hemodynamic nearly inert. It is nonexplosive; however, under extreme condi-
stability, possibly being the anesthetic of choice for cardiovas- tions, it may form molecular compounds with highly reactive
cularly compromised patients. Since 1990, there has been renewed elements, such as oxygen or fluoride. During anesthesia, it is
interest in xenon, and more studies were published examining extremely unlikely that xenon participates in a chemical reaction.
various aspects of clinical anesthesia with xenon. At the end of However, although biotransformation of xenon has not been
2005, xenon was approved for clinical use in Germany, and it was
approved in the rest of Europe in 2007. It is likely that approval
for the Northern American continent will follow. Although consi-
derable clinical experience of the use of xenon in anesthesia has
accumulated in adults, only very limited experience exists in pedi-
atric patients. In this chapter, general aspects of xenon pharma-
cology in anesthesia are reviewed, and aspects relevant to pediatric
anesthesia are emphasized.
TABLE 22-1. Physicochemical Properties and Relative

Anesthetic Potencies of Noble Gases (Reference Gas:
Nitrogen)
Relative Figure 22-1. Pharmacokinetics of inhalational anesthetics.
Molecular Lipid Anesthetic Compared with the inhalational anesthetics halothane, isoflu-
Gas Weight Solubility Potency rane, sevoflurane, desflurane as well as nitrous oxide, the uptake
of xenon is extremely rapid, thus rendering xenon anesthesia
He 4 0.015 0.2
highly adjustable. For example, when halothane is administered
Ne 20 0.019 0.3
for 20 minutes only little more than 50% of the inspired fraction
N2 28 0.067 1
is reached in the alveoli whereas more than 90% is reached after
Ar 40 0.14 2.3
only 5 minutes of xenon inhalation. Similarly, the elimination of
Kr 84 0.43 2.5
xenon is more rapid than that of any of the other inhalational
Xe 131 1.17 25.6
anesthetics. FA/FI = alveolar fraction/inspired fraction.
TABLE 22-2. Physicochemical Properties of Xenon and anesthetics such as volatile anesthetics act primarily on gamma-
Nitrous Oxide aminobutyric acid (GABA) A receptors. However, it was shown
that xenon potently inhibits N-methyl-D-aspartic acid (NMDA)
Xenon Nitrous Oxide receptor function and that the effect of xenon on GABAA receptors
Molecular diameter, Å 4.0055 3.879 is only minimal.5–8 However, xenon inhibits excitatory NMDA
Blood/gas partition coefficient 0.47 0.14 receptor channels. NMDA receptors have important functions in
Oil/gas partition coefficient 1.4 1.9 synaptic mechanisms that underlie learning, memory, and the
MAC (in humans) 1.05 0.71 perception of pain. In addition to xenon, the NMDA receptor is
Greenhouse effect – + also a target of the intravenous general anesthetics ketamine and,
Molecular weight 131.29 44.02 at least partially, nitrous oxide.5,9 The inhibition of the NMDA
Freezing point, °C –111.9 –90.0 receptor has been reported to be the main action of xenon and its
Boiling point, °C –108.2 –88.5 anesthetic and analgesic effects.10 A study compared the effects of
Density, g/L 5.40 1.81 nitrous oxide, xenon, isoflurane, and ethanol directly on nine
Viscosity (micropoises) 226 145 different recombined ligand-gated ion channels including GABAA,
Thermal conductivity, mW*cm–1*K–1 0.057 0.173 NMDA, 5-hydroxy-tryptamine (5-HT3), and acetylcholine (ACh)
Thermal capacity, cal*K–1*mol–1 4.97 9.19 receptors by employing a voltage clamp technique.11 Xenon ex-
erted a stronger effect on NMDA receptors than on GABAA
receptors, rendering this anesthetic distinctly different from
demonstrated, it is conceivable that xenon may be involved in isoflurane and ethanol, which exerted their highest potencies at
biochemical processes. GABAA receptors. Studies looking at ether, nitrous oxide, or xenon
already indicated that GABAA receptors are not as strongly
affected by xenon as by other anesthetics.5–8 In this respect, xenon
ACTIONS OF XENON is markedly different from other inhalational anesthetics.
AT SUBCELLULAR AND Another molecular target site shared by xenon with gaseous and
volatile anesthetics is the nicotinic acetylcholine receptor (nAChR).
CELLULAR LEVELS It has been demonstrated that central nervous system nAChRs,
Although the analgesic and anesthetic properties of xenon have especially those composed of the β2 subunit, are inhibited in their
been known for more than five decades, the exact mechanisms of function by many anesthetics at relevant concentrations.12–16 Xenon
action at the cellular or molecular level are not known yet. is a potent analgesic at subanesthetic concentrations.17,18 It has been
However, a number of studies have been performed to define speculated that this antinociceptive effect is caused by an action on
parameters that are relevant for the action of these compounds glutamate receptors, namely, the NMDA receptor, in a manner
(Figure 22–2). It is known that many anesthetics exert their actions similar to that of ketamine.19 A target site for xenon is part of the
at a variety of molecular targets. Among these, the superfamily of two pore-domain potassium channels. It was shown that xenon as
ligand-gated ion channels has been shown to be more likely to be well as nitrous oxide and cyclopropane activate the TREK-1 chan-
influenced in their function at clinical concentrations than other nel at clinical concentrations. By contrast, the TASK-3 channel,
receptor or channel proteins. It has been demonstrated that most which is very sensitive to volatile anesthetics such as halothane, is
not insensitive to xenon.20
ANESTHESIA AND MIMINUM

ALVEOLAR CONCENTRATION
In an early study, the minimum alveolar concentration (MAC) of
xenon was estimated to be 71% at 1 atm surrounding pressure21
(see Table 22–2). Later, xenon was described to be more potent in
an elderly population with a MAC of 63%.22 Accordingly, the
anesthetic potency of xenon is too weak for its use as a single
anesthetic. One cannot deliver more than 1 MAC of xenon at an
inspired oxygen fraction (FIO2) of 0.3, which is the standard for
most healthy patients. At a concentration of 1 MAC, however, it is
impossible to safely perform a surgical operation. The MAC of
volatile anesthetics has been reported to be decreased when xenon
is co-administered. It has been demonstrated in patients that
sevoflurane fails to attenuate the cardiovascular response when
Figure 22-2. Meyer-Overton correlation of inhalational anes- administered by itself.23 However, in combination with either
thetics: When anesthetic potency (minimal alveolar concentra- nitrous oxide or xenon, the cardiovascular response to skin inci-
tion [MAC]) is plotted against lipid solubility (oil/gas partition sion was completely blocked. A follow-up study evaluated whether
coefficient) on a bilogarithmic plot, most anesthetics are lying a difference in the effect of nitrous oxide or xenon in combination
on a straight line. Xenon obeys this so-called Meyer-Overton with sevoflurane existed. Forty-three patients undergoing elective
rule, supporting the view that the molecular target site that surgery were studied and the MAC was determined according to
binds xenon is of lipophilic nature. the up-and-down method.24 This study demonstrated that the
CHAPTER 22 ■ Xenon and Anesthesia: Pharmacology 349
suppression of cardiovascular responses by xenon and nitrous than propofol-based anesthesia.29 In another study in high-risk
oxide was similar at 70 vol%, possibly reflecting their nearly iden- patients undergoing aortic surgery with xenon or propofol anes-
tical analgesic properties. Although there is evidence that the thesia, global cardiac performance and myocardial contractility
MAC of xenon is age-dependent, there are currently no sufficient were assessed using transesophageal echocardiography and myo-
data for an exact MAC of xenon in children. cardial cell damage with troponin T and CK-MB (MB isoenzyme
of creatine kinase).30 No significant differences between groups
were found in global myocardial performance, myocardial con-
EFFECTS ON THE tractility, or laboratory values at any time during the study period.
CARDIOVASCULAR SYSTEM Duration of stay on the intensive care unit or in the hospital did
not differ significantly between the groups. It was concluded that
Xenon has been reported to possess a remarkably safe hemo-
there was no advantage of xenon-based anesthesia over total intra-
dynamic profile. A study in pigs was demonstrated that hemo-
venous anesthesia (TIVA) in high-risk surgical patients.30 However,
dynamic parameters as well as plasma catecholamine levels it was demonstrated that xenon increased parasympathetic and
remained within normal limits during xenon anesthesia. Even at reduced sympathetic activity in patients at high risk of cardiac
subanesthetic concentrations of xenon, a significant decrease of complications compared with propofol.31 Using heart rate vari-
adrenaline was observed, possibly reflecting the high analgesic ability as a measure of autonomic nervous system regulation, a
potency of xenon.25 In a study looking at the hemodynamic effects correlation to hemodynamics was demonstrated; however, there
of xenon versus. nitrous oxide, 32 adult patients undergoing was no benefit in terms of postoperative short- and long-term
gynecologic, plastic, or orthopedic surgery were evaluated.26 In outcome.31
each group, anesthesia was maintained using either 70 vol% These results of recent studies on cardiovascular risk patients
nitrous oxide or 70 vol% xeno; fentanyl was added when blood indicate that xenon may provide a more stable hemodynamic
pressure increased by more than 20% from baseline. The anes- control than TIVA and may exert beneficial effects on autonomic
thetist was unaware of the gas used. In this setting, it was found nervous system regulation. However, at present, there are no data
that incremental fentanyl was necessary in all patients receiving on a large group of patients in order to conclusively demonstrate
nitrous oxide and in only 50% of the patients receiving xenon, that cardiovascular outcome is improved when patients receive
whereas awareness did not occur in both groups. No differences in xenon anesthesia.32 Unfortunately, currently, no data are available
blood pressure, heart rate, or the changes during surgery were on hemodynamics in children under xenon anesthesia.
observed between the groups. By contrast to these clinical para-
meters, the adrenaline levels demonstrated a difference between
the nitrous oxide and the xenon groups. Whereas in the xenon EFFECT ON CEREBRAL CIRCULATION
group, the adrenaline level remained below the baseline levels
throughout the operation and returned to control values only at The effect of xenon on cerebral blood flow seems to vary accord-
the end of surgery, the nitrous oxide group showed a continuous ing to the model used and the species studied.33–36 In radiology,
increase in plasma adrenaline concentrations with a significant radioactive xenon isotopes have been in use for a long time for
determination of cerebral blood flow. In volunteers, administra-
difference at the end of the operation. In addition, the nitrous
tion of 33 vol% xenon lead to a significant increase in cerebral
oxide group showed increased adrenaline values immediately
perfusion. Increases in perfusion were also noted in patients with
postoperatively, returning to baseline only after about 6 hours
traumatic brain injury. Thus, some authors recommended the
postoperatively. There was no apparent difference in recovery time
prophylactic use of hyperventilation in patients receiving xenon
or quality of recovery, and the attending anesthetists were not able
for diagnostic purposes.37–40 An experimental setting involving
to tell which gas was used.26 In a subsequent study examining
swine demonstrated that xenon left cerebral autoregulation intact
otherwise healthy American Society of Anesthesiologists (ASA)
under different conditions.41 Studies using transcranial Doppler
class 1 patients undergoing open cholecystectomy or hysterec-
ultrasonography found differing results. Increases as well as
tomy, the effect of xenon was studied by echocardiography. No
nonsignificant changes in cerebral blood flow velocities have been
alterations in mean fractional area change were observed during
reported.27,42–44
induction with xenon.27
In a large multicenter trial of xenon in elective surgery on
224 patients, xenon exerted stable respiratory and circulatory EFFECTS ON THE
conditions. In comparison with the isoflurane group, the hemo-
dynamic parameters of the xenon group appeared superior.28
GASTROINTESTINAL TRACT
However, most of the earlier data were obtained in patients Xenon has a low blood/gas partition coefficient of 0.12 to 0.14.45,46
lacking cardiovascular risk factors. Recently, studies have become A publication compared the effects of xenon and nitrous oxide on
available elaborating on the hemodynamic effects of xenon in gut distention directly under well-controlled conditions.47 In
patients with pre-existing cardiovascular disease. Thus, it was 21 pigs, anesthesia was induced and maintained intravenously.
demonstrated in patients with low cardiac ejection fraction under- Three groups of animals were studied, one receiving 75 vol%
going implantation of a cardioverter-defibrillator that xenon xenon, one 75 vol% nitrous oxide, and one 75 vol% nitrogen
provided greater hemodynamic stability than propofol.29 Heart for 240 minutes. After a laparotomy was performed, segments of
rate was reduced in both groups, but mean arterial pressure 15 cm in length were isolated in a gas-tight manner, filled with
(MAP) remained stable in the xenon group and was reduced in 30 mL of air, and pressure was measured through an inserted
the propofol group without changes in left ventricular ejection catheter. In both the nitrous oxide and in the xenon group, the
fraction (LVEF) in both groups. Even in this high-risk group of volume of the bowel increased compared with the nitrogen control
patients, xenon anesthesia resulted in more stable hemodynamics group. In the nitrous oxide group, however, there was an increase
of up to 88 mL, whereas in the xenon group, the volume increased tion, the airway resistance was significantly higher in the xenon
to only 39 mL (21 mL control). There was also a significant in- group than the nitrous oxide group. Airway pressure did not differ
crease in intraluminal pressure in the nitrous oxide group com- during normal airway conditions; however, during bronchocon-
pared with the xenon and the control groups. No difference in striction, there was a significant increase in airway pressure in the
intraluminal pressure was found when the xenon group and the xenon group compared with the nitrous oxide group (Ppeak xenon
control group were compared. 33.2 ± 5.5; nitrous oxide 28.4 ± 5.7 cmH2O).54 Another study
The low partition-coefficient of xenon predicts a lower looked at the effect of xenon on respiratory mechanics under both
transport capacity of the blood and a low rate of diffusion of xenon normal conditions and bronchoconstriction.55 By contrast to the
into gas-filled volumes. However, the ability of various substances previously cited study, the authors did not administer 70 vol%
to diffuse into adjacent space is also influenced by their respective xenon throughout the study but instead used 50 vol% xenon
molecular diameters (xenon 4.0055 Å; see Table 22–1) and their during bronchoconstriction. This change in experimental con-
diffusion coefficients, which may be modified by a number of ditions possibly led to the finding that there was no difference in
factors such as the polarity of the substance. Inhalation of xenon airway resistance between normal ventilation and ventilation
is swine did not alter mesenteric metabolic balance compared with during bronchoconstriction.55 In addition, airway resistance in
intravenous anesthesia.48 One study in swine showed that xenon dogs is different from that in pigs and conditions are also different
does not alter mesenteric blood flow and, thus, may be of advan- if airway resistance is measured in an open-chest situation. The
tage for abdominal surgery.49 It may be concluded that xenon can main factor responsible for the change in airway resistances if one
be used in abdominal surgery when factors such as hemodynamic switches from nitrous oxide to xenon appears to be the change in
control are of concern. Data on the gastrointestinal effects of both viscosity and density of the gas as predicted by the laws of
xenon in pediatric anesthesia are still lacking. fluid dynamics.56 However, gas exchange was not affected during
ventilation with xenon.54 The authors of the first study concluded
that, although there is a change in respiratory mechanics during
XENON AND RESPIRATORY xenon anesthesia, these changes are not of clinical relevance for
MECHANICS the following reasons54: (1) During general anesthesia, the ventila-
tor and not the patient has to overcome increases in airway re-
The physical parameters of xenon render this gas distinctly
sistance, (2) the increase in airway resistance is small under
different from the other gases used in anesthesia; especially the
healthy conditions and only moderate during bronchoconstric-
high density and viscosity alter the physical properties of a gas
tion. and finally, (3) gas exchange does not deteriorate during
mixture used for anesthesia when a high fraction of xenon is used.
xenon anesthesia.
Some implications of this fact have to be dealt with by anesthetists:
In our own study in a neonatal lung model, we were able to
(1) Anesthesia machines need to be upgraded so they can deal
demonstrate that xenon can be safely administered even when
with the more dense and more viscous gas mixtures. (2) The
internal tube diameters of 3.0 to 4.5 mm are used as long as
behavior of monitoring devices for respiratory monitoring may be
weight-adjusted tidal volumes are used (10 mL/kg). When tidal
influenced. (3) Respiratory mechanics of patients may be altered,
volumes were increased, nonlaminar flow occurred and peak
especially in the case of patients whose lung function is com-
promised. (4) In neonates, small airway diameters may inhibit the pressures rose dramatically (unpublished data).
use of xenon because excessive breathing pressures may need to be
applied. Diffusion Hypoxia
Flowmeters have been demonstrated to be affected by the
different physical properties of xenon. Although most flowmeters As the inert gas volume moving between capillary blood and
are designed to correct their readings according to the composi- alveolar space differs with varying gas solubility, specific gases may
tion of the gas used, most of them are not designed for use with concentrate or dilute during uptake or elimination. This is the
xenon and may, thus, show false readings without compensating reason why an outpour of gas occurs at the end of a nitrous oxide–
for the possible errors. A study on the practicability of flowmeters based anesthesia, an effect called diffusion anoxia by Fink.57 The
for xenon anesthesia demonstrated that only rotating vanes give solubility of nitrous oxide is higher (0.47) than that of nitrogen
sufficiently accurate readings when xenon was used, whereas three (0.015); thus, the concentration of nitrous oxide is rising during
other types of flowmeters did not.50 washout in the alveolar space. The mechanism of hypoxia is
In addition, in patients with lung diseases, the physical pro- twofold: (1) oxygen may be displaced and oxygenation inhibited,
perties of a gas may affect respiratory mechanics.51–53 Both the (2) carbon dioxide may be diluted in the alveoli, thus decreasing
density of xenon and its viscosity are higher than those of other respiratory drive and ventilation. Because the solubility of xenon
clinically used gases, an effect that demanded a producer of anes- is smaller than that of nitrous oxide but higher than that of
thesia machines to redesign one of their machines for administra- nitrogen, it may be concluded that a similar effect also occurs
tion of xenon because its ventilator did break after only short during xenon anesthesia but may be less pronounced. In pigs,
periods of administration. diffusion hypoxia after nitrous oxide versus xenon anesthesia was
The effect of xenon on respiratory mechanics was studied in studied.58 The lungs of pigs were ventilated either with a mixture
comparison with nitrous oxide in pigs.54 Groups of eight pigs were of 30 vol% oxygen and 70% nitrous oxide or 70 vol% xenon for
ventilated either with 70 vol% nitrous oxide or 70 vol% xenon and 30 minutes. At the end of this period, all animals were ventilated
airway pressure as well as resistance was measured. Both groups of with 30 vol% oxygen and 70 vol% nitrogen. Arterial oxygen partial
animals were then subjected to a metacholine infusion for induc- pressures were determined during nitrogen washin. A ΔPO2 of
tion of bronchoconstriction and measurements were repeated. 17 mmHg was found in the nitrous oxide group. In the pigs receiv-
Both under normal conditions and throughout bronchoconstric- ing xenon, the ΔPO2 was much smaller (6 mmHg), thus, confirming
the notion that inert gas exchange is mainly determined by the crossing the blood-brain barrier.80,81 Xenon readily crosses the
blood/gas/patient coefficient (solubility in lipids). Although the blood-brain barrier, thus reaching a potential site of injury quickly
lipid solubility of xenon is greater than that of nitrous oxide, more and has been demonstrated not to exert neurotoxic effects.
xenon may be taken up during an anesthetic than nitrous oxide. In a rat model mimicking hypoxic-ischemic effects in new-
However, only the part of the gas that is actually dissolved in the borns possibly continuing after delivery, xenon was administered
blood and passes the lungs may diffuse into the alveolar space so to 7-day-old rats after they received a 90-minute unilateral carotid
that lipid solubility is only of minor importance to these effects. ligation.82 In xenon-treated animals, short-term neuroprotection
demonstrated by histology was present compared with animals
treated with nitrogen. Accordingly, xenon was proposed to be an
ORGAN PROTECTION effective treatment after perinatal hypoxia-ischemia. It was con-
Experimental settings demonstrated that xenon exerts protective cluded that xenon is devoid of neurotoxic effects and with mini-
effects on several organ systems. This was first demonstrated in mal other side effects, thus, presenting an ideal candidate for
its effects on the brain. Here, xenon possesses protective properties treatment of brain injury after human perinatal asphyxia.
in several models of neuronal injury. In hypoxic neurons, it was Xenon also induces preconditioning in neuronal tissues, thus,
demonstrated that xenon exerts its action through a calcium- preventing damage when administered before an injury occurs.83
dependent mechanism.59 However, xenon was also reported to This preconditioning action of xenon has been demonstrated in in
have no neurotoxic effect such as other NMDA antagonists; this vitro as well as in vivo models of neonatal asphyxia. These actions
has been questioned at least for higher concentrations of xenon.60,61 of xenon have been demonstrated to occur because prosurvival
The heart is another important organ that appears to be protected proteins are up-regulated83 (Figure 22–3).
by xenon. Similar to volatile anesthetics that exert a precondition- Because xenon as a therapeutic treatment is very expensive and
ing effect comparable with ischemic preconditioning, xenon has delivery systems for it are not widely available, a better mode of
been demonstrated to protect the myocardium through this action of delivering xenon to newborns suffering from hypoxic-
mechanism, too.62,63 ischemic injury might be to first administer hypothermia and, in
a second step, add xenon during the therapy.84 It has been de-
monstrated recently that this type of asynchronous administration
NEUROPROTECTION of xenon and hypothermia can also significantly reduce the
hypoxic-ischemic injury in neonatal rats.84 Asynchronous admini-
Perinatal hypoxic ischemia is a serious complication during stration of xenon and hypothermia at intervals of 1 and 5 hours
childbirth. It has been estimated that 2 to 4 per 1000 term infants significantly reduced cerebral infarctions in a rat model of hypoxic
suffer an episode of hypoxic ischemia during labor.64 Fifteen to
20% of the infants developing hypoxic ischemic encephalopathy
will die. Another quarter of the surviving children develop chronic
neurologic deficits such as cerebral palsy.65,66 When a hypoxic
ischemic insult occurs, an evolving process is started characterized
by an initial primary injury followed by a self-sustaining cascade
of events that lead to additional brain injury.67,68 The brain damage
is produced by apoptotic and necrotic processes.69,70 The initiation
of excitotoxicity by excess neurotransmitter release causes receptor
overstimulation and cell death. Up to date, cooling is the only
intervention that has been proved to be effective in many models
of in vivo hypoxic-ischemic injury as well as in clinical trials with
either selective head cooling or systemic hyperthermia.71–76 Studies
such as the Cool Cap Study showed significant benefits of the
treatment with mild hypothermia (34–35°C) in children suffering
from mild to moderate perinatal hypoxic ischemia.77
NMDA receptor antagonists have long been believed to possess
Neuronal survival
neuroprotective efficacy. In neuronal cell cultures as well as in an
in vivo mouse model, the effect of xenon on neuronal injury was
tested against nitrogen.60 Xenon at a concentration of 60% reduced Figure 22-3. Suggested model of xenon-induced neuropro-
lactate dehydrogenase release as a measure of cell integrity to tection. After activation of protein kinase C (PKC) by xenon
baseline values. Consequently, in vivo xenon reduced injury by mitogen-activated protein (MAP), mitogen-activated kinases
45% at a concentration of 75% in a concentration-dependent (MAPKs) such as p38 MAPK and extracellular signal–related
manner. This effect is in contrast to other NMDA antagonists that kinase (ERK) are phosphorylated. Subsequently, cyclic adeno-
have been proposed to exert neuroprotective effects. In preclinical sine monophosphate response element–binding protein (CREB)
studies, these drugs clearly reduced neuronal injury. When tested is phosphorylated into pCREB and induces several survival
clinically, unfortunately, these promising results could not be genes via CREB-binding protein (CPB). Thus, the proteins
translated into significant clinical effects.78,79 NMDA antagonists brain-derived neurotrophic factor (BDNF) and B-cell lym-
such as ketamine or MK801 have been shown to possess inherent phoma 2 protein (Bcl-2) are generated, enhancing cellular
neurotoxic effects, to produce effects at receptors or channels tolerance to hypoxic/ischemic injury. Through activation of
different from the NMDA receptor, thus provoking side effects, Ras, MAPKs are stimulated and thereby increase the protection
or to not reach the site of injury because of their difficulties in pathway. Adapted from reference 83.
In order to determine possible adverse effects of a long-term

exposure to xenon, dogs were exposed to 80 vol% xenon in oxygen
every third day for 2 weeks.94 At the end of the study, no side
effects of xenon such as morphologic, hematologic, or biochemical
parameters were found. By contrast to a long-term exposure to
nitrous oxide after xenon, no effects were noted on methionine
synthetase and vitamin B12 metabolism.
ECONOMIC AND ECOLOGIC ASPECTS

Because of its rarity, xenon is relatively expensive. Consequently,
many projects are under way to reduce the amount of xenon
needed for anesthesia. The use of closed systems in anesthesia
machines like the Physioflex (Draeger, Luebeck, Germany) allows
a saving of more than half of the xenon compared with its use
in standard anesthesia machines. By connecting the anesthesia
Figure 22-4. Global pathology scores for xenon- and/or machine to a scavenging device, a major fraction of the delivered
hypothermia-treated rats 10 weeks after hypoxic/ischemic brain xenon may be recovered. Unfortunately, no xenon scavenger sys-
injury. The score was assessed from HE-stained brain sections tems are for sale at the moment. It may be possible that systems
and injury was graded from 0 to 4 (mean ± sem). The combina- based on molecular sieves will become available in the near future.
tion of xenon and hypothermia results in additive protection Medicolegal issues prohibit the direct reuse of the recycled gas. The
against hypoxic/ischemic injury that is greater than the effects captured xenon needs to be transferred to the manufacturer to be
of either treatment by itself. Adapted from reference 85. cleaned and purified before it can be used on another patient. It
will depend on the manufacturers if this setup makes sense
ischemia.84 Recently, it was demonstrated that the combination economically. In the not too distant future, however, the use of
of xenon and hypothermia conferred greater protection after xenon may not be confined to only some highly specialized centers.
hypoxic-ischemic injury than either treatment alone. Functional
improvement was almost complete and was sustained long term85
(Figure 22–4). SUMMARY
General anesthetics have been demonstrated to alter synaptic As reflected by recent publications, hemodynamic stability of
function by modulating specific ligand-gated ion channels such xenon in adults may not be as superior as previously thought, and
as the GABAA receptor and the NMDA subtype of the glutamate data in the pediatric population are missing. Neuroprotection is an
receptor.86 It has been postulated that the synaptic actions of important issue, especially in the prevention and therapy of
general anesthetics may have long-term consequences, especially neonatal hypoxic-ischemic brain injury. The initial findings look
in the developing brain. The changes in neuronal tissues brought promising, although further clinical studies are necessary. Wide-
about by general anesthetics have been demonstrated to be very spread use of xenon is critically dependent on the availability of
similar in morphology and functional impairments to the effects adequate anesthesia machines and possibly scavenging systems.
of alcohol.87–89 Xenon not only does not affect neurodegeneration At present, xenon has not been approved for anesthesia in
but also even exerts effects against apoptosis induced by general children; rather, it has been registered for anesthesia only in adults
anesthetics such as isoflurane. This was demonstrated in both an and more clinical studies in children are necessary to determine
in vitro and an in vivo model. During late fetal and early postnatal whether the beneficial properties seen in adults such as rapid
life, there is an extremely rapid turnover of synapses with a high induction and emergence as well as a relative lack of adverse effects
level of physiologically occurring apoptosis.90,91 Exposure of will also be obtainable in neonates and children.
neonatal rats to general anesthetics produces an up to 50-fold
increase in the number of neurons degenerating and- these chan-
ges are also associated with the functional neurologic deficits REFERENCES
when tested in behavioral tests in later life.92 1. Altschuler EL. Xenon as neuroprotectant in acute stroke? Med Hypotheses.
2001;56:227–228.
2. Lawrence JH, Loomis WF, Tobias CA, et al. Preliminary observations on
TERATOGENIC AND TOXIC EFFECTS the narcotic effect of xenon with review of values for solubilities of gases
in water and oils. J Physiol. 1946;105:197–201.
In a study comparing the teratogenic effects of nitrous oxide and 3. Trudell JR, Koblin DD, Eger EI 2nd. A molecular description of how
xenon, pregnant rats were exposed to either 70 vol% nitrous oxide noble gases and nitrogen bind to a model site of anesthetic action. Anesth
Analg. 1998;87:411–418.
or xenon in 30 vol% oxygen.93 Twenty days after exposure, the 4. Cullen SC, Gross EG. The anesthetic properties of xenon in animals and
fetuses were evaluated for anomalies. The rats of the nitrous oxide human beings, with additional observations on krypton. Science. 1951;
group showed a high rate of fetal absorption, skeletal anomalies, 113:580–581.
and macroscopic anomalies such as encephalocele, anophthalmia, 5. Jevtovic-Todorovic V, Todorovic SM, Mennerick S, et al. Nitrous oxide
microphthalmia, and gastroschisis of up to 37%. By contrast, in (laughing gas) is an NMDA antagonist, neuroprotectant and neurotoxin.
Nat Med. 1998;4:460–463.
the xenon group, only 3% anomalies were found. Thus, it may be 6. Mennerick S, Jevtovic-Todorovic V, Todorovic SM, et al. Effect of nitrous
concluded that xenon does not exert teratogenic effects when oxide on excitatory and inhibitory synaptic transmission in hippocampal
compared with nitrous oxide.93 cultures. J Neurosci. 1998;18:9716–9726.
7. de Sousa SL, Dickinson R, Lieb WR, et al. Contrasting synaptic actions of 31. Hanss R, Bein B, Turowski P, et al. The influence of xenon on regulation
the inhalational general anesthetics isoflurane and xenon. Anesthesiology. of the autonomic nervous system in patients at high risk of perioperative
2000;92:1055–1066. cardiac complications. Br J Anaesth. 2006;96:427–436.
8. Dzoljic M, Van Duijn B. Nitrous oxide–induced enhancement of gamma- 32. Tonner PH. Xenon: one small step for anaesthesia? Curr Opin Anaes-
aminobutyric acid A–mediated chloride currents in acutely dissociated thesiol. 2006;19:382–384.
hippocampal neurons. Anesthesiology. 1998;88:473–480. 33. Fink H, Blobner M, Bogdanski R, et al. Effects of xenon on cerebral blood
9. Anis NA, Berry SC, Burton NR, et al. The dissociative anaesthetics, flow and autoregulation: an experimental study in pigs. Br J Anaesth. 2000;
ketamine and phencyclidine, selectively reduce excitation of central 84:221–225.
mammalian neurones by N-methyl-aspartate. Br J Pharmacol. 1983;79: 34. Obrist WD, Wilkinson WE. Regional cerebral blood flow measurement
565–575. in humans by xenon-133 clearance. Cerebrovasc Brain Metab Rev.
10. Franks NP, Dickinson R, de Sousa SL, et al. How does xenon produce 1990;2:283–327.
anaesthesia? Nature. 1998;396:324. 35. Plougmann J, Astrup J, Pedersen J, et al. Effect of stable xenon inhalation
11. Yamakura T, Harris RA. Effects of gaseous anesthetics nitrous oxide and on intracranial pressure during measurement of cerebral blood flow in
xenon on ligand-gated ion channels. Comparison with isoflurane and head injury. J Neurosurg. 1994;81:822–828.
ethanol. Anesthesiology. 2000;93:1095–1101. 36. Yao LP, Bandres J, Nemoto EM, et al. Effect of 33% xenon inhalation
12. Violet JM, Downie DL, Nakisa RC, et al. Differential sensitivities of on whole-brain blood flow and metabolism in awake and fentanyl-
mammalian neuronal and muscle nicotinic acetylcholine receptors to anesthetized monkeys. Stroke. 1992;23:69–74.
general anesthetics. Anesthesiology. 1997;86:866–874. 37. Darby JM, Yonas H, Pentheny S, et al. Intracranial pressure response to
13. Flood P, Ramirez-Latorre J, Role L. Alpha 4 beta 2 neuronal nicotinic stable xenon inhalation in patients with head injury. Surg Neurol. 1989;
acetylcholine receptors in the central nervous system are inhibited by 32:343–345.
isoflurane and propofol, but alpha 7-type nicotinic acetylcholine receptors 38. Hartmann A, Dettmers C, Schuier FJ, et al. Effect of stable xenon on
are unaffected. Anesthesiology. 1997;86:859–865. regional cerebral blood flow and the electroencephalogram in normal
14. Cardoso RA, Yamakura T, Brozowski SJ, et al. Human neuronal nicotinic volunteers. Stroke. 1991;22:182–189.
acetylcholine receptors expressed in Xenopus oocytes predict efficacy of 39. Kashiwagi S, Yamashita T, Nakano S, et al. The wash-in/washout protocol
halogenated compounds that disobey the Meyer-Overton rule. Anesthe- in stable xenon CT cerebral blood flow studies. AJNR Am J Neuroradiol.
siology. 1999;91:1370–1377. 1992;13:49–53.
15. Yamakura T, Chavez-Noriega LE, Harris RA. Subunit-dependent inhi- 40. Latchaw RE, Yonas H, Pentheny SL, et al. Adverse reactions to xenon-
bition of human neuronal nicotinic acetylcholine receptors and other enhanced CT cerebral blood flow determination. Radiology. 1987;163:
ligand-gated ion channels by dissociative anesthetics ketamine and 251–254.
dizocilpine. Anesthesiology. 2000;92:1144–1153. 41. Schmidt M, Marx T, Papp-Jambor C, et al. Effect of xenon on cerebral
16. Suzuki T, Ueta K, Sugimoto M, et al. Nitrous oxide and xenon inhibit the autoregulation in pigs. Anaesthesia. 2002;57:960–966.
human (alpha 7)5 nicotinic acetylcholine receptor expressed in Xenopus 42. Stapelfeldt CK, Hahn CP, Tonner PH, et al. Effect of xenon on carbon-
oocyte. Anesth Analg. 2003;96:443–448. dioxide reactivity in humans. Anesthesiology. 2000;93:A347.
17. Petersen-Felix S, Luginbuhl M, Schnider TW, et al. Comparison of the 43. Tonner PH, Stapelfeldt CK, Hahn CP, et al. Cerebral blood flow velocities
analgesic potency of xenon and nitrous oxide in humans evaluated by during xenon anesthesia. Anesthesiology. 2000;93:A377.
experimental pain. Br J Anaesth. 1998;81:742–747. 44. Stapelfeldt CK, Tonner PH, Scholz J. Xenon vs. isoflurane: effects on
18. Lynch C 3rd, Baum J, Tenbrinck R. Xenon anesthesia. Anesthesiology. cerebral blood flow and cerebral autoregulation in humans. Anesthesio-
2000;92:865–868. logy. 2001;95:A336.
19. Hudspith MJ. Glutamate: a role in normal brain function, anaesthesia, 45. Goto T, Suwa K, Uezono S, et al. The blood-gas partition coefficient of
analgesia and CNS injury. Br J Anaesth. 1997;78:731–747. xenon may be lower than generally accepted. Br J Anaesth. 1998;80:
20. Gruss M, Bushell TJ, Bright DP, et al. Two-pore-domain K+ channels are 255–256.
a novel target for the anesthetic gases xenon, nitrous oxide, and 46. Froeba G, Baeder S, Calzia E, et al. Xenon washin and washout time
cyclopropane. Mol Pharmacol. 2004;65:443–452. during controlled mechanically ventilation in an animal model. Appl
21. Cullen SC, Eger EI 2nd, Cullen BF, et al. Observations on the anesthetic Cardiopulm Pathophysiol. 1998;7:157–160.
effect of the combination of xenon and halothane. Anesthesiology. 1969; 47. Reinelt H, Schirmer U, Marx T, et al. Diffusion of xenon and nitrous oxide
31:305–309. into the bowel. Anesthesiology. 2001;94:475–477.
22. Nakata Y, Goto T, Ishiguro Y, et al. Minimum alveolar concentration 48. Pittner A, Nalos M, Theisen M, et al. Inhaling nitrous oxide or xenon does
(MAC) of xenon with sevoflurane in humans. Anesthesiology. 2001;94: not influence bowel wall energy balance during porcine bowel obstruc-
611–614. tion. Anesth Analg. 2002;94:1510–1516.
23. Nakata Y, Goto T, Ishiguro Y, et al. Anesthetic doses of sevoflurane to 49. Bogdanski R, Blobner M, Fink H, et al. Effects of xenon on mesenteric
block cardiovascular responses to incision when administered with xenon blood flow. Eur J Anaesthesiol. 2003;20:98–103.
or nitrous oxide. Anesthesiology. 1999;91:369–373. 50. Goto T, Saito H, Nakata Y, et al. Effects of xenon on the performance of
24. Dixon WJ. The up-and-down method for small samples. J Am Statist various respiratory flowmeters. Anesthesiology. 1999;90:555–563.
Assoc. 1965;60:967–978. 51. McIlroy MB, Mead J, Selverstone NJ, et al. Measurement of lung tissue
25. Marx T, Froeba G, Wagner D, et al. Effects on haemodynamics and viscous resistance using gases of equal kinematic viscosity. J Appl Physiol.
catecholamine release of xenon anaesthesia compared with total i.v. 1954;7:485–490.
anaesthesia in the pig. Br J Anaesth. 1997;78:326–327. 52. Drazen JM, Loring SH, Ingram RH Jr. Distribution of pulmonary
26. Boomsma F, Rupreht J, Man in ’t Veld AJ, et al. Haemodynamic and resistance: effects of gas density, viscosity, and flow rate. J Appl Physiol.
neurohumoral effects of xenon anaesthesia. A comparison with nitrous 1976;41:388–395.
oxide. Anaesthesia. 1990;45:273–278. 53. Wood LD, Engel LA, Griffin P, et al. Effect of gas physical properties and
27. Luttropp HH, Romner B, Perhag L, et al. Left ventricular performance flow on lower pulmonary resistance. J Appl Physiol. 1976;41:234–244.
and cerebral haemodynamics during xenon anaesthesia. A transoeso- 54. Calzia E, Stahl W, Handschuh T, et al. Respiratory mechanics during
phageal echocardiography and transcranial Doppler sonography study. xenon anesthesia in pigs: comparison with nitrous oxide. Anesthesiology.
Anaesthesia. 1993;48:1045–1049. 1999;91:1378–1386.
28. Rossaint R, Reyle-Hahn M, Schulte Am Esch J, et al. Multicenter 55. Zhang P, Ohara A, Mashimo T, et al. Pulmonary resistance in dogs: a
randomized comparison of the efficacy and safety of xenon and isoflurane comparison of xenon with nitrous oxide. Can J Anaesth. 1995;42:547–553.
in patients undergoing elective surgery. Anesthesiology. 2003;98:6–13. 56. Pedley TJ, Drazen JM. Aerodynamic theory. In: Fishman AP, Macklem
29. Baumert JH, Falter F, Eletr D, et al. Xenon anaesthesia may preserve PT, Mead J, et al., editors. Handbook of Physiology. Bethesda, Md: Williams
cardiovascular function in patients with heart failure. Acta Anaesthesiol & Wilkins; 1986. pp. 41–54.
Scand. 2005;49:743–749. 57. Fink BR. Diffusion anoxia. Anesthesiology. 1955;16:511–519.
30. Bein B, Turowski P, Renner J, et al. Comparison of xenon-based anaes- 58. Calzia E, Stahl W, Handschuh T, et al. Continuous arterial P(O2) and
thesia compared with total intravenous anaesthesia in high risk surgical P(CO2) measurements in swine during nitrous oxide and xenon elimi-
patients. Anaesthesia. 2005;60:960–967. nation: prevention of diffusion hypoxia. Anesthesiology. 1999;90:829–834.
59. Petzelt C, Blom P, Schmehl W, et al. Prevention of neurotoxicity in hypoxic 78. Dingledine R, Borges K, Bowie D, et al. The glutamate receptor ion
cortical neurons by the noble gas xenon. Life Sci. 2003;72:1909–1918. channels. Pharmacol Rev. 1999;51:7–61.
60. Wilhelm S, Ma D, Maze M, et al. Effects of xenon on in vitro and in vivo 79. Harada H, Kelly PJ, Cole DJ, et al. Isoflurane reduces N-methyl-D-
models of neuronal injury. Anesthesiology. 2002;96:1485–1491. aspartate toxicity in vivo in the rat cerebral cortex. Anesth Analg. 1999;
61. David HN, Leveille F, Chazalviel L, et al. Reduction of ischemic brain 89:1442–1447.
damage by nitrous oxide and xenon. J Cereb Blood Flow Metab. 2003; 80. Arrowsmith JE, Harrison MJ, Newman SP, et al. Neuroprotection of the
23:1168–1173. brain during cardiopulmonary bypass: a randomized trial of remace-
62. Weber NC, Toma O, Wolter JI, et al. The noble gas xenon induces mide during coronary artery bypass in 171 patients. Stroke. 1998;29:
pharmacological preconditioning in the rat heart in vivo via induction of 2357–2362.
PKC-epsilon and p38 MAPK. Br J Pharmacol. 2005;144:123–132. 81. Lynch DR, Gallagher MJ. Inhibition of N-methyl-D-aspartate receptors
63. Preckel B, Weber N, Schlack W. [Xenon—noble gas with organprotective by haloperidol: developmental and pharmacological characterization in
properties] (German). Anasthesiol Intensivmed Notfallmed Schmerzther. native and recombinant receptors. J Pharmacol Exp Ther. 1996;279:
2004;39:456–462. 154–161.
64. Vannucci RC, Perlman JM. Interventions for perinatal hypoxic-ischemic 82. Dingley J, Tooley J, Porter H, et al. Xenon provides short-term neuro-
encephalopathy. Pediatrics. 1997;100:1004–1014. protection in neonatal rats when administered after hypoxia-ischemia.
65. Shalak L, Perlman JM. Hypoxic-ischemic brain injury in the term infant— Stroke. 2006;37:501–506.
current concepts. Early Hum Dev. 2004;80:125–141. 83. Ma D, Hossain M, Pettet GK, et al. Xenon preconditioning reduces brain
66. Vannucci SJ, Hagberg H. Hypoxia-ischemia in the immature brain. J Exp damage from neonatal asphyxia in rats. J Cereb Blood Flow Metab.
Biol. 2004;207:3149–3154. 2006;26:199–208.
67. Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress. 84. Martin JL, Ma D, Hossain M, et al. Asynchronous administration of
A clinical and electroencephalographic study. Arch Neurol. 1976;33: xenon and hypothermia significantly reduces brain infarction in the
696–705. neonatal rat. Br J Anaesth. 2007;98:236–240.
68. Towfighi J, Zec N, Yager J, et al. Temporal evolution of neuropathologic 85. Hobbs C, Thoresen M, Tucker A, et al. Xenon and hypothermia combine
changes in an immature rat model of cerebral hypoxia: a light microscopic additively, offering long-term functional and histopathologic neuropro-
study. Acta Neuropathol. 1995;90:375–386. tection after neonatal hypoxia/ischemia. Stroke. 2008;39:1307–1313.
69. Yue X, Mehmet H, Penrice J, et al. Apoptosis and necrosis in the newborn 86. Franks NP. Molecular targets underlying general anaesthesia. Br J
piglet brain following transient cerebral hypoxia-ischaemia. Neuropathol Pharmacol. 2006;147 Suppl 1:S72–81.
Appl Neurobiol. 1997;23:16–25. 87. Anand KJ, Scalzo FM. Can adverse neonatal experiences alter
70. Scott RJ, Hegyi L. Cell death in perinatal hypoxic-ischaemic brain injury. brain development and subsequent behavior? Biol Neonate. 2000;77:
Neuropathol Appl Neurobiol. 1997;23:307–314. 69–82.
71. Thoresen M, Penrice J, Lorek A, et al. Mild hypothermia after severe 88. Balduini W, De Angelis V, Mazzoni E, et al. Long-lasting behavioral
transient hypoxia-ischemia ameliorates delayed cerebral energy failure in alterations following a hypoxic/ischemic brain injury in neonatal rats.
the newborn piglet. Pediatr Res. 1995;37:667–670. Brain Res. 2000;859:318–325.
72. Thoresen M, Bagenholm R, Loberg EM, et al. Posthypoxic cooling of 89. Jevtovic-Todorovic V, Hartman RE, Izumi Y, et al. Early exposure to
neonatal rats provides protection against brain injury. Arch Dis Child Fetal common anesthetic agents causes widespread neurodegeneration in the
Neonatal Ed. 1996;74:F3–F9. developing rat brain and persistent learning deficits. J Neurosci. 2003;
73. Gunn AJ, Gunn TR, de Haan HH, et al. Dramatic neuronal rescue with 23:876–882.
prolonged selective head cooling after ischemia in fetal lambs. J Clin 90. Okabe S, Kim HD, Miwa A, et al. Continual remodeling of postsynaptic
Invest. 1997;99:248–256. density and its regulation by synaptic activity. Nat Neurosci. 1999;2:
74. Tooley JR, Satas S, Porter H, et al. Head cooling with mild systemic 804–811.
hypothermia in anesthetized piglets is neuroprotective. Ann Neurol. 91. Hua JY, Smith SJ. Neural activity and the dynamics of central nervous
2003;53:65–72. system development. Nat Neurosci. 2004;7:327–332.
75. Eicher DJ, Wagner CL, Katikaneni LP, et al. Moderate hypothermia in 92. Ikonomidou C, Bosch F, Miksa M, et al. Blockade of NMDA receptors
neonatal encephalopathy: safety outcomes. Pediatr Neurol. 2005;32:18–24. and apoptotic neurodegeneration in the developing brain. Science.
76. Eicher DJ, Wagner CL, Katikaneni LP, et al. Moderate hypothermia in 1999;283:70–74.
neonatal encephalopathy: efficacy outcomes. Pediatr Neurol. 2005;32: 93. Lane GA, Nahrwold ML, Tait AR, et al. Anesthetics as teratogens: nitrous
11–17. oxide is fetotoxic, xenon is not. Science. 1980;210:899–901.
77. Gluckman PD, Wyatt JS, Azzopardi D, et al. Selective head cooling with 94. Burov NY, Kornienko LY, Arzamastev YV, et al. Study of xenon toxicity in
mild systemic hypothermia after neonatal encephalopathy: multicentre a subchronic experiment. Anestheziologiia i Reanimatologiia. 1998;3:
randomised trial. Lancet. 2005;365:663–670. 58–60.
Intravenous Agents 23
Peter D. Booker and Neroli Chadderton C H A P T E R
INTRODUCTION weight models are inappropriate for scaling infants and children to
adults because there is a nonlinear relationship between weight and
Infants and young children are not merely small versions of adults drug elimination capacity. Drug clearance in the very young is often
but are immature individuals in a continuous state of anatomic determined by the activity of the relevant hepatic cytochrome P450
and physiologic development. Hence, drug dosage schedules (CYP) enzyme; hence, the continuing efforts to determine the
determined in adults cannot necessarily be safely transferred to postnatal age when each CYP isoform attains adult levels.
children. Similarly, information about the pharmacology of intra- The purpose of this chapter is to outline the main age-related
venous anesthetic drugs obtained from studies in healthy children factors that influence drug pharmacokinetics and pharmacodyna-
cannot usually be extrapolated to critically ill infants. mics and to review the pharmacology of intravenous drugs
Pharmacologic studies tend to examine the effects of giving a commonly used to induce and maintain anesthesia in infants and
single drug to an individual, whereas in clinical practice, this is children.
unusual, because drug combinations are commonly employed.
Co-administration of interacting drugs may make it possible to
use lower doses of each individual drug and so reduce the inci- DEVELOPMENTAL FACTORS
dence of undesirable side effects. Studies of drug interactions in AFFECTING DRUG DISTRIBUTION
anesthesia have revealed that the mechanism can be pharmaco-
kinetic as well as pharmacodynamic. The nature of the interaction Anesthetic drugs exert their effects by binding reversibly to
may differ according to the end point studied, because the various various receptor proteins such as ion channels and/or intracellular
effects produced by one or more drugs are propagated through proteins. However, before a drug can exert an effect, it must pass
many different receptor complexes at different sites within the from its site of administration and reach its site(s) of action.
central nervous system (CNS). Plasma concentrations of drug do not always relate to clinical
The pharmacology of individual drugs used in pediatric effect, because drug plasma concentration does not necessarily
anesthesia can be discussed sensibly only once the most important correlate with concentration of drug near the receptor. This is
differences between infants, children, and adults affecting their because a drug molecule given intravenously must cross several
response to intravenous drug administration have been fully phospholipid membranes to reach its receptor. Small molecules
understood. For the purposes of this chapter, a neonate has a post- tend to cross membranes more rapidly than large ones, but a
conceptional age of between 38 and 44 weeks, an infant is between highly ionized molecule, whatever its size, will be unable to cross
1 and 12 months of age, and a child is between 1 year of age and passively through a lipid membrane and will have to use active or
puberty. Although these age groupings represent convenient labels facilitated transport mechanisms. In contrast, lipid-soluble drugs,
for comparative purposes, their validity and clinical application which are mostly un-ionized at physiologic pH, can cross lipid
are open to criticism, because physiologic maturation and deve- membranes in significant quantities by passive diffusion down-
lopment of vital organ function is a continuous and uninterrupted concentration gradients. The degree of drug ionization depends
process. Nevertheless, in general, it may be assumed that “pharma- on the dissociation constant (Ka) of the drug and on the local pH.
cologic maturation” takes place within the first year of life, though Most intravenous anesthetic drugs are weak bases (B) that com-
this does not imply that children older than 1 year should be given bine with hydrogen ions in solution to form a charged molecule:
a weight-related adult dose of drug. The dosage of many anesthetic
B + H+ ↔ BH+
drugs, when related to body weight, may need to be higher in
young children than in adults. The equilibrium will shift to the right in an acid pH. When the
Since the beginning of the 2000s, marked improvements have local pH equals the pKa of the drug, 50% of the drug will be
been seen, first, in our understanding of the pharmacokinetics of ionized. Hence, small changes in pH can affect the distribution of
intravenous drugs in the very young and, second, in the influence a drug with a pKa close to 7.4. The degree of ionization is only one
of pharmacogenomics on hepatic metabolism and drug receptors. of many physicochemical factors affecting the ability of a drug to
From birth onward, changes in drug pharmacokinetics occur as a passively diffuse through lipid membranes. The relative solubility
consequence of organ maturation, changes in body composition, of drug in blood and tissue, the blood-tissue partition coefficient,
and the ontogeny of drug elimination pathways. Traditionally, is another individual drug “constant” that can be assessed in vitro
we have used body weight or body surface area to adjust by measuring drug solubility in organic and aqueous solvents.
pharmacokinetic parameters to body size. However, these linear These physicochemical factors may vary between and within
tissues, but they are unaffected by a patient’s age or maturity. equilibrium with brain tissue, the rate of entry of drug is determined
However, other important factors influencing anesthetic drug largely by cerebral blood flow. Hence, onset times for intravenous
distribution are subject to developmental change. These include anesthetic agents tend to be shorter in early childhood than in
regional tissue perfusion, permeability of the blood-brain barrier neonates, adolescents, or adults.
(BBB), the relative size of body compartments into which the drug
is distributed, and the degree of protein binding.
Blood-Brain Barrier
The BBB allows precise control over the substances that leave or
Regional Blood Flow enter the brain. An elaborate network of complex tight junctions
The initial phase of distribution reflects regional blood flow. between specialized endothelial cells restricts the paracellular
Hence, a major determinant of drug distribution is cardiac output diffusion of hydrophilic molecules. Transcellular passage of
and how it is distributed to the various tissues of the body. Index- molecules is inhibited by a lack of fenestrations and very low
ing cardiac output to body surface area rather than weight pro- pinocytic activity in the endothelial cells. Specific transport sys-
vides a reasonable means of comparing grouped data. The tems selectively expressed in the barrier endothelial cell mem-
1-month-old infant has a cardiac index of about 2.6 L/min/m2, branes mediate the transport of nutrients into the CNS and of
which increases to 3.2 L/min/m2 by 1 year of age and 4.0 L/min/m2 toxic metabolites out of the CNS.
by 2 to 15 years.1,2 The permeability of the fetal BBB to large molecules is probably
Organs that are well-perfused, such as brain, heart, and liver, very similar to that of the adult BBB. In contrast, small molecules
are the tissues first exposed to the drug. The second phase of access fetal and neonatal brains more readily than they do adult
distribution involves other relatively well-perfused tissues such as brains.6 BBB function does not suddenly increase at a certain
skeletal muscle, with much slower tertiary distribution to relatively gestational age, but improves gradually throughout fetal brain
underperfused tissues of the body usually assuming importance development. Although the blood–cerebrospinal fluid (CSF)
only with long-term drug infusions. Acute changes in the neonatal barrier and BBB are not identical, developmental changes in the
circulation that affect organ blood flow take place in the first few blood-CSF barrier probably reflect analogous changes in the BBB.
days and weeks after birth, secondary to functional closure of the Two-month-old infants demonstrate CSF-to-plasma ratios of
ductus venosus and ductus arteriosus. In addition, differences in fentanyl similar to those of older children, suggesting that by the
relative organ mass and regional blood flow change with growth end of the neonatal period, BBB function approaches adult levels.7
and development during the first few months of life. Renal and The fully differentiated BBB consists of a complex system of
hepatic blood flows achieve adult levels by about 12 months of age. highly specialized endothelial cells, a large number of pericytes
The most important differences in regional perfusion between embedded in the basal membrane, perivascular macrophages, and
neonate, child, and adult are illustrated in Figure 23–1. astrocytic endfeet. Although endothelial cells form the barrier
Although cerebral mass as a proportion of body weight is much proper, the interaction with adjacent cells is a prerequisite for
higher in the infant than in the adult, mean cerebral blood flow normal barrier function. Pathologic conditions within the CNS,
per 100 g of brain tissue is similar in the neonate and in the adult such as ischemia, inflammation, infection, or tumor, which change
(50 mL/min).3 Mean cerebral blood flow increases during infancy the CNS microenvironment, are often accompanied by BBB
and early childhood to reach a peak of about 70 mL/min/100 g at dysfunction.8 Hence, not only the development but also the main-
about 3 to 8 years of age.4 Recent studies using a magnetic resonance tenance of the BBB is tightly regulated by the permanent
continuous arterial spin labeling technique have confirmed that interaction of endothelial cells with the neuroectoderm.
cerebral blood flow subsequently decreases with age from early The tight intercellular junction is composed of various trans-
childhood.5 Because highly lipophilic drugs in cerebral arterial membranous proteins and represents the main barrier to passive
blood diffuse rapidly across the BBB to achieve concentration diffusion of drugs with low lipophilicity, protein macromolecules,
and smaller hydrophilic molecules such as glucose. In addition,
drug-metabolizing enzymes, such as CYP450 hemoproteins, and
transport systems, such as adenosine triphosphate (ATP)–binding
cassette proteins, not only provide an enzymatic barrier to drug
entry but also promote drug efflux.8 Whereas drug bound to
plasma proteins will not normally cross the BBB, unbound lipo-
philic drugs passively diffuse across the BBB to achieve equilib-
rium very quickly. In addition, however, active transport of
lipophilic drugs across the BBB may occur in both directions.
Animal studies have shown that fentanyl is actively transported
across the BBB by a saturable ATP-dependent process that in-
creases fentanyl uptake two- to threefold over that achieved by
simple diffusion alone.9 Furthermore, ATP-binding cassette pro-
teins such as P-glycoprotein actively pump out opioids such as
fentanyl and morphine, reducing the tissue–to–blood partition
ratio that would exist because of passive diffusion alone. P-
Glycoprotein modulation significantly influences opioid brain
distribution and onset time, magnitude, and duration of analgesic
Figure 23-1. Regional blood flow expressed as a percentage of response.10 Genetic polymorphisms affecting P-glycoprotein–
cardiac output (C.O.): changes with age. From reference 220. related genes may explain some individual differences in CNS-
CHAPTER 23 ■ Intravenous Agents 357
active drug sensitivity.11 Many different classes of drugs are

substrates for P-glycoprotein, including antidepressants, anticon-
vulsants, antibiotics, antiarrhythmics, antiemetics, opioids, and
steroids, but not propofol or midazolam.12 Developmental changes
in P-glycoprotein function have not been identified.
Body Water Content

Water constitutes about 80% by weight of a preterm and 75% of a
term newborn baby.13 After birth, total body water (TBW) de-
creases rapidly over the first month of life to about 65% of body
weight, and then more gradually to achieve adult proportions
(55%) by about 12 years of age (Figure 23–2).14 From adolescence
onward, females have a mean TBW of about 50% of their body
weight, compared with about 55% in males. These figures slowly
decline throughout adulthood to about 46% and 43% for men and
women, respectively, by 60 years of age.15
At equilibrium, ionized water-soluble drugs will be uniformly Figure 23-3. Estimated change in fat content, expressed as a
distributed throughout the TBW and any changes in TBW will percentage of body weight, during infancy and early childhood.
have a significant effect on the distribution volume of water-soluble Data from reference 16, with permission.
drugs such as pancuronium. Conventionally, TBW is divided into
two discrete compartments: intracellular and extracellular fluid. gradually declining to 25% by 2 years of age (Figure 23–3).16
The former makes up about 35% of body weight at birth, but Gender differences in fat content become significant only just
quickly rises to 40% by 3 months of age. The proportion of body before and during puberty. By 11 years of age, fat still constitutes
weight contributed by intracellular water then falls in line with the about 25% of body weight in girls, whereas it declines to about
decrease in TBW until about 1 year of age, when it increases back 22% in boys.17 However, more than 10% of children in developed
up again to the adult value of 40% by 4 years of age. In contrast, the countries have a fat content more than 25% in excess of these
contribution of extracellular water to body weight decreases more reference figures.18
gradually from about 40% at birth to about 20% by 6 years of age. Superimposed upon these overall changes in fat content is the
Furthermore, the proportion of TBW found in each organ and the disproportionate growth of different organs. The CNS in the
relative size of intracellular and extracellular water in each organ neonate constitutes a higher proportion of body weight and has a
change with age. higher proportion of fat than in the adult. These developmental
changes in body and organ lipid content have obvious implications
for the apparent volume of distribution for highly lipid-soluble
Body Fat Content drugs such as propofol. Moreover, any increase in adipose tissue,
In the term neonate, fat constitutes about 12% of body weight, the which is often relatively poorly perfused, increases the potential
proportion rapidly increasing to 30% by 3 to 6 months, before for producing a “reservoir” of drug, which diffuses back into the
circulation along concentration gradients after drug administra-
tion has ceased.
Protein Binding
The low inherent solubility of highly lipophilic drugs in plasma
water makes reversible protein binding essential for their transport
in plasma, but only the unbound moiety can readily diffuse across
biologic membranes to reach receptor sites or be eliminated from
the body. Alterations in the degree of protein binding affect the
apparent volume of distribution of certain drugs. Although
albumin has a greater binding capacity than α1-acid glycoprotein
(AAG), AAG has a much greater drug affinity, particularly for
weakly basic drugs. Neonates and young infants may have rela-
tively low concentrations of albumin and AAG.19 However, plasma
protein binding is rarely of clinical significance even when drugs
are extensively bound, because any concentration gradient that
encourages passive diffusion of unbound drug from plasma to
tissue also results in dissociation of protein-bound drug. Hence, as
the total drug concentration in plasma decreases, the concentra-
Figure 23-2. Total body water as a percentage of body weight: tion of unbound drug tends to stay constant. Similarly, drug
changes during childhood. Data from reference 14, with dissociation from binding to plasma proteins is so fast that hepa-
permission. tic clearance and glomerular filtration of drugs are relatively
insensitive to changes in the concentrations of plasma proteins. lower than that of CYP3A4 by about two orders of magnitude.23
However, low concentrations of binding proteins may become CYP3A4 protein concentrations increase only gradually during
clinically relevant if a fast injection of an extensively bound drug the first 6 months of age. It has been suggested that the CYP3A4
is given at high dose, when pharmacodynamic effects may activity achieves adult levels by 4 years of age,23 however others
be transiently greater than would otherwise be expected. For have shown that activity may remain significantly lower than adult
instance, the induction dose of thiopental is significantly lower in levels even at 5 years of age.22
neonates than in older age groups and one of the reasons for this The CYP2C subfamily accounts for about 18% of the total adult
may relate to decreased binding of thiopental to plasma albumin; CYP450 content and is responsible for the metabolism of several
13% of the drug is unbound in newborns, 7% in adults.20 This important anesthetic drugs, including non-steroidal anti-inflam-
difference may be caused by competitive binding of available matory drugs, diazepam, and probably, thiopental.24 In the fetus,
receptor binding sites by bilirubin and/or structural differences CYP2C19 activity predominates, whereas postnatally, CYP2C9 is
between adult and fetal albumin.21 the principal enzyme. Fetal studies show progressive increases in
CYP2C9 activity during the second and third trimesters, to reach
levels about 30% of mature values at term. Postnatally, CYP2C9
DEVELOPMENTAL FACTORS expression is highly varied, suggesting that differences in develop-
AFFECTING DRUG ELIMINATION mental factors may have a genetic component. In about 50% of
individuals, adult levels are reached by 5 months of age, the re-
Metabolism and excretion together constitute the body’s mecha-
mainder taking up to 18 years. CYP2C19 activity remains at about
nisms for elimination of drugs, and both processes demonstrate
18% of mature values during fetal and early neonatal life, irre-
marked age-related variation.
spective of gestational age. Median CYP2C19 activity reaches
about 38% of adult values within 1 to 5 months of age but, the-
Hepatic Metabolism reafter, is highly variable, consistent with differences in develop-
mental factors having a genetic component.
Most anesthetic drugs are lipophilic compounds dependent on The CYP2B6 subfamily, one of the minor P450 enzymes, is
biotransformation to more water-soluble metabolites for elimi- expressed in human liver and some extrahepatic tissues. The
nation from the body. The principal site for drug metabolism is in number of substrates that are partially or completely metabolized
the liver, where complex groups of enzymes are concentrated in the by CYP2B6 includes alfentanil, ketamine, and propofol. Inter-
membranes of hepatocyte endoplasmic reticulum. The numerous individual variation in CYP2B6 activity may exceed 100-fold;
biotransformation reactions are conventionally classified into two significant factors in this variation include gender, ethnicity, and
main types, phase I and phase II, which often occur sequentially. postnatal age. The potential for substantial individual differences
Phase I reactions convert by oxidation, reduction, or hydrolysis, in the pharmacodynamics of drugs that are metabolized by
the parent drug to a more polar metabolite by introducing or CYP2B6 are obvious.
revealing a functional group such as a hydroxyl or ammonium Several enzymes involved in phase II conjugation reactions are
radical. Some phase I metabolites are renally excreted, whereas subject to substantial developmental and interindividual variation.
others may then undergo a phase II conjugation reaction. Phase II
The uridine 5⬘-diphosphate glucuronosyltransferase (UGT)
conjugation reactions include glucuronidation, methylation, and
superfamily of enzymes is divided into the UGT1A and UGT2B
sulphation, which serve to increase further the polarity of a
subfamilies, which contain nine and seven isoforms, respectively.
metabolite and promote its water solubility and renal excretion.
In general, activity of UGT isoforms is low in the neonate and
Many microsomal enzymes are polymorphically expressed and
increase to adult values throughout infancy and early childhood.
subject to considerable variability in activity during development.
Each of the 16 different isoforms achieves adult levels of activity at
The CYP450 enzymes are quantitatively the most important
different ages. For instance, UGT1A4 activity reaches adult values
hepatic microsomal oxidative enzymes. The oxidative biotransfor-
at 1.4 years of age,25 whereas UGT1A6 activity does not reach adult
mation of drugs involves multiple hepatic P450 enzymes that have
values until about 10 years.26 Given this wide variety of UGT1A
distinct substrate specificities and maturational sequences, which
isoform maturation, prediction of how developmental influences
result in varying rates of maturation of drug metabolism. The rate
of P450-mediated drug clearance cannot be extrapolated from will affect a specific isoform is impossible without the relevant
body weight adjustments or from data on P450 expression and clinical data.
regulation in adults. Prediction of drug clearance in the very Hepatic drug clearance is a function not only of microsomal
young depends largely on determining when the activity of the metabolic activity but also of hepatic blood flow. Hepatic blood
relevant CYP isoforms attains adult levels. Unfortunately, different flow will influence the hepatic clearance of a drug differently if
studies on the same CYP isoform often give very divergent results. metabolic activity is low or high. For drugs with a high intrinsic
The CYP3A subfamily is the most abundant group of CYP hepatic clearance, overall changes in hepatic clearance will be
enzymes in the human liver and is involved in the metabolism of proportional to changes in liver blood flow. In contrast, changes in
many anesthetic drugs, including midazolam, alfentanil, fentanyl, enzyme activity such as occur during maturation will influence
and propofol. Of its three isoforms, CYP3A4 is by far the most hepatic clearance only if the drug has a low intrinsic clearance,
important for postnatal drug metabolism and composes up to 50% whereas highly extracted drugs, such as propofol, will be essenti-
of total hepatic P450 enzyme activity in the adult.22 CYP3A5 is ally unaffected.
found in the kidney, lungs, and liver, and its expression shows
great individual and ethnic variation, though it is generally
independent of age.22 CYP3A7 predominates in the liver before
Extrahepatic Metabolism
birth and is gradually (but not totally) replaced by CYP3A4 during Important drug biotransformations also take place outside
the first few months of life. The catalytic activity of CYP3A7 is the liver. Many P450 enzymes, including CYP3A4, CYP2C, and
CYP2B, and phase II enzymes, including many UGT isoforms, are Hypovolemia and Hypotension
found in intestinal mucosal cells, renal microsomes, and lung
parenchymal cells, though they usually contribute less than 20% Hypovolemia and/or hypotension will result in reduced tissue
toward total body metabolic activity. Other important extrahepatic perfusion that can have profound effects on drug pharmaco-
drug biotransformations include esterase reactions in plasma and kinetics. The distribution of drugs between the blood and the
many other tissues. Nonspecific esterase activity may be reduced poorly perfused tissues will be restricted, which may result in
in neonates, though this does not appear to significantly compro- greater relative distribution to those tissues such as the brain
mise metabolism of drugs such as remifentanil.27 Furthermore, whose perfusion is maintained. Conversely, sick neonates may
remifentanil that crosses the placenta is rapidly metabolized by have impaired cerebral autoregulation, such that systemic hypo-
the term newborn.28 tension may result in subnormal cerebral blood flow and, hence,
reduced uptake of lipophilic drugs. In hypotensive children, drug
may become sequestered in poorly perfused fat, only to return to
Renal Excretion the vascular compartment when perfusion is restored to normal.
Renal excretion of drugs and their metabolites may be necessary If hepatic blood flow is significantly reduced, elimination of drugs
to avoid the potential toxicity associated with accumulation of that have a high intrinsic hepatic clearance, such as propofol, may
these compounds. However, highly lipophilic drugs are usually be compromised. However, lipophilic drugs are not the only type
only partially ionized at physiologic pH and may also be bound of drug to be affected by hypoperfusion. If renal perfusion is
to plasma proteins. These drugs are not readily filtered at the reduced, elimination of water-soluble drug and/or metabolites
glomerulus. The lipophilic nature of renal tubular membranes also may be significantly compromised.
facilitates the re-absorption of hydrophobic compounds following
glomerular filtration. Thus, the termination of action of anesthetic
drugs never depends solely on renal excretion. Nevertheless, the
Hypoxia
kidney is a major route of elimination not only for water-soluble Hypoxia can cause renal arteriolar vasoconstriction, which
drugs but also for water-soluble metabolites of lipophilic drugs. adversely affects both glomerular and tubular function. Similarly,
The two basic processes involved in the renal elimination of drugs decreased microsomal concentrations of CYP450 enzyme systems
are glomerular filtration and tubular excretion. may follow birth asphyxia. Experimental studies examining the
The glomerular filtration rate (GFR) of term neonates at birth, effects of hypoxia on the hepatic metabolism of certain drugs have
when indexed to their surface area, is about 10% that of the adult, produced conflicting results. The limited clinical data that are
but it increases rapidly in the early postnatal period, rising to 100% available suggest that water-soluble drug elimination in infants
of the figure expected for size by 1 year of age. The maturational with cyanotic congenital heart disease is not significantly different
changes in GFR are caused by a combination of increasing syste- from that in a matched acyanotic group.30
mic arterial blood pressure and decreasing renal vascular resis-
tance. Furthermore, the porosity of the glomerular membrane and
the area available for filtration increase as glomeruli differentiate Hypothermia
morphologically. Changes in the intrarenal distribution of blood Hypothermia is commonly induced during cardiac surgery and
may also lead an increase in GFR, as blood flow to the outer cortex used as a neuroprotective therapy after brain injury; hence, the
is enhanced compared with flow to the inner cortex and medulla. effects of temperature on drug pharmacokinetics can have impor-
This developmental change in GFR increases the clearance of tant clinical significance. Many clinical studies have shown that
drugs and metabolites eliminated by filtration, such as glycopyr- cardiopulmonary bypass utilizing profound hypothermia (18–
rolate. Hence, as would be expected, no significant age-dependent 24°C) significantly decreases clearance of certain lipophilic drugs
differences in glycopyrrolate clearance occur after the age of such as fentanyl.31 However, hypothermia is just one of several
6 months.29 Similarly, tubular function in the neonate is relatively factors that have the potential to reduce drug clearance, so phar-
poor but improves dramatically as renal mass and renal blood flow macokinetic interpretation of bypass studies is highly problema-
increase. Proximal tubular secretion assumes adult values by about tic.32 Neonates treated with mild hypothermia (33–34°C) for
6 months of age. The glucuronide metabolites of drugs such as perinatal asphyxia were shown to have a reduced morphine
morphine and propofol are dependent on proximal tubular clearance compared with a normothermic control group.33 Similar
secretion for their elimination. studies in hypothermic brain-injured adults have confirmed that
Renal metabolism of certain anesthetic drugs, such as propofol, even mild hypothermia (34–35°C) results in a marked decrease
can be clinically significant (see Pharmacology of individual in midazolam clearance, presumably owing to depressed CYP3A4/
drugs). Renal propofol clearance is not linked to GFR, but limited 5 activity.34 Reduced blood and tissue esterase activity secondary
by renal blood flow; developmental influences on this important to hypothermia causes a 20% decrease in remifentanil clearance.35
extrahepatic metabolic pathway are unknown. Therapeutic hypothermia not only affects drug disposition
by affecting enzymatic function but may also have effects on
GENERAL FACTORS AFFECTING regional blood flow and drug pharmacodynamics. Experimental
studies have demonstrated that depressed metabolic activity
DRUG PHARMACOKINETICS occurs during fentanyl and propofol infusions in hypother-
Certain pathophysiologic factors may have a significant influence mic animals, even after controlling for hypothermia effects on
on drug distribution and/or elimination and, although they are hepatic blood flow.34 Recent in vitro studies suggest that mild
not subject to developmental influence, may occur more fre- hypothermia (32°C) may suppress P-glycoprotein drug transport
quently in pediatric than in adult anesthetic practice. across the BBB.36
Cardiopulmonary Bypass to the presence of an agonist or antagonist and such down-

regulation may explain opioid tolerance.
The institution of cardiopulmonary bypass (CPB) has profound Human and animal experimental studies have confirmed that
effects on the plasma concentration of drugs. These changes occur significant change in receptor binding, density, and initiation of
secondary to a combination of factors, including acute hemodilu- secondary messenger systems can occur during development.
tion, altered plasma protein binding, hypotension, hypothermia, Postmortem human experimental studies, using quantitative
use of heparin, lung isolation, and sequestration on the surfaces of tissue autoradiography techniques with radioligands for opioid
the bypass circuit. Onset of CPB causes an immediate and subs- receptors, have shown that, although opioid receptor affinity does
tantial decrease in the plasma concentration of both water-soluble not change during development, opioid receptor distribution
and lipophilic drugs owing to hemodilution. The decrease in total and binding capacities show significant variation with postnatal
drug concentration is particularly large with fentanyl, alfentanil, age.40,41 In addition, animal experiments have suggested that
and thiopental, in which a significant proportion of drug under- benzodiazepine binding sites not only may show quantitative and
goes hydrophobic binding to the extracorporeal circuit.32 Hemo- qualitative age-related changes but also are distributed within the
dilution of plasma proteins would be expected to affect the protein brain differently in the term neonate than in the adult.42
binding of highly bound drugs such as alfentanil, midazolam, and
propofol. Propofol has been extensively studied in this respect: a
twofold increase in its free fraction and relatively unchanged total PHARMACOLOGY OF
plasma concentration during CPB were demonstrated, consistent INDIVIDUAL DRUGS
with theoretical predictions.37 Propofol pharmacodynamics dur-
ing CPB, as assessed using the bispectral index (BIS), are consis- This section does not attempt to be all-inclusive and is restricted
tent with this increase in unbound fraction.38 Similarly, many to discussing only those intravenous drugs that are commonly
highly lipophilic opioids with a high apparent volume of distribu- used in current pediatric anesthetic practice to induce or maintain
tion maintain relatively stable total drug concentrations during anesthesia.
initiation of CPB, because their rapid re-equilibration minimizes
any dilutional effect.
Propofol
In developed countries, propofol is now the most commonly used
Acid-base balance and Arterial intravenous induction agent. In addition, it has found widespread
Carbon Dioxide Pressure application in the maintenance of anesthesia, total intravenous
Alterations in blood pH lead to significant changes in the degree anesthetic techniques, and sedation, reflecting its generally favor-
of ionization of drugs with a pKa close to physiologic pH. For able pharmacokinetic and pharmacodynamic properties.
instance, 61% of thiopental is un-ionized at a pH of 7.4, whereas Propofol (2,6-di-isopropyl phenol) is a phenol derivative. It is
at a pH of 7.1, 76% of the drug is un-ionized. This decrease in almost completely insoluble in water and is supplied as an isotonic
ionization of thiopental alters its tissue distribution and increases emulsion, formulated in 1.2% purified egg lecithin, 10% soybean
its apparent volume of distribution. More important, acidosis oil, and 2.25% glycerol. This lipid carrier supports bacterial and
increases the potency of thiopental and accentuates the drug- yeast growth, so newer formulations contain antimicrobial agents
induced depression in myocardial contractility.39 such as ethylenediaminetetraacetic acid (EDTA), metabisulfite, or
Drugs with very high lipid solubility tend to have cerebral benzyl alcohol to retard growth of microorganisms. Nevertheless,
venous concentrations less than 50% of arterial concentrations when drawing up propofol in advance of a case, an aseptic tech-
after a single passage through the brain because of rapid uptake nique is advised.
across the BBB. Hence, the rate of lipophilic drug entry is largely
determined by cerebral blood flow. Perturbations in arterial Pharmacokinetics
carbon dioxide pressure (PaCO2) that cause significant alterations Propofol is highly lipid soluble, rapidly reaching effect sites in the
in global and regional cerebral blood flow will affect the uptake CNS. This is reflected by a rapid onset of action with loss of
and distribution of many anesthetic drugs in the brain. consciousness seen within one arm-brain circulation time follow-
ing bolus injection. The pharmacokinetics of propofol is most
commonly described using a three-compartment model: a large
DRUG-RECEPTOR INTERACTIONS central compartment, a (lean) peripheral compartment that is
The existence of specific drug receptors implies the existence of relatively well-perfused, and a deep peripheral (fat) compartment
endogenous ligands that exert their normal physiologic action by that has limited perfusion. The central compartment models
binding to these receptors, as occurs with opioids and benzodiaze- plasma concentrations of propofol. The size of this compartment
pines. The affinity of the drug molecule for the receptor and the parallels developmental changes in blood volume and plasma
proportion of receptors occupied determine the relative potency protein levels, and in children, the central compartment is nearly
of a drug at its site of action. However, it is not necessary for all twice the size of that in adults on a per-kilogram basis.43 This larger
receptors to be occupied to obtain maximum effect, as a large volume of distribution explains why small children require higher
proportion of receptors can be “spare.” The formation of a drug- infusion rates than adults to maintain the same blood concen-
receptor complex leads to the production of a pharmacologic trations of propofol. The central compartment is rapidly cleared by
signal that may initiate a further cascade of physicochemical redistribution to peripheral compartments, so that the arterial
reactions before a measurable response is produced. The total blood concentration of propofol starts to decrease about 1 minute
number of receptors in a given volume of tissue varies in response after bolus injection. Termination of drug effect occurs primarily
changes in CYP2B6 activity are relatively insignificant compared

with the 100-fold inter-individual differences demonstrable
throughout life (see Hepatic Metabolism). Propofol glucuroni-
dation is catalyzed by UGT1A9; no data exist to determine
developmental changes in this specific isoform. Nevertheless, it is
unsurprising that median propofol clearance in neonates is only
442 mL/min/70 kg, compared with values of 1957 mL/min/70 kg
in 1- to 3-year-old children, 1479 mL/min/70 kg in 4- to 7-year-
old children, and 1827 mL/min/70 kg in adults.53,54 It should be
noted that these (median) values hide a very wide interindividual
variation; for instance, propofol clearance varies more than 300%
in the neonatal period, making age-related changes seem almost
trivial by comparison.55
Pharmacodynamics
The hypnotic actions of propofol result from its interaction with
Figure 23-4. Context sensitive half-times (CSHTs) for propofol
the gamma-aminobutyric acid (GABA) A receptor.56 The GABAA
and remifentanil: changes with age. Data from references 45 and
receptor is a major mediator of rapid synaptic inhibition in the
brain. Binding of propofol to the GABAA receptor results in
an influx of chloride ions, leading to hyperpolarization of the
because of this redistribution, although metabolism of drug in the neuron: in consequence, the neuron becomes unresponsive to
central compartment also contributes, albeit at a slower rate. external stimuli. Propofol also influences presynaptic mechanisms
The peripheral fat compartments act as reservoirs for propofol. of GABAergic transmission, because a high concentration of
Hence, the volume of distribution and context-sensitive half-time neurotransmitter-gated ion channels is a prerequisite for rapid
(CSHT) of propofol are significantly greater in obese than in presynaptic transmission.57
nonobese patients.44 Similarly, in children aged 0.6 to 2 years, who The mean dose required for easy insertion of a laryngeal mask
have proportionally greater fat content as a percentage of body airway in 50% of unpremedicated children (3–12 y old) is 3.8 mg/
weight than adults, these peripheral compartments contain a large kg, significantly higher than that for adults (2.4 mg/kg).58,59
quantity of propofol following prolonged infusions.45 Redistribu- Premedication with midazolam, or pretreatment with a short-
tion of propofol from the peripheral fat compartments to the acting opioid, reduces mean dosage requirement by at least 30% in
central compartment occurs once concentrations in the central all age groups.58,60 Similarly, infusion rates for maintenance of
compartment fall below those in the peripheral compartments. In anesthesia and sedation with propofol are about 50% greater in
young and critically ill children, redistribution from the peripheral children than in adults.47,61
fat compartment is relatively slow and elimination of propofol There are, however, conflicting data on whether children
from the body may take many hours.46 These factors explain the require higher plasma concentrations than adults in order to
slower recovery and longer CSHT seen in the young child having achieve a comparable anesthetic endpoint. In a study by Munoz
a prolonged infusion (Figure 23–4).47 and colleagues, anesthesia was titrated to a BIS value of 50 and the
The liver is the principal site of propofol metabolism. Because effect site concentration of propofol was calculated for both adult
propofol has an extraction ratio of about 0.9, metabolism is and pediatric subjects.62 They found the predicted effect-site
dependent on hepatic blood flow; reduced metabolic clearance is concentration for children was 3.65 μg/mL, not significantly
seen in children with low cardiac output.46 Approximately 53% of different from that of 3.75 μg/mL for adults. In a comparable study
injected propofol is excreted in urine as the glucuronide and 38% by Rigouzzo and coworkers, in which anesthesia during surgery
as hydroxylated metabolites.48 Recent studies have demonstrated was titrated to a BIS of 50, the measured plasma propofol con-
that metabolic clearance by the kidney accounts for about 27% of centration was significantly higher in children than adults (4.3 ±
the total body clearance of propofol, owing to glucuronidation by 1.1 μg/mL vs 3.4 ± 1.2 μg/mL).63 Similarly, studies assessing
UGT1A9 found in renal cortical microsomes.49,50 A similar pro- adequate depth of anesthesia based on clinical parameters found
portion of propofol is converted to the glucuronide by UGT1A9 in the median effective dose (EC50) for propofol was greater in
hepatic microsomes. The hydroxylated metabolites are produced children than in adults.64,65 In contrast, one study using auditory
mainly by CYP2B6, with some contribution from CYP2C9 acti- evoked potentials as a measure of the depth of hypnosis found that
vity, in hepatic microsomes; activity of renal CYP2B6 and CYP2C9 the predicted effect-site concentration of 3.56 μg/mL for children
is insignificant.48 About 0.3% of propofol is excreted unchanged was much less than that predicted for adults (6.45 μg/mL).66 It is
in urine. likely that the differences in the pharmacokinetic models used to
Clearance of propofol in children changes with postnatal age calculate the effect-site and plasma concentrations account for the
and reflects maturation of CYP2B6 and UGT1A9 enzyme activity. discrepancies observed.
Developmental changes affecting CYP2B6 activity have not been Following an induction dose of propofol, mean arterial pres-
studied in detail, but sparse existing data suggest that infants sure (MAP) is reduced by 15 to 30% in healthy children, caused
younger than 10 months old have enzyme activity only about 14% mostly by a reduction in systemic vascular resistance (SVR).67–69
of those aged 2 years and older.51 On the basis of available clinical This decrease in SVR is caused by a combination of a reduction
data, it has been predicted that 50% of adult activity should be in sympathetic activity and smooth muscle relaxation. Animal
achieved by 1.3 years of age.52 Nonetheless, these developmental studies have suggested that propofol activates sarcolemmal
ATP- and calcium-sensitive potassium channels in arteriolar TABLE 23-1. Main Characteristics of Propofol
smooth muscle cells, causing closure of voltage-gated calcium
channels and subsequent small vessel vasorelaxation. Propofol Pharmacokinetic Characteristics
● Highly lipid soluble (loss of consciousness within one arm-
may also enhance the activity of endothelial nitric oxide synthase
(NOS) and the related cyclic guanosine monophosphate (cGMP) brain circulation time)
● Cessation of effect after single dose owing to redistribution
pathway, hence promoting local nitric oxide (NO) release.70
Propofol does not reduce pulmonary vascular resistance or (all ages)
● Volume of distribution in children twice that of adults
pulmonary artery pressure.68 In children with congenital heart
● Clearance: hepatic (62%); renal (27%)
disease, the combination of these hemodynamic changes may alter
● Hepatic extraction ratio = 0.9; renal extraction ratio = 0.7
the direction and magnitude of intracardiac shunts.
● Cytochrome P450 CYP2B6 activity reduced in neonates;
A fall in heart rate of up to 20% may also be observed after
propofol administration,67 although this is not a consistent finding highest in children 1–3 y
in children.68,69,71 Bradycardia can occur despite significant de- Pharmacodynamic Characteristics
creases in MAP. Risk factors in children include age younger than ● Dose-dependent CNS depression
2 years, poor American Society of Anesthesiologists (ASA) status, ● Mode of action: GABA agonist
A
concurrent use of opioid, and strabismus surgery, where it can ● Reductions in MAP, CO, and SVR more than those seen with
accentuate the oculocardiac reflex despite pretreatment with other induction agents
anticholinergics.72 Other rhythm disturbances (rarely) observed ● No change to PVR or PAP; therefore, may affect intracardiac
with propofol include junctional rhythm, complete heart block, shunting
asystole, and atrial premature beats.72 The mechanism(s) underly- ● Dose-dependent respiratory depression (less than that
ing this effect on myocardial conduction remain unclear, but produced by other induction agents)
recent in vitro studies have shown that propofol can modify the ● Depression of laryngeal/pharyngeal reflexes (less than that
activity of human atrial muscarinic cholinergic receptors.73 produced by other induction agents)
Although experimental and clinical studies have demonstrated ● Reduces cerebral oxygen consumption and ICP without
that propofol has negative inotropic effects, determining the reduction of CPP
precise cause has proved problematic.74,75 ● Spontaneous excitatory movements common on induction
Animal studies have shown that propofol attenuates and recovery
isoproterenol-stimulated increases in calcium ion influx, intra- ● Decreases intraocular pressure
cellular calcium ion concentration, and cyclic adenosine mono- ● Antiemetic properties
phosphate (cAMP) production.76 The inhibitory site of action
within the β adrenergic signal transduction pathway involves Clinical Use
activation of a protein kinase C (PKC)–dependent pathway. In ● Solubilized in egg lecithin, soybean oil, and glycerol
● Potential for bacterial contamination, so draw up using
addition, propofol may also decrease myofilament calcium ion
sensitivity,76 and modulate sodium-calcium exchanger function, aseptic technique
● IV induction dose for healthy children: 3–5 mg/kg
again mediated by effects on PKC-dependent pathways.78 It seems
● Duration of action of single dose: 5–10 min
probable that propofol activates one or more of the protein kinase
● Maintenance regimen in children > 3 yr of age: initial 60 min
isoforms involved in the regulation of intracellular calcium ion
concentration.74 Because these negative inotropic effects of pro- @ 15–13–11 mg/kg/h; subsequent 1–4 h @ 10–9 mg/kg/h
pofol are greater at higher heart rates, fast injection of propofol in Adverse Effects
sick infants and children is inadvisable. Even in healthy children, ● Cardiovascular: hypotension (common); arrhythmias (rare)
fast injection of propofol produces more hypotension than an ● Respiratory: respiratory depression; apnea; hiccups
equipotent dose of thiopental, though this effect is caused by ● Neurologic: transient seizure-like movements; opisthotonus
vasodilation rather than decreased contractility and is generally ● Pain on injection (reduce incidence by adding 1 mL lidocaine
well tolerated.69,71 1% to 20 mL propofol)
The major action of propofol on the CNS is dose-related hy- ● Propofol infusion syndrome (metabolic acidosis, rhabdo-
pnosis and sedation (Table 23–1). Propofol has no analgesic myolysis, renal and cardiac failure), usually following high-
properties. Neuroexcitatory phenomena, including involuntary dose exposure (>4 mg/kg/h for >48 h)
movement, seizure-like activity, tremor, opisthotonus, twitching, ● Anaphylaxis (rare); use with caution in patients with egg or
and coughing, may occur in children administered propofol, usu- nut allergies
ally at induction or emergence. Epileptiform activity coinciding
with this movement has not been shown in electroencephalogram CNS = central nervous system; CO = cardiac output; CPP = cerebral perfusion
pressure; GABAA = gamma-aminobutyric acid type A; ICP = intracranial
studies, and it has been postulated that these reflect subcortical
pressure; MAP = mean arterial pressure; PAP = pulmonary arterial pressure;
discharges. The use of a higher induction dose is less likely to be PVR = pulmonary vascular resistance; SVR = systemic vascular resistance.
associated with neuroexcitatory events. This dose-dependent
effect on CNS depression is also demonstrated when considering
propofol’s anticonvulsant activity; in subanesthetic dosesm pro- Cerebral autoregulation and cerebrovascular responsiveness to
pofol may exert proconvulsant effects, but at higher doses, carbon dioxide are preserved during propofol administration.80
propofol suppresses neuronal activity and is anticonvulsant. A Propofol infusions given to patients with either normal or elevated
recent controlled study of children with epilepsy confirmed that intracranial pressure result in reductions in cerebral metabolic rate
propofol possesses antiepileptic activity and did not promote and intracranial pressure without producing any significant
epileptic activity in any children without epilepsy.79 decrease in cerebral perfusion pressures. Cerebral blood flow is
decreased by propofol, in a dose-related manner, but the reduction A number of different strategies have alleviated, but not elimi-
exceeds the decrease in accompanying MAP, suggesting that nated, the severity and incidence of this problem. One simple and
propofol is a cerebral vasoconstrictor.81 Decreases in intraocular relatively effective method is to add 10 mg lidocaine (1 mL of 1%)
pressure are seen with propofol, similar to those observed with to 20 mLof propofol immediately before injection. Starting a
thiopental. remifentanil infusion before injecting the propofol is equally
Propofol is a respiratory depressant, probably acting directly effective, in adults, in reducing the incidence of pain to about
on the medullary respiratory center.82 Apnea following an induc- 30%.96 The injection pain is at least partially owing to generation
tion dose of propofol is seen in up to 40% of unpremedicated of bradykinin produced by contact between the lipid solvent and
children.83 During an infusion of propofol, minute ventilation is the plasma kallikrein-kinin system. Release of bradykinin causes
reduced, mainly because of a reduction in tidal volume, and de- hyperpermeability of the vein wall, such that the propofol in the
pression of ventilatory responses to hypercapnia and hypoxia have aqueous phase has access to free nerve endings, causing pain.
been observed.84 Animal studies have confirmed that propofol Soybean oil normally consists of long-chain triglyerides: use of a
impairs both central and peripheral (carotid body) chemoreceptor different formulation, containing a 1:1 ratio of long- and medium-
sensitivity, the magnitude of the depression relating to the severity chain triglycerides, decreases the concentration of aqueous-phase
of the hypoxia. The mechanism of this effect remains unclear, propofol and significantly reduces the incidence and severity of
though interaction with neuronal nicotinic acetylcholine re- injection pain in adults.97,98 Similarly, dilution of the new for-
ceptors, which have similarities with GABAA receptors, seems mulation to a 0.5% concentration reduced the incidence of severe
likely.85 discomfort to 23% in children.99 Addition of lidocaine is a more
Propofol has significant dose-dependent bronchodilating pro- effective prophylactic measure than use of the new formulation, at
perties, making it beneficial for use in asthmatics.86 Nonetheless, least in children,100 though recent adult clinical studies suggest that
some episodes of bronchospasm have been observed following best results will be obtained by using a combination of these
injection of propofol, most likely owing to an anaphylactoid strategies.101
reaction to one or more of the additives. Anaphylaxis to propofol
itself is rare, although the added formulation ingredients egg
Propofol Infusion Syndrome
lecithin and soybean oil can produce allergic reactions. Hence,
propofol should be used with caution in individuals with known Prolonged infusions of propofol have been associated with a rare,
allergies to eggs or nuts. Egg allergy is most common in infants but life-threatening, condition termed the propofol infusion
and then becomes progressively less of a problem as they get older; syndrome (PRIS). This syndrome is characterized by an otherwise
few children are allergic to egg after the age of 6. Metasulfite- unexplained metabolic acidosis and/or rhabdomyolysis with
containing formulations should be avoided in patients with sulfite cardiac and renal failure. Cardiac manifestations include arrhy-
allergies. thmias, bradycardia that is refractory to treatment including
Propofol depresses pharyngeal and laryngeal reflexes, so pacing, and circulatory collapse that is often resistant to large-
allowing atraumatic insertion of a laryngeal mask airway. Propofol volume infusion and high doses of inotropic drugs. Increases in
has been used as a sole agent to facilitate tracheal intubation in serum lactate, creatinine kinase, myoglobinuria, or hyperlipidemia
children, without use of muscle relaxants. However, in the absence may herald the onset of the syndrome. Specific electrocardiogra-
of a co-administered opioid, high doses (>6 mg/kg) may be re- phic changes, consisting of “coved” ST segment elevation in leads
quired to achieve acceptable intubating conditions. Propofol may V1 to V3, may precede cardiac instability and arrest.102
have a useful role in the management of laryngeal spasm, because Initial reports of PRIS were in critically ill children, many with
it has been shown that a small dose of propofol (0.8 mg/kg) can sepsis related to respiratory tract infections, although sub-
relieve laryngospasm in 77% of children.87 Similarly, it has been sequently, there have been reports in adults.103,104 Development of
shown that propofol 0.5 mg/kg, given just before extubation, can PRIS is usually associated with prolonged, high-dose infusions
significantly reduce the incidence of postextubation laryngeal (i.e., rates > 4 mg/kg/h for > 48 h). However, more recently, there
spasm in children undergoing adenotonsillectomy.88 have been anecdotal reports of this syndrome developing follow-
Propofol has useful antiemetic properties, and clinical studies ing short-term use of propofol infusions for anesthesia and
have shown that replacing an inhalation agent with intravenous sedation.105
propofol significantly reduces the incidence of postoperative The underlying pathophysiology remains poorly understood;
nausea and vomiting (PONV), even in high-risk patients.89,90 indeed, even the very existence of this “syndrome” remains a sub-
However, the effect, even after an infusion, is relatively short-lived, ject of controversy.106 It is true that causality is not unequivocally
because a minimum plasma concentration is necessary to produce proved by the available data. However, the consistency of reports
an antiemetic effect.91 The mechanism of action for this effect is from different institutions and from patients with different
thought to be indirect activation of cannabinoid receptors, because underlying disease processes, the specific temporal association
propofol inhibits fatty acid hydrolase, an enzyme that degrades with propofol infusions, together with plausible pathophysiologic
the endogenous cannabinoid receptor agonist anandamide.56 mechanisms, all strongly suggest a causal relationship.107
Propofol has relatively mild effects on immune function, It is probable that PRIS is the result of impaired fatty acid
particularly compared with drugs such as barbiturates, opioids, utilization.103,105 PRIS mimics some of the mitochondrial myopa-
and nitrous oxide.92 In vitro and clinical studies have shown that thies, conditions with mitochondrial DNA abnormalities that
propofol has no significant effect on neutrophil or lymphocyte result in specific defects in mitochondrial respiratory chain func-
function.93–95 Propofol has no significant effects on renal, meta- tion. It is debatable as to whether a propofol metabolite directly
bolic, or endocrine function. causes mitochondrial dysfunction or whether affected patients are
Pain on injection is the most commonly reported adverse effect particularly susceptible because of an unknown underlying mito-
in children, with a reported incidence ranging from 30 to 80%. chondrial disorder (Figure 23–5).
Figure 23-5. Summary of factors that

predispose to the development of the
“propofol infusion syndrome.”
Free fatty acids, derived from catecholamine-mediated lipoly- Thiopental

sis, are the most important fuel for the myocardium and skeletal
muscle under fasting conditions and in the critically ill. Long-term Thiopental is still used to induce anesthesia in children, but its
propofol infusion is associated with an increase in malonyl- popularity is on the wane, even in developing countries. Wherever
carnitine.108 Malonylcarnitine inhibits the mitochondrial transport it is readily available, propofol is now preferred to thiopental for
protein carnitine palmityl transferase, so preventing the entry of intravenous induction of anesthesia in children. The reason for
long-chain fatty acids into the mitochondria. Prolonged propofol this change in pediatric anesthetic practice resides in the different
infusions have been also associated with muscle cytochrome pharmacokinetic properties of the two drugs.
oxidase deficiency and decreased complex IV activity.109 These
anecdotal reports in children, suggesting that propofol inhibits Pharmacokinetics
critical enzymes involved in the mitochondrial electron trans-
port chain, have been confirmed in animal studies.103 Although Thiopental has a rapid onset of action because passive diffusion
medium- and short-chain free fatty acids can freely cross the into brain tissue from cerebral capillaries is facilitated by the drug’s
mitochondrial membrane, because they do not require enzyme- high lipid solubility. Hence, peak concentrations are reached in
mediated transfer, they cannot be utilized. This detrimental effect the brain and other well-perfused organs within one circulation
on fatty acid metabolism is further compounded by curtailed time. After injection, the concentration of thiopental in arterial
entry of long-chain fatty acids into the mitochondrion. ATP blood declines rapidly, owing to distribution to well-perfused
production is reduced, and the imbalance between energy demand tissue, followed by a slower decline in concentration lasting 40 to
and supply may lead to cardiac and skeletal muscle necrosis. The 50 minutes, owing to redistribution to less well perfused tissue.
propofol-induced block of mitochondrial fatty acid oxidation Hence, pharmacokinetic data are usually consistent with a three-
causes accumulation of fatty acids, which may be exacerbated both compartment model and do not appear to vary significantly with
by the influx of triglycerides contained in the propofol solvent and age after the neonatal period.111 The recovery of consciousness
by those given for reasons of nutrition. The resulting buildup of following a single sleep dose of thiopental is caused entirely by
toxic fatty acid intermediates, coupled with cellular hypoxia, redistribution of drug into muscle, because, although thiopental is
worsens the acidosis and promotes ventricular arrhythmias. extensively metabolized by the liver to inactive metabolites, elimi-
Some reports of the use of prolonged propofol infusions in nation of drug normally plays an insignificant role in termination
children receiving intensive care suggest that propofol is safe to of effect. Hence, although thiopental clearance is greater in young
use, albeit in lower doses and for shorter durations than those children than in adults, recovery time following a single injection
reported previously.110 Clearly, not all individuals administered is not age-related (Table 23–2).
propofol for prolonged periods develop PRIS, so some unex- Thiopental has a low hepatic extraction ratio (0.3), consistent
plained factor(s) is involved. Risk factors for PRIS include pro- with capacity-limited elimination. Hence, thiopental given by
longed propofol infusion, critical illness, low carbohydrate intake infusion leads to delayed recovery, because the relevant hepatic
leading to impaired regulation and metabolism of lipids in the oxidative enzyme systems quickly become saturated. Immature
liver, hepatic dysfunction, catecholamine administration, gluco- hepatic function in the neonate causes significantly reduced
corticoids, systemic inflammation, cytokine production, young clearance of drug and a prolonged elimination time.112
age, and subclinical mitochondrial disease (see Figure 23–5).
The management of PRIS is largely supportive. Propofol
administration should be stopped immediately and appropriate Pharmacodynamics
measures instituted to support cardiorespiratory function, includ- In common with other induction agents, the average dose of
ing extracorporeal membrane oxygenation (ECMO). A number thiopental required to induce anesthesia (ED50) in healthy children
of case reports attest to the usefulness of hemofiltration. is significantly reduced by premedication with sedative drugs.113
TABLE 23-2. Main Characteristics of Thiopental 7 years, 4.3 mg/kg in children 7 to 12 years, and 4.1 mg/kg in
children aged 12 to 16 years.114–116 Furthermore, the effect site
Pharmacokinetic Characteristics (brain) concentration of thiopental needed to induce anesthesia
● High lipid solubility (loss of consciousness within one
in neonates may be lower than in infants because the neonate has
circulation time) relatively immature cerebral cortical function, rudimentary
● Clearance greater in young children but recovery of
dendritic arborizations, and relatively few synapses.117
consciousness (following single dose) similar in all ages Infants and children recover more quickly after receiving
(depends on redistribution only) propofol for induction of anesthesia than after receiving an equipotent
● Hepatic extraction = 0.3; capacity limited elimination
dose of thiopental.118 The difference between the two drugs is usually
● Volume of distribution: no significant age-related variation
demonstrated in the completeness of recovery rather than time to
after the neonatal period extubation.119 Recovery of psychomotor skills is usually significantly
● Elimination half-time: age-dependent but no clinical
faster in children receiving propofol than in those receiving
implication after a single dose thiopental,120 though by 4 hours after awakening, there may be no
Pharmacodynamic Characteristics significant difference between groups.121 Recovery from anesthesia
● Mode of action: inhibits opening of Cl– channels and GABAA is more dependent on the maintenance agent than the induction agent
agonist in CNS for anesthesia lasting longer than 30 minutes.118 For children
● ED varies with age requiring daycare surgery, therefore, thiopental is not the induction
50
● Reduction in mean arterial pressure (less marked than with agent of choice, though for children requiring more major surgery,
propofol) it may still retain some advantages over its current competitors.
● Little direct effect on vascular smooth muscle
The reduction in MAP produced in healthy children by
● Cardiovascular depression by direct myocardial depression
inducing anesthesia using propofol is significantly greater than
and central inhibition of sympathetic activity that produced by an equipotent dose of thiopental.69 Thiopental
● Bronchoconstrictive effects
has little direct effect on vascular smooth muscle tone and causes
● Anticonvulsant properties and burst suppression EEG pattern
cardiovascular depression by centrally mediated inhibition of
at therapeutic doses sympathetic nervous activity and direct myocardial depression,
● Respiratory depression
the latter probably related to its effects on trans-sarcolemmal and
● Decreases intraocular pressure and intracranial pressure
sarcoplasmic reticulum calcium flux.122
● Depresses T lymphocyte function
One significant advantage that thiopental has over propofol is
● Recovery of psychomotor skills slower than that following use
that it does not cause pain on injection, even when injected into
of propofol small veins. Thiopental is slightly less expensive than propofol,
particularly if bulk solutions are used until depleted. The prepared
Clinical Use solution can be used safely for up to 6 days even when stored at
● 2.5% solution has pH 10.5; dilute for neonates room temperature and much longer if refrigerated.123 In contrast
● Chemically and bacteriologically stable for 24 h at room to propofol, the alkaline, bacteriostatic environment of the
temperature prepared thiopental solution (pH = 10.5) means that significant
● Contraindications: porphyria, status asthmaticus, allergy to bacterial colonization is extremely unlikely.124
barbiturates (unusual), cardiovascular collapse, respiratory
obstruction
● Induction dose (slow IV injection): <6 mo, 3–5 mg/kg; 6 mo– Ketamine
4 y, 6–8 mg/kg; >4 y, 4–6 mg/kg Ketamine has been in widespread use since the 1980s. Unlike
● Sleep state obtained in 10–30 s; duration of action 5–10 min
other anesthetic agents, ketamine produces profound analgesia as
Adverse Effects well as anesthesia, amnesia, and sedation. It produces “dissociative
● Cardiovascular: hypotension, arrhythmias anaesthesia,” a cataleptic state characterized clinically by a
● Respiratory: depression, apnea, laryngospasm, bronchospasm,
functional and electrophysiologic dissociation between thalamic,
cough, hiccup cortical, and limbic systems in the brain.
● Neurologic: prolonged somnolence, delirium, confusion,
Ketamine contains a chiral carbon and is available either as a
headache racemic compound of two enantiomers, R(–) and S(+) ketamine,
● Cutaneous: thrombophlebitis, tissue necrosis if extravascular
or as the single S(+) ketamine enantiomer. Racemic ketamine has
injection; ischemia if given by intra-arterial route; rash been withdrawn from clinical use in mainland Europe and
(secondary to histamine release) replaced with the S(+) enantiomer. Clinically, the anesthetic
● Anaphylaxis: rare
potency of the S(+) isomer is approximately four times that of the
R(–) isomer, attributable to the higher affinity of the S(+) isomer
CNS = central nervous system; ED50 = median effective dose; EEG = to the phencyclidine binding sites on the N-methyl-D-aspartate
electroencephalogram; GABAA = gamma-aminobutyric acid type A.
(NMDA) receptors. The S(+) enantiomer is twice as potent as the
racemate and exhibits different pharmacologic properties.125
The ED50 of thiopental also varies somewhat with age, owing Ketamine noncompetitively inhibits NMDA receptors within the
primarily to developmental changes in many of the factors CNS, although interactions with opioid, muscarinic, and dopami-
affecting drug distribution, as discussed earlier in the section on nergic receptors have also been demonstrated. However, the
Developmental Factors affecting Drug Distribution, as discussed results of interactions with receptors other than NMDA receptors
earlier. The ED50 in the neonate is 3.4 mg/kg, 6.3 mg/kg in infants, are observed only when the plasma concentrations of ketamine
3.9 mg/kg in children aged 1 to 4 years, 4.5 mg/kg in children 4 to exceed those seen normally in clinical practice.126
Pharmacokinetics TABLE 23-3. Main Characteristics of Ketamine

Ketamine is highly lipid-soluble and, after intravenous administra- Pharmacokinetic Characteristics
tion, rapidly distributes to well-perfused tissues, including sites of ● Highly lipid soluble
action within the CNS, and then more slowly to less well-perfused ● Termination of effect with redistribution
tissues. The onset of anesthesia is within 30 seconds of intravenous ● Volume of distribution: no significant age-related variation
administration of 2 mg/kg, and peak plasma concentrations are ● Hepatic extraction ratio = 0.9
achieved within 1 minute. The offset of hypnotic effect coincides ● Clearance reduced in neonates (reflecting reduced hepatic
with redistribution from brain to other tissues and occurs 10 to enzyme activity)
15 minutes after a single intravenous induction dose of racemic ● Clearance similar in adults and children
ketamine.127 Analgesic effects, which occur at lower plasma con- ● Higher clearance for S(+) ketamine than R(–) ketamine or
centrations, are more prolonged and may persist for up to 4 hours racemate
after bolus administration.126,128 ● Two major metabolites: norketamine and
Between 35 and 55% of ketamine is bound to serum albumin dehydronorketamine
at 37°C, the bound fraction being independent of plasma drug ● Norketamine has one third the potency of parent drug
concentrations but dependent on temperature and the presence
of metabolites. At 30°C, the average fraction of bound drug is 69% Pharmacodynamic Characteristics
for dehydronorketamine, 60% for ketamine, and 50% for ● Main effects: hypnosis, analgesia, amnesia
norketamine.129 The presence of metabolites reduces the fraction ● Mode of action: NMDA receptor antagonist
of ketamine bound to albumin from about 66 to 59%. ● Cardiac stimulator; MAP, heart rate, SVR, and CI maintained
Ketamine has a high hepatic extraction ratio (0.9), and clear- or increased
ance is dependent on hepatic drug flow. When pharmacokinetic ● PVR unchanged, therefore, little effect on intracardiac
parameters are modeled using allometric scaling, clearance in shunting

children (60–90 L/h/70 kg) is similar to that in adults (53–83 ● Respiratory function preserved
L/h/70 kg),128,130 though it is reduced in infants (39 L/h/70 kg).131 ● Preserves laryngeal and pharyngeal reflexes better than other
The decreased clearance in infants is caused by reduced hepatic anesthetic agents

microsomal activity. Ketamine undergoes extensive hepatic meta- ● Bronchodilator
bolism by the CYP450 isoforms CYP3A4, CYP2B6, and CYP2C9, ● Cerebral blood flow, ICP, and cerebral autoregulation
with the formation of norketamine by N-demethylation, and maintained if PaCO2 controlled

dehydronorketamine by oxidation.132 The maturation of these ● Intraocular pressure unchanged
different isoforms during the first year of life has been discussed
Previously (see Hepatic Metabolism). Clinical Use
Animal studies suggest that norketamine has an analgesic
● Available as racemate or as the S(+) enantiomer
● Dosing: induction 1–2 mg/kg
potency about one third that of the parent compound (Table 23–3).
● Maintenance: 10–50 μg/kg/min
Dehydronorketamine is inactive. These compounds undergo fur-
● Sleep state achieved within 30 s of administration of 2 mg/kg
ther biotransformation to glucuronide conjugates before excretion,
primarily in urine. The remaining drug is excreted in feces (3%) or induction dose
● Duration of action: 10–15 min after induction dose
sequestered in tissues (5%). The elimination half-life for norke-
● Duration of analgesia up to 4 h after single dose
tamine (1.13 h) in children is less than that of the parent compound
(2.1 h) and does not appear to change with age after infancy.128 Adverse Effects
Available pharmacokinetic data suggest that norketamine does not ● Hypersalivation may be associated with laryngospasm
have a significant effect on the duration of action of racemic (administer with antisialogogue)
ketamine, whether given by bolus injection or by infusion. ● Emergence reactions less likely in children than in adults
Clearance of S(+) ketamine (26–36 mL/kg/min) is much grea- ● Emergence reactions less likely if co-administered with
ter than that of R(–) ketamine (14 mL/kg/min) or of the racemate benzodiazepine
(15 mL/kg/min).133,134 This finding is consistent with the faster ● Spontaneous involuntary activity common; poor muscle
recovery demonstrated after S(+) isomer administration com- relaxation

pared with the racemate.126 R(–) ketamine inhibits the metabolism ● Postoperative emesis relatively common
of S(+) ketamine, probably by competitive interaction of the

CI = cardiac index; ICP = intracranial pressure; MAP = mean arterial pressure;
metabolizing enzymes.133 Thus far, there is no pharmacokinetic
NMDA = N-methyl-D-aspartate; PaCO2 = partial pressure of carbon dioxide in
data for the S(+) enantiomer administered to children, but the arterial blood; PVR = peripheral vascular resistance; SVR = systemic vascular
pharmacokinetic data for the racemate suggest that, after infancy, resistance.
there will be no significant difference from adult values. Further-
more, all reported pharmacokinetic data are subject to wide
variability, secondary not only to methodologic problems but also the racemate. When ketamine is used for maintenance of anes-
to the large interindividual variability of CYP expression; reported thesia by continuous infusion, an infusion rate of 3 to 5 mg/kg/h
genetic polymorphism of CYP isoforms may also be contributory is recommended, titrated against desired effect.135–137 The plasma
(see Hepatic Metabolism). concentration that produces anesthesia in 50% of children and
adults (EC50) is 2 mg/L; the EC95 for arousal (child becoming
conscious following moderate tactile or loud verbal stimulus) is
Pharmacodynamics about 1.0 mg/L.138
In children, an induction dose of intravenous racemic ketamine is In most individuals, ketamine stimulates the cardiovascular
2 mg/kg.127 S(+) ketamine doses are approximately 50 to 75% of system and an induction dose will maintain or increase heart rate,
MAP, SVR, and cardiac index.137,139 S(+) ketamine inhibits both are qualitatively different morphologic electroencephalographic
neuronal and extraneuronal catecholamine uptake and increases changes produced by each ketamine enantiomer, each of which is
efferent sympathetic neural outflow to muscle.140 Hence, con- dose-dependent.151 These differences at least partially account for
centration of plasma norepinephrine is increased. Animal studies the conflicting clinical evidence regarding the pro- and anti-
suggest that R(–) ketamine inhibits neuronal but not extra- convulsant effects that have been documented after racemic
neuronal uptake of catecholamines.141 In vitro studies of human ketamine administration.152 Ketamine has been used to treat
atrial myocardium show that racemic and S(+) ketamine increase refractory status epilepticus153 but has also provoked seizures in
myocardial contractility at clinically relevant concentrations by epileptic patients.154 The drug is probably best avoided in poorly
10.4 and 22.1%, respectively,142 probably by increasing norepine- controlled epileptic patients.
phrine concentration in the extracellular space.143 However, Historically, ketamine was contraindicated in patients with a
racemic and S(+) ketamine reduce myocardial contractility at high closed head injury. Early studies reported that ketamine adminis-
concentrations and during β adrenoreceptor blockade by 52.9 and tration was associated with increases in intracranial pressure,
57.4%, respectively.142,143 The negative inotropic effect of ketamine cerebral oxygen consumption, and cerebral blood flow. However,
observed during β adrenoreceptor blockade appears to be caused more recent studies in patients with traumatic brain injury, tumor,
by reduced calcium ion influx via L-type calcium channels. In or aneurysm have shown that, under conditions of controlled
conclusion, therefore, induction of anesthesia using ketamine is ventilation, ketamine does not increase intracranial pressure,
not advocated in patients taking β adrenoreceptor blockers or impair autoregulation, or reduce blood flow within the middle
those in whom chronic endogenous cardiac sympathetic stimula- cerebral artery.155 Furthermore, ketamine sedation affords better
tion is likely, such as patients in congestive cardiac failure. Keta- hemodynamic stability than opioids when used in patients with
mine given to these patients may cause hypotension, because the severe head injury. However, these properties may be lost if nitrous
direct negative inotropic effects of ketamine will be unmasked if oxide is used in combination.155
norepinephrine concentrations in the myocardium are low, owing Agitation and emergence reactions are the most commonly
to either pharmacologic inhibition or depletion of cardiac nore- reported adverse reactions associated with ketamine anesthesia.
pinephrine stores. Behavioral manifestations include altered mood, crying, halluci-
Another mechanism by which ketamine increases arterial nations, involuntary muscular movements, and delirium, some-
blood pressure is by its effect on vascular smooth muscle. In vitro times persisting for weeks. The incidence of these problems in
studies of human umbilical vein endothelial cells have shown that children younger than 10 years ranges from 0 to 48%, the variation
ketamine, at a clinically relevant concentration, decreases endo- depending largely on the definition of “behavioral reaction” and
thelial NOS.144 This is caused not only by pretranslational inhi- the duration of follow-up.137,156–158 Prior or concomitant adminis-
bition of endothelial nitric oxide synthase (eNOS) protein and tration of midazolam does not reliably reduce the incidence of
mRNA concentration but also through a post-translational de- reactions.156,157 Used in a lower “sedative” dose (0.5–1.5 mg/kg),
crease in eNOS activity. Ketamine also has a direct vasodilator and given together with intravenous midazolam, a study examin-
effect, but probably only at supraclinical concentrations: ketamine ing the use of ketamine in an emergency department found that
inhibits both the interactions of bradykinin with its B2 receptor the incidence of unpleasant emergence phenomena in children
and the trans-sarcolemmal influx of calcium ions through L-type aged between 6 months and 18 years was about 3% and that it did
voltage-dependent calcium channels, both mechanisms acting to not change significantly with age.159 Similarly, a Cochrane review
reduce intracellular calcium ion concentrations.144,145 confirmed that the incidence of psychotomimetic effects following
Peripheral vascular resistance (PVR) does not change signi- low-dose ketamine ranges from 0 to 9% in adults.160 When
ficantly in spontaneously breathing children given ketamine who equipotent doses are administered, there is a similar incidence in
have normal or elevated PVR, as long as they do not become emergence reactions in patients receiving S(+) ketamine and those
hypercarbic.139 As ketamine maintains pulmonary-to-systemic receiving the racemate.161
blood flow ratios, it has little effect on shunting magnitude or Respiratory function is generally preserved by ketamine. In
direction in children with cyanotic heart disease.146 Ketamine comparison with other anesthetic agents, respiratory rate, tidal
increases the QT interval in animals, and its sympathomimetic volume, functional residual capacity, and minute ventilation are
properties suggest that it should be avoided in children with long usually maintained in children given an intravenous bolus of
QT syndrome.147 In vitro experiments on human atrial myocar- 2 mg/kg and subsequent infusion of ketamine (2–4 mg/kg/h).135
dium have shown that racemic and S(+) ketamine induce precon- Decreased responsiveness to carbon dioxide may be produced,
ditioning, at least in part by stimulation of adrenergic receptors,148 although induced hypercapnia (end-tidal carbon dioxide pressure
and despite S(+) and R(-) ketamine both inhibiting sarcolemmal [ETCO2] ≥ 47 mmHg) is unusual.162,163 Nevertheless, anecdotal
ATP–sensitive potassium channels in a concentration-dependent reports of prolonged apnea after intramuscular administration of
manner.149 modest doses to healthy children continue to be reported.164–166
The dissociative anesthesia produced by ketamine is charac- Such episodes are presumably the result of a transient high con-
terized by analgesia, amnesia, and a lack of awareness of surroun- centration of ketamine within the CNS, coupled with decreased
dings, but this is not always associated with loss of consciousness. carbon dioxide responsiveness, in particularly susceptible indivi-
The patient may exhibit open eyes, nystagmus, vocalization, and duals. An anesthetic dose of ketamine induces less upper airway
spontaneous movements. Hypertonia is often observed with keta- relaxation than other intravenous anesthetic agents and, to some
mine, but this agent is safe to use in children susceptible to malig- extent, preserves airway and laryngeal reflexes.167,168 Incidents of
nant hyperpyrexia and in those with neurologic or neuromuscular troublesome laryngospasm have been reported during ketamine
disorders. Intraocular pressure is not significantly altered after anesthesia.169 It would seem prudent, therefore, that ketamine is
ketamine administration and may be the agent of choice if administered only by personnel with the relevant airway skills and
accurate measurement of intraocular pressure is required.150 There where facilities for airway management are readily available.
Ketamine has significant bronchodilator properties. It has been etomidate negatively influences adrenal function for at least
advocated as the induction agent of choice in children with severe 24 hours.183
asthma and as a treatment for children with asthma that is refrac- However, despite these conclusive reports, the use of etomidate
tory to conventional treatment.170,171 In vitro studies show that in some countries remains relatively high.184 Considering that the
ketamine has direct actions on bronchial smooth muscle, though main use for etomidate remains the shocked patient requiring
probably only at supraclinical concentrations. Animal studies intubation and intensive care, this is particularly worrisome. It is
suggest that ketamine acts principally by attenuating neurally our unambiguous advice that etomidate is absolutely contraindi-
mediated bronchoconstriction.172 The use of ketamine is asso- cated in shocked or septic children, because adrenal insufficiency
ciated with increased salivation and tracheobronchial mucous is common in such patients.185,186
secretions and is commonly administered with an antisialogogue
such as atropine (20 μg/kg) or glycopyrrolate (5–10 μg/kg), parti-
cularly because increased salivation may predispose to laryngo- TOTAL INTRAVENOUS ANESTHESIA
spasm. However, a recent study of over 1000 children given As well as delivery by single or multiple bolus dosing, intravenous
ketamine (admittedly at subanesthetic doses), but with no anti- anesthesia may also be delivered by continuous, variable-rate
sialogogue, found that only 4.2% required intervention (such as infusion(s), and this may form the basis of a complete anesthetic
suctioning) for excessive salivation.173 technique with induction and maintenance using only intravenous
Children undergoing adenotonsillectomy given only ketamine agents. In adult anesthetic populations, total intravenous anes-
and nitrous oxide have a 68% incidence of emesis in the first thesia (TIVA) is an increasingly common mode of anesthesia
4 hours after surgery, reducing to 18% from 4 to 24 hours.156 When delivery, brought about by developments in pharmacokinetic
combined with midazolam, the incidence of postoperative emesis modeling, technologic advances in delivery systems, and the
in the 24 hours after surgery was 25%.158 In contrast, the combi- introduction into clinical practice of suitable agents—namely,
nation of ketamine and propofol is associated with only a 2% propofol and remifentanil. In the pediatric population, these
incidence of emesis.174 A recent comparative study has confirmed techniques have not yet become mainstream because the phar-
that the incidence of postoperative emesis is much higher if macokinetics of appropriate agents have not been well described
ketamine is given as the sole anesthetic agent (38%), compared in children and there is a lack of suitable, licensed equipment. For
with administration together with propofol (7%).157 instance, the Diprifusor technology used in adults for propofol
infusion utilizes adult population pharmacokinetics, patient age,
and weight to estimate plasma propofol concentrations and is not
Etomidate licensed or programmed for use in children younger than 16 years.
Etomidate is a carboxylated imidazole hypnotic drug with a rapid When used in children, such devices programmed on the basis of
onset time and a short duration of action. It is frequently used in adult pharmacokinetic data consistently underperform.187 Work
adults with limited hemodynamic reserve because it does not on the development of a target-controlled infusion (TCI) system
usually provoke any significant change in cardiovascular status. for propofol in children that utilizes published kinetic parameters
Although reports of its use in children date back since the 1980s, for this population,188 the Paedfusor, is under way but as yet there
it is only relatively recently that properly conducted studies of its is no commercially available algorithm-controlled infusion device
effects in young children have been published. Various small-scale aimed at the pediatric market.
TIVA has a number of purported advantages over traditional
clinical studies have shown that a bolus dose of etomidate 0.3 mg/
inhalation anesthetic techniques, including controllability, rapid
kg given to children between 2 and 12 years of age does not pro-
and predictable recovery, fewer side effects, and reduction in air
duce any clinically significant changes in any measured hemo-
pollution. TIVA is particularly useful when inhalation agents are
dynamic parameter. These studies included children undergoing
contraindicated, such as in patients with Duchenne’s muscular
cardiac catheterization,175 children with severe traumatic brain
dystrophy. However, economic evaluation studies have shown that
injury,176 and children requiring rapid-sequence induction in the TIVA may be more costly than inhalational anesthesia when a
emergency department, including those with decompensated target-controlled anesthesia technique is used.189 Drug wastage is
shock.177,178 In one comparative study, it was shown that propofol a major factor in the increased cost involved.
produced better intubating conditions than etomidate, when both The underlying principle of TIVA is administration of an
were used in combination with remifentanil but without the use of anesthetic agent to produce a concentration of drug within the
a muscle relaxant.179 CNS (the effect site) that mimics the anesthetic requirements and
In 1984, it was shown that etomidate, when used for long-term avoids the peaks and troughs associated with intermittent bolus
sedation, resulted in an increased mortality rate in adult intensive dosing. Mathematical algorithms based on pharmacokinetic
care unit patients.180 Subsequently, it was established that etomi- models are used to calculate infusion rates. These pharmacokine-
date inhibits adrenal function mainly by inhibiting the enzyme tic models describe the elimination and redistribution of the drug
11β-hydroxylase, the final step in the biosynthesis of cortisol.181 and may include a lag time that accounts for the delay in drug
However, many clinicians have continued to use etomidate for concentration changes between the central compartment (blood)
induction of anesthesia, assuming that a single bolus dose was safe and the effect site. This lag time, or effect-site equilibration time,
and produced only transient and clinically insignificant hormonal is specific for each drug but dependent on many pharmacodyna-
changes. This assumption was based on small-scale studies in mic factors. The estimation of this variable makes it possible to
healthy adults undergoing elective surgery. Relevant pediatric model the concentration of drug at the effect site and improve
studies have shown, however, that even a single dose of etomidate precision of individual dosing requirement.
produces decreased adrenal function and 11β-hydroxylase acti- Delivery of intravenous anesthetic drugs by continuous
vity.182 Moreover, one recent study suggests that a single dose of infusion can have a significant effect on drug clearance and, hence,
TABLE 23-4. Infusion Rate Recommendations for TABLE 23-5. Infusion Rate Recommendations for
Propofol in Children Aged 3 to 11 Years for Target Propofol in Children Younger Than 3 Years, Based on
Blood Concentration of 3 μg/mL Clinical Effect
Propofol Infusion Rates Propofol Infusion Rates, mg/kg/h
Bolus dose 2.5 mg/kg Infusion rates <3 mo 3–6 mo 6–12 mo 1–3 y
Infusion rates ␮g/kg/h ␮g/kg/min First 10 min 25 20 15 12
Second 10 min 20 15 10 9
0–15 min 15 250
Third 10 min 15 10 — —
15–30 min 13 215
Fourth 10 min 10 — — —
30–60 min 11 185
Consecutive 1 h 5 5 5 —
1–2 h 10 165
Remaining time 2.5 2.5 2.5 6
2–4 h 9 150
From reference 192.
From reference 47.
recovery time. Clearance is dependent on both redistribution and DRUG INTERACTIONS

elimination of drug from the central compartment. After pro- Combinations of drugs are often used to maintain anesthesia
longed infusions, where equilibration has been reached between because no single agent offers all the components of anesthesia
the peripheral and the central compartments, redistribution may without producing unwanted effects. Drug interactions may occur
play only a minor role in clearance, at least initially. This has led between co-administered agents and these may be pharmaco-
to the introduction of the concept of the CSHT. The CSHT is the dynamic or pharmacokinetic. In some instances, these drug
time it takes for the drug concentration to decrease by 50% after interactions may be used purposefully to exploit the synergistic
stopping an infusion, where the context refers to the duration action of drugs, thereby reducing the doses required of each or
of the infusion. For example, propofol has a CSHT of less than either drug and the incidence or severity of adverse effects.
25 minutes after an infusion of 3 hours, and a CSHT of approxi-
mately 50 minutes after a 12-hour infusion.
One method of administering TIVA is by a TCI. TCI utilizes a Pharmacodynamic Interactions
computer-controlled syringe pump that controls the rate of
Propofol is often administered together with an opioid because it
infusion of a drug to attain a defined target concentration at the lacks any analgesic properties. In adult studies, remifentanil has
patient’s effect site. These are seldom used in pediatric practice. The been shown to decrease the dose of propofol required for induc-
commonly used alternative to TCI is a manually controlled regime; tion, the effect-site concentration of propofol, and time to loss
several have been proposed for use with propofol in pediatric of consciousness, as measured by loss of response to verbal
patients. McFarlan and associates47 developed a simple infusion stimuli.193,194 Time to return of consciousness after termination of
regime for children older than 3 years, based on pharmacokinetic propofol-remifentanil infusions is reduced. In children, remi-
work from Kataria and coworkers,190 to maintain a plasma con- fentanil halved the concentration of propofol required for laryn-
centration of about 3 μg/mL (Table 23–4). A recent assessment of geal mask and laryngeal tube insertion195 and decreased propofol
the performance of this regime found it was able to produce requirements for maintenance of anesthesia.196 Increasing the
distinct differences in plasma concentrations and there was no infusion rate of remifentanil to more than 25 ng/kg/min yields
significant differences between predicted and measured plasma minimal reductions in propofol requirements. The effect of remi-
concentrations.191 Steur and colleagues have reported a dosage fentanil on the BIS and electroencephalogram during propofol
scheme for children aged 1 to 3 years based on clinical assessment anesthesia is unclear, with some studies suggesting remifentanil
and not on target plasma concentrations (Table 23–5).192 These has an additive effect with propofol,193,197 whereas others suggest
studies have confirmed that age and weight are important cova- that it has no hypnotic effect in clinically relevant doses.198,199 Un-
riates in determining the infusion rate in children. fortunately, in anesthetic doses, remifentanil potentiates propofol’s
respiratory depressant and hypotensive effects, though children
Drugs Used in TIVA younger than 3 years are relatively tolerant to the respiratory
effects of this interaction.200 Similar interactions have been demon-
A useful drug for TIVA will exhibit a close relationship between strated with propofol and other opioids, including alfentanil,
plasma concentration and effect, expressed by a short equilibration fentanyl, and sufentanil.201 The effects of propofol on remifentanil
half-time, and a short CSHT. These properties will allow for rapid have also been studied using response surface modeling. Despite
onset and offset of action and the ability to rapidly titrate drug in propofol having no analgesic properties, when combined with
response to surgical stimuli and depth of anesthesia. Of the intra- remifentanil, the remifentanil requirements to ablate responses to
venous drugs in current use, those agents that are most suitable for laryngoscopy, intubation, and intra-abdominal surgical stimula-
TIVA and TCI are propofol and remifentanil (see Chapter 25). Other tion decrease with increasing concentration of propofol in a
agents that have been used for TIVA include ketamine, thiopental, synergistic manner.202 This effect has also been demonstrated with
etomidate, alfentanil, and fentanyl. Fentanyl and thiopental have long alfentanil.201
CSHTs, leading to prolonged recovery, and the side effect profiles There is no synergistic interaction between propofol and keta-
of etomidate and ketamine limit their use. Alfentanil has a shorter mine with regard to hypnosis or anesthesia and their effects are
CSHT than fentanyl, though it is still substantially longer than additive. The ED50 of propofol to produce apnea was unaffected
remifentanil if used for longer than 4 hours. by concomitant ketamine administration. However, ketamine
significantly reduces the hemodynamic effects associated with additive manner to produce loss of consciousness and immobility
propofol, minimizing changes in heart rate and arterial pressure.203 to surgical stimuli.210
Sedative agents also show synergism with propofol. Oral
premedication with midazolam reduces the dose of propofol
required for hypnosis and laryngeal mask airway insertion in ANESTHESIA AND NEUROAPOPTOSIS
children,58 but benzodiazepines do not reduce the dose of propofol General anesthesia causes widespread and dose-dependent neuro-
required to maintain anesthesia. In adults, the pineal hormone nal cell death (neuroapoptosis) in neonatal rats, guinea pigs, and
melatonin, which is an effective sedative premedication in both subhuman primates. The existing experimental data implicates
children and adults, has been shown to reduce the anesthesia NMDA antagonists and GABAA receptor agonists, so barbiturates,
induction dose for both propofol and thiopental.204 Qualitatively propofol, ketamine, benzodiazepines, etomidate, and all the in-
similar effects are expected in children. haled anesthetic agents including nitrous oxide are potentially
neurotoxic to the developing brain.211 The exact mechanism of
anesthesia-induced neurotoxicity is unknown.
Pharmacokinetic Interactions Unfortunately, the developing CNS shows marked interspecies
Pharmacokinetic interactions involve changes to the distribution, variation and correlating periods of brain growth and synap-
metabolism, or elimination of concomitantly administered drugs. togenesis between species as diverse as the rat, guinea pig, and
Almost all data relating to intravenous anesthetic agents are human is fraught with difficulty. Experimental animals were often
derived from studies in adults. subject to prolonged exposure of high doses of anesthetic agents,
In vitro studies demonstrate reduced clearance of drugs, not- often in concentrations exceeding those used clinically. Physiolo-
ably the opioids, by modulation of the CYP450 enzyme systems by gic parameters were not always monitored, so it is possible that
various anesthetic agents. Propofol, midazolam, diazepam, and derangements of oxygenation, cerebral perfusion, glucose, or
etomidate all inhibit activity of some P450 cytochromes. For hypothermia may have contributed to the effects seen. To com-
example, propofol inhibits CYP3A activity responsible for the plicate matters further, it has been shown that exposure to pain or
metabolism of alfentanil, which may partly explain prolonga- surgical stress can have long-term behavioral and physiologic
tion of the CSHT of alfentanil during combined infusion with effects in humans.212,213 Moreover, anesthetic agents may be neur-
propofol.205 oprotective.214
Hence, extrapolation of this experimental animal data to the
In practice, however, the majority of drug interactions are
human neonate remains problematic and controversial. Interna-
related to changes in hemodynamic factors, such as cardiac output
tional multicenter trials are ongoing, though it may be many years
and hepatic perfusion, which affect distribution and elimination.
before this issue is completely resolved. At this time, there is no
This is especially true for drugs that show high extraction ratios
evidence that any particular anesthetic technique is more dan-
and are more likely to be affected by changes to hepatic perfusion.
gerous to the immature brain than any other. The interested reader
Reductions in arterial pressure and SVR produced by propofol is referred to several recent reviews on the subject.215–218
alter the kinetics of all the opioids, including remifentanil, with
the result that plasma concentrations of these drugs are increased
in the presence of propofol, and subsequently, there are reduced CONCLUSIONS
dosage requirements for suppression of responses to stimuli.
Propofol reduces the volume of distribution and clearance of In the past, inhalation anesthesia was often considered the tech-
remifentanil by up to 40%.206 Propofol is itself a high extraction nique of choice for pediatric patients. However, modern intra-
drug and may be subject to pharmacokinetic interactions. In the venous anesthetic agents are effective and well tolerated and
presence of oral clonidine premedication, propofol shows reduced generally have good safety profiles, and the majority of direct
elimination and smaller propofol doses are required for hypnosis comparisons between inhaled and intravenous anesthetics have
failed to demonstrate significant differences in recovery times. The
and anesthesia, but time to return of consciousness after an
development and use of topical anesthetic creams have made
infusion is prolonged because of pharmacodynamic interaction.207
intravenous access less traumatic and intravenous induction of
There are (rare) specific circumstances when total intravenous
anesthesia a practical proposition in most children. Intravenous
anesthesia will be required, and inhalational agents contraindi- techniques reduce some of the deleterious consequences asso-
cated, as with children susceptible to malignant hyperpyrexia and ciated with the use of inhalation agents, especially given concerns
those with Duchenne’s muscular dystrophy. Similarly, there will over the role inhalation agents play as environmental polluters.
always be situations in which inhalation induction is preferred, Notably, nitrous oxide, a greenhouse gas, has been implicated in
for instance, in the needle-phobic child or when intravenous the destruction of the ozone layer, as has isoflurane.219
access is likely to be difficult. Practically, a combination of the two A major disincentive to the greater use of intravenous anes-
techniques remains popular, for reasons of both expense and thetic agents in the pediatric population is the relative paucity of
experience. Indeed, interactions between the intravenous agents pharmacokinetic and pharmacodynamic data, especially in the
and the inhalation anesthetic agents are commonly utilized by very young and critically ill. Where information in children is
anesthetists. The combination of nitrous oxide and propofol is an available, it is often limited in value by the relatively small number
example: inhalation of 66% nitrous oxide in oxygen for 1 minute of patients studied. Recent pediatric pharmacologic studies have
prior to intravenous induction with propofol reduces the induc- increased our understanding but have also highlighted the large
tion dose of propofol and time taken for induction. Similarly, interpatient variability and complexity of development-related
when propofol is used for maintenance of anesthesia, nitrous oxide changes.
reduces the risk of awareness, movement, and dose of propofol By about 2020, as the complex mechanisms underlying
required.208,209 Likewise, propofol and sevoflurane interact in an anesthesia are further elucidated, there exists the possibility of the
development of new intravenous anesthetic agents. In reality, 21. Kingston HGG, Kendrick A, Sommer KM, et al. Binding of thiopental in
however, commercial factors will limit anesthetic drug develop- neonatal serum. Anesthesiology. 1990;72:428–431.
22. Stevens JC, Hines RN, Gu C, et al. Developmental expression of the major
ment and it is unlikely that the near future will see the introduc- human hepatic CYP3A enzymes. J Pharmacol Exp Ther. 2003;307:
tion of completely new agents; novel application or reformulation 573–582.
of existing drugs appears more probable. 23. Bjorkman S. Prediction of cytochrome P450–mediated hepatic drug
Further exploration and elaboration into the developmental clearance in neonates, infants and children. Clin Pharmacokinet. 2006;45:
pharmacology of intravenous anesthetic agents are necessary. 1–11.
24. Koukouritaki S, Manro JR, Marsh SA, et al. Developmental expression of
Improving our understanding of infusion pharmacokinetics,
human hepatic CYP2C9 and CYP2C19. J Pharmacol Exp Ther. 2004;308:
effects of maturation, pharmacogenomics, and concentration- 965–974.
effect relationships in children will make currently available agents 25. Miyagi SJ, Collier AC. Pediatric development of glucuronidation:
more predictable and advance the development and increase the the ontogeny of hepatic UGT1A4. Drug Metab Dispos. 2007;35:
use of intravenous anesthesia in children. 1587–1592.
26. Edginton AN, Schmitt W, Voith B, Willmann S. A mechanistic approach
for the scaling of clearance in children. Clin Pharmacokinet. 2006;45:
683–704.
REFERENCES 27. Ross AK, Davis PJ, Dear GL, et al. Pharmacokinetics of remifentanil in
1. Sholler GF, Celermajer JM, Whight CM, Bauman AE. Echo Doppler anesthetized pediatric patients undergoing elective surgery or diagnostic
assessment of cardiac output and its relation to growth in normal infants. procedures. Anesth Analg. 2001;93:1393–1401.
Am J Cardiol. 1987;60:1112–1116. 28. Ngan Kee WD, Khaw KS, Ma KC, et al. Maternal and neonatal effects of
2. Sholler GF, Celermajer JM, Whight CM. Doppler echocardiographic remifentanil at induction of general anesthesia for cesarean delivery.
assessment of cardiac output in normal children with and without Anesthesiology. 2006;104:14–20.
innocent precordial murmurs. Am J Cardiol. 1987;59:487–488. 29. Rautakorpi P, Ali-Melkkilä T, Kaila T, et al. Pharmacokinetics of
3. Chiron C, Raynaud C, Mazière B, et al. Changes in regional cerebral blood glycopyrrolate in children. J Clin Anesth. 1994;6:217–220.
flow during brain maturation in children and adolescents. J Nucl Med. 30. Weekes LM, Keneally JP, Goonetilleke PH, Ramzan IM. Pharmacokinetics
1992;33:696–703. of alcuronium in children with acyanotic and cyanotic cardiac disease
4. Schoning M, Hartig B. Age dependence of total cerebral blood flow undergoing cardiopulmonary bypass surgery. Paediatr Anaesth. 1995;5:
volume from childhood to adulthood. J Cereb Blood Flow Metab. 1996;16: 369–374.
827–833. 31. Koren G, Barker C, Goresky G, et al. The influence of hypothermia on
5. Biagi L, Abbruzzese A, Bianchi MC, et al. Age dependence of cerebral the disposition of fentanyl: human and animal studies. Eur J Clin
perfusion assessed by magnetic resonance continuous arterial spin Pharmacol. 1987;32:373–376.
labeling. J Magn Reson Imaging. 2007;25:696–702. 32. Mets B. The pharmacokinetics of anesthetic drugs and adjuvants during
6. Engelhardt B. Development of the blood-brain barrier. Cell Tissue Res. cardiopulmonary bypass. Acta Anaesthesiol Scand. 2000;44:261–273.
2003;314:119–129. 33. Roka A, Melinda KT, Vasarhelyi B, et al. Elevated morphine concentra-
7. Hastings LA, Monitto CL, Lenox C, Yaster M. CSF and plasma fentanyl tions in neonates treated with morphine and prolonged hypothermia for
levels in children undergoing ventriculoperitoneal shunt surgery. hypoxic ischemic encephalopathy. Pediatrics. 2008;121:e844–e849.
Anesthesiology. 1997;87:A1063. 34. Tortorici MA, Kochanek PM, Poloyac SM. Effects of hypothermia on drug
8. Persidsky Y, Ramirez SH, Haorah J, Kanmogne GD. Blood-brain barrier: disposition, metabolism and response: a focus of hypothermia-mediated
structural components and function under physiologic and pathologic alterations on the cytochrome P450 enzyme system. Crit Care Med. 2007;
conditions. J Neuroimmune Pharmacol. 2006;1:223–236. 35:2186–2204.
9. Henthorn TK, Liu Y, Mahaptro M, Ng K-Y. Active transport of fentanyl 35. Russell D, Royston D, Rees PH, et al. Effect of temperature and cardio-
by the blood-brain barrier. J Pharmacol Exp Ther. 1999;289:1084–1089. pulmonary bypass on the pharmacokinetics of remifentanil. Br J Anaesth.
10. Hamabe W, Maeda T, Kiguchi N, et al. Negative relationship between 1997;79:456–459.
morphine analgesia and P-glycoprotein expression levels in the brain. 36. Jin J-S, Sakaeda T, Kakumoto M, et al. Effect of therapeutic moderate
J Pharmacol Sci. 2007;105:353–360. hypothermia on multidrug resistance protein 1–mediated transepithelial
11. Choudhari S, Klaassen CD. Structure, function, expression, genomic transport of drugs. Neurol Med Chir. 2006;46:321–327.
organization, and single nucleotide polymorphisms of human ABCB1 37. Hiraoka H, Yamamoto K, Okano N, et al. Changes in drug plasma con-
(MDR1), ABCC (MRP), and ABCG2 (BCRP) efflux transporters. Int centrations of an extensively bound and highly extracted drug, propofol,
J Toxicol. 2006;25:231–259. in response to altered plasma binding. Clin Pharmacol Ther. 2004;75:
12. Thuerauf N, Fromm MF. The role of the transporter P-glycoprotein for 324–330.
disposition and effects of centrally acting drugs and for the pathogenesis 38. Takizawa E, Hiraoka H, Takizawa D, Goto F. Changes in the effect of pro-
of CNS diseases. Eur Arch Psychiatry Clin Neurosci. 2006;256:281–286. pofol in response to altered plasma protein binding during normothermic
13. Friis-Hansen B. Water distribution in the foetus and newborn infant. Acta cardiopulmonary bypass. Br J Anaesth. 2006;96:179–185.
Paediatr Scand. 1983;305:7–11. 39. Thurston TA, Maldonado G, Mathew BP. Acidosis accentuates thiopental-
14. Wells JCK, Fewtrell MS, Davies PSW, et al. Prediction of total body water induced myocardial depression in vitro. Anesth Analg. 1996;83:636–638.
in infants and children. Arch Dis Child. 2005;90:965–971. 40. Reddy SC, Panigraphy A, White WF, Kinney HC. Developmental changes
15. Chumlea WC, Schubert CM, Reo NV, et al. Total body water volume for in neurotransmitter receptor binding in the human periaqueductal gray.
white children and adolescents and anthropometric prediction equations: J Neuropathol Exp Neurol. 1996;55:409–418.
the Fels longitudinal study. Kidney Int. 2005;68:2317–2322. 41. Kinney HC, White WF. Opioid receptors localize to the external granular
16. Butte NF, Hopkinson JM, Wong WW, et al. Body composition during the cell layer of the developing human cerebellum. Neuroscience. 1991;45:
first 2 years of life: an updated reference. Pediatr Res. 2000;47:578–585. 13–21.
17. Wells JCK, Fewtrell MS, Williams JE, et al. Body composition in normal 42. Clark AS, Robinson S, Henderson LP. Dynamics of GABA(A) receptor
weight, overweight and obese children: matched case-control analyses of binding in the ventromedial hypothalamus during postnatal development
total and regional tissue masses, and body composition trends in relation in the rat. Brain Res Dev Brain Res. 1997;103:195–198.
to relative weight. Int J Obesity. 2006;30:1506–1513. 43. Murat I, Billard V, Vernois J, et al. Pharmacokinetics of propofol after a
18. Kosti RI, Panagiotakos DB. The epidemic of obesity in children and single dose in children aged 1-3 years with minor burns. Anesthesiology.
adolescents in the world. Cent Eur J Public Health. 2008;14:151–159. 1996;84:526–532.
19. Booker PD, Taylor C, Saba G. Perioperative changes in α1-acid glycopro- 44. Gan TJ. Pharmacokinetic and pharmacodynamic characteristics of medi-
tein concentrations in infants undergoing major surgery. Br J Anaesth. cations used for moderate sedation. Clin Pharmacokinet. 2006;45:
1996;76:365–368. 855–869.
20. Russo H, Bressolle F. Pharmacodynamics and pharmacokinetics of 45. Schuttler J, Ihmsen H. Population pharmacokinetics of propofol: a multi-
thiopental. Clin Pharmacokinet. 1998;35:95–134. center study. Anesthesiology. 2000;92:727–738.
46. Rigby-Jones AE, Nolan JA, Priston MJ, et al. Pharmacokinetics of propofol 71. Wodey E, Chonow L, Beneux X, et al. Haemodynamic effects of propofol
infusions in critically ill neonates, infants and children in an intensive vs. thiopental in infants: an echocardiographic study. Br J Anaesth.
care unit. Anesthesiology. 2002;97:1393–1400. 1999;82:516–520.
47. McFarlan CS, Anderson BJ, Short TG. The use of propofol infusions in 72. Tramer MR, Moore RA, McQuay HJ. Propofol and bradycardia:
paediatric anaesthesia: a practical guide. Paediatr Anaesth. 1999;9: causation, frequency and severity. Br J Anaesth. 1997;78:642–651.
209–216. 73. Aguero Pena RE, Pascuzzo-Lima C, Granado Duque AE, Bonfante-
48. Al-Jahdari WS, Yamamoto K, Hiraoka H, et al. Prediction of total pro- Cabarcas RA. Propofol-induced myocardial depression: possible role of
pofol clearance based on enzyme activities in microsomes from human atrial muscarinic cholinergic receptors. Rev Esp Anesthesiol Reanim.
kidney and liver. Eur J Clin Pharmacol. 2006;62:527–533. 2008;55:81–85.
49. Takizawa D, Hiraoka H, Goto F, et al. Human kidneys play an important 74. Kanaya N, Gable B, Wickley PJ, et al. Experimental conditions are impor-
role in the elimination of propofol. Anesthesiology. 2005;102:327–330. tant determinants of cardiac inotropic effects of propofol. Anesthesiology.
50. Hiraoka H, Yamamoto K, Miyoshi S, et al. Kidneys contribute to the 2005;103:1026–1034.
extrahepatic clearance of propofol in humans but not lungs and brain. Br 75. Larsen JR, Torp P, Norrild K, Sloth E. Propofol reduces tissue-Doppler
J Clin Pharmacol. 2005;60:176–182. markers of left ventricle function: a transthoracic echocardiographic
51. Tateishi T, Nakura H, Asoh M, et al. A comparison of hepatic cytochrome study. Br J Anaesth. 2007;98:183–188.
P450 protein expression between infancy and postinfancy. Life Sci. 76. Kurokawa H, Murray PA, Damron DS. Propofol attenuates β-
1997;61:2567–2574. adrenoreceptor–mediated signal transduction via a protein kinase C–
52. Johnson TN, Rostami-Hodjegan A, Tucker GT. Prediction of the dependent pathway in cardiomyocytes. Anesthesiology. 2002;96:688–698.
clearance of eleven drugs and associated variability in neonates, infants 77. Wickley PJ, Shiga T, Murray PA, Damron DS. Propofol decreases
and children. Clin Pharmacokinet. 2006;45:931–956. myofilament Ca2+ sensitivity via a protein kinase C–, nitric oxide
53. Allegaert K, De Hoon J, Verbesselt R, et al. Maturational pharmacokine- synthase–dependent pathway in diabetic cardiomyocytes. Anesthesiology.
tics of a single intravenous dose of propofol. Paediatr Anaesth. 2007;17: 2006;104:978–987.
1028–1034. 78. Wickley PJ, Shiga T, Murray PA, Damron DS. Propofol modulates Na+-
54. White M, Kenny GNC, Schraag S. Use of target controlled infusion to Ca2+ exchange activity via activation of protein kinase C in diabetic
derive age and gender covariates for propofol clearance. Clin Pharmaco- cardiomyocytes. Anesthesiology. 2007;106:302–311.
kinet. 2008;47:119–127. 79. Meyer S, Shamdeen MG, Kegel B, et al. Effect of propofol on seizure-like
55. Allegaert K, Peeters MY, Verbesselt R, et al. Inter-individuality variability phenomena and electroencephalographic activity in children with
in propofol pharmacokinetics in preterm and term neonates. Br J Anaesth. epilepsy vs. children with learning difficulties. Anaesthesia. 2006;61:
2007;99:864–870. 1040–1047.
56. Solt K, Forman SA. Correlating the clinical actions and molecular 80. Karsli C, Luginbuehl I, Bissonnette B. The cerebrovascular response
mechanisms of general anesthetics. Curr Opin Anaesthesiol. 2007;20: to hypocapnia in children receiving propofol. Anesth Analg. 2004;99:
300–306. 1049–1052.
57. Vanlersberghe C, Camu F. Propofol. Handb Exp Pharmacol. 2008;182: 81. Karsli C, Luginbuehl I, Farrar M, Bissonnette B. Propofol decreases
227–252. cerebral blood flow velocity in anaesthetized children. Can J Anaesth.
58. Martlew RA, Meakin G, Wadsworth R, et al. Dose of propofol for 2002;49:830–834.
laryngeal mask airway insertion in children: effect of premedication with 82. Kashiwagi M, Okada Y, Kuwana S, et al. A neuronal mechanism of
midazolam. Br J Anaesth. 1997;76:308–309. propofol-induced central respiratory depression in newborn rats. Anesth
59. Goyagi T, Tanaka M, Nishiwaka T. Fentanyl decreases propofol require- Analg. 2004;99:49–55.
ment for laryngeal mask airway insertion. Acta Anaesthesiol Scand. 83. Manschot HJ, Meursing AEE, Axt P, et al. Propofol requirements for
2003;47:771–774. induction of anaesthesia in children of different age groups. Paediatr
60. Park H-J, Lee J-R, Kim CS, et al. Remifentanil halves the EC50 of propofol Anaesth. 1992;75:876–879.
for successful insertion of the laryngeal mask airway and laryngeal tube 84. Goodman NW, Black AMS, Carter JA. Some ventilatory effects of
in pediatric patients. Anesth Analg. 2007;105:57–61. propofol as sole anaesthetic agent. Br J Anaesth. 1987;59:1497–1503.
61. Pessenbacher K, Gutmann A, Eggenreich U, et al. Two propofol formula- 85. Jonsson MM, Lindahl SGE, Eriksson LI. Effect of propofol on carotid
tions are equivalent in small children aged 1 month to 3 years. Acta body chemosensitivity and cholinergic chemotransduction. Anesthesio-
Anaesthesiol Scand. 2002;46:257–263. logy. 2005;102:110–116.
62. Munoz HR, Cortinez LI, Ibacache ME, Leon PJ. Effect site concentrations 86. Bagcivan I, Cevit O, Yildirim MK, et al. Investigation of the relaxant
of propofol producing hypnosis in children and adults: comparison using effects of propofol on ovalbumin-induced asthma in guinea pigs. Eur J
the bispectral index. Acta Anaesthesiol Scand. 2006;50:882–887. Anaesthesiol. 2007;24:796–802.
63. Rigouzzo A, Girault L, Louvet N, et al. The relationship between bispectral 87. Afshan G, Chohan U, Qamar-Ul-Hoda M, Kamal RS. Is there a role of a
index and propofol during target-controlled infusion anesthesia: a small dose of propofol in the treatment of laryngeal spasm? Paediatr
comparative study between children and young adults. Anesth Analg. Anaesth. 2002;12:625–628.
2008;106:1109–1116. 88. Batra YK, Ivanova M, Shamsah M, et al. The efficacy of a subhypno-
64. Jeleazcov C, Ihmsen H, Schmidt J, et al. Pharmacodynamic modelling of tic dose of propofol in preventing laryngospasm following tonsillec-
the bispectral index response to propofol-based anaesthesia during tomy and adenoidectomy in children. Paediatr Anaesth. 2005;15:
general surgery in children. Br J Anaesth. 2008;100:509–516. 1094–1097.
65. Hammer GB, Litalien C, Wellis V, et al. Determination of the median 89. Tramer M, Moore A, McQuay H. Propofol anaesthesia and postoperative
effective concentration (EC50) of propofol during esophagogastro- nausea and vomiting: quantitative systematic review of randomized
duodenoscopy in children. Paediatr Anaesth. 2001;11:549–553. controlled studies. Br J Anaesth. 1997;78:247–255.
66. Cortinez LI, Munoz HR, Lopez R. Pharmacodynamics of propofol in 90. DeBalli P. The use of propofol as an antiemetic. Int Anesthesiol Clin.
children and adults: comparison based on the auditory evoked potentials 2003;41:67–77.
index. Rev Esp Anesthesiol Reanim. 2006;53:289–296. 91. White H, Black RJ, Jones M, Mar Fan GC. Randomized comparison of
67. Short SM, Aun CST. Haemodynamic effects of propofol in children. two anti-emetic strategies in high-risk patients undergoing day-case
Anaesthesia. 1991;46:783–785. gynaecological surgery. Br J Anaesth. 2007;98:470–476.
68. Williams GD, Jones TK, Hanson KA, Morray JP. The hemodynamic 92. Schneemilch CE, Hachenberg T, Ansorge S, et al. Effects of different
effects of propofol in children with congenital heart disease. Anesth Analg. anaesthetic agents on immune cell function in vitro. Eur J Anaesthesiol.
1999;89:1411–1416. 2005;22:616–623.
69. Aun CST, Sung RYT, O’Meara ME, et al. Cardiovascular effects of I.V. 93. Huettemann E, Jung A, Vogelsang H, et al. Effects of propofol vs
induction in children: comparison between propofol and thiopentone. Br methohexital on neutrophil function and immune status in critically ill
J Anaesth. 1993;70:647–653. patients. J Anesth. 2006;20:86–91.
70. Nagakawa T, Yamazaki M, Hatakeyama N, Stekiel TA. The mechanisms 94. Delogu G, Antonucci A, Moretti S, et al. Oxidative stress and mitochon-
of propofol-mediated hyperpolarization of in situ rat mesenteric vascular drial glutathione in human lymphocytes exposed to clinically relevant
smooth muscle. Anesth Analg. 2003;97:1639–1645. anesthetic drug concentrations. J Clin Anesth. 2004;16:189–194.
95. Inada T, Yamanouchi Y, Jomura S, et al. Effect of propofol and isoflurane 122. Komai H, Rusy BF. Effect of thiopental on Ca2+ release from sarcoplas-
anaesthesia on the immune response to surgery. Anaesthesia. 2004;59: mic reticulum in intact myocardium. Anesthesiology. 1994;81:946–952.
954–959. 123. Haws JL, Herman N, Clark Y, et al. The chemical stability and sterility of
96. Roehm KD, Piper SN, Maleck WH, Boldt J. Prevention of propofol- sodium thiopental after preparation. Anesth Analg. 1998;86:208–213.
induced injection pain by remifentanil: a placebo-controlled comparison 124. Crowther J, Hrazdil J, Jolly DT, et al. Growth of micro-organisms in
with lidocaine. Anaesthesia. 2003;58:165–170. propofol, thiopental and a 1:1 mixture of propofol and thiopental. Anesth
97. Ohmizo H, Obara S, Iwama H. Mechanism of injection pain with long Analg. 1996;82:475–478.
and long-medium chain triglyceride emulsive propofol. Can J Anaesth. 125. Geisslinger G, Hering W, Thomann P, et al. Pharmacokinetics and
2005;52:595–599. pharmacodynamics of ketamine enantiomers in surgical patients using
98. Allford MA, Mensah JA. Discomfort on injection: a comparison between a stereoselective analytical method. Br J Anaesth. 1993;70:666–671.
two formulations of propofol. Eur J Anaesthesiol. 2006;23:971–974. 126. Kohrs R, Durieux ME. Ketamine: teaching an old drug new tricks.
99. Soltesz S, Silomon M, Graf G, et al. Effect of a 0.5% dilution of propofol Anesth Analg. 1998;87:1186–1193.
on pain on injection during induction of anesthesia in children. 127. Herd D, Anderson BJ, Keene NA. Investigating the pharmacodynamics
Anesthesiology. 2007;106:80–84. of ketamine in children. Paediatr Anaesth. 2008;18:36–42.
100. Nyman Y, von Hofsten K, Georgiadi A, et al. Propofol injection pain in 128. Herd DW, Anderson BJ, Holford NHG. Modeling the norketamine
children: a prospective randomized double-blind trial of a new propofol metabolite in children and the implications for analgesia. Paediatr
formulation versus propofol with added lidocaine. Br J Anaesth. 2005; Anaesth. 2007;17:831–840.
95:222–225. 129. Hijazi Y, Boulieu R. Protein binding of ketamine and its active meta-
101. Bachmann-Mennenga B, Ohlmer A, Boedeker RH, et al. Preventing pain bolites to human serum. Eur J Clin Pharmacol. 2002;58:37–40.
during injection of propofol: effects of a new emulsion with lidocaine 130. Herd D, Anderson BJ. Ketamine disposition in children presenting for
addition. Eur J Anaesthesiol. 2007;24:33–38. procedural sedation and analgesia in a children’s emergency department.
102. Vernooy K, Delhaas T, Cremer OL, et al. Electrocardiographic changes Paediatr Anaesth. 2007;17:622–629.
predicting sudden death in propofol-related infusion syndrome. Heart 131. Hartvig P, Larsson E, Joachimsson P-O. Postoperative analgesia and
Rhythm. 2006;3:131–137. sedation following pediatric cardiac surgery using a constant infusion
103. Kam PCA, Cardone D. Propofol infusion syndrome. Anaesthesia. of ketamine. J Cardiothorac Vasc Anesth. 1993;7:148–153.
2007;62:690–701. 132. Hijazi Y, Boulieu R. Contribution of CYP3A4, CYP2B6 and CYP2C9
104. Rosen DJ, Nicoara A, Koshy N, Wedderburn RV. Too much of a good isoforms to N-demethylation of ketamine in human liver microsomes.
thing? Tracing the history of the propofol infusion syndrome. J Trauma. Drug Metab Dispos. 2002;30:853–858.
2007;63:443–447. 133. Ihmsen H, Geisslinger G, Schuttler J. Stereoselective pharmacokinetics
105. Fodale V, La Monaca E. Propofol infusion syndrome: an overview of a of ketamine:R(–)-ketamine inhibits the elimination of S(+)-ketamine.
perplexing disease. Drug Saf. 2008;31:293–303. Clin Pharmacol Ther. 2001;70:431–438.
106. Ahlen K, Buckley CJ, Goodale DB, Pulsford AH. The “propofol infusion 134. White M, de Graaff P, Renshof B, et al. Pharmacokinetics of S(+) keta-
syndrome”: the facts, their interpretation and implications for patient mine derived from target controlled infusion. Br J Anaesth. 2006;96:
care. Eur J Anaesthesiol. 2006;23:990–998. 330–334.
107. Fudickar A, Bein B, Tonner PH. Propofol infusion syndrome in anaes- 135. von Ungern-Sterberg BS, Regli A, Frei FJ, et al. A deeper level of keta-
thesia and intensive care medicine. Curr Opin Anaesthesiol. 2006;19: mine anesthesia does not affect functional residual capacity and
404–410. ventilation distribution in healthy preschool children. Paediatr Anaesth.
108. Wolf A, Weir P, Segar P, et al. Impaired fatty acid oxidation in propofol 2007;17:1150–1155.
infusion syndrome. Lancet. 2001;357:606–607. 136. Tugrul M, Camci E, Pembeci K, et al. Ketamine infusion versus isoflurane
109. Vasile B, Rasulo F, Candiani A, Latronico N. The pathophysiology of for the maintenance of anesthesia in the prebypass period in children
propofol infusion syndrome. Intensive Care Med. 2003;29:1417–1425. with tetralogy of Fallot. J Cardiothorac Vasc Anesth. 2000;14:557–561.
110. Cornfield DN, Tegtmeyer K, Nelson MD, et al. Continuous propofol 137. Singh A, Girotra S, Mehta Y, et al. Total intravenous anesthesia with
infusion in 142 critically ill children. Pediatrics. 2002;110:1177–1181. ketamine for pediatric interventional cardiac procedures. J Cardiothorac
111. Sorbo S, Hudson RJ, Loomis JC. The pharmacokinetics of thiopental in Vasc Anesth. 2000;14:36–39.
pediatric surgical patients. Anesthesiology. 1984;61:666–670. 138. Herd DW, Anderson BJ, Keene NA, Holford NHG. Investigating the
112. Garg DC, Goldberg RN, Woo-Ming RB, Weilder DJ. Pharmacokinetics pharmacodynamics of ketamine in children. Paediatr Anaesth. 2008;18:
of thiopental in the asphyxiated neonate. Dev Pharmacol Ther. 1988;11: 36–42.
213–218. 139. Williams GD, Philip BM, Chu LF, et al. Ketamine does not increase
113. Duncan BBA, Zaimi F, Newman GB, et al. Effect of premedication on the pulmonary vascular resistance in children with pulmonary hypertension
induction dose of thiopentone in children. Anaesthesia. 1984;39:426–428. undergoing sevoflurane anesthesia and spontaneous ventilation. Anesth
114. Westrin P, Jonmarker C, Werner O. Thiopental requirements for induc- Analg. 2007;105:1578–1584.
tion of anesthesia in neonates and in infants one to six months of age. 140. Kienbaum P, Heuter T, Pavlakovic G, et al. S(+)-ketamine increases
Anesthesiology. 1989;71:344–346. muscle sympathetic activity and maintains the neural response to
115. Jonmarker C, Westrin P, Larsson S, Werner O. Thiopental requirements hypotensive challenges in humans. Anesthesiology. 2001;94:252–258.
for induction of anesthesia in children. Anaesthesiology. 1987;67: 141. Lundy PM, Lockwood PA, Thompson G, Frew R. Differential effects of
104–107. ketamine isomers on neuronal and extraneuronal catecholamine uptake
116. Brett CM, Fisher DM. Thiopental dose-response relations in unpremedi- mechanisms. Anesthesiology. 1986;64:359–363.
cated infants, children, and adults. Anesth Analg. 1987;66:1024–1027. 142. Kunst G, Martin E, Graf BM, et al. Actions of ketamine and its isomers
117. Glantz LA, Gilmore JH, Hamer RM, et al. Synaptophysin and post- on contractility and calcium transients in human myocardium.
synaptic density protein 95 in the human prefrontal cortex from mid- Anesthesiology. 1999;90:1363–1371.
gestation into early adulthood. Neuroscience. 2007;149:582–591. 143. Hanouz JL, Persehaye E, Lammens S, et al. The inotropic and lusitropic
118. Runcie CJ, Mackenzie SJ, Arthur DS, Morton NS. Comparison of effects of ketamine in isolated human atrial myocardium: the effect of
recovery from anaesthesia induced in children with either propofol or adrenoreceptor blockade. Anesth Analg. 2004;99:1695.
thiopentone. Br J Anaesth. 1993;70:192–195. 144. Chen R-M, Chen T-L, Lin Y-L, et al. Ketamine reduces nitric oxide
119. Hannallah RS, Britton JT, Schafer PG, et al. Propofol anaesthesia in biosynthesis in human umbilical vein endothelial cells by down-
paediatric ambulatory patients: a comparison with thiopentone and regulating endothelial nitric oxide synthase expression and intracellular
halothane. Can J Anaesth. 1994;41:12–16. calcium levels. Crit Care Med. 2005;33:1044–1049.
120. Schroter J, Motsch J, Hufnagel AR, et al. Recovery of psychomotor 145. Akata T, Izumi K, Nakashima M. Mechanisms of direct inhibitory action
function following anaesthesia in children: a comparison of propofol of ketamine on vascular smooth muscle in mesenteric resistance arteries.
and thiopentone/halothane. Paediatr Anaesth. 1996;6:317–324. Anesthesiology. 2001;95:452–462.
121. Jones RD, Visram AR, Chan MM, et al. A comparison of three induction 146. Oklu E, Bulutcu FS, Yalcin Y, et al. Which anesthetic agent alters the
agents in paediatric anaesthesia—cardiovascular effects and recovery. hemodynamic status during pediatric catheterization? Comparison of
Anaesth Intensive Care. 1994;22:545–555. propofol versus ketamine. J Cardiothorac Vasc Anesth. 2003;17:686–690.
147. Booker PD, Whyte SD, Ladusans EJ. Long QT syndrome and anaes- 176. Bramwell KJ, Haizlip J, Pribble C, et al. The effect of etomidate on
thesia. Br J Anaesth. 2003;90:349–366. intracranial pressure and systemic blood pressure in pediatric patients
148. Hanouz J-L, Zhu L, Persehaye E, et al. Ketamine preconditions isolated with severe traumatic brain injury. Pediatr Emerg Care. 2006;22:90–93.
human right atrial myocardium. Anesthesiology. 2005;102:1190–1196. 177. Guldner G, Schultz J, Sexton P, et al. Etomidate for rapid-sequence
149. Kawano T, Oshita S, Takahashi A, et al. Molecular mechanisms intubation in young children: hemodynamic effects and adverse events.
underlying ketamine-mediated inhibition of sarcolemmal adenosine Acad Emerg Med. 2003;10:134–139.
triphosphate–sensitive potassium channels. Anesthesiology. 2005;102: 178. Zuckerbraun MS, Pitetti RD, Herr SM, et al. Use of etomidate as an
93–101. induction agent for rapid sequence intubation in a pediatric emergency
150. Blumberg D, Congdon N, Jampel H, et al. The effects of sevoflurane and department. Acad Emerg Med. 2006;13:602–609.
ketamine on intraocular pressure in children during examination under 179. Erhan E, Ugar G, Gunusen I, et al. Propofol—not thiopental or
anesthesia. Am J Ophthalmol. 2007;143:494–499. etomidate—with remifentanil provides adequate intubating condi-
151. White PF, Schuttler J, Shafer A, et al. Comparative pharmacology of the tions in the absence of neuromuscular block. Can J Anaesth. 2003;50:
ketamine isomers. Studies in volunteers. Br J Anaesth. 1985;57:197–203. 108–115.
152. Modica PA, Tempelhoff R, White PF. Pro- and anticonvulsant effects of 180. Watt I, Ledingham IM. Mortality amongst multiple trauma patients
anesthetics (part II). Anesth Analg. 1990;70:433–444. admitted to an intensive therapy unit. Anaesthesia. 1984;39:973–981.
153. Mewasingh LD, Sekhara T, Aeby A, et al. Oral ketamine in paediatric 181. de Jong FH, Mallios C, Jansen C, et al. Etomidate suppresses adreno-
non-convulsive status epilepticus. Seizure. 2003;12:483–489. cortical function by inhibition of 11 beta-hydroxylation. J Clin Endo-
154. Bennett DR, Madsen JA, Jordan WS, Wiser WC. Ketamine anesthesia crinol Metab. 1984;59:1143–1147.
in brain-damaged epileptics. Neurology. 1973;23:449–460. 182. den Brinker M, Joosten KFM, Liem O, et al. Adrenal insufficiency in
155. Himmelseher S, Durieux ME. Revising a dogma: ketamine for patients meningococcal sepsis: bioavailability cortisol levels and impact of
with neurological injury? Anesth Analg. 2005;101:524–534. interleukin-6 levels and intubation with etomidate on adrenal function
156. Erk G, Ornek D, Donmez NF, Taspinar V. The use of ketamine or and mortality. J Clin Endocrinol Metab. 2005;90:5110–5117.
ketamine-midazolam for adenotonsillectomy. Int J Pediatr Otorhino- 183. den Brinker M, Hokken-Koelega ACS, Hazelzet JA, et al. One single dose
laryngol. 2007;71:937–941. of etomidate negatively influences adrenocortical performance for at
157. Dalal PG, Taylor D, Somerville N, Seth N. Adverse events and behavioral least 24 h in children with meningococcal sepsis. Intensive Care Med.
reactions related to ketamine-based anesthesia for anorectal manometry 2008;34:163–168.
in children. Paediatr Anaesth. 2008;18:260–267. 184. Zed PJ, Mabasa VH, Slavik RS, Abu-Laban RB. Etomidate for rapid
158. Gloor A, Dillier C, Gerber A. Ketamine for short ambulatory procedures sequence intubation in the emergency department: is adrenal suppres-
in children: an audit. Paediatr Anaesth. 2001;11:533–539. sion a concern? Can J Emerg Med. 2006;8:347–350.
159. Hostetler MA, Davis CO. Prospective age-based comparison of beha- 185. Sarthi M, Lodha R, Vivekanandhan S, Arora NK. Adrenal status in
vioral reactions occurring after ketamine sedation in the ED. Am J Emerg children with septic shock using low-dose stimulation test. Pediatr Crit
Med. 2002;20:463–468. Care Med. 2007;8:23–28.
160. Bell RF, Dahl JB, Moore RA, Kalso E. Peri-operative ketamine for acute 186. Pizarro CF, Troster EJ, Damiani D, Carcillo JA. Absolute and relative
post-operative pain: a quantitative and qualitative systematic review adrenal insufficiency in children with septic shock. Crit Care Med.
(Cochrane review). Acta Anaesthesiol Scand. 2005;49:1405–1428. 2005;33:855–859.
161. Engelhardt W. Aufwachverhalten und psychomimetische reaktionen 187. Marsh B, White N, Morton N, Kenny GNC. Pharmacokinetic model
nach S(+) ketamine. Anaesthetist. 1997;46:S38–S44. driven infusion of propofol in children. Br J Anaesth. 1991;67:41–48.
162. Hamza J, Ecoffey C, Gross JB. Ventilatory response to CO2 following 188. Absalom A, Kenny G. “Paedfusor: pharmacokinetic data set. Br J
intravenous ketamine in children. Anesthesiology. 1989;70:422–425. Anaesth. 2005;95:110.
163. Kim G, Green SM, Denmark TK, Krauss B. Ventilatory response during 189. Gorce P, Pourriat JL. Economic aspects of concentration-oriented
dissociative sedation in children—a pilot study. Acad Emerg Med. anesthesia: intravenous agents. Best Pract Res Clin Anaesthesiol. 2001;15:
2003;10:140–145. 137–142.
164. Jonnavithula N, Kulkarni DK, Ramachandran G. Prolonged apnea with 190. Kataria BK, Ved SA, Nicodemus HF et al. The pharmacokinetics of
intramuscular ketamine: a case report. Paediatr Anaesth. 2008;18: propofol in children using three different data analysis approaches.
330–331. Anesthesiology. 1994;80:104–122.
165. Mitchell RK, Koury SI, Stone CK. Respiratory arrest after intramuscular 191. Engelhardt T, McCheyne AJ, Morton N, et al. Clinical adaptation of a
ketamine in a 2-year-old child. Am J Emerg Med. 1996;14:580–581. pharmacokinetic model of propofol plasma concentrations in children.
166. Smith JA, Santer LJ. Respiratory arrest following intramuscular ketamine Paediatr Anaesth. 2008;18:235–239.
injection in a 4-year-old child. Ann Emerg Med. 1993;22:613–615. 192. Steur RJ, Perez RS, de Lange JJ. Dosage scheme for propofol in children
167. Drummond GB. Comparison of sedation with midazolam and ketamine: under 3 years of age. Paediatr Anaesth. 2004;14:462–467.
effects on airway muscle activity. Br J Anaesth. 1996;76:663–667. 193. Bouillon TW, Bruhn J, Radulescu L, et al. Pharmacodynamic interaction
168. Carson IW, Moore J, Balmer JP, et al. Laryngeal competence with between propofol and remifentanil regarding hypnosis, tolerance of
ketamine and other drugs. Anesthesiology. 1973;38:128–133. laryngoscopy, bispectral index, and electroencephalographic approxi-
169. Cohen VG, Krauss B. Recurrent episodes of intractable laryngospasm mate entropy. Anesthesiology. 2004;100:1353–1372.
during dissociative sedation with intramuscular ketamine. Pediatr Emerg 194. Jee YS, Hong JY. Effects of remifentanil on propofol requirements for
Care. 2006;22:247–249. loss of consciousness in target-controlled infusion. Minerva Anestesiol.
170. Allen JY, Macias CG. The efficacy of ketamine in pediatric emergency 2008;74:17–22.
department patients who present with acute severe asthma. Ann Emerg 195. Park HJ, Lee JR, Kim CS, et al. Remifentanil halves the EC50 of propofol
Med. 2005;46:43–50. for a successful insertion of the laryngeal mask airway and laryngoscopy
171. Rock MJ, Reyes de al Rocha S, L’Hommedieu CS, Truemper E. Use of in pediatric patients. Anesth Analg. 2007;105:57–61.
ketamine in asthmatic children to treat respiratory failure refractory to 196. Drover DR, Litalien C, Wellis V, et al. Determination of the pharmaco-
conventional therapy. Crit Care Med. 1986;14:514–516. dynamic interaction of propofol and remifentanil during esophago-
172. Brown RH, Wagner EM. Mechanisms of bronchoprotection by anes- gastroduodenoscopy in children. Anesthesiology. 2004;100:1382–1386.
thetic induction agents: propofol vs. ketamine. Anesthesiology. 1999;90: 197. Ropcke H, Konen-Bergmann M, Cuhls M, et al. Propofol and remi-
822–828. fentanil pharmacodynamic interaction during orthopedic surgical pro-
173. Brown L, Christian-Kopp S, Sherwin TS, et al. Adjunctive atropine is cedures as measured by effects on bispectral index. J Clin Anesth. 2001;
unnecessary during ketamine sedation in children. Acad Emerg Med. 13:198–207.
2008;15:314–318. 198. Wang LP, McLoughlin P, Paech MJ, et al. Low and moderate remifentanil
174. Sarti A, Busoni P, Dell’Oste C, Bussolin L. Incidence of vomiting in infusion rates do not alter target-controlled infusion propofol con-
susceptible children under regional analgesia with two different centration necessary to maintain anesthesia as assessed by bispectral
anaesthetic techniques. Paediatr Anaesth. 2004;14:251–255. index monitoring. Anesth Analg. 2007;104:325–331.
175. Sarkar M, Laussen PC, Zurakowski D, et al. Hemodynamic responses to 199. Nieuwenhuijs DJ, Olofsen E, Romberg RR, et al. Response surface
etomidate on induction of anesthesia in pediatric patients. Anesth Analg. modeling of remifentanil-propofol interaction on cardiorespiratory
2005;101:645–650. control and bispectral index. Anesthesiology. 2003;98:312–322.
200. Barker N, Amari E, Malherbe S, Ansermino JM. Relationship between 210. Harris RS, Lazar O, Johansen JW, Sebel PS. Interaction of propofol and
age and spontaneous ventilation during intravenous anesthesia in sevoflurane on loss of consciousness and movement to skin incision
children. Paediatr Anaesth. 2007;17:948–955. during general anesthesia. Anesthesiology. 2006;104:1170–1175.
201. Vuyk J, Mertens MJ, Olofsen E, et al. Propofol anesthesia and rational 211. Fredriksson A, Ponten E, Grodh T, Eriksson P. Neonatal exposure to a
opioid selection. Determination of optimal EC50–EC95 propofol-opioid combination of N-methyl-D-asparatate and gamma-aminobutyric acid
concentrations that assure adequate anesthesia and a rapid return of type A receptor anesthetic agents potentiates apoptotic neurodegenera-
consciousness. Anesthesiology. 1997;87:1549–1562. tion and persistent behavioral deficits. Anesthesiology. 2007;107:
202. Mertens MJ, Olofsen E, Engbers FH, et al. Propofol reduces peri- 427–436.
operative remifentanil requirements in a synergistic manner: response 212. Sternberg WF, Scorr L, Smith LD, et al. Long term effects of neonatal
surface modeling of perioperative remifentanil-propofol interactions. surgery on adulthood pain behaviour. Pain. 2005;113:347–353.
Anesthesiology. 2003;99:347–359. 213. Hermann C, Hohmeister J, Demirakca S, et al. Long term alteration of
203. Hui TW, Short TG, Hong W, et al. Additive interactions between pain sensitivity in school-aged children with early pain experiences.
propofol and ketamine when used for anesthesia induction in female Pain. 2006;125:278–285.
patients. Anesthesiology. 1995;82:641–648. 214. Clarkson AN. Anesthetic-mediated protection/preconditioning during
204. Naguib M, Samarkandi AH, Moniem MA, et al. The effects of melatonin cerebral ischemia. Life Sci. 2007;80:1157–1175.
premedication on propofol and thiopental induction dose-response 215. Loepke AW, Soriano SG. An assessment of the effects of general
curves: a prospective, randomized, double-blind study. Anesth Analg. anesthetics on developing brain structure and neurocognitive function.
2006;103:1448–1452. Anesth Analg. 2008;106:1681–1707.
205. Mertens MJ, Vuyk J, Olofsen E, et al. Propofol alters the pharmacokine- 216. Wang C, Slikker W Jr. Strategies and experimental models for evaluating
tics of alfentanil in healthy male volunteers. Anesthesiology. 2001;94: anesthetics: effects on the developing nervous system. Anesth Analg.
949–957. 2008;106:1643–1658.
206. Bouillon T, Bruhn J, Radu-Radulescu L, et al. Non-steady state analysis 217. Rizzi S, Carter LB, Pri C, Jevtovic-Todorovic V. Clinical anesthesia causes
of the pharmacokinetic interaction between propofol and remifentanil. permanent damage to the fetal guinea pig brain. Brain Pathol. 2008;
Anesthesiology. 2002;97:1350–1362. 18:198–210.
207. Morris J, Acheson M, Reeves M, Myles PS. Effect of clonidine premedi- 218. Perouansky M. General anesthetics and long-term neurotoxicity. Handb
cation on propofol requirements during lower extremity vascular Exp Pharmacol. 2008;182:143–157.
surgery: a randomized controlled trial. Br J Anaesth. 2005;95:183–188. 219. Logan M, Farmer JG. Anaesthesia and the ozone layer. Br J Anaesth.
208. Ng JM, Hwang NC. Inhaling nitrous oxide reduces the induction dose 1989;63:645–647.
requirements of propofol. Anesth Analg. 2000;90:1213–1216. 220. Bjorkman S. Prediction of drug disposition in infants and children by
209. Akhtar TM, Kerr WJ, Kenny GN. Effect of nitrous oxide on post- means of phsyiologically based pharmacokinetic (PBPK) modelling:
operative nausea and vomiting during propofol anaesthesia for short theophylline and midazolam as model drugs. Br J Clin Pharmacol.
surgical operations. Eur J Anaesthesiol. 1993;10:337–341. 2005;59:691–704.
24 Ketamine
C H A P T E R Elsa Taylor
INTRODUCTION TABLE 24-1. Ketamine Bioavailability

Ketamine is a versatile drug that was introduced widely into Route Bioavailability, %
clinical practice in the early 1980s. Ketamine has had limited use
Oral 20%
in developed nations because of its unfavorable emergence profile.
Intramuscular 90%
There is a resurgence of interest in ketamine because of evolving
Rectal 25%
roles in pain medicine and procedural sedation. Its use in the
Intranasal 50%
head-injured patient was once considered unacceptable but has
Epidural/caudal 77%
moved through controversy to the suggestion that it may have a
role in neuroprotection. The use of ketamine in the first few From reference 113.
months of life is currently controversial.
using allometric one-quarter-power models are similar to those
in adults. Table 24–3 illustrates clearance changes with age.
PHARMACOLOGY Ketamine is metabolized in the liver by N-demethylation to
Chemistry and Preparations norketamine, which has potency one third that of ketamine.
Norketamine is further metabolized by oxidative metabolism to
Ketamine is a phencyclidine derivative, present as two isomers, the less potent dehydronorketamine or by hydroxylation followed
with a molecular weight of 237.5 daltons. Ketamine was histori- by conjugation with gluconoride to water-soluble products ex-
cally formulated as the racemic mixture of the S and R isomers creted by the kidney. Ketamine is also hydroxylated. The low oral
presented as a hydrochloride salt with a preservative (benzetho- bioavailability of ketamine results in significant levels of the active
nium chloride). The pH of this solution is 3.5 to 4.1. Preservative- metabolite norketamine. It is suggested that a ketamine blood
free forms are available. The S isomer is now more commonly
available in many countries.
Ketamine has an octanol buffer partition coefficient of 60 and TABLE 24-2. Ketamine Pharmacokinetic Parameters—
high lipid solubility and undergoes rapid redistribution. Ketamine Clearance, T / , and Volumes of Distributions Scaled to a
1
2
is 45 to 50% protein-bound. Ketamine is a weak base with a pKa 70-kg Person using One-Quarter-Power Allometric Models
of 7.5. At physiologic pH of 7.4, it is 44.3% un-ionized. It has a
pKa close to physiologic pH, and consequently, small changes in Parameter Value CV%
pH result in a wide variation in the ionized and un-ionized T / alpha
1
2 11–17 min
fractions. A fall in pH to 7.1 results in a change in the un-ionized T / beta
1
2 1.6–3.1 h
percentage to 28%. This slows the availability of ketamine at effect Initial volume of 38.7 L/70 kg 64
sites. By contrast to thiopentone, a weak acid, with pKa close to distribution (V1)
physiologic pH, the percentage of un ionized drug rises with Steady-state volume 102 L/70 kg 51.7
falling pH. Thiopentone has faster onset and a more pronounced of distribution
clinical effect with acidosis. Clearance 90 L/h/70 kg 38.1
Intercompartmental clearance 215 L/h/70 kg
Protein binding 50%
Pharmacokinetics Concentration steady state EC50 560 ng/mL
The pharmacokinetic (PK) profiles of the racemates S(+) and for sedation level ≥ 4 (arousal
R (–) isomers are similar. The oral, nasal, rectal, intramuscular, to verbal stimulus)
intravenous, epidural, and caudal routes all have clinical utility. Concentration steady state EC95 1500 ng/mL
Bioavailability differs depending on route of administration (Table for sedation ≤ 2 (rouses slowly
24–1). to consciousness with sustained
The PK parameters for a two-compartmental model for painful stimulus)
ketamine are presented in Table 24–2.1,2 The parameter estimates CV = between-subject variability; EC50 = median effective dose; EC95 = effective
are standardized to a 70-kg person using allometric one-quarter- dose at 95%.
power models. Parameter estimates in children when standardized From references 1, 2, and 5.
CHAPTER 24 ■ Ketamine 377
TABLE 24-3. Pharmacokinetic Parameters Scaled With Allometric One-Quarter-Power Models to Different
Age and Weight Children
Parameter Adult (70 kg) 12 Y (40 kg) 6 Y (20 kg) 2 Y (12 kg)
CL, L/h 60.2 (CV, 38.1%) 39.6 23.5 16
Central volume of distribution (V1), L 22 (CV 89.6%) 12.6 6.3 3.78
Intercompartmental clearance (Q), L/h 216 (CV 54.5%) 142.0 84.4 57.6
Peripheral volume of distribution (V2), L 129 (CV 30.9%) 73.7 36.9 22.1
CL = clearance; CV = between-subject variability.
From reference 6.
concentration of 40 ng/mL following oral ketamine is equianalge- either an intermittent decreasing dose regime or an infusion at a
sic to a concentration of 150 ng/mL of ketamine after intravenous de-escalating rate.6,7 The rate and/or repeat bolus size must decline
administration.3 This apparent paradox may be explained by the over time as tissues become saturated and elimination kinetics
greater norketamine concentrations following oral administration predominate over distribution kinetics. An appropriate infusion
and their contribution to analgesia. rate will avoid both peaks and troughs associated with intermittent
Very little ketamine (1–5%) is excreted unchanged in urine; dosing. The context-sensitive half-life rises with increasing
therefore, no dose adjustment is required for the short-term use of duration of infusion; therefore, timely arousal becomes more
ketamine in renal disease. However, the role of norketamine dur- elusive with increasing duration of anesthesia7 (Figure 24–1).
ing prolonged infusions has not been fully elucidated. Norketa- Thus, despite adjusting the rate of delivery to maintain steady-
mine is both renally excreted and further metabolized by the liver. state plasma levels, awakening becomes prolonged.
The relative importance of each clearance pathway has not been
investigated in renal disease. Account may need to be taken of
norketamine accumulation when a prolonged infusion is planned Mechanism of Action
in the child with renal impairment. Adult patients suffering renal The predominant clinical effects of ketamine are produced by
failure had ketamine concentrations 20% higher than those antagonism at the N-methyl-D-aspartate (NMDA) receptor.
without renal failure when ketamine was used for analgesia and Ketamine also interacts with the cholinergic (muscarinic and
sedation.4 During hemodialysis, 10% of the administered keta- nicotinic), dopaminergic D2 and opioidergic (mu and kappa)
mine is eliminated, but during continuous hemodiafiltration, only receptors.8 Ketamine has been reported to interfere with gamma-
0.5% of ketamine is eliminated in the ultradiafiltrate.4 aminobutyric acid (GABA) inhibition, but this is not significant at
Ketamine inhibits the activity of cytochrome P450 (CYP) usual clinical doses. Ketamine has higher affinity to interaction
CYP2D1 and CYP3A by 10- to 20% after a single dose. Ketamine with the phencyclidine-binding site on the NMDA receptor
is largely metabolized by the liver before renal excretion, so it compared with other receptors or voltage-gated channels. This
would be expected that the handling of ketamine would be altered suggests that, at subanesthetic doses, it is the primary binding
in liver disease. In humans free of liver and renal disease, 3% of site for ketamine and the receptor that accounts for its analgesic
ketamine metabolites are recovered in the feces (excreted in the effects. However, activation of monoaminonergic descending inhi-
bile) and 91% of ketamine and its metabolites are recovered in the bitory pathways by ketamine and interaction with the mu opioid
urine over a 5-day period. The literature provides little guidance receptors are also implicated in the analgesic effect of ketamine.
on the appropriate use of ketamine in liver disease. Metabolism is There is an NMDA-mediated decrease in the central nervous
probably maintained until moderate to severe liver failure. Single- system acetylcholine release. However, ketamine increases basal
dose or short (<10 min) infusions are likely to be clinically in-
discernible from the non–liver failure patient because of the
predominance of redistribution in termination of effect. Longer
infusions for either anesthesia or analgesia are likely to result in
higher blood concentrations and a longer duration of effect in the
patient with moderate to severe liver failure.
The plasma clearance at 16 to 19 mL/min/kg approximates liver
blood flow. Despite this high clearance, redistribution after an
intravenous bolus dose is important for the termination of clinical
effect.
There is a paucity of adult and pediatric data exploring the PK
and pharmacodynamic relationships. A 2.2-mg/kg dose of keta-
mine in the adult human results in plasma concentrations of
30,000 ng/mL within 30 seconds; these concentrations fall to 1000
ng/mL at around 10 minutes.1 Ketamine 1 mg/kg in children of
an average age of 8.3 years (range, 1.5–14 y) results in useful
sedation with blood concentrations at 10 minutes having fallen,
in the majority, to below 750 ng/mL.5 This is a concentration asso- Figure 24-1. The context-sensitive half-time after an infusion
ciated with arousal to stimuli. When used to provide anesthesia that maintains blood levels of 3000 ng/mL. From reference 7,
for longer than 10 minutes, it is more rational to give ketamine as with permission.
hippocampal acetylcholine release.9 There may be neurodevelop- The depth of sedation or anesthesia with ketamine cannot
mental differences in the central nervous system neurotransmitter be tracked with bispectral index monitoring (BIS), entropy
effects of ketamine. For example, the percentage increase of monitoring or auditory evoked potentials.13 The EEG effects of
acetylcholine in the basal hippocampus is greater in old rats ketamine result in a higher BIS or entropy value for a given depth
(>18 mo) than in young rats (<2 mo). Hippocampal cholinergic of sedation or anesthesia. Furthermore, the BIS or entropy value
mechanisms are essential for cognition, memory, and learning. does not decrease in a concentration-dependent manner with
Ketamine’s explicit interactions with receptors depend on the increasing ketamine sedation or anesthesia. Ketamine does not
ketamine concentration. For example, ketamine has two distinct suppress the midlatency auditory evoked potentials. When given
mechanisms of interaction with the NMDA receptor. It blocks the as the primary anesthetic, the midlatency auditory evoked poten-
open channel, reducing mean open time, and it binds to the closed tials remain similar to those in the awake state. An antihyperal-
receptor, decreasing the frequency of opening. Both mechanisms gesic dose or as a low-dose infusion during anesthesia with either
are in play at high concentrations of ketamine, whereas at low propofol or sevoflurane increases BIS and entropy values along
concentrations, the latter mechanism predominates. Ketamine is with between-subject variability. BIS, entropy monitors, and audi-
a use-dependent noncompetitive antagonist at the NMDA recep- tory evoked potential monitors correlate poorly with ketamine
tor in that the rate of onset and recovery are both increased with sedation depth. The use of ketamine with other primary anesthe-
increasing NMDA agonists.10 tic drugs can falsely suggest a lessening of sedative or anesthetic
NMDA receptors are evoked by pain signals and result in depth13 with these monitors despite a clinical increase in depth of
hyperexcitability of the dorsal route neurons. The resulting clinical anesthesia.
effects are hypersensitization, pain facilitation, and wind-up.
Opioids used in large doses induce tolerance to opioid effects and
also induce hyperalgesia. The mu receptor activation increases Other Organ System Effects
glutamate effectiveness at the NMDA receptor. Ketamine, by anta- Cardiovascular System
gonizing the NMDA receptor, blocks the development of opioid
tolerance. Ketamine is a sympathomimetic. There is an increase in circulat-
ing catecholamines from both centrally mediated stimulation and
inhibition of peripheral neuronal uptake. Ketamine also exhibits
Anesthesia Pharmacodynamics a moderate parasympatholytic effect on the heart,14 mediated
through a direct inhibition of both nicotinic and muscarinic
Ketamine produces “dissociative anaesthesia.” The primary sites of acetylcholine receptors, inhibition of NMDA-mediated acetylcho-
action are the cerebral cortex, thalamocortical pathways, and limbic line release, and decreased parasympathetic excitation in the
system and not the brainstem. Pharmacokinetic-pharmacodynamic brainstem.
(PK-PD) data in children support a graded sedation response to Increases in mean aortic pressure, pulmonary artery pressure,
ketamine and reject an all-or-nothing dissociated state.11 Anesthesia heart rate, and cardiac index occur. Individual response can vary
is likely in blood concentrations above 1100 ng/mL, awakening/ widely and the blood pressure rise does not correlate with pre-
arousal from anesthesia occurs at 500 to 1100 ng/mL and analgesia existing hypertension and may be attenuated by benzodiazepines.
at 60 to 150 ng/mL. These effects are on a continuum, and there is However, direct application of ketamine to cardiac myocytes
considerable between-subject variability. A study of children under- results in myocardial depression. The patient who is reliant on
going surgical procedures in a pediatric emergency department maximal sympathetic stimulation for cardiovascular stability may
estimated a median effective dose (EC50) for arousal of 560 ng/ experience cardiac depression with ketamine induction.
mL (90% confidence interval [CI] 220, 1170 ng/mL) and an
EC95 for a Children’s Hospital of Wisconsin Sedation Scale level 2
(rouses slowly to consciousness with sustained painful stimulus) of Respiratory System
1500 ng/mL.11 Pharyngeal and laryngeal reflexes remain active. Aspiration is less
Ketamine anesthesia/sedation produces a trancelike state with likely compared with other sedative or anesthetic agents, but may
associated amnesia, sedation, and analgesia. The patient appears still occur. Ketamine increases salivation. Laryngospasm can be
dissociated from the environment, but the eyes may remain open provoked by airway irritation from blood or secretions or by
and spontaneous involuntary movements can occur. Nystagmus pharyngeal stimulation. Antimuscarinics will reduce hypersaliva-
and hypertonus are common. Vital brainstem functions are pre- tion but not all clinicians advocate their routine use. Most con-
served. temporary use of ketamine for sedation omits an antimuscarinic
The morphologic electroencephalographic (EEG) changes with from the sedation guidelines.
ketamine are described by three phases. Phase 1: loss of alpha Resting respiratory rate, tidal volume, and minute ventilation in
rhythm (6–14 Hz) in combination with a decreased amplitude and children are unchanged by 2 mg/kg intravenous bolus of ketamine
frequency; phase 2: persistent rhythmic theta activity (4–6 Hz) followed by a 40 μg/kg/min infusion.15 Functional residual capa-
with increasing amplitude; phase 3: intermittent polymorphic city is preserved.16 Despite the unchanged nature of respiratory
delta activity (0.5–2 Hz) of large amplitude.12 Phases 1 to 3 are variables, the slope from the plot of minute ventilation versus end-
observed with the administration of racemate and S(+) ketamine. tidal CO2 decreases after a 2-mg/kg bolus. It returns to control
It is not possible to suppress the EEG activity beyond phase 2 with values during continued ketamine anesthesia with 40 μg/kg/min,15
R(–) ketamine. Maximum effect change (Emax) values of the suggesting respiratory depression only with higher blood con-
R (–) and S(+) are different when serum concentrations are related centrations.
to EEG changes. The potency ratios are 1:1.7:5.6 (R(–)-to-race- Low-dose ketamine (≤0.5 mg/kg) added to a propofol sedation
mate: S(+)). The R(–) enantiomer is a partial antagonist relative to regime attenuates propofol-induced hypoventilation.17
S(+) ketamine.12 Ketamine is a bronchodilator.
Other
Nausea and vomiting are increased compared with thiopentone or
propofol. Skeletal muscle tone is increased, but this rarely is
clinically problematic. Ketamine should be avoided in the hyper-
thyroid patient because marked hypertension can occur. Ketamine
use in acute intermittent porphyria is controversial. Biochemical
markers have been reported to rise with ketamine use without clinical
evidence of a porphyric crisis.18 If other nonporphyric agents are
available, they should be used in preference to ketamine. A small
rise in intraocular pressure occurs because of both increased tone
in the extraocular eye muscles and a rise in carbon dioxide pressure
(PCO2) in the spontaneously breathing patient. The increase in
intraocular pressure is less than that produced with laryngoscopy.
Adverse Effects
The side effect profile of ketamine includes hypertension, diplopia,
nystagmus, dizziness, confusion, seizures, cardiac arrythmias,
nausea, vomiting, sedation, and psychomimetic reactions. Psychic Figure 24-2. The decrement time to 50% (DC50) and to 80%
emergence phenomena such as dysphoria, altered body image, (DC80). DC50 is associated with reusability and DC80 with return
hallucinations, and vivid dreams occur in up to 10% of children to full consciousness. From reference 7, with permission.
during recovery from ketamine anesthesia/sedation. However,
only 1 to 2% of children presenting for anesthesia have distressing increasing duration of delivery (Figure 24–2). The target concen-
psychic emergence phenomena. Unpleasant emergence pheno- tration for anesthesia remains undefined and will vary depending
mena are less likely in children than in adults. Ketamine has both on supplemental agents used. A proposed target concentration of
proepileptic and antiepileptic effects. 3000 ng/mL can be maintained in children 1.5 to 12 years with a
loading dose of 2 mg/kg, followed by an infusion rate of 11 mg/
Drug Interactions kg/h for the first 20 min, 7 mg/kg/h from 20 to 40 min, 5 mg/kg/h
from 40 to 60 min, and 4 mg/kg/h from 1 to 2 h. However, arousal
Halothane decreases liver blood flow. Ketamine has a high ex- would be expected only 3 hours and 47 minutes after cessation of
traction ratio, and thus, ketamine clearance falls with a decrease in a 2-hour infusion in a 6-year-old child.7
liver blood flow. Other agents with more favorable wake-up characteristics
Diazepam reduces ketamine clearance by approximately 15% would usually be preferable to ketamine for procedures longer
and, consequently, prolongs the sedative effect of ketamine by both than 10 to 20 minutes. Niches because of resource constraints or
a PK (reduced clearance) and a PD mechanism (sedative effect of patient factors remain for the use of ketamine as the primary
diazepam).19 Ketamine decreases cytochrome P450 (CYP) CYP3A anesthetic agent. It can be used in combination with other agents
enzyme activity, and diazepam’s metabolism may also be slowed.20 to minimize ketamine disadvantages.
Methylphenidate, used commonly in the treatment of attention Ketamine provides a stable induction in trauma and patients
deficit hyperactivity disorder (ADHD), may lead to increased with major blood loss, provided sympathetic reserve has not been
deleterious effects with ketamine. Methylphenidate blocks the action exhausted. It is a reasonable choice for anesthesia in the child
of dopamine and norephinephrine transporters. These transporters presenting for biopsy with an anterior mediastinal mass who has
transport the neurotransmitters out of the synapse. Potentiation of airway and/or cardiovascular compromise. It provides more stable
ketamine’s dopamine and sympathetically mediated effects is hemodynamics than volatile anesthetic agents or fentanyl in
possible. This is a theoretical concern and is not backed by clinical preterm neonates.22 In the sick premature or term neonate under-
cases apart from Potentiation of ketamine’s dopamine and going surgery, this may translate into greater hemodynamic
sympathetically mediated effects such as severe nausea and stability and lower inotrope requirements. A case report favorably
vomiting might be possible in patients on methylphenidate. This discusses a propofol-ketamine combination for providing stable
is a theoretical concern and is not backed by clinical cases. hemodynamics for this group of patients.23 There is little objective
In combination with other proconvulsant drugs, such as cyclo- information to guide the anesthesia choice in this group of
sporine, ketamine may induce seizure activity.21 Paradoxically, patients, and there are growing neurodevelopmental concerns and
ketamine is known to have both proconvulsant and anticonvulsant questions around many drugs used in this vulnerable population.
effects. Caution and potential for interaction should be considered Some advocate ketamine as an agent of choice either alone
when combining ketamine with any chronic central nervous or in combination with propofol, midazolam, sevoflurane, or
system drug. dexmetomidine for cardiac catheter studies. A regime combining
ketamine with another agent, usually propofol, is preferable to
ketamine alone. Lowering the total amount of each agent leads to
CURRENT AREAS OF CLINICAL USE stable hemodynamics with timely arousal. In infants and children
Anesthesia with cardiac lesions that render them reliant on maintenance of
systemic vascular resistance for adequate pulmonary blood flow,
Ketamine can be used as a sole agent or with other adjuvants for ketamine provides stable anesthesia both prebypass for cardiac
anesthesia maintenance. The context-sensitive half-time rises with surgery and for noncardiac surgery.
Concern has been raised regarding the potential for increases Ketamine results in overall better quality of sedation judged by
in pulmonary vascular pressure to adversely affect shunt degree parents and procedural doctors, but a longer time to recovery
or direction in children with cyanotic heart disease. There has also thanh midazolam. Ketamine has more stable hemodynamics
been concern regarding the potential for sympathetic stimulation and less oxygen desaturation than propofol as the primary
to precipitate a hypercyanotic spell in children with tetralogy of sedating agent. Recovery, however, is longer with ketamine. Com-
Fallot. However, stable hemodynamics and shunt fractions have binations of ketamine and either midazolam or fentanyl compare
been demonstrated with the use of ketamine in children under- well to midazolam-fentanyl or propofol-fentanyl combinations
going cardiac catheter studies.24 Ketamine maintenance provides (Table 24–4).
stable hemodynamics, better pulmonary blood flow, lower The addition of midazolam to a ketamine sedation regime does
inotrope requirements, and better blood gases than isoflurane not prevent emergence phenomena and increases the incidence
maintenance for children with tetralogy of Fallot in the period of oxygen desaturation, but it does reduce the incidence of post-
before cardiopulmonary bypass.25 procedure emesis.37,44,45 Postprocedure emesis may also be de-
creased by the addition of ondansetron.46
Doses of ketamine commonly range from 2 to 5 mg/kg intra-
Deep Sedation and Anesthesia muscularly or 0.5 to 2 mg/kg intravneously in sedation protocols
for Procedures for procedural sedation.37 A dose of 1 mg/kg intravenously gives
Forced restraint of children for procedures is unacceptable in adequate sedation with a significantly shorter duration of sedation
many countries. Distraction techniques, play therapy, and analge- than 4 mg/kg intramuscularly.47 A recent time-concentration and
sia are all helpful in gaining a cooperative relaxed child. There sedation profile simulation provides a PK-PD–based guideline for
remain numerous occasions when these techniques are insuf- choice of intravenous dose and dosage regime. The key points are
ficient. When they fail, the options are either sedation or general the milligram per kilogram dose increases with decreasing age and
anesthesia. The majority of hospitals with a large pediatric com- size; a single dose greater than 1.5 mg/kg is associated with delayed
mitment have insufficient anesthesiologists to cover all situations recovery compared with smaller repeated top-up doses or an
in which pharmacologic assistance is required for procedural infusion.6
cooperation.
Ketamine is widely used by nonanesthesiologists in the United Analgesia
States, Canada, and Australasia for deep sedation for minor pro-
cedures in the emergency department, intensive care, burns suite, Ketamine has been investigated perioperatively as a sole analgesic
and cardiology, radiology, and endoscopy suites.26–31 The use of and as a co-analgesic for the prevention of hyperalgesia48 and
ketamine may also be extending beyond intrahospital use into allodynia, for the reduction of opioid use, and for the prevention
prehospital care for pain and infield extraction.32 The use of of acute opioid tolerance and opioid-induced hyperalgesia.49
ketamine in the United Kingdom and Europe is expanding for Ketamine may also have a role in the prevention48 and treatment
pediatric procedural sedation.33–37 Tensions exist between special- of complex pain.
ties with regard to domains of practice, competencies, training, Neuroplasticity in response to nociception and to analgesics
credentialing, and safety.38 Several decades of audits and research, may be significant in both acute and chronic pain outcomes after
largely from the United States, testify to a remarkable overall safety surgery. Postnociceptive neuroplasticity affects both excitatory
profile.27,34–37,39–41 and inhibitory pathways and spinal as well as supraspinal sites.
When ketamine is used for pediatric procedural sedation, The relationship of pain measures, analgesics, and neuroplasticity
oxygen desaturation is reported in 1 to 5% of patients and airway is poorly defined. Most clinical studies use pain scores or analgesic
obstruction in 0.5 to 1% of patients. Apnea is rare (<1%) but can use as outcome measures. Few formally seek to detect and quantify
occur,42 especially with rapid intravenous injection and larger neuroplasticity.
doses. Laryngospasm occurs in 0.1 to 0.4%42 of children under-
going procedural sedation except where there is instrumentation Ketamine As a Primary Analgesic
of the hypopharynx or larynx 29 when it occurs more frequently
(up to 9.5% reported). The majority of these airway incidents are Low-dose ketamine (≤0.5 mg/kg) has analgesic effects on both
managed without intubation of the airway.37,42 Emesis occurs in acute visceral pain and acute cutaneous pain.8 Ketamine has been
approximately 10% (0–43%)36,37,42 of children with the majority investigated as the primary analgesic in pediatric tonsillectomy in
occurring postprocedure and a minority intraprocedure.36 Emer- which it has been used instead of an opioid. This may be advanta-
gence phenomena are reported in 0 to 10% of children. Moderate geous in children with obstructive sleep apnea or abnormal
to severe emergence phenomena occur less than 2% of the time.31 airways. Ketamine (0.5 mg/kg) offers analgesia similar to that of
Nystagmus, ataxia, myoclonus, and opisthotonus are rarely clini- morphine (0.1–0.15 mg/kg),50,51 although higher initial pain scores
cally troublesome and resolve with recovery.37 and more frequent use of rescue paracetamol have been reported.52
Although serious adverse effects are rare, it is imperative that Postoperative vomiting and dreaming were equivalent to that in
ketamine sedation is undertaken only by those with the appr- control groups.53
opriate skills to rescue a child from general anesthesia or any of the
potential complications of ketamine sedation. Furthermore, it is Ketamine Perioperatively As Part
mandatory that suction, oxygen, and resuscitation equipment and of a Multimodal Analgesic Strategy
drugs are available.
Several groups favorably compare ketamine with other agents INTRAOPERATIVE USE: Intraoperative intravenous or epidural
for emergency department or procedural sedation.30,31,35,37,43 ketamine in doses of 0.1 to -0.5 mg/kg with or without an intra-
TABLE 24-4. Comparison of Ketamine With Other Agents for Procedural Sedation
Ketamine or Ketamine Prospective, Retrospective, and
Combination Compared With Key Results Number of Patients
IV ketamine 1 mg/kg and Intranasal midazolam Shorter time to adequate sedation, Prospective, single-blind,
midazolam 0.1 mg/kg 0.4 mg/kg better quality of sedation, longer randomized, 53 children31
recovery, more children at
deeper than required level of
sedation in ketamine group
Ketamine Midazolam Better sedation and less restraint Variety of regimes, IM, no
in ketamine group blinding, and no rando-
mizsation37
IV Ketamine 1 mg/kg and IV midazolam 0.1–0.15 mg/ Less procedural distress and less Prospective, randomized,
midazolam 0.1–0.15 mg/kg kg and fentanyl 1.6 μg/kg desaturation in ketamine group single-blind, 260 children114
IV ketamine 1 mg/kg with Propofol 2 mg/kg ± Slower onset, longer recovery, Prospective, 50 children35
midazolam 0.1 mg/kg morphine 0.1 mg/kg more stable hemodynamics, and
less desaturation in ketamine
group.
Ketamine 1 mg/kg with Fentanyl 1 μg/kg with Less restlessness Prospective, double-blind,
propofol 1.2 mg/kg propofol 1.2 mg/kg randomized, 32 children43
Ketamine and midazolam Propofol and fentanyl Similar sedation, quicker time to Prospective, not blinded,
titrated to effect, average titrated to effect, average ideal sedation, slower recovery, randomized, 113 patients115
dose 1.99 mg/kg and doses propofol 4.55 mg/ less oxygen desaturation in
0.04 mg/kg kg fentanyl 1.21 μg/kg ketamine group
Ketamine 1 mg/kg and 50% N2O in 50% O2 plus Procedural behavior similar Prospective, randomized, not
midazolam 0.1 mg/kg hematoma block between groups, but less pain blinded, 102 children116
and distress in N2O group, more
minor adverse effects, including
desaturation in ketamine group
Oral ketamine 10 mg/kg Oral midazolam 0.7 mg/kg Tolerance to long-acting injection Prospective, randomized,
better with ketamine, quicker double-blind, 59 children
onset with ketamine, more
dysphoric reactions with
midazolam
Ketamine 1 mg/kg Fentanyl 1 μg/kg Both groups 1.2 mg/kg propofol Prospective, randomized,
plus additional propofol prn; double-blind, 100 children117
more propofol required in
fentanyl group, more
restlessness in fentanyl group,
more minor postoperative side
effects in ketamine group
operative infusion of ketamine can reduce postoperative pain, reduced paracetamol use, and increased oral intake.67 Both oral
hyperalgesia, allodynia, and opioid requirements.54–64 Some intake and swallowing evoked pain may reflect the equivalent of
investigators fail to show a reduction in either pain or analgesic movement-related pain in limb and trunk surgery.
use.65,66 This inconsistency may be caused by inadequate ketamine Children (N = 30) undergoing major urologic surgery did not
dosing schedules or small doses of ketamine (<0.15 mg/kg) that demonstrate a clinically relevant difference between the S-
fail to add benefit on a background of multimodal analgesics ketamine (bolus 0.2 mg/kg, then infusion 5 μg/kg/min) and
including epidurals. Alternatively, ongoing intense pain or high placebo groups.66 A 0.5-mg/kg racemic ketamine bolus followed
opiate use may require continued NMDA antagonism for analgesic by a 4-μg/kg/min intraoperative infusion failed to decrease pain or
benefit to be seen. opioid use in the first 72 hours postoperatively in adolescent
Ketamine may have either a pre-emptive effect or a preventive scoliosis patients (N = 34).68
analgesic benefit. A literature review in 2004 found that only 60% KETAMINE FOR THE PREVENTION OF ACUTE OPIOID TOLERANCE
of ketamine studies seeking a preventive benefit demonstrated it.64 AND OPIOID-INDUCED HYPERALGESIA: Animal and human
Few pediatric studies assess the addition of intraoperative volunteer laboratory researches establish that acute opioid
ketamine to a multimodal pain regime and again results are mixed. tolerance and opioid-induced hyperalgesia occur and do so via
Ketamine (0.15 mg/kg) added to fentanyl 2 μg/kg did not modify separate pathways and mechanisms.69 The separation of tolerance
postoperative tonsillectomy pain.53 However, when added to and opioid-induced hyperalgesia is difficult in the clinical setting
fentanyl 1 μg/kg, it resulted in reduced swallowing evoked pain, because both are characterized by a decreased effect of a given
dose. High-dose opioids such as remifentanil greater than 0.1 mg/ POSTOPERATIVE MODALITIES: Ketamine can be beneficial
kg or large-dose fentanyl do result in hyperalgesia and acute opioid postoperatively for major surgery in adults as a separate constant-
tolerance.70–72 These findings are not consistently shown.73,74 Intra- rate infusion in addition to the primary pain treatment modality
operative remifentanil is associated with the development of (usually patient-controlled analgesia [PCA]).90 Decreased mecha-
clinically relevant increased opioid requirements postoperatively nical hyperalgesia, increased patient satisfaction, decreased mor-
in pediatric scoliosis surgery.68 phine consumption, and decreased pain both at rest and during
A multitude of receptors and mechanisms have been investi- mobilization with the use of postoperative ketamine infusion have
gated for their role in the development of the “pathologic pain” been demonstrated. Not all groups have shown benefit.91
processes of secondary hyperalgesia, opioid-induced hyperalgesia, Few studies have positive findings for ketamine added into a
and acute opioid tolerance. They include the NMDA receptor, morphine PCA.92 In the majority, adding ketamine into a morphine
postsynaptic density proteins -95 and -93, which connect the PCA is not beneficial.63,93,94 The dose administered by this method
NMDA receptors to the cytoskeleton and to key signaling systems may be too small to be effective. A single pediatric study with a
such as neuronal nitric oxide synthase, intracellular protein kinase postoperative ketamine infusion failed to show any analgesic
C, tyrosine kinase, nitric oxide synthetase, heme oxygenase, and benefit for children undergoing appendicectomy.95
increased cytokine production by glial cells.69 The NMDA receptor
is integral in the development and maintenance of “pathological” Clinical Implications for Ketamine in Acute Pain
pain. Ketamine can prevent the development of hyperalgesia and
acute opioid tolerance.72,75 Supplementing remifentanil-based Ketamine is morphine-sparing and may lead to improved pain
anesthesia with small-dose (4 μg/kg/min) ketamine reduces peri- control in some types of surgery. It is yet to be demonstrated
operative opioid requirements,54 but not always.65 Intraoperative whether the addition of ketamine to postoperative pain manage-
ketamine, in appropriate doses, failed to reduce postoperative ment leads to tangible benefits such as faster recovery, decreased
morphine requirements for pediatric scoliosis patients.65 Ketamine side effects, earlier resumption of oral intake, earlier return of
bowel function, or reduction of future complex pain.
may need to be infused postoperatively when there is ongoing
Ketamine is able to prevent the development of the rapid
intense pain and high opioid use because it is unrealistic to expect
tolerance that develops to remifentanil analgesia. When an infu-
intraoperative ketamine to cover the entire postoperative period.
sion of remifentanil is planned for longer than 1 hour, the addition
Ongoing noxious stimuli lead to secondary hyperalgeisa and high
of ketamine may be useful. However, in the presence of ongoing
opioid use results in opioid-related acute tolerance/hyperalgesia
intense pain and high opioid use, ketamine used only intra-
phenomena.
operatively may be insufficient.
KETAMINE FOR MORPHINE-RESISTANT PAIN: Acute pain that is
not easily controlled with morphine can be reduced by the Complex Pain
addition of ketamine.76 Adult patients in the postanesthetic care
unit (PACU) with morphine-resistant pain were randomized in a The NMDA receptor is implicated in central sensitization and
wind-up with the resulting allodynia and hyperalgesia seen in
double-blind trial to either morphine 30 μg/kg boluses or
complex pain. Human volunteers have decrease pain intensity and
ketamine 0.25 mg/kg and morphine 15 μg/kg. The ketamine
wind-up evoked by experimental stimuli in the presence of an
group had lower 10- and 120-minute pain scores, had fewer
NMDA antagonist. NMDA antagonists reduce hyperalgesia and
boluses to achieve analgesia, were less sedated, and had higher
allodynia associated with neuropathic pain following nerve
oxygen saturation of hemoglobin monitored with pulse oximetry
injuries, burns, or topical capsaicin in adult volunteer studies,
(SpO2), and had less nausea and vomiting.76
clinical studies, and case reports.8
NEUROAXIAL KETAMINE: Epidural (and caudal) ketamine gain
rapid access to the systemic circulation with a high bioavailability.
Epidural ketamine results in greater postoperative analgesia than Premedication
the same dose given systemically despite similar plasma con- Oral or rectal ketamine (1.5–6 mg/kg) has less ideal separation
centrations.77,78 This suggests that ketamine has a direct neuroaxial characteristics, a higher incidence of airway stridor, and occasional
action. psychomimetic adverse effects than a benzodiazepine.96,97 Higher
Caudal ketamine alone or with local anesthetic provides doses may provide good induction characteristics but prolong
analgesic benefit to children undergoing minor urologic and emergence.98 In combination with a benzodiazepine, it can provide
herniotomy surgery.79,80 The optimal dose of racemic ketamine superior anxiolysis and separation characteristics compared with
appears to be 0.5 mg/kg81 and that of S(+) ketamine appears to be a equipotent dose of either agent alone.99,100
1 mg/kg. Few studies have examined the comparison of ketamine
with other caudal additives such as clonidine, fentanyl, epine-
phrine, midazolam, tramadol, or neostigmine. Those that have Fringe Uses of Ketamine in Anesthesia
report that other additives may offer equal79,80 or superior82,83 Ketamine has been found to have beneficial effects for a diverse
analgesia. A combination of caudal additives may84 or may not85–87 range of minor anesthetic or perioperative problems. Oculo-
confer additional analgesic benefit, but this has been poorly cardiac reflex during pediatric strabismus surgery is less likely and
defined. Few studies have sought the comparison of caudal less profound with a ketamine-based anesthetic regime than with
ketamine with a multimodal oral regime or alternative regional propofol- and volatile-based regimes.101 Ketamine may enhance
blockade.88,89 the amplitude of motor evoked potentials especially in younger
Concern regarding the potential neurotoxicity of ketamine children in whom they are more difficult to elicit.102 Ketamine
applied directly to the neuroaxis persists. Short-term exposure to (0.5 mg/kg) has been found to be effective in both treating and
preservative-free ketamine appears to be safe. preventing postoperative shivering.103 This dose is as equally
effective as pethidine. Propofol injection pain is relieved more vacuolation in the cingulate and retrosplenic regions of the adult
successfully with 0.5 mg/kg of ketamine than with lignocaine.104 rat brain. Repeated large-dose ketamine increases apoptosis in the
Ketamine 0.2 mg/kg preinduction reduces postinduction with- developing rat and primate brain. Both immaturity and prolonged
drawal to rocuronium in pediatric patients.105 Ketamine in doses intense blockade of the NMDA receptor by ketamine are necessary
above 0.2 mg/kg prevents tourniquet-induced increases in arterial for increased brain apoptosis to occur. Signal transduction via
blood pressure.106 Interestingly, despite the potential psychomime- NMDA receptors is necessary to express neurotrophins and sur-
tic effects of ketamine premedication, there is reduced post- vival-promoting proteins. Large-dose NMDA receptor antagonists
operative delerium compared witho placebo or midazolam after during the vulnerable phase of synaptogenesis in the developing
sevoflurane anesthesia. Ketamine 0.5 mg/kg is also successful in rat brain lead to apoptosis, synaptic defects, and cognitive
managing paradoxical midazolam reaction in children.107 impairment.109 This vulnerable stage occurs postnatally in the rat,
prenatally in the full-term human, and postnatally in the prema-
ture human neonate. As with most other anesthetic agents, there
AREAS OF CONTROVERSY is insufficient evidence to determine how damaging, if at all,
Necessity for Fasting ketamine is to premature and full-term neonates. The large-dose
repeated exposure in laboratory animals does not have a clinical
Many emergency department ketamine sedation protocols man- therapeutic equivalent. We induce a less profound clinical NMDA
date either no minimum fasting period or a period shorter than blockade in our neonatal patients during anesthesia with ketamine
that required for general anesthesia.31,108 Airway reflexes are pre- and, if used for analgesia, a repetitive exposure without a profound
served with ketamine sedation and aspiration unlikely. Aspiration blockade.
pneumonitis is rare and no study or audit is large enough to Whereas NMDA receptors are integral in synaptogenesis and
definitively establish the safety of this practice. Current research neuronal survival, they also have key roles in cell death induced by
and audit reports demonstrate postprocedure vomiting, rare intra- excitotoxicity. Thus, the effect of unopposed persistent pain on the
procedure vomiting. and no reports of aspiration pneumonitis. developing brain must also be considered. Repetitive pain in the
premature human is associated with future learning difficulties
and emotional and behavioral changes.111 The clinical course of
Neuroprotection the premature neonate is complex, and it is impossible to currently
Modulation of excessive NMDA receptor stimulation is suggested determine the contribution of the many aspects of the preterm
as part of a multitargeted approach to lessen secondary brain neonates early life. Unopposed pain in neonatal rats detrimentally
injury. Preclinical studies report neuroprotective effects for alters both the structure and the function of the rat brain.111 These
racemic ketamine in cell and animal models. Regenerative effects effects are ameliorated by analgesic doses of ketamine. Further-
in cultured neurons are seen with S(+) ketamine. No human more, both the ketamine-treated groups (ketamine plus pain and
clinical trial data assess the neuroprotective effects of ketamine.109 ketamine alone) show similar brain structure and behavior to the
The 6-month outcomes after ketamine use for intensive care unit controls (pain-free, ketamine-free), whereas the treatment group
sedation in the head-injured adult patient are equitable to those (unopposed pain) had deleterious outcomes.
when an opioid-based regime is used. Questions clearly remain with the use of ketamine (and many
Intracranial pressure (ICP), cerebral blood flow (CBF), and other anesthetic agents) in neonates and especially premature neo-
cerebrospinal fluid (CSF) pressure remain the same in the pre- nates. However, current evidence would suggest that unopposed
sence of ketamine, provided normocapnia is maintained. A pig pain and surgery is not only unethical but also neurodevelop-
model demonstrates that cerebrovascular autoregulation is pre- mentally damaging. Ketamine may provide some protection for
served with ketamine,110 and this is likely to be true in humans the developing brain in the circumstance of prolonged pain or
too. In addition, the hemodynamic stimulation resulting from intense surgical stimulation. Certainly, high-dose ketamine in the
ketamine administration may improve cerebral perfusion. Inten- absence of surgical stimulation does not reflect clinical practice
sive care unit data indicate that when Ketamine is used for and we cannot translate current laboratory-based high-dose
sedation of head-injured patients, less vasopressers are required ketamine in rats into a meaningful therapeutic equivalent.
and the outcomes are the same compared with an opioid-based
sedation regime.109
Ketamine in association with nitrous oxide or hypercapnia has The Child with Pulmonary Hypertension
deleterious effects on CBF, cerebral metabolism, and ICP. In the Pediatric and animal studies have largely but not consistently
presence of nitrous oxide even with controlled ventilation, shown minimal, nonsignificant changes in pulmonary vascular
ketamine may increase CBF. resistance in those without pre-existing pulmonary hyperten-
Ketamine may be beneficial in the injured brain. Rat studies in sion.25 Maintaining normal pH, normocarbia, and normoxia is
brain ischemia found that ketamine decreased injury-triggered important in preventing significant changes in pulmonary vas-
cascades. There was dampening of interactions between the cular resistance in infants and children with congenital cardiac
NMDA receptor, postsynaptic density proteins, and protein disease. Ketamine can be used safely in the child without pre-
kinases. This ultimately resulted in reduced nitric oxide–related existing pulmonary hypertension. The use of ketamine in children
neurotoxicity and brain damage. with known raised baseline pulmonary vascular resistance, from
both cardiac and other causes, is more controversial.
Neurodevelopmental and Animal investigations demonstrate complex interactions of
ketamine with pulmonary vasculature. Ketamine causes direct
Neonatal Use of Ketamine vasodilation via mechanisms decreasing intracellular calcium in
In rodents and primates, profound NMDA blockade is neurotoxic. vascular smooth muscle. Ketamine also has an opposing effect on
High-dose (40 mg/kg) ketamine caused reversible pathologic endothelium-mediated vasodilation. The net clinical effect of
ketamine depends on the interplay of these direct, opposing 2. Grant I, Nimmo W, McNicol L, Clements J. Ketamine disposition in
mechanisms and the sympathetically mediated ketamine effects children and adults. Br J Anaesth. 1983;55:1107–1111.
3. Grant I, Nimmo W, Clements J. Pharmacokinetics and analgesic effects of
on the vasculature. Case reports detail the successful use of keta-
I.M. and oral ketamine. Br J Anaesth. 1981;53:805–810.
mine for anesthesia in patients with known pulmonary hyper- 4. Tsubo T, Sakai I, Okawa H, et al. Ketamine and midazolam kinetics
tension. Nonetheless, the use of ketamine in this group of patients during continuous hemofiltration in patients with multiple organ
is controversial. A recent open-label study of 18 children with pre- dysfunction syndrome. Intensive Care Med. 2001;27:1087–1090.
existing pulmonary hypertension of multiple etiologies demon- 5. Herd D, Anderson B. Ketamine disposition in children presenting for
strated no rise in pulmonary arterial pressure in spontaneously procedural sedation and analgesia in a children’s emergency department.
Paediatr Anaesth. 2007;17:622–629.
breathing children given ketamine in addition to 0.5 minimum 6. Dallimore D, Herd D, Short T, Anderson B. Dosing ketamine for pediatric
alveolar concentration (MAC) sevoflurane anesthesia.112 These procedural sedation in the emergency department. Pediatr Emerg Care.
authors argue that ketamine offers benefits to children with pul- 2008;24:529–533.
monary hypertension requiring anesthesia. Ketamine maintains 7. Dallimore D, Anderson B, Short T, Herd D. Ketamine anaesthesia
systemic vascular resistance and systemic arterial pressure and, in children—exploring infusion regimes. Paediatr Anaesth. 2008;18:
708–714.
thus, preserves coronary blood flow to the hypertensive right
8. Strigo I, Duncan G, Bushnell M, et al. The effects of racemic ketamine on
ventricle. Furthermore, this maintenance of systemic pressures painful stimulation of skin and viscera in human subjects. Pain. 2005;
might prevent the unfavorable left shift of the septum and con- 113:255–264.
sequent fall in cardiac output and coronary blood flow that can 9. Wang Y, Kikuchi T, Sakai M, et al. Age-related modifications of effects of
occur with lowered systemic pressures in the patient with pul- ketamine and propofol on rat hippocampal acetylcholine release studied
monary hypertension. Ketamine also preserves the ratio of pul- by in vivo brain microdialysis. Acta Anaesthesiol Scand. 2000;44:112–117.
10. Bhutta A. Ketamine: a controversial drug for neonates. Semin Perinatol.
monary and systemic blood flow better than other anesthetics in 2007;31:303–308.
patients with intracardiac shunt such as in Eisenmenger’s syn- 11. Herd D, Anderson B, Keene N, Holford N. Investigating the pharma-
drome. Finally, ketamine may increase cardiac performance me- codynamics of ketamine in children. Paediatr Anaesth. 2008;18:36–42.
diated through the sympathetic nervous system. 12. Schuttler J, Stanski D, White P, et al. Pharmacodynamic modeling of the
EEG effects of ketamine and its enantiomers in man. J Pharmacokinet
Biopharm. 1987;15:241–253.
NONANESTHESIA AND ANALGESIC 13. Vereecke H, Struys M, Mortier E. A comparison of bispectral index and
ARX-derived auditory evoked potential index in measuring the clinical
USES OR AREAS OF RESEARCH interaction between ketamine and propofol anaesthesia. Anaesthesia.
2003;58:957–961.
Ketamine is known to have anti-inflammatory effects. Ketamine 14. Penttila J, Maenpaa M, Laitio T, et al. Subanaesthetic doses of ketamine
suppresses natural killer cell activity, stabilizes neutrophil activa- impair cardiac parasympathetic regulation. Eur J Anaesthesiol. 2005;
tion, reduces the release of inflammatory mediators, and decreases 22:808–810.
tumor necrosis factor-␣, interleukin-6, and interleukin-8 levels. 15. Hamza J, Ecoffey C, Gross J. Ventilatory response to CO2 following intra-
These effects have been observed in vitro, in animal models, and venous ketamine in children. Anesthesiology. 1989;70:422–425.
16. Shulman D, Beardsmore C, Aronson B, Godfrey S. The effect of ketamine
in human patients receiving ketamine. on the functional residual capacity in young children. Anesthesiology.
Ketamine may have effects in ameliorating deleterious cascades 1985;62:551–577.
in sepsis and may have roles in immune modulation. Ketamine 17. Mortero R, Clark L, Tolan M, et al. The effects of small-dose ketamine on
may either exacerbate tumor metastasis after surgery by suppres- propofol sedation, postoperative mood perception, cognition, and pain.
sing natural killer cell activity or attenuate this effect because of Anesth Analg. 2001;92:1465–1469.
improved analgesia attenuating the suppression of natural killer 18. Kanbak M. Ketamine in porphyria. Anesth Analg. 1997;84:1395.
19. Domino E, Domino S, Smith R, et al. Ketamine kinetics in unmedicated
cell activity. These questions and the magnitude of effect, if any, are and diazepam-premedicated subjects. Clin Pharmacol Ther. 1984;36:
currently unable to be answered without further preclinical and 645–653.
clinical research. 20. Sweeney B, Bromilow J. Liver enzyme induction and inhibition: implica-
tions for anaesthesia. Anaesthesia. 2006;61:159–177.
21. Agarwal A, Raza M, Dhiraaj S, et al. Is ketamine a safe anesthetic for
CONCLUDING COMMENTS percutaneous liver biopsy in a liver transplant recipient immuno-
suppressed? Anesth Analg. 2005;100:85–86.
Ketamine was synthetized in 1962 during a search for an ideal 22. Friesen R, Henry D. Cardiovascular changes in preterm neonates re-
anesthetic. Although it falls short of the ideal anesthetic, it remains ceiving isoflurane, halothane, fentanyl, and ketamine. Anesthesiology.
an integral part of clinical practice since its introduction in the 1986;64:238–242.
23. Golden S. Combination propofol-ketamine anaesthesia in sick neonates.
1970s. Its unique characteristics offer safety and stability across Paediatr Anaesth. 2001;11:119–122.
diverse physical locations and patient groups. It is not a mainstay 24. Lebovic S, Reich D, Steinberg L, et al. Comparison of propofol versus
of pediatric anesthesia but is likely to remain as an agent able to fill ketamine for anaesthesia in pediatric patients undergoing cardiac
a number of niches in pediatric anesthesia and sedation. It has catheterization. Anesth Analg. 1992;74:490–494.
much to offer in furthering analgesia, although clarity of how best 25. Tugrul M, Camci E, Pembeci K, et al. Ketamine infusion versus isoflurane
for the maintenance of anesthesia in the prebypass period in children with
to use this agent in acute and chronic pain is still developing. It tetralogy of Fallot. J Cardiothorac Vasc Anesth. 2000;14:557–561.
may have the additional clinical benefits of neuroprotection and 26. Mason K, Michna E, DiNardo J, et al. Evolution of a protocol for
inflammatory modulation, but current research does not establish ketamine-induced sedation as an alternative to general anaesthesia for
the absolute presence or the magnitude of these effects. interventional radiologic procedures in pediatric patients. Radiology.
2002;225:457–465.
27. Hostetlier M, Davis C. Prospective age-based comparison of behavioral
REFERENCES reactions occurring after ketamine sedation in the ED. Am J Emerg Med.
2002;20:463–468.
1. Clements J, Nimmo W. Pharmacokinetics and analgesic effect of ketamine 28. Green S, Denmark T, Cline J, et al. Ketamine sedation for pediatric critical
in man. Br J Anaesth. 1981;53:27–30. care procedures. Pediatr Emerg Care. 2001;17:244–248.
29. Berkenbosch J, Graff G, Stark J. Safety and efficacy of ketamine sedation 54. Guignard B, Coste C, Costes H, et al. Supplementing desflurane-
for infant flexible fiberoptic bronchoscopy. Chest. 2004;125:1132–1137. remifentanil anaesthesia with small-dose ketamine reduces perioperative
30. Kennedy R, Luhmann J, Luhmann S. Emergency department mana- opioid analgesic requirements. Anesth Analg. 2002;95:103–108.
gement of pain and anxiety related to orthopedic fracture care: a guide to 55. Taura P, Fuster J, Blasi A, et al. Postoperative pain relief after hepatic resec-
analgesic techniques and procedural sedation in children. Pediatr Drugs. tion in cirrhotic patients: the efficacy of a single small dose of ketamine
2004;6:11–31. plus morphine epidurally. Anesth Analg. 2003;96:475–480.
31. Acworth J, Purdie D, Clark R. Intravenous ketamine plus midazolam is 56. Fu E, Miguel R, Scharf J. Preemptive ketamine decreases postoperative
superior to intranasal midazolam for emergency paediatric procedural narcotic requirements in patients undergoing abdominal surgery. Anesth
sedation. Emerg Med J. 2001;18:39–45. Analg. 1997;84:1086–1090.
32. Porter K. Ketamine in prehospital care. Emerg Med J. 2004;21:351–354. 57. Ozyalcin N, Yucel A, Camlica H, et al. Effect of pre-emptive ketamine on
33. Morton N. Ketamine for procedural sedation and analgesia in pediatric sensory changes and postoperative pain after thoracotomy: comparison
emergency medicine: a UK perspective. Paediatr Anaesth. 2008;18:25–29. of epidural and intramuscular routes. Br J Anaesth. 2004;93:356–361.
34. McGlone R, Howes M, Joshi M. The Lancaster experience of 2 to 2.5 mg/ 58. Aida S, Yamakura T, Baba H, et al. Preemptive analgesia by intravenous
kg intramuscular ketamine for paediatric sedation: 501 cases and analysis. low-dose ketamine and epidural morphine in gastrectomy: A randomised
Emerg Med. 2004;21:290–295. double-blind study. Anesthesiology. 2000;92:1624–1630.
35. Gottschling S, Meyer S, Krenn T, et al. Propofol versus midazolam/ 59. Argiriadou H, Himmelseher S, Papagiannopoulou P, et al. Improvement
ketamien for procedural sedation in pediatric oncology. J Pediatr Hematol of pain treatment after major abdominal surgery by intravenous S(+)-
Oncol. 2005;27:471–476. ketamine. Anesth Analg. 2004;98:1413–1418.
36. Ellis D, Husain H, Saetta J, Walker T. Procedural sedation in paediatric 60. Choe H, Young-Soon C, Kim Y, et al. Epidural morphine plus ketamine
minor procedures: a prospective audit on ketamine use in the emergency for upper abdominal surgery: improved analgesia from preincisional
department. Emerg Med J. 2004;21:286–289. versus postincisional administration. Anesth Analg. 1997;84:560–563.
37. Howes M. Ketamine for paediatric sedation/analgesia in the emergency 61. Elia N, Tramer M. Ketamine and postoperative pain—a quantitative
department. Emerg Med J. 2004;21:275–280. systematic review of randomised trials. Pain. 2004;113:61–70.
38. Morton N. Ketamine is not a safe, effective, and appropriate technique 62. Schmid R, Sandler A, Katz J. Use and efficacy of low-dose ketamine in
for emergency department paediatric procedural sedation. Emerg Med J. the management of acute postoperative pain: a review of current tech-
2003;21:272–273. niques and outcomes. Pain. 1999:111–125.
39. Green S, Krauss B. Ketamine is a safe, effective, and appropriate technique 63. Subramaniam K, Subramaniam B, Steinbrook R. Ketamine as adjuvant
for emergency department paediatric procedural sedation. Emerg Med J. analgesic to opioids: a quantitative and qualitative systematic review.
2004;21:271–272. Anesth Analg. 2004;99:482–495.
40. Krauss B, Green S. Training and credentialing in procedural sedation and 64. McCartney C, Sinha A, Katz J. A qualitative systemic review of the role of
analgesia in children: lessons from the United States model. Paediatr N-methyl-D-aspartate receptor antagonists in preventive analgesia. Anesth
Anaesth. 2008;18:30–35. Analg. 2004:1385–1400.
41. Green S, Johnson N. Ketamine sedation for pediatric procedures: part 2, 65. Engelhardt T, Zaarour C, Naser B, et al. Intraoperative low-dose ketamine
review and implications. Ann Emerg Med. 1990;19:1033–1046. does not prevent a remifentanil-induced increase in morphine require-
42. Roback M, Wathen J, Bajaj L, Bothner J. Adverse events associated with ment after pediatric scoliosis surgery. Paediatr Anaesth. 2008;107:
procedural sedation and analgesia in a pediatric emergency department: 1170–1175.
a comparison of common parenteral drugs. Acad Emerg Med. 2005;12: 66. Becke K, Albrecht S, Schmitz B, et al. Intraoperative low-dose S-ketamine
508–513. has no preventive effects on postoperative pain and morphine consump-
43. Tosun Z, Esmaoglu A, Coruh A. Propofol-ketamine vs propofol-fentanyl tion after major urological surgery in children. Paediatr Anaesth. 2005:
combinations for deep sedation and analgesia in pediatric patients 484–490.
undergoing burn dressing changes. Paediatr Anaesth. 2008;18:43–47. 67. Elhakim M, Khalafallah Z, El-fattah A, et al. Ketamine reduces
44. Sherwin T, Green S, Khan A, et al. Does adjunctive midazolam reduce swallowing-evoked pain after paediatric tonsillectomy. Acta Anaesthesiol
recovery agitation after ketamine sedation for pediatric procedures? A Scand. 2003;47:604–609.
randomised, double-blind, placebo-controlled trial. Ann Emerg Med. 68. Crawford M, Hickey C, Zaarour C, et al. Development of acute opioid
2000;35:229–238. tolerance during infusion of remifentanil for pediatric scoliosis surgery.
45. Wathen J, Roback M, Mackenzie T, Bothner J. Does midazolam alter the Anesth Analg. 2006;102:1662–1667.
clinical effects of intravenous ketamine sedation in children? A double- 69. Angst M, Clark J. Opioid-induced hyperalgesia. Anesthesiology. 2006;
blind randomized controlled emergency department trial. Ann Emerg 104:570–587.
Med. 2000;36:579–588. 70. Vinik H, Kissin I. Rapid development of tolerance to analgesia during
46. Langston W, Wathen J, Roback M, Bajaj L. Effect of ondansetron on the remifentanil infusion in humans. Anesth Analg. 1998;86:1307–1311.
incidence of vomiting associated with ketamine sedation in children: a 71. Guignard B, Bossard A, Coste C, et al. Acute opioid tolerance: intraopera-
double-blind, randomized, placebo-controlled trial. Ann Emerg Med. tive remifentanil increases postoperative pain and morphine requirement.
2008;52:30–34. Anesthesiology. 2000;93:409–417.
47. Roback M, Wathen J, Mackenzie T, Bajaj L. A randomized, controlled trial 72. Joly V, Richebe P, Guignard B, et al. Remifentanil-induced postoperative
of IV vs IM ketamine for sedation of pediatric patients receiving emer- hyperalgesia and its prevention with small-dose ketamine. Anesthesiology.
gency department orthopedic procedures. Ann Emerg Med. 2006;48: 2005;103:147–155.
605–612. 73. Cortinez L, Brandes V, Munoz H, et al. No clinical evidence of acute
48. De Kock M, Lavand’homme P, Waterloos H. “Balanced analgesia” in the opioid tolerance after remifentanil-based anaesthesia. Br J Anaesth. 2001;
perioperative period: is there a place for ketamine? Pain. 2001;92: 87:866–869.
373–380. 74. Schraag S, Checketts M, Kenny G. Lack of rapid development of opioid
49. Himmelseher S, Durieux M. Ketamine for perioperative pain manage- tolerance during alfentanil and remifentanil infusions for postoperative
ment. Anesthesiology. 2005;102:211–220. pain. Anesth Analg. 1999;89:753–761.
50. Marcus R, Victoria B, Rushman S, Thompson J. Comparison of ketamine 75. Laulin J, Maurette P, Corcuff J, et al. The role of ketamine in preventing
and morphine for analgesia after tonsillectomy in children. Br J Anaesth. fentanyl-induced hyperalgesia and susequent acute morphine tolerance.
2000;84:739–742. Anesth Analg. 2002;94:1263–1269.
51. Aspinall R, Mayor A. A prospective randomized controlled study of the 76. Weinbroum A. A single small dose of postoperative ketamine provides
efficacy of ketamine for postoperative pain relief in children after rapid and sustained improvement in morphine analgesia in the presence
adenotonsillectomy. Paediatr Anaesth. 2001;11:333–336. of morphine-resistant pain. Anesth Analg. 2003;96:789–795.
52. Umuroglu T, Eti Z, Ciftci H, Gogus Y. Analgesia for adenotonsillectomy 77. Koinig H, Marhofer P, Krenn C, et al. Analgesic effects of caudal and
in children: a comparison of morphine, ketamine and tramadol. Paediatr intramuscular S(+)-ketamine in children. Anesthesiology. 2000;93:976–980.
Anaesth. 2004;14:568–573. 78. Martindale S, Dix P, Stoddart P. Double-blind randomized controlled trial
53. O’Flaherty J, Lin C. Does ketamine or magnesium affect posttosillectomy of caudal versus intravenous S(+)-ketamine for supplementation of caudal
pain in children? Paediatr Anaesth. 2003;13:413–421. analgesia in children. Br J Anaesth. 2004;92:344–347.
79. Akbas M, Akbas H, Yegin A, et al. Comparison of the effects of clonidine 98. Tanaka M, Sato M, Saito A, Nishikawa T. Reevaluation of rectal ketamine
and ketamine added to ropivacaine on stress hormone levels and the premedication in children. Anesthesiology. 2000;93:1217–1224.
duration of caudal analgesia. Paediatr Anaesth. 2005;15:580–585. 99. Ghai B, Granhe R, Kumar A, Chari P. Cpmparitive evaluation of mida-
80. Choudhuri A, Dharmani P, Kumari N, Prakash A. Comparison of caudal zolam and ketamine with midazolam alone as oral premedication.
epidural bupivacaine with bupivacaine plus tramadol and bupivacaine Paediatr Anaesth. 2005;15:554–559.
plus ketamine for postoperative analgesia in children. Anaesth Intensive 100. Darlong V, Shende D, Subramanyam M, et al. Oral ketamine or mida-
Care. 2008;36:174–179. zolam or low dose combination for premedication in children. Anaesth
81. Panjabi N, Prakash S, Gupta P, Gogia A. Efficacy of three doses of keta- Intensive Care. 2004;32:246–249.
mine with bupivacaine for caudal analgesia in pediatric inguinal hernio- 101. Hahnenkamp K, Honemann C, Fischer L, et al. Effect of different anaes-
tomy. Reg Anaesth Pain Med. 2004;29:28–31. thetic regimes on the oculocardiac reflex during paediatric strabismus
82. Kumar P, Rudra A, Pan A, Acharya A. Caudal additives in pediatrics: a surgery. Paediatr Anaesth. 2000;10:601–608.
comparison among midazolam, ketamine, and neostigmine coadminis- 102. Erb T, Ryhult S, Duitman E, et al. Improvement of motor-evoked
tered with bupivacaine. Anesth Analg. 2005;101:69–73. potentials by ketamine and spatial facilitation during spinal surgery in
83. Gunes Y, Secen M, Ozcengiz D, et al. Comparison of caudal ropivacaine, a young child. Anesth Analg. 2005;100:1634–1636.
ropivacaine plus ketamine and ropivacaine plus tramadol administration 103. Dal D, Kose A, Honca M, et al. Efficacy of prophylactic keta-
for postoperative analgesia in children. Paediatr Anaesth. 2004;14: mine in preventing postoperative shivering. Br J Anaesth. 2005;95:
557–563. 189–192.
84. Hager H, Marhofer P, Sitzwohl C, et al. Caudal clonidine prolongs anal- 104. Barbi E, Marchetti F, Gerarduzzi T, et al. Pretreatment with intravenous
gesia from caudal S(+)-ketamine in children. Anesth Analg. 2002;94: ketamine reduces propofol injection pain. Paediatr Anaesth. 2003;13:
1169–1172. 764–768.
85. Almenrader N, Passariello M, D’Amico G, et al. Caudal additives for post- 105. Liou J, Hsu J, Liu F, et al. Pretreatment with small-dose ketamine reduces
operative pain management in children: S(+)-ketamine and neostigmine. withdrawal movements associated with injection of rocuronium on
Paediatr Anaesth. 2005;15:143–147. pediatric patients. Anesth Analg. 2003;97:1294–1297.
86. Wheeler M, Patel A, Suresh S, et al. The addition of clonidine 2 mcg/kg 106. Satsumae T, Yamaguchi H, Sakaguchi M, et al. Preoperative small-dose
does not enhance the postoperative analgesia of a caudal block using ketamine prevented tourniquet-induced arterial pressure increase in
0.125% bupivacaine and epinephrine 1:200000 in children: a prospective, orthopedic patients under general anesthesia. Anesth Analg. 2001;92:
double-blind, randomized study. Paediatr Anaesth. 2005;15:476–483. 1286–1289.
87. Passariello M, Almenrader N, Canneti A, et al. Caudal analgesia in 107. Golparvar M, Saghaei M, Sajedi P, Razavi S. Paradoxical reaction
children: S(+)-ketamine vs S(+)-ketamine plus clonidine. Paediatr following intravenous midazolam premedication in pediatric patients—
Anaesth. 2004;14:851–855. a randomized placebo controlled trial of ketamine for rapid tranquili-
88. Gauntlett I. A comparison between local anaesthetic dorsal nerve block zation. Paediatr Anaesth. 2004;14:924–930.
and caudal bupivacaine with ketamine for pediatric circumcision. 108. Treston G. Prolonged pre-procedure fasting time is unnecessary when
Paediatr Anaesth. 2003;13:38–42. using titrated intravenous ketamine for paediatric procedural sedation.
89. Findlow D, Aldrige L, Doyle E. Comparison of caudal block using bupi- Emerg Med Australas. 2004;16:145–150.
vacaine and ketamine with ilioinguinal block for orchidopexy in children. 109. Himmelseher S, Durieux M. Revising a dogma: ketamine for patients
Anaesthesia. 1997;52:1110–1113. with neurological injury? Anesth Analg. 2005;101:524–534.
90. Guillou N, Tanguy M, Seguin P, et al. The effects of small-dose ketamine 110. Schmidt A, Ryding E, Akeson J. Racemic ketamine does not abolish
on morphine consumption in surgical intensive care patients after major cerebrovascular autoregulation in the pig. Acta Anaesthesiol Scand. 2003;
abdominal surgery. Anesth Analg. 2003;97:843–847. 47:569–575.
91. Edwards N, Fletcher A, Cole J, Peacock J. Combined infusions of mor- 111. Anand K, Garg S, Rovnaghi C, et al. Ketamine reduces the cell death
phine and ketamine for postoperative analgesia. Can J Anaesth. 1993; following inflammatory pain in newborn rat brain. Pediatr Res. 2007;62:
48:124–127. 283–290.
92. Michelet P, Guervilly C, Helaine A, et al. Adding ketamine to morphine 112. Williams G, Philip B, Chu L, et al. Ketamine does not increase pulmo-
for patient-controlled analgesia after thoracic surgery: influence on mor- nary vascular resistance in children with pulmonary hypertension un-
phine consumption, respiratory function, and nocturnal desaturation. Br dergoing sevoflurane anaesthesia and spontaneous ventilation. Anesth
J Anaesth. 2007;99:396–403. Analg. 2007;105:1578–1584.
93. Sveticic G, Farzanegan F, Zmoos P, et al. Is the combination of morphine 113. Malinovsky J, Servin F, Cozian A, et al. Ketamine and norketamine
with ketamine better than morphine alone for postoperative intravenous plasma concentrations after I.V., nasal and rectal administration in
patient-controlled analgesia? Anesth Analg. 2008;106:287–293. children. Br J Anaesth. 1996;77:203–207.
94. Reeves M, Lindholm D, Myles P, et al. Adding ketamine to morphine for 114. Kennedy R, Porter F, Miller J, Jaffe D. Comparison of fentanyl/
patient-controlled analgesia after major abdominal surgery: a double- midazolam with ketamine/midazolam for pediatric orthopedic emer-
blinded, randomized controlled trial. Anesth Analg. 2001;93:116–120. gencies. Pediatrics. 1998;102:956–963.
95. Dix P, Martindale S, Stoddart P. Double-blind randomized placebo- 115. Godambe S, Elliot V, Matheny D, Pershad J. Comparison of propofol/
controlled trial of the effect of ketamine on postoperative morphine fentanyl versus ketamine/midazolam for brief orthopedic procedural
consumption in children following appendicectomy. Paediatr Anaesth. sedation in a pediatric emergency department. Pediatrics. 2003;112:
2003;13:422–426. 116–123.
96. Filatov S, Baer G, Rorarius M, Oikkonen M. Efficacy and safety of 116. Luhmann J, Shootman M, Luhmann S, Kennedy R. A randomized
premedication with oral ketamine for day-case adenoidectomy compared comparison of nitrous oxide plus hematoma block versus ketamine plus
with rectal diazepam/diclofenac and EMLA. Acta Anaesthesiol Scand. midazolam for emergency department forearm fracture reduction in
2000;44:118–124. children. Pediatrics. 2006;118:1078–1086.
97. Horiuchi T, Kawaguchi M, Kurehara K, et al. Evaluation of relatively low 117. Tosun Z, Aksu R, Guler G, et al. Propofol-ketamine vs propofol-fentanyl
dose of oral transmucosal ketamine premedication in children: a for sedation during pediatric upper gastrointestinal endoscopy. Paediatr
comparison with oral midazolam. Paediatr Anaesth. 2005;15:643–647. Anaesth. 2007; 17:983–988.
Opioid Analgesic Agents 25

Jason A. Hayes and Daisy T. Joo C H A P T E R
INTRODUCTION cases, however, opioids have similar receptor affinities but very
different physiologic effects. This is explained by different po-
In the past, the administration of analgesic drugs to pediatric tencies or ability to activate the receptors. For example, morphine,
patients was thought to be unnecessary and even unsafe. However,
it is now recognized that the management of pain is integral to the
care of children undergoing anesthesia and surgery. In addition,
the role of anesthesiologists as providers of pain control now
extends beyond the recovery room and includes not only surgical
patients but also those with pain secondary to medical conditions
such as cancer and sickle cell disease.
Opioid drugs have always been a central component of the
armamentarium available for the management of pain in children,
and significant advances in their use continue to be made. These
include the introduction of new agents with unique pharmaco-
kinetic and pharmacodynamic properties and new uses for
established opioids. Unfortunately, there continues to be a relative
paucity of data regarding the use of opioids in children.
This chapter summarizes current knowledge of opioid pharma-
cology, including the expanding role of pharmacogenetics, and
reviews opioid that are commonly used in children, with an em-
phasis on the effects of age on opioid pharmacology.
OPIOID RECEPTORS
Opioids produce analgesia by binding to opioid receptors, which
are located in the peripheral nervous system (following inflam-
mation); on pre- and postsynaptic neurons in the spinal cord
including those which form the ascending pain transmission Figure 25-1. Mu opioid receptor activation. A: In the absence of
pathway and, in particular, brain nuclei in the thalamus, midbrain, agonist binding, the receptor remains in an inactive state. The in-
and medulla as well as in neurons composing the descending hibitory G protein (Gi/o) consists of three subunits—alpha, beta,
inhibitory pathway that modulates spinal cord pain transmission.1 and gamma. It is bound to the guanosine 5′-diphosphate (GDP)
Activation of opioid receptors produces an analgesic response by at its alpha subunit. B: During binding with the opioid receptor
three main mechanisms.2 First, calcium ion entry through calcium agonist, a change in the shape of the receptor facilitates binding
channels is decreased resulting in a decrease in presynaptic exci- of the Gi/o with the receptor. C: The association between the opi-
tatory neurotransmitter release, that is, of glutamate. Second, oid receptor and the Gi/o reduces the affinity of the GDP to its al-
potassium ion efflux through specific potassium channels is en- pha subunit. The presence of Mg2+ ions favors the guanosine 5′-
hanced resulting in the hyperpolarization of postsynaptic neurons triphosphate (GTP) binding to the alpha subunit over the GDP.
and inhibition of action potentials. Third, there is inhibition of D: The GTP bound Galphai/o dissociates from Gbeta-gammai/o
adenyl cyclase activity and a reduction in intracellular cyclic which allows these components to modulate the proteins of the
adenosine monophosphate (cAMP). These processes occur via the effector adenyl-cyclase and the ion channels. The affinity of the
activation of an opioid receptor–associated G protein that regula- opioid receptor is reduced by the dissociation of the Gi/o sub-
tes transmembrane signaling through the activation of effect or units from the receptor. E: The intrinsic GTPase hydrolyzes the
proteins (Figure 25–1). GTP to GDP by releasing the phosphate anion which drives the
There are currently four known opioid receptors, mu, sigma, effector protein process. Yaster M, Kost-Bayerly S, Maxwell LG.
kappa, and delta, with subtypes of each. Different opioids have Opioids agonists and antagonists. In: Schechter NL, Berde CB,
different affinities for each receptor type, which partly explains Yaster M, editors. Pain in Infants, Children and Adolescents.
the different pharmacodynamic effects of each opioid. In some 2nd ed. Lippincott Williams & Wilkins, 2003, p. 71–85.
TABLE 25-1. Receptor Activity of Opioid Drugs Kappa1 opioid receptor stimulation produces analgesia at the spi-
nal level, sedation, miosis, and inhibition of antidiuretic hormone
Receptor Subtype release. Activation of kappa3 opioid receptors, which are the most
Drug Mu Kappa Sigma ubiquitous type of opioid receptor in the brain, produces supraspi-
nal analgesia. The role of the kappa2 opoid receptor is unknown.
Morphine +++ +
Hydromorphone +++
Meperidine +++ + Delta Receptors
Fentanyl +++ Delta opioid receptors are located in the pontine nucleus, amyg-
Sufentanil +++ dala, olfactory bulbs, and deep cortex. Both delta opioid receptor
Alfentanil +++ subtypes (delta1 spinal, delta2 supraspinal) produce euphoria and
Remifentanil +++ analgesia. Delta opioid receptors may have a role in the activation
Methadone +++ of the development of tolerance.
Tramadol ++ Although each opioid drug binds with relatively greater affinity
Oxycodone +++ ++ to mu1 opioid receptors in order to provide analgesia, there is also
Pentazocine –– ++ nonspecific binding of the opioid at other opioid receptor subtypes
Nalbuphine –– +/– – ++ resulting in varying side effect profiles. As well, opioids can be
Buprenorphine +/– – ++ classified into three categories depending upon their intrinsic
Naloxone –– –– –– activity or pharmacologic effect once bound to the opioid receptor.
Key: +++ = agonist; +/– – = partial agonist; – – = antagonist. Pure opioid receptor agonists, such as morphine and fentanyl,
Adapted from Yaster M, Kost-Byerly S, Maxwell LG. Opioid agonist and initiate cellular alterations resulting in the pharmacologic effect
antagonists. In: Schechter NL, Berde CB, Yaster M, editors. Pain in Infants, characterized by analgesia and commonly recognized opioid-
Children, and Adolescents. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; related side effects. Partial agonists or mixed agonist-antagonist
2003. pp. 181–224; and Miyoshi HR, Leckband SG. Systemic opioid analgesics.
In: Loeser JD, editor. Bonica’s Management of Pain. 3rd ed. Philadelphia:
opioids, such as nalbuphine, have some agonist effects when
Lippincott Williams & Wilkins; 2001. pp. 1682–1709. bound to opioid receptors but produce less than a maximal res-
ponse by competing with endogenous full agonists for binding
sites. These drugs are often full or partial agonists at the kappa and
nalbuphine, and naloxone each have similar affinities for the mu,
sigma opioid receptors and partial agonists or antagonists at the
kappa, and delta opioid receptors3 but almost opposite effects
mu opioid receptor. Pure opioid antagonists, such as naloxone,
(Table 25–1).
occupy the receptor-binding sites without producing any cellular
response (Table 25–2).
Mu Receptors
Mu opioid receptors are located in the cortex (cortical laminae III DEVELOPMENTAL ASPECTS
and IV, thalamus) and brainstem (periaqueductal gray matter) and
are the most common type of opioid receptor in the spinal cord All opioid receptors exist in the newborn. The development of
(substantia gelatinosa). Two subtypes have been identified: stimu- nociceptive pathways is well understood in animals but not in
lation of mu1 opioid receptors produces supraspinal analgesia humans. Ascending nociceptive pathways are immature at a time
(brainstem and higher), whereas activation of mu2 opioid receptors period corresponding to the third trimester of the human fetus:
produces spinal analgesia. The most common opioid side effects C fibers are not functionally mature, and Aβ fibers terminate in
such as respiratory depression, inhibition of gastrointestinal motility, the spinal cord. In addition, there may be an age-related change in
decreased heart rate, and sedation are mediated by mu2 opioid receptor function or location (pons and medulla in newborns)
receptors in the brainstem. Peripheral mu opioid receptors exist and based on findings of increased sensitivity of newborn rats to the
produce localized analgesia in the absence of systemic absorption.3 respiratory depressant effects of opioids despite a 40-fold higher
dose requirement for analgesia.4 Therefore, although neonates
experience pain, it probably differs considerably from that of an
Sigma Receptors adult. Otherwise, children appear to be similar to adults with res-
Sigma receptors tend to be concentrated in the brain in areas in- pect to opioid requirements and risk of side effects.5
volved in motor functions and in limbic areas, sensory areas, and
areas associated with endocrine function. Peripheral organs, such
as the gastrointestinal tract, liver, and kidneys, contain high con-
PHARMACOGENETICS
centrations of sigma opioid receptors. Two subtypes have been The effect of genetic differences on opioid pharmacokinetics,
postulated, but exact roles of each are not clear. With respect to pharmacodynamics, and interactions with other drugs is becoming
pain, sigma1 opioid receptor agonists, such as haloperidol, have better understood. One example is decreased or absent metabolism
been shown to potentiate opioid analgesia but have no intrinsic of codeine to morphine caused by mutations of cytochrome (CYP)
analgesic activity. P450 2D6. It has been estimated that 47% of children are poor
metabolizers and 4% are nonmetabolizers of codeine.6 Because
codeine is a much weaker mu opioid receptor agonist than mor-
Kappa Receptors phine, it has limited or no analgesic activity in such individuals.
Kappa opioid receptors are located in the hypothalamus, periaque- However, these patients still experience typical opioid-related side
ductal gray matter, and substantia gelatinosa of the spinal cord. effects owing to the binding of mu opioid receptors by codeine.
CHAPTER 25 ■ Opioid Analgesic Agents 389
TABLE 25-2. Equianalgesic Dose Ratiosa

Equipotent I.V. Ratio of Potency I.V. to p.o. Equipotent p.o. Ratio of Potency
Drug Dose, mg/kg to Morphine I.V. Conversion Ratio Dose, mg/kg to Morphine p.o. References
Morphine 0.1 1 1:2–3 0.2–0.3 1 48
Hydromorphone 0.02–0.03a 3.5–5b 1:5c 0.04–0.08 3.5–5b 40, 48, 84
Meperidine 0.50–1 0.1–0.14 1 :3 1–3 0.1–0.14 105, 275, 276
Fentanyl 0.01–0.0125 80–100 1:1d Minimum 70–100 40, 48, 137
12.5 μg/hd
Sufentanil 0.001–0.0025 400–1000 n/a n/a n/a 139
Alfentanil 0.04–0.0875 11–25 n/a n/a n/a 154, 158
Remifentanil 0.067–0.01 55–75 n/a n/a n/a 180
Methadone 0.1 1 1:1 0.1 4–14e 40, 48
Tramadol 1–2 0.07–0.14 1:1g 1–2 (tabs) 0.1 208–210, 277
2–3 (liquid)
Oxycodone 0.1 0.7–1 0.5–0.8:1 0.1 1.5–2 278–280
Pentazocine 0.2–0.4 0.25–0.5 1:3 0.6–1.2 0.25–0.5 244
Nalbuphine 0.05–0.2 1 n/ag n/a n/a 130, 255, 258
Buprenorphine 0.0015–0.003 40 1:2 0.006h 40 266, 267
a
Equianalgesic dose ratios apply to patients on stable doses of opioids and should be used as guidelines only. Appropriate patient evaluation and clinical judgment are
necessary before the use of equianalgesic dose ratios. Ranges reflect the high degree of interpatient variability.
b
If converting morphine → hydromorphone, use lower dose; if converting hydromorphone → morphine use higher dose.
c
Data from bioavailabilty studies with high variability reported (1:1–5).
d
Conversion to transdermal fentanyl patch based on average hourly consumption of intravenous fentanyl. Transition from fentanyl I.V. should be done in a stepwise
fashion.
e
Conversion ratio for morphine → methadone is highly dependent on dose of morphine: < 90 mg/d morphine p.o.:methadone p.o. = 4–9:1; 90–300 mg/day
morphine p.o.:methadone = 8–10:1; >300 mg/d morphine p.o.:methadone p.o. = 12–14:1.
f
Oral bioavailability increases from 68% to almost 100% with repeat doses.
g
n/a = not available in oral form.
h
Sublingual administration.
A study of CYP2D6 polymorphism in neonates found only 30% Cardiovascular

carried the “wild-type” with a normal level of activity.7 Duplications
of active CYP2D6 alleles can also result in increased activity levels In general, all opioids reduce the tone of the sympathetic nervous
resulting in an ultrarapid metabolizer phenotype, which occurs in system. Arterial hypotension may ensue in patients who require an
1 to 7% of the white population,8 with at least two reported cases of elevated sympathetic tone to maintain cardiac output and systemic
codeine-related morbidity.9,10 perfusion (hypovolemia, low cardiac output states). All opioids
The single nucleotide polymorphism (SNP) A118G of the reduce heart rate, with the exception of meperidine, which causes
mu opioid receptor causes a decreased potency of morphine, tachycardia.15 This may be related to the structural similarity
morphine-6β-glucuronide, and alfentanil at these receptors.8 between meperidine and atropine. Morphine may also cause a
However, heterozygous and homozygous carriers of the A118G reflex tachycardia in response to vasodilatation owing to histamine
SNP may benefit from protection against opioid- and metabolite- release. Bradycardia, particularly with fentanyl, is mediated by
related side effects, resulting in a broadened therapeutic index for stimulation of the central vagal nucleus and can be blocked phar-
opioid analgesics in such individuals.11,12 macologically with atropine. By contrast, remifentanil-induced
bradycardia appears to be mediated by parasympathetic activa-
tion or a direct negative chronotropic effect, which cannot be
OPIOID-RELATED ADVERSE EFFECTS blocked by antichiolinergic drugs,16 but resolves rapidly after
discontinuation of remifentanil administration.17 Meperidine
Respiratory has a dramatic detrimental effect on myocardial contractility18 and
Respiratory depression is dose-dependent and is most pronounced is not suitable for use as an anesthetic in patients with cardio-
with opioids that have a high affinity for mu opioid receptors vascular disease. Changes in vasomotor tone occur primarily
located in the brainstem, such as morphine, fentanyl, alfenatnil, because of histamine release after morphine and meperidine
remifentanil, and sufentanil. Small doses of opioids reduce respira- administration.19 Arterial dilatation occurs first in humans, fol-
tory rate and disrupt the rhythm of breathing. With increasing lowed by venodilatation, which lasts longer and results in a de-
doses, the tidal volume is reduced as well; however the dose- crease in preload.
response for respiratory depression is extremely variable between
patients.13 In addition, the increase in alveolar ventilation in
response to elevated arterial carbon dioxide pressure (PCO2) or
Gastrointestinal
decreased arterial oxygen pressure (PaO2) levels is blunted by All opioids reduce gastrointestinal motility by binding primarily
opioids.14 to mu and delta opioid receptors in the bowel, with little or no
central mechanisms.20 The effect on bowel peristalsis occurs at Management of Opioid-Related Side Effects
significantly lower doses than analgesic effects, and tolerance to
constipation does not develop as it does to other opioid effects, Although the severity of opioid side effects is generally dose-
such as analgesia.21 Opioids also produce an increase in tone of dependent, the potential for side effects varies from patient to
the pyloric sphincter, sphincter of Oddi, and ileocecal valve. There patient. Therefore, it may be possible to reduce the severity of side
is debate as to whether some opioids, such as morphine, produce effects in a patient by switching to a different opioid instead of
more biliary spasm and a greater increase in sphincter of Oddi reducing the dose. The addition of different classes of analgesic
tone than other pure mu opioid agoinsts (fentanyl, meperidine).22 agents, such non-steroidal anti-inflammatory drugs and N-methyl-
D-aspartate (NMDA) receptor antagonists, such as ketamine, may
However, one review suggests that there is no difference in this
effect between morphine and meperidine at equianalgesic doses.23 allow for a reduction in opioid consumption without loss of anal-
Opioid agonist-antagonists may cause less increase in sphincter gesic efficacy.
tone than pure agonists and may be the best choice in high-risk Opioid antagonists, such as naloxone, and mixed agonist-
patients.24 antagonists, such as nalbuphine, can be used to counteract opioid-
Opioids induce nausea and vomiting by binding to mu and related side effects. Studies in both adults and children have shown
that the incidence and severity of nausea and pruritus can be
delta opioid receptors present in the chemoreceptor trigger zone,
reduced without affecting analgesia.30 However, the incidence of
located in the area postrema of the medulla.25 Activation of
vomiting, sedation, and urinary retention appears to be un-
peripheral opioid receptors (mu and delta) located in the stomach
changed, and these drugs may be effective only for prevention, not
and small and large bowel decrease motility and delay gastric em-
treatment, of pruritus.31,32 Although epidural33 and oral34 naloxone
ptying. All opioids produce emetic symptoms when administered
has been shown to reduce postoperative ileus, a systematic review
in equianalgesic doses. concluded that insufficient evidence exists for the efficacy of
naloxone in the treatment of opioid-induced bowel dysfunction
Urinary Tract and that the incidence of anxiety or jitteriness caused by reversal
of central opioid effects may be higher.35 Two mu opioid receptor
Opioids can cause urinary retention by partially inhibiting para- antagonists that do not cross the blood-brain barrier, methyl-
sympathetic nerve innervation of the bladder, which causes total naltrexone and alvimopan, are currently in development. Studies
bladder relaxation and reduces the sensation of fullness, and by to date suggest that methylnaltrexone is an effective treatment for
increasing the tone of the bladder sphincter by sympathetic over- opioid-induced constipation and postoperative ileus in humans
stimulation.26 and nausea and vomiting in animals.35–37 Alvimopan has also been
shown to reduce postoperative ileus in humans with no detri-
mental effects on analgesia.35,38,39
Pruritus
Opioid-induced pruritus is mediated primarily by mu opioid
receptors located in multiple sites in the brain, such as the medul- PERIOPERATIVE PAIN MANAGEMENT
lary dorsal horn, and spinal cord.27 Activation of central dopamine Management of perioperative pain is an increasingly important
(D2) and serotonin (5-HT3) receptors may also play a role in component of modern pediatric anesthesia practice and often
mediating opioid-induced pruritus.27 Degranulation of mast cells involves the conversion of one opioid to another, because of side
and release of histamine by systemically administered opioids, effects or analgesic inefficacy, or from one route of administration
particularly morphine, are thought play a minor role in the to another, such as intravenous to oral dosing. Although all opioid
pathogenesis of opioid-induced pruritus. agonists produce similar analgesic effects at equipotent doses,
there is a large amount of interindividual variability in opioid
requirements, and equianalgesic dose ratios between opioids can
Drug Interactions vary depending on patient comorbidities, duration of treatment
There is growing evidence that the phenylpiperidine class of with opioids, and the dose of opioid before a switch from one
agent to another.40 A table of equianalgesic dose ratios is provided
opioid analgesics, such as meperidine, tramadol, methadone, and
as a guideline for conversion between opioids and routes of ad-
fentanyl (and congeners), are weak serotonin re-uptake inhibi-
ministration. However, dosing guidelines are an oversimplification
tors.28 When used in combination with monoamine oxidase
of a complex process, and exact doses should be guided by ap-
inhibitors (MAOIs), this group of opioids can potentially precipi- propriate patient assessment and clinical evaluation.
tate acute serotonin toxicity, which is characterized by neuromus- The use of parent-, nurse-, or patient-controlled analgesia
cular and autonomic hyperactivity and altered mental status. The (PCA) administration has become more widespread in children.41
vast majority of case reports have occurred with meperidine and A pump is programmed to deliver a bolus amount of drug on de-
tramadol. Serotonin toxicity occurs in a dose-dependent fashion mand, with or without a continuous infusion, with an appropriate
and is not idiosyncratic, as once thought. The serotonin re-uptake lockout interval and dose limit over 2 or 4 hours. The addition of
potency of fentanyl and its derivatives, such as remifentanil, is so a continuous or background infusion may not provide additional
low that its use in the presence of MAOIs is probably not strongly analgesia despite a larger cumulative dose of opioid42 but may be
contraindicated.28 Although the morphine analogues, including necessary for younger children. In children too young or physi-
codeine, oxycodone, and buprenorphine, do not appear to have cally incapable of using a PCA device, nurse- or parent-controlled
any serotonin re-uptake activity,28 toxicity with the combination of analgesia is an option. However, it has been suggested that nurses
oxycodone and a selective serotonin re-uptake inhibitor (SSRI; underestimate the severity of patients‘ pain and underdose relative
fluvoxamine) has been reported.29 to PCA.42
OPIOID TOLERANCE impedes passage across the blood-brain barrier. It is still active
systemically but provides minimal contribution to the analgesic
Opioid therapy for acute and chronic pain control is often com- efficacy of morphine.59 Morphine-3β-glucuronide is pharma-
plicated by the development of tolerance. Acquired tolerance is the codynamically inactive.60 Excretion of morphine-6β-glucuronide
reduction in analgesic effect resulting from repeated administra- is renal as opposed to hepatic for morphine; thus, accumulation
tions of an opioid. This is different from innate tolerance deter- can occur with renal impairment, making the metabolite the
mined by pharmacogenetic factors, which is apparent upon predominant agent responsible for analgesia and side effects.3,60
administration of the first dose of an opioid.43 From herein, this Neonates younger than 7 days old metabolize morphine to a lesser
discussion of tolerance refers to acquired tolerance to opioids. degree than older neonates, as evidenced by a lower ratio of
Cross-tolerance to other opioids often occurs with tolerance de- plasma morphine-6β-glucuronide to morphine despite similar
velopment to one of the opioids.44 doses.13
Mechanisms of opioid tolerance may include reduced inter-
nalization and membrane recycling of opioid receptors, superac-
tivation of adenyl cyclase and increase in intracellular cAMP, Pharmacodynamics
altered association of from inhibitory to stimulatory G proteins Analgesia following systemic administration is mediated pre-
with the opioid receptors, calcium channel up-regulation and dominantly by activation of supraspinal mu1 opioid receptors.
enhanced glutamate release, and postsynaptic NMDA receptor up- Morphine analgesia at the level of the spinal cord is mediated by
regulation.45 There are few if any studies on these mechanisms in mu2 opioid receptors, which has become more important with the
the pediatric population. Based on these mechanisms, which preuse of intrathecal and epidural routes of administration.61 Mor-
sumably are intact in the pediatric patient, strategies for opioid phine may also have a synergistic effect when administered con-
rotation, use of low-dose opioid receptor inhibition with naloxone, comitantly at spinal and supraspinal levels.3 Thus, intense
and use of NMDA receptor inhibitor therapy with methadone or analgesia after epidural or spinal morphine administration may
ketamine have been attempted with limited efficacy after opioid be explained by the combined effects of high concentrations at the
tolerance development. Unfortunately, tolerance to opioid admini- spinal cord and systemic levels similar to those after intramuscular
stration continues to hinder analgesic therapy with this class of injection.
medications for which there are few solutions. Oral morphine is available in immediate- and controlled-
release formulations. Short-acting morphine is administered every
3 to 4 hours as required, and long-acting every 12 hours. The dose
OPIOID AGONISTS of long-acting morphine is determined by dividing the total
amount of morphine administered over 24 hours into two doses.
Morphine Parenteral morphine can be given via intravenous, subcu-
Morphine provides analgesia that is equivalent to46 or better than47 taneous, and intramuscular routes approximately every 3 to
that provided by other opioids and is the standard against which 4 hours. A continuous intravenous infusion of morphine is com-
other opioids are evaluated. monly used in pediatric patients for postoperative analgesia at a
dose range of approximately 5 to 40 μg/kg/h. Postoperative
morphine requirements increase with gestational and postnatal
Pharmacokinetics age13,62 and noncardiac versus cardiac surgery.63 A steady-state
The bioavailability of oral morphine is approximately 38% (range plasma morphine concentration of 10 to 15 ng/mLl can be achie-
15–65%)48 owing to extensive metabolism in the intestinal mucosa ved in children after noncardiac surgery with a morphine infusion
and liver. The volume of distribution (Vd) is proportionately larger of 5 to 7.5 μg/kg/h at term birth, 8.5 to 12.5 μg/kg/h at 1 month of
in preterm than in full-term neonates and is independent of both age, 13.5 to 20 μg/kg/h at 3 months of age, 18 to 28 μg/kg/h at
gestational age and postnatal age in both groups.49 In preterm 1 year of age, and 16 to 25 μg/kg/h at 1 to -3 years of age.11,64 How-
infants, less than 20% of morphine is bound to plasma proteins ever, plasma morphine levels do not directly correlate with
compared with 35% in adults.48,50 The Vd reaches adult values analgesic efficacy owing to the low lipid solubility of morphine
within the first few months after birth. Morphine clearance is and its inability to cross the blood-brain barrier. Therefore, the
lowest in preterm infants (0.5–4 mL/kg/min) and highest in young dose for each patient must be titrated to effect carefully, because
children (20–40 mL/kg/min), with older children and adults there is a wide variation in the dose required to achieve analgesia.65
roughly in between (10–20 mLl/kg/min).5,49–54 The age-dependent In neonates, the duration of postoperative mechanical ventilation
changes in clearance result in large differences in elimination, directly correlates with the dose and duration of morphine
ranging from 10 to 20 hours in preterm infants to 1 to 2 hours in infusion.66 Intravenous administration of morphine by a PCAa
young children and 2 to 4 hours in older children and adults.50–54 device is commonly used in children older than 5 years.67
Although morphine elimination is primarily by hepatic metabo- Morphine can be administered into the epidural or caudal
lism, it is not significantly affected by liver disease. Approximately space as a single dose or continuous infusion either alone or in
10% of morphine is excreted unchanged in the urine.55 Sick pre- combination with other drugs, such as local anesthetics. Morphine
term infants, however, excrete larger amounts of unmetabolized has a relatively low lipid solubility compared with other opioids,
morphine than older children or adults.56 Morphine is glucuroni- such as fentanyl, and thus, relatively less morphine is absorbed
dated at the 3- and 6-positions by the age-dependent enzyme into the systemic circulation from the epidural space and cerebro-
uridine 5′¥-diphosphate gluronosyl transferase (UGT)-2B7 to spinal fluid. Plasma morphine concentrations are negligible for
morphine-3β-glucuronide and morphine-6β-glucuronide in at the first 2 hours after the administration of epidural morphine
least a 2:1 ratio, respectively.57,58 Morphine-6β-glucuronide is 100 0.025 mg/kg,68 and morphine is detectable in cerebrospinal fluid,
times more potent than morphine, but its greater hydrophilicity but not plasma, 18 hours after an intrathecal injection.69 Lumbar
epidural or caudal morphine can be administered as a bolus dose excitatory nervous system effects, including seizures in rats, but
of 25 to 100 μg/kg.62,68,70–72 The onset of analgesia of epidural there are no clinically relevant studies in humans supporting a
morphine occurs within 5 minutes.68 Single doses of epidural mor- neuroexcitatory effect of hydromorphone-3-glucuronide. Both
phine 0.025 and 0.05 mg/kg are equivalent in terms of analgesic unconjugated hydromorphone and its conjugated metabolites are
efficacy and duration of action (~7–8 h).68 Larger doses may result renally excreted. Approximately 6% of the parent drug is excreted
in a longer duration of action but will likely produce more severe in unconjugated form.89 The elimination half-life (t / ) of hydro-
1
2
side effects. A single dose of caudal morphine 30 μg/kg does not morphone is approximately 2.5 hours.83 In the presence of even
blunt the neuroendocrine stress response to surgery compared mild renal impairment, the plasma levels of hydromorphone-3-
with local anesthetic despite similar postoperative analgesia.73 glucuronide may reach 100 times that of the parent drug85 and may
Intrathecal morphine spreads in a cephalad direction with the flow potentially produce symptoms signs of opioid toxicity, including
of cerebrospinal fluid, reaching the brainstem within 6 hours after increasing pain.
administration. Thus, ventilatory depression is maximal 6 hours
after administration and lasts for over 18 hours.69 Infants do not
appear to be more sensitive to ventilatory depression than older
Pharmacodynamics
children.69 Doses of intrathecal morphine used in children un- The pharamcodynamic characteristics of hydromorphone are very
dergoing a variety of surgical procedures range from 2 to 30 μg/kg, similar to those of morphine, such that the World Health Orga-
but the trend is to use the lowest dose possible to minimize nization has recommended hydromorphone as the opioid alterna-
the incidence of side effects.74,75 The time to first postoperative tive to morphine. Hydromorphone provides equivalent analgesia
analgesic requirement appears to be dependent on the dose of to other potent opioids when given in equianalgesic doses for
intrathecal administered, with doses as low as 2 μg/kg showing chronic (primarily cancer-related) and acute (trauma, postopera-
benefit compared with placebo after pediatric scoliosis surgery.76 tive) pain.84,90
Although the administration of intrathecal morphine reduces Immediate-release hydromorphone has an onset of action of
postoperative opioid consumption, there does not appear to be a approximately 30 minutes and a duration of action of about
concomitant reduction in opioid-related side effects compared 4 hours. A typical oral dose is 40 to 80 μg/kg every 3 to 4 hours.
with intravenous opioids alone.76,77 The administration of intra- In children undergoing burn wound dressing care, immediate-
thecal morphine 5 μg/kg or higher, alone or with intrathecal release hydromorphone 60 μg/kg provided equivalent analgesia
sufenatnil, reduces intraoperative blood loss during scoliosis cor- to oral transmucosal fentanyl 10 μg/kg, with a low incidence of
rection surgery, possibly through a reduction of intraoperative side effects.91
mean arterial pressure.76–78 The onset of action of hydromorphone after intravenous
Morphine has been shown in animals to have a peripheral anal- administration is approximately 5 minutes, although peak effect
gesic effects via opioid receptors expressed in inflamed tissue.79,80 does not occur for 20 minutes owing to relatively low lipid solu-
Intra-articular injection in humans produces intense analgesia bility and delayed passage across the blood-brain barrier.46 Early
with no systemic absorption.81 studies described a lower incidence of side effects with hydro-
morphone than with morphine.92,93 However, a large systematic
review did not find any differences between the two opioids with
Hydromorphone respect to analgesic efficacy or side effect profile.90
Hydromorphone is a semisynthetic hydrogenated ketone deriva- The epidural–to–parenteral dose ratio of hydromorphone has
tive of morphine. Despite its similarities, hydromorphone is been estimated at 1:2.94 Hydromorphone may be preferable to
generally viewed as a second-line alternative to morphine and is either morphine or fentanyl for epidural administration in pedi-
often used as part of an opioid rotation in an attempt to improve atric patients.93 Epidural hydromorphone administered at 1 μg/
analgesia and reduce opioid-related side effects.82 kg/h provides equivalent analgesia to morphine with fewer side
effects and, potentially, may provide better analgesia than fentanyl
in cases in which the epidural catheter placement is not placed at
Pharmacokinetics the surgical level.93 When combined with local anesthetic, a
Oral hydromorphone is available in a liquid preparation and hydromorphone concentration of 10 μg/mL can be used.95 Caudal
immediate-release and controlled-release tablets. Oral bioavail- hydromorphone 10 μg/kg has been compared with caudal mor-
ability is approximately 60% with high interindividual variability83,84 phine 50 and 100 μg/kg in children undergoing urologic96 and
Maximum plasma levels are reached about 1 hour after ad- cardiac97 surgery, respectively. No significant differences in quality
ministration of an immediate-release dose83 and 4 to 6 hours after of analgesia and side effects were detected between the two
a controlled-release dose.85 The bioavailability of intranasal hydro- opioids.
morphone is approximately 55%, with a time to peak plasma
concentration of 20 to 25 minutes.46 The degree of lipid solubility
and Vd of hydromorphone (1.2 L/kg) are similar to that of mor- Meperidine
phine in adults.83,86 Approximately 7% of hydromorphone is protein Meperidine, or pethidine, is a synthetic opioid derived from
bound in adults.87 Systemic clearance of hydromorphone is de- phenylpiperidine.
pendent on hepatic blood flow and affinity to erythrocytes.87 The
clearance of hydromorphone in children shows great variability,
with a mean of 51 mL/kg/min88 compared with 14 mL/kg/min in Pharmacokinetics
adults.87 Hydromorphone is metabolized to hydromorphone-3- Meperidine can be administered orally in tablets and liquid form.
glucuronide in a ratio similar to that of morphine and morphine- Oral bioavailability is approximately 50%. The median steady-state
3β-glucuronide.85 This metabolite has been shown to produce volume of distribution in preterm and term neonates and infants
is 7.2 L/kg (range 3.3–11.0 L/kg),98 and 2.8 L/kg (standard devia- levels.113 Clearance of fentanyl is highest in infants, most likely
tion [sd] 0.6 L/kg) in children.99 Clearance of meperidine is ap- because of a higher hepatic blood flow per kilogram body weight.111
proximately 8 to 10 mLl/kg/min98 and is typically lower in Clearance in neonates correlates positively with postnatal age but
neonates and infants than in older children. Meperidine is is still greater than that in older children and adults.114 In patients
metabolized by N-demethylation to normeperidine, which is 50% with decreased hepatic blood flow or metabolic activity, such as
less active as meperidine as an analgesic but twice as active as a neonates undergoing abdominal surgery, clearance of fentanyl will
convulsant. Normeperidine is renally excreted or further meta- be reduced with a corresponding increase in the duration of
bolized to normeperidinic acid.60 Patients administered repeated action.115 Because of its high protein binding and lipid solubility,
doses of meperidine, particularly in the context of renal dys- large volume of distribution, and relatively high molecular weight,
function,100 are at increased risk of normeperidine accumulation fentanyl cannot be removed by hemodialysis.116 Metabolism of
and toxicity,101–103 which manifests as tremors, myoclonus, and fentanyl occurs in the liver by the CYP450 enzyme system. The
seizures. The metabolism of meperidine to normeperidine is activity level of this enzyme system reaches maturity within a few
approximately seven times less in neonates than adults.104 The weeks of birth and is not a significant limiting factor to metabolism
elimination t / in neonates and infants is also much longer (10.7 h,
1
2 and clearance. Fentanyl metabolites are inactive. Because fentanyl
range 3.3–59.4 h)98 than in older children (3.0 h, sd 0.5 h).99 has a high hepatic extraction ratio, its elimination is primarily
dependent on hepatic blood flow. A small amount of fentanyl is
Pharmacodynamics excreted unchanged by the kidneys and may accumulate in patients
with renal failure.116
The pharmacodynamic profile of meperidine is very similar to
that of morphine and offers no significant clinical benefits, other
than for the treatment of shivering. The negative aspects of Pharmacodynamics
meperidine have greatly reduced its use in children. These age-related differences in fentanyl pharmacokinetics trans-
The time to onset of analgesia of oral meperidine is approxi- late into different pharmacodynamics in pediatric patients com-
mately 15 to 30 minutes, with a time to peak plasma concentration pared with adults. For example, after cessation of a fentanyl
of 1 to 2 hours. infusion, the context-sensitive half-time for fentanyl elimination
Peak serum levels occur within 5 minutes after intravenous is significantly shorter in children.109 Despite larger bolus doses
administration in children.99 Meperidine is associated with fewer per kilogram body weight, plasma fentanyl concentrations are
opioid-related side effects than fentanyl when used for post- lower in infants than young children, which in turn, are lower than
operative analgesia in children.105 Meperidine has been used as part in adults.117 This translates into higher dose requirements for
of a “lytic cocktail” (meperidine-promethazine-chlorpromazine) children.117
to sedate children for nonpainful diagnostic procedures. However, A continuous infusion of fentanyl is commonly used to pro-
concerns regarding the safety of this mixture have been raised, with vide analgesia and sedation in mechanically ventilated pediatric
calls for strict guidelines for its use.106 Meperidine can be used patients. In this setting, fentanyl reduces the need for additional
to treat postoperative shivering, which appears to be mediated sedation and pharmacologic hemodynamic support118 and reduces
by binding to kappa opioid receptors.107 A smaller dose, such as markers of neuroendocrine stress response.119 Typical infusion rates
0.35 mg/kg, is usually effective.108 range from 0.5 to 2.5 μg/kg/h.118–120 A bolus dose of fentanyl 3 μg/kg
has been shown to reduce heart rate and measures of pain in
mechanically ventilated preterm neonates.121
Fentanyl Intravenous fentanyl for pediatric surgery blunts the peri-
Fentanyl, sufentanil, alfentanil, and remifentanil are synthe- operative hormonal stress response and provides greater hemo-
tic opioids belonging to the anilidopiperidine family of agents. dynamic stability compared to morphine.122 An initial bolus dose
These opioids have a higher potency of action that is selective for greater than 10 μg/kg has been shown to provide 75 to 90 minutes
the mu opioid receptor. of anesthesia in neonates,123 with a reduction in intraoperative and
postoperative catecholamine levels.124 Typical cumulative doses
for cardiac surgery are 50 to 150 μg/kg.122,125,126 The addition of a
Pharmacokinetics continuous fentanyl infusion at 10 μg/kg/h does not reduce the
The pharmacokinetics of fentanyl in children are best described by perioperative hormonal stress response compared with high-dose
a two-compartment model using both age and weight as cova- bolus fentanyl alone.125 Fentanyl 25 μg/kg, when combined with
riates.109 The bioavailability of fentanyl administered by the trans- low concentrations of isoflurane, may be as effective as much
mucosal route is approximately 33%.110 Fentanyl is highly lipid higher doses in controlling the neuroendocrine stress response
soluble compared with morphine and is widely distributed in and hemodynamic responses to surgical stimulation during the
tissues. The Vd at steady state is largest in term neonates and prebypass phase of pediatric cardiac surgery.126 Chest wall rigidity
infants, decreasing to mature levels by adolescence.111 Critically ill is a commonly mentioned side effect of rapid intravenous fentanyl
and neonates and children administered fentanyl by continuous administration in neonates and children. Doses as low as 2 μg/kg
infusion for longer than 24 hours have a larger steady-state volume can produce this effect.127 The mechanism may be increased
of distribution (15–17 L/kg) compared with children receiving muscle tone128 and can include muscles of the larynx,129 leading to
single-dose administration, with a resultant prolongation of the laryngospasm, and the tongue,127 resulting in complete airway
terminal elimination t / .111 Children with cyanotic heart disease
1
2 obstruction. The increase in muscle tone can be reversed with the
undergoing cardiac surgery have a smaller Vd and higher plasma administration of muscle relaxants or naloxone.129
fentanyl concentrations than adults.112 This appears to be related Because of its lipophilicity, epidural fentanyl does not spread
to the severity of hemodynamic disturbance as measured by PaO2 much beyond the level of administration and, therefore, must be
delivered at or near the level of surgery. Increasing the infusion Although drowsiness occurs in the majority (70%) of children,
rate to achieve analgesia at higher levels may result in higher respiratory depression appears to be much less common.149
fentanyl plasma levels, which may lead to opioid-related side Steady-state Vd is largest for neonates and infants younger than
effects. When compared with epidural morphine, the incidence 10 months of age (3.7–4.2 L/kg).141,145 By 2 to 8 years of age, the Vd
of side effects, such as nausea and vomiting and respiratory is reduced to approximately 2.9 L/kg,140 and in adults, this value
depression, are lower but the duration of analgesia is shorter.93 approaches 1.7 L/kg.143 Clearance of sufentanil is lowest in neo-
Epidural fentanyl is typically combined with local anesthetic at a nates and highest in infants and children,140,145 gradually decreas-
concentration 2 μg/mLl and provides improved analgesia coming to adult levels by 10 to 15 years of age.142,143 Therefore, larger
pared with local anesthetic alone.62,130 doses for maintenance of analgesia during surgery may be re-
Fentanyl is also available in an oral transmucosal formulation, quired in children.140 Clearance of sufentanil is reduced in children
which has been used for preoperative sedation and analgesia for with congenital heart disease.145
painful procedures or after injuries.91,131–133 Children are sedated The metabolism of sufentanil is mainly by O-demethylation
within 10 minutes of administration, but whether this translates and N-dealkylation in the liver. Decreased hepatic delivery will
into improved conditions at induction of anesthesia is controver- reduce sufentanil metabolism and clearance and increase elimi-
sial.110,134,135 Nausea or vomiting occurs in up to 30% of patients nation half-time.140 In children, increased levels of certain isozy-
and mild pruritus in up to 90%.134 Patients must be closely moni- mes of the CYP450 system have been reported,140 resulting in
tored for decreases in respiratory depression. Side effects are dose- enhanced metabolism and clearance of sufentanil compared with
dependent, and doses less than 15 μg/kg should be used in adolescents and adults. Renal elimination of sufentanil is minimal.
pediatric patients. Transmucosal fentanyl can also be administered In children with chronic renal failure, the Vd and rate of clearance
intranasally or by nebulizer. of unbound sufentanil are unchanged.142
The transdermal route offers an attractive method of fentanyl
administration in children with chronic stable opioid require- Pharmacodynamics
ments who cannot take oral medications or are not compliant with
Bolus doses of sufentanil 1 to 3 μg/kg reduce the response to
oral medications. Transdermal fentanyl patches are available in
surgical incision. Doses greater than 0.5 μg/kg used during short
12.5-, 25-, 50-, 75-, and 100-μg/h preparations. Conversion ratios
surgical procedures have been associated with a higher incidence
between intravenous and transdermal routes are controversial. In
of vomiting and respiratory depression.150 In pediatric cardiac
adults, a 1:1 conversion from intravenous to transdermal fentanyl
surgery, large doses of sufentanil 10 to 15 μg/kg have been used as
is generally recommended. Product monograph conversion ratios
an analgesic agent after induction145 and as the sole induction
for oral morphine to transdermal fentanyl appear to be very agent.141,144,145 Minimum serum levels of sufentanil required to
conservative (>100:1)136 compared with clinically determined maintain suppression of sympathetic-hemodynamic responses
ratios (70:1).137 Because the time to onset of analgesia is at least during cardiac surgery are greater for neonates than for infants,
12 hours, conversion to the transdermal route requires an overlap children, and adults.145 This suggests that the efficacy of sufentanil
of opioid therapies and should be done in a stepwise fashion.48 at mu opioid receptors may be reduced in neonates.
Children taking more than 30 mg/d of oral morphine can be Perioperative analgesia with epidural sufentanil 0.70 to 0.75 μg/
converted to transdermal fentanyl 12.5 μg/h. Compared with kg has been used successfully in children.149,151,152 The onset of
adults, children may take longer to reach steady-state plasma analgesia is rapid with a duration of over 3 hours.149 Administra-
concentrations, drug clearance is higher, and younger children tion of epidural sufentanil blunts the neuroendocrine stress
require comparatively higher doses.138 The suggested 72-hour response during cardiopulmonary bypass to a greater degree than
dosing schedule is probably not applicable in children and should intravenous sufantanil alone.152 Compared with fentanyl, epidural
be reduced to 48 hours instead.138 Given the limited doses available sufenatnil produces superior analgesia but a higher incidence of
and gradual onset and offset times, the transdermal route is not pruritus when administered as a continuous infusion.151
appropriate for the management of pain in the acute setting. In children, intranasal sufentanil has been used at a dose of 1.5
to 4.5 μg/kg with good effect for preoperative sedation and facili-
tates intubation after induction of anesthesia.153 A transdermal
Sufentanil formulation of sufentanil is currently under development. It has
Sufentanil is a synthetic opioid that is 5 to 10 times more potent the advantage over transdermal fentanyl in that it needs to be
than fentanyl.139 applied only once a week.
Pharmacokinetics Alfentanil
After intravenous administration, sufentanil plasma concentra- Alfentanil is a potent but short-acting synthetic opioid. Compared
tions decay biexponentially over time consistent with a two- with fentanyl, it has a fourfold shorter time to peak effect but
compartment pharmacokinetic model in some studies.140–142 In threefold reduced duration of action.154,155
other studies, the decay is more consistent with a triexponential,
three-compartment model.143–145 Maximum serum concentrations
are reached 10 minutes after an intranasal sufentanil dose of Pharmacokinetics
15 μg, with a bioavailability of approximately 56%.146 Epidural There is controversy as to whether a two-compartment or three-
sufentanil bolus doses between 10 and 75 μg are detectable in compartment model best describes alfentanil pharmacokinetics
serum within 2 to 5 minutes and can result in respiratory depres- in adults and children.156–161 Alfentanil has lower lipid solubility
sion in adults.147,148 In children, maximal serum levels occur than fentanyl and is highly protein-bound (>90%).157 Choice of
30 minutes after administration of epidural sufentanil 0.75 μg/kg. inhalational anesthetic agent and duration of anesthesia do not
affect alfentanil pharmacokinetics.162 The Vd of alfentanil has been pharmacokinetic parameters are more closely related to calcula-
reported to be 2.8 times greater in adults (0.57 L/kg) than in tions based on lean body mass than total body weight.172 Central
children (0.29 L/kg), presumably owing to lower body fat content Vd is 0.15 ± 0.099 L in a 70-kg adult.173 As with the other opioids,
in children.158 However, other studies in preterm infants and the Vd is largest in newborns (0.45 L/kg) and infants (0.31 L/kg),
children describe values similar to those in adults.161,163,160 Clear- decreasing to adult levels by age 2 years (0.24 L/kg).171 Plasma
ance is lowest in preterm infants (0.87 mL/kg/min)163 and com- levels decline in a biexponential fashion with an average distribu-
parable in infants (8.4 mL/kg/min),161 children (7.7–11.1 mL/kg/ tion t / (λ1) of 0.94 ± 0.57 minutes and average terminal t / (λ2)
1
2
1
2
min),161,164 and adults (5.9–7.6 mL/kg/min).161,164 Cardiopulmo- of 9.52 ± 3.95 minutes.173 Clearance is greatest in newborns
nary bypass increases the Vd, but clearance is not significantly and infants (90–92 mL/kg/min), gradually decreasing in child-
different.160,165 hood and adolescents (from 76 to 57 mL/kg/min) to adult levels
Alfentanil is rapidly eliminated by the liver through oxidation (46 mLl/kg/min).171 Clearance rates are not appreciably affected
(mono-oxygenase system)164 with only 1% excreted unchanged by by cardiopulmonary bypass.174 Because remifentanil is an anilo-
the kidneys. Both unbound (free) and bound fractions of alfen- piperidine with an ester tail,173 it undergoes ester hydrolysis by
tanil are extracted by the liver and metabolized.159 In liver failure, nonspecific serum and tissue esterases to a metabolite, GI90291,
there is reduced metabolism and clearance of alfentanil whereas which has a 4600-fold reduction in potency at the mu opioid
fentanyl, sufentanil, and remifentanil clearance is maintained.166 receptor.175–177 Patients with pseudocholinesterase deficiency have
The pharmacokinetic profile of alfentanil is unchanged in patients normal metabolism and clearance of remifentanil.178,179 Context-
with chronic renal failure.159 In patients with burn injuries, the sensitive t / and context-sensitive time for an 80% decrease in
1
2
unbound fraction, Vd, and clearance of alfentanil are decreased serum concentration of remifentanil are approximately 10 minutes
and elimination t / is increased.167 The elimination t / is shorter in
1
2
1
2
with infusion durations of up to 360 minutes.173 Elimination t / is 1
2
children compared with adults (63 min vs 95 min) owing to faster decreased in infants, children, and adolescents (3.4–3.7 min) com-
clearance and similar Vd.164 pared with neonates, preadolescents, and adults (5.3–5.7 min).171
Therefore, a higher infusion rate may be required in infants and
Pharmacodynamics young children.
Alfentanil has a faster onset and offset of action than fentanyl.
After a single bolus dose, redistribution is the most important Pharmacodynamics
mechanism for the termination of alfentanil’s effects, whereas Remifentanil is relatively selective for mu opioid receptors.180
elimination is more important after repeated doses or continuous However, activity at delta opioid receptors has been suggested in
infusion. Intravenous bolus doses of 10 to 100 μg/kg have been
the context of remifentanil-induced hyperalgesia and tolerance.181
used for induction of anesthesia in children.158,161,163,164,168,169 A
Compared with other anilidopiperidine opioids, remifentanil
minimum dose of 10 μg/kg is required for good to excellent
produces a deeper state of analgesia and anesthesia with more
intubation conditions.168 The pharmacokinetic profile of alfentanil
frequent episodes of bradycardia and hypotension.182 Postopera-
makes it an excellent choice for administration as a continuous
tive recovery and extubation times are shorter, but analgesia
infusion. The time to a 50% decrease in plasma levels of alfentanil
requirements are higher. Remifentanil does not increase the
gradually increases to approximately 60 minutes with infusion
incidence of postoperative nausea or vomiting in children or
durations of up to 3 hours, then remains relatively constant.170
Typical infusion rates are 1 to 3 μg/kg/min.165,169 For pediatric adults.182,183
cardiac surgery, bolus doses up to 200 μg/kg have been adminis- Remifentanil is particularly useful for neurosurgical anesthesia,
tered followed by repeat doses of 80 μg/kg, with patients ready for which requires agents that have minimal effects on intracranial
extubation 2 hours after surgery.160 Epidural alfentanil provides physiology and promote a rapid emergence from general anes-
only slightly better analgesia than intravenous alfentanil, with little thesia. With controlled ventilation, remifentanil does not increase
to no clinical advantage to its use.148 intracranial pressure in patients undergoing craniotomy184 and
does not affect cerebrospinal fluid formation or resorption rates.185
It has also been demonstrated to be useful in awake craniotomy
Remifentanil and for wake-up tests during corrective spinal procedures.186–188
Remifentanil is also beneficial for ophthalmologic surgery by
This highly potent opioid is the newest of the anilidopiperidine
reducing intraocular pressure, increasing intraocular compliance,
agents in use. It has a rapid onset of action and exceptionally short
and preventing increases in intraocular pressure associated with
T / . This property of remifentanil makes it particularly useful in
1
2
succinylcholine-facilitated intubation.189,190
neurosurgical and other procedures requiring intraoperative
wake-up tests, neuromonitoring, and rapid recovery of airway Remifentanil doses during sevoflurane anesthesia required to
reflexes at emergence from anesthesia. Pharmacodynamically, block both somatic and autonomic responses to surgical stimuli
remifentanil is similar to other opioids in terms of its ability to are higher in children 2 to 10 years old than in adults (0.22–0.27
produce analgesia, respiratory depression, nausea and vomiting, μg/kg/min vs 0.10–0.11 μg/kg/min, respectively).191
and somnolence. Remifentanil is administered almost exclusively There is a large safety margin in adults for remifentanil
by the intravenous route in clinical settings. Neuraxial administra- infusions of up to 2 μg/kg/min.177
tion in humans has not been reported. Remifentanil can also be administered as a bolus for intubation.
The calculated 95% effective dose (ED95) of remifentanil for
intubation without muscle relaxant with 5% sevoflurane in 100%
Pharmacokinetics oxygen is 0.75 μg/kg192 in children and 3 μg/kg with propofol
Unlike other opioids, remifentanil’s pharmacokinetics are highly 4 mg/kg in infants.193 Intranasal administration of remifentanil
predictable, with less interindividual variability.171 Remifentanil’s 4 μg/kg with sevoflurane 5% in nitrous oxide and oxygen provides
good to excellent intubating conditions in 92% of children after on spinal and peripheral nerves.207 Advantages of tramadol over
3 minutes.194 stronger opioids are a lower incidence of opioid-related side
The combination of remifentanil and propofol has been shown effects, with less than 10% of pediatric patients experiencing
to provide effective anesthesia in children undergoing short- nausea or vomiting and pruritus,208 and no clinically relevant
duration procedures such as lumbar puncture,195 esophagogastros- effects on heart rate or blood pressure. Excessive doses can result
copy,196 and radiologic imaging studies.197 The addition of a small in sympathomimetic side effects such as sweating, dysphoria, and
amount of remifentanil can greatly reduce the amount of propofol agitation. Tramadol increases the risk of seizure in patients taking
required, which may allow for more rapid emergence and shorter medications that lower the seizure threshold or those with a pre-
recovery times. existing seizure disorder.
Tramadol can be administered by parenteral, epidural/caudal,
oral, and rectal routes every 4 to 6 hours. Tramadol is formulated in
Tramadol tablet and liquid form, and a combined tramadol-acetaminophen
Tramadol is a synthetic derivative of codeine composed of two preparation is available. Larger dose appears to provide superior
enantiomers, (+) and (–) forms.198 Similar to other opioids, the analgesia with no increase in side effects.208
pharmacokinetic profile of tramadol is highly variable between Intermittent intravenous bolus doses should be administered
individuals. However, much of the variability is caused by poly- slowly to minimize side effects. When administered via a PCA
morphism of the enzyme responsible for metabolism and is not device, a bolus dose of tramadol 0.2 mg/kg has been used.209,210
age-related. The dose range for continuous intravenous infusion is 0.1 to
0.25 mg/kg/h. A pharmacokinetic study determined that an
analgesic serum concentration can be achieved with an intra-
Pharmacokinetics venous bolus of tramadol 1 mg/kg and maintained by an infusion
Tramadol bioavailability in adults is 68% after the first dose and 90 of 0.17 to 0.19 mg/kg/h in infants and children between 35 weeks
to 100% after subsequent doses.199 Absorption is more rapid in and 3 years of postconceptional age, decreasing to 0.12 mg/kg/h by
children than in adults.199 Maximum serum concentration is re- adulthood.201 This study, however, did not take into account
ached within 30 minutes after oral liquid tramadol 1.5 mg/kg and CYP450 2D6 polymorphism and its effects on analgesia mediated
remains above analgesic levels for 7 hours.200 The Vd reaches 120% by the O-desmethyltramadol metabolite.
of adult values by 1 year of age,201 then decreases to mature levels Tramadol has been injected into the caudal space for post-
(>2 L/kg) by 2 years of age.202 Tramadol and its metabolites are operative analgesia after pediatric herniorrhaphy and hypospadias
excreted primarily by the kidneys.203 Total body clearance is repair.211–214 The addition of tramadol 1.5 to 2 mg/kg to bupiva-
approximately 1.3 mL/kg/h in preterm neonates and reaches 84% caine increases the duration of analgesia threefold to greater than
of mature levels by 44 weeks of conceptional age.201 Clearance is 10 hours compared with bupivacaine alone with no increase in
highest in 2- to 8-year-olds (10.3 mL/kg/min).202 Tramadol is side effects.212 Caudal tramadol 2 mg/kg provides quality and
metabolized by CYP450 2D6 to 11 desmethylated compounds, of duration similar to those of caudal morphine 0.03 mg/kg.214 The
which O-demethyltramadol predominates.12,204 CYP450 2D6 prolonged duration of action of epidural tramadol is caused by
activity is detectable by 25 weeks of postconceptional age.201 slow diffusion across the dura to spinal cord receptors and not
Patients with decreased CYP450 2D6 enzyme function experience slow uptake into the systemic circulation.211 However, the risk of
reduced analgesic efficacy from tramadol and require higher doses neurotoxicity with tramadol in animals has not been determined.
of tramadol and more rescue analgesics for postoperative pain In addition, the efficacy and duration of analgesia between
relief.12,205 In a study of 82 neonates, only 24 expressed the wild- epidural/caudal and intravenous or oral routes are equivalent.215
type CYP450 2D6 polymorphism with normal activity.7 Of the For these reasons, it has been suggested that tramadol should not
remainder, 52 had “below-normal activity” polymorphisms and be administered by the epidural route in children.199
6 had “above-normal activity” polymorphisms. The degree of
tramadol metabolism correlated directly with CYP450 2D6 acti-
vity and gestational age. The elimination T / is approximately 3
1
2
Oxycodone
hours in children compared with greater than 5 hours in adults.202 Oxycodone is a semisynthetic opioid that is often administered in
combination with non-steroidal anti-inflammatory drugs such as
Pharmacodynamics acetaminophen and aspirin.
Tramadol produces analgesia through synergistic action of its
two enantiomers and their metabolites.204 The metabolite O- Pharmacokinetics
desmethyltramadol has an affinity for the mu opioid receptor that The pharmacokinetic profile of oxycodone is highly variable
is 200 to 300 times greater than that of the parent compound.199,204 between children of similar age and begins to approach that of
Thus, it is responsible for the majority of opioid-related analgesia. adults within the first few months of life.
The (+) enantiomer of tramadol is a weak agonist at mu opioid Oxycodone is available in tablet and liquid formulations. The
receptors and has almost no delta or kappa opioid receptor liquid form can be administered by orogastric and transmucosal
affinity.199 The (+) enantiomer inhibits the re-uptake and promotes (oral or nasal) routes.216 In infants and children, the time to peak
the release of serotonin, whereas the (–) enantiomer inhibits plasma concentration is similar for oral transmucosal and oro-
norepinephrine re-uptake and promotes its release.199 Because gastric routes (~200 min),217 with plasma levels detectable after
5-HT3 receptors play a role in the transmission of pain at the spinal 30 minutes and 60 minutes, respectively.217 Oral transmucosal
level, 5-HT3 antagonists may reduce the efficacy of tramadol.206 bioavailability is 55% compared with 37% for the orogastric
Some evidence indicates that tramadol has local anesthetic action route.217 There is no difference in the absorption characteristics
between oxycodone tablets or liquid.218 The pharmacokinetic there are no pharmacokinetic data from children younger than
profile of intranasal administration is similar to that of the oral 1 year of age. Values for Vd, elimination, and clearance are not
transmucosal route, with a bioavailability of 46% and median time dependent on age or weight in children 1 to 18 years of age.226 The
to peak plasma level of 25 minutes.216 The steady-state Vd (between bioavailability of oral methadone is approximately 80% in adults,
2 and 5 L/kg) is relatively constant across pediatric age groups219 with plasma levels detectable within 30 minutes of administra-
and is not significantly different from adult values.218 Similar to tion.227 Approximately 85% of the drug is bound to plasma
morphine, the lipid solubility of oxycodone is low, and protein proteins in adults.5 Methadone is very lipid soluble and, thus, has
binding is 38%.220 Clearance values increase with age but are highly a large volume of distribution (mean ± sd = 7.1 ± 2.5 L/kg in
variable, particularly in neonates (median 9.9 mL/min/kg, range children and 6.1 ± 2.4 L/kg in adults).228,229 The plasma clearance
2.3–17.2 mL/kg/min).219 After 2 months of age, values are similar rate of methadone in children 1 to 18 years of age is 5.4 ± 3.2
to those in older children and adults (10–15 mL/kg/min).219 mL/kg/min (mean ± sd), which is significantly lower than for
Oxycodone undergoes O-dealkylation by CYP450 2D6 to oxy- other opioids. Methadone is metabolized by N-demethylation in
morphone, which has mild intrinsic opioid activity and the liver to inactive pyrolidine and other metabolites that are
N-demethylation by CYP450 3A4 to noroxycodone, which has no excreted in the urine and bile, along with small amounts of the
opioid activity.60 Plasma levels of oxymorphone are undetectable parent drug.5 Acidification of the urine increases the amount of
in patients with normal renal function,221 and thus, it has no unchanged methadone excreted.5 The excretion of methadone is
significant pharmacodynamic effects. About 7% of oxycodone is unaffected by renal insufficiency. As oliguria worsens, increasing
excreted unchanged in the urine.221 The elimination T / of 1
2
amounts of methadone and metabolites are excreted in the bile,
oxycodone is inversely related to age and is especially variable in such that anuric patients excrete the entire daily amount of
neonates (median 4.4 hr, range 2.4–14.1 h).219 Values reach those methadone in the bile.230 Almost no methadone is removed from
of older children and adults (~2–3 h) within a few months of the plasma by hemodialysis.230
age.219 Renal dysfunction prolongs the elimination T / of oxy-
1
2
Plasma levels of methadone decrease in a biexponential fashion
codone and reduces the excretion of metabolites, such as oxy- after intravenous administration, with an initial rapid distribution
morphone, which may result in excessive opioid effects. phase followed by a long elimination phase. The distribution and
elimination T / are less in children (mean ± sd, 1.9 ± 0.88 min and
1
2
19.2 ± 13.6 min, respectively) than in adults (mean ± sd, 6.1 ± 5.7
Pharmacodynamics min and 35 ± 22 h, respectively).229
Although oxycodone is usually described as a mu opioid receptor
agonist, evidence from rats suggests that its antinociceptive effects Pharmacodynamics
may be mediated primarily by the kappa opioid receptor.222
Oxycodone has been extensively studied for the management of The clinical activity of methadone is caused almost exclusively by
acute, chronic, and cancer pain in adults. Relatively little data exist the R methadone isomer, which has a 10-time greater affinity than
on the use of oxycodone in children. S methadone for the mu1 and mu2 opioid receptors, and both have
Oxycodone is available in immediate-release and controlled- low affinity for delta and kappa opioid receptors.231
release formulations. Oral controlled-release oxycodone has been The duration of analgesia after a single oral dose of methadone
used in pediatric patients transitioned from intravenous PCA is approximately 4 hours, which reflects the short distribution T / .
1
2
morphine after scoliosis surgery.223 Pain control was equivalent, Reaching a steady-state plasma level may take between 2 and 10
and a greater number of patients reported no opioid-related side days of repeated doses owing to the large volume of distribution.232
effects when taking oxycodone. Once a steady-state concentration is reached, the dosing interval
Administration of a single dose of intravenous oxycodone 0.1 should be decreased from every 4 to 6 hours to 8 to 12 hours to
mg/kg to children after eye surgery results in a decrease in arterial avoid accumulation.
oxygen saturation and respiratory rate and a corresponding in- Oral methadone is used primarily for the management of
crease in end-tidal carbon dioxide levels in less than 8 minutes.224 cancer-related and other types of chronic pain in children233 and
The ventilatory depressant effects of oxycodone may be greater is usually started as an alternative to other opioids when inade-
than that of other opioids.225 quate pain relief or excessive opioid-related side effects are a
problem.234,235 The conversion to methadone often results in a
dramatic improvement in side effects and pain control, often with
Methadone a fraction of the equivalent morphine dose.234 Conversion ratios
Methadone is a synthetic opioid receptor agonist composed of a for morphine to methadone appear to vary inversely with the
racemic mixture of R and S enantiomers. Methadone has unique amount of morphine being administered (morphine-to-metha-
pharamcokinetic and pharmacodynamic properties, such as a long done ratio of 1:2 to 60:1).233 Thus, methadone may be particularly
elimination t / , and intrinsic NMDA receptor antagonist activity.
1
suitable for patients using high doses of mu opioid receptor
2
Agonism of the NMDA receptor is associated with hyperalgesia agonists owing to its higher intrinsic activity at the receptor, which
and opioid tolerance. These factors, among others, make metha- is inversely related to the degree of tolerance.236 Methadone has
done an excellent choice for patients with stable, chronic pain or been used to wean patients in the pediatric intensive care from
as an alternative when other opioids fail to provide adequate high-dose intravenous fentanyl infusions.237 The mean fentanyl
analgesia or produce intolerable side effects. dose at the start of the conversion was 5 μg/kg/h, and the mean
duration of fentanyl infusion was 18 days. The starting dose of
enteral methadone was approximately 0.5 mg/kg/d, and about one
Pharmacokinetics third of patients required an escalation in dose to 0.9 mg/kg/d.
Similar to other opioid drugs, there is substantial variability in the The median time to fentanyl discontinuation was 2.6 days and best
pharmacokinetic parameters of methadone among children, and correlated with the duration of fentanyl therapy.
Because of the rapid distribution but very slow elimination of in approximately 30 minutes.251 The Vd in children is 3.6 L/kg,
methadone, an intravenous loading dose large enough to maintain which is not significantly different from adults (4–5.5 L/kg).249
the plasma level above the minimal analgesic plasma concentra- Protein binding in young healthy adults has been estimated at
tion can provide prolonged postoperative analgesia.238 Methadone 50%.252 Clearance decreases with age from approximately 43 mL/
appears to have a slight advantage with respect to pain scores and kg/min in children to 23 mL/kg/min in elderly adults.249 Because
opioid consumption in the immediate postoperative period the Vd is constant but clearance decreases with age, the elimination
compared with equivalent doses of morphine given to children at t / of nalbuphine increases with age from 0.9 hours in children to
1
2
the start of surgery.41 However, administration of too large a dose over 2 hours in elderly adults.249 Neonates have the longest elimi-
of methadone (0.3 mg/kg) can result in significant postoperative nation t / at 4 hours owing to immature hepatic metabolic func-
1
2
hyperventilation or somnolence.41 Methadone produces a greater tion.253 Nalbuphine is extensively metabolized to two metabolites
and longer-lasting decrease in arterial oxygen saturation and and conjugates and is excreted primarily through the biliary
increase in exhaled CO2 than morphine or meperidine.225 system.252 Only 7% of a single dose is accounted for in the urine as
unchanged nalbuphine, its conjugates, and two metabolites.252
OPIOID AGONIST-ANTAGONISTS Pharmacodynamics

Mixed agonist-antagonist opioids are typically weak agonists at Currently, nalbuphine is available for parenteral administration
sigma and/or kappa opioid receptors and partial agonists or anta- only. Cumulative doses greater than 0.4 mg/kg fail to increase pain
gonists at the mu opioid receptor. As such, these drugs can pre- tolerance or reduce anesthetic requirements compared with mor-
cipitate opioid withdrawal in patients who have been receiving phine, suggesting a “ceiling effect” for analgesia.254,255 A similar
pure agonist opioids.239 An additional drawback to the use of effect occurs with respect to respiratory depression.256 Parenteral
mixed opioid agonists-antagonists is sex-related “antianalgesia.”240 nalbuphine has been used for preoperative sedation,245 intra-
Specifically, drugs that provide analgesia by predominantly kappa operative analgesia,257 and postoperative pain management in
opioid receptor activity provide significantly greater analgesia in children.130,258,259
women and may even cause increased pain in men, at lower doses. Although nalbuphine has gained popularity for the manage-
Co-administration of low-dose naloxone,241 morphine,242 or the ment of opioid-related side effects in adults, the only study in
sigma opioid receptor–active neuroleptics haloperidol and chlor- children showed no benefit with nalbuphine 50 μg/kg for the
promazine243 blocks the antianalgesic effects in males and may treatment of pruritus.31 In adults, a combination of morphine and
improve analgesia in females as well. nalbuphine administered in a 1:1 ratio via a PCA device may
provide the best balance of analgesia and prevention of pruritus.260
Pentazocine
Pharmacokinetics Buprenorphine
The pharmacokinetic parameters of pentazocine in children 4 to Buprenorphine is a semisynthetic derivative of thebaine.
8 years of age are similar to those in adults. The steady-state Vd is
4 L/kg with a clearance of 21 mL/kg/min and elimination t / of 1
2
Pharmacokinetics
3 hours. Over 85% of pentazocine is metabolized in the liver by
oxidation, and approximately 30% of the metabolites undergo Buprenorphine undergoes extensive first-pass metabolism, with
glucuronidation.244 an estimated oral bioavailability of 15% in adults.261 Sublingual
administration results in much higher plasma concentrations, with
an estimated bioavailability of over 50% in adults, but with
Pharmacodynamics significant interindividual variability.261 Buprenorphine is highly
Pentazocine has been used as a premedicant before surgery245 and (96%) bound to plasma proteins, with an estimated steady-state
for postoperative analgesia.246 A single intravenous dose provides Vd in children of 3.2 L/kg, which is similar to adults.262 Clearance
approximately 2.5 hours of analgesia.247 Pentazocine produces a is caused almost exclusively by hepatic extraction and metabolism.
quicker onset and greater change in respiratory parameters than Thus, patients with decreased hepatic blood flow will have a
roughly equipotent doses of morphine and meperidine, but other- prolonged duration of pharmacologic effect. Clearance after a
wise has a similar side effect profile.99,248 A ceiling effect for anal- single bolus dose in children is approximately 60 mL/kg/min,
gesia has been demonstrated with pentazocine 0.15 to 1.2 mg/ which is much higher than in adults.262 Buprenorphine undergoes
kg in adults. extensive hepatic metabolism to N-dealkylbuprenorphine (nor-
buprenorphine), which is considered to be an inactive metabolite.
The majority of buprenorphine and its metabolites are excreted
Nalbuphine through the biliary system, with the remainder eliminated in the
urine. The elimination t / in children aged 4 to 7 years is estimated
1
Pharmacokinetics 2
to be approximately 60 minutes compared with over 3 hours in

The bioavailability of oral nalbuphine increases with age, from adults.262 The difference is most likely caused by the higher rate of
11% in young adults to over 44% in elderly patients, presumably clearance in children.
because of the age-dependent decrease in hepatic blood flow.249
Peak plasma concentration of nalbuphine occurs approximately
1 hour after an oral dose (liquid or tablet).250 Intrarectal nalbu- Pharmacodynamics
phine administration appears to have greater bioavailability than Buprenorphine is a true partial agonist with higher affinity
the oral route with higher peak plasma concentrations achieved but weaker activity compared with morphine at the mu opioid
receptor.263 In animals, the dose-response curve of buprenorphine The usual starting dose for reversal of opioid-induced res-
exhibits a ceiling effect, and at doses above a certain level, the piratory depression in children is 0.01 mg/kg, with subsequent
pharmacologic effect may actually decrease with increasing dose.264 doses doubled until the desired clinical effect is achieved. Caution
Another unique feature of buprenorphine is the availability for must be used when administering naloxone to patients who have
sublingual administration with almost equal efficacy to the been receiving prolonged opioid therapy because a life-threatening
parenteral route, with an onset of analgesia within 30 to 60 minutes, withdrawal syndrome, characterized by tachycardia, tachypnea,
peak analgesic effect in 2 to 3 hours, and duration of analgesia of hypertension, dysrhythmias, anxiety, pupillary dilatation, and
6 to 9 hours.265 In adults, the administration of 0.4 mg sublingually sweating, can be precipitated.
provides similar analgesia to 0.2 to 0.3 mg of intramuscular bupre- The use of low-dose naloxone, administered intravenously as
norphine. Comparisons of buprenorphine and morphine for an infusion or mixed with opioids delivered by a PCA device or
postoperative pain in children demonstrated equivalent analgesic into the epidural space, can prevent or reduce the severity of some
efficacy with 1 to 2 hours longer mean duration of action with opioid-related side effects, particularly pruritus and nausea. In
buprenorphine.266,267 Sublingual buprenorphine, however, did not older children and adolescents receiving opioids for postoperative
have a similar long duration of action.266 The changes in ventilatory pain control, an infusion of naloxone at 0.25 μg/kg/h reduced the
parameters in children are greater with equianalgesic doses of incidence and severity of pruritus and nausea, but not vomiting,
buprenorphine than morphine.268 In particular, buprenorphine with no effect on analgesia or opioid consumption.30
causes a greater and longer-lasting decrease in respiratory rate, with
a later time to peak effect (45 min vs 11 min for morphine).268
Compared with parenteral buprenorphine, the caudal route SUMMARY
provides a much longer duration of analgesia (up to 24 hours), with Opioids remain the cornerstone of moderate to severe pain
a much lower incidence of nausea and vomiting.269,270 Doses for management in children, and a thorough understanding of
caudal buprenorphine are 2.5 to 4 μg/kg. Because of the high opioid pharmacology is necessary for the optimal use of these
binding affinity of buprenorphine for the mu opioid receptor, drugs. The “ultimate opioid,” one that offers intense analgesia with
reversal of buprenorphine-induced respiratory depression requires no side effects, has yet to be invented and may never be. Instead,
a relatively large dose of naloxone (~0.03–0.043 mg/kg) followed by the choice of opioid for an individual patient may depend on
an infusion (0.06 mg/h).271 Buprenorphine does not appear to have each person’s pharmacogenetic profile, which will be used to
any significant effects on cardiovascular parameters.267 predict which opioid will provide the greatest analgesia, at the
lowest dose, and with the least likelihood of side effects. Until
then, a rational approach to the use and choice of opioid therapy
OPIOID ANTAGONISTS should take into account factors such as intensity and duration
Naloxone of pain, available routes of administration, and patient age and
comorbidities, all of which can have a significant impact on
Naloxone has virtually no agonist activity at any of the opioid the pharmacokinetics and pharmacodynamics of a particular
receptors and reverses all opioid effects, including sedation, opioid.
respiratory depression, decreased gastrointestinal motility, and
analgesia.
REFERENCES
Pharmacokinetics 1. Inturrisi CE. Clinical pharmacology of opioids for pain. Clin J Pain.
2002;18:S3–S13.
Naloxone undergoes rapid glucuronidation in the liver with mini- 2. Law PY, Wong YH, Loh HH. Molecular mechanisms and regulation of
mal bioavailability after oral administration. Intramuscular injec- opioid receptor signaling. Annu Rev Pharmacol Toxicol. 2000;40:389–430.
tion of naloxone in term neonates produces peak plasma levels in 3. Pasternak GW. Pharmacological mechanisms of opioid analgesics. Clin
Neuropharmacol. 1993;16:1–18.
a mean time of 1.2 hours and acts as a “depot,” maintaining detect- 4. Thornton SR, Compton DR, Smith FL. Ontogeny of mu opioid agonist
able plasma levels for another 24 to 36 hours.272 The Vd and anti-nociception in postnatal rats. Brain Res Dev Brain Res. 1998;105:
clearance are approximately 2 L/kg and 10 mL/kg/min, respec- 269–276.
tively, in term neonates.272 Naloxone is primarily eliminated by 5. Olkkola KT, Hamunen K, Maunuksela EL. Clinical pharmacokinetics and
glucuronidation to naloxone-3-glucuronide.273 Because this meta- pharmacodynamics of opioid analgesics in infants and children. Clin
Pharmacokinet. 1995;28:385–404.
bolic pathway is typically deficient at birth, the elimination t / is
1
2
6. Younis RT, Lazar RH. History and current practice of tonsillectomy.
much longer in neonates than in adults (2.5–3.5 h vs 1 h, Laryngoscope. 2002;112:3–5.
respectively).272 7. Allegaert K, van Schaik RH, Vermeersch S, et al. Postmenstrual age and
CYP2D6 polymorphisms determine tramadol O-demethylation in criti-
cally ill neonates and infants. Pediatr Res. 2008;63:674–679.
Pharamcodynamics 8. Lotsch J, Skarke C, Liefhold J, et al. Genetic predictors of the clinical
response to opioid analgesics: clinical utility and future perspectives. Clin
The rapid onset of opioid antagonism is related to the high lipid Pharmacokinet. 2004;43:983–1013.
solubility of naloxone which allows for high concentrations to be 9. Koren G, Cairns J, Chitayat D, et al. Pharmacogenetics of morphine
rapidly achieved in the brain.274 For this same reason, the short poisoning in a breastfed neonate of a codeine-prescribed mother. Lancet.
duration of action of naloxone can be attributed to its rapid 2006;368:704.
diffusion from the central nervous system. Therefore, repeat bolus 10. Voronov P, Przybylo HJ, Jagannathan N. Apnea in a child after oral
codeine: a genetic variant—an ultra-rapid metabolizer. Paediatr Anaesth.
doses or an infusion may be required to prevent renarcotization 2007;17:684–687.
when the anatgonistic effects of naloxone wane in the presence of 11. Anderson BJ, Palmer GM. Recent developments in the pharmacological
a longer-acting opioid. management of pain in children. Curr Opin Anaesthesiol. 2006;19:285–292.
12. Lotsch J, Geisslinger G. Are mu-opioid receptor polymorphisms impor- 38. Herzog TJ, Coleman RL, Guerrieri JP Jr, et al. A double-blind, rando-
tant for clinical opioid therapy? Trends Mol Med. 2005;11:82–89. mized, placebo-controlled phase III study of the safety of alvimopan in
13. Bouwmeester NJ, Hop WC, van Dijk M, et al. Postoperative pain in the patients who undergo simple total abdominal hysterectomy. Am J Obstet
neonate: age-related differences in morphine requirements and meta- Gynecol. 2006;195:445–453.
bolism. Intensive Care Med. 2003;29:2009–2015. 39. Viscusi ER, Goldstein S, Witkowski T, et al. Alvimopan, a peripherally
14. Yaster M, Kost-Bayerly S, Maxwell LG. Opioid agonist and antagonists. In: acting mu-opioid receptor antagonist, compared with placebo in post-
Schechter NL, Berde CB, Yaster M, editors. Pain in Infants, Children and operative ileus after major abdominal surgery: results of a randomized,
Adolescents. 2nd ed. Baltimore: Lippincott Williams & Wilkins; 2003, double-blind, controlled study. Surg Endosc. 2006;20:64–70.
p. 181–225. 40. Pereira J, Lawlor P, Vigano A, et al. Equianalgesic dose ratios for opioids.
15. Foldes FF, Shiffman HP, Kronfeld PP. The use of fentanyl, meperidine or a critical review and proposals for long-term dosing. J Pain Symptom
alphaprodine for neuroleptanesthesia. Anesthesiology. 1970;33:35–42. Manage. 2001;22:672–687.
16. Chanavaz C, Tirel O, Wodey E, et al. Haemodynamic effects of remifen- 41. Berde CB, Beyer JE, Bournaki MC, et al. Comparison of morphine and
tanil in children with and without intravenous atropine. An echocardio- methadone for prevention of postoperative pain in 3- to 7-year-old
graphic study. Br J Anaesth. 2005;94:74–79. children. J Pediatr. 1991;119:136–141.
17. Briassoulis G, Spanaki AM, Vassilaki E, et al. Potentially life-threatening 42. Weldon BC, Connor M, White PF. Pediatric PCA: the role of concurrent
bradycardia after remifentanil infusion in a child. Acta Anaesthesiol Scand. opioid infusions and nurse-controlled analgesia. Clin J Pain. 1993;9:
2007;51:1130. 26–33.
18. Stanley TH, Liu WS. Cardiovascular effects of meperidine-N2O anesthesia 43. Dumas EO, Pollack GM. Opioid tolerance development: a pharmaco-
before and after pancuronium. Anesth Analg. 1977;56:669–673. kinetic/pharmacodynamic perspective. AAPS J. 2008;10:537–551.
19. Flacke JW, Flacke WE, Bloor BC, et al. Histamine release by four narco- 44. Pasternak GW. Incomplete cross tolerance and multiple mu opioid
tics: a double-blind study in humans. Anesth Analg. 1987;66:723–730. peptide receptors. Trends Pharmacol Sci. 2001;22:67–70.
20. Manara L, Bianchi G, Ferretti P, et al. Inhibition of gastrointestinal transit 45. Johnson SM, Fleming WW. Mechanisms of cellular adaptive sensitivity
by morphine in rats results primarily from direct drug action on gut changes: applications to opioid tolerance and dependence. Pharmacol Rev.
opioid sites. J Pharmacol Exp Ther. 1986;237:945–949. 1989;41:435–488.
21. Ling GS, Paul D, Simantov R, et al. Differential development of acute 46. Coda B, Tanaka A, Jacobson RC, et al. Hydromorphone analgesia after
tolerance to analgesia, respiratory depression, gastrointestinal transit intravenous bolus administration. Pain. 1997;71:41–48.
and hormone release in a morphine infusion model. Life Sci. 1989;45: 47. Vetter TR. Pediatric patient-controlled analgesia with morphine versus
1627–1636. meperidine 13. J Pain Symptom Manage. 1992;7:204–208.
22. Thune A, Baker RA, Saccone GT, et al. Differing effects of pethidine and 48. Patanwala AE, Duby J, Waters D, et al. Opioid conversions in acute care.
morphine on human sphincter of Oddi motility. Br J Surg. 1990;77: Ann Pharmacother. 2007;41:255–266.
992–995. 49. Anand KJ, Anderson BJ, Holford NH, et al. Morphine pharmacokinetics
23. Thompson DR. Narcotic analgesic effects on the sphincter of Oddi: a and pharmacodynamics in preterm and term neonates: secondary results
review of the data and therapeutic implications in treating pancreatitis.
from the NEOPAIN trial. Br J Anaesth. 2008;101:680–689.
Am J Gastroenterol. 2001;96:1266–1272.
50. McRorie TI, Lynn AM, Nespeca MK, et al. The maturation of morphine
24. McCammon RL, Stoelting RK, Madura JA. Effects of butorphanol,
clearance and metabolism. Am J Dis Child. 1992;146:972–976.
nalbuphine, and fentanyl on intrabiliary tract dynamics. Anesth Analg.
51. Choonara IA, McKay P, Hain R, et al. Morphine metabolism in children.
1984;63:139–142.
Br J Clin Pharmacol. 1989;28:599–604.
25. Kovac AL. Management of postoperative nausea and vomiting in
52. Lynn AM, Slattery JT. Morphine pharmacokinetics in early infancy.
children. Paediatr Drugs. 2007;9:47–69.
Anesthesiology. 1987;66:136–139.
26. Verhamme KM, Sturkenboom MC, Stricker BH, et al. Drug-induced
urinary retention: incidence, management and prevention. Drug Saf. 53. Pokela ML, Olkkola KT, Seppala T, et al. Age-related morphine kinetics
2008;31:373–388. in infants. Dev Pharmacol Ther. 1993;20:26–34.
27. Ganesh A, Maxwell LG. Pathophysiology and management of opioid- 54. Stanski DR, Greenblatt DJ, Lowenstein E. Kinetics of intravenous and
induced pruritus. Drugs. 2007;67:2323–2333. intramuscular morphine. Clin Pharmacol Ther. 1978;24:52–59.
28. Gillman PK. Monoamine oxidase inhibitors, opioid analgesics and 55. Brunk SF, Delle M. Morphine metabolism in man. Clin Pharmacol Ther.
serotonin toxicity. Br J Anaesth. 2005;95:434–441. 1974;16:51–57.
29. Karunatilake H, Buckley NA. Serotonin syndrome induced by fluvoxa- 56. Bhat R, Abu-Harb M, Chari G, et al. Morphine metabolism in acutely ill
mine and oxycodone. Ann Pharmacother. 2006;40:155–157. preterm newborn infants. J Pediatr. 1992;120:795–799.
30. Maxwell LG, Kaufmann SC, Bitzer S, et al. The effects of a small-dose 57. Coffman BL, Rios GR, King CD, et al. Human UGT2B7 catalyzes
naloxone infusion on opioid-induced side effects and analgesia in morphine glucuronidation. Drug Metab Dispos. 1997;25:1–4.
children and adolescents treated with intravenous patient-controlled 58. Jaffe JH, Martin WR. Opioid analgesics and antagonists. In: Goodman
analgesia: a double-blind, prospective, randomized, controlled study. and Gilman’s: The Pharmacological Basis of Therapeutics. New York:
Anesth Analg. 2005;100:953–958. Pergamon Press; 1990. pp. 485–521.
31. Nakatsuka N, Minogue SC, Lim J, et al. Intravenous nalbuphine 50 microg 59. Skarke C, Darimont J, Schmidt H, et al. Analgesic effects of morphine
× kg(–1) is ineffective for opioid-induced pruritus in pediatrics. Can J and morphine-6-glucuronide in a transcutaneous electrical pain model in
Anaesth. 2006;53:1103–1110. healthy volunteers. Clin Pharmacol Ther. 2003;73:107–121.
32. Kjellberg F, Tramer MR. Pharmacological control of opioid-induced 60. Lotsch J. Opioid metabolites. J Pain Symptom Manage. 2005;29:S10–S24.
pruritus: a quantitative systematic review of randomized trials. Eur J 61. Paul D, Bodnar RJ, Gistrak MA, et al. Different mu receptor subtypes
Anaesthesiol. 2001;18:346–357. mediate spinal and supraspinal analgesia in mice. Eur J Pharmacol.
33. Lee J, Shim JY, Choi JH, et al. Epidural naloxone reduces intestinal 1989;168:307–314.
hypomotility but not analgesia of epidural morphine. Can J Anaesth. 62. Kart T, Christrup LL, Rasmussen M. Recommended use of morphine in
2001;48:54–58. neonates, infants and children based on a literature review: part 2—
34. Liu M, Wittbrodt E. Low-dose oral naloxone reverses opioid-induced clinical use. Paediatr Anaesth. 1997;7:93–101.
constipation and analgesia. J Pain Symptom Manage. 2002;23:48–53. 63. Lynn A, Nespeca MK, Bratton SL, et al. Clearance of morphine in post-
35. McNicol ED, Boyce D, Schumann R, et al. Mu-opioid antagonists for operative infants during intravenous infusion: the influence of age and
opioid-induced bowel dysfunction. Cochrane Database Syst Rev. 2008; surgery. Anesth Analg. 1998;86:958–963.
2:CD006332. 64. Bouwmeester NJ, Anderson BJ, Tibboel D, et al. Developmental pharma-
36. Yuan CS. Methylnaltrexone mechanisms of action and effects on opioid cokinetics of morphine and its metabolites in neonates, infants and young
bowel dysfunction and other opioid adverse effects. Ann Pharmacother. children. Br J Anaesth. 2004;92:208–217.
2007;41:984–993. 65. Lynn AM, Nespeca MK, Bratton SL, et al. Intravenous morphine in post-
37. Yuan CS, Wei G, Foss JF, et al. Effects of subcutaneous methylnaltrexone operative infants: intermittent bolus dosing versus targeted continuous
on morphine-induced peripherally mediated side effects: a double-blind infusions. Pain. 2000;88:89–95.
randomized placebo-controlled trial. J Pharmacol Exp Ther. 2002;300: 66. El Sayed MF, Taddio A, Fallah S, et al. Safety profile of morphine following
118–123. surgery in neonates. J Perinatol. 2007;27:444–447.
67. McDonald AJ, Cooper MG. Patient-controlled analgesia: an appropriate 93. Goodarzi M. Comparison of epidural morphine, hydromorphone and
method of pain control in children. Paediatr Drugs. 2001;3:273–284. fentanyl for postoperative pain control in children undergoing orth-
68. Haberkern CM, Lynn AM, Geiduschek JM, et al. Epidural and intrave- opaedic surgery. Paediatr Anaesth. 1999;9:419–422.
nous bolus morphine for postoperative analgesia in infants. Can J 94. Halpern SH, Arellano R, Preston R, et al. Epidural morphine vs hydro-
Anaesth. 1996;43:1203–1210. morphone in post-caesarean section patients. Can J Anaesth. 1996;43:
69. Nichols DG, Yaster M, Lynn AM, et al. Disposition and respiratory effects 595–598.
of intrathecal morphine in children. Anesthesiology. 1993;79:733–738. 95. Tobias JD, Gaines RW, Lowry KJ, et al. A dual epidural catheter technique
70. Chabas E, Gomar C, Villalonga A, et al. Postoperative respiratory function to provide analgesia following posterior spinal fusion for scoliosis in
in children after abdominal surgery. A comparison of epidural and children and adolescents. Paediatr Anaesth. 2001;11:199–203.
intramuscular morphine analgesia. Anaesthesia. 1998;53:393–397. 96. Vetter TR, Carvallo D, Johnson JL, et al. A comparison of single-dose
71. Demiraran Y, Kocaman B, Akman RY. A comparison of the postoperative caudal clonidine, morphine, or hydromorphone combined with ropiva-
analgesic efficacy of single-dose epidural tramadol versus morphine in caine in pediatric patients undergoing ureteral reimplantation. Anesth
children. Br J Anaesth. 2005;95:510–513. Analg. 2007;104:1356–1363, table.
72. Leong CK, Ng AS, Chew SL. Caudal morphine in paediatric patients: a 97. Lavoie J. European Society of Anaesthesiologists Annual Congress.
comparison of two different doses in children after major urogenital London, 1–5 June 1996 [abstracts]. Br J Anaesth. 1996;76(Suppl 2):1–146.
surgery. Ann Acad Med Singapore. 1998;27:371–375. 98. Pokela ML, Olkkola KT, Koivisto M, et al. Pharmacokinetics and
73. Teyin E, Derbent A, Balcioglu T, et al. The efficacy of caudal morphine or pharmacodynamics of intravenous meperidine in neonates and infants.
bupivacaine combined with general anesthesia on postoperative pain and Clin Pharmacol Ther. 1992;52:342–349.
neuroendocrine stress response in children. Paediatr Anaesth. 2006;16: 99. Hamunen K, Maunuksela EL, Seppala T, et al. Pharmacokinetics of i.v.
290–296. and rectal pethidine in children undergoing ophthalmic surgery. Br J
74. Ganesh A, Rose JB, Wells L, et al. Continuous peripheral nerve blockade Anaesth. 1993;71:823–826.
for inpatient and outpatient postoperative analgesia in children. Anesth 100. Hassan H, Bastani B, Gellens M. Successful treatment of normeperidine
Analg. 2007;105:1234–1242, table. neurotoxicity by hemodialysis. Am J Kidney Dis. 2000;35:146–149.
75. Suominen PK, Ragg PG, McKinley DF, et al. Intrathecal morphine pro- 101. Danziger LH, Martin SJ, Blum RA. Central nervous system toxicity
vides effective and safe analgesia in children after cardiac surgery. Acta associated with meperidine use in hepatic disease. Pharmacotherapy.
Anaesthesiol Scand. 2004;48:875–882. 1994;14:235–238.
76. Gall O, Aubineau JV, Berniere J, et al. Analgesic effect of low-dose intra- 102. Adair JC, Gilmore RL. Meperidine neurotoxicity after organ trans-
thecal morphine after spinal fusion in children. Anesthesiology. 2001;94: plantation. J Toxicol Clin Toxicol. 1994;32:325–328.
447–452. 103. Saneto RP, Fitch JA, Cohen BH. Acute neurotoxicity of meperidine in an
77. Eschertzhuber S, Hohlrieder M, Keller C, et al. Comparison of high- and infant. Pediatr Neurol. 1996;14:339–341.
low-dose intrathecal morphine for spinal fusion in children. Br J Anaesth. 104. Caldwell J, Notarianni LJ. Disposition of pethidine in childbirth. Br J
2008;100:538–543. Anaesth. 1978;50:307–308.
78. Goodarzi M. The advantages of intrathecal opioids for spinal fusion in 105. Kotiniemi LH, Ryhanen PT, Valanne J, et al. Postoperative symptoms at
children. Paediatr Anaesth. 1998;8:131–134. home following day-case surgery in children: a multicentre survey of
79. Cox BM, Pasternak GW. Peripheral actions mediated by opioid receptors. 551 children. Anaesthesia. 1997;52:963–969.
In: Pasternak GW. (ed). The Opiate Receptors. Livingston, NJ: Humana 106. Cook BA, Bass JW, Nomizu S, et al. Sedation of children for technical
Press; 1988. pp. 357–488. procedures: current standard of practice. Clin Pediatr (Phila). 1992;31:
80. Stein C, Millan MJ, Shippenberg TS, et al. Peripheral opioid receptors 137–142.
mediating antinociception in inflammation. Evidence for involvement 107. Kurz M, Belani KG, Sessler DI, et al. Naloxone, meperidine, and
of mu, delta and kappa receptors. J Pharmacol Exp Ther. 1989;248: shivering. Anesthesiology. 1993;79:1193–1201.
1269–1275. 108. Kranke P, Eberhart LH, Roewer N, et al. Postoperative shivering in
81. Stein C, Comisel K, Haimerl E, et al. Analgesic effect of intra-articular children: a review on pharmacologic prevention and treatment. Paediatr
morphine after arthroscopic knee surgery. N Engl J Med. 1991;325:1123–1126. Drugs. 2003;5:373–383.
82. Katcher J, Walsh D. Opioid-induced itching: morphine sulfate and 109. Ginsberg B, Howell S, Glass PS, et al. Pharmacokinetic model-driven
hydromorphone hydrochloride. J Pain Symptom Manage. 1999;17:70–72. infusion of fentanyl in children. Anesthesiology. 1996;85:1268–1275.
83. Vallner JJ, Stewart JT, Kotzan JA, et al. Pharmacokinetics and bioavail- 110. Dsida RM, Wheeler M, Birmingham PK, et al. Premedication of
ability of hydromorphone following intravenous and oral administration pediatric tonsillectomy patients with oral transmucosal fentanyl citrate.
to human subjects. J Clin Pharmacol. 1981;21:152–156. Anesth Analg. 1998;86:66–70.
84. Murray A, Hagen NA. Hydromorphone. J Pain Symptom Manage. 2005; 111. Katz R, Kelly HW. Pharmacokinetics of continuous infusions of fentanyl
29:S57–S66. in critically ill children. Crit Care Med. 1993;21:995–1000.
85. Babul N, Darke AC, Hain R. Hydromorphone and metabolite pharma- 112. Koren G, Goresky G, Crean P, et al. Pediatric fentanyl dosing based on
cokinetics in children. J Pain Symptom Manage. 1995;10:335–337. pharmacokinetics during cardiac surgery. Anesth Analg. 1984;63:577–582.
86. Coda BA, Rudy AC, Archer SM, et al. Pharmacokinetics and bioavail- 113. Koren G, Goresky G, Crean P, et al. Unexpected alterations in fentanyl
ability of single-dose intranasal hydromorphone hydrochloride in healthy pharmacokinetics in children undergoing cardiac surgery: age related
volunteers. Anesth Analg. 2003;97:117–123, table. or disease related? Dev Pharmacol Ther. 1986;9:183–191.
87. Parab PV, Ritschel WA, Coyle DE, et al. Pharmacokinetics of hydromor- 114. Santeiro ML, Christie J, Stromquist C, et al. Pharmacokinetics of con-
phone after intravenous, peroral and rectal administration to human tinuous infusion fentanyl in newborns. J Perinatol. 1997;17:135–139.
subjects. Biopharm Drug Dispos. 1988;9:187–199. 115. Gauntlett IS, Fisher DM, Hertzka RE, et al. Pharmacokinetics of fentanyl
88. Collins JJ, Geake J, Grier HE, et al. Patient-controlled analgesia for in neonatal humans and lambs: effects of age. Anesthesiology. 1988;69:
mucositis pain in children: a three-period crossover study comparing 683–687.
morphine and hydromorphone. J Pediatr. 1996;129:722–728. 116. Dean M. Opioids in renal failure and dialysis patients. J Pain Symptom
89. Cone EJ, Phelps BA, Gorodetzky CW. Urinary excretion of hydromor- Manage. 2004;28:497–504.
phone and metabolites in humans, rats, dogs, guinea pigs, and rabbits. J 117. Singleton MA, Rosen JI, Fisher DM. Plasma concentrations of fentanyl
Pharm Sci. 1977;66:1709–1713. in infants, children and adults. Can J Anaesth. 1987;34:152–155.
90. Quigley C. Hydromorphone for acute and chronic pain. Cochrane Data- 118. Roth B, Schlunder C, Houben F, et al. Analgesia and sedation in neonatal
base Syst Rev. 2002;1:CD003447. intensive care using fentanyl by continuous infusion. Dev Pharmacol
91. Sharar SR, Bratton SL, Carrougher GJ, et al. A comparison of oral Ther. 1991;17:121–127.
transmucosal fentanyl citrate and oral hydromorphone for inpatient 119. Orsini AJ, Leef KH, Costarino A, et al. Routine use of fentanyl infusions
pediatric burn wound care analgesia. J Burn Care Rehabil. 1998;19: for pain and stress reduction in infants with respiratory distress
516–521. syndrome. J Pediatr. 1996;129:140–145.
92. Rapp SE, Egan KJ, Ross BK, et al. A multidimensional comparison of 120. Hartwig S, Roth B, Theisohn M. Clinical experience with continuous
morphine and hydromorphone patient-controlled analgesia. Anesth intravenous sedation using midazolam and fentanyl in the paediatric
Analg. 1996;82:1043–1048. intensive care unit. Eur J Pediatr. 1991;150:784–788.
121. Guinsburg R, Kopelman BI, Anand KJ, et al. Physiological, hormonal, 147. Koren G, Sandler AN, Klein J, et al. Relationship between the phar-
and behavioral responses to a single fentanyl dose in intubated and macokinetics and the analgesic and respiratory pharmacodynamics of
ventilated preterm neonates. J Pediatr. 1998;132:954–959. epidural sufentanil. Clin Pharmacol Ther. 1989;46:458–462.
122. Bovill JG, Sebel PS, Stanley TH. Opioid analgesics in anesthesia: with 148. Coda BA, Brown MC, Schaffer R, et al. Pharmacology of epidural
special reference to their use in cardiovascular anesthesia. Anesthesiology. fentanyl, alfentanil, and sufentanil in volunteers. Anesthesiology. 1994;81:
1984;61:731–755. 1149–1161.
123. Yaster M. The dose response of fentanyl in neonatal anesthesia. 149. Benlabed M, Ecoffey C, Levron JC, et al. Analgesia and ventilatory res-
Anesthesiology. 1987;66:433–435. ponse to CO2 following epidural sufentanil in children. Anesthesiology.
124. Anand KJ, Sippell WG, Aynsley-Green A. Pain, anaesthesia, and babies. 1987;67:948–951.
Lancet. 1987;2:1210. 150. Glenski JA, Friesen RH, Lane GA, et al. Low-dose sufentanil as a sup-
125. Gruber EM, Laussen PC, Casta A, et al. Stress response in infants plement to halothane/N2O anaesthesia in infants and children. Can J
undergoing cardiac surgery: a randomized study of fentanyl bolus, Anaesth. 1988;35:379–384.
fentanyl infusion, and fentanyl-midazolam infusion. Anesth Analg. 2001; 151. Cho JE, Kim JY, Kim JE, et al. Epidural sufentanil provides better anal-
92:882–890. gesia from 24 h after surgery compared with epidural fentanyl in
126. Duncan HP, Cloote A, Weir PM, et al. Reducing stress responses in the children. Acta Anaesthesiol Scand. 2008;52:1360–1363.
pre-bypass phase of open heart surgery in infants and young children: a 152. Bichel T, Rouge JC, Schlegel S, et al. Epidural sufentanil during paediatric
comparison of different fentanyl doses. Br J Anaesth. 2000;84:556–564. cardiac surgery: effects on metabolic response and postoperative out-
127. Muller P, Vogtmann C. Three cases with different presentation of come. Paediatr Anaesth. 2000;10:609–617.
fentanyl-induced muscle rigidity—a rare problem in intensive care of 153. Henderson JM, Brodsky DA, Fisher DM, et al. Pre-induction of anes-
neonates. Am J Perinatol. 2000;17:23–26. thesia in pediatric patients with nasally administered sufentanil.
128. Marty J, Desmonts JM. Effects of fentanyl on respiratory pressure- Anesthesiology. 1988;68:671–675.
volume relationship in supine anesthetized children. Acta Anaesthesiol 154. Cookson RF, Niemegeers CJ, Vanden BG. The development of alfentanil.
Scand. 1981;25:293–296. Br J Anaesth. 1983;55(Suppl 2):147S–155S.
129. Fahnenstich H, Steffan J, Kau N, et al. Fentanyl-induced chest wall 155. Brown JH, Pleuvry BJ, Kay B. Respiratory effects of a new opiate
rigidity and laryngospasm in preterm and term infants. Crit Care Med. analgesic, R 39209, in the rabbit: comparison with fentanyl. Br J Anaesth.
2000;28:836–839. 1980;52:1101–1106.
130. Ganesh A, Adzick NS, Foster T, et al. Efficacy of addition of fentanyl to 156. Hull CJ. The pharmacokinetics of alfentanil in man. Br J Anaesth.
epidural bupivacaine on postoperative analgesia after thoracotomy for 1983;55(Suppl 2):157S–164S.
lung resection in infants. Anesthesiology. 2008;109:890–894. 157. Bovill JG, Sebel PS, Blackburn CL, et al. The pharmacokinetics of
131. Mahar PJ, Rana JA, Kennedy CS, et al. A randomized clinical trial of oral alfentanil (R39209): a new opioid analgesic. Anesthesiology. 1982;57:
transmucosal fentanyl citrate versus intravenous morphine sulfate for 439–443.
initial control of pain in children with extremity injuries. Pediatr Emerg 158. Meistelman C, Saint-Maurice C, Lepaul M, et al. A comparison of
Care. 2007;23:544–548.
alfentanil pharmacokinetics in children and adults. Anesthesiology.
132. Miner JR, Kletti C, Herold M, et al. Randomized clinical trial of nebu-
1987;66:13–16.
lized fentanyl citrate versus i.v. fentanyl citrate in children presenting to
159. Chauvin M, Lebrault C, Levron JC, et al. Pharmacokinetics of alfentanil
the emergency department with acute pain. Acad Emerg Med. 2007;
in chronic renal failure. Anesth Analg. 1987;66:53–56.
14:895–898.
160. den Hollander JM, Hennis PJ, Burm AG, et al. Pharmacokinetics of
133. Borland M, Jacobs I, King B, et al. A randomized controlled trial com-
alfentanil before and after cardiopulmonary bypass in pediatric patients
paring intranasal fentanyl to intravenous morphine for managing acute
pain in children in the emergency department. Ann Emerg Med. 2007; undergoing cardiac surgery: part I. J Cardiothorac Vasc Anesth. 1992;6:
49:335–340. 308–312.
134. Epstein RH, Mendel HG, Witkowski TA, et al. The safety and efficacy of 161. Goresky GV, Koren G, Sabourin MA, et al. The pharmacokinetics of
oral transmucosal fentanyl citrate for preoperative sedation in young alfentanil in children. Anesthesiology. 1987;67:654–659.
children. Anesth Analg. 1996;83:1200–1205. 162. Maitre PO, Vozeh S, Heykants J, et al. Population pharmacokinetics
135. Feld LH, Champeau MW, van Steennis CA, et al. Preanesthetic medi- of alfentanil: the average dose-plasma concentration relationship
cation in children: a comparison of oral transmucosal fentanyl citrate and interindividual variability in patients. Anesthesiology. 1987;66:
versus placebo. Anesthesiology. 1989;71:374–377. 3–12.
136. Timm DM. Duragesic package labeling. Drug Intelligence and Clinical 163. Marlow N, Weindling AM, Van PA, et al. Alfentanil pharmacokinetics in
Pharmacy. 1991;25:1011. preterm infants. Arch Dis Child. 1990;65:349–351.
137. Donner B, Zenz M, Tryba M, et al. Direct conversion from oral mor- 164. Roure P, Jean N, Leclerc AC, et al. Pharmacokinetics of alfentanil in
phine to transdermal fentanyl: a multicenter study in patients with children undergoing surgery. Br J Anaesth. 1987;59:1437–1440.
cancer pain. Pain. 1996;64:527–534. 165. den Hollander JM, Hennis PJ, Burm AG, et al. Alfentanil in infants and
138. Zernikow B, Michel E, Anderson B. Transdermal fentanyl in childhood children with congenital heart defects. J Cardiothorac Anesth. 1988;2:
and adolescence: a comprehensive literature review. J Pain. 2007;8: 12–17.
187–207. 166. Tegeder I, Lotsch J, Geisslinger G. Pharmacokinetics of opioids in liver
139. Hilberman M, Hyer D. Potency of sufentanil. Anesthesiology. 1986;64: disease. Clin Pharmacokinet. 1999;37:17–40.
665–668. 167. Macfie AG, Magides AD, Reilly CS. Disposition of alfentanil in burns
140. Guay J, Gaudreault P, Tang A, et al. Pharmacokinetics of sufentanil in patients. Br J Anaesth. 1992;69:447–450.
normal children. Can J Anaesth. 1992;39:14–20. 168. McConaghy P, Bunting HE. Assessment of intubating conditions in
141. Davis PJ, Cook DR, Stiller RL, et al. Pharmacodynamics and pharma- children after induction with propofol and varying doses of alfentanil.
cokinetics of high-dose sufentanil in infants and children undergoing Br J Anaesth. 1994;73:596–599.
cardiac surgery. Anesth Analg. 1987;66:203–208. 169. Davis PJ, Chopyk JB, Nazif M, et al. Continuous alfentanil infusion in
142. Davis PJ, Stiller RL, Cook DR, et al. Pharmacokinetics of sufentanil in pediatric patients undergoing general anesthesia for complete oral
adolescent patients with chronic renal failure. Anesth Analg. 1988;67: restoration. J Clin Anesth. 1991;3:125–130.
268–271. 170. Shafer SL, Varvel JR. Pharmacokinetics, pharmacodynamics, and
143. Bovill JG, Sebel PS, Blackburn CL, et al. The pharmacokinetics of rational opioid selection. Anesthesiology. 1991;74:53–63.
sufentanil in surgical patients. Anesthesiology. 1984;61:502–506. 171. Ross AK, Davis PJ, Dear Gd GL, et al. Pharmacokinetics of remifentanil
144. Greeley WJ, de Bruijn NP. Changes in sufentanil pharmacokinetics in anesthetized pediatric patients undergoing elective surgery or
within the neonatal period. Anesth Analg. 1988;67:86–90. diagnostic procedures. Anesth Analg. 2001;93:1393–1401, table.
145. Greeley WJ, de Bruijn NP, Davis DP. Sufentanil pharmacokinetics in 172. Egan TD, Huizinga B, Gupta SK, et al. Remifentanil pharmacokinetics in
pediatric cardiovascular patients. Anesth Analg. 1987;66:1067–1072. obese versus lean patients. Anesthesiology. 1998;89:562–573.
146. Helmers JH, Noorduin H, Van PA, et al. Comparison of intravenous and 173. Glass PS, Hardman D, Kamiyama Y, et al. Preliminary pharmacokinetics
intranasal sufentanil absorption and sedation. Can J Anaesth. 1989;36: and pharmacodynamics of an ultra-short-acting opioid: remifentanil
494–497. (GI87084B). Anesth Analg. 1993;77:1031–1040.
174. Davis PJ, Wilson AS, Siewers RD, et al. The effects of cardiopulmonary 198. Raffa RB, Friderichs E, Reimann W, et al. Complementary and syner-
bypass on remifentanil kinetics in children undergoing atrial septal gistic antinociceptive interaction between the enantiomers of tramadol.
defect repair. Anesth Analg. 1999;89:904–908. J Pharmacol Exp Ther. 1993;267:331–340.
175. Hoke JF, Cunningham F, James MK, et al. Comparative pharmaco- 199. Bozkurt P. Use of tramadol in children. Paediatr Anaesth. 2005;15:
kinetics and pharmacodynamics of remifentanil, its principle metabolite 1041–1047.
(GR90291) and alfentanil in dogs. J Pharmacol Exp Ther. 1997;281: 200. Payne KA, Roelofse JA, Shipton EA. Pharmacokinetics of oral tramadol
226–232. drops for postoperative pain relief in children aged 4 to 7 years—a pilot
176. Cox EH, Langemeijer MW, Gubbens-Stibbe JM, et al. The comparative study. Anesth Prog. 2002;49:109–112.
pharmacodynamics of remifentanil and its metabolite, GR90291, in a 201. Allegaert K, Anderson BJ, Verbesselt R, et al. Tramadol disposition in
rat electroencephalographic model. Anesthesiology. 1999;90:535–544. the very young: an attempt to assess in vivo cytochrome P-450 2D6
177. Dershwitz M, Randel GI, Rosow CE, et al. Initial clinical experience with activity. Br J Anaesth. 2005;95:231–239.
remifentanil, a new opioid metabolized by esterases. Anesth Analg. 202. Saudan S, Habre W. [Pharmacokinetics of tramadol in children]
1995;81:619–623. (French). Ann Fr Anesth Reanim. 2007;26:560–563.
178. Davis PJ, Stiller RL, Wilson AS, et al. In vitro remifentanil metabolism: 203. Scott LJ, Perry CM. Tramadol: a review of its use in perioperative pain.
the effects of whole blood constituents and plasma butyrylcholinesterase. Drugs. 2000;60:139–176.
Anesth Analg. 2002;95:1305–1307, table. 204. Stamer UM, Bayerer B, Stuber F. Genetics and variability in opioid
179. Manullang J, Egan TD. Remifentanil’s effect is not prolonged in a patient response. Eur J Pain. 2005;9:101–104.
with pseudocholinesterase deficiency. Anesth Analg. 1999;89:529–530. 205. Stamer UM, Lehnen K, Hothker F, et al. Impact of CYP2D6 genotype on
180. James MK, Feldman PL, Schuster SV, et al. Opioid receptor activity of GI postoperative tramadol analgesia. Pain. 2003;105:231–238.
87084B, a novel ultra-short acting analgesic, in isolated tissues. J 206. De Witte JL, Schoenmaekers B, Sessler DI, et al. The analgesic efficacy
Pharmacol Exp Ther. 1991;259:712–718. of tramadol is impaired by concurrent administration of ondansetron.
181. Zhao M, Joo DT. Enhancement of spinal N-methyl-D-aspartate receptor Anesth Analg. 2001;92:1319–1321.
function by remifentanil action at delta-opioid receptors as a mechanism 207. Kapral S, Gollmann G, Waltl B, et al. Tramadol added to mepivacaine
for acute opioid-induced hyperalgesia or tolerance. Anesthesiology. prolongs the duration of an axillary brachial plexus blockade. Anesth
2008;109:308–317. Analg. 1999;88:853–856.
182. Komatsu R, Turan AM, Orhan-Sungur M, et al. Remifentanil for general 208. Finkel JC, Rose JB, Schmitz ML, et al. An evaluation of the efficacy and
anaesthesia: a systematic review. Anaesthesia. 2007;62:1266–1280. tolerability of oral tramadol hydrochloride tablets for the treatment of
183. Pinsker MC, Carroll NV. Quality of emergence from anesthesia and postsurgical pain in children. Anesth Analg. 2002;94:1469–1473, table
incidence of vomiting with remifentanil in a pediatric population. Anesth of contents.
Analg. 1999;89:71–74. 209. Ozalevli M, Unlugenc H, Tuncer U, et al. Comparison of morphine and
184. Warner DS, Hindman BJ, Todd MM, et al. Intracranial pressure and tramadol by patient-controlled analgesia for postoperative analgesia after
hemodynamic effects of remifentanil versus alfentanil in patients tonsillectomy in children. Paediatr Anaesth. 2005;15:979–984.
undergoing supratentorial craniotomy. Anesth Analg. 1996;83:348–353. 210. Chu YC, Lin SM, Hsieh YC, et al. Intraoperative administration of
185. Artru AA, Momota T. Rate of CSF formation and resistance to reabsorp- tramadol for postoperative nurse-controlled analgesia resulted in earlier
tion of CSF during sevoflurane or remifentanil in rabbits. J Neurosurg awakening and less sedation than morphine in children after cardiac
Anesthesiol. 2000;12:37–43. surgery. Anesth Analg. 2006;102:1668–1673.
186. Johnson KB, Egan TD. Remifentanil and propofol combination for 211. Prakash S, Tyagi R, Gogia AR, et al. Efficacy of three doses of tramadol
awake craniotomy: case report with pharmacokinetic simulations. J with bupivacaine for caudal analgesia in paediatric inguinal herniotomy.
Neurosurg Anesthesiol. 1998;10:25–29. Br J Anaesth. 2006;97:385–388.
187. Hans P, Bonhomme V, Born JD, et al. Target-controlled infusion of 212. Prosser DP, Davis A, Booker PD, et al. Caudal tramadol for postoperative
propofol and remifentanil combined with bispectral index monitoring analgesia in pediatric hypospadias surgery. Br J Anaesth. 1997;79:
for awake craniotomy. Anaesthesia. 2000;55:255–259. 293–296.
188. Kimball-Jones PL, Schell RM, Shook JP. The use of remifentanil infusion 213. Gunes Y, Secen M, Ozcengiz D, et al. Comparison of caudal ropivacaine,
to allow intraoperative awakening for intentional fracturing of the ropivacaine plus ketamine and ropivacaine plus tramadol administration
anterior cervical spine. Anesth Analg. 1999;89:1059–1061. for postoperative analgesia in children. Paediatr Anaesth. 2004;14:
189. Artru AA, Momota Y. Trabecular outflow facility and formation rate of 557–563.
aqueous humor during anesthesia with sevoflurane-nitrous oxide or 214. Ozcengiz D, Gunduz M, Ozbek H, et al. Comparison of caudal morphine
sevoflurane-remifentanil in rabbits. Anesth Analg. 1999;88:781–786. and tramadol for postoperative pain control in children undergoing
190. Alexander R, Hill R, Lipham WJ, et al. Remifentanil prevents an increase inguinal herniorrhaphy. Paediatr Anaesth. 2001;11:459–464.
in intraocular pressure after succinylcholine and tracheal intubation. 215. Murthy BV, Pandya KS, Booker PD, et al. Pharmacokinetics of tramadol
Br J Anaesth. 1998;81:606–607. in children after i.v. or caudal epidural administration. Br J Anaesth.
191. Munoz HR, Cortinez LI, Altermatt FR, et al. Remifentanil requirements 2000;84:346–349.
during sevoflurane administration to block somatic and cardiovascular 216. Takala A, Kaasalainen V, Seppala T, et al. Pharmacokinetic comparison
responses to skin incision in children and adults. Anesthesiology. of intravenous and intranasal administration of oxycodone. Acta
2002;97:1142–1145. Anaesthesiol Scand. 1997;41:309–312.
192. Min SK, Kwak YL, Park SY, et al. The optimal dose of remifentanil for 217. Kokki H, Rasanen I, Reinikainen M, et al. Pharmacokinetics of oxy-
intubation during sevoflurane induction without neuromuscular codone after intravenous, buccal, intramuscular and gastric administra-
blockade in children. Anaesthesia. 2007;62:446–450. tion in children. Clin Pharmacokinet. 2004;43:613–622.
193. Crawford MW, Hayes J, Tan JM. Dose-response of remifentanil for 218. Leow KP, Smith MT, Watt JA, et al. Comparative oxycodone pharma-
tracheal intubation in infants. Anesth Analg. 2005;100:1599–1604. cokinetics in humans after intravenous, oral, and rectal administration.
194. Verghese ST, Hannallah RS, Brennan M, et al. The effect of intranasal Ther Drug Monit. 1992;14:479–484.
administration of remifentanil on intubating conditions and airway 219. Pokela ML, Anttila E, Seppala T, et al. Marked variation in oxycodone
response after sevoflurane induction of anesthesia in children. Anesth pharmacokinetics in infants. Paediatr Anaesth. 2005;15:560–565.
Analg. 2008;107:1176–1181. 220. Poyhia R, Seppala T. Liposolubility and protein binding of oxycodone in
195. Hayes JA, Lopez AV, Pehora CM, et al. Coadministration of propofol vitro. Pharmacol Toxicol. 1994;74:23–27.
and remifentanil for lumbar puncture in children: dose-response and an 221. Poyhia R, Seppala T, Olkkola KT, et al. The pharmacokinetics and
evaluation of two dose combinations. Anesthesiology. 2008;109:613–618. metabolism of oxycodone after intramuscular and oral administration to
196. Drover DR, Litalien C, Wellis V, et al. Determination of the pharmaco- healthy subjects. Br J Clin Pharmacol. 1992;33:617–621.
dynamic interaction of propofol and remifentanil during esophagogas- 222. Ross FB, Smith MT. The intrinsic antinociceptive effects of oxycodone
troduodenoscopy in children. Anesthesiology. 2004;100:1382–1386. appear to be kappa-opioid receptor mediated. Pain. 1997;73:151–157.
197. Tsui BC, Wagner A, Usher AG, et al. Combined propofol and remifenta- 223. Czarnecki ML, Jandrisevits MD, Theiler SC, et al. Controlled-release
nil intravenous anesthesia for pediatric patients undergoing magnetic oxycodone for the management of pediatric postoperative pain. J Pain
resonance imaging. Paediatr Anaesth. 2005;15:397–401. Symptom Manage. 2004;27:379–386.
224. Olkkola KT, Hamunen K, Seppala T, et al. Pharmacokinetics and 251. Bessard G, Alibeu JP, Cartal M, et al. Pharmacokinetics of intrarectal
ventilatory effects of intravenous oxycodone in postoperative children. nalbuphine in children undergoing general anaesthesia. Fundam Clin
Br J Clin Pharmacol. 1994;38:71–76. Pharmacol. 1997;11:133–137.
225. Hamunen K. Ventilatory effects of morphine, pethidine and methadone 252. Errick JK, Heel RC. Nalbuphine. A preliminary review of its phar-
in children. Br J Anaesth. 1993;70:414–418. macological properties and therapeutic efficacy. Drugs. 1983;26:
226. Berde CB, Sethna NF, Holzman RS, et al. Pharmacokinetics of metha- 191–211.
done in children and adolescents in the perioperative period. Anesthe- 253. Nicolle E, Devillier P, Delanoy B, et al. Therapeutic monitoring of
siology. 1987;67:A519. nalbuphine: transplacental transfer and estimated pharmacokinetics in
227. Sawe J. High-dose morphine and methadone in cancer patients. Clinical the neonate. Eur J Clin Pharmacol. 1996;49:485–489.
pharmacokinetic considerations of oral treatment. Clin Pharmacokinet. 254. Murphy MR, Hug CC, Jr. The enflurane sparing effect of morphine,
1986;11:87–106. butorphanol, and nalbuphine. Anesthesiology. 1982;57:489–492.
228. Kaufmann JJ, Koski WS, Benson DN, et al. Narcotic and narcotic 255. Gal TJ, DiFazio CA, Moscicki J. Analgesic and respiratory depressant
antagonist pKa’s and partition coefficients and their significance in activity of nalbuphine: a comparison with morphine. Anesthesiology.
clinical practice. Drug Alcohol Depend. 1975;1:103–114. 1982;57:367–374.
229. Gourlay GK, Wilson PR, Glynn CJ. Pharmacodynamics and pharma- 256. Romagnoli A, Keats AS. Ceiling effect for respiratory depression by
cokinetics of methadone during the perioperative period. Anesthesiology. nalbuphine. Clin Pharmacol Ther. 1980;27:478–485.
1982;57:458–467. 257. Littlejohn IH, Tarling MM, Flynn PJ, et al. Post-operative pain relief in
230. Kreek MJ, Schecter AJ, Gutjahr CL, et al. Methadone use in patients with children following extraction of carious deciduous teeth under general
chronic renal disease. Drug Alcohol Depend. 1980;5:197–205. anaesthesia: a comparison of nalbuphine and diclofenac. Eur J Anaes-
231. Kristensen K, Christensen CB, Christrup LL. The mu1, mu2, delta, thesiol. 1996;13:359–363.
kappa opioid receptor binding profiles of methadone stereoisomers and 258. Liechti M, Feurer R, Gross D, et al. Prevention of postoperative nausea
morphine. Life Sci. 1995;56:PL45–50. and vomiting in children following adenotonsillectomy, using tropi-
232. Fainsinger R, Schoeller T, Bruera E. Methadone in the management of setron with or without low-dose dexamethasone. J Anesth. 2007;21:
cancer pain: a review. Pain. 1993;52:137–147. 311–316.
233. Davies D, DeVlaming D, Haines C. Methadone analgesia for children 259. Krechel SW, Helikson MA, Kittle D, et al. Intrathecal morphine (ITM)
with advanced cancer. Pediatr Blood Cancer. 2008;51:393–397. for postoperative pain control in children: a comparison with nalbu-
234. Sabatowski R, Kasper SM, Radbruch L. Patient-controlled analgesia with phine patient controlled analgesia (PCA). Paediatr Anaesth. 1995;
intravenous L-methadone in a child with cancer pain refractory to high- 5:177–183.
dose morphine. J Pain Symptom Manage. 2002;23:3–5. 260. Yeh YC, Lin TF, Lin FS, et al. Combination of opioid agonist and agonist-
235. Bruera E, Pereira J, Watanabe S, et al. Opioid rotation in patients antagonist: patient-controlled analgesia requirement and adverse events
with cancer pain. A retrospective comparison of dose ratios be- among different-ratio morphine and nalbuphine admixtures for post-
tween methadone, hydromorphone, and morphine. Cancer. 1996;78: operative pain. Br J Anaesth. 2008;101:542–548.
852–857. 261. Kuhlman JJ, Jr., Lalani S, Magluilo J Jr, et al. Human pharmacokinetics
236. Adams JU, Paronis CA, Holtzman SG. Assessment of relative intrinsic of intravenous, sublingual, and buccal buprenorphine. J Anal Toxicol.
activity of mu-opioid analgesics in vivo by using beta-funaltrexamine. J 1996;20:369–378.
Pharmacol Exp Ther. 1990;255:1027–1032. 262. Olkkola KT, Maunuksela EL, Korpela R. Pharmacokinetics of intra-
237. Lugo RA, MacLaren R, Cash J, et al. Enteral methadone to expedite venous buprenorphine in children. Br J Clin Pharmacol. 1989;28:
fentanyl discontinuation and prevent opioid abstinence syndrome in the 202–204.
PICU. Pharmacotherapy. 2001;21:1566–1573. 263. Hoskin PJ, Hanks GW. Opioid agonist-antagonist drugs in acute and
238. Gourlay GK, Willis RJ, Lamberty J. A double-blind comparison of the chronic pain states. Drugs. 1991;41:326–344.
efficacy of methadone and morphine in postoperative pain control. 264. Rance MJ. Animal and molecular pharmacology of mixed agonist-
Anesthesiology. 1986;64:322–327. antagonist analgesic drugs. Br J Clin Pharmacol. 1979;7(Suppl 3):
239. Jasinski DR, Mansky PA. Evaluation of nalbuphine for abuse potential. 281S–286S.
Clin Pharmacol Ther. 1972;13:78–90. 265. Bullingham RE, McQuay HJ, Moore RA, et al. An oral buprenorphine
240. Fillingim RB, Gear RW. Sex differences in opioid analgesia: clinical and and paracetamol combination compared with paracetamol alone: a
experimental findings. Eur J Pain. 2004;8:413–425. single dose double-blind postoperative study. Br J Clin Pharmacol. 1981;
241. Gear RW, Miaskowski C, Gordon NC, et al. Action of naloxone on 12:863–867.
gender-dependent analgesic and antianalgesic effects of nalbuphine in 266. Maunuksela EL, Korpela R, Olkkola KT. Comparison of buprenorphine
humans. J Pain. 2000;1:122–127. with morphine in the treatment of postoperative pain in children. Anesth
242. Gear RW, Gordon NC, Hossaini-Zadeh M, et al. A subanalgesic dose of Analg. 1988;67:233–239.
morphine eliminates nalbuphine anti-analgesia in postoperative pain. J 267. Maunuksela EL, Korpela R, Olkkola KT. Double-blind, multiple-dose
Pain. 2008;9:337–341. comparison of buprenorphine and morphine in postoperative pain of
243. Gear RW, Lee JS, Miaskowski C, et al. Neuroleptics antagonize nalbu- children. Br J Anaesth. 1988;60:48–55.
phine antianalgesia. J Pain. 2006;7:187–191. 268. Hamunen K, Olkkola KT, Maunuksela EL. Comparison of the ventila-
244. Dewey WL. The pharmacology of pentazocine. Int Anesthesiol Clin. tory effects of morphine and buprenorphine in children. Acta Anaes-
1973;11:139–153. thesiol Scand. 1993;37:449–453.
245. Rita L, Seleny F, Goodarzi M. Comparison of the calming and sedative 269. Kamal RS, Khan FA. Caudal analgesia with buprenorphine for post-
effects of nalbuphine and pentazocine for paediatric premedication. Can operative pain relief in children. Paediatr Anaesth. 1995;5:101–106.
Anaesth Soc J. 1980;27:546–549. 270. Girotra S, Kumar S, Rajendran KM. Caudal buprenorphine for post-
246. Waterworth TA. Pentazocine (Fortral) as postoperative analgesic in operative analgesia in children: a comparison with intramuscular
children. Arch Dis Child. 1974;49:488–490. buprenorphine. Acta Anaesthesiol Scand. 1993;37:361–364.
247. Hamunen K, Olkkola KT, Seppala T, et al. Pharmacokinetics and phar- 271. van Dorp E, Yassen A, Sarton E, et al. Naloxone reversal of buprenorphine-
macodynamics of pentazocine in children. Pharmacol Toxicol. 1993;73: induced respiratory depression. Anesthesiology. 2006;105:51–57.
120–123. 272. Moreland TA, Brice JE, Walker CH, et al. Naloxone pharmacokinetics in
248. Iisalo EU, Iisalo E. A comparison of high-dose pentazocine with pethi- the newborn. Br J Clin Pharmacol. 1980;9:609–612.
dine and diazepam in paediatric premedication. Ann Chir Gynaecol. 273. Weinstein SH, Pfeffer M, Schor JM, et al. Metabolites of naloxone in
1978;67:123–128. human urine. J Pharm Sci. 1971;60:1567–1568.
249. Jaillon P, Gardin ME, Lecocq B, et al. Pharmacokinetics of nalbuphine in 274. Ngai SH, Berkowitz BA, Yang JC, et al. Pharmacokinetics of naloxone
infants, young healthy volunteers, and elderly patients. Clin Pharmacol in rats and in man: basis for its potency and short duration of action.
Ther. 1989;46:226–233. Anesthesiology. 1976;44:398–401.
250. Lo MW, Schary WL, Whitney CC, Jr. The disposition and bioavailability 275. Habre W, McLeod B. Analgesic and respiratory effect of nalbuphine and
of intravenous and oral nalbuphine in healthy volunteers. J Clin pethidine for adenotonsillectomy in children with obstructive sleep
Pharmacol. 1987;27:866–873. disorder. Anaesthesia. 1997;52:1101–1106.
276. Pokela ML, Koivisto M. Physiological changes, plasma beta-endorphin 279. Silvasti M, Rosenberg P, Seppala T, et al. Comparison of analgesic ef-
and cortisol responses to tracheal intubation in neonates. Acta Paediatr. ficacy of oxycodone and morphine in postoperative intravenous patient-
1994;83:151–156. controlled analgesia. Acta Anaesthesiol Scand. 1998;42:576–580.
277. Marcou TA, Marque S, Mazoit JX, et al. The median effective dose of 280. Lauretti GR, Oliveira GM, Pereira NL. Comparison of sustained-release
tramadol and morphine for postoperative patients: a study of interac- morphine with sustained-release oxycodone in advanced cancer
tions. Anesth Analg. 2005;100:469–474. patients. Br J Cancer. 2003;89:2027–2030.
278. Kalso E, Vainio A. Morphine and oxycodone hydrochloride in the mana-
gement of cancer pain. Clin Pharmacol Ther. 1990;47:639–646.
26 Non-Opioid Analgesic Agents

C H A P T E R Greta M. Palmer
INTRODUCTION increasing PMA7 from 1.87 L/h/70 kg at 27 weeks to reach 84% of

the mature value (16.3 L/h/70 kg, Coefficient of variation (CV)
Nonopioid analgesics are used widely in the management of acute 40.4%) by 1 year of age.9,10 Clearance following I.V. acetaminophen
pediatric postoperative pain. They are used alone or as part of a administration similarly increased for neonates from 4.4 L/h–1/70
multimodal analgesic approach to reduce opioid requirements and kg–1 at 34 weeks to 6.3 L/h–1/70 kg–1 at 46 weeks PMA.3 Clearance
opioid-associated side effects. All agents used in adults are em- of acetaminophen has not been linked to postnatal age (PNA) in
ployed in children, but they are frequently used “off-license.” neonates.3,11
Children, particularly neonates, remain therapeutic orphans. Acetaminophen is predominantly metabolized by phase 2
Limited pediatric studies are available on the pharmacokinetics hepatic conjugation pathways (>95%) through both glucuronidation
(PK) and pharmacodynamics (PD) of commonly employed non- and sulfation, with renal excretion of the metabolites. Uridine 5⬘-
opioid analgesics and they are often small in sample size. Dose diphosphate glucuronosyltransferases (UGT) metabolize both
recommendations are commonly scaled down from adult sche- bilirubin (UGT1A1) and acetaminophen (UGT1A6). Neonates rely
dules. As we increase our understanding of the pharmacology more on sulfate pathways.8 The glucuronide-to-sulfate ratio
(including the pharmacogenomics) of these agents from the pre- increases with increasing PMA: from 0.12 in premature neonates
term and term neonate to the infant and older child age range, of 28 to 32 weeks PMA12 to 0.34 in term neonates (PNA 0–2 d).13
appropriate dosing recommendations can be made and then com- Oral dosing is subject to minimal first-pass metabolism and
parative effectiveness can be better assessed. oral bioavailability is high.8 Time to reach a plasma maximum
concentration (Cmax) after enteral administration will be in-
fluenced by the presence of food in the stomach, pathology, and
ACETAMINOPHEN (PARACETAMOL) the formulation used (elixir is more quickly absorbed than tablet).
Use and Formulations Available It is reached at 29 to 45 minutes in adults after oral adminis-
tration14 and 90 to 120 minutes after oral15 and 66 to 114 minutes
Acetaminophen is used widely in pediatrics as an antipyretic or a after nasogastric administration in infants, neonates, and child-
first-line nonopioid analgesic for mild to moderate pain relief. It ren.8 The absorption rate is slowest in premature neonates.5 Rectal
is available in multiple formulations that are all used in children. absorption is slow and variable: Cmax is reached at 150 minutes in
These include enteral preparations such as oral tablets (including children aged 1 to 17 years16 to 198 minutes in children aged a
soluble and extended release), drops, capsules, and suppository mean of 3.4 (standard deviation [sd] 0.5) years.17 Solution admi-
formulations. Two intravenous (I.V.) formulations exist; an I.V. nistered rectally is more rapidly absorbed than the triglyceride
prodrug (propacetamol, N-acetylpara-aminophenoldiethyl ami- or capsule suppositories with wide variability in bioavailability of
noacetic ester) that is hydroxylated to yield 50% acetaminophen, 50 to 92%. Relative bioavailability is higher with capsules than
and a more recent I.V. acetaminophen (perfalgan)1–4 that is solu- triglyceride-based suppositories and decreases with age.5 Depth
bilized in mannitol, sodium phosphate, and cysteine. of insertion of suppositories, leakage from the rectum, and in-
complete dissolution will influence the degree of absorption
achieved. Elimination half-life is 4.8 to 11 hours in preterm
Pharmacokinetics neonates, 1.6 to 1.7 hours in infants, and 2.6 to 2.8 hours in child-
Acetaminophen’s volume of distribution (Vd) is reported to deren.8 Some studies have estimated a longer half-life following rectal
crease with increasing age from 110 L/70 kg at 28 weeks of post- administration. This is likely influenced by continuing unac-
menstrual age (PMA) to 73 L/70 kg by 60 weeks.5 The magnitude counted absorption influencing elimination estimation. The use of
of this change may not be as great as originally reported because the I.V. acetaminophen formulations allows greater dosing ac-
a recent neonatal cohort aged 28 to 45 weeks PMA had a Vd of curacy with less PK variability attributable to absorption and more
76 L/70 kg (95% confidence interval [CI] 66–87)3 compared with rapid effect onset.11
the adult value of 66.6 L/70 kg. Clearance estimates using either
the enteral I.V. acetaminophen or the I.V. prodrug are similar for
neonates (5–6.8 L/h/70 kg).3,5–7 Clearance increases with age and
Mechanism of Action
is 10.8 L/h/70 kg at 60 weeks PMA5 and 12.5 to 14 L/h/70 kg in Acetaminophen’s mechanism of action is currently hypothesized
older children and adults.5,8,9 In neonates and infants, clearance as central only and mediated through descending serotoner-
following I.V. propacetamol administration was associated with gic pathway activation.18,19 Its primary site of action is still debated
CHAPTER 26 ■ Non-Opioid Analgesic Agents 407
Figure 26-1. Prostaglandin H2 synthetase

(PGHS) is the enzyme responsible for
metabolism of arachidonic acid to the unstable
prostaglandin H2 (PGH2). Formation of
tyrosine-385 radical (Tye385*) at the cyclooxy-
genase (COX) site … is dependent on the re-
duction of a ferryl protoporphyrin IX radical
cation (Fe4+ = OPP*+) at the peroxidase (POX)
site. Paracetamol is a reducing cosubstrate that
partially reduces (Fe4+= OPP•+), decreasing the
amount available for regeneration of Tyr385*.
Adapted from reference 113 by the author of
reference 18, with permission.
as either through prostaglandin synthesis inhibition at the 150 μmol/L were associated with 40% reduction in clearance.3
peroxidise site (POX) of the prostaglandin H2 synthetase (PGHS) Further understanding of acetaminophen metabolism is required
enzyme (Figure 26–1) or through an active metabolite (N- to interpret this clinical finding. No link with changes in other
arachodonolphenylamine) influencing cannabinoid receptors.18 liver function tests was demonstrable in this neonatal group.3
Pain on injection is a problem with I.V. propacetamol and
occurs less commonly with the I.V. acetaminophen formulation.1
Pharmacodynamics Slow infusion over 15 minutes is recommended.
A mean effect-site concentration of 10 mg/L is associated with pain
score reduction of 26% in children aged 2 to 15 years after - Dose and Licensing
tonsillectomy.20 Effect-site concentrations associated with analgesia
for the pains experienced as a neonate are unknown. Pain relief Oral and rectal formulations are licensed worldwide for use in the
occurs between 15 and 30 minutes after I.V. acetaminophen,1 older pediatric age groups. Some countries specify precautionary
consistent with a delay achieving effect-site concentrations use in term and preterm neonates. Licensing of the two I.V. formu-
(context-sensitive half-life [t / keo] 56 min21). These delays mirror
1
2 lations varies. Australian product information precautions against
plasma – cerebrospinal fluid (CSF) equilibration.15,22,23 The slow I.V. acetaminophen use in preterm neonates,3 whereas in Europe
rectal absorption maintains plasma concentrations longer than oral neither ise licensed for infants weighing less than 10 kg.27 I.V.
and formulations and this can be advantageous. Time to first rescue formulations are currently unavailable in the United States. Table
analgesia was longer after rectal dosing of 40 mg/kg compared with 26–1 lists the various acetaminophen doses used, studied, and
I.V. acetaminophen 15 mg/kg (median 10 h vs 7 h) after single- recommended for loading and maintenance in the various pedi-
dose use for tonsillectomy.4 I.V. acetaminophen was associated with atric age groups. Recommendations for doses of the I.V. for-
slightly higher postoperative pain scores but less sedation and mulations in preterm and term neonates either reduce the dose or
earlier preparedness for discharge than intramuscular meperidine increase the dosing frequency to allow for the reduced clearance
after tonsillectomy24 and dental restoration.25 that occurs in this age group.3,27,28
Use of the I.V. formulation should be restricted to patients who
cannot tolerate enteral or rectal formulations, to reduce hospital
Adverse Effects pharmacy budget expenditure.2,29 I.V. administration should not
Acetaminophen use is associated with a very low risk of serious replace oral premedication or intraoperative rectal administration
adverse events. Hepatotoxicity is the major concern with use of during routine anesthesia; nor should it replace postoperative oral
this agent and is related to production of the toxic metabolite or rectal administration unless severe vomiting, ileus, or diarrhea
N-acetyl-p-benzoquinone-imine (via phase 1 oxidative metabo- is expected. The superiority of the I.V. route over the oral and
lism). It is generally a problem of overdose, in which the usual rectal formulations is not yet proved. The latter routes are effective
phase 2 clearance pathway becomes saturated or when the meta- provided absorption is not impaired and doses are timed to allow
bolite “mop,” glutathione, is depleted.8 The latter occurs in syste- for differences in time to peak effect.29
mic illness such as prolonged fasting or vomiting, dehydration,
obesity, or pre-existing hepatic impairment. Children receiving
repeated doses of acetaminophen (>75–90 mg/kg/d) may show
NONSTEROIDAL ANTI-
abnormalities in liver function.26 Neonates may be somewhat INFLAMMATORY DRUGS
protected because of immaturity of oxidative clearance pathways.3
Unconjugated hyperbilirubinemia, a crude marker of glucuronide
Use and Formulations Available
conjugating function, is associated with reduced acetamino- The nonsteroidal anti-inflammatory drugs (NSAIDs) include a
phen clearance; serum unconjugated bilirubin concentrations of group of heterogeneous compounds with analgesic, antipyretic,
TABLE 26-1. Suggested Acetaminophen Dosing

Loading
Route Dose, mg/kg Maintenance Dose, mg/kg; Frequency Daily Maximum, mg/kg/d
Oral 20–40 10; q4h (United States) Older children
15–20; q4–6h Short-term 2–3 days: 90
Longer-term: 60
Premature neonates 30–34 wk PMA: 25–455,b
Rectal 40 (≤60) 20; q6h Infants > 3 mo: 80–908
Premature neonates > 32 wk PMA to infants
< 3 mo: 608
Premature neonates: 30 wk PMA: 25 (capsule)
or 30 (triglyceride)5
28–32 wk PMA: 308
I.V. propacetamol 30–4027 30; q6ha Double below recommendations
I.V. acetaminophen 10–2027,28 Children, infants: 15; q6ha,c Children, infants: 601,2
Term neonates: 1027–153,28; q6h. Term neonates ≥ 36 wks PMA: 4027–603
Preterm neonates 33–36 wk PMA: Preterm neonates 28–36 wk PMA: 20–403,27
7.528–12.53; every 63,28 to 827 h
Preterm neonates 28–32 wk PMA:
7.5–10; every 63 to 828 to 1227 h
PMA = postmenstrual age.
a
Every 4 h permitted in older children: the product information for I.V. acetaminophen recommends this for those patients weighing > 33 kg but pediatric centers
tend to reserve this frequency of dosing once children weigh > 45–50 kg.2
b
This dosing achieves a mean steady-state target concentration > 10 mg/L at trough.5
c
This dosing achieves a steady-state concentration in a term neonate between 10 and 23 mg/L.3
and anti-inflammatory effects. Acetaminophen lacks the latter 8 years, was associated with a higher relative bioavailability (1.26)
effect. These agents are used as first- or second-line analgesics in than oral administration of enteric-coated tablets and an earlier
children with mild to moderate pain. Their anti-inflammatory Cmax: 50 min versus 108 min.40 Clearance was estimated as
properties lead to use in inflammatory conditions such as arthritis, 45 L/h/70 kg,40 Recently, a larger population PK study of children
myalgia, ureteric and biliary colic, and dysmenorrhea and endo- aged 1 to 12 years (N = 70) given an oral suspension of diclofenac
metriosis. A further pediatric use is to induce patent ductus 1 mg/kg suggests that Cmax is achieved in less than 1 hour after
arteriosus (PDA) closure in ex–premature infants. Like aceta- this formulation, with a similar result for clearance of 54 L/h/
minophen, multiple formulations are available. These vary be- 70 kg.41 The PK after 20 mg/kg rectal ibuprofen administration
tween countries: oral tablet (including extended release), capsule, have been compared in postsurgical neonates, infants, and adults.42
syrup, rectal suppository, and parenteral forms. The Cmax was higher but reached later in adults and the half-life
was longer in infants aged 1 to 7 weeks.
NSAIDs exhibit stereoselectivity. In premature neonates (<28
Pharmacokinetics wk PMA), dosed with 10 mg/kg given within 6 hours after birth
The PK of NSAIDs have been explored in children of varying followed by two 5-mg/kg doses at 24-hour intervals, the half-
ages, and generally, the half-life decreases with increasing age as lives of ibuprofen enantiomers were approximately 10 hours for
does the volume of distribution.30,31 Clearance increases with age, R ibuprofen and 25.5 hours for S ibuprofen. The former has a
appearing to peak in infancy when scaled per kilogram.31 higher mean clearance: 12.7 mL/h versus 5.0 mL/h.43 The difference
Neonatal NSAID PK have been explored during use for PDA in the enantiomers half-lives was not as apparent after rectal admi-
closure. Ibuprofen clearance increases from 2.06 mL/h/kg at 22 to nistration in older infants and adults.42 PK predictions based on
31 weeks PMA32 to 9.49 mL/h/kg at 28 weeks PMA33 to 140 mL/ racemic assays may, therefore, underestimate the duration of effect
h/kg at 5 years.34 Data have also been reported for indomethacin in premature neonates. Single-isomer NSAIDs are being developed
and is similar35: clearance was 7.11 mL/h (standardized to 1.17 kg and may offer fewer adverse effects than the racemic combi-
median weight), increasing by approximately 3.4% per postnatal nations.44,45
day. Between-individual variability in clearance was 41% and CSF concentrations have been measured in infants and child-
between-occasion variability was 43%. ren after I.V. ibuprofen 10 mg/kg. These peaked and were higher
Ibuprofen is metabolized by the cytochrome P450 (CYP) than that of unbound plasma concentrations when sampled more
CYP2C9 and CYP2C8. CYP2C9 is variably expressed, and its gene than 30 minutes after dosing.46
demonstrates functional polymorphism.36,37 CYP2C9 activity is
low immediately after birth, increasing to peak at a young age.38
Diclofenac is principally metabolized by CYP2C9 and also by
Pharmacodynamics
CYP3A4 and 3A5. In humans, CYP2C9 forms a 4⬘-hydroxyl diclo- NSAIDs induce their effects centrally and peripherally by reducing
fenac derivative, which in animals has 30% of its parent’s activity.39 prostaglandin biosynthesis through COX enzyme inhibition on
Diclofenac’s PK have been investigated in children (N = 26) the PGHS enzyme. The commonly used NSAIDs vary in their
undergoing tonsillectomy, given 2 mg/kg followed by 1 mg/kg q8h. selectivity for the two major COX-isoforms (COX-1 and COX-2)
Rectal administration of diclofenac, in these children aged 2 to (Table 26–2).
TABLE 26-2. COX-2 Versus COX-1 Inhibitory after congenital heart surgery was not associated with increased
Concentration 50% (IC50) Ratio for the Commonly risk of bleeding complications.61 Intraventricular hemorrhage
Used NSAIDs (IVH) was not increased in neonates given ibuprofen to induce
PDA closure.60,62 Concern has been raised that I.V. indomethacin
NSAID COX-2/COX-1 IC50 may be associated with increased risk of IVH.63 The use of
Relatively “COX-1-Selective” NSAIDs in tonsillectomy (an operation with known risk of post-
Piroxicam 600 operative bleeding) has long been debated. The odds ratio (OR) of
Aspirin 166 posttonsillectomy hemorrhage with aspirin was significantly
Indomethacin 60 higher than in the ibuprofen and diclofenac group: 1.94 (95% CI
1.09–3.42) compared with 0.93 (95% CI 0.44–1.95) after assessing
Ibuprofen, ketorolac 6.7–7.0
seven studies (N = 1368).64 The conclusion was that NSAIDS but
Nearly Equal in their COX-1 vs not aspirin were safe.64 The incidence of postoperative bleeding
COX-2 Selectivity was nearly doubled by NSAIDs from 5.3 to 9.2% (OR 1.8; 95% CI
Diclofenac, naproxen 0.7–1.0 0.9–3.4), and the number requiring reoperation increased from
0.8 to 4.2% (OR 3.8; 95% CI 1.3–11.5) with a number-needed-to-
COX-2-Selective harm (NNH) of 29 in seven studies (N = 505).65 The largest
Numesulide, meloxicam 0.06–0.09 metanalysis (25 studies, N = 1853) determined that the rate of
Celecoxib 0.15 reoperation was significantly increased by NSAIDs with a lower
Rofecoxib 0.03 NNH of 60, concluding that NSAIDs should be used cautiously
COX = cyclooxygenase; IC50 = inhibitory concentration of 50%; NSAIDs = until further evidence is available.66 The most recent meta-analysis
nonsteroidal anti-inflammatory drugs. (13 studies; N = 955) drew the opposite conclusion, stating NSAID
Adapted from reference 110. use is not associated with an increased risk of bleeding requiring
either nonsurgical or surgical intervention (respective ORs: 1.23
Clinical pediatric studies after tonsillectomy47; myringotomy48; [95% CI 0.44–3.43] and 1.46 [95% CI 0.49–4.40]).67 Significantly
various surgery types49; orthopedic, urologic, and soft tissue sur- less nausea and vomiting was experienced in NSAID-treated
gery50; and inguinal hernia repair (IHR)51 comparing NSAIDs and tonsillectomy patients (OR 0.4, 95% CI 0.23–0.72).67 The latter
acetaminophen or different NSAIDs suggest similar effectiveness. benefit is an advantage of this drug class that has greater statistical
The combination of NSAID with acetaminophen is superior to and clinical weight (because it is a frequent and distressing symp-
use of either agent alone after orthopedic, urologic, and soft tissue tom with this surgery) than the theoretical disadvantage of the
surgery,50 IHR,51 tonsillectomy,52 and adenoidectomy.53 Compara- rarer possibility of increased blood loss that is not statistically
tive and combined effectiveness can be assessed only when ap- supported. NSAID use for pediatric tonsillectomy is frequent in
propriate doses of each drugs are used, and there is more study to the United Kingdom68 and New Zealand,69 whereas it is avoided in
be done in this area, particularly for repeat dosing.54 this surgery type in the United States and Australia. Cerebral
A plasma analgesic concentration has been reported after I.V. blood volume and flow and cerebral tissue oxygenation index have
ibuprofen 10 mg/kg for herniotomy (under spinal anaesthesia, N been assessed in neonates receiving ibuprofen and placebo, with-
= 19) and is a median of total (bound and unbound) ibuprofen 21 out significant differences between treatment groups.70
(range 10–25) mg/L and unbound ibuprofen 26 (15–157) μg/L.46 Aspirin-sensitive asthma was thought to be a disorder only
of adults. Cross-sensitivity with other NSAIDs became evident
and the new term NSAID-ERD was applied with episodes in
Adverse Effects children subsequently reported.71 Short-term ibuprofen use has
The risk of serious adverse events after short-term ibuprofen been reported without adverse effects in pediatric patients with
use in pediatrics is low.55 Adverse effects of NSAIDs include asthma. Hospitalization rates were low and did not differ from the
gastrointestinal symptoms and mucosal effects, renal and platelet acetaminophen-treated group, whereas outpatient visits were
dysfunction, and exacerbation of respiratory disease (NSAID- significantly lower (by 50%) in the ibuprofen-treated group.72
ERD) including bronchospasm in sensitive asthmatic patients. Single-dose oral (effervescent) diclofenac 1 to 1.5 mg/kg did not
Glomerular filtration rate is reduced by 20% in premature affect spirometry (tested at three time points up to 30 min post-
neonates treated with ibuprofen (independent of PMA).56 This dosing) in asthmatic children (N = 70).73 It has been suggested
reduction was associated with reduced aminoglycoside clear- that the use of NSAIDs can reduce severity of viral upper respira-
ance.57 Renal electrolyte balance (of sodium and potassium) is also tory tract infections (URTIs) in both children (anecdotally) and
altered as vasodilatory prostaglandin production in the renal adults in small-scale trials.74 Thus, only a subset of pediatric and
cortex is reduced.58 The use of NSAIDs in hypovolemic, septic, adult patients, with moderate to severe asthma associated with
and shocked patients in whom renal blood flow is compromised nasal disease, is felt to be at risk of NSAID-ERD.71 Patients with
is to be avoided, and there are precautions against use in patients mild asthma may improve with NSAID therapy in the setting of an
with renal impairment or on diuretics and angiotensin-converting URTI-associated asthma flare, because NSAID therapy modifies
enzyme inhibitors. Precipitation or exacerbation of renal failure the leukotriene response.72,74
has occurred in neonates,59,60 older children, and adults59 treated Nitric oxide–releasing NSAIDs offer increased potency and re-
with NSAIDs, usually in the setting of other hemodynamic com- duced side effects and may be the preferred therapy in the future.75
promise. Renal side effects are felt to be NSAID drug type–, dose-,
and duration-dependent.59
NSAIDs inhibit thromboxane synthesis exerting antiplatelet
Dose and Licensing
effects that, except for aspirin, are reversible, and bleeding time is Table 26–3 lists the doses of NSAIDs that are commonly employ-
usually only slightly increased with these agents. Use of ketorolac ed in children for fever, analgesia, and PDA closure. It has been
TABLE 26-3. Common Pediatric Nonsteroidal Anti-Inflammatory Drug Doses for Analgesiaa and Patent Ductus
Arteriosus Closure
NSAID Type Dose, mg/kg; frequency Maximum Dose
Analgesia
Ibuprofen oral: elixir, capsule/tablet 5–10; q6–8h 200–400 mg
(200 mg); parenteral (lower dose for fever) 600–800 mg may be used for acute
pain management
Diclofenac, oral: tablet (25–50 mg) 1–1.5; q8–12h 50–75 mg
Diclofenac, rectal suppository (12.5–100 mg) 1–2; q8–12h40,68 100 mg
Indomethacin, oral tablet rectal suppository 0.5–2; q12h 100 mg
Ketorolac, parenteral: varying preparations Loading doses 1 mg/kg (United States) 60 mg (United States)
(10–30 mg/mL) Maintenance: 0.5 mg/kg; q6h 20 mg
0.3 mg/kg q6h (Europe)49 10 mg
0.2–0.25 mg/kg q6h (Australia) Ketorolac therapy is limited to 5 d
duration.
NSAID for PDA closure
Ibuprofen I.V.56 and oral63 10 mg/kg then 5 mg/kg daily for 2 d
Ibuprofen I.V. 10, 5, 5 mg/kg daily for PNA < 70 h
(dosing independent of gestational age 14, 7, 7 mg/kg daily for PNA 70–108 h
adjusted for postnatal age (PNA)111) 18, 9, 9 mg/kg daily for PNA 108–180 h
Indomethacin I.V.112 0.2 mg/kg q12h for three doses
NSAID = nonsteroidal anti-inflammatory drug; PDA = patent ductus arteriosus; PNA = postnatal age.
a
A review article describes other dosing regimens.49
suggested that oral ibuprofen therapy for PDA closure may offer selective” NSAIDs while maintaining their beneficial analgesic and
a better adverse event profile over indomethacin,63 but study num- anti-inflammatory effects. They are effective for mild to moderate
bers are small. Optimal and maximum doses are debated; the latter pain and inflammatory conditions (prescribed for arthritic con-
because a ceiling effect has been suggested for NSAIDs.41 An oral ditions including juvenile chronic rheumatoid arthritis and
diclofenac PK study suggests that 1 mg/kg (maximum 50 mg) is hemophiliac arthropathy). They have been developed in capsule
optimal in children based upon comparison of simulated area (celecoxib), tablet (valdecoxib, which is a prodrug of parecoxib),
under the curves for plasma concentration compared with time and parenteral forms (parecoxib). Rofecoxib has been withdrawn.
in the initial 0 to 12 hours after 0.5 to 2 mg/kg.41 This needs to be
confirmed in a study of effectiveness.41
NSAIDs are licensed for use in children with the precaution in Pharmacokinetics
Australia that safety younger than the age of 2 years is not estab- The PK of these agents have not been studied in pediatrics.
lished. Licensing in the United Kingdom is limited for ibuprofen Limited adult data are available.76
to children weighing greater than 7 kg and for diclofenac to older
than 12 months for use in juvenile arthritis. Clinicians and hospital
pharmacopoeias generally recommend limitation of NSAID use Pharmacodynamics
for pain and fever in infants and children in Australia and the
United Kingdom to older than 6 months and in the United States COX-2–selective inhibitors are active centrally and peripherally.
in children older than 12 months. Pediatric anesthetists in the Relative COX-2/COX-1 ratios are 30:1 for celecoxib, 60:1 for
United Kingdom (N = 337) report prescribing NSAIDs in infants valdecoxib/parecoxib, 276:1 for rofecoxib, and 433:1 for lumari-
younger than this: 4% state they prescribe for those younger than coxib.76 The use of these agents is increasing in children, although
1 month, 19% for 1 to 3 months, 48% for 3 to 6 months, and 78% only a few pediatric perioperative studies are available that have
for 6 to 12 months of age.68 Short-term use (e.g., three doses) is involved rofecoxib in pediatric tonsillectomy. These trials have
well reported for PDA closure in neonates. The parenteral formu- studied different doses of rofecoxib administered at different times
lation of ketorolac, although licensed only for intramuscular use, perioperatively: single dosing with 0.625 mg/kg has been com-
is administered intravenously: pared with ibuprofen 5 mg/kg (combined with 20 mg/kg aceta-
minophen) and found to be inferior52; single dosing 1 mg/kg has
been compared with placebo and found to be superior77,78; and
CYCLOOXYGENASE-2–SELECTIVE multiple postoperative dosing (5 d) of 1 mg/kg (maximum 50 mg)
INHIBITORS (ALSO CALLED has been compared with acetaminophen 15 mg/kg q4h and found
to be superior in terms of pain scores on postoperative day 0
CYCLOOXYGENASE-2 RECEPTOR through to day 3 and for fluid intake on day 1.79 It has also been
ANTAGONISTS OR “COXIBS”) administered preoperatively and postoperatively for 3 days as
Use and Formulations Available 1 mg/kg daily and compared with q6h hydrocodone 0.2 mg/kg in
combination with acetaminophen (N = 40, aged 5–17 y).80 Pain
Cyclooxygenase-2 (COX-2) inhibitors are selective NSAIDs that scores were lower in the rofecoxib-treated patients only when
were developed to avoid the adverse effect profile of the “non- assessed after swallowing at 24 and 48 hours.
Adverse Effects is O-demethyl tramadol (M1), which is formed by CYP2D6. There

is evidence that CYP2D6 activity is present as early as 25 weeks
Rofecoxib was shown to cause less gastrointestinal ulceration, PMA.87,88 Formation clearance to M1 contributes to 26% of
whereas celecoxib had similar rates of ulceration to the NSAIDs tramadol clearance in neonates88 and increases with PMA.88,89 An
naproxen and diclofenac in adults following long-term use.81 Dy- understanding of the CYP2D6 enzyme’s polymorphism is in-
spepsia symptoms are similar to that experienced with NSAIDs, as
creasing.89,90 Individuals vary in their expression of functional
is the renal effect side effect profile. The COX-2 inhibitors were
alleles and, depending on the number, can be classified across a
initially thought to lack platelet effects and were used in conditions
spectrum from poor to normal to extensive to ultrametabolizers.
in which NSAIDs were relatively contraindicated owing to bleed-
ing risk. However, a concern regarding prothrombotic effects In addition, there is known age-associated maturation. This has
(possibly through effects upon the platelet-endothelial interface) been also been explored in children for codeine, which requires
has occurred with reports of increased cardiovascular and cere- CYP2D6 to convert to its active metabolite morphine.91 The
brovascular events in older adults and those with known vasculo- impact of this enzyme’s polymorphism upon tramadol’s PK, meta-
pathy.82 This resulted in rofecoxib’s subsequent withdrawal from bolism, and PD requires further exploration.87,89 Size and PMA,
the market. It is not certain how this risk relates to pediatric more than CYP2D6 polymorphism, are now felt to contribute to
patients. COX-2 inhibitors have been used and are probably safe the wide variability in the PK of tramadol seen in premature
in patients at risk of NSAID-ERD.71,83 Celecoxib is a sulfonamide neonates.88 Maturation of CYP2D6 is rapid and single nuclear
and is to be avoided in patients with sulfur allergy. Angioedema polymorphisms of this gene have considerable impact by 50 weeks
and rash can occur with these agents and fluid retention, particu- PMA.88 Tramadol clearance increases more rapidly from 5.5 L/
larly ankle edema, is also reported. h/70 kg at 25 weeks to 17.188 to 17.587 L/h/70 kg at 40 weeks PMA
and 19.4 L/h/70 kg by 45 weeks PMA, which is 80% that of the
adult value of 24 L/h/70 kg. The central volume of distribution
Dose and Licensing decreased from 25 weeks PMA (256 L/70 kg) to reach 120% of its
Pediatric dose-ranging studies of these agents are limited. Con- mature value by 87 weeks PMA.87 Other authors report similar
sequently, dose recommendations are scaled from adult dosing parameter values.92
including 1.5 to 3 mg/kg (maximum 200 mg) twice daily for oral The absorption characteristics after subcutaneous administra-
celecoxib and 1 mg/kg (maximum 40 mg) daily I.V. for parecoxib. tion have not been studied.
Lower doses have been used in adults of valdecoxib 10 to 20 mg
maximum daily. These agents are licensed only for use in adults
(>18 y of age). Pharmacodynamics
Tramadol has effect via its two enantiomers that influence nora-
drenaline and serotonin turnover and the mu opioid receptor
TRAMADOL centrally. It is uncertain whether analgesic action is effected
Use and Formulations Available primarily in the brain or at the spinal cord level. The active M1
metabolite has a mu opioid affinity approximately 200 to 300 times
Tramadol is effective for moderate to severe pain and is used greater than that of tramadol. Naloxone administration parti-
increasingly in pediatrics for perioperative analgesia.84 It has also ally inhibits tramadol’s analgesic effect by 30%. Analgesic effect
been used in postoperative shivering and chronic pediatric pain in children having urologic or abdominal surgery is associated
including complex regional pain syndrome. It is available in
with a plasma concentration of tramadol 100 ng/mL and M1 of
capsule (including extended release), oral drops, and parenteral
15 ng/mL.92
formulations. The latter has been used epidurally in children and
subcutaneously in adults. Some countries have a suppository form A review of tramadol’s effectiveness reports 20 positive studies
(100 mg), whereas the solution can be rectally administered or the or case series with administration through various routes in
capsule compounded for smaller rectal dose administration. In the pediatric setting.84 A few further comparative93–97 and PK
Europe and the United States, a combination preparation with studies85,87,88 or of adjunctive3 or rescue use98 are available, two of
acetaminophen is available. which were negative.93,94 All studies to date have had small sample
sizes and were performed across various pediatric age groups.
Doses assessed ranged from 0.5 to 3 mg/kg via oral,84 I.V. bolus,84,93
Pharmacokinetics intramuscular bolus,84 rectal (single and repeat dosing),84 and
Studies of systemic tramadol use in neonates and infants are caudal/epidural.84 I.V. bolus and infusions of 100 to 333 μg/
limited with minimal PK data. In adults, the bioavailability after kg/h84,85,87,90 and patient-controlled analgesia (PCA; 200 μg/kg
single oral dosing is 68%, which increases with repeat dosing. bolus)97 and nurse-controlled analgesia84 (300 μg/kg bolus) (10-
Cmax is reached at 2 hours after oral dosing, 0.5 hour in children min lockout) have also been assessed. Tramadol was compared
after oral drop and caudal administration, 0.3 hour after I.V. with itself at different doses, with opioids (intramuscular and I.V.
administration, and 2.4 hours after rectal administration.84 In the pethidine,84,93 nalbuphine,84 epidural,84,95 and PCA morphine97),
neonate, there is a significant delay (4 h after administration) NSAIDs,84,94 paracetamol,84 local anesthetic (nerve blocks84 and
before blood and CSF tramadol concentrations fully equilibrate.85 epidural84,95,96). The equianalgesic doses of the comparators are
Absorption from the rectal route was assessed in a small number not established. The majority of reports have been in adeno-
of children aged 1 to 6 years (B = 12) and demonstrated low tonsillectomy patients84,97; the other surgery types have included
interindividual variability.86 neurosurgery,84,85 urogenital,84,95 inguinal hernia,84,96 neonatal
Tramadol undergoes extensive liver metabolism and is subject general3,84,87,88,99 and cardiac84,87,88 surgery, post burns, multitrauma,
to first-pass effect after oral administration. Its primary metabolite and malignancy.84
Adverse Effects and Drug Interactions GLUCOSE AND SUCROSE

Flushing, sweating, dizziness, and nausea are frequent with rapid (SUGAR) SOLUTIONS
I.V. administration. Tramadol’s adverse effects are otherwise similar Use and Formulations Available
to those of opioids84 with similar or reduced rates of nausea and
vomiting (10–40%), sedation and fatigue, less constipation and Lay people and medical staff alike have used sugar to settle neo-
pruritus, and no pediatric reports of respiratory depression. nates over the decades. Sucrose (a disaccharide of glucose and
Sedation, if experienced, can be reversed in part by naloxone fructose), glucose (monosaccharide) or dextrose (which is the bio-
administration. A study in adult gynecology patients demonstrated logically active stereoisomer form: D-glucose) solutions of varying
oxygen desaturation with morphine but not with tramadol,100 and concentrations have been used.
a placebo-controlled study of children undergoing halothane
anesthesia showed lowest respiratory rates and highest end-tidal
Mechanism of Action and Efficacy
carbon dioxide pressure (ETCO2) recordings in pethidine-treated
patients 1 mg/kg compared with tramadol 1 and 2 mg/kg.101 A Cerebral opioid peptide systems have a role in emotional, stress,
postoperative neonatal study (N = 20, English abstract only and pain responses. Those in the ventral striatum are thought to
available) reports elevation of ETCO2 dose-dependently in asso- regulate the affective response to sugar-containing foods.103
ciation with tramadol infusions of 0.1 to 0.2 mg/kg/h, but this was Although it is not well understood, oral sugar solutions likely pro-
not placebo-controlled and comments that the neonates were vide analgesia for procedural pain in neonates possibly by endoge-
frequently asleep during the assessment period.99 The respiratory nous opioid mechanisms or pathways. Oral sucrose activates
impact of tramadol may require further evaluation. Abuse- neurons in the periaqueductal gray and nucleus raphe magnus,
dependence potential of tramadol is low. two brainstem sites involved in descending pain modulation.104
Tramadol lowers the seizure threshold and may cause seizures The interaction may even be indirect with glucose inducing release
in seizure-prone patients (i.e., epilepsy or head injury). The in- of endogenous opioids.105
cidence of seizures with tramadol is estimated as greater than 1%. A Cochrane review confirms that sucrose is effective for reduc-
These have occurred in the setting of overdose, but also with ing pain from single painful events (heel lance, venipuncture).106
higher than current dosing recommendations. Care should be This is affirmed in a recent large study in neonates of diabetic and
taken in administering tramadol in conjunction with other agents nondiabetic mothers alike.107 Repeat oral drops of a 24% sucrose
that alter monoamine oxidase turnover because serotonergic solution improved the effectiveness of local anesthetic eye drops to
syndrome can occur.84 Co-administration with the antiemetic relieve pain associated with eye examinations for retinopathy of
ondansetron (a serotonin [5-HT]3 antagonist that acts at other prematurity.108 A clinical policy document produced by an Emer-
5-HT receptor subtypes) significantly reduces the efficacy of gency Medical Services for Children expert panel summarizes the
tramadol102 (via 5-HT receptor effects and/or competition for literature for sucrose.109 They conclude that use in conjunction
CYP2D6 metabolism). with a pacifier may improve its effectiveness, that the optimal tim-
ing for administration is 2 minutes before the painful procedure,
and that the evidence is most established for neonates (including
Dose and Licensing those that are preterm) younger than 28 days having minor painful
Tramadol is not licensed for oral or parenteral use for children procedures. Sucrose has been used in older infants (<6 mo old),
younger than 16 years worldwide. There is significant study and but its effect is more modest than in neonates and possibly higher
off-license use of this agent in pediatrics. concentrations are required for benefit. Sucrose was not effective
Recommendations are for loading dose of up to 3 mg/kg then for reduction of the distress associated with bladder catheteri-
1 to 2 mg/kg (maximum 100 mg) q6h. orally or I.V. and 1.5 to zation.
3 mg/kg q6h rectally; some institutions use 4-hour dosing inter-
vals. Others document a loading dose 2 to 3 mg/kg and infusion
Adverse Effects
of 5 to 8 mg/kg/24 h (200–333 μg/kg/h) in neonates.90 The 1- to
2-mg/kg dose has been used as a single epidural injection, but Adverse events associated with sucrose administration have not
tramadol is not licensed for use via this route. Animal studies been reported. The Cochrane review affirms safety of its use.106
report neurotoxicity and, because systemic absorption is high Choking, which spontaneously resolved, has occurred in a
from the epidural space, continued administration by the epidural placebo-treated patient. Desaturation during the intervention
route is not recommended.84 Wound infiltration and use of trama- occurred infrequently and similarly in sucrose- and placebo-
dol in nerve blocks has been performed (in adults) and requires treated neonates.109
further assessment. Maximum dosing recommendations are for
8 or 400 mg daily, although some institutions use higher daily
maximums.
Dose
A bolus of tramadol hydrochloride 1 mg/kg will achieve a The optimally effective sucrose dose for preterm and/or term
target concentration of 300 μg/L. This concentration can be infants is not yet established: doses that have been used include
maintained by infusion of tramadol in different age groups of 0.1 mL of 24% to 2 mL of 50%; the most commonly studied
0.09 mg/kg/h at 25 weeks PMA, 0.14 mg/kg/h at 30 weeks PMA, dose is 2 mL of 24%. Sucrose use in combination with other
0.17 mg/kg/h at 35 weeks PMA, 0.18 mg/kg/h at 40 weeks PMA, behavioral (e.g., swaddling, kangaroo care) and pharmacologic
0.19 mg/kg/h at 50 weeks PMA to 1 year, 0.18 mg/kg/h at 3 years, (e.g., morphine, fentanyl) interventions requires further investi-
and 0.12 mg/kg/h in adulthood.87 gation.107
REFERENCES 27. Allegaert K, Murat I, Anderson BJ. Not all intravenous paracetamol
formulations are created equal. Paediatr Anaesth. 2007;17:811–812.
1. Murat I, Baujard C, Foussat C, et al. Tolerance and analgesic efficacy of a 28. Bartocci M, Lundeberg S. Intravenous paracetamol: the “Stockholm
new I.V. paracetamol solution in children after inguinal hernia repair. protocol” for postoperative analgesia of term and preterm neonates.
Paediatr Anaesth. 2005;15:663–670. Paediatr Anaesth. 2007;17:1120–1121.
2. Palmer GM, Chen SP, Smith KR, Hardikar W. Introduction and audit of 29. Livingstone HL, Marcus RJ. Which preparation of paracetamol? An audit
intravenous paracetamol at a tertiary paediatric teaching hospital. Anaesth of usage and costs. Paediatr Anaesth. 2007;17:1009–1010.
Intensive Care. 2007;35:702–706. 30. Dsida RM, Wheeler M, Birmingham PK, et al. Age-stratified pharmaco-
3. Palmer GM, Atkins M, Anderson BJ, et al. I.V. acetaminophen pharma- kinetics of ketorolac tromethamine in pediatric surgical patients. Anesth
cokinetics in neonates after multiple doses. Br J Anaesth. 2008;101: Analg. 2002;94:266–270.
523–530. 31. Litalien C, Jacqz-Aigrain E. Risks and benefits of nonsteroidal anti-
4. Capici F, Ingelmo PM, Davidson A, et al. Randomized controlled trial of inflammatory drugs in children: a comparison with paracetamol. Paediatr
duration of analgesia following intravenous or rectal acetaminophen after Drugs. 2001;3:817–858.
adenotonsillectomy in children. Br J Anaesth. 2008;100:251–255. 32. Aranda JV, Varvarigou A, Beharry K, et al. Pharmacokinetics and protein
5. Anderson BJ, van Lingen RA, Hansen TG, et al. Acetaminophen develop- binding of intravenous ibuprofen in the premature newborn infant. Acta
mental pharmacokinetics in premature neonates and infants: a pooled Paediatr. 1997;86:289–293.
population analysis. Anesthesiology. 2002;96:1336–1345. 33. Van Overmeire B, Touw D, Schepens PJ, et al. Ibuprofen pharmacokine-
6. Anderson BJ, Woollard GA, Holford NH. A model for size and age tics in preterm infants with patent ductus arteriosus. Clin Pharmacol Ther.
changes in the pharmacokinetics of paracetamol in neonates, infants and 2001;70:336–343.
children. Br J Clin Pharmacol. 2000;50:125–134. 34. Scott CS, Retsch-Bogart GZ, Kustra RP, et al. The pharmacokinetics of
7. Allegaert K, Anderson BJ, Naulaers G, et al. Intravenous paracetamol ibuprofen suspension, chewable tablets, and tablets in children with cystic
(propacetamol) pharmacokinetics in term and preterm neonates. Eur J fibrosis. J Pediatr. 1999;134:58–63.
Clin Pharmacol. 2004;60:191–197. 35. Smyth JM, Collier PS, Darwish M, et al. Intravenous indometacin in
8. Arana A, Morton NS, Hansen TG. Treatment with paracetamol in infants. preterm infants with symptomatic patent ductus arteriosus. A population
Acta Anaesthesiol Scand. 2001;45:20–29. pharmacokinetic study. Br J Clin Pharmacol. 2004;58:249–258.
9. Wurthwein G, Koling S, Reich A, et al. Pharmacokinetics of intravenous 36. Topic E, Stefanovic M, Samardzija M. Association between the CYP2C9
paracetamol in children and adolescents under major surgery. Eur J Clin polymorphism and the drug metabolism phenotype. Clin Chem Lab Med.
Pharmacol. 2005;60:883–888. 2004;42:72–78.
10. Anderson BJ, Pons G, Autret-Leca E, et al. Pediatric intravenous parace- 37. Garcia-Martin E, Martinez C, Tabares B, et al. Interindividual variability
tamol (propacetamol) pharmacokinetics: a population analysis. Paediatr in ibuprofen pharmacokinetics is related to interaction of cytochrome
Anaesth. 2005;15:282–292. P450 2C8 and 2C9 amino acid polymorphisms. Clin Pharmacol Ther.
11. Allegaert K, Van der Marel CD, Debeer A, et al. Pharmacokinetics of 2004;76:119–127.
38. Tanaka E. Clinically important pharmacokinetic drug-drug interactions:
single dose intravenous propacetamol in neonates: effect of gestational
role of cytochrome P450 enzymes. J Clin Pharm Ther. 1998;23:403–416.
age. Arch Dis Child Fetal Neonatal Ed. 2004;89:F25–F28.
39. Menasse R, Hedwall PR, Kraetz J. Pharmacological properties of diclo-
12. van Lingen RA, Deinum JT, Quak JM, et al. Pharmacokinetics and
fenac sodium and its metabolites. Scand J Rheumatol Suppl. 1978;22:
metabolism of rectally administered paracetamol in preterm neonates.
5–16.
Arch Dis Child Fetal Neonatal Ed. 1999;80:F59–F63.
40. van der Marel CD, Anderson BJ, Romsing J, et al. Diclofenac and meta-
13. Miller RP, Roberts RJ, Fischer LT. Acetaminophen elimination kinetics in bolite pharmacokinetics in children. Paediatr Anaesth. 2004;14:443–451.
neonates, children and adults. Clin Pharmacol Ther. 1976;19:284–294. 41. Standing JF, Howard RF, Johnson A, et al. Population pharmacokinetics
14. Ameer B, Divoll M, Abernethy DR, et al. Absolute and relative bioavail- of oral diclofenac for acute pain in children. Br J Clin Pharmacol.
ability of oral acetaminophen preparations. J Pharm Sci. 1983;72:955–958. 2008;66:846–853.
15. Anderson BJ, Holford NH, Woollard GA, Chan PL. Paracetamol plasma 42. Kyllonen M, Olkkola KT, Seppala T, Ryhanen P. Perioperative pharma-
and cerebrospinal fluid pharmacokinetics in children. Br J Clin Phar- cokinetics of ibuprofen enantiomers after rectal administration. Paediatr
macol. 1998;46:237–243. Anaesth. 2005;15:566–573.
16. Anderson BJ, Woolard GA, Holford NH. Pharmacokinetics of rectal 43. Gregoire N, Gualano V, Geneteau A, et al. Population pharmacokinetics
paracetamol after major surgery in children. Paediatr Anaesth. 1995;5: of ibuprofen enantiomers in very premature neonates. J Clin Pharmacol.
237–242. 2004;44:1114–1124.
17. Montgomery CJ, McCormack JP, Reichert CC, Marsland CP. Plasma 44. Jackson ID, Heidemann BH, Wilson J, et al. Double-blind, randomized,
concentrations after high-dose (45 mg.kg –1) rectal acetaminophen in placebo-controlled trial comparing rofecoxib with dexketoprofen
children. Can J Anaesth. 1995;42:982–986. trometamol in surgical dentistry. Br J Anaesth. 2004;92:675–680.
18. Anderson BJ. Paracetamol (acetaminophen): mechanisms of action. 45. Gaitan G, Herrero JF. Subanalgesic doses of dexketoprofen and HCT-2037
Paediatr Anesth. 2008;18:915–921. (nitrodexketoprofen) enhance fentanyl antinociception in monoarthritic
19. Pickering G, Esteve V, Loriot MA, et al. Acetaminophen reinforces des- rats. Pharmacol Biochem Behav. 2005;80:327–332.
cending inhibitory pain pathways. Clin Pharmacol Ther. 2008;84:47–51. 46. Kokki H, Kumpulainen E, Lehtonen M, et al. Cerebrospinal fluid distri-
20. Anderson BJ, Woollard GA, Holford NH. Acetaminophen analgesia in bution of ibuprofen after intravenous administration in children.
children: placebo effect and pain resolution after tonsillectomy. Eur J Clin Pediatrics. 2007;120:e1002–e1008.
Pharmacol. 2001;57:559–569. 47. Romsing J, Ostergaard D, Drozdziewicz D, et al. Diclofenac or acetamino-
21. Gibb IA, Anderson BJ. Paracetamol (acetaminophen) pharmacodyna- phen for analgesia in paediatric tonsillectomy outpatients. Acta Anaesthe-
mics: interpreting the plasma concentration. Arch Dis Child. 2008;93: siol Scand. 2000;44:291–295.
241–247. 48. Tay CLM, Tan S. Diclofenac or paracetamol for analgesia in paediatric
22. van der Marel CD, Anderson BJ, Pluim MAL, et al. Acetaminophen in myringotomy outpatients. Anaesth Intensive Care. 2002;30:55–59.
cerebrospinal fluid in children. Eur J Clin Pharmacol. 2003;59:297–302. 49. Kokki H. Nonsteroidal anti-inflammatory drugs for postoperative pain:
23. Allegaert K, Verbesselt R, Devlieger H, et al. Cerebrospinal fluid pharma- a focus on children. Paediatr Drugs. 2003;5:103–123.
cokinetics of paracetamol after intravenous propacetamol in a former 50. Hiller A, Meretoja OA, Korpela R, Piiparinen S, Taivainen T. The analge-
preterm infant. Br J Clin Pharmacol. 2004;57:224–225. sic efficacy of acetaminophen, ketoprofen, or their combination for pedi-
24. Alhashemi JA, Daghistani MF. Effects of intraoperative I.V. acetamino- atric surgical patients having soft tissue or orthopedic procedures. Anesth
phen vs I.M. meperidine on post-tonsillectomy pain in children. Br J Analg. 2006;102:1365–1371.
Anaesth. 2006;96:790–795. 51. Riad W, Moussa A. Pre-operative analgesia with rectal diclofenac and/or
25. Alhashemi JA, Daghistani MF. Effect of intraoperative intravenous paracetamol in children undergoing inguinal hernia repair. Anaesthesia.
acetaminophen vs. intramuscular meperidine on pain and discharge time 2007;62:1241–1245.
after paediatric dental restoration. Eur J Anaesthesiol. 2007;24:128–133. 52. Pickering AE, Bridge HS, Nolan J, Stoddart PA. Double-blind, placebo-
26. Kearns GL, Leeder JS, Wasserman GS. Acetaminophen overdose with controlled analgesic study of ibuprofen or rofecoxib in combination with
therapeutic intent. J Pediatr. 1998;132:5–8. paracetamol for tonsillectomy in children. Br J Anaesth. 2002;88:72–77.
53. Viitanen H, Tuominen N, Vaaraniemi H, et al. Analgesic efficacy of rectal 81. Bombardier C. An evidence-based evaluation of the gastrointestinal
acetaminophen and ibuprofen alone or in combination for paediatric day- safety of coxibs. Am J Cardiol. 2002;89(6A):21.
case adenoidectomy. Br J Anaesth. 2003;91:363–367. 82. Jones SF, Power I. Postoperative NSAIDs and COX-2 inhibitors: cardio-
54. Anderson BJ. Comparing the efficacy of NSAIDs and paracetamol in vascular risks and benefits. Br J Anaesth. 2005;95:281–24.
children. Paediatr Anaesth. 2004;14:201–217. 83. West PM, Fernandez C. Safety of COX-2 inhibitors in asthma patients
55. Lesko SM. The safety of ibuprofen suspension in children. Int J Clin Pract with aspirin hypersensitivity. Ann Pharmacother. 2003;37:1497–1501.
Suppl. 2003;135:50–53. 84. Bozkurt P. Use of tramadol in children. Paediatr Anaesth. 2005;15:
56. Allegaert K, Cossey V, Debeer A, et al. The impact of ibuprofen on renal 1041–1047.
clearance in preterm infants is independent of the gestational age. Pediatr 85. Allegaert K, de Hoon J, Verbesselt R, et al. Tramadol concentrations in
Nephrol. 2005;20:740–743. blood and in cerebrospinal fluid in a neonate. Eur J Clin Pharmacol.
57. Allegaert K, Cossey V, Langhendries JP, et al. Effects of co-administration 2005;60:911–913.
of ibuprofen-lysine on the pharmacokinetics of amikacin in preterm 86. Zwaveling J, Bubbers S, van Meurs AH, et al. Pharmacokinetics of rectal
infants during the first days of life. Biol Neonate. 2004;86:207–211. tramadol in postoperative paediatric patients. Br J Anaesth. 2004;93:
58. Taber SS, Mueller BA. Drug-associated renal dysfunction. Crit Care Clin. 224–227.
2006;22:357–374. 87. Allegaert K, Anderson BJ, Verbesselt R, et al. Tramadol disposition in
59. Andreoli SP. Acute renal failure in the newborn. Semin Perinatol. 2004; the very young: an attempt to assess in vivo cytochrome P-450 2D6
28:112–123. activity. Br J Anaesth. 2005;95:231–239.
60. Aranda JV, Thomas R. Systematic review: intravenous Ibuprofen in 88. Allegaert K, van den Anker JN, de Hoon JN, et al. Covariates of tramadol
preterm newborns. Semin Perinatol. 2006;30:114–120. disposition in the first months of life. Br J Anaesth. 2008;100:525–532.
61. Gupta A, Daggett C, Drant S, et al. Prospective randomized trial of 89. Allegaert K, Van den Anker JN, Verbesselt R, et al. O-Demethylation
ketorolac after congenital heart surgery. J Cardiothorac Vasc Anesth. of tramadol in the first months of life. Eur J Clin Pharmacol. 2005;61:
2004;18:454–457. 837–842.
62. Ment LR, Vohr BR, Makuch RW, et al. Prevention of intraventricular 90. Allegaert K, van Schaik RHN, Vermeersch S, et al. Postmenstrual age
hemorrhage by indomethacin in male preterm infants. J Pediatr. 2004;145: and CYP2D6 polymorphisms determine tramadol O-demethylation in
832–834. critically ill neonates and infants. Pediatr Res. 2008;63:674–679.
63. Cherif A, Jabnoun S, Khrouf N. Oral ibuprofen in early curative closure 91. Williams DG, Patel A, Howard RF. Pharmacogenetics of codeine meta-
of patent ductus arteriosus in very premature infants. Am J Perinatol. bolism in an urban population of children and its implications for
2007;24:339–345. analgesic reliability. BJA: Br J Anaesth. 2002;89:839–845.
64. Krishna S, Hughes LF, Lin SY. Postoperative hemorrhage with nonste- 92. Garrido MJ, Habre W, Rombout F, Troconiz IF. Population pharma-
roidal anti-inflammatory drug use after tonsillectomy: a meta-analysis. cokinetic/pharmacodynamic modelling of the analgesic effects of
Arch Otolaryngol Head Neck Surg. 2003;129:1086–1089. tramadol in pediatrics. Pharm Res. 2006;23:2014–2023.
65. Marret E, Flahault A, Samama C-M, Bonnet F. Effects of postoperative, 93. Ozer Z, Gorur K, Altunkan AA, et al. Efficacy of tramadol versus
nonsteroidal, antiinflammatory drugs on bleeding risk after tonsillec- meperidine for pain relief and safe recovery after adenotonsillectomy.
tomy: meta-analysis of randomized, controlled trials. Anesthesiology. Eur J Anaesthesiol. 2003;20:920–924.
94. Antila H, Manner T, Kuurila K, et al. Ketoprofen and tramadol for
2003;98:1497–1502.
analgesia during early recovery after tonsillectomy in children. Paediatr
66. Moiniche S, Romsing J, Dahl JB, Tramer MR. Nonsteroidal antiinflamma-
Anaesth. 2006;16:548–553.
tory drugs and the risk of operative site bleeding after tonsillectomy: a
95. Demiraran Y, Kocaman B, Akman RY. A comparison of the post-
quantitative systematic review. Anesth Analg. 2003;96:68–77.
operative analgesic efficacy of single-dose epidural tramadol versus
67. Cardwell M, Siviter G, Smith A. Non-steroidal anti-inflammatory drugs
morphine in children. Br J Anaesth. 2005;95:510–513.
and perioperative bleeding in paediatric tonsillectomy. Cochrane Database
96. Prakash S, Tyagi R, Gogia AR, Singh R. Efficacy of three doses of
Syst Rev. 2005:CD003591.
tramadol with bupivacaine for caudal analgesia in paediatric inguinal
68. Eustace N, O’Hare B. Use of nonsteroidal anti-inflammatory drugs in in- herniotomy. Br J Anaesth. 2006;97:385–388.
fants. A survey of members of the Association of Paediatric Anaesthetists 97. Ozalevli M, Unlugenc H, Tuncer U, et al. Comparison of morphine and
of Great Britain and Ireland. Paediatr Anaesth. 2007;17:464–469. tramadol by patient-controlled analgesia for postoperative analgesia after
69. Mills N, Anderson BJ, Barber C, et al. Day stay pediatric tonsillectomy— tonsillectomy in children. Paediatr Anaesth. 2005;15:979–984.
a safe procedure. Int J Pediatr Otorhinolaryngol. 2004;68:1367–1373. 98. Aydin ON, Ugur B, Ozgun S, et al. Pain prevention with intraoperative
70. Naulaers G, Delanghe G, Allegaert K, et al. Ibuprofen and cerebral oxy- ketamine in outpatient children undergoing tonsillectomy or tonsillec-
genation and circulation. Arch Dis Child Fetal Neonatal Ed. 2005;90: tomy and adenotomy. J Clin Anesth. 2007;19:115–119.
F75–6. 99. Mikhel’son VA, Zhirkova IuV, Beliaeva ID, et al. [Postoperative analgesia
71. Palmer GM. A teenager with severe asthma exacerbation following with tramal in newborn children using the method of continuous
ibuprofen. Anaesth Intensive Care. 2005;33:261–265. intravenous infusion] (Russian). Anest Reanimatol. 2003;1:24–28.
72. Lesko SM, Louik C, Vezina RM, Mitchell AA. Asthma morbidity after the 100. Houmes RJ, Voets MA, Verkaaik A, et al. Efficacy and safety of tramadol
short-term use of ibuprofen in children. Pediatrics. 2002;109:E20. versus morphine for moderate and severe postoperative pain with
73. Short JA, Barr CA, Palmer CD, et al. Use of diclofenac in children with special regard to respiratory depression. Anesth Analg. 1992;74:510–514.
asthma. Anaesthesia. 2000;55:334–337. 101. Bosenberg AT, Ratcliffe S. The respiratory effects of tramadol in children
74. Varner AE. Beneficial effect of nonsteroidal anti-inflammatory drugs and under halothane an anaesthesia. Anaesthesia. 1998;53:960–964.
cyclooxygenase-2 inhibitors in patients with asthma during viral infec- 102. Arcioni R, della Rocca M, Romano S, et al. Ondansetron inhibits the
tion. J Infect Dis. 2002;186:723; author reply 724. analgesic effects of tramadol: a possible 5-HT spinal receptor involve-
75. Levin RI. Theriac found? Nitric oxide-aspirin and the search for the ment in acute pain in humans. Anesth Analg. 2002;94:1553–1557, table
universal cure. J Am Coll Cardiol. 2004;44:642–643. of contents.
76. Tacconelli S, Capone ML, Patrignani P. Clinical pharmacology of novel 103. Kelley AE, Will MJ, Steininger TL, et al. Restricted daily consumption of
selective COX-2 inhibitors. Curr Pharm Des. 2004;10:589–601. a highly palatable food (chocolate Ensure(R)) alters striatal enkephalin
77. Sheeran PW, Rose JB, Fazi LM, et al. Rofecoxib administration to gene expression. Eur J Neurosci. 2003;18:2592–2598.
paediatric patients undergoing adenotonsillectomy. Paediatr Anaesth. 104. Anseloni VC, Ren K, Dubner R, Ennis M. A brainstem substrate for
2004;14:579–583. analgesia elicited by intraoral sucrose. Neuroscience. 2005;133:231–243.
78. Joshi W, Connelly NR, Reuben SS, et al. An evaluation of the safety and 105. Kracke GR, Uthoff KA, Tobias JD. Sugar solution analgesia: the effects
efficacy of administering rofecoxib for postoperative pain management. of glucose on expressed mu opioid receptors. Anesth Analg. 2005;101:64–
Anesth Analg. 2003;97:35–38, table of contents. 68, table of contents.
79. Vallee E, Carignan M, Lafrenaye S, Dorion D. Comparative study 106. Stevens B, Yamada J, Ohlsson A. Sucrose for analgesia in newborn
of acetaminophen-morphine versus rofecoxib-morphine for post- infants undergoing painful procedures. Cochrane Database Syst Rev.
tonsillectomy pain control. J Otolaryngol. 2007;36:264–269. 2004;3:CD001069.
80. Bean-Lijewski JD, Kruitbosch SH, Hutchinson L, Browne B. Post- 107. Taddio A, Shah V, Hancock R, et al. Effectiveness of sucrose analgesia in
tonsillectomy pain management in children: can we do better? Otolaryn- newborns undergoing painful medical procedures.[see comment].
gol Head Neck Surg. 2007;137:545–551. CMAJ. 2008;179:37–43.
108. Mitchell A, Stevens B, Mungan N, et al. Analgesic effects of oral sucrose 111. Hirt D, Van Overmeire B, Treluyer J-M, et al. An optimized ibuprofen
and pacifier during eye examinations for retinopathy of prematurity. dosing scheme for preterm neonates with patent ductus arteriosus, based
Pain Manag Nurs. 2004;5:160–168. on a population pharmacokinetic and pharmacodynamic study. Br J Clin
109. Mace SE, Brown LA, Francis L, et al. EMSC Panel on Critical Issues Pharmacol. 2008;65:629–636.
in the Sedation of Pediatric Patients in the Emergency Depart- 112. Aly H, Lotfy W, Badrawi N, et al. Oral Ibuprofen and ductus arteriosus
ment Clinical Policy: critical issues in the sedation of pediatric in premature infants: a randomized pilot study. Am J Perinatol. 2007;24:
patients in the emergency department. Ann Emerg Med. 2008;51: 267–270.
378–399. 113. Aronoff DM, Oates JA, Boutaud O. New insights into the mechanism of
110. Gilron I, Milne B, Hong M. Cyclooxygenase-2 inhibitors in post- action of acetaminophen: its clinical pharmacologic characteristics
operative pain management: current evidence and future directions. reflect its inhibition of the two prostaglandin H2 synthases. Clin Pharma-
Anesthesiology. 2003;99:1198–1208. col Ther. 2006;79:9–19.
Neuromuscular Blocking
27 Agents in Children
C H A P T E R Olli A. Meretoja and Hannu Kokki
INTRODUCTION Acetylcholine is continuously inactivated by acetylcholine-

sterase, an enzyme present in the junctional cleft. The amount
Neuromuscular blocking drugs (NMBDs; muscle relaxants) are of released acetylcholine and its capacity to attach with the
commonly used to enable smooth endotracheal intubation in postjunctional acetylcholine receptor determines whether the
pediatric practice. During surgical procedures, muscle relaxants ion channel of the muscle cell membrane will be open or closed.
are used, as adjuncts to general anesthetics and analgesics, to Because the same receptive sites are the binding sites of nondepo-
prevent muscle movements and to provide muscle flaccidity larizing muscle relaxants, the competition between acetylcholine,
making surgical procedures easier and safer to perform. These the muscle relaxant, and acetylcholinesterase ultimately deter-
drugs are also used to facilitate mechanical ventilation in intensive mines the probability of a successful neurotransmission across the
care patients who fail to respond to sedation alone. junctional cleft.
Muscle relaxants act at the neuromuscular junction. Striated Since about 2000, we have witnessed significant changes in the
muscle fibers are in close contact with motor nerve terminals to use of muscle relaxants. Our understanding of the overall actions
form neuromuscular junctions containing millions of receptors of muscle relaxants and performance of different compounds has
per single muscle fiber. A nerve impulse will generate an ejection expanded. This, combined with the knowledge of the variability of
of the neurotransmitter, acetylcholine, from the storage vesicles of the effects of NMBDs both in healthy children and in children
the nerve terminals into the junctional cleft (a narrow space with diseases and conditions that may affect the neuromuscular
between the nerve terminal and the motor endplate of the muscle block, has resulted in more rational and safe use of muscle
fiber). The postjunctional acetylcholine receptor consists of five relaxants in pediatric patients.
protein subunits in a rosette shape with a central ion channel The use of muscle relaxants has declined in pediatric anesthesia
(Figure 27–1). and intensive care.1,2 There have been several reasons for this
Two receptive sites, formed by αε and αδ subunits, are the development. First, the current widespread use of laryngeal mask
binding sites for acetylcholine and the NMBDs. The ion channel airway has decreased the number of patients requiring tracheal
activation takes place only if both receptive sites are simu- intubation to maintain the airway. Contrary to endotracheal tube
ltaneously attached with acetylcholine molecules. Activation of placement, laryngeal mask airway is inserted without aid from
the receptor allows sodium and potassium currents to cross the muscle relaxants. Second, the introduction of the short-acting
ion channel based on their concentration gradients. Sodium anesthetics and analgesics remifentanil, propofol, and sevoflurane
current into the muscle cell is enhanced by the negative resting has allowed intubation and maintenance of sufficient muscle
potential inside the cell. This current makes the inside of a muscle flaccidity during procedures without muscle relaxation.3 However,
cell less negative. If hundreds of thousands of receptors become a balanced approach combining intravenous or inhalation anes-
activated simultaneously, the depolarization will create an action thesia with intravenous analgesia and muscle relaxation provides
potential with subsequent contraction of the muscle fiber. the best intubating conditions with the lowest level of adverse
effects. Third, the common use of regional anesthesia techniques
as adjuncts to general anesthesia has also decreased the need
for muscle relaxants because higher concentrations of local
anesthetics produce not only analgesia but also muscle relaxation.
In these cases, there is no need for repeat doses or continuous
infusion of muscle relaxant, only the intubation dose may be
sufficient. A constant need for deep muscle paralysis during
surgery is uncommon, and consequently, the dose of muscle
relaxant should be administered according to surgical needs.
Sugammadex, a novel NMBD antagonist, may allow more liberal
use of muscle relaxants especially in daycase surgery because the
Figure 27-1. A schematic view of an acetylcholine receptor risk of residual curarization becomes minimal.
with five subunits and a central ion channel in a cell membrane Contrasting this overall decrease in the use of muscle relaxants,
of a muscle fiber. The α subunits contain the binding site for the benefits of muscle relaxants in other situations have been
acetylcholine and muscle relaxants. In neonates, the ε subunit is recognized. It has been demonstrated that the use of a muscle
replaced by a γ subunit. relaxant facilitates intubation in nonemergency conditions in
CHAPTER 27 ■ Neuromuscular Blocking Agents in Children 417
neonates, thereby decreasing the incidence and duration of muscle relaxant doses are minimal, and halothane may decrease
hypoxia and time and number of attempts needed to successfully relaxant dosage by a maximum of 20 to 30%.
complete the procedure. During muscle relaxation with mivac- It was long uncertain how neonates, infants, or children differ
urium, easy mask ventilation and superior intubation conditions from adults in their response to nondepolarizing muscle relaxants.
are achieved, permitting a high success rate.4,5 Some early studies showed neonates to be particularly sensitive to
The impact of residual neuromuscular blockade on patients’ the effects of pancuronium and D-tubocurarine.11–14 Conflicting
safety is better recognized since the beginning of the 2000s. Now results also existed because of nonuniform or absent monitoring
it is understood that full recovery of neuromuscular function (i.e., or different anesthesia methods.15–17 More recent pharmacokinetic
train-of-four [TOF] ratio > 0.9) at the end of surgery is mandatory and pharmacodynamic studies have made it possible to better
before the patient can be required to breathe spontaneously and understand infants’ sensitivity and children’s resistance to non-
in order to avoid the risk of aspiration associated with the im- depolarizing muscle relaxants.18–20
pairment of pharyngeal muscle function.6 Recent studies have It is mandatory to monitor the neuromuscular function while
established a high between-individual variation in the response to using neuromuscular blockers in clinical practice because of
muscle relaxants. There are up to fivefold differences in both the significant between-individual variability in the response and
onset time and the duration of block even with short-acting the numerous pharmacodynamic interactions with other drugs
compounds. Thus, the monitoring of block level is essential for given during anesthesia. There are no clinical clues, especially
safe use of relaxants and in order to avoid residual block after during inhalation anesthesia, to guess the depth of neuromuscular
surgery. blockade before the child is fully awake after anesthesia.
The high between-individual variation in the response is the
main reason why priming, once a popular approach, is not used
anymore. In sensitive children, even the small priming dose of DEVELOPMENTAL PHYSIOLOGY
muscle relaxant may provide relatively deep muscle blockade, IN NEUROMUSCULAR FUNCTION
whereas in more-resistant children, a small priming dose achieves
minimal response. General Considerations
There are two main types of NMBDs: (1) competitive, non- The five subunits of a postjunctional acetylcholine receptor are
depolarizing muscle relaxants and (2) depolarizing neuromuscular the two α, one β, δ, and ε subunits. Both α subunits are stereo-
blockers. The nondepolarizing muscle relaxants may further be chemically different owing to their neighbor subunits (see Figure
divided into two structurally different types: the aminosteroidal 27–1). This may result in different affinity of the two α subunits
muscle relaxants and the benzylisoquinolinium muscle relaxants. with acetylcholine or NMBD molecules. Neonates have a γ subunit
This division is important because sugammadex, a novel new instead of an ε subunit in their neuromuscular receptor. New
neuromuscular antagonist, encapsulates aminosteroidal non-
neuromuscular receptors are created every minute because their
depolarizing muscle relaxants, but it does not interact with the
survival times are 1 to 2 weeks. If nondepolarizing relaxant mole-
benzylisoquinolinium relaxants or with succinylcholine. Thus,
cules are attached to one or both α subunits—or more precisely at
benzylisoquinolinium relaxants could be used when neuromus-
the ␣ε and ␣δ borders—of the receptor, the ion channel cannot
cular block is needed shortly after sugammadex administration.
become activated. Because only a fraction of receptors need to
Moreover, some benzylisoquinolinium compounds have unique
patterns of elimination: atracurium and cisatracurium undergo become activated simultaneously to generate contraction of a
partial spontaneous degradation via Hofmann elimination, and muscle fiber, at least 75% of the receptors have to be blocked by a
mivacurium is inactivated mainly by plasma cholinesterase. Thus, muscle relaxant to diminish the muscle contraction. Muscle
the changes in the hepatic and renal function only marginally paralysis will be established when 75 to 92% of the receptors are
affect the pharmacokinetics of these three compounds. blocked simultaneously.
All inhalation anesthetics enhance the action of nondepo- There are basically three ways to overcome the muscle paraly-
larizing muscle relaxants.7,8 The potentiation seems to be of a phar- sis. The first is to increase the amount of acetylcholine to promote
macodynamic origin.9 This is important to remember especially acetylcholine to swamp muscle relaxant in competition for the αε
when repeat doses or continuous infusion of neuromuscular and the αδ binding sites. This can be done by reducing the met-
blocker is used. When inhalation anesthetics are used concur- abolic breakdown of acetylcholine with cholinesterase inhibitors
rently with muscle relaxants, smaller and less frequent dosages are like neostigmine or edrophonium. Because the amount of acetyl-
required. A growing body of data has shown that the potentiation choline released during nerve stimulation is limited, cholinesterase
is both time- and age-dependent.10 In infants, it may take up to inhibitors cannot reverse a very profound neuromuscular block.
45 minutes before the maximum potentiation is achieved, whereas The second way to overcome muscle paralysis is to wait until the
in school-age children, the maximal potentiation in present only concentration of the muscle relaxant in junctional clefts decreases
after 90 minutes. In addition, there seems to be some differences low enough to allow acetylcholine to dominate the competition
between different inhalation anesthetics in their potential for for binding sites. The muscle relaxant concentration will decrease
pharmacodynamic interaction with muscle relaxants. Both iso- by at least two important phenomena: (1) by metabolic breakdown
flurane and sevoflurane inhalation may decrease the need of or excretion related to elimination half-life and (2) by redistribu-
muscle relaxants by up to 50 to 70% compared with the dosage tion from the junctional cleft to elsewhere in the body. Metabolism
needed during a total intravenous anesthesia. With isoflurane and is important when using relaxants with a short elimination half-
sevoflurane, the enhancement is dose-dependent, but with similar life (e.g., mivacurium, atracurium, or cisatracurium) and redistri-
minimum alveolar concentrations (MAC), both seem to provide bution for drugs such as rocuronium or vecuronium.
similar potentiation of the block. Nitrous oxide and halothane are A new approach to reverse muscle relaxation induced with
less potent adjuvants; the effects of nitrous oxide inhalation on the aminosteroidal muscle relaxants is the administration of
the cyclodextrin sugammadex that will encapsulate rocuronium type II fibers during neuromuscular block, the diaphragm func-
and, to a lesser degree, vecuronium and pancuronium. Sugam- tion is better preserved than that of peripheral muscles.
madex enables the reversal of even deep blockade in a relatively It should be remembered that, during the recovery from muscle
short time, a scenario that was not possible with other existing paralysis, neonates start to express diaphragmatic movements at a
reversal agents. deeper level of neuromuscular block monitored from the hand
Succinylcholine is the only depolarizing muscle relaxant muscles than older pediatric patients.18 It has also been clinical
currently in use.21 Its mode of action is not fully understood and observed that the human diaphragm requires close to twice the
differs from that of competitive muscle relaxants. Succinylcho- amount of muscle relaxant than hand muscles to become equally
line has great affinity to neuromuscular receptors and acts like paralyzed.27–29
acetylcholine: when succinylcholine molecules are associated with Differences in the body composition during growth may
both receptive sites of the receptor, the ion channel will become explain some of the differences in dose requirement. During early
activated and, if the numbers are large enough, ion currents life, there are major changes in the water, fat, and muscle com-
will establish a muscle contraction. Because the motor endplate partments of the human body.30 NMBDs are distributed to a
may remain depolarized owing to the continuous presence of theoretical space that mirrors the volume of the extracellular fluid
succinylcholine, no further neurotransmission will be generated compartment. This volume is close to 40% of the body weight in
and no more channel activation can take place. Prolonged depo- neonates and decreases to 22% of body weight by 1 year of age to
larization of the endplate may also produce desensitization of the remain relatively constant thereafter.30–32 The fat compartment
receptor that prevents further neurotransmission. A muscle increases from 12 to 30% of body weight during the first year of
paralysis will follow the primary muscle contractions. The muscle life. Thereafter, its relative size diminishes toward puberty.
flaccidity produced by succinylcholine wears off within minutes The muscle compartment decreases during the first year of life
owing to diffusion of succinylcholine from neuromuscular junc- to one tenth of the total body mass. Thereafter, the proportion of
tion and its rapid metabolic breakdown. the muscle compartment in relation to body weight increases to
Neuromuscular transmission is immature in neonates and reach a maximum of one third of body weight by the end of the
infants until the age of 2 months.22,23 The response to tetanic nerve active growth of a child. The increase in the proportion of muscle
stimulation and the rate of muscle contraction are less in neonates compartment is fastest after the age of 3 to 4 years.30 The actively
and infants than in children (Figure 27–2). Tetanic fade in young growing muscle tissue contributes a massive number of new
infants may indicate that newborns deplete their readily releasable acetylcholine receptors. New receptors may be more resistant to
acetylcholine vesicles more quickly than children. This may be nondepolarizing muscle relaxants, and because of their great
caused by a small quantal release of acetylcholine in neonatal number, large doses of relaxants are required to block activation
neuromuscular transmission.24 Timing of events that contribute of ion channels in children. Adults have relatively more fat and
to maturation of neuromuscular transmission is multifactorial. In less muscle tissue in their body than children, and thus, the need
general, this maturation process depends more on the duration of for muscle relaxant per kilogram of body weight is higher in
extrauterine life than on postconceptional age. children than in adults. However, to avoid excessive dosage in
The type of muscle fibers influences the response to muscle obese children, dose should be calculated on the basis of ideal
relaxants. Type I fibers (slow-twitch, high-oxidative) are generally weight for height.
more sensitive to nondepolarizing muscle relaxants than type II Table 27–1 shows effective doses of muscle relaxants (ED95; a
fibers (fast-twitch).25 The character of muscle fibers changes dose that produces a 95% neuromuscular block) in infants,
during infancy. Although 55% of muscle fibers in the diaphragm children, and adolescents. These data have been taken from the
of 2-year-old children are slow “marathon fibers” (type I) only 25% studies in which at least two different pediatric age groups have
in a term newborn and only 10% of the diaphragmatic muscle been analyzed. Although several investigators have found that
fibers in a premature neonate of less than 37 weeks’ gestation are children require greater doses of nondepolarizing muscle relaxants
slow-type fibers.26 Because the neonatal diaphragm has fewer type
I fibers that are more sensitive to neuromuscular blockers than the TABLE 27-1. ED95 Doses of Muscle Relaxants (in μg/kg)
During Nitrous Oxide–Opioid Anesthesia in Infants,
Children, and Adultsa
Compound Infants Children Adults References
Alcuronium 196 271 220 53, 231
Atracurium 231 327 210 124, 231
Cisatracurium 43 47 48 137, 143, 232
Doxacuriumb 25 53 41 66
Mivacurium 129 139 80 154, 156, 233
Pancuronium 66 93 67 55, 231
Pipecuronium 48 75 59 70, 71
Rocuronium 251 409 350 101
D-Tubocurarine 414 499 480 53, 231
Figure 27-2. The neuromuscular response of a neonate and an Vecuronium 47 81 43 82, 231
older infant to a steadily increasing stimulation frequency from Succinylcholineb 700 430 270 189, 191
1 to 100 Hz. The neonate cannot sustain the response, which is a
Values are mean.
reduced by more than 50%. Modified from reference 235. b
Denotes that adult data are for adolescents.
TABLE 27-2. Distribution Volume at Steady State and Total Plasma Clearance of Nondepolarizing Muscle Relaxants in
Infants and Children
Vss, mL/kg) CLp, mL/kg/min)
Compound Infants Children Adults Infants Children Adults References
Atracurium 210 129 100 7.9 6.8 5.3 37
Cisatracurium — 207 118 10.0 6.8 3.7 77, 81
Pipecuronium 225 185 208 1.5 2.3 2.5 38
Rocuronium 231 165 194 4.2 6.7 4.5 39
D-Tubocurarine 520 410 300 3.3 4.0 3.0 33
Vecuronium 357 204 269 5.6 5.9 5.2 35
CLp = total plasma clearance; Vss = volume at steady state.
Taken all the data together, infants have 42% greater Vss than children. For atracurium, the CLp is 16%, and for cisatracurium, 47% greater in infants than in children.
For other muscle relaxants, infants have a 26% smaller CLp than children.
(in mg/kg of body weight) than any other age group of patients, ment each other have been proposed. Meretoja and coworkers
the observation has not been fully explained. Changes in extra- investigated drug synergism and found children to have greater
cellular fluid volume cannot offer a proper explanation because synergism between atracurium and vecuronium than infants.40,41
this volume (as a percentage of total body weight) is relatively Synergism was explained by saying that, if one type of muscle
unchanged after the first year of life.30–32 relaxant diminishes the likelihood of a relaxant of different
structure becoming attached to the second ␣. subunit–receptive
sites of the same receptor (␣ε vs␣δ), then more separate receptors
Pharmacokinetic Principles become occupied and fewer relaxant molecules are needed for a
During the first year of life, the distribution volume of muscle neuromuscular block than in the case of a single muscle relaxant
relaxants decreases when calculated as milligrams per kilogram (Figure 27–3).40 Infants’ low degree of synergism could be explain-
of body weight (Table 27–2). On an average, infants have a 42 ± ed if any nondepolarizing muscle relaxant occupies predominantly
20% greater distribution volume of nondepolarizing muscle only one of the two α subunit–receptive sites in infants as opposed
relaxants than children.33–39 However, infants require a 20 to 50% to two relaxant molecules in children and adults.41 Consequently,
lower plasma concentration of muscle relaxants than children or infants use the relaxant molecules most efficiently, which is
adults to produce the same level of neuromuscular block (Table reflected in a low required plasma concentration. In children and
27–3).33,35,37,39 Because the dose requirement is the product of the adults, a greater proportion of relaxant molecules are wasted by
required concentration times distribution volume, dose require- attachment to the second set of ␣. subunits of the receptors that
ments of muscle relaxants (in mg/kg) are fairly similar in infants are already blocked by the presence of one relaxant molecule
and in adults (see Table 27–1). (see Figure 27–3).
Because the age-related changes in distribution volume and Wareham and colleagues explained the low required plasma
required plasma concentration are drug-specific, different muscle concentration of muscle relaxants in neonates and young infants
relaxants have slightly different age-dependent potencies. Fur- based on analysis of the quantal content of released acetylcholine
thermore, elimination of muscle relaxants from the body takes vehicles in growing rats.24 The authors found that neonatal rats
place via metabolism, renal or hepatic excretion, or spontaneous had a smaller amount of acetylcholine released upon a nerve
degradation. All these depend on the maturation of elimination stimulation than older rats. It was suggested that a smaller concen-
pathways and explain the different age-dependent time duration tration of muscle relaxants are needed to compete with this low
of effect of various muscle relaxants. Total plasma clearance of concentration of acetylcholine to establish a neuromuscular block.
This results in a small safety factor for neuromuscular trans-
nondepolarizing muscle relaxants D-tubocurarine, pipecuronium,
mission in neonates and infants.24
rocuronium, and vecuronium are 10 to -40% smaller in infants
than in children.33–35,38,39 Plasma clearance of atracurium takes
place partially by spontaneous degradation, which results in Importance of Anesthesia and
different pattern of drug elimination (see Table 27–2).
The question remains: why do infants require a smaller plasma
Monitoring Technique
concentration of muscle relaxants than children or adults for a The type of anesthesia and monitoring technique employed
standard neuromuscular block? Two theories that may supple- greatly influences the results from muscle relaxant studies.
TABLE 27-3. Plasma Concentration of Muscle Relaxants (in ng/mL) Required for 50% Neuromuscular Blocka
Compound Infants Children Adults References
Atracurium 363 ± 118 444 ± 121 436 ± 122 37
Rocuronium 1190 ± 380 1650 ± 380 820 ± 160 39, 234
D-Tubocurarine 270 ± 60 420 ± 140 530 ± 140 33
Vecuronium 57 ± 18 110 ± 28 94 ± 34 35
a
Values are mean ± sd.
Figure 27-4. A: Adductor pollicis electromyographic (EMG)

response to train-of-four stimulations at 10-second intervals.
The responses before rapacuronium 2.5 mg/kg (mark 1) repre-
sent 100% neuromuscular function. Twenty seconds after ra-
pacuronium, the first EMG response has decreased to 3% of
control, which indicates a 97% neuromuscular block (arrow).
B: Adductor pollicis EMG response to single-twitch stimulations
Figure 27-3. Different patterns of surgical neuromuscular at 10-second intervals. The control responses before rapacuro-
block. A: In children and adults, most receptors are occupied nium 1.0 mg/kg (mark 1) represent 100% neuromuscular func-
by two relaxant molecules. This means a “two-molecule block.” tion. Twenty seconds after rapacuronium, the EMG response
B: In infants, most receptors may be occupied by only one has decreased to 8% of control, which indicates a 92% neuro-
relaxant molecule. This means a “single-molecule block.” muscular block (arrow).
C: When synergism takes place, most receptors are occupied
by only one type of relaxant molecules. A = atracurium; V = A third objective monitoring technique uses acceleration of the
vecuronium. moving thumb and transforms this acceleration to mimic force
based on simple mathematics. This acceleromyography has been
A mechanomyographic (MMG) force transducer has long been shown to not be interchangeable with the other techniques but
regarded as a gold standard of neuromuscular monitoring. How- correlates with results from EMG monitoring in children.47,48
ever, electromyographic (EMG) recordings have values similar to Volatile anesthetic agents potentiate the effects of muscle
those from neuromuscular studies, for example, a force measure-
relaxants; isoflurane and sevoflurane produce a greater potentia-
ment and an adductor pollicis EMG recording produced similar
tion than halothane (Figure 27–5).7,8,49,50 However, this potentia-
dose-potencies: ED50 of mivacurium was 51 μg/kg from MMG
studies and 52 μg/kg from EMG studies, whereas those for tion is not an all-or-none phenomenon but bears a clear time- as
doxacurium were 19 and 19 μg/kg, respectively.42–45 In all these well as age-dependent pattern. Maximal potentiation of neuro-
studies, a TOF mode of stimulation was used at 10-second inter- muscular block produced by 1 MAC end-tidal concentration of
vals. A standardized stimulation interval is crucial because, when halothane or isoflurane was not established before 60 minutes of
TOF stimulation is used less frequently, the ED values of muscle inhalation of the volatile agent (Figure 27–6).10 Younger children
relaxants increase. A 30% difference in ED values has been obser- develop maximal potentiation quicker than older children (Figure
ved if stimulation is given once every 10 seconds instead of once 27–7). This potentiation makes comparisons between studies
every 20 seconds (Figure 27–4).46 performed under inhalational anesthesia difficult.
Figure 27-5. Dose-response curves of vecuronium during

nitrous oxide–opioid, –halothane, and –sevoflurane anesthesia.
Vecuronium has greatest potency during sevoflurane and lowest
potency during opioid anesthesia. Modified from reference 50. Figure 27-7. Children younger than 6 years old express a faster
potentiation of the neuromuscular block produced by isoflurane
Jalkanen and Meretoja have shown that 30 minutes of inha- than older children even though the maximal potentiation is
lation of 1.5% isoflurane produces much shorter onset and similar. From reference 10.
longer duration of neuromuscular block than inhalation for
10 minutes of the same concentration of isoflurane.51 Thus, the LONG-ACTING MUSCLE RELAXANTS
degree of potentiation may be different in separate studies
even though the basic anesthesia (e.g., halothane or isoflurane) Long-acting muscle relaxants are characterized by the establish-
has been the same. This interaction between inhalation anesthetics ment of surgical relaxation for 30 to 60 min after a 1.5 × ED95 dose
and muscle relaxants is especially important when the influence of (Table 27–4). Time to complete spontaneous recovery of the
age on the response to muscle relaxants is to be evaluated. The neuromuscular function after this dose is 60 to 150 minutes with
effects of nitrous oxide inhalation, barbiturates, and opioids a 25 to 75% recovery time of 30 to 60 minutes. Most long-acting
on muscle relaxant effects are minimal. This is the reason why muscle relaxants undergo little or no metabolism.
pharmacodynamic data are taken from studies carried out under Long-acting muscle relaxants should not be used in routine
nitrous oxide–barbiturate/propofol–opioid anesthesia whenever elective surgery owing to the slow spontaneous recovery of
possible. neuromuscular function and the risk of residual neuromuscular
Figure 27-6. The effect of duration

of inhalational anesthesia on infusion
rate of mivacurium to maintain a
constant 95% neuromuscular block.
The maximal potentiation is reached
not before 60 to 90 minutes of 1
minimum alveolar concentration
(MAC) end-tidal concentration of
the inhalational agent. The degree
of potentiation is sensitive to the
duration of inhalational anesthesia
if that is shorter than 1 hour. From
reference 10.
TABLE 27-4. Main Clinical Characteristics of Long-Acting Muscle Relaxants in Children

Compound First Dose, mg/kg Onset Time, min Clinical Duration, min Reversal Necessary? Common Side Effects
Alcuronium 0.30 3–4 30 Yes No
Doxacurium 0.05 5–7 40 Yes No
Pancuronium 0.10 2–3 30 Yes CV
Pipecuronium 0.10 2–3 40 Yes No
D-Tubocurarine 0.50 4–5 40 Yes CV, histamine
CV = cardiovascular.
block in the recovery room. When long-acting muscle relaxants 50% is bound to plasma proteins. Up to 75% of the dose ad-
are used, careful monitoring of neuromuscular function is manda- ministered is excreted unchanged in the urine and 10 to 12% in the
tory to properly control the depth of relaxation and to ensure bile. Only a small fraction of a dose is metabolized. Biliary excre-
sufficient recovery of neuromuscular function, that is, a TOF ratio tion is more important in patients with renal impairment, in
greater than 0.9 after surgery. whom the effects may become prolonged. Because of ganglion
These agents may be indicated for maintenance of muscle blockade and histamine release associated with D-tubocurarine, it
paralysis during long surgical procedures owing to their low direct frequently produces a fall in blood pressure and a reflex tachy-
drug costs. Some of these agents (e.g., doxacurium) have such a cardia and may also produce significant bronchospasm.
long onset time (time from administration to maximal effect) that The pattern of dose-requirement age-dependency of D-
they are not optimal agents to induce paralysis for endotracheal tubocurarine has not been reviewed since three pediatric dose-
intubation. Long-acting muscle relaxants are useful in certain response studies were carried out during the 1970s through
clinical situations such as cardiovascular anesthesia because of their 1990s.16,52,53 Patients in the oldest study received varying concen-
relatively safe cardiovascular profile. However, D-tubocurarine may trations of halothane.16 The study could not demonstrate any
produce hypotension. Pancuronium is associated with sympatho- difference in the ED95 between neonates, infants, and children.
mimetic effects, whereas doxacurium and pipecuronium are The average ED95 was 320 μg/kg, with greater variability of re-
devoid of cardiovascular adverse effects (Table 27–5). Doxacurium, sponse in younger patients.
owing to its lack of cardiovascular or cumulative properties, may be Goudsouzian and associates also evaluated D-tubocurarine in
an appropriate choice in pediatric intensive care units. Alcuronium one age group of children under a nitrous oxide–thiopental–
may give more protection against an oculocardiac reflex than opioid anesthesia and found an ED95 of 600 μg/kg.52 The last of
D-tubocurarine, pancuronium, or vecuronium. the three studies included infants, children, and adolescents
during nitrous oxide–thiopental–opioid anesthesia.53 That study
also failed to find statistical age-related differences in ED95 even
D-Tubocurarine though values in infants were 20% lower than values in children
D-Tubocurarine is a monoquaternary isoquinolinium muscle (414 μg/kg vs 499 μg/kg) (see Table 27–1).
relaxant with a molecular weight of 771.7 daltons (Da). Less than The onset time of D-tubocurarine is shorter in infants than
that in children.53,54 Time to establish a 90% neuromuscular block
was 1.6 and 5.2 minutes in infants and children, respectively,
TABLE 27-5. Cardiovascular Effects of Muscle Relaxants following a dose of 400 μg/kg during halothane anesthesia.54 The
and Their Antagonists 5-minute onset time of D-tubocurarine is clinically so long that it
is unpractical (and sometimes unsafe) to use this agent for endo-
Alcuronium Minimal effects tracheal intubation.16,34 Duration of effect and rate of spontaneous
Atracurium No effects (possibility for histamine release) recovery of neuromuscular function following D-tubocurarine
Cisatracurium No effects are similar in infants and children16,34 and may be slightly longer
Doxacurium No effects in infants.54
Edrophonium Bradycardia (cholinergic) Two pediatric pharmacokinetic D-tubocurarine studies are
Mivacurium Minimal effects (possibility for histamine conflicting.33,34 Both studies demonstrate that neonates and infants
release) have a larger distribution volume than children or adults. Fisher
Neostigmine Bradycardia (cholinergic) and coworkers noticed that neonates and infants require a lower
Pancuronium Tachycardia, increased blood pressure plasma concentration of curare than children or adults to maintain
(vagolytic action) a standard neuromuscular block.33 By contrast, Matteo and
Pipecuronium No effects colleagues did not find any difference in the plasma concentration
Rapacuronium No data available of curare between neonates, infants, children, and adults required
Rocuronium Increase in heart rate and blood pressure to produce similar degrees of neuromuscular block (see Table
(vagolytic effect)
27–3).34 Both studies showed that elimination of D-tubocurarine
Succinylcholine Multiple arrhythmias (cholinergic)
was slower in neonates and infants than in children or adults (see
D-Tubocurarine Decreased blood pressure (ganglion
Table 27–2). This would indicate a prolonged duration of effect in
blockade, histamine release)
infancy after multiple doses or a large single dose. The 24-hour
Vecuronium No effects (possibility for bradycardia with
urinary excretion of D-tubocurarine is much less in neonates than
opioids)
in adults (27% vs 45% of a total dose).34
Figure 27-8. The dose-response curves of long-acting nondepolarizing muscle relaxants in infants (I)
and children (C).53,55,66 The curves for children are to the right of the respective curves for infants.
Pancuronium onset time to 90% neuromuscular block following pancuronium

70 during halothane anesthesia is 1.3 minutes in infants and 2.7
Pancuronium is a steroidal bisquaternary muscle relaxant with a minutes in children 10 years of age (see Table 27–5).56 Larger doses
molecular weight of 732.7 Da. About 80% may be bound to plasma of pancuronium establish 95% neuromuscular block more quickly,
proteins. Pancuronium is partially (15–20%) deacetylated in for example, a dose of 150 μg/kg has an onset time of 1.3 ± 0.6
the liver to produce 3-OH, 17-OH, and 3,17-diOH metabolites, minutes in children 2 to 8 years old.57
the first of which has a weak neuromuscular activity. A major In children, pancuronium has a much shorter clinical duration
proportion of pancuronium is excreted in the urine (40–60%) and of effect than D-tubocurarine. This duration following an ED95
in the bile (11%). Slightly prolonged effect can be expected when dose is 18 to 24 minutes after pancuronium and 41 minutes
pancuronium is given to patients with renal or hepatic failure. after D-tubocurarine.16,17,55 In addition, the rate of spontaneous
The dose producing a 95% neuromuscular block is 30% less in neuromuscular recovery is much faster after pancuronium than
infants than in children (Figure 27–8; see Table 27–1).28,55 When after D-tubocurarine; time from 5 to 25% recovery of muscular
pancuronium is used during balanced general anesthesia without force takes place in 16 minutes when pancuronium and in
volatile inhalation agents, the initial dose is generally 0.1 mg/kg. 32 minutes when D-tubocurarine is used during halothane
This is only 1.1 to 1.2 times greater than the ED95 dose for children anesthesia.52
during a nitrous oxide-thiopental-opioid anesthesia.52,55 In infants The duration of neuromuscular block following an equipotent
and children the ED95 values of pancuronium are 30% less dur- dose of pancuronium (e.g., an ED95 dose) is similar in infancy and
ing nitrous oxide–halothane than during nitrous oxide–opioid childhood.17,55,56 The hourly requirement of pancuronium to
anesthesia.17,28,52,55 maintain 95% neuromuscular block in children is, on average,
The maximal effect following pancuronium is reached faster 60 μg/kg (65% of an ED95 dose) (Table 27–7).55 Following an initial
in infants than in children or adults (Table 27–6), for example, the dose, incremental doses of pancuronium are usually required
TABLE 27-6. Onset Time (Time From Intravenous Administration to Maximum Response) of Muscle Relaxants in
Pediatric Patientsa
Onset Time, Min
Compound Dose, ␮g/kg Infants Children Adolescents References
Alcuronium 200 1.5 2.4 2.9 53
Atracurium 500 1.2 1.7 2.2 122, 130
Cisatracurium 150 1.9 2.9 3.7 139, 142
Mivacurium 300 1.6 1.8 2.9 162
Pancuroniumb 70 1.3 2.4 3.0 56
Rocuroniumb 600 1.1 1.3 2.0 106
Vecuroniumb 70 1.5 2.4 2.9 85
D-Tubocurarine 400 1.7 2.7 2.5 53
Succinylcholine 1000 — 0.7 0.9 186
a
Data are in min and collected from studies in which at least two different age groups are evaluated.
b
Denotes that data for adolescents are from adults.
TABLE 27-7. Average Hourly Maintenance Requirement of infants than in children (see Table 27–1).53 This age-dependency
Nondepolarizing Muscle Relaxants for 90–95% Neuromuscular is similar to that observed with pancuronium.29,55 The maximal
Block in Children During Nitrous Oxide–Opioid Anesthesiaa effect after alcuronium is reached faster in infants than in children
(see Table 27–6). In children, time to maximum neuromuscular
Compound μg/kg/h ED95 Doses/h References block is reached within 4.3 ± 2.8 minutes after a dose of 0.3
mg/kg.62
Alcuronium 110 ± 25 0.4 64
When alcuronium is used during general anesthesia without
Atracurium 530 ± 70 1.6 116
volatile agents, the first dose is generally 0.3 mg/kg. This is only
Cisatracurium 120 ± 19 2.5 143
slightly greater than the ED95 for children (0.27 mg/kg) and pro-
Doxacurium 56 ± 12 1.1 66
duces an early recovery of neuromuscular function.47 This early
Mivacurium 950 ± 50 6.8 156
recovery creates the false impression that alcuronium is an agent
Pancuronium 59 ± 15 0.6 55
with intermediate duration. Alcuronium is, however, a clear long-
Pipecuroniumb 38 ± 8 0.7 74
acting agent with a plasma clearance of 2.7 ± 1.3 mL/kg/min and
Rocuronium 1000 ± 140 2.2 7
an elimination half-life of 131 ± 57 minutes in children.63 Phar-
Vecuronium 154 ± 51 1.9 93
macokinetic data suggest that alcuronium has a shorter onset time
ED95 = 95% effective dose. and duration of effect in children than in adults.63
a
Values are mean ± sd. Rate of spontaneous recovery after alcuronium is somewhat
b
Denotes halothane anesthesia. slower than recovery after pancuronium.64 The hourly require-
ment to maintain 95% neuromuscular block in children is 0.11
within the next 30 to 45 minutes for maintenance of muscle mg/kg. This is 40% of the individual ED95 (see Table 27–7).64 This
relaxation. Thus, surgical relaxation can be maintained for almost requirement is less than that for pancuronium and, together
2 hours by incremental doses of pancuronium totaling the same as with pharmacokinetic data, indicates that alcuronium is a longer-
the dose used for endotracheal intubation. acting agent than pancuronium in children. Comparisons between
In clinical practice, incremental doses of one quarter of the alcuronium and D-tubocurarine are not possible because of a lack
initial dose of pancuronium are required every 20 to 40 minutes. of sufficient data. Surgical relaxation can be maintained with
The infusion requirement of pancuronium was found to be similar alcuronium for 2 to 3 hours by incremental doses totaling the
in pediatric intensive care unit as during general anesthesia, that same as the dose used for endotracheal intubation. In clinical
is, 59 μg/kg/h during the first day of infusion.58 practice, an incremental dose of one fifth of the initial dose is
Meakin and associates analyzed the reversal of 90% neuro- usually required every 30 to 40 minutes.
muscular block induced by pancuronium in babies, infants, If the same dose in milligrams per kilogram of body weight
and children. They found that edrophonium produced quicker is used for all pediatric age ranges, it is occasionally difficult
neuromuscular recovery than neostigmine and that the recovery to reverse residual neuromuscular block at the end of short-
of the TOF ratio was fastest in babies.59 Neuromuscular recovery duration anesthesia because alcuronium is more potent in
was noticed to be more rapid in children than in adults. In general, neonates and infants. Therefore, younger patients are particularly
neuromuscular recovery is slower when a deeper level of block is prone to postoperative problems such as compromised spontane-
to be reversed; when neostigmine 36 to 40 μg/kg was used at 90% ous breathing.
or 75% neuromuscular block induced by pancuronium, it took After reversal of residual neuromuscular blockade, the
6 to 7 minutes or 2 to 3 minutes, respectively, until the TOF ratio neuromuscular function recovers much slower following the use
recovered to 0.70.59,60 of alcuronium than following an intermediate-acting muscle
The pharmacokinetics of pancuronium in children are poorly relaxant in children.65 It took up to 13 minutes to attain a TOF
described and there are no studies comparing pharmacokinetics ratio of 0.70 and even 26 minutes to attain a TOF ratio of 0.9 when
between different age groups. Volume of distribution (203 ± alcuronium-induced 85% neuromuscular block was reversed with
36 mL/kg) and plasma clearance (1.7 ± 0.2 mL/kg–1/min–1) of neostigmine 50 μg/kg in children.65 These times were significantly
pancuronium are associated with a long elimination half life longer than the 10 minutes required to attain a TOF ratio of 0.9
(103 ± 23 min) in children under halothane anesthesia.61 Plasma when atracurium was used in that same study.
concentrations of pancuronium at constant neuromuscular block
levels are similar to the required concentrations of vecuronium
in children. Doxacurium
Doxacurium is a bisquaternary benzylisoquinolinium muscle
relaxant with a molecular weight of 1106.1 Da. It is mainly
Alcuronium excreted unchanged in urine and bile but is also slowly hydrolyzed
Alcuronium is a semisynthetic agent derived from toxiferine, by plasma cholinesterase. The neuromuscular effects are slightly
a naturally occurring alkaloid. It is a bisquaternary molecule prolonged in patients with renal failure. Doxacurium does not
and has a molecular weight of 827.9 Da. It is mainly excreted produce vagal or sympathetic blockade and has only minimal
unchanged in the urine (80–85%) with small amounts excreted in effect on histamine release. Therefore, doxacurium is unlikely to
the bile. The neuromuscular effects of alcuronium are markedly cause untoward cardiovascular effects (see Table 27–5).
prolonged in patients with renal impairment. Alcuronium has Doxacurium is the most potent NMBD available. The reported
minimal effects on blood pressure. It may cause a mild histamine ED95 of doxacurium in 2- to 12-year-old children is 27 to 32 μg/kg
release. during halothane anesthesia.42,43 During balanced anesthesia
Only one study has evaluated the dose-response of alcuronium without halogenated inhalation agents, the ED95 of doxacurium
in pediatric patients. In that study, the ED95 dose was 30% less in is 25 μg/kg in infants, 53 μg/kg in children, and 41 μg/kg in
adolescents.66 Thus, doxacurium presents with a typical pediatric found that the neuromuscular block recovers significantly slower
age-related profile: children require greater doses than either after repeated administration than after a single dose.74 This would
infants or adolescents (see Table 27–1). However, the magnitude suggest that the plasma concentration of pipecuronium after a
of age-related changes seems to be greater with doxacurium than single dose decreases quicker in infants than in children and adults
with any other muscle relaxant: infants’ requirement is 50% less owing to significant early distribution. When a large or repeated
than the requirement of children (see Figure 27–8). dose is administered, plasma concentration decreases slowly in
Doxacurium has a long onset of action in children even at high infants owing to slow clearance and the typical long duration of
doses. This fits well with the theory that the more potent the effect is present. Thus, pipecuronium is a long-acting agent in all
muscle relaxant, the more prolonged the onset of action. The onset age groups.
time is 7 minutes after 30 μg/kg of doxacurium and 3 to 5 min after The 25 to 75% recovery time after an ED95 of pipecuronium is
a dose of 50 μg/kg.42,43 This long onset time is likely related to the similar in infants and children, averaging 25 minutes.71–73 Hourly
greater molar potency of doxacurium: when only a small number maintenance requirements of pipecuronium for 90 to 95%
of molecules are administered to establish an effect, then the neuromuscular block are 38 μg/kg in children and 32 μg/kg in
concentration gradient at the neuromuscular junction becomes infants during halothane anesthesia. These requirements represent
small and it takes longer to reach the maximal effect. More rapidly 0.7 to 0.8 × ED95/hr,74 typical for a long-acting muscle relaxant
acting relaxants are preferable for endotracheal intubation. (see Table 27–7).
Doxacurium has a long duration of action, like D-tubocurarine The only pharmacokinetic study of pipecuronium in pediatric
or pancuronium. In children, clinical duration of effect and the patients showed that plasma clearance of pipecuronium is smaller
25 to 75% recovery time after doxacurium 50 μg/kg are 44 to in infants than in children or adults (see Table 27–2).38 Differences
51 minutes and 30 to 33 minutes, respectively, during halothane in plasma clearance may explain the long duration of effect when
anesthesia.42,43 Although these times are close to those after repeated or large doses of pipecuronium are administered to
pancuronium administration, they are much shorter than the infants. Volume of distribution were not found to be different
respective times after doxacurium in adults.67 Volatile anesthetics between the age groups but the elimination half-life was longest in
do not affect the recovery times of doxacurium when equipotent infants (135, 69, and 61 min in infants, children, and adults).38
doses are used.68 When doxacurium-induced neuromuscular block
is reversed with neostigmine 40 μg/kg at 25% of neuromuscular
recovery, the TOF ratio recovers to 0.70 in 4.2 ± 4.2 minutes.60 Reversal of Long-Acting Muscle Relaxants
However, the recovery to TOF ratio greater than 0.9 has not been A major hazard of long-acting muscle relaxants is the potential for
established, but it presumably should be significantly longer. residual neuromuscular blockade. In one study, half of the children
The long duration of action and lack of cardiovascular effects paralyzed with alcuronium had a TOF ratio of less than 0.70
make doxacurium an alternative for use in intensive care units. at arrival into a postanesthesia care unit (PACU) and only a few
However, the spontaneous recovery of neuromuscular function
had a TOF ratio greater than 0.9.65 When reversed from 15% of
after doxacurium infusion lasting several days may be very slow.69
neuromuscular recovery, time from neostigmine 50 μg/kg to a
The hourly maintenance requirement of doxacurium is 56 μg/kg
TOF ratio of greater than 0.90 was significantly longer in the
in children during nitrous oxide–opioid anesthesia for a 90 to 95%
alcuronium group than in the atracurium group (26 ± 15 min vs
neuromuscular block.66 This requirement represents 1.1 × ED95
10 ± 5 min). This difference is expected to be even greater if
and is greater than the respective value for pancuronium (see Table
reversal takes place at deeper levels of neuromuscular block
27–7). This may indicate that maintenance doses of doxacurium
(Figure 27–9).65 Consequently, an intermediate-acting muscle
have a shorter duration of effect than maintenance doses of
pancuronium.
Pipecuronium
Pipecuronium has a steroidal structure close to that of pan-
curonium with a molecular weight of 762.7 Da. A major pro-
portion (40%) of the administered dose is excreted unchanged
in the urine, and consequently, the duration of action is prolonged
in renal failure. A smaller proportion is deacetylated in the
liver and excreted in the bile. Pipecuronium has no significant
cardiovascular or histamine-related effects.
The ED95 of pipecuronium in children during nitrous oxide
opioid anesthesia is 70 to 84 μg/kg,70–73 and 48 to 62 μg/kg during
halothane anesthesia.45,46,48 Infants have 30% and neonates 40%
smaller ED95 values than children (see Table 27–1).71,74 Neonates
and infants younger than 1 year have similar potencies.72
Pipecuronium differed from all other nondepolarizing muscle
relaxants in that its ED95 has a significantly shorter clinical Figure 27-9. Time to train-of-four ratio of 0.90 after reversal of
duration of action in infants than in children and adults.71,73,74 This atracurium or alcuronium from different levels of neuromuscu-
rapid recovery in infants is, however, seen only with low single lar block. The deeper the block at the time of reversal, the longer
doses. When pipecuronium was given in small incremental doses it takes for full neuromuscular recovery. Times for alcuronium
to maintain a 90 to 95% neuromuscular block in infants, it was are longer than those for atracurium. From reference 65.
relaxant seems to offer a safer recovery profile than a long-acting It is important to note that unnecessarily high doses of muscle
muscle relaxant in pediatric patients. relaxants bring about far extended duration of neuromuscular
Bevan and coworkers studied reversibility of neuromuscular block and do not improve intubation conditions.78,79 Sugammadex
block induced by the long-acting muscle relaxants doxacurium and may increase the use of intermediate-acting muscle relaxants
pancuronium.60 No difference between these two agents was found especially in daycase surgery because the risk of residual curariza-
for the dose of neostigmine needed or in the time to sufficient tion becomes negligible.
recovery. The dose of neostigmine needed for reversal was less in
children than in adults and neuromuscular recovery after reversal
was significantly faster in children than previously reported in Vecuronium
adults.60 In addition, infants recover from pancuronium-induced Vecuronium is a monoquaternary steroidal muscle relaxant with
neuromuscular block quicker than adults when either edropho- a molecular weight of 637.7 Da. Vecuronium is an example of
nium or neostigmine is used for reversal.59 agents that have a fairly short duration of clinical effect but a
Residual postoperative neuromuscular block in pediatric day- relatively long elimination half-life. The intermediate duration
care setting has been found to be minimal at 15 to 18 minutes after of effect is caused by its rapid redistribution from effect site. It is
reversal of either atracurium, vecuronium, or pancuronium with partially (30–40%) deacetylated to 3-OH, 17-OH, and 3,17-diOH
neostigmine 60 μg/kg.75 However, the level or duration of neuro- metabolites in the liver; the 3-OH metabolite has moderate muscle
muscular block was not documented in that study. In general, relaxant properties.
it takes longer and interindividual variability may be greater Because of its relatively long elimination half-life and the
when more profound neuromuscular block is to be reversed (see metabolite effects, vecuronium has a slow neuromuscular recovery
Figure 27–9). if administered as prolonged infusion.80,81 Consequently, vec-
Special care should be taken to avoid any overdose of long- uronium is not indicated for assisted ventilation in intensive care.
acting muscle relaxants because it takes one elimination half-life About 30% of vecuronium is excreted unchanged in urine.
to return to a correct level of block if twice the estimated dose has Vecuronium has a prolonged effect in patients with liver failure.
been given. This would mean an extra hour of deep neuromuscular Vecuronium has little vagolytic or ganglion blocking activity, and
block, in contrast to only 20 to 30 minutes for an intermediate- it does not produce significant adverse cardiovascular effects (see
acting agent. Sugammadex may be used in emergency situations to Table 27–5).
reverse pancuronium-induced neuromuscular block. Whether Vecuronium has been studied extensively in pediatric patients.
sugammadex is able to reverse pipecuronium-induced block has The age-dependency of the potency of vecuronium is one of the
not been evaluated. greatest among muscle relaxants (Figure 27–10). During nitrous
oxide–opioid anesthesia, the ED95 is 47 to 48 μg/kg in neonates
INTERMEDIATE-ACTING and infants younger than 1 year, 81 μg/kg for children 3 to 10 years
old, and 55 μg/kg for adolescents 12 to 15 years old.82 Variance of
MUSCLE RELAXANTS the ED95 in 10 different age groups was 20 ± 5% μg/kg with a range
Intermediate-acting muscle relaxants are characterized by esta- from 22 to 103 μg/kg.82
blished surgical relaxation for 15 to 30 minutes after 1.5 × ED95 This fivefold between-individual variability in response sug-
(Table 27–8). Time to complete spontaneous recovery of the gests that it is not good clinical practice to administer a constant
neuromuscular function following this dose is 30 to 60 minutes dose of vecuronium to every pediatric patient. The average ED
with a 25 to -75% recovery time of 10 to 20 minutes. values of vecuronium are 40% less in infants and 30% less in ado-
The use of intermediate-acting nondepolarizing muscle re- lescents than in children (see Table 27–1).82,83 Volatile anesthetic
laxants allows improved control of neuromuscular block and low agents have a significant effect on ED values; halothane reduces
incidence of postoperative residual paralysis in children.65 Some ED values by 30%, isoflurane by 40%, and sevoflurane by 60% (see
intermediate-acting agents have particular beneficial characteris- Figure 27–5).50,84
tics, such as the short onset time with rocuronium76 or the short When vecuronium is used to establish muscle relaxation during
and predictable elimination half-lives of atracurium and cisatra- general anesthesia, the first dose is commonly 100 μg/kg. This
curium.36,37,77 These advantages make intermediate-acting muscle dose is ideal only for children and should be reduced to 70 μg/kg
relaxants preferred for most surgical cases when children are ex- in neonates and infants. Onset time of a paralyzing dose of
tubated and spontaneously breathing postoperatively. These agents vecuronium, 70 μg/kg during halothane anesthesia, is 1.5 ± 0.6
can be used successfully for endotracheal intubation in patients in and 2.4 ± 1.4 minutes in infants and children, respectively,83,85–88
whom mask ventilation is possible awaiting onset of sufficient but shorter onset times have been reported.89,90 The onset times of
neuromuscular block. vecuronium are shorter in infants and children than in young
TABLE 27-8. Main Clinical Characteristics of Intermediate-Acting Muscle Relaxants in Children

a
Atracurium 0.50 1.5–2.0 25–35 Yes Histamine if rapid
Cisatracurium 0.10 2.0–2.5 25–35 Yesa No
Rocuronium 0.60 1.0–1.5 20–30 Yesa No
Vecuronium 0.10 1.5–2.5 20–35 Yesa No
a
Not necessary if no fade in double-burst stimulation for the last 15 min.
100% longer recovery times of neuromuscular function than

children after similar milligrams per kilogram of body weight
doses (Figure 27–11).85,88,89 Even if an equipotent dose of vec-
uronium (an ED95 dose) is administered in infants, children, and
adults, infants have longer duration of effect and slower rate of
recovery of neuromuscular function than older patients.91
It has been speculated that spontaneous recovery after a single
bolus of vecuronium takes place during the distribution phase
of the drug in children but during the elimination phase in
infants.89,91 This would result in a short duration and fast recovery
in children but in a long duration and slow recovery in infants.
Vecuronium is an intermediate-acting muscle relaxant; in children,
the duration of effect following vecuronium is one third that of D-
tubocurarine and half that of pancuronium.83,92
Maintenance requirements of vecuronium are 60% less in
neonates and infants and 40% less in adolescents than in children
Figure 27-10. The 95% effective dose (ED95) value of vecuro- (62 μg/kg/h vs 154 μg/kg/h vs 89 μg/kg/h).93 Variance of the infu-
nium in 10 different age groups of pediatric patients.82 The one sion requirement did not depend on the age of a patient and
standard deviation (sd) range shows that individual variation averaged 26%. However, because the smallest infusion rate was
is very much the same across different age groups even though 37 μg/kg/h and the greatest 270 μg/kg/h, it would be impossible to
mean ED95 values differ greatly. The same uniform variation can administer an individual requirement of vecuronium without
be seen in Table 14–1. appropriate neuromuscular monitoring.
Halothane and isoflurane reduce the vecuronium infusion
adults (see Table 27–6). However, even these onset times of requirement in children by 25% and 40%, respectively.94 The same
vecuronium are more than twice those of succinylcholine.90 study also found that neuromuscular recovery after 2 hours of
The rate of neuromuscular recovery and the duration of clinical vecuronium infusion is rather rapid and predictable. As a constant
effect are comparable after vecuronium 70 μg/kg during halo- dose of vecuronium can maintain a 90% neuromuscular block
thane anesthesia and after 100 μg/kg during thiopental-opioid for three times longer in infants than in children, and because
anesthesia.85,88,89 Vecuronium is unusual in that infants have a the maintenance requirement of vecuronium is much less in
Figure 27-11. Spontaneous recovery of neuromuscular function after an individual ED95 dose of vecuro-
nium or rocuronium in infants and children.91,101 Rocuronium is intermediate-acting also in infants, whereas
vecuronium becomes a long-acting agent in infants.
infants than in children in terms of ED equivalents, vecuronium activity. Clinical effects of rocuronium become prolonged in
is regarded to mirror a long-acting muscle relaxant in infants patients with liver failure.
younger than 1 year old (see Figure 27–11).95 Rocuronium has some vagolytic activity and large doses are
After an initial vecuronium dose of 100 μg/kg in children, associated with increases in heart rate and blood pressure.
the first increment is usually required within 20 minutes. If Rocuronium has no significant cardiovascular side effects after
subsequent doses are one third of the initial dose, these doses normal clinical doses. However, there has been a lot of discussion
are required every 10 to 15 minutes. In neonates and infants, the on the potential of rocuronium to elicit anaphylaxis. In some
first increment after the initial dose of 70 μg/kg is required countries, there have been claims of increased risk that has not
within 30 to 40 minutes. If subsequent doses are one third of been reported from other countries.96 Rocuronium produces a
this initial dose, they are needed on an average every 20 to 30 min- rather strong local pain when injected rapidly. This pain sensation
utes. During volatile anesthesia, the doses should be reduced can be minimized by prophylactic use of remifentanil, alfentanil,
appropriately. or a small dose of ketamine.97–99 One percent lidocaine 0.1 mL/kg
The volume of distribution is greater in infants than in children is less effective to prevent such pain.100
(357 ± 70 mL/kg vs 204 ± 116 mL/kg), whereas plasma clearances Infants, children, and adults have an ED95 of 251, 409, and
are similar (5.6 ± 1.0 mL/kg/min vs 5.9 ± 2.4 mL/kg/min) (see 350 μg/kg, respectively, during nitrous oxide–thiopental–opioid
Table 27–2).35 This produces a longer mean residence time (and anesthesia (see Table 27–1).101 Thus, ED values of rocuronium are
the duration of action) in infancy (66 min vs 34 min). Infants also 30% less in infants and 20% less in adults than in children.
had a greater neuromuscular sensitivity for vecuronium than A similar age-dependent pattern could be established also when
children (see Table 27–3). Another study in children found that a target-controlled infusion of rocuronium was used.102 EC50 were
both the distribution volume and the total plasma clearance of calculated to be 650, 1200, and 950 ng/mL in infants, children, and
vecuronium were 1.6 times greater than those of pancuronium.61 adults, respectively.
Elimination half-lives of vecuronium and pancuronium were Rocuronium has a lower potency than either pancuronium
similar. It was explained that vecuronium had a shorter duration of or vecuronium, whose ED95 values in infants and children are
action than pancuronium owing to its greater lipophilicity and one quarter and one fifth, respectively, of the ED95 of rocuro-
active liver uptake, which favors a rapid decline of plasma concen- nium (Figure 27–12).101 The ED values of rocuronium are 20%
tration early after administration.61 This kinetic explanation lower during halothane than during nitrous oxide–opioid
corroborates nicely with the clinical observations of age-dependent anesthesia.101,103–105
dynamic effects of vecuronium. The onset time of rocuronium is 1 to 1.5 minutes following
a 2 × ED95 in both infants and children during different types
of anesthesia (see Table 27–6).103–110 Rocuronium has clearly a
Rocuronium shorter onset time than either atracurium or vecuronium.109
Rocuronium is a monoquaternary vecuronium derivative, that is, However, in children, this onset time is about twice as long as
a steroid-based nondepolarizing muscle relaxant with a molecular that after succinylcholine,104,107 whereas in infants, it is somewhat
weight of 609.7 Da. About 30% of rocuronium is bound to plasma closer to that after succinylcholine.106 The short onset time of
proteins. It undergoes significant redistribution, rendering rocuro- rocuronium is attributed to its relatively low potency that
nium a muscle relaxant with intermediate duration of effect. One requires large molar doses to be administered for a desired effect.
third of rocuronium is excreted unchanged in urine. The main Several studies have confirmed that excellent or good intubation
metabolite, 17-OH-rocuronium, has weak neuromuscular blocking conditions can be reached within 60 seconds in children when
Vecuronium Rocuronium Rapacuronium

Infants Children Infants Children Infants Children
95
Neuromuscular block (%)
50
5
10 50 100 500 1000
Muscle relaxant (µg/kg)

Figure 27-12. The dose-response curves of vecuronium, rocuronium, and rapacuronium in infants and
children.82,101 Vecuronium is roughly four times as potent as rocuronium, which is four times as potent as
rapacuronium.
either succinylcholine or rocuronium has been used to induce dependent on physiologic pH and temperature.36,37 Atracurium is
paralysis.105,107–109,111,112 also inactivated by nonspecific plasma esterases. Both elimination
Duration of effect and rate of recovery from neuromuscular pathways are independent of renal or liver function.
block after rocuronium are very similar to those after vecuronium. Laudanosine, a central nervous system stimulant, is a major
In children, clinical duration of effect of rocuronium 600 μg/kg metabolite of atracurium but has not been reported to produce
is 21 to 29 minutes,103–105,107,109–111,113 and the 25 to 75% recovery adverse effects in children.120 Atracurium can be administered as
time is 9 to 11 minutes.103,111 This same dose of rocuronium had a prolonged infusion to maintain its pharmacodynamic character-
duration of effect twice as long in infants as in children.106 istics. It is excreted in the urine and bile, mostly as inactive meta-
Rocuronium mirrors vecuronium: it behaves like a long-acting bolites. Atracurium does not have any vagolytic or ganglion
agent in infancy. blocking activity, but it may release histamine, especially after
However, when used on a basis of an individual ED95, rocuro- large or rapidly administered doses. Atracurium has negligible
nium, unlike vecuronium, had a roughly similar duration of action cardiovascular effects after normal clinical doses administered
in infants, children, and adults (see Figure 27–11).39,101 Based on slowly (see Table 27–5).
these studies, it is apparent that neuromuscular recovery after a Atracurium has been studied extensively in pediatric patients.
small dose of rocuronium (1 × ED95) is terminated by distribution Four groups of investigators have determined the ED95 of atra-
rather than elimination. By contrast, recovery from a larger dose curium in pediatric patients.121–124 A detailed study was under-
of rocuronium (2 × ED95) will take longer in infants than in taken during nitrous oxide–thiopental–opioid anesthesia in 10 age
children because of slower elimination of rocuronium in infancy. groups.124 The study showed neonates and infants to have
Timing of posttetanic count numbers can predict the sponta- ED values that are 30% less than those for older children or
neous recovery of a profound rocuronium-induced neuromus- adolescents—a typical finding for most nondepolarizing muscle
cular block.114 Woloszczuk-Gebicka and colleagues showed that relaxants (see Table 27–1). Others have confirmed this age-
the infusion requirement of rocuronium to maintain a 90 to 99% dependency of the potency of atracurium even though it seems
neuromuscular block averaged 1.0 mg/kg/h during nitrous oxide– like mechanomyography has produced 30 to 40% lower ED values
fentanyl anesthesia.7 This rate was reduced by 20 to 30% during for atracurium than electromyography (ED95 in children 200–230
halothane or isoflurane and by 50% during sevoflurane anesthesia. μg/kg vs 320–350 μg/kg).121–124 Halothane anesthesia reduces the
The maintenance requirement of rocuronium in pediatric ED values by 20%.121,123 If these results are interpreted clinically, a
intensive care unit was estimated to average 0.8 mg/kg/h.115 In sufficient initial dose of atracurium for all pediatric patients would
general, the hourly maintenance requirement of an intermediate- be 400 to 500 μg/kg during balanced anesthesia. This dose repre-
acting muscle relaxant is 1.6 to 2.2 × ED95 (see Table 27–7).7,93,116,117 sents often more than 1.5 × ED95 and produces good intubation
O’Kelly and associates found that the plasma clearance of conditions within 2 minutes after intravenous administration.125,126
rocuronium increased with increasing body weight in infants and Maximum neuromuscular block after atracurium occurs
children from 3 months to 8 years of age.118 Vuksanaj and Fisher quicker in neonates and infants than in children or adolescents.
did not confirm this finding because they found heavier patients The maximum effect after a small dose of 150 μg/kg is reached in
to have lower clearance than patients with lower body weight–to– 2.6 minutes in neonates, 3.3 minutes in infants, and 5.5 minutes in
children and adolescents.124 The respective onset times are 1.1, 1.2,
height ratios in an age range of 4 to 11 years.119 They also found
and 1.7 minutes after a 500-μg/kg dose.122 The onset time of
older children to have a longer elimination half-life of rocuronium.
atracurium in children is similar to or somewhat shorter than the
However, results of this last study may be biased by an inclusion
onset time of vecuronium, D-tubocurarine, or pancuronium (see
of grossly overweight older children. In obese children, dosage of
Table 27–6).127–129
muscle relaxants should be based on ideal body weight for their
Atracurium is an intermediate-acting neuromuscular blocking
age and height.
agent in all age groups of pediatric patients. The rate of sponta-
Wierda and coworkers showed that infants have a smaller neous recovery after a constant dose (mg/kg of body weight) is
plasma clearance, larger distribution volume, and lower con- only minimally effected by the age of the patient.121,122,130–132 In
centration for 50% neuromuscular block than children (see Tables some of these studies, the duration of effect after either a constant
27–2 and 27–3).39 The study also showed that infants have a more or an equipotent dose of atracurium has been slightly shorter,131
than 100% longer mean residence time than children. The similar,121,122 or slightly longer132 in infants than in children. The
pharmacokinetic dynamic modeling verified that following a large differences in the duration of effect have always been of no signi-
or constant dose of rocuronium infants have a slower rate of ficant clinical importance. The clinical duration of effect of a
recovery of neuromuscular function and a longer duration 500-μg/kg dose of atracurium is 29 to 37 minutes in pediatric
of effect than children.39 This means that not only redistribution patients.121,122,126 This duration is one third to one half of that
but also reduced clearance play an important role in the longer following a long-acting muscle relaxant.128,130,131
duration of effect of a large dose of rocuronium in infancy. Hourly atracurium requirements in children for maintenance
of 95% neuromuscular block during nitrous oxide–barbiturate–
opioid anesthesia is 0.5 to 0.6 mg/kg/h (see Table 27–7).116,133,134
Atracurium This result has been consistent, although the methods of evaluating
Atracurium is a benzylisoquinolinium muscle relaxant with the neuromuscular block have been either mechanomyography
a molecular weight of 1243.5 Da. Atracurium is composed of or electromyography. In infants, the infusion requirement is similar
10 different stereoisomers, one of which is cisatracurium, and this to children’s requirement,116,135 but neonates require 25% less.116
isomer is responsible for most pharmacologic properties. About Halothane, isoflurane, and enflurane reduce these infusion require-
80% of atracurium is bound to plasma proteins. It is broken down ments by 20%, 35%, and 50%, respectively.133,134 These infusion
spontaneously by a nonenzymatic Hofmann elimination that is rates mean that increments of one third of the initial dose of
atracurium are required approximately every 15 minutes to similar to those following atracurium. The clinical duration after
maintain a deep surgical relaxation. 150 μg/kg of cisatracurium is slightly (20%) longer in infants than
Atracurium is an agent that may produce histamine liberation. in children, whereas the 25 to 75% recovery times are similar.142
The greater the bolus dose and the quicker it is administered, the Cisatracurium is noncumulative because repeated bolus doses
more histamine is likely to be released. The amount of histamine produce exactly similar durations of neuromuscular block.
liberation and the severity of untoward reactions caused by Maintenance requirement of cisatracurium for a 90 to 95%
histamine are less in children than in adults.129 High doses of neuromuscular block during halothane anesthesia is 90 to 100 μg/
atracurium may be associated with hypotension, particularly if kg/h.117,141 During nitrous oxide–narcotic anesthesia, the infusion
the dose is administered rapidly. However, normal clinical doses requirement is 120 μg/kg/h in both infants and children.143 This
of atracurium injected slowly do not have any cardiovascular means that cisatracurium is required approximately 2.2 × ED95 in
effects.128 an hour, similar to the requirements for other intermediate-acting
Pharmacokinetics of atracurium show that infants have a 30 to muscle relaxants (see Table 27–7). No drug-related adverse effects
60% greater volume of distribution and a 20 to 70% greater total of cisatracurium have been reported in children even though an
plasma clearance than children (see Table 27–2).36,37 These studies infant erroneously received a massive dose of 860 μg/kg.144
found that the elimination half-life of atracurium is very similar
in infants and children (14-20 min). The steady-state plasma
concentration resulting in 50% neuromuscular block did not Reversal of Intermediate-
differ between infants, children, or adults (363, 444, or 436 ng/mL, Acting Muscle Relaxants
respectively).37 The pharmacokinetics of atracurium is in accord- Meistelman and associates found that time from administra-
ance with the clinical findings that recovery from neuromuscular
tion of neostigmine 30 μg/kg to a TOF ratio of 0.70 was shorter
effects of atracurium is minimally affected by age.
when a lower degree of vecuronium-induced paralysis was
antagonized.145 This time was reduced from 10 to 3 minutes when
Cisatracurium a 75% instead of a 99% block was reversed. Total time elapsed from
the 99% block to full recovery was similar, indicating that there
Cisatracurium is one of the 10 stereoisomers of atracurium was no advantage to antagonizing an intense neuromuscular block
and has the same molecular weight as the parent drug. It is also in children. This was confirmed with atracurium in a study that
spontaneously degraded by Hofmann elimination and possibly clearly showed time to full recovery of neuromuscular function is
metabolized by nonspecific esterases.77 The potency of cisatrac- similar whether the block is antagonized at deep level or whether
urium in children is three to four times greater than that of atrac- spontaneous recovery is allowed before reversal.146
urium,117 Thus, the concentration of metabolites of cisatracurium, Reversal of vecuronium-induced 90% neuromuscular block
including laudanosine, is one third to one fourth of those after an is similar in infants, children, and adults during halothane
equipotent dosing of atracurium, which is an important safety anesthesia.147 The residual block was less than 5% and the TOF
factor.120 Cisatracurium does not release histamine and will ratio had recovered to greater than 0.80 within 8 minutes after
provide an even more stable hemodynamic profile than atrac- neostigmine 30 μg/kg in both infants and children.
urium. Cisatracurium constitutes approximately 15% of racemic Kirkegaard-Nielsen and coworkers reversed an atracurium-
atracurium.136 Therefore, cisatracurium provides about 60% of the
induced 90% neuromuscular block in infants and children by
neuromuscular blocking activity of atracurium.
either neostigmine 50 μg/kg or edrophonium 1.0 mg/kg.148 The
In a study in children 2 to 12 years old during 1 MAC halothane
reversal was fastest in the youngest age groups after either anti-
anesthesia, the ED50 and ED95 doses of cisatracurium were 23 and
cholinesterase. Time to attain a TOF ratio of 0.70 was 4 minutes in
41 μg/kg.117 It was estimated that during nitrous oxide–opioid
neonates and infants, 6 minutes in 2- to 10-year-old children, and
anesthesia, the ED95 value would be 55 μg/kg.137 In infants, the
8 minutes in adolescents. Edrophonium established a faster onset
onset time of cisatracurium is shorter and the duration of action
of effect, whereas final recovery was greater with neostigmine,
is longer than those in older children.138
At a dose of cisatracurium 150 μg/kg in infants and children which also had less variable effect. The authors recommended the
during halothane and opioid anesthesia, 100% of infants and 94% use of neostigmine for routine pediatric practice.148 Gwinnutt and
of children have good or excellent intubation conditions at colleagues also found neostigmine more effective than edropho-
2 minutes.139 Keenan and colleagues showed that 98% of children nium in children.146 The effectiveness of neostigmine to reverse a
had acceptable (good or excellent) intubation conditions at cisatracurium-induced neuromuscular block is similar to that of
90 seconds after cisatracurium 0.2 mg/kg during both halothane atracurium.117
and an opioid anesthesia.140 The time from neostigmine 50 μg/kg to a TOF ratio of greater
Because cisatracurium is four times more potent than racemic than 0.90 was shorter when atracurium instead of alcuronium was
atracurium, higher multiples of ED95 doses are needed for similar reversed from 85% neuromuscular block (10 ± 5 min vs 26 ± 15
onset. The time to maximal effect after a 2 × ED95 of cisatracurium min).65 Fewer children arrived in the postanesthesia recovery
is 2.5 ± 0.8 minutes in children under halothane anesthesia.117 This room with TOF ratio of less than 0.70 if atracurium was used to
time is roughly similar during thiopental-opioid and during maintain muscle paralysis. Thus, an intermediate-acting muscle
halothane anesthesia (see Table 27–6).137 A 90% block is reached relaxant offers a safer recovery profile than a long-acting muscle
within 1.7 ± 0.4 minutes. These times are 1 minute longer than relaxant in pediatric patients. Fifteen to 18 minutes after reversal,
those of an equipotent dose of atracurium or vecuronium. there was a very low incidence of residual postoperative neuro-
Clinical duration of effect following a 2 × ED95 during muscular block in a pediatric daycare setting when atracurium,
halothane or opioid anesthesia is 27 to 31 minutes with a 25 to vecuronium, or pancuronium was antagonized with neostigmine
75% recovery time of 10 to 11 minutes.117,137,139,141 These times are 60 μg/kg.75
TABLE 27-9. Main Clinical Characteristics of Short-Acting Muscle Relaxants in Children

Mivacurium 0.25 1.5–2.0 6–10 No Histamine if rapid
Rapacuronium 2.50 0.7–1.1 6–10 No Bronchospasma
Succinylcholine 1.00 0.6–0.9 2–4 No Several serious effectsb
a
Removed from clinical use in 2001 because of even fatal complications.
b
Arrhythmias, hyperkalemia, rhabdomyolysis, myoglobinuria, increased intraocular pressure, increased salivation, masseter spasm, hypersensitivity, muscle pain,
and malignant hyperthermia.
When rapid reversal of deep paralysis is necessary, such as in The ED95 is 103 to 139 μg/kg during nitrous oxide–opioid anes-
the scenario “can’t ventilate, can’t intubate,” sugammadex may be thesia and 85 to 95 μg/kg during nitrous oxide–halothane
used to reverse neuromuscular block induced with rocuronium anesthesia.44,45,156,157 These doses are 30 to 40% greater than the
or vecuronium. However, there are no pediatric data to suggest ED95 dose for adults (see Table 27–1).158
appropriate timing or dosing of sugammadex in this scenario. In children, times to 90 and 100% neuromuscular block after a
Based on adult studies, it is possible to antagonize rocuronium- 2 × ED95 dose of mivacurium during halothane or balanced
induced deep block early after its administration or when 1 to anesthesia are 1.1 to 1.7 and 1.4 to 2.4 minutes in different
2 posttetanic counts are detected when high enough doses of studies.44,45,157,159–162 In infants, these times are half a minute
sugammadex are used. shorter.153,155,162 Conditions for endotracheal intubation are
good or excellent in infants and children at 1.5 min after either
SHORT-ACTING MUSCLE RELAXANTS 0.2 or 0.3 mg/kg of mivacurium, that is, 2 to 3 × ED95, during
different anesthesia methods.157,162,163 One study showed that
Short-acting muscle relaxants establish surgical relaxation for mivacurium 0.2 mg/kg establishes better intubation conditions
10 to 15 minutes after 1.5 × ED95 (Table 27–9). Time to complete than remifentanil 1 to 3 μg/kg during propofol anesthesia.164
spontaneous recovery of the neuromuscular function after this For clinical purposes, it would be safest to administer maximally
dose is 15 to 30 minutes with a 25 to 75% recovery time of 4 to 0.25 mg/kg of mivacurium as a rapid intravenous injection
8 minutes. because greater doses produce significant amount of histamine
Short-acting muscle relaxants guarantee even more precise release.160–162
control of neuromuscular block than intermediate-acting agents. Spontaneous recovery from mivacurium-induced neuro-
Mivacurium does not normally (assuming that there is no ab- muscular block is fast irrespective of dose or duration of its
normality or deficiency of the cholinesterase) present with post- administration. Clinical duration of effect after a dose of 0.2 to
operative residual paralysis. This is because of its short distribution 0.3 mg/kg is 7 to 9 minutes with time to full neuromuscular
and elimination half-lives and relatively fast de-occupancy of recovery of 14 to 19 minutes in infants and children.153,155,157,165 The
acetylcholine receptors from their attachments. This is the reason 25 to 75% recovery time of 3.5 to 4.4 minutes after mivacurium is
why it is usually unnecessary to pharmacologically reverse the not affected by age of a child, dose of mivacurium, or anesthesia
residual effects of mivacurium. Mivacurium is an ideal agents for method.44,45,153,161,165,166 In children, 0.2 mg/kg and 0.3 mg/kg
daycare surgery, and it can be used successfully for endotracheal of mivacurium have a 2.5 times longer clinical duration of effect
intubation in situations in which prolonged relaxation is not and four times longer 25 to 75% recovery times as equipotent
needed.4,5 doses of succinylcholine (10 min vs 4 min and 4 min vs 1 min,
respectively).159 The very fast rate of neuromuscular recovery
after mivacurium makes it necessary to carefully monitor the
Mivacurium neuromuscular function to avoid large fluctuations of muscular
Mivacurium is a benzylisoquinolinium muscle relaxant with a activity during surgery.
molecular weight of 940.2 Da. It is metabolized by plasma Short duration and fast recovery makes mivacurium easy to
cholinesterase at a rate of 70 to 85% that of succinylcholine into administer as a continuous infusion. A new steady neuromuscular
inactive metabolites. Renal or liver failure is associated with response is established within less than 10 minutes after an infusion
slightly prolonged duration of effect of mivacurium. The duration rate change. The steady-state infusion requirement of mivacurium
of clinical effect of mivacurium, like that of succinylcholine, is does not depend on the age of a pediatric patient.150,153,154 Infusion
markedly prolonged in patients with homozygous atypical rate to maintain a 90 to ⫺95% neuromuscular block averages 0.78
cholinesterase. Mivacurium may release histamine at large doses to 0.95 mg/kg/h during nitrous oxide–opioid anesthesia.154,156,166,167
(0.25–0.3 mg/kg) to produce skin flushing and possible hypoten- This represents 6.6 to 6.8 times an individual ED95 of mivacurium
sion and tachycardia. per hour (see Table 27–7).154,156
Mivacurium consists of three stereoisomers, two of these The infusion requirement of mivacurium has been found to
being short-acting agents with elimination half-lives of 1.8 to 1.9 correlate with plasma cholinesterase activity.166,168 Children who
minues.149 These isomers constitute greater than 90% of the recover from succinylcholine-induced neuromuscular block
neuromuscular activity of mivacurium. Plasma clearance of these quickly would also recover from mivacurium-induced neuro-
trans-trans and cis-trans isomers are 60 to 90% greater in children muscular block quickly.169 One MAC of halothane and isoflurane
than in adults.150,151 Mivacurium seems to be a unique agent in reduces the infusion requirement of mivacurium exponentially
that infants and children have similar ED values of the drug.152–155 with time (see Figure 27–6). The maximal reductions were 32%
and 70%, respectively, when the volatile anesthetic was admin- curium is desired, mivacurium should not be used after another
istered for more than 1 hour.50 Sevoflurane potentiates mivac- nondepolarizing muscle relaxant.
urium to the same extent as isoflurane.160,168 Mivacurium can be administered after succinylcholine. Under
Because of fast spontaneous recovery, it may not be necessary propofol–nitrous oxide–alfentanil anesthesia, succinylcholine had
to antagonize the residual effects of mivacurium at the end of no effect on the duration of action of mivacurium in children.169
surgery169–171 However, it should be remembered that neuro- Under halothane anesthesia, the clinical duration of mivacurium-
muscular block after mivacurium can be significantly prolonged induced paralysis became prolonged if preceded by succinylcholine
because of a decreased level of plasma cholinesterase or the because of long exposure of halothane and subsequent potentiation
presence of an atypical plasma cholinesterase. of the effects of mivacurium.159
Mivacurium After Another Muscle Relaxant Rapacuronium

Mivacurium has a significant interaction potential with other Rapacuronium was a recently introduced nondepolarizing com-
nondepolarizing neuromuscular blockers. If it is used in adjunct pound. Rapacuronium is a steroidal monoquaternary vecuronium
with another intermediate- or long-acting muscle relaxant, the derivative with a molecular weight of 650 Da. It was characterized
duration of action of mivacurium is prolonged and it behaves as a short-acting muscle relaxant owing to its fast redistribution
like intermediate-acting compounds. For example, when a 10-μg/ from effect site to other tissues.
kg dose of mivacurium is administered at 25% recovery of In infants and children, rapacuronium’s potency was lower than
pancuronium-induced neuromuscular block, surgical relaxation that of any other nondepolarizing muscle relaxant. The ED95
lasts another half hour in adults with that tiny dosage of mivac- during nitrous oxide–thiopental anesthesia was 0.7 mg/kg in
urium (Figure 27–13).172 When a small dose of pancuronium (one infants and 1.5 mg/kg in children.179 Maximal neuromuscular effect
sixth of an ED95) instead of saline was used as a priming dose after rapacuronium was established within 0.7 to 1.1 minutes in
before mivacurium 0.20 mg/kg, maximal neuromuscular block infants and young children. This was likely related to the low
became established more quickly (1.8 min vs 3.0 min).173 However, potency and great molar dose administered.180 Intubation con-
clinical duration of neuromuscular block was several times longer ditions were good or excellent in infants and children within less
when pancuronium was the priming agent (21 min vs 9 min). than 1 minute after rapacuronium of at least 1.5 × ED95. Neuro-
Disadvantages of prolonged neuromuscular block are far greater muscular function recovered completely after this dose in 8 to 16
than the benefit of a short onset time when mivacurium is minutes in infants and young children and in 16 to 23 minutes in
preceded by pancuronium. Synergism is the likely explanation for children older than 7 years. A 25 to 75% recovery time was 2.1 to
these interactions. 3.8 minutes in infants and young children and 4.2 to 6.0 minutes
Interaction between mivacurium and either atracurium, in older children.181
cisatracurium, or vecuronium has been evaluated.174–177 Jalkanen Unfortunately, the use of rapacuronium was associated with a
and associates administered 1 ED50 of either atracurium, relatively high incidence of severe bronchospasm including
mivacurium, or vecuronium, or a combination of a half ED50 mortality,182 and the compound was voluntarily withdrawn from
mivacurium together with a half ED50 of either atracurium or the market in 2001.
vecuronium. Potencies of the combinations were 36 to 48% greater
than potencies of the parent agents.174 If mivacurium is ad-
ministered after atracurium or cisatracurium, the duration of DEPOLARIZING MUSCLE RELAXANTS
effect is expected to mirror that of an intermediate-acting muscle
relaxants.177 Subsequent requirements of mivacurium are very
Succinylcholine
small early after onset of block, but increase steadily during the Succinylcholine has a molecular structure of diacetylcholine
90 minutes after the previous bolus dose of either atracurium, with a molecular weight of 397.3 Da. Plasma cholinesterase
rocuronium, or vecuronium.175,176,178 These results indicate that (pseudocholinesterase) produces its rapid hydrolysis with an
mivacurium does not behave like a short-acting agent if preceded elimination half-life of less than a minute. In patients with atypical
by a longer-acting muscle relaxant. If rapid recovery after miva- cholinesterase, the effects are prolonged. The neuromuscular
Mivacurium 10 µg/kg preceded by

Pancuronium
100 Mivacurium
Neuromuscular recovery (%)
80
60
40 Figure 27-13. The neuromuscular function

following a tiny 10-μg/kg dose of mivacurium
20
when administered at 25% neuromuscular
Mean ± SEM recovery after mivacurium or pancuronium.172
0
The clinical duration of effect is 30 minutes and
0 20 40 60 80
time to complete recovery more than an hour
Time following mivacurium (min) when pancuronium preceded mivacurium.
effects become prolonged also if succinylcholine is administered as exact mechanism of increased muscle tension produced by
a continuous infusion to induce a phase II block (characterized succinylcholine is not known. Masseter muscles themselves
by fade). are more sensitive to the neuromuscular blocking effects of
Succinylcholine stimulates all cholinergic autonomic receptors succinylcholine than are hand muscles.193
and is typically associated with frequent cardiac arrhythmias Goudsouzian and Liu found that young infants, mean age of
including sinus bradycardia, junctional rhythms, and ventricular 2 months, required a much greater infusion rate of succinylcholine
arrhythmias ranging from single premature beats to ventricular than older infants, mean age of 6 months, to maintain a 95%
fibrillation. Other severe adverse effects of succinylcholine include neuromuscular block. The infusion rates during halothane
hyperkalemia, rhabdomyolysis, myoglobinemia, malignant hyper- anesthesia were 25 and 9 mg/kg/h, respectively.200 Both rates were
thermia, increased intragastric and intraocular pressure, masseter greater than the rate required by children, 6 mg/kg/h. This great
spasm, increased salivation and bronchial secretions, muscle requirement in younger patients would indicate higher plasma
pains, and hypersensitivity. clearance of succinylcholine in infancy than in childhood.
Since the beginning of 2000, there has been a lot of controversy Succinylcholine has a prolonged effect in children with abnor-
and discussion on the use of succinylcholine, especially in mal plasma cholinesterase or myasthenia gravis.201 Adults with an
children, because of its rare but life-threatening adverse effects.21 abnormal plasma cholinesterase gene in one chromosome have a
Since the mid-1990s in the United States, succinylcholine was 50% prolonged effect and those with an abnormal gene in two
considered contraindicated in children and adolescents, except chromosomes have at least a three times prolonged effect after
when used for emergency tracheal intubation or in instances in succinylcholine.202
which immediate securing of the airway is necessary.183,184 Fasciculation and gross muscular movements after succinyl-
However, this view met much criticism and the U.S. Food and choline are common in infants and children.203 Fasciculation can
Drug Administration was advised to reconsider banning the be prevented by a priming dose of a nondepolarizing muscle
routine use in children and instead to update the package insert relaxant,203,204 volatile anesthetic agent,205,206 or an opioid.204,207 The
about the potential risks of succinylcholine.185 precurarization technique prevents myoglobinemia and serum
Succinylcholine is still the muscle relaxant with the shortest creatine kinase concentrations from increasing even in young
onset time (see Table 27–6). The onset time of a paralyzing dose children.203,208 However, precurarization does not prevent the
(1.0 mg/kg) of succinylcholine is 0.6 to 0.9 minutes.57,86,159,186–188 succinylcholine-induced increase in jaw tension.188 Other adverse
Cook and coworkers compared onset times of equipotent doses effects of succinylcholine include hyperkalemia, risk of hyper-
of succinylcholine and mivacurium in infants and in children.159 pyrexia, and increased intracranial and intraocular pressure.
They found that onset times of these muscle relaxants differed The risk for malignant hyperthermia is especially high in
minimally in infants, a finding indicating that infants have such children with muscular dystrophies. Normally, serum potassium
short onset times of muscle relaxants that succinylcholine is hardly rises 0.1 to 0.2 mmol/L after succinylcholine 1 mg/kg. In large
needed for routine tracheal intubation. Succinylcholine does burns, massive release of potassium between the second and the
not influence the level or duration of paralysis induced by a sixth week may cause rises in serum potassium (>4 mmol/L)
nondepolarizing muscle relaxant given after succinylcholine.169,189 sufficient to cause cardiac arrest. The extent of rise is related to
By contrast to nondepolarizing muscle relaxants, the dose- burn area and the dose. In addition, the depth and duration of
requirement of succinylcholine is greater in neonates and infants neuromuscular block produced by succinylcholine are related to
than in children or adolescents.186,190,191 Infants have 70% greater the time and extent of the burn.209 Hyperkalemia may also occur
ED95 of succinylcholine than children (700 μg/kg vs 410 μg/kg).191 in patients with spinal injuries after major trauma.
In children, the ED95 is 70% greater than in adolescents (450 μg/kg Dysrhythmias after succinylcholine, especially bradycardia
vs 270 μg/kg) (see Table 27–1).186 during inhalational anesthesia, are common. These are present
A dose of 1.5 to 2.0 mg/kg (i.e., 2 × ED95) is commonly used more frequently if repeated doses of succinylcholine are used.
for neonates and infants compared with 1.0 to 1.5 mg/kg (i.e., A classic method aiming to prevent succinylcholine-induced heart
2–3 × ED95) in older patients to establish muscle relaxation rate changes has been administration of an anticholinergic agent
sufficient for endotracheal intubation. Because these doses are before succinylcholine.210 However, a group from Toronto evalu-
several times ED95, a longer period of muscle relaxation is achieved ated the use of atropine when 1- to 6-year-old children were given
than with the minimal sufficient intubating dose.186,191 After a 1.0 placebo or atropine 10 to 20 μg/kg before succinylcholine.211,212
to 1.5 mg/kg dose of succinylcholine, the neuromuscular block They found that atropine is not at all necessary before succi-
recovers spontaneously in 4 to 5 minutes in both infants and nylcholine and recommended reconsideration when using an
children.190 anticholinergic agent to prevent cardiac arrhythmias feared with
Tachyphylaxis and phase II block develop in children when succinylcholine.
succinylcholine is administered at a dose of 3.0 ± 1.8 and 4.1 ± 2.7 Succinylcholine has been the traditional drug to provide good
mg/kg, respectively.192 or excellent intubation conditions within 1 minute after its ad-
Succinylcholine produces an increase in the resting tension of ministration. Partly because of a fear for serious adverse effects of
different skeletal muscles.193 This increase is most significant in succinylcholine, several anesthesiologists have practiced tracheal
masticatory muscles during volatile anesthesia.193–197 The reduc- intubation by using the nondepolarizing muscle relaxant that is
tion in mouth opening and jaw stiffness may last for more than subsequently used for maintenance of relaxation. This practice has
10 minutes.194,196 Masseter spasm is a situation in which jaw been very successful in pediatric patients because onset times of
stiffness prevents normal mouth opening after induction of muscle relaxants are relatively short. Tracheal intubation without
general anesthesia and may occur with a frequency of 1% after using a muscle relaxant has been documented in several publica-
succinylcholine in halothane anesthesia.198 Children with strabis- tions to be successful when propofol together with different doses
mus may be even more likely to establish a masseter spasm.199 The of alfentanil has been employed.213–215
REVERSAL OF MUSCLE RELAXATION with renal impairment. Side effects of neostigmine include those
typical for excessive cholinergic stimulation: salivation, abdominal
There are currently several ways to recover neuromuscular func- cramps, nausea, and vomiting. Atropine or glycopyrrolate given
tion following the use of nondepolarizing muscle relaxants. First, simultaneously with neostigmine will minimize these untoward
spontaneous recovery allows the muscle relaxant molecules muscarinic effects.
to become metabolized, redistributed, or excreted, whereas the The classic antagonist for nondepolarizing muscle relaxants is
amount of acetylcholine remains “constant” around the neuro- neostigmine. Distribution half-life and steady-state distribution
muscular junction. This process can take a long time especially volume of neostigmine are similar in infants, children, and
when the elimination half-lives of relaxants are commonly long. adults.217 However, plasma clearance tends to be greatest in infants
Exceptions are mivacurium, atracurium, and cisatracurium whose and produces a relatively short elimination half-life in infants
neuromuscular blocking properties may be allowed to wear off and children compared with adults (39 to 48 min vs 67 min).217
owing to rapid elimination. Smaller doses of neostigmine are needed in infants and children
The second possibility is to use anticholinesterases that de- than in adults when doxacurium, D-tubocurarine, mivacurium,
crease the breakdown of acetylcholine in neuromuscular cleft and pancuronium, and rocuronium are reversed.60,171,217,218
increase the concentration of acetylcholine available to compete The dose of 30 to 50 μg/kg can be used for all pediatric age
with muscle relaxant molecules. If the neuromuscular block is very groups, together with atropine 20 μg/kg or glycopyrrolate 10 μg/kg.
intense, that is, the concentration of a muscle relaxant in the cleft The maximum effect after neostigmine is reached in no less than
is great, anticholinesterases cannot override the effects of relaxant 5 to 10 minutes after intravenous administration, although the
molecules. Only a relatively shallow block can be effectively patient is usually extubated much earlier.59,65,145,147,148,217 The time
antagonized by anticholinesterases. taken to reach sufficient muscle power (i.e., TOF ratio > 0.9) after
The third possibility is to use the novel chelating agent sugam- neostigmine is much longer when a long-acting rather than an
madex that irreversibly removes rocuronium and vecuronium intermediate-acting relaxant is used.65
from their effect sites and, thus, allows normal acetylcholine con-
centration to have an effect at neuromuscular receptors. Sugam-
madex creates an irreversible and inert complex with these Edrophonium
steroidal muscle relaxants and abolishes their effects. Sugam-
Edrophonium has similar anticholinergic effects and adverse
madex is capable of antagonizing deep block and even rocuronium
effects to neostigmine. It does not affect the function of pseu-
very soon after its administration. Sugammadex opens a new page
docholinesterase. Edrophonium has a molecular weight of 201.7
to human pharmacology.
Da. In humans, it has a faster onset of effect than neostigmine. It
Neuromuscular monitoring is a prerequisite for reversal of
does not affect the metabolic breakdown of mivacurium and may
neuromuscular block. Before any change in neuromuscular
be a preferred agent to reverse intense neuromuscular block
transmission can be recorded, 75 to 80% of the neuromuscular
induced by mivacurium. However, purified human pseudo-
receptors have to be occupied by a nondepolarizing muscle
cholinesterase may become a drug of choice for this purpose.
relaxant.216 At the time of 95% neuromuscular block, 90% of the
The major proportion of edrophonium is eliminated via the
receptors are occupied. The more receptors are blocked, the less is
kidneys and renal failure may increase its elimination half-life
the reserve of muscular power. Even after complete reversal, a
threefold. This is more than the respective increase observed with
major proportion of acetylcholine receptors remain occupied by
muscle relaxant clearance and guarantees a good recovery profile
a muscle relaxant. The longer this occupancy lasts, the longer the
if an adequate dose at the correct level of block is administered.
elimination half-life of a particular muscle relaxant.
Edrophonium has a significantly shorter onset time than
The deeper the neuromuscular block at the time of reversal,
neostigmine.59,148,170,219 Distribution half-lives and the steady-state
the longer it takes until sufficient neuromuscular recovery takes distribution volume of edrophonium are similar in infants,
place (see Figure 27–9).65,145,147 A study evaluating antagonism children, and adults.219 Plasma clearance is greater in infants than
of alcuronium and atracurium in children found that, if the in adults and produces a slightly shorter elimination half-life in
clinician’s decision to remove an endotracheal tube is based solely infants and children than in adults (73 to 99 min vs 126 min).219
on clinical signs of recovery, neuromuscular block is still By contrast to neostigmine, larger doses of edrophonium
significant, 32 ± 20%, and the TOF ratio is only 0.50 ± 0.18.65 This were needed in infants and children than in adults when D-
means that patients having a long-acting muscle relaxant will have tubocurarine was reversed.219 However, in clinical anesthesia,
increased risk for residual paralysis if objective neuromuscular constant doses of edrophonium produced faster reversal in infants
monitoring is not used. and children than in adults.59 Edrophonium 1.0 mg/kg produced
early recovery of atracurium-induced neuromuscular block than
Neostigmine neostigmine 50 μg/kg in five age groups of infants and children.148
However, final recovery became more complete with neostigmine
Neostigmine is an anticholinesterase that inhibits the function of and the authors recommended neostigmine for routine pediatric
acetylcholinesterase. In addition, neostigmine has some inhibitory anesthesia.
effect on pseudocholinesterase and may reduce the breakdown Edrophonium 1.0 mg/kg reverses a cisatracurium-induced 90%
of succinylcholine and mivacurium. It has a molecular weight neuromuscular block in children within 3 minutes, whereas
of 223.3 Da. Neostigmine is hydrolyzed by cholinesterases and also in adults, an adequate reversal was not established within the
metabolized in the liver. It and its metabolites are excreted in 10 minutes of follow-up.220 If edrophonium is used to reverse a
the urine. less than 90% neuromuscular block (two or three visualized twitch
Renal failure produces a prolonged effect of neostigmine to responses after a TOF stimuli), the dose of 1.0 mg/kg may be used
favor successful reversal of neuromuscular block even in patients for all pediatric patients.
Sugammadex
Anticholinesterases are far from ideal reversal agents for muscle
relaxants. They cannot reverse a profound neuromuscular block,
are slow in onset, have numerous side effects, and require
co-administration of anticholinergic agents. Sugammadex is a
completely different molecule that consists of eight sugar molecules
in a ring structure like a donut.221 It is classified as a gamma-
cyclodextrin. The ring structure is hydrophilic from outside and
lipophilic from inside. Sugammadex has a very strong binding
affinity to rocuronium, which is bound irreversibly inside the
donut hole. The complex has no significant pharmacologic activity
and is eliminated from the body via urine without metabolism.
When sugammadex chelates rocuronium, its free fraction
decreases in the central compartment. More rocuronium is then
transferred from the effect site into serum (down its concentration
gradient) to further bind with sugammadex. This process conti-
nues rapidly until the effect-site concentration of rocuronium Figure 27-14. Relationship between the dose of sugammadex
becomes too low to compete significantly with acetylcholine. and time till recovery of a train-of-four ratio to 0.9 in four age
Consequently, the neuromuscular block is reversed via removal groups of patients. Sugammadex was administered when the
of rocuronium from the effect site. The strong binding affinity of second-twitch response became detectable with a train-of-four
sugammadex to rocuronium allows 1 mg/kg of sugammadex to stimulation. From reference 222.
chelate up to 0.15 mg/kg of rocuronium.
Sugammadex has a slightly lower capacity to bind vecuronium induced neuromuscular block faster than neostigmine does for a
and lower still for pancuronium (two other aminosteroidal muscle cisatracurium-induced neuromuscular block.230
relaxants) compared with rocuronium. However, it can be used to The only currently available pediatric data on sugammadex
antagonize the neuromuscular effects of vecuronium and, in consist of four age groups of patients: infants from 28 days to
emergency cases, may be tried for reversal of pancuronium. 23 months, children from 2 to 11 years, adolescents from 12 to
Sugammadex does not have any clinically significant antagonism 17 years, and adults from 18 to 65 years of age.222 Each patient
of benzylisoquinolinium-induced neuromuscular block, and these received rocuronium 0.6 mg/kg under nitrous oxide–propofol–
compounds may be used if subsequent muscle relaxation is opioid anesthesia. The neuromuscular block was reversed when
required shortly after sugammadex administration. the second-twitch response became detectable with a TOF
Only one pediatric study has been carried out with sug- stimulation. Times from reversal to a recovery of TOF ratio greater
ammadex.222 Adult studies show that when sugammadex 4 or than 0.9 were of similar magnitude in all age groups of patients
8 mg/kg is given 3 minutes after rocuronium 0.6 mg/kg, full (Figure 27–14). With a 2- or 4-mg/kg dose of sugammadex, these
neuromuscular recovery, TOF ratio greater than 0.9, is attained times were 0.6 to 1.4 minutes in all study groups. In this small
within 2 minutes.223 If sugammadex is given 5 or 15 minutes after study, no sugammadex-related adverse effects were detected.
the rocuronium 0.6 mg/kg, recovery is faster with the same doses No significant changes in heart rate, blood pressure or corrected
of sugammadex owing to a lower serum concentration of rocur- QT-time were noted. However, owing to the limited number of
onium at the time of reversal.224 If rocuronium is reversed when pediatric patients administered sugammadex, it is too early make
two twitch responses are detected with a TOF stimulation, a any conclusions on sugammadex safety.
2-mg/kg dose of sugammadex is adequate for rapid reversal.225
If rocuronium 1.2 mg/kg is to be antagonized with sugam-
madex at 3 minutes after its administration, a higher dose of CONCLUSIONS
sugammadex, 12 or 16 mg/kg, is required for rapid effect.226 There
is a very similar type of dose-effect curve for vecuronium and Muscle relaxants are used to facilitate endotracheal intubation
rocuronium that show that, when a dose of sugammadex is and, less often, to maintain muscle relaxation during a surgical
increased, the full neuromuscular recovery is attained faster.227 In procedure or in the intensive care unit. Currently, we have so many
adults, sugammadex seems to have very similar effects whether muscle relaxants available that it may be difficult to select the
rocuronium is antagonized under sevoflurane–nitrous oxide– optimal for everyday use. The high incidence of residual neuro-
oxygen or under propofol–nitrous oxide–oxygen anesthesia.228 muscular block with long-acting muscle relaxants has limited their
Sacam and colleagues compared the antagonizing properties use to few specific indications.
of neostigmine, edrophonium, and sugammadex and reported the The intermediate-acting muscle relaxants cisatracurium and
fastest effect with sugammadex.229 They antagonized rocuronium rocuronium have superior neuromuscular and safety profiles than
at an average of 90% neuromuscular block level. Time until TOF their predecessors (atracurium and vecuronium, respectively).
ratio greater than 0.9 was 1.8 minutes with sugammadex, 5.5 Rocuronium has a significantly shorter onset time than cisatra-
minutes with edrophonium, and 17.4 minutes with neostigmine. curium. Conversely, cisatracurium has the unique unchanged
Within 5 minutes from the reversal agent, no edrophonium clinical profile even in children with metabolic, renal, or hepatic
patient and 1 neostigmine patient had attained the required TOF diseases. Both agents can be used for endotracheal intubation and
ratio of 0.9 as opposed to all 20 sugammadex patients.229 Another for maintenance of muscle relaxation, but rocuronium is clearly
recent study showed that sugammadex reverses a rocuronium- preferred when a rapid-sequence induction is required.
Sugammadex may change some anesthesia practices because it 15. Churchill-Davidson HC, Wise RP. The response of the newborn to muscle
allows more liberal use of muscle relaxants than currently used. relaxants. Can Anaesth Soc J. 1964;11:1–6.
16. Goudsouzian NG, Donlon JV, Savarese JJ, Ryan JF. Re-evaluation of
This means that we may use muscle relaxants for endotracheal dosage and duration of action of D-tubocurarine in the pediatric age
intubation or very short surgical procedures more widely than we group. Anesthesiology. 1975;43:416–425.
have done in the past. Mivacurium is the shortest-acting non- 17. Goudsouzian NG, Ryan JF, Savarese JJ. The neuromuscular effects of
depolarizing muscle relaxant. However, owing to the individual pancuronium in infants and children. Anesthesiology. 1974;41:95–98.
variation in response it may take up to 20 to 30 minutes until 18. Meretoja OA. Neuromuscular blocking agents in paediatric patients:
full recovery of neuromuscular function. Therefore, very short influence of age on the response. Anaesth Intensive Care. 1990; 18:440–448.
19. Goudsouzian NG. Neuromuscular blocking agents in children. Paediatr
procedures have usually been carried out without muscle re- Anaesth. 1991;1:75–88.
laxants. Sugammadex together with rocuronium or vecuronium 20. Gronert BJ, Brandom BW. Neuromuscular blocking drugs in infants and
may allow us to reconsider our clinical practices. children. Pediatr Clin North Am. 1994;41:73–91.
Muscle relaxants will remain one of the corner stones of 21. Sparr HJ, Johr M. Succinylcholine—Update. Anaesthesist. 2002;51:
pediatric anesthesia. Much of the old mist has disappeared and 565–575.
22. Goudsouzian NG. Maturation of neuromuscular transmission in the
there is a clear picture of their effects in different pediatric patients. infant. Br J Anaesth. 1980;52:205–213.
Muscle relaxants may be life-saving when correctly used, and the 23. Goudsouzian NG, Standaert FG. The infant and the myoneural junction.
correct use always requires proper monitoring of neuromuscular Anesth Analg. 1986;65:1208–1217.
function. 24. Wareham AC, Morton RH, Meakin GH. Low quantal content of the
Neuromuscular monitoring by at least a peripheral neuro- endplate potential reduces safety factor for neuromuscular transmission
in the diaphragm of the newborn rat. Br J Anaesth. 1994;72:205–209.
stimulator is necessary owing to the wide interindividual and age- 25. Day NS, Blake GJ, Standaert FG, Dretchen KL. Characterization of the
related variability of the neuromuscular response of neonates, train-of-four response in fast and slow muscles: effect of D-tubocurarine,
infants, and children and owing to the marked and also individual pancuronium, and vecuronium. Anesthesiology. 1983;58:414–417.
potentiation of neuromuscular block by inhalational anesthetics. 26. Keens TG, Bryan AC, Levison H, Ianuzzo CD. Developmental pattern of
The cost of muscle relaxants in children is low compared with new muscle fiber types in human ventilatory muscles. Appl Physiol. 1978;44:
909–913.
intravenous or inhalational anesthetics, and economic reasons are
27. Donati F, Antzaka C, Bevan DR. Potency of pancuronium at the diaphragm
justifiable to limit the use of neuromuscular blocking agents in and the adductor pollicis muscle in humans. Anesthesiology. 1986;65:1–5.
pediatric anesthesia and intensive care. 28. Laycock JRD, Donati F, Smith CE, Bevan DR. Potency of atracurium
and vecuronium at the diaphragm and the adductor pollicis muscle.
Br J Anaesth. 1988;61:286–291.
REFERENCES 29. Laycock JRD, Baxter MK, Bevan JC, et al. The potency of pancuronium
at the adductor pollicis and diaphragm in infants and children. Anes-
1. Meakin GH. Role of muscle relaxants in pediatric anesthesia. Curr Opin thesiology. 1988;68:908–911.
Anaesthesiol. 2007;20:227–231. 30. Friis-Hansen B. Body composition during growth. In vivo measurements
2. Playfor S, Jenkins I, Boyles C, et al. Consensus guidelines for sustained and biochemical data correlated to differential anatomical growth.
neuromuscular blockade in critically ill children. Paediatr Anaesth. Pediatrics. 1971;47:264–274.
2007;17:881–887. 31. Widdowson EM. Changes in body proportions and composition during
3. Klemola UM, Hiller A. Tracheal intubation after induction of anaesthesia growth. In: Davis JA, Dubbing D, editors. Scientific Foundation of
in children with propofol-remifentanil or propofol-rocuronium. Can J Paediatrics. London: William Heinemann Medical Books Ltd.; 1974.
Anaesth. 2000;47:854–859. pp. 153–163.
4. Roberts KD, Leone TA, Edwards WH, et al. Premedication for non- 32. Radde IC: Growth and drug distribution. In: MacLeod SM, Radde IC,
emergent neonatal intubations: a randomized, controlled trial comparing editors. Textbook of Pediatric Clinical Pharmacology. Massachusetts 1985.
atropine and fentanyl to atropine, fentanyl, and mivacurium. Pediatrics. pp. 44–55.
2006;118:1583–1591. 33. Fisher DM, O’Keeffe C, Stanski DR, et al. Pharmacokinetics and pharma-
5. Dempsey EM, Al Hazzani F, Faucher D, Barrington KJ. Facilitation of codynamics of D-tubocurarine in infants, children, and adults. Anesthesio-
neonatal endotracheal intubation with mivacurium and fentanyl in the logy. 1982;57:203–208.
neonatal intensive care unit. Arch Dis Child Fetal Neonatal Ed. 2006;
34. Matteo RS, Lieberman IG, Salanitre E, et al. Distribution, elimination,
91:F279–F282.
and action of D-tubocurarine in neonates, infants, children, and adults.
6. Murphy GS. Szokol JW. Marymont JH. et al. Residual paralysis at the time
Anesth Analg. 1984;63:799–804.
of tracheal extubation. Anesth Analg. 2005;100:1840–1845.
35. Fisher DM, Castagnoli K, Miller RD. Vecuronium kinetics and dynamics
7. Woloszczuk-Gebicka B, Lapczynski T, Wierzejski W. The influence of
halothane, isoflurane and sevoflurane on rocuronium infusion in in anesthetized infants and children. Clin Pharmacol Ther. 1985;37:
children. Acta Anaesthesiol Scand. 2001;45:73–77. 402–406.
8. Woloszczuk-Gebicka B. Mivacurium infusion requirement and sponta- 36. Brandom BW, Stiller RL, Cook DR, et al. Pharmacokinetics of atracurium
neous recovery of neuromuscular transmission in children anaesthetized in anaesthetized infants and children. Br J Anaesth. 1986;58:1210–1213.
with nitrous oxide and fentanyl, halothane, isoflurane or sevoflurane. 37. Fisher DM, Canfell PC, Spellman MJ, Miller RD. Pharmacokinetics and
Paediatr Anaesth. 2002;12:511–518. pharmacodynamics of atracurium in infants and children. Anesthesiology.
9. Woloszczuk-Gebicka B, Wyska E, Grabowski T, et al. Pharmacokinetic- 1990;73:33–37.
pharmacodynamic relationship of rocuronium under stable nitrous 38. Tassonyi E, Pittet J-F. Schopfer CN. et al. Pharmacokinetics of pipecuro-
oxide–fentanyl or nitrous oxide–sevoflurane anaesthesia in children. nium in infants, children and adults. Eur J Drug Metab Pharmacokinet.
Paediatr Anaesth. 2006;16:761–768. 1995;20:203–208.
10. Meretoja OA, Wirtavuori K, Taivainen T, Olkkola KT. Time course 39. Wierda JMKH, Meretoja OA, Taivainen T, Proost JH. Pharmacokinetics
of potentiation of mivacurium by halothane and isoflurane in children. and pharmacokinetic-dynamic modelling of rocuronium in infants and
Br J Anaesth. 1996;76:235–238. children. Br J Anaesth. 1997;78:690–695.
11. Stead AL. The response of the newborn infant to muscle relaxants. 40. Meretoja OA, Brandom BW, Taivainen T, Jalkanen L. Synergism between
Br J Anaesth. 1955;27:124–130. atracurium and vecuronium. Br J Anaesth. 1993;71:440–442.
12. Bush GH, Stead AL. The use of D-tubocurarine in neonatal anaesthesia. 41. Meretoja OA, Taivainen T, Jalkanen L, Wirtavuori K. Synergism between
Br J Anaesth. 1962; 34:721–728. atracurium and vecuronium in infants and children during nitrous oxide–
13. Lim HS, Davenport HT, Robson JC. The response of infants and children oxygen–alfentanil anaesthesia. Br J Anaesth. 1994;73:605–607.
to muscle relaxants. Anesthesiology. 1964;25:161–168. 42. Sarner JB, Brandom BW, Cook DR, et al. Clinical pharmacology of dox-
14. Bennett EJ, Ramamurthy S, Dalal FY, Salem MR. Pancuronium and the acurium chloride (BW A938U) in children. Anesth Analg. 1988;67:
neonate. Br J Anaesth. 1975;47:75–78. 303–306.
43. Goudsouzian NG, Alifimoff JK, Liu LMP, et al. Neuromuscular and 68. Kern C, Tassonyi E, Rouge J-C, et al. Doxacurium pharmacodynamics in
cardiovascular effects of doxacurium in children anaesthetized with children during volatile and opioid-based anaesthesia. Anaesthesia.
halothane. Br J Anaesth. 1989;62:263–268. 1996;51:361–364.
44. Sarner JB, Brandom BW, Woelfel SK, et al. Clinical pharmacology of 69. Brandom BW, Yellon RF, Lloyd ME, et al. Recovery from doxacurium
mivacurium chloride (BW B1090U) in children during nitrous oxide– infusion administered to produce immobility for more than four days
halothane and nitrous oxide–narcotianesthesia. Anesth Analg. 1989;68: in pediatric patients in the intensive care unit. Anesth Analg. 1997;84:
116–121. 307–314.
45. Goudsouzian NG, Alifimoff JK, Eberly C, et al. Neuromuscular and 70. Pittet JF, Tassonyi E, Morel DR, et al. Pipecuronium-induced neuro-
cardiovascular effects of mivacurium in children. Anesthesiology. 1989; muscular blockade during nitrous oxide–fentanyl, isoflurane, and
70:237–242. halothane anesthesia in adults and children. Anesthesiology. 1989;71:
46. Meretoja OA, Taivainen T, Brandom BW, Wirtavuori K. Frequency of a 210–213.
train-of-four ulnar nerve stimulation influences neuromuscular response. 71. Pittet JF, Tassonyi E, Morel DR, et al. Neuromuscular effects of pipecuro-
Br J Anaesth. 1994;72:686–687. nium bromide in infants and children during nitrous oxide–alfentanyl
47. Meretoja OA, Werner MU, Wirtavuori K, Luosto T. Comparison of thumb anesthesia. Anesthesiology. 1990;72:432–435.
acceleration and thenar EMG in a pharmacodynamic study of alcuronium. 72. Praefort L. Etude pharmacodynamique du bromure de pipécuronium
Acta Anaesthesiol Scand. 1989;39:545–548. (Arduan) chez le nouveau-né, le nourisson et l’enfant. Cach Anesth.
48. McCluskey A, Meakin G, Hopkinson JM, Baker RD. A comparison of 1990;38:79–85.
acceleromyography and mechanomyography for determination of the 73. Sarner JB, Brandom BW, Dong ML, et al. Clinical pharmacology of pipe-
dose-response curve of rocuronium in children. Anaesthesia. 1997;52: curonium in infants and children during halothane anesthesia. Anesth
345–349. Analg. 1990;71:362–366.
49. Miller RD, Eger EI II, Way WL, et al. Comparative neuromuscular effects 74. Meretoja OA, Erkola O. Pipecuronium revisited: dose-response and
of Forane and halothane alone and in combination with D-tubocurarine maintenance requirement in infants, children and adults. J Clin Anesth.
in man. Anesthesiology. 1971;35:38–42. 1997;9:125–129.
50. Taivainen T, Meretoja OA. The neuromuscular blocking effects of 75. Baxter MRN, Bevan JC, Samuel J, et al. Postoperative neuromuscular
vecuronium during sevoflurane, halothane and balanced anaesthesia in function in pediatric day-care patients. Anesth Analg. 1991;72:504–508.
children. Anaesthesia. 1995;50:1046–1049. 76. Nava-Ocampo AA, Velazquez-Armenta Y, Moyao-Garcia D, Salmeron J.
51. Jalkanen L, Meretoja OA. The influence of the duration of isoflurane Meta-analysis of the differences in the time to onset of action between
anaesthesia on neuromuscular effects of mivacurium. Acta Anaesthesiol rocuronium and vecuronium. Clin Exp Pharmacol Physiol. 2006;33:
Scand. 1997;41:248–251. 125–130.
52. Goudsouzian NG, Martyn JJA, Liu LMP, Ali HH. The dose response effect 77. Imbeault K, Withington DE, Varin F. Pharmacokinetics and phar-
of long-acting nondepolarizing neuromuscular blocking agents in macodynamics of a 0.1 mg/kg dose of cisatracurium besylate in children
children. Can Anaesth Soc J. 1984;31:246–250. during N2O/O2/propofol anesthesia. Anesth Analg. 2006;102:738–743.
53. Meretoja OA, Brown TCK, Clare D. Dose-response of alcuronium and d- 78. Eikermann M, Hunkemoller I, Peine L, et al. Optimal rocuronium dose
tubocurarine in infants, children, and adolescents. Anaesth Intensive Care. for intubation during inhalation induction with sevoflurane in children.
1990;18:449–451. Br J Anaesth. 2002;89:277–281.
54. Smith CE, Baxter M, Bevan JC, et al. Accelerated onset and delayed 79. Eikermann M, Renzing-Kohler K, Peters J. Probability of acceptable
recovery of D-tubocurarine blockade with pancuronium in infants and intubation conditions with low dose rocuronium during light sevoflurane
children. Can J Anaesth. 1987;34:555–559.
anaesthesia in children. Acta Anaesthesiol Scand. 2001;45:1036–1041.
55. Meretoja OA, Luosto T. The dose-response characteristics of pancuro-
80. Burmester M, Mok Q. Randomised controlled trial comparing cisatra-
nium in neonates, infants, and children. Anaesth Intensive Care. 1990;
curium and vecuronium infusions in a paediatric intensive care unit.
18:455–459.
Intensive Care Med. 2005;31:686–692.
56. Bevan JC, Donati F, Bevan DR. Attempted acceleration of the onset of
action of pancuronium. Effects of divided doses in infants and children. 81. Reich DL, Hollinger I, Harrington DJ, et al. Comparison of cisatracurium
Br J Anaesth. 1985;57:1204–1208. and vecuronium by infusion in neonates and small infants after congenital
57. Cunliffe M, Lucero VM, McLeod ME, et al. Neuromuscular blockade for heart surgery. Anesthesiology. 2004;101:1122–1127.
rapid tracheal intubation in children: comparison of succinylcholine and 82. Meretoja OA, Wirtavuori K, Neuvonen PJ. Age-dependence of the dose-
pancuronium. Can Anaesth Soc J. 1986;33:760–764. response curve of vecuronium in pediatric patients during balanced
58. Tobias JD, Lynch A, McDuffee A, Garrett JS. Pancuronium infusion for anesthesia. Anesth Analg. 1988;67:21–26.
neuromuscular block in children in the pediatric intensive care unit. 83. Goudsouzian NG, Martyn JJA, Liu LMP, Gionfriddo M. Safety and
Anesth Analg. 1995;81:13–16. efficacy of vecuronium in adolescents and children. Anesth Analg. 1983;
59. Meakin G, Sweet PT, Bevan JC, Bevan DR. Neostigmine and edropho- 62:1083–1088.
nium as antagonists of pancuronium in infants and children. Anes- 84. Pittet J-F, Melis A, Rouge J-C, Morel DR, et al. Effect of volatile anesthetics
thesiology. 1983;59:316–321. on vecuronium-induced neuromuscular block in children. Anesth Analg.
60. Bevan JC, Purday JP, Reimer EJ, Bevan DR. Reversal of doxacurium and 1990;70:248–252.
pancuronium neuromuscular blockade with neostigmine in children. Can 85. Fisher DM, Miller RD. Neuromuscular effects of vecuronium (ORG
J Anaesth. 1994;41:1074–1080. NC45) in infants and children during N2O, halothane anesthesia.
61. Meistelman C, Agoston S, Kersten UW, et al. Pharmacokinetics and Anesthesiology. 1983;58:519–523.
pharmacodynamics of vecuronium and pancuronium in anaesthetized 86. Koscielniak-Nielsen ZJ, Bevan JC, Popovic V, et al. Onset of maximum
children. Anesth Analg. 1986;65:1319–1323. neuromuscular block following succinylcholine or vecuronium in four
62. Keneally JP, Goonetilleke PH, Ramzan IM. Delayed onset of alcuronium age groups. Anesthesiology. 1993;79:229–234.
effect in children with cyanotic congenital heart disease. Anaesth Intensive 87. Friesdorf W, Schultz M, Fösel TH, Altemeyer K-H. Pharmakodynamik
Care. 1993;21:197–200. von Vecuronium im Kleinkindesalter bei intravenöser Narkoseeinleitung
63. Ramzan IM, Keneally JP, Goonetilleke PH. Disposition and efficacy of mit Ketamin. Anaesthesist. 1986;35:99–102.
alcuronium in young children undergoing elective surgery. Paediatr 88. Motsch J, Hutschenreuter K, Ismaily AJ, vonBlohn K. Vecuronium bei
Anaesth. 1993;3:235–238. Sauglingen und Kleinkindern: klinische und neuromuskulare Effekte.
64. Meretoja OA, Brown TCK. Maintenance requirement of alcuronium in Anaesthesist. 1985;34:382–387.
paediatric patients. Anaesth Intensive Care. 1990;18:452–454. 89. Kalli I, Meretoja OA. Duration of action of vecuronium in infants and
65. Meretoja OA, Gebert R. Postoperative neuromuscular block following children anaesthetized without potent inhalational agents. Acta Anaes-
atracurium or alcuronium in children. Can J Anaesth. 1990;37:743–746. thesiol Scand. 1989;33:29–33.
66. Taivainen TR, Meretoja OA. Potency of doxacurium in infants, children 90. Reynolds PI, Fang WB, VanDerSpek AFL. The onset of ablation of the
and adolescents under N2O-O2-alfentanil anesthesia. J Clin Anesth. evoked adductor pollicis muscle twitch in children: a clinical perspective.
1996;8:225–228. Can J Anaesth. 1988;35:576–580.
67. Dresner DL, Basta SJ, Ali HH, et al. Pharmacokinetics and pharmaco- 91. Taivainen T, Praefort L, Meretoja OA. Duration of action of an equipotent
dynamics of doxacurium in young and elderly patients during isoflurane dose of vecuronium in infants and in children. Paediatr Anaesth. 1993;
anesthesia. Anesth Analg. 1990;71:498–502. 3:75–78.
92. Ferres CJ, Crean PM, Mirakhur RK. An evaluation of ORG NC 45 117. Meretoja OA, Taivainen T, Wirtavuori K. Pharmacodynamic effects
(vecuronium) in paediatric anaesthesia. Anaesthesia. 1983;38:943–947. of 51W89, an isomer of atracurium, in children during halothane anaes-
93. Meretoja OA. Vecuronium infusion requirements in pediatric patients thesia. Br J Anaesth. 1995;74:6–11.
during fentanyl-N2O-O2 anesthesia. Anesth Analg. 1989;68:20–24. 118. O’Kelly B, Fiset P, Meistelman C, Ecoffey C. Pharmacokinetics of rocuro-
94. Woelfel SK, Dong M-L, Brandom BW, et al. Vecuronium infusion nium bromide in paediatric patients. Eur J Anaesthesiol (Suppl). 1994;
requirements in children during halothane–narcotic–nitrous oxide, 11:57–58.
isoflurane–narcotic–nitrous oxide, and narcotic–nitrous oxide anes- 119. Vuksanaj D, Fisher DM. Pharmacokinetics of rocuronium in children
thesia. Anesth Analg. 1991;73:33–38. aged 4–11 years. Anesthesiology. 1995;82:1104–1110.
95. Meretoja OA. Is vecuronium a long-acting neuromuscular blocking 120. Fodale V, Santamaria LB. Laudanosine, an atracurium and cisatracurium
agent in neonates and infants. Br J Anaesth. 1989;62:184–187. metabolite. Eur J Anaesthesiol. 2002;19:466–473.
96. Harboe T, Guttormsen AB, Irgens A, et al. Anaphylaxis during anesthesia 121. Goudsouzian N, Liu LMP, Gionfriddo M, Rudd GD. Neuromuscular
in Norway: a 6-year single-center follow-up study. Anesthesiology. 2005; effects of atracurium in infants and children. Anesthesiology. 1985;62:
102:897–903. 75–79.
97. Liou JT, Hsu JC, Liu FC, et al. Pretreatment with small-dose ketamine 122. Meakin G, Shaw EA, Baker RD, Morris P. Comparison of atracurium-
reduces withdrawal movements associated with injection of rocuronium induced neuromuscular blockade in neonates, infants and children. Br
in pediatric patients. Anesth Analg. 2003;97:1294–1297. J Anaesth. 1988;60:171–175.
98. Oh AY, Seo KS, Goo EK, et al. Prevention of withdrawal movement 123. Brandom BW, Rudd GD, Cook DR. Clinical pharmacology of atra-
associated with injection of rocuronium in children: comparison of curium in paediatric patients. Br J Anaesth. 1983;55:117S–121S.
remifentanil, alfentanil and fentanyl. Acta Anaesthesiol Scand. 2007; 124. Meretoja OA, Wirtavuori K. Influence of age on the dose-response
51:1190–1193. relationship of atracurium in paediatric patients. Acta Anaesthesiol
99. Kim JY, Kwak HJ, Kim JY, et al. Prevention of rocuronium-induced Scand. 1988;32:614–618.
withdrawal movement in children: a comparison of remifentanil with 125. Ved SA, Chen J, Reed M, Fleming N. Intubation with low-dose
alfentanil. Paediatr Anaesth. 2008;18:245–250. atracurium in children. Anesth Analg. 1989;68:609–613.
100. Shevchenko Y, Jocson JC, McRae VA, et al. The use of lidocaine for 126. Lavery GG, Mirakhur RK. Atracurium besylate in paediatric anaesthesia.
preventing the withdrawal associated with the injection of rocuronium Anaesthesia. 1984;39:1243–1246.
in children and adolescents. Anesth Analg. 1999;88:746–748. 127. Grundmann U, Ismaily JA, Kleinschmidt S, Motsch J. Vergleichende
101. Taivainen T, Meretoja OA, Erkola O, et al. Rocuronium in infants, Untersuchungen von Atracurium und Vecuronium fur mittellang
children and adults during balanced anaesthesia. Paediatr Anaesth. dauernde operative Eingriffe bei Säuglingen und Kleinkindern. Anäes-
1996;6:271–275. thesiol Intensivmed Notfallmed Schmerzther. 1991;26:25–28.
102. Saldien V, Vermeyen KM, Wuyts FL. Target-controlled infusion of 128. Montgomery CJ, Steward DJ. A comparative evaluation of intubating
rocuronium in infants, children, and adults: a comparison of the doses of atracurium, D-tubocurarine, pancuronium and vecuronium in
pharmacokinetic and pharmacodynamic relationship. Anesth Analg. children. Can J Anaesth. 1988;35:36–40.
2003;97:44–49. 129. Goudsouzian NG, Young ET, Moss J, Liu LMP. Histamine release during
103. Woelfel SK, Brandom BW, Cook DR, Sarner JB. Effects of bolus the administration of atracurium or vecuronium in children. Br J Anaesth.
administration of ORG-9426 in children during nitrous oxide–halothane 1986;58:1229–1233.
anesthesia. Anesthesiology. 1992;76:939–942. 130. Goudsouzian NG, Liu LMP, Cote CJ, et al. Safety and efficacy of atra-
104. Woolf RL, Crawford MW, Choo SM. Dose-response of rocuronium curium in adolescents and children anesthetized with halothane. Anes-
bromide in children anesthetized with propofol: a comparison with thesiology. 1983;59:459–462.
succinylcholine. Anesthesiology. 1997;87:1368–1372. 131. Brandom BW, Woelfel SK, Cook DR, et al. Clinical pharmacology of
105. Hopkinson JM, Meakin G, McCluskey A, Baker RD. Dose-response atracurium in infants. Anesth Analg. 1984;63:309–312.
relationship and effective time to satisfactory intubation conditions after 132. Meretoja OA, Kalli I. Spontaneous recovery of neuromuscular function
rocuronium in children. Anaesthesia. 1997;52:428–432. after atracurium in pediatric patients. Anesth Analg. 1986;65:1042–1046.
106. Woelfel SK, Brandom BW, McGowan FX, et al. Neuromuscular effects of 133. Brandom BW, Cook DR, Woelfel SK, et al. Atracurium infusion
600 μg kg –1 of rocuronium in infants during nitrous oxide–halothane requirements in children during halothane, isoflurane, and narcotic
anaesthesia. Paediatr Anaesth. 1994;4:173–176. anesthesia. Anesth Analg. 1985;64:471–476.
107. Stoddart PA, Mather SJ. Onset of neuromuscular blockade and intubating 134. Goudsouzian N, Martyn J, Rudd GD, et al. Continuous infusion of
conditions one minute after the administration of rocuronium in atracurium in children. Anesthesiology. 1986;64:171–174.
children. Paediatr Anaesth. 1998;8:37–40. 135. Goudsouzian NG. Atracurium infusion in infants. Anesthesiology. 1988;
108. McDonald PF, Sainsbury DA, Laing RJ. Evaluation of the onset time and 68:267–269.
intubation conditions of rocuronium bromide in children. Anaesth 136. Wastila WB, Maehr RB, Turner GL, et al. Comparative pharmacology
Intensive Care. 1997;25:260–261. of cisatracurium (51W89), atracurium, and five isomers in cats. Anes-
109. Scheiber G, Ribeiro FC, Marichal A, et al. Intubating conditions and thesiology. 1996;85:169–177.
onset of action after rocuronium, vecuronium, and atracurium in young 137. Meretoja OA, Taivainen T, Wirtavuori K. Cisatracurium during
children. Anesth Analg. 1996;83:320–324. halothane and balanced anaesthesia in children. Paediatr Anaesth.
110. Vuksanaj D, Skjonsby B, Dunbar BS. Neuromuscular effects of 1996;6:373–378.
rocuronium in children during halothane anaesthesia. Paediatr Anaesth. 138. Soltesz S, Silomon M, Mencke T, et al. Neuromuskulare Blockade mit
1996;6:277–281. Cisatracurium bei Saulingen und Kindern. Verlauf unter Sevoflura-
111. Fuchs-Buder T, Tassonyi E. Intubating conditions and time course of nanasthesie. Anaesthesist. 2002;51:374–377.
rocuronium-induced neuromuscular block in children. Br J Anaesth. 139. Meakin GH, Meretoja OA, Perkins RJ, et al. Tracheal intubation condi-
1996;77:335–338. tions and pharmacodynamics following cisatracurium in infants and
112. Cheng CAY, Aun CST, Gin T. Comparison of rocuronium and suxame- children undergoing halothane and thiopental-fentanyl anesthesia.
thonium for rapid tracheal intubation in children. Paediatr Anaesth. Paediatr Anaesth. 2007;17:113–120.
2002;12:140–145. 140. Kenaan CA, Estacio RL, Bikhazi GB. Pharmacodynamics and intubating
113. Ross AK, Dear GL, Dear RB, et al. Onset and recovery of neuromuscular conditions of cisatracurium in children during halothane and opioid
blockade after two doses of rocuronium in children. J Clin Anesth. anesthesia. J Clin Anesth. 2000;12:173–176.
1998;10:631–635. 141. Brandom BW, Woelfel SK, Ference A, et al. Effects of cisatracurium in
114. Baykara N, Woelfel S, Fine GF, et al. Predicting recovery from deep children during halothane–nitrous oxide anesthesia. J Clin Anesth. 1998;
neuromuscular block by rocuronium in children and adults. J Clin 10:195–199.
Anesth. 2002;14:214–217. 142. Taivainen T, Meakin GH, Meretoja OA, et al. The safety and efficacy of
115. Tobias JD. Continuous infusion of rocuronium in a paediatric intensive cisatracurium 0.15 mg.kg(–1) during nitrous oxide–opioid anaesthesia
care unit. Can J Anaesth. 1996;43:353–357. in infants and children. Anaesthesia. 2000;55:1047–1051.
116. Kalli I, Meretoja OA. Infusion of atracurium in neonates, infants and 143. de Ruiter J, Crawford MW. Dose-response relationship and infu-
children. A study of dose-requirements. Br J Anaesth. 1988;60:651–654. sion requirement of cisatracurium besylate in infants and children
during nitrous oxide–narcotic anesthesia. Anesthesiology. 2001;94: 167. Alifimoff JK, Goudsouzian NG. Continuous infusion of mivacurium in
790–792. children. Br J Anaesth. 1989;63:520–524.
144. Brandom BW. The effects of 0.86 mg/kg of cisatracurium in an infant. 168. Bevan JC, Reimer EJ, Smith MF, et al. Decreased mivacurium require-
Anesthesiology. 1996;83:688–689. ments and delayed neuromuscular recovery during sevoflurane
145. Meistelman C, Debaene B, d’Hollander A, et al. Importance of the level anesthesia in children and adults. Anesth Analg. 1998;87:772–778.
of paralysis recovery for a rapid antagonism of vecuronium with 169. Jalkanen L, Meretoja OA, Taivainen T. Effect of succinylcholine on sub-
neostigmine in children during halothane anesthesia. Anesthesiology. sequently administered mivacurium in children. Acta Anaesthesiol
1988;69:97–99. Scand. 1995;39:1024–1027.
146. Gwinutt CL, Walker RWM, Meakin G. Antagonism of intense 170. Bevan DR, Kahwaji R, Ansermino JM, et al. Residual block after miva-
atracurium-induced neuromuscular block in children. Br J Anaesth. curium with or without edrophonium reversal in adults and children.
1991;67:13–16. Anesthesiology. 1996;84:362–367.
147. Debaene B, Meistelman C, d’Hollander A. Recovery from vecuronium 171. Bevan JC, Tousignant C, Stephenson C, et al. Dose responses for
neuromuscular blockade following neostigmine administration in neostigmine and edrophonium as antagonists of mivacurium in adults
infants, children, and adults during halothane anesthesia. Anesthesiology. and children. Anesthesiology. 1996;84:354–361.
1989;71:840–844. 172. Erkola O, Rautoma P, Meretoja OA. Mivacurium when preceded by
148. Kirkegaard-Nielsen H, Meretoja OA, Wirtavuori K. Reversal of pancuronium becomes a long-acting muscle relaxant. Anesthesiology.
atracurium-induced neuromuscular block in paediatric patients. Acta 1996;84:562–565.
Anaesthesiol Scand. 1995;39:906–911. 173. Brandom BW, Meretoja OA, Taivainen T, Wirtavuori K. Accelerated onset
149. Lien CA, Schmidt VD, Embree PB, et al. The pharmacokinetics and and delayed recovery of neuromuscular block induced by mivacurium
pharmacodynamics of the stereoisomers of mivacurium in patients preceded by pancuronium in children. Anesth Analg. 1993;76:998–1003.
receiving nitrous oxide/opioid/barbiturate anesthesia. Anesthesiology. 174. Jalkanen L, Meretoja OA, Taivainen T, et al. Synergism between atra-
1994;80:1296–1302. curium and mivacurium compared with that between vecuronium and
150. Markakis DA, Lau M, Brown R, et al. The pharmacokinetics and steady mivacurium. Anesth Analg. 1994;79:998–1002.
state pharmacodynamics of mivacurium in children. Anesthesiology. 175. Goudsouzian NG, Denman W, Matta E. Mivacurium after atracurium in
1998;88:978–983. children. Anesth Analg. 1994;79:345–349.
151. Ostergaard D, Gatke MR, Berg H, et al. The pharmacodynamics and 176. Denman W, Goudsouzian N. Mivacurium infusion requirements
pharmacokinetics of mivacurium in children. Acta Anaesthesiol Scand. following vecuronium: Different response between adults and children.
2002;46:512–518. Can J Anaesth. 1995;42:597–602.
152. Meretoja OA, Taivainen T. Mivacurium chloride in infants and children. 177. Jalkanen L, Rautoma P, Taivainen T, Meretoja OA. The pharmacodyna-
Acta Anaesthesiol Scand (Suppl). 1995;39:41–44. mics of mivacurium preceded by atracurium or cisatracurium in
153. Goudsouzian NG, Denman W, Schwartz A, et al. Pharmacodynamic and children. Anesth Analg. 1998;86:62–65.
hemodynamic effects of mivacurium in infants anesthetized with 178. Goudsouzian N, Martyn JA. Potentiation of mivacurium by rocuronium
halothane and nitrous oxide. Anesthesiology. 1993;79:919–925. is age- and time-dependent: a study in children, adolescents, and young
154. Meretoja OA, Taivainen T, Wirtavuori K, Olkkola K. Pharmacodynamics and elderly adults. J Clin Pharmacol. 1997; 37:649–655.
of mivacurium in infants. Br J Anaesth. 1994;73:490–493. 179. Meretoja OA, Taivainen T, Jalkanen L, Wirtavuori K. A fast-onset short-
155. Woelfel SK, Brandom BW, McGowan FX Jr, Cook DR. Clinical acting nondepolarizing muscle relaxant, ORG 9487, in infants and
pharmacology of mivacurium in pediatric patients less than two years children. Br J Anaesth. 1996;76:A304.
old during nitrous oxide-halothane anesthesia. Anesth Analg. 1993; 180. Bowman WC, Rodger IW, Houston J, et al. Structure:action relationships
77:713–720. among some desacetoxy analogues of pancuronium and vecuronium in
156. Meretoja OA, Olkkola KT. Pharmacodynamics of mivacurium in anesthetized cats. Anesthesiology. 1988;69:57–62.
children, using a computer-controlled infusion. Br J Anaesth. 1993;71: 181. Meakin GH, Meretoja OA, Motsch J, et al. A dose-ranging study of
232–237. rapacuronium in pediatric patients. Anesthesiology. 2000;92:1002–1009.
157. McCluskey A, Meakin G. Dose-response and minimum time to 182. Rajchert DM, Pasquariello CA, Watcha MF, Schreiner MS. Rapa-
satisfactory intubation conditions after mivacurium in children. curonium and the risk of bronchospasm in pediatric patients. Anesth
Anaesthesia. 1996;51:438–441. Analg. 2002;94:488–493.
158. Savarese JJ, Ali HH, Basta SJ, et al. The clinical neuromuscular pharma- 183. Morell RC, Berman JM, Royster RI, et al. Revised label regarding use of
cology of mivacurium chloride (BW B1090U). A short-acting non- succinylcholine in children and adolescents: I. Anesthesiology. 1994;
depolarizing ester neuromuscular blocking drug. Anesthesiology. 1988; 80:242–245.
68:723–732. 184. Badgwell JM, Hall SC, Lockhart C. Revised label regarding use of
159. Cook DR, Gronert BJ, Woelfel SK. Comparison of the neuromuscular succinylcholine in children and adolescents: II. Anesthesiology. 1994;
effects of mivacurium and suxamethonium in infants and children. Acta 80:243–245.
Anaesthesiol Scand (Suppl). 1995;39:35–40. 185. Bevan DR. Succinylcholine. Can J Anaesth. 1994;41:465–468.
160. Kaplan RF, Garcia M, Hannallah RS. Mivacurium-induced neuro- 186. Brown TCK, Meretoja OA, Bell B, Clare D. Suxamethonium—
muscular blockade during sevoflurane and halothane anaesthesia in electromyographic studies in children. Anaesth Intensive Care. 1990;18:
children. Can J Anaesth. 1995;42:16–20. 473–476.
161. Shorten GD, Crawford MW, St. Louis P. The neuromuscular effects of 187. Plumley MH, Bevan JC, Saddler JM, et al. Dose-related effects of
mivacurium chloride during propofol anesthesia in children. Anesth succinylcholine on the adductor pollicis and masseter muscles in
Analg. 1996;82:1170–1175. children. Can J Anaesth. 1990;37:15–20.
162. Brandom BW, Meretoja OA, Simhi E, et al. Age related variability in the 188. Smith CE, Saddler JM, Bevan JC, et al. Pretreatment with non-depolariz-
effects of mivacurium in paediatric surgical patients. Can J Anaesth. ing neuromuscular blocking agents and suxamethonium-induced
1998;45:410–416. increases in resting jaw tension in children. Br J Anaesth. 1990;64:
163. Simhi E, Brandom BW, Lloyd ME, et al. Intubation in children after 577–581.
0.3 mg/kg of mivacurium. J Clin Anesth. 1997;9:576–581. 189. Brown TC, Meretoja OA, Clare D, Bell B. Does suxamethonium
164. Blair JM, Hill DA, Wilson CM, Fee JPH. Assessment of tracheal influence the subsequent dose requirements of alcuronium and its
intubation in children after induction with propofol and different doses reversibility in children? Anaesth Intensive Care. 1990;18:479–482.
of remifentanil. Anaesthesia. 2004;59:27–33. 190. Cook DR, Fischer CG. Neuromuscular blocking effects of succi-
165. Meretoja OA, Theroux M. Can final EMG baseline be used as a reference nylcholine in infants and children. Anesthesiology. 1975;42:662–665.
to calculate neuromuscular recovery? Acta Anaesthesiol Scand. 1997; 191. Meakin G, McKiernan EP, Morris P, Baker RD. Dose-response curves
41:492–496. for suxamethonium in neonates, infants and children. Br J Anaesth.
166. Brandom BW, Sarner JB, Woelfel SK, et al. Mivacurium infusion 1989;62:655–658.
requirement in pediatric surgical patients during nitrous oxide– 192. DeCook TH, Goudsouzian NG. Tachyphylaxis and phase II block
halothane and during nitrous oxide–narcotic anesthesia. Anesth Analg. development during infusion of succinylcholine in children. Anesth
1990;71:16–22. Analg. 1980;59:639–643.
193. Plumley MH, Bevan JC, Saddler JM, et al. Dose-related effects of 216. Hull CJ. Pharmacodynamics of non-depolarizing neuromuscular
succinylcholine on the adductor pollicis and masseter muscles in blocking agents. Br J Anaesth. 1982;54:169–182.
children. Can J Anaesth. 1990;37:15–20. 217. Fisher DM, Cronnelly R, Miller RD, Sharma M. The neuromuscular
194. Van Der Spek AF, Fang WB, Ashton-Miller JA, et al. Increased pharmacology of neostigmine in infants and children. Anesthesiology.
masticatory muscle stiffness during limb muscle flaccidity associated 1983;59:220–225.
with succinylcholine administration. Anesthesiology. 1988;69:11–16. 218. Abdulatif M, Mowafi H, al-Ghamdi A, el-Sanabary M. Dose-response
195. Saddler JM, Bevan JC, Plumley MH, et al. Jaw muscle tension after relationships for neostigmine antagonism of rocuronium-induced
succinylcholine in children undergoing strabismus surgery. Can J neuromuscular block in children and adults. Br J Anaesth. 1996;77:
Anaesth. 1990; 37:21–25. 710–715.
196. Van Der Spek AF, Reynolds PI, Fang WB, et al. Changes in resistance to 219. Fisher DM, Cronnelly R, Sharma M, Miller RD. Clinical pharmacology
mouth opening induced by depolarizing and non-depolarizing of edrophonium in infants and children. Anesthesiology. 1984;61:
neuromuscular relaxants. Br J Anaesth. 1990;64:21–27. 428–433.
197. Van Der Spek AF, Fang WB, Ashton-Miller JA, et al. The effects of 220. Abdulatif M, El-Sanabary M. Edrophonium antagonism of cisatracurium-
succinylcholine on mouth opening. Anesthesiology. 1987;67:459–465. induced neuromuscular block: dose requirements in children and adults.
198. Schwartz L, Rockoff MA, Koka BV. Masseter spasm with anesthesia: Anaesth Intensive Care. 2001;29:364–370.
incidence and implications. Anesthesiology. 1984;61:772–775. 221. Hunter JM, Flockton EA. The doughnut and the hole: a new
199. Carroll JB. Increased incidence of masseter spasm in children with pharmacological concept for anaesthetists. Br J Anaesth. 2006;97:123–
strabismus anesthetized with halothane and succinylcholine. Anes- 126.
thesiology. 1987;67:559–561. 222. Plaud B, Meretoja O, Pohl B, et al. Reversal of rocuronium-induced
200. Goudsouzian NG, Liu LMP. The neuromuscular response of infants neuromuscular blockade with sugammadex in paediatric and adult
to a continuous infusion of succinylcholine. Anesthesiology. 1984;60: surgical patients. Anesthesiology. 2009;110:284–294.
97–101. 223. Gijsenbergh F, Ramael S, Houwing N, van Iersel T. First human exposure
201. Brown TC, Meretoja OA, Bell B, Clare D. Responses to small doses of of Org 25969, a novel agent to reverse the action of rocuronium bromide.
suxamethonium in four children with abnormal cholinesterase—a case Anesthesiology. 2005;103:695–703.
report. Anaesth Intensive Care. 1990;18:477–478. 224. Sparr HJ, Vermeyen KM, Beaufort AM, et al. Early reversal of profound
202. Viby-Mogensen J. Succinylcholine neuromuscular blockade in subjects rocuronium-induced neuromuscular blockade by sugammadex in a
heterozygous for abnormal plasma cholinesterase. Anesthesiology. randomized multicenter study: efficacy, safety, and pharmacokinetics.
1981;55:231–235. Anesthesiology. 2007;106:935–943.
203. Cozanitis DA, Erkola O, Klemola UM, Mäkelä V. Precurarisation in 225. Sorgenfrei IF, Norrild K, Larsen PB, et al. Reversal of rocuronium-
infants and children less than three years of age. Can J Anaesth. 1987; induced neuromuscular block by the selective relaxant binding agent
34:17–20. sugammadex: a dose-finding and safety study. Anesthesiology. 2006;104:
204. Lindgren L, Saarnivaara L. Effect of competitive myoneural blockade 667–674.
and fentanyl on muscle fasciculations caused by suxamethonium in 226. de Boer HD, Driessen JJ, Marcus MA, et al. Reversal of rocuronium-
children. Br J Anaesth. 1983;55:747–751. induced (1.2 mg/kg) profound neuromuscular block by sugammadex:
205. Lindgren L, Saarnivaara L. Enflurane inhibits muscle fasciculations a multicenter, dose-finding and safety study. Anesthesiology. 2007;107:
caused by suxamethonium in children. Acta Anaesthesiol Scand. 1986; 239–244.
30:444–446. 227. Suy K, Morias K, Cammu G, Hans P, et al. Effective reversal of moderate
206. Randell T, Yli-Hankala A, Lindgren L. Isoflurane inhibits muscle rocuronium- or vecuronium-induced neuromuscular block with
fasciculations caused by succinylcholine in children. Acta Anaesthesiol sugammadex, a selective relaxant binding agent. Anesthesiology. 2007;
Scand. 1993;37:262–264. 106:283–288.
207. Yli-Hankala A, Randell T, Varpula T, Lindgren L. Alfentanil inhibits 228. Vanacker BE, Vermeyen KM, Struys MM, et al. Reversal of rocuronium-
muscle fasciculations caused by suxamethonium in children and in induced neuromuscular block with the novel drug sugammadex is
young adults. Acta Anaesthesiol Scand. 1992;36:588–591. equally effective under maintenance anesthesia with propofol or
208. Asari H, Inoue K, Maruta H, Hirose Y. The inhibitory effect of intravenous sevoflurane. Anesth Analg. 2007;104:563–568.
D-tubocurarine and oral dantrolene on halothane-succinylcholine- 229. Sacan O, White P, Tufanogullari B, Klein K. Sugammadex reversal of
induced myoglobinemia in children. Anesthesiology. 1984;61:332–333. rocuronium-induced neuromuscular blockade: a comparison with
209. Brown TCK, Bell B. Electromyographic responses to small doses of neostigmine-glycopyrrolate and edrophonium-atropine. Anesth Analg.
suxamethonium in children after burns. Br J Anaesth. 1987;59:1017– 2007;104:569–574.
1021. 230. Flockton EA, Mastronardi P, Hunter JM, et al. Reversal of rocuronium-
210. Lerman J, Chinyanga HM. The heart rate response to succinylcholine induced neuromuscular block with sugammadex is faster than reversal
in children: a comparison of atropine and glycopyrrolate Can Anaesth of cisatracurium-induced block with neostigmine. Br J Anaesth. 2008;
Soc J. 1983;30:377–381. 100:622–630.
211. Shorten GD, Bissonnette B, Hartley E, Nelson W. It is not necessary to 231. Shanks CA. Pharmacokinetics of the nondepolarizing neuromuscular
administer more than 10 μg kg–1 of atropine to older children before relaxants applied to calculation of bolus and infusion dosage regimens.
succinylcholine. Can J Anaesth. 1995; 42:8–11. Anesthesiology. 1986;64:72–86.
212. McAuliffe G, Bissonnette B, Boutin C. Should the routine use of atropine 232. Belmont MR, Lien CA, Quessy S, et al. The clinical neuromuscular
before succinylcholine in children be reconsidered? Can J Anaesth. pharmacology of 51W89 in patients receiving nitrous oxide/opioid/
1995;42:724–729. barbiturate anesthesia. Anesthesiology. 1995;82:1139–1145.
213. Hiller A, Klemola UM, Saarnivaara L. Tracheal intubation after 233. Savarese JJ, Ali HH, Basta SJ, et al. The clinical neuromuscular phar-
induction of anaesthesia with propofol, alfentanil and lidocaine without macology of mivacurium chloride (BW B1090U). A short-acting
neuromuscular blocking drugs in children. Acta Anaesthesiol Scand. nondepolarizing ester neuromuscular blocking drug. Anesthesiology.
1993;37:725–729. 1988;68:723–732.
214. McConaghy P, Bunting HE. Assessment of intubating conditions in 234. Plaud B, Proost JH, Wierda JM, et al. Pharmacokinetics and phar-
children after induction with propofol and varying doses of alfentanil. Br macodynamics of rocuronium at the vocal cords and the adductor
J Anaesth. 1994;73:596–599. pollicis in humans. Clin Pharmacol Ther. 1995;58:185–191.
215. Steyn MP, Quinn AM, Gillespie JA, et al. Tracheal intubation without 235. Crumrine RS, Yodlowski EH. Assessment of neuromuscular function in
neuromuscular block in children. Br J Anaesth. 1994;72:403–406. infants. Anesthesiology. 1981;54:29–32.
Pharmacology of Local Anesthetics 28

Jean Xavier Mazoit C H A P T E R
INTRODUCTION steric bulk, nonspecific binding, and departure from linearity in all
binding and partition processes). There is, therefore, an astound-
Cocaine was first isolated by Niemann in 1860 and used for its ing complexity of the numerous mutually interacting processes
local anesthetic properties by Köller in 1884. Since then, numerous governing LA diffusion and ease of access to the site of action.
molecules have been synthesized as local anesthetics (LAs).1 Two
principal chemical compounds have been synthesized and used
for clinical purposes. Amino esters (commonly used drugs are Chirality
2-chloroprocaine, procaine, and tetracaine) were synthesized from Some molecules, although sharing the same primary formula
the early 1900s to the late 1930s by German chemists. Amino (i.e., all atoms in the molecule are identical) possess different
amides have been synthesized from the early 1940s until now
by Swedish chemists. Amino esters are degraded in plasma by
pseudocholinesterases. Their hepatic metabolism is minimal.
Amino amides are more stable molecules that undergo hepatic
metabolism.
STRUCTURE AND
PHYSICOCHEMICAL PROPERTIES
LAs are weak bases with molecular weights between 220 and 288
Da. Their structure comprises an aromatic ring, an intermediate
chain, and a hydrophilic residue. They are usually categorized as
amino esters and amino amides, depending on the link between
the aromatic ring (hydrophobic moiety) and the intermediate
chain (Figures 28–1 and 28–2). Substitution on the aromatic
nucleus, steric bulk, and pKa (i.e., the pH at which half the mole-
cules are in the charged [ionized] form and half are in the un-
charged [free base] form) modulate hydrophobicity. Stability of
the ester bond governs the rate of hydrolysis of the ester molecule.
Partition between organic solvents and buffers, which reflects the
degree of solubility of LAs in biologic membranes, is relatively
high (between 1.7 [procaine] and 800 [etidocaine] [octanol:buffer
partition]) (Table 28–1).2 All LAs in clinical use have a tertiary
amine group between the intermediate chain and the hydrophilic
residue. The tertiary amine group leads to equilibrium between
ionized (water-soluble) and nonionized (lipid soluble) forms of
the molecule. Their pKa varies between 7.6 (mepivacaine) and 8.9
(procaine). At the physiologic plasma pH of 7.40, about 60 to 85%
of amide molecules and more than 90% of esters molecules are
in the ionized form, thus leading to free diffusion in the body
aqueous compartment. In the same physiologic conditions,
cellular pH is much lower (between 6.80 and 7.25), leading to a Figure 28-1. Structure of local anesthetics. Two chemical
much greater quantity of the ionized moiety (Table 28–2). LAs formulas are available, the ester family (left) and the amide
cross phospholipid membranes mostly in their unionized form. family (right). Lower portion: The bupivacaine molecule,
The number of molecules able to cross membranes is proportional with the hydrophobic aromatic ring that is common to both
to their structure (i.e., molecules in the unionized form), the esters and amides (left) and the hydrophilic residue (right). In
proportionality factor being hydrophobicity (this simple scheme aqueous solution, the tertiary amine is protonated. At pH 7.40
does not take into account numerous confounding factors such as and 32–40°C, more than 75% of amide molecules are ionized.
Figure 28-2. Amide local anesthetics. Properties of the different agents are related to the hydrophobicity and the length of the
residue on the amine group. Note that ropivacaine’s structure is very close to that of bupivacaine with only one carbon less in the lat-
eral chain.
geometrical conformations: these are stereoisomers. Optical iso- from nonchiral reagents, an equal quantity of both enantiomers
merism occurs when a molecule is different from its mirror image. is formed: this is a racemic mixture. Some amide LAs (mepiva-
This isomerism is said to be chiral and the two mirror images are caine, prilocaine, bupivacaine) have an asymmetrical carbon that
called enantiomers.3 Chiral centers (usually a carbon atom) are confers important stereoselective differences between the levoro-
characterized by the RS convention, which is based on the priority tatory and the dextrorotatory forms. In the case of bupivacaine,
(based on molecular weight) of order of rotation of substituents: binding to serum proteins is stereoselective.4 However, stereo-
if the substituents are circulating clockwise, the molecule is “R”; if specificity appears to vary depending on the ionic channel and
they circulate counterclockwise, the molecule is “S.” Enantiomers tissue studied.5–10 Moreover the S enantiomers (ropivacaine and
are able to rotate polarized light to the right (dextrorotatory isomer levobupivacaine) are less toxic for the heart than the correspond-
[+]) or to the left (levorotatory isomer [–]), but there is absolutely ing racemic mixture.9,10 To date, ropivacaine and levobupivacaine
no relationship between the order of substitution (R or S) and the are the only LAs available as pure enantiomers.
direction in which the molecule rotates polarized light. For
example, S bupivacaine rotates polarized light to the left; this is
the S(–) bupivacaine or levobupivacaine, whereas the S mepiva-
Presentation
caine rotates polarized light to the right and is labeled S(+) mepi- LAs are presented as hydrochloride salts, which are more soluble
vacaine. Numerous molecules such as sugars or amino acids are than the free base forms. The solvent is saline and pH is maintained
naturally chiral. However, when these molecules are synthesized between 4.0 and 5.5 for perfect solubility.1 Solutions with epinephrine
TABLE 28-1. Physicochemical Properties of Local Anesthetics

Molecular Distribution Protein Onset Duration
Drug Weight, Da pKaa Coefficientb Binding, % of Action of Action Potencyc
Esters
Procaine 236 8.9 1.7 6 Long 1h 0.5
Chloroprocaine 271 9.1 9.0 ? Short 1/ –1 h 0.5–1
2
Tetracaine 264 8.4 221 80 Long 3–4 h 4
Amides
Lidocaine 234 7.8 43 65 Short 11/2–2 h 1
Prilocaine 220 8.0 25 55 Short 11/2–2 h 1
Mepivacaine 246 7.7 21 75 Short 11/2–2 h 1
Bupivacaine 288 8.1 346 95 Intermediate 3–31/2 h 4
Etidocaine 276 7.9 800 95 Short 3–4 h 4
Ropivacaine 274 8.1 115 94 Intermediate 3h 3.5–4
apKa at 37°C.
bOctanol:buffer partition.
cPotency is relative to lidocaine.
CHAPTER 28 ■ Pharmacology of Local Anesthetics 443
TABLE 28-2. Fraction of Local Anesthetic Molecules in MECHANISM OF ACTION AND OTHER
Ionized Form at Normal pH in Plasma and Tissue EFFECTS AT THE CELLULAR LEVEL
Drug Plasma, % Tissue, % Mechanism of Action at the
(pH 7.40) (pH 7.10) Molecular and Cellular Levels
Procaine 97 99
Living organisms are characterized by the production of an
Chloroprocaine 95 98
electric gradient across cell membranes. Whereas water freely diffuses
Tetracaine 93 96 across the lipid bilayer, ionic movements are strictly controlled. In
Lidocaine 76 86 the fifties, Hodgkin and Huxley demonstrated that nerve conduction
Prilocaine 76 86 was mediated by ionic channels, for which they received the Nobel
Mepivacaine 61 76 Prize in 1963. LAs mainly act by inactivating fast sodium channels
Bupivacaine 83 91 that initiate the action potential. Whereas numerous toxins act at
Etidocaine 66 80 the outer part of the phospholipid bilayer, LAs act at the inner
Ropivacaine 83 91 (cytosolic) part of the membrane and they must traverse it before
From Denson DD, Mazoit JX. Physiology and pharmacology of local anesthetics. acting on the sodium channel.
In: Sinatra RS, Hord AH, Ginsberg. B, et al., editors. Acute pain: mechanisms
and management. St. Louis: Mosby-Year Book; 1992, pp. 124–139.
Action on Excitable Membranes12–14
The electric gradient between the inner and the outer sides of
usually contain 5 μg/mL epinephrine (1/200,000). Additives such the lipid bilayer is maintained primarily by the Na+-K+ATPase
as ethylenediaminetetraacetic acid (EDTA) and para-oxibenzoate (Na+ pump).14 This pump continuously exchanges three Na+ for
have often been added in the past, particularly in solution with two K+ with an energy consumption of one molecule of adenosine
epinephrine and in ester solutions. Amide LAs are perfectly stable triphosphate (ATP). The respective outside and inside concentra-
molecules,11 and commercial solutions are free of preservative and tions are 145 and 12 mM for Na+ and 4 and 155 mM for K+. The
antioxidants (except for the drugs used for topical anesthesia). potential created (governed by the Nernst equation) is negative
Solutions containing epinephrine are stable in modern presentations. on the inner side of the membrane relative to the outer side (if
However, they still contain metabisulfite. It is not recommended the outer potential is arbitrarily defined as zero, the resting inner
to prepare solutions with freshly added epinephrine because (1) the potential is between –80 and –95 mV). Similarly Ca2+ is conti-
pH will remain low because of the pH of the LA solution itself, and nuously driven out of the cell or into intracellular vesicles (sarco-
(2) it is not sensible to take solutions prepared with great care in plasmic reticulum). When a nerve axon (or a Purkinje fiber)
controlled areas and then to add another solution prepared with is stimulated, an action potential is created that propagates along
the minimal manipulations that might lead to precipitation of the the nerve fiber (or myocardium) (Figure 28–3). This action
solution or to contamination with living organisms or foreign potential results from opening of the Na+ and K+ channels. The
material. Moreover, the clinical benefit of alkalinization is now contribution of calcium channels also occurs, especially at the
questioned by a great number of authors. cardiac level.1
Figure 28-3. Action potential. Left: A typical action potential (AP). The two main ionic conductances
generating an AP are sodium channel conductance (gNa+) and potassium channel conductance (gK+). Top
right: A typical AP from a nerve axon (a). Bottom right: A typical AP from a Purkinje fiber in the heart (b).
A larger proportion of calcium channels is the primary factor explaining the presence of a prolonged plateau
characterizing APs in Purkinje fibers.
Techniques Used to Study Channel Physiology13 have been described. The sodium channels are also classified
Direct recording of the action potential current is less and less depending on the ability of tetrodotoxin (TTX, a toxin extracted
commonly used as a tool for studying nerve physiology. Two main from the fugu fish) to block the channels at nanomolar concentra-
techniques are used: (1) the voltage clamp technique applied to tions (TTXs, sensitive) or at micromolar concentrations (TTXr,
whole cells (axons, myocytes) where the two sides of the mem- resistant). This latter classification has important implications for
brane are held at a predetermined voltage and the current flowing the involvement of sodium channels in pain transmission.17,18
between them is recorded; and (2) the patch clamp technique CHANNEL PHYSIOLOGY14,15: Numerous stochastic or determinis-
applied to small membrane patches. This allows the recording of tic models have been applied since the original empirical model used
a very small number of channels, whereas the whole-cell voltage by Hodgkin and Huxley was devised. Ionic channels have differ-
clamp technique permits the summation of a great number of ent states: the closed state (C) and the resting state (R), from which
signals (Figure 28–4). the channel can rapidly become permeable to Na+ ions, and the open
state (O) (Figure 28–6). During the open state, Na+ ions flow through
The Sodium Channel the channel and the membrane rapidly becomes depolarized. Then,
the channel rapidly (1–2 ms) passes into the inactivated state (I),
STRUCTURE: The sodium channel is a massive glycoprotein with during which the channel is insensitive to any stimulation. After
a molecular weight of 316 kDa (Figure 28–5).14,15 It consists of a 5 to 10 milliseconds of hyperpolarization, the channel returns to
central pore surrounded by four homologous structures. These the resting state (R). The probability (in Markovian stochastic mod-
structures exhibit important interspecies and intraspecies dif- els) or rate constant (in deterministic kinetic models) of passing from
ferences, the latter being the most meaningful. For example, one state to another is not symmetrical: LAs bind more tightly to
sodium channels from the nerve node of Ranvier markedly differ the channel in its open and inactivated state rather than in its rest-
from those of ventricular Purkinje cells in both their structure and ing state (see Effect of LAs on Na Channels).
their function. To date, nine channel isoforms have been identified EFFECT OF LAS ON NA CHANNELS: LAs mainly act by preventing
(Nav 1.1–1.9)16 (Table 28–3). These isoforms differ by their alpha sodium channels from opening. LAs, class I antiarrhythmic agents
subunit. In addition, four isoforms of the auxiliary beta subunit and anticonvulsants such as phenytoin and carbamazepine, act by
inhibiting ionic currents flowing through voltage-dependent
1 sodium channels.14 They bind to the channel preferentially in the
We only consider voltage dependant channels involved in nerve (or
open and inactivated states, rather than in the resting state. In
cardiac) conduction. However, even with this restriction, the “channel
addition, when the drug binds to the receptor, an allosteric change
family” has more variety than presented here.
in receptor conformation occurs, modifying drug affinity for the
Figure 28-4. Measurement of channel activity by the voltage clamp. Left: The classical axial wire
technique (A). The transmembrane potential (E) measured between an intracellular electrode (E⬘) and
a ground electrode is held constant at a determined value by means of a current (I) instantaneously
delivered by electrode I⬘. Time and voltage (E) are independent variables and I is the dependent variable.
B: In the double-gap technique, the extracellular compartment is divided by gaps of insulating solutions
such as sucrose or vaseline with precisely determined solutions between the gaps. C: The patch-clamp
method. A glass micropipette filled with an electrolyte solution measures the channel activity of a small
“patch” of membrane attached to it. The solution is chosen using the same criteria for choosing the sub-
stance filling of gaps in the voltage clamp method, and to the membrane side exposed (right). Right:
Four of the techniques used to record single-channel activity by the gigaseal-recording patch-clamp
technique. A–C: Adapted from reference 13.
receptor. This phenomenon is called a use-dependent block. When

the frequency of stimulation of the preparation increases, the
intensity of the block increases, creating a frequency-dependent
block (or phasic block), which superimposes its effect on the basal
tonic block (Figure 28–7). These phenomena represent the classic
modulated receptor model.12,14,19–23
Unlike toxins that act at the outer surface of the channel, LAs
must cross the phospholipid bilayer to produce action both inside
the membrane in their unionized free base form (hydrophobic
pathway) and inside the pore itself (hydrophilic pathway).12,14,24
Agents that are neutral at intracellular pH produce a block of
immediate maximum intensity (tonic block), whereas the intensity
of the block induced by ionized agents such as lidocaine or bupiva-
caine increases with the frequency of stimulation. Hydrophobicity
is the major determinant of drug potency. Hydrophobicity is not
the only factor governing the potency of LAs and their ability to
produce a phasic block. The latency of action and the rate of
dissociation from the receptor also depend on molecular weight.20
Finally, pKa and the intracellular-extracellular pH gradient also
have a major effect: dissociation of ligand from its receptor is 10
to 50 times slower at pH 6.2 than at pH 9.21 Quaternary amides,
which are permanently charged, act by the hydrophilic pathway.
Today, their use is limited to research purposes, although some
authors anticipate future clinical use.25 The EC50 (concentration
leading to half-maximum blockade) of LAs varies from a few μM
to several hundred μM. The stereospecificity of blockade is also
highly variable. It is difficult to make precise comparisons because
Figure 28-5. The sodium channel. The large glycoprotein form- the channel preparations vary from human cloned channels
ing the core of the channel is constituted by four alpha subunits expressed in mouse cells (without beta subunit effects) to isolated
(I–IV) surrounded by beta subunits. B and C: Three-dimen- cardiomyocytes or papillary muscles. The electrophysiologic con-
sional representations of the channel. D: A molecule of etido- ditions also vary (e.g., holding potential, pulse protocol, frequency
caine is shown bound at the inner part of the pore to the IV S6 of stimulation for measuring the phasic block). Typically, heart
fraction on the right of part A. B: ScTx, TTX, and S-S represent preparations are more sensitive and stereospecific than nerve. The
the toxin binding sites at the outer part of the channel, and P bupivacaine EC50 of the cardiac Nav 1.5 channel is between 1 μM
represents sites of phosphorylation at the inner part, thus allow- (R(+) bupivacaine and 1.6 μM (S(–) bupivacaine in isolated
ing modulation of channel activity. A–D: Adapted from Catter- cardiomyocytes and cloned channel transfected cells.7,8 However,
all WA. Cellular and molecular biology of voltage-gated sodium in the latter case, the block becomes markedly stereospecific in
channels. Physiol Rev. 1992;72:S15–S48, and reference 19. the inactivated state of the channel, which explains the much
TABLE 28-3. Sodium Channel Isoforms and Their Function
Nav 1.1 TTXs Pathophysiology: Up-regulated in DRG and dorsal horn

Channel distribution: Cell bodies of central neurons neurons after nerve injury; rapid recovery from inac-
Functions: Action potential initiation and repetitive firing tivation contributes to hyperexcitability following nerve
in neurons; excitation-contraction coupling in cardiac injury.
myocytes Pharmacologic target: Local anesthetics; antiepileptic
Pharmacologic target: Local anesthetics (CNS and cardiac drugs
toxicity); antiepileptic drugs; antiarrhythmic drugs
Nav 1.4 TTXs
Nav 1.2 TTXs Channel distribution: Skeletal muscle
Channel distribution: Central neurons Functions: Action potential initiation and conduction
Functions: Action potential initiation and conduction; repetitive Pharmacologic target: Local anesthetics; antiepileptic drugs;
firing antiarrhythmic drugs
Pathophysiology: A point mutation has been reported to cause
Nav 1.5 TTXr
inherited febrile seizures and epilepsy
Channel distribution: Cardiac myocytes, certain brain neurons
Pharmacologic target: Local anesthetics; antiepileptic drugs
Functions: Action potential conduction
Nav 1.3 TTXs Pathophysiology: Long QT syndrome and idiopathic ventricular
Channel distribution: CNS embryonic, cardiac myocytes fibrillation
Functions: Action potential initiation and conduction; repetitive Pharmacologic target: Antiarrhythmic drugs; cardiac toxicity
firing of local anesthetics
(Continued)
TABLE 28-3. Sodium Channel Isoforms and Their Function (Continued)
Nav 1.6 TTXs Nav 1.8 TTXr

Channel distribution: Cell bodies and nodes of Ranvier, Channel distribution: Small and medium-sized DRG neurones
astrocytes, and Schwann cells in the CNS; DRG; nodes of and their axons
Ranvier of sensory and motor axons in the PNS; cardiac Functions: Action potential in DRG neurones
myocytes Pathophysiology: Visceral pain, neuropathic pain; inflammatory
Functions: Action potential initiation and transmission pain
Pharmacologic target: Antiepileptic drugs; analgesic drugs Pharmacologic target: Local anesthetics; potential target for
analgesic drugs
Nav 1.7 TTXs
Channel distribution: All types of DRG neurons, sympathetic Nav 1.9 TTXr
neurons, Schwann cells, and neuroendocrine cells Channel distribution: c-Type DRG neurones, trigeminal
Functions: Action potential initiation and transmission in neurones and their axons; preferentially expressed in
peripheral neurons nociceptive DRG neurons
Pathophysiology: Mutation leads to insensitivity to pain, Functions: Nav 1.9 current is increased by inflammatory
inflammatory pain mediators such as PGE2
Pharmacologic target: Local anesthetics in the PNS Pathophysiology: Inflammatory pain
Pharmacologic target: Local anesthetics
CNS = central nervous system; DRG = dorsal root ganglion; Nav = voltage channel isoform of sodium; PNS = peripheral nervous system; TTXr = tetrodotoxin-
resistant channels; TTXs = tetrodotoxin-sensitive channels.
higher toxicity of the R(+) enantiomer compared with the S(–) four transmembrane domains and two pores (often referred to as
enantiomer.8 Conversely, most Na+ channels expressed in nerve the two-pore channels). Potassium channels are blocked by LAs,
fibers are more resistant to the effects of LAs, with EC50 ranging but some at very high concentrations and some at very low con-
from approximately 100 μM to 800 μM for lidocaine and from centrations. Voltage-gated delayed rectifiers channels Kv1.1, 1.2,
approximately 50 to 150 μM for bupivacaine.5,26–28 Interestingly, 1.3 are responsible of repolarization in nerves and are blocked at
whole cardiac tissue preparations, such as cardiac papillary concentrations above 100 μM.34,35 In the heart, K+ channels are
muscle,29 are more sensitive to the effects of LAs than isolated blocked at low concentrations similar to or slightly higher than
channels. those blocking Na+ channels. Two channels are of particular
importance, the K v1.5 channel and the hERG (ether-à-go-go–
Effect of LAs on Other Channels related gene) channel.36–38 These are considered as the two major
channels involved in the long QT syndromes.39,40 Moreover, their
POTASSIUM CHANNELS: LAs also block potassium channels.30,31 stereospecificity for LAs binding is important. The EC50 of
The family of potassium channels comprises a huge number of bupivacaine binding to the K v1.5 channel ranges from 4.1 μM for
different channels32,33 that can be broadly classified into three the R(+) enantiomer to 27.3 μM for the S(–) enantiomer.36 Other
families: channels containing six transmembrane segments and K+ channels are blocked by amide LAs (e.g., two-pore channels
one pore including the voltage-gated Kv subfamily and the hERG and APT channels) at concentrations higher than those blocking
family among others; channels containing two transmembrane the just-mentioned channels.41,42 Also, the association of the
domains and one pore (inward-rectifiers); channels containing channels with their subunits and other stabilizing proteins modify
Figure 28-6. Schematic diagram of the

modulated receptor hypothesis. R, O, and
I = rested, open, and inactivated states of
the channel (drug-free states); R-D, O-D,
and I-D = the corresponding drug-
associated states (D = drug); k is (i = R, O,
or I) = association rate constants; lis =
dissociation rate constants associated
with transitions between drug-free and
blocked states. HH = the Hogdkin-
Huxley rate constants between drug-free
states; HH⬘ = rate constants governing
transitions between drug-associated
states. The latter rate constants have their
voltage dependence shifted to more nega-
tive potentials than HH. This model has
been refined since the mid-1990s, but the
concept is still the same. Adapted from
reference 29.
“calcium” current in ventricular myocytes from rats46 and 112 μM

in isolated cardiomyocytes.47 The latter value appears more realis-
tic because the global calcium current in whole cells represents
not only true calcium current but also part of potassium and
sodium currents. Interestingly, all experiments that studied R(+)
and S(–) bupivacaine action on Ca2+ channels failed to demonst-
rate any stereospecific effect. This is consistent with the fact that
no stereospecific effect of bupivacaine on contractility was found
in whole animals.48,49
Other Effects at the Cellular Level

Effect on the Mitochondria
LAs impair mitochondrial metabolism.50 Bupivacaine has been
found to uncouple oxidative phosphorylation.51 The uncoupling
effect has been blamed for bupivacaine cardiotoxicity.52 However,
mitochondrial respiration impairment has been observed only at
concentrations 100 to 1000 times higher than those measured in
serum, even after massive intoxication. This effect is not stereo-
specific, and ropivacaine appears less toxic than bupivacaine on
mitochondrial metabolism.53,54 Conversely, this effect may explain
the muscular toxicity observed after LA administration.55
Action on Inflammation Process

and Platelet Function
Amide LAs possess anti-inflammatory properties. They decrease
inflammation mediated by leukocytes and platelet aggregation in
vitro and in vivo.56,57 They decrease leukocyte priming and the
Figure 28-7. Characterization of the phasic block (also called production of free radicals.58,59 Accordingly, lidocaine has been
use-dependent or frequency-dependent block) with lidocaine proposed as adjunct treatment for acute respiratory distress syn-
(top) and bupivacaine (bottom). Tracings are of sodium drome.60 LAs, when used at the wound site, may decrease inflam-
channel currents from nodes of Ranvier after stimulations at a matory mediators and reduce pain by a mechanism independent
frequency of 10 Hz. The first trace obtained after drug applica- of nerve conduction.61,62 Systemically administered lidocaine has
tion corresponding to the tonic block is labeled 0. Successive
been shown to have antinociceptive effects on neuropathic pain.63
depolarizations induce a phasic block that adds its effects to
LAs, by limiting the neuropathic inflammatory processes, can
those of the tonic (basal) block until steady state is attained
prevent and even treat complex regional pain syndrome in adults
(traces labeled 1–60). Adapted from Chernoff DM, Ph.D.
and in children.64,65 It has been suggested that lidocaine may speed
thesis cited in reference 12.
recovery after surgery.66 However, other authors have not repro-
duced these benefits from intravenous lidocaine, and the subject
both the affinity and the frequency dependence of the receptors is still debated.67
for LAs. This is why preparations made of intact tissue, organ, or
whole animal often behave differently from channels cloned from
DNA sequence and transfected in cells. MECHANISM OF ACTION ON
CALCIUM CHANNELS: Voltage-gated calcium channels are group- NERVE CONDUCTION
ed into three major families.43 Among these, L-type, high-voltage– Nerve Conduction
activated, dihydropyridine-sensitive channels are responsible for
excitation-contraction coupling in the heart and pacemaker acti- Nerve impulse conduction in nonmyelinated axons is related to the
vity. The T-type, low-voltage channels are responsible for repetitive propagation of the transmembrane electrical gradient flowing along
firing at the central nervous system (CNS) and pacemaker activity the fiber (Figure 28–8). The impulse cannot flow upstream because
in the heart. In the peripheral nervous system, Ca2+ channels are the region that has been depolarized is not sensitive to any
not as important as in the CNS. In pituitary gland cells, Xiong and stimulation (refractory state) for 5 to 10 milliseconds. Myelin is an
Strichartz reported high EC50concentrations for inhibition of Ca2+ excellent electric insulator, and therefore, in myelinated axons, the
channels, 2.6 mM and 0.18 mM for lidocaine and bupivacaine, impulse propagation is not continuous but rather discontinuous from
respectively.44 In the heart, EC50 are much lower. Coyle and Spe- one node of Ranvier to the next. There are almost no Na+ channels
ralakis showed that lidocaine and bupivacaine blocked the slow between nodes in myelinated axons; conversely, the density of
(calcium-dependent) part of the action potential of guinea- channels is very high at nodes.13 The intensity of the electric field
pig papillary muscle at an EC50 of 94 and 9 μM, respectively.45 created is sufficient to permit the depolarization of two and even
Further studies reported contrasting results with EC50 between three nodes forward. Nodes act as amplifiers along the fiber. The
approximately 10 μM in an experiment measuring the whole limiting step for conduction time is the node of Ranvier itself. LAs
TABLE 28-4. Classification of Nerve Fibers

Nonmyelinated Fibers
C Cutaneous sensitivity mainly to
temperature
Postganglionic sympathetic
(vasomotricity)
Myelinated Fibers
B Preganglionic sympathetic
(vasomotricity)
Figure 28-8. Nerve propagation. The AP flows continuously in
Aα Motricity
nonmyelinated fibers (top). Because of the refractory period fol-
Aβ Motricity, pressure, proprioception
lowing depolarization, the influx cannot propagate backward. In
Aγ Muscle tone
myelinated axons, influx is generated by the successive depolar-
Aδ Pain, temperature (sensitivity to cold),
ization at nodes of Ranvier. These nodes possess a great number
touch (pinprick)
of channels that together generate an electric field that enables
the forward depolarization of one, two, or even three nodes. Pain is mostly conducted by Aδ fibers.
Conduction is much faster in myelinated than in nonmyelinated
fibers. Moreover, because the distance between nodes increases Decremental Conduction
as the fiber diameter increases, conduction becomes more rapid
as the thickness of the fiber increases. The maximum velocity Decremental conduction is directly related to the phenomenon of
(~100 m/s) occurs in Aα fibers, which conduct motor influx. use-dependence: the intensity of the block is directly related to the
Thus, the time that elapses between decision-making in the cere- frequency of impulse stimulation (Figure 28–9).68,69 Consider a
bral cortex level and the execution of the motor command to 4-cm-long nerve segment bathed by bupivacaine 0.2 mM in
move a muscle in the foot is about 1.5 times longer for a tall bas- cerebrospinal fluid (CSF) at the T6 or T8 level. In this 4-centimeter
ketball player than for a shorter fighter pilot. length, Aβ fibers possess about 25 nodes whereas Aδ fibers have
twice that number. After the first stimulation, the intensity of the
action potential progressively decreases from one node to the next
need to block more than two or three nodes to interrupt nerve (in successive nodes, fewer and fewer channels attain the depolari-
conduction in myelinated axons. This requirement forms the basis zation threshold because of the regular decrease in electrical field
for the differential block mechanism (see Differential Nerve and the tonic block caused by the LA). After the 4-cm length,
Block). In the heart, conduction is much more complicated. nerve conduction will normally be restored to its initial settings.
Auricular and ventricular conduction depends on sodium channels, Nevertheless, because nerve conduction is propagated by trains of
whereas nodal conduction is mostly dependent on calcium channel impulse with a frequency greater than 10 Hz and because of the
activity,46 although sodium channels may take some part in use-dependent block, nerve conduction will rapidly fail. Because
auriculoventricular conduction.47 Aδ fibers possess twice the number of nodes as Aβ fibers, this
phenomenon will be more important with Aδ than with Aβ fibers
(i.e., with fibers conducting pain and vasomotor tone rather than
Differential Nerve Block with fibers conducting proprioception and motricity).
The effect of LAs is not the same for all axons. Nonmyelinated fibers
and thinly myelinated fibers are more sensitive to LAs than Developmental Aspects
thickly myelinated fibers (Table 28–4). This is not the result of Myelinization begins during the third trimester of pregnancy and is
increasing thickness of the myelin sheath but rather of increasing incomplete at birth. After birth, myelinization progresses rapidly
distance between adjacent nodes of Ranvier.68,69 In fact, large, thick and is almost complete at 3 to 4 years. A final step, corresponding
fibers generally have greater distance between nodes than thin fibers. to the process of motor and intellectual maturation, continues until
The impulse may skip over two or sometimes three consecutive adolescence. In rats, peripheral neurologic maturation is almost
nodes of Ranvier. There are 15 to 25 nodes/cm in Aδ fibers, whereas complete at the age of 3 weeks.70,71 Nodes of Ranvier are fully mature
there are only 6 nodes/cm in Aβ fibers. This effect is reinforced by at the age of 2 to 3 weeks in rats. Interestingly, the internode distance
the phenomenon of decremental conduction (see Decremental is similar between rats aged 2 weeks and adult rats. Experiments
Conduction). Differential blockade takes place at the spinal level comparing the effect of varying concentrations of bupivacaine
(for central blocks). It is mainly observed at the upper level of anes- and ropivacaine in rats showed that the dose of bupivacaine or
thesia because spinal roots length increases along the spine. At the ropivacaine inducing blocks of similar duration was identical in rats
thoracic level, roots are relatively short (~3 cm for an adult at aged 2 weeks and in rats aged 10 weeks, despite a difference in body
T4–6) and the number of nodes is a crucial element of blockade, weight of more than eight times72 (Figure 28–10). This may explain
whereas at the caudal level, roots are very much longer (15 cm for why infants and children need a fixed dose, independent of age or
an adult) and the block is rather an all-or-none phenomenon. It is body size, instead of weight-scaled dosing (constant mg/mL).73 This
important to remember that the sympathetic innervation does not may also contribute to the short spinal anesthesia duration
have the same distribution as sensory or motor innervation of the in neonates and infants. In addition, infants and children need
body. This simple fact explains why sympathetic blockade disap- only low concentrations to achieve blocks of intensity and dura-
pears more rapidly than sensory or motor block. tion similar to those in adults. At concentrations higher than 2 to
Figure 28-9. Computer simulation of nerve conduction shows the effect of phasic block on decremental conduction. Top: A myeli-
nated axon whose middle part is bathed in a solution of local anesthetic. Bottom: The APs generated by successive nodes. Left: After
stimulation of the nerve fiber, depolarization propagates from node to node. In the bathed part, the intensity of AP progressively de-
creases because fewer and fewer channels attain the depolarization threshold. However, the first node after the bathed portion fully
depolarizes, thus permitting transmission of nerve conduction. Because nerve conduction occurs by sequential depolarization, the
phasic block is then involved in the same manner as depicted in Figure 28–7, and because the phasic block adds its effects to those
of the basal tonic block, conduction is more and more impaired, and AP transmission completely stops after a few nodes. Right: The
effect obtained after 10 stimulations at 50 Hz. Modified from Raymond SA, Thalhammer JG, Strichartz GR. Axonal excitability:
endogenous and exogenous modulation. In: Dimitrijevic MR (ed). Altered Sensation and Pain. Recent Achievement in Restorative
Neurology. Vol. 3. Basel: Karger; 1990, cited in reference 68.
3 mg/mL bupivacaine or ropivacaine, a prolonged motor blockade

is often observed. This is consistent with the observation made by
Benzon and coworkers in the rabbit vagus nerve that similar
concentrations led to motor blockade of greater intensity in younger
animals than in older ones.74
Onset and Duration of Action and Potency

Our knowledge of the factors governing these parameters is
inversely proportional to the number of papers, opinions, and
hypotheses devoted to this subject.
The Onset of Action

The onset of action is mainly dependent of the amount of free base
available for crossing the nerve fiber. Drugs with a low pKa
Figure 28-10. Duration of sciatic nerve sensory block in infant (lidocaine, mepivacaine) that are close to the pKa of extracellular fluids
rats is related to the dose of bupivacaine used. Rats aged 5 days are mostly in the neutral form, and therefore, easily diffuse across
had prolonged block compared with older subjects. Two-week- membranes. Their onset of action is shorter than the onset of drugs
old rats had a duration of block similar to that of 10-week-old with higher pKa (tetracaine, bupivacaine). Some authors have tried
rats despite an eight times difference in body weight. This obser- to increase this free base moiety by either changing the molecule itself
vation is probably because the internode distance is fixed after or by adding sodium bicarbonate (see Other Techniques Used to
the age of 1 to 2 week. Drawn from the data in reference 72. Increase Onset, Potency, and Duration of the Block).
Potency and Duration of Action Opioids

Potency and duration of action depend mainly on hydrophobicity Morphine (33–50 μg/kg) has been used to prolong the duration
and molecular weight. Potency is dependent on solubility in lipids, of analgesia after caudal anesthesia.89 However, the main use of
which favors diffusion across cellular membranes. Higher con- opioids is in combination with LAs for continuous epidural
centrations of those drugs with lower lipid solubility such as pro- analgesia.90 Morphine, fentanyl, and sufentanil have been
caine or chloroprocaine are needed to produce a block of similar used.90–93 Continuous infusion of epidural fentanyl provides the
intensity to drugs with higher lipid solubility and higher molecular same quality of analgesia as morphine with fewer adverse effects
weight such as tetracaine, bupivacaine, or etidocaine. The duration provided that infusion is administered at the right dermatome
of action is governed by the same factors. The environment of level. Lerman and colleagues questioned the interest in fentanyl
the nerve structures also plays an important role. For example, associated with levobupivacaine,94 but they injected fentanyl at the
epidural fat markedly retains highly hydrophobic drugs such as lumbar level for surgery often in the upper abdomen. Side effects
bupivacaine or etidocaine and this contributes to the duration of like nausea and vomiting or urinary retention also frequently oc-
action of these drugs (see Epinephrine). cur with epidural opioids. Then, this very effective technique for
patients undergoing major surgery usually requires concomitant
use of gastric and urinary catheters.
Tachyphylaxis
Tachyphylaxis is characterized by the time-dependent decrease in Ketamine
the observed effect of a drug: the same dose produces an effect of
lower intensity and/or shorter duration. Tachyphylaxis has long Ketamine has also been proposed to prolong the duration of
postoperative analgesia provided by epidural (usually caudal) LAs.
been noted both with esters and amides with either central (usually
Both racemic and S(–) ketamine can be used provided that the
epidural) block and peripheral blocks.75 Both pharmacokinetic
solution used does not contain any preservative. The usual dose is
factors, such as macroscopic changes in local distribution of the
0.5 mg/kg racemic ketamine or 1 mg/kg S(–) ketamine.95,96 How-
drug molecules or modifications of diffusion capacity across nerve
ever, some controversies still exist on the possible neurotoxicity of
sheets and cellular membranes, and/or pharmacodynamic factors ketamine.97
involving regulation of pain transmission have been advocated to
explain tachyphylaxis.
Other Techniques Used to Increase Onset,
Potency, and Duration of the Block
Adjuvant Drugs Increasing the pH of solutions is supposed to increase the free base
Adjuvants are often used to shorten the onset of action or increase moiety and, therefore, the fraction able to cross membranes. How-
the duration of action of LAs. They are also used to decrease the ever, alkalinization has shown inefficacy and perhaps toxicity.98
peak concentration, thus permitting the use of higher doses. Encapsulation of LAs in microspheres is another method of
Adjuvants other than epinephrine are usual for neuroaxial blocs. increasing the duration of action.99,100 This technique of slow
release is at present under investigation to assess its total safety
both for spinal cord and for the concentration released. The asso-
Epinephrine ciation of LAs with other molecules such as TTX or capsaicin is
Epinephrine is the most commonly used adjuvant. Its addition to also under investigation.25,101 Mixtures of LAs (especially the 1:1
LAs results in decreasing the peak concentration,76–78 increasing mixture of lidocaine and bupivacaine) are very popular. Studies
the duration of postoperative analgesia in children younger than performed in children lack a definite opinion on the subject.
4 years of life after caudal anesthesia79 and facilitating detection of However, in a study performed in adults receiving epidural
an inadvertent intravascular injection.80,81 The usual concentration anesthesia, Seow and associates have clearly shown that, although
is 5 μg/mL (1/200,000). In infants, it has been suggested that the the addition of lidocaine to bupivacaine decreases the duration of
use of 1/200,000 epinephrine might have been responsible for action compared with bupivacaine alone, the onset of action is not
ischemic neurologic syndromes leading to definitive sequelae after significantly decreased when lidocaine is added to bupivacaine102
central blocks because of a decrease in spinal blood flow.82 These (Figure 28–11). Another goal of mixing LAs is to decrease the
authors recommend the use of epinephrine at a concentration not concentration of epinephrine by using a 1:1 mixture of a plain
greater than 1/400,000 before the age of 1 year. However, because solution and a solution with epinephrine 1/200,000, resulting in a
the S enantiomers, ropivacaine and levobupivacaine, are marketed solution with 1/400,000 epinephrine that is claimed to be less toxic
only as plain solutions, this problem with epinephrine no longer in infants.82
exists.
PHARMACOKINETICS103
Clonidine LAs are different from other anesthetic drugs. They are supposed
Clonidine increases the duration of action and the quality of to act at the site of injection, and local concentration governs the
analgesia when added to LAs injected spinally or epidurally.83,84 effect. Systemic disposition is the only elimination pathway, and
Clonidine is supposed to act at the dorsal part of the spinal cord brain and cardiac absorption are side effects. Absorption from
by facilitating the descending inhibitory pathway,85 but a systemic the injection site, systemic disposition, hepatic metabolism, and
action seems probable,86,87 explaining why clonidine is also effec- renal elimination of metabolites are the rule for amide LAs. Plasma
tive when used for peripheral block.88 The usual dose varies from degradation by cholinesterases is the main metabolic pathway
1 to 2 μg/kg. for esters.
Binding to Blood Components

The use of a continuous perineural infusion of LA for postopera-
tive pain relief has regained some interest in infants, although this
practice is not without risk.104,105 The importance of binding of LAs
to blood components has regained some practical interest. Binding
of esters to serum proteins varies from 6% (procaine) to 76%
(tetracaine) (see Table 28–1). Amides bind to red blood cells and
serum proteins with a blood–to–plasma concentration ratio be-
tween 65 and 80% and a serum protein binding between 65 and
96% (Table 28–5; see also Table 28–1). Drug binding in blood
protects against adverse effects caused by high drug concentra-
tions because only unbound molecules are free to cross the blood-
brain barrier and the heart capillary wall. This is not always the
case because a complex relationship exists between rate of binding
Figure 28-11. Effect of mixing local anesthetics (LAs) on the to erythrocytes, rate of binding to serum proteins, rate of crossing
onset and duration of block after epidural injection at the L1–2 membranes, and organ transit time. Often, drugs largely bound
interspace. 4L = 4 volumes of lidocaine and 0 volume of bupiva- to serum proteins are rapidly cleared at the hepatic level, especially
caine; 4B = 0 volume of lidocaine and 4 volumes of bupivacaine. because of prolonged transit time and complex cooperativity
Left: The time to onset depending on the dermatome in ques- between binding sites. Amide LAs are exclusively cleared by the
tion. No difference between the different solutions is seen. liver and their hepatic extraction ratio is dependent on the free
Right: The duration of anesthesia. Adding lidocaine to bupiva- fraction (fu) in blood. Also, at first sight, toxicity of LA is depen-
caine decreases the duration of anesthesia, but no effect on the dent on the free drug concentration, although this assumption has
onset of anesthesia is seen. Modified from reference 102. been shown to be true only during prolonged infusion.
TABLE 28-5. Amides Binding to Serum Proteinsa

Author C fu Comments
␮g/mL %
Lidocaine
McNamara, 1981107
Adults 1.4 29 In vitro, ultrafiltration
Lerman 1989b
Neonates (AAG 48 In vivo, 5 min after 1.5 mg/kg
= 0.33 g/L) I.V., ultrafiltration
Infants (AAG 32
= 0.46 g/L)
Children (AAG 26
= 0.66 g/L)
Adolescents 26
(AAG = 0.63 g/L)
Bupivacaine
Veering, 1991109
Adult females 0.5 5.3 ± 1.6 In vitro, equilibrium dialysis
Adult males — 4.5 ± 1.2
Mazoit, 1996
Adults S(–) bupivacaine 1.0 μg/mL–1 fu = 7% 16 μg/mL–1 fu = 18% In vitro, ultrafiltration
R(+) bupivacaine 1.0 μg/mL–1 fu = 5% 16 μg/mL–1 fu = 16%
Groen, 1998187
Adults S(–) bupivacaine 0.4 ± 0.1 3.2 In vivo, equilibrium dialysis
R(+) bupivacaine 0.4 ± 0.1 4.9
Mazoit, 1988117
Infants (1–6 mo) 0.97 ± 0.42 19 ± 8 In vivo, after 2.5 mg/kg caudal,
Meunier, 1998123 ultrafiltration
Infant (1 m) fu = 23% (30 min after 1.25 mg/kg epidural as bolus), fu = 13% (after 0.375 mg/kg/h
during 48 h), ultrafiltration
Infant (7 mo) fu = 5.2% (30 min after 1.25 mg/kg epidural as bolus), fu = 3.8% (after 0.375 mg/kg/h
during 48 h)
(Continued)
TABLE 28-5. Amides Binding to Serum Proteinsa (Continued)

Author C fu Comments
Ropivacaine
Lee, 1989110
Adult 1.43 ± 0.40 6±1 In vivo after 50 mg I.V. in 15
min, ultrafiltration
Emanuelsson, 1995c
Adult 0.4 4.7 In vivo after 21 h infusion,
1.2 6.1 ultrafiltration
AAG = α1-acid glycoprotein; C = the concentration at which fu has been measured; fu = free fraction.
aData are mean ± SD.
bLerman J, Strong HA, LeDez KM. Effects of age on the serum concentration of alpha1-acid glycoprotein and the binding of lidocaine in pediatrics. Clin Pharmacol
Ther. 1989;46:219–25.
cEmanuelsson BM, Zaric D, Nydahl PA et al. Pharmacokinetics of ropivacaine and bupivacaine during 21 hours of continuous epidural infusion in healthy male
volunteers. Anesth Analg. 1995;81:1163–8.
Binding to Red Blood Cells BINDING TO AAG: The AAG or orosomucoid is also called stress
LAs have a low affinity for red blood cells (the blood–to–plasma protein. It is the major protein involved in amide binding in serum.
concentration ratio for amides lies between 60 and 85%).103,106 AAG is a glycoprotein with multiple physical states. The mono-
However, binding to red blood cells appears to be linear (i.e., not meric moiety has a molecular weight between 38,800 and 48,000
saturable), and this may become meaningful when binding to Da depending on numerous factors.113 The extent of polymeri-
serum proteins (especially to α1-acid glycoprotein [AAG]) zation and the association to fatty acids may lead to marked
becomes saturated. Unfortunately, very few studies of LA binding differences in properties of the molecule. All basic drugs bind to
in blood have taken this important action into account (red blood AAG. However, AAG concentration in serum is relatively low
cells represent > 40% of blood volume), especially in infants with (0.50–1.0 g/L in adults). AAG concentration is very low at birth
physiologic anemia. The best reference paper is still from Tucker and increases slowly during the first year of life (Figure 28–14).
and coworkers who studied lidocaine, mepivacaine, and After 1 year of age, orosomucoid concentration remains unchan-
bupivacaine binding.106 At a total concentration of 2 μg/mL, the ged until at least the age of 80 years.114 AAG concentration mark-
blood–to–plasma concentration ratio was 0.78, 0.72, and 0.60 for edly increases during inflammatory processes such as cancer,
lidocaine, mepivacaine, and bupivacaine, respectively. At 20 burns, and the postoperative period.115–118 In the postoperative
μg/mL, this same ratio was 0.91, 0.91, and 0.83. These authors period, the increase occurs during the first 3 to 6 hours after sur-
have shown that the concentration ratio between washed red cells gery. It is important to remember that acidosis markedly decreases
and buffer varied between 2.0 for lidocaine and 2.7 for the affinity of AAG to LAs, particularly bupivacaine.119,120
bupivacaine. Moreover, this ratio was constant over a wide range
of concentrations. Thus, red blood cells may be considered as a
buffer system reaching significance when toxic concentrations
occur (i.e., >2–3 μg/mL for bupivacaine or >7–10 μg/mL for
lidocaine), especially in infants with a low AAG concentration
(Figure 28–12). On the contrary, anemia seems to favor a rapid
rise in free drug concentration. This is most likely to occur in
infants younger than 6 months who have not yet reached their
definitive adult AAG concentration and have a low, though
physiologic, hematocrit.
Binding to Serum Proteins

Esters are rapidly hydrolyzed by esterases in plasma, and protein
binding occurs only in toxic situations. Amide LAs bind tightly to
serum proteins. At total serum concentrations of up to 10 μg/mL
for lidocaine and up to 2.5 μg/mL for bupivacaine, the fu observed Figure 28-12. Lidocaine, mepivacaine, and bupivacaine binding
in adults varies between 25 and 45% for lidocaine and between (fraction of total concentration in whole blood) at 2 μg/mL (left
4 and 7% for bupivacaine and ropivacaine.4,107–111 Like all weak bars) and 20 μg/mL in blood (right bars). Mepivacaine is
bases, amide LAs mainly bind to AAG and to human serum slightly more highly bound than lidocaine and the fu is nearly
albumin (HSA) with minimal binding to α2 proteins and no constant in the concentration range studied. At 2 μg/mL bupiva-
binding to β globulins.112 HSA has a low affinity but a high (almost caine in blood (which represents the upper limit of nontoxic
nonsaturable) capacity for LAs, whereas AAG has a very high concentrations), fu is low (~5%) and most of the drug is bound
affinity for them. Unfortunately, AAG is 50 to 80 times less to serum proteins. At 20 μg/mL (which represents a highly
abundant than HSA (especially before the age of 6 mo) and the toxic concentration), fu is much greater (~20%) and the buffer
capacity of binding is relatively low (i.e., saturation occurs rapidly capacity of erythrocytes becomes evident. Drawn from adult
at concentrations usually observed in serum) (Figure 28–13). data obtained in reference 106.
Figure 28-13. Left panel: Free lidocaine (dotted line) and free bupivacaine (solid line) concentrations in serum as a func-
tion of total concentration. This simulation was calculated using average adult parameters from references 107 and 108.
Inset: An enlargement of the first part of the curve (at clinical concentrations). When total bupivacaine concentrations are
greater than 2–4 μg/mL, binding capacities are partly saturated and the free concentration increases dramatically. Right
panel: The effect of α1-acid glycoprotein (AAG) concentration on bupivacaine binding in serum. Middle curve: The free
versus total bupivacaine concentration in an adult subject with normal AAG binding capacity. Lower curve: Drawn with
parameters from a subject with twice this binding capacity (e.g., a subject with metastatic cancer). Upper part: Drawn with
parameters from a subject with half this normal binding capacity (e.g., an infant aged 1–2 mo). Adapted from Mazoit JX,
Vigué B. Les associations d’anesthésiques locaux sont-elles dangereuses? Ann Fr Anesth Réanim. 1988;7:211–215.
Figure 28-14. α1-Acid glycoprotein (AAG)

and human serum albumin (HSA) concen-
trations in serum as a function of age. Upper
panel: Free fraction of sufentanyl is plotted
against AAG concentration for different aged
patients. Lower panels: The concentration of
AAG (left) and HSA (right), in a sample of
11 infants aged 1–6 months, plotted against
age. Upper panels: Adapted from reference
116. Lower panels: Drawn from data ob-
tained in reference 117.
BINDING TO HSA: HSA is the most abundant protein in serum

with an average concentration of 40 g/L in adult. Acidic drugs such
as thiopental bind strongly to HSA, to one site in particular.121 This
site is common to all acidic drugs and to bilirubin. Basic drugs
such as amide LAs bind less specifically to has, and the site
responsible for acidic drugs binding is not involved. Although the
affinity of LAs for HSA is much lower than the affinity of LAs for
AAG, the enormous binding capacity of HSA renders this protein
important in the binding equilibrium process. When binding to
AAG is saturated, two systems continue to bind LA, erythrocytes
and HSA. HSA concentration is slightly lower at birth when
compared with the values measured in older children. However,
changes in binding induced by the variations in HSA content are
generally of no practical clinical significance. Almost all circums-
tances that may lead to decrease in HSA induce an increase in Figure 28-15. Bupivacaine free fraction (fu) in serum as a func-
AAG that compensates or overcompensates for that change. It is tion of age in 11 infants aged 1–6 months after 2.5 μg/kg caudal
important to remember that HSA binds LA in children with bupivacaine. The curve corresponds to the AAG concentration
nephrotic syndrome. This disease is characterized by a decrease depicted in Figure 28–14, lower left panel. As AAG increases
in albumin concentration in serum. AAG is not concomitantly with age, fu decreases and the usual adult value (~5%) is reached
increased so that protein binding is expected to be markedly after the age of 6 months. From reference 117.
decreased in these circumstances.
Acidosis is a cause of increased unbound drug. Renal failure
and hyperbilirubinemia are known to increase the fu of acidic INTERACTION AND DISPLACEMENT FROM BINDING SITES WITH
drugs. However, the fu of basic drugs does not seem to be in- OTHER DRUGS: Interactions at the binding sites have long been
creased in hyperbilirubinemia (personal data not published). The thought to be of paramount importance. Drugs with a low thera-
effect of renal failure on the fu of basic drugs is known to be peutic ratio such as bupivacaine may be displaced from their
variable. Renal insufficiency has a number of different etiologies serum protein binding sites by other molecules. This phenomenon
that can lead to a decrease, an increase, or no change in AAG or is not considered to be as important as it was believed to be some
HSA concentrations. For example, Chauvin and colleagues did not years ago.129 However, displacement between LAs may be ob-
find any difference in fu between a group of American Society of served, and it is important to remember that mixtures of LAs
Anesthesiologists (ASA) 1 patients and a group of patients with possess the toxicity of their most toxic component.130
renal failure (fu = 6.8 ± 0.8% vs 8.2 ± 3.0%, respectively).122 This
result is in accordance with the fact that AAG concentration was Tissue Binding
similar in both groups (0.89 ± 0.30 mg/L vs 1.01 ± 0.47 mg/L,
respectively). Tissue binding is an important, though largely unknown, para-
meter in local and general disposition of drugs. Global, non-
PROTEIN BINDING EVOLUTION DURING THE FIRST YEAR OF specific tissue binding can be estimated from distribution data.131
LIFE: Neonates have only one fifth to one third the AAG serum Table 28–6 displays the relative percentage of amide LAs that
concentration observed in adults116–118 (see Figure 28–14). They distribute in the body. It is evident that the vast majority of amide
also have a lower HSA concentration. However, HSA concentra- molecules are bound in tissue.
tion changes between birth and 6 to 9 months are much less
important than the difference in AAG concentration. The net
result is a lower binding capacity during the first 6 to 9 months of Local Disposition and Absorption
life compared with children or adults. This leads to a higher fu in Into the Bloodstream
infants younger than 6 to 9 months than in children or adults 117,123
(Figure 28–15). Young infants have also a decreased intrinsic Concentration at the Site of Action
hepatic clearance of LAs. The combination of decreased clearance Amide LAs are usually considered to have a bioavailability of one
and increased free fraction in infancy relative to the values and metabolism is exclusively hepatic. Absorption is slow and
encountered in children and adults explains the high bupivacaine varies depending on local conditions. Absorption after ilioingui-
concentrations observed at this age.124–128 noiliohypogastric block is faster than after caudal injection. From
adult studies, we may extrapolate that the speed of absorption
CHANGES IN PROTEIN BINDING IN THE POSTOPERATIVE decreases from head to foot for peripheral blocks and from
PERIOD: In the postoperative period, AAG concentration in- thoracic to caudal epidural space (with the possible exception of
creases rapidly. Six hours after surgery, the binding capacities are children not yet walking). This is the consequence of the degree of
markedly increased in adults, children, and infants.115,118,123 How- vascularization of tissues in relation with hydrostatic pressure
ever, neonates and young infants have a markedly lower basal (humans are bipeds).
AAG concentration than children or adults. The increase in AAG Concentrations of LAs are very high at the site of action (Table
concentrations observed after surgery is proportional to the basal 28–7), and neurologic complications following spinal anesthesia
concentrations, and AAG concentrations observed 24 to 48 hours have been attributed to these excessive concentrations that lead to
after surgery are lower in young infants than in older subjects in a direct toxic effect on nerve fibers.132 Local disposition contributes
the same circumstances.123 to both onset and duration of action as well as to absorption into
TABLE 28-6. Lidocaine and Bupivacaine Distribution in Body Compartments

For each drug, the fraction in each compartment has been calculated using Øie and Tozer’s formula131:
f
V = Vp (1 + R E /I ) + f u Vp (VE /VP − R E /I ) + VR u
fu R
where VP = the plasma volume (3 L); VE = the extracellular volume (12 L); VR = the remaining volume (total body water – VE)
(27 L); RE/I = the ratio of the number of binding sites in the extracellular space and the number of sites in plasma (usually 1.4);
fu = the free fraction in plasma; and fu the free fraction in the compartment VR. Thus, fu is estimated to be 0.14 for lidocaine,
R R
0.03 for bupivacaine, and 0.06 for ropivacaine. It is clear that, if tissue binding is the determining factor of volume of distribution,
plasma binding plays also an important role, inverse to that of tissue binding. Any increase in fu leads to an increase in V, whereas
any increase in fu leads to a decrease in V.
R
The figures are approximate and must be interpreted with care.

Lidocaine Mepivacaine Bupivacaine Etidocaine Ropivacaine
In extracellular fluids 0.13 0.11 0.14 0.06 0.18
Outside extracellular fluids 0.87 0.10 0.86 0.94 0.82
Free 0.19 0.10 0.04 0.02 0.05
Bound to plasma proteins 0.03 0.03 0.05 0.02 0.06
Bound to extracellular proteins 0.06 0.07 0.12 0.05 0.15
Bound inside cells 0.74 0.80 0.83 0.92 0.74
(including red blood cells)
the bloodstream. The latter phenomenon has been well studied Local Disposition and Absorption
for epidural anesthesia. Absorption from the site of action may After Spinal Injection
vary with age. However, few authors have studied this dependence
Spinal anesthesia requires a higher dose (mg/kg) in infants than in
and results are not totally conclusive. Some factors such as the
amount of fat in the epidural space133 or an increased mucosal older children, and the duration of the block is brief. It is com-
vascularization134 have been advocated to explain discrepancies monly believed that the volume of CSF (relative to weight) toge-
between adults, children, and infants. In the next section, we ther with a more rapid CSF turnover in infants than in children
describe the details of absorption for different routes of injection. and adults may explain why spinal anesthesia duration is shorter
Between-individual variability is a significant factor for absorption despite the larger dose. In fact, the pharmacokinetics of LAs in the
variability. Ester and amide LAs have different dispositions after CSF are unknown, particularly in the pediatric age group. At the
their absorption into the systemic circulation. However, neither cephalic level, neonates and infants have a lower CSF volume and
undergoes significant local metabolism or degradation. Bioavail- turnover than children and adults.135 The shorter length of nerve
ability is then considered complete for all LAs. roots in infants than in adults and the relatively fixed internode
TABLE 28-7. Cerebrospinal Fluid Concentrations of Local Anesthetic Solutions After Spinal and Epidural Injectiona
1 μg/mL lidocaine (base) = 4.3 μM (mol/L), 1 μg/mL bupivacaine = 3.5 μM, 1 μg/mL tetracaine = 3.8 μM
Lidocaine Bupivacaine Tetracaine
Concentrations in the Bottle
5% 214 mM 1% 38 mM
2% 85 mM 0.5% 17 mM 0.5% 19 mM
1% 43 mM 0.25% 9 mM
Minimum Concentrations Needed to Block the Nerve (at the Outer Part of the Fiber)
0.5–1.5 mM 0.2–0.6 mM 0.25–0.6 mM
b
Average Concentration in CSF (Perfect Mixing in Half CSF Volume Is Supposed)
Spinal Epidural Spinal Epidural Spinal
100 mg (2 mL 5%) 400 mg (20 mL 2%) 15 mg (3 mL 0.5%) 100 mg (20 mL 0.5%) 20 mg (2 mL 1%)
9.5–13.4 mM 0.8–5.3 mM 1.1–3.2 mM 0.15–1.1 mM 1.7–4.8 mM
CSF = cerebrospinal fluid.
aAbout 2–5% of the dose injected in the epidural space crosses the meninges. This amount is significant and epidural anesthesia acts mainly by a delayed spinal
anesthesia.122,123 Sodium channel blockade occurs at in vitro concentrations outside the nerve fiber between 0.15 and 1.5 mM depending on the agent. Because of the
concentration gradient between fluids surrounding the nerve (or the cord) and the nerve fibers, the concentration bathing nerves or the cord needs to be higher.
Depending of the model used, CSF lidocaine concentration leading to neurologic sequelae is between 20 and 60 mM.
bCSF volume measured using MRI between T2 and S2 was found between 32 and 90 mL (median 50 mL) (Fink BR. Mechanisms of differential axial blockade in
epidural and subarachnoid anesthesia. Anesthesiology. 1989;70:851–858). The volume of CSF (relative to weight) in which anesthetic molecules distributes is about
four times greater in neonates and infants than in adults.118
distance contribute. In addition, because dural surface area is

related to body surface area rather than to weight, it is not sur-
prising that LA clearance from CSF will be higher in younger
patients because the main factor governing clearance is the dural
surface area.136
Local Disposition and Absorption

After Epidural Injection
THE EPIDURAL SPACE: The epidural space is not as empty as it is
commonly asserted. It is a fatty region between the dura matter
and the vertebrae with numerous veins in the anterior portion.137
Although the epidural space is very compliant, intraepidural
pressure increases markedly after injection. For instance, after
injection of a volume as small as 2 mL in an adult, pressure in the
epidural space reaches 20 mmHg 138 (Figure 28–16). This in-
creased pressure is immediately transmitted to the CSF, and it has
been shown that the increased pressure in CSF lasted for more
than 10 to 20 minutes.138,139 The magnitude of this increase is
dependent on basal intracranial pressure. Patients with increased
intracranial pressure and decreased cerebral compliance will have
an increase in intracranial pressure that is of greater intensity and
greater duration than in normal subjects. Apart from direct action
on the nerve roots during their passage through the epidural
space, LAs act by crossing the meninges.140,141 Despite inaccuracies
in the measurement of the fraction of drug that crosses the menin- Figure 28-17. Upper panel: Fraction of lidocaine (open circles)
ges, an estimate of 2 to 3% of the injected dose is appears to do and bupivacaine (solid circles) absorbed from the epidural space
so.140–143 into the bloodstream in two patients. Three hours after a single
THE EPIDURAL SPACE AS A RESERVOIR: The balance between injection in the epidural space, 50% of bupivacaine and 30% of
systemic absorption and local disposition of a drug depends on lidocaine remain in the epidural space. Lower panel: The effect
local properties of the epidural space. In fact, after epidural of this delayed absorption on the decline in concentration in
injection, a drug is absorbed by epidural fat, which is the main blood (“flip-flop” effect). Lower curve (triangles and dotted
component of this body compartment and an important factor of line),The concentration observed after intravenous injection of a
local disposition. In a series of experiments using an elegant small amount of deuterated bupivacaine. Upper curve (squares
isotopic method in a series of experiments, Burm and associates and solid line):The concentration of bupivacaine injected epidu-
have shown that systemic absorption is a slow process with a half- rally at the same time in the same subject. The slow decline in
life between 2 and 4 hours depending on the agent studied144–147 bupivacaine concentration after epidural injection is caused by
(Figure 28–17). Numerous factors such as drug hydrophobicity, continued absorption. Adapted from reference 144.
anatomic location, the addition of epinephrine, and the age of the
patient govern the rate of absorption. The more hydrophobic the molecules, the more they are retained by epidural fat, slowing
absorption. Bupivacaine is between lidocaine and etidocaine in
speed of absorption. Absorption from the epidural space is a
biphasic process. After a single epidural injection of bupivacaine,
30% of the dose is rapidly absorbed (Table 28–8). A much slower
absorption process follows so that the absorption half-life is much
longer than the elimination half-life from the central compart-
TABLE 28-8. Fraction Absorbed and Their Corresponding

Half-lives for Absorption From the Epidural Spacea
Lidocaine Bupivacaine Ropivacaine
Fα 0.38 0.29 0.52
T / α, min
1
2 9 8 14
Fβ 0.58 0.64 0.48
T / β, min
1
2 82 371 252
Figure 28-16. Pressure measured in the lumbar epidural Total recovery 0.96 0.91 0.87
space after a 2-mL injection (solid circles) or a 6-mL injection F α and F β = fractions for the rapid and slow absorption processes; T1/2α and T /
1
2
(open circles). Pressure remains high for more than 30 minutes. β = the corresponding half-lives.
Adapted from reference 138. aData are from adult volunteers.76,144,147
than in children and in children than in adults.148,149 In a study

done in children aged 1 to 8 years, ropivacaine Tmax was inversely
related to age, from 115 minutes in children aged 1 to 2 years to
30 minutes in children aged 5 to 8 years.150 This phenomenon
seems to be less pronounced with levobupivacaine.151
Local Disposition and Absorption

After Other Routes
The level of injection is an important parameter affecting absorp-
tion. Injections in the cephalic part of the body have more rapid
absorption than caudal injection. This is true for central blocks
and an epidural block performed at the cervical level renders
higher systemic concentrations than a caudal epidural. This is
Figure 28-18. Continuous postoperative epidural analgesia: also true in other parts of the body: a subcutaneous injection in
simulation of bupivacaine concentrations in a child with an the scalp or face has very rapid absorption (because of increased
initial bupivacaine clearance of 10 mL/min/kg and a final clear- circulation in these areas) whereas foot or knee blocks produce
ance of 2 mL/min/kg. This child received an initial dose of 1.875 only slow rises in concentration with much lower peak con-
mg/kg bupivacaine (0.75 mL/kg bupivacaine 0.25% with epi- centrations.
nephrine) in the operating room, followed by a re-injection of
1.25 mg/kg (0.5 mL/kg) 90 minutes after the first injection. The ABSORPTION AFTER TOPICAL ANESTHESIA OF THE AIRWAY: It
child was transferred to the postanesthesia care unit after sur- was long thought that topical anesthesia of the airway for ear, nose,
gery and postoperative analgesia was begun 150 minutes after and throat procedures was dangerous in children younger than
the first injection. Thereafter, two different modalities of analge- 4 years of age because rapid absorption may lead to toxic blood
sia are represented: continuous infusion or intermittent injec- concentrations. It seems that this assumption must be reviewed in
tions, both based on the same dosing. Continuous infusion ran view of recent papers showing that precisely controlled adminis-
at a rate of 0.25 mg/kg/h (0.1 mL/kg/h with a 0.25% solution or tration allow the use of topical anesthesia with lidocaine without
0.2 mL/kg/h of a 0.125% solution. Because of the delay between risk.152
the last injection in the operating room and the infusion start, ABSORPTION AFTER TOPICAL CUTANEOUS ANESTHESIA OR
bupivacaine concentration begins to decline. If the continuous AFTER SUBCUTANEOUS INJECTION: Eutectic mixtures of local
infusion is not started immediately after the last bolus dose, the anesthetic (EMLA) creams have now replaced unsafe combina-
amount of drug in the epidural space decreases and the time tions of lidocaine, tetracaine, and epinephrine (LAT) and
needed to recover analgesia may be prolonged. Serum concen- tetracaine-epinephrine-cocaine (TAC).153-155 However, care should
tration decreases in a similar manner, albeit with a lag time be- be taken in neonates and infants because prilocaine may induce
cause epidural fat possesses buffering properties. The second methemoglobinemia; observed, for example, when infants are
dosing pattern is represented by intermittent bolus injections treated with trimethoprim-sulfamethoxazole.155 Dibucaine is an
through the epidural catheter. The first bolus is given 4 hours amide LA commonly used for topical anesthesia in adults. How-
after the last injection in the operating room. The dosing is ever, this agent is toxic when ingested and acute poisoning in
1 mg/kg every 3 hours from 4 to 20 hours, then every 4 hours children has been described.156
(0.4 mL/kg bupivacaine 0.25% or 0.8 mL/kg bupivacaine 0.125%
or 1 mL/kg bupivacaine 0.1%). As previously noted, the shape of ABSORPTION AFTER OTHER ROUTES: After intercostal block,
the curve shows an initial decline in concentration and then a absorption is rapid, leading to high concentrations in the blood.157
progressive rise until steady state is reached. The final concentra- As with intercostal blocks, interpleural analgesia may lead to high
tion is relatively high (>2 μg/mL) and steady state is not reached peak concentrations.158,159
until the second day of infusion. This is caused by the progres- RE-INJECTIONS: Re-injections are often required in the operating
sive decrease in clearance owing both to the decreased free frac- room. Toxicity is a concern in neonates and infants and the choice
tion (related to the increase in AAG concentration in serum in lies between (1) using a short-acting drug with limited toxicity but
the postoperative period) and to the decrease in intrinsic hepatic necessitating frequent re-injections or (2) using a long-acting drug
clearance. The practice of re-injections (top-up doses) leads to that is more toxic but needs less frequent re-injections. Short-
peaks and valleys with the risk of toxic reactions. Adapted from acting drugs are less hydrophobic and are much more rapidly
Mazoit JX, Bruguerolle B. In: Murat I et al. Anesthésie locoré- absorbed than long-acting drugs. Therefore, during the first hours
gionale chez l’enfant. Conférence d’experts. Ann Fr Anesth Re- of anesthesia, short-acting drugs rapidly accumulate in the blood-
anim. 1997;16:985–1029. stream, whereas long-acting drugs remain at the site of injection
for a much longer period of time (see Figure 28–17). Moreover, it
ment. This phenomenon, called the “flip-flop” effect, is important is important to note that top-up doses may lead to sudden
because kinetic parameters measured after a nonintravenous transient increases in plasma concentration with the potential risk
injection are imprecise.144–147 The epidural reservoir fills up when of toxicity (see Figure 28–18).
more injections are performed. During prolonged administration,
top-up doses may then be deleterious (Figure 28–18). It seems that
epidural fat is less abundant in neonates and infants than in older
Systemic Distribution
children and in adults.133 However, the time to maximum peak More than 50% of amide LA molecules are ionized at pH 7.40
concentration (Tmax) of ropivacaine is much longer in infants and, therefore, their volumes of distribution are important
TABLE 28-9. Bupivacaine and Ropivacaine Pharmacokinetics in Infants and Children Compared With Adultsa
B/P fu Vss, Lb CLT/f, mL/min/kg CLU/f, mL/min/kg T / , hb
1
2
Bupivacaine
I.V. adults 0.6 0.05 0.85–1.3 4.5–8.1 ≈100 1.8
Epidural adults 4-5.6 5.1–10.6
Infants caudal single shot 0.16 (0.05–0.35) 3.9 7.1
Children (5–10 y) 2.7 10
Infants epidural prolonged (0.06–0.24)c 5.5–7.5c 36–73
(0.03–0.18)d 3.5–4d 36–73
Ropivacaine
I.V. adults 0.7 0.05 0.5–0.6 4.2–5.3 ≈100 1.7
Epidural adults 4.0–5.7 ≈70 2.9–5.4
Caudal single shot 50–58
Neonates 0.07
Infants 0.05–0.10 2.1 5.2
Children 5.2 (1.3–7.3) 2.4 7.4 151
Epidural prolonged 2.4 4.26
Neonates
Infants 2.4 6.15
Children 0.04 8.5 220
Levobupivacaine
I.V. adults
Caudal single shot 0.045 0.72 4.2 116 2.6
Infants 6.3e
B/P = blood–to–plasma concentration ratio; CL = clearance; CL/f = total body clearance over bioavailability (T = total fraction; U = unbound fraction); fu = free
fraction in serum; T1/2 = terminal half-life; Vss = volume of distribution at steady state. For adults, a mean body weight of 75 kg has been assumed.
aNote the differences in T1 between I.V. and epidural injections (owing to the flip-flop), the differences in CL between adults, children, and infants and between I.V.,
/2
single-shot epidural, and prolonged epidural administrations. These differences, because of the uncovering of a deep compartment effect (and possibly a decrease in
intrinsic clearance with time), are simply explained by the concept of context-sensitive half-life. After caudal or epidural injection, the maximum concentration
(Cmax) occurs 20(30 min (Tmax) after lidocaine, mepivacaine, or bupivacaine injection. Tmax is delayed after ropivacaine (45–70 min).
bApparent value, T , and volumes measured after non-I.V. injections are overestimated because of a flip-flop effect (see text).
/
1 2
cAfter 3 h infusion.
dAfter 48 h infusion, CLT decreases with time because protein binding increases. For references, see reference 103.
eSampling was very short (4 h), thus leading to overestimation of CL.
(Table 28–9). This is reinforced by the fact that neonates and infants
have a greater water content relative to that of adults. It is difficult
to accurately measure the volume of distribution after a non-
intravenous injection of LA (the absorption half-life from the site
of injection is usually longer than the elimination half-life, leading
to the flip-flop effect). Although volumes of distribution calculated
after nonintravenous routes of administration are markedly
overestimated, it is probable that LAs distribute to a larger volume
in neonates and in infants than in adults. If this hypothesis is true,
distribution into a large volume may reduce peak serum concen-
trations after a single administration, but not after several re-injections.
The apparent bupivacaine volume of distribution appears to be greater
in infants than adults.117 This large volume of distribution leads also
to a much lower venous concentration than arterial concentrations
that can last 2 to 3 hours after injection (Figure 28–19).
Figure 28-19. Arterial and venous plasma concentrations of Extraction by the Organs
lidocaine and bupivacaine after epidural injection of lidocaine Extraction of drugs by organs is a complex function of transit time
400 mg (2% solution with epinephrine 1/200,000) or bupiva- through the organ and of association and dissociation rate cons-
caine 150 mg (0.75% solution with epinephrine 1/200,000). tants with proteins and red blood cells. After systemic absorption,
Distribution into peripheral tissues leads to a difference between LA molecules pass through the lung, where a significant part may
arterial and venous concentrations. This difference that may be be retained before reaching the brain, heart, or liver. Depending on
as high as 40% lasts for 2–3 hours after injection. Adapted from their ability to cross membranes in the liver, drugs have been
Mather LE, Cousins MJ. Local anaesthetics and their current classified as restrictively and nonrestrictively cleared (by the
clinical use. Drugs. 1979;18:185–205. liver).160 For restrictively cleared drugs, the fu is considered as
the limiting factor of organ extraction. In fact, amide LAs follow operative pain relief. This may not be the case after a rapid rise in
the free drug principle for their hepatic extraction (see Hepatic concentration.
Extraction and Clearance), but it seems that extraction by other
organs does not follow this rule. For example, the amount of lidocaine MYOCARDIAL EXTRACTION: Among the huge number of papers
or bupivacaine available for brain extraction after a single bolus published on bupivacaine cardiac toxicity, almost none has
injection in the rat appears to be greater than the free moiety,161,162 reported bupivacaine binding and/or extraction by the heart.
but these two drugs do not follow the same kind of departure from Lidocaine and bupivacaine myocardial extraction in isolated
the free drug rule. Other drugs such as quinidine have also shown rabbit hearts has been shown to be less intense than might be
a myocardial extraction different from that predicted by the free expected.8,169,170 The bupivacaine myocardium–to–perfusate con-
drug rule.163 The phenomenon of organ extraction is complex and centration ratio was only twice that of lidocaine at steady state.
poorly understood, but it has important therapeutic and toxic Moreover, upon discontinuation of the infusion, washout from the
implications.164,165 heart was similar for both drugs with a terminal half-life of about
10 minutes. However, in this preparation, coronary blood flow was
LUNG EXTRACTION: During the first few minutes after rapid maintained constant throughout the study. Therefore, it seems
intravenous injection, amide LAs are retained by the lung.166,167 possible to speculate that as soon as coronary blood flow is main-
Bupivacaine seems to be more bound in the lung than lidocaine. tained (with cardiac massage as the extreme measure), bupiva-
However, saturation occurs rapidly and the lung cannot totally caine washout from the heart might be rapid.
prevent a rapid increase in blood concentration.167
BRAIN EXTRACTION: After a rapid rise in arterial concentration,
brain extraction appears to be much higher than predicted by the Elimination
free drug rule (Figure 28–20).161,162 This rapid transfer across the Metabolism
blood-brain barrier has been questioned by Marathe and cowor- ESTERS: Like succinylcholine, cocaine, or heroin, esters are hydro-
kers,168 but these authors based their arguments on near steady- lyzed in serum, red blood cells, and liver by nonspecific esterases
state experiments. The rapid and slow rise in concentrations or pseudocholinesterases.171,172 Only cocaine undergoes significant
observed after injection must be distinguished from observations
hepatic metabolism. Because of their rapid degradation in blood,
after continuous infusion. Bupivacaine toxicity appears to be
esters have long been thought to be very safe agents.173 The end-
closely related to the free drug concentration rather than to the
products of ester metabolism are inactive and relatively nontoxic,
total concentration during continuous administration for post-
although para-aminobenzoic acid resulting from ester metabolism
can induce severe allergic reactions.174 Some patients have reduced
cholinesterase blood concentrations. There are a great number of
plasma cholinesterases genotypes, leading to wide variations in
plasma cholinesterase activity. These variations can be functionally
differentiated into three or four main categories172 (Table 28–10).
This categorization of individuals according to their dibucaine
number is based on the fact that all amide LAs are potent
inhibitors of cholinesterases.175 Thus, mixtures of amide and ester
LAs carry a potential risk of toxicity. Similarly, the duration of
action of succinylcholine might be increased by the concomitant
use of an amide LA.176 In patients with esterase deficiency, ester
concentrations in blood rapidly reach high concentrations.177
However, neither procaine nor 2-chloroprocaine appears to be
responsible for severe toxic reactions such as those that occur with
long-lasting agents like tetracaine.
AMIDES: Amide LAs undergo exclusive hepatic metabolism by the
cytochrome P450 (CYP450) system. They are metabolized to
more polar products, which are excreted by the kidney (Figure
28–21). Some of the metabolites are active, with possible toxicity
if accumulated.177 However, measured concentrations of meta-
Figure 28-20. Effect of protein binding on first-pass cerebral bolites are always lower than those associated with toxicity.
extraction of bupivacaine in the rat. 3H-Bupivacaine and 14C- Lidocaine is mainly metabolized into glycine-xylidide (GX)
butanol mixed with aliquots of human serum containing various and mono-ethyl-glycine-xylidide (MEGX) by CYP1A2 and to a
concentrations of AAG have been measured in brain after bolus lesser extent by CYP3A4.178,179 Bupivacaine (both the racemic
injection into the carotid artery. The difference between the the- mixture and levobupivacaine) is predominantly metabolized into
oretical curve calculated from in vitro binding parameters and pipecoloxylidide (PPX) by CYP3A4,180 which is very immature
the experimental curve is impressive. It appears that, contrary to before the age of 3 weeks and not fully effective before the age of
the free drug principle, a large number of bupivacaine molecules 1 year.181,182 Ropivacaine is mainly metabolized into 3⬘- and 4⬘-
are available to cross the blood-brain barrier at first pass. How- OH-ropivacaine by the CYP1A2 and to a minor extent to PPX by
ever, although the in vivo exchangeable amount was about eight CYP3A4.183 However, the major difference between these two
times higher than the in vitro exchangeable amount (inset), enzymatic systems is that CYP3A4 reaches 80 to 90% of the adult
these two quantities appears strictly linearly related. Modified capacity by the age of 9 to 12 months, whereas CYP1A2 may not
from reference 162. be totally mature before the age of 4 years. CYP3A4 possess a less
TABLE 28-10. Frequency of Cholinesterases Genetic (CYP3A4 and CYP3A7), and 3-OH-ropivacaine (CYP1A2). The
Variations Leading to Decreased Metabolic Activity concentration of 3-OH-ropivacaine in urine increases from birth
Characterized by Their Dibucaine Numbera to the age of 6 months.184 Studies measuring the differences in
microsomal metabolism of bupivacaine enantiomers are still
Dibucaine lacking, despite the fact that both urinary excretion of S(–) and
Frequency Number R(+) bupivacaine and intrinsic clearance are stereospecific in
Homozygous typical Normal >70 humans.185–187 The S(–) enantiomer (levobupivacaine) has a
Heterozygous 1/480 40–70 slightly greater intrinsic clearance than the R(+) enantiomer.186
Homozygous atypical 1/2500 20–40
Homozygous J, H ≈1/150,000 < 20 Hepatic Extraction and Clearance
aThis table holds for Caucasian subjects. Some populations such as Alaskan Hepatic metabolism can be divided in two categories that are
Eskimos, Afrikaner South Africans, or Vysya castle group in India are at much dependent on whether their hepatic extraction ratio is high (>60–
greater risk. 70%) or low (<20–30%).160 Drugs with a high hepatic extraction
ratio are not restrictively cleared and their clearance mainly
efficient fetal equivalent, CYP3A7. CYP1A2 has no fetal equi- depends on hepatic blood flow (i.e., cardiac output); these agents
valent.181 Interestingly, Bösenberg and colleagues measured the are called flow-limited drugs. Drugs with a low hepatic extrac-
principal metabolites of ropivacaine in urine, pipecoloxylidide tion ratio depend on the fu and intrinsic hepatic clearance (the
Figure 28-21. Metabolism of lidocaine (left), bupivacaine (top right), and ropivacaine (bottom right). Only the major pathways in
humans are represented. Lidocaine metabolites are active or toxic but their concentrations in plasma are far below the threshold for
effect in adults. Bupivacaine metabolites are neither active nor toxic at the concentrations usually encountered. Although ropiva-
caine’s prominent metabolic pathways are similar to those of bupivacaine, some differences not shown on the figure do exist. Dotted
lines correspond to multiple steps not represented on the figure.
metabolic capacity of microsomes); these agents are called rate- consider that such an effect may occur in humans, although chro-
limited drugs. Lidocaine, which has an extraction ratio of 65%, is nopharmacokinetics has demonstrated to be of clinical relevance
considered nonrestrictively cleared whereas bupivacaine and ropi- in many fields.202
vacaine, which have extraction ratios of 35% in adults, are
considered restrictively cleared. Infants exhibit a lower bupiva-
caine extraction ratio than that in children and adults. Lidocaine Pharmacokinetic Basis of
clearance has been shown to be reduced in the presence of low Prescription in Infants
cardiac output.188,189 Lidocaine clearance is also markedly de- During anesthesia, toxic reactions may occur during or immedi-
creased after several hours of continuous administration.190 This ately after the first injection of the drug or after several injections.
may appear paradoxical because lidocaine clearance is considered During prolonged administration for postoperative analgesia, toxic
flow-dependent. However, this phenomenon is caused by micro- reactions usually appear several hours (or days) after infusion
somal inhibition by lidocaine metabolites such as MEGX.188,191,192 initiation.104,105 Precise guidelines based on the pharmacokinetics
Lidocaine plasma concentrations may be 30 to 40% greater than and pharmacodynamics of LAs, particularly in infants younger
expected and cause CNS toxicity. This is one explanation for the than 6 months in whom clearance is reduced, should be adhered to.
loss of popularity of lidocaine in cardiology. In neonates and infants younger than 3 months, the free drug
The elimination of bupivacaine and of ropivacaine is con- concentration may be elevated despite total concentrations that are
sidered rate-limited (i.e., almost independent of hepatic blood flow below the threshold for toxicity.117,123,124,127,184 In these patients,
and cardiac output, but highly dependent on the metabolic capa- clinical manifestations of toxicity may be noticed during careful
city of microsomes and on the fu in serum). Decreased clearance examination.127
might be expected in hepatic failure. However, regional anesthesia After single-shot administration, the Tmax of bupivacaine and
is generally contraindicated in this case because of clotting levobupivacaine is always close to 25 to 30 minutes, whatever the
disorders and it is uncommon for patients with hepatic failure to route. This is not the case with ropivacaine. Ropivacaine has a
receive bupivacaine. However, clearance of rate-limited drugs also delayed Tmax, particularly after caudal injection, and this is more
depends on unbound drug concentration (free drug is the only important with the younger patients. However, the maximum
moiety available for metabolism). AAG concentration increases concentration observed with ropivacaine is similar to that of
during the postoperative period and the fu decreases. Total bupivacaine.
bupivacaine concentration continues to rise over several days of In parallel to their low clearance, infants have a possible greater
continuous administration both in adults193 and in infants.123 The volume of distribution than children or adults. This is because of
apparent decrease in total clearance is of little clinical consequence the large water content observed in infants younger than 4 to
because the intrinsic clearance is relatively fixed (at least after 6 months. Thus, after a single injection, the low clearance seems
several hours of infusion) and the free unbound drug concentra- offset by the large volume of distribution. However, after re-
tion rapidly reaches a steady-state plateau. injections or prolonged infusion over several days, steady-state
Bupivacaine clearance is low at birth and increases during the conditions are determined by clearance. Moreover, because of the
first year(s) of life.117,123,148,151,194 Ropivacaine clearance is also very low AAG concentration observed at this age group, concentration
low at birth and during the first 2 to 3 months of life.184,195 In a may increase rapidly to cause toxicity. Finally, at the age of 1 month,
study comparing neonates and infants, ropivacaine clearance was it is usual to observe a bupivacaine clearance of 3 to 5 mL/min/kg
five to six times lower in neonates younger than 30 days than in and a fu of 15 to 25% at the time of first injection. After 1 or 2 days
infants aged 1 year.184 CYP1A2 activity is low at birth and the full of continuous perineural infusion for postoperative pain relief,
metabolic capacity may not be attained before the age of 4 to clearance decreases to 1 to 2 mL/min/kg and the fu is 8 to 16%.
8 years.196 It is probable that all amide LAs exhibit comparable low Guidelines for prescription based on these considerations are given
clearance in neonates and young infants. at the end of the chapter.
After a single-shot injection, clearance of bupivacaine, levobu-
pivacaine, and ropivacaine is close to 5 to 8 mL/kg/min after the age
of 3 years.94,103,148,196,197 During continuous infusion of bupivacaine
ACTION ON THE ORGANS
or ropivacaine, a clearance higher than 3 to 4 mL/min/kg cannot be Action on the CNS
expected.103,123,148,184,198 During continuous perineural infusion, it is
common to observe an increase in serum concentrations during Anticonvulsant/Convulsant Effects
the 36 to 50 hours because of the increase in protein binding caused LAs are antiepileptics at lower concentrations. Indeed, anticonvul-
by the inflammatory process (see Local Disposition and sants either act on the gamma-aminobutyric acid (GABA)–
Absorption After Epidural Injection). However, it has been shown glutamate regulation or block sodium channels such as phenytoin.
that contrary to adults, infants and children develop tachyphylaxis At serum concentrations lower than 5 to 7 μg/mL, lidocaine pos-
less rapidly and that 0.2 to 0.3 mg/kg is an adequate dose for sesses anticonvulsant properties (supposedly related to its sodium
postoperative pain relief in the pediatric age group123,199 (see Table channel blocking effect), and this agent is still used as an anti-
28–12 for detailed dosing recommendations). convulsant, particularly in infants.203,204 The usual dose is 2 mg/kg
slow bolus, followed by a continuous infusion of 2 to 3 mg/kg/h.
At concentrations higher than 7 to 10 μg/mL, lidocaine causes
Chronopharmacokinetics convulsions because of imbalance between neuronal structures.
Absorption, distribution, metabolism, and elimination of LAs are Finally, at serum concentrations higher than 15 to 20 μg/mL,
influenced by many different physiologic functions, all of which lidocaine induces global depression with coma and cardiovascular
vary with time. Such variations in pharmacokinetics have been collapse. A direct effect of LAs on the GABA-mediated Cl– cur-
demonstrated in animals.199–201 However, it seems premature to rents may also be implicated in the generation of convulsions at
high concentrations.205 A relative insensitivity to the convulsant specific and frequency-dependent. Their effect on the eHERG and
effects of lidocaine, bupivacaine, and ropivacaine has been de- on the Kv 1.5 potassium channels explain why they may induce
monstrated in newborn sheep, pigs, and rats in comparison with torsades de pointes or ventricular fibrillation in subjects with long
adults.206,207 QT syndrome. Their moderate effect on Ca2+ currents explains a
weak effect on the atrioventricular conduction and on contrac-
Analgesic Effect of Intravenous Lidocaine tility. It is interesting to note that the latter effect is not stereo-
specific.
Intravenous lidocaine induces analgesia, particularly in patients
with peripheral neuropathy.208 This effect seems to result from a
direct effect of lidocaine on spontaneous bursts of injured Aδ and Action on Blood Vessels
C fibers.209,210 This subject is under investigation and this effect may The effect of LAs on blood vessels is not fully understood. Their
soon be elucidated. The analgesic effect of lidocaine seems to be direct action is different from the effect mediated by the sym-
selective: pain resulting from orthopedic surgery appears to be pathetic system, which is mainly vasodilation owing to sympa-
poorly reduced,211 whereas visceral pain and pain related to peri- thetic blockade. Until recently, S(–) enantiomers (ropivacaine and
pheral neuropathy appear to be more sensitive to this therapy.212–214 levobupivacaine) were considered to be exclusively vasoconstric-
tors, whereas lidocaine and bupivacaine were considered as pure
vasodilators.226 LAs may exert either vasodilation or vasoconstric-
Action on the Cardiovascular System tion depending on concentration and the nature of the vessel.
Action on the Heart Lidocaine and bupivacaine have long been thought to exert a
dilating effect, whereas ropivacaine and levobupivacaine seemed
LAs are potent sodium channel blockers. Lidocaine is the typical to have only vasoconstrictive effects.226,227 However, these dif-
class Ib antiarrhythmic agent. LAs mainly act by preventing ferences may simply be related shifts in the dose-response curves.
fast inward sodium channels from opening. However, this block All LAs exhibit a biphasic action, constriction at low concentra-
has two components: the tonic block is time-insensitive and tions, dilation at higher concentrations. Vasodilation exerted by
concentration-dependent, whereas the phasic block (also called LAs appears to be both endothelium-dependent through the nitric
use-dependent or frequency-dependent block) depends on the oxide–cyclic guanosine monophosphate pathway and the prost-
rate of depolarization. When the rate of impulse increases, the aglandin system as well as endothelium-independent mediated
intensity of the phasic block increases, thus leading to the anti- through anti-inflammatory properties.228–231 The difference in
arrhythmic properties of lidocaine and the cardiotoxic effects of effect on arteries and venules is simply a difference in the dose-
bupivacaine. This difference between LA action is explained by effect relationship.
differences between the time constants of blocking—whether the
channels are in the resting, open activated, or inactivated states.29
Brain type (Nav 1.1, NaV 1.3, Nav 1.6) and cardiac-specific sodium TOXICITY OF LAS
channels (Nav 1.5) are present in the cardiac muscle.215,216 Nav 1.5
are present in the intercalated disks at the cell-to-cell junction and LAs may exert toxic effects at the local site of injection (local
propagate the action potential, whereas the brain-type channels toxicity) and after absorption into the bloodstream (systemic
are located in the transverse tubular system where they transmit toxicity). Both toxic effects may be attributed either to the LA
the signal from the cell surface to the inner part of tubules. Brain- agent itself or to additives.
type channels contribute to synchronization of contraction and
Nav 1.5 contribute to the propagation of the action potential.
The effect produced by lidocaine seems much greater in
Local Toxicity
newborn rodents than in adults,217,218 whereas the effect produced Neuronal Toxicity
by bupivacaine seems to be similar in fetus, newborn, infant, and The toxic effect of LAs on nerve fibers were rediscovered in 1991
adult animals.219,220 Newborns and infants are thought to be more when cauda equina syndromes were described in adults after spi-
prone than adults to the phasic block produced by tertiary amine nal anesthesia using lidocaine injected through microcatheters.232–
agents such as bupivacaine because of their higher heart rate.220 234 Transient neurologic symptoms have also been described after
LAs are also potent potassium channel blockers.30,31 Even lidocaine the use of 0.5% bupivacaine and 5% lidocaine.235,236 The com-
blocks K-ATP channels.221 This action is presumed to partly pounds involved in local toxicity are mainly lidocaine and tetra-
explain the favorable antiarrhythmic properties of lidocaine. The caine; lidocaine 5% is no longer marketed in numerous countries.
effects of LAs on calcium current are less important. Lidocaine Pediatric spinal anesthesia is commonly performed in ex–
seems to act through its effects on Na channels and by its direct premature infants recovering from respiratory distress syndrome.
effects on the Na+-Ca2+ exchange. Bupivacaine and tetracaine have The duration of action is shorter than in adult patients; therefore,
a more potent effect on calcium channels in the heart.45–47,222 This the drugs generally used are tetracaine and bupivacaine.237,238
may explain why bupivacaine is thought to produce atrioventri- However, the advantages of spinal anesthesia in former preterm
cular block. However, LAs decrease contractility in isolated organs babies have been questioned and safety is not absolute.239,240
as well as decrease heart rate in intact animals and humans.59,223,224
In dogs, bupivacaine does not appear to depress the myocardial
contractile force more than lidocaine until a concentration greater Myotoxicity
than 4 to 5 μg/mL is reached.225 LAs can cause myotoxicity, and bupivacaine has been implicated.
In summary, by inhibiting Na+ and K+ currents, LAs depress This effect has been related to calcium homeostasis disorder.241,242
atrial and ventricular conduction. In addition to slowing conduc- This effect is not enantioselective, and the lack of stereoselectivity
tion velocity, they increase dispersion. These effects are stereo- is important because levobupivacaine is presumably as toxic
as racemic bupivacaine, whereas ropivacaine appears less toxic may occur before any sign of CNS toxicity, especially in young
than bupivacaine. This perturbation of calcium homeostasis infants.104,250 Levobupivacaine seems to be much less toxic for
seems related to the toxic effect of LAs on mitochondrial func- the heart than dextrobupivacaine or the racemic mixture9,10,251
tion.53,55 Care should be exercised in certain circumstances such (Figure 28–22). Ropivacaine is synthesized as a single levorotatory
as regional anesthesia for eye surgery (the oculomotor muscles are isomer such as levobupivacaine with only one carbon less on its
particularly sensitive), in children with myopathies (bupivacaine hydrophylic residue. It is also less toxic than racemic bupiva-
is an in vitro model of Duchenne’s myopathy), and perhaps in caine.252,253 However, it seems that CNS and cardiovascular system
children with mitochondrial cytopathy. It is important to dif- toxic manifestations occur at the same time with these two pure
ferentiate between central blocks, which have proven efficacy and enantiomers. This is important because cardiac arrest may be
safety in these circumstances, and peripheral blocks in which the concealed by seizures that delay the diagnosis. At toxic concentra-
injection may be directly in contact of muscle.243 tions, bupivacaine slows intra-atrial and intraventricular conduc-
tion with increased PR duration and major QRS widening9,10,254
Systemic Toxicity (Figure 28–23). Arrhythmias such as ventricular tachycardia (even
torsades de pointes255) or profound bradycardia may occur. These
At blood concentrations just above those measured after normal arrhythmias are often followed by either ventricular fibrillation or
absorption from injection site, LAs exert toxic effects. The con- asystole.256 A major collapse occurs coupled with a concomitant
centration leading to toxicity is usually directly related to LA limited decrease in the myocardial contractile force.
potency. Most agents exert neurologic toxicity at lower concentra- Subjective and objective signs of CNS toxicity usually precede
tions, followed by cardiac toxicity at higher concentrations. This is cardiac manifestations in adults during continuous infusion for
not true for racemic bupivacaine. Cardiac toxic reactions usually pain relief, but this is not always the case in infants.104 General
appear at the same time as the neurologic manifestations with anesthesia, commonly administered with regional anesthesia in
ropivacaine and levobupivacaine. In adults, the concentration ratio pediatric patients, may conceal CNS manifestations.257 The
for toxicity between bupivacaine and lidocaine is 4:1. The systemic increased threshold for CNS toxicity in infants compared with
concentrations attained are never high enough to block other adults206,207 and the equal sensitivity to bupivacaine cardiotoxi-
ganglia or affect neuromuscular transmission. city220 may explain why cardiac signs may not be preceded by any
sign of CNS toxicity. Also, because of their higher heart rate,
CNS Toxicity newborns and infants are thought to be more prone than adults to
At low to moderate plasma concentrations (1–5 μg/mL), lidocaine the frequency-dependent blockade of sodium channel produced
possesses anticonvulsant properties.203,204 The first signs of CNS by tertiary amine agents such as bupivacaine (Figure 28–24).
toxicity are subjective (dizziness, tinnitus, sensation of drowsi- Cardiac complications require urgent and appropriate therapeutic
ness). Objective signs (shivering, muscular twitching, tremors measures including oxygenation, ventilation, and cardiac massage.
initially involving the face) immediately precede the occurrence Cardiac output is dependent on heart rate in infants, and
of seizures. Subjective signs are not observed in patients under increasing that rate might be essential especially in the presence of
general anesthesia or in very young patients. Seizures may repre- high-degree intraventricular block (and also during episodes
sent the first sign of toxicity. In patients under general anesthesia, of torsades de pointes). Conversely, it must be remembered
hypercarbia is a factor facilitating the emergence of seizures that increasing heart rate also increases the phasic (frequency-
because of a direct effect on CNS and also because it increases the dependent) block.257 Prolonged cardiac massage has proved to be
fu of drug. At the highest concentration, a global CNS depres- effective in adults.258 In fact, bupivacaine washout from the heart
sion occurs with respiratory depression followed by apnea and seems to be rapid when coronary perfusion is maintained in the
collapse. Seizures may occur (1) rapidly after either a massive isolated rabbit preparation.170 Phenytoin, which mainly acts by
inadvertent intravenous injection or a rapid absorption at the site blocking sodium channels,259 is supposed to bind competitively to
of administration or (2) several hours (even days) after initiation the same receptor as bupivacaine.104 Its use has been recom-
of perineural infusion for postoperative analgesia owing to mended,104 but as with lidocaine, deleterious effects seem to be
accumulation.105,244,245 In adults, convulsions occurring intra- additive.260 Despite its arrhythmogenic potential, epinephrine
operatively are usually free of major consequences when treated appears to be the only useful drug, but it requires careful titration
immediately,246 but this might not be the same when seizures and using boluses of 0.01 μg/kg261 in order to avoid ventricular
respiratory depression occur on the ward during prolonged tachycardia or fibrillation.
infusion. The treatment of convulsions, respiratory depression, The use of a lipid emulsion (“lipid rescue”) has totally trans-
and/or coma is basically the same in children as it is in adults: formed the treatment of both neurologic and cardiac toxicity of LAs.
(1) oxygenation and airway management and (2) treatment of Since the first publication of the use of Intralipid in rats,262 lipid
seizures, if still persistent after oxygenation, by using small doses emulsions have been successfully used in humans.247–249,263 They act
of benzodiazepines or thiopental. A rapid infusion of a lipid by binding LA molecules, and therefore, they rapidly decrease the
emulsion (1 mL/kg Intralipid 20% as a bolus followed by a rapid plasma concentration of anesthetics.262,264 A rapid bolus injection of
infusion) seems to have revolutionized the treatment of systemic 1 to 2 mL/kg of Intralipid 20% followed by the rapid infusion of
toxicity.247–249 6 to 8 mL/kg is recommended by some authors.247,249 There is no
reason to continue the administration once signs resolve.
Cardiovascular System Toxicity
Toxic cardiac manifestations occur at concentrations usually much Allergy
higher that those at which CNS toxicity occurs. This is not true Allergy to LAs is rare and amide agents may exhibit antiallergenic
for racemic bupivacaine with which cardiac toxic manifestations properties.265 Most often “allergic” reactions reported by patients
Figure 28-22. Left panel: Effect of bupivacaine on the QRS duration in an isolated rabbit heart preparation (Langendorff prepara-
tion). Hearts were retrogradely infused at a constant flow with two successive infusions of bupivacaine (8 μg/mL from 0–5 min,
then 2 μg/mL from 5–20 min). Bupivacaine is stopped thereafter. The perfusate did not contain any protein, so the entire drug was
unbound. From bottom to top: The effects of racemic bupivacaine (a), R(+) bupivacaine (b), and S(–) bupivacaine. Inset: Individual
values are represented together with the mean ± standard deviation (sd) value of the group. The time scale is the same as the scale
of the large graphs. Note the different scales used for representing QRS duration. Because ropivacaine is very similar to levo (S-)
bupivacaine, it may be assumed from these results that the effect of ropivacaine on QRS duration will be almost the same as those
induced by levobupivacaine. Right panel: The effects of lidocaine and of bupivacaine on QRS widening in the same rabbit heart
preparation as a function of perfusate concentration. Bupivacaine (open symbols) induced a 15 times longer increase in QRS dura-
tion than lidocaine (solid triangles). However, C50, the free concentration leading to half Emax (the maximum theoretical effect),
was the same for both drugs (13–16 μg/mL). Left panel: Adapted from reference 9. Right panel: Adapted from Mazoit JX, Ph.D.
thesis, Université de Paris René Descartes.
during dental surgery may be attributed to epinephrine.266 In fact, headache, vertigo, and hypoxia occur. Death, though rare, can
allergy is a concern almost exclusively with esters because these occur when the concentration exceeds 70%. Treatment of
agents have para-aminobenzoic acid as a metabolite.174,267 Solu- methemoglobinemia consists of intravenous methylene blue (1–7
tions with epinephrine contain metabisulfite, which may induce mg/kg) in order to convert methemoglobin to hemoglobin.
adverse reactions.268 Some rare cases of proven allergy to amide Prilocaine is contraindicated in infants younger than 6 to 9 months
agents have been published.269–271 and care should be taken in young children for whom dose should
be limited to 3 to 4 mg/kg. EMLA cream contains prilocaine.
Methemoglobinemia However, in the absence of predisposing factors such as
hemoglobinopathies, glucose-6-phosphate dehydrogenase defi-
In neonates and infants, methemoglobinemia may develop several ciency, and exposure to aniline dyes and oxidants (sulfonamides,
hours after the administration of prilocaine, benzocaine, and nitrites, nitrates, antimalarials, trimethoprim-sulfamethoxazole, or
occasionally, lidocaine.272 In patients prone to methemoglobine- inhaled nitric oxide), the use of EMLA cream in normal amounts
mia, O-toluidine, which is a normal metabolite of prilocaine, (2.5 g, i.e., half a small tube) is usually safe, even in neonates.273–275
accumulates. This powerful oxidizing agent may accumulate in
erythrocytes especially in neonates and infants in whom the
erythrocyte content of methemoglobin reductase is lower than in Breast Feeding
adults. Patients become cyanotic when methemoglobin exceeds 20 LAs are excreted in milk. In the study published by Ortega and
to 30% of the total hemoglobin content, when dyspnea, tachycardia, associates,276 the average milk-to-serum ratios were 1, 0.35, and
0.6 for lidocaine, bupivacaine, and PPX, respectively. However,

none of these molecule undergoes significant absorption after oral
administration.
IN SUMMARY: THE BASIS FOR

PRESCRIPTION GUIDELINES
Table 28–11 displays the concentrations usually encountered in
serum with bupivacaine, ropivacaine, and levobupivacaine, and
Table 28–12 displays the recommended dosage for LA drugs
commonly used in pediatrics.
Metabolism of Amide LAs is

Incomplete at Birth
Figure 28-23. Ventricular epicardial mapping. Schematic draw-
ing of the preparation used to map the velocities of the AP at the Microsomal capacity increase rapidly after birth, and the rapid
surface of an isolated heart preparation with a 256-pin electrode. maturation of the CYP450 system allows adequate metabolism
θT and θL = the transversal and longitudinal velocities. LAs in- after 2 or 3 weeks of life. It is wise to use LAs carefully in neonates.
crease the effective refractory period (like all antiarrhythmic With that in mind, it is of particular importance to remember that
drugs). However, the ventricular conduction velocity is also de- a neonate born after 42 weeks of gestation from a nonsmoking
creased (particularly by long-acting drugs such as bupivacaine). mother without any history of alcohol intake or drug abuse, anti-
The net result is a decrease in the wavelength, leading to an in- biotics, or other medication intake may be at greater risk of low
creased chance of re-entry phenomena. This is why lignocaine is metabolism than a premature baby receiving antibiotics and other
no longer used as a type Ib antiarrhythmic drug. Because of the drugs for more than 3 to 5 days. The maturation of the CYP450
phasic block, there is a further decrease in velocity when the enzymes are dependent not only on age but also on induction by
heart rate increases. Adapted from reference 254. xenobiotics. The low AAG serum concentration observed in
Figure 28-24. Increases in QRS duration (ventricular conduction velocity) in neonatal or adult isolated rabbit hearts are
shown as a function of heart rate (from 180 to 360 beats/min) and dose of bupivacaine. The intensity of the block is similar
in the two groups. However, because neonates and infants have a higher heart rate than adults, they are at greater risk of
arrhythmias. Modified from reference 20.
TABLE 28-11. Absorption of Bupivacaine Versus TABLE 28-12. Local Anesthetic Dosage Recommendationsa
Ropivacaine After Single-Shot Administration
Ropivacaine 2 mg/mL or levobupivacaine 2.5 mg/mL
(Central Block, Venous Concentrations)
Single Shot or First Maintenance (0.625–1.25 mg/
Dose Cmax Tmax
Injection, mg/kg/h Dose, mg/kg mL solution)
Bupivacaine
Central Blocks
Adults epidural
Caudal 2 mg/kg ≤ 60 mg
100 mg 0.5%a 0.53 21
Lumbar or thoracic 1.2–1.7 0.2 (<1 mo)
Children (caudal)
Epidural 0.2–0.3 (1–6 mo)
1–6 mo 2.5 mg/kg 0.5% 0.6–1.9 28
0.3–0.4 (>6 mo)
5.5 y 2.5 mg/kg 0.25% 0.96–1.64 29
Children (lumbar or thoracic epidural) Peripheral Blocks
3–36 mo 3.75 mg/kg 0.5%∗ 1.35 20 ≤1 mg/kg See Epidural
1–10 y 1.875 mg/kg 0.25%∗ 0.55–1.10 20
Spinal Anesthesia
Children (ilioinguinal block)
1 mg/kg < 3 kg; 0.5–1 mg/kg 3–8 kg; 0.4 mg/kg > 8 kg; 0.2 mg/
10–15 kg 0.25 mL/kg 0.5% 0.43–4.0 18
kg > 25 kg
15–30 kg — 0.35–1.34 16
(These doses are for racemic bupivacaine 5 mg/mL. For
Ropivacaine ropivacaine or for levobupivacaine, dosing must be slightly
Adults epidural increased in children greater than 6–8 kg.)
150 mg 0.75% 1.09 25 a
Racemic bupivacaine may be used for spinal anesthesia or penile block. For all
Children (caudal) other blocks, only ropivacaine or levobupivacaine is recommended.
0–3 mo 2 mg/kg 0.2% 0.42–1.58 10–143
3–12 mo — 0.41–1.28 7–67
1–7 y 2 mg/kg 0.2% 0.49–1.05 65 to 6 years. The usual dose of 5 μg/mL (1/200,000) is considered
Children (lumbar epidural) by some authors to be excessive and may induce spinal cord
3–11 mo 1.7 mg/kg 0.2% 0.55–0.72 60 ischemia in young infants.82 However, the new S(–) enantiomers
12–48 mo — 0.54–0.75 60 (ropivacaine and levobupivacaine) are marketed as plain solu-
Children (ilioinguinal block) tions without epinephrine because of a moderate vasoconstrictive
1–2 y 3 mg/kg 0.5% 0.68–1.84 45 effect.
3–4 y — 0.90–4.77 52
5–12 y — 0.64–4.77 45
Spinal Anesthesia
Levobupivacaine
Adults epidural Spinal anesthesia is almost exclusively indicated for lower abdo-
127.5 mg 0.75% 1.20 15 minal surgery in ex–premature infants. Three solutions are com-
Children (caudal) monly used: hyperbaric tetracaine (0.5%), hyperbaric bupivacaine,
<1 y 2 mg/kg 0.2% 0.80 30 and isobaric bupivacaine. Doses are given in Table 28–12.
a With adrenaline.
Agents and Dosage
neonates and infants until the age of 6 months is a second factor Anesthesia of short duration may be performed with 1% lidocaine
that leads to potential increased toxicity of LA. The volume of (maximum 8–10 mg/kg with epinephrine in single dose).
distribution seems to be increased in infants and, although this Mepivacaine can be used instead of lidocaine but it is important to
may offer partial protection from an excessive concentration after note that this agent is poorly metabolized until the age of 3 to 4
a single injection, saturation of body compartments occurs rapidly weeks and that its serum protein binding profile does not seem to
favor young infants. Better drugs are ropivacaine and levobupiva-
and re-injections (top-up doses) are expected to cause exces-
caine. These two agents have the advantage of providing prolon-
sive peak concentrations. It appears reasonable to perform re-
ged postoperative analgesia when used as a single-shot injection
injections with greater care in infants younger than 6 months. using a concentration of 2 mg/mL with associated general anes-
After the age of 4 to 6 months, hepatic clearance and protein thesia during the intraoperative period. In addition, these agents
binding are similar to those of adult patients; accumulation in induce little motor blockade compared with racemic bupivacaine
blood is not as likely as in younger infants. Therefore, re-injections when used for caudal or lumbar epidural analgesia.277–280 The
can be performed as they are in adults. However, it is evident that, maximum recommended dose for single-shot caudal injection is
in light of these factors, some newborns or young infants may 2 mg/kg, irrespective of age.277–279 The usual dose is 0.4 to 0.75
benefit from techniques usually performed in older subjects mL/kg of a 2-mg/mL solution 280,281 for lumbar epidural injection.
because the balance between risk and benefit may favor regional For peripheral nerve blocks, a dose of 0.5 mL/kg of a 2-mg/mL
techniques. solution is also adequate.282,283 A distinction needs to be made
Use of epinephrine as an adjuvant, especially for epidural between neonates and infants younger than 3 months, on one
anesthesia, decreases peak LA concentrations and increases the hand, and infants older than 3 months and children, on the other
duration of postoperative analgesia, at least until the age of 4 hand, for maintenance dosing (most publications deal with epi-
dural administration).184,195 In neonates younger than 2 weeks, it is 17. Cummins TR, Sheets PL, Waxman SG. The roles of sodium channels
wise to maintain analgesia with no more than 0.15 mg/kg/h of a in nociception: implications for mechanisms of pain. Pain. 2007;131:
243–257.
dilute solution (usually 0.1%). Between the ages of 2 weeks and 18. Amir R, Argoff CE, Bennett GJ, et al. The role of sodium channels in
3 months, 0.25 to -0.3 mg/kg/h of a 0.1% solution is usually chronic inflammatory and neuropathic pain. J Pain. 2006;7(5 Suppl 3):
adequate. In older infants and in children, a larger dose is often S1–S29.
needed for epidural analgesia (0.4 mg/kg/h). The addition of 19. Ragsdale DS, McPhee JC, Scheue T, et al. Molecular determinants of state-
opioids appears necessary for epidural administration after major dependent block of Na+ channels by local anesthetics. Science. 1994;265:
1724–1728.
surgery. 20. Courtney KR. Structure-activity relations for frequency-dependent
sodium channel block in nerve by local anesthetics. J Pharmacol Ther.
1980;213:114–119.
Adjuvants 21. Chernoff DM, Strichartz GR. Lidocaine and bupivacaine block of sodium
channels—recovery kinetics correlate with potency for phasic block.
Clonidine (1–2 μg/kg bolus for caudal or epidural blocks) is also Biophys J. 1988,53:537a.
used in infants older than 4 to 6 months to increase the duration 22. Hondeghem LM, Katzung BG. Time- and voltage-dependent interactions
of the block and the duration and quality of postoperative of antiarrhythmic drugs with cardiac sodium channels. Biochim Biophys
analgesia. However, some authors inject clonidine intravenously to Acta. 1977;472:373–398.
23. Ragsdale DS, McPhee JC, Scheuer T, et al. Common molecular determi-
achieve a similar quality of postoperative analgesia.88 The main- nants of local anesthetic, antiarrhythmic, and anticonvulsant block of
tenance dose for an epidural infusion is 0.08 to 0.12 μg/kg/h.284 voltage-gated Na+ channels. Proc Natl Acad Sci USA. 1996;93:9270–9275.
Clonidine is also effective for peripheral blocks.285 24. Hille B. Local anesthetics: hydrophilic and hydrophobic pathways for the
Preservative-free ketamine (0.25 mg/kg of S(+) ketamine or drug receptor reaction. J Gen Physiol. 1977;69:497–515.
0.5 mg/kg racemic ketamine) prolongs the analgesia provided by 25. Binshtok AM, Bean BP, Woolf CJ. Inhibition of nociceptors by TRPV1-
mediated entry of impermanent sodium channel blockers. Nature. 2007;
caudal LAs286,287). However, ketamine must be used with care 449:607–610.
because this drug exerts neural toxicity.97 26. Wang GK, Wang SY. Altered stereoselectivity of cocaine and bupivacaine
isomers in normal and batrachotoxin-modified Na+ channels. J Gen
Physiol. 1992;100:1003–1020.
REFERENCES 27. Sheets MF, Hanck DA.Outward stabilization of the S4 segments in
domains III and IV enhances lidocaine block of sodium channels. J
1. Cartwright PD, Fyhr P. The manufacture and storage of local anesthetics. Physiol. 2007;582:317–334.
Reg Anesth. 1988;13:1–12. 28. Chevrier P, Vijayaragavan K, Chahine M. Differential modulation of Nav
2. Strichartz GR, Sanchez V, Arthur R, et al. Fundamental properties of local 1.7 and Nav 1.8 peripheral nerve sodium channels by the local anesthetic
anesthetics. II. Measured octanol:buffer partition coefficients and pKa
lidocaine. Br J Pharmacol. 2004;142:576–584.
values of clinically used drugs. Anesth Analg. 1990;71:158–170.
29. Clarkson CW, Hondeghem LM. Mechanism for bupivacaine depression
3. Nau C, Strichartz GR. Drug chirality in anesthesia. Anesthesiology. 2002;
97:497–502. of cardiac conduction: fast block of sodium channels during the action
4. Mazoit JX, Cao LS, Samii K. Binding of bupivacaine to serum proteins, potential with slow recovery from block during diastole. Anesthesiology.
isolated albumin and isolated alpha1-acid glycoprotein. Differences 1985;62:396–405.
between the two enantiomers are partly due to cooperativity. J Pharmacol 30. Courtney KR, Kendig JJ. Bupivacaine is an effective potassium channel
Exp Ther. 1996;256:109–115. blocker in heart. Biochim Biophys Acta. 1988;939:163–166.
5. Vladimirov M, Nau C, Mok WM, et al. Potency of bupivacaine stereoiso- 31. Bräu ME, Vogel W, Hempelmann G. Fundamental properties of local
mers tested in vitro and in vivo: biochemical, electrophysiological, and anesthetics: half-maximal blocking concentrations for tonic block of Na+
neurobehavioral studies. Anesthesiology. 2000;93:744–755. and K+ channels in peripheral nerve. Anesth Analg. 1998;87:885–889.
6. Nau C, Vogel W, Hempelmann G, et al. Stereoselectivity of bupivacaine in 32. Alexander SP, Mathie A, Peters JA. Ion channels. Br J Pharmacol. 2007;
local anesthetic-sensitive ion channels of peripheral nerve. Anesthesiology. 150(Suppl 1):S96–S121.
1999;91:786–795. 33. Tamargo J, Caballero R, Gómez R, et al. Pharmacology of cardiac potas-
7. Nau C, Wang SY, Strichartz GR, et al. Block of human heart hH1 sodium sium channels. Cardiovasc Res. 2004;62:9–33.
channels by the enantiomers of bupivacaine. Anesthesiology. 2000;93: 34. Komai H, McDowell TS. Local anesthetic inhibition of voltage-activated
1022–1033. potassium currents in rat dorsal root ganglion neurons. Anesthesiology.
8. Valenzuela C, Snyders DJ, Bennett PB, et al. Stereoselective block of car- 2001;94:1089–1095.
diac sodium channels by bupivacaine in guinea pig ventricular myocytes. 35. Nilsson J, Madeja M, Arhem P. Local anesthetic block of Kv channels: role
Circulation. 1995;92:3014–3024. of the S6 helix and the S5–S6 linker for bupivacaine action. Mol
9. Mazoit JX, Boïco O, Samii K. Myocardial uptake of bupivacaine: II. Pharmacol. 2003;63:1417–1429.
Pharmacokinetics and pharmacodynamics of bupivacaine enantiomers 36. Valenzuella C, Delpon E, Tamkun MM, et al. Stereoselective block of a
in the isolated perfused rabbit heart. Anesth Analg. 1993;77:477–482. human cardiac potassium channel (Kv1.5) by bupivacaine enantiomers.
10. Mazoit JX, Decaux A, Bouaziz H, et al. Comparative ventricular electro- Biophys J. 1995;69:418–427.
physiologic effect of racemic bupivacaine, levobupivacaine, and ropiva- 37. Valenzuella C, Delpon E, Franqueza L, et al. Effects of ropivacaine on a
caine on the isolated rabbit heart. Anesthesiology. 2000;93:784–792. potassium channel (hKv1.5) cloned from human ventricle. Anesthesiology.
11. Allen LV, Stilles ML, Wang PD, et al. Stability of bupivacaine hydrochlo-
1997;86:718–728.
ride, epinephrine hydrochloride, and fentanyl citrate in portable infusion-
38. González T, Arias C, Caballero R. et al. Effects of levobupivacaine, ropiva-
pump reservoirs. Am J Hosp Pharm. 1993;50:714–715.
12. Butterworth JF, Strichartz GR. Molecular mechanisms of local anesthesia: caine and bupivacaine on HERG channels: stereoselective bupivacaine
a review. Anesthesiology. 1990;72:711–734. block. Br J Pharmacol. 2002;137:1269–1279.
13. Hille B (ed). Ionic Channels of Excitable Membranes. 3rd ed. Sinauer 39. Siebrands CC, Binder S, Eckhoff U, et al. Long QT 1 mutation KCNQ1A
Associates Inc., Sunderland, MA; 2001, p. 814. 344V increases local anesthetic sensitivity of the slowly activating delayed
14. Catterall WA. Molecular mechanisms of gating and drug block of sodium rectifier potassium current. Anesthesiology. 2006;105:511–520.
channels. Novartis Found Symp. 2002;241:206–218. 40. Karle CA, Kiehn J. An ion channel “addicted” to ether, alcohol and co-
15. Yu FH, Yarov-Yarovoy V, et al. Overview of molecular relationships in the caine: the HERG potassium channel. Cardiovasc Res. 2002;53:6–8.
voltage-gated ion channel superfamily. Pharmacol Rev. 2005;57:387–395. 41. Kawano T, Oshita S, Takahashi A, et al. Molecular mechanisms of the
16. Catterall WA, Goldin AL, Waxman SG. International Union of Pharmaco- inhibitory effects of bupivacaine, levobupivacaine, and ropivacaine on
logy. XLVII. Nomenclature and structure-function relationships of sarcolemmal adenosine triphosphate–sensitive potassium channels in the
voltage-gated sodium channels. Pharmacol Rev. 2005;57:397–409. cardiovascular system. Anesthesiology. 2004;101:390–398.
42. Kindler CH, Paul M, Zou H, et al. Amide local anesthetics potently inhibit 67. Martin F, Cherif K, Gentili ME, et al. Lack of impact of intravenous
the human tandem pore domain background K+ channel TASK-2 lidocaine on analgesia, functional recovery, and nociceptive pain
(KCNK5). J Pharmacol Exp Ther. 2003;306:84–92. threshold after total hip arthroplasty. Anesthesiology. 2008;109:118–123.
43. Catterall WA, Perez-Reyes E, Snutch TP, et al. International Union of 68. Raymond SA, Strichartz GR. The long and short of differential block
Pharmacology. XLVIII. Nomenclature and structure-function relation- [editorial]. Anesthesiology. 1989;70:725–728.
ships of voltage-gated calcium channels. Pharmacol Rev. 2005;57: 69. Fink BR. Mechanisms of differential axial blockade in epidural and
411–425. subarachnoid anesthesia. Anesthesiology. 1989;70:851–858.
44. Xiong Z, Strichartz GR. Inhibition by local anesthetics of Ca2+ channels 70. Vabnick I, Novaković SD, Levinson SR, et al. The clustering of axonal
in rat anterior pituitary cells. Eur J Pharmacol. 1998;363:81–90. sodium channels during development of the peripheral nervous system.
45. Coyle DE, Speralakis N. Bupivacaine and lidocaine blockade of calcium- J Neurosci. 1996;16:4914–4922.
mediated slow action potentials in guinea-pig ventricular muscle. J Exp 71. Rasband MN, Trimmer JS. Developmental clustering of ion channels at
Pharmacol Ther. 1987;242:1001–1005. and near the node of Ranvier. Dev Biol. 2001;236:5–16.
46. Zapata-Sudo G, Trachez MM, Sudo RT, et al. Is comparative cardiotoxicity 72. Kohane DS, Sankar WN, Shubina M, et al. Sciatic nerve blockade in
of S(–) and R(+) bupivacaine related to enantiomer-selective inhibition of infant, adolescent, and adult rats: a comparison of ropivacaine with
L-type Ca(2+) channels? Anesth Analg. 2001;92:496–501. bupivacaine. Anesthesiology. 1998;89:1199–1208.
47. Rossner KL, Freese KJ. Bupivacaine inhibition of L-type calcium current 73. Berde C. Local anesthetics in infants and children: an update. Paediatr
in ventricular cardiomyocytes of hamster. Anesthesiology. 1997;87: Anaesth. 2004;14:387–393.
926–934. 74. Benzon HT, Strichartz GR, Gisen AJ, et al. Developmental neuro-
48. Chang DH, Ladd LA, Copeland S, et al. Direct cardiac effects of intra- physiology of mammalian peripheral nerves and age-related differential
coronary bupivacaine, levobupivacaine, and ropivacaine in the sheep. Br sensitivity to local anaesthetics. Br J Anaesth. 1988;61:754–710.
J Pharmacol. 2001;132:649–658. 75. Bromage PR, Pettigrew RT, Crowell DE. Tachyphylaxis in epidural anal-
49. Groban L, Deal DD, Vernon JC, et al. Does local anesthetic stereoselec- gesia. I. Augmentation and decay of local anesthesia. J Clin Pharmacol.
tivity or structure predict myocardial depression in anesthetized canines? 1969;9:30–38.
Reg Anesth Pain Med. 2002;27:460–468. 76. Burm AGL, Van Kleef JW, Gladines MPRR, et al. Epidural anesthesia with
50. Garlid KD, Nakashima RA. Studies on the mechanism of uncoupling by lidocaine and bupivacaine: effects of epinephrine on the plasma con-
amine local anesthetics. Evidence for mitochondrial proton transport centration profiles. Anesth Analg. 1986;65:1281–1284.
mediated by lipophilic ion pairs. J Biol Chem. 1983;258:7974–7980. 77. Mazoit JX, Benhamou D, Veillette Y, et al. Clonidine and or adrenaline
51. Dabadie P, Bendriss P, Erny P, et al. Uncoupling effects of local anesthetics decrease lignocaine plasma peak concentration after epidural injection. Br
on rat liver mitochondria. FEBS Lett. 1987;226:77–82. J Clin Pharmacol. 1996;42:242–245.
52. Eledjam JJ, de La Coussaye JE, Brugada J, et al. In vitro study on mecha- 78. Doyle E, Morton NS, McNicol LR. Plasma bupivacaine levels after fascia
nisms of bupivacaine-induced depression of myocardial contractility. iliaca compartment block with and without adrenaline. Paediatr Anaesth.
Anesth Analg. 1989;69:732–735. 1997;7:121–124.
53. Sztark F, Nouette-Gaulain K, Malgat M, et al. Absence of stereospecific 79. Warner MA, Kunkel SE, Offord KO, et al. The effects of age, epinephrine,
effects of bupivacaine isomers on heart mitochondrial bioenergetics. and operative site on duration of caudal analgesia in pediatric patients.
Anesthesiology. 2000;93:456–462. Anesth Analg. 1987;66:995–998.
54. Sztark F, Malgat M, Dabadie P, et al. Comparison of the effects of bupi- 80. Narchi P, Mazoit JX, Cohen S, et al. Heart rate response to an epidural
vacaine and ropivacaine on heart cell mitochondrial bioenergetics. test dose with and without atropine pretreatment. Br J Anaesth. 1991;
Anesthesiology. 1998;88:1340–1349. 66:583–586.
55. Nouette-Gaulain K, Sirvent P, Canal-Raffin M, et al. Effects of intermittent 81. Desparmet J, Mateo J, Ecoffey C, et al. Efficacy of an epidural test dose in
femoral nerve injections of bupivacaine, levobupivacaine, and ropivacaine children anesthetized with halothane. Anesthesiology. 1990;72:249–251.
on mitochondrial energy metabolism and intracellular calcium homeos- 82. Flandin-Bléty C, Barrier G. Accidents following extradural analgesia in
tasis in rat psoas muscle. Anesthesiology. 2007;106:1026–1034. children. The results of a retrospective study. Paediatr Anaesth. 1995;5:
56. Erikson AS, Sinclair R, Cassuto J, et al. Influence of lidocaine on leukocyte 41–46.
function in the surgical wound. Anesthesiology. 1992;77:74–78. 83. Jamali S, Monin S, Begon C, et al. Clonidine in pediatric caudal anes-
57. Hollmann MW, Durieux ME. Local anesthetics and the inflamma- thesia. Anesth Analg. 1994;78:663–666.
tory response: a new therapeutic indication? Anesthesiology. 2000;93: 84. Ivani G, De Negri P, Conio A, et al. Ropivacaine-clonidine combination
858–875. for caudal blockade in children. Acta Anaesthesiol Scand. 2000;44:446–449.
58. Beloeil H, Asehnoune K, Moine P, et al. Bupivacaine’s action on the 85. Eisenach J, Detweiler D, Hood D. Hemodynamic and analgesic actions
carrageenan-induced inflammatory response in mice: cytokine produc- of epidurally administered clonidine. Anesthesiology. 1993;78:277–287.
tion by leukocytes after ex-vivo stimulation. Anesth Analg. 2005 Apr;100: 86. Bonnet F, Boïco O, Rostaing S, et al. Postoperative analgesia with extra-
1081–1086. dural clonidine. Br J Anaesth. 1989;63:465–469.
59. Pu Q, Mazoit JX, Cao LS, et al. Effect of lignocaine in myocardial contu- 87. Hansen TG, Henneberg SW, Walther-Larsen S, et al. Caudal bupivacaine
sion: an experiment on rabbit isolated heart. Br J Pharmacol. 1996;118: supplemented with caudal or intravenous clonidine in children undergo-
1072–1078. ing hypospadias repair: a double-blind study. Br J Anaesth. 2004;92:
60. DePietro MR, Eichacker PQ. Lidocaine for acute lung injury: questions 223–227.
still to answer. Crit Care Med. 2000;28:589–591. 88. Hansen TG, Henneberg SW, Walther-Larsen S, et al. Caudal bupivacaine
61. Fletcher D, Kayser V, Guilbaud G. The influence of the timing of bupi- supplemented with caudal or intravenous clonidine in children under-
vacaine infiltration on the time course of inflammation induced by two going hypospadias repair: a double-blind study. Br J Anaesth. 2004;92:
carrageenin injections seven days apart. Pain. 1997;69:303–309. 223–227.
62. Kissin I, Lee SS, Bradley EL Jr. Effect of prolonged nerve block on 89. Krane EJ, Tyler DC, Jacobson LE. The dose response of caudal morphine
inflammatory hyperalgesia in rats: prevention of late hyperalgesia. in children. Anesthesiology. 1989;71:48–52.
Anesthesiology. 1998;88:224–232. 90. Cucchiaro G, Dagher C, Baujard C, et al. Side-effects of postoperative
63. Rowbotham MC, Reisner-Keller LA, Fields HL. Both intravenous lido- epidural analgesia in children: a randomized study comparing morphine
caine and morphine reduce the pain of postherpetic neuralgia. Neurology. and clonidine. Paediatr Anaesth. 2003;13:318–323.
1991;41:1024–1028. 91. Lejus C, Roussière G, Testa S, et al. Postoperative extradural analgesia in
64. Linchitz RM, Raheb JC. Subcutaneous infusion of lidocaine provides children: comparison of morphine with fentanyl. Br J Anaesth. 1994;
effective pain relief for CRPS patients. Clin J Pain. 1999;15:67–72. 72:156–159.
65. Dadure C, Motais F, Ricard C, et al. Continuous peripheral nerve blocks 92. Lejus C, Surbled M, Schwoerer D, et al. Postoperative epidural analgesia
at home for treatment of recurrent complex regional pain syndrome I in with bupivacaine and fentanyl: hourly pain assessment in 348 paediatric
children. Anesthesiology. 2005;102:387–391. cases. Paediatr Anaesth. 2001;11:327–332.
66. Kaba A, Laurent SR, Detroz BJ, et al. Intravenous lidocaine infusion 93. Benlabed M, Ecoffey C, Levron JC, et al. Analgesia and ventilatory res-
facilitates acute rehabilitation after laparoscopic colectomy. Anesthesiology. ponse to CO2 following epidural sufentanil in children. Anesthesiology.
2007;106:11–18; discussion. 1987;67:948–951.
94. Lerman J, Nolan J, Eyres R, et al. Efficacy, safety, and pharmacokinetics 122. Chauvin M, Mazoit JX, Andrivon F, et al. Bupivacaine pharmacokinetics
of levobupivacaine with and without fentanyl after continuous epidu- during axillary brachial plexus block in renal failure. Anesthesiology.
ral infusion in children: a multicenter trial. Anesthesiology. 2003;99: 1987;67:A261.
1166–1174. 123. Meunier JF, Mazoit JX, Goujeard E, et al. Bupivacaine concentrations in
95. Semple D, Findlow D, Aldridge LM, et al. The optimal dose of ketamine infants with biliary atresia. Anesthesiology. 1998;89:A1248.
for caudal epidural blockade in children. Anaesthesia. 1996;51:1170–1172. 124. Smith T, Moratin P, Wulf H. Smaller children have greater bupivacaine
96. De Negri P, Ivani G, Visconti C, et al. How to prolong postoperative anal- plasma concentrations after ilioinguinal block. Br J Anaesth. 1996;76:
gesia after caudal anaesthesia with ropivacaine in children: S-ketamine 452–455.
versus clonidine. Paediatr Anaesth. 2001;11:679–683. 125. Peutrell JM, Holder K, Gregory M. Plasma bupivacaine concentrations
97. Eisenach JC, Yaksh TL. Epidural ketamine in healthy children—what’s associated with continuous extradural infusions in babies. Br J Anaesth.
the point? Anesth Analg. 2003;96:626. 1997; 78:160–162.
98. Benhamou D, Labaille T, Bonhomme L, et al. Alkalinization of epidural 126. Larsson BA, Lonnqvist PA, Olsson GL. Plasma concentrations of bupi-
0.5 bupivacaine for cesarean section. Reg Anesth. 1989;14:240–243. vacaine in neonates after continuous epidural infusion. Anesth Analg.
99. Haynes DH, Kirkpatrick AF. Ultra-long-duration local anesthesia 1997;84:501–505.
produced by injection of lecithin-coated methoxyflurane microdroplets. 127. Luz G, Innerhofer P, Bachmann B et al. Bupivacaine plasma con-
Anesthesiology. 1985;63:490–499. centrations during continuous epidural anesthesia in infants and child-
100. Boogaerts J, Declercq A, Lafont N, et al. Toxicity of bupivacaine encap- ren. Anesth Analg. 1996; 82:231–234.
sulated into liposomes and injected intravenously: comparison with 128. Mazoit JX. Pharmacokinetic/pharmacodynamic modeling of anesthet-
plain solutions. Anesth Analg. 1993;76:553–555. ics in children: therapeutic implications. Paediatr Drugs. 2006;8:139–50.
101. Kohane DS, Smith SE, Louis DN, et al. Prolonged duration local anes- 129. Rolan PE. Plasma protein binding displacement interactions—why are
thesia from tetrodotoxin-enhanced local anesthetic microspheres. Pain. they still regarded as clinically important? Br J Clin Pharmacol. 1994;37:
2003;104:415–421. 125–128.
102. Seow LT, Lips FJ, Cousins MJ, et al. Lidocaine and bupivacaine mixtures 130. Mets B, Janicki PK, James MF, et al. Lidocaine and bupivacaine cardio-
for epidural blockade. Anesthesiology. 1982;56:177–183. respiratory toxicity is additive: a study in rats. Anesth Analg. 1992;75:
103. Mazoit JX, Dalens BJ. Pharmacokinetics of local anaesthetics in infants 611–614.
and children. Clin Pharmacokinet. 2004;43:17–32. 131. Øie S, Tozer TN. Effect of altered plasma protein binding on apparent
104. Maxwell LG, Martin LD, Yaster M. Bupivacaine-induced cardiac toxicity volume of distribution. J Pharm Sci. 1979;68:1203–1205.
in neonates: successful treatment with intravenous phenytoin. Anes- 132. Bedford RF. From the FDA: five % lidocaine for spinal anesthesia.
thesiology. 1994;80:682–686. Anesthesiology. 1995;83:33A.
105. McCloskey JJ, Haun SE, Deshpande JK. Bupivacaine toxicity secondary 133. Busoni P. Anatomy. In: St. Maurice CL, Schulte Steinberg O, editors.
to continuous caudal epidural infusion in children. Anesth Analg. 1992; Regional Anaesthesia in Children. Appleton & Lange/Mediglobe,
75:287–290. Fribourg, Switzerland,1990, pp. 25–38.
106. Tucker GT, Boyes RN, Bridenbaugh PO, et al. Binding of anilide-type 134. Eyres RL, Kild J, Oppenheim R, et al. Local anaesthetic plasma levels in
local anesthetics in human plasma: I. Relationships between binding, children. Anaesth Intensive Care. 1978;6:243–247.
physicochemical properties, and anesthetic activity. Anesthesiology. 135. Wachi A, Kudo S, Sato K. Characteristics of cerebrospinal fluid circula-
1970;33:287–303. tion in infants as detected with MR velocity imaging. Childs Nerv Syst.
107. McNamara PJ, Slaughter RL, Pieper JA, et al. Factors influencing serum 1995;11:227–230.
protein binding of lidocaine in humans. Anesth Analg. 1981;60:395–400. 136. Higuchi H, Adachi Y, Kazama T. Factors affecting the spread and dura-
108. Denson DD, Coyle DE, Thompson GA, et al. Alpha1-acid glycoprotein tion of epidural anesthesia with ropivacaine. Anesthesiology. 2004;101:
and albumin in human serum bupivacaine binding. Clin Pharmacol 451–460.
Ther. 1984;35:409–415. 137. Eckenhoff JE. The vertebral venous plexus. Can Anaesth Soc J. 1971;18:
109. Veering BT, Burm AGL, Gladines MPRR, et al. Age does not influence 487–495.
the serum protein binding of bupivacaine. Br J Clin Pharmacol. 1991;32: 138. Thomas PS, Gerson JI, Strong G. Analysis of human epidural pressures.
501–503. Reg Anesth. 1992;17:212–215.
110. Lee A, Fagan D, Lamont M, et al. Disposition kinetics of ropivacaine in 139. Grocott HP, Mutch WA. Epidural anesthesia and acutely increased
humans. Anesth Analg. 1989;69:736–738. intracranial pressure. Lumbar epidural space hydrodynamics in a
111. Emanuelsson BM, Persson J, Sandin S, et al. Intraindividual and porcine model. Anesthesiology. 1996;85:1086–1091.
interindividual variability in the disposition of the local anesthetic 140. Bromage PR. Mechanism of action of extradural analgesia. Br J Anaesth.
ropivacaine in healthy subjects. Ther Drug Monit. 1997;19:126–131. 1975;46:504–508.
112. Mather LE, Thomas J. Bupivacaine binding to plasma protein fractions. 141. Bromage PR, Joyal AC, Binney JC. Local anesthetic drugs: penetration
J Pharm Pharmacol. 1978;30:653–654. from the spinal extradural space into the neuraxis. Science. 1963;140:
113. Kremer JMH, Wilting J, Jansen LHM. Drug binding to human α-1-acid 392–394.
glycoprotein in health and disease. Pharmacol Rev. 1988;40:1–47. 142. Lund PC, Covino BG. Distribution of local anesthetics in man following
114. Veering BT, Burm AGL, Souverijn JHM, et al. The effect of age on serum epidural anesthesia. J Clin Pharmacol. 1967;7:324–329.
concentrations of albumin and α1-acid glycoprotein. Br J Clin Pharmacol. 143. Wilkinson GR, Lund PC. Bupivacaine levels in plasma and cerebrospinal
1990;29:201–206. fluid following peridural administration. Anesthesiology. 1970;33:482–486.
115. Edwards DJ, Lalka D, Cerra F, et al. Alpha1-acid glycoprotein concentra- 144. Burm AGL, Vermeulen NPE, Van Kleef JW, et al. Pharmacokinetics of
tion and protein binding in trauma. Clin Pharmacol Ther. 1982;31:62–67. lidocaine and bupivacaine in surgical patients following epidural
116. Meistelman C, Benhamou D, Barre J, et al. Effects of age on plasma administration. Simultaneous investigation of absorption and dis-
protein binding of sufentanil. Anesthesiology. 1990;72:470–473. position kinetics using stable isotopes. Clin Pharmacokinet. 1987;13:
117. Mazoit JX, Denson DD, Samii K. Pharmacokinetics of bupivacaine 191–203.
following caudal anesthesia in infants. Anesthesiology. 1988;68:387–391. 145. Burm AGL, Van Kleef JW, Vermeulen NPE, et al. Pharmacokinetics of
118. Booker PD, Taylor C, Saba G. Perioperative changes in α1-acid glycopro- lidocaine and bupivacaine following subarachnoid administration in
tein concentrations in infants undergoing major surgery. Br J Anaesth. surgical patients: simultaneous investigation of absorption and dis-
1996;76:365–368. position kinetics using stable isotopes. Anesthesiology. 1988;69:584–592.
119. Denson DD, Coyle DE, Thompson GA, et al. Bupivacaine protein 146. Burm AGL. Clinical pharmacokinetics of epidural and spinal anesthesia.
binding in the term parturient: effects of lactic acidosis. Clin Pharmacol Clin Pharmacokinet. 1989;16:283–311.
Ther. 1984;35:702–709. 147. Emanuelsson B-M, Persson J, Alm C, et al. Systemic absorption and
120. Denson DD, Myers JA, Thompson GA, et al. The influence of diazepam block after epidural injection of ropivacaine in healthy volunteers.
on the serum protein binding of bupivacaine at normal and acidic pH. Anesthesiology. 1997;87:1309–1317.
Anesth Analg. 1984;63:980–984. 148. McCann ME, Sethna NF, Sullivan LJ, et al. Pharmacokinetics of lumbar
121. He XM, Carter DC. Atomic structure and chemistry of human serum epidural ropivacaine in children and adolescents. Anesthesiology. 1998;
albumin. Nature. 1992;358:209–215. 89:A1251.
149. Habre W, Bergesio R, Johnson C, et al. Plasma ropivacaine concentra- 175. Kalow W, Genest K. A method for the detection of atypical forms of
tions following caudal analgesia in children. Anesthesiology. 1998; 89: human serum cholinesterase. Determination of dibucaine numbers. Can
A1245. J Biochem Physiol. 1957;35:339–346.
150. Lönnqvist PA, Westrin P, Larsson BA, et al. Ropivacaine pharmacoki- 176. Raj PP, Ohlweiler D, Hitt BA, et al. Kinetics of local anesthetic esters and
netics after caudal block in 1-8 year old children. Br J Anaesth. 2000; the effects of adjuvant drugs on 2-chloroprocaine hydrolysis. Anesthe-
85:506–511. siology. 1980;53:307–314.
151. Chalkiadis GA, Eyres RL, Cranswick N, et al. Pharmacokinetics of 177. Strong JM, Mayfield DE, Atkinson AJ, et al. Pharmacological activity,
levobupivacaine 0.25% following caudal administration in children metabolism and pharmacokinetics of glycinexylidine. Clin Pharmacol
under 2 years of age. Br J Anaesth. 2004;92:218–222. Ther. 1975;17:184–194.
152. Sitbon P, Laffon M, Lesage V, et al. Lidocaine plasma concentrations in 178. Wang JS, Backman JT, Taavitsainen P, et al. Involvement of CYP1A2 and
pediatric patients after providing airway topical anesthesia from a CYP3A4 in lidocaine N-deethylation and 3-hydroxylation in humans.
calibrated device. Anesth Analg. 1996;82:1003–1006. Drug Metab Dispos. 2000;28:959–965.
153. Ernst AA, Marvez E, Nick TG, et al. Lidocaine adrenaline tetracaine gel 179. Orlando R, Piccoli P, De Martin S, et al. Cytochrome P450 1A2 is a major
versus tetracaine adrenaline cocaine gel for topical anesthesia in linear determinant of lidocaine metabolism in vivo: effects of liver function.
scalp and facial lacerations in children aged 5 to 17 years. Pediatrics. Clin Pharmacol Ther. 2004;75:80–88.
1995;95:255–258. 180. Gantenbein M, Attolini L, Bruguerolle B, et al. Oxidative metabolism of
154. Smith GA, Strausbaugh SD, Harbeck-Weber C, et al. Comparison of bupivacaine into pipecolylxylidine in humans is mainly catalyzed by
topical anesthetics without cocaine to tetracaine-adrenaline-cocaine and CYP3A. Drug Metab Dispos. 2000;28:383–385.
lidocaine infiltration during repair of lacerations: bupivacaine-norepine- 181. Hines RN, McCarver DG. The ontogeny of human drug-metabolizing
phrine is an effective new topical anesthetic agent. Pediatrics. 1996;97: enzymes: phase I oxidative enzymes. J Pharmacol Exp Ther. 2002;300:
301–307. 355–360.
155. Russell SC, Doyle E. A risk-benefit assessment of topical percutaneous 182. McCarver DG, Hines RN. The ontogeny of human drug-metabolizing
local anaesthetics in children. Drug Saf. 1997;16:279–287. enzymes: phase II conjugation enzymes and regulatory mechanisms. J
156. Dayan PS, Litovitz TL, Insley Crouch B, et al. Fatal accidental Dibucaine Pharmacol Exp Ther. 2002;300:361–366.
poisoning in children. Ann Emerg Med. 1996;28:442–445. 183. Arlander E, Ekström G, Alm C, et al. Metabolism of ropivacaine in
157. Rothstein P, Arthur GR, Feldman HS, et al. Bupivacaine for intercostal humans is mediated by CYP1A2 and to a minor extent by CYP3A4: an
nerve blocks in children: blood concentrations and pharmacokinetics. interaction study with fluvoxamine and ketoconazole as in vivo inhi-
Anesth Analg. 1986;65:625–632. bitors. Clin Pharmacol Ther. 1998;64:484–491.
158. Giaufre E, Bruguerolle B, Rastello C, et al. New regimen for interpleural 184. Bösenberg AT, Thomas J, Cronje L, et al. Pharmacokinetics and efficacy
block in children. Paediatr Anaesth. 1995;5:125–128. of ropivacaine for continuous epidural infusion in neonates and infants.
159. Weston PJ, Bourchier D. The pharmacokinetics of bupivacaine following Paediatr Anaesth. 2005;15:739–749.
interpleural nerve block in infants of very low birthweight. Paediatr 185. Fawcett JP, Kennedy J, Kumar A, et al. Stereoselective urinary excretion
Anaesth. 1995;5:219–222. of bupivacaine and its metabolites during epidural infusion. Chirality.
160. Wilkinson GR, Shand DG. A physiological approach to hepatic drug 1999;11:50–55.
clearance. Clin Pharmacol Ther. 1975;18:377–390. 186. Burm AG, van der Meer AD, van Kleef JW, et al. Pharmacokinetics of the
161. Pardridge WM, Sahiyama R, Fierer G. Transport of propraponol and enantiomers of bupivacaine following intravenous administration of the
lidocaine through the rat blood-brain barrier. J Clin Invest. 1983;71: racemate. Br J Clin Pharmacol. 1994;38:125–129.
900–908. 187. Groen K, Mantel M, Zeijlmans PW, et al. Pharmacokinetics of the
162. Terasaki T, Pardridge WM, Denson DD. Differential effect of plasma enantiomers of bupivacaine and mepivacaine after epidural administra-
protein binding of bupivacaine on its in vivo transfer into the brain and tion of the racemates. Anesth Analg. 1998;86:361–366.
salivary glands of rats. J Pharmacol Exp Ther. 1986;239:724–729. 188. Bax NDS, Tucker GT, Woods HF. Lidocaine and indocyanine green
163. Morgan DJ, Huang JL. Albumin decreases myocardial permeability of kinetics in patients following myocardial infarction. Br J Clin Pharmacol.
unbound quinidine in perfused rat heart. J Pharmacol Exp Ther. 1994; 1980;10:353–361.
268:283–290. 189. Tucker GT, Bax NDS, Lennard MS, et al. Effects of α-adrenoceptor
164. Morgan DJ. Permeability of myocardial capillaries to hydrophilic drugs: antagonists on the pharmacokinetics of lignocaine. Br J Clin Pharmacol.
the paracellular pathway. Clin Exp Pharmacol Physiol. 1996;231: 1984;17:21S–28S.
975–979. 190. le Lorrier J, Gredin, D, Lapout Y, et al. Pharmacokinetics of lidocaine
165. Wood M. Drug distribution: less passive, more active? [editorial] Anes- after intravenous infusions in uncomplicated myocardial infarction. Ann
thesiology. 1997;87:1274–1276. Intern Med. 1977;87:700–702.
166. Jorfeldt L, Lewis DH, Lofstrom JB, et al. Lung uptake of lidocaine in man 191. Lennard MS, Tucker GT, Woods HF. Time-dependent kinetics of ligno-
as influenced by anaesthesia, mepivacaine infusion or lung insufficiency. caine in the isolated perfused rat liver. J Pharmacokinet Biopharm.
Acta Anaesthesiol Scand. 1983;27:5–9. 1983;11:165–173.
167. Sharrock NE, Mather LE, Go G, Sculco TP. Arterial and pulmonary 192. Thompson AH, Elliot HL, Kelman AW, et al. The pharmacokinetics and
arterial concentrations of the enantiomers of bupivacaine after epidural pharmacodynamics of lignocaine and MEGX in healthy subjects. J
injection in elderly patients. Anesth Analg. 1998;86:812–817. Pharmacokinet Biopharm. 1987;15:101–115.
168. Marathe PH, Shen DD, Artru AA, et al. Effect of serum protein binding 193. Veering BT, Burm AG, Feyen HM, et al. Pharmacokinetics of bupiva-
on the entry of lidocaine into brain and cerebrospinal fluid in dogs. caine during postoperative epidural infusion: enantioselectivity and role
Anesthesiology. 1991;75:804–812. of protein binding. Anesthesiology. 2002;96:1062–1069.
169. Mazoit JX, Kantelip JP, Orhant EE, et al. Myocardial uptake kinetics of 194. Chalkiadis GA, Anderson BJ, Tay M, et al. Pharmacokinetics of
lidocaine: pharmacokinetics and pharmacodynamics in the isolated levobupivacaine after caudal epidural administration in infants less than
perfused heart of the rabbit. Br J Pharmacol. 1990;101:843–846. 3 months of age. Br J Anaesth. 2005;95:524–529.
170. Mazoit JX, Orhant EE, Boïco O, et al. Myocardial uptake of bupivacaine: 195. Rapp HJ, Molnar V, Austin S, et al. Ropivacaine in neonates and infants:
I. Pharmacokinetics and pharmacodynamics of lidocaine and bupivacaine a population pharmacokinetic evaluation following single caudal block.
in the isolated perfused rabbit heart. Anesth Analg. 1993;77:469–476. Paediatr Anaesth. 2004;14:724–732.
171. Tucker GT, Mather LE. Clinical pharmacokinetics of local anesthetics. 196. Lonnqvist PA, Westrin P, Larsson BA, et al. Ropivacaine pharmacokine-
Clin Pharmacokinet. 1979;4:241–278. tics after caudal block in 1-8 year old children. Br J Anaesth. 2000;
172. Pantuck EJ. Plasma cholinesterase: gene and variations. Anesth Analg. 85:506–511.
1993;77:380–386. 197. Hansen TG, Ilett KF, Reid C, et al. Caudal ropivacaine in infants: popula-
173. Kuhnert BR, Kuhnert PM, Prochaska AL, et al. Plasma levels of 2- tion pharmacokinetics and plasma concentrations. Anesthesiology.
chloroprocaine in obstetric patients and their neonates after epidural 2001;94:579–584.
anesthesia. Anesthesiology. 1980;53:21–25. 198. Desparmet J, Meistelman C, Barre J, et al. Continuous epidural infusion
174. Eggleston ST, Lush LW. Understanding allergic reactions to local of bupivacaine for postoperative pain relief in children. Anesthesiology.
anesthetics. Ann Pharmacother. 1996;30:851–857. 1987;67:108–110.
199. Lutsch EF, Morris RW. Circadian periodicity in susceptibility to lidocaine 226. Iida H, Watanabe Y, Dohi S, et al. Direct effects of ropivacaine and
hydrochloride. Science. 1967;156:100–102. bupivacaine on spinal pial vessels in canine. Assessment with closed
200. Bruguerolle B, Prat M. Temporal changes in bupivacaine kinetics. J spinal window technique. Anesthesiology. 1997;87:75–81.
Pharm Pharmacol. 1987;39:148–149. 227. Iida H, Ohata H, Iida M, et al. The differential effects of stereoisomers
201. Attolini L, Gantenbein M, Lorec AM, et al. Seasonal variations in the of ropivacaine and bupivacaine on cerebral pial arterioles in dogs. Anesth
kinetics of bupivacaine in the mouse. Eur J Drug Metab Pharmacokinet. Analg. 2001;93:1552–1556.
1996;21:257–260. 228. Gherardini G, Samuelson U, Jernbeck J, et al. Comparison of vascular
202. Bruguerolle B. Chronopharmacokinetics. Current status. Clin Pharma- effects of ropivacaine and lidocaine on isolated rings of human arteries.
cokinet. 1998;35:83–94. Acta Anaesthesiol Scand. 1995;39:765–768.
203. Hellstrom-Westas L, Westgren U, et al. Lidocaine for treatment of severe 229. Minamoto Y, Nakamura K, Toda H, et al. Suppression of acetylcholine-
seizures in newborn infants. I. Clinical effects and cerebral electrical induced relaxation by local anesthetics and vascular NO–cyclic GMP
activity monitoring. Acta Paediatr Scand. 1988;77:79–84. system. Acta Anaesthesiol Scand. 1997;41:1054–1060.
204. Hattori H, Yamano T, Hayashi K, et al. Effectiveness of lidocaine infusion 230. Lin PL, Huang HH, Fan SZ, et al. Effect of ropivacaine on endothelium-
for status epilepticus in childhood: a retrospective multi-institutional dependent phenylephrine-induced contraction in guinea pig aorta. Acta
study in Japan. Brain Dev. 2008;30:504–512. Anaesthesiol Scand. 2007;51:1388–1393.
205. Nordmark J, Rydqvist B. Local anaesthetics potentiate GABA-mediated 231. Hahnenkamp K, Nollet J, Strümper D, et al. Bupivacaine inhibits
Cl– currents by inhibiting GABA uptake. Neuroreport. 1997;8:465–468. thromboxane A2–induced vasoconstriction in rat thoracic aorta. Anesth
206. Bagdwell JM, Heavner JE, Kytta J. Bupivacaine toxicity in young guinea Analg. 2004;99:97–102.
pigs is age-dependent and is affected by volatile anesthetics. Anesthe- 232. Rigler ML, Drasner K, Krejcie TC, et al. Cauda equina syndrome after
siology. 1990;73:297–303. continuous spinal anesthesia. Anesth Analg. 1991;72:275–281.
207. Satas S, Johannessen SI, Hoem NO, et al. Lidocaine pharmacokinetics 233. Lambert DH, Hurley RJ. Cauda equina syndrome and continuous spinal
and toxicity in newborn pigs. Anesth Analg. 1997;85:306–312. anesthesia. Anesth Analg. 1991;72:817–819.
208. Boas RA, Covino BG, Shahnarian A. Analgesic responses to I.V. ligno- 234. Auroy Y, Narchi P, Messiah A, et al. Serious complications related to
caine. Br J Anaesth. 1982;54:501–505. regional anesthesia. Results of a prospective survey in France. Anesthe-
209. Strichartz G. Protracted relief of experimental neuropathic pain by siology. 1997;87:479–486.
systemic local anesthetics. How, where, and when. Anesthesiology. 1995; 235. Schneider M, Ettlin T, Kaufmann M et al. Transient neurologic toxicity
83:654–655. after hyperbaric subarachnoid anesthesia with 5% lidocaine. Anesth
210. Persaud N, Strichartz GR. Micromolar lidocaine selectively blocks pro- Analg. 1993;76:1154–1157.
pagating ectopic impulses at a distance from their site of origin. Pain. 236. Hampl KF, Schneider MC, Ummenhofer W, et al. Transient neurologic
2002;99:333–340. symptoms after spinal anesthesia. Anesth Analg. 1995;81:1148–1153.
211. Martin F, Cherif K, Gentili ME, et al. Lack of impact of intravenous 237. Harnik EV, Hoy GR, Potoliecchio S, et al. Spinal anesthesia in premature
lidocaine on analgesia, functional recovery, and nociceptive pain infants recovering from respiratory distress syndrome. Anesthesiology.
threshold after total hip arthroplasty. Anesthesiology. 2008;109:118–123. 1986;64:95–99.
212. Kaba A, Laurent SR, Detroz BJ, et al. Intravenous lidocaine infusion faci- 238. Mahé V, Ecoffey C. Spinal anesthesia with isobaric bupivacaine in
litates acute rehabilitation after laparoscopic colectomy. Anesthesiology. infants. Anesthesiology. 1988;68:601–603.
2007;106:11–18. 239. Craven PD, Badawi N, Henderson-Smart DJ, et al. Regional (spinal, epi-
213. Bach FW, Jensen TS, Kastrup J, et al. The effect of intravenous lidocaine dural, caudal) versus general anaesthesia in preterm infants undergoing
on nociceptive processing in diabetic neuropathy. Pain. 1990;40:29–34. inguinal herniorrhaphy in early infancy. Cochrane Database Syst Rev.
214. Brose WG, Cousins MJ. Subcutaneous lidocaine for treatment of 2003;3:CD003669.
neuropathic cancer pain. Pain. 1991;45:145–148. 240. Bonnet MP, Larousse E, Asehnoune K, et al. Spinal anesthesia with
215. Maier SK, Westenbroek RE, Schenkman KA, et al. An unexpected role bupivacaine decreases cerebral blood flow in former preterm infants.
for brain-type sodium channels in coupling of cell surface depolarization Anesth Analg. 2004;98:1280–1283.
to contraction in the heart. Proc Natl Acad Sci U S A. 2002;99:4073–4078. 241. Newman RJ, Radda GK. The myotoxicity of bupivacaine, a 31P N.M.R.
216. Maier SK, Westenbroek RE, McCormick KA, et al. Distinct subcellular investigation. Br J Pharmacol. 1983;79:395–399.
localization of different sodium channel α and β subunits in single ven- 242. Zink W, Bohl JR, Hacke N, et al. The long term myotoxic effects of
tricular myocytes from mouse heart. Circulation. 2004;109:1421–1427. bupivacaine and ropivacaine after continuous peripheral nerve blocks.
217. Jeck CD, Rosen MR. Use-dependent effects of lidocaine in neonatal and Anesth Analg. 2005;101:548–554.
adult ventricular myocardium. J Pharmacol Exp Ther. 1990;255:738–743. 243. Murat I, Esteve C, Montay G, et al. Pharmacokinetics and cardiovascular
218. Xu YQ, Pickoff AS, Clarkson CW. Developmental changes in the effects effects of bupivacaine during epidural anesthesia in children with
of lidocaine on sodium channels in rat cardiac myocytes. J Pharmacol Duchenne muscular dystrophy. Anesthesiology. 1987;67:249–252.
Exp Ther. 1992;262:670–676. 244. Agarwal R, Gutlove DP, Lockhart CH. Seizures occurring in patients re-
219. Sun LS, Rosen MR. The electrophysiologic effects of bupivacaine on ceiving continuous infusion of bupivacaine. Anesth Analg. 1992;75:
adult, neonatal, and fetal guinea pig papillary muscles. Anesthesiology. 284–286.
1991;74:893–839. 245. Berde CB. Convulsion associated with pediatric regional anesthesia.
220. Simon L, Kariya N, Edouard A, et al. Effect of bupivacaine on the isolated Anesth Analg. 1992;75:164–166.
rabbit heart: developmental aspect on ventricular conduction and 246. Brown DL, Ransom DM, Hall JA, et al. Regional anesthesia and
contractility. Anesthesiology. 2004;101:937–944. local anesthetic–induced systemic toxicity: seizure frequency and
221. Olschewski A, Brau ME, Olschewski H, et al. ATP-dependent potassium accompanying cardiovascular changes. Anesth Analg. 1995;81:321–
channel in rat cardiomyocytes is blocked by lidocaine. Possible impact 328.
on the antiarrhythmic action of lidocaine. Circulation. 1996;93:656–659. 247. Rosenblatt MA, Abel M, Fischer GW, et al. Successful use of a 20% lipid
222. Gyorke S, Lukyanenko V, Gyorke I. Dual effects of tetracaine on spon- emulsion to resuscitate a patient after a presumed bupivacaine-related
taneous calcium release in rat ventricular myocytes. J Physiol (Lond). cardiac arrest. Anesthesiology. 2006;105:217–218.
1997;500:297–309. 248. Spence AG. Lipid reversal of central nervous system symptoms of
223. Pitkanen M, Feldman HS, Arthur GR, et al. Chronotropic and inotropic bupivacaine toxicity. Anesthesiology. 2007;107:516–517.
effects of ropivacaine, bupivacaine, and lidocaine in the spontaneously 249. Ludot H, Tharin JY, Belouadah M, et al. Successful resuscitation after
beating and electrically paced isolated perfused rabbit heart. Reg Anesth. ropivacaine and lidocaine-induced ventricular arrhythmia follow-
1992;17:183–192. ing posterior lumbar plexus block in a child. Anesth Analg. 2008;106:
224. Edouard A, Berdeaux A, Langloys J, et al. Effects of lidocaine on 1572–1574.
myocardial contractility and baroreflex control of heart rate in conscious 250. Matsumiya N, Dohi S, Takahashi H, et al. Cardiovascular collapse in an
dogs. Anesthesiology. 1986;64:316–321. infant after caudal anesthesia with a lidocaine-epinephrine solution.
225. Fujita Y. Comparative direct effects of lidocaine and bupivacaine on Anesth Analg. 1986;65:1074–1076.
regional myocardial function in dogs at noncardiovascular toxic levels. 251. Bardsley H, Gristwood R, Baker H, et al. A comparison of the cardio-
Anesth Analg. 1994;78:1158–1163. vascular effects of levobupivacaine and rac-bupivacaine following
intravenous administration to healthy volunteers. Br J Clin Pharmacol. 271. Warrington RJ, McPhillips S. Allergic reaction to local anesthetic agents
1998;46:245–249. of the amide group. J Allergy Clin Immunol. 1997;100:855.
252. Scott DB, Lee A, Fagan D, et al. Acute toxicity of ropivacaine compared 272. Lund PG, Cwik JG. Propitocaine (Eitanest) and methemoglobinemia.
with that of bupivacaine. Anesth Analg. 1989;69:563–569. Anesthesiology. 1965;26:569–577.
253. Knudsen K, Beckman Suurkula M, Blomberg S, et al. Central nervous 273. Russell SC, Doyle E. A risk-benefit assessment of topical percutaneous
and cardiovascular effects of I.V. infusions of ropivacaine, bupivacaine local anaesthetics in children. Drug Saf. 1997;16:279–287.
and placebo in volunteers. Br J Anaesth. 1997;78:507–514. 274. Taddio A, Stevens B, Craig K, et al. Efficacy and safety of lidocaine-
254. de La Coussaye J, Brugada J, Allessie MA. Electrophysiologic and arrhy- prilocaine cream for pain during circumcision. N Engl J Med. 1997;336:
thmogenic effects of bupivacaine. A study with high-resolution ventricular 1197–1201.
epicardial mapping in rabbit hearts. Anesthesiology. 1992;77:32–41. 275. Taddio A, Ohlsson A, Einarson TR, et al. A systematic review of
255. Kasten GW. High serum bupivacaine concentrations produce rhythm lidocaine-prilocaine cream (EMLA) in the treatment of acute pain in
disturbances similar to torsades de pointes in anesthetized dogs. Reg neonates. Pediatrics. 1998;101:E1.
Anesth. 1986;11:20–26. 276. Ortega D, Viviand X, Lorec AM, et al. Excretion of lidocaine and
256. Albright GA. Cardiac arrest following regional anesthesia with etido- bupivacaine in breast milk following epidural anesthesia for cesarean
caine and bupivacaine. Anesthesiology.1979;51:285–287. delivery. Acta Anaesthesiol Scand. 1999;43:394–397.
257. Ved SA, Pinosky M, Nicodemus H. Ventricular tachycardia and brief 277. Ingelmo PM, Locatelli BG, Sonzogni V, et al. Caudal 0.2% ropivacaine is
cardiovascular collapse in two infants after caudal anesthesia using a less effective during surgery than 0.2% levobupivacaine and 0.2%
bupivacaine-epinephrine solution. Anesthesiology. 1993;79:1121–1123. bupivacaine: a double-blind, randomized, controlled trial. Paediatr
258. Davis NL, de Jong RH. Successful resuscitation following massive Anaesth. 2006;16:955–961.
bupivacaine overdose. Anesth Analg. 1982;61:62–64. 278. Locatelli B, Ingelmo P, Sonzogni V, et al. Randomized, double-blind,
259. Spinelli W, Rosen MR. Frequency-dependent actions of phenytoin in phase III, controlled trial comparing levobupivacaine 0.25%, ropivacaine
adult and young canine Purkinje fibers. Pharmacol Exp Ther. 1986;238: 0.25% and bupivacaine 0.25% by the caudal route in children. Br J
794–801. Anaesth. 2005;94:366–371.
260. Simon L, Kariya N, Pelle-Lancien E, et al. Bupivacaine-induced QRS 279. Ivani G, De Negri P, Lonnqvist PA, et al. Caudal anesthesia for minor
prolongation is enhanced by lidocaine and by phenytoin in rabbit hearts. pediatric surgery: a prospective randomized comparison of ropivacaine
Anesth Analg. 2002;94:203–207. 0.2% vs levobupivacaine 0.2%. Paediatr Anaesth. 2005;15:491–494.
261. Carpenter TC, Stenmark KR. High-dose epinephrine is not superior to 280. De Negri P, Ivani G, Tirri T, et al. A comparison of epidural bupivacaine,
standard-dose epinephrine in pediatric in-hospital cardiopulmonary levobupivacaine, and ropivacaine on postoperative analgesia and motor
arrest. Pediatrics. 1997;99:403–408. blockade. Anesth Analg. 2004;99:45–48.
262. Weinberg GL, VadeBoncouer T, Ramaraju GA, et al. Pretreatment or re- 281. Ingelmo P, Locatelli BG, Frawley G, et al. The optimum initial pediatric
suscitation with a lipid infusion shifts the dose-response to bupivacaine- epidural bolus: a comparison of four local anesthetic solutions. Paediatr
induced asystole in rats. Anesthesiology. 1998;88:1071–1075. Anaesth. 2007;17:1166–1175.
263. Weinberg GL. Lipid infusion therapy: translation to clinical practice. 282. Tsuchiya N, Ichizawa M, Yoshikawa Y, et al. Comparison of ropivacaine
Anesth Analg. 2008;106:1340–1342. with bupivacaine and lidocaine for ilioinguinal block after ambula-
264. Mazoit JX, Le Guen R, Beloeil H, et al. Binding of long-lasting local tory inguinal hernia repair in children. Paediatr Anaesth. 2004;14:
anesthetics to lipid emulsions. Anesthesiology. 2009;110:380–386. 468–470.
265. Okada S, Hagan JB, Kato M, et al. Lidocaine and its analogues inhibit 283. Thornton KL, Sacks MD, Hall R, et al. Comparison of 0.2% ropivacaine
IL-5–mediated survival and activation of human eosinophils. J Immunol. and 0.25% bupivacaine for axillary brachial plexus blocks in paediatric
1998;160:4010–4017. hand surgery. Paediatr Anaesth. 2003;13:409–412.
266. Lipp M, Dick W, Daubländer M, et al. Exogenous and endogenous 284. De Negri P, Ivani G, Visconti C, et al. The dose-response relationship
plasma levels of epinephrine during dental treatment under local for clonidine added to a postoperative continuous epidural infusion of
anesthesia. Reg Anesth. 1993;18:6–12. ropivacaine in children. Anesth Analg. 2001;93:71–76.
267. Reynolds F. Adverse effects of local anaesthetics. Br J Anaesth. 1987;59: 285. Cucchiaro G, Ganesh A. The effects of clonidine on postoperative anal-
78–95. gesia after peripheral nerve blockade in children. Anesth Analg. 2007;
268. Napke E, Stevens DG. Excipients and additives: hidden hazards in drug 104:532–537.
products and in product substitution. Can Med Assoc J. 1984;131: 286. Panjabi N, Prakash S, Gupta P, et al. Efficacy of three doses of ketamine
1449–1452. with bupivacaine for caudal analgesia in pediatric inguinal herniotomy.
269. Thomas AD, Caunt JA. Anaphylactoid reaction following local anaes- Reg Anesth Pain Med. 2004;29:28–31.
thesia for epidural block. Anaesthesia. 1993;48:50–52. 287. Martindale SJ, Dix P, Stoddart PA. Double-blind randomized controlled
270. Cuesta-Herranz J, de las Heras M, Fernandez M, et al. Allergic reaction trial of caudal versus intravenous S(+)-ketamine for supplementation of
caused by local anesthetic agents belonging to the amide group. J Allergy caudal analgesia in children. Br J Anaesth. 2004;92:344–347.
Clin Immunol. 1997;99:427–428.
Adjuvants to Local Anesthetics 29

Dilip Pawar C H A P T E R
INTRODUCTION retention, and respiratory depression has stimulated interest in

alternative agents with reduced adverse effect profiles.
Adjuvant is derived from Latin (ad = “to,” juvare = “help,” -ant Subsequently, drugs such as ketamine and clonidine were
denotes action) and defined in Stedman’s Medical Dictionary as, shown to increase the duration of action of LA caudal block.3,4
“that which aids or assists; denoting a remedy that is added to a Adjuvants like ketamine, clonidine, and morphine on their own
prescription to assist or increase the action of the main ingredient.” can produce analgesia neuraxially. The mechanism by which
A wide range of drugs are used today as adjuvants to local anes- adjuvants prolong the duration of analgesia is primarily based
thetics (LAs). These act at a variety of secondary sites of action, on our understanding of the pharmacologic profile of these drugs
different from that of the LA, and yet enhance the duration of and their site of action. Transmission of nociceptive stimuli is
action of the LA. Some of these drugs also improve the quality of primarily through well-described pain pathways. Other pathways
analgesia produced by the LAs. involving opiate, N-methyl-D-aspartate (NMDA), and α2 adren-
LAs are used primarily to block conduction in peripheral ergic receptors influence pain transmission. It is probably because
nerve axons and their terminals. This is achieved by blocking both LAs and adjuvants act at multiple and different sites that
the voltage-gated Na+ channels; ion channels that cause rapid analgesia is improved, evident by lower pain scores when adju-
depolarization during the first phase of the action potential in vants are added to LAs. The molecular mechanism contributing
excitable cells. LAs also block voltage-gated Ca2+ channels and prolongation of analgesia is not yet elucidated. However, this lack
various types of K+ channels that may moderate Na+ channel of understanding of the mechanism should not be a hindrance to
block.1 clinical practice.
Single-shot caudal epidural is one of the most commonly
performed regional blocks in infants and children. Sanders, in a
survey in the United Kingdom, reported that 96% of pediatric COMMONLY USED ADJUVANTS
anesthesiologists use caudal anesthesia in their clinical practice.2 Epinephrine
The main limitation of caudal block is the relatively short duration
of postoperative analgesia even with the use of relatively long- Epinephrine is an endogenous catecholamine that produces
acting LA agents such as bupivacaine or ropivacaine. Caudal a dose-related action. At low doses, it stimulates β2 receptors
catheter has been used to administer repeated doses, but this producing arterial vasodilatation. Higher doses cause arterial vas-
technique has not gained popularity because of the concern for oconstriction by stimulating α1 and α2 receptors. Vasoconstriction
infection. reduces blood flow and slows systemic uptake of LAs, maintaining
concentration at the site of action for a longer period of time. It
also reduces the peak plasma concentration, thereby decreasing
RATIONALE OF USE OF ADJUVANTS the potential for toxicity. This not only prolongs the period of
blockade by 50% but also decreases the systemic absorption of LAs
In an attempt to prolong the duration of a single-shot caudal by one third.5
analgesia, adjuvants to LA solution have been employed. The first It has long been thought that the prolongation of LA action
adjuvant used with LA was epinephrine (adrenaline). It was by epinephrine is caused by vasoconstriction only. It is now
initially used to decrease the toxic effect of LA by slowing the understood that epinephrine can exert intrinsic analgesic effect
absorption through vasoconstriction. This led to an increased (produce segmental hypoalgesia) after epidural administration.
concentration of LA available at the nerve for a longer duration, It gets absorbed into cerebrospinal fluid (CSF) and most likely
increasing the duration of the block. Sanders reported use of stimulates the α2 adrenoreceptors at the primary afferent terminals
adjuvants by 58% of pediatric anesthesiologists while performing in the spinal cord.6
caudal block in the United Kingdom. The most frequently used Commonly available premixed solutions contain 1:200,000 or
were ketamine (32%), clonidine (26%), diamorphine (13%), and 5 μg/mL of epinephrine. It seems to be effective in prolonging the
fentanyl (21%).2 duration of action of short-acting LA agents such as lidocaine and
Opioids, especially morphine, have been commonly used in the 2-chloroprocaine compared with that of bupivacaine. It has been
caudal space either alone or as an adjuvant to consistently increase used with the longer-duration LAs bupivacaine and ropivacaine,
the duration of analgesia. The potential of opioid adjuvants to primarily to test for intravenous administration of LA during
produce adverse effects like nausea, vomiting, pruritus, urinary epidural administration.7
There is a concern of decreased blood supply to the spinal cord been reported to prolong a duration of analgesia when used
when adrenaline-containing solutions are used. In animal studies, without LA at a dose of 1 mg/kg from 13 hours24 to 16.6 hours.25
bolus doses of subarachnoid epinephrine of up to 200 μg directly Differences in the heterogeneity of the study design make it
into the CSF did not decrease spinal cord blood flow in cats or difficult to compare the two medicants but an attempt has been
dogs.8 There was no evidence of spinal cord ischemia in humans made to represent analgesic duration in Figure 29–1.
even after administration of very large bolus doses of adrenaline Ketamine has been used in combination with tramadol14 and
(≤1000 μg) directly into the CSF.9 clonidine4,25 without LA. Gunduz and associates reported an
increase of only 14 minutes with the addition of tramadol 2 mg/kg
to S(+) ketamine 1 mg/kg.14 Hager and coworkers reported an
Ketamine increase in duration of analgesia of 9.4 and 8.5 hours with cloni-
Ketamine is a partially water-soluble (10 times more soluble than dine 1 μg/kg and 2 μg/kg, respectively, compared with ketamine
thiopentone) phencyclidine derivative with a pKa of 7.5. It is 1 mg/kg. Passariello and colleagues reported no increase in the
currently available both as a racemic mixture of two enantomers duration of analgesia with ketamine 0.5 mg/kg with clonidine
(R(–) and S(+) in aqueous solution (with sodium chloride 1 μg/kg compared with ketamine 1 mg/kg alone. These conflicting
and benzethonium chloride) and as a single enantomer (S(+) reports involve differing drug concentrations. Ketamine has yet to
ketamine). S(+) Ketamine has an approximately fourfold greater be fully studied as an adjuvant to LAs. If this combination is
affinity for the NMDA receptors than the R(–) enantomer. established to be effective, it would be an ideal alternative to opioids.
Ketamine is a NMDA receptor blocker. NMDA receptors
have a role in excitatory synaptic transmission, plasticity, and Adverse Effects
neurogeneration in the central nervous system. NMDA receptors
have been identified in myelinated and unmyelinated axons in The preservative benzethonium chloride is neurotoxic; a
peripheral somatic tissues. Local administration of glutamate preservative-free ketamine should be administered neuraxially.
results in nociceptive responses that are attenuated by peripheral There has been a debate about possible preservative-free keta-
administration of NMDA antagonists. Ketamine probably en- mine neurotoxicity, although animal studies show no detrimental
hances the LA effect of bupivacaine through this mechanism. In neurotoxicity after intrathecal ketamine.27,28 The origin of this
addition, ketamine has LA properties. It produces anesthetic block neurotoxicity debate goes back as far as 1999 when Ikonomidov
after spinal administration.10 and associates reported that the NMDA receptor antagonist
Ketamine is an anesthetic agent with strong analgesic potency. MK801 and ketamine produced evidence of neurotoxicity.29
It has been used in infants and children in a wide range of appli- Vranken and coworkers reported spinal neurotoxicity after
cations.11 Ketamine as an adjunct for caudal analgesia was reported continuous intrathecal administration of S(+) ketamine infusion
by Naguib and associates in 1991, 3 years before the first published for 3 weeks in a patient with terminal cancer–related neuropathic
report on clonidine.12 Sanders reported ketamine is the most pain.30 The cause of neurotoxicity produced by ketamine is
frequently used adjuvant by pediatric anesthesiologists in the unknown. The preservatives benzethonium chloride and chlor-
United Kingdom. Ketamine adjuvant use has been reported with butanol have been implicated. Stortz and colleagues reported
a variety of LAs such as lidocaine, bupivacaine, ropivacaine, and spinal neurotoxicity after long-term intrathecal infusion of keta-
levobupivacaine (Table 29–1). mine in a patient with cancer.31 That ketamine had benzethonium
The most commonly used LA was bupivacaine at a concen- chloride as a preservative and was administered along with bupi-
tration of 0.25%. Ketamine has been used at doses of 0.25 mg/kg vacaine, morphine, and clonidine. The risk of spinal toxicity is
to 1 mg/kg. Semple and coworkers18 and Panjabi and colleagues19 probably higher after prolonged subarachnoid administration for
conducted dose-response studies with ketamine 0.25 mg/kg, cancer pain.
0.5 mg/kg, and 1 mg/kg combined with bupivacaine 0.25%. The In recent years, there are reports of neuroapoptosis after
optimal dose to produce longer-duration analgesia without exposure to general anesthetic agents that include ketamine,
significant side effects was 0.5 mg/kg. No major hemodynamic nitrous oxide, isoflurane, halothane, and propofol in the devel-
disturbance, psychological, neurologic, or respiratory conse- oping brain of animals.32–34 Anesthesia induces neuroapoptosis
quences have been reported with ketamine 0.5 mg/kg following throughout the forebrain structure in the neonatal rat brain. The
single-shot caudal administration in children (Table 29–2). Both neurons of the ventral horn of the spinal cord are more susceptible
groups reported a higher incidence of behavioral adverse effects to anesthetic injury.34 Even a subminimal concentration of
in the ketamine 1 mg/kg group.18,19 The analgesic efficacy of S(+) isoflurane exposure for 1 hour can induce apoptosis in mice.35
ketamine after caudal or intravenous administration has been These are serious concerns and the U.S. Food and Drug
assessed.22 Patients administered caudal bupivacaine 0.25% were Administration (FDA) constituted a panel to review available data
given additional S(+) ketamine 0.5 mg/kg either caudally or and make recommendations. The FDA panel determined that
intravenously. The median time to first analgesic was longer in the “based on current knowledge and lack of appropriate alternative,
caudal ketamine group (10 h) than in the intravenous ketamine there is no scientific basis to recommend changes in clinical
group (4.6 h), indicating that the principal analgesic effect of S(+) practice.”36 As yet, no permanent neurologic injury has been
ketamine results from local neuraxial rather than any systemic reported from use of single-shot caudal ketamine. There should be
effect.22 no hesitation to continue using ketamine in the epidural space.
The preservative-free S(+) ketamine is reportedly twice as
potent as the racemic mixture because of its greater affinity to Clonidine
NMDA receptors. As adjuvant to ropivacaine, it prolongs the
duration of action by 10.3 hours23 and 11.7 hours,21 durations Clonidine is an α2 adrenergic agonist with 200-fold selectivity for
similar to that with racemic ketamine. S(+) Ketamine has also α2 over α1 adrenoreceptors (Table 29–3). It is moderately lipid-
TABLE 29-1. Details of Studies with Ketamine As an Adjuvant to Local Anesthetics
Results: Duration Increased Duration
Bissonette-029-(F)
Author Surgery N Age Study Groups Assessment Tool of Analgesia Remarks of Analgesia
Naguib12 Hernia 50 3–3.5 y A) Bupivacaine Three-point A) Not reported
0.25% pain scale B) Less analgesic
B) Bupivacaine 0.25% + requirement in 24 h
4/13/11
ketamine 0.5 mg/kg in bupivacaine-

C) Ketamine 0.5 mg/kg ketamine group
Cook13 Orchidopexy 60 1–10 y A) Bupivacaine 0.25% with OPS A) 3.2 h Median values 9.3 h
4:17 PM
adrenaline 1:200,000 B) 5.8 h

B) Bupivacaine 0.25% + C) 12.5 h
clonidine 2 μg/kg
C) Bupivacaine 0.25% +
ketamine 0.5 mg/kg
Page 475
Gunduz14 Hernia, genital 62 1–10 y A) Ketamine 0.25 mg/kg + CHEOPS A) 1206 ± sd 377.5 min 20.1 h
lidocaine 2% B) 1220.5 ± sd 392.6
B) Ketamine 0.25 mg/kg + min
Tramadol 2 mg/kg
Johnston15 Orchidopexy 40 1–5 y A) Bupivacaine 0.25% + OPS A) 9.5 h 8–9.5 h
ketamine 0.5 mg/kg B) 8 h
B) Bupivacaine 0.125% +
ketamine 0.5 mg/kg
Akbas16 Hernia 80 2–12 y A) Ropivacaine 2% Mod OPS A) 4 ± sd 3.2 h 10 h
Circumcision B) Ropivacaine 2% + B) 10 ± sd 4.3 h
ketamine 0.5 mg/kg C) 14 ± sd 3.1 h
C) Ropivacaine 2% +
clonidine 1 μg/kg
Güneş17 Hernia 99 1–10 y A) Ropivacaine 4% CHEOPS A) 1006 ± sd 506 min 19.8 h
B) Ropivacaine 2% + B) 1188 ± sd 403 min
ketamine 0.25 mg/kg C) 1377 ± sd 204 min
CHAPTER 29
C) Ropivacaine 2% +
■
tramadol 1 mg/kg
Semple18 Orchidopexy 60 ≤9 y A) Bupivacaine 0.25% + Mod OPS A) 7.9 h Delirium with 7.9 h
ketamine 0.25 mg/kg B) 11.0 h ketamine 11 h
B) Bupivacaine 0.25% + C) 16.5 h 1 mg/kg 16.5 h
ketamine 0.5 mg/kg
ketamine 1 mg/kg
Panjabi19 Hernia 60 6 mo–10 y A) Bupivacaine 0.25% + AIIMS A) 8.84 ± sd 5.63 h Delirium with 8.8 h
ketamine 0.25 mg/kg B) 22.14 ± sd 3.92 h ketamine 22.1 h
B) Bupivacaine 0.25% + C) 21.8 ± sd 1.16 h 1 mg/kg 21.8 h
ketamine 0.5 mg/kg
Adjuvants to Local Anesthetics
ketamine 1.0 mg/kg
475
(Continued)
476
Bissonette-029-(F)
PART 2
TABLE 29-1. Details of Studies with Ketamine As an Adjuvant to Local Anesthetics (Continued)
■

4/13/11
Marhofer20 Hernia 49 3 mo–6 y A) S(+) Ketamine 0.5 mg/kg OPS A) 203 ± sd 117 min S(+) Ketamine
B) S(+) Ketamine 1 mg/kg B) 273 ± sd 123 min compared with
Pharmacology
C) Bupivacaine 0.25% with C) 300 ± sd 96 min bupivacaine

4:17 PM
adrenaline 1:100,000 not as adjuvant

De Negri21 Hernia 63 1–5 y A) Ropivacaine 2% CHEOPS A) 291 ± sd 30 min 11.7 h
B) Ropivacaine 2% + B) 492 ± sd 23 min
clonidine 2 μg/kg C) 701 ± sd 33 min
Page 476
C) Ropivacaine 2% + S(+)
ketamine 0.5 mg/kg
Martindale22 Hernia 60 3 mo–6 y A) Bupivacaine 0.25% Mod OPS A) 4.75 h I.V. vs caudal 10 h
Orchidopexy B) Bupivacaine 0.25% & I.V. B) 4.6 h
S(+) Ketamine 0.5 mg/kg C) 10 h
C) Bupivacaine 0.25% + S(+)
ketamine caudal 0.5 mg/kg
De Negri23 Hernia 20 1–7 y A) Ropivacaine 2% OPS A) 285 ± sd 25 min 10.3 h
B) Ropivacaine 1% + S(+) B) 620 ± sd 15 min
ketamine 0.5 mg/kg
Hager24 Hernia 53 1 mo–6 y A) S(+) Ketamine 1 mg/kg A) 13.3 ± sd 9.2 h 13.3 h
B) S(+) Ketamine 1 mg/kg + B) 22.7 ± sd 3.5 h
clonidine 1 μg/kg C) 21.8 ± sd 5.2 h
C) S(+) Ketamine 1 mg/kg +
clonidine 2 μg/kg
Passariello25 Hernia 40 1–5 y A) S(+) Ketamine 1 mg/kg CHEOPS A) 1004 ± sd 106 min 16,6 h
Orchidopexy B) S(+) ketamine 0.5 mg/kg + B) 1200 ± sd 499 min
clonidine 1 μg/kg
Locatelli26 64 3 mo–6 y A) Levobupivacaine 0.15% + CHEOPS A) 145.5 min Median value 2.4–2.8 h
ketamine 0.5 mg/kg B) 167.5 min
B) Levobupivacaine 0.175% + C) 94.5 min
ketamine 0.5 mg/kg
C) Levobupivacaine 0.2%
AIIMS = All India Institute of Medical Sciences pain discomfort scale; CHEOPS = Children’s Hospital of Eastern Ontario Pain Scale; Mod OPS = modified Objective Pain Scale; OPS = Objective Pain Scale;
sd = standard deviation.
CHAPTER 29 ■ Adjuvants to Local Anesthetics 477
TABLE 29-2. Practical Points About Ketamine As an TABLE 29-3. Mechanism of Clonidine Analgesia
Adjunct to Local Anesthetics 1. Stimulation of α2 adrenergic receptors located on the dorsal
1. Ketamine (both racemic and S(+) ketamine) prolong the horn of the spinal cord.
duration of analgesia for bupivacaine 0.25% and ropivacaine 2. Clonidine also stimulates intermediate spontaneously active
0.2%. neurons located in the deeper layers of the dorsal horn of the
2. The optimal caudal dose is 0.5 mg/kg. spinal cord.
3. The duration of analgesia is 8–12 h after caudal epidural. 3. Clonidine may induce nitric oxide release when administered
4. Psychomimetic and behavioral symptoms are not seen after neuraxially, thereby causing its analgesic effect.
single-shot caudal ketamine 0.5 mg/kg. 4. Nonspinal mechanisms:
5. Neurotoxicity has been reported after prolonged a) Clonidine strengthens the depression of nerve fiber
subarachnoid use in cancer patients. action potentials produced by local anesthetics.
b) Clonidine exerts local analgesic effect intra-articularly.
From reference 40.
soluble and has a large volume of distribution and a relatively
long elimination half-life of 12 to 24 hours.37,38 Potts and associates
describe a clonidine pharmacokinetic in children from 1 week Akbas and associates reported an increased duration of 10 hours
to 14 years. Clearance at birth was 3.8 L/h/70 kg and matured with with clonidine as an adjuvant to ropivacaine 2%.48 Jamali and
a half-time of 25.7 weeks to reach 82% of the adult rate by 1 year coworkers reported an increase of 8.9 hours with bupivacaine
of age. The population parameter estimates were clearance 0.25% with epinephrine 1:200,000.42 Motsch and colleagues used
14.6 L/h/70 kg, central volume of distribution 62.5 L/70 kg, peri- a dose of 5 μg/kg with bupivacaine 0.175% and reported an
pheral volume distribution 119 L/h/70 kg, and intercompartment increase of 6.5 hours.50 The duration of analgesia reported in other
publications is less than 6.5 hours and is generally increased only
clearance 157 L/h/70 kg.39
up to 4.6 hours.
The use of clonidine in clinical practice is commonly limited by
Klimscha and associates in 1998 had reported an analgesia
hypotension and bradycardia mediated via central mechanisms.
increase of only 14 minutes with clonidine 1 or 2 μg/kg.44 A
It also induces sedation owing to depression of the locus cerebeus, number of reports have been published in which no additional
a brainstem nucleus that has been implicated in the sleep- benefit could be demonstrated when clonidine was added to LA
wake cycle. for caudal block.7,51–53 The exact cause of failure to demonstrate
Successful demonstration of epidural bupivacaine prolonga- the benefit of clonidine in these studies is speculative. De Mey
tion by clonidine in adults led to evaluation in pediatric caudal and associates51 and Sharpe and colleagues52 attributed this to
blockade. Clonidine has been used as adjuvant to bupivacaine, low volumes of bupivacaine. The studies of Joshi and coworkers53
lidocaine, mepivacaine, and ropivacaine.The duration of analgesia and Wheeler and colleagues7 used higher volumes, so LA volume
produced by clonidine in studies is detailed in Table 29–4 and alone is unable to explain these observations. It is unlikely that
Figure 29–2. epinephrine masked the effects of clonidine because epinephrine
There is an increased duration of analgesia with addition of was used only in Wheeler and colleagues’ study. Three of the
clonidine 1 to 2 μg/kg to LA, although the prolongation is less than studies that failed to demonstrate any beneficial effect of clonidine
that observed with ketamine (Table 29–5; see also Figure 29–2). used bupivacaine 0.125% (whereas De Mey and associates used
Figure 29-1. Duration of analgesia with

ketamine as adjuvant. The duration of
analgesia produced by the local anesthetic
when reported is represented as blue in
the staked bar.
TABLE 29-4. Details of Studies with Clonidine As an Adjuvant 478
Results: Duration Increase Duration
Bissonette-029-(F)
PART 2
Lee41 Lower limb 46 1–10 y A) Bupivacaine 0.25% Mod OPS A) 5.2 ± sd 1.2 h 4.6 h
■
orthopedic B) Bupivacaine 0.25% + B) 9.8 ± sd 2.1 h

surgery clonidine 2 μg/kg
Jamali42 Subumbilical 45 1–7 y A) Bupivacaine 0.25% OPS A) 460 ± sd 439 min 8.9 h
4/13/11
B) Bupivacaine 0.25% with B) 377 ± sd 341 min

epinephrine 1:200,000 C) 987 ± sd 341 min
Pharmacology
4:17 PM
clonidine 1 μg/kg
Cook13 Orchidopexy 60 1–10 y A) Bupivacaine 0.25% with OPS A) 3.2 h 2.6 h
epinephrine 1:200,000 B) 5.8 h
B) Bupivacaine 0.25% + C) 12.5 h
clonidine 2 μg/kg
Page 478
ketamine 0.5 mg/kg
Luz43 Hernia 36 A) Bupivacaine 0.18% + A) 6.3 ± sd 3.3 h Almost half the 6.3–24 h
Circumcision clonidine 1 μg/kg B) 7.1 ± sd 3.4 h children did
Orchidopexy B) Bupivacaine 0.18% + not require
morphine 30 μg/kg any analgesia
in first 24 h
Klimscha44 Hernia 36 6 mo–6 y A) Bupivacaine 0.25% Observational A) 346 min Median value, 0.22 h
B) Bupivacaine 0.25% with discomfort B) 300 min discharged
epinephrine 1:200,000 scale C) 360 min after 6 h from
C) Bupivacaine 0.25% + D) 360 min PACU and 8 h
clonidine 1 μg/kg E) 77 min from ward
D) Bupivacaine 0.25% +
clonidine 2 μg/kg
E) Saline
Constant45 Vesicoureteric 64 6 mo–9 y A) Bupivacaine 0.25% with CHEOP > 5 y, A) 174 min 1.6 h
reflux epinephrine 1:200,000 + VAS > 5 y B) 253 min
lidocaine 1% C) 265 min
B) Bupivacaine 0.25% with D) 287 min
epinephrine 1:200,000 +
lidocaine 1% + fentanyl
1 μg/kg
C) Bupivacaine 0.25% with
lidocaine 1% + clonidine
1.5 μg/kg
D) Bupivacaine 0.25% with
Clonidine 0.75 μg/kg +
fentanyl 0.5 μg/kg
Ivani46 Subumbilical 42 1–10 y A) Mepivacaine 1% OPS A) 143 min 1.2 h
Bissonette-029-(F)
B) Mepivacaine 1% + clonidine B) 218 min

2 μg/kg
Ivani47 Subumbilical 40 A) Ropivacaine 2% OPS 11/20 vs 18/20 Median 1.6 h
4/13/11
B) Ropivacaine 2% + clonidine managed without

2 μg/kg analgesia for 24 h
Akbas48 Hernia 75 A) Ropivacaine 2% OUCHER A) 4 ± sd 3.23 h 10 h
Circumcision B) Ropivacaine 2% + clonidine 1 μg/kg B) 14 ± sd 3.1 h
4:17 PM
C) Ropivacaine 2% + ketamine C) 10 ± sd 4.32 h

0.5 mg/kg
Vetter49 Ureteric 60 6 mo–6 y A) Ropivacaine 2% + clonidine 2 μg/kg FLACC A) 33 ± sd 36 min 0.5 h
reimplant B) Ropivacaine 2% + hydromor- B) 105 ± sd 197 min
Page 479
phone 10 μg/kg C) 178 ± sd 251 min

C) Ropivacaine 2% + morphine
50 μg/kg
Motsch50 Minor surgical 40 A) Bupivacaine 0.175% Smiley A) 14.4 ± sd 10.9 h High incidence 6.5 h
procedure B) Bupivacaine 0.175% + clonidine analogue B) 20.9 ± sd 7.4 h of bradycardia
5 μg/kg scale and hypoten-
sion in cloni-
dine group
De Mey51 Hypospadias 60 8 mo–13 y A) Bupivacaine 0.25% CHEOP > 5 y Analgesia 0h
B) Bupivacaine 0.25% + clonidine VAS > 5 y Same
1 μg/kg
C) Bupivacaine 0.25% + sufentanil
0.5 μg/kg
D) Bupivacaine 0.25% + clonidine
0.5 μg/kg + sufentanil 0.25 μg/kg
Sharpe52 Circumcision 74 1–9 y A) Bupivacaine 0.25% Categorical A) 280.7 ± sd 0.8 h 1.7 h
B) Bupivacaine 0.25% + clonidine observer 171.6 min
CHAPTER 29
1 μg/kg pain score B) 327.8 ± sd 188.3 min

■
C) Bupivacaine 0.25% + clonidine by parents C) 382.0 ± sd 200.6 min

2 μg/kg
Joshi53 Hernia 36 6 mo–6 y A) Bupivacaine 0.125% with saline FACES scale A) 200 ± sd 366 min 0.4 h
Circumcision B) Bupivacaine 0.125% + clonidine B) 224 ± sd 320 min
Orchidopexy 2 μg/kg
Wheeler7 Hernia 30 2–8 y A) Bupivacaine 0.125% with OPS A) 70.9 ± sd 23.5 min 0.2 h
Circumcision epinephrine 1:100,000 B) 84.5 ± sd 45.0 min
Orchidopexy B) Bupivacaine 0.125% with epineph-
rine 1:200,000 + clonidine 2 μg/kg
CHEOPS = Children’s Hospital of Eastern Ontario Pain Scale; FACES = FACES pain scale; FLACC = Face, Legs, Activity, Cry, and Consolability pain scale; Mod OPS = modified Objective Pain Scale; OPS = Objective
Pain Scale; OUCHER = Six faces self reporting pain scale; PACU = postanesthesia care unit; sd = standard deviation; VAS = Visual Analogue Scale.
479
Figure 29-2. Duration of analgesia with

clonidine as adjuvant. The duration of
analgesic action of local anesthetics is
represented as blue in the staked bars.
0.25%). Positive effects were reported with higher concentrations fall in oxygen saturation below 80% 20 minutes later. Further
of bupivacaine. Is it that synergistic action may require a minimum episodes of apnea followed that required mask ventilation or
degree of blockade with LA? Is it that better study design of the tactile stimulation and oxygen therapy.56 Oxycardiorespiragraphy
latter studies brought out the difference? on the fifth postoperative day revealed an abnormal breathing
Clonidine has also been used in combination with fentanyl45 pattern that probably contributed to the postoperative apnea.
and sufentanil51 as adjuvants without any significant increase in Fellmann and associates reported apnea in a former premature
duration of analgesia with these drugs. Its combination with infant who underwent hernia repair under caudal block (with
ketamine has conflicting results.24,25 bupivacaine 0.125% with epinephrine 1:200,000 and clonidine
1.5 μg/mL solution 1.2 mL/kg) at 38 weeks postmenstrual age
Adverse Effects (2540 g). Fifteen minutes after the block, the baby developed
apnea, bradycardia, hypotension, and a fall in oxygen saturation
Clonidine is associated with sedation, hypotension, and brady- that was managed with oxygen therapy alone. This child sub-
cardia. Sedation is dose-dependent. Bradycardia is caused by an sequently had an uneventful hernia repair under caudal block
increased in vagal tone resulting from central stimulation of without clonidine at 35 weeks postmenstrual age.57 Postoperative
parasympathetic outflow as well as reduced sympathetic drive. apnea has also been reported in a preterm neonate who received
Hypotension results from stimulation of α2 inhibitory nerves in caudal clonidine 1.25 μg/kg for hernia repair.58
the medullary vasomotor center of the brainstem.54 The hemo- The safety of clonidine as an adjunct for LA in neonates
dynamic side effects are less pronounced in children than in has been reported by Rochette and associates in a case series of
adults. Like sedation, they are dose-dependent. Motsch and collea- 75 neonates, half of them former preterm infants. All were sched-
gues reported lower systolic pressure and heart rate during the uled for elective hernia repair and all received spinal subarach-
first 3 postoperative hours in children who received clonidine noid block with plain isobaric bupivacaine 0.5% alone or with
5 μg/kg–1 compared with controls, although systolic pressures addition of clonidine 0.25 μg/kg, 0.5 μg/kg, 1 μg/kg, or 2 μg/kg.
in both groups were similar intraoperatively. Only 1 child out of The incidence of transient hypotension occurred more often
20 required atropine to treat bradycardia; no other resuscitative with clonidine 2 μg/kg. The duration of spinal block increased
measures were needed for other children given this relatively high from 67 minutes (range 58–82) in controls to 111 minutes (range
dose of clonidine.51 The addition of lower doses to LAs for neu- 93–125) in the group receiving clonidine 1 μg/kg. No significant
raxial analgesia is unlikely to increase the degree of hypotension.55 deleterious hemodynamic or respiratory side effects were recorded
Postoperative apnea has been reported in a 2-week-old term from infants given clonidine 1 μg/kg. With clonidine 2 μg/kg, the
neonate after hernia repair and orchidopexy. The baby had caudal duration of analgesia showed a ceiling effect but the incidence
clonidine 2.2 μg/kg with ropivacaine 0.2% 1 mL/kg. The baby of hypotension and caffeine use in the postanesthesia care unit
suffered apnea accompanied by bradycardia, hypotension, and a were increased.59
TABLE 29-5. Practical Points About Clonidine As an Ketamine and clonidine were mainly studied in minor daycare
Adjunct to Local Anesthetics surgical procedures. There are consistent reports of increased
duration of analgesia, although many reports do not mention
1. Clonidine 1–2 μg/kg prolongs the duration of analgesia of quantitative duration. The duration of analgesia is shown in
bupivacaine 0.25%. Figure 29–3.
2. Clonidine does not prolong the duration of analgesia of Lönnqvist questioned the use of caudal morphine in view of
bupivacaine 0.125%. the risk of respiratory depression and a higher incidence of other
3. The duration of analgesia after a caudal supplementation to adverse effects.74 The incidence of adverse effects following caudal
an epidural block is 4–6 h. opioids is dose-dependent and can be minimized by appropriate
4. Clonidine 1 μg/kg as a single-shot caudal does not usually dose and titration to analgesic need (Table 29–8). The use of lower
cause hypotension, bradycardia, or undue sedation. doses of caudal morphine has decreased the incidence of side
5. Clonidine may produce apnea in newborns. effects without compromising analgesia. Teyin and associates
reported effective postoperative pain relief with caudal morphine
30 μg/kg.72 I have been using caudal morphine (30–50 μg/kg)
Postoperative apnea in former premature infants up to along with bupivacaine since the late 1980s without any incidence
50 weeks postmenstrual age is well recognized. The contribution
of respiratory depression. Recently, we concluded a study
from caudal clonidine to the incidence of apnea is speculative.
combining morphine 30 μg/kg with ketamine 0.5 μg/kg and
Absence of life-threatening apnea in the case series from Rochette
bupivacaine 0.125% for caudal block in children undergoing
and associates is reassuring, but larger cohorts are required to
thoracic and upper abdominal surgery. Fifty percent of children
establish safely.
did not require any analgesia at all in the entire postoperative
period and the rest were pain-free for 24 hours.
Morphine Valley and Bailey reported 11 cases (8%) of clinically impor-
tant hypoventilation. Ten of these occurred in infants; 8 patients
Morphine has been used neuraxially in adults since 1979.60 It is were younger than 3 months old. Seven of them had received
the most commonly used opioid, with an excellent safety record intravenous opioids in addition to caudal morphine,68 which
for local neuraxial injury. has been identified as a risk factor for respiratory depression in
Opioids diffuse in the spinal cord and exert spinal analgesia adults.69 Infants younger than 3 months of age have reduced
by modulating Aδ and C fibers to decrease afferent nociceptive morphine clearance, resulting in higher plasma concentrations
input.61 Both mu and delta receptor agonists act presynaptically that contribute to respiratory depression. Mayhew and cowork-
by inhibiting Ca2+ influx. Postsynaptically, mu receptor agonists ers reported a case series of 500 children, including 23 neo-
increase K+ conductance and hyperpolarize ascending neurons.
nates, who received caudal morphine 30 to 40 μg/kg without any
Opioids have minimal effect on dorsal root axons and somato-
episode of clinically significant respiratory depression.70 Rosen
sensory evoked potentials.62
and Rosen reported 16 children undergoing open heart surgery
The administration of epidural opioids for postoperative
who received caudal morphine 75 μg/kg as well as intravenous
pain is well established in infants and children. Epidural opioids
opioid supplementation without any incidence of respiratory
provide analgesia without the sympathetic or motor block asso-
depression.71
ciated with LAs. Neuraxial, as opposed to systemic, administration
Intrathecal morphine has been used effectively in adults and
reduces the supraspinal adverse effects of sedation and respiratory
children. It has been used in spinal, cardiac, and neurosurgical
depression. However, dose-dependent adverse effects like pruritus,
nausea, and urinary retention occur. procedures and for long-term management of cancer pain in
Morphine has been used in infants and children as an adjunct children. Doses ranged from 10 to 30 μg/kg and there was a high
to lidocaine, bupivacaine, and ropivacaine or has been admini- incidence of adverse effects.75–83 Ganesh and colleagues used
stered alone (Table 29–6). lower-dose morphine (4–5 μg/kg) intrathecally in 187 children.
The dose of morphine in initial studies was 100 μg/kg, whereas They reported adequate analgesia in the first 24 hours with 80%
later studies used reduced doses of 30 to 50 μg/kg. Krane and of patients not requiring rescue opioids in the first 8 hours and
coworkers reported a duration of analgesia of 10.0 hours (± 52% receiving only oral analgesics in the first 24 hours.84
standard deviation [sd] 3.3), 10.4 hours (± sd 4.2), and 13.3 hours Epidural morphine alone or as an adjuvant has been in use in
(± sd 4.7) for caudal morphine at a dose of 33 μg/kg, 67 μg/kg, adults since the early 1980s as well as in children. The fear of
and 100 μg/kg, respectively.65 Castillo-Zamora and colleagues respiratory depression seems to be overemphasized and has
attempted to minimize the dose of single-dose caudal or lumber contributed to inadequate analgesia in the postoperative period.
epidural morphine further. They used doses of 11.2 μg/kg, 15 μg/
kg, or 20 μg/kg and reported similar duration of analgesia for up Other Adjuvants
to 12 hours.73 The incidence of other side effects like pruritus,
urinary retention, and respiratory depression was absent with A number of other adjuvants are reported, although their popula-
11.2 μg/kg (Table 29–7), although nausea and vomiting were rity in clinical practice is limited. This is because of limited pro-
reported in more than 45% of patients.73 They attributed this high longation of postoperative analgesia or an increased incidence
incidence of postoperative nausea and vomiting (PONV) to of adverse effects compared with clonidine, ketamine, and mor-
prolonged fasting longer than 8 hours and the use of a facemask phine. Lönnqvist appealed to resist using alternative adjuncts74
for maintaining anesthesia with resulting swallowed air. because often drugs are trialed for the sake of publication only.
Morphine has been used in major surgical procedures such Testing the limits of the caudal block in children is cautioned
as orthopedic, upper abdominal, thoracic, and cardiac surgery. against.4
482
TABLE 29-6. Details of Studies With Morphine As Adjuvant

Bissonette-029-(F)
PART 2
Author N Age Surgery Study Group of Analgesia Pain Scale Used Remarks of Analgesia
■
Jensen63 22 2–9 y Circumcision A) Bupivacaine 0.5% A) 245–515 min 7.2 h

Hypospadias B) Morphine 50 μg/kg B) 610–2145 min
4/13/11
Krane64 46 1–16 y Genitourinary A) IV Morphine 50–200 A) 45 min Five-point 7h

Lower limb μg/kg B) 5 h observer scale
orthopedics B) Bupivacaine 0.25% with C) 12 h
Pharmacology
epinephrine 1:200,000
4:17 PM
C) Lidocaine 1% +
morphine μg/kg or
morphine 100 μg/kg
Krane65 32 1.2–7.9 y Major surgery A) Lidocaine 1% + A) 10.0 ± sd 3.3 h One patient in 10–13.3 h
Page 482
below diaphragm morphine 33 μg/kg B) 10.4 ± sd 4.2 h 100-μg group

B) Lidocaine 1% + C) 13.3 ± sd 4.7 h had respiratory
morphine 67 μg/kg depression
C) Lidocaine 1% +
morphine 100 μg/kg
Marco Valls66 28 2–12 y Urologic surgery A) Morphine 50 μg/kg A) 20 ± sd 5 h Physiologic and 20 h
B) Bupivacaine 0.5% clinical data
C) No drug
Wolf 67 30 9 mo–11 y Orchidopexy A) Bupivacaine 0.125% 8/15 needed analge- 24 h
B) Bupivacaine 0.125% + sia (A), no anal-
morphine 50 μg/kg gesia needed (B)
Valley 68 136 1–16 y (54% 60% Abdominal, A) Duramorph 70 μg/kg 80% good, 7% fair,
<1 y) 38% thoracic, 12% poor
2% orthopedics
Gülec69 60 1–12 y Hernia, urogenital A) Bupivacaine 0.125% A) 8.2 ± sd 1.3 h 6.85 h
B) Bupivacaine 0.125% + B) 14.5 ± sd 1.6 h
morphine 50 μg/kg C) 21.2 ± sd 1.2 h
midazolam 50 μg/kg
Mayhew70 500 3 mo–16 y 39% Orthopedic, Bupivacaine 0.175% or 6–24 h Retrospective study 6.24 h
29% genitouri- bupivacaine 0.25% +
nary, 20% morphine 30 μg/kg–1 or
abdominal, bupivacaine 0.25% +
4% craniofacial morphine 40 μg/kg
Rosen71 32 2–12 y Open heart surgery A) Morphine 75 μg/kg in 6 (range 2–12) h Decreased analgesia 6 h
saline requirement in
24 h
Bissonette-029-(F)
4/13/11
4:17 PM
Luz43 36 6 mo–6 y Hernia A) Bupivacaine 0.18% + A) 6.3 ± sd 3.3 h Almost half the 6.3–24 h
Page 483
Circumcision clonidine 1 μg/kg B) 7 ± sd 3.4 h children did not

Orchidopexy B) Bupivacaine 0.18% + require any anal-
morphine 30 μg/kg gesia in first 24 h
Teyin72 28 4–16 y Hernia A) Morphine 30 μg/kg Comparable 0h
Hydrocele B) Bupivacaine 0.25%
Hypospadias
Castillo- 45 1–15 y Open reduction of A) Morphine 11.2 μg/kg >12 h >12 h
Zamora73 hip with pelvic B) Morphine 15 μg/kg
osteotomy C) Morphine 20 μg/kg
or femoral
osteotomy
Vetter49 60 6 mo–6 y Ureteric reimplant A) Ropivacaine 2% + A) 33 ± sd 36 min FLACC 0.5 h
clonidine 2 μg/kg B) 105 ± sd 197 min
B) Ropivacaine 2% + C) 178 ± sd 251 min
hydromorphone
10 μg/kg
CHAPTER 29
C) Ropivacaine 2% +
■
morphine 50 μg/kg
FLACC = Faces, Legs, Activity, Cry, and Consolability pain scale.
483
TABLE 29-7. Measures to Improve the Safety of TABLE 29-8. Practical Points About Morphine As an
Caudal Morphine Adjunct to Local Anesthetics
1. It should not be administered to daystay children. 1. Morphine prolongs the duration of analgesia of bupivacaine
2. Use in only children undergoing major surgery. 0.25% for 12–24 h.
3. All the children should be monitored in a high-dependency 2. An effective dose of caudal morphine as adjuvant is 30–50
area for at least 24 h. μg/kg.
4. Children should be monitored for sedation score, respiratory 3. Adverse effects like respiratory depression, nausea, vomiting,
rate, pain score, and pulse oximetry. Sedation precedes pruritus, and urinary retention are dose-dependent and can
respiratory depression, and it is possible to preempt be minimized by dose reduction.
respiratory depression by monitoring sedation. 4. Concomitant use of I.V. opioids may increase the risk of
5. Strict protocols limiting the use of supplemental I.V. respiratory depression.
opioids should be followed because the concomitant use 5. Avoided in daystay patients and used for patients after major
of I.V. opioids increases the risk of serious respiratory surgical procedures who are monitored in a high-
depression. dependency area for at least 24 h.
From reference 85.
Fentanyl fentanyl 1 μg/kg was used as adjuvant to 1% lidocaine and 0.25%

Fentanyl is the most favored adjuvant for continuous infusion bupivacaine mix.45 Subsequent studies by Joshi and associates,90
at a concentration of 1 to 2 μg/mL in the LA solution. Larman Campbell and coworkers,91 Gaitinin and colleagues,92 and Baris
and associates, in a multicenter study, could not demonstrate and associates93 could not demonstrate any additional analgesic
any beneficial effect of fentanyl as an adjuvant when used with advantage of adjuvant with bupivacaine over bupivacaine alone.
low concentrations of levobupivacaine (0.0625–0.125%).86 It is Despite these unfavorable results, fentanyl was used by 21% of
believed that the analgesic effect of fentanyl infusion is mediated pediatric anesthetists in the United Kingdom in 2002 as adjuvant
through systemic uptake and supraspinal effect.87,88 to single-shot caudal. Fentanyl should not be used as an adjunct to
When fentanyl is used as an adjunct for single-shot caudal, LA in single-shot caudal block.
results are inconclusive. Gharsallah and coworkers reported Intrathecal fentanyl has been used commonly as an adjuvant
equianalgesic potency of fentanyl 1 μg/kg or fentanyl 0.5 μg/kg to bupivacaine in adult surgical and obstetric populations.
with bupivacaine 0.25%, although the incidence of PONV was Intrathecal fentanyl 0.25 μg/kg, 0.5 μg/kg, or 1 μg/kg with 0.5%
higher with fentanyl 1 μg/kg.89 Constant and colleagues reported hyperbaric bupivacaine (0.5 mg/kg in infants < 5 kg, 0.4 mg/kg in
an increase of only 79 minutes’ duration of analgesia when infants 5–10 kg) was given to 58 infants undergoing lower
Figure 29-3. Duration of anal-

gesia with morphine as adjuvant.
The duration of local anesthetic
where mentioned is represented
in blue in the staked bar. Results
from Mayhew and coworkers are
shown as two bars representing
most patients up to 24 hours and
some patients up to 6 hours.70
abdominal and urologic procedures. Fentanyl 1 μg/kg increased Butorphenol

the duration of subarachnoid block significantly to 74 ± sd Singh and coworkers evaluated the efficacy of caudal butorphenol
6 minutes from 51 ± sd 5 minutes in the control group. The quality with or without bupivacaine in children aged 1 to 10 years under-
of analgesia was also observed to be better.94 One of the limitations going infraumbilical surgery. Butorphanol 25 μg/kg with 0.25%
of subarachnoid block in children has been its short duration of bupivacaine was compared with butorphanol 25 μg/kg or bupi-
action. The results of this study might increase the use of subara- vacaine 0.25% alone. The duration of analgesia increased consi-
chnoid block in infants. derably in the combined butorphanol-bupivacaine group to 14.5 ±
sd 4.8 hours compared with 8.8 ± sd 4.8 hours for bupivacaine and
Diamorphine 6.8 ± sd 2.9 hours for butorphanol, respectively.104
Sanders reported that 13% of pediatric anesthetists in the United
Kingdom regularly used diamorphine as an adjuvant to LA.2 How- Midazolam
ever, few published studies are available. Kelleher and coworkers Midazolam is a water-soluble benzodiazepine. It exerts its anal-
reported the use of diamorphine 30 μg/kg with bupivacaine 0.25% gesic effect through the gamma-aminobutyric acid benzodiaze-
(0.5 mL/kg) and demonstrated a median duration of analgesia of pine system in the spinal cord. In children undergoing inguinal or
11.0 hours (range 8.6–14.2) compared with 8.5 hours (5.8–10.8) urogenital surgery, Gülec and colleagues reported that bupivacaine
for bupivacaine 0.25% alone.95 0.25% combined with midazolam 50 μg/kg produced a mean
duration of analgesia of 21.1 ± sd 1.2 hours compared with 14.5 ±
Tramadol sd 1.6 hours for bupivacaine 0.25% combined with morphine
50 μg/kg and 8.1 ± sd 1.3 hours for plain bupivacaine.69
Tramadol is a synthetic analogue of codeine. It is a racemic Naguib and associates could not demonstrate similar prolong-
mixture of two enantiomers. The (+) enantiomer has a mode- ation of analgesic effect after caudal midazolam 50 μg/kg alone
rate affinity for the opioid receptor and inhibits serotonin uptake, compared with bupivacaine 0.25%. However, midazolam 50 μg/kg
whereas the (–) enantiomer is a potent norepinephrine inhibi- as an adjuvant to bupivacaine 0.25% significantly increased the
tor. The analgesic effectiveness of epidural tramadol is contro- duration of analgesia compared with midazolam or bupivacaine
versial. alone.105 Mahajan and coworkers also reported an increase in the
Prakash and colleagues conducted a dose-response study of duration of analgesia produced by caudal midazolam 50 μg/kg
caudal tramadol with bupivacaine 0.25% in children aged 2 to with bupivacaine 0.25% to 11 ± sd 5 hours from 7.4 ± sd 2.1 hours
8 years. They compared tramadol 1 mg/kg, 1.5 mg/kg, and 2 mg/ for bupivacaine alone.106
kg. The duration of analgesia was 8 ± sd 0.9 hours, 11 ± sd 1 hours, Kumar and colleagues compared the effectiveness of caudal
and 12 ± sd 0.9 hours, respectively. They suggested that tramadol midazolam, ketamine, and neostigmine as adjuvant to bupivacaine
2 mg/kg was the optimal dose.96 0.25% in children aged 5 to 10 years scheduled for hernia repair.107
Ozkan and associates compared the effect of caudal tramadol The duration of analgesia was longer in the neostigmine and
2 mg/kg with bupivacaine 0.25% and reported a superior analgesia midazolam groups than in the ketamine and bupivacaine-alone
with tramadol.97 Senel and coworkers reported longer duration of groups.
analgesia for the tramadol-bupivacaine group by 13.5 ± sd 2.2 Despite the results of these studies, regular caudal adminis-
hours than the bupivacaine or tramadol-only group.98 Güneş and tration of midazolam seems to be controversial and has not gained
colleagues observed an increased duration of 6.3 hours with popularity.
tramadol as an adjuvant to ropivacaine 0.2% in children aged 1 to
10 years scheduled for hernia repair.17 Contrarily, Gunduz and Neostigmine
associates99 and Prosser and coworkers100 could not demonstrate
any significant increase in the duration of analgesia with tramadol The acetylcholine inhibitor neostigmine has been investigated as
as an adjuvant to bupivacaine 0.25%. a neuraxial analgesic adjuvant. An animal model has suggested
Murthy and colleagues published a pharmacokinetic study.101 that it plays a role in spinal analgesia through stimulation of
They reported that caudal tramadol is absorbed systemically and cholinergic receptors in the substantia gelatinosa and superficial
is equally effective as intravenous administration.101 Published data laminae of the dorsal horn of the spinal cord.108
do not support a regular usage of tramadol as an adjuvant to LAs. Abdulatif and El-Sanabary examined the analgesic effect
of caudal neostigmine, bupivacaine, or a mixture of both in
children.109 Time for first rescue analgesia was 22.8 ± sd 2.9 hours
Buprenorphine in the neostigmine 2 μg/kg with bupivacaine 0.25% group
Buprenorphine is a partial agonist with a very high affinity for the compared with 8.1 ± sd 5.9 hours and 5.2 ± sd 2.1 hours for the
mu opioid receptors in the spinal cord. Girotra and associates bupivacaine- and neostigmine-only groups, respectively. However,
compared caudal buprenorphine 4 μg/kg with morphine 50 μg/kg very high incidences of PONV were reported, 25% in the neostig-
in children aged 1 to 10 years.102 They reported a duration of mine group and 30% in the neostigmine-bupivacaine group.
action for buprenorphine of 25.6 hours compared with 19.9 hours Almenrader and associates studied the use of S(+) ketamine
with morphine. with or without preservative-free neostigmine 10 μg/kg.110 The
Kamal and Khan reported buprenorphine 2.5 μg/kg as an analgesia effect was marginally prolonged in the neostig-
adjuvant to bupivacaine 0.5% and claimed good analgesia for up mine group, but as in Abdulatif and El-Sanabury’s study, the
to 24 postoperative hours.103 This study, however, was terminated incidence of PONV increased to 30% from zero in the ketamine
prematurely because of a high incidence of PONV (80%). group.
Batra and coworkers conducted a dose-response study of databanks. Analysis, however, was possible in only 17 studies.
caudal neostigmine 10, 20, 30, 40, and 50 μg/kg in children aged Fifty-nine studies (48%) were discarded because of poor study
2 to 8 years scheduled for hypospadias surgery.111 Along with the design and 12 studies were excluded because of inappropriate
prolongation of duration of analgesia, a dose-dependent increase outcome measures. Many practical and methodologic factors in
in the incidence of PONV from 15 to 45% was reported. the design and performance of clinical pediatric trials limit the
Mahajan and colleagues published a dose-response study quality and quantity of available research data. This not only has
of neostigmine as an adjuvant to bupivacaine 0.25%.112 The dose impact on the grading of recommendations in clinical practice
of neostigmine used was considerably less than the previous two guidelines but also should be considered by individual practi-
studies. They reported prolongation of analgesia to 16.6 ± sd 4.9 tioners when reading and interpreting published data.118 While
hours, 17.2 ± sd 55 hours, and 17.0 ± sd 5.8 hours, respectively, reviewing the literature for this chapter, we noticed that some
for neostigmine 2, 3, and 4 μg/kg compared with 5.1 ± sd 2.3 hours studies have excellent study design but most did not. Factors in
for bupivacaine only. The incidence of PONV, however, was these studies that could contribute to inadequate study sensitivity
similar in the all groups. are outlined in Table 29–9.
In view of the high incidence of nausea and vomiting associated
with the use of caudal neostigmine, it should not be recommended
for caudal administration in children. SUMMARY
A single dose of caudal morphine, ketamine, or clonidine as an
adjuvant to LA does result in prolongation of postoperative
PERIPHERAL NERVES analgesia. Fentanyl is the most widely used adjuvant in epidural
AND ADJUVANTS infusion. We have an adequate choice of drug options capable of
Although adjuvants have been used with LAs for peripheral nerve achieving prolonged postoperative analgesia after caudal block
blocks in adults, the published literature for children is scarce and that are effective and have an acceptable adverse effect and safety
results are inconclusive. profile.
Kaabachi and associates used clonidine as an adjuvant to
bupivacaine 0.25% for ilioinguinal and iliohypogastric nerve TABLE 29-9. Factors Limiting Interpretation of Local
block in 98 infants and children aged between 1 and 12 years and Anesthetic Adjunct Studies
compared it with bupivacaine 0.25% alone.113 There was no dif-
ference in the rate of rescue analgesia in the first 6 hours. 1. Inadequate sample size. The number of patients studied was
Cucchiaro and Ganesh114 reviewed the regional anesthesia data- too small; often 10 or 15 per group.
base of Children’s Hospital of Philadelphia from October 2002 to 2. Patient population. Most of the studies have included
December 2005. Children (N = 215) underwent infraclavicular, heterogeneous age groups ranging from a few months to
8–10 y and adolescents. Inclusion of children across a wide
lumbar plexus, femoral, fascia iliaca, and sciatic nerve block for
range increases the sample size but at the cost of increased
postoperative analgesia. There were 47% of children who received
variability because of age-related changes in physiology,
bupivacaine or ropivacaine alone and 53% clonidine as an
disease spectrum, pharmacokinetics, and analgesic
adjuvant to either of these LAs. The sensory block was extended
requirements.
by a few hours by clonidine in both groups. 3. Surgical procedures. The majority of the trials involve minor
Giannoni and coworkers compared saline, ropivacaine 1%, and surgical procedure such as hernia repair, circumcision, and
clonidine 1 μg/kg with ropivacaine 1% for local infiltration in the hypospadias, which are less painful procedures, and
tonsillar fossae in children before tonsillectomy.115 The children differentiation of the effect of the analgesic can be difficult to
in clonidine-ropivacaine group had better pain relief from post- establish.
operative days 2 through 5. 4. Use of pain measure tools. Many studies use one assessment
Ivani and colleagues conducted a pilot study of 40 children aged tool for all age groups. Age-appropriate tools have not been
1 to 2 years scheduled for hernia repair.116 Children received either used for assessment of pain even though studies include
a caudal block or an ilioinguinal iliohypogastric nerve block with infants through to older children and even adolescents,
ropivacaine 0.2% and clonidine 2 μg/kg. Fourteen children in the which confound data interpretation. The most commonly
caudal group and 9 children in ilioinguinal-iliohypogastric group used tool was the OPS of Broadman and colleagues or its
did not require rescue analgesia. No difference in maximum pain modifications, which is validated for adolescents only and
scores was detected between the groups. not for infants and nonverbal children,119 and modifications
are not validated at all.
5. Outcome measure. Time to first analgesia has been taken as
EVALUATING THE LITERATURE the end point of analgesic duration. However, time to first
Kester Brown, in his memoirs, mentioned that the most useful analgesia is dependent on other factors such as duration of
thing that he learned at university was from a comment by his anesthesia, intraoperative analgesia, timing and dose of other
bacteriology professor, Willy Tulloch, “Not to believe everything analgesic drugs, all of which are poorly accounted for.
written in the books.”117 6. The pain assessment was from 6–24 h only and not until
Assermino and associates systematically reviewed non-opioid children were pain-free. It is difficult to record the total
additives to LAs for caudal block in children.3 They collected a analgesic consumption.
total of 183 potentially relevant studies from Medline and MBASE OPS = Objective Pain Scale.
TABLE 29-10. Side Effects Observed With the Commonly Used Adjuvants
Ketamine Ketamine Clonidine Clonidine Morphine Morphine
Side Effects 0.5 mg/kg > 0.5 mg/kg 1 μg/kg 2 μg/kg ≤ 50 μg/kg > 50 μg/kg
Heart rate – – –/↓ –/↓ – –
Blood pressure – – –/↓ –/↓ – –
Respiratory –/Apnea in –/Apnea in –/↓ In higher
neonates neonates doses
Sedation – – Y YY – –
PONV Y Y Y YY YY YY
Pruritus – – – – Y Y
Urinary retention Y Y Y Y YY YY
Delirium – Y at 1 mg/kg–1 – – – –
Y = yes, mild effect; YY = yes, moderate effect; – = no change or effect; ↓ = decrease; PONV = postoperative nausea and vomiting.
However, there is no doubt that every caudal adjuvant carries Basic Sciences for Clinical Practice. 2nd ed. Mosby/Elsevier; Philadephia,
some risk, although small (Table 29–10). The report of adverse PA; 2006. pp. 393–401.
2. Sanders JC. Paediatric regional anaesthesia, a survey of practice in the
effects of a particular drug should enlighten us to use it cautiously United Kingdom. Br J Anaesth. 2002;89:707–710.
rather than condemn it outright. As in life, everything cannot be 3. Ansermino M, Basu R, Vandebeek C, Montgomery C. Nonopioid addi-
described in terms of black and white; there are gray zones, even tives to local anaesthetics for caudal blockade in children: a systematic
in our understanding of how these drugs act and their response review. Paediatr Anaesth. 2003;13:561–573.
variability in different age groups. There is an urgent need for 4. de Beer DAH, Thomas ML. Caudal additives in children—solutions or
problems? Br J Anaesth. 2003;90:487–498.
improvement in our study designs for evaluation of drugs and 5. Sedt DB, Jebson PJR, Braid B, et al. Factors affecting plasma levels of
techniques to improve quality of pain relief. It is important to lignocaine and prilocaine. Br J Anaesth. 1972;44:1040–1049.
understand developmental changes in nociceptive processing and 6. Curatolo M, Petersen Felix S, Arendt-Nielsen L, et al. Epidural epi-
analgesic action in varying age groups of the pediatric study nephrine and clonidine. Segmental analgesia and effects on differential
population. In the absence of new longer-acting local anesthetic pain modalities. Anesthesiology. 1997;87:785–794.
7. Wheeler M, Patel A, Suresh S, et al. The addition of clonidine 2 microg.
agents and until any other alternative technique to prolong the kg–1 does not enhance the postoperative analgesia of a caudal block
caudal block is established, the clinical practice of caudal adjuvant using 0.125% bupivacaine and epinephrine 1:200,000 in children: a
is likely to continue. Safety as well as the effectiveness of the adju- prospective, double-blind, randomized study. Paediatr Anaesth. 2005;15:
vant should be the main criteria for choosing the right adjuvant for 476–483.
any particular situation. 8. Poster SS, Albin MS, Watson WA, et al. Spinal cord and cerebral blood
flow response to subarchnoid injection of local anaesthetics with or
Present-day acute pain services employ skilled staff and use without epinephrine. Acta Anaesthesiol Scand. 1985;29:330–338.
costly equipment such as epidural infusions or patient-controlled 9. Bromage PR. Neurological complications of subarchnoid and epidural
analgesia therapy. Let’s think of a therapeutic approach in which anaesthesia. Acta Anaesthesiol Scand. 1997;41:439–444.
a single drug administration or technique in the intraopera- 10. Brockmeyer DM, Kendig JJ. Selective effects of ketamine on amino acid–
mediated pathways in neonatal rat spinal cord. Br J Anaesth. 1995;74:
tive period can provide excellent postoperative analgesia without 79–84.
any additional intervention of supplementary analgesia. If this 11. Friesen RH, Morrison JE. The role of ketamine in the current practice of
therapeutic measure can be supplemented easily by oral analgesic paediatric anaesthesia. Paediatr Anaesth. 1994;4:79–82.
medication in appropriate dose, it would not only reduce the 12. Naguib M, Sharif A, Seraj M, et al. Ketamine for caudal analgesia
cost but also improve patient satisfaction. If we can manage to do in children: comparison with caudal bupivacaine. Br J Anaesth. 1991;67:
559–564.
that, it will be a blessing especially for those situations in which 13. Cook B, Grubb DJ, Aldridge LA, et al. Comparison of the effects of
resources are limited, which is the situation for most children in adrenaline, clonidine and ketamine on the duration of caudal anal-
the world. Neuraxial ketamine, clonidine, and morphine have the gesia produced by bupivacaine in children. Br J Anaesth. 1995;75:
potential to provide that ideal situation. Morphine has had an 698–701.
excellent neuraxial safety profile in adults and children for almost 14. Gunduz M, Ozalevli M, Ozbek H, Ozcengiz D. Comparison of caudal
ketamine with lidocaine or tramadol administration for post operative
three decades. Let’s explore the possibility of minimizing adverse analgesia of hypospadias surgery in children. Paediatr Anaesth. 2006;
effects, possibly by reducing the dose further in combination with 16:158–163.
other drugs in a large multicenter study. 15. Johnston P, Findlow D, Aldridge LM, Doyle E. The effect of ketamine on
Caudal block is like a trusted old friend. The adjuvants have 0.25% and 0.125% bupivacaine for caudal epidural blockade in children.
been in clinical practice for a long time. We should explore the Paediatr Anaesth. 1999;9:31–34.
16. Akbas M, Titiz TA, Ertugrul F, et al. Comparison of the effect of ketamine
possibility of safer combination of drugs and make best use of their added to bupivacaine and ropivacaine on stress hormone levels and the
combined strength. Then only can we foster and nurture the old duration of caudal analgesia. Acta Anaesthesiol Scand. 2005;49:1520–1526.
friendship with caudal block appropriately. 17. Güneş Y, Seçen M, Ozcengiz D, et al. Comparison of caudal ropiva-
caine, ropivacaine plus ketamine and ropivacaine plus tramadol admini-
stration for postoperative analgesia in children. Paediatr Anaesth. 2004;
REFERENCES 18.
14:557–563.
Semple D, Findlow D, Aldridge LM, Doyle E. The optimal dose of
1. Mc Dowell TS, Durieux ME. Pharmacology of local anesthetics. ketamine for caudal epidural blockade in children. Anaesthesia. 1996;
In: Hemmings HC Jr, Hopkins PM, editors. Foundations of Anesthesia: 51:1170–1172.
19. Panjabi N, Prakash S, Gupta P, Gogia AR. Efficacy of three doses of 43. Luz G, Innerhofer P, Oswald E, et al. Comparison of clonidine 1 mg kg–1
ketamine with bupivacaine for caudal analgesia in pediatric inguinal with morphine 30 mg kg–1 for postoperative caudal analgesia in children.
herniotomy. Reg Anesth Pain Med. 2004;29:28–31. Eur J Anaesthesiol. 1999;16:42–46.
20. Marhofer P, Krenn CG, Plöchl W, et al. S(+)-ketamine for caudal block in 44. Klimscha W, Chiari A, Michalek-Sauberer A, et al. The efficacy and safety
paediatric anaesthesia. Br J Anaesth. 2000;84:341–345. of a clonidine/bupivacaine combination in caudal blockade for pediatric
21. De Negri P, Ivani G, Visconti C, de Vivo P. How to prolong post- hernia repair. Anesth Analg. 1998;86:54–61.
operative analgesia after caudal anaesthesia with ropivacaine in children: 45. Constant I, Gall O, Gouyet L, et al. Addition of clonidine or fentanyl to
S-ketamine versus clonidine. Paediatr Anaesth. 2001;11:679–683 local anaesthetics prolongs the duration of surgical analgesia after single
22. Martindale SJ, Dix P, Stoddart PA. Double-blind randomized controlled shot caudal block in children. Br J Anaesth. 1998;80:294–298.
trial of caudal versus intravenous S(+)-ketamine for supplementation of 46. Ivani G, Mattioli G, Rega M, et al. Clonidine-mepivacaine mixture vs.
caudal analgesia in children. Br J Anaesth. 2004;92:344–347. plain mepivacaine in paediatric surgery. Paediatr Anaesth. 1996;6:
23. De Negri P, Ivani G, Visconti C, et al. Caudal S(+)-ketamine with 0.1% 111–114.
ropivacaine in children: evaluation of postoperative analgesia. Paediatr 47. Ivani G, De Negri P, Conio A, et al. Ropivacaine-clonidine combination
Anaesth. 2001;11:755–756. for caudal blockade in children. Acta Anaesthesiol Scand. 2000;44:
24. Hager H, Marhofer P, Sitzwohl C, et al. Caudal clonidine prolongs 446–449.
analgesia from caudal S(+)-ketamine in children. Anesth Analg. 2002; 48. Akbas M, Akbas H, Yegin A, et al. Comparison of the effects of clonidine
94:1169–1172. and ketamine added to ropivacaine on stress hormone levels and the
25. Passariello M, Almenrader N, Canneti A, et al. Caudal analgesia in duration of caudal analgesia. Paediatr Anaesth. 2005;15:580–585.
children: S(+)-ketamine vs S(+)-ketamine plus clonidine. Paediatr Anaesth. 49. Vetter TR, Carvallo D, Johnson JL, et al. A comparison of single-dose
2004;14:851–855. caudal clonidine, morphine, or hydromorphone combined with ropi-
26. Locatelli BG, Frawley G, Spotti A, et al. Analgesic effectiveness of caudal vacaine in pediatric patients undergoing ureteral reimplantation. Anesth
levobupivacaine and ketamine. Br J Anaesth. 2008;100:701–706. Analg. 2007;104:1356–1363.
27. Botgbjerg FM, Svensson BA, Frigast C, et al. Histopathology after 50. Motsch J, Böttiger BW, Bach A, et al. Caudal clonidine and bupivacaine
repeated intrathecal injections of preservative-free ketamine in the rabbit: for combined epidural and general anaesthesia in children. Acta Anaes-
a light and electron microscopic examination. Anesth Analg. 1994;79: thesiol Scand. 1997;41:877–883.
105–111. 51. De Mey JC, Strobbet J, Poelaert J, et al. The influence of sufentanil and/
28. Brock-Utne JG, Kallichurum S, Mankowitz E, et al. Intrathecal ketamine or clonidine on the duration of analgesia after a caudal block for hypospa-
with preservative—histological effects on spinal nerve roots of baboons. dias repair surgery in children. Eur J Anaesthesiol. 2000;17:379–382.
S Afr Med J. 1982;61:440–441. 52. Sharpe P, Klein JR, Thompson JP, et al. Analgesia for circumcision in a
29. Ikonomidov C, Bosch F, Miksa M, et al. Blockage of NMDA receptors paediatric population: comparison of caudal bupivacaine alone with
and apoptotic neurodegeneration in the developing brains. Science. 1999; bupivacaine plus two doses of clonidine. Paediatr Anaesth. 2001;11:
283:70–74. 695–700.
30. Vranken J, Troost D, Wegener J, et al. Neuropathological findings after 53. Joshi W, Connelly NR, Freeman K, Reuben SS. Analgesic effect of
continuous intrathecal administration of S(+) ketamine for the manage- clonidine added to bupivacaine 0.125% in paediatric caudal blockade.
ment of neuropathic cancer pain. Pain. 2005;117:231–235. Paediatr Anaesth. 2004;14:483–486.
31. Stotz M, Oehen HP, Gerber H. Histological findings after long term 54. Aantaa R, Scheinin M. Alpha2-adrenergic agents in anaesthesia. Acta
infusion of intrathecal ketamine for chronic pain: a case report. J Pain Anaesthesiol Scand. 1993;37:433–438.
Symptom Manage. 1999;18:223–228. 55. De Kock M, Versailles H, Colinet B, et al. Epidemiology of the adverse
32. Lu LX, Yan JH, Carter LB, Jevtovic-Todorovic V. General anaesthesia hemodynamic events occurring during “clonidine anesthesia”: a pro-
activates BDNF-dependent neuroapoptosis in the developing rat brain. spective open trial of intraoperative intravenous clonidine. J Clin Anesth.
Apoptosis. 2006;11:1603–1615. 1995;7:403–410.
33. Fredriksson A, Ponten E, Gordh T, Eriksson P. Neonatal exposure to a 56. Breschan C, Krumpholz R, Likar R, et al. Can a dose of 2 μg kg–1 caudal
combination of N-methyl-D-aspartate and gamma-amino butyric acid clonidine cause respiratory depression in neonates? Paediatr Anaesth.
type A receptor anaesthetic agents potentiates apoptotic neurodegener- 1999;9:81–83.
ation and persistent behavioural deficits. Anesthesiology. 2007;107: 57. Fellmann C, Gerber AC, Weiss M. Apnoea in a former preterm infant
427–436. after caudal bupivacaine with clonidine for inguinal herniorrhaphy.
34. Kim J, Yao A, Atherley R, et al. Neurons in the ventral spinal cord are Paediatr Anaesth. 2002;12:637–640.
more depressed by isoflurane, halothane and propofol than neurons in 58. Bouchut J-C, Dubois R, Godard J. Clonidine in preterm-infant caudal
the dorsal spinal cord. Anesth Analg. 2007;105:1020–1026. anesthesia may be responsible for postoperative apnea. Reg Anesth Pain
35. Johnson SA, Young C, Olney JW. Isoflurane induced neuro apoptosis in Med. 2001;26:83–85.
the developing brain of non hypoglycemic mice. J Neurosurg Anesthesiol. 59. Rochette A, Raux O, Troncin R, et al. Clonidine prolongs spinal anesthesia
2008;20:21–28. in newborns: a prospective dose-ranging study. Anesth Analg. 2004;98:
36. McGowan FX, Davis PJ. Anaesthetic-related neurotoxicity in the devel- 56–59.
oping infant of mice, rats, monkeys and, possibly humans. Anesth Analg. 60. Wang JK, Nauss LA, Thomas JE. Pain relief by intrathecally applied
2008;106:1599–1602. morphine in man. Anesthesiology. 1979;50:149–151.
37. Gaumann DM, Brunet PC, Jirounek P. Hyperpolarizing afterpotentials in 61. Hamber EA, Viscomi CM. Intrathecal lipophilic opioids as adjuncts to
C fibres and local anesthetic effects of clonidine and lidocaine. surgical spinal anesthesia. Reg Anesth Pain Med. 1999;24:255–263.
Pharmacology. 1994;48:21–29. 62. Schneider SP, Eckert WA, Light AR: Opioid activated postsynaptic, inward
38. Guyenet PG, Cabot JB. Inhibition of sympathetic preganglionic neurons rectifying potassium currents in whole cell recordings in substantia
by catecholamines and clonidine: mediation by an adrenergic receptor. gelatinosa neurons. J Neurophysiol. 1998;80:2954–2962.
J Neurosci. 1981;1:908–917. 63. Jensen BH. Caudal block for postoperative pain relief in children after
39. Potts AL, Larsson P, Eksborg S, et al. Clonidine disposition in children; a genital operations. A comparison between bupivacaine and morphine.
population analysis. Paediatr Anaesth. 2007;17:924–933. Acta Anaesthesiol Scand. 1981;25:373–375.
40. Bonnet F, Marret E, Vaselis RA. Anesthetic adjuvants and other CNS 64. Krane EJ, Jacobsen LE, Lynn AM, et al. Caudal morphine for post-
drugs. In: Hemmings HC Jr, Hopkins PM, editors. Foundations of operative analgesia in children: a comparison with caudal bupivacaine
Anesthesia: Basic Sciences for Clinical Practice. 2nd ed. Mosby/Elsevier; and intravenous morphine. Anesth Analg. 1987;66:647–653.
Philadephia, PA; 2006. pp. 337–347. 65. Krane EJ, Tyler DC, Jacobsen LE. The dose response of caudal morphine
41. Lee JJ, Rubin AP. Comparison of a bupivacaine-clonidine mixture with in children. Anesthesiology. 1989;71:48–52.
plain bupivacaine for caudal analgesia in children. Br J Anaesth. 1994; 66. Marco Valls J, Mabrok MM, Arques Teixidor P, et al. Postoperative anal-
72:258–262. gesia using caudal morphine in pediatric surgery: randomized double-
42. Jamali S, Monin S, Begon C, et al. Clonidine in pediatric caudal anes- blind study compared with bupivacaine. Rev Esp Anestesiol Reanim.
thesia. Anesth Analg. 1994;78:663–666. 1989;36:88–92.
67. Wolf AR, Hughes D, Wade A, et al. Postoperative analgesia after paediatric 91. Campbell FA, Yentis SM, Fear DW, Bissonnette B. Analgesic efficacy and
orchidopexy: evaluation of a bupivacaine-morphine mixture. Br J Anaesth. safety of a caudal bupivacaine-fentanyl mixture in children. Can J
1990;64:430–435. Anaesth. 1992;39:661–664.
68. Valley RD, Bailey AG. Caudal morphine for postoperative analgesia 92. Gaitinin LA, Somri M, Vaida SJ, et al. Does the addition of fentanyl to
in infants and children: a report of 138 cases. Anesth Analg. 1991;72: bupivacaine in caudal epidural block have an effect on the plasma level
120–124. of catecholamines in children? Anesth Analg. 2000;90:1029–1033.
69. Gülec S, Büyükkidan B, Oral N, et al. Comparison of caudal bupiva- 93. Baris S, Karakaya D, Kelsaka E, et al. Comparison of fentanyl-
caine, bupivacaine-morphine and bupivacaine-midazolam mixtures bupivacaine or midazolam-bupivacaine mixtures with plain bupivacaine
for post-operative analgesia in children. Eur J Anaesthesiol. 1998;15: for caudal anaesthesia in children. Paediatr Anaesth. 2003;13:126–131.
161–165. 94. Batra YK, Lokesh VC, Panda NB, et al. Dose response study of
70. Mayhew JF, Brodsky RC, Blakey D, Petersen W. Low dose caudal mor- intrathecal fentanyl added to bupivacaine in infants undergoing lower
phine for postoperative analgesia in infants and children: a case report of abdominal and urologic surgery. Paediatr Anaesth. 2008;18:613–619.
500 cases. J Clin Anesth. 1995;7:640–642. 95. Kelleher AA, Black A, Penman S, Howard R. Comparison of caudal
71. Rosen KR, Rosen DA. Caudal epidural morphine for the control of bupivacaine and diamorphine with caudal bupivacaine alone for repair
pain following open-heart surgery in children. Anesthesiology. 1989;70: of hypospadias. Br J Anaesth. 1996;77:586–590.
418–421. 96. Prakash S, Tyagi R, Gogia AR, et al. Efficacy of three doses of tramadol
72. Teyin E, Derbent A, Balcioglu T, Cokmez B. The efficacy of caudal with bupivacaine for caudal analgesia in paediatric inguinal herniotomy.
morphine or bupivacaine combined with general anesthesia on post- Br J Anaesth. 2006;97:385–388.
operative pain and neuroendocrine stress response in children. Paediatr 97. Ozkan S, Poçan S, Bahar A, et al. The effect of caudal bupivacaine versus
Anaesth. 2006;16:290–296. tramadol in post-operative analgesia for paediatric patients. J Int Med
73. Castillo-Zamora C, Castillo-Peralta LA, Nava-Ocampo AA. Dose Res. 2003;31:497–502.
minimization study of single-dose epidural morphine in patients 98. Senel AC, Akyol A, Dohman D, Solak M. Caudal bupivacaine-tramadol
undergoing hip surgery under regional anesthesia with bupivacaine. combination for postoperative analgesia in pediatric herniorrhaphy.
Paediatr Anaesth. 2005;15:29–36. Acta Anaesthesiol Scand. 2001;45:786–789.
74. Lönnqvist PA. Adjuncts to caudal block in children—quo vadis? Br J 99. Gunduz M, Ozcengiz D, Ozbek H, Isik G. A comparison of single dose
Anaesth. 2005;95:431–433. caudal tramadol, tramadol plus bupivacaine and bupivacaine adminis-
75. Gall O, Aubineau JV, Berniere J, et al. Analgesic effect of low-dose tration for postoperative analgesia in children. Paediatr Anaesth. 2001;
intrathecal morphine after spinal fusion in children. Anesthesiology. 11:323–326.
2001;94:447–452. 100. Prosser DP, Davis A, Booker PD, Murray A. Caudal tramadol for post-
76. Dalens B, Tanguy A. Intrathecal morphine for spinal fusion in children. operative analgesia in paediatric hypospadias surgery. Br J Anaesth.
Spine. 1988;13:494–498. 1997;79:293–296.
77. Harris MM, Kahana MD, Park TS. Intrathecal morphine for postoperative 101. Murthy BVS, Pandya KS, Booker PD, et al. Pharmacokinetics of
analgesia in children after selective dorsal root rhizotomy. Neurosurgery. tramadol in children after I.V. or caudal epidural administration. Br J
1991;28:519–522. Anaesth. 2000;84:346–349.
78. Dews TE, Schubert A, Fried A, et al. Intrathecal morphine for analgesia 102. Girotra S, Kumar S, Rajendran KM. Comparison of caudal morphine
in children undergoing selective dorsal rhizotomy. J Pain Symptom and buprenorphine for postoperative analgesia in children. Eur J
Manage. 1996;11:188–181. Anaesth. 1993;10:309–312.
79. Suominen PK, Ragg PG, McKinley DF, et al. Intrathecal morphine 103. Kamal RS, Khan FA. Caudal analgesia with buprenorphine for post-
provides effective and safe analgesia in children after cardiac surgery. Acta operative pain relief in children. Paediatr Anaesth. 1995;5:101–106.
Anaesthesiol Scand. 2004;48:875–882. 104. Singh V, Kanaujia A, Singh GP. Efficacy of caudal butorphanol. Indian J
80. Tobias JD, Mateo C, Ferrer MJ, et al. Intrathecal morphine for post- Pediatr. 2006;73:147–150.
operative analgesia following repair of frontal encephaloceles in children: 105. Naguib M, El Gammer M, Elhattab YS, Seraj M. Midazolam for caudal
comparison with intermittent, on demand dosing of nalbuphine. J Clin analgesia in children: comparison with caudal bupivacaine. Can J
Anesth. 1997;9:280–284. Anaesth. 1995;42:758–764.
81. Meignier M, Ganansia MF, Lejus C, Testa S. Intrathecal morphine therapy 106. Mahajan R, Batra YK, Grover VK, Kajal J. A comparative study of caudal
in children with cancer. Cah Anesthesiol. 1992;40:487–490. bupivacaine and midazolam-bupivacaine mixture for post-operative
82. Galloway K, Staats PS, Bowers DC. Intrathecal analgesia for children with analgesia in children undergoing genitourinary surgery. Int J Clin
cancer via implanted infusion pumps. Med Pediatr Oncol. 2000;34: Pharmacol Ther. 2001;39:116–120.
265–267. 107. Kumar P, Rudra A, Pan AK, Acharya A. Caudal additives in pediatrics:
83. Jones SE, Beasley JM, Macfarlane DW, et al. Intrathecal morphine for a comparison among midazolam, ketamine, and neostigmine coadmin-
postoperative pain relief in children. Br J Anaesth. 1984;56:137–140. istered with bupivacaine. Anesth Analg. 2005;101:69–73.
84. Ganesh A, Kim A, Casale P, Cucchiaro G. Low-dose intrathecal mor- 108. Yaksh TL, Dirksen R, Harty GJ. Antinociceptive effects of intrathecally
phine for postoperative analgesia in children. Anesth Analg. 2007;104: injected cholinomimetic drugs in the rat and cat. Eur J Pharmacol. 1985;
217–276. 117:81–88.
85. Shapiro A, Zohar E, Zaslansky R, et al. The frequency and timing of 109. Abdulatif M, El-Sanabary M. Caudal neostigmine, bupivacaine, and
respiratory depression in 1524 postoperative patients treated with their combination for postoperative pain management after hypospadias
systemic or neuraxial morphine. J Clin Anesth. 2005;17:537–542. surgery in children. Anesth Analg. 2002;95:1215–1218.
86. Larman J, Nolan J, Eyres R, et al. Efficacy, safety, and pharmacokinetics of 110. Almenrader N, Passariello M, D’Amico G, et al. Caudal additives for
levobupivacaine with and without fentanyl after continuous epidural postoperative pain management in children: S(+)-ketamine and
infusion in children: a multicenter trial. Anesthesiology. 2003;99: neostigmine. Paediatr Anaesth. 2005;15:143–147.
1166–1174. 111. Batra YK, Arya VK, Mahajan R, Chari P. Dose response study of caudal
87. Ginosar Y, Reley ET, Angst MS. The site of action of epidural fentanyl in neostigmine for postoperative analgesia in paediatric patients under-
humans: the difference between infusion and bolus administration. going genitourinary surgery. Paediatr Anaesth. 2003;13:515–521.
Anesth Analg. 2003;97:1428–1438. 112. Mahajan R, Grover VK, Chari P. Caudal neostigmine with bupivacaine
88. Coda BA, Brown MC, Schaffer R, et al: Pharmacology of epidural produces a dose-independent analgesic effect in children. Can J Anaesth.
fentanyl, alfentanil, and sufentanil in volunteers. Anesthesiology. 1994;81: 2004;51:702–706.
1149–1161. 113. Kaabachi O, Zerelli Z, Methamem M, et al. Clonidine administered
89. Gharsallah A, Atallah T, Hmouda H, et al. Evaluation of 2 dosages of as adjuvant for bupivacaine in ilioinguinal-iliohypogastric nerve block
fentanyl in caudal anesthesia: a prospective randomized double-blind does not prolong postoperative analgesia. Paediatr Anaesth. 2005;15:
study. Cah Anesthesiol. 1996;44:419–421. 586–590.
90. Joshi W, Connelly NR, Dwyer M, et al. A comparison of two con- 114. Cucchiaro G, Ganesh A. The effects of clonidine on postoperative anal-
centrations of bupivacaine and adrenaline with and without fentanyl in gesia after peripheral nerve blockade in children. Anesth Analg. 2007;
paediatric inguinal herniorrhaphy. Paediatr Anaesth. 1999;9:317–320. 104:532–537.
115. Giannoni C, White S, Enneking FK, Morey T. Ropivacaine with or 117. Walker SM. Pain in children: recent advances and ongoing challenges. Br
without clonidine improves pediatric tonsillectomy pain. Arch Otolaryn- J Anaesth. 2008;101:101–110.
gol Head Neck Surg. 2001;127:1265–1270. 118. Brown K. Catalyst: The Medical Memoirs of a World Anaesthe-
116. Ivani G, Conio A, De Negri P, et al. Spinal vs peripheral effects of adjunct tist. Melbourne, Australia: Bolga Publishing House Pty Ltd; 2004.
clonidine: comparison of the analgesic effect of a ropivacaine-clonidine p. 132.
mixture when administered as a caudal or ilioinguinal-iliohypogastric 119. Broadman LM, Rice LJ, Hannallah RS. Testing the validity of an
nerve blockade for inguinal surgery in children. Paediatr Anaesth. 2002; objective pain scale for infants and children. Anesthesiology. 1988;69:
12:680–684. A770.
Pharmacology of Premedication
and Sedative Agents in Children 30
George A. Chalkiadis C H A P T E R
INTRODUCTION Pharmacokinetics
Several advances since the early 1990s have changed the INTRANASAL: Peak plasma concentration (peak CP) (mean [sd]
requirements for premedication. These include the introduction of 72.2 [27.3] ng/mL) occurred in a mean time of 10.2 minutes (sd
technologies for topical anesthesia before intravenous (I.V.) can- 2.0) after 0.1 mg/kg intranasal midazolam2 and 12 minutes after
nulation and child-friendly anesthesia induction and treatment 0.2 mg/kg. Bioavailability was 0.55.3
rooms, the recognition that play, distraction, and positioning for ORAL: Adolescents absorb oral midazolam more slowly than
comfort are effective, and allowing parents to accompany the child children aged 2 to 12 years.4 Peak CP occurred 30 to 60 minutes
into the induction or treatment room in many hospitals. In addi- after oral administration in children younger than 12 years.5,6
tion, antisialagogue and anticholinergic premedication to dry Bioavailability was 0.27 to 0.36 after oral midazolam administra-
secretions and prevent bradycardia and hypotension is no longer tion as a result of first-pass metabolism that is avoided with buccal
necessary with modern anesthetic agents. Routine rectal and administration.5,7,8 Buccal midazolam has a mean time to clinical
intramuscular (I.M.) premedication would be considered unac- response of 5 minutes in children with prolonged seizures.9
ceptable in many hospitals today. Premedication drugs are still
necessary to allay anxiety and to facilitate induction of anesthesia RECTAL: After 0.35 mg/kg and 0.5 mg/kg rectal midazolam, mean
in the uncooperative or fearful child, with the aim of avoiding peak CP (71 ng/mL and 246 ng/mL) were observed after 7.5 and
forceful restraint. 12.5 minutes, respectively. After 2 hours, the mean CP after
Many early premedication studies suffered from methodologic 0.5 mg/kg was 120 ng/mL.10
problems including the absence of randomization, insufficient Midazolam is hydroxylated (by cytochrome P450 [CYP]3A4)
power, variable drug administration times, multiple drug admini- in the liver to its less active metabolites, 1- and 4-OH midazolam;
stration, and lack of control groups or statistical analysis. Few the former is more important quantitatively and contributes
studies identified the time interval to peak effect of any given clinically to midazolam’s sedative effects.6 Both are glucuronidated
premedicant with the result that drugs may have been investigated and excreted in the urine.11
before, during, or after their peak sedative effect. Midazolam pharmacokinetics (PK) can be highly variable in
Interestingly, problems with premedication that plague the children, especially if they require extracorporeal membrane
modern-day anesthetist such as paradoxical excitation preopera- oxygenation (ECMO), intensive care, or prolonged sedation or
tively and postoperatively were significant problems even with have undergone major fluid shifts.12–14 Its clearance (CL) is reduced
what we would regard as heavy-handed polypharmacy that was in preterm infants, with prolongation of elimination half-life
practiced in earlier years. (T / ) and reduced 1-OH midazolam CP consequent to immature
1
2
CYP3A4 activity. CL increases when corrected for weight between

1 and 2 years of age (0.78 L/kg/h) and then declines exponentially
BENZODIAZEPINES with body weight to adult values (0.38–0.66 L/kg/h).6 Elimination
The benzodiazepines (BZs) are lipid-soluble molecules that exert t / was reported to be 0.5 to 3.5 hours and is age-dependent.3–6
1
2
their anxiolytic, sedative, and amnestic actions by binding to the

gamma-aminobutyric acid (GABA)–BZ receptor complex. Pharmacodynamics
Midazolam plasma concentrations correlate with clinical effect.
Midazolam When both midazolam and 1-OH midazolam concentrations are
included, the sedation score can be predicted in 86% of children.6
Midazolam first synthesized in 1976, is water-soluble in an acidic Sedation and anxiolysis were maximal 20 minutes after intranasal
aqueous solution, and is highly lipid-soluble at physiologic pH. In administration and 30 minutes after oral, sublingual, and rectal
some markets, midazolam is available in a tablet form. The paren- administration consistent with the PK data just discussed.1,15 Seda-
teral preparation is often administered via the oral, intranasal, tion after intranasal midazolam was evident within 5 minutes.16
buccal, rectal, and I.M. routes. This preparation tastes bitter, and In a review of the published literature (1995–2006), oral mida-
its nasal administration is very irritating. Although 77% of child- zolam 0.5 mg/kg reduced separation anxiety and distress at induc-
ren cried after oral, sublingual, intranasal, or rectal midazolam tion of anesthesia. Recovery times were not significantly delayed.
administration, 75% accepted the face mask for induction of There was no consistent evidence suggesting reduced emergence
anesthesia well after this premedicant.1 agitation. An oral dose of 0.5 mg/kg midazolam 20 to 30 minutes
before surgery was recommended. Higher doses results in ataxia Lorazepam

and prolonged sedation.17
Two hours after 0.3 mg/kg rectal midazolam, 72% of children Lorazepam, a 2’chloro-substitution product of oxazepam, was
were considered to be sedated.18 A recent review on procedural synthesized in 1971. It is less lipid-soluble than diazepam and
sedation stated that the duration of oral midazolam is 60 to midazolam. This results in a longer onset time and duration of
90 minutes.19 This highlights an important point that relates to action. Profound amnesia occurs. Lorazepam is well absorbed
duration of action. Absence of full recovery equates to some orally and is conjugated in the liver to its inactive glucuronide and
sedation, but this does not reflect the duration of maximal (and excreted in the urine. Its elimination T / is 10 to 14 hours.11
1
2
optimal) sedation. When the time course of sedation after oral Oral lorazepam 0.05 mg/kg was palatable and produced a che-
midazolam was investigated, 85% and 96% were satisfactorily erful demeanor preoperatively but was associated with restless-
sedated at 15 and 30 minutes, respectively. A steady and rapid ness, vomiting, and retrograde amnesia postoperatively.31 Oral
decline was then observed such that 66% and 60% were sedated at lorazepam 0.025 mg/kg the night before reconstructive burns
45 and 60 minutes, respectively.20 surgery in children resulted in less self-reported perioperative
Paradoxical excitation occurs in some children soon after in- anxiety.32 In a dose-finding study in children undergoing lumbar
gestion or at emergence. Flumazenil reduces emergence agitation puncture or bone marrow aspiration, premedication with oral
and the time to discharge.21 With increasing dose, delayed emer- lorazepam 0.02 to 0.09 mg/kg produced adequate sedation for the
gence from anesthesia is more likely.22 procedure.33
Diazepam Temazepam
Diazepam was synthesized in 1959. It is a highly lipophilic, lipid- Temazepam is rapidly absorbed from the gastrointestinal tract.
soluble (but not water-soluble) BZ. Diazepam is available as a Mean time to peak CP is 1.4 hours in adults. It is metabolized
tablet, an oral elixir, an I.V. lipid emulsion, and a clear fluid in principally in the liver to temazepam glucuronide and excreted in
propylene glycol and alcohol. Less than half of children older than the urine. A small amount is demethylated to oxazepam and
4 years administered crushed diazepam tablets in raspberry syrup eliminated as the glucuronide. The metabolites are inactive. Its
as a premedicant found it unpalatable.23 elimination T / is 10 hours.
1
2
Effective sedation was obtained in 93% of children who re-

Pharmacokinetics ceived oral temazepam 0.5 mg/kg.34 Increasing doses of tema-
Diazepam is rapidly and completely absorbed. Peak CP occurs zepam elixir 0.5, 1.0, or 1.5 mg/kg administered to children
within 2 hours after oral and within 30 minutes after rectal 90 minutes before induction of anesthesia did not demonstrate
(1 mg/kg) administration.24 Diazepam is metabolized in the liver any clinical benefit. The sedation obtained was similar to that from
by N-demethylation to its active metabolite desmethyldiazepam trimeprazine 3 mg/kg. Although more children receiving trime-
and by C-3-hydroxylation to N-methyloxazepam. Both are in turn prazine 4 mg/kg were either asleep or sedated compared with
metabolized to oxazepam, which is conjugated with glucuronide those who received temazepam 1 mg/kg, no difference was obser-
and excreted in the urine. Both diazepam and desmethyldiazepam ved in response to behavior during induction of anesthesia when
are metabolized slowly, accounting for diazepam’s long elimination a parent accompanied the child. Recovery time was 1 hour shorter
T / (20–50 h) and low CL (0.2–0.5 mL/kg/min). Its distribution T /
1
2
1
2
in those who received temazepam.35
is 30 to 40 minutes, explaining its shorter duration of action.11
There was no relationship between diazepam CP and recall at
induction in children.25 KETAMINE
The first clinical trials that investigated the utility of ketamine, an
Pharmacodynamics N-methyl-D-aspartate (NMDA) receptor antagonist, were con-
ducted in 1965. Its main advantages were its wide margin of safety,
ORAL: Oral diazepam 0.25 mg/kg administered to children older hemodynamic stability, and the preservation of airway reflexes
than 4 years a mean time of 84 minutes (sd 36) before the induc- while producing a dissociative state and analgesia. Vivid dreams
tion of anesthesia without a parent present was no better than and hallucinations that were thought to be less marked in young
placebo, midazolam, or alprazolam with regards to preoperative children were problematic at emergence.
anxiolysis or behavior at induction.23 When the same dose was Various formulations of racemic ketamine exist including a
given 2 hours prior, one third of children were assessed to have transmucosal lollipop, an oral elixir, and a lozenge.36,37 The paren-
unsatisfactory induction of anesthesia.26 Doubling the dose teral preparation was mixed with a sweet syrup in most studies to
(0.5 mg/kg) resulted in over 90% of children rated to have a disguise its unpleasant taste. A preservative-free formulation of
satisfactory reaction to induction.27 In other studies, oral diazepam S(+) ketamine that has approximately twice the potency of the
0.3 mg/kg sedated children but did not ease induction of anes- racemate has superseded the racemic preparation in Europe.38 The
thesia28 and 0.5 mg/kg 1 hour before induction of anesthesia S(+) enantiomer is four times more potent than R(–) ketamine
resulted in most children being asleep or awake and calm at induc- while exhibiting less of the psychomimetic effects attributed to the
tion, but was no more effective than placebo.29 Oral diazepam R(–) enantiomer.
before I.V. ketamine sedation for bone marrow aspiration resulted
in fewer bad dreams and more gradual onset and offset of sleep.30
RECTAL: Rectal diazepam 0.5 mg/kg produced sedation in 86% of
Pharmacokinetics
children on arrival at the operating room and 65% underwent Ketamine is metabolized mainly by N-demethylation to its less-
smooth induction. active metabolite norketamine, a process mediated by the CYP3A4
CHAPTER 30 ■ Pharmacology of Premedication and Sedative Agents in Children 493
isoenzyme. Norketamine is subsequently hydroxylated to hydro- Intranasal

xynorketamine, conjugated, and then excreted in urine. Peak Intranasal ketamine 6 mg/kg 20 to 40 minutes before induction
norketamine CP is reached 1 hour after I.V. administration. Norke- was more effective than the combination of I.M. pethidine
tamine has a shorter elimination T / (1.1 h) than ketamine.39
1
2
1 mg/kg and promethazine 1 mg/kg and facilitated acceptance of
A two-compartment model best describes ketamine elimina- the facemask for inhalational induction in 78% of children.51
tion. After I.V. bolus administration (1–1.5 mg/kg) in children,
almost all had a CP greater than 0.1 mg/L after 10 minutes, a level
associated with analgesia in adults. CL was estimated at 90 L/h/ Intramuscular
70 kg.40 I.M. ketamine 2 mg/kg was rapidly effective (mean time 2.7 min)
In adults, distribution T / is relatively slow (11–16 min). Keta-
1
2 facilitating facemask acceptance in all children who were initially
mine is very lipid-soluble, resulting in a large volume of distri- uncooperative.52 Ketamine I.M. 2 to 3 mg/kg, produced rapid
bution (3.1 L/kg). CL is high, accounting for ketamine’s short sedation (within 16 min). After 5 mg/kg intramuscularly, 82% of
elimination T / (2–3 h).41 Bioavailability by the oral and I.M. routes
1
2 children were asleep and 15% separated calmly from their parents,
was 0.16 and 0.93, respectively.42 In children, ketamine CP were and 3% required restraint subsequently for facemask application
similar to those reported in adults except at later times. Absorption and insertion of an I.V. cannula.53
after I.M. injection was more rapid in children and larger con-
centrations of norketamine were detected, suggesting that CL may
be greater in children when expressed as L/h/kg.43 Rectal
After 3 or 9 mg/kg intranasal administration in children, mean Rectal ketamine produced dose-dependent sedation after
peak CP of 496 ng/mL and 2104 ng/mL were observed after 20 and 45 minutes, with 10 mg/kg facilitating separation from parents in
21 minutes, respectively. Bioavailabilty was 0.5.44 88% compared with 31% of those who received either 5 or 7 mg/
After 9 mg/kg rectal administration in children, a mean peak kg. None receiving the higher dose required restraint with face-
CP of 632 ng/mL occurred after 42 minutes. Bioavailability was mask application, but time to spontaneous eye opening after the
0.25. Norketamine concentrations peaked earlier and were higher cessation of anesthesia was prolonged.22 S(+) Ketamine 1.5 mg/
than after intranasal administration of the same dose, reflecting kg administered rectally resulted in only 30% of children being
greater first-pass metabolism when ketamine is administered per tired or asleep after 20 minutes and 25% showed prolonged
rectum.44 excitation at the time of facemask application during inhalational
induction.15
Pharmacodynamics
Ketamine for Sedation and Analgesia
In an early study of nine children, plasma concentrations in child-
ren on awakening (0.8–4.0 μg/mL) were higher than those found Oral
in adults.43 A more recent study in 43 children demonstrated an Oral ketamine 10 mg/kg provided good analgesia and sedation for
arousal median effective dose (EC50) of 0.52 mg/L, similar to that 90% of children undergoing bone marrow aspiration and lumbar
for the ability to recall, suggesting that amnesia for events ceases puncture. After 30 and 45 minutes, 77% and 87% of children were
as the child wakes. Using the Children’s Hospital of Wisconsin sedated, respectively. There was little improvement in sedation
Sedation Scale, a CP of 1 mg/mL was associated with a sedation beyond 45 minutes. Discharge within 2 hours occurred in 59%,
level of 3 or less (arouses to consciousness with moderate tactile or with the remainder needing up to 4 hours to recover.54
loud verbal stimulus) in 95% of children, whereas 1.5 mg/mL was
associated with a sedation score of 2 or less (rouses slowly to
consciousness with sustained painful stimulus) in 95% of child- Intravenous
ren.45 Following the administration of 3 and 6 mg/kg of oral I.V. ketamine 1 or 1.5 mg/kg was used for sedation in the emer-
ketamine, 17% and 9% were able to recall facemask application gency department (ED) setting to facilitate fracture manipulation
for inhalation induction in one study,46 and 58% and 22% in and laceration repair. Plasma concentrations associated with
another,47 respectively. Administered intravenously, anesthesia is arousal occurred 10 minutes after the lower and 15 minutes after
achieved within 30 seconds and maximal effectiveness occurs the higher dose.45 The dose required for sedation decreases with
within 1 minute after rapid I.V. administration of 2 mg/kg. This is increasing age. A smaller initial bolus with a subsequent half-dose
consistent with an equilibration T / of 11 seconds found in
1
2 top-up at 8 minutes achieved the same sedation level with earlier
children.48 recovery.48
Ketamine for Premedication Intramuscular

I.M. ketamine 2 or 2.5 mg/kg was used for sedation after analgesia
Oral and distraction techniques had failed in children undergoing
Oral ketamine (6 mg/kg) produced effective sedation in most minor procedures in an ED. A supplemental dose of 1 mg/kg was
children. In children with autism, 7 mg/kg was administered needed in 5%.55 All children who received 4.5 mg/kg or greater
30 minutes before induction of anesthesia with good effect in were adequately sedated for ED procedures.56 Children receiving
86%. The mean time spent in the recovery room was 42 minutes I.M. ketamine 4 mg/kg for orthopedic procedures reported less
and the mean time to hospital discharge was 158 minutes.49 pain, and observers less distress, than those receiving I.V. ketamine
Increasing the dose from 4 to 8 mg/kg or from 3 to 6 mg/kg 1 mg/kg; however, the longer recovery times (median 129 min
afforded faster onset and less distress with parental separation, I.V. vs 80 min) in the I.M. group led to the premature termination of
cannulation, and facemask application.47,50 the study.57
Intranasal TABLE 30-1. Ketamine Characteristics

Intranasal ketamine 3 mg/kg provided adequate sedation for Sedation is dose dependent.
dental procedures in children.58 Time to maximal sedation is variable after oral administration.
Dose- and possibly route-dependent vomiting, nystamus, There is a small but significant incidence of acute disorientation
hallucinations, excessive oral secretions, and tongue fasciculation in the first 20 min after oral ketamine administration.
are common.46,47,50 A small number of children experienced severe Onset is faster with reduced likelihood of disorientation when
disorientation and hallucinations 10 to 20 minutes after oral keta- oral midazolam is co-administered with oral ketamine.
mine 6 mg/kg.59,60 Hallucinations were reported in 12% of children Intramuscular and intravenous administration result in rapid
after 1 mg/kg intravenously but not after 3 mg/kg oral or rectal onset of sedation.
administration.61 Less-frequent adverse effects include airway Recovery times are longer with increasing dose.
obstruction, respiratory depression, rash, and laryngospasm that Failure to achieve adequate sedation is more common with
in the ED setting are less common after ketamine than after mida- lower doses.
zolam and fentanyl combinations.55,62 Emergence reactions were Side effects including nystagmus and vomiting are dose-
not observed in children receiving nasal ketamine 6 mg/kg. dependent.
Salivation was copious in 12% of children, similar to the control
group.51 Whereas nystagmus was frequently observed after I.M.
ketamine 2 mg/kg, salivation and emergence reactions were not hydrate is detectable for several hours after the single administra-
observed.47,52 After intranasal S(+) ketamine 1 to 2 mg/kg, exces- tion of 50 mg/kg in neonates, infants, and toddlers. It is metabo-
sive salivation was not observed.16 Concerns have been raised lized to dichloroacetic acid (DCA) and trichloroethanol (TCE).
regarding the potential for ketamine to cause neuronal apoptosis TCE undergoes glucuronidation in the liver. It subsequently
in the developing brain.63 undergoes enterohepatic circulation before conversion to trich-
loroacetic acid (TCA). In adults, this results in a long elimination
T / for its inactive metabolite TCA (89–94 h),69 an effect that was
1
2
Combination Therapy more pronounced when three 500 mg doses were administered at
Oral ketamine 3 mg/kg in combination with oral midazolam 48-hour intervals.70 In neonates, infants, and children, TCA CP
0.25 mg/kg produced shorter time to parental separation and fails to decline up to 6 days after a single administration.71 Limited
recovery compared with 6 mg/kg and 0.5 mg/kg of each drug alone, data suggest that free TCE was positively correlated with serum
bilirubin, implying that individuals with impaired capacity for
respectively.64 This same drug combination in higher dose (oral
glucuronidation may be very sensitive to the central nervous
ketamine 6 mg/kg and oral midazolam 0.4 mg/kg 20–30 min before
system depressant effects of chloral hydrate that are attributed to
inhalational induction) resulted in all children aged 1.5 to 7 years
free-TCE CP.70 This has implications for neonates and young
being calm or asleep, and 85% did not struggle with facemask ap-
infants in whom glucuronidation is immature especially with
plication, whereas in the lower doses, 71% had good sedation and
repeat dosing. This risk is greatest in preterm neonates. The
79% did not require restraint during facemask application. Oral elimination T / for TCE in preterm infants (31–37 wk), full-term
1
2
ketamine 10 mg/kg in combination with oral trimeprazine 3 mg/kg neonates (38–42 wk), and infants and young children (57(708 wk)
or midazolam 1 mg/kg produced effective premedication in was 39.8 hours, 27.8 hours, and 9.7 hours, respectively.71
children with congenital heart disease.65 Conversely, oral ketamine
8 or 10 mg/kg in combination with diazepam 0.1 mg/kg provided
good conditions for dental procedures in only 28% and 44% of Pharmacodynamics
anxious preschool children, respectively.66 The addition of oral
ketamine 3 mg/kg to oral midazolam 0.5 mg/kg premedication did Onset time after oral chloral hydrate is summarized in Table
not prolong emergence after sevoflurane anesthesia.67 30–2. A recent study in which oral chloral hydrate 30 mg/kg was
administered to former preterm infants at term was terminated
Premedication before anesthesia with 2 mg/kg intranasal S(+)
early because of a significant increase in bradycardic events.72
ketamine in combination with 0.2 mg/kg midazolam was more
These were more pronounced in neonates who had a lower gesta-
effective than the same midazolam dose alone or with 1 mg/kg
tional age at birth. Increased sedation was observed up to 12 hours
S(+) ketamine in facilitating inhalational induction but not
after administration.
separation from parents, 10 minutes after its administration.16
No effect on CO2 chemoreceptor function was found 20 to
Rectal racemic ketamine 3 mg/kg or S(+) ketamine 1.5 mg/kg in 70 minutes after chloral hydrate 50 mg/kg was administered to
combination with midazolam has been used for premedication neonates and very young infants. Tidal volume fell in young
with unimpressive results.15,68 Ketamine characteristics are sum- infants (mean age 21 wk),73 and in infants recovering from bron-
marized in Table 30–1. chiolitis, arterial oxygen desaturation has been reported. In cats
and rabbits, chloral hydrate depresses genioglossus activity but not
that of the diaphragm, suggesting that upper airway obstruction
CHLORAL HYDRATE may occur, especially in children with obstructive sleep apnea and
Chloral hydrate was first synthesized in 1832 and has been used as tracheo- and laryngomalacia.74
a sedative or hypnotic since 1869. It tastes bitter.
Common Uses
Pharmacokinetics AUDIOLOGY: Middle ear pressure rises in infants and young
Chloral hydrate is rapidly absorbed from the gastrointestinal tract children with normal ears 40 to 60 minutes after chloral hydrate
after oral and rectal administration. In contrast to adults, chloral administration.75
TABLE 30-2. Onset Time After Oral Chloral Hydrate dose augmentation (mean total dose 78 mg/kg) after a mean initial
dose of 72 mg/kg. In another study, adequate sedation for MRI
Chloral Hydrate Onset Time, min, was achieved in 64% and 87% of patients receiving a mean initial
Age Dose, mg/kg mean (sd) [range] dose of 70 mg/kg and 96 mg/kg, respectively; after dose aug-
Neonates86 [9–40] mentation, adequate sedation was achieved in 92% and 100%,
Infants85 50 16 (11) respectively.80
Infants (mean 50–100 23.5 (13.4) Failure after chloral hydrate administration for sedation for
age 4.9 mo)84 MRI scanning is least likely in children aged younger than 1 year,83
Mean age 13.3 mo 75–100 25 (4.7) [5–50] although figures vary.81 Over half of children aged 1 to 5 years,
(sd 9.3)200 administered 80 mg/kg initially, required dose augmentation to a
Mean age 28.2 mo Mean 86.6 39.1 (20.5) total of 100 mg/kg. Scans were successfully completed in 91%.83
(sd 18.1)87 (sd 10.0) After 100 mg/kg of chloral hydrate, sedation was successful in 96%
Mean age 4.2 y Mean 71.9 28 (14) of children younger than 4 years and 81% of children older than
(sd 1.7)91 (sd 11.1) 4 years.84 Another study reported 30% failure in children older
<3 y Mean 87 25 than 5 years.83
Mean age 38 mo Mean 64 (sd 2) 28 (2) Data from published studies regarding onset time for sedation
(sd 31)80 after oral administration are summarized in Table 30–1. After oral
Mean age 38 mo Mean 93 (sd 2) 21 (1) administration, the duration of sedation was 61.2 minutes (sd
(sd 31)80 31.9)81 and 86 minutes (sd 36)85 in infants, and ranged from 5 to
Mean age 51.6 mo 50 43.8 240 minutes in neonates.86 Sedation time in children (mean age
[range 36–75] 28.2 mo [sd 18.1]) who received a mean dose of 86.6 mg/kg was
Range 0.3 mo–4.3 y196 50–100 29 (8–69) 164.5 minutes (sd 85.9).87 Recovery occurred in 80.6 minutes (sd
15.6, range 35–120) in children (mean age 13.3 mo [sd 9.3]) who
sd = standard deviation. received 75 to 100 mg/kg.82 However, resedation or prolonged or
delayed sedation has been reported. Sedation has been observed
DENTISTRY: Chloral hydrate 50 mg/kg provided sufficient seda- for up to 12 hours after 30 mg/kg oral chloral hydrate in ex–
tion in combination with nitrous oxide to perform dental proce- premature infants at term postconceptional age.72 In older infants
dures of 40 minutes’ mean duration in children aged 3 to 6 years. and children, drowsiness the day after 75 mg/kg single dosage has
been reported. Drowsiness lasted longer than 4 hours in 28% of
ELECTROENCEPHALOGRAPHY: Chloral hydrate has little effect on children who received a mean dose of 78 mg/kg, whereas normal
the background electroencephalographic activity.76 activity was resumed after 4 hours in 54%. After 50 mg/kg, 74%
MAGNETENCEPHALOGRAPHY: Chloral hydrate premedication did and 94% of infants and children (6 mo–5 y) fulfilled discharge
not suppress interictal activity and localization of ictal activity on criteria within 3 and 6 hours of administration, respectively.88
magnetencephalographic scan.77 After rectal administration of 75 mg/kg of chloral hydrate in
young children, 82% were effectively sedated within 15 minutes
OPHTHALMOLOGIC EXAMINATION: Laser photocoagulation for and 94% within 30 minutes.89 The median duration of effective
the treatment of retinopathy of prematurity in combination with sedation was 0.75 hour.89
sub-Tenon block was successful.78 Visual evoked potentials can be Adverse effects may persist for 6 hours or longer and include
reliably obtained after chloral hydrate. Chloral hydrate (100 mg/kg prolonged sedation,72,90 motor imbalance (1.6–68%).87,90 agitation
for the first 10 kg plus 50 mg/kg for each additional kg) adminis- and hyperactivity (1.4–29%),84,87,90 vomiting (1.7–15%),84,87,91 res-
tered to children younger than 6 years has no effect on intraocular piratory obstruction (2.4%),87 and depression (4%).84,87 Paradoxical
pressure in children with normal and high intraocular pressures.79 excitement before sedation was reported in 18%. In former pre-
term neonates administered 30 mg/kg orally, sedation was ob-
ECHOCARDIOGRAPHY: PREMEDICATION FOR ANESTHESIA. As a
served for up to 12 hours after its administration, resulting in
premedicant before anesthesia, 75 mg/kg provided better
reduced oral intake and more bradycardic events.72
anxiolysis than 25 or 50 mg/kg in children younger than 5 years,
whereas in children older than 5 years, all doses provided good
anxiolysis.23 Toxicity and Safety
RADIOLOGY STUDIES. Chloral hydrate has been used to provide Numerous publications report on the use of chloral hydrate in
sedation for computed tomography (CT) and magnetic resonance combination with other drugs such as hydroxyzine, promethazine,
imaging (MRI). Adequate sedation for children undergoing MRI and nitrous oxide.82 The addition of a second drug to facilitate ade-
was more likely after an initial dose of 100 mg/kg than 70 mg/kg, quate sedation after poor initial response increased the likelihood
with a faster rate of onset and no difference in the time to spon- for adverse events.92
taneous awakening and adverse outcomes.80 In an analysis of 95 case reports of adverse sedation-related
Movement in the MRI scanner occurred in 22.5% of infants events, 20 were related to chloral hydrate. Thirteen of the chloral
receiving chloral hydrate (50–100 mg/kg), with the result that the hydrate–related cases resulted in death or permanent neurologic
scan was aborted (3.9%) continued after repositioning or bundling damage and, of these, chloral hydrate was the sole sedative ad-
(5.9%) or after additional or rescue sedation (11.7%).81 An incre- ministered in 7 instances. Four patients received known overdoses,
mental approach to dosing resulted in a 97% and a 100% success 2 received an unknown amount of drug, and the last received
rate for infants undergoing MRI scans and CT scans, respectively.82 60 mg/kg orally. It was unclear from the publication whether the
The success rate for adequate sedation rose from 89% to 98% with latter had other associated significant risk factors (8 of 13 did).93
In 1095 children undergoing transthoracic echocardiography and ␣2 AGONISTS

who received chloral hydrate (38% of whom were classified
American Society of Anesthesiologists [ASA] 3 or 4), minor inter- When stimulated, α2 adrenoceptors inhibit the release of noradre-
vention was required in 7% and major intervention in 0.5%. Age naline and sympathetic activity, decrease BP and HR, and produce
younger than 6 months was the only predictor for adverse events. sedation, anxiolysis, and analgesia. They produce sedation by
Cyanosis, hospitalization, ASA class, oxygen requirement, and the binding to receptors in the locus coeruleus and analgesia by bind-
use of additional sedative medication were not. A 20% or more ing to spinal cord receptors located in the dorsal horn that are
reduction in heart rate (HR) or blood pressure (BP) was seen in present from early development.
24% and 59% of patients, respectively. Apnea has been reported
in children with congenital heart disease. Supraventricular tachy-
cardia after chloral hydrate administration has been reported in Clonidine
children receiving inotropic drugs after surgical repair of complex Clonidine is a highly lipophilic drug that was first used as an
congenital heart disease.94 After overdosage, chloral hydrate has antihypertensive agent in 1966. Its affinity for α2 adrenoceptors is
been reported to cause arrhythmias95 and severe esophageal burn 220 times that for α1 adrenoceptors.
in an 8-month-old infant.96
The majority of serious life-threatening or fatal adverse reports
after chloral hydrate administration have occurred in high-risk Pharmacokinetics
children and, one could assume, poorly monitored environments, Pooled data from five studies undertaken on children with a mean
because neither clinician supervision nor details of monitoring are age of 4 years (sd 3.6 y, range 1 wk–14 y) were combined for
provided in the case reports.97 Children receiving chloral hydrate population PK analysis. The absorption T / from the epidural
1
2
experienced fewer cardiorespiratory problems than those who space (0.98 h) was slower than that from the rectum (0.26 h). The
received either pentobarbital or propofol for MRI sedation.81 In relative bioavailability from both routes was unity. There was a lag
the absence of cardiorespiratory disease and obstructive sleep time of 2.3 minutes before absorption began in the rectum. The
apnea, and with appropriate monitoring, chloral hydrate can be
mean time to peak CP (median 0.77 ng/mL) after rectal admini-
safely administered in doses of 50 to 100 mg/kg for sedation. Table
stration of 2.5 μg/kg clonidine in children aged 14 to 48 months
30–3 summarizes chloral hydrate characteristics.
occurred at 51 minutes (range 29–70).99 CL at birth was 3.8 L/h/
70 kg and matured with a T / of 25.7 weeks to reach 82% of adult
1
2
TRICLOFOS CL by 1 year of age and is greatest between 1 and 5 years of age

using linear per-kilogram models. Distribution T / was 12 minutes
1
2
Triclofos is the phosphoric ester of trichloroethanol and shares the and elimination T / was 9 hours, similar to adult values. Context-
1
2
same active metabolite with chloral hydrate. It is more palatable sensitive T / was calculated for various ages after an infusion of
1
2
and less of a gastric irritant than chloral hydrate. In published 0.3 μg/kg/h and ranged from 6.75 hours after a 10-hour infusion
trials, the dose administered was 70 to 75 mg/kg. It did not inhibit at 10 years of age to 11.75 hours in a neonate and increased with
the Hering-Breuer reflex in healthy infants and had minimal effect
longer infusion duration because of return of drug from peripheral
on respiratory rate, HR, and oxygen saturation in infants and
compartments after infusion ceased.100 Transdermal patches are
young children.98
not suitable as premedication agents because therapeutic clonidine
CP are not achieved for 2 to 3 days after application.
TABLE 30-3. Chloral Hydrate Characteristics Between 40 and 60% of clonidine will undergo hepatic bio-
Can result in prolonged sedation or resedation particularly in transformation after I.V. administration. CYP4502D6 is involved
sick and ex–premature neonates. in the formation of its major metabolite, p-OH clonidine. Approxi-
Most effective in producing adequate sedation in children mately half is excreted unchanged by the kidneys but is subject to
younger than 1 y. considerable between-individual variation. Thus, renal immatu-
Less effective in producing adequate sedation in children older rity or failure may extend the elimination T / of clonidine to
1
2
than 4 y. 40 hours or more.

Used primarily for painless procedures (e.g., MRI, CT,
transthoracic echocardiography). Pharmacodynamics
Can be administered in doses ranging from 50 to 100 mg/kg
orally (maximum 2 g). SEDATION, ANALGESIA, AND AMNESIA: Sedation, analgesia, and
Onset time is variable: amnesia are dose-dependent.101 Satisfactory preoperative sedation
in children occurred with CP in the range of 0.3 to 0.8 μg/L,102
● Faster with higher dose. whereas in adults, 1.5 to 2.0 μg/L has been reported to result
● Top-up doses can be given after 20 min if initial dose is low in analgesia. In children aged 1 to 6 years, the mean time to
and ineffective. become drowsy or fall asleep after intranasal clonidine 4 μg/kg
Offset time is variable. was 47.5 minutes (sd 19.4).103
Children receiving chloral hydrate should be monitored with CARDIOVASCULAR: A mean reduction in mean arterial BP of
pulse oximetry, and those with congenital heart disease 26.3% (sd 13.6) was reported in children after the administration
should also have noninvasive blood pressure monitoring. of 2.5 μg/kg intravenously. The time for 75% of the BP reduction
Should not be administered to children with obstructive sleep to occur was 21.3 minutes (sd 25.6).104 In children, oral clonidine
apnea. 4 μg/kg reduces the intraoperative lability of BP and HR. Although
CT = computed tomography; MRI = magnetic resonance imaging. oral clonidine premedication reduced HR and BP for up to
10 hours postoperatively, no child had postoperative hypotension cinexylidide (MEGX) CP in children receiving continuous thoracic
or bradycardia that required treatment. epidural lidocaine.122
RESPIRATORY: Oral clonidine 4 μg/kg did not attenuate the
increase in minute volume induced by hypercapnia in children Clonidine for sedation
aged 3 to 13 years receiving sevoflurane.105 This is consistent with ELECTROENCEPHALOGRAPHY: Oral clonidine was used to suc-
the observation that epidural clonidine 1 μg/kg did not induce an cessfully perform EEG studies in 85% of children aged 2.2 to
increase in transcutaneous carbon dioxide pressure (PCO2) in 16.9 years (median 6) with autism, some of whom had previously
children aged 9 months to 7 years.106 Three case reports of apnea failed sedation with chloral hydrate.115
after caudal epidural clonidine administration (1.25–2 μg/kg) sug-
gest that caution should be exercised in neonates.107–109 INTENSIVE CARE: Clonidine by continuous I.V. infusion (0.1–3.6
μg/kg/h), with and without midazolam, has been used for sedation
in the intensive care unit after pediatric cardiac surgery.123,124 Oral
Clonidine for Premedication clonidine (3–5 μg/kg q8h) was used in combination with mor-
ORAL: After oral clonidine 4 μg/kg was administered 60 to 90 phine and lorazepam to achieve adequate sedation in children
minutes prior, 63% of children aged 7 to 12 years were either undergoing mechanical ventilation for single-organ respiratory
drowsy or asleep.110 In children aged 1 to 6 years, the mean time to failure.125 There were no adverse hemodynamic effects including
become drowsy or fall asleep after the same dose was 38 minutes. HR and rhythm, cardiac index, and BP.123–125
The mean time to peak sedative effect was 46.0 minutes (sd 15.7).
“Steal induction,” in which inhalational induction was performed Dexmedetomidine
without waking the child who was cradled in a parent’s arms, was
successful in 60 to 66%. If children woke during transfer to the Dexmedetomidine, the D-isomer of medetomidine used in veteri-
theater, smooth induction was unlikely. In children with autism, nary medicine, is highly lipophilic and eight times more selective
the mean time to adequate sedation for electroencephalographic for α2 than α1 adrenoreceptors than clonidine (1620:1 vs 220:1). It
(EEG) study was 58 minutes (range 15–135). No child was reis supplied as a clear, colorless, isotonic solution (100 μg/mL) that
ported to have found the taste of oral clonidine unpleasant in two contains no preservatives, additives, or chemical stabilizers. Intra-
studies in which the I.V. formulation was mixed with syrup.103,111 nasal dexmedetomidine was well tolerated in children and adults.
Emergence quality was reported in two studies. After clonidine None complained of smell, taste, local irritation, or pain.126,127
premedication, over 90% of children were calm on waking.103,111
Oral clonidine 4 μg/kg, but not 2 μg/kg, was effective in reducing Pharmacokinetics
sevoflurane-induced agitation in children aged 1 to 6 years.112 In adults, oral, buccal, and I.M. bioavailability was 16%, 82%, and
The mean time to discharge from the postanesthesia care unit 104%, respectively.128 Dexmedetomidine exhibits a rapid distribu-
was 53.7 minutes (sd 23.6) after oral clonidine 4 μg/kg.113 The tion phase (T / 6 min). It is over 90% protein-bound129 and under-
1
2
mean time to hospital discharge after the same dose was 179 goes extensive biotransformation in the liver that involves direct
minutes (sd 52).114 When used for EEG sedation, the mean time glucuronidation and CYP2A6-mediated hydroxylation producing
for return to baseline sedation score was 105 minutes (range 20– inactive metabolites. Hepatic impairment reduces CL. Its terminal
195) in children with autism.115 elimination T / in children aged 2 to 12 years after a single I.V.
1
2
Table 30–4 summarizes clonidine’s characteristics. Additional dose was 1.8 hours, similar to that in adults (2 h). There was no
benefits from clonidine premedication include reduced post- evidence of dose-dependent PK.129 After a mean infusion duration
operative nausea and vomiting after strabismus surgery; better of 18.8 hours (range 8–24) at 0.2 to 0.7 μg/kg/h in infants and
analgesia and reduced analgesic requirements; dose-dependent children (aged 4 mo–7.9 y) terminal elimination T / was 2.65 hours
1
2
reduction in minimum alveolar concentration (MAC) of sevo- (sd 0.88).130 CL matured during the first year of life to reach 87% of
flurane for skin incision,116 tracheal intubation, tracheal extuba- the adult value by 1 year.131
tion, and laryngeal mask insertion117 in children aged 2 to 11 years;
and attenuation of the surgical stress response118,119
Oral clonidine 4 μg/kg blunted the increase in HR after I.V. Pharmacodynamics
atropine in awake children aged 8 to 13 years120 but did not alter Dexmedetomidine has minimal respiratory depressant effects,
the effectiveness of simulated epidural test dose using adrenaline making it particularly useful when planning to extubate patients
and isoprenaline in children aged 1 to 7 years receiving sevo- in the intensive care setting.127,132–138
flurane.121 In addition, it reduced lidocaine and monoethylgly- Dexmedetomidine induces EEG activity similar to that seen in
natural sleep by reducing sympathetic activity and the level of
arousal. The sedation it produces is different from other sedative
TABLE 30-4. Clonidine Characteristics drugs in that it is not GABAmimetic. After dexmedetomidine,
children are easily aroused, and one study noted that, despite satis-
Dose-dependent sedation.
factory sedation to facilitate parental separation, some children
Good oral and rectal bioavailability.
became distressed when they were aroused at induction of anes-
Reduces heart rate and blood pressure.
thesia.127 Adult patients receiving dexmedetomidine in the inten-
Apnea is a risk in neonates especially if ex–premature.
sive care unit complained of awareness. It is unclear what dose of
Optimal timing 30–60 min prior.
dexmedetomidine produces anxiolysis or amnesia; although it
Dose oral 4 μg/kg.
Benefits include postoperative analgesia. is used as a premedicant and administered intramuscularly in
adults, anxiolysis has been reported when higher doses were used.
Increasing I.V. dosage is associated with increased sedation and modine 2 to 3 μg/kg was administered to children aged 4 months
analgesia and decreased isoflurane requirements, amnesia, HR, to 19 years. After a mean of 28 minutes (range 10–45), adequate
BP, and cardiac output.139,140 sedation to facilitate CT scan was achieved in only 65%.145
Dexmedetomidine reduces intraocular pressure. There is
evidence that, in rats, dexmedetomidine decreases the convulsive OTHER PROCEDURES: Dexmedetomidine has been used in con-
potency of racemic bupivacaine and levobupivacaine. junction with incremental doses of midazolam to provide sedation
Transient hypertension may occur secondary to initial vaso- for fiberoptic intubation in children. Propofol for rescue sedation
constriction from stimulation of peripheral α2B receptors located has been used in conjunction with dexmedetomidine to provide
on vascular smooth muscle. To prevent this, the initial bolus dose sedation for children undergoing radiotherapy, cardiac catheteri-
should be administered slowly over 10 minutes. Subsequently, the zation, and awake craniotomy.138,146,147
activation of α2 receptors in the central nervous system leads to a OFFSET: After CT scan (mean duration 8.6 min [sd 5.4, range
reduction in sympathetic outflow with possible peripheral gan- 1–36]), mean time spent in the recovery room was 27 minutes
glion blockade and a reduction in BP and bradycardia. Brady- (sd 16.2, range 4–110).144 The mean recovery time after dexme-
cardia may be more likely in neonates and young infants because detomidine bolus 0.92 μg/kg (sd 0.36) and infusion 0.69 μg/kg/h
of their relatively unopposed high vagal tone. Although a reduc- (sd 0.32) for procedures averaging less than 1 hour’s duration
tion in BP and HR relative to baseline has been observed in older was 84 minutes (sd 42).133 After 1 μg/kg bolus and 0.5 to 0.7 μg/
children, clinically significant hypotension and bradycardia are kg/h maintenance, the mean recovery time was 24 minutes
uncommon. (sd 17.6) and the mean time to discharge was 32 minutes
(sd 20.1).136
Dexmedetomidine for Premedication
INTRANASAL: Intranasal dexmedetomidine 1 μg/kg was more Dexmedetomidine for Intensive Care Sedation
effective than 0.5 μg/kg in producing satisfactory sedation to Adequate postoperative sedation was achieved in spontaneously
separate children (aged 2–12 y) from parents (75% vs 59%). Of breathing and mechanically ventilated children who had under-
those who were sedated after the higher dose, 71% allowed I.V. or gone cardiac and thoracic surgery with an initial dexmedeto-
inhalational induction without showing signs of distress or midine bolus of 0.32 μg/kg (sd 0.15) and continuous infusion
awakening.127 of 0.30 μg/kg/h (sd 0.05). Children younger than 1 year required
more rescue boluses.134 In a randomized trial comparing mida-
ORAL: Oral dexmedetomidine (2.6 μg/kg [sd 0.83]) in 13 children zolam and dexmedetomidine for sedation in children requir-
aged 4 to 14 years produced effective sedation in 11 patients who
ing mechanical ventilation, dexmedetomidine 0.5 μg/kg/h was
had failed in previous attempts to sedate. The time to effective
superior and less effective in children younger than 1 year.148,149
sedation for I.V. cannula insertion or parental separation ranged
Dexmedetomidine provided adequate sedation in 65 children
from 30 to 62 minutes.141
(aged 0.6(17 y) with burn injuries who had been inadequately
TRANSMUCOSAL: Transmucosal dexmedetomidine 1 μg/kg sedated with BZ and opioid infusions. The mean duration of
45 minutes before induction in children 7 to 12 years was as effec- infusion was 11 days (range 2–50) with a maximum infusion rate
tive as oral midazolam 0.5 mg/kg or clonidine 4 μg/kg adminis- of 2 μg/kg/h. No tachyphylaxis was observed.150 Dexmedeto-
tered 30 and 90 minutes before induction, respectively.113 Children midine has been used successfully to treat opioid and BZ
who received dexmedetomidine were less sedated 30 minutes after withdrawal in infants and children.149,151
arrival into recovery. The mean time to discharge after arrival into Dexmedetomidine advantages are summarized in Table 30–5.
recovery was 41.4 minutes (sd 20.6).
TABLE 30-5. Dexmedetomidine Has a Number of

Dexmedetomidine for Procedural Sedation Theoretical Advantages Over Other Sedative Agents
MAGNETIC RESONANCE IMAGING: I.V. dexmedetomidine pro- Minimal respiratory depression.
duced insufficient sedation for MRI in one study,142 but a higher Elimination half-life is not prolonged and clearance is mature in
dose (loading dose 2–3 μg/kg and maintenance infusion rate 2 early infancy.
μg/kg/h) provided adequate sedation in 97.6% of children (mean Mimics normal sleep EEG activity. Patients are easily aroused,
age 4.5 y [sd 3.4, range 0.2–17.9]).143 In children aged 1 to 7 years, but may appear distressed.
I.V. dexmedetomidine (1 μg/kg bolus and continuous infusion Administered by the nasal, oral, and transmucosal routes for
0.5–0.7 μg/kg/h) produced adequate sedation for MRI in 80% in premedication in children.
19 minutes (sd 8.2). When sedation was inadequate, a single dose Used successfully to produce sedation for MRI, CT scan, and
of midazolam 50 μg/kg was sufficient to perform the MRI.136 Co- cardiac catheterization, but may need supplementation with
induction with ketamine and dexmedetomidine, followed by other sedative agents.
dexmedetomidine infusion, provided adequate sedation for MRI Used successfully for intensive care sedation where more other
in children with trisomy 21 and obstructive sleep apnea.137 agents have failed and to treat opioid and benzodiazepine
COMPUTED TOMOGRAPHY: Dexmedetomidine 2 to 4 μg/kg bolus withdrawal. It may have a place for use in children pending
intravenously and 1.0 μg/kg/h by maintenance infusion was extubation from mechanical ventilation because of its
sufficient for sedation in children undergoing CT scan,144 but a minimal effect on ventilation.
single bolus of 2 to 3 μg/kg was not.145 The mean time to achieve CT = computed tomography; EEG = electroencephalographic; MRI = magnetic
adequate sedation was 10.5 minutes (sd 4.2). Buccal dexmedeto- resonance imaging.
OPIOIDS When intranasal sufentanil 2 μg/kg was compared with intra-

nasal midazolam 0.2 mg/kg, 71% of the children receiving
Fentanyl midazolam cried compared with only 20% of those who were
Oral transmucosal fentanyl citrate (OTFC) has been studied ex- administered sufentanil. Separation of children from their parents
tensively in children, leading to the U.S. Food and Drug Admini- was similar for both drugs; however, the sufentanil group was
stration’s (FDA) approving its use in children over 2 years and more sedated, more cooperative during anesthesia induction, and
10 kg in weight. The OTFC preparation is commercially available more likely to experience nausea and vomiting.
in a lollipop form. Oral fentanyl solution is unpleasant, whereas
the OTFC is well accepted by children. Children took 20 minutes
to finish the prescribed dose. Pentazocine
Pentazocine is a mu opioid receptor antagonist and a kappa opioid
Pharmacokinetics receptor agonist. It was thought less likely to cause opioid induced
respiratory depression. It was administered as an oral (2 mg/kg)
Compared with adults, the bioavailability of OTFC in children and I.M. premedicant (0.5 mg/kg) in children.
aged 3 to 10 years was lower (0.52 vs 0.36, respectively), suggesting
that children were more likely to swallow a larger proportion of
any given dose with a resultant increase in first-pass metabolism. I.M. Opioids
Peak CP was lower (adults 3.0 and children 1.0 ng/mL) and time
to mean peak CP longer (adults 22 min [sd 2.5], children 53 min I.M. pentazocine or morphine administered 45 minutes previously
[sd 40]) and more variable in children.152 Peak CP was half and the produced dose-dependent sedation and anxiolysis such that 81%
time taken to reach it double after ingestion of oral fentanyl solu- and 60% of children were not crying during induction of anes-
tion compared with OTFC in adults. More variability was ob- thesia, respectively. Emergence agitation was uncommon. Nausea
served in children administered the oral fentanyl solution (mean and vomiting were uncommon preoperatively and more common
peak CP 1.8, sd 1.2 ng/mL; mean time to peak CP 1.7 h [sd 1.6]).153 postoperatively (morphine 11.3% vs pentazocine 6.6%). I.M.
An oral fentanyl buccal tablet preparation has been studied in nalbuphine was similar to pentazocine. Papaveretum 0.4 mg/kg,
adults. Its advantage is greater bioavailability (F = 0.65) and more pethidine 1 to 2 mg/kg, or morphine 0.2 mg/kg was often com-
rapid and complete absorption than OTFC. Its absorption charac- bined with scopolamine and administered 1 hour preoperatively.
teristics are not affected by mucositis or buccal dwell time.154–156 Although these agents produced effective sedation, children did
not like I.M. injections and half vomited after papaveretum and
scopolamine.28
Pharmacodynamics
In children, the onset and depth of sedation is dose-dependent.
Time to peak sedation is 30 to 45 minutes.157 After 10 to 15 μg/kg, Rectal Opioids
50% of children were sedated or asleep at this time. This per-
The mean bioavailability of 0.2 mg/kg rectal morphine admini-
centage increased to 80% after 15 to 20 μg/kg.158
stered to children preoperatively was 0.35 (range 0.18–0.59) with
OTFC produces preoperative anxiolysis, increased likelihood
a hydrogel formulation and 0.27 (range 0.06–0.93) when a paren-
of cooperation at induction, less emergence phenemona post-
teral solution was used. The hydrogel formulation is less painful on
operatively, and delayed postanesthesia care unit discharge.157–159
administration.160
As a premedicant, OTFC 15 to 20 μg/kg was as effective as oral
midazolam 0.5 mg/kg.158 The same dose produced sedation in 25%
of children undergoing bone marrow aspiration or lumbar punc- Dextromethorphan
ture and effective analgesia within 30 minutes.
Pre- (8–30%) and postoperative (40–80%) nausea and vomiting Dextromethorphan is an isomer of the codeine analogue levor-
are common.157,159 Pruritis (in up to 75%) occurs mainly pre- phanol. Its analgesic effects are mediated through noncompetitive
operatively and is dose-dependent and mild.157,159 Postoperative antagonism of NMDA receptors. It undergoes extensive first pass
respiratory depression necessitating assisted ventilation and/ metabolism and O-demethylation by CYP2D6. Poor and extensive
or naloxone after 10 to 15 μg/kg was reported in one study.159 metabolizers have been identified. There is conflicting evidence
Ondansetron or droperidol did not reduce the incidence of that dextromethorphan may reduce secondary but not primary
postoperative nausea or vomiting.157,159 hyperalgesia; this effect may be delayed for up to 2 hours after peak
CP.161 In children undergoing tonsillectomy, oral dextromethor-
phan 1 mg/kg administered 30 to 60 minutes prior reduced intra-
Sufentanil operative fentanyl administration, postoperative pain scores, and
Sufentanil’s high lipid solubility results in a rapid onset of effect. morphine consumption compared with placebo in two studies162,163
Over half the children aged 6 months to 7 years protested during but not in another.164
the administration over 15 to 20 seconds of intranasal sufentanil
in doses of 1.5, 3.0, and 4.5 μg/kg. Within 10 minutes, most child- BARBITURATES
ren were calm when separated from their parents; however, only
25% willingly accepted a facemask for induction of anesthesia. Barbiturates can be classified as long-, medium-, short-, and
Postoperative vomiting occurred in 25% or more in each group, ultrashort-acting. The latter act very briefly owing to rapid
rising to 75% of those administered 4.5 μg/kg. Chest wall stiffness redistribution that terminates their action. Elimination T / , how-
1
2
occurred in up to half of children and was marked in 25% receiv- ever, are long. Their lipid solubility results in rapid onset of action,
ing the higher dose. whereas those with a short T / α will have rapid offset of action.
1
2
Methohexitone the mean time to discharge was 79.3 minutes (sd 30.9).171 Sedation
was most likely successful in children undergoing CT scan (97%)
Methohexitone is an ultrashort-acting barbituate that is rapidly compared with MRI (69%).
redistributed and metabolized and has little hangover effect. It was
administered rectally as a premedicant and induction agent,
rapidly inducing sleep before separating the child from their Secobarbitone (Quinalbarbitone)
parents in doses of 10 to 50 mg/kg. Bioavailability by the rectal
Secobarbitone is a short-acting barbiturate that is well absorbed
route has been estimated at 17% with a sixfold variation in
from the gastrointestinal tract. It was commonly used to sedate
children. Elimination T / was 3.2 hours and CL 17.9 mL/min/kg.165
1
2
children for radiologic procedures. It is also thought to have
Methohexitone may induce seizures in children with epilepsy. contributed to the deaths of Jimi Hendrix and Marilyn Monroe.
Onset time when administered rectally (5–7 mg/kg) for non-
Methohexitone for Premedication invasive diagnostic procedures was 10 to 15 minutes. Children
and Induction of Anesthesia were fit for discharge 45 minutes after the procedure. It was
administered orally (7.5 mg/kg up to a maximum of 200 mg) with
INTRAMUSCULAR: I.M. methohexitone 5.5 mg/kg was adminis- a 10% failure rate for CT scanning. The mean time to effective
tered to 750 children younger than 15 years who may or may not sedation was 27 minutes (range 10–50). The mean time to dis-
have received scopolamine or atropine. Spontaneous eye closure charge home was 212 minutes (range 30–380).172 Secobarbitone
occurred within 5 minutes of administration in 80% of children, 2 mg/kg intramuscularly was also used for premedication.11 It was
but did not occur at all in 9%. A vigorous struggle was described also used (4 mg/kg intramuscularly) as part of a cocktail that in-
in 8% at the time of facemask application. Eight percent of child- cluded pethidine (1 mg/kg), promethazine (1 mg/kg), and atro-
ren made no attempt to clear their airway when it was obstructed, pine (0.016 mg/kg). Mean time to induce sleep was 53 minutes.
limiting methohexitone’s utility as a premedicant.
RECTAL: Rectal administration and dosage were investigated in
one study of children aged 3 months to 7 years. The induction of
Pentobarbitone
sleep was more rapid in those receiving 30 mg/kg (mean 6.7, sd Pentobarbitone is a short-acting barbiturate with a relatively fast
1.6 min) compared with those who received 20 or 25 mg/kg (mean onset of action that allows dose titration to response when ad-
7.8, sd 2.2; and 7.2, sd 2.3 min, respectively). The percentage asleep ministered intravenously.
by 15 minutes were 93%, 84%, and 87% for the 30-, 25-, and
20-mg/kg doses, respectively. No hemodynamic or respiratory
complications were noted.
Intramuscular
In another study, 25 mg/kg rectal methohexitone was adminis- I.M. pentobarbitone 2 mg/kg was used for premedication.11 For
tered to children aged 6 months to 5 years, inducing sleep in a mean CT sedation, an initial dose of 5 to 6 mg/kg was administered,
time of 8.6 minutes (range 4–22). One child did not fall asleep. supplemented by a further 1 to 3 mg/kg if required. Induction time
Hiccough was encountered in 8% and 1 patient required assisted was 30 to 45 minutes, recovery time was 70 minutes, and there
ventilation. Recovery times were similar to those who received I.V. was a 3% failure rate.
thiopentone without premedication for induction. Return of full
consciousness occurred between 30 and 60 minutes.166 Physostig- Intravenous
mine postoperatively did not expedite discharge from the recovery
I.V. pentobarbitone produced effective sedation for MRI and CT
room (mean stay 34 min) after myringotomy.167
scaning (failure rate in children with I.V. titration < 1%).173 The
addition of midazolam to I.V. pentobarbitone 2 to 6 mg/kg was
Methohexitone for Sedation not shown to reduce the failure rate and served only to prolong
time to discharge. The mean time to sedation after pentobarbitone
INTRAMUSCULAR: I.M. methohexitone 10 mg/kg was used for
was 6.5 minutes (sd 4.4) and time to discharge was 106 minutes (sd
CT scan sedation in children aged 2 months to 5 years. The mean
34).173 Mean time to discharge was reported as 55 minutes in a
time to induce sleep was 3.3 minutes (sd 0.4). Arousal occurred
cohort that included more children younger than 3 years. Adverse
after 50 minutes and children were alert after 86 minutes.168
effects included paradoxical reactions (1.6–14%), vomiting (0.6%),
INTRAVENOUS: I.V. methohexitone (mean loading dose 2.3 [sd and severe oxygen desaturation (<1–7.5%).91,173
0.7]’ mean total dose 6.1 [sd 3.3] mg/kg) was used for MRI
sedation. Hypoventilation and apnea were observed in a small
proportion and 5% moved, necessitating some MRI sequences to Thiopentone
be repeated. Discharge times were rapid (mean 3.5 min [range 0.6– Rectal
40]).169 Methohexitone was used in combination with remifentanil
Rectal thiopentone (25–45 mg/kg) was administered for CT scan
to provide sedation and analgesia for children undergoing brief
sedation. The mean onset time was 8 minutes. A top-up dose was
painful procedures. Time to discharge (geometric mean 5.0 min)
required in 20% of children; effective sedation was not achieved in
was shorter than when a propofol and fentanyl infusion was used
3%. The mean duration of sedation was 2.75 hours.174 In another
(geometric mean 16.2 min).170 Airway support was necessary in a
study, rectal thiopentone 25 mg/kg was administered for CT,
number of patients.
nuclear medicine, and MRI scan sedation. Although the mean
RECTAL: Rectal methohexitone 25 mg/kg was used for sedation time to scan was 12.2 minutes, an unstated number of children
in children undergoing CT or MRI scans. The mean onset time received a second dose of 15 mg/kg if they were still awake
was 8 to 9 minutes.171 The mean sleep time was 46 minutes and 20 minutes after the first administration. Mean time to discharge
was 71 minutes. Adverse effects included transient oxygen desa- and the oculocardiac reflex (7.5 μg/kg intramuscularly).180,181 Oral
turation in 11%. Rectal irritation and discharge (20%), prolonged bioavailability is low (0.03),182 explaining its failure to attenuate
drowsiness or ataxia (9%), and vomiting (5%) occurred after cardiovascular depression in infants receiving halothane after its
discharge.175 oral administration.183 Glycopyrrolate administration in children
resulted in lower gastric volumes and acidity compared with sco-
polamine or placebo.184 Given as premedication, it may increase
ETOMIDATE the likelihood for sore throat postoperatively.185
Etomidate is a carboxylated imidazole derivative that produces
rapid onset and offset of sleep, possesses a high therapeutic index,
and does not decrease systemic arterial pressure or cerebral Scopolamine
perfusion pressure.11 These features led to its use in the radiology Scopolamine (hyoscine), a tertiary amine, crosses the blood-brain
and ED settings for procedural sedation in children.176–178 In these barrier causing amnesia, drowsiness, euphoria, and fatigue. It was
studies, initial boluses of 0.1 to 0.3 mg/kg intravenously were used commonly used in combination with pethidine, papaveretum, or
with further boluses if required up to a total of 0.5 mg/kg. morphine. Given alone, it sometimes caused delirium that was less
In children (mean age 8.3 y [sd 3.7]) undergoing fracture re- likely to occur with concomitant opioid administration and that
duction who received fentanyl 1 μg/kg, the times taken for induc- could be reversed with physostigmine. Its effect on the HR was
tion and recovery were shorter after etomidate 0.2 mg/kg (2 and less pronounced than that of atropine.11
11.8 min, respectively) than after midazolam 0.1 mg/kg (4 and As a premedication agent (8 μg/kg intramuscularly), scopola-
24 min, respectively).178 More patients in the etomidate group were mine’s sedative, antisialagogue, and antiemetic effects were parti-
adequately sedated (92% vs 36%). Pain on injection and myoclonus cularly useful when opioids were co-administered and when ether
were often noted. When etomidate in doses up to 0.4 mg/kg was was used. Rectal administration has been reported, although its
used for CT scan sedation, the failure rate was high (24%) when advantage was unclear. Transdermal scopolamine applied the
compared to I.V. pentobarbitone. However, induction and sedation night before surgery reduced postoperative nausea and vomiting
times were shorter and more parents perceived their child to have in children undergoing strabismus surgery.
returned to baseline by discharge from hospital in the etomidate
group.177 Using a higher initial bolus dose (0.3 mg/kg) with up to
two 0.15-mg/kg boluses reduced the failure rate to less than 1%.176 ANTIHISTAMINES
Hydroxyzine
ANTICHOLINERGICS Hydroxyzine is a derivative of both diphenylmethane and pipera-
Anticholinergic drugs were often administered preoperatively. zine and chemically unrelated to phenothiazine. It is a central
Their I.V. administration at the time of induction or if and when nervous system depressant and was used primarily for its sedative,
they should they be necessary is as effective. anxiolytic, and antiemetic properties as a premedicant in pre-
ference to phenothiazine derivatives that were thought more likely
to induce extrapyramidal side effects. It is also an antihistamine.
Atropine Although there are multiple publications regarding its use as a
Atropine is a tertiary amine that crosses the blood-brain barrier. premedicant in children, poor study design prevents definitive
It was used to prevent bradycardia and hypotension often seen in conclusions regarding its effectiveness. Hydroxyzine was almost
infants receiving halothane, arrhythmias during cyclopropane always used in combination with one or more other drugs includ-
anesthesia, and for its antisialagogue properties, particularly in ing pentobarbitone, secobarbitone, chloral hydrate, pethidine,
infants and for surgery in the oropharynx. No sedation occurred atropine, scopolamine, midazolam, diazepam, and nitrous oxide.
but palpitations were sometimes troublesome. It was thought to
protect against bradycardia secondary to vagal stimulation such
as that that occurred with traction on the spermatic cord and
Promethazine
extraocular muscles. Atropine was usually administered by I.M. Despite its widespread use, there are little pharmacologic data on
injection 30 minutes before induction of anesthesia in doses of 10 promethazine in children. Some unreferenced data are available
to 20 μg/kg, after which peak CP was reached within 5 minutes.11 in textbooks. They state that promethazine is well absorbed after
Oral atropine 20 μg/kg was effective within 25 minutes in oral administration and that its onset of action occurs within 30 to
infants and children aged 1 to 15 months in attenuating cardio- 60 minutes.
vascular depression during halothane anesthesia. There was no Promethazine is an H1 histamine receptor antagonist with anti-
advantage in administering 40 μg/kg.179 After rectal administra- muscarinic and antiemetic properties. Compared with trimepra-
tion, atropine peak CP was reached after 15 minutes and was only zine, it is less sedating but may have a cumulative effect with
30% of that seen after I.M. administration of the same dose.11 repeated administration. Promethazine 1 mg/kg each night for
3 nights led to central apneas and upper airway obstruction that
had not been present previous in infants.186 Sedation at induction
Glycopyrrolate of anesthesia after promethazine 1 mg/kg was assessed as
Glycopyrrolate is a synthetic quaternary drug that crosses the inadequate in 61% of children, although the interval between
blood-brain barrier poorly. It is two to five times as potent an premedication and induction was highly variable.187
antisialagogue compared with atropine.11 It protects against Children undergoing myringotomy receiving paracetamol
bradycardia without causing tachycardia (5 μg/kg intravenously), 20 mg/kg or a combination of paracetamol 12 mg/kg, codeine
0.5 mg/kg, and promethazine 0.65 mg/kg. Those who received the trimeprazine took longer to wake but experienced less distress in
promethazine-containing mixture took longer to open their eyes the recovery room and had half the incidence of vomiting than
and resume oral intake. Late sedation was observed, although the other groups.27
there was no difference in the time to discharge.188 A study com-
paring oral hydroxyzine 0.5 mg/kg, promethazine 0.5 mg/kg,
diazepam 0.1 mg/kg, and placebo administered for premedication MELATONIN
1 hour before induction did not detect any differences between Melatonin, a hormone secreted by the pineal gland, is important
the groups with regards to anxiolysis, quality of induction, or in regulating the diurnal rhythm of sleep. Early reports suggested
emergence time.189 that it may be effective to induce sleep for EEG and MRI scanning,
particularly in children who had been sleep deprived. Of children
administered 10 mg orally, 65% fell asleep within 35 minutes.194,195
Chlorpromazine More recently, melatonin 3 mg or 6 mg was not shown to con-
The discovery that the phenothiazine chlorpromazine, although tribute to sedation when given before chloral hydrate or a mixture
having no intrinsic analgesic actions, enhanced opioid analgesia of temazepam and droperidol196 and was no more effective than
and its use in neurolept analgesia and its antiemetic properties led placebo after 3 or 0.5 mg/kg.197
to its use alone and as part of the “lytic cocktail.”190 It also had As a premedicant in children aged 2 to 5 years, oral melatonin
sympatholytic properties that were useful if surface cooling 0.25 or 0.5 mg/kg administered 1 hour prior facilitated separation
hypothermia was employed. Little data exist in children regarding from parents and facemask acceptance while reducing post-
its pharmacology or effectiveness as a premedicant. It is still used operative excitement. Sleep disturbance in the 2 weeks after
as a sedative (0.5–1 mg/kg). In adults, chlorpromazine has a rapid surgery was less than in children who had received midazolam
distribution T / (2 h) and a long elimination T / (30 h).11
1
2
1
2 premedication.198
Trimeprazine (Alimemazine) COMBINATION PREMEDICATION

Trimeprazine is a H1 histamine receptor antagonist with antimus- Many of the premedicants described have been used in combi-
carinic properties. Its sedative effects are more pronounced than nation and administered by a variety of routes that precludes
those of promethazine because of its central anticholinergic acti- further conclusion. Some were effective but not always, and it is
vity. It also antagonizes the effects of dopamine and noradrenaline. difficult to compare their efficacy and side effects in light of
After its oral administration in children, the elimination T / of 1
2 modern anesthesia practice. An excellent review of the history of
trimeprazine was estimated to be 6.8 hours.191 the “lytic cocktail” that contained pethidine, promethazine, and
Trimeprazine enjoyed popularity as an oral premedicant and chlorpromazine and a critical appraisal of its use is highly recom-
sedative in children for some years after its introduction in 1959. mended.199
It produced good preoperative sedation, antiemesis, and amnesia.
Its major drawback was prolonged postoperative sedation, with
children taking 10 hours or more to regain normal functioning. REFERENCES
Case reports of unexplained hypotension, bradycardia, and res- 1. Kogan A, Katz J, Efrat R, Eidelman LA. Premedication with midazolam
piratory depression within 30 to 80 minutes of its administration in young children: a comparison of four routes of administration. Paediatr
in children with fever or upper respiratory tract infections were Anaesth. 2002;12:685–689.
also disturbing. Other side effects include extrapyramidal effects, 2. Walbergh EJ, Wills RJ, Eckhert J. Plasma concentrations of midazolam in
hypothermia, disturbing dreams, and hallucinations. children following intranasal administration. Anesthesiology. 1991;74:
233–235.
Administered 1.5 to 2 h before anesthesia, no difference was 3. Rey E, Delaunay L, Pons G, et al. Pharmacokinetics of midazolam in
found in distress at induction or recovery time when children were children: comparative study of intranasal and intravenous administration.
administered 2 or 4 mg/kg. Trimeprazine 2 mg/kg administered Eur J Clin Pharmacol. 1991;41:355–357.
orally 90 minutes before induction was as effective as midazolam 4. Reed MD, Rodarte A, Blumer JL, et al. The single-dose pharmacokinetics
0.5 mg/kg or placebo 30 minutes before induction.192 The same of midazolam and its primary metabolite in pediatric patients after oral
and intravenous administration. J Clin Pharmacol. 2001;41:1359–1369.
doses of trimeprazine and midazolam were compared with diaze-
5. Payne K, Mattheyse FJ, Liebenberg D, Dawes T. The pharmacokinetics of
pam 0.25 mg/kg with droperidol 0.25 mg/kg in older children, but midazolam in paediatric patients. Eur J Clin Pharmacol. 1989;37:267–272.
in this study, less attention was paid to the timing of premedicant 6. Johnson TN, Rostami-Hodjegan A, Goddard JM, et al. Contribution of
drug administration. A higher proportion of children who re- midazolam and its 1-hydroxy metabolite to preoperative sedation in
ceived trimeprazine experienced postoperative behavioral dis- children: a pharmacokinetic-pharmacodynamic analysis. Br J Anaesth.
turbance.193 Children receiving oral trimeprazine 3 mg/kg were 2002;89:428–437.
7. Malinovsky JM, Populaire C, Cozian A, et al. Premedication with mida-
less likely to be asleep and more likely to be distressed at the induc- zolam in children. Effect of intranasal, rectal and oral routes on plasma
tion of anesthesia than those given an oral mixture composed of midazolam concentrations. Anaesthesia. 1995;50:351–354.
trimeprazine 1 mg/kg, droperidol 0.15 mg/kg, and methadone 8. Marshall J, Rodarte A, Blumer J, et al. Pediatric pharmacodynamics of
0.08 mg/kg administered 2.5 hours prior. Administered 1 to more midazolam oral syrup. Pediatric Pharmacology Research Unit Network.
than 2 hours prior, good preoperative and prolonged postoperative J Clin Pharmacol. 2000;40:578–589.
9. Chattopadhyay A, Morris B, Blackburn L, et al. Buccal midazolam and
sedation were reported after trimeprazine 3 mg/kg.187 In children
rectal diazepam for epilepsy. Lancet. 1999;353:1798.
aged 1 to 10 years, oral trimeprazine 4 mg/kg administered 2 hours 10. Kraus GB, Gruber RG, Knoll R, Danner U. [Pharmacokinetic studies
before anesthesia was as effective as diazepam 0.5 mg/kg and pen- following intravenous and rectal administration of midazolam in
tobarbitone 3 mg/kg for preoperative sedation. Those receiving children] (German). Anaesthesist. 1989;38:658–663.
11. Wood M. Intravenous anesthetic agents. In: Wood M, Wood AJJ (eds). 37. Humphries Y, Melson M, Gore D. Superiority of oral ketamine as an
Drugs and Anesthesia: pharmacology for anesthesiologists. 2nd ed. analgesic and sedative for wound care procedures in the pediatric patient
Baltimore: Williams & Wilkins. 1990, p. 390. with burns. J Burn Care Rehabil. 1997;18:34–36.
12. de Wildt SN, Kearns GL, Hop WC, et al. Pharmacokinetics and meta- 38. White M, de Graaff P, Renshof B, et al. Pharmacokinetics of S(+) ketamine
bolism of oral midazolam in preterm infants. Br J Clin Pharmacol. 2002; derived from target controlled infusion. Br J Anaesth. 2006;96:330–334.
53:390–392. 39. Herd DW, Anderson BJ, Holford NH. Modeling the norketamine meta-
13. Lee TC, Charles BG, Harte GJ, et al. Population pharmacokinetic model- bolite in children and the implications for analgesia. Paediatr Anaesth.
ing in very premature infants receiving midazolam during mechanical 2007;17:831–840.
ventilation: midazolam neonatal pharmacokinetics. Anesthesiology. 1999; 40. Herd D, Anderson BJ. Ketamine disposition in children presenting for
90:451–457. procedural sedation and analgesia in a children’s emergency department.
14. Peeters MY, Prins SA, Knibbe CA, et al. Pharmacokinetics and phar- Paediatr Anaesth. 2007;17:622–629.
macodynamics of midazolam and metabolites in nonventilated infants 41. Clements JA, Nimmo WS. Pharmacokinetics and analgesic effect of
after craniofacial surgery. Anesthesiology. 2006;105:1135–1146. ketamine in man. Br J Anaesth. 1981;53:27–30.
15. Marhofer P, Freitag H, Hochtl A, et al. S(+)-Ketamine for rectal premedi- 42. Clements JA, Nimmo WS, Grant IS. Bioavailability, pharmacokinetics,
cation in children. Anesth Analg. 2001;92:62–65. and analgesic activity of ketamine in humans. J Pharm Sci. 1982;71:
16. Weber F, Wulf H, el Saeidi G. Premedication with nasal S-ketamine and 539–542.
midazolam provides good conditions for induction of anesthesia in 43. Grant IS, Nimmo WS, McNicol LR, Clements JA. Ketamine disposition
preschool children. Can J Anaesth. 2003;50:470–475. in children and adults. Br J Anaesth. 1983;55:1107–1111.
17. Cox RG, Nemish U, Ewen A, Crowe MJ. [Evidence-based clinical update: 44. Malinovsky JM, Servin F, Cozian A, et al. Ketamine and norketamine
does premedication with oral midazolam lead to improved behavioural plasma concentrations after I.V., nasal and rectal administration in
outcomes in children?] (French). Can J Anaesth. 2006;53:1213–1219. children. Br J Anaesth. 1996;77:203–207.
18. Lindh-Stromberg U. Rectal administration of midazolam for conscious 45. Herd DW, Anderson BJ, Keene NA, Holford NH. Investigating the phar-
sedation of uncooperative children in need of dental treatment. Swed macodynamics of ketamine in children. Paediatr Anaesth. 2008;18:36–42.
Dent J. 2001;25:105–111. 46. Funk W, Jakob W, Riedl T, Taeger K. Oral preanaesthetic medication for
19. Krauss B, Green SM. Procedural sedation and analgesia in children. children: double-blind randomized study of a combination of midazolam
Lancet. 2006;367:766–780. and ketamine vs midazolam or ketamine alone. Br J Anaesth. 2000;84:
20. Weldon BC, Watcha MF, White PF. Oral midazolam in children: effect of 335–340.
time and adjunctive therapy. Anesth Analg. 1992;75:51–55. 47. Sekerci C, Donmez A, Ates Y, Okten F. Oral ketamine premedication in
21. McGlone R, Fleet T, Durham S, Hollis S. A comparison of intramuscular children (placebo controlled double-blind study). Eur J Anaesthesiol.
ketamine with high dose intramuscular midazolam with and without 1996;13:606–611.
intranasal flumazenil in children before suturing. Emerg Med J. 2001;18: 48. Dallimore D, Herd DW, Short T, Anderson BJ. Dosing ketamine for
34–38. pediatric procedural sedation in the emergency department. Pediatr
22. Tanaka M, Sato M, Saito A, Nishikawa T. Reevaluation of rectal ketamine Emerg Care. 2008;24:529–533.
premedication in children: comparison with rectal midazolam. Anesthe- 49. van der Walt JH, Moran C. An audit of perioperative management of
siology. 2000;93:1217–1224. autistic children. Paediatr Anaesth. 2001;11:401–408.
23. Anderson BJ, Exarchos H, Lee K, Brown TC. Oral premedication in 50. Turhanoglu S, Kararmaz A, Ozyilmaz MA, et al. Effects of different doses
children: a comparison of chloral hydrate, diazepam, alprazolam, midazolam of oral ketamine for premedication of children. Eur J Anaesthesiol. 2003;
and placebo for day surgery. Anaesth Intensive Care. 1990;18: 185–193. 20:56–60.
24. Sonander H, Arnold E, Nilsson K. Effects of the rectal administration of 51. Weksler N, Ovadia L, Muati G, Stav A. Nasal ketamine for paediatric
diazepam. Diazepam concentrations in children undergoing general premedication. Can J Anaesth. 1993;40:119–121.
anaesthesia. Br J Anaesth. 1985;57:578–580. 52. Hannallah RS, Patel RI. Low-dose intramuscular ketamine for anesthesia
25. Fell D, Gough MB, Northan AA, Henderson CU. Diazepam premedi- pre-induction in young children undergoing brief outpatient procedures.
cation in children. Plasma levels and clinical effects. Anaesthesia. 1985; Anesthesiology. 1989;70:598–600.
40:12–17. 53. Bhatt S, Neupane B. Intramuscular ketamine pre-medication to separate
26. Van der Walt JH, Nicholls B, Bentley M, Tomkins DP. Oral premedication children from their parents. Nepal Med Coll J. 2005;7:131–133.
in children. Anaesth Intensive Care. 1987;15:151–157. 54. Tobias JD, Phipps S, Smith B, Mulhern RK. Oral ketamine premedication
27. van der Walt JH, Jacob R, Murrell D, Bentley M. The perioperative effects to alleviate the distress of invasive procedures in pediatric oncology
of oral premedication in children. Anaesth Intensive Care. 1990;18:5–10. patients. Pediatrics. 1992;90:537–541.
28. Schofield NM, White JB. Interrelations among children, parents, preme- 55. McGlone RG, Howes MC, Joshi M. The Lancaster experience of 2.0 to
dication, and anaesthetists in paediatric day stay surgery. Br Med J. 1989; 2.5 mg/kg intramuscular ketamine for paediatric sedation: 501 cases and
299:1371–1375. analysis. Emerg Med J. 2004;21:290–295.
29. Parnis SJ, Foate JA, van der Walt JH, et al. Oral midazolam is an effective 56. Green SM, Hummel CB, Wittlake WA, et al. What is the optimal dose of
premedication for children having day-stay anaesthesia. Anaesth Intensive intramuscular ketamine for pediatric sedation? Acad Emerg Med. 1999;
Care. 1992;20:9–14. 6:21–26.
30. Tamminga RY, Noordhoek M, Kroon J, Faber-Nijholt R. Ketamine anes- 57. Roback MG, Wathen JE, MacKenzie T, Bajaj L. A randomized, controlled
thesia with or without diazepam premedication for bone marrow trial of I.V. versus I.M. ketamine for sedation of pediatric patients re-
punctures in children with acute lymphoblastic leukemia. Pediatr Hematol ceiving emergency department orthopedic procedures. Ann Emerg Med.
Oncol. 2000;17:383–388. 2006;48:605–612.
31. Peters CG, Brunton JT. Comparative study of lorazepam and trimeprazine 58. Abrams R, Morrison JE, Villasenor A, et al. Safety and effectiveness of
for oral premedication in paediatric anaesthesia. Br J Anaesth. 1982;54: intranasal administration of sedative medications (ketamine, midazolam,
623–628. or sufentanil) for urgent brief pediatric dental procedures. Anesth Prog.
32. McCall JE, Fischer CG, Warden G, et al. Lorazepam given the night before 1993;40:63–66.
surgery reduces preoperative anxiety in children undergoing reconstruc- 59. Filatov SM, Baer GA, Rorarius MG, Oikkonen M. Efficacy and safety of
tive burn surgery. J Burn Care Rehabil. 1999;20:151–154. premedication with oral ketamine for day-case adenoidectomy compared
33. Henry DW, Burwinkle JW, Klutman NE. Determination of sedative and with rectal diazepam/diclofenac and EMLA. Acta Anaesthesiol Scand.
amnestic doses of lorazepam in children. Clin Pharm. 1991;10:625–629. 2000;44:118–124.
34. Smith GB, Hughes DG, Kumar V. Temazepam in fast dispensing dosage 60. Gingrich BK. Difficulties encountered in a comparative study of orally
form as a premedication for children. Anaesthesia. 1985;40:368–371. administered midazolam and ketamine. Anesthesiology. 1994;80:1414–
35. Padfield NL, Twohig MM, Fraser AC. Temazepam and trimeprazine 1415.
compared with placebo as premedication in children. An investigation 61. Ozdemir D, Kayserili E, Arslanoglu S, et al. Ketamine and midazolam for
extended into the first 2 weeks at home. Br J Anaesth. 1986;58:487–493. invasive procedures in children with malignancy: a comparison of routes
36. Cioaca R, Canavea I. Oral transmucosal ketamine: an effective preme- of intravenous, oral, and rectal administration. J Trop Pediatr. 2004;50:
dication in children. Paediatr Anaesth. 1996;6:361–365. 224–228.
62. Roback MG, Wathen JE, Bajaj L, Bothner JP. Adverse events associated radiologic imaging: preliminary results. AJR Am J Roentgenol. 2003;180:
with procedural sedation and analgesia in a pediatric emergency depart- 1125–1128.
ment: a comparison of common parenteral drugs. Acad Emerg Med. 2005; 86. McCarver-May DG, Kang J, Aouthmany M, et al. Comparison of chloral
12:508–513. hydrate and midazolam for sedation of neonates for neuroimaging
63. Young C, Jevtovic-Todorovic V, Qin YQ, et al. Potential of ketamine and studies. J Pediatr. 1996;128:573–576.
midazolam, individually or in combination, to induce apoptotic neuro- 87. Cortellazzi P, Lamperti M, Minati L, et al. Sedation of neurologically
degeneration in the infant mouse brain. Br J Pharmacol. 2005;146: impaired children undergoing MRI: a sequential approach. Paediatr
189–197. Anaesth. 2007;17:630–636.
64. Darlong V, Shende D, Subramanyam MS, et al. Oral ketamine or mida- 88. Morriss T, Dyson J, Thompson A, et al. Sedation for MRI scans further
zolam or low dose combination for premedication in children. Anaesth evidence for change. Paediatr Nurs. 2007;19:41.
Intensive Care. 2004;32:246–249. 89. Treluyer JM, Andre C, Carp PF, et al. Sedation in children undergoing
65. Auden SM, Sobczyk WL, Solinger RE, Goldsmith LJ. Oral ketamine/ CT scan or MRI: effect of time-course and tolerance of rectal chloral
midazolam is superior to intramuscular meperidine, promethazine, and hydrate. Fundam Clin Pharmacol. 2004;18:347–350.
chlorpromazine for pediatric cardiac catheterization. Anesth Analg. 2000; 90. Malviya S, Voepel-Lewis T, Prochaska G, Tait AR. Prolonged recovery
90:299–305. and delayed side effects of sedation for diagnostic imaging studies in
66. Sullivan DC, Wilson CF, Webb MD. A comparison of two oral ketamine- children. Pediatrics. 2000;105:E42.
diazepam regimens for the sedation of anxious pediatric dental patients. 91. Malviya S, Voepel-Lewis T, Tait AR, et al. Pentobarbital vs chloral
Pediatr Dent. 2001;23:223–231. hydrate for sedation of children undergoing MRI: efficacy and recovery
67. Trabold B, Rzepecki A, Sauer K, Hobbhahn J. A comparison of two characteristics. Paediatr Anaesth. 2004;14:589–595.
different doses of ketamine with midazolam and midazolam alone as oral 92. Sanborn PA, Michna E, Zurakowski D, et al. Adverse cardiovascular and
preanaesthetic medication on recovery after sevoflurane anaesthesia in respiratory events during sedation of pediatric patients for imaging
children. Paediatr Anaesth. 2002;12:690–693. examinations. Radiology. 2005;237:288–294.
68. Beebe DS, Belani KG, Chang PN, et al. Effectiveness of preoperative 93. Cote CJ, Karl HW, Notterman DA, et al. Adverse sedation events in
sedation with rectal midazolam, ketamine, or their combination in young pediatrics: analysis of medications used for sedation. Pediatrics. 2000;
children. Anesth Analg. 1992;75:880–884. 106:633–644.
69. Zimmermann T, Wehling M, Schulz HU. [The relative bioavailability and 94. Hirsch IA, Zauder HL. Chloral hydrate: a potential cause of arrhythmias.
pharmacokinetics of chloral hydrate and its metabolites] (German). Anesth Analg. 1986;65:691–692.
Arzneimittelforschung. 1998;48:5–12. 95. Young JB, Vandermolen LA, Pratt CM. Torsade de pointes: an unusual
70. Merdink JL, Robison LM, Stevens DK, et al. Kinetics of chloral hydrate manifestation of chloral hydrate poisoning. Am Heart J. 1986;112:
and its metabolites in male human volunteers. Toxicology. 2008;245: 181–184.
130–140. 96. Lin YC, Ma JY. Severe esophageal burn following chloral hydrate
71. Mayers DJ, Hindmarsh KW, Sankaran K, et al. Chloral hydrate disposition overdose in an infant. J Formos Med Assoc. 2006;105:235–237.
following single-dose administration to critically ill neonates and 97. Anyebuno MA, Rosenfeld CR. Chloral hydrate toxicity in a term infant.
children. Dev Pharmacol Ther. 1991;16:71–77. Dev Pharmacol Ther. 1991;17:116–120.
72. Allegaert K, Daniels H, Naulaers G, et al. Pharmacodynamics of chloral 98. Jackson EA, Rabbette PS, Dezateux C, et al. The effect of triclofos
hydrate in former preterm infants. Eur J Pediatr. 2005;164:403–407. sodium sedation on respiratory rate, oxygen saturation, and heart rate in
73. Turner DJ, Morgan SE, Landau LI, LeSouef PN. Methodological aspects infants and young children. Pediatr Pulmonol. 1991;10:40–45.
of flow-volume studies in infants. Pediatr Pulmonol. 1990;8:289–293. 99. Lonnqvist PA, Bergendahl HT, Eksborg S. Pharmacokinetics of cloni-
74. Hershenson M, Brouillette RT, Olsen E, Hunt CE. The effect of chloral dine after rectal administration in children. Anesthesiology. 1994;81:
hydrate on genioglossus and diaphragmatic activity. Pediatr Res. 1984;18: 1097–1101.
516–519. 100. Potts AL, Larsson P, Eksborg S, et al. Clonidine disposition in children;
75. Abdul-Baqi KJ. Chloral hydrate and middle ear pressure. J Laryngol Otol. a population analysis. Paediatr Anaesth. 2007;17:924–933.
1991;105:421–423. 101. Inomata S, Kihara S, Miyabe M, et al. The hypnotic and analgesic
76. Thoresen M, Henriksen O, Wannag E, Laegreid L. Does a sedative dose effects of oral clonidine during sevoflurane anesthesia in children:
of chloral hydrate modify the EEG of children with epilepsy? Electroence- a dose-response study. Anesth Analg. 2002;94:1479–1483, table of
phalogr Clin Neurophysiol. 1997;102:152–157. contents.
77. Szmuk P, Kee S, Pivalizza EG, et al. Anaesthesia for magnetoencephalo- 102. Sumiya K, Homma M, Watanabe M, et al. Sedation and plasma
graphy in children with intractable seizures. Paediatr Anaesth. 2003;13: concentration of clonidine hydrochloride for pre-anesthetic medication
811–817. in pediatric surgery. Biol Pharm Bull. 2003;26:421–423.
78. Ah-Chan J, Rubinstein A, Patel CK. Anterior sub-Tenon’s anesthesia for 103. Almenrader N, Passariello M, Coccetti B, et al. Steal-induction after
the treatment of retinopathy of prematurity. J Pediatr Ophthalmol Stra- clonidine premedication: a comparison of the oral and nasal route.
bismus. 2008;45:186–188. Paediatr Anaesth. 2007;17:230–234.
79. Jaafar MS, Kazi GA. Effect of oral chloral hydrate sedation on the intrao- 104. Lonnqvist PA, Bergendahl H. Pharmacokinetics and haemodynamic
cular pressure measurement. J Pediatr Ophthalmol Strabismus. 1993;30: response after an intravenous bolus injection of clonidine in children.
80. Marti-Bonmati L, Ronchera-Oms CL, Casillas C, et al. Randomised 105. Nishina K, Mikawa K, Uesugi T, Obara H. Oral clonidine does not change
double-blind clinical trial of intermediate-versus high-dose chloral ventilatory response to carbon dioxide in sevoflurane-anesthetized
hydrate for neuroimaging of children. Neuroradiology. 1995;37:687–691. children. Paediatr Anaesth. 2004;14:1001–1004.
81. Dalal PG, Murray D, Cox T, et al. Sedation and anesthesia protocols used 106. Dupeyrat A, Goujard E, Muret J, Ecoffey C. Transcutaneous CO2 tension
for magnetic resonance imaging studies in infants: provider and pharma- effects of clonidine in paediatric caudal analgesia. Paediatr Anaesth.
cologic considerations. Anesth Analg. 2006;103:863–868. 1998;8:145–148.
82. Vade A, Sukhani R, Dolenga M, Habisohn-Schuck C. Chloral hydrate 107. Fellmann C, Gerber AC, Weiss M. Apnoea in a former preterm infant
sedation of children undergoing CT and MR imaging: safety as judged after caudal bupivacaine with clonidine for inguinal herniorrhaphy.
by American Academy of Pediatrics guidelines. AJR Am J Roentgenol. Paediatr Anaesth. 2002;12:637–640.
1995;165:905–909. 108. Bouchut JC, Dubois R, Godard J. Clonidine in preterm-infant caudal
83. Low E, O’Driscoll M, MacEneaney P, O’Mahony O. Sedation with oral anesthesia may be responsible for postoperative apnea. Reg Anesth Pain
chloral hydrate in children undergoing MRI scanning. Ir Med J. 2008; Med. 2001;26:83–85.
101:80–82. 109. Breschan C, Krumpholz R, Likar R, et al. Can a dose of 2microg.kg(–1)
84. Greenberg SB, Faerber EN, Aspinall CL, Adams RC. High-dose chloral caudal clonidine cause respiratory depression in neonates? Paediatr
hydrate sedation for children undergoing MR imaging: safety and efficacy Anaesth. 1999;9:81–83.
in relation to age. AJR Am J Roentgenol. 1993;161:639–641. 110. Reimer EJ, Dunn GS, Montgomery CJ, et al. The effectiveness of cloni-
85. Rooks VJ, Chung T, Connor L, et al. Comparison of oral pentobarbital dine as an analgesic in paediatric adenotonsillectomy. Can J Anaesth.
sodium (nembutal) and oral chloral hydrate for sedation of infants during 1998;45:1162–1167.
111. Almenrader N, Passariello M, Coccetti B, et al. Premedication in 135. Hammer GB, Philip BM, Schroeder AR, et al. Prolonged infusion of
children: a comparison of oral midazolam and oral clonidine. Paediatr dexmedetomidine for sedation following tracheal resection. Paediatr
Anaesth. 2007;17:1143–1149. Anaesth. 2005;15:616–620.
112. Tazeroualti N, De Groote F, De Hert S, et al. Oral clonidine vs mida- 136. Koroglu A, Demirbilek S, Teksan H, et al. Sedative, haemodynamic and
zolam in the prevention of sevoflurane-induced agitation in children. respiratory effects of dexmedetomidine in children undergoing magnetic
a prospective, randomized, controlled trial. Br J Anaesth. 2007;98: resonance imaging examination: preliminary results. Br J Anaesth. 2005;
667–671. 94:821–824.
113. Schmidt AP, Valinetti EA, Bandeira D, et al. Effects of preanesthetic 137. Luscri N, Tobias JD. Monitored anesthesia care with a combination of
administration of midazolam, clonidine, or dexmedetomidine on post- ketamine and dexmedetomidine during magnetic resonance imaging in
operative pain and anxiety in children. Paediatr Anaesth. 2007;17: three children with trisomy 21 and obstructive sleep apnea. Paediatr
667–674. Anaesth. 2006;16:782–786.
114. Mikawa K, Nishina K, Shiga M. Prevention of sevoflurane-induced 138. Munro HM, Tirotta CF, Felix DE, et al. Initial experience with dexme-
agitation with oral clonidine premedication. Anesth Analg. 2002;94: detomidine for diagnostic and interventional cardiac catheterization in
1675–1676. children. Paediatr Anaesth. 2007;17:109–112.
115. Mehta UC, Patel I, Castello FV. EEG sedation for children with autism. 139. Khan ZP, Munday IT, Jones RM, et al. Effects of dexmedetomidine on
J Dev Behav Pediatr. 2004;25:102–104. isoflurane requirements in healthy volunteers. 1: Pharmacodynamic and
116. Inomata S, Kihara S, Yaguchi Y, et al. Reduction in standard MAC and pharmacokinetic interactions. Br J Anaesth. 1999;83:372–380.
MAC for intubation after clonidine premedication in children. Br J 140. Ebert TJ, Hall JE, Barney JA, et al. The effects of increasing plasma con-
Anaesth. 2000;85:700–704. centrations of dexmedetomidine in humans. Anesthesiology. 2000;93:
117. Nishina K, Mikawa K, Uesugi T, Obara H. Oral clonidine premedica- 382–394.
tion reduces minimum alveolar concentration of sevoflurane for laryn- 141. Zub D, Berkenbosch JW, Tobias JD. Preliminary experience with oral
geal mask airway insertion in children. Paediatr Anaesth. 2006;16: dexmedetomidine for procedural and anesthetic premedication. Paediatr
834–839. Anaesth. 2005;15:932–938.
118. Mikawa K, Maekawa N, Nishina K, et al. Efficacy of oral clonidine 142. Heard CM, Joshi P, Johnson K. Dexmedetomidine for pediatric MRI
premedication in children. Anesthesiology. 1993;79:926–931. sedation: a review of a series of cases. Paediatr Anaesth. 2007;17:888–892.
119. Mikawa K, Nishina K, Maekawa N, et al. Attenuation of the catechola- 143. Mason KP, Zurakowski D, Zgleszewski SE, et al. High dose dexme-
mine response to tracheal intubation with oral clonidine in children. detomidine as the sole sedative for pediatric MRI. Paediatr Anaesth.
Can J Anaesth. 1995;42:869–874. 2008;18:403–411.
120. Nishina K, Mikawa K, Maekawa N, Obara H. Oral clonidine premedica- 144. Mason KP, Zgleszewski SE, Prescilla R, et al. Hemodynamic effects of
tion blunts the heart rate response to intravenous atropine in awake dexmedetomidine sedation for CT imaging studies. Paediatr Anaesth.
children. Anesthesiology. 1995;82:1126–1130. 2008;18:393–402.
121. Shiga M, Nishina K, Mikawa K, et al. Oral clonidine premedication does 145. Lami RO, Pereira AC. Transmucosal dexmedetomidine for computed
not change efficacy of simulated epidural test dose in sevoflurane- tomography sedation. Paediatr Anaesth. 2008;18:349–378.
anesthetized children. Anesthesiology. 2000;93:954–958. 146. Shukry M, Ramadhyani U. Dexmedetomidine as the primary sedative
122. Inomata S, Tanaka E, Miyabe M, et al. Plasma lidocaine concentrations agent for brain radiation therapy in a 21-month old child. Paediatr
during continuous thoracic epidural anesthesia after clonidine preme- Anaesth. 2005;15:241–242.
dication in children. Anesth Analg. 2001;93:1147–1151. 147. Everett LL, van Rooyen IF, Warner MH, et al. Use of dexmedetomidine
123. Ambrose C, Sale S, Howells R, et al. Intravenous clonidine infusion in in awake craniotomy in adolescents: report of two cases. Paediatr
critically ill children: dose-dependent sedative effects and cardiovascular Anaesth. 2006;16:338–342.
stability. Br J Anaesth. 2000;84:794–796. 148. Tobias JD, Berkenbosch JW. Sedation during mechanical ventilation in
124. Pohl-Schickinger A, Lemmer J, Hubler M, et al. Intravenous clonidine infants and children: dexmedetomidine versus midazolam. South Med J.
infusion in infants after cardiovascular surgery. Paediatr Anaesth. 2008; 2004;97:451–455.
18:217–222. 149. Tobias JD. Dexmedetomidine to treat opioid withdrawal in infants
125. Arenas-Lopez S, Riphagen S, Tibby SM, et al. Use of oral clonidine for following prolonged sedation in the pediatric ICU. J Opioid Manag.
sedation in ventilated paediatric intensive care patients. Intensive Care 2006;2:201–205.
Med. 2004;30:1625–1629. 150. Walker J, Maccallum M, Fischer C, et al. Sedation using dexmedeto-
126. Yuen VM, Irwin MG, Hui TW, eet al. A double-blind, crossover assess- midine in pediatric burn patients. J Burn Care Res. 2006;27:206–210.
ment of the sedative and analgesic effects of intranasal dexmedeto- 151. Finkel JC, Elrefai A. The use of dexmedetomidine to facilitate opioid
midine. Anesth Analg. 2007;105:374–380. and benzodiazepine detoxification in an infant. Anesth Analg. 2004;
127. Yuen VM, Hui TW, Irwin MG, Yuen MK. A comparison of intranasal 98:1658–1659, table of contents.
dexmedetomidine and oral midazolam for premedication in pediatric 152. Wheeler M, Birmingham PK, Dsida RM, et al. Uptake pharmacokinetics
anesthesia: a double-blinded randomized controlled trial. Anesth Analg. of the Fentanyl Oralet in children scheduled for central venous access
2008;106:1715–1721. removal: implications for the timing of initiating painful procedures.
128. Anttila M, Penttila J, Helminen A, et al. Bioavailability of dexmedetomi- Paediatr Anaesth. 2002;12:594–599.
dine after extravascular doses in healthy subjects. Br J Clin Pharmacol. 153. Wheeler M, Birmingham PK, Lugo RA, et al. The pharmacokinetics of
2003;56:691–693. the intravenous formulation of fentanyl citrate administered orally in
129. Petroz GC, Sikich N, James M, et al. A phase I, two-center study of the children undergoing general anesthesia. Anesth Analg. 2004;99:1347–
pharmacokinetics and pharmacodynamics of dexmedetomidine in 1351; table of contents.
children. Anesthesiology. 2006;105:1098–1110. 154. Darwish M, Kirby M, Jiang JG. Effect of buccal dwell time on the
130. Diaz SM, Rodarte A, Foley J, Capparelli EV. Pharmacokinetics of pharmacokinetic profile of fentanyl buccal tablet. Expert Opin Phar-
dexmedetomidine in postsurgical pediatric intensive care unit patients: macother. 2007;8:2011–2016.
preliminary study. Pediatr Crit Care Med. 2007;8:419–424. 155. Darwish M, Kirby M, Robertson P, et al. Absorption of fentanyl from
131. Potts AL, Warman GR, Anderson BJ. Dexmedetomidine disposition in fentanyl buccal tablet in cancer patients with or without oral mucositis:
children: a population analysis. Paediatr Anaesth. 2008;18:722–730. a pilot study. Clin Drug Investig. 2007;27:605–611.
132. Enomoto Y, Kudo T, Saito T, et al. Prolonged use of dexmedetomidine in 156. Darwish M, Kirby M, Robertson P Jr, et al. Absolute and relative
an infant with respiratory failure following living donor liver transplan- bioavailability of fentanyl buccal tablet and oral transmucosal fentanyl
tation. Paediatr Anaesth. 2006;16:1285–1288. citrate. J Clin Pharmacol. 2007;47:343–350.
133. Berkenbosch JW, Wankum PC, Tobias JD. Prospective evaluation of 157. Ashburn MA, Streisand JB, Tarver SD, et al. Oral transmucosal fentanyl
dexmedetomidine for noninvasive procedural sedation in children. citrate for premedication in paediatric outpatients. Can J Anaesth. 1990;
Pediatr Crit Care Med. 2005;6:435–439; quiz 440. 37:857–866.
134. Chrysostomou C, Di Filippo S, Manrique AM, et al. Use of dexmedeto- 158. Howell TK, Smith S, Rushman SC, et al. A comparison of oral trans-
midine in children after cardiac and thoracic surgery. Pediatr Crit Care mucosal fentanyl and oral midazolam for premedication in children.
Med. 2006;7:126–131. Anaesthesia. 2002;57:798–805.
159. Binstock W, Rubin R, Bachman C, et al. The effect of premedication with 179. Miller BR, Friesen RH. Oral atropine premedication in infants attenuates
OTFC, with or without ondansetron, on postoperative agitation, and cardiovascular depression during halothane anesthesia. Anesth Analg.
nausea and vomiting in pediatric ambulatory patients. Paediatr Anaesth. 1988;67:180–185.
2004;14:759–767. 180. Mirakhur RK, Jones CJ, Dundee JW, Archer DB. I.M. or I.V. atropine or
160. Lundeberg S, Hatava P, Lagerkranser M, Olsson GL. Perception of pain glycopyrrolate for the prevention of oculocardiac reflex in children
following rectal administration of morphine in children: a comparison undergoing squint surgery. Br J Anaesth. 1982;54:1059–1063.
of a gel and a solution. Paediatr Anaesth. 2006;16:164–169. 181. Rautakorpi P, Ali-Melkkila T, Kaila T, et al. Pharmacokinetics of
161. Duedahl TH, Dirks J, Petersen KB, et al. Intravenous dextromethorphan glycopyrrolate in children. J Clin Anesth. 1994;6:217–220.
to human volunteers: relationship between pharmacokinetics and anti- 182. Rautakorpi P, Manner T, Ali-Melkkila T, et al. Pharmacokinetics and
hyperalgesic effect. Pain. 2005;113:360–368. oral bioavailability of glycopyrrolate in children. Pharmacol Toxicol.
162. Dawson GS, Seidman P, Ramadan HH. Improved postoperative pain 1998;83:132–134.
control in pediatric adenotonsillectomy with dextromethorphan. Laryn- 183. Cartabuke RS, Davidson PJ, Warner LO. Is premedication with oral
goscope. 2001;111:1223–1226. glycopyrrolate as effective as oral atropine in attenuating cardiovascular
163. Hasan RA, Kartush JM, Thomas JD, Sigler DL. Oral dextromethorphan depression in infants receiving halothane for induction of anesthesia?
reduces perioperative analgesic administration in children undergoing Anesth Analg. 1991;73:271–274.
tympanomastoid surgery. Otolaryngol Head Neck Surg. 2004;131: 184. Salem MR, Wong AY, Mani M, et al. Premedicant drugs and gastric
711–716. juice pH and volume in pediatric patients. Anesthesiology. 1976;44:
164. Rose JB, Cuy R, Cohen DE, Schreiner MS. Preoperative oral dextrome- 216–219.
thorphan does not reduce pain or analgesic consumption in children 185. Stratelak PA, White W, Wenzel D. The effect of glycopyrrolate preme-
after adenotonsillectomy. Anesth Analg. 1999;88:749–753. dication on postoperative sore throat. AANA J. 1996;64:545–548.
165. Bjorkman S, Gabrielsson J, Quaynor H, Corbey M. Pharmacokinetics 186. Kahn A, Hasaerts D, Blum D. Phenothiazine-induced sleep apneas in
of I.V. and rectal methohexitone in children. Br J Anaesth. 1987;59: normal infants. Pediatrics. 1985;75:844–847.
1541–1547. 187. Ong BC, Ng AS, Chew SL. Oral premedications in paediatric day
166. Goresky GV, Steward DJ. Rectal methohexitone for induction of anaes- surgery. Singapore Med J. 1996;37:139–142.
thesia in children. Can Anaesth Soc J. 1979;26:213–215. 188. Ragg P, Davidson A. Comparison of the efficacy of paracetamol versus
167. Hannallah RS, Abramowitz MD, McGill WA, Epstein BS. Rectal paracetamol, codeine and promethazine (Painstop) for premedication
methohexitone induction in pediatric outpatients: physostigmine does and analgesia for myringotomy in children. Anaesth Intensive Care.
not enhance recovery. Can Anaesth Soc J. 1985;32:231–234. 1997;25:29–32.
168. Varner PD, Ebert JP, McKay RD, et al. Methohexital sedation of children 189. Desjardins R, Ansara S, Charest J. Pre-anaesthetic medication in pae-
undergoing CT scan. Anesth Analg. 1985;64:643–645. diatric day-care surgery. Can Anaesth Soc J. 1981;28:141–148.
169. Kessler P, Alemdag Y, Hill M, et al. [Intravenous sedation of sponta- 190. Schechter NL, Weisman SJ, Rosenblum M, et al. The use of oral trans-
neously breathing infants and small children before magnetic resonance mucosal fentanyl citrate for painful procedures in children. Pediatrics.
tomography. A comparison of propofol and methohexital] (German). 1995;95:335–339.
Anaesthesist. 1996;45:1158–1166. 191. Sponheim S, Aune H, Gulliksen M, Morland J. Pharmacokinetics of
170. Bauman LA, Cannon ML, McCloskey J, et al. Unconscious sedation in trimeprazine in children. Pharmacol Toxicol. 1990;67:243–245.
children: a prospective multi-arm clinical trial. Paediatr Anaesth. 2002; 192. Mitchell V, Grange C, Black A, Train J. A comparison of midazolam with
12:674–679. trimeprazine as an oral premedicant for children. Anaesthesia. 1997;52:
171. Pomeranz ES, Chudnofsky CR, Deegan TJ, et al. Rectal methohexital 416–421.
sedation for computed tomography imaging of stable pediatric emer- 193. Patel D, Meakin G. Oral midazolam compared with diazepam-
gency department patients. Pediatrics. 2000;105:1110–1114. droperidol and trimeprazine as premedicants in children. Paediatr
172. Simpson JH, West CD, Law PJ. Paediatric sedation for CT scanning: the Anaesth. 1997;7:287–293.
safety and efficacy of quinalbarbitone in a district general hospital 194. Johnson K, Page A, Williams H, et al. The use of melatonin as an alter-
setting. Br J Radiol. 2000;73:7–9. native to sedation in uncooperative children undergoing an MRI exa-
173. Mason KP, Zurakowski D, Karian VE, et al. Sedatives used in pediatric mination. Clin Radiol. 2002;57:502–506.
imaging: comparison of IV pentobarbital with IV pentobarbital with 195. Wassmer E, Carter PF, Quinn E, et al. Melatonin is useful for recording
midazolam added. AJR Am J Roentgenol. 2001;177:427–430. sleep EEGs: a prospective audit of outcome. Dev Med Child Neurol.
174. Burckart GJ, White TJ 3rd, Siegle RL, et al. Rectal thiopental versus an 2001;43:735–738.
intramuscular cocktail for sedating children before computerized 196. Sury MR, Fairweather K. The effect of melatonin on sedation of children
tomography. Am J Hosp Pharm. 1980;37:222–224. undergoing magnetic resonance imaging. Br J Anaesth. 2006;97:
175. Glasier CM, Stark JE, Brown R, et al. Rectal thiopental sodium for 220–225.
sedation of pediatric patients undergoing MR and other imaging studies. 197. Isik B, Baygin O, Bodur H. Premedication with melatonin vs midazolam
AJNR Am J Neuroradiol. 1995;16:111–114. in anxious children. Paediatr Anaesth. 2008;18:635–641.
176. Baxter AL, Mallory MD, Spandorfer PR, et al. Etomidate versus pento- 198. Samarkandi A, Naguib M, Riad W, et al. Melatonin vs. midazolam
barbital for computed tomography sedations: report from the Pediatric premedication in children: a double-blind, placebo-controlled study. Eur
Sedation Research Consortium. Pediatr Emerg Care. 2007;23:690–695. J Anaesthesiol. 2005;22:189–196.
177. Kienstra AJ, Ward MA, Sasan F, et al. Etomidate versus pentobarbital for 199. Reappraisal of lytic cocktail/demerol, phenergan, and thorazine (DPT)
sedation of children for head and neck CT imaging. Pediatr Emerg Care. for the sedation of children. American Academy of Pediatrics Com-
2004;20:499–506. mittee on Drugs. Pediatrics. 1995;95:598–602.
178. Di Liddo L, D’Angelo A, Nguyen B, et al. Etomidate versus midazolam 200. Wheeler DS, Jensen RA, Poss WB. A randomized, blinded comparison
for procedural sedation in pediatric outpatients: a randomized con- of chloral hydrate and midazolam sedation in children undergoing
trolled trial. Ann Emerg Med. 2006;48:433–440, 440 e431. echocardiography. Clin Pediatr (Phila). 2001;40:381–387.
Pharmacology of Vagal Blockers

and Antagonist Agents 31
Martin Jöhr C H A P T E R
VAGAL BLOCKERS
Vagal blockers are mainly used as anticholinergic agents to prevent
vagal disorders in pediatric anesthesia (Table 31–1).
Years ago, they were considered as an inevitable premedicant in
children. Despite a trend to omit routine administration of vagal
blockers to adults,1 many authorities believe that they are useful for
infants and children, given as a premedicant or given intravenously
at induction. The vagal response is more intense in infants and
young children than in adults, and cardiac output is highly depen-
dent on heart rate. The currently available anticholinergic agents
(Figure 31–1) have different preferences of action (Table 31–2).
Controversy on the Clinical Use of

Vagal Blockers in Pediatric Anesthesia
Scientific knowledge is clear with respect to the effects of anticho-
linergic agents on heart rate. Unclear, however, is the value of the
administration of atropine, glycopyrrolate, or scopolamine on a
routine basis to all pediatric patients.2 Overall, the use of anti-
cholinergic medication is declining in pediatric anesthesia.3 Pedi-
atric anesthetists essentially take two different positions.
TABLE 31-1. The Main Effects of Cholinergic

Stimulation and Inhibition Figure 31-1. Chemical structure of vagolytic agents.
Cholinergic Effects of
Postganglionic Cholinergic Effect of Atropine Anticholinergic Agents Are Still a Standard
Fibers Stimulation Administration for All Pediatric Patients
Eye Myosis Mydriasis and Inhalational inductions are often performed in pediatric patients,
increase in in whom dry mucous membranes may be advantageous and air-
intraocular way complications can be reduced.4 The vagal response is more
pressure intense in infants and young children than in adults, and cardiac
Heart Bradycardia Tachycardia output is highly dependent on heart rate. Atropine ensures a high
Bronchi Broncho- Bronchodilation cardiac output, is usually not related to severe side effects, and
constriction allows critical situations to be avoided. If bradycardia is already
Digestive tract Gastric/bowel Decreases spasms present, the onset of even intravenous (I.V.) atropine is delayed.5
spasms Even modern I.V. induction techniques, for example, propofol in
Urinary tract Ureter and Decreases spasms combination with remifentanil, can provoke severe bradycardia
bladder spasm and prophylactic atropine may be life-saving.
Sweating glands Hypersudation Inhibition of
(sympathetic sweating Routine Use of Anticholinergic
cholinergic fibers) Agents Is Not Essential
Salivary glands Hypersalivation Antisialogogue effect
Although it was mandatory to block secretions and vagal reflexes
Lower esophageal Sphincter Decreases sphincter
in the era of ether anesthesia, this is no longer necessary with
sphincter contraction tone
modern inhalational agents. Halothane, and especially sevoflurane,
TABLE 31-2. Currently Available Anticholinergic Agents

Atropine Glycopyrrolate Scopolamine (Hyoscine)
Ammonium compound Tertiary Quaternary Tertiary
Speed of onset ++ + ++
Duration of action + +++ +
Oral or rectal administration + – +
CNS effects + (Stimulation) – +++ (Sedation)
Tachycardia +++ ++ +
Antisialogogue effect + ++ +++
Antiemetic effect – – ++
Effective in motion sickness – – ++
CNS = central nervous system.
allows a smooth inhalational induction without excessive secre- PHYSICOCHEMICAL PROPERTIES: Atropine is an ester of tropine,
tions. Sevoflurane itself even promotes tachycardia without an organic base (tertiary amine), and tropic acid, an aromatic acid.
atropine. The use of suxamethonium in pediatric anesthesia is Its molecular weight is 289 Da.
declining, for which the routine use of atropine has been advo-
cated.6,7 The high incidence of bradycardia in pediatric patients is PHARMACOKINETIC PROPERTIES: Protein binding is 50%, and the
most often related to the occurrence of hypoxemia, in which volume of distribution is 2 to 4 L/kg. Because of the increased
oxygen and not atropine is the mainstay of treatment. Drying volume of distribution, the elimination half-life is twice as long
mucous membranes makes them more friable, and mucociliary (6.9 h) in infants than in adult patients.14,15 Infants need a higher
clearance is reduced for several hours after a single dose of atro- dose to produce an increase in heart rate.16
pine.8 Furthermore, atropine interferes with temperature regula- METABOLISM: Metabolism is hepatic by N-demethylation follow-
tion and rapidly lowers the lower esophageal sphincter pressure in ed by conjugation with glucuronic acid. The drug is partly meta-
infants and children.9 Scopolamine can be used as a sedative bolized and partly eliminated unchanged by the kidneys.17,18
premedication, but benzodiazepines (e.g., midazolam) or clonidine
is a more suitable drug. The anesthetic community has never MODE OF ACTION: Atropine antagonizes the muscarinic effects of
looked seriously at the side effects of anticholinergic agents: the dry acetylcholine. Specific action is on muscarinic receptors, both
mouth that is very uncomfortable for the patient and the friable peripheral and central, mainly located in tissues supplied by post-
mucous membranes. ganglionic parasympathetic fibers. Atropine produces the most
Since the late 1980s, the author and other pediatric anes- effective cardiac vagal block and the least drying effects (see Table
thesiologists have no longer administered anticholinergic agents 31–2).
routinely, without any evidence of harm. From today’s point of COMMERCIAL PRESENTATION: Atropine sulfate. Conservation at
view, anticholinergic agents, in common with other drugs, should ambient temperature (15–30°C). U.S. Food and Drug Admini-
be used only when clearly indicated (Table 31–3). A vagal blocker, stration (FDA) risk category C.
preferably atropine, should, however, always be drawn up and
immediately available throughout anesthesia. CLINICAL INDICATIONS: (1) Premedication (for its anticholinergic
properties; see Chapter 37), (2) prevention and treatment of
bradycardia (e.g., auriculoventricular block), (3) reversal of muscle
Atropine relaxants in conjunction with anticholinesterase agents, (4)
complementary treatment of bronchospasm, and (5) an antidote
DRUG CATEGORY: Atropine is an anticholinergic agent with para- against anitcholinesterase or organophosphate poisoning.
sympatholytic, antispasmodic, bronchodilatatory, and mydriatic
properties.
CONTRAINDICATIONS: Glaucoma, tachycardia, hyperthermia.
Careful use is advised in children with obstructive valvular heart
disease who may not tolerate tachycardia; in cases of paralytic
TABLE 31-3. Potential Indications for the Use ileus, hemorrhagic proctocolitis, gastroesophageal reflux; and
of Anticholinergic Agents in children with impaired mucociliary clearance (e.g., in cystic
fibrosis).
Clinical Situation Intention Reference
DOSAGE AND ROUTES OF ADMINISTRATION: The recommended
Difficult airway; Reduced secretions,
dose (Table 31–4) is 20 μg/kg intravenously; a minimum dose of
fiberoptic intubation improved view, of
10 μg/kg intravenously is needed to achieve one half the maximal
unproven benefit
increase of heart rate and promote sinus rhythm.16 After intra-
Airway endoscopy Reduced secretions, 10
muscular (I.M.) administration of 20 μg/kg, the time to peak effect
improved view, of
is 25 minutes19; however, for most anesthesiologists, I.M. preme-
unproven benefit
dication is no longer acceptable. A much faster onset is provided
Ketamine anesthesia Reduced secretions 11
by I.M. injection into the tongue by the submental approach.20
Squint surgery Reduced severity of the 12, 13
Schematically, the oral dose should be at least twice the I.V. dose.
oculocardiac reflex
Oral atropine, 20 and 40 μg/kg, was shown to attenuate halothane-
CHAPTER 31 ■ Pharmacology of Vagal Blockers and Antagonist Agents 509
TABLE 31-4. Clinically Used Doses of Atropine PHARMACOKINETICS AND METABOLISM: Distribution volume is
0.2 L/kg. Only 10 to 25% of the total dose is absorbed from the
Route of Commonly Used gastrointestinal tract.33 Glycopyrrolate is excreted unchanged in
Indication Administration Doses both bile and urine.34
Premedication I.V., S.C., I.M. 10–20 μg/kg CLINICAL USE AND DOSAGE: Glycopyrrolate is especially suitable
(routine use, Oral, rectal 30 μg/kg for antagonizing parasympathomimetic side effects of neostig-
(see Chapter 37) mine. The recommended dose is 10 μg/kg intravenously, half the
Bradycardia I.V. 20 μg/kg dose of atropine, together with 50 μg/kg of neostigmine. The drug
I.M. submental 20 μg/kg is as effective as atropine in preventing the oculocardiac reflex.35
tracheally 50–100 μg/kg For the treatment of acute bradycardia, however, atropine is still
(emergency) the drug of choice.
Reversal of muscle 20 μg/kg (together
relaxants with anticholines-
terase agents) Scopolamine (Hyoscine)
Bronchospasm Inhalation (rarely Children 50 μg/kg DRUG CATEGORY: Scopolamine is an anticholinergic agent. It is a
used, replaced q4–6h tertiary amine and has, by contrast to atropine, profound CNS
by ipratropium) Adolescents 25 μg/kg effects, such as sedation and amnesia. Scopolamine antagonizes
q4–6h the muscarinic effects of acetylcholine. Furthermore, the drug has
I.V. 20 μg/kg moderate antiemetic activity. Scopolamine is less effective in
blocking the cardiac vagal response and has a greater drying effect
than atropine.
induced cardiovascular depression in infants,21 with the onset of
action occurring at approximately 25 minutes. However, atropine PHARMACOKINETICS AND METABOLISM: Scopolamine has a
30 μg/kg orally was less reliable than 20 μg/kg intramuscularly.19 distribution volume of 1.4 L/kg and undergoes enzymatic hy-
Rectal administration of 30 μg/kg atropine in conjunction with a drolysis to scopine and tropic acid. The pharmacokinetics of sco-
sedative drug is commonly used in pediatric practice.22,23 Atropine polamine and especially their relation to clinical response are
50 μg/kg given intratracheally rapidly increases heart rate in poorly understood.18
anesthetized children,24 whereas after 20 μg/kg, the onset of action CLINICAL USE AND DOSAGE: The drug has largely been used as
is delayed.25 Therefore, in emergency situations, 50 to 100 μg/kg a sedative premedication (10 μg/kg intramuscularly) in conjunc-
should probably be used; however, the current American guideli- tion with I.M. morphine before cardiac surgery; resorption is
nes recommend only 30 μg/kg.26 The maximum I.V. dose in child- especially predictable after injection in the deltoid muscle.36 Rectal
ren is 50 μg/kg. administration of a slightly higher dose (25 μg/kg) compares
ADVERSE EFFECTS AND OVERDOSE: Adverse effects are dose-
favorably with I.M. application.37 The inclusion of morphine-
scopolamine in the premedication may be highly effective in
dependent (increasing order): (1) Mouth dryness, mydriasis,
reducing arrhythmias during adenoidectomy38 but causes respi-
accommodation paralysis, constipation, (2) tachycardia, headache,
ratory depression.39 In children with congenital heart disease, I.M.
hyperthermia, (3) irritability, facial erythema, urinary retention,
morphine-scopolamine causes hypercarbia and desaturation to a
and (4) confusion, delirium, convulsion, coma. The side effects
similar extent as oral midazolam,40 and therefore, monitoring
are usually related to the vagolytic action. Small doses of atropine remains essential. Overall, the use of scopolamine as a sedative
can initially lower the pulse rate by a mechanism still under premedication is declining, and in the author’s opinion, benzo-
debate.27 Because this phenomenon occurs also in vagotomized diazepines (e.g., midazolam) or clonidine is a more suitable drug.
animals, a central action may not be essential. Different affinities A scopolamine patch can be used prophylactically for motion
to subtypes of muscarinic receptors may be important. In contrast sickness41 and postoperative vomiting42–44 with moderate effective-
to adults,28 central nervous system (CNS) effects (e.g., agitation or ness.
delirium) do not seem to be a clinical problem in children; how-
ever, overdosage29 and intoxication30,31 have been reported. True ADVERSE EFFECTS AND OVERDOSE: Mydriasis owing to ocular
allergies to atropine are extremely rare, if they exist at all. Transient contamination41 as well as sedation44 and delirium45 may compli-
cutaneous reactions, however, after I.V. administration or local cate the use of scopolamine, even after topical application.
reactions after ophthalmic use are occasionally seen. DRUG INTERACTIONS: Sedative/hypnotic drugs may potentiate
DRUG INTERACTIONS: No major drug interactions occur pro- the CNS depressant effects of scopolamine.
vided atropine is not mixed with other agents in the same syringe.
The treatment of reflex bradycardia induced by vasoconstrictors Ipratropium
with atropine can result in severe hypertension.
Ipratropium is a quaternary ammonium compound and is, there-
fore, poorly absorbed when delivered via inhalation and has few
Glycopyrrolate extrapulmonary effects46; but ocular contamination has also been
reported.47,48 Although 90% of the inhaled drug is swallowed, only
DRUG CATEGORY: Glycopyrrolate is an anticholinergic agent with 1% of the total dose is absorbed systemically. The drug is used in
pronounced antisialogogue activity.32 It is a quaternary ammonium the treatment of asthma and bronchospastic disorders in conjunc-
compound and penetrates the CNS poorly. Therefore, it antago- tion with topical steroids and β stimulants.49,50 Unlike atropine,
nizes muscarinic effects of acetylcholine only outside the CNS. ipatropium has no negative effects on mucociliary clearance.
CHOLINESTERASE INHIBITORS
Anticholinesterases are mainly used to antagonize residual
neuromuscular blockade51 (neuromuscular blocking agents and their
reversal are discussed in Chapter 27). Inhibition of acetylcholines-
terase prolongs the lifetime of acetylcholine competing with the
nondepolarizing relaxant; repeated occupation of the receptors by
acetylcholine occurs, leading to reopening of ion channels. The effect
of anticholinesterases is not restricted only to inhibition of
acetylcholinesterase but also includes prejunctional acetylcholine
releasing effects and some direct effects on the postjunctional
receptor. Neostigmine and pyridostigmine are themselves hydro-
lyzed by acetylcholinesterase similarly to acetylcholine, but much
more slowly, whereas edrophonium is not.
Successful and timely reversal of neuromuscular blockade with
actylcholinesterase inhibitors is possible only when plasma levels
of the curare compound are low; this indicates that some clinical
recovery has already occurred. Reversal is substantially more rapid
in younger age groups.52–54 After administration of the anticholi-
nesterase, reversal has to be reassessed using neuromuscular
monitoring in addition to clinical signs such as sustained head lift
in older children and adolescents55 or leg lift in neonates and infants
(Table 31–5).56
Figure 31-2. Dose-response curves for neostigmine in infants,
Neostigmine children, and adults. Reproduced with permission from
DRUG CATEGORY: Neostigmine is a cholinesterase inhibitor, reference 57.
mainly used to antagonize residual neuromuscular blockade. It
binds to the enzyme and is broken down similar to acetylcholine, been some reports on the neuraxial administration of neostigmine
but much more slowly. to children61–63; however, because of relevant side effects, this
approach is mainly of theoretical interest, and in the author’s
PHARMACOKINETICS AND METABOLISM: Neostigmine has a opinion, there is no place for neuraxial neostigmine in pediatric
distribution volume of 0.5 to 1.0 L/kg and is partly metabolized. anesthesia.
The elimination half-life of neostigmine is shorter in infants Infants and children require a smaller dose (about two thirds)
(39 min standard deviation [sd] 5) and children (48 min sd 16) to antagonize residual neuromuscular blockade than adults57
than in adults (67 min sd 8), whereas distribution volumes are (Figure 31–2). There is, therefore, no justification for the excessive
similar.57 Renal failure delays plasma clearance of neostigmine and doses of neostigmine formerly used in pediatric anesthesia.
edrophonium as much as or more than that of pancuronium. Compared with edrophonium, neostigmine has been shown
CLINICAL INDICATIONS AND DOSAGE: Neostigmine 50 μg/kg is to produce less variable and more complete recovery after
well established for the reversal of residual neuromuscular block- atracurium-induced blockade52; 50 μg/kg neostigmine is, there-
ade. Neostigmine in smaller doses (e.g., 10 μg/kg as a continuous fore, preferred for reversal in pediatric patients by most authorities.
infusion over 30 minutes) may occasionally be used in post- ADVERSE EFFECTS: Signs of increased parasympathomimetic
operative paralytic ileus. Neostigmine, 10 to 40 μg/kg intramus- stimulation may occur (e.g., bradycardia, atrioventricular block,
cularly or subcutaneously as needed, or orally (according to effect, increased oral and bronchial secretions, or emesis and abdominal
~2 mg/kg/d), is used in myasthenia gravis.58 For chronic treat- cramps). The time course of action of neostigmine is suitably
ment, however, oral pyridostigmine is the drug of choice. matched by glycopyrrolate; simultaneous administration of both
Intrathecal neostigmine has been reported to produce spinally drugs in a ratio of 1:5 results in a stable heart rate.
mediated analgesia in a dose-dependent fashion.59,60 There have
Edrophonium
TABLE 31-5. Cholinesterase Inhibitors
DRUG CATEGORY: Edrophonium is a cholinesterase inhibitor,
Neostigmine Edrophonium mainly used to antagonize residual neuromuscular blockade.
Onset of action 7–11 min 1–2 min PHARMACOKINETIS AND METABOLISM: Edrophonium has a dis-
Duration of action ++ + tribution volume of 1.1 L/kg; in part, hepatic metabolism occurs
(clinical duration 1–2 h by conjugation with glucuronic acid. Elimination half-life and
with both drugs) distribution volumes of edrophonium are similar in infants,
Usual dose 50 μg/kg 1.0 mg/kg children, and adults.64
Vagolytic agent of choice Glycopyrrolate Atropine
Elimination 50% renal 70% renal MODE OF ACTION: Edrophonium inhibits acetylcholinesterase.
T/ Edrophonium has a more pronounced prejunctional effect than
1 β
2 20–80 min 30–110 min
neostigmine; however, the clinical importance of this finding is
not completely understood. Edrophonium shows the greatest glaucoma and convergent strabismus. Because the drug is syste-
selectivity between acetylcholinesterase and plasma cholinesterase, mically absorbed and inactivates plasma cholinesterase, prolonged
the serum esterase that hydrolyzes succinylcholine and miva- action of succinylcholine and probably mivacurium can occur.74
curium. This is, however, not of clinical significance in the anta- The drug is rarely used in children, however.
gonism of a mivacurium-induced blockade because the difference
in selectivity is minimal at clinically reached concentrations.65
Furthermore, at the time when reversal is attempted, the plasma SELECTIVE RELAXANT
concentrations of mivacurium are already very low, and in patients BINDING AGENTS
with atypical cholinesterase, metabolism is minimal anyway.
Selectively binding and encapsulating the active compound is a
CLINICAL INDICATIONS AND DOSAGE: Edrophonium is preferred new concept for reversing neuromuscular blockade.75,76 The first
to neostigmine by some clinicians for reversing neuromuscular drug of this class used in medicine is sugammadex, a modified
blockade because of its faster onset of action and probably fewer gamma-cyclodextrin that specifically encapsulates and binds the
muscarinic side effects. Smaller doses of edrophonium (e.g., 0.03– aminosteroid neuromuscular blocking agents: Rocuronium
0.1 mg/kg) may be used for diagnostic purposes in cases of myas- > vecuronium >> pancuronium. By contrast to cholinesterase inhi-
thenia gravis. By contrast to neostigmine, infants and children bitors, sugammadex can successfully reverse even very profound
require equal or slightly higher doses than adults to antagonize blockade (e.g., 3 min after the administration of rocuronium
neuromuscular blockade.64 A dose of 1 mg/kg is usually recom- 1.2 mg/kg).77 High-dose rocuronium followed by sugammadex
mended. Compared with neostigmine, edrophonium provides a could have a profile similar to that of succinylcholine.
more rapid onset52,54 of reversal, but a less reliable final recovery.52
In particular, profound degrees of blockade are less reliably anta-
gonized by edrophonium.66,67 Sugammadex
ADVERSE EFFECTS: The time course of action of edrophonium DRUG CATEGORY: Sugammadex (designation Org 25969) is a
requires a rapid-acting vagolytic agent68; atropine 10 μg/kg modified gamma-cyclodextrin with a lipophilic core and a hydro-
30 seconds before edrophonium 1 mg/kg ensures minimal cardio- philic periphery (Figure 31–3). The molecular weight of sugam-
vascular changes.64 madex sodium salt is 2178 Da.
PHARMACOKINETICS AND METABOLISM: Sugammadex rapidly
Pyridostigmine binds rocuronium; equimolar doses should be sufficient to
antagonize the blockade (~4 mg sugammadex antagonizes 1 mg
Pyridostigmine has a slightly slower onset of action than neostig- rocuronium). Most sugammadex is excreted unchanged in the
mine. However, the drug is rarely used in pediatric anesthesia. urine. Sugammadex is biologically inactive, does not bind to
Oral pyridostigmine has a place in the treatment of myasthenia plasma proteins, and appears to be safe and well tolerated.
gravis.69,70 It has to be given in up to 10 times higher doses com-
pared with the I.V. route: 0.3 to 4 mg/kg orally every 4 to 6 hours CLINICAL USE AND DOSAGE: The recommended doses depend
may be required. The treatment of myasthenia gravis requires the on the depth of the blockade (Table 31–6). At the time of this
expertise a pediatric neurologist.
Physostigmine
DRUG CATEGORY: Physostigmine, a cholinesterase inhibitor, is a
tertiary ammonium compound and, therefore, has profound CNS
effects.
PHARMACOKINETICS AND METABOLISM: The drug has an elimi-
nation half-life of 20 to 30 minutes. It is destroyed by hydrolysis at
the ester linkage.
CLINICAL USE AND DOSAGE: A dose of 10 to 30 μg/kg intra-
venously (a typical initial pediatric dose is 0.5 mg) can be used to
treat unwanted CNS effects of scopolamine or atropine71; careful
monitoring for bradycardia is essential. Toxicity associated with
physostigmine consists mostly of seizures and cardiac arrhythmia
and occurs when used in the absence of anticholinergic symptoms.
In any case, its routine administration in case of emergence
delirium cannot be recommended.72 For intoxications with long-
acting compounds (e.g., biperidine), a continuous infusion with Figure 31-3. Sugammadex, a gamma-cyclodextrin, is encapsu-
30 μg/kg/h may be suitable.73 lating rocurium. Reproduced with permission from Bom A,
Bradley M, Cameron K, et al. A novel concept of reversing
neuromuscular block: chemical encapsulation of rocuronium
Echothiopate Iodide bromide by a cyclodextrin-based synthetic host. Angew Chem
Echothiopate iodide (phospholine iodide), an irreversible cho- Int Ed Engl. 2002;41:266–270. Copyright Wiley-VCH Verlag
linesterase inhibitor, is exclusively used topically for open-angle GmbH & Co. KGaA.
TABLE 31-6. Currently Used Doses of Sugammadex TABLE 31-7. Dosage of Naloxone
Indication Features Dose, mg/kg Indication Recommended Dose of Naloxone
Routine reversal Onto three twitches in 2 Side Effects of Systemic
the train-of-four Opioids
Profound blockade Yes it is OK, Merci. 4 Respiratory depression 1–2 μg/kg, repeated q2–3min as
needed
Emergency reversal Early after rocuronium 16
Side Effects of Neuraxial
up to 1.2 mg/kg
Morphine 1–4 μg/kg, repeated q2–3min as
needed;
writing, the clinical experience with sugammadex in children is Respiratory depression 3–5 μg/kg/h continuous infusion
still very limited. and somnolence
Urinary retention 1–2 μg/kg; 3–5 μg/kg/h continuous
infusion
OPIOID ANTAGONISTS Pruritus 1–2 μg/kg; 0.5–1.0 μg/kg/h
continuous infusion
Naloxone Nausea and vomiting 0.5–1.0 μg/kg/h continuous
DRUG CATEGORY: Naloxone is a pure opioid antagonist with a infusion, limited efficacy
greater affinity for mu receptors than for delta or kappa receptors Suspected opioid 0.1 mg/kg for infants and children
(the partial antagonists, e.g., nalbuphine, are discussed in Chapter intoxication in the ≤ 20 kg or ≤5 y
25). The use of nalorphine, a less specific antagonist, is no longer emergency setting 2.0 mg for children > 20 kg or > 5 y
considered to be state-of-the-art. (titration using smaller doses
may be advantageous)
PHARMACOKINETICS AND METABOLISM: After I.V. admini-
Neonatal resuscitation 0.01–0.1 mg/kg intravenously,
stration, the onset of action is seen within 30 to 90 seconds. Naloxone intramuscularly, or intratra-
is metabolized primarily in the liver by conjugation with glucuronic cheally (emergency setting
acid, with an elimination half-life of 60 to 90 minutes in adults and 0.1 mg/kg)
over 3 hours in neonates. The duration of action is substantially
shorter than that of most opioid agonists. Naloxone can be given
intratracheally as well as intravenously or intramuscularly. in adults. This approach, however, has not entered clinical practice.
Nalmefene has a terminal half-life of 8.7 hours in children,87 which
CLINICAL USE AND DOSAGE: Naloxone’s indication is the reversal is similar to that seen in adults. However, experience with these
of unwanted opioid effects such as respiratory depression, pruri- drugs in pediatric patients is very limited. Naltrexone has been used
tus, and urinary retention. Careful titration is essential (Table with moderate success in autistic children.88
31–7) to restore adequate spontaneous ventilation without reversal
of analgesia. An initial dose of 1 to 2 μg/kg intravenously, repeated
every 2 to 3 minutes as needed, is usually adequate. Substantially ANTAGONIST OF BENZODIAZEPINES
higher doses are used for neonatal resuscitation or in the emergency
setting.26 Flumazenil
The author’s strong belief is that there is no place for routine DRUG CATEGORY: Flumazenil is a specific competitive antago-
opioid antagonism in pediatric anesthesia. The drug may be nist at the benzodiazepine receptor, which is associated with
occasionally used, however, to antagonize side effects of neuraxial receptors for gamma-aminobutyric acid (GABA), the most
opioids such as urinary retention or pruritus.78 Prophylactic important inhibitory neurotransmitter in the CNS. Stimulation of
naloxone for this indication is not consistently effective; a high the GABA pathways produces anxiolysis, sedation, and muscle
incidence of urinary retention in children was still reported after relaxation. Flumazenil reverses these effects of benzodiazepines
intrathecal morphine despite a prophylactic naloxone infusion.79 (Table 31–8).
The co-administration of I.V. naloxone with I.V. morphine in
order to reduce the incidence of side effects was reported to be PHARMACOKINETICS AND METABOLISM: Flumazenil has a
beneficial in some80–82 but not all83,84 studies. Despite encouraging shorter duration of action than most benzodiazepines. The
results in children,82 today, this concept is rarely used. volume of distribution is 0.77 to 1.6 L/kg, the elimination half-life
is 0.7 to 1.3 hours, and the drug is cleared rapidly by the liver,
ADVERSE EFFECTS: The side effects are caused by the abrupt metabolized, and excreted in the urine.90 Because the duration and
cessation of the opioid effects. Therefore, severe pain and sym- degree of reversal depend on the plasma concentration of benzo-
pathetic activation with hypertension and tachycardia can result. diazepine as well as the amount of flumazenil given, the sedative
and respiratory depressant effects of the benzodiazepine may last
Naltrexone, Nalmefene longer than the antagonism produced by flumazenil.91
Naltrexone and nalmefene are both orally active, long-acting, pure CLINICAL USE AND DOSAGE: Flumazenil is usually administered
opioid antagonists with a greater affinity for mu-receptors than for intravenously. Rectal92,93 and sublingual administration is feasible,
delta or kappa receptors. Oral naltrexone85 and nalmefene86 have but the onset of action is slower.94 After endotracheal admini-
both been reported to reduce the side effects of epidural morphine stration of 1 mg flumazenil to adults, the peak plasma concentration
TABLE 31-8. Reciprocal Dose Effects of Benzodiazepine ANTAGONISTS OF

Agonists and Flumazenil COAGULATION DISORDERS
Flumazenil Postulated Protamine
Reversal Receptor
Effect BZ Agonist of the Effect Occupancy, % DRUG CATEGORY: Protamine sulfate is a polycationic, strongly
basic protein with a molecular weight of approximately 4500 Da.
Anxiolysis Low dose High dose 20–30 It is extracted from the mature testes of fish of the family
needed needed Samonidae. Protamine combines ionically with heparin to form a
Anticonvulsive 20–30 stable complex that is devoid of anticoagulant activity.
effect
Slight sedation 20–30 PHARMACOKINETICS AND METABOLISM: The antiheparin activity
Reduced attention 20–30 starts 30 to 60 seconds after protamine administration and peaks
Amnesia 50 at about 5 minutes, with a clinical duration of approximately
Intense sedation 50 2 hours. Protamine is eliminated by renal and hepatic pathways; in
Muscle relaxation 60–90 animals, the half-life of the heparin-protamine complex was found
Hypnosis High dose Low dose 60–90 to be 24 minutes.
BZ = benzodiazepine. CLINICAL USE AND DOSAGE: Protamine is used to antagonize
From reference 89. excess heparin after cardiopulmonary bypass or accidental heparin
overdose. Protamine has limited effectiveness against low-
is attained within 1 minute after administration.95 A dose of 10 μg/ molecular-weight heparin,111,112 and it is not active at all against
kg flumazenil intravenously may be effective after moderate doses fondaparinux. One unit of protamine inactivates 1 unit of heparin;
of midazolam; the rectal doses may be higher (e.g., 50 μg/kg). however, the exact ratio depends on the type of heparin used.
Although effective,96 antagonism of benzodiazepine effects Because heparin is eliminated with a dose-dependent half-life of
is rarely indicated. There is no place for routine antagonism 1 to 5 hours, the protamine dose may be reduced depending on the
of bezodiazepine-induced sedation and anxiolysis in pediatric timing of heparin administration (Table 31–10). After high doses,
anesthesia. Flumazenil, however, may be useful in certain cir- for example, after cardiopulmonary bypass, an identical number of
cumstances (Table 31–9). units of protamine as that of heparin is often administered,
Paradoxical reactions to benzodiazepines occasionally occur.97,98 although individualized dosing may be advantageous.113
More common causes of agitation, however, are inadequate seda-
tion and medical interventions in a frightened child. In true ADVERSE EFFECTS AND OVERDOSE: Various side effects occur
paradoxical reactions, flumazenil can be successfully used.99,100 (Table 31–11).115 Rapid administration causes hypotension owing
Even in delayed postoperative agitation after preoperative to pulmonary vasoconstriction, myocardial depression, and
midazolam, the use of flumazenil may be advantageous.101 histamine release116–118; anaphylactic or anaphylactoid reactions
Flumazenil-induced reversal of midazolam has been reported may occur.119 Therefore, protamine should be given as a slow
for the wake-up test during scoliosis surgery.102,103 infusion.120 Female sex, larger protamine dose, and smaller
Flumazenil reverses benzodiazepine-induced airway obstruc- heparin dose are each associated with increased risk.121 Despite
tion.104,105 In the author’s experience, in rare cases, this effect has limited effectiveness,122 many protocols include the prophylactic
been helpful to ameliorate postoperative airway obstruction in administration of histamine antagonists (e.g., clemastine 0.02 mg/
children with obstructive sleep apnea. kg). An especially high incidence of anaphylactic reactions has
Although the use of flumazenil in comatose adult patients for been reported in adult insulin-treated diabetics.123
the diagnosis of drug overdose is being reexamined,106,107 there is In the absence of heparin, protamine interacts with platelets
still a place for the empirical administration of both naloxone and and many proteins, including fibrinogen; these interactions may
flumazenil in children.108 In comas not caused by benzodiazepines, account for its own anticoagulant activity.
flumazenil was not consistently effective.109
ADVERSE EFFECTS: The main problems are inadequate sedation Desmopressin
and anxiety after acute benzodiazepine withdrawal. Seizures have
also been reported.110 DRUG CATEGORY: Desmopressin (DDAVP) is a synthetic analogue
(1-desamino-8-D-arginine-vasopressin) of the natural hormone
vasopressin. The molecular changes produce prolonged antidiuretic
TABLE 31-9. The Clinical Use of Flumazenil in
Pediatric Anesthesia
Route of TABLE 31-10. Protamine Dosage in Relation to Time
Indications Administration of Heparin Administration
Paradoxical reactions to benzodiazepines I.V. or rectal Delay After Heparin

Wake-up test in scoliosis surgery I.V. Administration Protamine Dosage
Benzodiazepine overdose I.V. <30 min 1.0 unit protamine/1 unit heparin
Diagnostic use in a comatose children I.V. 30–60 min 0.5 unit protamine/1 unit heparin
Postoperative airway obstruction after I.V. <2 h 0.25 unit protamine/1 unit heparin
benzodiazepine premedication
From reference 114.
TABLE 31-11. Side Effects of Protamine TABLE 31-12. Dosage of Desmopressin in the Treatment
of Diabetes Insipidus
Cardiovascular System Hypotension, Flush, Bradycardia
Infants Children Adolescents
Respiratory system Bronchoconstriction, dyspnea,
pulmonary hypertension Intravenously or 0.1 μg as 0.4–1.0 μg 1–4 μg
Allergic reactions Anaphylactic or anaphylactoid intramuscularly needed 1–2 × daily 1–2 × daily
reactions Nasally 1.0 μg as 5–15 μg 10–40 μg
Overdose Increased bleeding needed 1-2 × daily 1–2 × daily
Orally 0.1–0.2 mg 0.1–0.2 mg
3 × daily 3 × daily
activity and reduced cardiovascular effects compared with the original
substance, L-arginine-vasopressin. The vasopressin2 (V2) effect
stimulates endothelial cells to release von Willebrand’s factor, In general, in patients without a pre-existing bleeding disorder,
tissue plasminogen activator (TPA), and certain prostaglandins. DDAVP is not considered effective for prevention of bleeding (e.g.,
PHARMACOKINETICS AND METABOLISM: DDAVP is during cardiac132–136 or scoliosis137–139 surgery). Reduced bleeding
metabolized in the liver and different other sites with a terminal has, however, been reported in one trial.140
half-life of 4 to 5 hours, independent of the way of administration. For the treatment of diabetes insipidus, DDAVP can be admini-
stered by various routes: I.V., I.M., intranasal, or oral (Table
CLINICAL USE AND DOSAGE: DDAVP induces release of von
31–12). Administration of DDAVP is part of some treatment
Willebrand’s factor, TPA and certain prostaglandins by the endo-
concepts for enuresis nocturna.141
thelial cells. It therefore ameliorates hemostasis in most patients
with von Willebrand’s disease (type I vWD),124,125 mild hemophilia ADVERSE EFFECTS AND OVERDOSE: The side effects after rapid
A (with a residual factor VIII activity > 10%),126 and a variety of administration of large doses include flushing, hypotension, and
congenital and acquired thrombopathies.127,128 DDAVP has been tachycardia. Especially in pediatric patients, careful observation
postulated to reduce bleeding in aspirin-pretreated adult cardiac for water retention leading to hyponatremia and brain edema is
patients,129 but this is of questionable value.130 needed.142–144 Regular monitoring of urine output, urine osmola-
Specialized hematologic advice should be obtained in each rity, serum osmolarity, and serum concentrations of sodium and
individual case; in type IIb vWD, DDAVP administration is potassium ise essential.
generally contraindicated, because thrombocytopenia may result.
In Glanzmann’s thrombasthenia, the drug is not effective.
The usual I.V. dose of DDAVP to improve hemostasis is 0.4 μg/ Aprotinin, Tranexamic Acid,
kg IV over 30 minutes, starting 1 to 1.5 hours before surgery. Intra- Aminocaproic Acid
nasal administration of 300 μg may be appropriate in adolescents
These drugs inhibit proteinases and are used to reduce bleeding
with vWD for minor surgery or dental extractions.131
thought to be caused by hyperfibrinolytic states (Table 31–13),
When the drug is administered during or immediately before
surgery, the release of TPA and induction of fibrinolysis may most often in conjunction with cardiac surgery.145,146 For aprotinin,
theoretically be a problem. However, the concentrations of TPA prophylactic administration is essential; tranexamic acid and
tend to fall much more rapidly compared with Factor VIII levels aminocaproic acid can be used therapeutically. There is currently
(Fig. 31–4). Co-administration of tranexamic acid or aminocaproic a discussion concerning the safety of aprotinin; at the time of this
acid has been recommended. writing, this drug has been temporarily withdrawn from the
market.
Aprotinin
DRUG CATEGORY: Aprotinin, a highly basic polypeptide, is a
proteinase inhibitor that binds to a variety of enzymes (e.g.,
plasmin, trypsin, and kallikrein). Although the mechanism of
action has not yet been clearly established, it appears that aprotinin
has a protective effect on platelet function147 and an antifibrinolytic
activity via direct inhibition of plasmin and the kinin-kallikrein
system. Aprotinin may also partially inhibit the intrinsic coagula-
tion pathway. Overall, evidence indicates that aprotinin attenuates
the systemic inflammatory response associated with cardiopul-
monary bypass.148–150
PHARMACOKINETICS AND METABOLISM: Aprotinin is of bovine
origin and is metabolized in peripheral cells to small metabolites.
Figure 31-4. Time course of release of Factor VIII, von Wille- CLINICAL USE AND DOSAGE: Aprotinin reduced blood loss after
brand factor (vWf) and tissue plasminogen activator (tPA) after pediatric cardiac surgery in some151–153 but not all154 trials. It has
the administration of 0.4 μg/kg desmopressin. The plasma level become a routine part of practice (Table 31–14) in a large number
of tPA rapidly decreases. Reproduced with permission from ref- of pediatric heart centers155,156 and is recommended especially for
erence 128. reoperations and complex surgery with multiple suture lines.
TABLE 31-13. Comparison of Aprotinin and Tranexamic Acid and Aminocaproic Acid
Aprotinin Tranexamic Acid and Aminocaproic Acid
Source Bovine Synthetic
Costs Very high Low
Elimination Peripheral metabolism Renal elimination, unchanged
Mechanism of action Multifactorial Inhibition of fibrinolysis
Side effects Allergic reactions Rare, myopathy reported
Renal failure
Increased long-term mortality in adults
Cardiac surgery Clearly effective Moderately effective
Miscellaneous indications Liver transplantation Oral bleeding (especially in conjunction with
hemophilia or von Willebrand’s disease)
Pediatric lung transplantation Bleeding from the lower urinary tract
Major orthopedic surgery Gastrointestinal bleeding
Hereditary angioneurotic edema
Bleeding during fibrinolytic treatment
Aprotinin reduces blood loss157 and improves hemodynamic fibrinolysis in renal bleeding, however, can lead to obstructive
stability158 in liver transplantation. Positive effects have also been uropathy, and the drug is therefore contraindicated.
reported in pediatric lung transplantation159 and scoliosis sur- Aminocaproic acid is theoretically capable of competitively
gery.160 In adults, decreased blood loss was shown after major inhibiting thrombolytic agents such as streptokinase, urokinase,
orthopedic surgery161 and in total hip162,163 and knee164 replace- and TPA. However, the profound hemostatic deficits after fib-
ment. Improved hemostatis was not evident, however, after aortic rinolytic therapy are a result of the interaction of circulating fibrin
surgery.165 and fibrinogen degradation products with the platelet surface and
with fibrinogen polymerization.
ADVERSE EFFECTS: The main drawbacks of aprotinin are the
Aminocaproic acid has been used to reduce postoperative
potential for anaphylactic reactions166 and the substantial cost. The
cardiac surgical bleeding in adults168 and children.173 A loading
drug should be administered by slow infusion; a test dose of 10,000
dose of 100 to 200 mg/kg is infused over 30 to 60 minutes, which
units some minutes in advance is recommended.
is followed by 30 mg/kg/h.174
In adults, the use of aprotinin has been related to an increased
mortality in cardiac surgery167 and to a higher rate of renal failure Aminocaproic acid is administered in conjunction with
after cardiac168 or spine surgery.169 No adverse effects of aprotinin DDAVP or factor replacement therapy to reduce oral bleeding in
on renal or hepatic function have been reported in pediatric patients with hemophilia A, hemophilia B, or vWD. The drug is
studies so far.155 The incidence of deep venous162,163 or arterial also used to prevent exacerbations in patients with hereditary
graft170 thrombosis is not increased. In vitro coagulation is in- angioneurotic edema.
fluenced by aprotinin: if kaolin is employed as an activator of the ADVERSE EFFECTS: Severe side effects rarely occur, but hypoten-
activated clotting time (ACT), aprotinin is bound to this activator sion, bradycardia, and arrhythmias have been reported following
and is, therefore, unable to develop its anticoagulatory properties rapid I.V. administration. With prolonged treatment, muscle pain
in vitro. The celite ACT produces reliable results.171 and rhabdomyolysis may occur. A reversible myopathy has been
described in a child.175
Aminocaproic Acid
DRUG CATEGORY: Aminocaproic acid (epsilon-aminocaproic acid Tranexamic Acid
[EACA]), a synthetic lysine analogue, is a competitive inhibitor of DRUG CATEGORY: Tranexamic acid is a lysine analogue that
plasminogen and plasmin. Most of the drug is recovered unmeta- competitively binds to the lysine-binding sites of plasmin
bolized in the urine. and plasminogen. It inhibits fibrinolysis with a 6- to 10-fold
CLINICAL USE AND DOSAGE: Aminocaproic acid is indicated in greater potency than aminocaproic acid and is used for similar
the treatment of bleeding owing to primary fibrinolysis. Fibrinoly- indications.
sis associated with surgery of the lower genitourinary tract has PHARMACOKINETICS: The drug is eliminated unchanged by the
been successfully treated with aminocaproic acid.172 Inhibition of kidneys with a terminal elimination half life of 1.9 to 2.7 hours in
adults.
TABLE 31-14. Dosage of Aprotinin for Cardiac Surgery CLINICAL USE AND DOSAGE: Tranexamic acid has been shown to
Before Sternotomy 30,000 units/kg reduce blood loss after adult cardiac surgery.168 In pediatric
patients, a single dose of 50 mg/kg showed only a moderate effect
CPB priming dose 30,000 units/kg in subgroups.176 Efficacy is improved using higher doses followed
During surgery 7000 units/kg/h continuous infusion by a continuous infusion (Table 31–15).177 Beneficial effects have
CPB = cardiopulmonary bypass. been shown in spine surgery as well.178
TABLE 31-15. High-dose Treatment with Tranexamic

Acid for Repeat Cardiac Surgery
Before Sternotomy 100 mg/kg
CPB priming dose 100 mg/kg
During surgery 10 mg/kg/h continuous infusion
CPB = cardiopulmonary bypass.
From reference 177.
TABLE 31-16. Tranexamic Acid in Oral Bleeding in

Hemophilia Patients
Intravenous route 3 × 10 mg/kg, ≤3 × 1.0 g
Oral route 3 × 25 mg/kg (≤3 × 1.5 g)
Mouth wash for 5% prepared by diluting 10%
cooperative children I.V. solution 1:1 with saline
Smaller doses of tranexamic acid (Table 31–16) are effective in Figure 31-5. Schematic view of the coagulation pathway.
conjunction with DDAVP or factor replacement therapy to reduce
oral bleeding in patients with hemophilia A, hemophilia B, or Factor VIII
vWD.126
DRUG CATEGORY: Coagulation factor, a plasma-derived or
ADVERSE EFFECTS: Severe side effects rarely occur, although recombinant protein, molecular weight 270 kDa, in lyophilized
rhabdomyolysis and renal insufficiency have also been re- form to be stored at 2° to 8°C, and to be used within 3 hours after
ported. Inhibition of fibrinolysis in renal bleeding can lead to reconstitution. The currently used plasma-derived products are
obstructive uropathy, and tranexamic acid is therefore contrain- monoclonal antibody–purified and undergo a viral attenuation
dicated. process with a solvent detergent or by pasteurization.
PHARMACOKINETIC PROPERTIES: One unit of Factor VIII raises
Antihemophilic Factors the plasma level by approximately 2% (0.02 U/mL). Its half-life in
the circulation is biphasic, averaging approximately 12 hours.
Congenital (e.g., hemophilia A and B) or acquired defects of the
CLINICAL USE AND DOSAGE: Factor replacement therapy guidelines
coagulation pathway (Figure 31–5) may need factor replacement for hemorrhage related to hemophilia are outlined in Table 31–18.
therapy. It is important to specify that, even in case of mild forms In addition of factor replacement, antifibrinolytics are used in oral
of hemophilia (Table 31–17), in which spontaneous bleeding bleeding (see Chapters 32 and 53), and prednisone, 1 to 2 mg/kg/d
rarely occurs, replacement therapy is crucial in case of major for 5 to 7 days in case of hematuria.
trauma or surgery. Specialized hematologic advice should be Subsequent dosing usually includes 50% of the initial dose
obtained in each individual case. every 8 to 12 hours for Factor VIII and every 12 to 24 hours for
A variety of plasma-derived or recombinant products are Factor XI. In severe bleeding, continuous infusions may be
available throughout the different countries. The increase in considered when high-purity preparations are available. Rigorous
quality since about 2000 has markedly increased cost. daily laboratory monitoring of factor levels is mandatory.
TABLE 31-17. Laboratory and Clinical Manifestations of Hemophilia

Factor VIII/IX activity level Severe Moderate Mild
Normal 50–150% (0.5–1 U/ml) < 1% 1–5% > 5%
% of all hemophilia A 70 15 5
% of all hemophilia B 50 30 20
Bleeding Manifestations
Age of onset <1 y 1–2 y 2 y–adult
Neonatal symptoms PCB usually PCB usually PCB one
ICH occasionally ICH uncommonly ICH rare
Muscle/joint hemorrhage “Spontaneous” Minor trauma Major trauma
CNS hemorrhage High risk Moderate risk Rare
Postsurgical hemorrhage without Frank bleeding, severe Wound bleeding common Wound bleeding with factor
prophylaxis < 3%
Oral hemorrhage after tooth extraction Usual Common Often
CNS, central nervous system; ICH, intracranial hemorrhage; PCB, postcircumcision bleeding.
Adapted from Hathaway W, Goodnight S: Disorders of hemostasis and thrombosis, New York, McGraw-Hill, 1993.
TABLE 31-18. Guidelines for Factor Replacement Therapy PHARMACOKINETIC PROPERTIES: One unit of Factor IX raises the
for Hemorrhage in Hemophilia plasma level by approximately 1% (0.01 U/mL), having a larger
volume of distribution than that of Factor VIII. Factor IX has a
Hemophilia Hemophilia plasma half-life averaging approximately 24 hours.
Hemostatic A Initial B Initial
Factor Dose Factor Dose Factor CLINICAL USE AND DOSAGE: Factor replacement therapy guide-
Bleeding Level, % VIII, U/kg VIII, U/kg lines for hemorrhage related to hemophilia are outlined in Table 31–
18, the guidelines for prophylactic substitution are in Table 31–19.
Mild 15–25 15–25 25–30
● Low-risk site
Low-purity, Factor IX–containing concentrates can be used to
replace all vitamin K–dependent factors in order to acutely
Moderate 25–50 25–40 40–60
● Joint, muscle
antagonize oral anticoagulation.
Severe >60 50–70 80–100 ADVERSE EFFECTS: As with Factor VIII, the risks of potential virus
● CNS bleeding
transmission and inhibitor development exist (see Chapter 53). Low-
● Mouth floor
purity, Factor IX–containing concentrates can contain significant
or tongue amounts of activated Factors VII and X and prothrombin; therefore,
● Trauma or surgery
these products have been implicated as causes of disseminated
CNS = central nervous system. intravascular coagulation and thrombosis.
Prophylactic factor replacement is proposed to reduce the Factor VII

incidence of hemarthroses with subsequent irreversible joint DRUG CATEGORY: Factor VII is plasma-derived coagulation factor
injury (Table 31–19). Implanted central venous access devices may in lyophilized form to be stored at 2° to 8°C, for immediate use
be useful. after reconstitution.
Recombinant or highly purified products do not contain von PHARMACOKINETIC PROPERTIES: One unit of Factor VII raises
Willebrand factor, which has a critical role in platelet function and the plasma level by approximately 2% (0.02 U/mL). The half-life
thrombus formation and is the carrier protein for Factor VIII in in the circulation averages 4 to 6 hours.
plasma.
CLINICAL USE AND DOSAGE: The product is exclusively used in
ADVERSE EFFECTS: During the early 1980s, high percentages of the case of isolated Factor VII deficiency. Initial dosing is similar
patients with hemophilia were infected with HIV and hepatitis C. to that for Factor VIII, but repeat doses have to be given more
Donor screening, as well as modern purifying and viral inacti- often, every 6 to 8 hours.
vation technologies, minimized these risks. Recombinant products
appear to be safe.
Development of polyclonal antibodies to Factor VIII or IX Activated Factor VII
that “inhibit” factor coagulant activity is one of the most life- DRUG CATEGORY: Activated Factor VII is a recombinant acti-
threatening complications. Inhibitors develop in 20 to 33% of per- vated coagulation factor, in lyophilized form to be stored at 2° to
sons with moderate to severe hemophilia A; however, inhibitors 8°C, a glycoprotein, similar to the human plasma–derived com-
occur only in 1 to 4% of persons with hemophilia B; inhibitors are pound.
measured in Bethesda units (BUs). The treatment for bleeding in
PHARMACOKINETIC PROPERTIES: The half-life in the circulation
the presence of an inhibitor can be challenging: in cases with low
averages 3 hours.
Bethesda titers, replacement therapy with higher doses of factor
is feasible. Further options are activated Factor VII, temporary CLINICAL USE AND DOSAGE: The product is indicated in normal
removal of the antibody by plasmapheresis, or the use of porcine or hemophiliac patients with inhibitors against Factor VIII or
Factor VIII or prothrombin complex concentrates. IX.179 The initial dosing is 60 to 120 μg/kg as I.V. injection, re-
peated doses may be administered every 2 to 4 hours. It is being
Factor IX increasingly used in uncontrollable hemorrhage of other origin in
adults and in children.180,181 The rationale for its use in hemorrhage
DRUG CATEGORY: Coagulation factor, a plasma-derived glyco- is that it will only induce coagulation at those sites where tissue
protein, molecular weight 68 kDa, in lyophilized form to be stored factor is also present and, therefore, initiates clot formation,
at 2° to 8°C and to be used within 3 hours after reconstitution. sealing the disrupted vessel.
The currently used products are purified and undergo a viral
attenuation process.
Factor I, Fibrinogen
DRUG CATEGORY: Factor I, fibrinogen, is a plasma-derived coa-
TABLE 31-19. Guidelines for Prophylactic Factor gulation factor in lyophilized form to be stored at 2° to 8°C, for
Replacement in Hemophilia immediate use after reconstitution. It is a glycoprotein with a
molecular weight of 340 kDA.
Dose, U/kg Number of Doses
Hemophilia A 20–30 3 Doses weekly
PHARMACOKINETIC PROPERTIES: The metabolic half-life averages
96 to 144 hours. Fibrinogen is an acute-phase protein, elevated in
Hemophilia B 30–40 2 Doses weekly
any form of inflammation.
CLINICAL USE AND DOSAGE: Sufficient amounts of fibrinogen TABLE 31-20. Dosage of N-Acetylcysteine as a
are needed to form a stable hemostatic plug or clot. The product Mucolytic Drug
is indicated in acute bleeding when insufficient clot firmness is
suspected (e.g., by modified thrombelastography). The commonly Infants 2 × 100 mg daily orally
used initial dose is 30 mg/kg, given as a rapid I.V. infusion. The Children 2–7 y of age 2 × 200 mg daily orally
perioperative treatment of congenital afibrinogenemia requires Children > 7 y and adults 3 × 200 mg daily orally
specialized hematologic advice.182 Intensive treatment, all pediatric 2–3 × 300 mg intravenously
age groups daily
ANTAGONIST OF
MALIGNANT HYPERTHERMIA ANTAGONIST OF ACETAMINOPHEN
(PARACETAMOL) TOXICITY
Dantrolene
DRUG CATEGORY: Dantrolene is a hydantoin drug initially used
N-Acetylcysteine
for the treatment of spasticity. Its primary action is to reduce DRUG CATEGORY: N-Acetylcysteine, a modified amino acid,
sarcoplasmatic reticular release of calcium and thereby to lower molecular weight 163.2 Da, is used for mucolysis and for treatment
intramyoplasmatic calcium concentrations. This makes dantrolene of acetaminophen toxicity.
highly effective for the treatment of malignant hyperthermia
PHARMACOKINETICS AND METABOLISM: It is rapidly metabolized
(MH).183 The management of malignant hyperthermia is discussed to cysteine, a precursor of glutathione. Oral N-acetylcysteine is
in Chapter 81. rapidly absorbed; the peak plasma level occurs at about 1 hour.
PHARMACOKINETICS AND METABOLISM: Dantrolene is meta- The drug is eliminated with a half-life of 1 to 5 hours, in part by
bolized to 5-OH-dantrolene, which has 50% of the activity renal excretion.
of dantrolene. After a single dose of 2.4 mg/kg, whole blood con- CLINICAL USE AND D OSAGE: N-Acetylcysteine has a free
centrations have been reported to exceed 3 μg/mL for appro- sulfhydryl group that enables S-S bond in mucus to be split.
ximately 6.5 hours. The concentrations decreases with an N-Acetylcysteine therefore has mucolytic properties, and can be
elimination half-life of 10 hours.184 A significant placental transfer used systemically or by topical administration (Table 31–20). A
occurs, the fetal-maternal ratio averages 0.4.185 4.8% solution is considered to be isotonic.
COMMERCIAL PRESENTATION: Each vial contains 20 mg of N-Acetylcysteine is the treatment of choice in acetaminophen
lyophilized dantrolene, sodium hydroxide, and 3 g of mannitol (to (paracetamol) poisoning and, when administered less than
16 hours and even up to 24 hours after acute ingestion, has a pro-
make the solution isotonic). The drug has to stored protected from
found effect in lowering morbidity and mortality. N-Acetylcysteine
light at ambient temperature (15°–25°C). Reconstitution is time-
reduces the extent of acetaminophen-induced glutathione
consuming and can be done only with sterile water.
depletion and thereby lessens the amount of toxic intermediate
CLINICAL USE AND DOSAGE: An I.V. dose of 2.5 mg/kg is the metabolites (Fig. 31–6). The risk of hepatic damage can be asses-
mean effective dose for treating clinical MH episodes. Repeated sed by correlating the time of ingestion with a single acetamino-
doses at 1 to 2 mg/kg may be given, as needed, up to 10 mg/kg. phen plasma estimation (Figure 31–7).190 As a rough guide,
Following initial control of the MH crisis, a continuous infusion ingestion of more than 150 mg/kg of acetaminophen should be
of 10 mg/kg/d is recommended by some authorities.183,186 considered potentially toxic. Severe liver toxicity is probable after
The present consensus is that, in most instances, prophylactic 250 mg/kg and certain after 350 mg/kg in adults. Little is known
dantrolene is not needed in MH-susceptible patients. If used, the about the toxic potential of the protracted administration of
dose is 2.5 mg/kg intravenously, given only just before induction, repeated excessive doses of acetaminophen, the most common
because clinically significant muscle weakness is induced even
with oral dantrolene prophylaxis.187 On rare occasions, however,
trigger-free anesthesia may also be followed by MH reactions in
the immediate postoperative period.188
For the treatment of spasticity, dantrolene 1 to 2 mg/kg/d orally,
is occasionally used. Because fever of other origin is also lowered
by dantrolene,189 response to dantrolene cannot by itself confirm
the diagnosis of MH.
ADVERSE EFFECTS AND OVERDOSE: The side effects include
drowsiness, dizziness, and fatigue. Because dantrolene can cause
significant muscle weakness, leading to difficulty in swallowing
or even respiratory insufficiency,187 careful observation of the
patient is mandatory. Significant potentiation of neuromuscular
blocking drugs can be seen on mechanical recordings, but not
when electromyographic techniques are used. After repeated
infusions, thrombophlebitis is common. Liver toxicity, cholestasis, Figure 31-6. Metabolism of acetaminophen; N-acetylcysteine
may be a problem with long-term oral treatment. restores glutathione and prevents toxicity.
TABLE 31-22. Drug-Induced Methemoglobinemia

of Anesthetic Importance
Local anesthetics Prilocaine,203–205 benzocaine,206,207
lidocaine208,209
Antimicrobial and Dapsone,210,211 chloroquine, sulfonamide
antiseptic agents derivates, phenazopyridine
Vasodilatators Amyl nitrate, nitroglycerine, sodium
nitroprusside
Analgesic-antipyretic Acetanilid, p-aminosalicylic acid,
agents phenacetin
Surface-acting agents Silver nitrate, aniline dyes212
Miscellaneous Nitric oxide213
From reference 202.
immediately reduced by two enzymatic systems, the nicotinamide

adenine dinucleotide, reduced form (NADH)–methemoglobin
Figure 31-7. Acetaminophen toxicity nomogram. It is mainly reductase and the nicotinamide adenine dinucleotide phosphate,
based on adult data, but is commonly applied to children too. reduced form (NADPH)–methemoglobin reductase. The con-
Redrawn after reference 190. centration of MetHb under normal condition is therefore kept
under less than 1% of the total hemoglobin.
cause of toxicity in children.191–194 If in doubt, treatment with When MetHb rises to 10%, cyanosis is usually detectable clini-
N-acetylcysteine should immediately be started (Table 31–21). cally. Symptoms appear at concentrations above 20%, and con-
With early initiation, oral treatment seems to be safe.195,196 With centrations exceeding 70% may be fatal. However, an elevated
delayed diagnosis and in severe cases, I.V. treatment is recom- MetHb concentration always reduces the margin of safety of the
mended.197 N-Acetylcysteine is an extremely safe drug and even oxygen carrying system and may put certain patients at risk
delayed administration will not worsen liver failure should it (e.g., small infants, children with cardiac or pulmonary disease).
develop. However, if liver function abnormalities are already Congenital methemoglobinemia is caused either by insufficient
present, it is probably too late for N-acetylcysteine treatment to be production of the enzyme NADH-methemoglobin reductase or
of any use. by abnormal hemoglobin (Hb M) variants.
Acquired methemoglobinemia is most commonly induced in
ADVERSE EFFECTS: The most prominent side effect is often an young infants by nutritive factors, mainly nitrate-contaminated
exorbitant amount of liquid secretions that may become difficult water199 or inadequately stored vegetables,200,201 providing too
for the patient to deal with. With I.V. administration, anaphylactoid much oxidative stress to hemoglobin in the presence of a still
reactions occasionally occur, but treatment can usually be continued immature MetHb reductase system.
after symptomatic medication.198 The high reductive potential of In addition, drug-induced methemoglobinemia has been asso-
N-acetylcysteine can cause instability of mixtures with other drugs ciated with a number of agents (Table 31–22).
or leads to problems in case of contact with medical equipment. In anesthetic practice, prilocaine is the most common cause of
methemoglobinemia. Because MetHb reductase reaches adult
activity only at the age of 3 months,203 severe methemoglobinemia
ANTAGONISTS OF can occur in small infants even after moderate doses of prilo-
METHEMOGLOBINEMIA caine.203–205 Methemoglobinemia has been also reported after topi-
cal use of prilocaine, EMLA (eutectic mixture of local anesthetics)
Methemoglobin (MetHb) is a derivative of normal hemoglobin in
Cream205,214; but clinically relevant MetHb concentrations are
which the iron of the heme complex has been oxidized from the
rarely reached212,215 (local anesthetics are discussed in Chapter 28).
ferrous (Fe2+) to the ferric (Fe3+) form. It does not combine with
Although lidocaine-induced methemoglobinemia has been
oxygen and, thus, does not take part in oxygen transport. Further-
reported,208,216 it is unlikely to cause relevant MetHb concentra-
more, the oxygen-binding curve is shifted to the left. In normal
tions in clinically used doses.209
red blood cells, MetHb is continually being formed, but it is
Methemoglobinemia influences pulse oximeter (SpO2) read-
ings; it has a high absorption of light at both currently used
TABLE 31-21. N-Acetylcysteine in Acetaminophen wavelengths, 660 and 940 nm. Therefore, at moderate levels of
(Paracetamol) Overdose MetHb below 10%, SpO2 is reduced by approximately 1% for each
2% of MetHb; high MetHb concentrations will drive SpO2 toward
I.V. administration 150 mg/kg over 15 min 85% regardless of oxygen tension.217 Therefore, even with methe-
50 mg/kg over the next 4 h moglobinemia of known origin, MetHb has to be measured in case
100 mg/kg over the next 16 h of SpO2 readings below 90% (Figure 31–8).
(infusions mixed in 5% dextrose)
Oral administration 140 mg/kg loading dose
(if I.V. N- 70 mg/kg q4h (17 doses) Methylene Blue
acetylcysteine (A dose should be repeated if vomiting
is not available) occurs within 1 h of administration)
DRUG CATEGORY: Methylene blue, a color dye, is used to mark
fistula tracts or as an antidote in case of methemoglobinemia.
confusions have been reported after methylene blue 5 to 7.5 mg/kg

in order to stain the parathyroid glands.220–222 The drug has the
potential for direct neurotoxicity and must not be administered
close to neural structures. Methylene blue causes intense colora-
tion of all body fluids; the child and parents have to be warned in
advance.
Ascorbic Acid
Ascorbate and other antioxidant nutrients are presumed to play a
pivotal role in minimizing the damage from oxidative products,
including free radicals.223 In patients with acquired methemo-
globinemia, ascorbic acid has only a modest activity224 and does
not reliably reduce methemoglobin levels.225 It is occasionally
given as a nutritive additive in patients with congenital methemo-
globinemia226; however, reliable data on optimal dosing and
efficacy are not available.
Figure 31-8. Dependence of oxygen saturation of hemoglobin

(SaO2) and the pulse oximeter results (SpO2) on the methemo- REFERENCES
globin concentration. Reproduced with permission from 1. Mirakhur RK, Clarke RSJ, Dundee JW, et al. Anticholinergic drugs in
reference 217. anaesthesia, a survey of their present position. Anaesthesia. 1978;33:
133–138.
2. Jöhr M. Is it time to question the routine use of anticholinergic agents in
PHYSICOCHEMICAL PROPERTIES: Soluble in water and ethanol, paediatric anaesthesia? Paediatr Anaesth. 1999;9:99–101.
the drug is usually commercialized as 1 to 2% aqueous solutions, 3. Rautakorpi P, Manner T, Kanto J. A survey of current usage of anticho-
molecular weight 319.9 Da, maximal light absorbency at 668.6 nm. linergic drugs in paediatric anaesthesia in Finland. Acta Anaesthesiol
During storage, the drug should be protected from heat and light. Scand. 1999;43:1057–1059.
4. Shaw CA, Kelleher AA, Gill CP, et al. Comparison of the incidence of
PHARMACOKINETICS AND METABOLISM: Fifty-three to 97% of complications at induction and emergence in infants receiving oral
the drug is absorbed from the gastrointestinal tract. Methylene atropine vs no premedication. Br J Anaesth. 2000;84:174–178.
blue is reduced in peripheral tissues and undergoes slow renal 5. Zimmerman G, Steward DJ. Bradycardia delays the onset of action of
elimination. Overall, its pharmacokinetics are poorly understood. intravenous atropine in infants. Anesthesiology. 1986;65:320–322.
6. Blanc VF. Atropine and succinylcholine: beliefs and controversies in
CONTRAINDICATIONS: Methylene blue should not be given to Paediatr Anaesth. Can J Anaesth. 1995;42:1–7.
patients with glucose-6-phosphate dehydrogenase deficiency, 7. Shorten GD, Bissonnette B, Hartley E, et al. It is not necessary to adminis-
ter more than 10 μg/kg of atropine to older children before succinyl-
because the hexose monophosphate shunt regenerates NADPH. choline. Can J Anaesth. 1995;42:8–11.
With deficient NADPH regeneration, methylene blue may cause 8. Annis P, Landa J, Lichtiger M. Effects of atropine on velocity of tracheal
hemolytic anemia. Methylene blue will also be ineffective in the mucus in anesthetized patients. Anesthesiology. 1976;44:74–77.
presence of Hb M variants. Exchange transfusion is effective in 9. Opie JC, Chaye H, Steward DJ. Intravenous atropine rapidly reduces lower
such situations. The drug has been associated with jejunal atresia esophageal sphincter pressure in infants and children. Anesthesiology.
1987;67:989–990.
after intra-amniotic injection during pregnancy.218 10. Cowl CT, Prakash UB, Kruger BR. The role of anticholinergics in bron-
MODE OF ACTION: Methylene blue acts as an electron carrier for choscopy. A randomized clinical trial. Chest. 2000;118:188–192.
11. Heinz P, Geelhoed GC, Wee C, et al. Is atropine needed with ketamine
the NADPH-methemoglobin reductase and causes a marked sedation? A prospective, randomised, double blind study. Emerg Med J.
increase in its normally insignificant activity; therefore, MetHb is 2006;23:206–209.
rapidly reduced. 12. Gilani SM, Jamil M, Akbar F,et al. Anticholinergic premedication for
prevention of oculocardiac reflex during squint surgery. J Ayub Med Coll
CLINICAL USE AND DOSAGE: In case of symptomatic methe- Abbottabad. 2005;17:57–59.
moglobinemia, methylene blue 1 to 2 mg/kg diluted with normal 13. Mirakhur RK, Jones CJ, Dundee JW, et al. I.M. or I.V. atropine or gly-
saline is infused over 5 minutes. The delay of action is only a few copyrrolate for the prevention of oculocardiac reflex in children under-
minutes; the maximal effect is reached at 1 hours. Additional going squint surgery. Br J Anaesth. 1982;54:1059–1063.
14. Pihlajamäki K, Kanto J, Aaltonen L, et al. Pharmacokinetics of atropine in
dosing, up to a total of 7 mg/kg, may necessary. In case of congeni- children. Int J Clin Pharmacol Ther Toxicol. 1986;24:236–239.
tal disorders, oral treatment is theoretically feasible (1–1.5 mg/ 15. Virtanen R, Kanto J, Iisalo E, et al. Pharmacokinetic studies on atro-
kg/d), however, specialized hematologic advice should be obtained. pine with special reference to age. Acta Anaesthesiol Scand. 1982;26:
Further use of methylene blue involves viral attenuation in 297–300.
blood products and cytoprotective effects in conjunction with 16. Palmisano BW, Setlock MA, Brown MP, et al. Dose-response for atropine
antineoplastic therapy. and heart rate in infants and children anesthetized with halothane and
nitrous oxide. Anesthesiology. 1991;75:238–242.
ADVERSE EFFECTS AND OVERDOSE: Rapid administration of 17. Hinderling PH, Gundert-Remy U, Schmidlin O. Integrated pharmacoki-
methylene blue leads to transient spurious readings with SpO2,217 netics and pharmacodynamics of atropine in healthy humans. I: pharma-
cokinetics. J Pharm Sci. 1985;74:703–710.
as long as venous and arterial concentrations differ significantly. 18. Kanto J, Klotz U. Pharmacokinetic implications for the clinical use of
High levels of methylene blue directly oxidize hemoglobin to atropine, scopolamine and glycopyrrolate. Acta Anaesthesiol Scand. 1988;
cause methemoglobinemia.219 Prolonged altered mental state and 32:69–78.
19. Gervais HW, El Gindi M, Radermacher PR, et al. Plasma concentration 48. Woelfle J, Zielen S, Lentze MJ, et al. Unilateral fixed dilated pupil in an
following oral and intramuscular atropine in children and their clinical infant after inhalation of nebulized ipratropium bromide. J Pediatr.
effects. Paediatr Anaesth. 1997;7:13–18. 2000;136:423–424.
20. Sullivan KJ, Berman LS, Koska J, et al. Intramuscular atropine sulfate in 49. Everard ML, Bara A, Kurian M, et al. Anticholinergic drugs for wheeze in
children: comparison of injection sites. Anesth Analg. 1997;84:54–58. children under the age of two years. Cochrane Database Syst Rev. 2005;3:
21. Miller BR, Friesen RH. Oral atropine premedication in infants attenuates CD001279.
cardiovascular depression during halothane anesthesia. Anesth Analg. 50. Stoodley RG, Aaron SD, Dales RE. The role of ipratropium bromide in
1988;67:180–185. the emergency management of acute asthma exacerbation: a meta-
22. Olsson GL, Bejersten A, Feychting H, et al. Plasma concentrations of analysis of randomized clinical trials. Ann Emerg Med. 1999;34:8–18.
atropine after rectal administration. Anaesthesia. 1983;38:1179–1182. 51. Bevan DR, Donati F, Kopman AF. Reversal of neuromuscular blockade
23. Bejersten A, Olsson GL, Palmér L. The influence of body weight on review article. Anesthesiology. 1992;77:785–805.
plasma concentration of atropine after rectal administration. Acta 52. Kirkegaard-Nielsen H, Meretoja OA, Wirtavuori K. Reversal of
Anaesthesiol Scand. 1985;29:782–784. atracurium-induced neuromuscular block in paediatric patients. Acta
24. Howard RF, Bingham RM. Endotracheal compared with intravenous Anaesthesiol Scand. 1995;39:906–911.
administration of atropine. Arch Dis Child. 1990;65:449–450. 53. Bevan JC, Purday JP, Reimer EJ, et al. Reversal of doxacurium and pan-
25. Jorgensen BG, Ostergaard D. Tracheal administration of atropine in curonium neuromuscular blockade with neostigmine in children. Can J
children—effect on heart rate. Paediatr Anaesth. 1997;7:461–463. Anaesth. 1994;41:1074–1080.
26. Part 12: Pediatric Advanced Life Support. Circulation. 2005;11224(Suppl 54. Meakin G, Sweet PT, Bevan JC, et al. Neostigmine and edrophonium as
IV):167–187. antagonists of pancuronium in infants and children. Anesthesiology.
27. Dauchot P, Gravenstein JS. Effects of atropine on the electrocardiogram 1983;59:316–321.
in different age groups. Clin Pharmacol Ther. 1971;12:274–280. 55. Engbaek J, Ostergaard D, Viby-Mogensen J, et al. Clinical recovery and
28. Smith DS, Orkin FK, Gardner SM, Zakeosian G. Prolonged sedation in train-of-four ratio measured mechanically and electromyographically
the elderly after intraoperative atropine administration. Anesthesiology. following atracurium. Anesthesiology. 1989;71:391–395.
1979;51:348–349. 56. Mason LJ, Betts EK. Leg lift and maximum inspiratory force, clinical signs
29. Saarnivaara L, Kautto UM, Iisalo E, et al. Comparison of pharmacokinetic of neuromuscular blockade reversal in neonates and infants. Anesthesio-
and pharmacodynamic parameters following oral or intramuscular logy. 1980;52:441–442.
atropine in children. Atropine overdose in two small children. Acta Anaes- 57. Fisher DM, Cronnelly R, Miller RD, et al. The neuromuscular pharma-
thesiol Scand. 1985;29:529–536. cology of neostigmine in infants and children. Anesthesiology. 1983;59:
30. Gillick JS. Atropine toxicity in a neonate. Br J Anaesth. 1974;46:793–794. 220–225.
31. Mackenzie AL, Pigott JFG. Atropine overdose in three children. Br J 58. Briassoulis G, Hatzis T, Liakopoulou T, et al. Continuous neostigmine
Anaesth. 1971;43:1088–1090. infusion in post-thymectomy juvenile myasthenic crisis. J Child Neurol.
32. Warran P, Radford P, Manford MLM. Glycopyrrolate in children. Br J 2000;15:747–749.
Anaesth. 1981;53:1273–1276. 59. Ho KM, Ismail H, Lee KC, et al. Use of intrathecal neostigmine as an
33. Rautakorpi P, Manner T, Ali-Melkkila T, et al. Pharmacokinetics and oral adjunct to other spinal medications in perioperative and peripartum
bioavailability of glycopyrrolate in children. Pharmacol Toxicol. 1998;83: analgesia: a meta-analysis. Anaesth Intensive Care. 2005;33:41–53.
132–134. 60. Hood DD, Eisenach JC, Tuttle R. Phase I safety assessment of intrathecal
34. Rautakorpi P, Ali-Melkkila T, Kaila T, et al. Pharmacokinetics of gly- neostigmine methylsulfate in humans. Anesthesiology. 1995;82:331–343.
copyrrolate in children. J Clin Anesth. 1994;6:217–220. 61. Mahajan R, Grover VK, Chari P. Caudal neostigmine with bupivacaine
35. Meyers EF, Tomeldan SA. Glycopyrrolate compared with atropine in produces a dose-independent analgesic effect in children. Can J Anaesth.
prevention of the oculocardiac reflex during eye-muscle surgery. 2004;51:702–706.
Anesthesiology. 1979;51:350–352. 62. Turan A, Memis D, Basaran UN, et al. Caudal ropivacaine and neostig-
36. Kentala E, Scheinin H, Kaila T, et al. Pharmacokinetics and clinicla effects mine in pediatric surgery. Anesthesiology. 2003;98:719–722.
of intramuscular scopolamine plus morphine. Acta Anaesthesiol Scand. 63. Abdulatif M, El Sanabary M. Caudal neostigmine, bupivacaine, and their
1998;42:323–328. combination for postoperative pain management after hypospadias
37. Guldbrand P, Mellström A. Rectal versus intramuscular morphine- surgery in children. Anesth Analg. 2002;95:1215–1218.
scopolamine as premedication in children. Acta Anaesthesiol Scand. 1995; 64. Fisher DM, Cronnelly R, Sharma M, Miller RD. Clinical pharmacology of
39:224–227. edrophonium in infants and children. Anesthesiology. 1984;61:428–433.
38. Sigurdsson GH, Lindahl S, Norden N. Influence of premedication on the 65. Yang HS, Goudsouzian N, Martyn JA. Pseudocholinesterase-mediated
sympathetic and endocrine responses and cardiac arrhythmias during hydrolysis is superior to neostigmine for reversal of mivacurium-induced
halothane anaesthesia in children undergoing adenoidectomy. Br J paralysis in vitro. Anesthesiology. 1996;84:936–944.
Anaesth. 1983;55:961–968. 66. Rupp SM, McChristian JW, Miller RD, et al. Neostigmine and edropho-
39. Sigurdsson GH. Respiratory effects of premedication during enflurane nium antagonism of varying intensity neuromuscular blockade induced
N2O anaesthesia in children. Acta Anaesthesiol Scand. 1985;296:632–634. by atracurium, pancuronium, or vecuronium. Anesthesiology. 1986;64:
40. Alswang M, Friesen RH, Bangert P. Effect of preanesthetic medication on 711–717.
carbon dioxide tension in children with congenital heart disease. J 67. Donati F, Smith CE, Bevan DR. Dose-response relationships for edropho-
Cardiothorac Vasc Anesth. 1994;8:415–419. nium and neostigmine as antagonists of moderate and profound atra-
41. Nachum Z, Shupak A, Gordon CR. Transdermal scopolamine for curium blockade. Anesth Analg. 1989;68:13–19.
prevention of motion sickness: clinical pharmacokinetics and therapeutic 68. Azar I, Pham AN, Karambelkar DJ, Lear E. The heart rate following
applications. Clin Pharmacokinet. 2006;45:543–566. edrophonium-atropine and edrophonium-glycopyrrolate mixtures.
42. Kranke P, Morin AM, Roewer N, et al. The efficacy and safety of trans- Anesthesiology. 1983;59:139–141.
dermal scopolamine for the prevention of postoperative nausea and 69. Brown TC, Gebert R, Meretoja OA, et al. Myasthenia gravis in children
vomiting: a quantitative systematic review. Anesth Analg. 2002;95:133–143. and its anaesthetic implications. Anaesth Intensive Care. 1990;18:466–472.
43. Horimoto Y, Tomie H, Hanzawa K, et al. Scopolamine patch reduces 70. Batocchi AP, Evoli A, Palmisani MT, et al. Early-onset myasthenia gravis:
postoperative emesis in paediatric patients following strabismus surgery. clinical characteristics and response to therapy. Eur J Pediatr. 1990;150:
Can J Anaesth. 1991;38:441–444. 66–68.
44. Doyle E, Byers G, McNicol LR, et al. Prevention of postoperative nausea 71. Frascogna N. Physostigmine: is there a role for this antidote in pediatric
and vomiting with transdermal hyoscine in children using patient- poisonings? Curr Opin Pediatr. 2007;19:201–205.
controlled analgesia. Br J Anaesth. 1994;72:72–76. 72. Funk W, Hollnberger H, Geroldinger J. Physostigmine and anaesthesia
45. Hamborg-Petersen B, Nielsen MM, Thordal C. Toxic effect of scopola- emergence delirium in preschool children: a randomized blinded trial.
mine eye drops in children. Acta Ophthalmol Copenh. 1984;62:485–488. Eur J Anaesthesiol. 2008;25:37–42.
46. Gross NJ. Ipatropium bromide. N Engl J Med. 1988;319:486–494. 73. Kretz F-J. Langzeitsedierung. In: Kretz F-J, editor. Anästhesie, Intensiv-
47. Udy A. A 10-year-old child with status asthmaticus, hypercapnia and a und Notfallmedizin bei Kindern. Stuttgart, New York: Georg Thieme
unilateral dilated pupil. Paediatr Anaesth. 2005;15:1120–1123. Verlag; 1998. pp. 182–184.
74. Cavallaro RJ, Krumperman LW, Kugler F. Effect of echothiophate therapy 99. Sanders JC. Flumazenil reverses a paradoxical reaction to intravenous
on the metabolism of succinylcholine in man. Anesth Analg. 1968;47: midazolam in a child with uneventful prior exposure to midazolam.
75. Naguib M. Sugammadex: another milestone in clinical neuromuscular 100. Thakker P, Gallagher TM. Flumazenil reverses paradoxical reaction to
pharmacology. Anesth Analg. 2007; 04:575–581. midazolam in a child. Anaesth Intensive Care. 1996;24:505–507.
76. Miller RD. Sugammadex: an opportunity to change the practice of 101. Voepel-Lewis T, Mitchell A, Malviya S. Delayed postoperative agitation
anesthesiology? Anesth Analg. 2007;104:477–478. in a child after preoperative midazolam. J Perianesth Nurs. 2007;22:
77. de Boer HD, Driessen JJ, Marcus MA, et al. Reversal of rocuronium- 303–308.
induced 1.2 mg/kg profound neuromuscular block by sugammadex: a 102. Koscielniak-Nielsen ZJ, Stens-Pedersen HL, Hesselbjerg L. Midazolam-
multicenter, dose-finding and safety study. Anesthesiology. 2007;107: flumazenil versus propofol anaesthesia for scoliosis surgery with wake-
239–244. up tests. Acta Anaesthesiol Scand. 1998;42:111–116.
78. Rose JB, Francis MC, Kettrick RG. Continuous naloxone infusion in 103. Godat L, Ravussin PA, Chiolero R, et al. Flumazenil et réveil peropéra-
paediatric patients with pruritus associated with epidural morphine. toire lors de la chirurgie de la scoliose. Ann Fr Anesth Réanim. 1990;9:
Paediatr Anaesth. 1993;3:255–258. 6–10.
79. Krechel SW, Helikson MA, Kittle D, et al. Intrathecal morphine ITM for 104. Oshima T, Masaki Y, Toyooka H. Flumazenil antagonizes midazolam-
postoperative pain control in children: a comparison with nalbuphine induced airway narrowing during nasal breathing in humans. Br J
patient controlled analgesia PCA. Paediatr Anaesth. 1995;5:177–183. Anaesth. 1999;82:698–702.
80. Gan TJ, Ginsberg B, Glass PS, et al. Opioid-sparing effects of a low-dose 105. Litman RS, Hayes JL, Basco MG, et al. Use of dynamic negative airway
infusion of naloxone in patient-administered morphine sulfate. Anes- pressure DNAP to assess sedative-induced upper airway obstruction.
thesiology. 1997;87:1075–1081. Anesthesiology. 2002;96:342–345.
81. Cepeda MS, Alvarez H, Morales O, et al. Addition of ultralow dose 106. Gueye PN, Hoffman JR, Taboulet P, et al. Empiric use of flumazenil in
naloxone to postoperative morphine PCA: unchanged analgesia and comatose patients: limited applicability of criteria to define low risk. Ann
opioid requirement but decreased incidence of opioid side effects. Pain. Emerg Med. 1996;27:730–735.
2004;107:41–46. 107. Weinbroum AA, Flaishon R, Sorkine P, et al. A risk-benefit assessment
82. Maxwell LG, Kaufmann SC, Bitzer S, et al. The effects of a small-dose of flumazenil in the management of benzodiazepine overdose. Drug Saf.
naloxone infusion on opioid-induced side effects and analgesia in 1997;17:181–196.
children and adolescents treated with intravenous patient-controlled 108. Perry HE, Shannon MW. Diagnosis and management of opioid- and
analgesia: a double-blind, prospective, randomized, controlled study. benzodiazepine-induced comatose overdose in children. Curr Opin
Anesth Analg. 2005;100:953–958. Pediatr. 1996;8:243–247.
83. Sartain JB, Barry JJ, Richardson CA, et al. Effect of combining naloxone 109. Devictor D, Tahiri C, Lanchier C, et al. Flumazenil in the treatment of
and morphine for intravenous patient-controlled analgesia. Anesthe- hepatic encephalopathy in children with fulminant liver failure. Intensive
siology. 2003;99:148–151. Care Med. 1995;21:253–256.
84. Cheung CL, van Dijk M, Green JW, et al. Effects of low-dose naloxone on 110. McDuffee AT, Tobias JD. Seizure after flumazenil administration in a
opioid therapy in pediatric patients: a retrospective case-control study. pediatric patient. Pediatr Emerg Care. 1995;11:186–187.
Intensive Care Med. 2007;33:190–194. 111. Wiernikowski JT, Chan A, Lo G. Reversal of anti-thrombin activity using
85. Abboud TK, Afrasiabi A, Davidson J, et al. Prophylactic oral naltrexone protamine sulfate. Experience in a neonate with a 10-fold overdose of
with epidural morphine: effect on adverse reactions and ventilatory enoxaparin. Thromb Res. 2007;120:303–305.
responses to carbon dioxide. Anesthesiology. 1990;72:233–237. 112. Crowther MA, Berry LR, Monagle PT, et al. Mechanisms responsible for
86. Konieczko KM, Jones JG, Barrowcliffe MP, et al. Antagonism of the failure of protamine to inactivate low-molecular-weight heparin. Br
morphine-induced respiratory depression with nalmefene. Br J Anaesth. J Haematol. 2002;116:178–186.
1988;61:318–323. 113. Codispoti M, Ludlam CA, Simpson D, et al. Individualized heparin and
87. Rosen DA, Morris JL, Rosen KR, et al. Nalmefene to prevent epidural protamine management in infants and children undergoing cardiac
narcotic side effects in pediatric patients: a pharmacokinetic and safety operations. Ann Thorac Surg. 2001;71:922–927.
study. Pharmacotherapy. 2000;20:745–749. 114. Dalens B. Protamine. In: Dalens B, editor. Médicaments en anesthésie.
88. Elchaar GM, Maisch NM, Augusto LM, et al. Efficacy and safety of Paris: Éditions Pradel; 1996. pp. 514–515.
naltrexone use in pediatric patients with autistic disorder. Ann Pharmaco- 115. Park KW. Protamine and protamine reactions. Int Anesthesiol Clin.
ther. 2006;40:1086–1095. 2004;42:135–145.
89. Whitwam JG, Amrein R. Pharmacology of flumazenil. Acta Anaesthesiol 116. Boigner H, Lechner E, Brock H, et al. Life threatening cardiopulmonary
Scand. 1995;39(Suppl 108):3–14. failure in an infant following protamine reversal of heparin after
90. Sugarman JM, Paul RI. Flumazenil: a review. Pediatr Emerg Care. 1994;10: cardiopulmonary bypass. Paediatr Anaesth. 2001;11:729–732.
37–43. 117. Lowenstein E, Johnston WE, Lappas DG, et al. Catastrophic pulmonary
91. Collins S, Carter JA. Resedation after bolus administration of midazolam vasoconstriction associated with protamine reversal of heparin. Anes-
to an infant and its reversal by flumazenil. Anaesthesia. 1991;46:471–472. thesiology. 1983;59:470–473.
92. Carbajal R, Simon N, Blanc P, et al. Rectal flumazenil to reverse 118. Morel DR, Zapol WM, Thomas SJ, et al. C5a and thromboxane
midazolam sedation in children. Anesth Analg. 1996;82:895. generation associated with pulmonary vaso- and broncho-constriction
93. Lopez-Herce J, Lopez de Sa E, Garcia de Frias E. Reversal of midazolam during protamine reversal of heparin. Anesthesiology. 1987;66:597–604.
sedation with rectal flumazenil in children. Crit Care Med. 1994;22:1204. 119. Westaby S, Turner MW, Stark J. Complement activation and anaphylac-
94. Heniff MS, Moore GP, Trout A, et al. Comparison of routes of flumazenil toid response to protamine in a child after cardiopulmonary bypass. Br
administration to reverse midazolam-induced respiratory depression in Heart J. 1985;53:574–576.
a canine model. Acad Emerg Med. 1997;4:1115–1118. 120. Comunale ME, Maslow A, Robertson LK, et al. Effect of site of venous
95. Palmer RB, Mautz DS, Cox K, et al. Endotracheal flumazenil: a new route protamine administration, previously alleged risk factors, and pre-
of administration for benzodiazepine antagonism. Am J Emerg Med. 1998; operative use of aspirin on acute protamine-induced pulmonary
16:170–172. vasoconstriction. J Cardiothorac Vasc Anesth. 2003;17:309–313.
96. Jones RDM, Lawson AD, Andrew LJ, et al. Antagonism of the hypnotic 121. Seifert HA, Jobes DR, Ten Have T, et al. Adverse events after protamine
effect of midazolam in children: a randomized, double-blind study of administration following cardiopulmonary bypass in infants and
placebo and flumazenil administered after midazolam-induced anaes- children. Anesth Analg. 2003;97:383–389.
thesia. Br J Anaesth. 1991;66:660–666. 122. Kanbak M, Kahraman S, Celebioglu B, et al. Prophylactic administration
97. Golparvar M, Saghaei M, Sajedi P, et al. Paradoxical reaction following of histamine 1 and/or histamine 2 receptor blockers in the prevention of
intravenous midazolam premedication in pediatric patients—a rando- heparin- and protamine-related haemodynamic effects. Anaesth Inten-
mized placebo controlled trial of ketamine for rapid tranquilization. sive Care. 1996;24:559–563.
Paediatr Anaesth. 2004;14:924–930. 123. Gupta SK, Veith FJ, Ascer E, et al. Anaphylactoid reactions to protamine:
98. Mancuso CE, Tanzi MG, Gabay M. Paradoxical reactions to benzodiaze- an often lethal complication in insulin-dependent diabetic patients
pines: literature review and treatment options. Pharmacotherapy. 2004; undergoing vascular surgery. J Vasc Surg. 1989;9:342–350.
24:1177–1185.
124. Mannucci PM. Treatment of von Willebrand’s disease. N Engl J Med. 150. Mojcik CF, Levy JH. Aprotinin and the systemic inflammatory response
2004;351:683–694. after cardiopulmonary bypass. Ann Thorac Surg. 2001;71:745–754.
125. Federici AB, Mannucci PM. Management of inherited von Willebrand 151. Costello JM, Backer CL, de Hoyos A, et al. Aprotinin reduces operative
disease in 2007. Ann Med. 2007;39:346–358. closure time and blood product use after pediatric bypass. Ann Thorac
126. DiMichele D. Hemophilia 1996. New approach to an old disease. Pediatr Surg. 2003;75:1261–1266.
Clin North Am. 1996;43:709–736. 152. Mossinger H, Dietrich W, Braun SL, et al. High-dose aprotinin reduces
127. Cattaneo M. Review of clinical experience of desmopressin in patients activation of hemostasis, allogeneic blood requirement, and duration of
with congenital and acquired bleeding disorders. Eur J Anaesth. 1997; postoperative ventilation in pediatric cardiac surgery. Ann Thorac Surg.
14(Suppl 14):10–14. 2003;75:430–437.
128. Lethagen S. Desmopressin—a haemostatic drug: state-of-the-art review. 153. Carrel TP, Schwanda M, Vogt PR, et al. Aprotinin in pediatric cardiac
Eur J Anaesth. 1997;14(Suppl 14):1–9. operations: a benefit in complex malformations and with high-dose
129. Flordal PA. Pharmacological prophylaxis of bleeding in surgical patients regimen only. Ann Thorac Surg. 1998;66:153–158.
treated with aspirin. Eur J Anaesth. 1997;14(Suppl 14):38–41. 154. Boldt J, Knothe C, Zickmann B, et al. Comparison of two aprotinin
130. Pleym H, Stenseth R, Wahba A, et al. Prophylactic treatment with dosage regimens in pediatric patients having cardiac operations. J Thorac
desmopressin does not reduce postoperative bleeding after coronary Cardiovasc Surg. 1993;105:705–711.
surgery in patients treated with aspirin before surgery. Anesth Analg. 155. Backer CL, Kelle AM, Stewart RD, et al. Aprotinin is safe in pediatric
2004;98:578–584. patients undergoing cardiac surgery. J Thorac Cardiovasc Surg. 2007;134:
131. Lethagen S, Flordal P, Van Aken H, et al. The UK guidelines for the use 1421–1426.
of desmopressin in patients with von Willebrand’s disease. Eur J Anaesth. 156. Groom RC, Akl BF, Albus R, et al. Pediatric cardiopulmonary bypass: a
1997;14(Suppl 14):19–22. review of current practice. Int Anesthesiol Clin. 1996;34:141–163.
132. Seear MD, Wadsworth LD, Rogers PC, et al. The effect of desmopressin 157. Molenaar IQ, Warnaar N, Groen H, et al. Efficacy and safety of anti-
acetate DDAVP on postoperative blood loss after cardiac operations in fibrinolytic drugs in liver transplantation: a systematic review and meta-
children. J Thorac Cardiovasc Surg. 1989;98:217–219. analysis. Am J Transplant. 2007;7:185–194.
133. Oliver WC Jr, Santrach PJ, Danielson GK, et al. Desmopressin does not 158. Milroy SJ, Cottam S, Tan KC, et al. Improved haemodynamic stability
reduce bleeding and transfusion requirements in congenital heart with administration of aprotinin during orthotopic liver transplantation.
operations. Ann Thorac Surg. 2000;70:1923–1930. Br J Anaesth. 1995;75:747–751.
134. Hackmann T, Gascoyne RD, Naiman SC, et al. A trial of desmopressin 159. Jaquiss RD, Huddleston CB, Spray TL. Use of aprotinin in pediatric lung
1-desamino-8-D-arginine vasopressin to reduce blood loss in uncom- transplantation. J Heart Lung Transplant. 1995;14:302–307.
plicated cardiac surgery. N Engl J Med. 1989;321:1437–1443. 160. Cole JW, Murray DJ, Snider RJ, et al. Aprotinin reduces blood loss during
135. Horrow JC, Van Riper DF, Strong MD, et al. Hemostatic effects of spinal surgery in children. Spine. 2003;28:2482–2485.
tranexamic acid and desmopressin during cardiac surgery. Circulation. 161. Capdevila X, Calvet Y, Biboulet P, et al. Aprotinin decreases blood loss
1991;84:2063–2070. and homologous transfusions in patients undergoing major orthopedic
136. Reynolds LM, Nicolson SC, Jobes DR, et al. Desmopressin does not surgery. Anesthesiology. 1998;88:50–57.
decrease bleeding after cardiac operation in young children. J Thorac 162. Janssens M, Joris J, David JL, et al. High-dose aprotinin reduces blood
Cardiovasc Surg. 1993;106:954–958. loss in patients undergoing total hip replacement surgery. Anesthesiology.
137. Alanay A, Acaroglu E, Ozdemir O, et al. Effects of deamino-8-D-arginin 1994;80:23–29.
vasopressin on blood loss and coagulation factors in scoliosis surgery. A 163. Murkin JM, Shannon NA, Bourne RB, et al. Aprotinin decreases blood
double-blind randomized clinical trial. Spine. 1999;24:877–882. loss in patients undergoing revision or bilateral total hip arthroplasty.
138. Theroux MC, Corddry DH, Tietz AE, et al. A study of desmopressin and Anesth Analg. 1995;80:343–348.
blood loss during spinal fusion for neuromuscular scoliosis. Anesthe- 164. Thorpe CM, Murphy WG, Logan M. Use of aprotinin in knee replace-
siology. 1997;87:260–267. ment surgery. Br J Anaesth. 1994;73:408–410.
139. Guay J, Reinberg C, Poitras B, et al. A trial of desmopressin to reduce 165. Ranaboldo CJ, Thompson JF, Davies JN, et al. Prospective randomized
blood loss in patients undergoing spinal fusion for idiopathic scoliosis. placebo-controlled trial of aprotinin for elective aortic reconstruction. Br
Anesth Analg. 1992;75:405–410. J Surg. 1997;84:1110–1113.
140. Salzman EW, Weinstein MJ, Weintraub RM, et al. Treatment with 166. Ryckwaert Y, Barthelet Y, Bonnet-Boyer MC, et al. Anaphylactic shock
desmopressin acetate to reduce blood loss after cardiac surgery: a after a test-dose of aprotinin in pediatric orthopedic surgery in France.
double-blind randomized trial. N Engl J Med. 1986;314:1402–1406. Ann Fr Anesth Réanim. 1999;18:904–908.
141. Robson WL, Leung AK, Norgaard JP. The comparative safety of oral 167. Mangano DT, Miao Y, Vuylsteke A, et al. Mortality associated with
versus intranasal desmopressin for the treatment of children with aprotinin during 5 years following coronary artery bypass graft surgery.
nocturnal enuresis. J Urol. 2007;178:24–30. JAMA. 2007;297:471–479.
142. Larney V, Dwyer R. Hyponatraemic convulsions and fatal head injury 168. Brown JR, Birkmeyer NJ, O’Connor GT. Meta-analysis comparing the
secondary to desmopressin treatment for enuresis. Eur J Anaesthesiol. effectiveness and adverse outcomes of antifibrinolytic agents in cardiac
2006;23:895–897. surgery. Circulation. 2007;115:2801–2813.
143. Lebl J, Kolska M, Zavacka A, et al. Cerebral oedema in enuretic children 169. Okubadejo GO, Bridwell KH, Lenke LG, et al. Aprotinin may decrease
during low-dose desmopressin treatment: a preventable complication. blood loss in complex adult spinal deformity surgery, but it may also
Eur J Pediatr. 2001;160:159–162. increase the risk of acute renal failure. Spine. 2007;32:2265–2271.
144. Das P, Carcao M, Hitzler J. DDAVP-induced hyponatremia in young 170. Lemmer LH, Stanford W, Bonney SL, et al. Aprotinin for coronary
children. J Pediatr Hematol Oncol. 2005;27:330–332. bypass opeations: efficacy, safety, and influence on early saphenous vein
145. McEwan A. Aspects of bleeding after cardiac surgery in children. graft patency. A multicenter, randomized, double-blind, placebo-
Paediatr Anaesth. 2007;17:1126–1133. controlled study. J Thorac Cardiovasc Surg. 1994;107:543–553.
146. Fremes SE, Wong BI, Lee E, et al. Metaanalysis of prophylactic drug 171. Dietrich W, Dilthey G, Spannagl M, et al. Influence of high-dose
treatment in the prevention of postoperative bleeding. Ann Thorac Surg. aprotinin on anticoagulation, heparin requirement, and celite- and
1994;58:1580–1588. kaolin-activated clotting time in heparin-pretreated patients undergoing
147. Van Oeveren W, Harder MP, Roozendaal KJ, et al. Aprotinin protects open-heart surgery. Anesthesiology. 1995;83:679–689.
platelets against the initial effect of cardiopulmonary bybass. J Thorac 172. Osborne RW. Safety and efficacy of epsilon-aminocaproic acid in
Cardiovasc Surg. 1990;99:788–797. postprostatectomy bleeding. Curr Ther Res. 1982;31:839.
148. McEvoy MD, Reeves ST, Reves JG, et al. Aprotinin in cardiac surgery: a 173. Chauhan S, Das SN, Bisoi A, et al. Comparison of epsilon aminocaproic
review of conventional and novel mechanisms of action. Anesth Analg. acid and tranexamic acid in pediatric cardiac surgery. J Cardiothorac
2007;105:949–962. Vasc Anesth. 2004;18:141–143.
149. Yun TJ, Rho JR. Aprotinin attenuates the elevation of pulmonary 174. Bennett-Guerrero E, Sorohan JG, Canada AT, et al. ε-Aminocaproic acid
vascular resistance after cardiopulmonary bypass. J Korean Med Sci. plasma levels during cardiopulmonary bypass. Anesth Analg. 1997;85:
2006;21:25–29. 248–251.
175. Winter SS, Chaffee S, Kahler SG, et al. Epsilon-aminocaproic acid– 201. Murone AJ, Stucki P, Roback MG, et al. Severe methemoglobinemia
associated myopathy in a child. J Pediatr Hematol Oncol. 1995;17:53–55. due to food intoxication in infants. Pediatr Emerg Care. 2005;21:
176. Zonis Z, Seear M, Reichert C, et al. The effect of preoperative tranexamic 536–538.
acid on blood loss after cardiac operations in children. J Thorac 202. Chawla R, Kundra P, Bhattacharya A. Asymptomatic methaemo-
Cardiovasc Surg. 1996;111:982–987. globinaemia and its implications. Acta Anaesthesiol Scand. 1998;42:
177. Reid RW, Zimmerman AA, Laussen PC, et al. The efficacy of tranexamic 736–738.
acid versus placebo in decreasing blood loss in pediatric patients 203. Nilsson A, Engberg G, Henneberg S, et al. Inverse relationship between
undergoing repeat cardiac surgery. Anesth Analg. 1997;84:990–996. age-dependent erythrocyte activity of methaemoglobin reductase and
178. Shapiro F, Zurakowski D, Sethna NF. Tranexamic acid diminishes prilocaine-induced methaemoglobinaemia during infancy. Br J Anaesth.
intraoperative blood loss and transfusion in spinal fusions for duchenne 1990;64:72–76.
muscular dystrophy scoliosis. Spine. 2007;32:2278–2283. 204. Duncan PG, Kobrinsky N. Prilocaine-induced methemoglobinemia in
179. Konkle BA, Ebbesen LS, Erhardtsen E, et al. Randomized, prospective a newborn infant. Anesthesiology. 1983;59:75–76.
clinical trial of recombinant factor VIIa for secondary prophylaxis 205. Frayling IM, Addison GM, Chattergee K, et al. Methemoglobinemia in
in hemophilia patients with inhibitors. J Thromb Haemost. 2007;5: children treated with prilocaine-lignocaine cream. Br Med J. 1990;301:
1904–1913. 13–14.
180. Agarwal HS, Bennett JE, Churchwell KB, et al. Recombinant factor seven 206. Anderson ST, Hajduczek J, Barker SJ. Benzocaine-induced methemo-
therapy for postoperative bleeding in neonatal and pediatric cardiac globinemia in an adult: accuracy of pulse oximetry with methemoglo-
surgery. Ann Thorac Surg. 2007;84:161–168. binemia. Anesth Analg. 1988;67:1099–1101.
181. Mathew P. The use of rFVIIa in non-haemophilia bleeding conditions in 207. Seibert RW, Seibert JJ. Infantile methemoglobinemia induced by a
paediatrics. A systematic review. Thromb Haemost. 2004;92:738–746. topical anesthetic, cetacaine. Laryngoscope. 1984;94:816–817.
182. Santacroce R, Cappucci F, Pisanelli D, et al. Inherited abnormalities of 208. Burne D. Methaemoglobinaemia following lignocaine letter. Lancet.
fibrinogen: 10-year clinical experience of an Italian group. Blood Coagul 1964;2:971.
Fibrinolysis. 2006;17:235–240. 209. Weiss LD, Generalovich T, Heller MB, et al. Methemoglobin levels
183. Krause T, Gerbershagen MU, Fiege M, et al. Dantrolene—a review of its following intravenous lidocaine administration. Ann Emerg Med. 1987;
pharmacology, therapeutic use and new developments. Anaesthesia. 16:323–325.
2004;59:364–373. 210. McDonald RD, McGuigan MA. Acute dapsone intoxication: a pediatric
184. Lerman J, McLeod ME, Strong HA. Pharmacokinetics of intravenous case report. Pediatr Emerg Care. 1997;13:127–129.
dantrolene in children. Anesthesiology. 1989;70:625–629. 211. Trillo RA, Aukburg S. Dapsone-induced methemoglobinemia and pulse
185. Shime J, Gare D, Andrews J, et al. Dantrolene in pregnancy: lack of oximetry. Anesthesiology. 1992;77:594–596.
adverse effects on the fetus and newborn infant. Am J Obstet Gynecol. 212. Hjelt K, Lund JT, Scherling B, et al. Methaemoglobinaemia among
1988;159:831–834. neonates in a neonatal intensive care unit. Acta Paediatr. 1995;84:
186. Wappler F. Malignant hyperthermia. Eur J Anaesthesiol. 2001;18: 365–370.
632–652. 213. Hermon MM, Burda G, Golej J, et al. Methemoglobin formation in
187. Watson CB, Reierson N, Norfleet EA. Clinically significant muscle children with congenital heart disease treated with inhaled nitric oxide
weakness induced by oral dantrolene sodium prophylaxis for malignant after cardiac surgery. Intensive Care Med. 2003;29:447–452.
hyperthermia. Anesthesiology. 1986;65:312–314. 214. Kumar AR, Dunn N, Naqvi M. Methemoglobinemia associated with a
188. Carr AS, Lerman J, Cunliffe M, et al. Incidence of malignant hyper- prilocaine-lidocaine cream. Clin Pediatr. 1997;36:239–240.
thermia reactions in 2,214 patients undergoing muscle biopsy. Can J 215. Reinhold P, Storms FJ. Application of “EMLA” in term and preterm
Anaesth. 1995;42:281–286. neonates—Met-Hb-reductase-activity and methaemoglobinaemia. Acta
189. Inada H, Jinno S, Kohase H, et al. Postoperative hyperthermia of un- Anaesthesiol Scand. 1995;39(Suppl 105):176.
known origin treated with dantrolene sodium. Anesth Prog. 2005;52: 216. Neuhaeuser C, Weigand N, Schaaf H, et al. Postoperative methemo-
21–23. globinemia following infiltrative lidocaine administration for combined
190. Rumack BH, Peterson RC, Koch GG, et al. Acetaminophen overdose. anesthesia in pediatric craniofacial surgery. Paediatr Anaesth. 2008;18:
662 cases with evaluation of oral acetylcysteine treatment. Arch Intern 125–131.
Med. 1981;141:380–385. 217. Barker SJ, Tremper KK, Hyatt J. Effects of methemoglobinemia on
191. Mahadevan SB, McKiernan PJ, Davies P, et al. Paracetamol induced pulse oximetry and mixed venous oximetry. Anesthesiology. 1989;70:
hepatotoxicity. Arch Dis Child. 2006;91:598–603. 112–117.
192. Ranganathan SS, Sathiadas MG, Sumanasena S, et al. Fulminant hepatic 218. Van Der Pol JG, Wolf H, Boer K, et al. Jejunal atresia related to the use
failure and paracetamol overuse with therapeutic intent in febrile of methylene blue in genetic amniocentesis in twins. Br J Obstet
children. Indian J Pediatr. 2006;73:871–875. Gynaecol. 1992;99:141–143.
193. Bridger S, Henderson K, Glucksman E, et al. Deaths from low dose 219. Bilgin H, Özcan B, Bilgin T. Methemoglobinemia induced by methylene
paracetamol poisoning. BMJ. 1998;316:1724–1725. blue pertubation during laparoscopy. Acta Anaesthesiol Scand. 1998;42:
194. Rivera-Penera T, Gugig R, Davis J, et al. Outcome of acetaminophen 594–595.
overdose in pediatric patients and factors contributing to hepatotoxicity. 220. Ng BK, Cameron AJ, Liang R, et al. Serotonin syndrome following
J Pediatr. 1997;130:300–304. methylene blue infusion during parathyroidectomy: a case report and
195. Kanter MZ. Comparison of oral and I.V. acetylcysteine in the treat- literature review. Can J Anaesth. 2008;55:36–41.
ment of acetaminophen poisoning. Am J Health Syst Pharm. 2006;63: 221. Mihai R, Mitchell EW, Warwick J. Dose-response and postoperative
1821–1827. confusion following methylene blue infusion during parathyroidectomy.
196. Betten DP, Cantrell FL, Thomas SC, et al. A prospective evaluation of Can J Anaesth. 2007;54:79–81.
shortened course oral N-acetylcysteine for the treatment of acute 222. Bach KK, Lindsay FW, Berg LS, et al. Prolonged postoperative disorien-
acetaminophen poisoning. Ann Emerg Med. 2007;50272–279. tation after methylene blue infusion during parathyroidectomy. Anesth
197. Whyte IM, Francis B, Dawson AH. Safety and efficacy of intravenous Analg. 2004;99:1573–1574.
N-acetylcysteine for acetaminophen overdose: analysis of the Hunter 223. Padh H. Vitamin C: newer insights into its biochemical functions. Nutr
Area Toxicology Service HATS database. Curr Med Res Opin. 2007;23: Rev. 1991;49:65–70.
2359–2368. 224. Dotsch J, Demirakca S, Cryer A, et al. Reduction of NO-induced methe-
198. Bailey B, McGuigan MA. Management of anaphylactoid reactions to moglobinemia requires extremely high doses of ascorbic acid in vitro.
intravenous N-acetylcysteine. Ann Emerg Med. 1998;31:710–715. Intensive Care Med. 1998;24:612–615.
199. Gupta SK, Gupta RC, Seth AK, et al. Methaemoglobinaemia in areas 225. Kortgen A, Janneck U, Vetsch A, et al. [Methemoglobinemia due to pri-
with high nitrate concentration in drinking water. Natl Med J India. locaine after plexus anesthesia. Reduction by prophylactic adminis-
2000;13:58–61. tration of ascorbic acid?] (German). Anaesthesist. 2003;52:1020–1026.
200. Sanchez-Echaniz J, Benito-Fernandez J, Mintegui-Raso S. Methemo- 226. Da Silva SS, Sajan IS, Underwood JP III. Congenital methemoglo-
globinemia and consumption of vegetables in infants. Pediatrics. 2001; binemia: a rare cause of cyanosis in the newborn—a case report.
107:1024–1028. Pediatrics. 2003;112:e158–e161.
Anticoagulants 32
Gordon T. C. Wong C H A P T E R
INTRODUCTION pathway. The extrinsic pathway consists of the transmembrane

receptor tissue factor (TF) and plasma Factors VII and VIIa
Anticoagulation in the pediatric population lacks evidence- (FVII/FVIIa). The intrinsic pathway, also known as the contact
based treatment recommendations, particularly in the newborn. pathway, consists of plasma Factors XI, IX, and VIII (FXI, FIX,
Phase I and II studies usually include only consenting adults. and FVIII). Although conceptually convenient, such a “division”
Difficulties performing clinical trials in this special population are does not account for clinical observations of bleeding and
notorious1 with a low incidence of thromboembolic events in thrombotic disorders.
children. Dosing regimes are extrapolated from adult studies Current understanding recognizes the binding of FVII to TF
and therapies, despite differences in pediatric disease profiles and as the pivotal initiating step in clot formation. TF is constitutively
ontogeny of the haemostatic system. Further, for those on long- expressed in all cells except endothelium and circulating red blood
term anticoagulation, changes in body weight, diet, treatment cells2,3 and can be considered as the cell surface receptor for FVII
compliance, and illness progression all influence response to (Figure 32–1). Emerging work points to a role of blood-borne
therapy. Consequently, close monitoring of coagulation status TF in the propagation of the clot.4 Small amount of circulating
is required. FVII exists in its active form (FVIIa)5 and binds to TF when endo-
thelium is breeched (Figure 32–2A). It is this TF-VIIa complex
that activates surrounding TF-VII complexes (see Figure 32–2B)
OVERVIEW OF THE and TF-VIIa in turn converts FX to FXa and also FIX to FIXa with
COAGULATION PROCESS minimal contribution from the contact pathway.6 The small
The coagulation cascade involves a series of amplifying reactions. amount of thrombin generated then propagates the clot formation
Coagulation factors are proteins that function as either enzymes (Figure 32–3).
or cofactors. Calcium is required for some reactions; it binds Thrombin has roles as both a coagulation effector and a
the proteins to a phospholipid surface to form a quaternary regulator as well as a role in clot formation and lysis.7 It cleaves
complex that speeds up the reactions. Negatively charged phos- fibrinogen into fibrin monomers and activates coagulation Factors
pholipid surfaces bring the proteins closer together that further FV, FVIII, FXI, and FXIII, as well as platelets. It also activates
improves the effectiveness of the cascade. The coagulation sys- thrombin-activatable fibrinolysis inhibitor (TAFI), fibrinolysis,
tem is traditionally divided into an extrinsic and an intrinsic and the naturally occurring anticoagulant protein C.
Figure 32-1. Normally, blood constituents

are separated from the subendothelial
tissue by an intact endothelium.
Figure 32-2. A: Vessel injury leads to

formation of a platelet plug and exposes
tissue factor to circulating FVII/FVIIa.
B: Binding of FVIIa to tissue factor
increases its proteolytic activity and
B TF-VIIa complexes activate nearby
TF-FVII complexes. TF = tissue factor.
NATURAL ANTICOAGULANT heparin cofactor II (HCII). Indirect inhibitors include the protein
C–protein S–thrombomodulin system. A third system involves
SYSTEMS AND FIBRINOLYSIS the protein tissue factor pathway inhibitor (TFPI).
Several systems of naturally occurring proteins prevent uncon- AT is a serine protease inhibitor that cleaves a number of
trollable clot propagation, mainly through direct or indirect enzymes in the coagulation cascade. This inhibition is strongly
inhibition of thrombin generation or activity. Direct inhibitors of potentiated by the glycosaminoglycans and naturally occurring or
thrombin include antithrombin (AT), α2 macroglobulin, and exogenous heparins. α2 Macroglobulin also binds to and inhibits
Figure 32-3. TF-VIIa complex converts

FX to Xa and FIX into FIXa that, in turn,
generate small amount of thrombin,
thus initiating the coagulation process.
Thrombin then propagates the clot
via converting fibrinogen into fibrin
monomers and activating FV, FVIII, FXI,
FXIII, and platelets. TF = tissue factor.
CHAPTER 32 ■ Anticoagulants 527
serine proteases but quantitatively less compared with AT. TABLE 32-1. Common Indications for Anticoagulation in
Likewise, HCII binds and neutralizes thrombin activity in a the Pediatric Patient Population
stoichiometric 1:1 fashion.
Thrombomodulin is a cell surface receptor that binds thro- Absolute Indication Relative Indication
mbin.8 Bound thrombin lacks the ability to either cleave fibrinogen Thromboembolic complications Myocardial infarction
or activate FV, FVIII, or platelets, but retains its ability to activate Some forms of cerebrovas-
protein C.9 Protein C is a vitamin K–dependent factor (VKDF) Prophylaxis
cular accidents
and, when activated, is a serine protease that neutralizes FVa and Prosthetic heart valves
FVIIIa. This activity of active protein C is augmented by the Cardiac catheterization Prophylaxis Likely
cofactor protein S, another VKDF. Indwelling central arterial Endovascular stents
TFPI is produced by endothelial cells10 and monocytes11 catheters Blalock-Taussig or Glenn
and binds the active site of FXa and together binds to and inhibits shunts
Other Indications
TF-FVIIa complex to prevent further FIXa production. It is a more Fontan circulation
Kawasaki’s disease
potent antithrombotic than heparin or AT. Indwelling central venous
Cardiomyopathy
Fibrinolysis is a major feedback mechanism that prevents catheters
Extracorporeal circuitry
excessive clot formation. Plasmin is a serine protease that lyses ● Cardiopulmonary bypass
Atrial fibrillation
clots by converting fibrin into fibrin degradation products. It ● Extracorporeal membrane
circulates as plasminogen, the inactive zymogen that becomes oxygenation
activated after binding to fibrin. Activation is linked to FXIIa, ● Hemodialysis
FXIa, kallikrein, tissue plasminogen activator, and urokinase. ● Continuous extravascular
There is also a number of naturally occurring plasmin inhibitors, hemoperfusion techniques
the primary one of which is α2 antiplasmin.
Modified from reference 115.
DEVELOPMENTAL HEMOSTASIS and in the first 3 months are reduced.18,19 The diminished activity
The pediatric hemostatic system is functionally adequate at birth, of AT and HCII from decreased plasma concentrations is cou-
because neonates suffer from neither uncontrollable hemor- nteracted by the increased inhibition of thrombin from higher
rhage nor life-threatening clotting problems. The system at birth concentrations of α2 macroglobulin, resulting in only a small net
is immature by adult standards and continues to evolve during slower inhibition of thrombin.
childhood. Coagulation factors first appear around 10 weeks of
gestational age and do not cross the placenta. The neonate’s ability INDICATIONS FOR
to generate thrombin is delayed, with a reduction in overall ca-
pacity, and remains at 26% less than adult levels throughout
ANTICOAGULATION
childhood.12,13 At birth, the VKDFs (II, VII, IX, and X), the contact The indications for anticoagulation are similar for adults and
factors (XII, XI, high-molecular-weight kininogen, and prekalli- children, but there are age-related differences in the frequency
krein), and the four inhibitors (AT, HCII, protein C, and protein S) of specific indications (Table 32–1). The risk of deep venous
are approximately half that of adult values.14 The pattern of thrombosis (DVT) and thromboembolism (TE) appear to increase
maturation in the postnatal period differs for different proteins. with age and are relatively rare in children.20,21 However, secondary
FVII increases rapidly after birth in both premature and full-term thrombosis in children with underlying health problems domi-
infants but remains remain less than adults for most of childhood15 nates thromboembolic complications and is overwhelmingly
as is the case with FII. However, even in early infancy, fibrinogen, related to the presence of indwelling vascular devices. The age-
FV, FVIII, FXIII, α2 macroglobulin, α1AT, and C1 esterase inhi- related incidence of thrombosis may reflect the biphasic age
bitor are similar to or increased above adult values.14 Other factors distribution of diseases that require long-term vascular devices.
increase toward adult concentrations at around 6 months of life, Approximately half of infants younger than 6 months old and close
where VKDFs and contact factors are within 80 to 90% of adult to a third of older children with venous TE have underlying
values. AT concentrations approach adult values by 3 months cardiac defects.22 Large devices in small-diameter vessels may
and remain relatively steady throughout childhood and decrease contribute to this peak. Upper limb venous thrombosis, although
to adult values at the third decade. Plasma concentrations of rare in adults, is very common in the young. A thrombus can easily
thrombomodulin are increased during childhood but decrease to extend into the heart and through the pulmonary valve, causing
adult concentrations during the teenage years. obstruction to cardiac output. The higher incidence of malignancy
Coagulation system components mature at different rates. and the maturation of the coagulation system may account for the
These differences confer upon the young an altered profile for second peak of TE around adolescence.
hemostatic disorders and response to therapy. For example, the
reduced rate and amount of thrombin generation during infancy
reduce the risk of thromboembolic but not necessarily hemor- INDIVIDUAL AGENTS
rhagic complications. The lower VKDFs at birth16 render them at
risk of hemorrhagic diseases of the newborn. The reduced vitamin
Unfractionated Heparin
K–dependent enzyme metabolism in the immature liver may con- Heparin is a naturally occurring sulfated glycosaminoglycan
tribute to increased resistance to warfarin therapy.17 The response found predominantly in mast cells. Commercially available pre-
to heparin may be lessened because AT concentrations at birth parations are derived from porcine or bovine tissues, which are
TABLE 32-2. Pharmacokinetic Data of Heparin is adjusted accordingly. Thromboelastography is also used in some
centers to gauge heparin activity.
Gestational Age, wk 25–28 29–32 33–36 Adult Bleeding complications from heparinization are uncommon,
Plasma T / , min
1
2 41.6 35.5 35.5 63.3 but this may reflect the low dose of heparin commonly used.32,33
Volume of distribution, 81 73.3 57.8 36.6 Should bleeding occur, stopping the infusion is usually all that is
mL/kg required owing to increased clearance in the young. If more urgent
Clearance, mL/kg/min 1.49 1.43 1.37 0.43 reversal is required, protamine sulfate can be administered in a
concentration of 10 mg/mL at a rate not exceeding 5 mg/min.31
From reference 30.
Cases of heparin-induced osteoporosis have been documented in
children.34–36
homogenized and treated with proteolytic enzymes or extracted at Although rare, immune-mediated heparin-induced thrombo-
elevated pH and temperatures.23 The purified products have a cytopenia (HIT) is serious given the number of patients who get
range of molecular weight from 3000 to 35,000 daltons (Da) with exposed to this compound and its potential to develop life-
a mean of around 12000 Da. threatening complications. Even minute amounts of heparin
After intravenous (I.V.) injection, about a third of the heparin exposure, such as that used for maintaining catheter patency, can
binds to AT24,25 and causes a conformational change at its pro- trigger HIT.37 A paradoxical thrombotic state may develop from
teolytic site. This increases the natural anticoagulant activity of immune complex–mediated platelet activation and thrombin
AT by up to 1000 times. It is the inhibition of thrombin and FXa generation. The reported incidence ranges from 0 to 2.3%.38 Two
that is primarily responsible for heparin’s anticoagulant activity. groups are at most risk: newborns and infants younger than
Simultaneous binding of thrombin and AT by heparin is required 4 years old undergoing cardiac surgery, and teenagers treated with
for thrombin inhibition but not for the FXa inhibition. At much heparin for thrombosis.39 Both clinical and laboratory criteria have
higher doses, heparin catalyzes thrombin inhibition by HCII. to be satisfied for the confirmation of this condition. They include
Heparin also blocks platelet activation by thrombin in the presence the presence of a triggering agent, a substantial fall in platelet
of AT26 and inhibits von Willebrand’s factor (vWf)–dependent count (usually ≥ 50%), the typical timing of the onset of thrombo-
platelet function.27,28 Clearance of heparin is dose-dependent, cytopenia with or without thromboembolic complications, and
involving a combination of a rapid saturable and a much slower the presence of heparin-dependent antibodies.38 Intermediate to
nonsaturable first-order mechanism, the latter of which is largely high probability of HIT requires immediate cessation of hepa-
renal.29 Age-dependent characteristics also play a role in its rin and alternative anticoagulation by danaparoid, lepirudin, or
clearance (Table 32–2).30 argatroban, with appropriate laboratory monitoring to prevent a
Systemic heparin is administered to pediatric patients using a thrombotic or bleeding complication.40 Thrombotic complications
weight-based nomogram to achieve an adult therapeutic activated as well as the original indication for anticoagulation must be
partial thromboplastin time (aPTT) (Table 32–3).31 This “Toronto addressed. Warfarin and other vitamin K antagonists should be
protocol” was initially evaluated prospectively by Andrew and withheld initially until the platelet count normalizes.
coworkers.32 The original I.V. bolus of 50 U/kg achieved a thera-
peutic range in only 60% of the sample, increasing to 90% with a
bolus of 75 to 100 U/kg. The maintenance I.V. infusion rate is
Low-Molecular-Weight Heparin
determined according to age and weight, with the highest initial Low-molecular-weight heparin (LMWH) or fractionated heparin
dose used for infants (see Chapter 18). Complications from is prepared primarily from depolymerization of unfractionated
bleeding were rare (2%) whereas recurrent thrombotic disease was heparin (UFH), resulting in molecules with a range of molecular
more common (7%) with this protocol. The measurement of aPTT weight from 3800 to 6000 Da.
is most commonly used to monitor heparin therapy and the dose Anti-FXa activity does not require simultaneous binding of AT
and thrombin and therefore predominates in LMWH. LMWH
preparations can contain molecules greater than 18 saccharide
Table 32-3. Recommendation for Heparin Doses
units and therefore retain anti-FII activity. The ratio of anti-Xa to
Most Hold Adjust Time After anti-IIa activity ranges from approximately 2:1 to 4:1, depending
Recent Bolus, Infusion Infusion Rate Change for on the preparation (Table 32–4).
aPTT, s units/kg For, min Rate By, % Repeat aPTT, h Potential advantages of LMWH use in children include its ease
of administration via the subcutaneous (S.C.) route, a minimal
<50 50 0 +10 4
requirement for laboratory monitoring and dose adjustments,
50–59 0 0 +10 4
minimal drug or dietary interactions, and a reduction in the
60–85 0 0 0 Next day
86–95 0 0 –10 4 incidence of HIT. It may reduce the risk of osteoporosis associated
96–120 0 30 –10 4 with long-term UFH use. There may be less bleeding possibly
>120 0 60 –15 4 from reduced platelet, endothelium, and vWF binding.27,41,42
The lack of protein binding by LMWH confers a higher
aPTT = activated partial thromboplastin time bioavailability and more predictable anticoagulant activity than
This protocol recommends a loading dose of 75 U/kg and an initial maintenance
UFH when administered in fixed doses. The half-life is generally
dose of 20 U/kg/h (>1 y) or 28 U/kg/h (<1 y). The therapeutic aPTT range is
between 60 to 85 seconds. A blood assay for aPTT four hours after every
two- to fourfold longer than UFH and clearance is mainly via
infusion rate adjustment and a daily complete blood count plus aPTT once the renal route. On the basis of target anti-FXa activity and every
target range is achieved are recommended. 12 hour administration of enoxaparin on a per-kilogram basis,
Adapted from reference 31. infants younger than 2 months required 50% more drug to achieve
TABLE 32-4. Summary of Properties of Commercially Available Low-Molecular-Weight Heparins

Average Molecular Defractionation and Preparation
DRUG Weight, Da Method (Species of Origin) Anti-Xa:IIa Ratio
Ardeparin sodium 5500–6500 Peroxidative depolymerization (porcine) 1.8:1
Certoparin sodium 5600 Amyl nitrate depolymerization (porcine) 2:1
Dalteparin sodium 5600–6400 Nitrous acid depolymerization (porcine) 2:1
Enoxaparin sodium 4500 Benzylation and alkaline depolymerization (porcine) 2.7:1
Nadroparin calcium 4300 Nitrous acid depolymerization (porcine origin) 3.2:1
Parnaparin sodium 4500–5000 Cupric acid and hydrogen peroxide degradation 3:1
(porcine or bovine)
Reviparin sodium 4150 Nitrous oxide depolymerization (porcine) 3.5:1
Tinzaparin sodium 6500 Controlled enzymatic depolymerization (porcine) 1.9:1
Adapted from references 116 and 117.
the same end point than older children, the latter of which was Warfarin
comparable with adults levels.43,44 Peak anti-FXa levels occurred
2 to 6 hours after dosing. Similarly, children under 5 kg required Warfarin is a coumarin derivative that remains the mainstay of
50 IU/kg of reviparin, compared with 30 IU/kg required by their oral anticoagulation, despite disadvantages that include a narrow
heavier (and older) counterparts, to achieve similar target levels.45 therapeutic index, long onset and offset of action, and possible
Nohe and colleagues investigated the effectiveness and safety of prothrombotic tendency during start of therapy (owing to differ-
dalteparin using plasma anti-FXa activity for prophylaxis and ential effects on VKDFs). Drug interactions with warfarin are
management of arterial and venous thrombosis in pediatric common.56 Altered absorption can occur with conditions such as
patients (N = 48; age 31 wk’ gestation–18 y). Prophylactic and fat malabsorption or other diarrheal diseases, and metabolism can
therapeutic anti-FXa levels were achieved with daily subcutaneous be significantly changed with hepatic dysfunction. Warfarinized
dosages of 95 U/kg standard deviation (sd) 52 U/kg and 129 U/kg patients must be cognizant of ingesting food containing vitamin
sd 43, respectively.46 K1. Factors including an age-related dose response, the presence
Children on long-term LMWHs are at higher risk of increased of an underlying chronic illness that necessitated anticoagulation,
changes in weight and diet, along with compliance issues affect
concentrations owing to reduced clearance from the underlying
predominantly the young. Concentrations of some VKDFs may
illness or unaccounted weight changes altering dose prediction,
be only 50% of adult values at different stages of life.16,18,19 The
and monitoring is therefore warranted. LMWHs have minimal
capacity of older children to generate thrombin is also decreased
effect on aPTT, and monitoring of LMWH activity relies upon
to 75% compared with adults with similar International Normal-
anti-FXa assay. Protamine tends to reverse the anti-FIIa rather
ized Ratio (INR).57
than the anti-FXa activity47 and does not fully neutralize LMWH.
Warfarin interferes with the metabolism of vitamin K (ReVK),
This differential reversal may be explained on the basis of reduced which is required for the posttranslational carboxylation reaction
sulfate charge in the lower-molecular-weight fractions.48 If proof glutamic residues on Factors II, VII, IX, X, protein S, and pro-
tamine is to be used, the maximal dose is 1 mg/100 U if LMWH tein C. The activities of these VKDFs will then fall in accordance
was last administered within 3 to 4 hours.49 to their plasma half-lives, those with shorter half-lives being
affected first.
Danaparoid Warfarin is a mixture of R and S enantiomers, the latter of
which is about five times more potent.58,59 Warfarin is essentially
Danaparoid sodium is a mixture of low-molecular-weight completely absorbed enterally, reaching a maximum plasma
heparinoid glycosaminoglycuronans that is purified from porcine concentration between 2 and 6 hours in adults, and is extensively
gut mucosa. The anticoagulant effect is mainly from FXa and FIIa protein-bound. It undergoes stereoselective metabolism by hepatic
inhibition, at a ratio of greater than 20:1. It has minimal effect on microsomes, whereby the S isomer is oxidized and excreted in the
platelet function and low cross-reactivity with HIT antibodies bile and the R isomer is metabolized to an inactive alcohol and
when compared with UFH and LMWH. It is the most reported excreted in urine. The elimination half-life is about 36 to 42 hours
anticoagulant used for pediatric patients affected by HIT.50 in adults.60 The terminal half-life of warfarin is about a week,
Bioavailability after S.C. injection approaches 100%. Clearance although the effective half-life is much shorter, in the range of
is through the kidneys. The half-lives of elimination of anti-FXa 20 to 60 hours.
and thrombin generation–inhibiting activities are approximately A pharmacodynamic model for the effect of warfarin on the
25 and 7 hours, respectively.51 There is no specific antidote for the synthesis of clotting factors (prothrombin complex) is described in
reversal of this agent. Danaparoid has little effect on aPTT or Chapter 18. Prothrombin complex synthesis is inhibited 50% at a
prothrombin time (PT)52 and, therefore, should be monitored by warfarin concentration of about 1.5 mg/L in adults. Warfarin
anti-FXa assays that are calibrated with danaparoid and not with concentrations associated with therapeutic anticoagulation are of
UFH or LMWH.53 An initial loading dose is 30 U/kg I.V. followed similar magnitude. The prothrombin complex synthesis rate is
by an infusion of 1.2 to 2.0 U/kg/h.54 Target anti-FXa levels are about 5%/h/70 kg and the elimination half-life estimated from
0.4 to 0.6 IU/mL and 0.5 to 0.8 IU/mL for standard and high doses, changes in PT is approximately 17 hours in adults,61 but data in
respectively.55 children are few.
TABLE 32-5. Protocol for Oral Anticoagulation for Pentasaccharide-based compounds catalyze AT-mediated FXa
Children to Maintain International Normalized Ratio inhibition. Direct thrombin inhibitors bind directly to thrombin
Between 2 and 3 to mediate effects. Compounds that can activate protein C cause
degradation of FVa and FVIIIa.
Day 1 LD of 0.2 mg/kg on Day 1 if Baseline INR 1.0–1.3
INR Action Pentasaccharides: Fondaparinux
Days 2–4 1.1–1.3 Repeat LD and Idraparinux
1.4–1.9 Give 50% of LD Synthetic analogues of a specific five-residue sequence in heparin
2.0–3.0 Give 50% of LD can potentiate AT inhibition of FXa. The sequence is highly specific
3.1–3.5 Give 25% of LD for FXa inhibition because it is too short to link AT to thrombin.
>3.5 Withhold until INR < 3.5 It also has minimal plasma protein binding other than to AT. Both
and recommence at 50% fondaparinux and idraparinux can be given subcutaneously.
of previous dose Fondaparinux is the first in this class of indirect selective FXa
Maintenance 1.1–1.4 Increase dose by 20% inhibitors. It can be given on a daily basis (half-life 13–20 h).
therapy 1.5–1.9 Increase dose by 10% Maximal plasma concentration is reached 2 hours after S.C.
2.0–3.0 No change administration.70,71 It is almost exclusively excreted unchanged
3.1–3.5 Decrease dose by 10% from the kidney and should be used cautiously in those with renal
>3.5 Withhold until INR < 3.5 impairment and avoided in those with kidney failure. Routine
and recommence at 80% monitoring for dose adjustments is not required, but its anti-
of previous dose coagulant effect can be measured by anti-FXa activity.
Fondaparinux binds to and causes a conformational change in
INR = International Normalized Ratio; LD = loading dose.
AT and increases its affinity to FXa.72 Irreversible complexes are
produced that inactivate FXa. Thereafter, the fondaparinux is
released from the complex unaltered, free for another reaction
The starting dose is 0.2 mg/kg, with subsequent dose adjust- with AT. The action of this drug is unaffected by protamine.
ments made according to nomograms and therapeutic monitoring Rapid reversal for surgery or for significant bleeding may require
(Table 32–5).31 With these typical regimes, 79% target INR are procoagulants such as recombinant FVIIa (rFVIIa). In healthy
achieved in less than 7 days, the actual time being age-dependent.
volunteers, rFVIIa can normalize aPTT and PT and thrombin
The median times to achieve INR are 2 to 5 days for infants and
generation during fondaparinux treatment.73 Fondaparinux has
3 days for teenagers.62 Because protein C has the shortest half-life
been successfully reversed with rFVIIa in combination with
among the VKDFs, there could be a prothrombotic tendency
transexemic acid in a case of postoperative hemorrhagic shock.74
when starting warfarin without heparin or if the patient is loaded
Fondaparinux does not interact with aspirin or warfarin, nor
too quickly, especially in those with protein C deficiency. The
does it bind to platelet or platelet factor 4 (PF4). It is nonreactive
maintenance doses for infants average approximately 0.32 mg/kg
to sera from HIT-affected patients.75 These factors suggest that
and 0.09 mg/kg for teenagers.63–67
The monitoring of warfarin effectiveness is based on measuring HIT is unlikely to occur with fondaparinux and may be considered
the PT and INR. The recommended frequency of monitoring may as an option for anticoagulation in HIT-affected patients.
vary but is four times during the first week. Because the highest risk Idraparinux is a more highly sulfated and, hence, negatively
of hemorrhage occurs during the first 6 to 12 weeks of therapy, charged derivative of fondaparinux. It has almost 10 times the
weekly monitoring is suggested for this period. Thereafter, the inter- affinity for binding to AT compared with fondaparinux, and thus,
val between monitoring should not exceed 4 to 6 weeks,31 bearing in its plasma half-life mirrors that of AT of around 80 hours.76 The
mind the relative difficulty in maintaining stability in children. dose-independent elimination half-life of idraparinux gives
Reversing the effect of warfarin may be achieved with a potential for weekly dosing. However, major bleeding propensity
combination of exogenous vitamin K, fresh frozen plasma (FFP), may increase with dose. Results of ongoing phase III trials have
or prothrombin concentrate (PC), depending on the indication.31 not yet been published
For those with no bleeding who require rapid reversal, S.C. or I.V.
vitamin K can be given. Children not requiring anticoagulation
after reversal may be given 0.1 mg/kg (2–5 mg), whereas the dose
Direct Thrombin Inhibitors: Recombinant
is reduced to 0.5 to 2 mg for those requiring anticoagulation Hirudin and Synthetic Hirulogues
again in the near future. For those with non–life-threatening but Direct thrombin inhibitor (DTI) binds directly onto thrombin
significant bleeding that will not cause morbidity, 0.5 to 2 mg of molecules to interfere with their enzymatic function, producing a
vitamin K along with 20 mL/kg of FFP should be given. For those more predictable anticoagulant effect. They inactivate both fibrin-
with life-threatening bleeding that will likely cause morbidity, bound and fluid-phase thrombin. Formation of fibrin is inhibited,
5 mg of vitamin K should be given and consideration should be as well as thrombin-mediated feedback activation of FV, FVIII,
given along with PC at 50 U/kg instead of FFP 20 mL/kg. FXI, and thrombin-induced platelet aggregation. Further, they are
unaffected by the large amounts of PF4 present in the vicinity
of vascular injury and platelet-rich thrombi. Bivalent DTIs bind
NEWER ANTICOAGULANTS to both the active (catalytic) and the fibrinogen-binding site
Anticoagulants that interfere with specific parts of the co- (exosite 1) of thrombin, whereas univalent DTIs bind only to the
agulation system are under various stages of development.68,69 active site.77
Recombinant Hirudin: Lepirudin and Desirudin fashion. It has a short plasma half-life of 45 minutes and under-
Hirudin is a naturally occurring, potent thrombin inhibitor from goes mainly hepatobiliary metabolism.90 It is administered by
the blood-sucking leech Hirudo medicinalis.78 Recombinant tech- continuous I.V. infusion. The effect on aPTT is concentration-
nology has enabled this compound to be produced in sufficient dependent, and this relationship is similar in pediatric patients
quantities for therapeutic use. It is a bivalent DTI that binds and healthy adults. For the pediatric population, an initial dose
thrombin in a ratio of 1:1, with high affinity and specificity. of 0.75 μg/kg/min is recommended with adjustment of 0.25 μg/
Although the bond between thrombin and hirudin is noncovalent, kg/min every 2 to 4 hours, not exceeding 3.0 μg/kg/min.91 aPTT
it is essentially irreversible owing to the high affinity. This is a should be checked 2 hours after bolus administration or any dose
major limitation because there is no specific antidote. There are no adjustment and at least once daily.92 Pediatric patients with hepatic
effects on platelets and plasma proteins.79 Currently, lepirudin and impairment or elevated bilirubin levels most likely secondary to
desirudin are the two commercially available compounds, both cardiac complications should be dosed at a quarter of the normal
having small structural and pharmacologic differences from the dose. Activated clotting time may also be used for those receiving
natural hirudin. After S.C. administration, plasma concentrations larger doses, such as during cardiopulmonary bypass. It is ap-
peak at 90 to 180 minutes80 and redistribute into the extravascular proved for the treatment of HIT and should be considered for use
space. Redistribution back into plasma may occur after cessation in this condition in those with renal insufficiency.
of prolonged use. It has a plasma half-life of 60 to 100 minutes.
Clearance of free hirudin and hirudin-thrombin complexes is ANTIFIBRINOLYTICS
largely by glomerular filtration. The half-life is greatly increased
in patients with renal insufficiency81 and should best be avoided Agents in this class include the two synthetic derivatives of lysine,
in these patients. The activity of hirudin can be monitored aminocaproic acid (EACA) and tranexamic acid (TA), and the
using escarin clotting time or chromogenic measurement of serine protease inhibitor aprotinin. In addition to their use as a
lepirudin concentration. In the absence of availability of these part of blood conservation strategy in cardiac anesthesia, TA is
tests, laboratory-based, but not point-of-care aPTT measure- being used to reduce blood loss in corrective spinal surgery.93–95
ments, can provide a reasonable guide to therapy.82 Specific pediatric pharmacokinetic data are scarce. Administration
Lepirudin is licensed for treatment of HIT complicated by regimens extrapolated from adults may over- or underestimate
arterial or venous thrombosis and as an alternative to heparin for actual pediatric requirements depending on age and maturation.96
cardiopulmonary bypass in these patients. No formal dose-finding TA and EACA competitively inhibit plasminogen and prevent
studies are available for children. A regimen comprising an excessive plasmin formation by occupying the former’s lysine-
omitted loading dose of 0.2 mg/kg followed by infusion of 0.03 to binding site. It also prevents the binding of plasminogen to fibrin.
0.05 mg/kg/h for neonates or 0.1 to 0.22 mg/kg/h for older Both agents appear equally effective in reducing postoperative
children is described.83 Favorable outcomes have been reported blood loss and blood product requirements in children with
in seven of eight pediatric cases using lepirudin in the treatment cyanotic heart disease undergoing corrective surgery when
of HIT.50 Antibodies are formed in up to 74% of those exposed to compared with controls.97 Aprotinin, conversely, is a nonspecific
recombinant hirudin, and re-exposure associated anaphylaxis has serine protease inhibitor. It rapidly inactivates free plasmin but
been reported with lepirudin.84 has little effect on bound plasmin. Despite having different modes
of action, the combined use of these agents does confer additive
benefits.98
Hirulogues: Bivalirudin and Argatroban TA and EACA are both distributed throughout most body
Bivalirudin is a 20-amino acid synthetic polypeptide analogue of tissues and are mainly excreted via the kidney, although there may
hirudin. This bivalent DTI binds to thrombin in a noncompetitive be extrarenal metabolism of EACA. Renal insufficiency reduces
nature. However, thrombin is able to cleave the polypeptide and their clearance.99 Aprotinin is entirely filtered by the kidneys and
render the bivalirudin remnant susceptible to competition for undergoes metabolism in the proximal renal tubules.100
binding from other substrates, such as fibrinogen. Thrombin can Pediatric dosing for antifibrinolytics remains poorly defined
therefore regain its usual hemostatic activities. The plasma half- owing to a lack of concentration-response data, along with devel-
life is 25 minutes after I.V. infusion85 and clearance is decreased opmental differences in hemostatic system and pharmacokine-
by only 21% and 24% in moderate and severe renal failure, tic variables. Doses of 30,000 to 50,000 KIU/kg of aprotinin at
respectively. Approximately 20% of unchanged drug is cleared via induction with a similar dose added to the pump prime have
the kidney, with the remainder presumably undergoing proteolysis been used in pediatric cardiac surgery.101,102 A loading dose of TA
intracellularly.86 Activity may be monitored by activated clotting of 100 mg/kg followed by 10 mg/kg/h reduces blood loss in both
time.87 A pilot dose-finding study has been conducted in infants acyanotic and cyanotic congenital heart disease patients. However,
younger than 6 months.88 In this study, 37.5% of patients had doses as low as 10 to 50 mg/kg loading with repeat dosing has been
complete or partial resolution of their thrombosis by 48 to effective when compared with control.97,103 On a molar basis,
72 hours; 2 of the 16 patients met the study criteria for major TA is at least seven times more potent than EACA.104 Pediatric
bleeding, which resolved with a reduction in the drug infusion pharmacokinetic study of EACA suggests that a larger initial dose,
rate. It has also been used successfully in an infant with AT defi- faster infusion rate, and an additional dose on cardiopulmonary
ciency undergoing cardiac stent placement to relieve a stenosed bypass are needed to maintain concentrations similar to that
conduit.89 It is currently licensed as an alternative to heparin of adults.105
patients with or without HIT who require percutaneous coronary Thrombotic complications with the use of antifibrinolytic
interventions. agents are an ever-present threat. Fortunately, reports of cases are
Argatroban is an L-arginine derivative, univalent DTI that rare. Anaphylactic reactions to aprotinin are more frequently
binds noncovalently to active site of thrombin in a competitive reported and the risk is increased with re-exposure to the agent,
especially if it occurs within 6 months.106 Concerns about renal selectively deficient in promoting Factor VII activation. Blood. 1993;81:
dysfunction after aprotonin use in adults107,108 may limit future 734–744.
6. Bauer KA. Activation of the Factor VII–tissue factor pathway. Thromb
use, although these negative results have not been reported in Haemost. 1997;78:108–111.
children.109 7. Crawley JTB, Zanardelli S, Chion CKNK, Lane DA. The central role of
thrombin in hemostasis. J Thromb Haemost. 2007;5(Suppl 1):95–101.
8. Esmon NL, Owen WG, Esmon CT. Isolation of a membrane-bound
ANTIPLATELET AGENTS: ASPIRIN cofactor for thrombin-catalyzed activation of protein C. J Biol Chem.
1982;257:859–864.
Salicylic acid is a time-tested compound originally extracted 9. Esmon CT. Thrombomodulin as a model of molecular mechanisms that
from natural plants such as willow and myrtle. Acetylsalicylic modulate protease specificity and function at the vessel surface. FASEB J.
acid, or aspirin, is widely used as an analgesic, antipyretic, anti- 1995;9:946–955.
10. Bajaj MS, Kuppuswamy MN, Saito H, et al. Cultured normal human
inflammatory, and antiplatelet agent. Its therapeutic effect stems hepatocytes do not synthesize lipoprotein-associated coagulation
from its irreversible inhibition of cyclooxygenase. This results in inhibitor: evidence that endothelium is the principal site of its synthesis.
inhibition of thromboxane A2 production such that platelet aggre- Proc Natl Acad Sci U S A. 1990;87:8869–8873.
gation and release are impaired. New platelets are required for the 11. McGee MP, Foster S, Wang X. Simultaneous expression of tissue factor
body to regain platelet function. Interestingly, neonatal platelets and tissue factor pathway inhibitor by human monocytes. A potential
mechanism for localized control of blood coagulation. J Exp Med. 1994;
are hyporeactive to thrombin, adenosine diphosphate/epinephrine, 179:1847–1854.
and thromboxane A2,110 but bleeding times are shorter.111 12. Andrew M, Mitchell L, Vegh P, Ofosu F. Thrombin regulation in children
When taken orally, 80 to 100% of the drug will be absorbed but differs from adults in the absence and presence of heparin. Thromb
bioavailability is only around 70% owing to first-pass metabolism. Haemost. 1994;72:836–842.
13. Schmidt B, Ofosu FA, Mitchell L, et al. Anticoagulant effects of heparin
Salicylic acid is metabolized in the liver, with a plasma half-life of in neonatal plasma. Pediatr Res. 1989;25:405–408.
2 to 4.5 hours. The metabolites are excreted in the urine. Renal 14. Andrew M, Monagle P, Brooker L. Developmental hemostasis: relevance
excretion of salicylic acid becomes increasingly important as the to thrombotic complications in pediatric patients. In: Andrew M, Monagle
metabolic pathways become saturated (zero-order metabolism) P, Brooker L (Eds.) Thromboembolic Complications During Infancy
with overdose. and Childhood. Hamilton, Ontario, and London: B.C. Decker, Inc; 2000.
pp. 5–46.
Therapeutic antiplatelet effects can be achieved with doses as 15. Andrew M, Vegh P, Johnston M, et al. Maturation of the hemostatic
low as 30 mg/d in adults.112 Aspirin in children may be prescribed system during childhood. Blood. 1992;80:1998–2005.
for Blalock-Taussig shunts or other endovascular stents, in doses 16. Andrew M, Paes B, Milner R, et al. Development of the human coagu-
of 1 to 5 mg/kg/d.113 Higher doses of 6 to 20 mg/kg/d may be used lation system in the full-term infant. Blood. 1987;70:165–172.
for mechanical prosthetic valves.111 Aspirin is used to prevent 17. Takahashi H, Ishikawa S, Nomoto S, et al. Developmental changes in
pharmacokinetics and pharmacodynamics of warfarin enantiomers in
thrombotic complications in Kawasaki’s disease and doses greater Japanese children. Clin Pharmacol Ther. 2000;68:541–555.
than 80 mg/kg/d are used in the acute phase.114 18. Andrew M, Paes B, Milner R, et al. Development of the human coagulation
system in the healthy premature infant. Blood. 1988;72: 1651–1657.
19. Andrew M, Paes B, Johnston M. Development of the hemostatic system
CONCLUSIONS in the neonate and young infant. Am J Pediatr Hematol Oncol. 1990;12:95–
104.
Anticoagulation in the young is and will remain a challenging 20. Silverstein MD, Heit JA, Mohr DN, et al. Trends in the incidence of deep
proposition for the pediatric physician in the foreseeable future. vein thrombosis and pulmonary embolism: a 25-year population-based
Practitioners must be vigilant for the threat of HIT with the use of study. Arch Intern Med. 1998;158:585–593.
21. Torn M, Bollen WL, van der Meer FJ, et al. Risks of oral anticoagulant
heparins. Newer anticoagulants, though having a more predictable therapy with increasing age. Arch Intern Med. 2005;165:1527–1532.
pharmacologic profile, are still not ideal for pediatric use. For 22. Monagle P. Anticoagulation in the young. Heart. 2004;90:808–812.
long-term use, the agent should be nonparental; be resilient to 23. Linhardt RJ, Gunay NS. Production and chemical processing of low mole-
changes in developmental hemostasis, diet, or body weight; be cular weight heparins. Semin Thromb Hemost. 1999;25(Suppl 3):5–16.
readily reversible; and require minimal monitoring. In the acute or 24. Lam LH, Silbert JE, Rosenberg RD. The separation of active and inactive
forms of heparin. Biochem Biophys Res Commun. 1976;69:570–577.
perioperative setting, an agent should also be easily monitored, 25. Andersson LO, Barrowcliffe TW, Holmer E, et al. Anticoagulant properties
nonallergenic, rapidly titratable, and reversible. The quest, there- of heparin fractionated by affinity chromatography on matrix-bound
fore, continues. antithrombin III and by gel filtration. Thromb Res. 1976;9:575–583.
26. Cofrancesco E, Colombi M, Manfreda M, Pogliani EM. Effect of heparin
and related glycosaminoglycans (GAGs) on thrombin-induced platelet
REFERENCES aggregation and release. Haematologica. 1988;73:471–475.
27. Sobel M, McNeill PM, Carlson PL, et al. Heparin inhibition of von
1. Massicotte MP, Sofronas M, deVeber G. Difficulties in performing clinical Willebrand factor–dependent platelet function in vitro and in vivo. J Clin
trials of antithrombotic therapy in neonates and children. Thromb Res. Invest. 1991;87:1787–1793.
2006;118:153–163. 28. Sobel M, Soler DF, Kermode JC, Harris RB. Localization and charac-
2. Drake TA, Morrissey JH, Edgington TS. Selective cellular expression of terization of a heparin binding domain peptide of human von Willebrand
tissue factor in human tissues. Implications for disorders of hemostasis and factor. J Biol Chem. 1992;267:8857–8862.
thrombosis. Am J Pathol. 1989;134:1087–1097. 29. Hirsh J, Raschke R. Heparin and low-molecular-weight heparin: the
3. Fleck RA, Rao LV, Rapaport SI, Varki N. Localization of human tissue factor Seventh ACCP Conference on Antithrombotic and Thrombolytic
antigen by immunostaining with monospecific, polyclonal anti-human Therapy. Chest. 2004;126:188S–203S.
tissue factor antibody [republished from Thromb Res. 1990;57:765–781]. 30. McDonald MM, Jacobson LJ, Hay WW Jr, Hathaway WE. Heparin
Thromb Res. 1990;59:421–437. clearance in the newborn. Pediatr Res. 1981;15:1015–1018.
4. Reinhardt C. New locations of intravascular tissue factor: indications. 31. Michelson AD, Bovill E, Monagle P, Andrew M. Antithrombotic therapy
Hamostaseologie. 2007;27:55–58. in children. Chest. 1998;114:748S–769S.
5. Morrissey JH, Macik BG, Neuenschwander PF, Comp PC. Quantitation 32. Andrew M, Marzinotto V, Massicotte P, et al. Heparin therapy in pediatric
of activated Factor VII levels in plasma using a tissue factor mutant patients: a prospective cohort study. Pediatr Res. 1994;35:78–83.
33. Andrew M, David M, Adams M, et al. Venous thromboembolic compli- 58. Breckenridge A, Orme M, Wesseling H, et al. Pharmacokinetics and
cations (VTE) in children: first analyses of the Canadian Registry of VTE. pharmacodynamics of the enantiomers of warfarin in man. Clin Pharmacol
Blood. 1994;83:1251–1257. Ther. 1974;15:424–430.
34. Avioli LV. Heparin-induced osteopenia: an appraisal. Adv Exp Med Biol. 59. O’Reilly RA. Studies on the optical enantiomorphs of warfarin in man.
1975;52:375–387. Clin Pharmacol Ther. 1974;16:348–354.
35. Schuster J, Meier-Ruge W, Egli F. [Pathology of osteopathy following 60. O’Reilly R. Warfarin metabolism and drug-drug interactions. In: Wessler
heparin therapy] (German). Dtsch Med Wochenschr. 1969;94:2334–2338. S, Becker C, Nemerson Y, editors. The New Dimensions of Warfarin
36. Murphy MS, John PR, Mayer AD, et al. Heparin therapy and bone Prophylaxis: Advances in Experimental Medicine and Biology. New York:
fractures. Lancet. 1992;340:1098. Plenum; 1986. pp. 205–212.
37. Ranze O, Rakow A, Ranze P, et al. Low-dose danaparoid sodium catheter 61. Holford NH. Clinical pharmacokinetics and pharmacodynamics of
flushes in an intensive care infant suffering from heparin-induced warfarin. Understanding the dose-effect relationship. Clin Pharmacokinet.
thrombocytopenia. Pediatr Crit Care Med. 2001;2:175–177. 1986;11:483–504.
38. Risch L, Huber AR, Schmugge M. Diagnosis and treatment of heparin- 62. Streif W, Andrew M, Marzinotto V, et al. Analysis of warfarin therapy in
induced thrombocytopenia in neonates and children. Thromb Res. pediatric patients: a prospective cohort study of 319 patients. Blood.
2006;118:123–135. 1999;94:3007–3014.
39. Klenner AF, Lubenow N, Raschke R, Greinacher A. Heparin-induced 63. Bradley LM, Midgley FM, Watson DC, et al. Anticoagulation therapy in
thrombocytopenia in children: 12 new cases and review of the literature. children with mechanical prosthetic cardiac valves. Am J Cardiol. 1985;
Thromb Haemost. 2004;91:719–724. 56:533–535.
40. Greinacher A, Warkentin TE. Treatment of heparin-induced thrombo- 64. Carpentieri U, Nghiem QX, Harris LC. Clinical experience with an oral
cytopenia: An Overview. In: Warkentin TE, Greinacher A, editors. Heparin- anticoagulant in children. Arch Dis Child. 1976;51:445–448.
Induced Thrombocytopenia. 4th ed. New York: Informa Healthcare USA; 65. Doyle JJ, Koren G, Cheng MY, Blanchette VS. Anticoagulation with
2007. pp. 283–317. sodium warfarin in children: effect of a loading regimen. J Pediatr. 1988;
41. Salzman EW, Rosenberg RD, Smith MH, et al. Effect of heparin and 113:1095–1097.
heparin fractions on platelet aggregation. J Clin Invest. 1980;65:64–73. 66. Hathaway W, Corrigan J. Report of Scientific and Standardization
42. Barzu T, Molho P, Tobelem G, et al. Binding of heparin and low molecular Subcommittee on Neonatal Hemostasis. Normal coagulation data for
weight heparin fragments to human vascular endothelial cells in culture. fetuses and newborn infants. Thromb Haemost. 1991;65:323–325.
Nouv Rev Fr Hematol. 1984;26:243–247. 67. Tait RC, Ladusans EJ, El-Metaal M, et al. Oral anticoagulation in paedi-
43. Massicotte P, Adams M, Marzinotto V, et al. Low-molecular-weight atric patients: dose requirements and complications. Arch Dis Child.
heparin in pediatric patients with thrombotic disease: a dose finding 1996;74:228–231.
study. J Pediatr. 1996;128:313–318. 68. Balasa VV. New anticoagulants: a pediatric perspective. Pediatr Blood
44. Punzalan RC, Hillery CA, Montgomery RR, et al. Low-molecular-weight Cancer. 2005;45:741–752.
heparin in thrombotic disease in children and adolescents. J Pediatr 69. Weitz JI, Hirsh J, Samama MM. New anticoagulant drugs: the Seventh
Hematol Oncol. 2000;22:137–142. ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest.
45. Massicotte P, Julian JA, Marzinotto V, et al. Dose-finding and phar- 2004;126:265S–286S.
macokinetic profiles of prophylactic doses of a low molecular weight 70. Boneu B, Necciari J, Cariou R, et al. Pharmacokinetics and tolerance of the
heparin (reviparin-sodium) in pediatric patients. Thromb Res. 2003; natural pentasaccharide (SR90107/Org31540) with high affinity to
109:93–99. antithrombin III in man. Thromb Haemost. 1995;74:1468–1473.
46. Nohe N, Flemmer A, Rumler R, et al. The low molecular weight heparin 71. Donat F, Duret JP, Santoni A, et al. The pharmacokinetics of fondaparinux
dalteparin for prophylaxis and therapy of thrombosis in childhood: a sodium in healthy volunteers. Clin Pharmacokinet. 2002;41(Suppl 2):
report on 48 cases. Eur J Pediatr. 1999;158(Suppl 3):S134–S139. 1–9.
47. Massonnet-Castel S, Pelissier E, Bara L, et al. Partial reversal of low 72. Olson ST, Swanson R, Raub-Segall E, et al. Accelerating ability of synthetic
molecular weight heparin (PK 10169) anti-Xa activity by protamine sulfate: oligosaccharides on antithrombin inhibition of proteinases of the clotting
in vitro and in vivo study during cardiac surgery with extracorporeal and fibrinolytic systems. Comparison with heparin and low-molecular-
circulation. Haemostasis. 1986;16:139–146. weight heparin. Thromb Haemost. 2004;92:929–939.
48. Crowther MA, Berry LR, Monagle PT, Chan AKC. Mechanisms 73. Bijsterveld NR, Moons AH, Boekholdt SM, et al. Ability of recombinant
responsible for the failure of protamine to inactivate low-molecular- Factor VIIa to reverse the anticoagulant effect of the pentasaccharide
weight heparin. Br J Haematol. 2002;116:178–186. fondaparinux in healthy volunteers. Circulation. 2002;106:2550–2554.
49. Andrew M, deVeber G. Low molecular weight heparin. In: Andrew M, 74. Huvers F, Slappendel R, Benraad B, et al. Treatment of postoperative
deVeber G, (eds) Pediatric Thromboembolism and Stroke Protocols. bleeding after fondaparinux with rFVIIa and tranexamic acid. Neth J Med.
Hamilton, Ontario and London: B.C. Decker, Inc; 1997, p. 6–10. 2005;63:184–186.
50. Risch L, Fischer JE, Herklotz R, Huber AR. Heparin-induced thrombo- 75. Savi P, Chong BH, Greinacher A, et al. Effect of fondaparinux on platelet
cytopenia in paediatrics: clinical characteristics, therapy and outcomes. activation in the presence of heparin-dependent antibodies: a blinded
Intensive Care Med. 2004;30:1615–1624. comparative multicenter study with unfractionated heparin. Blood.
51. Product Monograph—HIT Orgaron. Scarborough, Ontario. 2005;105:139–144.
52. Ibbotson T, Perry CM. Danaparoid: a review of its use in thromboembolic 76. Herbert JM, Herault JP, Bernat A, et al. Biochemical and pharmacological
and coagulation disorders. Drugs. 2002;62:2283–2314. properties of SANORG 34006, a potent and long-acting synthetic
53. Laposata M, Green D, Van Cott EM, et al. College of American Pathologists pentasaccharide. Blood. 1998;91:4197–4205.
Conference XXXI on Laboratory Monitoring of Anticoagulant Therapy: 77. Warkentin TE. Bivalent direct thrombin inhibitors: hirudin and
the clinical use and laboratory monitoring of low-molecular-weight bivalirudin. Best Pract Res Clin Haematol. 2004;17:105–125.
heparin, danaparoid, hirudin and related compounds, and argatroban. Arch 78. Wallis RB. Hirudins: from leeches to man. Semin Thromb Hemost. 1996;
Pathol Lab Med. 1998;122:799–807. 22:185–196.
54. Monagle P, Chan A, Massicotte P, et al. Antithrombotic therapy in 79. Markwardt F. Hirudin as alternative anticoagulant—a historical review.
children: the Seventh ACCP Conference on Antithrombotic and Semin Thromb Hemost. 2002;28:405–414.
Thrombolytic Therapy. Chest. 2004;126:645S–687S. 80. Salzet M. Leech thrombin inhibitors. Curr Pharm Des. 2002;8:493–503.
55. Severin T, Zieger B, Sutor AH. Anticoagulation with recombinant hirudin 81. Lefevre G, Duval M, Gauron S, et al. Effect of renal impairment on the
and danaparoid sodium in pediatric patients. Semin Thromb Hemost. pharmacokinetics and pharmacodynamics of desirudin. Clin Pharmacol
2002;28:447–454. Ther. 1997;62:50–59.
56. Hirsh J, Fuster V, Ansell J, Halperin JL. American Heart Association/ 82. Deitcher SR, Topoulos AP, Bartholomew JR, Kichuk-Chrisant MR.
American College of Cardiology Foundation guide to warfarin therapy. Lepirudin anticoagulation for heparin-induced thrombocytopenia.
Circulation. 2003;107:1692–1711. J Pediatr. 2002;140:264–266.
57. Massicotte P, Leaker M, Marzinotto V, et al. Enhanced thrombin regula- 83. Klenner AF, Greinacher A. Heparin-induced thrombocytopenia in child-
tion during warfarin therapy in children compared to adults. Thromb ren. In: Warkentin TE, Greinacher A, editors. Heparin-Induced Thrombo-
Haemost. 1998;80:570–574. cytopenia. 4th ed. New York: Informa Healthcare USA; 2007. pp. 503–517.
84. Greinacher A, Lubenow N, Eichler P. Anaphylactic and anaphylactoid pediatric patients having cardiac operations. J Thorac Cardiovasc Surg.
reactions associated with lepirudin in patients with heparin-induced 1993;105:712–720.
thrombocytopenia. Circulation. 2003;108:2062–2065. 102. Mossinger H, Dietrich W, Braun SL, et al. High-dose aprotinin reduces
85. Fox I, Dawson A, Loynds P, et al. Anticoagulant activity of Hirulog, a activation of hemostasis, allogeneic blood requirement, and duration of
direct thrombin inhibitor, in humans. Thromb Haemost. 1993;69:157–163. postoperative ventilation in pediatric cardiac surgery. Ann Thorac Surg.
86. Robson R, White H, Aylward P, Frampton C. Bivalirudin pharma- 2003;75:430–437.
cokinetics and pharmacodynamics: effect of renal function, dose, and 103. Zonis Z, Seear M, Reichert C, et al. The effect of preoperative tranexamic
gender. Clin Pharmacol Ther. 2002;71:433–439. acid on blood loss after cardiac operations in children. J Thorac
87. Cheneau E, Canos D, Kuchulakanti PK, et al. Value of monitoring Cardiovasc Surg. 1996;111:982–987.
activated clotting time when bivalirudin is used as the sole anticoagu- 104. Verstraete M. Clinical application of inhibitors of fibrinolysis. Drugs.
lation agent for percutaneous coronary intervention. Am J Cardiol. 1985;29:236–261.
2004;94:789–792. 105. Ririe DG, James RL, O’Brien JJ, et al. The pharmacokinetics of epsilon-
88. Young G, Tarantino MD, Wohrley J, et al. Pilot dose-finding and safety aminocaproic acid in children undergoing surgical repair of congenital
study of bivalirudin in infants <6 months of age with thrombosis. heart defects. Anesth Analg. 2002;94:44–49.
J Thromb Haemost. 2007;5:1654–1659. 106. Dietrich W, Spath P, Ebell A, Richter JA. Prevalence of anaphylactic
89. Zamora R. Successful anticoagulation with bivalirudin in antithrombin- reactions to aprotinin: analysis of two hundred forty-eight reexposures
deficient pediatric patient undergoing stent placement. Catheter to aprotinin in heart operations. J Thorac Cardiovasc Surg. 1997;113:
Cardiovasc Interv. 2006;68:292–295. 194–201.
90. Swan SK, Hursting MJ. The pharmacokinetics and pharmacodynamics 107. Mangano DT, Tudor IC, Dietzel C. The risk associated with aprotinin
of argatroban: effects of age, gender, and hepatic or renal dysfunction. in cardiac surgery. N Engl J Med. 2006;354:353–365.
Pharmacotherapy. 2000;20:318–329. 108. Karkouti K, Beattie WS, Dattilo KM, et al. A propensity score case-control
91. Hursting MJ, Dubb J, Verme-Gibboney CN. Argotroban anticoagulation comparison of aprotinin and tranexamic acid in high-transfusion-risk
in pediatric patients: a literature analysis. J Pediatr Hematol Oncol. cardiac surgery. Transfusion. 2006;46:327–338.
2006;28:4–10 109. Szekely A, Sapi E, Breuer T, et al. Aprotinin and renal dysfunction after
92. Lewis BE, Hursting MJ. Argatroban therapy in heparin-induced thro- pediatric cardiac surgery. Paediatr Anaesth. 2008;18:151–159.
mbocytopenia. In: Warkentin TE, Greinacher A, editors. Heparin-Induced 110. Rajasekhar D, Kestin AS, Bednarek FJ, et al. Neonatal platelets are less
Thrombocytopenia. New York: Marcel Dekker, Inc; 2004. pp. 437–474. reactive than adult platelets to physiological agonists in whole blood.
93. Sethna NF, Zurakowski D, Brustowicz RM, et al. Tranexamic acid Thromb Haemost. 1994;72:957–963.
reduces intraoperative blood loss in pediatric patients undergoing 111. Andrew M, Monagle P, Brooker L. Antiplatelet agents and alternatives to
scoliosis surgery. Anesthesiology. 2005;102:727–732. standard anticoagulation therapy. In: Andrew M, Monagle P, Brooker L
94. Thompson GH, Florentino-Pineda I, Poe-Kochert C, et al. The role of (Eds.) Thrombotic Complications during Infancy and Childhood.
amicar in decreasing perioperative blood loss in idiopathic scoliosis. Hamilton, Ontario, and London: B.C. Decker, Inc; 2000. pp. 385–398.
Spine. 2005;30:S94–S99. 112. A comparison of two doses of aspirin (30 mg vs. 283 mg a day) in
95. Shapiro F, Zurakowski D, Sethna NF, et al. Tranexamic acid diminishes patients after a transient ischemic attack or minor ischemic stroke. The
intraoperative blood loss and transfusion in spinal fusions for Duchenne Dutch TIA Trial Study Group. N Engl J Med. 1991;325:1261–1266.
muscular dystrophy scoliosis. Spine. 2007;32:2278–2283. 113. Hathaway WE. Use of antiplatelet agents in pediatric hypercoagulable
96. Anderson BJ, Meakin GH. Scaling for size: some implications for states. Am J Dis Child. 1984;138:301–304.
paediatric anaesthesia dosing. Paediatr Anaesth. 2002;12:205–219. 114. Durongpisitkul K, Gururaj VJ, Park JM, Martin CF. The prevention of
97. Chauhan S, Das SN, Bisoi A, et al. Comparison of epsilon aminocaproic coronary artery aneurysm in Kawasaki disease: a meta-analysis on the
acid and tranexamic acid in pediatric cardiac surgery. J Cardiothorac efficacy of aspirin and immunoglobulin treatment. Pediatrics. 1995;96:
Vasc Anesth. 2004;18:141–143. 1057–1061.
98. Bulutcu FS, Ozbek U, Polat B, et al. Which may be effective to reduce 115. Andrew M. Indications and drugs for anticoagulation therapy in
blood loss after cardiac operations in cyanotic children: tranexamic acid, children. Thromb Res. 1996;81:S61–73.
aprotinin or a combination? Paediatr Anaesth. 2005;15:41–46. 116. Messmore HL, Coyne E, Wehrmacher WH, et al. Studies comparing
99. Nilsson IM. Clinical pharmacology of aminocaproic and tranexamic low molecular weight heparin with heparin for the treatment of
acids. J Clin Pathol Suppl (R Coll Pathol). 1980;14:41–47. thromboembolism: a literature review. Curr Pharm Des. 2004;10:1001–
100. Bojanov G, Belani KG. APROTININ—an update for the perioperative 1010.
physician. Ann Card Anaesth. 2005;8:75–80. 117. Duplaga BA, Rivers CW, Nutescu E. Dosing and monitoring of low-
101. Dietrich W, Mossinger H, Spannagl M, et al. Hemostatic activation molecular-weight heparins in special populations. Pharmacotherapy.
during cardiopulmonary bypass with different aprotinin dosages in 2001;21:218–234.
Pharmacology of
Vasopressive Agents 33
Robert Whitty C H A P T E R
INTRODUCTION maffin tissue and the central nervous system. Epinephrine is taken
up by storage vesicles and released by exocytosis (Figure 33–1).
Vasopressors are pharmacologic agents that result in constriction During adrenergic nerve transmission, only a small proportion
of vascular smooth muscle resulting in an increase in systemic of norepinephrine binds to adrenoreceptors. The majority is
vascular resistance. The term vasopressor is often loosely used to actively transported back into the preganglionic nerve terminal
incorporate the inotropic agents that enhance cardiac contractility and returned to storage vesicles within the cytoplasm.
and chronotropes that enhance heart rate. Both vasopressors and Catecholamine clearance form the blood is rapid. Epineph-
inotropic/chronotropic agents work via receptors of the sympa- rine and norepinephrine have half-lives of 1 or 2 minutes. The
thetic nervous system (Table 33–1).
Vasopressors either directly or indirectly stimulate the sympa-
thetic nervous system via its receptors. Direct-acting vasopressors
stimulate sympathetic receptors only. Indirect-acting vasopressors
promote the release of norepinephrine (noradrenaline).
BIOSYNTHESIS AND
METABOLISM OF THE NATURALLY
OCCURRING CATECHOLAMINES
Dopamine, norepinephrine (noradrenline), and epinephrine
(adrenaline) are the naturally occurring catecholamines that are
manufactured in the adrenal medulla.
The amino acid tyrosine is the precursor in the biosynthetic
pathway of the naturally occurring catecholamines. Tyrosine is
hydroxylated to didroxyphenylalanine (DOPA). DOPA is con-
verted to dopamine by the enzyme DOPA decarboxylase. Dopa-
mine is then transported into storage vesicles in the sympathetic
nerve endings where dopamine beta-hydroxylase catalyzes the
addition of a beta-hydroxyl group, forming norepinephrine.
Norepinephrine is methylated to epinephrine by phenyletha-
nolamine-N-methyl transferase (PNMT), which occurs in the
mainly in the adrenal medulla but also is in extra-adrenal chro-
TABLE 33-1. Principal Vasopressors and Their

Stimulated Receptors
Vasopressor Receptor Stimulated
Norepinephrine Beta1, alpha1, alpha2
Epinephrine Beta1, beta2, alpha1, alpha2
Dopamine Dopaminergic beta1, alpha1
Phenylephrine Alpha1, alpha2
Metaraminol Beta1, beta2, alpha1, alpha2
Ephedrine Beta1, alpha1
Vasopressin V1, V2
Dobutamine Beta1, beta2, alpha1 Figure 33-1. Biosynthesis of the naturally occurring
catecholamines.
catecholamines are metabolized by two enzymes, monoamineoxi- striction of the systemic circulation is always much greater than
dase (MAO) and catechol-O-methyl transferase (COMT), which that of the pulmonary circulation even at the higher dose range.
are present in most tissues in the body but concentrated in This is because young infants and neonates have underdeveloped
the liver, kidney, and intestines. MAO catalyzes the oxidative sympathetic innervation and a reduced store of norepinephrine;
deamination of catecholamines to aldehydes, which are then these require higher infusion doses than older children to achieve
oxidized to carboxylic acids and alcohols by aldehyde and alcohol the desired pharmacologic effect.11 However, in preterm neonates,
dehydrogenases.
signs of cardiovascular alpha stimulation may occur at lower
The second major metabolic pathway is catalyzed by COMT.
doses than beta stimulation because beta receptor maturation
Epinephrine and norepinephrine are methylated to normetane-
lags behind alpha receptor maturation in the development of
phrine and metanephrine, respectively. COMT converts these
metabolites to 3-metho-oxy-4-hydroxy-mandelic acid (VMA). the adrenergic system. The preterm neonate also has immature
VMA is the principal end product of catecholamine metabolism metabolic and elimination pathways, leading to an increased
that is excreted in the urine. dopamine concentration.1,3,12,13
DOPAMINE Pharmacokinetics and Pharmacodynamics

Dopamine is considered to follow first-order kinetics with plasma
Dopamine is a naturally occurring endogenous catecholamine
concentrations correlating with infusion rates.14–17 However, con-
and a precursor of norepinephrine and epinephrine. It is widely
siderable between-individual variability of plasma dopamine
used in all pediatric age groups1–4 and is often the first-line vaso-
concentrations with dopamine infusion has also been demon-
pressor used by many clinicians for the treatment of fluid-resistant
strated,18–20 particularly in children younger than 2 years in whom
hypotension in neonates.5–7
plasma clearance is twice that of an adult.11,21,22 Dopamine is
metabolized by COMT and MAO and excreted as homovanillic
Cardiovascular Effects acid in the urine. Dopamine is also taken up by the sympathetic
nerve terminals and converted to norepinephrine or stored in
Dopamine stimulates dopamine, serotonin, β1, β2, and α1 adren- vesicles.23,24 Approximately 25% of infused dopamine is converted
ergic receptors, and it should be used according to its phar- to norepinephrine in the synaptic terminals.25
macologic effect rather than adhering to strict dosing regimens In addition to its hemodynamic effects, dopamine activates
(Table 33–2). Dopamine receptors are located in the central the renin-angiotensin system and stimulates serotonin receptors.
nervous system and in the peripheral vasculature, adrenergic It inhibits thyrotropin, gonadotropin, growth hormone, and
nerve endings, and renal tubules. D1 dopamine receptors sti- prolactin secretion. Prolactin secretion modulates antidiuretic
mulation results in cerebral, renal, coronary, and mesenteric hormone (ADH) and aldosterone production,12,26–30 increases
vasodilatation.7,8 retention of sodium and water, and promotes natriuresis.
The pharmacologic effects of dopamine depend on the dose One advantage of dopamine over other vasopressor agents is
infused. At a low infusion rate, dopamine receptors increase renal that, at lower doses, it may be infused peripherally over a short
blood flow and, hence, increase urinary output. At moderate doses,
period. However, extravasation may cause skin necrosis.
beta receptors are stimulated, increasing cardiac output. When
infused at a high rate, dopamine caused peripheral vasocon-
striction and a rise in systemic vascular resistance9 (Table 33–3). EPINEPHRINE
Another vasopressor should be considered in addition to
or instead of dopamine when infusion rates greater than 20 μg/ Epinephrine (adrenaline) is a naturally occurring catecholamine
kg/min are required. Tachycardia and tachyarrhythmias may and is synthesized in sympathetic nerve terminals and the adrenal
occur at moderate doses in children10 but occur more commonly medulla from the amino acid phenylalanine.
in adults.
Dopamine’s effect on the pulmonary blood vessels is less well
understood. Dopaminergic receptors are present in the pulmonary
Cardiovascular Effects
vasculature, and it is thought to cause pulmonary vasoconstriction Epinephrine stimulates β1 and β2 adrenergic receptors, resulting in
in preterm neonates. However, dopamine-induced vasocon- increased myocardial contractility and vasodilatation of blood
TABLE 33-2. Dosing Regimens for Principal Vasopressors

Drug Infusion Concentration Range of Dose, μg/kg/min Range of Dose, mL/h
Epinephrine 0.3 mg/kg in 50 mL 5% dextrose or N/S 0.1–2.0 1–20
Norepinephrine 0.3 mg/kg in 50 mL 5% dextrose or N/S 0.1–1.0 1–10
Dopamine 15 mg/kg in 50 mL 5% dextrose or N/S 2–20 0.4–4.0
Vasopressin 0.3 mg/kg in 50 mL 5% dextrose or N/S 0.0001–0.002 1–20
Milronone 1.0 mg/kg in 50 mL 5% dextrose or N/S 0.33–0.99 1–3
Dobutamine 15 mg/kg in 50 mL 5% dextrose or N/S 2–20 0.4–4.0
N/S = normal saline.
The Handbook of Clinical Practice. Department of Critical Care Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada. 2001
CHAPTER 33 ■ Pharmacology of Vasopressive Agents 537
TABLE 33-3. Effects of Different Dopamine Infusion Rates same dose of epinephrine is used as if it were being administered
intravenously. The ET route requires 10 times the I.V. dose to
Infusion Rate, Receptors Physiologic achieve similar plasma concentrations.
μg/kg/min Stimulated Effects Racemic epinephrine was traditionally nebulized for the treat-
1–2 DA1 Increased renal blood flow and ment of laryngotracheobronchitis (croup) by stimulating alpha1
urinary output receptors that caused vasoconstriction and reduction of subglottic
2–10 Beta1, beta2 Increased cardiac contractility mucosal swelling. The racemic mixture contained equal amounts
and output of D and L isomers. However, I.V. preparations of epinephrine are
>10 Alpha1 Increased peripheral vascular equally effective when nebulized for croup. The typical nebulized
resistance and blood pressure dose is 0.5 mL/kg of 1:1000 epinephrine (maximum dose 5 mL),
and it may be repeated every 15 minutes if required.
DA = dopamine.
vessels supplying skeletal muscle.31,32 At low infusion rates (<0.01 NOREPINEPHRINE

μg/kg/min), systemic vascular resistance in reduced or unchanged
Norepinephrine (noradrenaline) is a naturally occurring cate-
but myocardial contractility in increased. At moderate doses
cholamine that is found in the brain and at the postganglionic
(0.04–0.10 μg/kg/min), myocardial contractility and heart rate
neurones of the sympathetic nervous system. It is secreted by the
increase with minimal effect on the peripheral vasculature. At
adrenal medulla.
higher infusion doses (>2.0 μg/kg/min), alpha effects become
prominent, causing a rise in peripheral vascular resistance.
Epinephrine dosing for cardiac arrest has been the subject of Cardiovascular Effects
much controversy.33,34 The dose for intravenous (I.V.) epinephrine
during cardiac arrest is 0.01 mg/kg and a high dose is considered Norepinephrine stimulates alpha1, alpha2, and beta1 receptors with
to be 0.1 mg/kg and above. The American Heart Association minimal effect on beta2 receptors. The result of this is unopposed
recommends the use of a standard dose initially,35 but should there vasoconstriction causing a rise in systolic and diastolic blood
be no response, then either a second standard dose or the high pressure and a reflex slowing of the heart rate. The consequent
dose may be used. There is high individual variability in response increase in afterload increases myocardial oxygen demand, which
to epinephrine,36 and although higher doses of epinephrine have may lower cardiac output.55–57 Pulmonary vascular resistance is
been associated with improved coronary and cerebral blood flow also increased. Norepinephrine also causes vasoconstriction of the
during cardiopulmonary resuscitation (CPR),37–39 doses greater renal and mesenteric vascular beds.58–61 However, blood flow is
than 0.05 mg/kg maybe harmful during in-hospital CPR.40,41 maintained because of the increased perfusion pressure. In fluid-
resuscitated hypotensive oliguric patients, norepinephrine caused
a rise in blood pressures that improved renal blood flow,62–67
Pharmacokinetics and Pharmacodynamics increased glomular filtration rate,68–70 and a rise in urine output.
Plasma concentration is linearly related to dose, and hence, Norepinephrine, unlike dopamine, does not interfere with the
epinephrine follows first-order pharmacokinetics. As with many hypothalamic pituitary axis,64,71 but the combination of both may
infusions, there is between-individual variability, particularly in be beneficial in resistant septic shock.72 It should not be infused
critically ill children. Plasma half life is 2 to 3 minutes with steady- peripherally because extravasation may result in limb and digital
state plasma concentrations achieved after 10 to 15 minutes. The ischemia and skin necrosis.73,74
principal pathway of metabolism of epinephrine by is O-methylation Norepinephrine has no effect on beta2 receptors and so its effect
to metanephrine by COMT. Deamination by MAO occurs at on bronchial smooth muscle and smooth muscle elsewhere in the
multiple sites. Epinephrine is then excreted in the urine as VMA. body is minimal. It also produces less anxiety and agitation than
Its beta2 effects also result in relaxation of smooth muscle epinephrine because there is minimal stimulation of the cerebral
in the bronchial tree. Epinephrine, because of its hydroxyl group cortex.75
on the –beta carbon atom of the side chain, is a more potent vaso-
pressor than dopamine.42 It does, however, have more metabolic Pharmacokinetics and Pharmacodynamics
adverse effects. Epinephrine infusions cause a rise in plasma
lactate.43–48 Other metabolic effects include insulin suppression, Norepinephrine infusion rates, when used within the recom-
glycogenolysis, gluconeogenesis, and decreased clearance of mended range, demonstrate a linear relationship with plasma
glucose—all of which collectively increase serum glucose.49–52 concentrations. This is consistent with single-compartment, first-
Epinephrine-associated hypokalemia may also occur as a result order elimination kinetics.76,77 The pharmacodynamic effects of
of beta2 receptor stimulation53,54 and may also cause central nerv- norepinephrine infusion do not follow such a linear path. This is
ous system excitation that manifests as headache, tremor, and attributed to between-patient variability, adrenoreceptor down-
agitation. Epinephrine directly accelerates the sinoatrial node, regulation, and adrenal suppression from sepsis and drugs.78,79
hence, it has proarrhythmic properties. Norepinephrine is inactivated by oxidative deamination cata-
Epinephrine is available for I.V. administration as 1:1000 lyzed by MAO and O-methylation carried out by COMT. The
(1 mg/mL) or 1:10,000 (100 μg/mL) as an aqueous solution two reactions occur in either order. The aldehyde products of
of adrenaline hydrochloride. the MAO reaction are oxidized to their corresponding acids.
Epinephrine may also be administered via the interosseous or Epinephrine and norepinephrine are converted to vanillyl
endotracheal (ET) route. When administered interosseously, the mandelate, which is excreted in the urine.
DOBUTAMINE prevent the breakdown of cAMP by the isoenzyme phospho-

diesterase. This, in turn, results in increased calcium availability
Cobutamine is a synthetic catecholamine derived from iso- to cardiac muscle and improved cardiac contractility. The oppo-
proterenol (isoprenaline). It is composed of a racemic mixture of site occurs in the peripheral vascular smooth muscle where
two isomers. a diminished availability of calcium leads to vascular smooth
muscle relaxation and consequent vasodilatation, hence the term
ionodilator.88
Cardiovascular Effects
Dobutamine directly stimulates predominantly beta1 receptors.
It also has weaker β2 and alpha1 adrenoreceptor activity. The Cardiovascular Effects
L isomer acts on alpha receptors and the D isomer acts on both Milronone reduces preload and afterload and intracardiac filling
beta receptors; beta1 stimulation by dobutamine results in pressures,88,89 reducing myocardial oxygen consumption. PDEIs
increased myocardial contractility. The weak beta2 activity results act indirectly act on beta receptors and are not subject to tachy-
in peripheral vasodilatation, inducing reduced afterload. The net phylaxis or beta1 desensitization as is the case with other vaso-
effect of both beta1, beta2, and alpha1 stimulation leads to increased pressors.90,91 A major theoretical advantage of milrinone is that it
cardiac output, decreased left ventricular filling pressure, improves myocardial diastolic dysfunction and more readily
decreased systemic vascular resistance, and either an increase or lowers pulmonary vascular resistance.88 It has also been shown to
a decrease in blood pressure. Although dobutamine is a strong improve cardiac output in neonates who have low cardiac output
ionotropic agent it, has moderate chronotropic activity, and is not states after cardiopulmonary bypass and in the treatment of
associated with the tachycardia at doses less than 10 μg/kg/min, nonischemic heart failure that most commonly occurs in patients
doses up to 20 μg/kg/min may be used. Doses up to 20 μg/kg/min with congenital heart defects. Hemodynamic effects are similar in
may be used, but as for all vasopressors, the dose should be titrated both adults and children.92
to effect because of between-individual variability. Although PDEIs may cause serious arrhythmias in adults, these
In the premature neonate, dobutamine raises blood pressure as arrhythmias have not been observed in children.93
alpha1 receptor activity is more pronounced than beta receptor Milrinone has been used successfully in conjunction with other
activity because of the slower maturation of the beta receptor.80 vasopressors in septic shock,94 despite concerns that peripheral
Dobutamine may also lower pulmonary vascular resistance, vasodilator effects may be undesirable in hypotensive patients.
although the mechanism of this effect is not fully understood. Milrinone is renally cleared, and dosing should be adjusted in
Septic patients with a high cardiac output and a high systemic those with renal impairment. It has a longer half-life than other
vascular resistance may benefit from dobutamine.72,81 vasopressors, greater than 2 hours in those with normal renal
function, and the effect is reduced when infusions are used for
longer than 48 hours. A clearance of 9 L/h/70 kg is reported in
Pharmacokinetics and Pharmacodynamics adults with congestive heart failure. We might anticipate reduced
clearance in neonates in whom renal function is immature. This
There is conflicting evidence as to whether dobutamine follows
has been confirmed in 26-week postmenstrual age infants who
linear or nonlinear kinetics, and clearance in both critically ill and
had a clearance of 0.96 L/h/70 kg.95
noncritically ill children is variable.82–85 Onset of action occurs
Milronone has a larger volume of distribution and is more
within 2 minutes with peak effect occurring within 10 minutes. rapidly cleared in children than in adults, and a larger loading
Plasma half-life is less that 3 minutes and is caused by redistri- dose, and perhaps a greater initial infusion rate, may be necessary
bution and metabolism by COMT. in children to achieve serum concentrations within the desired
Dobutamine works on a cellular level through its action on range and produce an optimal cardiovascular response.96
beta1 receptors by activating guanine nucleotide regulatory cascade
(via G proteins). This leads to increased adenylate cyclase activity
and increased conversion of adenosine triphosphate to cyclic VASOPRESSIN
adenosine monophosphate (cAMP). Intracellular cAMP promotes
release of calcium from the sacroplasmic reticulum. Calcium is Vasopressin is an endogenous hormone produced by the posterior
used by contractile proteins to increase contractility. Dobutamine pituitary gland and is also called ADH. Vasopressin and its syn-
maybe infused peripherally; inadvertent extravasation is unlikely thetic analogue terlipressin have been widely used for the treat-
to produce significant cutaneous vasoconstriction or necrosis. ment of diabetes insipidus, variceal hemorrhage, and hepatorenal
syndrome.97,98 Vasopressin is released in response to a rise in
serum osmolality above 287 mOsm/kg.99 The osmoreceptors,
PHOSPHODIESTERASE located peripherally in the portal system and centrally in the
INHIBITORS (AMRINONE, third ventricle, detect rises in serum osmolality, which may be a
consequence of hypovolemia.
MILRINONE, ENOXIMONE)
Milrinone and enoximone are specific phosphodiesterase III
inhibitors (PDEIs) and are derivatives of amrinone. The use of Cardiovascular Effects
amrinone was curtailed because of its long context-sensitive half- Because of its vasoactive properties, vasopressin has been studied
life and its adverse effect profile that included thrombocytopenia in relation to septic shock states and in resuscitation after cardiac
and gastrointestinal effects.86,87 arrest. Vasopressin mediates its action via the V1 receptors located
Milronone is a bipyrinine inotrope/vasodilator that selectively in vascular smooth muscle in the splanchnic, renal, and coronary
promotes cAMP levels in cardiac and vascular muscle. PDEIs circulations.100,101
V2 and V3 receptors are less important and are located in the mechanism. It also increases glycogen breakdown, stimulates the
nephron and anterior pituitary, respectively. They also respond release of corticotrophin from the anterior pituitary, and is a mild
directly to vasopressin to stimulate water retention. stimulant of platelet aggregation.
It has been shown that vasopressin concentrations are main-
tained and even rise in hypovolemic and cardiogenic shock
but drop dramatically in septic shock.102–106 Hence, vasopressin ISOPRENALINE
supplementation in septic shock states, particularly catecholamine- Isoprenaline is a synthetic catecholamine with potent beta1 and β2
resistant shock, became a focus for many studies.107–113 In adults, activity with no alpha activity.
doses greater than 0.04 U/min (i.e., supraphysiologic doses) cause
critical increases in myocardial oxygen consumption, in addition
to intense renal, mesenteric, and pulmonary vasoconstriction.57 Cardiovascular Effects
Vasopressin and terlipressin have been shown to be effective
adjunctive pressors in the management of norepinephrine and Both myocardial contractility and heart rate are increased with
refractory shock. The bolus dose for vasopressin is 0.01 to 0.3 U/ both systolic and diastolic pressures decreased. Blood supply is
kg/min with an infusion range of 0.0002 to 0.002 U/kg/min.114 diverted from vital organs to muscle and skin, and this can
Terlipressin doses vary from 7 μg/kg every 12 hours115 to 10 μg/kg potentiate myocardial ischemia and arrhythmias. Isoprenaline is
given hourly.116 Larger children are given boluses of between used therapeutically in torsades de pointes because it reduces the
0.5 and 1 mg.117,118 Its role in pediatric septic shock has been less QT interval.
well studied, although animal studies and case series reports Its inotropic effects occur at an infusion of 0.015 μg/kg/min.
have been promising.119,120 There are no clear guidelines as to when At rates greater than 0.02 μg/kg/min, tachyarrhythmias and
vasopressin infusions should be started in septic shock. A large ventricular irritability occur. Profound hypotension may also
adult study56 and a small study on low-birthweight infants have occur because of the unopposed beta2 stimulation. Isoprenaline
suggested commencing vasopressin infusions121 before norepi- has now been superseded by dopamine and dobutamine, which
nephrine has reached 0.6 μg/kg/min. Neither vasopressin nor have a lower incidence of malignant arrhythmias. However, it may
terlipressin is recommended as first-line agents in the treatment of still be of use in the treatment of bradycardia unresponsive to
septic shock but rather adjuncts should norepinephrine fail to atropine, β blocker overdose and atrioventricular conduction
maintain blood pressure. block, particularly in denervated hearts. Other effects include
Vasopressin during resuscitation after cardiac arrest in adults pulmonary vasodilatation and bronchodilatation.
has been shown to improve short-term outcomes (survival to
hospital admission).122–124 Wenzel and coworkers125 conducted a
large prospective study involving over 1000 adult patients com- DOPEXAMINE
paring vasopressin 0.04 U and epinephrine 1 mg intravenously. Dopexamine is a synthetic analogue of dopamine that is about
They reported similar outcomes in both the vasopressin- and the 60 times more potent. It has pronounced beta2 and DA1 activity
epinephrine-treated patients after ventricular fibrillation and with minor beta1 and DA2 activity and no alpha activity. Dopexa-
pulseless electrical activity arrests. In patients who had asystolic mine does decrease norepinephrine re-uptake, but its predomi-
arrest, however, vasopressin improved survival rates. Vasopressin as nant effect is afterload reduction owing to renal and mesenteric
a resuscitative drug in pediatric cardiac arrests is less well studied.
vasodilatation. Myocardial contractility is improved by virtue of its
Mann and colleagues’ case series suggested that vasopressin given
potent beta2 activity.
after epinephrine resulted in a return to spontaneous circulation
Dopexamine also cause pulmonary vasodilatation and may
after prolonged cardiac arrest.126 Animal studies have demonstrated
impair hypoxic vasoconstriction and, hence, may worsen pulmo-
a benefit of vasopressin used with epinephrine,127,128 but further
nary shunting. Infusion rates range between 0.5 and 6 μg/kg/min.
studies are needed to validate its use in pediatric patients. One
theoretical advantage of vasopressin over other vasopressors used Dopexamine has been associated with a rise in arterial pressure
during cardiac arrest is that severe acidosis does not alter its and a rise in urine output in critically ill neonates.132 In older
effectiveness.129 Vasopressin has also been shown to preserve renal children following surgery for congenital heart disease, dobut-
blood flow, creatinine clearance, and renal function better than amine was associated with a significant rise in cardiac index and
norepinephrine when used to maintain systemic vascular resist- heart rate.
ant in septic shock.130 Currently, American Heart Association
guidelines state that there is insufficient evidence to recommend Pharmacokinetics and Pharmacodynamics
for or against the routine use of vasopressin during cardiac arrest
in children.131 Its pharmacokinetic profile has not been fully elucidated. Infusion
rates range between 0.5 and 6 μg/kg/min and its plasma half-life
is 6 to 7 minutes. It is cleared from the circulation and taken up by
Pharmacokinetics and Pharmacodynamics extraneuronal tissues and the liver where it is metabolized by
Vasopressin is metabolized by tissue peptidases, 33% being elimi- COMT and MAO.
nated by the kidney and renally excreted. It has an elimination
half-life of approximately 10 to 35 minutes. It can be administered
subcutaneously, intramuscularly, or intravenously. Its analogue
PHENYLEPHRINE
desmopressin is usually given intranasally as snuff or spray. Vaso- Phenylephrine is a postsynaptic alpha1 adrenergic receptor agonist
pressin increases renal lumen permeability to water. Vasopressin with little beta activity, similar to norepinephrine. Aside from
secretion is enhanced by stimulation of the renin-angiotensin its vasoconstrictive properties, it is most commonly used as a
mydriatic and nasal decongestant. Parenteral administration of 13. Seri I. Dopamine and natriuresis. Mechanism of action and develop-
phenylephrine causes a rise in systolic and diastolic pressures; mental aspects. Am J Hypertens. 1990;3:82S–86S.
14. Banner W Jr, Vernon DD, Dean JM, Swenson E. Nonlinear dopamine
cardiac output is slightly decreased; and peripheral resistance is pharmacokinetics in pediatric patients. J Pharmacol Exp Ther. 1989;
considerably increased, which may cause a reflex bradycardia. 249:131–133.
Most vascular beds are constricted; pulmonary, renal, splanchnic, 15. Padbury JF, Agata Y, Baylen BG, et al. Pharmacokinetics of dopamine in
cutaneous, and limb blood flows are reduced, but coronary blood critically ill newborn infants. J Pediatr. 1990;117:472–476.
flow is increased. The recommended bolus dose is 2 to 10 μg/kg 16. Juste RN, Moran L, Hooper J, Soni N. Dopamine clearance in critically ill
patients. Intensive Care Med. 1998;24:1217–1220.
and an infusion may run at 1 to 5 μg/kg/min. 17. Le CP, Malledant Y, Tanguy M, Le VR. Steady-state pharmacokinetics of
dopamine in adult patients. Crit Care Med. 1993;21:1652–1657.
18. Jarnberg PO, Bengtsson L, Ekstrand J, Hamberger B. Dopamine infusion
METARAMINOL in man. Plasma catecholamine levels and pharmacokinetics. Acta
Anaesthesiol Scand. 1981;25:328–331.
Metaraminol acts directly on postsynaptic alpha1 receptors and 19. MacGregor DA, Smith TE, Prielipp RC, et al. Pharmacokinetics of
indirectly to cause norepinephrine release from sympathetic nerve dopamine in healthy male subjects. Anesthesiology. 2000;92:338–346.
terminals presynaptically. Metaraminol increases systolic and 20. Patel HC, Menon DK, Tebbs S, et al. Specialist neurocritical care and
diastolic blood pressure blood pressure as a result of its alpha1 outcome from head injury. Intensive Care Med. 2002;28:547–553.
21. Allen E, Pettigrew A, Frank D, et al. Alterations in dopamine clearance
stimulation but also causes a rise in cardiac output owing to its and catechol-O-methyltransferase activity by dopamine infusions in
stimulation of the beta1 receptors. Hence, reflex bradycardia is less children. Crit Care Med. 1997;25:181–189.
likely to occur with metaraminol than with phenylephrine.133 The 22. Notterman DA, Greenwald BM, Moran F, et al. Dopamine clearance in
recommended dose is 10 μg/kg. critically ill infants and children: effect of age and organ system
dysfunction. Clin Pharmacol Ther. 1990;48:138–147.
23. Zaritsky A, Miles M. Too much pharmacokinetics? Crit Care Med.
1993;21:1620–1622.
EPHEDRINE 24. Zaritsky A, Lotze A, Stull R, Goldstein DS. Steady-state dopamine
Ephedrine is a sympathomimetic amine that acts directly and clearance in critically ill infants and children. Crit Care Med. 1988;16:
217–220.
indirectly on the adrenergic beta1, beta2, and alpha1 receptors. 25. Goodall M, Alton H. Metabolism of 3-hydroxytyramine (dopamine) in
Direct stimulation occurs postsynaptically on the adrenergic human subjects. Biochem Pharmacol. 1968;17:905–914.
receptors and indirect stimulation promotes the release on 26. Leblanc H, Lachelin GC, bu-Fadil S, Yen SS. Effects of dopamine infusion
norepinephrine presynaptically. Consequently, it has chronotropic on pituitary hormone secretion in humans. J Clin Endocrinol Metab.
and inotropic effects on the heart and increases peripheral vascu- 1976;43:668–674.
lar resistance. Ephedrine is also used as a bronchodilator because 27. Sulyok E, Seri I, Tulassay T, et al. The effect of dopamine administration
on the activity of the renin-angiotensin-aldosterone system in sick
of its beta2 effects and a nasal decongestant owing to its alpha preterm infants. Eur J Pediatr. 1985;143:191–193.
vasoconstrictive effects. Tachyphylaxis may occur owing to nor- 28. Carey RM, Thorner MO, Ortt EM. Effects of metoclopramide and
epinephrine depletion. bromocriptine on the renin-angiotensin-aldosterone system in man.
Dopaminergic control of aldosterone. J Clin Invest. 1979;63:727–735.
29. De ZF, Van Den BG, Devlieger H, et al. Dopamine inhibits growth
REFERENCES hormone and prolactin secretion in the human newborn. Pediatr Res.
1993;34:642–645.
1. Cuevas L, Yeh TF, John EG, et al. The effect of low-dose dopamine 30. Kurtz A, Della BR, Kuhn K. Cyclosporine A enhances renin secretion
infusion on cardiopulmonary and renal status in premature newborns and production in isolated juxtaglomerular cells. Kidney Int. 1988;33:
with respiratory distress syndrome. Am J Dis Child. 1991;145:799–803. 947–953.
2. Seri I, Tulassay T, Kiszel J, Csomor S. The use of dopamine for the 31. Chamiedes L, Kazinski MF, (eds). Textbook of Advanced Pediatric Life
prevention of the renal side effects of indomethacin in premature infants Support. American Heart Association; 1994. pp. 6-1–6-18, 7–5.
with patent ductus arteriosus. Int J Pediatr Nephrol. 1984;5:209–214. 32. Goetting MG. Progress in pediatric cardiopulmonary resuscitation. Emerg
3. Seri I, Tulassay T, Kiszel J, et al. Cardiovascular response to dopamine in Med Clin North Am. 1995;13:291–319.
hypotensive preterm neonates with severe hyaline membrane disease. Eur 33. Carpenter TC, Stenmark KR. High-dose epinephrine is not superior to
J Pediatr. 1984;142:3–9. standard-dose epinephrine in pediatric in-hospital cardiopulmonary
4. Zaritsky A, Chernow B. Use of catecholamines in pediatrics. J Pediatr. arrest. Pediatrics. 1997;99:403–408.
1984;105:341–350. 34. Young KD, Seidel JS. Pediatric cardiopulmonary resuscitation: a collective
5. Seri I, Noori S. Diagnosis and treatment of neonatal hypotension outside review. Ann Emerg Med. 1999;33:195–205.
the transitional period. Early Hum Dev. 2005;81:405–411. 35. Guidelines 2000 for cardiopulmonary resuscitation and emergency
6. Seri I. Cardiovascular, renal, and endocrine actions of dopamine in cardiovascular care. Circulation. 291(Suppl I):I1–I342. 2000.
neonates and children. J Pediatr. 1995;126:333–344. 36. Fisher DG, Schwartz PH, Davis AL. Pharmacokinetics of exogenous
7. Seri I. Circulatory support of the sick preterm infant. Semin Neonatol. epinephrine in critically ill children. Crit Care Med. 1993;21:111–117.
2001;6:85–95. 37. Brown CG, Werman HA, Davis EA, et al. Comparative effect of graded
8. Seri I, Abbasi S, Wood DC, Gerdes JS. Regional hemodynamic effects of doses of epinephrine on regional brain blood flow during CPR in a swine
dopamine in the sick preterm neonate. J Pediatr. 1998;133:728–734. model. Ann Emerg Med. 1986;15:1138–1144.
9. Hoffmann BB. Catecholamines and sympathomimetic drugs. In: 38. Chase PB, Kern KB, Sanders AB, et al. Effects of graded doses of
Lefkowitz RJ, editor. Goodman and Gilman’s Pharmacologic Basis of epinephrine on both noninvasive and invasive measures of myocardial
Therapeutics. New York: Pergamon; 1990. pp. 187–243. perfusion and blood flow during cardiopulmonary resuscitation. Crit
10. Guller B, Fields AI, Coleman MG, Holbrook PR. Changes in cardiac Care Med. 1993;21:413–419.
rhythm in children treated with dopamine. Crit Care Med. 1978;6: 39. Gonzalez ER, Ornato JP, Garnett AR, et al. Dose-dependent vasopressor
151–154. response to epinephrine during CPR in human beings. Ann Emerg Med.
11. Steinberg C, Notterman DA. Pharmacokinetics of cardiovascular drugs 1989;18:920–926.
in children. Inotropes and vasopressors. Clin Pharmacokinet. 1994;27: 40. Perondi MB, Reis AG, Paiva EF, et al. A comparison of high-dose and
345–367. standard-dose epinephrine in children with cardiac arrest. N Engl J Med.
12. Seri I, Tulassay T, Kiszel J, et al. Effect of low-dose dopamine infusion on 2004;350:1722–1730.
prolactin and thyrotropin secretion in preterm infants with hyaline 41. Sharman M, Meert KL. What is the right dose of epinephrine? Pediatr
membrane disease. Biol Neonate. 1985;47:317–322. Crit Care Med. 2005;6:592–594.
42. Runciman WJ, Moris JL. Adrenoreceptor agonists. In: Feldman SA, Paton 68. Imig JD, Deichmann PC. Afferent arteriolar responses to ANG II involve
W, Scurr C. (eds). Mechanisms of Drugs in Anaesthesia. London: Edward activation of PLA2 and modulation by lipoxygenase and P-450 pathways.
Arnold; 1993. pp. 262–291. Am J Physiol. 1997;273:F274–F282.
43. Corrall RJ, Frier BM, Davidson NM, French EB. Hormonal and substrate 69. Pelayo JC. Renal adrenergic effector mechanisms: glomerular sites for
responses during recovery from hypoglycaemia in man during beta prostaglandin interaction. Am J Physiol. 1988;254:F184–F190.
1-selective and non-selective beta-adrenergic blockade. Eur J Clin Invest. 70. Inscho EW, Carmines PK, Navar LG. Prostaglandin influences on afferent
1981;11:279–283. arteriolar responses to vasoconstrictor agonists. Am J Physiol. 1990;259:
44. Bearn AG, Billing B, Sherlock S. The effect of insulin on hepatic F157–F163.
carbohydrate metabolism and splanchnic blood flow in man. J Physiol. 71. Van Den BG, De ZF. Anterior pituitary function during critical illness
1951;114:5–6. and dopamine treatment. Crit Care Med. 1996;24:1580–1590.
45. Pellicer A, Valverde E, Elorza MD, et al. Cardiovascular support for low 72. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign:
birth weight infants and cerebral hemodynamics: a randomized, blinded, international guidelines for management of severe sepsis and septic shock:
clinical trial. Pediatrics. 2005;115:1501–1512. 2008. Crit Care Med. 2008;36:296–327.
46. Day NP, Phu NH, Bethell DP, et al. The effects of dopamine and 73. Dunser MW, Mayr AJ, Tur A, et al. Ischemic skin lesions as a complica-
adrenaline infusions on acid-base balance and systemic haemodynamics tion of continuous vasopressin infusion in catecholamine-resistant
in severe infection. Lancet. 1996;348:219–223. vasodilatory shock: incidence and risk factors. Crit Care Med. 2003;31:
47. Kolendorf K, Moller BB. Lactic acidosis in epinephrine poisoning. Acta 1394–1398.
Med Scand. 1974;196:465–466. 74. Hayes MA, Yau EH, Hinds CJ, Watson JD. Symmetrical peripheral
48. Totaro RJ, Raper RF. Epinephrine-induced lactic acidosis following gangrene: association with noradrenaline administration. Intensive Care
cardiopulmonary bypass. Crit Care Med. 1997;25:1693–1699. Med. 1992;18:433–436.
49. Brockman RP. Effects of epinephrine on the net hepatic uptake of lactate, 75. McMurray TJ, Lavery GG. Ionotropic drugs. In: McCaughey W, Clarke
pyruvate, and glycerol in sheep. Can J Physiol Pharmacol. 1991; 69: RSJ, Fee JPH, et al. (eds). Anaesthetic Physiology and Pharmacology. 1st
475–479. edition. Churchill Livingstone, New York, 1997. pp. 367–368.
50. Rizza R, Haymond M, Cryer P, Gerich J. Differential effects of epineph- 76. Johnston AJ, Steiner LA, O’Connell M, et al. Pharmacokinetics and
rine on glucose production and disposal in man. Am J Physiol. 1979; pharmacodynamics of dopamine and norepinephrine in critically ill
237:E356–E362. head-injured patients. Intensive Care Med. 2004;30:45–50.
51. Issekutz B, Jr. Effect of epinephrine on carbohydrate metabolism in 77. Calvey TN. Pharmacokinetics. In: Williams SE, editor. Principles and
exercising dogs. Metabolism. 1985; 34:457–464. Practice of Pharmacology for Anaesthetists. Oxford: Blackwell Science;
52. Rizza RA, Haymond MW, Miles JM, et al. Effect of alpha-adrenergic 2008. pp. 36–68.
stimulation and its blockade on glucose turnover in man. Am J Physiol. 78. Garcia-Sainz JA, Vazquez-Prado J, del Carmen ML. Alpha 1-adrenoceptors:
1980;238:E467–E472. function and phosphorylation. Eur J Pharmacol. 2000;389:1–12.
53. Brown MJ, Brown DC, Murphy MB. Hypokalemia from beta2-receptor 79. Annane D. Corticosteroids for septic shock. Crit Care Med. 2001;29
stimulation by circulating epinephrine. N Engl J Med. 1983;309:1414– (7 Suppl):S117–S120.
1419. 80. Roze JC, Tohier C, Maingueneau C, et al. Response to dobutamine and
54. Wahr JA, Parks R, Boisvert D, et al. Preoperative serum potassium levels dopamine in the hypotensive very preterm infant. Arch Dis Child. 1993;
and perioperative outcomes in cardiac surgery patients. Multicenter Study 69(1 Spec No):59–63.
of Perioperative Ischemia Research Group. JAMA. 1999;281:2203–2210. 81. Keeley SR, Bohn DJ. The use of inotropic and afterload-reducing agents
55. Landry DW, Levin HR, Gallant EM, et al. Vasopressin pressor hyper- in neonates. Clin Perinatol. 1988;15:467–489.
sensitivity in vasodilatory septic shock. Crit Care Med. 1997;25:1279– 82. Driscoll DJ, Gillette PC, Duff DF, et al. Hemodynamic effects of dobuta-
1282. mine in children. Am J Cardiol. 1979;43:581–585.
56. Luckner G, Dunser MW, Jochberger S, et al. Arginine vasopressin in 83. Berg RA, Donnerstein RL, Padbury JF. Dobutamine infusions in stable,
316 patients with advanced vasodilatory shock. Crit Care Med. 2005;33: critically ill children: pharmacokinetics and hemodynamic actions. Crit
2659–2666. Care Med. 1993;21:678–686.
57. Holmes CL, Walley KR, Chittock DR, et al. The effects of vasopressin on 84. Berg RA, Padbury JF, Donnerstein RL, et al. Dobutamine pharma-
hemodynamics and renal function in severe septic shock: a case series. cokinetics and pharmacodynamics in normal children and adolescents.
Intensive Care Med. 2001;27:1416–1421. J Pharmacol Exp Ther. 1993;265:1232–1238.
58. Meier-Hellmann A, Reinhart K. Effects of catecholamines on regional 85. Habib DM, Padbury JF, Anas NG, et al. Dobutamine pharmacokinetics
perfusion and oxygenation in critically ill patients. Acta Anaesthesiol and pharmacodynamics in pediatric intensive care patients. Crit Care
Scand Suppl. 1995;107:239–248. Med. 1992;20:601–608.
59. Pawlik W, Shepherd AP, Jacobson ED. Effect of vasoactive agents on 86. Bailey JM, Levy JH, Kikura M, et al. Pharmacokinetics of intravenous
intestinal oxygen consumption and blood flow in dogs. J Clin Invest. milrinone in patients undergoing cardiac surgery. Anesthesiology. 1994;
1975;56:484–490. 81:616–622.
60. Shepherd AP, Pawlik W, Mailman D, et al. Effects of vasoconstrictors on 87. Kikura M, Lee MK, Safon RA, et al. The effects of milrinone on platelets
intestinal vascular resistance and oxygen extraction. Am J Physiol. in patients undergoing cardiac surgery. Anesth Analg. 1995; 81:44–48.
1976;230:298–305. 88. Chang AC, Atz AM, Wernovsky G, et al. Milrinone: systemic and
61. Di Giantomasso D, May CN, Bellomo R. Norepinephrine and vital organ pulmonary hemodynamic effects in neonates after cardiac surgery. Crit
blood flow. Intensive Care Med. 2002;28:1804–1809. Care Med. 1995;23:1907–1914.
62. Desjars P, Pinaud M, Bugnon D, Tasseau F. Norepinephrine therapy has 89. Bailey JM, Miller BE, Lu W, et al. The pharmacokinetics of milrinone
no deleterious renal effects in human septic shock. Crit Care Med. 1989; in pediatric patients after cardiac surgery. Anesthesiology. 1999;90:
17:426–429. 1012–1018.
63. Martin C, Papazian L, Perrin G, et al. Norepinephrine or dopamine for the 90. Colucci WS, Wright RF, Braunwald E. New positive inotropic agents in
treatment of hyperdynamic septic shock? Chest. 1993;103:1826–1831. the treatment of congestive heart failure. Mechanisms of action and recent
64. LeDoux D, Astiz ME, Carpati CM, Rackow EC. Effects of perfusion clinical developments. N Engl J Med. 1986;314:349–358.
pressure on tissue perfusion in septic shock. Crit Care Med. 2000;28: 91. Evans DB. Overview of cardiovascular and physiologic and pharma-
2729–2732. cologic aspects of the phosphodiesterase III inhibitors. Am J Cardiol.
65. Di Giantomasso D, Morimatsu H, May CN, Bellomo R. Intrarenal blood 1989;63:9A–11A.
flow distribution in hyperdynamic septic shock: effect of norepinephrine. 92. Feneck RO. Intravenous milrinone following cardiac surgery: I. effects of
Crit Care Med. 2003;31:2509–2513. bolus infusion followed by variable dose maintenance infusion. The
66. Zhang H, Smail N, Cabral A, et al. Effects of norepinephrine on regional European Milrinone Multicentre Trial Group. J Cardiothorac Vasc Anesth.
blood flow and oxygen extraction capabilities during endotoxic shock. 1992;6:554–562.
Am J Respir Crit Care Med. 1997;155:1965–1971. 93. Hoffman TM, Wernovsky G, Atz AM, et al. Efficacy and safety of
67. Treggiari MM, Romand JA, Burgener D, et al. Effect of increasing milrinone in preventing low cardiac output syndrome in infants and
norepinephrine dosage on regional blood flow in a porcine model of children after corrective surgery for congenital heart disease. Circulation.
endotoxin shock. Crit Care Med. 2002;30:1334–1339. 2003;107:996–1002.
94. Barton P, Garcia J, Kouatli A, et al. Hemodynamic effects of I.V. 115. Matok I, Leibovitch L, Vardi A, et al. Terlipressin as rescue therapy for
milrinone lactate in pediatric patients with septic shock. A prospective, intractable hypotension during neonatal septic shock. Pediatr Crit Care
double-blinded, randomized, placebo-controlled, interventional study. Med. 2004;5:116–118.
Chest. 1996;109:1302–1312. 116. Zeballos G, Lopez-Herce J, Fernandez C, et al. Rescue therapy with
95. Paradisis M, Jiang X, McLachlan AJ, e. Population pharmacokinetics and terlipressin by continuous infusion in a child with catecholamine-
dosing regimen design of milrinone in preterm infants. Arch Dis Child resistant septic shock. Resuscitation. 2006;68:151–153.
Fetal Neonatal Ed. 2007; 92:F204–F209. 117. Salluh JI, Martins GA, Santino MS, et al. Early use of terlipressin in
96. Ramamoorthy C, Anderson GD, Williams GD, Lynn AM. Pharma- catecholamine-resistant shock improves cerebral perfusion pressure
cokinetics and side effects of milrinone in infants and children after in severe traumatic brain injury. Acta Anaesthesiol Scand. 2007;51:
open heart surgery. Anesth Analg. 1998;86:283–289. 505–508.
97. Ioannou GN, Doust J, Rockey DC. Systematic review: terlipressin in 118. Peters MJ, Booth RA, Petros AJ. Terlipressin bolus induces systemic
acute oesophageal variceal haemorrhage. Aliment Pharmacol Ther. vasoconstriction in septic shock. Pediatr Crit Care Med. 2004;5:112–115.
2003;17:53–64. 119. Rodriguez-Nunez A, Fernandez-Sanmartin M, Martinon-Torres F, et al.
98. Moreau R. Hepatorenal syndrome in patients with cirrhosis. J Gastroenterol Terlipressin for catecholamine-resistant septic shock in children. Intensive
Hepatol. 2002;17:739–747. Care Med. 2004;30:477–480.
99. Antunes-Rodrigues J, de Castro M, Elias LL, et al. Neuroendocrine 120. Westphal M, Bone HG, Van AH, Sielenkamper AW. Terlipressin for
control of body fluid metabolism. Physiol Rev. 2004;84:169–208. haemodynamic support in septic patients: a double-edged sword?
100. Share L. Role of vasopressin in cardiovascular regulation. Physiol Rev. Lancet. 2002;360:1250–1251.
1988;68:1248–1284. 121. Meyer S, Gottschling S, Baghai A, et al. Arginine-vasopressin in
101. Altura BM. Dose-response relationships for arginine vasopressin and catecholamine-refractory septic versus non-septic shock in extremely
synthetic analogs on three types of rat blood vessels: possible evidence low birth weight infants with acute renal injury. Crit Care. 2006;10:R71.
for regional differences in vasopressin receptor sites within a mammal. 122. Stiell IG, Hebert PC, Wells GA, et al. Vasopressin versus epinephrine for
J Pharmacol Exp Ther. 1975;193:413–423. inhospital cardiac arrest: a randomised controlled trial. Lancet. 2001;
102. Landry DW, Levin HR, Gallant EM, et al. Vasopressin deficiency contri- 358:105–109.
butes to the vasodilation of septic shock. Circulation. 1997;95:1122–1125. 123. Lindner KH, Dirks B, Strohmenger HU, et al. Randomised comparison
103. Asfar P. Terlipressin in chronic hyperdynamic endotoxic shock: is it safe? of epinephrine and vasopressin in patients with out-of-hospital
Intensive Care Med. 2003;29:154–155. ventricular fibrillation. Lancet. 1997;349:535–537.
104. Lodha R, Vivekanandhan S, Sarthi M, Kabra SK. Serial circulating 124. Guyette FX, Guimond GE, Hostler D, Callaway CW. Vasopressin
vasopressin levels in children with septic shock. Pediatr Crit Care Med. administered with epinephrine is associated with a return of a pulse in
2006;7:220–224. out-of-hospital cardiac arrest. Resuscitation. 2004;63:277–282.
105. Sharshar T, Blanchard A, Paillard M, et al. Circulating vasopressin levels 125. Wenzel V, Krismer AC, Arntz HR, et al. A comparison of vasopressin
in septic shock. Crit Care Med. 2003;31:1752–1758. and epinephrine for out-of-hospital cardiopulmonary resuscitation.
106. Reid IA. Role of vasopressin deficiency in the vasodilation of septic N Engl J Med. 2004;350:105–113.
shock. Circulation. 1997;95:1108–1110. 126. Mann K, Berg RA, Nadkarni V. Beneficial effects of vasopressin in
107. Forrest P. Vasopressin and shock. Anaesth Intensive Care. 2001;29: prolonged pediatric cardiac arrest: a case series. Resuscitation. 2002;52:
463–472. 149–156.
108. Tsuneyoshi I, Yamada H, Kakihana Y, et al. Hemodynamic and 127. Voelckel WG, Lurie KG, McKnite S, et al. Effects of epinephrine and
metabolic effects of low-dose vasopressin infusions in vasodilatory septic vasopressin in a piglet model of prolonged ventricular fibrillation and
shock. Crit Care Med. 2001;29:487–493. cardiopulmonary resuscitation. Crit Care Med. 2002;30:957–962.
109. Dunser MW, Mayr AJ, Ulmer H, et al. The effects of vasopressin on 128. Voelckel WG, Lindner KH, Wenzel V, et al. Effects of vasopressin and
systemic hemodynamics in catecholamine-resistant septic and post- epinephrine on splanchnic blood flow and renal function during and
cardiotomy shock: a retrospective analysis. Anesth Analg. 2001;93:7–13. after cardiopulmonary resuscitation in pigs. Crit Care Med. 2000;28:
110. Dunser MW, Mayr AJ, Ulmer H et al. Arginine vasopressin in advanced 1083–1088.
vasodilatory shock: a prospective, randomized, controlled study. 129. Eichinger MR, Walker BR. Enhanced pulmonary arterial dilation to
Circulation. 2003; 107:2313–2319. arginine vasopressin in chronically hypoxic rats. Am J Physiol. 1994;
111. Patel BM, Chittock DR, Russell JA, Walley KR. Beneficial effects of short- 267:H2413–H2419.
term vasopressin infusion during severe septic shock. Anesthesiology. 130. Guzman JA, Rosado AE, Kruse JA. Vasopressin vs norepinephrine in
2002;96:576–582. endotoxic shock: systemic, renal, and splanchnic hemodynamic and
112. Rosenzweig EB, Starc TJ, Chen JM, et al. Intravenous arginine- oxygen transport effects. J Appl Physiol. 2003;95:803–809.
vasopressin in children with vasodilatory shock after cardiac surgery. 131. American Heart Association. Pediatric Basic and Advanced Life
Circulation. 1999;100(19 Suppl):II182–II186. Support. Circulation. 2005;112:III-73–III-90.
113. Malay MB, Ashton RC Jr, Landry DW, Townsend RN. Low-dose vaso- 132. Kawczynski P, Piotrowski A. Circulatory and diuretic effects of
pressin in the treatment of vasodilatory septic shock. J Trauma. 1999; dopexamine infusion in low-birth-weight infants with respiratory failure.
47:699–703. Intensive Care Med. 1996;22:65–70.
114. Lechner E, Dickerson HA, Fraser CD Jr, Chang AC. Vasodilatory shock 133. Drugdex editorial staff. Metaraminol (Drug Evaluation). In: Hutchison TA,
after surgery for aortic valve endocarditis: use of low-dose vasopressin. Shahan DR, eds. Drugdex System. Greenwood Village, Colorado, Micromedex,
Pediatr Cardiol. 2004;25:558–561. 2001.
34 Antiemetic Agents
C H A P T E R Mario J. da Conçeicao
INTRODUCTION receptor activation, although the evidences suggest that emesis is

most likely a side effect (or an indirect effect) of these agents and
Postoperative vomiting (POV) continues to be a frequent and does not relate to their anesthetic action. The high incidence of
important cause of morbidity in children. It is important to define POV after throat and middle ear surgery is unsurprising consi-
the meanings of nausea, retching, and vomiting: nausea is a dering the activation of the vestibular afferent pathways involved
subjective sensation, vomiting is expulsion of stomach contents, in motion sickness and of the auricular vagus branch, which
and retching is the expulsive effort. The feature that distinguishes supplies the tympanum. The surgical trauma to the pharynx after
retching from vomiting is the expulsion of stomach contents. tonsillectomy causes edema and sensitization of the glosso-
Retching and vomiting can be grouped together under the com- pharyngeal afferents contributing to observed POV. It is easy to
mon term emetic episode.1 Vomiting is a complex behavior that understand that similar processes may be induced by the presence
presumably conveys a survival advantage in that it promotes the of an orotracheal tube even after the tube is removed. Manipula-
rapid expulsion of ingested toxins. tion, displacement, and traction of gut and mesentery during
POV is more commonly studied in children than postoperative abdominal surgery stimulate vagal afferents supplying the upper
nausea because of a child’s inability to effectively express subjective gut and release of 5-hydroxytryptamine (5-HT) from the entero-
sensations and distress after experiencing nausea. POV is one of chromaffin cells. 5-HT release can cause both direct activation of
the leading postoperative complaints from parents and the leading the afferents and produce long-lasting sensitization to other
cause of unplanned readmission to the hospital after day surgery.1 stimuli.
POV occurs twice as frequently in children as in adults. The The mechanisms of emesis can be divided into three com-
incidence increases until puberty and then decreases to adult rates. ponents (Figures 34–1 and 34–2):
Gender differences are not seen before puberty. Severe vomiting
can be associated with dehydration, postoperative bleeding, pul- 1. Afferent inputs go to the central nervous system (CNS),
monary aspiration, and wound dehiscence. Although children relaying the signals of emetic stimuli.
have an increased potential for dehydration and the resulting phy- 2. These signals are received, recognized, and centrally processed.
siologic impairments, other associated results such as a delay in They then form integrated emetic efferent signals coming from
hospital discharge or an overnight or longer hospital admission the CNS.
also must be considered.2 Adequate POV control adds significant 3. These motor and chemical efferent pathways relay signals that
improvement in patient’s and parents’ satisfaction.3 The cause of lead to the coordinate respiratory gastrointestinal and abdomi-
POV is multifactorial with differing contributions depending nal muscle expulsive actions of vomiting.
upon the clinical situation.
Abdominal Visceral Afferents

HOW DO POSTOPERATIVE NAUSEA Gut afferents may be viewed as the second line of defense against
AND VOMITING OCCUR? poisoning from food once first-line defenses of vision, taste, and
If nausea and vomiting could be considered natural responses, smell have been circumvented.4 Contrary to popular belief, the
making up components of the body’s defense system against stomach alone does not actively expel its contents during vomit-
ingested toxins, why then should anesthesia and surgery induce ing. The stomach, esophagus, and their relevant sphincters are all
nausea and vomiting? Are there particular special features about relaxed during vomiting. Contraction of the diaphragm and the
anesthesia and surgery that relate to this disturbing problem? The abdominal muscles generates most of the force that expels gastric
reason is that some feature of anesthesia and surgery activates contents. The vagus is the major nerve involved in the detection of
triggers for the emetic system. We do not have a satisfactory ans- emetic stimuli; its abdominal course contains 80 to 90% afferent
wer to the question proposed as the heading to this section, even fibers. Electrical stimulation of the vagal afferents is capable of
though it is possible to identify several of the likely explanations. inducing emesis within 20 seconds and confirms the potential
The question could perhaps be addressed in a different way: how of this pathway for rapid ejection of gastric contents.5 Two types of
do various components of anesthesia and surgery that contribute vagal afferent fibers are involved in emetic response. These mecha-
to POV trigger detection systems developed primarily to detect noreceptors are located in the muscular wall of the gut and acti-
ingested toxins? It is unclear whether the emetic effects of anes- vated by both contraction and distention. Overeating, causing
thetics relate to anesthetic action or to a side effect such as opioid distention of the gastric antrum or intestinal obstruction, may
CHAPTER 34 ■ Antiemetic Agents 545
Area Postrema
Application of chemicals to the dorsal surface of the brainstem
can induce emesis, and it was assumed that this was through direct
stimulation of the vomiting center located in this region. However,
it has been demonstrated that stimuli were detected by cells of
the area postrema, a U-shaped structure a few millimeters long
located in the caudal part of the fourth ventricle in the region of
the obex.7 This region is termed the chemoreceptor trigger zone
(CTZ) for emesis.8 It is assumed that all chemicals in the circula-
tion may induce emesis by this route.
Vestibular System
The vestibular labyrinthine system is essential for induction of
emesis by motion. There is limited evidence that the vestibular
system could be involved directly in the emetic response to some
drugs. However, motion sickness appears to be a predictor of both
PONV and the response to antiemetic prophylaxis.9 Although its
predictive value was fairly low, there is a strong association
between motion sickness and POV in pediatric populations.10 It is
recognized that higher cerebral influences also have a role in the
motor components of the emetic reflex, although the precise role
remains unclear. Input from the brainstem (e.g., limbic system)
can induce nausea and vomiting. These higher inputs appear to
Figure 34-1. The vomiting mechanism. have a mainly facilitatory role in modulating the sensitivity of the
brainstem emetic mechanism rather than acting as primary
induce vomit by stimulation of these afferents. The chemoreceptors detectors of the stimuli.
located in the mucosa of the upper gut are responsible for the
monitoring of several intraluminal stimuli. They respond, for
example, to acid, alkali, and hypertonic solutions and mucosal THE VOMITING REFLEX
stroking. Vagotomy reduces or even abolishes emesis induced by The vagal motor neurons supplying the gut and heart, the dorsal
irritants such as hypertonic sodium solution.6 and ventral respiratory groups regulating the phrenic nerve out-
put, and the presympathetic neurons that maintain sympathetic
tone to the heart and blood vessel all contribute to the well-known
vomiting pattern.11 This vomiting reflex is complex (Figure
34–3), and no single brainstem nuclei that could be in charge of
output coordination has been identified.
Figure 34-2. Peripheral and central mechanisms in the control

of emesis. Figure 34-3. Motor components of the vomiting reflex.
RISK FACTORS FOR POV IN CHILDREN risk pediatric patients. The antiemetic mechanism of propofol is
still unclear, and it does not appear related to blockade of dopa-
Age, a history of POV with anesthesia, and particular types of minergic receptors.
surgery have been identified as risk factors for POV in children The two most common emetic surgical procedures in children
(Table 34–1).12 Although efforts have been made to develop and are strabismus repair and tonsillectomy with or without adenoi-
validate a risk score that predicts the probability of POV in pedi- dectomy. Ear, nose, and throat (ENT) operations, particularly,
atric patients, controversial and unresolved issues remain.13 An remain one of the most frequently performed pediatric surgical
evaluation of a score for predicting POV in children (POVOC procedures worldwide.18 POV is one of the most common post-
score) had sufficient accuracy comparable with results in adult operative complications associated with these procedures.19 Trige-
patients, but strabismus surgery, a major risk factor, was not minal nerve stimulation, swallowed blood causing gastrointestinal
included.14 The evaluation has indicated that, even in the absence irritation, and the use of diathermy are all contributing factors
of strabismus surgery, the POVOC score allows estimation of the peculiar to ENT operations that increase POV. Tracheal intubation
risk of POV in pediatric patients. In order to ensure that the and the use of opioids or nitrous oxide have all been implicated as
POVOC score is valid for all types of surgery, a further evaluation anesthetic factors increasing the rate of POV.20
in a large-scale survey with rigorous assessment of emetic symp- POV after strabismus surgery remains a common and distres-
toms would be helpful. The introduction into daily practice of sing problem with a high incidence and increased morbidity after
predictive score could decrease POV incidence, enhance the such surgery. Emesis occurs because of eye manipulation or pain.
effectiveness of treatment, discriminate which children needs A number of drugs and strategies have been used with some
prophylaxis, and improve antiemetic trial design.15 success including the use of peribulbar block. Success found with
Consensus guidelines for managing postoperative nausea and the regional anesthesia could be caused by the inhibition of the
vomiting (PONV) are inadequate for children, although a number afferent pathway of the occuloemetic reflex.21
of patient characteristics, anesthesia, and surgery-related factors Pain, sight, smell, taste, and emotion are sensations leading to
have been identified as important in deciding those children most information sent to the higher centers in the brain, stimulating
likely to suffer from POV.9 A history of previous POV, strabismus and activating the vomiting reflex via neurotransmitters that
surgery, long-duration anesthesia, age older than 5 years, and include acetylcholine. Opioids are well recognized as a cause of
opioid use are important factors increasing the risk of POV. vomiting that act through stimulation of trigger zones, increased
Motion sickness in adults appears to be a predictor of PONV, vestibular sensitivity, gastric stasis, or impaired intestinal motility
responding to antiemetic prophylaxis.9 A correlation between and constipation.22 Nitrous oxide causes vomiting, and the avoi-
motion sickness in children and POV is reported, although the dance of nitrous oxide reduces the risk of PONV by an average of
positive predictive value was only 64%.9 A history of previous 28% in adults.23 The diffusion of nitrous oxide into the middle ear
motion sickness is insufficiently precise to be recommended as with stimulation of the vestibular apparatus and bowel distention
the sole basis for a clinical decision-making. When children were with serotonin release are among possible mechanisms. Most of
given halothane or sevoflurane anesthesia for inguinal surgery, these data come from adult studies, and it is suggested that there
those with a history of motion sickness (MS+) vomited more than is similar action in children. By contrast, there is no decrease in
those without such a history (MS–) regardless of the inhalation POV after pediatric tonsillectomy attributable to omission of
anesthetic used. However, MS– children displayed a higher inci- nitrous oxide in children.24 Children undergoing chemotherapy
dence of vomiting when halothane rather than sevoflurane was and radiotherapy are more likely to suffer from POV. The cyto-
used.16 According to currently available evidence, there are no toxic drugs cause mobilization of serotonin (5-HT) from mucosal
clinically important differences in the incidence of POV with the enterochromaffin cells that excites 5-hydroxytryptamine3 (5-HT3)
use of sevoflurane, desflurane, or isoflurane for maintenance of on mucosal vagal afferents and possibly centrally in the area
anesthesia. There is general agreement, however, that the inci- postrema, inducing POV. The severity of the problem varies with
dence of POV is higher with volatile agents when compared with the chemotherapeutic drug cocktail administered; antiemetic
intravenous anesthesia (e.g., propofol).17 Studies in both children treatment is successful for most of these patients.25 Ingested toxic
and adults have shown that the incidence of POV is decreased with substances can induce PONV that may be life-saving. Mediators,
the use of propofol. The use of propofol for induction alone has no or even the circulating substance, act directly on trigger zones,
clinically relevant effect on POV. Infusions of propofol for main- leading to induction of PONV. The routine use of cholinesterase
tenance of anesthesia showed better reduction of POV in high- inhibitors to antagonize residual neuromuscular block may be
associated with increased postoperative emesis in children.
TABLE 34-1. Important Factors for Postoperative Edrophonium may offer advantages over the use of neostigmine
Vomiting in Children for antagonism of neuromuscular block.26
The duration of surgery and anesthesia also increases the
In children, POV is better described than nausea. incidence of POV. The reasons remain unclear but can possibly be
Gender is not important before puberty. related to increased accumulation of emetogenic anesthetic agents.
Risk decreases after puberty. It has been documented that 48% of pediatric patients experienced
Specific operations increase the risk consistently. POV when surgery duration was greater than 30 minutes com-
Motion sickness–positive children are more than twice as likely pared with 34% when surgery duration was less than 30 minutes.27
to vomit.
Vomiting incidence is twice as frequent among children as
among adults. ANTIEMETIC AGENTS
Risk scores remain controversial, The use of antiemetic agents in infants and children without a clear
POV = postoperative vomiting. purpose is not recommended. There are only few situations in which
antiemetic agents are indicated and possibly effective, and these include min/kg.34,35 Like metoclopramide, droperidol can be administered
POV. Several types of antiemetics could be used in the management by oral, intramuscular, or intravenous routes. Droperidol was
of POV: gastrointestinal prokinetic drugs, which enhance gastric and more effective than placebo in the prevention of POV in children.36
upper intestinal motility with antido paminergic actions It has a good antinausea effect and a less pronounced antiemetic effect.
(metoclopramide; phenothiazines as perphenazine); butyrophenones Pediatric studies focus on the antiemetic effect.37 This may explain
(droperidol), and 5-HT3 antagonists (ondansetron or tropisetron). why ondansetron has been shown to be a better drug for prophylaxis
There are also reports of an association between antiemetic activity of POV in children but not in adults.38 The doses employed range
and central anticholinergic agents (hyoscine and atropine) and from 40 to 80 μg/kg, and the effectiveness increases with dose.
some antihistamine receptor type 1 antagonists (cyclizine). These Droperidol causes sedation or even drowsiness in the recovery period,
drugs are all reported in children, although their efficacy in fully which can be accompanied of dysphoria and extrapyramidal
stopping POV is undetermined. Other gastrointestinal prokine- effects. A warning from the U.S. Food and Drug Administration
tic drugs such as cisapride or domperidone are not frequently (FDA) emphasizes that the use of droperidol, according to some
used in children because of adverse effects.26 A single dose of reports, causes serious electrocardiogram rhythm changes.
dexamethasone has been reported to be effective for PONV Considering this current status, droperidol should be used for POV
prophylaxis without evidence of significant side effects. It has also prevention and treatment in children only in selected cases.
been suggested that dexamethasone might be especially effective Curiously, the drug has been used safely since the late 1970s. Similar
against late POV.27 warning from FDA alerts for increasing risk of prolonged QT
syndrome after use of benzodiazepines, volatile anesthetics, and
Dopaminergic Antagonists opioids. Domperidone, unlike metoclopramide, does not pass the
blood-brain barrier and CNS side effects are rare. Because the CTZ
The receptor in the CTZ most closely associated with POV is the is outside the blood-brain barrier, domperidone does have an
dopamine2 receptor (D2). This explains the antiemetic effect of antiemetic effect here. Domperidone raises lower esophageal
D2 receptor antagonists like butyrophenones, metoclopramide, sphincter pressure, increases the amplitude of gastric and duodenal
and domperidone. Under normal conditions, dopamine inhibits contractions, and accelerates small intestinal transit. In children, it
the release of acetylcholine in the myenteric plexus by acting at seems domperidone is quite effective in the treatment of gastroparesis.
presynaptic D2 dopaminergic receptors. D2 receptor antagonists Its use in POV is not as common because of adverse effects like extra-
such as metoclopramide also have prokinetic effects, enhancing pyramidal symptoms and possible interference with cardiac rhythm.
the release of acetylcholine.28
Phenothiazines
Metoclopramide Phenothiazines also exert their antiemetic effect at the D2 chemo-
Structurally related to procainamide (2-methoxy-5- receptors in the CTZ. Promethazine is administered in doses
chloroprocainamide), metoclopramide has been used extensively ranging from 0.25 to 0.5 mg/kg to a maximum of 25 mg,
since the earlyh 1980s in the treatment and prevention of PONV and perphenazine has been shown to be effective for POV pro-
by oral intramuscular, and intravenous routes in both children and phylaxis in children at doses of 0.7 mg/kg with minimal sedative
adults. The pharmacokinetics are described for neonates.29 effects.
Metoclopramide acts primarily as a dopamine antagonist in the CNS,
specifically at the CTZ. It has selective peripheral cholinergic
stimulant effects on the proximal gastrointestinal tract, although 5-HT3 Antagonists
the real role of its direct action on the gastrointestinal tract and
This class of drugs is thought to act by highly selective and efficient
consequent antiemetic effect still remains unclear. Some of its
antagonism of 5-HT3 receptors located in the brain with a high
antiemetic activity could be account for by its effect at the 5-HT3
density occurring in the area postrema and the nucleus tratus
receptor, particularly at high doses.30 At high doses, above 0.5
solitarius. Ondansetron, granisetron, tropisetron, and dolasetron
mg/kg/d, metoclopramide blocks not only D2 receptors but also the
are the most known drugs from this class. They can be admini-
central and local receptors for serotonin. This antiserotinergic action
stered by oral or intravenous routes. In addition to having a central
in children may possibly cause greater clinical effect.31 However, the
site of action, they may act peripherally in the gastrointestinal
use of metoclopramide is strongly associated with extrapyramidal
tract, stimulating afferent vagal fibers that, in turn, cause 5-HT
reactions, especially in young patients. It is important to note that
release in the area postrema.39 The peak plasma concentration
most of studies employing metoclopramide in children neglect to
after 8 mg orally in adults occurs at about 1.5 hours. Ondansetron
mention that children, especially females, are at increased risk of
acute dystonic reactions such as extrapyramidal syndromes, is bound to plasma proteins to a moderate extent (75%) with a
although the incidence of this adverse event has never been volume of distribution of approximately 160 L. Its terminal plasma
established.32 Sedation and delayed recovery from anesthesia are half-life is approximately 3 hours, with 5% excreted renally.
reported for adult patients.33 Hydroxylation followed by glucuronide or sulfate conjugation in
the liver is the major route of excretion. Clearance is 541 mL/min.
Normally, the intravenous preparation is an isotonic aqueous
Butyrophenones solution compatible with 0.9% sodium chloride, 5% glucose, and
Butyrophenones are potent neuroleptics, and from this class of drugs, Ringer’s lactate solution.40 Clinically, some studies have reported
droperidol is most familiar to anesthesiologists. In adults, droperidol’s ondansetron 0.1 mg/kg to be a superior drug to metoclopramide
distribution half-life is approximately 10 minutes, the elimination 0.5 mg/kg for the prophylactic control of POV in children un-
half-life is 2 hours, and plasma clearance approximately 15 mL/ dergoing tonsillectomy.32
Although it is assumed that the major site of action of the of POV should take into account resources, patient’s and parents’
selective serotonin antagonists is the CTZ, a major effect of 5-HT3 preferences, surgical setting, and risk factors.44 Prophylaxis ap-
receptor antagonists is at the enteric level, where they block re- pears to be different from treatment. In the treatment approach,
ceptors in the peripheral ends of vagal afferents, thus blocking only children who actually deserve antiemetic drugs will eventu-
serotonin-stimulated vagal afferent input to the central pattern ally receive those antiemetics, reducing the risk of drug-induced
generator and reducing the perception of emetic stimuli. harm.45 At the other extreme, the strategy most likely to achieve
Side effects with this class of drug are rare and may include the lowest incidence of POV would be to administer all antiemetic
headache, flushing at the intravenous site of administration, and interventions to all patients without any risk stratification, in-
headedness. In adults, there are reports of prolongation of the QRS creasing acquisition costs and needlessly exposing patients who
complex and PR interval, although no change in heart rhythm or have no propensity for POV. Further, the efficacy of some antie-
hemodynamics was documented in children. metic drugs that have been used for decades is unreported.
Vomiting is a common symptom of many disease states. The
differential diagnosis of the child with vomiting varies with the
Steroids age of the patient. Congenital anatomic, genetic, or metabolic
Dexamethasone 150 μg/kg, as well as other glucocorticoids like disorders are more frequent in neonatal period, whereas peptic,
methylprednisolone, is also associated with prevention of early and infectious, and psychogenic problems are more commonly seen
late vomiting. The exact mechanism of action is unknown. It is with increasing age. In preoperative evaluation, the anesthe-
supposed to be consequence of the decreased enteric prostaglandin siologist must remain alert to these problems, especially gastroeso-
synthesis. However, steroids are better combined with other phageal reflux, because of the high risk for POV.
antiemetic drugs for synergistic effect rather than as the sole agent. Hypovolemia has been associated with increased postoperative
PONV attributable to gut mucosal hypoperfusion.46,47 Gut ische-
mia results in release of 5-HT, which is a potent trigger of PONV.
Dimenhydramine Although the mechanism of hydration in reduction of PONV is
not clear, intravenous fluid therapy contributed to reduced POV
Dimenhydrinate is available for use as a theoclate salt of diphenhy-
after pediatric strabismus surgery.48,49
dramine that can be administered orally, intravenously, and as a
Some proposed steps to a successful POV management strategy
suppository. Dimenhydrinate 0.5 mg/kg was found to be as clini-
are shown in Figure 34–4. Unfortunately, this kind of algorithm
cally effective as ondansetron with few serious adverse effects.
may be satisfactory only when applied to specific patient popula-
Although it was synthesized to avoid the sedative effects of
tions. It is suggested that the single most important factor reducing
diphenhydramine, sedation and dry mouth as well as other mus-
POV is the number of antiemetic interventions administered.41
carinic effects do occur. Some evidence support the use of Without prophylaxis, there is a high incidence of POV (≤73%)
dimenhydrinate as prophylaxis in children at moderate and high after high-risk surgical procedures such as tonsillectomy,50 and
risk of POV.41 It has been used as an agent for rescue therapy in this adverse event is the most common cause of delayed discharge
established POV in children. or overnight admission in day case tonsillectomy. POV is also
associated with increased bleeding, aspiration of gastric contents,
dehydration, and electrolyte disturbance.51 Among the prophylac-
ALGORITHMS, PROPHYLAXIS, tic measures described for high-risk patient groups, the 5-HT3
AND TREATMENT receptor antagonists and dexamethasone are consistently at the
The identification of risk factors is an important step toward
improved control of POV. Patients with risk factors are thought to
benefit most from a prophylactic anti-POV strategy.42 Countering
known risk factors reduced POV (Table 34–2). Most algorithms
for the prevention of PONV are adult-based and reliability in
children is uncertain. Stepwise18,43 or dichotomous44 models for
emetic control suggest that a combination of antiemetic interven-
tions increases effectiveness, although a gold standard algorithm
for adults or children remains elusive. The rational management
TABLE 34-2. How to Reduce Baseline Risk

If NMBD reversal is required, use edophronium instead of
neostigmine.
Avoid or minimize the opioid perioperative use.
Avoid postoperative use of morphine.
Avoid nitrous oxide especially in ENT or strabismus surgeries.
Avoid. if possible. volatile anesthetic agents.
Use propofol for induction and maintenance, if indicated.
Use regional anesthesia, if indicated.
Do not neglect hydration.
ENT = ear, nose, and throat; NMBD = neuromuscular blocking drug. Figure 34-4. Algorithm for prevention of postoperative vomiting.
TABLE 34-3. Antiemetic Drugs Used in Postoperative Vomiting: Dose and Possible Mechanism of Action
Drug Receptor Mechanism Dose
Metoclopramide D2 D2 blockade at the CTZ and enteric nervous system. In high dose, 0.25–0.5 mg/kg
(5-HT3) has 5-HT3 activity enterically.
Ondansetron 5-HT3 5-HT3 receptor blockade most important at the enteric level but 0.1–0.3 mg/kg
Granisetron 5-HT3 possibly some effect at the CTZ. 0.4–0.5 mg/kg
Tropisetron 5-HT3 0.1–0.2 mg/kg
Droperidol D2 D2 receptor blockade at the CTZ. Central anxiolysis and sedation. 50–80 μg/kg
Dexamethasone — Unknown, decreased enteric prostaglandin synthesis. 1–1.5 mg/kg
Domperidone D2 D2 receptor blockade at enteric nervous system. 50 μg/kg
Promethazine D2 D2 receptor blockade at the CTZ. 0.25–0.5 mg/kg
Perphenazine D2 0.7 mg/kg
Dimenhydrinate H1 Antagonist 0.5 mg/kg
CTZ = chemoreceptor trigger zone; D2 = dopamine2 receptor; 5-HT3 = 5-hydroxytryptamine3.
From references 12 and 38.
forefront.52,53 Dexamethasone with ondasentron is a useful com- suggest that propofol has an emetic effect.61 When propofol was used
bination53,54 because ondansetron is most effective against early along with nitrous oxide, rather than halothane for pediatric
vomiting54 whereas dexamethasone is effective against both early tonsillectomy, there was no differences in end points such as
and late nausea and vomiting.37,55 The sole use of 5-HT3 receptor unplanned admissions or discharge times.62
antagonists is not as efficient as when they are combined with Midazolam used in subhypnotic dose has been effective in
dexamethasone.18 There were no differences among the com- decreasing PONV incidence without untoward sedative effect in
bination of dexamethasone 2 mg or 4 mg with ondasentron 2 mg adult studies.55 Although there are no available studies for child-
or 4 mg in adult prophylaxis.52 Optimal combinations of dexame- ren, treatment using ondansetron 4 mg compared with midazolam
thasone with 5-HT3 antagonists in children require investiga- 2 mg given intravenously before the end of surgery did not provide
tion.37,52,54,55 The prophylactic antiemetic doses recommended for superior benefit in decreasing the incidence of PONV in female
children at risk for POV are shown in Table 34–3. adult patients, whereas midazolam was effective in decreasing the
The use of opioids, especially morphine, for treatment of post- incidence of PONV without increasing recovery time or level of
operative pain contributes to POV in high-risk surgical proce- sedation.63
dures, although the use of ondasentron could minimize this
problem.56 Some authors propose the use of alternative post-
operative pain control techniques, rendering the use of morphine
Combination of Antiemetics
in conjunction with 5-HT3 antagonists unnecessary.57 There has been a growing interest of combining antiemetics from
Ondasentron and tropisetron have been studied extensively for different classes for POV prophylaxis and treatment. In addition
POV prophylaxis in children at doses ranging from 50 to 100 μg/ to enhancing efficacy, a synergistic interaction between combi-
kg. The class of 5-HT3 antagonists is effective in preventing nations of two or more antiemetics might also permit a reduction
vomiting and is commonly used as antiemetics of first choice in in total dose, thereby reducing side effects. The physiologic basis
children. There is a consensus that the evidence supports the for combining different antiemetics is based in the multimodal
administration of 5-HT3 antagonists at the end of surgery rather aspects of vomiting and the major receptor systems involved in its
than before induction. etiology: dopaminergic, serotonergic, histaminergic, and choliner-
Droperidol has a role in the prophylaxis of POV, although low- gic. The neurokinin-1 (NK-1) receptor could also be involved with
dose droperidol in children has not been explored. However, the the triggering of vomiting. The mainstay of POV management
risk of extrapyramidal symptoms, high level of sedation, and today is to employ antagonists at these receptors. However, the
electrocardiogram rhythm changes found with droperidol restrict antiemetic prophylaxis or treatment with a combination of agents
its use for patients who have failed all other therapies. 12 still is controversial.64
Metoclopramide has been used extensively since the early 1980s in The evidence collected for pediatric patients shows that com-
the treatment and prevention of PONV for adult patients. The effec- bination therapy should be the approach planned for children at
tiveness of this drug is now in doubt. When it was used in high risk of POV. The most common choice is a 5-HT3 antagonist
standard clinical doses, or even larger doses, it was ineffective for and a second drug, usually dexamethasone, with an acceptable
both PONV prophylaxis and treatment.42,58 Although adult studies side effect profile. Antiemetic rescue therapy should be adminis-
demonstrated metoclopramide 20 mg to be comparable with tered to patients who have an emetic episode after surgery. When
ondansetron 8 mg, metoclopramide showed no worthwhile effect POV occurs within the first 6 hours, it is not recommended to
in children.59 There is no unanimous agreement among authors administer a repeat dose of the prophylactic antiemetic. After
about the use of metoclopramide for POV prophylaxis.17,60 Evidence 6 hours, any of the drugs used for prophylaxis, except dexame-
for the effectiveness of midazolam and perphenazine is still thasone, could be used.
controversial, and the results for dimenhydrinate, droperidol,
gastric aspiration, and acupuncture deserve better understanding Nonpharmacologic Approach
and reliable clinical trials to verify their effectiveness. Propofol has
gained a reputation as the intravenous anesthetic agent least likely A variety of different nonpharmacologic options aredescribed in
to cause POV. Studies comparing propofol with other anesthetics order to prevent or treat POV in children. However, the data are
still insufficient to allow any definite conclusion about this subject. 5. Andrews PL, Davis CJ, Bingham S, et al. The abdominal visceral inner-
When compared with placebo, the nonpharmacologic alternatives vation and the emetic reflex: pathways, pharmacology, and plasticity. Can
J Physiol Pharmacol. 1990;68:325–345.
were more effective in preventing PONV, although no benefit was 6. Andrews PL. Physiology of nausea and vomiting. Br J Anaesth. 1992;69
found within the pediatric population.65 (7 Suppl 1):2S–19S.
The best promise in this field looks to be the stimulation of the 7. Wang SC, Borison HL. A new concept of organization of the central
so-called P6 acupuncture point. The stimulation of the P6 acu- emetic mechanism: recent studies on the sites of action of apomorphine,
puncture point (acupressure, acupuncture, or electrical-laser copper sulfate and cardiac glycosides. Gastroenterology. 1952;22:1–12.
8. Leslie RA. Comparative aspects of the area postrema: fine-structural
stimulation) compared with antiemetic drugs in preventing considerations help to determine its function. Cell Mol Neurobiol. 1986;6:
PONV was found to be equally effective in adults. The P6 point is 95–120.
located in the wrist, and when stimulated in children, it was also 9. Fujii Y, Toyooka H, Tanaka H. Antiemetic effects of granisetron on post-
found to be of some benefit in reducing the incidence of POV.66 operative nausea and vomiting in patients with and without motion
sickness. Can J Anaesth. 1996;43:110–114.
Acupuncture was found more effective than acupressure or electri- 10. Thomas M, Woodhead G, Masood N, Howard R. Motion sickness as a
cal stimulation. The current status supports acustimulation of P6 predictor of postoperative vomiting in children aged 1–16 years. Paediatr
as a promising method of preventing POV in children, and it Anaesth. 2007;17:61–63.
could be considered as an alternative treatment to antiemetic 11. Miller AD. Respiratory muscle control during vomiting. Can J Physiol
Pharmacol. 1990;68:237–241.
medications for pediatric high-risk POV patients. 12. Gan TJ, Meyer T, Apfel CC, et al. Consensus guidelines for managing
postoperative nausea and vomiting. Anesth Analg. 2003;97:62–71, table
of contents.
WHAT IS LACKING ABOUT POV? 13. Eberhart LH, Geldner G, Kranke P, et al. The development and validation
of a risk score to predict the probability of postoperative vomiting in
Robust data for antiemetic treatment in established PONV for pediatric patients. Anesth Analg. 2004;99:1630–1637, table of contents.
adults or children are lacking. Evidence-based treatment strategies 14. Eberhart LH, Morin AM, Guber D, et al. Applicability of risk scores for
that take into account all possible antiemetic interventions have postoperative nausea and vomiting in adults to paediatric patients. Br J
not yet been established.36, 62 There are few trials that report both Anaesth. 2004;93:386–392.
15. Kranke P, Eberhart LH, Toker H, et al. A prospective evaluation of the
short and long postoperative observation periods. Report of a POVOC score for the prediction of postoperative vomiting in children.
delay until the antiemetic treatment shows effect would be also Anesth Analg. 2007;105:1592–1597, table of contents.
useful. Few studies show the impact of antiemetic administration 16. Busoni P, Sarti A, Crescioli M, et al. Motion sickness and postoperative
timing on either the incidence or the appearance of POV during vomiting in children. Paediatr Anaesth. 2002;12:65–68.
17. Bolton CM, Myles PS, Nolan T, Sterne JA. Prophylaxis of postoperative
the first 24 or 48 hours postoperatively in children undergoing vomiting in children undergoing tonsillectomy: a systematic review and
high-risk surgical procedures. This information is fundamental meta-analysis. Br J Anaesth. 2006;97:593–604.
for establishing additional prophylactic measures to reduce POV. 18. Gross D, Reuss S, Dillier CM, et al. Early vs late intraoperative admini-
There is a lack of reliable documentation about the adverse drug stration of tropisetron for the prevention of nausea and vomiting in
children undergoing tonsillectomy and/or adenoidectomy. Paediatr
reactions as well. Anaesth. 2006;16:444–450.
The experience with 5-HT3 receptor antagonists used singly or 19. Ewah BN, Robb PJ, Raw M. Postoperative pain, nausea and vomiting
in combination with dexamethasone or droperidol in both pre- following paediatric day-case tonsillectomy. Anaesthesia. 2006;61:
vention and treatment of POV is encouraging mainly in high-risk 116–122.
patients. Propofol and midazolam used perioperatively could be 20. Gupta N, Kumar R, Kumar S, et al. A prospective randomised double
blind study to evaluate the effect of peribulbar block or topical application
good alternatives for induction and maintenance of anesthesia, of local anaesthesia combined with general anaesthesia on intra-operative
decreasing the incidence of POV. and postoperative complications during paediatric strabismus surgery.
The importance of controlling POV has increased with the Anaesthesia. 2007;62:1110–1113.
current emphasis on rapid postoperative discharge in day cases 21. Tramer MR. Treatment of postoperative nausea and vomiting. BMJ.
2003;327:762–763.
surgeries. The decreased use of preoperative opioids, attention to 22. Divatia JV, Vaidya JS, Badwe RA, Hawaldar RW. Omission of nitrous
speed in operative procedures, care with perioperative hydration, oxide during anesthesia reduces the incidence of postoperative nausea
adequate postoperative pain management, and POV prophylaxis, and vomiting. A meta-analysis. Anesthesiology. 1996;85:1055–1062.
among others, are important factors decreasing the incidence of 23. Pandit UA, Malviya S, Lewis IH. Vomiting after outpatient tonsillectomy
and adenoidectomy in children: the role of nitrous oxide. Anesth Analg.
POV. Despite these improvements, POV still remains a problem 1995;80:230–233.
for children, particularly those at high risk after tonsillectomy or 24. Robinson DL, Carr BA. Delayed vomiting in children with cancer after
strabismus surgery. receiving moderately high or highly emetogenic chemotherapy. J Pediatr
Oncol Nurs. 2007;24:70–80.
25. Watcha MF, Safavi FZ, McCulloch DA, et al. Effect of antagonism of
REFERENCES mivacurium-induced neuromuscular block on postoperative emesis in
children. Anesth Analg. 1995;80:713–717.
1. Korttila K. The study of postoperative nausea and vomiting. Br J Anaesth. 26. Vandenplas Y, Benatar A, Cools F, et al. Efficacy and tolerability of
1992;69(7 Suppl 1):20S–23S. cisapride in children. Paediatr Drugs. 2001;3:559–573.
2. Kovac AL. Management of postoperative nausea and vomiting in 27. Fozard JR. Neuronal 5-HT receptors in the periphery. Neuropharma-
children. Paediatr Drugs. 2007;9:47–69. cology. 1984;23:1473–1486.
3. Hofer CK, Zollinger A, Buchi S, et al. Patient well-being after general 28. Galligan JJ. Motility and pharmacologic therapies. In: Schuster MM
anaesthesia: a prospective, randomized, controlled multi-centre trial CM, Koch KL, editors. Schuster Atlas of Gastrointestinal Motility in
comparing intravenous and inhalation anaesthesia. Br J Anaesth. 2003;91: Health and Disease. 2nd ed. Hamilton, Ontario: B.C. Decker, Inc; 2002.
631–637. pp. 399–410.
4. Davis CJ, Harding RK, Leslie RA. The organization of vomiting as 29. Kearns GL, van den Anker JN, Reed MD, Blumer JL. Pharmacokinetics
a protective reflex. In: Davis CJ, Lake-Bakaar GV, Grahame-Smith of metoclopramide in neonates. J Clin Pharmacol. 1998;38:122–128.
DG, editors. Nausea and Vomiting: Mechanisms and Treatment. Berlin: 30. Baines DB. Postoperative nausea and vomiting in children. Paediatr
Springer-Verlag; 1986. pp. 65–75. Anaesth. 1996;6:7–14.
31. Pasricha PJ, Pehlivanov N, Sugumar A, Jankovic J. Drug insight: from 49. Gan TJ. Postoperative nausea and vomiting—can it be eliminated? JAMA.
disturbed motility to disordered movement—a review of the clinical 2002;287:1233–1236.
benefits and medicolegal risks of metoclopramide. Nat Clin Pract 50. Goodarzi M, Matar MM, Shafa M, et al. A prospective randomized
Gastroenterol Hepatol. 2006;3:138–148. blinded study of the effect of intravenous fluid therapy on postoperative
32. Bolton CM, Myles PS, Carlin JB, Nolan T. Randomized, double-blind nausea and vomiting in children undergoing strabismus surgery. Paediatr
study comparing the efficacy of moderate-dose metoclopramide and Anaesth. 2006;16:49–53.
ondansetron for the prophylactic control of postoperative vomiting in 51. Dillier CM, Weiss M, Gerber AC. [Tropisetron for prevention of nausea
children after tonsillectomy. Br J Anaesth. 2007;99:699–703. and vomiting in children undergoing tonsillectomy and/or adenoidec-
33. Pang WW, Wu HS, Lin CH, et al. Metoclopramide decreases emesis but tomy] (German). Anaesthesist. 2000;49:275–278.
increases sedation in tramadol patient-controlled analgesia. Can J 52. Rose JB, Watcha MF. Postoperative nausea and vomiting in paediatric
Anaesth. 2002;49:1029–1033. patients. Br J Anaesth. 1999;83:104–117.
34. Fischler M, Bonnet F, Trang H, et al. The pharmacokinetics of droperidol 53. Paech MJ, Rucklidge MW, Lain J, et al. Ondansetron and dexamethasone
in anesthetized patients. Anesthesiology. 1986;64:486–489. dose combinations for prophylaxis against postoperative nausea and
35. Stead SW, Beatie CD, Keyes MA, Isenberg SJ. Effects of droperidol dosage vomiting. Anesth Analg. 2007;104:808–814.
on postoperative emetic symptoms following pediatric strabismus 54. Kim MS, Cote CJ, Cristoloveanu C, et al. There is no dose-escalation
surgery. J Clin Anesth. 2004;16:34–39. response to dexamethasone (0.0625–1.0 mg/kg) in pediatric tonsillectomy
36. Watcha MF. Management of postoperative vomiting in pediatric patients. or adenotonsillectomy patients for preventing vomiting, reducing pain,
Curr Opin Anaesthesiol. 2003;16:575–583. shortening time to first liquid intake, or the incidence of voice change.
37. Tramer MR. A rational approach to the control of postoperative nausea Anesth Analg. 2007;104:1052–1058, tables of contents.
and vomiting: evidence from systematic reviews. Part I. Efficacy and harm 55. Tramer MR. A rational approach to the control of postoperative nausea
of antiemetic interventions, and methodological issues. Acta Anaesthesiol and vomiting: evidence from systematic reviews. Part II. Recommen-
Scand. 2001;45:4–13. dations for prevention and treatment, and research agenda. Acta Anaes-
38. Kranke P, Eberhart LH, Gan TJ, et al. Algorithms for the prevention of thesiol Scand. 2001;45:14–19.
postoperative nausea and vomiting: an efficacy and efficiency simulation. 56. Henzi I, Walder B, Tramer MR. Dexamethasone for the prevention of
Eur J Anaesthesiol. 2007;24:856–867. postoperative nausea and vomiting: a quantitative systematic review.
Anesth Analg. 2000;90:186–194.
39. Gore S, Gilmore IT, Haigh CG, et al. Colonic transit in man is slowed
57. Anderson BJ, Ralph CJ, Stewart AW, et al. The dose-effect relationship for
by ondansetron (GR38032F), a selective 5-hydroxytryptamine receptor
morphine and vomiting after day-stay tonsillectomy in children. Anaesth
(type 3) antagonist. Aliment Pharmacol Ther. 1990;4:139–144.
Intensive Care. 2000;28:155–160.
40. Russell D, Kenny GN. 5-HT3 antagonists in postoperative nausea and
58. White MC, Nolan JA. An evaluation of pain and postoperative nausea
vomiting. Br J Anaesth. 1992;69(7 Suppl 1):63S–68S.
and vomiting following the introduction of guidelines for tonsillectomy.
41. McCall JE, Stubbs K, Saylors S, et al. The search for cost-effective pre- Paediatr Anaesth. 2005;15:683–688.
vention of postoperative nausea and vomiting in the child undergoing 59. Polati E, Verlato G, Finco G, et al. Ondansetron versus metoclopramide
reconstructive burn surgery: ondansetron versus dimenhydrinate. J Burn in the treatment of postoperative nausea and vomiting. Anesth Analg.
Care Rehabil. 1999;20:309–315. 1997;85:395–399.
42. Apfel CC, Kranke P, Katz MH, et al. Volatile anaesthetics may be the 60. Quaynor H, Raeder JC. Incidence and severity of postoperative nausea
main cause of early but not delayed postoperative vomiting: a rando- and vomiting are similar after metoclopramide 20 mg and ondansetron
mized controlled trial of factorial design. Br J Anaesth. 2002;88: 8 mg given by the end of laparoscopic cholecystectomies. Acta Anaes-
659–668. thesiol Scand. 2002;46:109–113.
43. Drake R, Anderson BJ, Persson MA, Thompson JM. Impact of an antie- 61. Balli P. The use of propofol as antiemetic. Int Anesthesiol Clin. 2003;41:
metic protocol on postoperative nausea and vomiting in children. 66–77.
Paediatr Anaesth. 2001;11:85–91. 62. Ved SA, Walden TL, Montana J, et al. Vomiting and recovery after
44. Tramer MR. Rational control of PONV—the rule of three. Can J Anaesth. outpatient tonsillectomy and adenoidectomy in children. Comparison of
2004;51:283–285. four anesthetic techniques using nitrous oxide with halothane or propofol.
45. Wagner DS, Yap JM, Bradley KM, Voepel-Lewis T. Assessing parents Anesthesiology. 1996;85:4–10.
preferences for the avoidance of undesirable anesthesia side effects in their 63. Unlugenc H, Guler T, Gunes Y, Isik G. Comparative study of the antie-
children undergoing surgical procedures. Paediatr Anaesth. 2007;17: metic efficacy of ondansetron, propofol and midazolam in the early
1035–1042. postoperative period. Eur J Anaesthesiol. 2004;21:60–65.
46. Kazemi-Kjellberg F, Henzi I, Tramer MR. Treatment of established post- 64. Lee Y, Wang JJ, Yang YL, et al. Midazolam vs ondansetron for preventing
operative nausea and vomiting: a quantitative systematic review. BMC postoperative nausea and vomiting: a randomised controlled trial. Anaes-
Anesthesiol. 2001;1:2. thesia. 2007;62:18–22.
47. Gan TJ, Mythen MG, Glass PS. Intraoperative gut hypoperfusion may be 65. Habib AS, Gan TJ. Combination antiemetics: what is the evidence? Int
a risk factor for postoperative nausea and vomiting. Br J Anaesth. 1997; Anesthesiol Clin. 2003;41:119–144.
78:476. 66. Lee A, Done ML. The use of nonpharmacologic techniques to prevent
48. Gan TJ, Mythen MG. Does perioperative gut-mucosa hypoperfusion postoperative nausea and vomiting: a meta-analysis. Anesth Analg. 1999;
cause postoperative nausea and vomiting? Lancet. 1995;345:1123–1124. 88:1362–1369.
35 Resuscitation Agents
C H A P T E R Craig Sims
INTRODUCTION
Resuscitation agents are the drugs and fluids required in the man-
agement of the acutely ill child before, during, or after anesthesia
and surgery. They may be required in either the operating room
or the intensive care unit. They are often needed urgently, yet they
may be an unfamiliar group of drugs because of infrequent use.
The catecholamines and other adrenergic agonists form the
backbone of this group of drugs. The catecholamines all share a
common chemical structure that includes a benzene ring hydrox-
ylated at positions 3 and 4 and an ethylamine side chain with a
terminal amine group. Epinephrine, norepinephrine, and dopa-
mine are the endogenous catecholamines, and dobutamine,
dopexamine, and isoproterenol are synthetic catecholamines. They
all exert their effects via adrenergic receptors, and all increase
myocardial contractility, oxygen consumption, and heart rate, as
well as increasing the propensity to develop arrhythmias.
ADRENERGIC RECEPTORS
AND AGONISTS
The catecholamines, sympathomimetic amines, and related agents
are among the most important drugs for the resuscitation of
critically ill children. They are administered to increase perfusion
pressure, increase cardiac output and oxygen delivery, and mani-
pulate regional vascular resistance. These actions are mediated by
a mechanism involving adrenergic receptors that are members Figure 35-1. Schematic diagram showing the cascade of intra-
of a superfamily of over 1500 G protein–coupled receptors. At least cellular events following binding of an agonist to a beta receptor.
10 adrenergic and dopaminergic receptor subtypes have been AC = adenylyl cyclase; Gs = stimulatory G protein.
identified using molecular biology techniques. They are all charac-
terized by the presence of seven transmembrane domains that form
loops and binding sites. The functions of many of these receptor and positive inotropy and lusitropy (Figure 35–1). Chronic beta1
subtypes are still not clear, and clinically they remain classified on stimulation also affects gene transcription, cell growth, and cell
the basis of their physiologic and biochemical responses into alpha1 death. Alpha receptors also act through a cascade, though they use
and alpha2, beta1 and beta2, and dopaminergic D1 and D2. the Gi protein that results in either a reduction in adenylyl cyclase
Adrenergic receptors on the cell surface are the first part activity or the hydrolysis of membrane-bound phospholipids to
of a cascade that amplifies the binding of a single molecule of form other compounds, including those leading to increased entry
agonist. They are part of a complex of three interacting proof calcium into the cell.
teins: adrenergic receptor, guanine nucleotide binding protein All parts of the cardiovascular system have both alpha and beta
(G protein), and effector enzymes or ion channels. The cascade of receptors. Adrenergic receptors on the myocardium include beta1
events after alpha and beta receptor binding has been described (80%), a significant number of beta2, and some alpha receptors
in detail.1–3 After an agonist binds, the adrenergic receptor under- that are not associated with any nerve terminals. Alpha receptors
goes a conformational change allowing interaction with a mediating vasoconstriction predominate in the peripheral
G protein. There are three types of G protein: stimulatory (Gs), circulation, but there are also beta2 and dopaminergic receptors
inhibitory (Gi) and a third, Gq. Beta receptors are associated with mediating vasodilatation. Although each of the catecholamines
a Gs protein, and after receptor activation, the cascade results in has varying degrees of specificity for the different receptor
enzyme phosphorylation, increased calcium entry into the cytosol, subtypes dependent on its plasma concentration, this distinction
CHAPTER 35 ■ Resuscitation Agents 553
TABLE 35-1. Receptor Activity During Infusions of Adrenergic Agonists

Receptor Activity
Infusion Dose, ␮g/kg/min Alpha Beta1 Beta2 Dopaminergic
Epinephrine 0.05–0.1 + +++ ++
0.1–0.2 +++ ++ ++
Norepinephrine 0.05–0.1 ++++ ++ +/–
Dopamine <5 – + + +++
5–10 + ++ +
>10 +++ ++ +
Dobutamine 2.5–15 + +++ ++ –
Isoproterenol 0.05–1 – ++++ +++ –
is of limited clinical use (Table 35–1). There is no consistent myocardium has less reserve to respond to exogenous catechola-
relationship between the plasma concentration of catecholamine mines. However, there is enhanced response to intracellular levels
and its clinical effect because the pharmacokinetics and the body’s of calcium, and animal studies suggest this may be caused by
reflex cardiovascular responses change during illness. For these increased amounts of the different isoforms of myosin light chains,
reasons, their effects during resuscitation will differ from those and of troponin I and T. Finally, the extracellular collagen matrix
seen under healthy conditions. Continuous titration of dose of the heart develops over the first 6 months with increasingly
against clinical response is the appropriate technique of adminis- efficient transfer of the contractile force of the myofibrils to the
tration. All of the catecholamines have a short half-life, and steady- blood within the ventricles.4
state concentrations are reached within 5 to 10 minutes of starting
a continuous infusion. All potent, vasoactive agents should be
given by a linear piston syringe pump rather than a peristaltic
Changes in Adrenergic Receptors
pump, especially if flow rates lower than 5 ml/h are being used. With Disease and Catecholamine Use
Delivery should be as close to the patient as possible, with small The number and distribution of adrenergic receptors change
volume extensions. in response to disease and catecholamine administration, sig-
nificantly limiting the effectiveness of catecholamine therapy.
Developmental Changes in Heart failure is associated with elevated endogenous catechola-
mine levels and results in receptor changes similar to those seen
Adrenergic Receptors and the Myocardium with the use of exogenous catecholamines. The most rapid of
Sympathetic innervation is incomplete in the newborn, but these changes occurs within minutes of therapy and is receptor
parasympathetic innervation is intact at birth. The parasympa- desensitization.2,4 G protein–coupled receptor kinase (GCRK)
thetic predominance gradually decreases until around 6 months phosphorylates occupied beta receptors, causing them to be
of age. Adrenergic receptors are present and functional from an
early gestational age, but the number of beta receptors increases
and the number of alpha receptors decreases with development. TABLE 35-2. Summary of Major Differences Between
Approximately 80% of ventricular adrenoceptors are beta1, and Neonatal and Mature Hearts
this proportion of beta1 and beta2 receptors probably stays con- Neonatal Mature
stant with maturation. However, neonatal animal models suggest
that the function of the receptors may change with maturation. Contractility Limited Normal
The role of the beta receptors in neonatal animal models is Heart rate High Low
different from that in adults—beta2 receptor stimulation results dependence
in intracellular changes similar to that seen after beta1 stimula- Innervation Parasympathetic pre- Complete
tion in adults, and hence beta2 stimulation plays a much greater dominates Sym-
role in mediating the response to catecholamines in the neonate. pathetic incomplete
Also, there may be changes in the function of alpha receptors Predominant site Sarcolemma Sarcoplasmic
such that stimulation in the neonate results in tachycardia rather of calcium flux reticulum
than the bradycardia seen later in development. Whether these Dependence on High Lower
changes in alpha and beta receptor function also occur in humans normal intra-
is not clear.4 cellular calcium
The myocardium of the neonate and infant is different from the β Adrenergic Down-regulated Normal
older child (Table 35–2). The myofibrils are poorly organized with receptors Insensitive
a random orientation rather than the parallel and well-organized 80% beta1, beta2 80% beta1, beta2
arrangement seen in the adult. The neonatal myocardium develops behavior similar to different mecha-
less tension per gram than adult hearts, and it is less compliant, beta1 nism to beta1
relying more on heart rate to maintain or augment cardiac output. Myocardial Disorganized Organized
At birth and over the weeks after birth, high levels of endogenous structure myofibrils myofibrils
catecholamines support the transitional circulation. The neonatal Adapted from reference 5.
internalized and degraded. Slower, but also important, is a fall in TABLE 35-4. Noncardiovascular Effects of
the number of beta1 receptors resulting in a lower receptor density Epinephrine Infusions
on the cell surface with nearly equal proportions of beta1 and beta2
receptors. As a result, less cyclic adenosine monophosphate Effect Mechanism
(cAMP) and downstream signaling effectors are formed within Metabolic Increased glucose and Insulin resistance,
the myofibril. Interestingly, animal work suggests the opposite free fatty acids increased glucagons
may occur in neonates, with an enhanced response to beta recep- Increased lactate and cortisol
tor stimulation than would normally cause desensitization in Reduced plasma potas- Increased glycogenoly-
the adult.4,5 sium, magnesium, sis
calcium, phosphate Transcellular shift
Increased oxygen
POSITIVE INOTROPIC AGENTS consumption
The catecholamines improve inotropy by enhancing the release Immunomo- Decreased neutrophil
of Ca2+ from the sarcoplasmic reticulum, increasing the intracel- dulatory adherence, chemo-
lular calcium concentration. Although this leads to positive taxis, and phagocytic
inotropy in the short term, intracellular calcium plays a critical capacity; increased
role in cell death and apoptosis, and increased calcium con- platelet aggregation;
centration appears to be detrimental in the long term. Beta1 Reduced tumor ne-
agonists and phosphodiesterase-3 inhibitors have been found crosis factor release
detrimental during the long-term treatment of heart failure from monocytes
because they contribute to the development of malignant ven-
tricular tachyarrhythmias and increase the incidence of sudden
cardiac death.6–8 Other positive inotropic drugs work through Pharmacokinetics
different mechanisms and are discussed separately (Table 35–3). Epinephrine follows first-order kinetics, and plasma concentration
is linearly related to the infused dose.9 Endogenous concentrations
of epinephrine vary widely with disease and activity, but range
Epinephrine (Adrenaline) between 50 and 400 ng/L. Concentrations reached in children
Epinephrine is the single most important drug in both adult and during I.V. infusion rates of 0.03 to 0.2 μg/k/min are 670 to 9430
pediatric cardiac resuscitation. It is used to treat asystole, severe pg/mL.10 Healthy, resting adults have concentrations less than
bradycardia, ventricular fibrillation (VF), electromechanical 100 pg/mL, and sick adults 200 to 1200 pg/mL. There is substantial
dissociation, and anaphylaxis. Epinephrine is released primarily between-individual variability, particularly in critically ill patients,
by the adrenal medulla and, unlike norepinephrine, functions as and therefore, the infusion rate must be titrated against effect.
a circulating hormone. At physiologic concentrations, epinephrine Epinephrine is methylated by catechol-O-methyl transferase
acts on beta1 and beta2 receptors to improve myocardial per- (COMT) and deaminated by monoamine oxidase (MAO) at
formance and dilate blood vessels supplying skeletal muscle. At multiple sites. Clearance is 15.6 to 79.2 mL/min/kg (similar to
the much higher concentrations achieved during intravenous dobutamine and dopamine). Plasma half-life is 2 to 2.5 minutes.
(I.V.) infusions, it continues to act on beta1 receptors, but also
causes vasoconstriction via alpha stimulation in the peripheral Epinephrine in Cardiac Arrest
circulation. Epinephrine stimulates beta2 receptors on bronchial Epinephrine is the mainstay of advanced pediatric life support
smooth muscle, which results in bronchodilatation and inhibi- because of its beneficial effects on cerebral and myocardial blood
tion of mast cell degranulation. The other effects of epinephrine flow. During external cardiac massage, myocardial perfusion
outside the cardiovascular system are summarized in Table 35–4. occurs during the relaxation cycle of chest compression. Coronary
Epinephrine increases the blood sugar level by the activation perfusion pressure during this time depends on the difference
of hepatic glycogen phosphorylase and conversion of glycogen between the aortic diastolic pressure and the right atrial diastolic
to glucose. It simultaneously inhibits the further synthesis of pressure (or central venous pressure). A coronary perfusion pres-
glycogen. Epinephrine has a molecular weight of 183.2 Da, and is sure of at least 30 mmHg is required, and return to spontaneous
very slightly soluble in water. Its solutions are acidic, and it must circulation is unlikely if this is not achieved. Chest compression
not be mixed with alkaline solutions. alone cannot give a high enough coronary perfusion pressure
TABLE 35-3. Classification of Positive Inotropic Agents

Agent Effector Site Molecular Mechanism Effect on Intracellular [Ca2+]
Catecholamines β1 Adrenergic receptor Increases cAMP Increases
Phosphodiesterase inhibitors Phosphodiesterase Increases cAMP Increases
Digoxin Sarcolemmal Na+-K+-ATPase Increases Ca2+ stored in Increases
sarcoplasmic reticulum
Calcium sensitizers Troponin C–Ca2+ complex Increases sensitivity myofilament No effect
to Ca2+
cAMP = cyclic adenosine monophosphate.
beyond the first few minutes because of the peripheral vaso- osseous (I.O.) routes are the preferred means of administering
dilatation that rapidly occurs during cardiac arrest. Exogenously drugs. A saline flush helps peripherally administered drugs behave
administered epinephrine acts on alpha receptors near the vas- like they were administered centrally. The endotracheal route is a
cular lumen to cause vasoconstriction.11 Blood is shunted from poor alternative, and the intracardiac route is no longer used.
skeletal and splanchnic beds to the heart and brain. Aortic dias-
tolic pressure increases markedly with only a minor increase in INTRAVENOUS: I.V. administration is safe and simple and is the
central venous pressure and results in a coronary perfusion first choice of route. During external cardiac massage in adults,
pressure of 25 to 30 mmHg during both systole and diastole. epinephrine given intravenously via the antecubital fossa reaches
Epinephrine must be given early, when peripheral vessels are a peak arterial concentration at 1.5 to 3 minutes,18 and this is
still responsive and before local metabolic vasodilator effects shortened by 40% if the epinephrine is followed by a 0.25-mL/kg
predominate, and then repeatedly, to increase the aortic diastolic flush.19 Central venous administration of drug results in a faster
and coronary perfusion pressures.12,13 Although there is a massive onset, higher peak concentration, and more potent effect than
rise in endogenous catecholamines during cardiac arrest, their peripheral administration, but this is not usually recommended
effect on the circulation is inadequate. because of the practical difficulties and complications of inser-
Other vasopressors have been studied for use in cardiac arrest. tion.18 In adults, I.V. access should be obtained in vessels above
In adults, pure alpha agonists are attractive because of the avoi- the diaphragm, where venous return during external cardiac
dance of the potentially deleterious effects of postarrest tachy- massage is better. In infants and small children, cardiac output and
cardia and increased myocardial oxygen consumption resulting perfusion pressure during external cardiac massage are higher and
from beta stimulation. However, the lack of effectiveness of the any site is acceptable.
pure alpha agonists methoxamine and phenylephrine suggests
INTRAOSSEOUS: I.O. administration can be quickly and
that beta effects are important, although the mechanism is un-
known. Norepinephrine may be an alternative to epinephrine successfully used for a wide variety of drugs and resuscitation
because of its effects on alpha and beta1 receptors. It has been fluids in children of any age, including neonates.20 Drug delivery
found effective in resuscitation from arrest in VF but not asphyxial to the central circulation is similar to peripheral or central I.V.
arrest.14,15 Vasopressin is of interest and is discussed separately. In administration, and no dose adjustment is required.21,22
children, however, epinephrine firmly remains the agent of choice TRACHEAL: Tracheal administration may be used for epinephrine,
because its deleterious effects are believed to be less of a problem lidocaine, atropine, midazolam, and vasopressin, but not for
than in adults. calcium or sodium bicarbonate.23,24 Epinephrine is the drug most
DOSE OF EPINEPHRINE DURING CARDIAC ARREST: The dose of likely to be administered by the tracheal route. Plasma concen-
epinephrine during cardiac arrest is 10 μg/kg, repeated every few trations of epinephrine after tracheal administration to animals
minutes16,17 (Table 35–5). High-dose epinephrine (100 μg/kg) was are about one tenth of those after I.V. administration. This may
initially thought to be of potential benefit in children and to be result in transient beta effects rather than alpha effects with
better tolerated postarrest than in adults. However, it is now detrimental effects on blood pressure and outcome. Increasing
known that high-dose epinephrine may cause a hyperadrenergic the dose by a factor of 10 gives similar plasma concentrations
state after the return to spontaneous circulation and a worse to I.V. epinephrine, but there is also a depot effect owing to local
24-hour survival rate. High doses may be considered in excep- vasoconstriction and lymphatic storage. The result of this is a
tional circumstances such as β blocker overdose. lower peak and slower plasma concentration decline after endo-
tracheal epinephrine (Figure 35–2). Trapping of epinephrine in
ROUTES OF ADMINISTRATION: Drugs can be administered by
the lungs can also act as a reservoir after resuscitation and cause
three different routes during resuscitation. The I.V. and intra- severe hypertension, particularly in adults.
The site of absorption after endotracheal administration
TABLE 35-5. Epinephrine and Other Resuscitation Drug includes the alveolar capillary network and the mucosa of the tra-
Doses for Cardiac Arrest in Children chea and bronchi.18 Epinephrine must be diluted before adminis-
tration to improve absorption. Various models and techniques
Drug Dose Role have been used in studies of ETT administration. There are
Epinephrine I.V. or I.O.: 10 μg/ First-line drug for probably no important clinical differences in effect between the
kg, q3min cardiac arrest different techniques, particularly because the overall efficacy
ETT: 100 μg/kg of the route is poor. Absorption is faster if water is used as the
Amiodarone I.V. or I.O.: 5 mg/kg First-line antiarrhy- diluent, possibly because water is hypotonic and moves faster from
thmic for VF or alveoli into the vascular space.25 The most practical method is to
pulseless VT use 100 μg/kg epinephrine (0.1 mL/kg of 1:1000 solution) mixed
Atropine I.V. or I.O.: 0.02 mg/ For bradycardia with an equal volume of water or saline (Table 35–6). This is a
kg unresponsive to poor alternative to the I.V. and I.O. routes, and drugs given by the
ETT 0.03 mg/kg ventilation and ENDOTRACHEAL route should be re-administered when
circulatory support vascular access is obtained.26
Lidocaine I.V. or I.O.: 1 mg/kg Use if amiodarone not INTRAMUSCULAR AND SUBCUTANEOUS: Anaphylactic reactions
ETT: 2–3 mg/kg available in the community are treated with epinephrine from an
Sodium 1 mL/kg of 8.4% Consider for prolonged autoinjector. Plasma epinephrine concentrations are higher and
bicarbonate solution arrest achieved earlier after intramuscular (I.M.) injection than after
ETT, = endotracheal tube;VF = ventricular fibrillation; VT = ventricular subcutaneous (S.C.) injection. The plasma concentration after 0.01
tachycardia. mg/kg reaches approximately 2100 pg/mL 8 minutes after I.M.
TABLE 35-7. Nebulized Epinephrine Doses and Dilutions

Agent Dose
Racemic epinephrine 0.05 mL/kg diluted with normal
2.25% saline to 4–5 mL
L-Isomer epinephrine 0.05 mL/kg diluted with normal
1% nebulizer solution saline to 4 mL
Epinephrine 1:1000 0.5 mL/kg (maximum 5 mL), use
(I.V. preparation) undiluted in nebulizer bowl
Nebulized Epinephrine
Both the I.V. preparations and the endogenous forms of epineph-
rine and norepinephrine are L-isomers, and this form is suitable
for nebulization. Racemic epinephrine contains equal amounts
of D and L isomers and is used for nebulization in croup. It was
historically chosen in preference to L-epinephrine because it was
incorrectly believed to cause fewer cardiovascular problems.31,32
Nebulized epinephrine stimulates α adrenergic receptors and
reduces mucosal swelling by vasoconstriction. The doses are
given in Table 35–7. Onset is immediate, and it can be given as
Figure 35-2. Plasma concentrations after intravenous and frequently as every 15 minutes if indicated clinically. Continuous
tracheal epinephrine in dogs. Ten times the intravenous dose of nebulized epinephrine can be delivered in the intensive care unit
epinephrine must be given via the endotracheal tube (ETT) to by mixing 5 mg/kg (0.5 mL/kg of the 1% solution) in 500 mL of
achieve similar plasma concentrations, but the high ETT dose saline delivered by a pump into the nebulizer chamber at 20 mL/h.
also has a prolonged effect that may be problematic after resusci-
tation. Data from Schüttler J, Hörnchen U, Stoeckel H, Hahn N.
[Endobrachial administration of adrenaline in cardiopulmonary Toxicity and Precautions
resuscitation: pharmacokinetic and dynamic studies in the dog] The effects of epinephrine infusions on regional blood flow are of
(German). Langenbecks Arch Chir. 1987;370:119–127. concern in children. Pulmonary vascular resistance (PVR) and
pulmonary blood flow are affected by the pre-existing PVR,
coexisting hypoxia, and epinephrine dose and duration. At low
injection, compared with 1800 pg/mL 34 minutes after S.C. doses, PVR falls, pulmonary blood flow increases,
. . and there may
injection. Furthermore, most children given I.M. injections reach be worsening of ventilation-perfusion (V/Q) mismatch. Higher
the peak concentration by 5 minutes.27 doses increase the PVR.
Epinephrine is a potent renal vasoconstrictor. Vasoconstriction
is mediated by alpha receptors and is relatively unopposed by the
Therapeutic Use few beta2 receptors in the renal vascular bed. However, restoration
Epinephrine is also indicated for treatment of the hypoten- of renal perfusion pressure is more important than isolated effects
sive, bradycardic child who has been unresponsive to ventilation on the vasculature, and urine output often increases because of
and fluid loading. Adult work has shown that there is little increased cardiac output. Nevertheless, renal vasoconstriction is a
difference between epinephrine and norepinephrine in septic major reason for a reluctance to use epinephrine as a first-line
shock.28–30 Epinephrine is prepared as an infusion of 0.3 mg/kg therapy for shock. Epinephrine interacts with volatile anesthetics
made up to 50 mL, so that 1 mL/h equals 0.1 μg/kg/min. The and, in particular, halothane in hypercarbic patients to pro-
infusion is usually started at 0.05 to 0.1 μg/kg/min and increased duce arrhythmias. Doses of epinephrine as high as 10 μg/kg are
as required. Epinephrine is often used when other inotropic acceptable in children, although patients studied were given
agents have not been effective. It is not compatible with sodium epinephrine in conjunction with lidocaine.
bicarbonate.
Norepinephrine
TABLE 35-6. Volume of Water to Be Added to
Norepinephrine is a naturally occurring catecholamine released
Epinephrine 0.1 mg/kg for Tracheal Administration
from adrenergic nerve terminals. Endogenous norepinephrine is
During Cardiac Arrest
taken up into sympathetic neurones after its release, and there is
Volume of Water Added to very little circulating in the plasma. Exogenous norepinephrine
Age Epinephrine 0.1 mg/kg has a plasma half-life of 2 to 2.5 minutes, and the clearance is
24 to 40 mL/min/kg in adults.9 It is broken down by COMT and
Newborn 0.7 mL
MAO and removed from the plasma by neuronal and non-
Infant 1–2 mL
neuronal tissue uptake. Norepinephrine has a molecular weight
Small child 2–5 mL
Large child 5–10 mL of 169.2 Da, and because it is strongly acidic in solution, it cannot
be mixed with alkaline solutions.
TABLE 35-8. Summary of Inotrope Pharmacokinetics in vessels. Salt and water excretion is increased, with the increase
Children Compared With Adults in sodium excretion being greater than the increase in renal
blood flow. Dopamine also exhibits significant endocrine effects
Drug Pharmacokinetics independent of its cardiovascular actions. The release of thyroid-
Adrenergic Agonists stimulating hormone is reduced, and even low doses of dopa-
Epinephrine Probably reduced clearance in mine block the rise in serum prolactin seen as part of the stress
children compared with adults response.34 Dopamine is acidic in solution and has a molecular
Dobutamine Large variability in clearance weight of 189.6 Da.
Dopaminergic Agents
Dopamine Increased clearance in children Pharmacokinetics
<2y Dopamine has a redistribution half-life of less than 2 minutes and
an elimination half-life of 7 minutes.9 About 25% of exogenous
Phosphodiesterase inhibitors dopamine is taken up into presynaptic neurones by a dopamine
Amrinone Reduced clearance, prolonged transporter and converted to norepinephrine, although the
half-life in neonates proportion taken up varies owing to polymorphism of the gene
Enoximone Similar to adults controlling beta-hydoxylase. The remainder is either sulfated by
Milrinone Increased volume of distribu- the enzyme phenol sulfotransferase or broken down by MAO
tion, increased clearance and COMT. Clearance in children younger than 2 years is twice
Calcium Sensitizers that of older children and adults, though there is a great amount
Levosimendan Similar to adults of between-individual variation. At steady state, the plasma con-
centration may vary fourfold among patients receiving the same
infusion rate.35,36 Neonates and young infants also have reduced
myocardial sensitivity to dopamine, resulting from incomplete
Norepinephrine acts primarily on α and β1 adrenergic recep- sympathetic innervation and reduced norepinephrine stores. For
tors and has little effect on beta2 receptors. Doses over 0.1 μg/ these reasons, children younger than 12 months, and especially
kg/min increase systemic vascular resistance (SVR) and blood those younger than 6 months, may be less responsive to dopamine
pressure and reduce renal blood flow. Heart rate is either and need higher infusion rates to achieve the same effect as older
unchanged, or there is a reflex slowing. PVR increases and cardiac children and adults.36 Clearance may be reduced in children with
output is unchanged or decreases. It is used to increase SVR in marked renal or hepatic disease37 and increased during concomi-
spinal cord shock and, in association with other agents, for the tant dobutamine infusion. MAO inhibitors not only block the
treatment of septic shock. Although norepinephrine is often used breakdown of dopamine but also increase the neuronal stores of
in the treatment of septic shock in adults, children with septic norepinephrine released by dopamine.
shock more often have an increased SVR and a low cardiac output,
and thus, dopamine is frequently used for treatment (Table 35–8). Therapeutic Use
Norepinephrine is given as an infusion commencing at 0.05 to
Dopamine is used as an inotropic and vasopressor agent in
0.1 μg/kg/min and increased up to 0.5 to 1 μg/kg/min. Although
critically ill neonates, infants, and children, in whom it is less likely
hyperglycemia and other metabolic effects can occur, they are
to cause severe tachycardia or arrhythmias than epinephrine.
much less pronounced during norepinephrine than during
At lower doses, it increases contractility and cardiac output, and
epinephrine therapy.
at higher doses, it increases heart rate and SVR. Dopamine can
be used as the first line of inotropic support in neonates and
Dopamine children.38–40 However, children younger than 12 months, and
especially younger than 6 months, may be less responsive to dopa-
Dopamine is the biosynthetic precursor of norepinephrine and is mine because of reduced epinephrine stores in nerve terminals
released from peripheral and central neurones. Its hemodynamic that can be released. Epinephrine should be used if there is a poor
effects result from actions at specific dopaminergic receptors, from response to dopamine or perhaps as a first line for cold hypo-
direct and indirect actions on α and β adrenergic receptors, and dynamic shock. A low-dose dopamine infusion increases urine
from causing the release of endogenous norepinephrine from output during critical illness, but it is doubtful that there is any
nerve terminals. The latter is responsible for up to 50% of its renal protective effect.41,42 Dopamine infusions can be prepared
effects, particularly at higher doses.33 In higher doses, actions on using 15 mg/kg diluted to 50 mL (1 mL/h = 5 μ/kg/min),
the specific dopaminergic receptors are overshadowed by effects commencing at 5 μg/kg/min for shock states. The usual upper
resulting from α and β adrenergic receptor stimulation (see Table dose limit is 10 to 20 μg/kg/min, but there is some evidence for
35–1). The predominant cardiovascular effects of dopamine at higher doses in neonates.43
normal plasma concentrations relate its actions on beta1 receptors.
Cardiac output and PVR increase. Heart rate increases are dose-
dependent, and tachycardia contributes to the increase in cardiac Toxicity and Precautions
output at infusion rates above 7.5 μg/kg/min. Low infusion rates of dopamine can be given temporarily through
There are at least five subtypes of dopaminergic receptors, a peripheral I.V. line. However, extravasation can result in skin
though they are functionally divided into subclasses D1 and necrosis.44 If this occurs, it should be treated with either local
D2. Stimulation of D1 receptors causes vasodilatation of renal infiltration of a phentolamine solution (2 mg in 5 mL saline) or
(particularly cortical), cerebral, coronary, and splanchnic blood topical glyceryl trinitrate. Infusion rates of 7.5 μg/kg/min or
greater increase PVR in the absence of concomitant pulmonary if there is no coronary artery obstruction and blood pressure is
vasodilators,45 and other catecholamines should be used in maintained.
patients with pre-existing pulmonary hypertension. Dopamine
increases myocardial oxygen demand, decreases ventricular
compliance, and increases end-diastolic pressure and afterload. Isoproterenol (Isoprenaline)
Tachycardia and tachyarrhythmias can limit the dose able to Isoproterenol is a synthetic catecholamine that is a nonspecific
be given. beta receptor agonist and possesses inotropic, chronotropic, and
vasodilatory properties. Its molecular weight is 211.3 Da. It is the
most arrhythmogenic of the catecholamines, a problem that
Dobutamine significantly restricts its use. Because it increases heart rate and
Dobutamine is an inodilator and acts by direct stimulation of reduces blood pressure, myocardial oxygen delivery may be
cardiac beta and alpha receptors to give a positive inotropic effect reduced.49 It is also a bronchodilator, but the specific beta2 agonist
with variable chronotropic and peripheral vascular effects. It is a albuterol is a safer alternative. Other catecholamines are inotropic
racemic mixture (molecular weight 337.8 Da), with the (–) isomer with less tachycardia, and isoproterenol is now used primarily for
acting as a partial alpha1 agonist, and the (+) isomer stimulating bradyarrhythmias, and complete heart block when transvenous
beta1 and beta2 receptors. The advantages of dobutamine over pacing is not immediately practical. Isoproterenol increases
dopamine are (1) it has limited chronotropic effect; (2) it is conduction velocity, shortens atrioventricular (AV) node con-
relatively cardioselective and does not increase SVR; and (3) it does duction time, and directly stimulates the sinoatrial node. Isopro-
not depend on endogenous stores of norepinephrine for its terenol is broken down by COMT and taken up by nonneuronal
actions.38 It is a more titratable inodilator than either levosimen- tissue. It has a plasma half-life of 1.5 to 4.2 minutes. The dose is
dan or the phosphodiesterase inhibitors. Dobutamine increases 1 μg/kg as a bolus if required, and the infusion dose is 0.05 to
cardiac output by increasing stroke volume. The heart rate remains 0.5 μg/kg/min.9
fairly stable at infusions less than 10 μg/kg/min but can increase
more markedly even at low doses in some patients.46 SVR most
commonly falls, but may remain unchanged or even increased, Phosphodiesterase Inhibitors
and so there is an unpredictable effect on blood pressure. PVR
The phosphodiesterase (PDE) inhibitors amrinone, milrinone,
decreases at low doses.
and enoximone improve contractility and reduce peripheral
vascular resistance and PVR. They are termed inodilators.
Pharmacokinetics Although they increase mortality in chronic heart failure, they
Dobutamine has redistribution and elimination half-lives of 2 and remain useful agents in the acute setting because they have a
26 minutes, respectively, and a volume of distribution (Vd) of 0.2 positive inotropic action independent of the beta receptor
L/kg. The reported clearance in children is extremely variable, and complex. They may also have some anti-inflammatory effects in
it is not even clear whether its pharmacokinetics follow linear or septic shock. However, their use is limited by the side effects
nonlinear kinetics.47,48 This finding may reflect the very large of hypotension, thrombocytopenia, and their long duration of
between-individual variability in its pharmacokinetics. The wide action. The enzyme PDE ends the actions of cAMP by converting
variability in hemodynamic responses and clearance kinetics it to adenosine monophosphate (AMP) (Figure 35–3). There are
indicates that dobutamine infusions must be titrated individually. five families of PDEs, and at least 25 different isoenzymes.
Metabolism is by COMT, hepatic glucuronidation, and extra- Theophylline is a nonspecific inhibitor of PDE. These inodilators
neuronal uptake. affect the isoenzyme peak III (PDE III) and act on the heart
and peripheral and pulmonary circulations, with lesser effects
Therapeutic Use elsewhere. The isoenzyme PDE V is found in high concentra-
tions in the pulmonary vasculature and is inhibited by sildenafil,
Dobutamine is suitable for patients with low cardiac output but
which is useful in the treatment of pulmonary hypertension in
normal or high SVR (e.g., after cardiac bypass, cardiomyopathy, or
neonates.50
newborns with primary myocardial dysfunction). Dobutamine
The PDE inhibitors bypass β adrenergic receptors; a parti-
does not usually cause vasoconstriction, and it is not suitable as a
cularly advantageous trait in patients with longstanding conges-
first-line agent to treat hypotension from septic shock. Dopamine
tive cardiac failure in which beta receptor down-regulation has
has been shown to be better than dobutamine in treating hypo-
occurred. Their mechanism may also be synergistic with drugs
tension in neonates.40 An infusion of dobutamine is prepared by
acting at adrenergic receptors, leading to lower-dose catechola-
using 15 mg/kg of dobutamine diluted to a total of 50 mL (1 mL/h
= 5 μg/kg/min). The infusion is commenced at 2.5 to 5 μg/kg/ mine requirements. A loading dose of the PDE inhibitor is
min and increased as necessary to 20 μg/kg/min. Although a required because they all have long elimination half-lives. Changes
higher dose can be used, changing to another agent should in infusion rates are slow to take effect, and it may be difficult to
be considered. titrate therapy. Cardiac output increases through a combination
of positive inotropy and changes in the loading conditions of the
myocardium. Blood pressure, PVR and SVR, and filling pressures
Toxicity and Precautions all decrease. PDE inhibitors are less arrhythmogenic, cause less
Tachycardia may be a problem with dobutamine and is an indi- tachycardia than catecholamines, and do not increase myocardial
cation to reduce the dose or change to another agent. Arrhythmias oxygen demand. Only milrinone can be diluted with glucose-
can occur, but less commonly than with dopamine. Dobutamine containing solutions, but all PDE inhibitors can be administered
increases myocardial oxygen demand, but supply is also increased into a line that is infusing dextrose.
5.2 hours and undergoes oxidation in the liver. Hepatic disease

increases the Vd and reduces clearance. Severe hepatic dysfunction
is a contraindication to its use. Enoximone is of benefit after pedi-
atric cardiac surgery and in infants and children with septic shock
not responsive to beta receptor agonist therapy.56 The loading dose
is 1 mg/kg if given during cardiopulmonary bypass, or otherwise
0.5 mg/kg over 1 hour. The maintenance infusion is 10 μg/kg/min.
The infusion is prepared using enoximone 15 mg/kg in 50 mL
saline or water (do not mix with any other solution and avoid
contact with glass). A rate of 1 mL/h corresponds to 5 μg/kg/min.
Adverse effects include hypotension with high infusion doses
or inadequate volume loading and ventricular arrhythmias.
Thrombocytopenia does not appear to be a problem with its use.
Enoximone is manufactured and dissolved in a propylene glycol
and alcohol vehicle, and hyperosmolality should be checked by
measuring the osmolal gap if treatment continues for 3 days
or more.57
Milrinone
Milrinone has a shorter half-life, is more potent, and is less likely
to cause thrombocytopenia than amrinone. It has a molecular
weight of 211.2 Da and is 70% protein bound. The pharmaco-
kinetics of milrinone have been well studied, albeit with different
modeling techniques in different studies. It has a larger Vd at
steady state and faster clearance in children than in adults. Steady-
state concentrations in children are lower than in adults given
similar doses. Vd is small and stays fairly constant over the pediat-
Figure 35-3. Schematic diagram showing phosphodiesterase ric age range (Table 35–9). However, the clearance in neonates
inhibition preventing the breakdown of cyclic adenosine is lower than infants and children and dosage adjustment is
monophosphate (cAMP) and increasing Ca2+ release from sar- required.58,59 The majority of milrinone (80–85%) is excreted
coplasmic reticulum. AC = adenylyl cyclase; Gs = stimulatory unchanged in the urine during the first 24 hours, making it the
G protein. best PDE inhibitor to use if there is severe hepatic dysfunction.
The loading dose of 50 to 75 μg/kg is given undiluted over 20 to
Amrinone 60 minutes, followed by an infusion at 0.25 to 0.5 μg/kg/min. A
lower bolus and infusion rate has been suggested for preterm
Amrinone was the first available PDE inhibitor and is a bypiridine
neonates.60 It does not bind to bypass circuitry. The prophylactic
derivative with a molecular weight of 187.2 Da. It is metabolized
use of milrinone reduces the incidence of low cardiac output
at a much slower rate in neonates. It has a half-life in adults of
syndrome after cardiac surgery in children from 26 to 12%,61 and
3.6 hours, infants and children 6.8 hours, and neonates 22.2 hours.
it may be of benefit in neonates with pulmonary hypertension not
The Vd in children is 1 to 1.7 L/kg and is larger than in adults. responsive to inhaled nitric oxide.62 The main adverse effects are
Elimination is by glucuronidation and acetylation, although 10 to hypotension, tachyarrhythmias, and thrombocytopenia after 12
40% is excreted unchanged in urine.51 The rate of acetylation is to 24 hours of treatment.59 Also of concern is the reliance on renal
affected by acetylator phenotype. Slow acetylators have about 45% function for its excretion, and the infusion dose should be reduced
the rate of metabolism of fast acetylators. Approximately 20% of in patients with renal failure.
administered amrinone binds to cardiopulmonary bypass tubing.
A total loading dose of 2 to 4.5 mg/kg is divided into two or three
boluses over 3 to 5 minutes, given 10 minutes apart, with close Levosimendan
observation of blood pressure and volume status. The infusion
Levosimendan is a myofilament calcium sensitizer with positive
rate in children is 5 to 10 μg/kg/min, with a maximum dose of
inotropic and vasodilatory properties. Calcium sensitizers increase
10 mg/kg/d. The infusion rate in neonates is lower, at 2.5 to
5 μg/kg/min.52–54 Reversible thrombocytopenia occurs in 2 to 4%
of patients. This is caused by a nonimmune, peripheral destruction TABLE 35-9. Pharmacokinetic Parameters for Milrinone
of platelets, through an unknown mechanism. It is not related to in Different Pediatric Age Groups
dose or duration of treatment and has limited the use of amrinone,
Volume of
increasing interest in other agents.
Distribution, Clearance, Elimination
L/kg mL/kg/min Half-life, h
Enoximone
Preterm neonate 0.6 0.6 10.3
Enoximone is an imidazole derivative with a molecular weight Neonate 0.5 1.6 3.7
248.3 Da. It has pharmacokinetics that are similar in adults and Infant 0.9 3.8 3.2
infants.55 Its Vd in neonates and infants is 3.8 L/kg and clearance Child 0.7 5.9 1.9
is approximately 10 mL/kg/min. It has an elimination half-life of
contractility by increasing the sensitivity of myofilaments to TABLE 35-10. Pharmacokinetics of Levosimendan

calcium. They differ from catecholamines and PDE inhibitors in in Children
that they do not increase calcium concentration in the myofibril.
This difference is of importance. Although increased calcium Age 3–6 Mo >6 Mo Adults
concentration leads to positive inotropy in the short term, it T / elimination
1
2.3 h 1.6 h 1.1–1.4 h
2
appears to be detrimental in the long term, with an increased Vdss 0.43 L/kg 0.35 L/kg 0.33–0.39 L/kg
mortality owing to sudden cardiac death in adults.7 Increased Clearance 3.8 mL/ 3.6 mL/ 3–3.6 mL/
calcium concentration is also the final step in cellular apoptosis min/kg min/kg min/kg
and death. Levosimendan also does not adversely affect the
myocardial oxygen supply-to-demand relationship or predispose Vdss = volume of distribution at steady state.
to arrhythmias.
The mechanism of action of levosimendan within the similar to those of the parent drug. Both of these metabolites have
myofilaments has been described in detail.6 Levosimendan binds long half-lives of around 80 hours in adults, resulting in a pro-
to cardiac troponin C during systole, stabilizing the troponin C- longed therapeutic effect from a 24-hour infusion of levosimen-
Ca2+ complex and prolonging the interaction of actin and myosin dan. The pharmacokinetics of levosimendan have been studied in
filaments (Figure 35–4). The binding of levosimendan to troponin children after a single dose of 12 μg/kg during cardiac catheterisa-
C is dependent on calcium concentration, such that levosimen- tion.64 The pharmacokinetic profile in children is broadly similar
dan releases from the troponin C-Ca2+ complex when the calcium to that in adults, but children aged younger than 6 months have a
concentration falls during diastole. Levosimendan is also a longer elimination half-life than older children (Table 35–10).
potassium channel agonist. Vasodilatation of peripheral, pulmo- Levosimendan produces a dose-dependent increase in heart rate
nary, and coronary vessels occurs via the opening of several and may slightly decrease blood pressure owing to peripheral
types of K+ channels (including voltage-dependent, adenosine vasodilatation. It has a proarrhythmic potential, but this does not
triphosphate [ATP]–sensitive, and Ca2+-activated forms).63 Finally, seem to be a common problem in practice. Early, published experi-
it inhibits PDE III in vitro, but this effect is not clinically ence in children is limited to those with severe heart failure.65 The
significant. use of levosimendan allows for substantial reduction or cessation
Levosimendan is 97% protein bound and has a small Vd. It is of catecholamine infusions. Levosimendan is likely to become
eliminated by metabolism, with a terminal elimination half-life widely used in children after cardiac surgery and in pediatric
after I.V. administration of about 1 hour. Most is conjugated with intensive care. It is an alternative or adjunct to beta1 agonists in
glutathione to inactive metabolites. Approximately 5% is reduced children with heart failure. It may replace catecholamines or allow
by bacteria in the intestinal lumen to produce an inactive a period of treatment without catecholamines to reduce the
intermediate OR 1855. It is absorbed from the intestine and likelihood of desensitization. However, it is difficult to titrate
acetylated to produce the active metabolite OR 1896. The amount against effect, and this limits its role in acutely unstable patients.
of OR 1896 produced depends on the acetylator status of the Dosage is an initial bolus of 6 to 12 μg/kg over 10 minutes, then a
patient, with fast acetylators having higher levels of the active 24-hour infusion at 0.05 to 0.2 μg/kg/min.6,65
metabolite. This active metabolite has hemodynamic properties
SODIUM BICARBONATE
Sodium bicarbonate is the most controversial resuscitation
drug. Arterial, venous, and intracellular hypercapnia and acido-
sis develop rapidly during cardiac arrest. Arterial carbon dioxide
pressure (PaCO2) is corrected, or even overcorrected, because
of effective ventilation in the presence of poor pulmonary blood
flow during cardiac massage. Therefore, arterial blood gases often
show normocapnia, or even hypocapnia. However, the venous and
intracellular blood gases remain hypercapnic and severely acidotic.
Cerebral and myocardial intracellular acidosis occurs rapidly
because of the accumulation of carbon dioxide, as well as the
production of lactic acid and the hydrolysis of ATP from anaerobic
metabolism. During cardiopulmonary resuscitation, the PaCO2 in
myocardial cells is greater than 300 mmHg (40 kPa) and pH is less
than 6.5.66 This severe acidosis impairs myocardial contractility
and automaticity and opposes the effects of catecholamines and
defibrillation. Sodium bicarbonate administration is aimed
at correcting the acidosis during cardiac arrest and improving
the effectiveness of catecholamines and defibrillation. However,
problems exist when large doses are used (Table 35–11), and it
does not improve outcome in adults.
One major concern is that sodium bicarbonate may para-
doxically increase the intracellular PaCO2 by the reaction:
Figure 35-4. Schematic diagram showing intracellular binding
of levosimendan to cardiac troponin C within the myofibril. HCO3⫺⫹H⫹→H2CO3→H2O⫹CO2
TABLE 35-11. Adverse Effects and Problems After the plasma in the management of hyperkalemia, tricyclic over-
Intravenous Sodium Bicarbonate Infusion dose, and pulmonary hypertensive crises. It can also be used for
the treatment of symptomatic hyponatremia. The dose is calcu-
Hypernatremia lated based on the difference between the measured and desired
Hyperosmolarity sodium concentration and the total body water volume. Once the
Extracellular fluid overload sodium concentration is above 120 mmol/L, further correction
Overshoot alkalosis should depend on the cause and whether the hyponatremia is
Hypocalcemia acute or chronic.
Left shift of O2 dissociation curve
Hypokalemia
Venous hypercapnia, paradoxical intracellular acidosis, CSF CALCIUM
acidosis
Calcium is important for excitation, contraction coupling, and AV
Cerebral vasodilation, raised ICP, peri- and intraventricular
node conduction. It increases blood pressure by increasing the
hemorrhage
Hemodynamic changes SVR and improves inotropic function of the heart in the presence
of hypocalcemia. Cardiac output may actually fall when calcium
CSF = cerebrospinal fluid; ICP = intracranial pressure. is given in the presence of normal serum calcium. It is attractive
as a resuscitation agent because many inotropic agents act by
One mmol/kg of sodium bicarbonate forms 22.4 mL/kg of increasing intracellular calcium. However, it is no longer used in
carbon dioxide (compared with the normal production of 4–6 the management of asystole because of lack of evidence to support
mL/kg/min) which must be eliminated.66 The carbon dioxide is its use and concerns about it being part of the pathway leading to
formed within the plasma and quickly enters cells to form H+ ions. apoptosis and cell death.7 Calcium has a plasma concentration of
The resultant intracellular acidosis is one of the main arguments 2.1 to 2.6 mmol/L and is bound to albumin (45%) and complexed
against the use of sodium bicarbonate, but its severity and duration to citrate and phosphate (10%). The normal total calcium level is
are disputed.67,68 lower in neonates because of low albumin concentrations. The
Sodium bicarbonate is not recommended in adult cardiac remaining ionized calcium is physiologically active and has a
arrest. However, there are several differences between adult and normal range of 1.12 to 1.32 mmol/L. Calcium concentrations are
pediatric cardiac arrest. First, children are often hypoxic and increased with acidosis and decreased with infused albumin and
acidotic before arresting. Second, cardiac massage in children blood. Calcium chloride is commonly used in children for the
results in better pulmonary blood flow than in adults, and lastly, correction of hypocalcemia and may have greater bioavailability
there is no evidence that sodium bicarbonate use worsens outcome than calcium gluconate.73 Calcium can cause skin and muscle
in children. For these reasons, sodium bicarbonate is often used necrosis if it extravasates, but necrosis can also occur if there has
in prolonged pediatric cardiac arrest.69 However, the evidence been no extravasation.74 The risk of tissue injury can be reduced
supporting its use in children and neonates is not strong,70,71 and by central venous administration, perhaps by diluting before
it should be used only after effective ventilation epinephrine has administration and using calcium gluconate rather than chloride.
failed to restore spontaneous circulation. The dose is 1 mmol/kg The doses of calcium are shown in Table 35–12, and adminis-
(the 8.4% solution is 1 mmol/mL), repeated after 10 minutes. This tration must be slow to prevent bradycardia and peripheral vaso-
hyperosmolar solution should be given slowly in premature dilatation.75
neonates to reduce the risk of intracranial hemorrhage.
Sodium bicarbonate is also used for the treatment of metabolic
acidosis and low plasma bicarbonate concentration occurring in MAGNESIUM SULFATE
shock and severe diarrheal or biliary bicarbonate loss. Although Magnesium is the second most plentiful intracellular cation after
the kidneys can contribute to the replacement of bicarbonate, this potassium, with less than 1% of the total body store found in the
may take several days. Exogenous alkali is therefore often used to serum.76 The ionized fraction is physiologically active and is
rapidly correct severe acidosis (pH < 7.1 or base deficits > 10), important in a host of vital enzymatic reactions, neuromuscular
even if the cause of the acidosis can be reversed.72 The dose should function, and conformation of macromolecules such as DNA. A
be modest, given slowly, and guided by arterial blood gas values low serum level of magnesium is common in seriously ill children,
before and after use. The dose can be an empirical 1 mmol/kg, or but it is not known whether it results in any consequences or is
according to the “half-correction” formula: instead a reflection of the children’s physiologically stressed state.77
Number of mmol required = Furthermore, low serum magnesium may not indicate total body
[body weight (kg) × 0.3 × base deficit]/2.
TABLE 35-12. Calcium Chloride and Gluconate Contain
Infants less than 5 kg have a larger extracellular fluid volume,
Different Amounts of Elemental Calcium and Require
and the correction constant of 0.5 rather than 0.3 is used in the
Different Doses
formula. A continuous infusion may be necessary if bolus therapy
is not effective. Total doses approaching or exceeding 10 mmol/kg Calcium Chloride 10% Calcium Gluconate 10%
should be considered very large and adverse effects such as those
Elemental 27.2 mg/mL (0.7 9.0 mg/mL (0.22
in Table 35–11 watched for carefully.
calcium mmol/mL) mmol/mL)
Although sodium bicarbonate has a limited and unproven
Dose 0.1–0.2 mL/kg 0.2–0.5 mL/kg
place in the management of cardiac arrest, it has several other
(maximum 10 mL) (maximum 20 mL)
more defined uses. Sodium bicarbonate can be given to alkalinize
depletion, because several agents, including epinephrine infusions, dose is 100 μg/kg in children and 150 to -200 μg/kg in infants,
promote intracellular shift. Alkalosis and hypoalbuminemia followed by 200 to 300 μg/kg if not successful. All doses should be
reduce the measured level of magnesium. If magnesium is low, halved if given into a central vein. The maximum single dose is
Na+/K+-ATPase activity is reduced and there is loss of potassium 500 μg/kg or 6 mg in children and 300 μg/kg in neonates, though
from the intracellular space with subsequent renal potassium loss. this dose can be repeated if required.83,84 Major side effects are
Replacement with potassium will be ineffective until magnesium uncommon and short-lived. They include transient hypoten-
is replenished. Magnesium should be given for hypomagnesemia sion and bradycardia and brief asystole. Awake patients report
and torsades de pointes VT, but there is insufficient evidence to dyspnea, chest pain, and nausea as well as facial flushing. Adeno-
recommend for or against its routine use in cardiac arrest.17 sine may result in a brief sympathetic rebound that can accelerate
Magnesium acts as a bronchodilator by inhibiting the release of a tachyarrhythmia that is not converted. Another problem is the
calcium from the sarcoplasmic reticulum. There is good evidence re-initiation of SVT soon after reversion to sinus rhythm. Bron-
that I.V. magnesium is of benefit in children with acute severe chospasm outlasting the adenosine can also sometimes occur in
asthma who have not responded to albuterol (salbutamol) and patients with or without pre-existing asthma.
anticholinergic agents.78,79 The dose is 25 to 75 mg/kg (maxi-
mum 2 g; 0.1–0.3 mmol/kg), given over 20 minutes. Nebulized Toxicity and Precautions
magnesium (2.5 mL of 6.3% solution) has the advantage of faster
administration but appears to have no benefit over nebulized The dose should be halved in patients taking dipyridamole (which
albuterol. inhibits the uptake of adenosine into red blood cells) and doubled
Magnesium sulfate 1 g is equivalent to 4 mmol, 8 mEq, or if taking theophylline (which is a competitive inhibitor of the
98 mg of elemental magnesium. Hypotension, bradycardia, or A1 adenosine receptor). It should be used cautiously, if at all, in
asystole may occur if it is administered too quickly. Plasma levels patients with asthma.
over 2.5 mmol/L or loss of deep tendon reflexes is an indication
to stop magnesium therapy. Patients with renal disease are at Esmolol
particular risk of hypermagnesemia during therapy.
Esmolol is an ultrashort-acting β1 adrenergic blocker administered
intravenously for the acute control of narrow-complex tachy-
ANTIARRHYTHMIC DRUGS cardia, for the treatment and prevention of hypercyanotic spells
in children with tetralogy of Fallot, and for the treatment of
Antiarrhythmic drugs are relatively toxic and can either cause new
hypertension during and after various types of surgery.85,86 It is
arrhythmias or worsen existing arrhythmias (proarrhythmia). For
broken down by esterases in red blood cells, which are not blocked
this reason, it is always important to be confident that the arrhyth-
by cholinesterase inhibitors such as neostigmine. As with other
mia present actually needs treatment. It should be a potentially
β blockers, esmolol exerts most of its antiarrhythmic activity by
life-threatening arrhythmia, associated with hemodynamic insta-
delaying conduction through the AV node.
bility or disabling symptoms.
Esmolol has a very short half-life that permits titration of
β blockade in acute situations and also limits the duration of any
Adenosine adverse effects. Distribution and terminal elimination half-lives
are 1 to 2 and 9 minutes, respectively. Its Vd is less in children
Adenosine is a purine nucleoside that is used as first-line (2 L/kg) than in adults (3.5 L/kg).86,87 Onset of activity is within
treatment of supraventricular tachycardia (SVT) in children and 2 minutes, with 90% of steady-state β blockade reached within
adults.80–82 Adenosine is an endogenous molecule that acts by 5 minutes. There is full recovery from β blockade within 18 to
binding to specific adenosine receptors in the atrium, sinus node, 30 minutes after stopping the infusion. Therapy is started with a
and AV node. Receptor binding initiates an intracellular cascade loading dose of 500 μg/kg over 1 minute, followed by an infusion
involving G proteins and slows the sinus rate and AV conduction of 25 to 100 μg/kg/min. If this is not successful, the 500-μg/kg
velocity. This slowing of conduction velocity is only transient but bolus can be repeated and the infusion increased until a maximum
terminates the re-entry wave responsible for SVT. rate of 200 μg/kg/min is reached. Doses higher than this are
unlikely to be effective.
Pharmacokinetics
Adenosine has a serum half-life of less than 10 seconds owing to Amiodarone
its rapid uptake by red blood cells and the endothelial system. It is
totally cleared from the plasma in less than 30 seconds but has a Amiodarone is an iodine derivative of benzofurane (molecular
duration of action of 1 to 2 minutes. weight 681.8 Da) that is effective for serious ventricular and
supraventricular arrhythmias.88,89 Although it has many side
effects, particularly with chronic administration, amiodarone has
Therapeutic Use the advantage of a low negative inotropic effect. It causes diffuse
Adenosine is the drug of choice for SVT because of its rapid effect, slowing of conduction through complex electrophysiologic
successful conversion to sinus rhythm in greater than 75% of effects. I.V. amiodarone causes β blockade and slows conduction
patients, and relative lack of adverse effects. It can also be used to through the AV node. Sodium or potassium channel blockade
help differentiate between the ventricular and the supraventricular is also partly responsible for the antiarrhythmic effects after
causes of broad-complex tachycardia. It is not effective in the chronic oral administration, and possibly after I.V. administration.
treatment of VT, atrial flutter, or fibrillation. A rapid bolus is given Amiodarone is extremely lipophilic, with a Vd greater than 60 to
through a large vein, or preferably, a central venous line. The initial 100 L/kg in adults. After a single I.V. dose, the plasma level falls
over 4 hours owing to redistribution. Its elimination half-life is VASODILATORS

long and variable at 1 to 2 weeks90 and is dependent on the dura-
tion of therapy. Therapeutic plasma levels range from 1 to 2.5 μg/ Vasodilators are nonselective and act on the systemic and
mL. Although rate slowing may occur sooner, reversion of arrhy- pulmonary circulations. When given systemically, oxygenation
thmias often takes many hours. Amiodarone undergoes hepatic may deteriorate because of an increase in blood flow to poorly
metabolism to an active metabolite, but this does not accumulate ventilated lung units and worsening of intrapulmonary shunt.
sufficiently after I.V. amiodarone to have a significant effect. When given as pulmonary vasodilators, systemic hypotension and
The main role of amiodarone as a resuscitation agent is for the hemodynamic instability may result. Inhaled nitric oxide and
treatment of shock-refractory or recurrent VT or ventricular inhaled or parenteral prostaglandins are increasingly used when
fibrillation (VF), in which it can be used as an alternative to pulmonary vasodilatation is required.
lidocaine. Evidence extrapolated from studies in adults17,91 and
children92 shows increased survival to hospital admission (but
not discharge) when amiodarone is compared with placebo or
Sodium Nitroprusside
lidocaine for shock-resistant VF. It can also be used for the Sodium nitroprusside is a potent vasodilator that acts on venous
treatment of SVT as a second-line agent after adenosine. In acute and arterial vessels.94 It is converted by glutathione and other
situations, a loading dose of 5 mg/kg is given rapidly intravenously reducing agents in smooth muscle cells to its active metabolite
or intraosseously in cardiac arrest or over 20 to 60 minutes in nitric oxide. Nitroprusside is easily titratable because it has
perfusing tachycardias. Transient hypotension during the load- immediate onset, a short half-life, and effects that disappear 2 to
ing dose is the most frequent adverse event reported with I.V. 4 minutes after it is stopped. Cardiac output is either unchanged
amiodarone and can be treated with fluid infusion. Hypotension or increased if preload is adequate. The initial infusion dose is
is not as common in children as in adults. It has been attributed to 0.3 to 0.5 μg/kg/min, and it is usually effective at doses under
the vasoactive solvents of the standard formulation and is not 3 μg/kg/min. Doses greater than this should be used only briefly
dose-related but is related to the rate of infusion. A new aqueous and not exceed 10 μg/kg/min. Concurrent therapy with esmolol
formulation does not contain vasoactive excipients and may 200 to 400 μg/kg/min reduces the nitroprusside requirement and
be administered safely by rapid administration without hypo- prevents a reflex increase in plasma catecholamines and renin,
tension. A continuous infusion of 5 to 15 μg/kg/min is given after which work against achieving a stable, lower blood pressure.95
the loading dose. Amiodarone should not be used with procai- Other agents should be considered if the infusion is not rapidly
namide or lidocaine because all of these agents can prolong the effective or if tachyphylaxis occurs. Nitroprusside is best diluted
QT interval. Caution is needed in patients receiving β blockers
with dextrose and should be protected from light during infusion.
and calcium channel blockers, because amiodarone causes
Cyanide and thiocyanate toxicity are particularly likely in patients
additive suppression of the sinus and AV nodes. I.V. amiodarone
with hepatic compromise, renal failure, or poor nutritional state.
causes peripheral vasodilatation, sinus bradycardia, and negative
Rebound hypertension and dose-dependent alterations in platelet
inotropy from noncompetitive blockade of α and β adrenergic
receptors. It may also cause AV block and ventricular arrhy- aggregation are other problems with its use.
thmias. Pulmonary toxicity has occurred after only a few days of
treatment, and care should be taken if there is serious pre-existing Nitroglycerin
pulmonary disease. There is minimal antithyroid action after
I.V. amiodarone. Nitroglycerin (molecular weight 227.1 Da) is predominantly
a venodilator but also acts on arterial vessels at doses used
to induce hypotension. It is thought to act by generating nitric
Lidocaine oxide but may work by stimulating soluble guanylate cyclase
Lidocaine is a sodium channel blocking agent useful for the and forming cyclic guanosine monophosphate (cGMP).96 Nitro-
treatment of serious ventricular arrhythmias. It decreases glycerin is broken down in the liver, with a half-life of 2 to
automaticity, increases the VF threshold, and exhibits only weak 3 minutes. Polyethylene-lined (not polyvinylchloride) syringes
myocardial depressant and proarrhythmic properties. However, and tubing should be used. The initial dose is 0.5 to -1 μg/kg/
lidocaine increases the defibrillation threshold and increases the min, increased as necessary by the same amount every few
energy required for defibrillation during acidosis. It may be minutes to a maximum of 10 μg/kg/min. It has a slower, less
effective more by preventing the immediate recurrence of VF than abrupt onset than nitroprusside, and tolerance to its effects
by facilitating defibrillation.18,93 There is little evidence to show develops within 24 hours.
that it promotes the conversion of VT or VF to sinus rhythm in
any setting, and amiodarone has replaced it in adult cardiac arrest
protocols.91
Hydralazine
Lidocaine redistributes rapidly after I.V. administration and is Hydralazine (molecular weight 196.6 Da) has a modest
extensively metabolized in the liver. Neonates have an increased Vd antihypertensive effect if used alone because of reflex tachycardia,
(2.8 L/kg, adult 1.1 L/kg), and longer elimination half-life (3.2 h, increased stroke volume, and fluid retention. Metabolism after I.V.
adult 1.8 h). Clearance is similar in both age groups. The dose of administration is by various hepatic pathways, resulting in a half-
lidocaine is 1 to 2 mg/kg followed by an infusion of 10 to 50 life of 1 hour, which is not affected by fast or slow acetylator status,
μg/kg/min. The therapeutic plasma level is 2 to 6 μg/mLl. Adverse as is the case with chronic oral use. The I.V. dose is a bolus of 0.1
effects include conduction abnormalities and central nervous to 0.2 mg/kg (maximum 10 mg), repeated after 20 minutes if
system effects of drowsiness, disorientation, tinnitus, twitching, required. Onset is 5 to 20 minutes, and duration of action is up to
and seizures. 5 hours.
VASOCONSTRICTORS adults with septic shock treated with low-dose vasopressin or low-
dose norepinephrine.106
Vasopressin and Terlipressin
Vasopressin (arginine vasopressin, antidiuretic hormone) is a Phenylephrine
nonopeptide released from the posterior pituitary gland in
response to increased osmolarity and hypovolemia.97–99 During Phenylephrine is a sympathomimetic thath acts selectively on
resuscitation, it is given as a vasoconstrictor. Desmopressin alpha1 receptors in the systemic and pulmonary circulations. It
(DDAVP) is a synthetic analogue of vasopressin that has anti- causes vasoconstriction, increased SVR and blood pressure, and
diuretic activity but minimal pressor effect. It is used to treat reflex slowing of the heart rate. Pulmonary vascular resistance also
diabetes insipidus and to increase Factor VIIIc activity and increases, but to a lesser extent than in the systemic circulation.
the level of von Willebrand factor. Terlipressin (triglycyl-lysine Because it is not a catecholamine, phenylephrine is not broken
vasopressin) is a prodrug that is converted to lysine vasopressin down by COMT and has a long half-life of 2.5 hours. It is used to
in the circulation. It has a similar pharmacodynamic profile but a treat hypotension, to increase SVR, and to reduce intracardiac
significantly longer half-life than vasopressin. shunting (e.g., during hypercyanotic spells in tetralogy of Fallot).
Vasopressin acts via a receptor with three subtypes, each A bolus dose of 40 to 100 μg/kg lasts 5 to 10 minutes and can be
coupled to a G protein. V1 receptors are vascular and result in followed by an infusion of 2 to 5 g/kg/min. Pulmonary edema is
vasoconstriction through a mechanism involving Gq, phospho- reported after phenylephrine ocular drops in children.
lipase C, and increased intracellular calcium. V2 receptors are
renal and mediate an antidiuretic effect and also mediate release
of von Willebrand factor from vascular endothelium. V3 receptors
Metaraminol
are responsible for the actions of vasopressin on the central nerv- Metaraminol has a direct action on α and β adrenoreceptors
ous system. Under physiologic conditions, the role of vasopressin (predominately the former) and also enters nerve terminals where
is the regulation of water balance, with normal concentrations less it displaces norepinephrine. It can eventually act as a false neu-
than 4 pg/mL. Vasopressin does not increase blood pressure in rotransmitter. A dose of 10 μg/kg has a duration of 20 minutes.
health but does in septic shock both through direct vasoconstric-
tion and by restoring vascular sensitivity to catecholamines.
Exogenously administered vasopressin is not protein-bound and, BRONCHODILATORS
in adults, has a Vd of 140 mL/kg. It undergoes renal elimination Inhaler Devices
(65%) and metabolism by peptidases (35%), with a half-life of
24 minutes. Terlipressin has an elimination half-life of 50 minutes β Adrenergic agonists are administered as an aerosol, formed by
and effect half-life of 6 hours in adults. either a small-volume nebulizer or a metered-dose inhaler (MDI).
Vasopressin plasma concentrations increase 10-fold in shock Particles sized 1 to -5 μm reach the smooth muscle of the distal
states but fall back toward normal after 24 hours in hemorrhagic bronchi, particles 5 to 10 μm only reach the first six generations of
and septic shock. Septic shock is associated with vasopressin airway, and particles 10 to 15 μm deposit in the mouth. In small-
deficiency but markedly increased sensitivity to low doses of exog- dose nebulizers, a jet of oxygen at 6 to 8 L/min creates a Bernoulli
enous vasopressin. In patients who have catcholamine-resistant effect and pulls medication from the reservoir and a baffle in front
septic shock, rescue treatment with vasopressin may reduce of the jet stream removes larger particles.107,108 The medication
catecholamine requirements and increase blood pressure.100 It is diluted with saline to 3 to 4 mL and administration takes 10 to
may also have a role in the treatment of shock owing to vaso- 15 minutes. Children older than 6 months have a peak inspiratory
dilatation after cardiopulmonary bypass.97,101 Vasopressin is attrac- flow higher than 6 L/min and entrain room air that dilutes the
tive as a vasoconstrictor in cardiac arrest because it increases nebulized agent during inspiration. The dose inhaled by these
cerebral and myocardial blood flow more than epinephrine and older children is independent of body size, and the dose inhaled
has a longer half-life. Studies in adults have shown inconsistent per kilogram of body weight gradually reduces as they grow.
efficacy,102 and a series of pediatric cases has been reported.103 Children younger than 6 months have low peak inspiratory flows
However, it neither improves nor worsens survival from cardiac and inhale more concentrated nebulized agent (Figure 35–5).
arrest and is currently suggested as a second-line agent after They receive a much larger dose than adults when compared as
epinephrine has failed.17 Terlipressin has also been studied as an dose per kilogram. However, they automatically adjust the size of
adjunct to epinephrine in prolonged pediatric resuscitation, but their own doses because smaller infants have smaller tidal volumes
its role is not yet clear.104 than larger infants.109 Only 9 to 12% of the total nebulized dose
The adverse effects of vasopressin mostly relate to ischemia, reaches the patient and much less reaches the bronchi. During
although most reports are from patients who were also at risk of endotracheal intubation and positive-pressure ventilation,
ischemia from their illness. Intestinal and peripheral limb most of the dose nebulized into the circuit is deposited in the
ischemia have been reported, and skin necrosis occurs both with endotracheal tube, and only 2 to 3% reaches the lung. MDIs give
and without extravasation.105 The dose of vasopressin in cardiac particles mostly 2 to 5 μm in diameter. They are very effective
arrest in adults is most commonly 40 U and 0.5 to 0.8 U/kg in when used with a spacer or other valved holding chamber devices
children. The dose in septic shock ranges from 0.001 to 0.1 that hold the particles for up to 20 secound and allow inhalation
U/kg/h, perhaps with 0.01 to 0.04 U/kg/h being more common. over several breaths.110 Only 6 to 9% of the dose enters the lung.
Titration to achieve a blood pressure may increase coronary, MDIs have five to seven times the potency of nebulizers, so that
mesenteric, and skin ischemia compared with use of a low, 4 puffs of albuterol (0.36 mg) via a large-volume spacer is equiv-
constant infusion.98 There is no difference in 28-day mortality in alent to 2.5 mg nebulized. MDIs can also be used in intubated
Figure 35-5. Effect of air entrainment on inhaled dose from nebuliser. Children, but not infants, entrain air during inspiration
while receiving nebulized drugs. Inspiratory flow exceeds nebulizer flow in children, and room air is entrained. In infants, inspira-
tory flow does not exceed nebulizer flow, and a smaller mass of undiluted drug is inhaled. Modified from reference 109.
patients, with about 2% of the dose entering the lungs.111 They after 30 minutes, and last 2 to 5 hours. Its Vd is 156 L, and its renal
should be connected to the inspiratory limb of the circuit and clearance is 290 mL/min. It undergoes extensive metabolism in
actuated at the onset of inspiration. Humidification should the liver and is also excreted unchanged in the urine, with an
be stopped for a few minutes beforehand. MDIs are increasingly elimination half-life of 2.7 to 5 hours.115
used instead of nebulizers in patients with severe asthma, though In acute severe asthma, larger and more frequent doses of beta
they have yet to be evaluated in patients requiring intensive care agonist are required because the bioavailability and duration of
therapy for their asthma. action are markedly affected by the degree of bronchoconstric-
tion. Undertreatment with beta agonists is a bigger problem
than catecholamine toxicity. Younger children and infants need
β Adrenergic Agonists larger doses than older children.116 In severe asthma, albuterol is
β Adrenergic agonists have a rapid onset and large therapeutic- nebulized undiluted (5 mg/mLl) at frequent intervals with cardiac
to-toxic ratio, and their inhalation is the preferred treatment for monitoring in intensive care. Continuously nebulized albuterol
bronchoconstriction. They cause bronchodilatation by stimulation can be used as an alternative to nebulizer doses more frequent
of beta2 receptors on the smooth muscle membrane of bronchi, than every half hour.117 Albuterol 6 mg/kg is added to a 500-mL
inhibit mast cell degranulation, reduce mucous gland secretion, bag of normal saline and pumped into the nebulizer chamber at
increase mucociliary clearance, and improve intrinsic respiratory 20 mL/h. This gives a dose of 4 μg/kg/min and is equivalent to a
muscle contractility.112 Beta2 agonists have been characterized as half-hourly nebulized dose. I.V. albuterol can be used if there is a
those that directly activate the receptor (albuterol), those that are poor response to high-dose nebulized beta2 agonist, or if it is
taken up into a membrane depot (formoterol), and those that thought that the drug is not reaching the lower airway because of
severe bronchospasm or mucous plugging. The dose is a 5-μg/kg
interact with a receptor-specific auxiliary binding site (salmeterol).
bolus over 10 minutes, then an infusion at 1 to 5 μg/kg/min.
These differences in mechanism of action are reflected in the
A single I.V. bolus of 15 μg/kg of albuterol improved the subse-
kinetics of airway smooth muscle relaxation and bronchodi-
quent treatment of children with asthma in the emergency
latation in patients with asthma.113 The response to albuterol is
department.118 The dose of both inhaled and I.V. albuterol is
affected by genetic polymorphisms in the gene for the beta
frequently limited by tachycardia and tremor and occasionally
adrenoceptor, notably the presence of arginine residues at the 16th
by tachyarrythmia. Beta2 agonists can also cause hypokalemia
position of the receptor (Arg/Arg).114 Approximately 16% of the
through intracellular shifts.
population has the Arg/Arg genotype and has diminished asthma
control with regular albuterol.
Anticholinergics
Albuterol (Salbutamol) Ipratoprium is a quaternary anticholinergic that is nebulized and
Albuterol (molecular weight 239 Da) is the most widely used beta2 acts on more proximal airways than beta agonists. It has a slower
agonist in children. Its effects begin within 5 to 15 minutes, peak onset but longer duration of action. It is less effective alone than
TABLE 35-13. Plasma Elimination Half-lives for are 55 to 110 μmol/L (10–20 mg/L) when used as a bronchodilator.
Theophylline During Growth A bolus dose of aminophylline 1 mg/kg increases the plasma
theophylline concentration by 10 μmol/L (2 mg/L). If the plasma
Premature
level is measured 20 minutes after the loading dose and 4 to
Age Neonate Neonate 1 Mo–1 Y 1–15 Y Adult
6 hours into the maintenance infusion, it can be used to assess
Elimination 14–58 20–35 5.6 1.4–8 3.5–8 clearance and adjust the infusion rate.124 Adverse effects such as
half-life, h nausea and vomiting, restlessness, and tachycardia frequently
restrict the use of aminophylline in the treatment of acute severe
Based on data from reference 122.
asthma.
albuterol, but albuterol given with ipratoprium is more effective
than albuterol alone.119 However, it is not known whether there is CORTICOSTEROIDS
any benefit to continuing the combination of ipratoprium and
albuterol beyond the first few nebulizations. The dose is 0.5 mg All corticosteroids are chemical modifications of natural
every 4 to 6 hours. Nebulized atropine causes many systemic side glucocorticoids and are used for their glucocorticoid (anti-
effects and is not recommended. inflammatory) and mineralocorticoid (salt-retaining) properties.
They have direct effects on metabolic and other functions of tissues
and also facilitate the actions of other hormones.125,126 Steroids
Aminophylline and Theophylline increase vascular reactivity to catecholamines and other vasoac-
tive substances, probably by increased expression of adrenergic
Aminophylline is the soluble salt of theophylline with ethylene- receptors in the vascular wall. They also inhibit non-neuronal
diamine. Aminophylline 100 mg is approximately equivalent
norepinephrine reuptake. Cortisol is the naturally occurring,
to 80 mg of theophylline. Aminophylline is given intravenously
endogenous glucocorticoid, and hydrocortisone sodium suc-
as a bronchodilator and to prevent apnea in preterm infants.
cinate is the pharmaceutical preparation of cortisol. Cortisol
Theophylline is a methylxanthine that relaxes bronchial smooth
binds to intracellular glucocorticoid receptors, which then enter
muscle; increases myocardial and skeletal muscle (particularly
the cell nucleus and affects gene expression and protein synthe-
diaphragmatic) contractility, heart rate, and urine output; and
sis. Although most of its effects are slow in onset (several hours),
stimulates the central nervous system. It is a nonspecific PDE in-
there may also be some immediate effects via membrane-bound
hibitor and an adenosine antagonist. It also has anti-inflammatory
glucocorticoid receptors. Cortisol circulates in free, active form
actions.120 Theophylline is 60% protein-bound and has a Vd of
(~5%) and a protein-bound form (predominantly to cortisol-
0.4 to 0.6 L/kg. Neonates have less protein binding and a higher Vd
binding globulin). Apart from dexamethasone, synthetic glucoco-
than older children and adults. The metabolism of theophylline
rticoids also bind to cortisol-binding globulin. All are metabolized
varies with age. Hepatic demethylation in term neonates is
in the liver.
poor but increases markedly during the first year of life. It then
gradually decreases again to reach adult levels around 16 years of
age. In preterm neonates, about 50% of theophylline is excreted Therapeutic Use
unchanged in the urine, but a significant amount is converted
to caffeine. These changes in metabolism are reflected in the The dosage and effects of the three commonly used I.V. steroids
changing clearance and half-life during growth (Table 35–13). are given in Table 35–14. Hydrocortisone is used for replacement
When plasma concentrations are in the therapeutic range, therapy in patients with adrenal insufficiency, but its high
theophylline metabolism is first order. In patients who have theo- mineralocorticoid activity limits its role in anti-inflammatory
phylline overdose, metabolism is zero order because metabolic therapy. The physiologic replacement dose is 0.2 mg/kg every
pathways become saturated. In this situation, the plasma con- 8 hours intravenously. Corticosteroids have been studied in
centration falls linearly with time, and reduction to nontoxic patients with septic shock, because this condition is often com-
concentrations is slowed. The concentration at which pathways plicated by adrenal insufficiency and steroids improve vascular
become saturated is lower in children (~32 mg/L) than in adults reactivity. It seems likely that children also have this state of
(67 mg/L).121 relative adrenal insufficiency during septic shock.127 A meta-
I.V. aminophylline continues to have a place in the manage- analysis suggests that low-dose corticosteroids for 5 to 11 days
ment of acute severe asthma in children when inhaled β adren- reduces mortality in adults with septic shock.128
ergic agonists are not effective alone.123 The loading dose is Methylprednisolone has an intermediate duration of action,
9 mg/kg (maximum 500 mg) over 1 hour, then a maintenance high anti-inflammatory activity, and relatively low mineralocor-
dose in children 1 to 9 years of 1.1 mg/kg/min and 0.7 mg/kg/min ticoid activity and is used for the treatment of conditions requiring
in children older than 9 years. Therapeutic plasma concentrations some mineralocorticoid activity in addition to anti-inflammatory
TABLE 35-14. Relative Potencies and Effects of Parenteral Corticosteroids

Anti-inflammatory Salt-Retaining Plasma Duration Equivalent
Agent Potency Potency Half-life, h of Action Dose, mg
Hydrocortisone 1 1 1.5 Short 20
Methylprednisolone 5 0.5 2.3 Intermediate 4
Dexamethasone 25 0 3 Long 0.75
effects, such as severe asthma. The I.V. dose is 0.5 to 1 mg/kg loop of Henle, increasing sodium, potassium, and calcium in the
(maximum 120 mg) every 6 hours. Methylprednisolone (I.V. tubular fluid. This nephron site normally reabsorbs approximately
bolus of 30 mg/kg followed by 5.4 mg/kg/h for 23 h) may improve 20% of filtered sodium, but furosemide can cause excretion of up
neurologic outcome when given in the first 8 hours after spinal to 20%. However, the effectiveness of furosemide depends on the
cord injury. Although still commonly used in this setting, its amount of sodium being filtered, and if this is reduced because
benefit is at best modest, and its role is being increasingly ques- of disease, effectiveness is reduced. I.V. furosemide takes 5 to
tioned. The treatment carries risks including infection, myopathy, 10 minutes to work and lasts 2 hours. Plasma half-life is 28.6 hours
avascular necrosis, and death.129 in preterm neonates, 8.6 hours in neonates, and only 0.7 to
Dexamethasone has minimal mineralocorticoid activity, 1.5 hours in adults.133 The I.V. dose is 0.5 to 1 mg/kg every 6 to
high anti-inflammatory action, and a long duration of action. 12 hours (daily in preterm neonates). An infusion of 0.1 to 1 mg/
It is best when maximum anti-inflammatory activity alone kg/h can be used to reduce fluctuations in diuresis that occurs with
is needed, such as in edema associated with upper airway pro- bolus dosing. Most adverse effects relate to abnormalities of fluid
blems and brain tumors. The I.V. dose is 0.1 to 0.25 mg/kg every and electrolyte balance, although ototoxicity can occur with rapid
6 hours and 0.6 mg/kg (maximum 12 mg) as a stat dose for upper I.V. administration.
airway edema.
ANTICONVULSANTS
Toxicity and Precautions
Generalized tonic-clonic status epilepticus is a medical emergency
Short-term I.V. use of steroids is generally safe, although problems that carries a significant risk of mortality and permanent brain
have been reported. Hyperglycemia and hypokalemia are com- damage.134 Although status epilepticus is defined as generalized
mon. Therapy for approximately 2 weeks or more will result in the convulsions lasting 30 minutes or more, tonic-clonic contractions
many metabolic problems associated with chronic steroid use. persisting beyond 4 or 5 minutes may not stop spontaneously and
can become prolonged. The longer the duration of the seizure, the
more difficult it is to terminate.135 Benzodiazepines, phenytoin,
DIURETICS and phenobarbital are the three main drugs for initial seizure
Mannitol control, though there is little published comparison of them
(Table 35–15).
Mannitol is an osmotic diuretic commonly used to reduce
intracranial pressure and to prevent or treat acute renal failure. It
most likely reduces intracranial pressure by increasing plasma Benzodiazepines
osmolarity and drawing water from the brain. However, it is
The benzodiazepines act on gamma-aminobutyric acid
difficult to demonstrate that clinically effective doses alter the
A (GABAA) receptors to potentiate synaptic inhibition136 and are
water content of the brain, and other, less plausible mechanisms of
very commonly used because of their rapid onset and wide safety
action have also been proposed. Although a damaged blood-brain
margin. The onset of action after I.V. administration is less than
barrier reduces the effective tonicity of mannitol, it also increases
the hydraulic conductance of the blood-brain barrier, which 3 minutes, but the duration of action is also short because of
enhances removal of water from the brain. Therefore, it is difficult redistribution from the brain, particularly after diazepam.
to predict the net effectiveness of mannitol when the blood-brain Although lorazepam is more lipid-soluble than diazepam and
barrier is damaged.130 enters the brain more slowly, its onset time is similar to that
Mannitol is not metabolized by the body but is filtered at the of diazepam. Lorazepam is long-acting and is usually effective for
glomerulus; there is no tubular reabsorption. It is eliminated in 12 to 24 hours. It may cause less respiratory depression than
the urine with a half-life of 0.25 to 1.7 hours in adults and 4 hours diazepam. Respiratory depression occurs particularly with clona-
in children with raised intracranial pressure.131 Renal failure zepam, or if other central nervous system depressant drugs
greatly prolongs the half-life. The dose is 0.25 to 1 g/kg, which are used. Benzodiazepines are often used as a first step to stop
reduces intracranial pressure within minutes, and has a maximal
effect after 20 to 40 minutes. Doses of 1.4 g/kg have been reported, TABLE 35-15. Antiepileptic Treatment of Status Epilepticus
but the dose-response relationship for mannitol and intracranial
pressure is not known.132 Mannitol induces a urine volume five Initial treatment Lorazepam 0.1 mg/kg or diazepam
times greater than its own volume. It also reduces blood viscosity 0.2–0.4 mg/kg
by reducing hematocrit and altering red blood cell membrane Then if seizures persist Repeat lorazepam or diazepam
properties and acts as a scavenger of oxygen free radicals. Side after 10 min
effects include hypotension secondary to peripheral vasodilatation Then if seizures persist Phenytoin 18 mg/kg (or pheno-
and release of histamine from pulmonary basophils if adminis- after 10 more min barbitone 20 mg/kg if already on
tered too quickly, rebound increases in intracranial pressure after phenytoin) and rectal paral-
prolonged therapy, and dilutional hyponatremia in acute renal dehyde 0.4 mL/kg with olive oil
failure owing to accumulation. Then if seizures persist Thiopentone 4 mg/kg with rapid-
after 20 more min sequence induction of
anesthesia and intubation
Furosemide If no IV access Buccal midazolam 0.5 mg/kg or
Furosemide (molecular weight 330.8 Da) is secreted into the rectal diazepam 0.5 mg/kg
tubular fluid and blocks chloride transport in the thick ascending Based on references 134 and 137.
seizures, followed by a loading dose of phenytoin. The I.V. doses and arrhythmias. If seizures persist 20 to 30 minutes after this
are given in Table 35–15. Repeat doses can be given after several dose, another 3- to 5-mg/kg dose can be given once or twice at
minutes, although subsequent doses are less effective and recovery 20-minute intervals. Doses greater than 20 mg/kg in neonates
is delayed because of accumulation of the drug or its metabolites. may necessitate mechanical ventilation. Maintenance doses
Diazepam can be given rectally (0.5 mg/kg diluted with saline), are started after 12 to 24 hours, and the therapeutic range is 60 to
although midazolam 0.5 mg/kg given bucally between the 120 μmol/L (15–30 mg/L)
gum and the cheeks may be more effective.137,138 Lorazepam and
midazolam can be given intramuscularly.
Paraldehyde
Paraldehyde is a second-line anticonvulsant, used when the other
Phenytoin and Fosphenytoin three drugs have failed to stop seizures. It is only given rectally
Phenytoin prolongs the inactivation of sodium channels, reducing and in a dose of 0.4 mL/kg of the 5% solution, mixed with an equal
the ability of neurones to fire at high frequencies. It is effective volume of olive oil. Onset is 10 to 20 minutes, and the dose can
against most forms of seizures and does not depress respiration or be repeated after 2 to 4 hours, a maximum of four to six times in
conscious state. However, phenytoin has limited aqueous solubility 24 hours. It should not be left in plastic syringes for longer than a
and contains propylene glycol, which contributes to infusion site few minutes.
reactions, hypotension and arrhythmias, and precipitation after
mixture with dextrose or I.M. injection. Phenytoin is 90% protein-
bound, and the free fraction enters the central nervous system REFERENCES
and is responsible for its efficacy and toxicity. It has a Vd of 0.6 1. Insel P. Adrenergic receptors—evolving concepts and clinical impli-
L/kg, but the unbound drug is much more extensively distributed. cations. N Engl J Med. 1996;334:580–585.
Protein binding is reduced in neonates, who thus have therapeutic 2. Dorn GW, Molkentin JD. Manipulating cardiac contractility in heart
free concentrations at lower total phenytoin concentrations than failure: data from mice and men. Circulation. 2004;109:150–158.
3. Zaugg M, Schaub MC. Genetic modulation of adrenergic activity in the
older children. The metabolic pathways for phenytoin in the liver heart and vasculature: implications for perioperative medicine. Anes-
are saturated at plasma concentrations above 10 mg/L, resulting thesiology. 2005;102:429–446.
in zero-order kinetics. The half-life at low concentrations is 6 to 4. Booker PD. Pharmacological support for children with myocardial
24 hours, but at therapeutic concentrations, half-life increases dysfunction. Pediatr Anesth. 2002;12:5–25.
to 20 to 60 hours. Small increases in dose will cause large increases 5. Andropoulos DB, Ogletree ML. Physiology and molecular biology of the
developing circulation. In: Lake CL, Booker PD, editors. Pediatric Cardiac
in plasma concentration. The therapeutic plasma range is 10
Anesthesia. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2004.
to 20 mg/L (40–80 μmol/L). A loading dose of 15 to 20 mg/kg pp. 30–48.
(maximum 1.5 g) diluted with saline is given over 20 minutes 6. Toller WG, Stranz C. Levosimendan, a new inotropic and vasodilator
and has an onset of 20 to 25 minutes. Administration should agent. Anesthesiology. 2006;104:556–569
be slowed if hypotension, bradycardia, arrhythmias, or QT pro- 7. Wetzel RC. Calcium: a double edged sword. Pediatr Crit Care Med.
2007;8:300–301.
longation occurs. If seizures stop during the loading dose, the rate
8. Lehtonen LA, Antila S, Pentikainen PJ. Pharmacokinetics and pharma-
should be slowed to reduce the risk of toxicity. Phenytoin remains codynamics of intravenous inotropic agents. Clin Pharmacokinet.
effective for 24 hours, at which time the maintenance dose is 2004;43:187–203.
begun. Fosphenytoin is a water-soluble replacement for pheny- 9. Steinberg C, Notterman DA. Pharmacokinetics of cardiovascular drugs in
toin.139 It is a prodrug with a formation half-life of 8 to 15 minutes children. Clin Pharmacokinet. 1994;27:345–367.
10. Fisher DG, Schwartz PH, Davis AL. Pharmacokinetics of exogenous
and is converted completely by tissue phosphatases to phenytoin
epinephrine in critically ill children. Crit Care Med. 1993;21:111–117.
(because of differences in molecular weight, 150 mg of fosphe- 11. Brown C, Wiklund L, Bar-Joseph G, Miller B. Future directions for
nytoin yields 100 mg of phenytoin) Because it does not contain resuscitation research, IV. Innovative advanced life support pharmacology.
propylene glycol, it can be given faster than phenytoin, at the Resuscitation. 1996;33:163–177.
equivalent of 1.5 to 3 mg/kg/min of phenytoin. Administration 12. Paradis NA, Martin GB, Rivers EP. Coronary perfusion pressure and the
return of spontaneous circulation in human cardiopulmonary resuscita-
may be associated with parasthesia or pruritus. Onset time is
tion. JAMA. 1990;263:1106–1113.
similar to that of phenytoin, but it causes less local and systemic 13. Zaritsky A. Pediatric resuscitation pharmacology. Ann Emerg Med. 1993;
reactions. 22:445–455.
14. Lindner KH, Ahnefeld FW. Comparison of epinephrine and norepi-
nephrine in the treatment of asphyxial cardiac arrest in a porcine model.
Phenobarbital Crit Care Med. 1989;17:437–441.
15. Lindner KH, Ahnefeld FW. Epinephrine versus norepinephrine in
Phenobarbital stops seizures by the same mechanism as prehospital ventricular fibrillation. Am J Cardiol. 1991;67:427–428.
benzodiazepines and is the first-line treatment of seizures in 16. Perondi MM, Reis AG, Paiva EF, et al. A comparison of high-dose and
neonates and infants. Although it is not as sedating as other standard-dose epinephrine in children with cardiac arrest. N Engl J Med.
2004;350:1722–1730.
barbiturates, phenobarbital is still very sedating compared with 17. The International Liaison Committee on Resuscitation. The International
other anticonvulsants.134 It reaches peak levels in the brain after Liaison Committee on Resuscitation (ILCOR) consensus on science with
60 minutes, but seizure control is usually within 10 to 20 minutes. treatment recommendations for pediatric and neonatal patients: Pediatric
It is 40 to 60% bound to plasma and tissue proteins and has basic and advanced life support. Pediatrics. 2006;117:e955–975.
a Vd of 0.5 L/kg. It is metabolized in the liver and also excreted 18. Vincent R. Drugs in modern resuscitation. Br J Anaesth. 1997;79:
188–197.
unchanged in the urine. The half-life is 100 hours in adults, 19. Emerman CL, Pinchak AC, Hancock D, Hagen JF. The effect of bolus
longer in neonates, but only 40 to 70 hours in children. A loading injection on circulation times in cardiac arrest. Am J Emerg Med. 1990;
dose of 20 to 30 mg/kg is given slowly to avoid hypotension 8:190–193.
20. Ellemunter H, Simma, B, Trawoger R, Maurer H. Intraosseous lines in 49. Maguire JF, O’Rourke PP, Colan SD, et al. Cardiotoxicity during treatment
preterm and full term infants. Arch Dis Child. 1999;80:74F–75F. of severe childhood asthma. Pediatrics. 1991;88:1180–1186.
21. Warren DW, Kissoon N, Mattar A, et al. Pharmacokinetics from multiple 50. Shah PS, Ohlsson A. Sildenafil for pulmonary hypertension in neonates.
intraosseous and peripheral intravenous site injections in normovolemic Cochrane Database Syst Rev. 2007;3:CD005494
and hypovolemic pigs. Crit Care Med. 1994;22:838–843. 51. Lawless S, Burckart G, Diven W, et al. Amrinone pharmacokinetics in
22. Bohn D. Intraosseous vascular access: from the archives to the ABC. neonates and infants. J Clin Pharmacol. 1988;28:283–284.
Crit Care Med. 1999;27:1053–1054 52. Sorenson GK, Ramamoorthy C, Lynn AM, et al. Hemodynamic effects
23. Johnston C. Endotracheal drug delivery. Pediatr Emerg Care. 1992;8: of amrinone in children after Fontan surgery. Anesth Analg. 1996;82:241.
94–97. 53. Bailey JM, Miller BE, Kanter KR, et al. A comparison of the hemodynamic
24. Zaritsky A. Endotracheal epinephrine in cardiac arrest. Crit Care Med. effects of amrinone and sodium nitroprusside in infants after cardiac
1994;22:1071–1072. surgery. Anesth Analg. 1997;84:294.
25. Wentzel V, Prengel AW, Lindner KH. A strategy to improve endobronchial 54. Lattinen P, Happonen JM, Sairanen H, et al. Amrinone versus dopamine-
drug administration. Anesth Analg. 2000;91:255–256. nitroglycerine after reconstructive surgery for complete atrioventricular
26. Ushay HM, Notterman DA. Pharmacology of pediatric resuscitation. septal defect. J Cardiothorac Vasc Anesth. 1997;11:870.
Pediatr Clin North Am. 1997;44:207–233. 55. Booker PD, Gibbons S, Stewart JIM, et al. Enoximone pharmacokinetics
27. Simons FE, Roberts JR, Gu X, Simons KJ. Epinephrine absorption in in infants. Br J Anaesth. 2000;85:205–210.
children with a history of anaphylaxis. J Allergy Clin Immunol. 1998; 56. Ringe HR, Varnholt V, Gaedicke G. Cardiac rescue with enoximone in
101:33–37. volume and catecholamine refractory septic shock. Pediatr Crit Care Med.
28. Mullner M, Urbanek B, Havel C, et al. Vasopressors for shock. Cochrane 2003;4:471–475.
Database Syst Rev. 2004;3:CD003709. 57. Booker PD. Pharmacological support for children with myocardial
29. Annane D, Vignon P, Renault A, et al. Norepinephrine plus dobutamine dysfunction. Pediatr Anesth. 2002;12:5–25.
vs epinephrine alone for management of septic shock: a randomised trial. 58. Ramamoorthy C, Anderson GD, Williams GD, Lynn AM. Pharmaco-
Lancet. 2007;370:676–684. kinetics and side effects of milrinone in infants and children after open
30. Myburgh JA, Higgins A, Jovanovska A, et al. A comparison of epinephrine heart surgery. Anesth Analg. 1998;86:283–289.
and norepinephrine in critically ill patients. Intensive Care Med. 2008; 59. Bailey JM, Hoffman TM, Wessel DL, et al. A population pharmacokine-
34:2226–2234. tic analysis of milrinone in pediatric patients after cardiac surgery.
31. Waisman Y, Klein BL, Boenning DA, et al. Prospective randomized J Pharmacokinet Pharmacodyn. 2004;31:43–59.
double-blind study comparing L-epinephrine and racemic epinephrine 60. Paradisis M, Jiang X, McLachlan AJ, et al. Population pharmacokinetics
aerosols in the treatment of laryngotracheitis (croup). Pediatrics. 1992; and dosing regimen design of milrinone in preterm infants. Arch Dis
89:302–306. Child Fetal Neonatal Ed. 2007; 92:F204–F209.
32. Cherry JD. Croup. N Engl J Med. 2008;358:384–391. 61. Hoffman TM, Wernovsky G, Atz AM, et al. Efficacy and safety of
33. Seri I. Cardiovascular, renal and endocrine actions of dopamine in milrinone in preventing low cardiac output syndrome in infants and
neonates and children. J Pediatr. 1995;126:333–344 children after corrective surgery for congenital heart disease. Circulation.
34. Bailey AR, Burchett KR. Effect of low-dose dopamine on serum concen- 2003;107:996–1002.
tration of prolactin in critically ill patients. Br J Anaesth. 1997;78:97–99. 62. McNamara PJ. Milrinone improves oxygenation in neonates with severe
35. Allen E, Pettigrew A, Frank D, et al. Alterations in dopamine clearance persistent pulmonary hypertension of the newborn. J Crit Care. 2006;
and catechol-O-methyltransferase activity by dopamine infusions in 21:217–222.
children. Crit Care Med. 1997;25:181–189. 63. Pagel PS. Levosimendan in cardiac surgery: a unique drug for the
36. Notterman DA, Greenwald BM, Moran F, et al. Dopamine clearance in treatment of perioperative left ventricular dysfunction or just another
critically ill infants and children: effect of age and organ system inodilator searching for an application? Anesth Analg. 2007;104:759–761.
dysfunction. Clin Pharmacol Ther. 1990;48:138–147. 64. Turanlahti M, Boldt T, Palkama T, et al. Pharmacokinetics of levosi-
37. Zaritsky AL, Lotze A, Stull R. Steady state dopamine clearance in critically mendan in pediatric patients evaluated for cardiac surgery. Pediatr Crit
ill infants and children. Crit Care Med. 1988;16:217–220. Care Med. 2004;5:457–462.
38. Dasgupta SJ, Gill AB. Hypotension in the very low birthweight infant: the 65. Namachivayam P, Crossland DS, Butt WW, Shekerdemian LS. Early
old, the new, and the uncertain. Arch Dis Child Fetal Neonatal Ed. 2003; experience with levosimendan in children with ventricular dysfunction.
88:F450–F454. Pediatr Crit Care Med. 2006;7:445–448.
39. Carcillo JA, Fields AI. Clinical practice parameters for hemodynamic 66. Zaritsky A. Bicarbonate in cardiac arrest: the good, the bad and the
support of pediatric and neonatal patients in septic shock. Crit Care Med. puzzling. Crit Care Med. 1995;23:429–431.
2002; 30:1365–1377. 67. Goldsmith DJ, Forni LG, Hilton PJ. Bicarbonate therapy and intracellular
40. Subhedar NV, Shaw NJ. Dopamine versus dobutamine for hypotensive acidosis. Clin Sci. 1997;93:593–598.
preterm infants. Cochrane Database of Systematic Reviews. 2003;3: 68. Vukmir RB, Bircher N, Safar P. Sodium bicarbonate in cardiac arrest: a
CD001242. reappraisal. Am J Emerg Med. 1996;14:192–206.
41. Debaveye YA, Van den Berghe GH. Is there still a place for dopamine in 69. Schindler M, Bohn D, Edmonds J. Cardiopulmonary resuscitation in
the modern intensive care unit? Anesth Analg. 2004;98:461–468. children. N Engl J Med. 1997;336:1325–1326.
42. Prins I, Plötz FB, Uiterwaal CSPM, van Vught AJ. Low-dose dopamine in 70. Lokesh L, Kumar P, Murki S, Narang A. A randomized controlled trial of
neonatal and paediatric intensive care: a systematic review. Intensive Care sodium bicarbonate in neonatal resuscitation-effect on immediate
Med. 2001;27: 206–210. outcome. Resuscitation. 2004;60:219– 223.
43. Seri I, Evans J. Controversies in the diagnosis and management of 71. Aschner JL, Poland RL. Sodium bicarbonate: basically useless therapy.
hypotension is the newborn infant. Curr Opin Pediatr. 2001;13:118–123. Pediatrics. 2008;122:831–835.
44. Denkler KA, Cohen BE. Reversal of dopamine extravasation injury with 72. Adrogue HJ, Madias NE. Management of life threatening acid-base
topical nitroglycerin ointment. Plast Reconstr Surg. 1989;84:811–813. disorders. N Engl J Med. 1998; 338:26–34.
45. Booker PD, Evans C, Franks R. Comparison of haemodynamic effects of 73. Broner CW, Stidham GL, Westenkirchner DF, Watson DC. A prospective
dopamine and dobutamine in young children undergoing cardiac surgery. randomized double blind comparison of calcium chloride and calcium
Br J Anaesth. 1995;74:419–423. gluconate therapies for hypocalcemia in critically ill children. J Pediatr.
46. Bohn DJ, Poirier CS, Edmanods JF, Barker GA. Hemodynamic effects of 1990: 117, 986–9.
dobutamine after cardiopulmonary bypass in children. Crit Care Med. 74. Semple P, Booth C. Calcium chloride: a reminder. Anaesthesia. 1996;
1980;8:367–371. 51:93.
47. Habib DM, Padbury JF, Anas NG, et al. Dobutamine pharmacokinetics 75. Ushay HM, Notterman DA. Pharmacology of pediatric resuscitation.
and pharmacodynamics in pediatric intensive care patients. Crit Care Pediatr Clin North Am. 1997;44:207–233.
Med. 1992;20:601–608. 76. Fawcett WJ, Haxby EJ, Male DA. Magnesium: physiology and pharma-
48. Berg RA, Donnerstein RL, Padbury JF. Dobutamine infusions in stable, cology. Br J Anaesth. 1999;83:302–320.
critically ill children. Pharmacokinetics and hemodynamic actions. Crit 77. Foley C, Zaritsky A. Should we measure ionized calcium? Crit Care Med.
Care Med. 1993;21:678. 1998;26:1949–1950.
78. Mohammed S, Goodacre S. Intravenous and nebulised magnesium 108. Everard ML. Aerosol delivery to children. Pediatr Ann. 2006;35:630–
sulphate for acute asthma: systematic review and meta-analysis. Emerg 636.
Med J. 2007;24:823–830. 109. Collis GC, Cole CH, LeSouef PN. Dilution of nebulized aerosols by air
79. Rowe BH, Camargo CA. The role of magnesium sulfate in the acute and entrainment in children. Lancet. 1990;336:341–343.
chronic management of asthma. Curr Opin Pulm Med. 2008;14:70–76 110. Amirav I, Newhouse M. Metered dose inhaler accessory devices in acute
80. Losek JD, Endom E, Dietrich A, et al. Adenosine and pediatric supraven- asthma. Arch Pediatr Adolesc Med. 1997;151:876–882.
tricular tachycardia in the emergency department: multicentre study 111. O’Doherty MJ. Thomas SHL. Nebuliser therapy in the intensive care
and review. Ann Emerg Med. 1999;33:185–191. unit. Thorax. 1997;52(Suppl 2):S56–S59.
81. Bink-Boelkens MT. Pharmacologic management of arrhythmias. Pediatr 112. Nelson HS. Beta-Adrenergic bronchodilators. N Engl J Med. 1998;333:
Cardiol. 2000;21:508–515. 499–507.
82. Manole MD, Saladino RA. Emergency department management of the 113. Johnson M. The beta-adrenoceptor. Am J Respir Crit Care Med. 1998;
pediatric patient with supraventricular tachycardia. Pediatr Emerg Care. 158:S146–S153.
2007;23:176–185. 114. Foroughi S, Thyagarajan, Stone KD. Advances in pediatric asthma and
83. Dixon J, Foster K, Wylie J, Wren C. Guidelines and adenosine dosing in atopic dermatitis. Curr Opin Pediatr. 2005;17:658–663.
supraventricular tachycardia. Arch Dis Child. 2005;90:1190–1191. 115. Taburet AM, Schmit B. Pharmacokinetic optimisation of asthma
84. Rosenthal E. Pitfalls in the use of adenosine. Arch Dis Child. 2006;91:451. treatment. Clin Pharmacokinet. 1994;26:396–418.
85. Weist D. Esmolol: a review of its therapeutic efficacy and pharma- 116. Turner DJ, Landau LI, Le Souef PN. The effect of age on bronchodilator
cokinetic characteristics. Clin Pharmacokinet. 1995;28:190–202. responsiveness. Pediatr Pulmonol. 1993;15:98–104.
86. Weist DB. Pharmacokinetics of esmolol in children, Clin Pharmacol 117. Craig VL, Bigos D, Brilli RJ. Efficacy and safety of continuous albuterol
Ther. 1991;49:618–623. nebulization in children with severe status asthmaticus. Pediatr Emerg
87. Adamson PC, Rhodes LA, Saul JP, et al. The pharmacokinetics of Care. 1996;12:1–5.
esmolol in pediatric subjects with supreventricular arrhythmias. Pediatr 118. Browne GJ, Penna AS, Phung X, Soo M. Randomised trial of intravenous
Cardiol. 2006;27:420–427. salbutamol in early management of acute severe asthma in children.
88. McKee M. Amiodarone—an “old” drug with new recommendations. Lancet. 1997;349:301–305.
Curr Opin Pediatr. 2003;15:193–199. 119. Ward MJ. Nebulisers for asthma. Thorax. 1997;52:S45–S48.
89. Burri S, Hug MI, Bauersfeld U. Efficacy and safety of intravenous 120. Aubier M, Barnes PJ. Theophylline and phosphodiesterase inhibitors.
amiodarone for incessant tachycardias in infants. Eur J Pediatr. 2003; Eur Respir J. 1995;8:347–348.
162:880–884. 121. Anderson BJ, Holford NHG, Woolard GA. Aspects of theophylline
90. Saul JP, Scott WA, Brown S, et al. Intravenous amiodarone for incessant clearance in children. Anaesth Intensive Care. 1997;25:497–501.
tachyarrhythmias in children. Circulation. 2005;112:3470–3477. 122. Walson PD: Paediatric clinical pharmacology and therapeutics. In:
91. Thompson A, Balser JR. Perioperative cardiac arrhythmias. Br J Anaesth. Speight TM, Holford NHG, editors. Avery’s Drug Treatment. 4th ed. New
2004;93:86–94. Zealand, Adis International; 1997. p. 134. Adis Press International,
92. Perry JC, Fenrich AL, Hulse JE, et al. Pediatric use of intravenous Auckland, New Zealand.
amiodarone: efficacy and safety in critically ill patients from a 123. Mitra A, Bassler D, Watts K, et al. Intravenous aminophylline for acute
multicenter protocol. J Am Coll Cardiol. 1996;27:1246 –50. severe asthma in children over two years receiving inhaled bron-
93. Bossaert LL. Fibrillation and defibrillation of the heart. Br J Anaesth. chodilators. Cochrane Database Syst Rev. 2005;2:CD001276
1997;79:203–213. 124. Holford NHG, Tett S. Therapeutic drug monitoring: the strategy of
94. Friederich JA, Butterworth JF. Sodium nitroprusside: twenty years and target concentration intervention. In: Speight TM, Holford NHG,
counting. Anesth Analg. 1995;81:152–162. editors. Avery’s Drug Treatment. 4th ed. New Zealand: Adis International;
95. Edmondson R, Del Valle O, Shah N, et al. Esmolol for potentiation of 1997. p. 247. Adis Press International, Auckland, New Zealand.
nitroprusside-induced hypotension: impact on cardiovascular, adren- 125. Jung C, Inder WJ. Management of adrenal insufficiency during the stress
ergic and renin-angiotensin systems in man. Anesth Analg. 1989;69: of medical illness and surgery. Med J Aust. 2008;188:409–413.
202–206. 126. Shulman DI, Palmert MR, Kemp SF. Adrenal insufficiency: still a cause
96. Kleschyov AL, Oelze M, Daiber A, et al. Does nitric oxide mediate the of morbidity and death in childhood. Pediatrics. 2007;119:e485–e494.
vasodilator activity of nitroglycerin? Circ Res. 2003;93:e104–e112. 127. Carcillo JA. What’s new in pediatric intensive care. Crit Care Med.
97. Kam P, Williams S, Yoong F. Vasopressin and terlipressin: pharmacology 2006;34:S183–S190.
and its clinical relevance. Anaesthesia. 2004;59:993–1001. 128. Annane D, Bellissant E, Bollaert PE, et al. Corticosteroids for severe
98. Barrett L, Singer M, Clapp L. Vasopressin: mechanisms of action on the sepsis and septic shock: a systematic review and meta-analysis. BMJ.
vasculature in health and in septic shock. Crit Care Med. 2007;35:33–40. 2004;329:480–488.
99. Wolf A. Vasopressin in paediatric practice. Pediatr Anesth. 2008;18:579– 129. Hurlbert RJ. Strategies of medical intervention in the management of
581. acute spinal cord injury. Spine. 2006;31(11 Suppl):S16–S21.
100. Meyer S, Gortner L, McGuire W, et al. Vasopressin in catecholamine- 130. Paczynski RP. Osmotherapy. Crit Care Clin. 1997;13:105–129.
refractory shock in children. Anaesthesia. 2008;63:228–234. 131. MacDonald JT, Uden DL. Intravenous glycerol and mannitol therapy in
101. Lechner E, Hofer A, Mair R, et al. Arginine-vasopressin in neonates with children with intracranial hypertension. Neurology. 1982;32:437.
vasodilatory shock after cardiopulmonary bypass. Eur J Pediatr. 132. Sorani MD, Manley GT. Dose-response relationship of mannitol and
2007;166:1221–1227. intracranial pressure: a meta-analysis. J Neurosurg. 2008;108:80–87.
102. Aung K, Htay T. Vasopressin for cardiac arrest: a systematic review and 133. Wells TG. The pharmacology and therapeutics of diuretics in the
meta-analysis. Arch Intern Med. 2005;165:17–24. pediatric patient. Pediatr Clin North Am. 1990;37:463–492.
103. Mann K, Berg R, Nadkarni V. Beneficial effects of vasopressin in 134. Friedman MJ, Sharieff GQ. Seizures in children. Pediatr Clin North Am.
prolonged pediatric cardiac arrest: a case series. Resuscitation. 2002; 2006;53:257–277.
52:149–156. 135. The Status Epilepticus Working Party. The treatment of convulsive status
104. Matok I, Vardi A, Augarten A, et al. Beneficial effects of terlipressin in epilepticus in children. Arch Dis Child. 2000;83:415–419.
prolonged pediatric cardiopulmonary resuscitation: a case series. Crit 136. Korpi ER, Mattila MJ, Wisden W, Lüddens H. GABA(A)-receptor
Care Med. 2007;35:1161–1164. subtypes: clinical efficacy and selectivity of benzodiazepine site ligands.
105. Inui D, Ohto J, Nishimura M. Massive melena due to arginine- Ann Med. 1997;29:275–282.
vasopressin for septic shock in two pediatric patients. Paediatr Anaesth. 137. McIntyre J, Robertson S, Norris E, et al. Safety and efficacy of buccal
2008;18:90–91. midazolam versus rectal diazepam for emergency treatment of seizures
106. Russell JA, Walley KR, Singer J, et al. Vasopressin versus norepinephrine in children: a randomised controlled trial. Lancet. 2005;366:205–210.
infusion in patients with septic shock. N Engl J Med. 2008;358:877–887. 138. Wiznitzer M. Buccal midazolam for seizures. Lancet. 2005;366:182–183.
107. O’Callaghan C, Barry PW. The science of nebulised drug delivery. 139. Fischer JH, Patel TV, Fischer PA. Fosphenytoin. Clinical pharma-
Thorax. 1997;42(Suppl 2):S31–S44. cokinetics and comparative advantages in the acute treatment of
seizures. Clin Pharmacokinet. 2003;42:33–58.
Anesthesia Management
and Techniques
III
P A R T
Preoperative Evaluation, Laboratory

36 Testing, and Preparation for
Anesthesia and Surgery
C H A P T E R
Robin G. Cox
INTRODUCTION procedures being done in an office setting or nonhospital surgical

facility. The need for a meaningful preoperative assessment and
As with adult practice, patterns of surgical and interventional interaction with the child and family is crucial in such environ-
treatment for children have evolved over the years, requiring that ments, because there is sometimes little in the way of medical
the anesthesiologist adapt to new models of health care delivery. backup should a complication occur. Patient selection for office-
Pediatric anesthesiologists have been leaders in the provision of based procedures is therefore critical.
ambulatory care, and the specialty continues to push the limits of Increasingly, children are undergoing more complex pro-
what can be achieved on an outpatient basis. At the Alberta cedures. “Minimally invasive” techniques, performed in either
Children’s Hospital, Calgary, Canada, 80% of elective pediatric interventional radiology suites or specialized operating rooms, are
surgical cases are carried out as day procedures (2006/2007 data). becoming routine. Fetal surgery3 and EXIT4 procedures continue
Even when medically complex patients require a postoperative stay, to be explored (See Chapter 120), and robotic surgery is likely the
they are rarely admitted preoperatively. This means that systems way of the future. Surgery is also being performed with MRI
have to be developed to ensure that the preoperative interaction present in the operating room, either throughout the case or
between child, family, and anesthesiologist can still occur in a episodically with a mobile magnet.5 All such procedures have
thorough, yet unhurried fashion. If the preoperative assessment implications for anesthetic care that will affect the evaluation and
process is comprehensive, this may minimize the need for last- informed consent process.
minute cancellations because of unrecognized medical concerns.1,2 There are four main purposes of the preanesthetic interaction
Quite apart from the trend toward ambulatory care, there are with the child and the family. These are
other changes in practice that affect the preoperative evaluation
process. The number of anesthetic procedures for children outside 1. To conduct an appropriate medical evaluation of the child that
of the operating room continues to expand. Initially, this was will guide the anesthetic plan, including optimization of the
largely confined to oncology procedures and some radiologic child’s condition preoperatively.
2. To aid with anxiolysis for both child and family.
investigations, notably magnetic resonance imaging (MRI).
3. To provide information, education, and preoperative instruc-
Countless other types of interventions now demand the services of
tions for the family.
the anesthesiologist, for example, radiotherapy, diagnostic and
4. To obtain informed consent and assent when appropriate.
interventional cardiac catheterization, magnetoencephalography,
endoscopies, as well as a variety of other “noninvasive” radiologic These goals are explored in further detail.
procedures. Brief painful procedures, such as chest tube removal
and burn dressings, may warrant specialized anesthetic care.
Often, the children receiving treatment in remote sites have PREANESTHETIC EVALUATION
medically complex cases and anxiety issues, making the need for
thorough preanesthetic evaluation all the more important.
Models of Evaluation
In addition to the trend toward ambulatory care in a hospital The days when children were admitted the night before sur-
setting, there is also the move in some countries toward more gery and assessed by the anesthesiologist are largely over.
572 PART 3 ■ Anesthesia Management and Techniques
Anesthesiologists have, therefore, developed models of evaluation investigations are still the foundations of the evaluation, and these
to accommodate this change. There is no one perfect system of are now discussed in more depth.
evaluation, although a face-to-face interview with the anesthe-
siologist is still the cornerstone of the assessment. Generally, the
first knowledge that the family will have of the proposed pro- Routine Evaluation of the Healthy Child
cedure will be gained at the treating physician’s office, whether this The routine evaluation of the healthy child requires that the
is a surgeon, pediatrician, or other specialist. This provides an anesthesiologist approach the child and family in an unhurried,
opportunity for some patient evaluation by a physician other than empathetic manner, interacting with the child as much as possible
the anesthesiologist. In the case of healthy children undergoing in the circumstances. It is useful to review the patient’s medical
minor procedures, this does not often add much to what the anes- record in advance, so that basic information such as the age of the
thesiologist will determine in due course, but with more complex child, the procedure to be performed, and significant past medical
children, this assessment can be invaluable. As an example, when issues are identified. It does not inspire much confidence if the
a cardiologist schedules a child for interventional cardiac cathe- anesthesiologist is unclear on such information when approaching
terization, full details of the anatomy and physiologic status of the the family. Before delving into the history, it is worth tactfully
child can be identified, together with a recent echocardiogram. In clarifying who is present with the child. All varieties of family
many institutions, a history and physical examination must be structure exist, and it is not always clear who is the parent or legal
completed and documented before anesthesia, and this is usually guardian. Sometimes relatives, friends, or translators may be
supplementary to the anesthesiologist’s assessment. present, but large crowds should be discouraged. Ideally, the
Preoperative telephone evaluations can be invaluable in evaluation should be conducted in a private, quiet area, but this
pediatric practice. The distance from home to the facility may be is not always easy in some facilities. If possible, the family and
significant, and the telephone interview becomes a useful tool to anesthesiologist should be seated to reinforce the unrushed
gather data as well as an opportunity to provide instructions nature of the encounter and for the anesthesiologist to appear less
and answer questions. Most often, such interviews are conducted intimidating to the child. Interruptions from surgical residents
by a nurse, and the information is recorded either on paper or and others should also be discouraged.
electronically for the attention of the anesthesiologist. Telephone The content of the history can be focused to a large degree, but
interviews have been shown to reduce the number of last- it is often wise to begin with some open-ended questions,9 for
minute cancellations because of illness, failure to adhere to diet example, “How are you feeling today?” “Do you have any partic-
instructions, and failure to attend.1,2 Unexpected admission rates ular concerns?” or “How did the anesthetic go last time?” Such
are also lower in cases in which a telephone screening process is questions often reveal important information and also allow the
used.1,2 There is also some evidence that a history obtained by child and family to mention things that they feel are important.
a suitably trained nurse may be superior to that obtained by a As a minimum, the history should include the age of the child, any
medical resident.6 past surgical or anesthetic experiences, any past or current medical
Various software programs can be used to process information conditions (requiring a visit or admission to hospital), medications
obtained at the time of the telephone interview. At the Alberta (prescribed, nonprescribed, and alternative), allergies, family
Children’s Hospital, Calgary, Canada, the preanesthetic clinic history of anesthetic problems, and any history of intercurrent
uses CareSuite Preop Manager (PICIS, Wakefield, MA) when illness (particularly respiratory tract infection). The younger
conducting the telephone interview. This program provides an the child, the more relevant the birth history and neonatal
electronic record and is linked to CareSuite Anesthesia Manager period become.
(PICIS, Wakefield, MA), the intraoperative automated anesthesia Physical examination begins the moment the anesthesiolo-
record and database. Anesthesiologists have the ability to view any gist lays eyes on the child. Much can be learned from astute
preoperative record from an appropriate workstation. observation during the interview. Features such as the demeanor,
Hospitals vary considerably in the proportion of children who nutritional status, and activity are noted. Physical signs such as the
will attend a formal face-to-face preanesthetic clinic. Some will presence of a small mandible, respiratory tract infection, pallor,
see virtually every child at a separate visit, whereas others are tachypnea, or malaise, may be apparent. The admitting nurse will
highly selective and will see only more complex patients for a often obtain the vital signs; however, these may have been taken
formal anesthesia consultation. There are clearly pros and cons to with an agitated child and usually may need to be repeated.
these two approaches. There may be other options also. Temperature estimation is important, especially in the presence
Our pediatric surgical colleagues have already explored the of a respiratory tract infection. Infrared (IR) thermometers have
utility of telehealth as a tool for evaluating children in remote largely replaced older technology and are generally well tolerated
locations. This involves the child and family being interviewed by children. The tympanic IR thermometer has been shown to be
and evaluated via a remote audiovisual link. The initial experience reasonably reliable,10 although some expertise is required in its
with these methods has been positive, with a high level of patient use; ideally, the ear canal should be free of wax for accurate
satisfaction and no demonstrable untoward outcomes in the small readings. The temporal artery IR thermometer is easy to use and
numbers studied to date.7,8 There is no reason why anesthesiolo- has been shown to be more accurate than the tympanic one11;
gists could not explore the same methods in selected cases, which however, both routes are less sensitive than the rectal route for
can include such technology as tale-auscultation. Whether such detecting fever.12
interactions would be required routinely versus an evaluation on Oxygen saturation measurement is becoming a routine
the day of surgery is still open to question. vital sign conducted preoperatively, and a low saturation in the
Whichever system of assessment is chosen, the traditional presence of a respiratory infection is an important “red flag” that
components of history taking, physical examination, and further there may be significant lower respiratory tract disease.
CHAPTER 36 ■ Preoperative Evaluation, Laboratory Testing, and Preparation for Anesthesia and Surgery 573
Physical examination is conducted at the most opportune pathology are key. As an example, appendectomy is one of the
moment. In toddlers, if the child is quiet and settled in the parent’s more com-mon surgical procedures carried out on an emergency
lap, this is often a good time to examine the heart and lungs. basis in children. When the patient is a teenager with a short
Auscultation is best performed first, because this is the best chance history of pain (24–48 h), it is unlikely that there will be features
of having a quiet child. Lungs should be auscultated anteriorly, of severe sepsis present. In younger children, however, and with
laterally, and posteriorly, because findings may be confined to one longer histories, the chance of perforation, generalized peritonitis,
lobe. If a cardiac murmur is heard, the child will need to be and associated sepsis is more likely.19 An evaluation of the airway
examined in both the supine and the upright positions. Palpation is particularly important in emergency cases, particularly if a
of the precordium is a valuable part of the examination, because rapid-sequence induction is planned.
cardiac hyperactivity and/or thrills point to organic disease. The fasting status is determined, as with elective cases, but in
There may be external clues that the airway may be difficult, the emergency scenario, the history may be uncertain, and the
notably a high-arched palate or small mandible on lateral inspec- child who is in pain, on narcotics, or systemically unwell should be
tion. It is not always easy to get a small child to open the mouth, assumed to have full stomach.20,21
but this should be attempted. The presence of loose teeth should It is particularly important to evaluate the child’s hemodynamic
be determined, particularly in children of ages 6 to 10 years. status in emergency cases. Hemodynamic instability may be
Syndromes known to be associated with a difficult airway (e.g., related to hemorrhage, sepsis, or third-space losses. In a child, an
hemifacial microsomia) may be evaluated by more formal scoring apparently minor injury, such as a scalp laceration, may lead to
systems, such as that proposed by Uezono and coworkers.13 significant hemorrhage. Children have a remarkable ability
Preoperative physical examination remains an important to maintain a normal blood pressure in the earlier phases of
process and provides an opportunity to screen the child for compensated shock. When frank hypotension occurs, the child
unknown disease. There are reports of significant abnormalities may have progressed to uncompensated shock, which can rapidly
being detected by the anesthesiologist before elective surgery.14 become irreversible. The early signs of shock must, therefore,
Interviewing a teenager poses certain challenges. Teenagers be looked for carefully. These include tachycardia and, most
vary considerably in their attitude toward their parent/guardian important, decreased peripheral perfusion—commonly reported
and authority in general, so some flexibility is required. Teenagers as capillary refill time in seconds. Toes or fingertips are convenient
may be particularly concerned with their body image and privacy places to evaluate perfusion. Other important signs of impending
is essential. It may be that the patient wishes to disclose some- shock are thirst, pallor (from vasoconstriction), oliguria, and
thing without the parent/guardian present, such as a history of altered mental state, such as confusion or irritability.
smoking,15 alcohol or recreational drug use, or possible pregnancy.
Although it is not standard to routinely interview the teenager
Evaluation of the Child With Comorbidity
separately, circumstances may require this on occasion.
Once the history and physical examination are complete, Ex–Premature Infants
the anesthesiologist is able to assign an American Society of Prematurity is defined as a birth occurring before 37 weeks of
Anesthesiologists (ASA) Physical Status Grade (Table 36–1).16 This postconceptional age (PCA). Although many ex–premature babies
is widely used in pediatric circles, but moderate to poor interrater encounter no medical complications, there are others who may
reliability has been shown.17,18 Even though this grading system is have a host of medical sequelae; in general, these are more
not perfect, it is used to drive local policies, such as selection of significant the earlier the PCA. As examples, the baby may have
patients for ambulatory care or early discharge from recovery developed intraventricular hemorrhage, bronchopulmonary
rooms. A specific grading system for pediatric use has been dysplasia, patent ductus arteriosus, acute renal failure, necrotizing
proposed, but this is not available at present.18 enterocolitis, or retinopathy of prematurity (ROP). Even those
who are apparently healthy are still considered at risk for post-
operative apnea for a period as long as 60 weeks PCA.22,23 Ex–
Evaluation of Emergency and Urgent Cases premature babies often present for inguinal hernia repair,24
Evaluation of emergency and urgent cases demands special atten- or treatment of ROP, at an age when they are still at risk for
tion. The nature of the proposed procedure and the underlying postoperative apnea. There is some urgency with both of these
surgical procedures, because the hernia may incarcerate25 or vision
may deteriorate if surgery is delayed.
TABLE 36-1. American Society of Anesthesiologists Preoperative evaluation of the ex–premature baby requires
Physical Status Classification a detailed assessment of comorbidities. It should be remembered
that the baby may have undergone a long and difficult time in
1. A normal healthy patient
the neonatal intensive care unit and that there may have been
2. A patient with mild systemic disease
difficulties conceiving and supporting the pregnancy. Parents
3. A patient with severe systemic disease that limits activity,
of such infants are generally very knowledgeable about their
but is not incapacitating
child’s condition and understandably protective of their child’s
4. A patient with an incapacitating systemic disease that is a
interests. As well, the neonatologists who have been involved
constant threat to life in the baby’s care may have strong views on such matters as
5. A moribund patient not expected to survive 24 hours with or avoidance of intubation, particularly if it was previously difficult
without operation to extubate the child. These are important perspectives to
In the event of emergency operation, precede the number consider.
with an E In conducting the preoperative evaluation, it is crucial to
From reference 16. determine the gestational age (GA) at birth, the PCA, and the
current hemoglobin level. Coté and colleagues’ combined analysis glycopyrrolate in children with URIs does not appear to reduce
is still the best evidence that we have concerning risk factors for the incidence of perioperative respiratory adverse events.48
postoperative apnea in ex–premature infants.26 They determined Choice of anesthetic agent may be important. Sevoflurane appears
that the three most important predictors for the occurrence to be satisfactory in the presence of a URI, but it has only been
of postoperative apnea are GA, PCA, and anemia.26,27 There is no compared in this context with halothane.49 It would make sense
absolute PCA at which the apnea risk becomes zero, and insti- to avoid more irritating agents, such as desflurane or isoflurane.
tutions vary in their policies for postoperative admission. The Children with reactive airway disease are a significant concern
most conservative admit and monitor all ex–premature infants for the anesthesiologist. Most of these have documented asthma;
younger than 60 weeks’ PCA. When discussing the perioperative however, some children may be undiagnosed, and a history of a
plan with families, it is worth discussing the measures that might chronic nocturnal cough may be the only clue that there is airway
be considered, for example., a regional technique28 and the use reactivity.50 It is important to remember that the child who
of caffeine.29 There is no clear evidence that blood transfusion wheezes may in fact have other pathology, such as a foreign body,
reduces the incidence of postoperative apnea in ex–premature tracheal stenosis, or tracheomalacia.51 Infants with bronchiolitis
infants; however, a reduction in spontaneous apneic episodes has present with similar issues to the asthmatic child, although they
been shown in anemic ex–premature infants after transfusion.30 are best delayed unless the surgery is urgent.52 The ex–premature
If anemia is significant, therefore, there is an argument for infant and the baby recovering from bronchiolitis may exhibit
preoperative transfusion. The evidence for apnea risk in full-term airway reactivity for a prolonged period.53
babies is weaker than for ex–premature infants, but there are In evaluating the child with asthma, it is important to note
sufficient case reports to warrant admitting and monitoring these whether the disease has ever lead to hospital admissions, intensive
babies before 44 weeks’ PCA.31,32 care unit admissions, or even mechanical ventilation. The degree
of compliance with medications, and the amount of β agonist use
are key points. Unless the procedure is urgent, the presence of
Respiratory Disorders wheezes on auscultation is an indication to postpone surgery.
One of the most common comorbidities encountered in pediatric Regarding preoperative management, it is wise to continue the
anesthesia is the presence of an upper respiratory infection child’s regular inhaled asthma medications up to the time of
(URI).23,33,34 A runny nose, however, does not always signify surgery. If the parent has omitted the child’s usual medications,
infection, so the history must be structured to differentiate they can be given on arrival to the surgical facility. It has been
infection from allergy. In the presence of a likely viral infection, shown in asthmatics that tracheal intubation is associated with
the anesthesiologist must address two issues, namely, whether to an increase in respiratory system resistance54,55; this effect can be
proceed with anesthesia and how to minimize complications prevented by the use of preanesthetic inhaled salbutamol.56–58 In
if anesthesia is undertaken. Numerous studies have pointed to a addition, it has been shown that propofol causes less wheezing
higher incidence of adverse events associated with anesthesia than thiobarbiturates in patients with asthma59 and that the
in children with URIs35–40; however, serious sequelae are rare.33 laryngeal mask airway causes less bronchoconstriction than tra-
cheal intubation.54 The anesthetic plan should take these various
Independent risk factors for adverse respiratory events in children
findings into account.
with active URIs include use of an endotracheal tube (ETT) in
An increasing number of children presenting for anesthesia
a child younger than 5 years old, prematurity, reactive airway
have overt or occult obstructive sleep apnea syndrome (OSAS).60
disease, paternal smoking, airway surgery, copious secretions, and
Younger children with OSAS generally have adenotonsillar
nasal congestion.41–43 Although it has not been formally studied, it hypertrophy; whereas in older children, OSAS is more often
would seem reasonable to assume that a low preoperative oxygen related to obesity (See Chapter 62). A subset of children with
saturation points to lower respiratory disease and that this would OSAS have craniofacial anomalies or Down syndrome. Children
be an additional risk factor. with OSAS are at significant risk of perioperative respiratory and
The decision to proceed must take into account the urgency of cardiovascular complications, with a reported incidence up to
the surgery, the severity of symptoms, the nature of the procedure 20%.61 Those at highest risk are the very young (<2 y) and those
and type of anesthesia required, presence of comorbidities, and with significant comorbidity.61,62
other social and geographic factors. It is no longer tenable to Younger children differ from adults in terms of OSAS
simply postpone all children with a URI.44,45 Children may symptoms. Daytime somnolence and obesity, common with adult
experience six to eight URIs per year, and although these are OSAS, are rare features in young children. Young children may
mainly self-limited viral infections, there may be evidence of present with failure to thrive, behavioral problems, and poor
airway hyperreactivity for several weeks following the infection.33 school performance.63 Symptoms are not reliable predictors of
Particularly over the winter months, therefore, many children the severity of OSAS; snoring is present in 10 to 15% of children,
either have a URI or are in the recovery period from one. Most but OSAS is prevalent in only 1 to 3% children.62 Investigations
anesthesiologists are prepared to anesthetize at least some children such as polysomnography are not routinely available in all
with URIs45; one reasonable approach is nicely illustrated in an centers. Overnight oximetry provides evidence as to the severity
algorithm suggested by Tait and Malviya (Figure 36–1).33 of OSAS and is a cheaper option than a full polysomnogram.64
If the decision is made to proceed with anesthesia in a child A preoperative oxygen saturation nadir of 80% is a predictor for
with a URI, can any measures minimize the risk of adverse events? postoperative respiratory complications after adenotonsillec-
It has been shown that endotracheal intubation is associated with tomy in 50% of children with OSAS.65 A preoperative apnea and
more adverse events and that the laryngeal mask, if practical, is hypopnea index of greater than five events per hour is also
associated with fewer complications.46 Preoperative bronchodila- predictive of such complications.65 There is also a high incidence
tion (albuterol or ipratropium) has not been shown to be effective of postoperative complications in children who undergo urgent
in reducing adverse respiratory events.47 The routine use of adenotonsillectomy.66 The anesthetic plan for the child with OSAS
Figure 36-1. Suggested algorithm for the

assessment and anesthetic management
of the child with an upper respiratory
infection. ETT = endotracheal tube; Hx =
history; LMA = laryngeal mask airway;
URI = upper respiratory infection. From
reference 33.
should include scheduling the child early in the day,67 very cautious however, a child presents with a previously undetected cardiac
use of opiates,68–70 and postoperative admission and monitoring.71 murmur. Innocent murmurs have been reported with an incidence
Cystic fibrosis is another respiratory condition worth con- varying between 8 and 96%.74 The incidence of true CHD in
sidering.72,73 The key with this condition is close collaboration children lies closer to 0.5%, and most of these children are already
between the family, the various pediatric services involved, and diagnosed when they present for anesthesia. The chances of
the anesthesiologist. Preoperative preparation is crucial and a newly heard murmur being related to organic heart disease are,
should include chest physiotherapy, antibiotics, and bronchodila- therefore, slim. Nevertheless, the anesthesiologist should be aware
tors. Inhalational induction may be prolonged and complicated of the features of the three most common innocent murmurs,
by vigorous episodes of coughing; therefore, it is reasonable to Still’s murmur, pulmonary flow murmur, and venous hum
consider an intravenous induction for most of these children. (Table 36–2), as well as the features of a clearly pathologic murmur.
“Red flags” pointing to organic disease include diastolic,
pansystolic, or late systolic murmurs, thrills, murmurs in infancy,
Cardiac Disorders and associated cardiac signs. Unfortunately, many murmurs
Children with known congenital heart disease (CHD) present are not clearly innocent or pathologic. For instance, it may be
particular challenges for the anesthesiologist. Far more commonly, impossible clinically to differentiate an innocent pulmonary flow
TABLE 36-2. Innocent Murmurs in Childhood important to review the general health of the child as well as
impairment of motor function, intellectual function, and seizure
Murmur Location Features potential. A child with severe cerebral palsy may have normal or
Still’s murmur Lower left sternal Vibratory, early systolic, high intelligence, so it is important always to assume a high level
edge, radiating medium to low of intellectual functioning when addressing the child, unless the
to apex pitched, grade 1–3, record indicates otherwise. Pain may be difficult to assess in the
child with cerebral palsy, but the family or care provider may be
loudest supine,
particularly helpful in describing how the child expresses pain.
changes or diminishes
New tools of pain assessment for children with cerebral palsy have
when upright
also been developed.80
Pulmonary flow Left sternal border Blowing, midsystolic,
Certain muscular disorders are of particular interest to the
murmur at two to three grade 1–3, loudest anesthesiologist. The group of disorders known as dystrophin-
interspace supine, changes or opathies (e.g., Duchenne and Becker muscular dystrophy) have
diminishes when the potential to develop sudden hyperkalemia in the presence
upright, normal of volatile agents or succinylcholine.81,82 At the preanesthetic visit,
second heart sound a trigger-free anesthetic should be planned.82 These children often
Venous hum Supra- and/or Whirring, continuous, develop cardiomyopathies as they grow older,81 so a recent echo-
infraclavicular, variable intensity, cardiogram to evaluate ventricular function is useful. Pulmonary
louder on right sound, loudest sitting, function testing is also essential in more advanced cases.
changes or diminishes Many previously obscure diseases are being recognized as
when supine variants of mitochondrial myopathy. These conditions require a
thorough preoperative assessment of functional organ system
reserve,83 and it has been suggested that parental presence at
murmur from that of an atrial septal defect.75 The anesthesiologist induction may be helpful in cases with sensory deprivation and
must then decide whether it is safe to proceed with anesthesia or that excessive preoperative fasting should be avoided.83
delay the surgery, pending a cardiology opinion. In general, if the Autistic children can present special challenges for families
surgery is minor and the child is asymptomatic with no signs of and caregivers alike.84 Generally, these children are physically
cardiac compromise, it is acceptable to proceed with appropriate well and their main problems are behavioral. Attention to detail,
precautions, including antibiotic prophylaxis when indicated. In such as minimizing auditory stimuli, tailoring the experience
such cases, the parents should be advised to seek further follow- to the individual’s needs and characteristics, planning for an early
up with their regular physician. discharge, and judicious premedication are useful measures.
The child with CHD merits special attention. The spectrum of Some autistic children react in a paradoxical way to midazolam;
disease is wide and includes those who are uncorrected, who have severely autistic children may fare better with oral ketamine for
had surgical correction, or who may have just had a palliative or premedication.84
part of a staged procedure. There is good evidence that the anes- Children with known or suspected malignant hyperthermia
thetic risk in some children with CHD is significant, particularly sensitivity (MHS) present little difficulty with modern anesthesia.
those with hypoplastic left heart syndrome.76–78 These risks should A trigger-free anesthetic is planned. It must be remembered that
be properly disclosed to the family, and close communication with some of the newer anesthetic machines need longer flushing times
the child’s cardiologist is crucial, particularly for the more complex than older machines. It is wise to schedule these patients first in
cases. With known or suspected CHD, the anesthesiologist should the day to allow for adequate preparation. Oral midazolam, topical
ask about symptoms of cardiac failure, such as rapid breathing, anesthetic cream over suitable veins, and nitrous oxide will facili-
failure to thrive, sweating, and feeding difficulties. Clinical signs tate an intravenous induction in anxious children. It has been
of cardiac failure in infancy include tachypnea, tachycardia, shown that MHS children need to be monitored for only 4 hours
cardiomegaly, hepatomegaly, and truncal edema. In considering in the hospital after a minor procedure.85
the child with CHD, the three key questions to be addressed are Children with seizure disorders may be at risk if their
seizure control is poor or if they are on multiple anticonvulsants.
1. What is the precise anatomy? This includes the structure of the Anesthesia may have a somewhat unpredictable effect on seizure
heart and any subsequent surgical corrections. control, and anesthetic drugs may interact with anticonvulsants,
2. Is there a significant shunt, and if so, in what direction? causing oversedation. Conversely, enzyme induction from seizure
3. Is there evidence of complications—cardiac failure, ventricular medications may increase anesthetic needs. It is prudent to
dysfunction, pulmonary hypertension, or arrhythmia? arrange for monitoring of these children until they have fully
Frequently, the best information to answer these questions recovered from the effects of anesthesia, to re-establish their
comes from a recent echocardiogram, but some patients may have regular anticonvulsant regime as soon as possible, and to involve
angiographic or MRI studies that will clarify the situation further. their neurologist as required.
The question of antibiotic prophylaxis must also be addressed; and
the reader is referred to the latest guidelines from the American
Metabolic and Endocrine Disorders
Heart Association.79
Diabetes mellitus (DM) is increasing in incidence in North
American children, with type 1 DM accounting for the majority of
Neurologic and Musculoskeletal Disorders cases. Children tend to be prone to instability in their glycemic
Infants and children with neurologic handicap frequently present control, and many are treated with complex regimes. The princi-
for diagnostic and surgical procedures requiring anesthesia. It is ples of perioperative management are simple, however:
1. To optimize the child’s preoperative state. bronchus compression, pleural effusion, or tracheal compression
2. To ensure as rapid return as possible to the preanesthetic state. are at the greatest risk.92 The problem is that the cause of some
3. To avoid hypoglycemia. of these effects may require sedation or anesthesia to allow appro-
4. To avoid extreme hyperglycemia and/or ketosis. priate evaluation and investigation. A suitable algorithm should,
5. To adequately treat pain and postoperative nausea and vomiting, therefore, be agreed upon in each institution dealing with these
because these may compromise glycemic control. patients.91
The anesthesiologist should be aware of the various regimes of Children with HIV infection present many challenges for
insulin therapy that are in common use in children. These include the anesthesiologist.93 The preoperative process should follow
combinations of intermediate- and short-acting insulins; long- traditional lines, with particular attention paid to the possible
acting insulin supplemented with short-acting insulin at meal involvement of multiple organ systems, tuberculosis comorbidity,
times; or subcutaneous insulin infusions.86,87 Newer modalities of adverse reactions and drug interactions of antiretroviral agents,
insulin administration (e.g., inhaled or orally absorbed insulin) pain evaluation, and plans to prevent HIV transmission within the
are the subject of investigation. Regimes are evolving rapidly, so it facility. As with all patients, confidentiality must be maintained
is wise to seek the assistance of the child’s regular endocrinologist with these patients.
or pediatrician when planning perianesthetic care. One question The child with sickle cell disease requires careful evaluation
that sometimes arises concerns the use of dexamethasone in preoperatively. The most crucial factors to assess are dehydration,
diabetic children. Although a glucocorticoid might lead to hyper- hypoxemia, vascular stasis, hypothermia, acidosis, and infection.94
glycemia,88 the antiemetic and anti-inflammatory benefits of Symptoms and signs of end-organ damage, such as respiratory
dexamethasone may outweigh this concern in selected cases (e.g., compromise from previous episodes of acute chest syndrome,
with tonsillectomy or eighth molar extractions). should be sought. Although a preoperative hemoglobin and
There appears to be a current epidemic of obesity in children, hemoglobin S level should be obtained, it remains unclear whether
particularly in North America, and some of these children develop there is a benefit to preoperative blood transfusion, particularly
type 2 DM. Obesity may also be a feature of syndromes such for minor procedures.94–96 It should be remembered that children
as Prader-Willi; however, these children are usually identified by with sickle cell disease often have a history of painful crises and
the pediatrician. Prader-Willi syndrome has many implications they may be tolerant of opiate analgesics. Because opiate require-
for the anesthesiologist, notably the risk of sleep apnea and ment may vary considerably between patients with sickle cell
postoperative respiratory failure.89 disease, patient-controlled analgesia or a regional technique is
Countless other metabolic disorders may have implications often a reasonable approach to discuss with the family.97
for the anesthesiologist, particularly those involving the urea
cycle. The keys to managing such children are the avoidance of
dehydration, hypoglycemia, and hyperammonemia. The choice
Syndromes (Trisomy 21 As an Example)
of intraoperative fluids is important. Avoiding lactate and pro- Countless syndromes have implications and challenges for the
viding glucose may be particularly important in some situations. anesthesiologist.98,99 Examples include urticaria pigmentosa,
Close liaison with the metabolic specialists is essential, because epidermolysis bullosa, and familial dysautonomia. Anesthesiolo-
there may be specific regimes that are useful for particular condi- gists should have access to material, either text or web-based,
tions (e.g., sodium benzoate, arginine, citrulline, and sodium that will serve to rapidly identify all the key features of all such
phenylbutyrate regimes in cases of ornithine transcarbamylase syndromes and their implications for anesthesia.
deficiency).90 Trisomy-21 (Down syndrome) is described as one example of
a common syndrome with abnormalities of all body systems,
many of these influencing anesthetic care.100,101 The most crucial
Oncologic, Immunologic, systems for the anesthesiologist to evaluate in these children are
and Hematologic Disorders respiratory, cardiovascular, and musculoskeletal. It is important
Malignancy is encountered fairly frequently in the pediatric popu- to realize that the degree of cognitive challenge is very variable in
lation, and many of these patients require repeated procedures children with Down syndrome. Many of these children are highly
under anesthesia. The family of a child newly diagnosed with functional, and it is wise to assume that they will understand much
cancer must be approached with compassion because this may of what is happening to them; they should be spoken with directly,
represent one of the most challenging situations that they will have just as with any other child.
faced in their lives. The anesthesiologist can do much to make the Preoperative evidence of respiratory tract infection has been
child’s experiences with procedures as comfortable and stress-free found in up to 23% of cases102 and should be sought; a history of
as possible. Judicious use of premedication, avoidance of parental recurrent croup will alert the anesthesiologist to the possibility of
separation, close attention to pain control, and postoperative subglottic stenosis. Particular attention should be paid to the
nausea and vomiting (PONV) prevention are all measures that airway; the degree of macroglossia present and the presence
will help to alleviate the stress that the child and, hence, the family of stridor should be noted. Subglottic stenosis is likely to be
will experience. Children who are “frequent flyers” for minor undetectable unless very severe.
oncologic procedures (e.g., lumbar puncture or radiotherapy) Children with Down syndrome have a high incidence of OSAS.
often develop a close rapport with a sympathetic anesthesiologist, One study of 53 children with Down syndrome demonstrated
whom they may see on a regular basis. abnormal nap polysomnograms in 77% and abnormal overnight
Certain oncologic conditions are associated with increased risk polysomnograms in 100%.103 Interestingly, in this study, 57% of
for complications, notably those with an anterior mediastinal children did not have a history suggestive of OSAS.
mass.91,92 It would appear that children who present with orth- CHD is found in approximately 40% of children with Down
opnea, upper body edema, great vessel compression, mainstem syndrome.99 Often, this is well documented and details of previous
cardiac surgery, medications, and recent cardiologic evaluations family history, those with known or suspected anemia, those with
with echocardiographic reports are available. Children with sickle symptomatology, and those undergoing high-risk pro-
Down syndrome are particularly prone to develop pulmonary cedures involving hypothermia or interference with the circulation
hypertension, related to either a left-to-right shunt, impaired (e.g., tourniquets).114
development of alveoli and pulmonary vasculature, and/or arterial Coagulation testing should be reserved for children with
hypoxemia owing to chronic upper airway obstruction.99 Evidence possible coagulopathy identified by history, physical examination,
of residual anatomic defects, cardiac failure, or pulmonary hyper- or family history; or for those undergoing major surgery. Some
tension should be evaluated preoperatively. It has been known for centers, however, demand that children undergoing adenoton-
years that children with Down syndrome may have a poorly sillectomy undergo routine preoperative coagulation testing.
developed sympathetic nervous system,104 and this makes them This has been shown to provide low sensitivity and to be a poor
particularly prone to bradycardia with anesthesia.105 The resting predictor of perioperative bleeding.116
heart rate should, therefore, be noted. Down syndrome children The issue of preoperative pregnancy testing in children is
respond normally to atropine106; this drug should be available controversial. There is little doubt that some teenagers may be
at induction. pregnant when presenting for surgery. Studies of female adoles-
Children with Down syndrome have been shown to have cents screened preoperatively for pregnancy have revealed a 0.9
atlantoaxial instability (AAI) in 7 to 36% of cases.107 Despite this to 1.2% incidence of positive testing.117,118 Several authors have
high incidence, the incidence of anesthesia-related complications proposed that routine pregnancy testing be made mandatory,
related to this is exceedingly rare.107 It is important to structure and some hospitals have introduced such policies. This, however,
the history and physical examination to identify children with is an ethical and logistical minefield, and as Duncan and Pope
neurologic findings, but in the absence of significant symptoms point out “we must maintain an awareness of the impact of our
or signs, the need for routine radiographic evaluation remains decisions on the overall cost to the healthcare system and ensure
controversial. In one survey, 171 North American members of the that policies required for access to our services are both ethical
Society for Pediatric Anesthesia, only 18% reported routinely and responsible within a societal context.”119
obtaining radiographs in asymptomatic children.108 It would seem Children undergoing highly complex procedures clearly
prudent, however, to obtain radiographs109 in any case with signs
require comprehensive investigations. As an example, a teenager
or symptoms or in which the head will be in a nonneutral position.
scheduled to undergo surgical correction of scoliosis may require:
Signs of AAI on radiographs are an indication for further surgical
blood work (CBC, electrolytes, UA, creatinine, coagulation tests,
evaluation preoperatively. This topic is well covered in a review
blood group, and cross-match), UA, radiographs (chest antero-
article.107
posterior and lateral), pulmonary function tests, electrocardio-
gram, and echocardiogram. In all likelihood, this patient will have
Investigations had extensive imaging studies (computed tomography [CT] or
MRI), and these may be available on-line for the anesthesiologist
At one time, it was routine practice to obtain a complete blood to review.
count (CBC) and urinalysis (UA) before anesthesia. It has been
shown conclusively that this is not required.110–113 In children with
no abnormalities in the history or physical signs, anemia is rare, ANXIOLYSIS
and mild even if present. Some children, however, do require a
CBC. The premature baby may be more at risk for postoperative Anxiety is common whenever a child requires anesthesia.
apnea if anemic,26,27 so a CBC is useful to help quantify the apnea This anxiety is not limited to the child; the family is often just as
risk. Children who have significant comorbidity and/or who anxious, if not more so, than the child. High anxiety at induction
are undergoing major procedures merit a preoperative CBC, at has been shown in at least half of children.120 Risk factors for
least to determine their baseline status. There is very little value in anxiety include younger age, behavioral problems with previous
routine preoperative UA analysis in otherwise healthy children.110 health care attendances, longer procedures, more than five pre-
Routine testing for sickle cell disease (SCD) is commonly vious admissions, and anxious parents.120 Anxiety is unpleasant
performed in so-called at-risk populations. This practice has been for the child and may have other adverse effects, such as a higher
called into question recently.114 The population at risk is essentially requirement for postoperative analgesia and a higher incidence of
any ethnic group whose origins arose in malaria-infected areas. emergence delirium or postoperative anxiety.121,122
This includes those of African, Hispanic, Mediterranean, Middle Apart from the presence of a calm, confident, friendly, and
Eastern, and Asian Indian heritage. Of note, in 12 to 17% of infants approachable anesthesiologist, several specific strategies may help
diagnosed with SCD, neither parent was of African ancestry.114,115 to decrease the incidence of anxiety that can be planned at the
With the increasing number of children of blended racial origin, preanesthetic visit. Perhaps the most effective intervention is the
the number of patients to potentially screen is huge, and to what use of premedication. There is no doubt that oral midazolam
benefit? There is very little of clinical significance in those effectively reduces anxiety at induction of anesthesia.123 Other
with sickle cell trait, so identification of this condition does not sedatives (e.g., clonidine, ketamine) have their advocates.124,125 See
generally aid in anesthetic management. In a study from a large Chapter 37
pediatric institution, which reviewed 1906 children of African Other strategies to reduce anxiety include hypnosis,126 music,127
ancestry who were screened for SCD, only 1 case of SCD was acupuncture,128 clowns,129 and orientation programs.130 These non-
identified in a child who had a negative family history.114 That pharmacologic approaches have had some success; however, they
child had SCD, with a hemoglobin of 112 g/L. The message seems generally require resources and expertise. Acupuncture been
to be that preoperative screening for SCD should be undertaken shown to reduce anxiety in the parent; however, it seems that
selectively; this might include those with a positive or unknown the children also demonstrate less anxiety at induction when
the parent receives acupuncture.128 Orientation programs vary The issue of chewing gum in the preoperative period has been
widely in their content130 and, hence, their benefit. It is being in- the subject of some debate. Adult studies have found conflicting
creasingly recognized, however, that an intensive, family-centered, results in terms of the effect of gum-chewing on gastric fluid
behaviorally oriented preoperative program can be more effective volumes and pH.149,150 A recent pediatric study, however, did show
at reducing anxiety than other, simpler, cheaper orientation larger gastric fluid volumes in children who chewed gum before
methods.131,132 anesthesia.151 Reassuringly, the gastric pH was higher in the gum-
Perhaps the most questionable anxiolytic intervention is chewing subjects. There was no difference between sugared and
parental presence at induction of anesthesia (PPIA).133 Numerous sugar-free gum. An additional hazard of gum is that it may remain
studies have evaluated PPIA over the years, and the majority do undetected in the oral cavity and lead to subsequent aspiration.
not seem to show an overall benefit in terms of anxiety reduc- It is important, therefore, to include gum in the list of items to
tion.134,135 It does appear though that children older than 4 years avoid on the day of surgery. If a child does arrive chewing gum, the
and those with nonanxious parents derive some benefit from effects should be similar to ingesting clear fluids, so a delay of
PPIA.134 Irrespective of whether it actually helps the child or not, 2 hours would seem to be justifiable.
most parents wish to be present at induction.134,136 Interestingly, in
one study, 90% of parents rated themselves as being helpful to their
child at induction, whereas only 12% were rated as being helpful
Preoperative Medications
by the anesthesiologist.134 Finally, there is some evidence that Children who are on regular medications should generally
PPIA, in combination with oral midazolam premedication, may continue taking these up to the time of surgery. This is particularly
reduce the incidence of emergence delirium.137 important with cardiac medications, bronchodilators, and anti-
Most anesthesiologists have adopted a flexible approach to convulsants. Children who are on oral anticoagulants may need
PPIA.138 There are certainly some children, such as those with to be switched to heparin; this is done in consultation with a
special needs or language barriers, the very anxious child, and hematologist.
the repeatedly hospitalized child, who seem to benefit from Apart from the child’s regular medications and sedative pre-
PPIA. Because parents seem to appreciate the chance to be with medicants, some other preoperative drugs may be considered. It is
their child at induction, it can be assumed that the practice will common practice in many centers to administer acetaminophen
continue to increase.139 It would make sense, however, that PPIA orally to children in the preoperative period. There have been
be accompanied by a formal educational program for the parents, conflicting results of this therapy before myringotomy152,153;
so that they at least know what to expect and how they can be however, there is some evidence of a morphine-sparing effect
helpful to their child.133 There is evidence that such programs in children who might be predicted to require opiates.154 This
reduce anxiety in the parent,140 so presumably the child might latter study showed a clear dose response, with doses of rectal
benefit also. acetaminophen in the 40- to 60-mg/kg being superior to 20 mg/kg
or placebo.154 It is known that the relative bioavailability of rectal
versus oral acetaminophen is 0.54,155 and some authors have
PREOPERATIVE INSTRUCTIONS recommended rectal loading doses of 40 m/kg to account for
AND INFORMATION SHARING this.156 It must be remembered, however, that the therapeutic
window for acetaminophen is narrow. Care must be taken to avoid
Fasting Instructions acetaminophen overdose.157 Even in a child with no risk factors
Fasting instructions need to be very clear and leave no room for hepatotoxicity; the maximum 24-hour dose is 90 mg/kg, by
for confusion. Standard fasting intervals for children are pro- whatever route, to a maximum of 4 g.
vided in Table 36–3, and the topic is covered in more detail in The use of anticholinergic agents before induction of anesthe-
Chapter 37. Essentially, based on extensive research, it is safe sia is controversial158 and has waned with the advent of modern
to allow clear fluids up to 2 hours preinduction in elective inhalational agents. Most anesthesiologists do not administer an
patients.141–146 Furthermore, prolonged fasting may be delete- anticholinergic routinely but reserve it for selected indications
rious, particularly in infants.147 Even with liberalization of pre- (e.g., strabismus repair,159 Down syndrome,105,106 before succinyl-
operative fluid intake, it appears that the incidence of aspiration choline,160,161 and during bronchoscopy). A prudent anesthe-
in children undergoing anesthesia is very low.148 There is scant siologist, however, has atropine (and succinylcholine) drawn up
evidence, however, to support a definite fasting period for when anesthetizing children, unless contraindicated.160
solid food and much depends on the nature and quantity of the
food ingested.
Information Sharing
The preanesthetic visit is an opportunity for the anesthesiologist
TABLE 36-3. Fasting Guidelines for Elective Surgery
to address any concerns that the child or parent may have. There
in Children should always be an invitation for the family to ask questions
Substance Minimum Fasting Period, h about the anesthetic in an unhurried manner. Even if the family
has few questions, the anesthesiologist should outline the plan for
Clear fluid 2 anesthetic care that the child will receive. A brief description of
Breast milk 4 the type of anesthesia is appropriate, and the method of induction
Formula or nonhuman milk 6 may be a matter of negotiation (children often appreciate having
Solid food 8 some control over what is happening to them). The requirement
From reference 141. for invasive lines or regional blocks can be discussed at this time.
Much of the information to be provided pertains to postoperative health care providers.179,180 One aspect of communication that is
care. The plan for pain control,162 emergence delirium,163 and sometimes overlooked is the ability of the family and the child to
PONV prevention164,165 needs to be outlined. provide feedback on their overall experience. Many centers are
now incorporating such programs into their practice or have
evaluated parental preferences181–183; this can only aid in improving
CONSENT AND ASSENT our outcomes after anesthesia in children.
The preoperative interaction concludes with the anesthesiologist
obtaining consent from the parent or legal guardian and assent
from the child when appropriate. The information sharing process
REFERENCES
should mean that families are aware of what will take place and 1. Kleinfeldt AS. Preoperative phone calls: reducing cancellations in
the anticipated benefits and risks of these interventions. Specific pediatric day surgery. AORN J. 1990;51:1559–1564.
2. Patel RI, Hannallah RS. Preoperative screening for pediatric ambulatory
interventions, such as invasive lines, blood transfusion, and surgery: evaluation of a telephone questionnaire method. Anesth Analg.
regional blocks, should be identified and explained as part of the 1992;75:258–261.
consent process. The child may have questions too, and these 3. Robinson MB. Frontiers in fetal surgery anesthesia. Int Anesthesiol Clin.
should be answered truthfully in an age-appropriate fashion. 2006;44:1–15.
Families are often concerned about the risk of anesthesia. 4. Marwan A, Crombleholme TM. The EXIT procedure: principles, pitfalls,
and progress. Semin Pediatr Surg. 2006;15:107–115.
Specific questions often concern morbidity, mortality, awareness, 5. Archer DP, McTaggart Cowan RA.Intraoperative mobile magnetic
blood component transfusion, and regional techniques, partic- resonance imaging for craniotomy lengthens the procedure but does not
ularly epidural or spinal anesthesia. Families should be made increase morbidity. Can J Anaesth. 2002;49:420–426.
aware that the risk for each child varies, depending on the age and 6. Rushforth H, Bliss A, Burge D, et al. A pilot randomized controlled trial
condition of the child, as well as the surgical procedure to be of medical versus nurse clerking for minor surgery. Arch Dis Child.
2000;83:222–226.
performed. If numerical indicators of risk are requested by the 7. Miller GG, Levesque K. Telehealth provides effective pediatric surgery
family, these can be provided with the caveat that these are average care to remote locations. J Pediatr Surg. 2002;37:752–754.
numbers only (Table 36–4).166–172 8. Postuma R, Loewen L. Telepediatric surgery: capturing clinical outcomes.
Although the focus should be on anesthetic risk, inevitably this J Pediatr Surg. 2005;40:813–818.
is influenced by surgical decisions. For example, a surgeon may 9. Silverman JD, Kurtz SM, Draper J. Skills for communicating with patients.
opt to perform a pyloromyotomy laparoscopically, despite some Oxford: Radcliffe Publishing Ltd.; 2005. pp. 57–105.
10. Nimah MM, Bshesh K, Callahan JD, et al. Infrared tympanic ther-
evidence that open pyloromyotomy is associated with fewer com- mometry in comparison with other temperature measurement techniques
plications than the laparoscopic procedure173 and that the anes- in febrile children. Pediatr Crit Care Med. 2006;7:48–55.
thetic concerns may be greater with the laparoscopic approach. 11. Greenes DS, Fleisher GR. Accuracy of a noninvasive temporal artery
In this situation, the anesthesiologist must disclose all the anes- thermometer for use in infants. Arch Pediatr Adolesc Med. 2001;155:
thetic risks to the family but should avoid commenting on specific 376–381.
12. Hebbar K, Fortenberry JD, Rogers K, et al. Comparison of temporal artery
surgical risks that are the domain of the surgeon.
thermometer to standard temperature measurements in pediatric
Assent implies the agreement of the child as to what is about intensive care unit patients. Pediatr Crit Care Med. 2005;6:557–561.
to occur. This becomes more relevant the older the child. Most 13. Uezono S, Holzman RS, Goto T, et al. Prediction of difficult airway
anesthesiologists are very uncomfortable forcing anesthesia in school-aged patients with microtia. Paediatr Anaesth. 2001;11:
on an unwilling teenager for elective surgery.174 Both consent and 409–413.
14. Rutherford J, Stevenson R. Careful physical examination is essential in
assent for anesthesia-related research purposes are topics unto
the preoperative assessment of children for dental extractions under
themselves and are beyond the scope of this chapter.175–178 general anesthesia. Paediatr Anaesth. 2004;14:920–923.
15. Kulig JW; American Academy of Pediatrics Committee on Substance
Abuse. Tobacco, alcohol, and other drugs: the role of the pediatrician
CONCLUSION in prevention, identification, and management of substance abuse.
Pediatrics. 2005;115:816–821.
When considering the preanesthetic evaluation and preparation 16. American Society of Anesthesiologists. New classification of physical
process, it becomes clear that the key to good outcomes is excellent status. Anesthesiology. 1963;24:111.
communication between the family and all the care providers 17. Ragheb J, Malviya S, Burke C, et al. An assessment of interrater reliability
of the ASA Physical Status Classification in pediatric surgical patients.
involved, as well as excellent communication between the various Paediatr Anaesth. 2006;16:928–931.
18. Aplin S, Baines D, De Lima J. Use of the ASA Physical Status Grading
System in pediatric practice. Paediatr Anaesth. 2007;17:216–222.
TABLE 36-4. Quantification of Anesthesia-Related 19. Nance ML, Adamson WT, Hedrick HL. Appendicitis in the young
Risks in Children child: a continuing diagnostic challenge. Pediatr Emerg Care. 2000;16:
160–162.
Complication Risk Reference 20. Murat I. Airway protection in children with a full stomach. Ann Fr Anesth
Reanim. 2003;22:659–662.
Anesthesia-related mortality 0–0.36:10,000 166–169 21. Jöhr M. Anaesthesia for the child with a full stomach. Curr Opin
Permanent neurologic damage 1:10,000 170 Anaesthesiol. 2007;20:201–203.
from epidural anesthesia 22. Fisher DM. When is the ex–premature infant no longer at risk for apnea?
Awareness 0.8–1.2:100 171 Anesthesiology. 1995;82:807–808.
HIV infection per unit transfused 23. Bryson GL, Chung F, Cox RG, et al: Patient selection in ambulatory
1:4,000,000 172
anesthesia: an evidence-based review, part 2. Can J Anaesth. 2004;51:
Hepatitis B infection per unit 1:31,000 172 782–794.
transfused 24. Peevy KJ, Speed FA, Hoff CJ. Epidemiology of inguinal hernia in preterm
Hepatitis C infection per unit 1:3,000,000 172 neonates. Pediatrics. 1986;77:246–247.
transfused 25. Stylianos S, Jacir NN, Harris BH. Incarceration of inguinal hernia in
infants prior to elective repair. J Pediatr Surg. 1993;28:582–583.
26. Coté CJ, Zaslavsky A, Downes JJ, et al. Postoperative apnea in former 53. Korhonen P, Laitinen J, Hyödynmaa E, et al. Respiratory outcome in
preterm infants after inguinal herniorrhaphy. A combined analysis. school-aged, very-low-birth-weight children in the surfactant era. Acta
Anesthesiology. 1995;82:809–822. Paediatr. 2004;93:316–321.
27. Welborn LG, Hannallah RS, Luban NL, et al. Anemia and post- 54. Kim ES, Bishop MJ. Endotracheal intubation, but not laryngeal mask
operative apnea in former preterm infants. Anesthesiology. 1991;74: airway insertion, produces reversible bronchoconstriction. Anesthesiology.
1003–1006. 1999;90:391–394.
28. Craven PD, Badawi N, Henderson-Smart DJ, et al. Regional (spinal, 55. Habre W, Scalfaro P, Sims C, et al. Respiratory mechanics during sevo-
epidural, caudal) versus general anaesthesia in preterm infants under- flurane anesthesia in children with and without asthma. Anesth Analg.
going inguinal herniorrhaphy in early infancy. Cochrane Database Syst 1999;89:1177–1181.
Rev. 2003;3:CD003669. 56. Kil HK, Rooke GA, Ryan-Dykes MA, et al. Effect of prophylactic
29. Henderson-Smart DJ, Steer P. Prophylactic caffeine to prevent bronchodilator treatment on lung resistance after tracheal intubation.
postoperative apnea following general anesthesia in preterm infants. Anesthesiology. 1994;81:43–48.
Cochrane Database Syst Rev. 2001;4:CD000048. 57. Maslow AD, Regan MM, Israel E, et al. Inhaled albuterol, but not
30. Sasidharan P, Heimler R. Transfusion-induced changes in the breathing intravenous lidocaine, protects against intubation-induced broncho-
pattern of healthy preterm anemic infants. Pediatr Pulmonol. 1992;12: constriction in asthma. Anesthesiology. 2000;93:1198–1204.
170–173. 58. Scalfaro P, Sly PD, Sims C, Habre W. Salbutamol prevents the increase
31. Tetzlaff JE, Annand DW, Pudimat MA, et al. Postoperative apnea in a full- of respiratory resistance caused by tracheal intubation during
term infant. Anesthesiology. 1988;69:426–428. sevoflurane anesthesia in asthmatic children. Anesth Analg. 2001;93:
32. Coté CJ, Kelly DH. Postoperative apnea in a full-term infant with a 898–902.
demonstrable respiratory pattern abnormality. Anesthesiology. 1990;72: 59. Pizov R, Brown RH, Weiss YS, et al. Wheezing during induction of
559–561. general anesthesia in patients with and without asthma. A randomized,
33. Tait AR, Malviya S. Anesthesia for the child with an upper respiratory blinded trial. Anesthesiology. 1995;82:1111–1116.
tract infection: still a dilemma? Anesth Analg. 2005;100:59–65. 60. Warwick JP, Mason DG. Obstructive sleep apnoea syndrome in children.
34. Nichols DG, Yaster M. Victims of our own success or quo vadis pediatric Anaesthesia. 1998;53:571–579.
anesthesia? Anesth Analg. 2007;104:255–257. 61. Rosen GM, Muckle RP, Mahowald MW, et al. Postoperative respiratory
35. Tait AR, Knight PR. The effects of general anesthesia on upper respiratory compromise in children with obstructive sleep apnea syndrome: can it be
tract infections in children. Anesthesiology. 1987;67:930–935.
anticipated? Pediatrics. 1994;93:784–788.
36. DeSoto H, Patel RI, Soliman IE, et al. Changes in oxygen saturation
62. Brown KA. What we don’t know about childhood obstructive sleep
following general anesthesia in children with upper respiratory infection
apnoea. Paediatr Anaesth. 2001;11:385–389.
signs and symptoms undergoing otolaryngological procedures. Anesthe-
63. Carroll JL, Loughlin GM: Diagnostic criteria for obstructive sleep apnea
siology. 1988;68:276–279.
syndrome in children. Pediatr Pulmonol. 1992;14:71–74.
37. Cohen MM, Cameron CB. Should you cancel the operation when a
64. Brouillette RT, Morielli A, Leimanis A, et al. Nocturnal pulse oximetry as
child has an upper respiratory tract infection? Anesth Analg. 1991;72:
282–288. an abbreviated testing modality for pediatric obstructive sleep apnea.
38. Rolf N, Coté CJ. Frequency and severity of desaturation events during Pediatrics. 2000;105:405–412.
general anesthesia in children with and without upper respiratory 65. Wilson K, Lakheeram I, Morielli A, et al. Can assessment for obstructive
infections. J Clin Anesth. 1992;4:200–203. sleep apnea help predict postadenotonsillectomy respiratory compli-
39. Levy L, Pandit UA, Randel GI, et al. Upper respiratory tract infections cations? Anesthesiology. 2002;96:313 –322.
and general anaesthesia in children. Peri-operative complications and 66. Brown KA, Morin I, Hickey C, et al. Urgent adenotonsillectomy: an
oxygen saturation. Anaesthesia. 1992;47:678–682. analysis of risk factors associated with postoperative respiratory
40. Schreiner MS, O’Hara I, Markakis DA, et al. Do children who experience morbidity. Anesthesiology. 2003;99:586–595.
laryngospasm have an increased risk of upper respiratory tract infection? 67. Koomson A, Morin I, Brouillette R, et al. Children with severe OSAS who
Anesthesiology. 1996;85:475–480. have adenotonsillectomy in the morning are less likely to have post-
41. Parnis SJ, Barker DS, Van Der Walt JH. Clinical predictors of anaesthetic operative desaturation than those operated in the afternoon. Can
complications in children with respiratory tract infections. Paediatr J Anaesth. 2004;51:62–67.
Anaesth. 2001;11:29–40. 68. Brown KA, Laferriere A, Moss IR. Recurrent hypoxemia in young
42. Tait AR, Malviya S, Voepel-Lewis T, et al. Risk factors for perioperative children with obstructive sleep apnea is associated with reduced opioid
adverse respiratory events in children with upper respiratory tract requirement for analgesia. Anesthesiology. 2004;100:806–810.
infections. Anesthesiology. 2001;95:299–306. 69. Brown KA, Laferrière A, Lakheeram I, et al. Recurrent hypoxemia in
43. Rachel Homer J, Elwood T, Peterson D, et al. Risk factors for adverse children is associated with increased analgesic sensitivity to opiates.
events in children with colds emerging from anesthesia: a logistic Anesthesiology. 2006;105:665–669.
regression. Paediatr Anaesth. 2007;17:154–161. 70. Moss IR, Brown KA, Laferrière A. Recurrent hypoxia in rats during
44. Tait AR, Reynolds PI, Gutstein HB. Factors that influence an anesthe- development increases subsequent respiratory sensitivity to fentanyl.
siologist’s decision to cancel elective surgery for the child with an upper Anesthesiology. 2006;105:715–718.
respiratory tract infection. J Clin Anesth. 1995;7:491–499. 71. Nixon GM, Kermack AS, McGregor CD, et al. Sleep and breathing on the
45. Coté CJ. The upper respiratory tract infection (URI) dilemma: fear of a first night after adenotonsillectomy for obstructive sleep apnea. Pediatr
complication or litigation? Anesthesiology. 2001;95:283–285. Pulmonol. 2005;39:332–338.
46. Tait AR, Pandit UA, Voepel-Lewis T, et al. Use of the laryngeal mask 72. Walsh TS, Young CH. Anaesthesia and cystic fibrosis. Anaesthesia.
airway in children with upper respiratory tract infections: a comparison 1995;50:614–622.
with endotracheal intubation. Anesth Analg. 1998;86:706–711. 73. Della Rocca G. Anaesthesia in patients with cystic fibrosis. Curr Opin
47. Elwood T, Morris W, Martin LD, et al. Bronchodilator premedication does Anaesthesiol. 2002;15:95–101.
not decrease respiratory adverse events in pediatric general anesthesia. 74. McEwen AI, Birch M, Bingham R. The preoperative management of the
Can J Anaesth. 2003;50:277–284. child with a heart murmur. Paediatr Anaesth. 1995;5:151–156.
48. Tait AR, Burke C, Voepel-Lewis T, et al. Glycopyrrolate does not reduce 75. Smythe JF, Teixeira OH, Vlad P, et al. Initial evaluation of heart murmurs:
the incidence of perioperative adverse events in children with upper are laboratory tests necessary? Pediatrics. 1990;86:497–500.
respiratory tract infections. Anesth Analg. 2007;104:265–270. 76. Baum VC, Barton DM, Gutgesell HP. Influence of congenital heart disease
49. Rieger A, Schroter G, Philippi W, et al. A comparison of sevoflurane with on mortality after noncardiac surgery in hospitalized children. Pediatrics.
halothane in outpatient adenotomy in children with mild upper 2000;105:332–335.
respiratory tract infections. J Clin Anesth. 1996;8:188–197. 77. Torres A Jr, DiLiberti J, Pearl RH, et al. Noncardiac surgery in children
50. Desager KN, Nelen V, Weyler JJ, et al. Sleep disturbance and daytime with hypoplastic left heart syndrome. J Pediatr Surg. 2002;37:1399–1403.
symptoms in wheezing school-aged children. J Sleep Res. 2005;14:77–82. 78. Sümpelmann R, Osthaus WA. The pediatric cardiac patient presenting
51. Kingston HG, Hirshman CA. Perioperative management of the patient for noncardiac surgery. Curr Opin Anaesthesiol. 2007;20:216–220.
with asthma. Anesth Analg. 1984;63:844–855. 79. Wilson W, Taubert KA, Gewitz M, et al. Prevention of infective endo-
52. Cox RG: Repair of incarcerated inguinal hernia in an infant with acute carditis: guidelines from the American Heart Association. Circulation.
viral bronchiolitis. Can J Anaesth. 2004;51:68–71. 2007;116:1736–1754.
80. Breau LM, Finley GA, McGrath PJ, et al. Validation of the Non- 110. O’Connor ME, Drasner K. Preoperative laboratory testing of children
Communicating Children’s Pain Checklist—Postoperative Version. undergoing elective surgery. Anesth Analg. 1990;70:176–180.
Anesthesiology. 2002;96:528–535. 111. Hackmann T, Steward DJ, Sheps SB. Anemia in pediatric day-surgery
81. Morris P. Duchenne muscular dystrophy: a challenge for the patients: prevalence and detection. Anesthesiology. 1991;75:27–31.
anaesthetist. Paediatr Anaesth. 1997;7:1–4. 112. Steward DJ. Screening tests before surgery in children. Can J Anaesth.
82. Hayes J, Veyckemans F, Bissonnette B. Duchenne muscular dystrophy: 1991;38:693–695.
an old anesthesia problem revisited. Paediatr Anaesth. 2008;18:100–106. 113. Roy WL, Lerman J, McIntyre BG. Is preoperative haemoglobin testing
83. Shipton EA, Prosser DO. Mitochondrial myopathies and anaesthesia. justified in children undergoing minor elective surgery? Can J Anaesth.
Eur J Anaesthesiol. 2004;21:173–178. 1991;38:700–703.
84. van der Walt JH, Moran C. An audit of perioperative management of 114. Crawford MW, Galton S, Abdelhaleem M. Preoperative screening for
autistic children. Paediatr Anaesth. 2001;11:401–408. sickle cell disease in children: clinical implications. Can J Anaesth. 2005;
85. Yentis SM, Levine MF, Hartley EJ. Should all children with suspected or 52:1058–1063.
confirmed malignant hyperthermia susceptibility be admitted after 115. Shafer FE, Lorey F, Cunningham GC, et al. Newborn screening for sickle
surgery? A 10-year review. Anesth Analg. 1992;75:345–350. cell disease: 4 years of experience from California’s newborn screening
86. Chadwick V, Wilkinson KA. Diabetes mellitus and the pediatric program. J Pediatr Hematol Oncol. 1996;18:36–41.
anesthetist. Paediatr Anaesth. 2004;14:716–723. 116. Asaf T, Reuveni H, Yermiahu T, et al. The need for routine pre-operative
87. Rhodes ET, Ferrari LR, Wolfsdorf JI. Perioperative management of coagulation screening tests (prothrombin time PT/partial thrombo-
pediatric surgical patients with diabetes mellitus. Anesth Analg. 2005; plastin time PTT) for healthy children undergoing elective tonsillectomy
101:986–999. and/or adenoidectomy. Int J Pediatr Otorhinolaryngol. 2001;61:217–222.
88. Hans P, Vanthuyne A, Dewandre PY, et al. Blood glucose concentration 117. Hennrikus WL, Shaw BA, Gerardi JA. Prevalence of positive preoper-
profile after 10 mg dexamethasone in non-diabetic and type 2 diabetic ative pregnancy testing in teenagers scheduled for orthopedic surgery.
patients undergoing abdominal surgery. Br J Anaesth. 2006;97:164–170. J Pediatr Orthop. 2001;21:677–679.
89. Legrand R, Tobias JD. Anesthesia and Prader-Willi syndrome: prelimi- 118. Azzam FJ, Padda GS, DeBoard JW, et al. Preoperative pregnancy testing
nary experience with regional anesthesia. Paediatr Anaesth. 2006;16: in adolescents. Anesth Analg. 1996;82:4–7.
712–722. 119. Duncan PG, Pope WD. Medical ethics and legal standards. Anesth Analg.
90. Schmidt J, Kroeber S, Irouschek A, et al. Anesthetic management of 1996;82:1–3.
patients with ornithine transcarbamylase deficiency. Paediatr Anaesth. 120. Davidson AJ, Shrivastava PP, Jamsen K, et al. Risk factors for anxiety at
2006;16:333–337. induction of anesthesia in children: a prospective cohort study. Paediatr
91. Hammer GB. Anaesthetic management for the child with a mediastinal Anaesth. 2006;16:919–927.
mass. Paediatr Anaesth. 2004;14:95–97. 121. Kain ZN, Caldwell-Andrews AA, Maranets I, et al. Preoperative anxiety
92. Anghelescu DL, Burgoyne LL, Liu T, et al. Clinical and diagnostic imaging and emergence delirium and postoperative maladaptive behaviors.
findings predict anesthetic complications in children presenting with Anesth Analg. 2004;99:1648–1654.
malignant mediastinal masses. Paediatr Anaesth. 2007;17:1090–1098. 122. Kain ZN, Mayes LC, Caldwell-Andrews AA, et al. Preoperative anxiety,
93. Leelanukrom R, Pancharoen C. Anesthesia in HIV-infected children. postoperative pain, and behavioral recovery in young children
Paediatr Anaesth. 2007;17:509–519. undergoing surgery. Pediatrics. 2006;118:651–658.
94. Marchant WA, Walker I. Anaesthetic management of the child with 123. Cox RG, Nemish U, Ewen A, et al. Evidence-based clinical update: does
sickle cell disease. Paediatr Anaesth. 2003;13:473–489. premedication with oral midazolam lead to improved behavioral
95. Vichinsky EP, Haberkern CM, Neumayr L, et al., and the Preoperative outcomes in children? Can J Anaesth. 2006;53:1213–1219.
Transfusion in Sickle Cell Disease Study Group. A comparison of 124. Bergendahl H, Lönnqvist P-A, Eksborg S. Clonidine in paediatric
conservative and aggressive transfusion regimens in the perioperative anaesthesia: review of the literature and comparison with benzo-
management of sickle cell disease. N Engl J Med. 1995;333:206–213. diazepines for premedication. Acta Anaesthesiol Scand. 2006;50:135–143.
96. Hirst C, Williamson L. Preoperative blood transfusions for sickle cell 125. Bozkurt P. Premedication of the pediatric patient—anesthesia for the
disease. Cochrane Database Syst Rev. 2001:3:CD003149. uncooperative child. Curr Opin Anaesthesiol. 2007;20:211–215.
97. Yaster M, Kost-Byerly S, Maxwell LG. The management of pain in sickle 126. Calipel S, Lucas-Polomeni MM, Wodey E, et al. Premedication in
cell disease. Pediatr Clin North Am. 2000;47:699–710. children: hypnosis versus midazolam. Paediatr Anaesth. 2005;15:
98. Bissonnette B, Luginbuel I, Marciniak B, et al. Syndromes: Rapid 275–281.
Recognition and Perioperative Implications. New York: McGraw-Hill 127. Kain ZN, Caldwell-Andrews AA, Krivutza DM, et al. Interactive music
Medical Publishing Division; 2006. therapy as a treatment for preoperative anxiety in children: a rando-
99. Butler MG, Hayes BG, Hathaway MM, Begleiter ML. Specific genetic mized controlled trial. Anesth Analg. 2004;98:1260–1266.
diseases at risk for sedation/anesthesia complications. Anesth Analg. 128. Wang SM, Maranets I, Weinberg ME, et al. Parental auricular
2000;91:837–855. acupuncture as an adjunct for parental presence during induction of
100. Mitchell V, Howard R, Facer E. Down’s syndrome and anaesthesia. anesthesia. Anesthesiology. 2004;100:1399–1404.
Paediatr Anaesth. 1995;5:379–384. 129. Vagnoli L, Caprilli S, Robiglio A, et al. Clown doctors as a treatment for
101. Meitzner MC, Skurnowicz JA. Anesthetic considerations for patients preoperative anxiety in children: a randomized, prospective study.
with Down syndrome. AANA J. 2005;73:103–107. Pediatrics. 2005;116:e563–e567.
102. Beilin B, Kadari A, Shapira Y, et al. Anaesthetic considerations in facial 130. O’Byrne KK, Peterson L, Saldana L. Survey of pediatric hospitals’
reconstruction for Down’s syndrome. J R Soc Med. 1988;81:23–26. preparation programs: evidence of the impact of health psychology
103. Marcus CL, Keens TG, Bautista DB, et al. Obstructive sleep apnea in research. Health Psychol. 1997;16:147–154.
children with Down syndrome. Pediatrics. 1991;88:132–139. 131. Kain ZN, Caldwell-Andrews AA, Mayes LC, et al. Family-centered
104. Keele DK, Richards C, Brown J, et al. Catecholamine metabolism in preparation for surgery improves perioperative outcomes in children: a
Down’s syndrome. Am J Ment Defic. 1969;74:125–129. randomized controlled trial. Anesthesiology. 2007;106:65–74.
105. Borland LM, Colligan J, Brandom BW. Frequency of anesthesia-related 132. Maclaren J, Kain ZN. Pediatric preoperative preparation: a call for
complications in children with Down syndrome under general anesthesia evidence-based practice. Paediatr Anaesth. 2007;17:1019–1020.
for noncardiac procedures. Paediatr Anaesth. 2004;14:733–738. 133. Lerman J. Anxiolysis—by the parent or for the parent? Anesthesiology.
106. Wark HJ, Overton JH, Marian P. The safety of atropine premedication in 2000;92:925–927.
children with Down’s syndrome. Anaesthesia. 1983;38:871–874. 134. Kain ZN, Mayes LC, Caramico LA, et al. Parental presence during
107. Hata T, Todd MM. Cervical spine considerations when anesthetizing induction of anesthesia. A randomized controlled trial. Anesthesiology.
patients with Down syndrome. Anesthesiology. 2005;102:680–685. 1996;84:1060–1067.
108. Litman RS, Zerngast BA, Perkins FM. Preoperative evaluation of the 135. Kain ZN, Mayes LC, Wang SM, et al. Parental presence during induction
cervical spine in children with trisomy-21: results of a questionnaire of anesthesia versus sedative premedication: which intervention is more
study. Paediatr Anaesth. 1995;5:355–361. effective? Anesthesiology. 1998;89:1147–1156.
109. Abramson PJ, Todd NW, Holt PJ, et al. Neck flexion and extension in 136. Kain ZN, Caldwell-Andrews AA, Wang SM, et al. Parental intervention
children with Down syndrome: a somatosensory study. Laryngoscope. choices for children undergoing repeated surgeries. Anesth Analg.
1995;105:1209–1212. 2003;96:970–975.
137. Arai YC, Ito H, Kandatsu N, et al. Parental presence during induction 160. Blanc VF. Atropine and succinylcholine: beliefs and controversies in
enhances the effect of oral midazolam on emergence behavior of paediatric anaesthesia. Can J Anaesth. 1995;42:1–7.
children undergoing general anesthesia. Acta Anaesthesiol Scand. 161. Shorten GD, Bissonnette B, Hartley E, et al. It is not necessary to
2007;51:858–861. administer more than 10 micrograms kg–1 of atropine to older children
138. Kain ZN, Caldwell-Andrews AA, Krivutza DM, et al. Trends in the before succinylcholine. Can J Anaesth. 1995;42:8–11.
practice of parental presence during induction of anesthesia and the 162. Wolf AR. Tears at bedtime: a pitfall of extending paediatric day-case
use of preoperative sedative premedication in the United States, 1995– surgery without extending analgesia. Br J Anaesth. 1999;82:319–320.
2002: results of a follow-up national survey. Anesth Analg. 2004;98: 163. Vlajkovic GP, Sindjelic RP. Emergence delirium in children: many
1252–1259. questions, few answers. Anesth Analg. 2007;104:84–91.
139. Kain ZN, Mayes LC, Wang SM, et al. Parental presence and a sedative 164. Bolton CM, Myles PS, Nolan T, et al. Prophylaxis of postoperative
premedicant for children undergoing surgery: a hierarchical study. vomiting in children undergoing tonsillectomy: a systemic review and
Anesthesiology. 2000;92:939–946. meta-analysis. Br J Anaesth. 2006;97:593–604.
140. McEwen A, Moorthy C, Quantock C, et al. The effect of videotaped 165. Goodarzi M, Matar MM, Shafa M, et al. A prospective randomized
preoperative information on parental anxiety during anesthesia blinded study of the effect of intravenous fluid therapy on postoperative
induction for elective procedures. Paediatr Anaesth. 2007;17:534–539. nausea and vomiting in children undergoing strabismus surgery.
141. Coté CJ, Goudsouzian NG, Liu LM, et al. Assessment of risk factors Paediatr Anaesth. 2006;16:49–53.
related to the acid aspiration syndrome in pediatric patients—gastric pH 166. Morray JP, Geiduschek JM, Ramamoorthy C, et al. Anesthesia-related
and residual volume. Anesthesiology. 1982;56:70–72. cardiac arrest in children: initial findings of the Pediatric Perioperative
142. Splinter WM, Schaefer JD, Zunder IH. Clear fluids three hours before Cardiac Arrest (POCA) Registry. Anesthesiology. 2000;93:6–14.
surgery do not affect the gastric fluid contents of children. Can J Anaesth. 167. Tay CL, Tan GM, Ng SB. Critical incidents in paediatric anaesthesia: an
1990;37:498–501. audit of 10,000 anaesthetics in Singapore. Paediatr Anaesth. 2001;
143. Schreiner MS, Triebwasser A, Keon TP. Ingestion of liquids compared 11:711–718.
with preoperative fasting in pediatric outpatients. Anesthesiology. 168. Murat I, Constant I, Maud’huy H. Perioperative anaesthetic morbidity in
1990;72:593–597. children: a database of 24,165 anaesthetics over a 30-month period.
144. Schwartz DA, Connelly NR, Theroux CA, et al. Gastric contents in Paediatr Anaesth. 2004;14:158–166.
children presenting for upper endoscopy. Anesth Analg. 1998;87: 169. Bhananker SM, Ramamoorthy C, Geiduschek JM, et al. Anesthesia-
757–760. related cardiac arrest in children: update from the Pediatric Perioperative
145. Schreiner MS. Gastric fluid volume: is it really a risk factor for Cardiac Arrest Registry. Anesth Analg. 2007;105:344–350.
pulmonary aspiration? Anesth Analg. 1998;87:754–756. 170. Llewellyn N, Moriarty A. The national pediatric epidural audit. Paediatr
146. Ferrari LR, Rooney FM, Rockoff MA. Preoperative fasting practices in Anaesth. 2007;17:520–533.
pediatrics. Anesthesiology. 1999;90:978–980. 171. Davidson AJ, Huang GH, Czarnecki C, et al. Awareness during
147. Friesen RH, Wurl JL, Friesen RM. Duration of preoperative fast anesthesia in children: a prospective cohort study. Anesth Analg.
correlates with arterial blood pressure response to halothane in infants. 2005;100:653–661.
Anesth Analg. 2002;95:1572–1576. 172. Kleinman S, Chan P, Robillard P. Risks associated with transfusion
148. Warner MA, Warner ME, Warner DO, et al. Perioperative pulmonary of cellular blood components in Canada. Transfus Med Rev. 2003;17:
aspiration in infants and children. Anesthesiology. 1999;90:66–71. 120–162.
149. Dubin SA, Jense HG, McCranie JM, et al. Sugarless gum chewing before 173. Hall NJ, Van Der Zee J, Tan HL, Pierro A. Meta-analysis of laparoscopic
surgery does not increase gastric fluid volume or acidity. Can J Anaesth. versus open pyloromyotomy. Ann Surg. 2004;240:774–778.
1994;41:603–606. 174. Lewis I, Burke C, Voepel-Lewis T, et al. Children who refuse anesthesia
150. Søreide E, Holst-Larsen H, Veel T, et al. The effects of chewing gum on or sedation: a survey of anesthesiologists. Paediatr Anaesth. 2007;
gastric content prior to induction of general anesthesia. Anesth Analg. 17:1134–1142.
1995;80:985–989. 175. Tait AR, Voepel-Lewis T, Malviya S. Do they understand? (Part I):
151. Schoenfelder RC, Ponnamma CM, Freyle D, et al. Residual gastric parental consent for children participating in clinical anesthesia and
fluid volume and chewing gum before surgery. Anesth Analg. 2006; surgery research. Anesthesiology. 2003;98:603–608.
102:415–417. 176. Tait AR, Voepel-Lewis T, Malviya S. Do they understand? (Part II):
152. Bennie RE, Boehringer LA, McMahon S, et al. Postoperative analgesia assent of children participating in clinical anesthesia and surgery
with preoperative oral ibuprofen or acetaminophen in children research. Anesthesiology. 2003;98:609–614.
undergoing myringotomy. Paediatr Anaesth. 1997;7:399–403. 177. Denham EJ, Nelson RM. Self-determination is not an appropriate model
153. Bhananker SM, Azavedo L, MacCormick J, et al. Topical lidocaine and for understanding parental permission and child assent. Anesth Analg.
oral acetaminophen provide similar analgesia for myringotomy and tube 2002;94:1049–1051.
placement in children. Can J Anaesth. 2006;53:1111–1116. 178. Erb TO, Schulman SR, Sugarman J. Permission and assent for clinical
154. Korpela R, Korvenoja P, Meretoja OA. Morphine-sparing effect of research in pediatric anesthesia. Anesth Analg. 2002;94:1155–1160.
acetaminophen in pediatric day-case surgery. Anesthesiology. 1999;91: 179. American Academy of Pediatrics. Section on Anesthesiology. Evaluation
442–447. and preparation of pediatric patients undergoing anesthesia. Pediatrics.
155. Anderson BJ, Holford NH, Woollard GA, et al. Perioperative pharmaco- 1996;98:502–508.
dynamics of acetaminophen analgesia in children. Anesthesiology. 180. Maxwell LG. Age-associated issues in preoperative evaluation, testing,
1999;90:411–421. and planning: pediatrics. Anesthesiol Clin North Am. 2004;22:27–43.
156. Birmingham PK, Tobin MJ, Fisher DM, et al. Initial and subsequent 181. Le T, Drolet J, Parayno E, Rosmus C, et al. Follow-up phone calls after
dosing of rectal acetaminophen in children: a 24-hour pharmacokinetic pediatric ambulatory surgery for tonsillectomy: what can we learn from
study of new dose recommendations. Anesthesiology. 2001;94:385–389. families? J Perianesth Nurs. 2007;22:256–264.
157. Heubi JE, Barbacci MB, Zimmerman HJ. Therapeutic misadventures 182. Jones DT, Yoon MJ, Licameli G. Effectiveness of postoperative follow-up
with acetaminophen:hepatoxicity after multiple doses in children. telephone interviews for patients who underwent adenotonsillectomy:
J Pediatr. 1998;132:22–27. a retrospective study. Arch Otolaryngol Head Neck Surg. 2007;133:
158. Jöhr M. Is it time to question the routine use of anticholinergic agents in 1091–1095.
paediatric anaesthesia? Paediatr Anaesth. 1999;9:99–101. 183. Gidman W, Elliott R, Payne K, et al. A comparison of parents and
159. Mirakhur RK, Jones CJ, Dundee JW, et al. I.M. or I.V. atropine or pediatric anesthesiologists’ preferences for attributes of child daycase
glycopyrrolate for the prevention of oculocardiac reflex in children surgery: a discrete choice experiment. Paediatr Anaesth. 2007;17:
undergoing squint surgery. Br J Anaesth. 1982;54:1059–1063. 1043–1052.
Premedication, Sedation,
37 and Preoperative Fasting
C H A P T E R William M. Splinter and Jarmila Kim
PREOPERATIVE SEDATION Advanced, family-centered preoperative preparation programs

not only are as effective as oral midazolam for preoperative anxiety
OF CHILDREN reduction but also reduce the incidence of emergence delirium
Children undergoing anesthesia and surgery can experience and analgesics requirements in the recovery area.10
significant anxiety and distress during the preoperative period. Up Although the presence of parents at the induction of anesthesia
to 50% of children undergoing surgery are reported to exhibit has become commonplace in some centers, the incidence and
significant anxiety preoperatively.1,2 Preoperative sedation, or the attitude toward it vary widely. In a 1996 survey, 58% of American
commonly simplified term premedication, is often administered anesthesiologists allowed parental presence in fewer than 5% of
to children to allay this anxiety. Factors that may increase anxiety cases, whereas 84% of British anesthesiologists allowed parental
include separation from the family, anticipation of postoperative presence in more than 75% of cases.11 This discrepancy may be
pain, fear of surgery and/or anesthesia, loss of independence, attributable to the availability of induction rooms and cultural,
and fear of death.3,4 This anxiety can be of minor importance and anesthetic, medicolegal, economic, and resource-based differences
intervention is not indicated, but in other situations, the parent(s) and not necessarily evidence-based factors. There has been limited
and/or child may become quite dysfunctional and a variety of study of factors surrounding this issue. Although the majority of
anxiolytic interventions may be beneficial. parents prefer to accompany their children during induction of
Anxiety can be divided into state-anxiety and trait-anxiety. anesthesia or minor medical procedures, parental presence is not
State-anxiety is a transitory emotional condition that consists always effective.11 Kain and coworkers studied some of these issues
of feelings of tension, apprehension, nervousness, and worry. This when they divided parents and their children preoperatively into
state fluctuates in intensity over time. Trait-anxiety refers to three groups: a control group, a parental-presence group, and a
individual differences in anxiety proneness, being a personality premedication group (oral midazolam 0.5 mg/kg).12 The parent
trait that remains relatively stable over time.5 High state-anxiety and child in the premedication group demonstrated the least
scores indicate high levels of anxiety at the time of evaluation, amount of anxiety at critical points (separation and induction of
whereas high levels of trait-anxiety indicate an anxious personality anesthesia) during the preoperative period.12 Children were also
disposition.6 found to be calmer if they were older than 4 years, if their tem-
Preoperative anxiety is exhibited in several ways. Depending perament had lower levels of activity and impulsivity, or if they
upon the age of the child, this anxiety may be exhibited verbally had parental presence.13,14 Parent satisfaction ratings are very
and/or behaviorally. Crying, silence, pallor, agitation, deep breathing, high with parental presence and nearly all parents (>97%) feel they
trembling, urinary retention, violent actions, tense muscles, and help their child during induction of anesthesia and judge their
other activities may be signs and symptoms of the anxious child. presence during this time as positive. However, some parents
This stress usually peaks at the time of induction of anesthesia.7 become distraught at the sight of their child at induction. With
Interventions currently available to treat and/or prevent the current information available, parental presence at induction
preoperative anxiety fall into three major categories: (1) providing of anesthesia should be considered a “therapeutic option” but
hospital-based preparation programs before surgery, (2) adminis- should be used at the discretion of the attending anesthesiologist
tration of sedatives and anxiolytics before surgery, and (3) parental and not the parent.12
presence at induction of anesthesia. Preoperative preparation The aims of premedication vary among individual anesthesi-
programs have been in existence since the early 1960s, and initially, ologists, parents, and children. The goals should include decreased
the programs were exclusively information-oriented. Evidence- psychological stress of both patient and parent(s) by allaying
based recommendations for such programs suggest that (1) infor- apprehension, uncertainty, fear, or excitement and should facilitate
mation on both procedural and sensory aspects of the procedure separation of the child from the parent. Other desirable properties
should be included, (2) coping skills should be taught via a peer include a rapid and predictable onset and offset, select amnestic
model, (3) written materials alone are not effective and preparation properties, ease of administration, low cost, facilitation of induction
should be provided at least 5 days in advance for children older of anesthesia, analgesic and antiemetic properties and minimal
than 6 years and no more than a week in advance for children adverse interactions with other medication, and patient physiology.
younger than 6 years.8 A survey of 34 children’s hospitals and The large quantity of literature published on premedication for
24 community hospitals with pediatric surgery revealed that most children suggests that the ideal agent has yet to be produced.
preoperative programs do not meet evidence-based criteria mainly Generally, the following are accepted indications for pre-
because of cost and time constraints.9 medication:
CHAPTER 37 ■ Premedication, Sedation, and Preoperative Fasting 585
TABLE 37-1. Children Who Should Be Carefully and rectal routes are most commonly used. Although popular,
Assessed Before and Monitored After Administration the efficacy of drugs administered by these routes is not always
of Sedative Premedication predictable because of marked fluctuations in bioavailability and
a substantial first-pass effect.15–19
1. Children with central or obstructive apnea syndrome.131
2. Children with adenotonsillar hypertrophy.
3. Children with functional macroglossia, for example, Oral
hypertrophy of the tongue (Down syndrome, Beckwith- Oral is usually the most acceptable route.20,21 Issues of concern
Weideman syndrome) or relative micrognathism (Pierre- include medication palatability, volume required, onset, duration
Robin syndrome). of action, behavior during recovery, interaction with other
4. Children with neurologic impairment, including medications, and side effects.
gastroesophageal reflux, dysphagia, or impaired cough.
5. Children with muscular dystrophy.
6. Infants less than 10 kg. Midazolam
7. Children with cyanotic heart disease (they may become more A large-scale U.S. survey indicated that oral midazolam is the
cyanotic or develop hypercarbia). preoperative sedative of choice for children in 90% of cases.22
A dose of 0.5 mg/kg to a maximum of 15 to 20 mg produces con-
sistent preoperative anxiolysis with a wide margin of safety.23
1. Children who have had previous surgical experiences, because Increasing the dose above 0.5 mg/kg typically does not enhance
they are generally aware of the discomforts related to the its sedative and anxiolytic effects.24 Infants and children under-
upcoming surgery.15 going cardiovascular surgery, however, had decreased agitation
2. Children who will not separate from their parents easily. on induction, improved sedation, and increased SpO2 (oxygen
3. Children for whom the anesthesiologist is of the opinion that saturation of hemoglobin monitored with pulse oximetry) after
parental presence at the time of induction would not be of 1.5 mg/kg versus 0.5 mg/kg.25
benefit.15 Sedation and anxiolysis can be observed 10 minutes after
4. Children with neurologic or developmental disabilities and administration26 and within 20 minutes in the majority of
mental health issues causing behavioral disorders, autism, or children.23 The onset of sedation can be reduced by 4 minutes with
other personality disorders. the addition of antacids (sodium citrate) to the oral midazolam.27
5. Children who require a smooth anesthetic induction with The peak effect is seen at 30 minutes, and by 45 minutes, the
minimal crying or struggling (e.g., children with cyanotic heart incidence of satisfactory separation scores begins to decline.28
disease). Anxiolysis and light sedation can still be present up to 2 hours
6. Adolescents who show significant degrees of anxiety. after administration.16,29
(Adolescents in particular are often fearful of loss of control, Awakening times appear to be minimally delayed by mida-
loss of body image, and dying under anesthesia and may be zolam. There is inconsistent evidence that discharge times are
quite anxious despite outward attempts of “bravado.”) increased by midazolam premedication.28,30–33 In a recent review,
The risks of preoperative premedication include respiratory it was concluded that oral midazolam reduces both separation
and induction anxiety in healthy children and has minimal effect
depression, loss of protective reflex control, and a paradoxical
on recovery times.34 Given that the sedative, amnestic and anxi-
response to the drug. The physical status, age, and underlying
olytic properties of midazolam are relatively brief and begin to
surgical pathology may modify the risks. For example, emergency
wane after 45 to 60 minutes, the timing of its administration is
surgery, a full stomach, head injury, and abdominal trauma may
important. In order to avoid disruptions in the operating room
markedly affect the need for premedication. In a normal healthy
schedule, the specific timing of premedication administration
child, these risks are minimal, but when complications arise,
should ideally be determined by the anesthesiologist assigned to
they are usually caused by a relative overdosage. However, some
the case. If given too early and the child is no longer adequately
children who are at increased risk and discretion should be
sedated on arrival in the operating room, consideration should be
used with premedication (Table 37–1). These patients, especially given to repeating the oral midazolam using a reduced dosage
those with a history of obstructive sleep apnea, require very close (~0.25 mg/kg) and, if warranted, reorganizing the operating room
observation after receiving premedication. schedule to accommodate this.
Incredibly, there is still no consensus on the benefits of pre- The major problem with midazolam is its bitter taste, even
medication in children, especially infants. That said, a sedated, when mixed with flavored syrup. The commercially prepared
cooperative child invariably reduces the anxiety level in those midazolam syrup, introduced in 1998, has an improved taste and
parents whose own anxiety and fears may be contributing signi- a lower pH than the intravenous preparation.35 This lowered pH
ficantly to the preoperative behavior of the child. Parents and increases its bioavailability, but the dose may be unpredictable if a
patients, therefore, obtain different potential benefits from preme- crystalline precipitate is present.36 From time to time, a child may
dication. These include amnesia, anxiolysis (patient and parent), expectorate an unpalatable oral premedicant. Although an attempt
analgesia, and increased cooperation. can be made to repeat the oral dose, this will probably be futile,
and an alternative route of administration should be considered.
In a recent survey of members of the Society for Pediatric Anes-
SEDATIVE PREMEDICATIONS thesia in the United States, 45% of the respondents had cancelled
Sedative premedication can be administered by various routes that 1 or more cases during their career because the child had refused
will determine the doses and the onset times (Table 37–2). Oral to take the premedication.37 These rare events affect operating
TABLE 37-2. Premedicant Drugs

Agent Route Dose Onset, min Common Adverse Effects
Benzodiazepines
Midazolam Oral 0.3–0.7 mg/kg (max. 15 mg) 15–30 Respiratory depression
Nasal 0.1–0.2 mg/kg (max. 3.0–10.0 mg) 5–10 Postoperative excitation
Rectal 0.5–1.0 mg/kg 15–30
Diazepam Oral 0.1–0.3 mg/kg (max. 10 mg) 30–60 Excitation
Dissociative
Ketamine Oral 3–8 mg/kg 10–15 Secretions
Nasal 3–5 mg/kg Increased blood pressure
I.M. 2–5 mg/kg (max. 150 mg) 2–5 Increased intracranial pressure
Rectal 0.3–0.5 mg/kg
Opioids
Morphine I.M. 0.1–0.2 mg/kg (max. 5.0 mg) 15–30
Meperidine I.M. 0.5–1.0 mg/kg (max. 5.0 mg) 15–30 Respiratory depression
Pruritus
Prolonged duration
Fentanyl (lollipops) Oral 10–15 mg/kg (max. 250 mg) 5–15 Itching
Respiratory depression
Sufentanil Nasal 1.5–3.0 mg/kg (max. 50 mg) 5–10 Itching
Respiratory depression
α2 Agonists
Clonidine Oral 2–4 μg/kg Prolonged sedation
Rectal 2–5 μg/kg
Dexmedetomidine Oral/nasal 1–4 μg/kg Transient hypotension and
bradycardia
Barbiturates
Pentobarbital Oral 3.0 mg/kg (max. 30 mg) 60 Prolonged duration
Postoperative excitation
Methohexital Rectal (10% 30 mg/kg (max. 500 mg) 5–10 Rectal irritation
solution) Respiratory depression
Pentothal Rectal (5–10%) 30 mg/kg (max. 500 mg) 5–10 Prolonged duration
Others
Melatonin Oral 0.25–0.5 mg/kg 30–60 None reported
room efficiency and may have consequences related to delayed reactions.40 Abnormal postoperative behavior as the result of a
surgery and treatment. relative overdose of midazolam can be rapidly reversed with
Although midazolam usually provides effective preoperative flumazenil using 10-μg/kg increments to a maximum of 1 mg
anxiolysis, many clinicians are aware that some children still intravenously.
exhibit significant distress despite premedication. Satisfactory Midazolam has been compared with other pharmacologic
anxiolysis occurs in 97.5% of children receiving midazolam, agents. When compared with oral chloral hydrate, both pre-
whereas only 86% have a “satisfactory anxiety rating” at facemask operative and postoperative behaviors were considered better
application.24 There appears to be a subgroup of children that are in the midazolam group.41 Oral midazolam is similar to rectal
“midazolam nonresponders.” This group tends to be younger, methohexital with respect to separation at induction, sedation,
more anxious preoperatively, and higher on the emotionality and recovery scores.42 When compared with zolpidem, a short-
subscale of the EASI (Emotionality, Activity, Sociability, and acting nonbenzodiazepine hypnotic, both provided equally
Impulsivity) Instrument of Child Temperament.38,39 effective sedation and anxiolysis.43 Oral etomidate 1.3 mg/kg was
Midazolam may also have adverse effects postoperatively. compared with midazolam and sedation was similar, but recov-
Preoperative oral midazolam has been noted to increase or have ery and discharge times after etomidate were decreased.44 Oral
no effect on postoperative emergence delirium or agitation.33,40 ketamine 5 mg/kg had similar onset time and sedative effect, but
The data addressing behavioral outcomes, such as nightmares, delayed recovery.45 Rectal thiopentone 35 mg/kg led to better
temper tantrums, and bed wetting, in the first few weeks post- sedation and lower anxiety scores but prolonged recovery times.46
operatively are inconsistent.34 Doses exceeding 0.5 mg/kg or When compared with trimeprazine 2 mg/kg and to diazepam-
associated with more side effects in the recovery period, including droperidol both 0.25 mg/kg, sedation and anxiolysis were
loss of balance and head control, blurred vision, and dysphoric improved after midazolam.47
Fentanyl of compensatory homeostatic reflexes is highly desirable in pedi-

Oral transmucosal fentanyl citrate (OTFC or “fentanyl lollipop”) atric anesthesia. Although clonidine can induce hypotension
is a formulation of fentanyl citrate embedded in a sweetened and bradycardia, no serious adverse effects, such as pronounced
matrix that dissolves in a child’s mouth. It has been used by some hypotension and bradycardia, have been reported in children
with success as a premedicant.48–51 Fentanyl readily crosses the when using doses of clonidine less than 10 μg/kg.62
mucosal barrier of the oral cavity and peak blood levels are usually Dexmedetomidine is an imidazole α2 agonist that is similar to
achieved 15 to 30 minutes after sucking is initiated.52 It loses clonidine but with an even higher α2/α1 specificity ratio of 1600:1
efficacy and bioavailability when chewed or swallowed. OTFC (compared with clonidine 200:1). Its elimination half-life is 1.5 to
was similar to that of an oral solution of meperidine, diazepam, 3 hours. Given its unique mechanism of action and limited effects
and atropine.49 Overall, it does not appear to be cost-effective or on cardiorespiratory function, it may offer specific advantages
as a premedicant for oral administration. Data in children are
beneficial, given its side effects of respiratory depression, pruritus,
limited, although preliminary experience suggests that an oral or
and vomiting.48,50,53,54 Some anesthesiologists have ethical concerns
transmucosal dose of 1 to 4 μg/kg may be a useful alternative.70
delivering a premedicant sedative in lollipop form.
Children who received intranasal dexmedetomidine 2 μg/kg were
more likely to be asleep before entering the operating than those
Ketamine who received oral midazolam.71 Both medications were similar in
Oral ketamine is a popular alternative to oral benzodiazepines but effectiveness during induction and emergence of anesthesia. Oral
has a high hepatic first-pass effect.55 A dose of 6 mg/kg is well midazolam 0.5 mg/kg, oral clonidine 4 μg/kg, or transmucosal
tolerated and predictably provided sedation by 20 to 25 minutes, dexmedetomidine 1 μg/kg regimens are all comparable in terms of
leading to a calm separation from parent and good induction reducing preoperative anxiety; however, the α2 agonists were
conditions.56 Oral ketamine was not associated with respiratory associated with less perioperative sympathetic stimulation and
depression, tachycardia, or emergence phenomena,56 but adverse less postoperative pain.72 Further prospective trials are needed to
events (oxygen desaturations, laryngospasm, and hallucinations) more clearly define the effective dose as well as to compare oral
are common.57 Ketamine 5 to 6 mg/kg has also been successfully dexmedetomidine with other premedicants.
administered in “lollipop” form.58
Melatonin
Pentobarbital Melatonin is a hormone involved in the diurnal rhythm of sleep
Barbiturates were used for many years as oral premedicants before and is a potentially useful oral natural-sleep agent. The sleep-
the advent of midazolam. Their onset of action is slow and their inducing properties of melatonin differ from those of benzo-
duration is long. Pentobarbital 3 mg/kg to a maximum of 30 mg diazepines. It does not suppress rapid eye movement sleep and
has an onset time of 1 hour and duration of action of over does not induce “hangover” effects. In a recent dose-finding study,
6 hours.59 The clear disadvantage is prolonged sedation, restricting melatonin 0.25 and 0.5 mg/kg orally was as effective as midazolam
its use to in-patient surgery. Conversely, the long duration of in alleviating preoperative anxiety in children and had a tendency
action ensures that the patient is adequately premedicated for an toward faster recovery and a lower incidence of excitement
extended time period, an advantage in the event that a surgical postoperatively.73 Melatonin, like other premedications, decreased
case be delayed for any reason. the induction dose of propofol and thiopental.74
α2 Agonists Nasal
Recently, oral α2 adrenoreceptor agonists, such as clonidine Premedicants administered intranasally include midazolam,
and dexmedetomidine, have been used as oral premedicants in opioids, and ketamine. Side effects, such as respiratory depression,
children.60 Clonidine provides effective anxiolysis and sedation may develop rapidly with intranasal administration, mandating
with a high degree of parent satisfaction.60–65 Oral clonidine in that this route should be used only in an environment in which
doses ranging from 1 to 4 μg/kg produces postoperative analgesia, personnel and equipment are immediately available to intervene
less postoperative vomiting, perioperative hemodynamic stability, when necessary.
and fewer requirements for intraoperative inhalation agents. Intranasal premedication can be administered by two
A lower incidence of emergence agitation has been reported in methods:75 intranasal drops or intranasal spray. Accurate dosage
children premedicated with clonidine.66 When compared with is necessary, and rapid onset is achieved when the nasal route is
midazolam, it has a significantly better taste and, thus, minimal used.76,77 However, the patient’s experience, although short-lived,
refusal to swallow the drug. Clonidine lacks the psychotropic is usually unpleasant and may also cause apprehension and
quality of benzodiazepines and will cause a state of sedation more fear.75–79 For many, the discomfort associated with intranasal
similar to normal tiredness-sleepiness in which the patient can administration of some medications is similar to that with intra-
easily be awoken to perform various tests.67,68 Unfortunately, the muscular administration.
onset is delayed up to 90 minutes and the offset may extend well Several studies have compared intranasal administration of
into the postanesthetic recovery period. Many anesthesiologists premedicants. When 100 μg/kg intranasal midazolam was com-
may be willing to accept its slow onset of sedation if clinical pared with 10 μg/kg intranasal alfentanil, the sedation was similar
advantages are provided during the perioperative period. It has but there was no nasal burning among the children receiving
been suggested that it may enhance the antiemetic effect of alfentanil whereas 70% of the midazolam-treated children noted
propofol after strabismus surgery.69 The ability of α2 agonists to nasal burning.43 Intranasal sufentanil in a dose of 1.5 to 3 μg/kg
decrease sympathetic nervous system activity without inhibition was compared with intranasal midazolam 0.1 to 0.3 mg/kg.
Intranasal midazolam was associated with improved sedation, Rectal clonidine despite a very high bioavailability, a slow time to
higher oxygen saturations, improved chest wall compliance, and peak (52 min), and a long elimination half-life (12.5 h).95
less vomiting.80–83 Rectal administration has been compared with other modes of
Ketamine is another alternative intranasal premedicant.84–86 delivery. Rectal midazolam was compared with oral midazolam.96
Effective doses include 3, 4, 6, and 8 mg/kg.84–86 When compared Both modes were effective, but rectal administration was much
with the combination of intramuscular promethazine and meperi- better tolerated. Rectal administration is not an option in older
dine, intranasal ketamine 6 mg/kg provided better sedation children for aesthetic reasons and the large volume required to
whereas the recovery patterns were similar.84 When compared deliver the requisite dose.
with placebo, the ketamine-treated children were rapidly sedated
(15 min), tolerated the administration well, had easier separation,
and were more cooperative in the operating room. Postanesthetic Intramuscular/Subcutaneous/Biojector
recovery and discharge were not delayed.85 Needle phobia and the increased efficacy of the alternate routes
Intranasal clonidine has also been studied in children. of administration have reduced intramuscular or subcutaneous
Although 4 μg/kg produces sedation and anxiolysis, the onset of administration of premedicant drugs to those rare circumstances
clinical effects was significantly slower than with oral clonidine in which other routes of administration are not possible such as in
(i.e., 48 min vs 38 min).71 the noncompliant combative adolescent, the mentally deranged
patient, or the extremely upset and otherwise unmanageable child.
In this situation, intramuscular ketamine 2 to 10 mg/kg, which
Rectal has a relatively rapid onset of 3 to 10 minutes, is useful. The larger
Rectal premedication was perhaps the route of choice for pre- doses may delay recovery.90 When a difficult child refuses the mask
operative sedation before the advent of the more predictable and when intravenous induction of anesthesia is not practical, a
oral regimes.87 Its use varies among individual anesthesiologists, small, 2-mg/kg, sedating dose of intramuscular ketamine has been
centers, regions, and countries.1 Mode of administration also shown to be effective.97
varies markedly. Although rectal administration, using a variety Intramuscular midazolam 0.1 to 0.2 mg/kg combined with
of agents, has been reported in continental Europe, its popularity intramuscular ketamine 1 to 2 mg/kg in children undergoing
and acceptance elsewhere have been limited. bilateral myringotomies significantly prolonged recovery and
Methohexital 30 mg/kg is the rectal drug of choice, having a delayed discharge times.98
relatively predictable onset, short duration, and lack of com- Historically, a mixture of opioids and an antisialogogue
plications.88,89 About 85% of children fall asleep after this dose with given intramuscularly has been used Onset was 30 to 60 minutes
an average onset time of 6 minutes. Of those who do not sleep, and the duration long. These combinations produced anxiolysis,
only 4% are not adequately sedated.89 Hiccups (13%) and sedation, amnesia, and analgesia in a predictable fashion.
defecation (10%) are the most common side effects.89 Oxygen The biojector jet injection “needleless” system has been recently
desaturation and airway obstruction are uncommon, but may be introduced. This device was studied in 40 children who received
life-threatening.89 Rectal thiopentone 30 mg/kg has a relatively midazolam doses ranging from 0.05 to 0.3 mg/kg.99 Sedation was
predictable onset, but it is associated with more prolonged dura- achievable at doses starting at 0.1 mg/kg, but crying on injection
tion of action.90 Both drugs may produce respiratory depression was common and a major downside of this approach. Complete
and significant rectal mucosal irritation. At the present time, their patient cooperation is not required and its uses overcome the
use is limited to children younger than 5 years in whom oral problem of children who refuse premedication, expectorate their
premedication has failed. After administration, all children given premedicant, or expel rectally administered medication.
rectal premedicant drugs should be carefully monitored for
respiratory depression. When rectal methohexital was compared Sublingual
with rectal pentobarbital premedication, the efficacy was similar
but emergence delirium or agitation after pentobarbital was Although more rapid in onset than oral or rectal administration,
a concern.91 the sublingual route has not gained popularity in the younger
Ketamine and the benzodiazepines may also be given rectally pediatric age groups. It may be suitable, however, for the older,
to achieve sedation,92 but their effect by this route is less pre- more inherently cooperative child. Sublingual midazolam induces
dictable. Midazolam may be given rectally at doses of 0.15 to more rapid (by 15 min), effective sedation with a dose of at least
5 mg/kg.19,93 The recommended dose to achieve adequate seda- 0.5 mg/kg.100
tion and acceptance of the facemask was 0.35 mg/kg,93 whereas
the 1 mg/kg resulted in effective sedation with negligible effects
on postanesthesia care unit discharge times.94 Beebe and col- Drug Combinations
leagues compared four groups, placebo, rectal midazolam (0.5 mg/ It is advantageous, where possible, to use only one drug to produce
kg), rectal ketamine (3mg/kg), and both midazolam and keta- preoperative sedation. However, no single premedication has
mine.94 The midazolam-treated patients, especially in the combi- universal acceptance. In those situations in which a previous
nation group, were better sedated, but they had a prolonged premedicant has failed or it is essential that the premedication
recovery.94 Premedication with rectal midazolam 0.3 mg/kg was is successful, a combination of drugs can be highly effective.
compared with rectal clonidine 5 μg/kg in patients undergoing For example, Warner and associates reported a 100% successful
adenotonsillectomy.67 Immediate postoperative analgesia was parental separation after midazolam plus ketamine, whereas
enhanced in the clonidine group; postoperative sedation was midazolam alone was associated with only a 75% success rate at
increased for the first 24 hours, which was preferred by a majority parental separation.101 They reported a similar improvement in
of parents when compared with an alert and ambulating child.67 successful mask induction.
TABLE 37-3. Combinations of Sedative and Anxiolytic negativism.108 A more elaborate study by Kain and colleagues
Premedications Used Prior to Induction of Anesthesia observed the opposite.109 In their study, postoperative behavior
was better in the midazolam group (0.5 mg/kg) during days 1 to
1. Pentobarbital 3 mg/kg orally 2 h preoperatively, plus 7 postoperatively. Payne and associates have had results similar
morphine 0.1 mg/kg I.M. 1 h preoperatively, and to those of Kain and colleagues, more specifically, midazolam
scopolamine 0.01 mg/kg I.M. 1 h preoperatively132 premedication was associated with a lower incidence of night-time
2. Ketamine 4 mg/kg plus midazolam 0.4 mg/kg p.o.101 crying and awakening.107 The likelihood of negative postoperative
3. Ketamine 3 mg/kg plus midazolam 0.5 mg/kg p.o.133,134 behaviors increases if the child is anxious during induction.110
4. Ketamine 2.5 mg/kg plus midazolam 0.25 mg/kg p.o.135 A lower incidence of apathy/withdrawn behavior was observed
5. Ketamine 1–2 mg/kg plus midazolam 0.1–0.2 mg/kg I.M.98 after a temazepam or trimeprazine premedication.111 Trimepra-
6. Meperidine 1.2 mg/kg, atropine 16 μg/kg, and diazepam zine premedication was associated with less restlessness and
120 μg/kg p.o.136 decreased vomiting in the recovery period when compared with
7. Ketamine 3 mg/kg plus midazolam 0.5 mg/kg p.o.137 oral lorazepam.112
In summary, children often require premedication before
anesthesia to alleviate patient and parental anxiety, to provide
Some medications are not very effective when used solely, but analgesia and/or amnesia, and to facilitate separation from parents
when combined with other medications, the effect is synergistic before induction of anesthesia. The benefits and risks of each drug
with improved efficacy. The classic combination was the so-called should be balanced against to the child’s personality, the severity
lytic cocktail, a mixture of pethidine, promethazine, and chlor-
of disease, the type of surgery, and the monitoring available.
promazine.102 Combinations of drugs that have been used with
A variety of drugs is available and may be used alone or in combi-
success are included in Table 37–3.
nation to achieve the desired response with minimal adverse
Multiple studies have addressed combining oral ketamine and
effects. In addition, nonpharmacologic approaches are often
oral midazolam in smaller than usual doses in order to improve
beneficial and should be applied where appropriate.
success and minimize the side effects and improve postanesthesia
care unit discharge times. When compared with either ketamine
or midazolam alone, faster onset time, faster time to maximum PREOPERATIVE FASTING
sedation, earlier parental separation, and faster recovery times
were noted when the combination was used. Originally, the importance of preoperative fasting was not
Combinations may be considered in children who have had a appreciated, but after several reports of regurgitation and reflux
traumatic experience with their previous surgery or in children of gastric contents, the value of having gastric contents (both
with congenital cyanotic heart disease. liquid and solid components) at a nadir before anesthesia was
High-risk children have been studied only to a limited extent, appreciated. The minimal fast was rapidly replaced by an all-
and generally, premedication has been well tolerated and good inclusive, extensive fast. This resulted in a reduction of gastric
results have been obtained.103 Comparing oral 0.5 mg/kg mida- contents, but at the cost of a dehydrated, thirsty, hungry, and un-
zolam and atropine with the combination of oral meperidine happy patient and distressed parents. In debilitated, chronically
3 mg/kg, pentobarbital 4 mg/kg, and atropine resulted in similar malnourished patients, fasting may also lead to hypoglycemia
vital signs and onset of action, but there was less sedation in the and ketosis. It is clearly not desirable to have children, especially
midazolam-treated children before cardiac surgery.104 Levine neonates and young infants, undergo a prolonged period of fasting
and coworkers, comparing oral midazolam (0.75 mg/kg) and a before general anesthesia
combination of pentobarbitone, morphine, and atropine in Gastric contents can be split into two constituents: solid and
children with cyanotic congenital heart disease,105 found that the liquid. Each has a specific gastric-emptying time. Solids empty
oral midazolam-treated patients did very well and concluded from the stomach quite slowly, unaltered by liquids, and follow
that oral midazolam was safe and effective and avoided oxygen zero-order kinetics113 (Table 37–4). Normally, liquids empty quickly
desaturations associated with intramuscular injections. When from the stomach because they follow first-order kinetics.114,115
oral transmucosal fentanyl citrate was compared with the oral Isotonic solutions, such as normal saline, do not interact with
combination of meperidine, diazepam, and atropine, the combi- duodenum osmotic receptors and rapidly empty from the stomach
nation was considered superior to the “fentanyl lollipop” among (see Table 37–4). Aqueous solutions containing glucose and pro-
children with congenital heart disease.106 teins do interact with receptors in the duodenum and have gastric
half-lives of approximately 10 minutes.
RECOVERY
TABLE 37-4. Gastric Emptying Times for
Recovery from premedication is not always without complication Healthy Individuals
or additional benefits. Premedication may delay recovery from
anesthesia and discharge from the hospital.28,30–32 Gastric Contents Gastric Half-life
Studies on the effect of premedication on postoperative Clear isotonic liquids 3–5 min
behavior have yielded mixed results. Benefits include improved Clear liquids containing 10 min
quality of sleep the first night after surgery.31,107 McGraw and protein, lipids, and glucose
Kendrick observed improved behavior oral midazolam but Full meal Average 8 h to empty; 10–30%
only preoperatively. In the postoperative period, more of the remains after 6–8 h
midazolam-treated children had behavioral problems such as Light snack (e.g., cracker) 1–2 h
night terrors, nightmares, food rejection, fussiness, anxiety, and
After a routine fast, the volume of gastric contents is not children. In practice, it is simpler to extend these guidelines to
dependent on ingested food, but rather on the residual from oral 3 hours in order to facilitate rescheduling of operations. The solid-
and gastric secretions. These secretions are produced at a rate of food fast should be prolonged when compared with the clear-fluid
0.4 to 2 mL/kg/h, and the nadir gastric volume present at steady fast. The historic no-solids-after-midnight has a proven safety
state varies from patient to patient. record and is practical. Similarly, a 4-hour fast for breast milk and
Several large, well-controlled studies of perioperative fasting a 6-hour fast for nonhuman milk have a proven safety record and
were performed after anesthetists became more aware of the are easily complied with.
physiology of gastric emptying.116–126 Studies in infants, children,
and youths have demonstrated that unlimited, clear, aqueous fluids
may be ingested by healthy patients up to 2 hours before elective CONCLUSION
surgery, without increasing residual gastric contents. Investigations There are multiple arguments for and against the use of premedi-
of solid food ingestion are generally inadequate. Gastric emptying cation in children.138 Sedative medications offer proper conditions
of solid food can be assessed by aspiration plus gastroscopy or to minimize the psychological impact associated with anesthesia
by radiolabeling. Based upon the investigations of the gastric and surgery, although its practice has been largely influenced by
emptying of small meals, one would expect that a minimal meal several factors such as cultural beliefs and hospital practices over
(e.g., a cracker) would require less than 2 hours to be evacuated time. Furthermore, the nature of expectations and responses for
from the stomach of a healthy patient. By contrast, a very large both parent and child vary greatly in different environments
meal would often require approximately 8 hours to empty. around the world.138
Formula, cow’s milk, and breast milk represent a conundrum. In contrary, preoperative fasting has evolved considerably over
Formula and cow’s milk are generally treated as a solid food, the years and offers clear guidelines in regards to the optimal
whereas breast milk is mostly a clear liquid and the solid food practice in children. This approach has contributed to significantly
component empties relatively rapidly from the stomach. Thus, reduce the stress associated with long periods of deprivation of
breast milk requires a fast somewhere between a full solid meal fluids before anesthesia and surgery.
and a clear fluid. One can either empirically fast these children
from breast milk for 4 hours or individualize treatment and follow
the infant’s feeding pattern (i.e., if the baby feeds by breast every REFERENCES
3 h, then a 3-h fast before elective surgery is appropriate). 1. Kain ZN, Mayes LC, Bell C, et al. Premedication in the United States: a
Patients with significant debilitating disease undergoing status report. Anesth Analg. 1997;84:427–432.
elective surgery have not been studied extensively. Many of these 2. Davidson AJ, Shrivastava PP, Jamsen K, et al. Risk factors for anxiety at
patients, including patients with symptomatic heart disease, induction of anesthesia in children: a prospective cohort study. Paediatr
gastrointestinal disease, or increased intracranial pressure, have Anaesth. 2006;16:919–927.
3. Egan KJ, already LB, Nessly M, Greer BE. Self-administration of
been noted to delay gastric emptying. The fasting guidelines for midazolam for postoperative anxiety: a double blinded study. Pain.
this group of patients should optimally be on an individual basis 1992;49:3–8.
or, alternatively, conservative guidelines should be used. 4. Markland D. Anxiety, relation and anesthesia for day-care surgery.
The appropriate duration of the preoperative fast for patients Br J Clin Psychol. 1993;32:493–504.
5. Papay JP. Assessment of anxiety and achievement in kindergarten and
undergoing emergent and urgent surgery is determined after
first and second-grade children. J Abnorm Child Psychol. 1986;14:
assessing many issues, such as the type of food ingested before 279–286.
and after the injury, time from food ingestion to time of injury, 6. Thomas V. Psychological characteristics and the effectiveness of pain
severity and location of the injury, time from injury to induc- controlled analgesia. Br J Anaesth. 1995;74:271–276.
tion of anesthesia, and medication given to the patient after the 7. Kain ZN, Mayes LC, Caramico LA, et al. Parental presence during
induction of anesthesia. A randomized controlled trial. Anesthesiology.
injury.127,128 1996;84:1060–1067.
In summary, several preoperative fasting guidelines have been 8. MacLaren J, Kain ZN. Pediatric preoperative preparation: a call for
proposed,123–126,129,130 and these guidelines are summarized in Table evidence-based practice. Paediatr Anaesth. 2007;17:1019–1020.
37–5. A 2-hour fast from clear fluids is acceptable for healthy 9. O’Byrne K, Peterson L, Saldana L. Survey of pediatric hospitals’
preparation programs: evidence of the impact of health psychology
research. Health Psychol. 1997;16:147–154.
TABLE 37-5. Recommendations for Preoperative Fast 10. Kain ZN, Caldwell-Andrews AA, Mayes LC, et al. Family-centered
preparation for surgery improves perioperative outcomes in children.
State Recommendation Anesthesiology. 2007;106:65–74.
11. Kain ZN, Ferris CA, Mayes LC, et al. Parental presence during induction
Fluids of anesthesia: practice differences between the United States and Great
Healthy patient Minimum 2 h Britain. Paediatr Anaesth. 1996;6:187–193.
Ill patient Minimum 4 h 12. Kain ZN, Mayes LC, Wang S-M, et al. Parental presence during induction
of anesthesia versus sedative premedication. Which intervention is more
Emergency surgery Individualized care effective? Anesthesiology. 1998;89:1147–1156.
Milk 13. Kain ZN, Mayes LC, Caldwell-Andrews AA, et al. Predicting which
children benefit most from parental presence during induction of
Breast milk Minimum 4 h anesthesia. Paediatr Anaesth. 2006;16:627–634.
Nonhuman milk Minimum 6 h 14. Bevan JC, Johnston C, Haig MJ, et al. Preoperative parental anxiety
predicts behavioral and emotional responses to induction of anesthesia in
Solids children. Can J Anaesth. 1990;37:177–182.
Elective surgery No solids on day of surgery (minor 15. Rosen DA, Rosen KR, Hannallah RS. Anaesthesia induction in children.
deviations need individual care) Ability to predict cooperation. Paediatr Anaesth. 1993;3:365–370.
Emergency surgery Individualized care 16. Payne K, Mattheyse FJ, Liebenberg D, et al. The pharmacokinetics of
midazolam in paediatric patients. Eur J Clin Pharm. 1989;37:267–272.
17. Feld LM, Negus JB, White PF. Oral midazolam preanesthetic medication 43. VandenHoven MD, Applegate RL, Isaacs WB, et al. Zolpidem or
in pediatric outpatients. Anesthesiology. 1990;73:831–834. midazolam for premedication of pediatric patients. Anesthesiology. 1997;
18. Saint-Maurice C, Meistelman C, Rey E, et al. The pharmacokinetics of 87:A1030.
rectal midazolam for premedication in children. Anesthesiology. 1986; 44. Lauretti GR, Garcia LV, Reis P. Comparison between oral etomidate
65:536–538. administration versus oral midazolam as a premedicant for pediatric day
19. Spear RM, Yaster M, Berkowitz ID, et al. Preinduction of anesthesia in case anesthesia. Anesthesiology. 1995;83:A1135.
children with rectally administered midazolam. Anesthesiology. 1991; 45. Alderson PJ, Lerman J. Oral premedication for paediatric ambulatory
74:670–674. anaesthesia: a comparison of midazolam and ketamine. Can J Anaesth.
20. Nicolson SC, Betts EK, Jobes DR, et al. Comparison of oral and intra- 1994;41:221–226.
muscular preanesthetic medication for inpatient surgery. Anesthesiology. 46. Lyons B, Cregg N, Conway F, et al. Premedication for ambulatory surgery
1989;71:8–10. in preschool children: a comparison of oral midazolam and rectal
21. Brzustowicz RM, Nelson DA, Betts EK, et al. Efficacy of oral pre- thiopentone. Can J Anaesth. 1995;42:473–478.
medication for pediatric outpatient surgery. Anesthesiology. 1984;60: 47. Patel D, Meakin G. Oral midazolam compared with diazepam-droperidol
475–477. and trimeprazine as premedicants in children. Paediatr Anaesth. 1997;7:
22. Kain ZN, Caldwell-Andrews AA, Krivutza D, et al. Trends in the practice 287–293.
of parental presence during induction of anesthesia and the use of 48. Friesen RH, Lockhart CH: Oral transmucosal fentanyl citrate for
preoperative sedative premedication in the United States, 1995–2002: preanaesthetic medication of paediatric day surgery patients with and
results of a follow-up national survey. Anesth Analg. 2004;98:1252–1259. without droperidol as a prophylactic anti-emetic. Anesthesiology. 1992;
23. Suresh S, Cohen IJ, Matuszczak M, et al. Dose ranging, safety, and efficacy 76:46–51.
of a new oral midazolam syrup in children. Anesthesiology. 1998;89: 49. Nelson PS, Streisand JB, Mulder SM, et al. Comparison of oral
A1313. transmucosal fentanyl citrate and an oral solution of meperidine,
24. Coté CJ, Cohen IT, Suresh S, et al. A comparison of three doses of a diazepam, and atropine for premedication in children. Anesthesiology.
commercially prepared oral midazolam syrup in children. Anesth Analg. 1989;70:616–621.
2002;94:37–43. 50. Feld LH, Champeau MW, van Steenis CA, et al. Preanesthetic medication
25. Masue T. Oral high-dose midazolam premedication for infants and in children: a comparison of oral transmucosal fentanyl citrate versus
children undergoing cardiovascular surgery. Paediatr Anaesth. 2003; placebo. Anesthesiology. 1989;71:374–377.
13:662–667. 51. Stanley TH, Leiman BC, Rawal N, et al. The effects of oral transmucosal
26. Levine MF, Spahr-Schopfer IA, Hartley E, et al. Oral midazolam pre- fentanyl citrate premedication on preoperative behavioral responses and
medication in children: the minimum time interval for separation from gastric volume and acidity in children. Anesth Analg. 1989;69:328–335.
parents. Can J Anaesth. 1993;40:726–729. 52. Wheeler M, Birmingham PK, Dsida RM, et al. Uptake kinetics of the
27. Lammers CR, Rosner J, Crockett DE, et al. Oral midazolam with an Fentanyl Oralet in children: implications for pretreatment for painful
antacid increases the speed of onset of sedation in children prior to procedures. Anesthesiology. 1998;89:A1311.
general anesthesia. Anesth Analg. 1999;88:S300. 53. Epstein RH, Mendel HG, Witkowski TA, et al. The safety and efficacy of
28. Weldon BC, Watcha MF, White PF. Oral midazolam in children: effect of oral transmucosal fentanyl citrate for preoperative sedation in young
time and adjunctive therapy. Anesth Analg. 1992;75:51–55. children. Anesth Analg. 1996;83:1200–1205.
29. Jones RDM, Visram AR, Kornberg JP, et al. Synergistic interaction 54. Ginsberg B, Dear RB, Margolis JO, et al. Oral transmucosal fentanyl citrate
between midazolam and propofol. Br J Anaesth. 1992;69:240–245. as an anaesthetic premedication when dosed to an opioid effect vs total
30. McMillan CO, Spahr-Schopfer IA, Sikich N, et al. Premedication of opioid consumption. Paediatr Anaesth. 1998;8:413–418.
children with oral midazolam. Can J Anaesth. 1992;39:545–550. 55. Lin C, Durieux M. Ketamine and kids: an update. Paediatr Anaesth.
31. McCluskey A, Meakin GH. Oral administration of midazolam as a 2005;15:91–97.
premedicant for paediatric day-case anaesthesia. Anaesthesia. 1994;49: 56. Gutstein HB, Johnson KL, Deard MB, et al. Oral ketamine preanesthetic
782–785. medication in children. Anesthesiology. 1992;76:28–33.
32. Cray SH, Dixon JL, Heard CMB, et al. Oral midazolam premedication for 57. Gingrich BK. Difficulties encountered in a comparative study of orally
paediatric day case patients. Paediatr Anaesth. 1996;6:265–270. administered midazolam and ketamine [letter]. Anesthesiology. 1994;80:
33. Lapin SL, Auden SM, Goldsmith LJ, et al. Effects of sevoflurane anaes- 1414–1415.
thesia on recovery in children: a comparison with halothane. Paediatr 58. Cioaca R, Caneva AI. Oral transmucosal ketamine: an effective
Anaesth. 1999;9:299–304. premedication in children. Paediatr Anaesth. 1996;6:361–365.
34. Cox RG. Evidence-based clinical update: does premedication with oral 59. Dundee JW, Nair SG, Assaf RA, et al.: Pentobarbitone premedication for
midazolam lead to improve behavioral outcome? Can J Anaesth. 2006; anaesthesia. Anaesthesia. 1996;31:1025–1031.
53:1213–1219. 60. Mikawa K, Maekawa N, Nishina K, et al. Efficacy of oral clonidine
35. Brosius KK, Bannister CF. Midazolam premedication in children: a premdication in children. Anesthesiology. 1993;79:926–931.
comparison of two oral dosage formulations on sedation score and plasma 61. Nishina K, Mikawa K, Shiga M, et al. Oral clonidine premedication
midazolam levels. Anesth Analg. 2003;96:392–395. reduces minimum alveolar concentration of sevoflurane for tracheal
36. Khalil SN. A pediatric trial comparing midazolam/Syrpalta mixture with intubation in children. Anesthesiology. 1997;87:1324–1327.
premixed midazolam syrup (Roche). Paediatr Anaesth. 2003;13:205–209. 62. Nishina K, Mikawa K, Shiga M, et al. Clonidine in paediatric anaesthesia.
37. Lewis I, Burke C, Voepel-Lewis T, et al. Children who refuse anesthesia Paediatr Anaesth. 1999;9:187–202.
or sedation: a survey of anesthesiologists. Paediatr Anaesth. 2007;17: 63. Nishina K, Mikawa K, Maekawa N, et al. Oral clonidine premedication
1134–1142. blunts the heart rate response to intravenous atropine in awake children.
38. Finley GA, Stewart SH, Buffett-Jerrott S, et al. High levels of impulsivity Anesthesiology. 1995;82:1126–1130.
may contraindicate midazolam premedication in children. Can J Anaesth. 64. Nishina K, Mikawa K, Maekawa N, et al. Clonidine decreases the dose of
2006;53:73–78. thiamylal required to induce anesthesia in children. Anesth Analg.
39. Kain ZN, MacLaren J, McClain BC, et al. Effects of age and emotionality 1994;79:766–768.
on the effectiveness of midazolam administered preoperatively to 65. Reimer EJ, Dunn GS, Montgomery CJ, et al. The effectiveness of clonidine
children. Anesthesiology. 2007;107:545–552. as an analgesic in paediatric adenotonsillectomy. Can J Anaesth.
40. Viitanen H, Annila P, Viitanen M, et al. Midazolam premedication delays 1998;45:1162–117.
recovery from propofol-induced sevoflurane anesthesia in children 66. Constant I, Leport Y, Richard P, et al. Agitation and changes of Bispectral
1–3 yr. Can J Anaesth. 1999;46: 766–71. Index and EEG-derived variables during sevoflurane induction in
41. Lawhorn CD, Brown RE, Schmitz ML, et al. A comparative study of children: clonidine premedication reduces agitation compared with
midazolam versus chloral hydrate as a preoperative medicant in pediatric midazolam. Br J Anaesth. 2004;92:504–511.
outpatients. Anesth Analg. 1995;80:S268. 67. Bergendahl HT, Lonnqvist PA, Eksborg S, et al. Clonidine versus mida-
42. Pilato MA, Everts E, Yemen T, et al. Premedication in pediatric outpatient zolam as premedication in children undergoing adeno-tonsillectomy: a
surgery: comparison of oral midazolam to rectal methohexital. Anesth prospective, randomized, controlled clinical trial. Acta Anaesthesiol Scand.
Analg. 1991;72:S214. 2004;48:1292–1300.
68. Hall JE, Uhrich TD, Ebert TJ. Sedative, analgesic and cognitive effects of 94. Beebe DS, Belani KG, Chang P-N, et al. Effectiveness of preoperative
clonidine infusions in humans. Br J Anaesth. 2001;86:5–11. sedation with rectal midazolam, ketamine, or their combination in
69. Gulhas N, Turkoz A, Durmus M, et al. Oral clonidine premedication does young children. Anesth Analg. 1992;75:880–884.
not reduce postoperative vomiting in children undergoing strabismus 95. Lonnqvist PA, Bergendahl HTG, Eksborg S. Pharmacokinetics of
surgery. Acta Anaesthesiol Scand. 2003;47:90–93. clonidine after rectal administration in children. Anesthesiology. 1994;
70. Zub DJ, Berkenbosch JW, Tobias JD. Preliminary experience with oral 81:1097–1101.
dexmedetomidine for procedural and anesthetic premedication. Paediatr 96. Khazin V, Ezra S. Comparison of rectal to intranasal administration of
Anaesth. 2005;15:932–938. midazolam for premedication in children. Mil Med. 1995;160:579–581.
71. Almenrader N, Passariello M, Coccetti B, et al. Steal induction after 97. Hannallah RS, Patel RI. Low-dose intramuscular ketamine for anesthesia
clonidine premedication: a comparison of the oral and nasal route. pre-induction in young children undergoing brief outpatient procedures.
Paediatr Anaesth. 2007;17:230–234. Anesthesiology. 1989;70:598–600.
72. Schmidt AP, Valinetti EA, Bandeira D, et al. Effects of preanesthetic 98. Verghese ST, Hannallah RS, Patel RI, et al. Ketamine and midazolam is
administration of midazolam, clonidine, or dexmedetomidine on postoperative an inappropriate preinduction combination in uncooperative children
pain and anxiety in children. Paediatr Anaesth. 2007;17:667–674. undergoing brief ambulatory procedures. Paediatr Anaesth. 2003;13:
73. Samarkandi A, Naguib M, Riad W, et al. Melatonin vs midazolam 228–232.
premedication in children: a double-blind, placebo-controlled study. Eur 99. Greenberg RS, Maxwell LG, Zahurak M, et al. Preanesthetic medication
J Anaesthesiol. 2005;22:189–196. of children with midazolam using the biojector jet injector. Anesthe-
74. Naguib M, Samarkandi AH, Moniem MA, et al. The effects of melatonin siology. 1995;83:264–269.
premedication on propofol and thiopental induction dose-response 100. Khalil S, Philbrook L, Rabb M, et al. Sublingual midazolam premedi-
curves: a prospective, randomised, double-blind study. Anesth Analg. cation in children: a dose response study. Paediatr Anaesth. 1998;8:
2006;103:1448–1452. 461–465.
75. Griffith N, Howell S, Mason DG. Intranasal midazolam for premedication 101. Warner DL, Cabaret J, Velling D. Ketamine plus midazolam, a most
of children undergoing day-case anaesthesia: comparison of two delivery effective paediatric oral premedicant. Paediatr Anaesth. 1995;5:293–295.
systems with assessment of intra-observer variability. Br J Anaesth. 1998; 102. Laub M, Sjogren P, Holm-Knudsen R, et al. Lytic cocktail in children.
81:865–869. Anaesthesia. 1990;45:110–112.
76. Davis PJ, Tome JA, McGowan FX, et al. Preanesthetic medication with 103. Burnett YL. Midazolam preop. effects on sedation, ventilation, and
intranasal midazolam for brief pediatric surgical procedures. Anesthe- oxygen saturation in higher risk children. Anesth Analg. 1993;76:S30.
siology. 1995;82:2–5. 104. Grunwald Z, Froese N, Nicolson SC, et al. Oral midazolam is not an
77. Lejus C, Renaudin M, Testa S, et al. Midazolam for premedication in acceptable preanesthetic medication for children undergoing cardiac
children: intranasal vs intrarectal administration. Anesth Analg. 1993; surgery. Anesth Analg. 1994;78:S142.
76:S217. 105. Levine MF, Hartley EJ, MacPherson BA, et al. Oral midazolam
78. Karl HW, Rosenberger JL, Larach MG, et al. Transmucosal administration premedication for children with congenital cyanotic heart disease
of midazolam for premedication of pediatric patients comparison of the
undergoing cardiac surgery: a comparative study. Can J Anaesth. 1993;
nasal and sublingual routes. Anesthesiology. 1993;78:885–891.
40:934–938.
79. Fishbein M, Lugo RA, Woodland J, et al. Evaluation of intranasal mida-
106. Goldstein-Dresner MC, Davis PJ, Kretchman E, et al. Double-blind
zolam in children undergoing esophagogastroduodenoscopy. J Pediatr
comparison of oral transmucosal fentanyl citrate with oral meperidine,
Gastroenterol Nutr 1997;25:261–6.
diazepam, and atropine as preanesthetic medication in children with
80. Henderson JM, Brodsky, DA, Fisher DM, et al.: Pre-induction of anaes-
congenital heart disease. Anesthesiology. 1991;74:28–33.
thesia in paediatric patients with nasally administered sufentanil.
Anesthesiology. 1998;68:671–675. 107. Payne KA, Coetzee AR, Mattheyse FJ, et al. Behavioural changes in
81. Karl HW, Keifer AT, Rosenberger JL, et al.: Comparison of the safety and children following minor surgery—is premedication beneficial? Acta
efficacy of intranasal midazolam or sufentanil for preinduction of Anaesth Belg. 1992;43:173–179.
anaesthesia in paediatric patients. Anesthesiology. 1992;76:209–215. 108. McGraw TT, Kendrick A. Oral midazolam premedication and
82. Wilton NCT, Leigh J, Rosen D, et al. Preanesthetic sedation of preschool postoperative behaviour in children. Paediatr Anaesth. 1998;8:117–121.
children using intranasal midazolam. Anesthesiology. 1988;69:972–975. 109. Kain ZN, Mayes LC, Wang S-M, et al. Postoperative behavioural out-
83. Zedie N, Amory DW, Wagner BKJ, et al. Comparison of intranasal mida- comes in children. Effects of sedative premedication. Anesthesiology.
zolam and sufentanil premedication in pediatric outpatients. Clin 1999;90:758–765.
Pharmacol Ther. 1996;59:341–348. 110. Kain ZN, Wang SM, Mayes LC, et al. Distress during the induction of
84. Weksler N, Ovadia L, Muati G, et al. Nasal ketamine for paediatric anesthesia and postoperative behavioral outcomes. Anesth Analg.
premedication. Can J Anaesth. 1993;40:119–121. 1999;88:1042–1047.
85. Diaz JH. Intranasal ketamine preinduction of paediatric outpatients. 111. Padfield NL, Twohig MM, Fraser ACL. Temazepam and trimeprazine
Paediatr Anaesth. 1997;7:273–278. compared with placebo as premedication in children. Br J Anaesth.
86. Diaz JH, Guarisco JL, Buhrman WC, et al. Intranasal ketamine pre- 1986;58:487–493.
medication of infant outpatients: a blinded, controlled study. Anesthe- 112. Peters CG, Brunton JT. Comparative study of lorazepam and trimeprazine
siology. 1993;79:A1140. for oral premedication in paediatric anaesthesia. Br J Anaesth. 1982;54:
87. Goresky GV, Steward DJ: Rectal methohexatone for induction of 623–628.
anaesthesia in children. Can Anaesth Soc J. 1979;26:213–215. 113. Moore JG, Christian PE, Coleman RE. Gastric emptying of varying meal
88. Barry CT, Lawson R, Davidson DG. Recovery from methohexitone and weight and composition in man: evaluation by dual liquid- and solid-
thiopentone. Anaesthesia. 1967;22:228–234. phase isotopic method. Dig Dis Sci. 1981;26:16–22.
89. Audenhart SM, Montgomery CL, Thompson DE, et al. A prospective 114. Minami H, McCallum RW. The physiology and pathophysiology of
study of rectal methohexital: efficacy and side effects in 648 cases. Anesth gastric emptying in humans. Gastroenterology. 1984;86:1592–1610.
Analg. 1995;81:957–961. 115. Erskine L, Hunt JN. The gastric emptying of small volumes given in
90. Ryhanen P, Kangas T, Rantakyla S. Premedication for outpatient adeno- quick succession. J Physiol. 1981;313:335–341.
idectomy: comparison between ketamine and pethidine. Laryngoscope. 116. Maltby JR, Lewis P, Martin A, et al. Gastric fluid volume and pH in
1980;90:494–500. elective patients following unrestricted oral fluid until three hours before
91. Christensen PA, Balslev T, Hasellstrom L. Comparison of methohexital surgery. Can J Anaesth. 1991;38:425–429.
and pentobarbital for premedication in children. Acta Anaesthesiol Scand. 117. Splinter WM, Schaefer JD. Ingestion of clear fluids is safe for adolescents
1990;34:478–481. up to 3 hours before anaesthesia. Br J Anaesth. 1991;66:48–52.
92. Malinovsky J-M, Lejus C, Servin F, et al. Plasma concentrations of 118. Splinter WM, Schaefer JD. Unlimited clear fluid ingestion two hours
midazolam after I.V., nasal or rectal administration in children. Br J before surgery in children does not affect volume or pH of stomach
Anaesth. 1993;70:617–620. contents. Anaesth Intensive Care. 1990;18:522–526.
93. Saint-Maurice C, Esteve C, Holzer J, et al. Premedication par le midazolam 119. van der Walt JH, Carter JA. The effect of different preoperative feeding
intrarectal. Recherche de la dose efficace en anesthesie pediatrique. Ann Fr regimens on plasma glucose and gastric volume and pH in infancy.
Anesth Reanim. 1984;3:181–184. Anaesth Intensive Care. 1986;14:352–359.
120. Miller BR, Tharp JA, Issacs WB. Gastric residual volume in infants and 131. Litman R. Airway obstruction after oral midazolam. Anesthesiology.
children following a 3-hour fast. J Clin Anesth. 1990;2:301–305. 1996; 85:1217–1218.
121. Phillips S, Hutchison S, Davidson T. Preoperative drinking does not 132. Shearer WM: The evolution of premedication. Br J Anaesth. 1960;32:
affect gastric contents. Br J Anaesth. 1993;70:6–9. 54–62.
122. van der Walt JH, Foate JA, Murrell et al. A study of preoperative fasting 133. Funk W, Riedl T, Schickendantz J, et al. Low dose oral ketamine
in infants aged less than three months. Anaesth Intensive Care. 1990; augments midazolam premedication in paediatric patients. Br J Anaesth.
18:527–531. 1998;80:A489.
123. Coté CJ. NPO after midnight for children—a reappraisal. Anesthesiology. 134. Lin YC, Moynihan RJ, Hackel A. A comparison of oral midazolam,
1990;72:589–592. oral ketamine, and oral midazolam combined with ketamine as
124. Goresky GV, Maltby JR. Fasting guidelines for elective surgical patients. preanesthetic medication for pediatric outpatients. Anesthesiology. 1993;
Can J Anaesth. 1990;37:493–495. 79:A1177.
125. Miller DC. Why are children starved? Br J Anaesth. 1990;64:409–410.
135. Ghai B, Grandhe RP, Kumar A, et al. Comparative evaluation of
126. Strunin L. How long should patients fast before surgery? Time for new
midazolam and ketamine with midazolam alone as oral premedication.
guidelines. Br J Anaesth. 1993;70:1–3.
127. Bricker SRW, McLuckie A, Nightingale DA. Gastric aspirates after Paediatr Anaesth. 2005;15:554–559.
trauma in children. Anaesthesia. 1989;44:721–724. 136. Pywell CA, Hung Y-J, Hagelhout J. Oral midazolam versus me-
128. Schurizek BA, Rybro L, Boggild-Madsen NB, et al. Gastric volume and peridine, atropine, and diazepam: a comparison of premedicants
pH in children for emergency surgery. Acta Anaesthesiol Scand. in pediatric outpatients. J Am Assoc Nurs Anesth. 1995;63:124–
1986;30:404–408. 130.
129. Brady M, Kinn S, Ness V, et al. Preoperative fasting for preventing 137. Funk W, Jakob W, Riedl T, et al. Oral preanaesthetic medication for
preoperative complications in children. Cochrane Database Syst Rev. children: double-blind randomized study of a combination of mida-
2009;4:CD005285. zolam and ketamine vs midazolam or ketamine alone. Br J Anaesth.
130. The Royal College of Nursing. Perioperative fasting in adults and 2000;84:335–340.
children. A national guideline. Available at: Rcn.org.uk/resources/ 138. Rosenbaum A, Kain ZN, Larsson P, et al. The place of premedication in
guidelines Accessed July 2, 2010. pediatric practice. Paediatr Anaesth. 2009;19:817–829.
38 Anesthesia Equipment
C H A P T E R Francis Veyckemans
INTRODUCTION ● A monitoring apparatus with at least electrocardiogram (ECG),

SpO2, PETCO2, noninvasive blood pressure (NIBP) monitor, and
Anesthesia providers need to understand the functioning of the a temperature probe.
equipment (e.g., breathing system, ventilator) to avoid misuse. ● Means to prevent hypothermia: air-conditioning, an overhead
They should also know the specific physiologic and technical radiant warmer, a warming mattress, a forced-air and/or a fluid-
limitations of the monitoring devices in use (e.g., pulse oximetry, warming device.
capnography) to avoid incorrect interpretation of the information ● Blankets to cover the child’s body during induction and awak-
provided. These monitors and equipment should be not only ening.
checked before use but also regularly maintained to prevent ● At least one infusion pump.
dysfunction. Moreover, for the sake of safety, the information ● An emergency call button to obtain immediate help in case of need.
given by a monitor and the functioning of any equipment should ● A telephone in order to be able to contact the ward or the cen-
be regularly double-checked using clinical examination of the tral laboratory without leaving the room.
patient and information provided by other devices: for example,
auscultation, SpO2 oxygen saturation of hemoglobin monitored Moreover, in addition to the cart containing the anesthetic
with pulse oximetry), PETCO2 (end-tidal carbon dioxide pressure), drugs and the equipment needed for airway management and,
and PIP (peak inspiratory pressure) to ensure that the child is intravascular access material as described earlier, the operating
adequately ventilated by the anesthesia machine. room should be equipped with two smaller carts:
Last, elementary rules of hygiene should be observed when
manipulating these devices to reduce the risk of contamination
● One cart for the equipment to be used to control the airway
and/or nosocomial infections. (Table 38–1).
The purpose of this chapter is to give the reader up-to-date
● One cart for the equipment to be used to obtain vascular access
information concerning monitors and equipment used in child- (Table 38–2).
ren during either standard general anesthesia or more complex Care should be taken to avoid restocking contaminated
procedures. The equipment used to perform regional anesthesia in equipment (e.g., a used but not yet disinfected laryngoscope blade)
pediatric patients is described in Chapters 44 through 51. Many
brands of equipment are quoted as examples, but neither the
author nor the editors have any conflict of interest concerning the TABLE 38-1. Standard Equipment of the Airway Cart
devices described. ● Facemask adapted to the child’s face.
For a more detailed description of some equipment, the reader ● 3 TTs: the size calculated according to the child’s age + one
is invited to read more elaborate reference such as Dorsch and size larger and one size smaller.
Dorsch’s Understanding Anesthesia Equipment, 5th edition, edited ● 1 LMA, according the child’s body weight or size (if
by Dorsch JA and Dorsch SE (Wolters Kluwer, Lippincott Williams overweight): it is either the foreseen airway device or a rescue
& Wilkins; 2008). in case of unforeseen difficult intubation and/or ventilation.
● 1 laryngoscope with blades (straight and/or curved) adapted
to the child’s size.
ORGANIZATION OF THE ● 1 Magill’s forceps.
OPERATING ROOM1 ● 1 malleable stylet or bougie.
Standard Equipment ● 1 silicone spray to lubricate the TT.
● Cuff pressure-monitoring device if a cuffed TT or a cuffed
A pediatric operating room should be equipped with supraglottic will be used.
● A cart containing all drugs and devices necessary to achieve safe
● Precut tape or gauze string to fix the TT or LMA.
anesthesia (e.g., vascular access device, airways and tracheal
● Lidocaine solution to be sprayed on the child’s cords or
tubes, anesthetic drugs, and fluids). lidocaine jelly to be applied on the outer surface of the distal
● An anesthesia ventilator and a manual resuscitator adapted to end of the TT or LMA (optional).
the child’s size to allow emergency ventilation in case of failure
● Recipient (e.g., kidney basin) to collect used items and to keep
of the ventilator. them separated from clean or sterile equipment.
● A suction apparatus. LMA = laryngeal mask airway; TT = tracheal tube.
CHAPTER 38 ■ Anesthesia Equipment 595
TABLE 38-2. Standard Equipment of the Intravascular 2. Notes on airway management (mask, supraglottic airway,
Access Cart tracheal tube size, quality of intubation), intravascular access
(intravenous [I.V.], intra-arterial, central venous, size of
● Intravascular cannulas of different sizes. cannula, number of attempts, and complications), and regional
● Alcohol, chlorhexidine, or povidone-iodine (Betadine) swabs anesthesia technique.
for skin disinfection. 3. Type of breathing system and/or ventilator used, including
● Tourniquet. settings (fresh gas flow [FGF], fractional concentration of
● Gauze swabs (disinfection, dressing) and tape (dressing). oxygen in inspired gas [FIO2], and rate).
● Special container for sharps disposal. 4. Drugs, doses, and composition of I.V. fluids administered.
● Small roll (e.g., made with gauze swabs or a roll of tape) 5. Record of vital signs. This is important because it provides
adapted to the size of the child’s wrist to stabilize it in trends of information. Handwritten records are recorded every
hyperextension to cannulate the radial or ulnar artery. 5 minutes, which limits the accuracy because it is completed
● 19-Gauge needles to make a hole in the skin before after the event (e.g., laryngospasm) has occurred. Automated
intravenous or intra-arterial catheterization (optional). record-keeping improves accuracy and completeness of the
● Syringes filled with well-identified anesthetic drugs (type and perioperative data, but it is costly and also records artifacts.
dilution adapted to the individual patient).
The postanesthesia care chart should include
1. A summary of relevant information regarding the child’s health,
on these carts. Proper rules must be followed: for example, the procedure performed, drugs and I.V. fluids administered, type
immediate storage of any contaminated equipment in a dedicated and size of airway used, and intraoperative events.
kidney dish placed on the cart. A functional laryngoscope 2. Precise orders for pain management, antiemesis, fluid admi-
should always be available during induction, maintenance, nistration.
and recovery whatever the technique used to control the upper 3. Records of vital signs, pain and sedation scores, recovery score,
airway. drugs and fluids administered, and any event occurring during
If a regional anesthesia technique is foreseen, a separate cart the recovery period.
should be used in order to prevent accidental contamination and
avoid errors during injections caused by syringes containing other Precise orders for the ward or ambulatory unit nurses at the
medications than local anesthetics. time of discharge must include analgesics, timing of first oral
intake, I.V. fluids rate and composition, antiemetics, among other
things.
Special Equipment
Special equipments that cannot be stored in each operating room Maintenance of Equipment
because of its cost or size should be available in a special place near
a group of operating rooms, in order to be quickly available in case All equipment should be checked regularly (between cases, e.g.,
of need, including laryngoscope, suction) or at the beginning of the procedure (e.g.,
anesthesia machine; Table 38–3) and maintained according to the
1. A small operating room automatic laboratory to measure blood
electrolytes, glycemia, and hematocrit.
2. A difficult intubation trolley, with supraglottic airways and a TABLE 38-3. Main Points of the Anesthetic
range of devices that can be used in case of difficult intubation Pre-Use Checklist
(see the section “Equipment for Difficult Intubation (Except
Supraglottic Airways,” later). 1. Emergency ventilation equipment (e.g., Ambu bag)
3. A cardiac defibrillator with pediatric pads, usually kept in the available and functioning.
operating room for heart surgery. 2. Central and cylinder O2, air, and N2O supplies: present and
4. A malignant hyperthermia trolley stocked with dantrolene (see correctly connected.
Chapter 81). For the sake of safety, this equipment should be 3. Functioning of the flowmeters and of the emergency O2
checked daily and/or after each use. bypass.
5. A refrigerator allowing storage of blood, blood products as well 4. Vaporizer(s): filling level, connection, filler cap closed.
as ice and iced saline bags must be available. 5. Electrical supply to the anesthesia machine and monitors:
switch on.
6. Calibration of FIo2 monitor.
Anesthetic Records 7. Calibration of all monitoring devices (e.g., PETCO2).
The anesthesia records must be a legible and complete report of 8. CO2 absorbent: color, freshness, and humidity.
preoperative evaluation; all accurate events occurring during 9. Leak test of the anesthesia machine and breathing system,
induction, maintenance, and recovery; as well as the postanesthesia including the low-pressure system.
care with postoperative orders. Electronic chart recording has 10. Scavenging system: correct assembly and functioning,
become widely used, ensuring better recording, quality control absence of obstruction.
evaluations, research, and medicolegal purposes. 11. Correct functioning of the anesthesia machine and
The anesthesia record should document all aspects of anes- breathing system in the controlled ventilation mode (to be
thetic care: adapted to the particular ventilator/breathing system used).
1. Preuse check of the anesthesia equipment, identification of 12. Correct functioning of the suction apparatus.
anesthesiologists and surgeons, time of starting the case. FIo2 = fractional concentration of oxygen in inspired gas; PETCO2 = end-tidal CO2.
manufacturer’s specifications. Moreover, proper documentation Clinical Observation

of regular inspections and repairs is important for both safety and
medicolegal reasons. Whatever the accuracy and sensitivity of the monitoring in use,
there is no substitute for the continuous presence of a well-trained
and vigilant anesthesiologist. Interpretation of the “numbers and
Hygiene curves” displayed on the screen must be assessed in accordance
with the child’s physical status and in function of the interfering
The operating room is a zone at high risk for nosocomial infection,
events. Physical signs not provided by the monitoring equip-
especially for more susceptible patients such as neonates or ment are
immunocompromised (posttransplant, cancer, HIV) and members
of the health care team. Guidelines must be used to ensure proper ● Signs of pending airway obstruction: retractions, paradoxical
hygienic principles in daily practice. chest and abdominal wall movement, stridor that most often
Hands should be washed before starting a new case, per- precedes any physiologic value changes on the monitor.
forming invasive procedures and manipulating blood, body fluids, ● Eyes (size of pupils, divergence of gaze, lacrimation) to estimate
secretions, contaminated items, and other situations whether or the depth of anesthesia.
not gloves are worn. Alcoholic handwashing solutions must be ● Capillary refill time to evaluate the child’s peripheral circulation
available in the operating room. Anesthesiologists should wear and intravascular volume.
gloves when handling equipment that has been or will come in ● Color, temperature, and dryness of the skin and mucosa.
contact with the patient’s blood, saliva, or secretions. These gloves ● Palpation of a peripheral pulse, the strength of which may
should be removed before handling other items (e.g., ventilator, change despite sustained normal invasive blood pressure (BP)
monitors, drugs) in order to minimize contamination. Work sur- measurements.
faces (anesthesia machine, carts, trolley, operating room table) ● Pulsatility of the mesenteric vessels provide a qualitative assess-
should be cleaned with a detergent between cases, and any blood ment of splanchnic perfusion during laparotomy.
or other secretions spills should be wiped up as soon as possible. ● Palpation of the fontanelle in the neonate and small infant to
It is important to separate all used equipment from those that are estimate the patient’s volemia or intracranial pressure.
still sterile or clean. The most efficient way to achieve this is to ● Volume and color of urine during bladder catheterization.
establish a routine whereby used equipment is placed in a special Knowing the stage of the procedure undertaken and observing
receptacle (e.g., a kidney basin) physically separate from the the surgical field are also important because these may explain
clean area. major hemodynamic changes that may be anticipated or rapidly
The recommended cleaning or disinfection methods are reversed: for example, bradycardia caused by traction on the
described for each equipment. extraocular muscles during strabismus surgery, or systemic
hypotension caused by compression of the inferior vena cava
during major abdominal surgery.
PREPARATION OF THE
OPERATING ROOM
Stethoscope
As a rule, everything must be ready for use before the child enters
the operating room: The use of a stethoscope, whether precordial or esophageal,
is a cheap, safe, and continuous way to easily monitor circu-
● Adequate equipment for airway and intravascular access. lation and ventilation. Chest auscultation allows confirmation of
● Drugs appropriate to the child’s size (see Tables 38–1 and tracheal intubation (except in the premature infant and small
38–2). infant in whom it must be correlated with chest expansion), the
● The anesthetic machine, breathing system, and monitoring have diagnosis of cardiac (murmur, air emboli) or pulmonary (bron-
been checked using a checklist (see Table 38–3). However, local chospasm, bronchial intubation) pathologies, and the assess-
modifications of these checklists are sometimes necessary to ment of heart rate and sounds. Although 35% of British pediatric
adapt to specific types of equipment: for example, the test to de- anesthesiologists never use a precordial or esophageal stethoscope
tect a leak in the low-pressure part (i.e., the vaporizer and its in their practice because they feel that its role has been superseded
connections) should be adapted to the design of the anesthesia by other monitors,3 this is not the opinion of the main author of
machine.2 The full checklist should be completed daily before this book.
starting the first anesthesia, and an abbreviated form of it should
also be used between cases in order to verify the parts of equip- Indications
ment that have been changed.
● The operating room is adequately warmed, and equipment In addition to its use for cardiopulmonary auscultation, a
used to prevent the occurrence of accidental hypothermia dur- stethoscope is useful at the beginning of an inhalation induction
ing induction of anesthesia must be functional and turned on. because it is quick and easy to place and does not frighten the
child; during patient transport, when other portable monitors
are unavailable or may fail; or to monitor ventilation in awake
MONITORING neonates undergoing locoregional anesthesia.
Monitoring devices are used in anesthesia to detect deviations
from normal values and unexpected life-threatening events Limits
(“safety monitors”) and to help maintain proper anesthetic care However, in clinical practice, the accuracy of the information
(“management monitors”). given by either a precordial or an esophageal stethoscope is often
limited because (1) changes in heart rate are quantitative: whether as a stethoscope, palpation of a peripheral pulse, pulse oximetry,
it increases or decreases, an ECG trace is necessary to know the and BP measurement.
exact cardiac rhythm present; (2) changes in heart sounds may
occur rapidly during inhalation induction with halothane,4 but
Description
can be difficult to hear or interpret in the noisy environment
of the operating room; and (3) it always depends on the level of The normal pediatric ECG tracing changes with age and shows
attention of the anesthesiologist, which may vary during long several differences from the adult: as a rule, heart rate decreases
procedures. whereas the intervals (PR, QT) and duration (QRS) increase with
increasing age. The right ventricle predominates in early infancy
owing to the dominant right ventricular mass, and the T-wave is
Precordial Stethoscope larger in infants because the electrodes are closer to the heart. This
In order to monitor both ventilation and circulation, the pre- larger T-wave can lead to erroneous double-counting of the heart
cordial stethoscope should be positioned over the left sternal rate if both QRS and T are interpreted as a cardiac complex by the
border, at the second or third intercostal space. However, it must monitor. The presence of an adjustable gain on the cardiac
be displaced to distinguish between esophageal, tracheal, or monitor is useful to eliminate this artifact. Lead II gives the best
bronchial intubation. The chest piece can be fixed to the skin with P-wave configuration and is, therefore, most useful to diagnose
a piece of tape or an adhesive ring (e.g., Double-Stick disks). rhythm abnormalities. Cardiac dysrhythmias are rare in children,
their occurrence should always alert the anesthesiologist who
should rule out:
Esophageal Stethoscope
● Hypoxia (bradycardia) and/or hypercapnia (atrial or ventricu-
The esophageal stethoscope should be used in patients only lar ectopics).
when the trachea is intubated. It consists of a disposable soft ● Too light anesthesia (bradycardia, tachycardia).
catheter with holes in its distal 2 to 3 cm. These holes are covered ● An overdose of halogenated agents (nodal rhythm) or local
with a cuff. More sophisticated models have been designed in anesthetic.
which a thermistor or an ECG lead is incorporated. It is positioned ● An unsuspected intracardiac conduction defect (e.g., Wolff-
in the mid-esophagus, where breath and heart sounds are best Parkinson-White or long Q-T syndrome).
transmitted and of maximum intensity. ● A malignant hyperthermia crisis or rhabdomyolysis (ventricu-
An esophageal stethoscope should not be used in case of lar ectopics, asystole).
esophageal atresia; neck dissection because it may confer a firmer
feel to the esophagus that might then be mistaken for the trachea; Conversely, it is very important to note that potentially
laser surgery of the airway because of its inflammability. dangerous levels of hypercapnia or hypoxia can be achieved with-
Complications have occasionally been reported when using out being accompanied with dysrhythmias until cardiovascular
an esophageal stethoscope: esophageal burns caused by current collapse occurs!
leakage in esophageal stethoscopes incorporating an ECG or
temperature lead; airway obstruction following insertion of Indications
the esophageal stethoscope into the trachea, beside the tracheal An ECG monitoring should be used for every pediatric anesthesia
tube5; and hypoxemia owing to compression of aortopulmonary in order to provide a beat-to-beat measurement of heart rate and
collateral vessels in an infant with complex cyanotic heart disease.6 to allow for the immediate diagnosis of any dysrhythmia. The
analysis of the ECG signal can give useful clinical information
such as
Electrocardiography
● Prominent T-wave and ST-segment changes in case of acciden-
Goal and Limits tal I.V. injection of an epinephrine-containing local anesthetic
Electrocardiography is the most accurate method to measure heart solution8 (Figure 38–1).
rate and diagnose dysrhythmias. However, it may give a false sense ● Prominent T-waves in case of hyperkalemia caused by
of security, especially in neonates and infants, because a normal rhabdomyolysis after the administration of succinylcholine
ECG may still be present in spite of a significant fall of cardiac and/or halogenated agents in children with unsuspected dys-
output particularly when halothane is used.7 Therefore, an ECG is trophinopathy (e.g., Duchenne’s muscular dystrophy) or sus-
not a substitute for other monitors of tissue perfusion and BP such ceptibility to malignant hyperthermia (see Chapter 81), by
Figure 38-1. Modification of the electrocardiogram (ECG; huge T-wave) following accidental administration of 0.1–0.2 mL/kg of
levobupivacaine with epinephrine 1/400,000 during performance of a caudal block in a 4-kg baby under sevoflurane anesthesia
TABLE 38-4. Practical Aspects of Intraoperative pulse oximeters can measure only two forms of hemoglobin that,
Electrocardiography in Children according to the absorption spectra of those wavelengths, are
oxyhemoglobin (HbO2) and deoxyhemoglobin (Hb). At each
1. Snap the electrodes on the leads before applying them on the wavelength, both the nonpulsatile and the pulse-added absorb-
child’s skin. ance are measured and allow the calculation of a ratio, R, that has
2. In small infants, use small, flexible, and adhesive electrodes. been empirically related to oxygen saturation (SaO2) measured in
3. In small infants, place the electrodes on the proximal part of arterial blood of healthy nonsmoking adult volunteers: a ratio
the limbs in order to lessen the baseline drift caused by the of 1 corresponds to an SpO2 of 85%. Good functioning of all pulse
movements of the thorax. oximeters is, therefore, based on the two assumptions that
4. Do not apply electrodes on the nipples.
5. Check the path of the electrocardiographic leads to make 1. The only pulsatile absorbance present is that of arterial blood.
sure there is no risk of pressure necrosis. 2. The patient has normal hemoglobin A and no dyshemoglobins
6. Adjust the gain of the monitor in order to obtain an easily in his or her blood.
interpretable tracing (P-wave) and to avoid double-counting Pulse oximeters measure what is called functional satura-
of QRS and T. tion (i.e., HbO2/HbO2 + Hb). By contrast, the co-oximeters used in
the blood gas laboratory use more wavelengths of light and are,
massive transfusion, or occurring at the time of reperfusion dur- thus, able to measure all sorts of hemoglobin present in the patient’s
ing organ transplantation. blood. They measure what is called fractional saturation, HbO2/
● ST segment changes in case of cardiac ischemia caused by in- HbO2 + Hb + dysHb, where dysHb mainly represents carboxy-
sufficient coronary perfusion9,10 or myocardial hypertrophy (COHb) and methemoglobin (MetHb).The normal percentage of
(e.g., glycogenesis II, mucopolysaccharidosis). dyshemoglobin is less than 2%. The most recent pulse oximeters
● A prolonged QT interval in case of hypocalcemia. (e.g., Rad-57 by Masimo) uses up to 12 wavelengths of light and
are able to measure both SpCO (very close to COHb), SpMet (close
Practical points concerning the application of ECG electrodes to MetHb) and even SpHb (total Hb).12 Their availability will
are given in Table 38–4. improve the noninvasive diagnosis and management of CO
poisoning (acute burns), methemoglobinemia,13 and anemia. It
Artifacts should, however, be kept in mind that, despite that major techno-
logic progress, SpO2 readings from those 8- to 12-wavelengths
The large number of electrical equipments in the operating
pulse oximeters are still obtained according to the “classic”
room and pediatric intensive care unit (PICU) increases the risk
of interference with the ECG. To name few, possible sources of 2-wavelengths algorithm and, therefore, subject to the same errors
artifacts are evoked potentials monitoring, electrostimulation, as described under “Physiologic Limitations,” later: interpreting
hemodialysis machine, high-frequency oscillation (HFO), mag- SpO2 taking into account SpCO and SpMet is mandatory.12 The
netic resonance imaging (MRI), electrical current leakage from mean difference (“error”) between SpO2 and HbO2 measured by a
fluid administration or warming devices, and extracorporeal co-oximeter is called bias, whereas the standard deviation of this
shock wave lithotrypsy. These artifacts can mimic supraventricular difference is called precision. Although most manufacturers claim
or ventricular arrhythmia and must be confirmed using clinical that their pulse oximeter is accurate to within ± 3% of the line of
examination (a palpable pulse), comparison with the information identity between SpO2 and HbO2, bias and precision values are
from other monitoring devices (e.g., SpO2), and the “on-off test” often greater. A monitor integrating in the same low-pressure ear
of the suspected cause of artifact.11 probe a pulse oximeter and a transcutaneous CO2 Severinghaus
electrode (see “Special Monitoring,” later) (e.g., Tosca) can be used
in children, even neonates14 (Figure 38–2).
Pulse Oximetry A technology similar to classic or “transmission” pulse goni-
Goal and Indication ometry is called reflectance or surface sensor goniometry. The
source of multiple wavelengths of red and infrared light is placed
Continuous pulse oximetry gives a beat-to-beat measurement of beside and very close to the detector, which measures light that
the oxygen saturation of hemoglobin, a physiologic criterion that is reflected from the underlying tissues to determine HbO2.
is difficult to evaluate clinically because cyanosis is a late and not Nonhomogeneity of the optical path between emission and
a reliable sign of hypoxemia. It should be used whenever a patient
measurement, as well as the rather weak signal reflected, limits
undergoes anesthesia or sedation. However, situations exist in
the precision of the measure. The underlying tissue must be
which pulse oximetry may give misleading or inaccurate infor-
well perfused to avoid loss of the signal. The probe is flat and
mation; its basic principles must, therefore, be understood to
can be placed on flat surfaces such as the forehead or small infant
correctly interpret the readings displayed.
chest or cheek. The skin of the lower forehead, just above the
eyebrows, is a good location because its blood supply comes
Description from the supraorbital artery and this area is less sensitive to
Briefly, pulse oximetry measures the absorption of two wave- vasoconstrictive stimuli such as cold. The results of transmission
lengths of light (660 and 940 nm) between a light source and a and surface pulse oximetry are usually similar but care must be
photodetector. The pulsatile expansion of the arteriolar bed taken to avoid placing the probe over a vein or artery. The same
interposed between the source and the detector produces a pulse- technology is used in a miniature pediatric esophageal pulse
added increase in the path length of the light beam and, thus, an oximetry probe that has been successfully tested in a few patients.15
increase of its absorbance. Because only two wavelengths are used, Near-infrared spectroscopy is an optical technology that measures
A B
Figure 38-2. A: Combined SpO2 (oxygen saturation of hemoglobin monitored with pulse oximetry) and PtcCO2 (transcutaneous
partial pressure of carbon dioxide) sensor (Tosca) placed at the right ear of a 2.4-kg prematurely born infant undergoing laser ther-
apy for retinopathy of prematurity under sedation. A small catheter is also inserted in the nasal O2 prongs to obtain a capnogram
and check upper airway patency. B: Monitor shows the measured values.
tissue oxygenation and is described under “Neurophysiologic TABLE 38-5. Physiologic Limitations of Pulse Oximetry
Monitoring,” later.
1. Oxyhemoglobin dissociation curve
● Plateau ⇒ poor monitoring of hyperoxia
Physiologic Limitations ⇒ poor monitoring of hypoventilation once supplemental
The first limitation of pulse oximetry is linked to the sigmoid O2 is given
shape of the HbO2 dissociation curve, which plateaus once arterial ● HbF, beta-thalassemia ⇒ shift to the left: lower PaO for
2
oxygen pressure (PaO2) is greater than 80 mmHg. Pulse oximetry same SpO2!
is, therefore, not a monitor of hyperoxia because, above that level, ● Acidosis, HbSS ⇒ shift to the right
important changes in PaO2 may occur with only small changes 2. Abnormal absorption spectrum of hemoglobin: extremely
in HbO2 (Table 38–5). In the same way, SpO2 can be used as an rare, e.g., Hb Köln, Hb Milwaukee
indirect monitor of ventilation (e.g., in the postoperative period) 3. Anemia: no problem as long as Hb > 5 g/dL
only if the patient is breathing room air. In case of hypoventilation, 4. Presence of dyshemoglobin
arterial carbon dioxide pressure (PaCO2) and alveolar carbon ● COHb: overestimation of SpO by an amount close to
2
dioxide pressure (PACO2) rise and, according to the alveolar COHb %
gas equation, PAO2 and thus PaO2 fall, leading to hemoglobin ● MetHb: if < 20%, SpO decreases by about half of MetHb %
2
desaturation. However, in the presence of an increased FIO2, N2 is ● If > 20%, SpO = 85%
2
washed out and PAO2 will rise even if PACO2 increases and the 5. Reduced perfusion
monitoring of SpO2 will fail to detect hypoventilation until it is ● Hypothermia: no problem if core temperature > 30°C
very severe.16 ● Hypovolemia:
Fetal hemoglobin (HbF) constitutes 50 to 80% of total • Increased variability of plethysmogram with IPPV
hemoglobin at birth and decreases to adult levels after 5 months (see text)
of age. The absorption spectra of HbF and adult hemoglobin • Loss of signal (but presence of signal ≠ adequate
(HbA) are very close and the presence of HbF, therefore, does not perfusion!)
interfere with SpO2 measurement. However, the HbFO2 6. Dyes
dissociation curve is shifted to the left, which means that, for a ● Bilirubin: no influence except if acute hemolysis (⇑ COHb)
similar SpO2 reading, the actual PaO2 is lower. Moreover, a COHb ● Nail polish: effect variable ⇒ position probe sideways
level higher than 2 to 3% may be present during the first week of ● Meconium staining of the skin: possible falsely low SpO
2
life because of physiologic hemolysis. This also interferes with the ● Intravenous methylene blue, indigo carmine, indocyanine
measurement of SpO2. The combination of a variable percentage green: short-lived low SpO2
of HbF, the leftward shift of its oxyhemoglobin dissociation curve, ● Subcutaneous Isosulfan or patent blue: progressive
and the possible presence of COHb do not support the statement spurious decrease in SpO2
that, in preterm infants, it is safe to maintain SpO2 below 95%17 or 7. Venous pulsations: e.g., tricuspid regurgitation: falsely low
93%18 to avoid hyperoxemia and prevent the development of SpO2
retinopathy of prematurity. Although those upper limits of SpO2 COHb = carboxyhemoglobin; Hb = hemoglobin; HbSS = hemoglobin SS; IPPV =
will indeed identify the majority of episodes of hyperoxemia, SpO2 intermittent positive-pressure ventilation; MetHb = methemoglobin; PaO2 =
readings in the normal range can also be associated with a very arterial oxygen pressure; SpO2 = percutaneous oxygen hemoglobin saturation as
low PaO2 in that population. Intermittent comparison of SpO2 read with a pulse oximeter.
with arterial PaO2 and HbO2, or measurements of transcutaneous which methemoglobin level ranges between 15 and 30%, pulse
arterial oxygen pressure (PtCO2) are safer to avoid hyperoxemia. oximetry is unreliable because this hemoglobin has a decreased
One should be cautious when comparing SpO2 with the HbO2 oxygen affinity.20
measured by a co-oximeter because part of HbF is measured as Reduced peripheral perfusion affects the performance of pulse
COHb by some co-oximeters. To avoid this pitfall, the laboratory oximetry. Although the disappearance of the plethysmographic
should be informed of the presence of HbF in the blood sample in signal is a sign of poor peripheral perfusion, the presence of an
order to use an algorithm compensating for it. Lastly, when oximeter waveform and the measurement of an SpO2 do not imply
comparing SpO2 and HbO2 in neonates and infants, it is important adequate tissue blood flow. Conversely, when using a pulse
to check whether the measurements are made on the same side of oximeter that does not automatically “normalize” the gain of its
the ductus arteriosus. If not, the discrepancy could be caused by plethysmographic display, increased variation of the peaks of the
right-to-left shunting at the ductal level. pulse waveform and/or intermittent dysfunction of the pulse
In case of shift to the right of the oxyhemoglobin dissociation oximeter during positive-pressure ventilation is a sign of hypo-
curve (increased 2,3-diphosphoglycerate [2,3–DPG] levels as volemia (Figure 38–3).21 In adults undergoing volume-controlled
during infancy to compensate for so-called physiologic anemia, ventilation in the operating room or intensive care unit, respi-
hemoglobin SS (HbSS), acidosis, hyperthermia, or other problems), ratory variations in pulse oximeter waveform (i.e., variations in
the PaO2 that can be inferred from SpO2 is higher than usual. local blood volume) can be used to evaluate ventilation-induced
Some hemoglobins have an abnormal absorption spectrum, cyclic changes in left ventricular stroke volume and thus preload
and pulse oximeter readings are affected in these cases.19 The and predict responsiveness to fluid loading in case of hypotension.
presence of anemia does not interfere with pulse oximetry as long The latest models of pulse oximeters (e.g., Masimo Radical 7)
as the total hemoglobin level is greater than 5g/dL, but it should be provide the automatic and continuous measurement of the
borne in mind that a normal SpO2 does not reflect the patient’s dynamic changes in perfusion index during a complete respirator
O2-carrying capacity. cycle: this is called the plethysmography variation index (PVI). It is
COHb levels in excess of 2% are present in cases of CO calculated from
poisoning (e.g., victims of flame burns) and of acute hemolysis [PImax – PImin/PImax] × 100
because the metabolism of hemoglobin produces equimolar
amounts of bilirubin and CO. COHb is read by pulse oximeters where PI is the perfusion index. For each PI calculation, the
as if it was HbO2, and SpO2 is, therefore, overestimated by an variable amount of light absorption of the infrared signal (AC) is
amount close to but usually somewhat less than the percentage of indexed against its constant nonpulsatile absorption (CD) and
HbCO.12 expressed as a percentage:
MetHb, whether congenital (e.g., HbM Boston) or acquired, is
PI = AC/DC × 100
a rarer cause of dysfunction of pulse oximetry. MetHb strongly
absorbs light at both wavelengths used to measure SpO2 and its For PVI, a threshold value of 11.5 to14% has been proposed in
influence is, therefore, concentration-dependent: if less than adults, but it should be interpreted with caution because changes
20% MetHb is present, the SpO2 is decreased by about half the in vasomotor tone or the use of vasoconstricting agents could
percentage of MetHb; if more than 20% MetHb is present, SpO2 is affect it.21 Moreover, interpretation of PVI should take into
85% regardless of the actual HbO2 because the absorption ratio is account that tidal volume (VT), level of positive end-expiratory
equal to 1.12 However, in case of Hemoglobin M (Milwaukee), in pressure (PEEP), and respiratory rate modify ventilation-induced
Figure 38-3. Simultaneous variations

of the plethysmographic waveform of
the pulse oximeter (lower tracing) and
the invasive arterial blood pressure
(radial artery, upper tracing) during
controlled ventilation in an infant with
moderate hypovolemia.
cyclic changes in left ventricular stroke volume. The use of PVI TABLE 38-6. Technical Limitations of Pulse Oximetry
to evaluate fluid responsiveness is still under investigation in
pediatric animal models.22 1. Calibration and accuracy
● Quality of the signal: waveform and/or heart rate similar
In dark-skinned patients, pulse oximeters tend to overestimate
HbO2 in case of hypoxia.23 In case of hypothermia, SpO2 under- to ECG
● Inaccuracy increases when SaO < 80% (e.g., cyanotic
estimates HbO2 when core temperature becomes less than 30°C. 2
Because its absorption spectrum peaks below 600 nm, bilirubin congenital heart disease)
has no effect on the measurement of SpO2.24 However, in case of 2. Delay of response
● Response time faster if probe centrally placed
hemolytic jaundice, the presence of high levels of COHb interferes
● Depends on averaging time chosen
with SpO2 measurement. Moreover, the presence of bilirubin levels
greater than 20 mg/dL affects the good functioning of some 3. Motion artifact
co-oximeters.24 In these cases, the laboratory should be informed 4. Interference of other light sources
● Fluctuating light sources: shield the probe
of the presence of hyperbilirubinemia in order to correct the
● Neuronavigation: shield the probe with aluminum foil
co-oximeter readings accordingly. Otherwise, spuriously high
● Incorrectly placed probe (optical shunt): visual control of
levels of COHb and MetHb will be reported.
Although nail polish should theoretically have no influence the probe
on pulse oximetry because its absorbance is continuous and 5. Electrical or magnetic interferences
nonpulsatile, some colored nail polishes cause an underestimation ECG = electrocardiogram; SaO2 = arterial oxygen saturation.
of saturation. It is recommended to place the oximeter probe
sideways on the finger if colored nail polish is present. or false alarm in awake patients, several brands of pulse oximeters
In the same way, meconium staining of the neonate’s skin could are equipped with new algorithms canceling the noise signal that
produce low SpO2 readings.25 Because of their light absorption is common to both wavelengths and improving detection of true
characteristics, the I.V. injection of dyes such as methylene blue, hypoxemic events.29
indigo carmine, indocyanine green, or fluorescein causes erro- Ambient light should have no influence because it is measured
neously low SpO2 readings. Fortunately, because of the rapid when the light-emitting diodes in the probe are off and its effect
dilution and distribution of the dye in the body, this effect is very is subtracted during light transmission by the probe. However,
short-lived. A blood sample for in vitro measurement should fluctuating light sources such as fluorescent or xenon lights
not be taken within a few minutes of the injection because co- can cause problems because they are flickering at frequencies
oximeters are subjected to the same interference. In the same similar to the harmonics of the light-emitting diodes. The probe
way, the subcutaneous injection of isosulfan blue or patent blue should be shielded with cloth or opaque material. The infrared
(to map pathologic lymph nodes or lymphatic vessels) produces a pulse waves of the frameless stereotactic neurosurgical position-
progressive decrease in SpO2 during 5 to 40 minutes and a falsely ing systems (“neuronavigation”) reduce the accuracy of pulse
elevated methemoglobinemia on co-oximetry. PaO2 should be oximetry. This can be prevented by shielding the probe with
checked if there is any doubt about the patient’s oxygenation.26 aluminum foil.30
The presence of venous pulsations, such as in case of tricuspid A more insidious cause of error is malpositioning of the probe.
regurgitation, produces falsely low SpO2 readings. Unfortunately, This produces an optical shunt or penumbra effect because part of
the degree of interference cannot be predicted from the peak the light is transmitted without any tissue absorption. This is more
central venous pressure (CVP) value measured.27 likely in children in whom too large a probe is used. Barker and
coworkers tested the response to hypoxemia of different brands
Technical Limitations of pulse oximeters with probes malpositioned in such a way that
heart rate measurement was still correct and that no error message
Before an SpO2 reading is interpreted, the quality of the signal
was displayed on the monitor screen.31 The results varied greatly
received by the probe should be confirmed by a good plethys-
depending on the actual HbO2, brand, and model. They concluded
mographic waveform and/or a heart rate similar to the one
that, to prevent this potential cause of error, the probe in use
measured with the ECG (Table 38–6). Moreover, the measured should always be visible to the user.
SpO2 is only as accurate as the empirical calibration curve included Electrocautery is another annoying cause of failure of pulse
in the pulse oximeter software. There are small differences oximetry. When using pulse oximetry in the MRI suite, care
between the measurements obtained with different brands of pulse should be taken to use specially designed equipment in order to
oximeters. All pulse oximeters become more inaccurate when avoid interference with SpO2 measurement and/or imaging or
HbO2 is lower than 75 to 80%. even skin burns.32
The response time to both desaturation and resaturation also
varies according to the brand of the pulse oximeter and to the site
of measurement. In children as in adults, both saturation and Possible Complications
desaturation are detected 50 to 60% earlier by sensors placed Skin burns have been reported when using probes during MRI,32
centrally (ear, cheek, and tongue) than in those placed peripherally either probes with small defects or probes from another brand of
(finger, toe).28 The response time also depends on the averaging oximeter.33 Burns are also reported during perioperative photo-
time used in the pulse oximeter. The shortest one should be dynamic chemotherapy owing to photosensitivity to red light. In
selected, although this usually increases the sensitivity to motion this situation, the probe should be used for only few minutes and
artifact. at rotating sites.34
The performance of pulse oximeters is affected by motion. To Pressure necrosis can also occur if the probe is left in place on
reduce motion artifact, which is the most common cause of failure a single site for a long period of time, especially during hypo-
TABLE 38-7. Rules for the Optimal Use of Pulse Oximetry of cyanotic heart disease,36 if the child’s position is changed or
during laparoscopy. The PaCO2-PETCO2 difference is sometimes
1. Verify probe integrity before use. negative in healthy children,37 namely in the presence of minimal
2. Avoid mixing of probes and monitors of different brands. alveolar deadspace, or in some cases of laparoscopic surgery38 (see
3. Do not use clip-on ear probe on the extremities of children Chapter 60).
< 10 kg (risk of pressure necrosis). The technical variables are the site of sampling, the FGF, the
4. Check the quality of the signal received by the probe type of breathing circuit, the respiratory rate, and in case of
● Good waveform and heart rate similar to ECG monitor.
sidestream capnometry, the aspiration flow rate. The smaller the
5. Direct visual control of probe position. child, the more important these technical variables are.
6. Remember pulse oximeter measures SpO2 not PaO2.
7. In case of doubt: check the patient’s condition before blaming INDICATIONS: Capnography is included in the standards of
the equipment. monitoring during anesthesia. It allows
8. In case of control with arterial blood gases: inform the ● Confirmation of the correct placement of the tracheal tube (TT)
laboratory if
● Presence of HbF.
or supraglottic airway.
● Presence of bilirubin levels > 20 mg/dL.
● Assessment of the adequacy of ventilation.
● Recognition of metabolic (e.g., malignant hyperthermia),
ECG = electrocardiogram; HbF = fetal hemoglobin; PaO2 = arterial oxygen hemodynamic (e.g., embolism, cardiac arrest), or respiratory
pressure; SaO2 = arterial oxygen saturation; SpO2 = percutaneous oxygen
(e.g., bronchospasm, residual muscular blockade) events.
hemoglobin saturation as read with a pulse oximeter.
● Monitoring of airway equipment patency: disconnection,
exhausted CO2 absorber, malfunction of a valve.
thermia. The probe should be checked frequently and changed if ● For research.
necessary during long-lasting procedures. Cliplike ear probes
should not be used in children weighing less than 10 kg because
DESCRIPTION: Gas for analysis of CO2 may be aspirated from the
the pressure applied to the skin is excessive and often exceeds the
airway and transported to the analyzing chamber (sidestream or
infant’s mean arterial pressure, resulting in the loss of signal, often
aspirating capnography) or analyzed as it passes through a sensor
simulating desaturation.35 Proper rules when using pulse oximetry
placed into the breathing circuit (mainstream or flow-through
are summarized in Table 38–7.
capnography). The advantages and disadvantages of both tech-
niques are summarized in Table 38–8. The CO2 can be measured
Respiratory Gas Monitoring using either infrared analysis, mass spectrometry, acoustic
spectrometry, or Raman scattering. If PETCO2 is measured at the
The measurement of inspired and expired O2, CO2, and volatile
connection of the breathing circuit, it is called proximal PETCO2;
agent concentration enables the anesthesiologist to continuously
if it is measured in the TT or supraglottic airway, that is, distal to
check the good functioning of the ventilatory equipment and
the connection with the breathing circuit, it is called distal
evaluate noninvasively the adequacy of the patient’s ventilation
PETCO2.
(PETCO2).
TABLE 38-8. Comparison of Mainstream and Sidestream

Capnography Capnography Advantages and Disadvantages
Carbon dioxide monitoring measures breath-to-breath partial
pressure of inspired and expired CO2. Capnometry is the measure- Mainstream
ment of CO2 partial pressure and capnography is the continuous No response delay
graphic display of this measurement. If the graphic display is Delicate sensor close to the patient
calibrated, capnography includes capnometry. In practice, ⇒ Kinking? disconnection? burn?
capnography usually refers to both capnometry and capnography. ⇑ Deadspace (! in infants)
Analysis of the capnographic waveform is essential to verify the Interferences in presence of blood, water or secretions in
adequacy of gas sampling and to interpret capnometry. PETCO2 is the cuvette
the partial pressure of exhaled CO2 measured at the end of each Accurate even at rapid-cleaning of cuvette between cases
tidal breath. Respiratory rates—not usable in nonintubated patient
No scavenging needed—no measurement of other gases
PHYSIOLOGY: The two working principles when measuring
PETCO2 are (1) the end-tidal gas sample is composed mostly of Sidestream
alveolar gas and (2) the concentration of CO2 in the alveolar gas is Light adapter—transport time to sensor causes response
very close to PaCO2 and can be used to noninvasively estimate delay
its value. Distal sampling easy—sampling site critical for accuracy
However, the degree to which PETCO2 approximates PaCO2 is Evacuation of expired gases
subject to many variables that are either physiologic or technical. OK in nonintubated patient—risk of obstruction of sampling
tube
Physiologically, the difference between PaCO2 and PETCO2
Measurement of other gases—risk of leaks in the connections
is usually slightly positive (0–5 mmHg) and increases when
Accurate zeroing—risk of distortion of the expired gas wave
deadspace ventilation increases, for instance, in the presence
during aspiration to sensor
of lung disease or cyanotic congenital heart problem. This
Accuracy affected by rapid respiratory rate (>40 breaths/min)
difference remains usually stable intraoperatively, except in case
A B
Figure 38-4. A: Sampling of expired air at the nostril of a high-risk ex–premature infant undergoing inguinal hernia repair under
awake caudal blockade. B: Capnogram obtained.
MAINSTREAM CAPNOMETRY: The main advantage of main- the obstruction is relieved.41 Clinical signs of hypoventilation (slow
stream capnometry is the absence of response delay even at rapid and/or shallow breathing) or upper airway obstruction (stridor
ventilation rates.39 Although the latest pediatric sensors present and/or retractions) should help in interpreting the displayed
a small deadspace, the sensor is close to the child’s face, causing PETCO2.
a risk of disconnection, kinking, and pressure or burn injury When using a TT, sampling can be performed with a catheter
because the sensor is heated to prevent water condensation. The inserted through the wall of the TT, via the sampling port of the
main disadvantages of mainstream capnography are elbow connector, or via a specially designed TT connector or the
● It is not usable in nonintubated patients. sampling line of specially designed TTs. If the TT is connected to
● The sensor needs to be cleaned and disinfected between cases. a Mapleson D circuit, sampling distal to the point at which the
● It measures only CO2, not O2 nor volatile anesthetics. tracheal tube connector narrows to the diameter of the TT is
necessary to avoid mixing of expired gases with inspired gas flow.42
SIDESTREAM CAPNOMETRY: The main advantages of sidestream When using a laryngeal mask airway (LMA) with a circle
circuit and spontaneous or controlled ventilation, sampling at
capnometry are the possible simultaneous sampling and measure-
the elbow connector gives accurate results in children43 and in
ment of inspired/expired volatile anesthetics and the multiple
infants less than 10 kg.44 If an LMA is used in children breathing
possibilities of remote sampling. For example, the sampling tube
spontaneously through a nonrebreathing circuit, expired gas
can be taped adjacent to the external nares to monitor breathing
should be sampled at the distal end of the shaft of the LMA. Even
in unsedated infants undergoing surgery under regional anesthe-
sia (Figure 38–4) or in children in the recovery room. It can also
be connected to nasal oxygen cannulas to monitor ventilation in TABLE 38-9. Ideal Site for End-tidal Gases Sampling
children receiving supplemental O2 undergoing deep sedation or According to the Airway Control Device and Breathing
in the recovery room.40 Sidestream spirometry can be combined System in Use
with capnography to measure ventilatory parameters such as
compliance and resistance and display volume-pressure and flow- Facemask
volume waveforms. Spontaneous ventilation ⇒ special cannula through elbow
connector
The site of sampling is critical to obtain accurate PETCO2
measurements. The optimal site of sampling varies with the TT
airway device and the breathing system used. As a rule of thumb, ⇒ Sampling distal to the TT connector
the more distal the sampling site, the more accurate PETCO2 is to
Supraglottic Airways
PaCO2 (Table 38–9). When using a facemask and a T-piece system
Spontaneous ventilation and connected to a nonrebreathing
during inhalation anesthesia, the difference between PaCO2
circuit
and PETCO2 is smaller when expired gas sampling is performed ⇒ Special cannula inserted into the shaft of the LMA
through a few-centimeters-long cannula inserted through a Controlled ventilation and connected to a circle system:
sampling port into the elbow connector between the circuit and ⇒ Elbow connector between circuit and patient
the mask than when it is obtained at the elbow connector.37 The
PETCO2 obtained under those conditions should be interpreted If an HME has been placed, sampling should be performed
cautiously because high FGF can result in an artificially low either in it or distal to it, i.e., between the patient and
PETCO2 owing to mixing with the expired gases. Last but not the HME.
least, partial upper airway obstruction can result in an apparently HME = heat and moisture exchanger; LMA = laryngeal mask airway; TT =
normal to low PETCO2 and hypoventilation can go unnoticed until tracheal tube.
TABLE 38-10. Interpretation of the Capnogram

● Sudden disappearance: disconnection, obstruction, cardiac
arrest, embolism, or automatic zeroing of the device?
● Gradual decrease of PETCO : hypoventilation, decreased
2
cardiac output?
● Slow increase of PETCO : hypoventilation, fever, exhausted
2
CO2 absorbent?
● Increase of PICO : rebreathing, artifact caused by rapid
2
respiratory rate?
● Rapid increase of PETCO : malignant hyperthermia?
2
● Transient and short-lived increase in PETCO : injection of
2
blood or NaHCO3?
● Gradual increase of PETCO and/or PICO : faulty
2 2
unidirectional valve?
● Sharp upstroke of the plateau: bronchospasm, kinking
Figure 38-5. Sidestream capnography via a connector included of TT?

● Curare cleft: residual curarization?
in a heat and moisture exchanger (HME).
● Cardiac oscillations: slow respiratory rate ⇒ respiratory
depression?
so, although the PaCO2-PETCO2 difference is low (2.02 ± In case of esophageal intubation, there is either no PETCO2
6.9 mmHg), the correlation with PaCO2 remains poor (r2 = 0.5). waveform or only a few small humps of decreasing height if
This is probably caused by the shaft of the LMA being larger than some CO2 was present in the child’s stomach after induction
the TT and the presence of the pharyngeal cavity is bypassed in of anesthesia. Bronchial intubation may present with either
case of tracheal intubation.45 decreased or increased PETCO2.
Conversely, whatever the airway device used, if an HME or
bacterial filter is inserted in the breathing system, the PETCO2 PETCO2 = end-tidal CO2; PICO2 = inspired concentration of CO2; TT =
tracheal tube.
measured at the machine side of the filter is lower than at the
patient side (Figure 38–5). This difference is caused by an increased
deadspace, which is larger during spontaneous than controlled INTERPRETATION OF DATA: In infants and children ventilated with
ventilation.46 a circle circuit, the normal capnogram has the same waveform as in
Last, the monitor sampling rate should be the same as for adults, that is, a sharp upstroke at the beginning of expiration
adults, that is, between 100 and 240 mL/min, ideally 150 mL/min, followed by a slightly ascending plateau phase interrupted by
because lower flow rates may not capture the peak expired CO2, the next inspiration. The information obtained is similar and
giving unreliable measurements and a blunted capnogram falsely summarized in Table 38–10.
suggesting rebreathing. Although these high sampling rates were It should be kept in mind that the presence of a plateau does not
initially thought to extract large volumes of gas from the lungs always mean that PETCO2 accurately reflects PaCO2. A plateau can
of small infants, their safety has been demonstrated. Sampling be present despite a large PaCO2-PETCO2 difference in case of
150 mL/min in a 4-kg infant breathing at 25 breaths/min with an ● Proximal sampling in infants less than 10 kg.
inspiration-to-expiration (I:E) ratio of 1:1 aspirates 6 mL from the ● Increased deadspace ventilation (lung disease).
VT at each breath, which represents 15% of the volume (4 × 10 mL). ● Shunting of pulmonary circulation (cyanotic congenital heart
The loss of VT decreases at lower I:E ratios as well as in larger disease).
children and increases if sampling rate increases. The expired gases
sampled can be re-injected into the ventilator circuit, eliminated Conversely, in infants and because of the rapid respiratory rates
via the scavenging system, or eliminated in the operating room used, PETCO2 is sometimes close to PaCO2 even in the absence
atmosphere. In case of low-flow anesthesia, the volume of gas of a flat plateau phase on the capnogram. In these cases, the
aspirated should be compensated for if it is not returned to the difference between PaCO2 and PETCO2 should be measured with
breathing circuit. an arterial or central venous blood sample.
The disadvantages of sidestream capnometry are The capnographic baseline can be erroneously elevated in
the presence of very high respiratory rates (>40 breaths/min).
● The risk of obstruction of the sampling tube with water or se- The inspired concentration of carbon dioxide (PICO2) increases
cretions. progressively with respiratory rate when sidestream capnography
● The presence of some transport delay, that is, the time required is used during controlled ventilation with a circle circuit.39 This
to suction the gas sample into the analyzer cuvette. It varies from artifactual elevation of the PICO2 is partly caused by the parabolic
1.6 to 5.2 seconds and becomes longer as the length of the sam- distortion of the CO2 sample as it travels through the sampling
pling line increases. It also delays the dynamic response of the line. Because of laminar flow, gas near the wall of the catheter
capnometer (i.e., rise time of the measured signal once the gas moves more slowly than gas in the middle of it. This mechanical
sample reaches the cuvette), which may affect accuracy in case phenomenon may lead to partial fusion of the beginning of one
of rapid respiratory rate.47 When using sidestream capnography, sample with the end of the previous one and, thus, to elevation
one should always bear in mind that both the PETCO2 and the of the baseline without actual rebreathing. Conversely, if the
capnogram signal are delayed. This transport delay could lead to capnometer response time (transport delay + dynamic response)
an incorrect diagnosis of esophageal intubation. exceeds the time for one breath, the analyzer will measure
inappropriately low PETCO2 and elevated PICO2. Both parabolic Blood Pressure
distortion and capnometer response time are minimized when
using short sampling lines. BP should be measured during anesthesia to ensure ade-
Lastly, in the presence of a large leak around the TT, PETCO2 is quate perfusion of all organs. The most accurate method of BP
inaccurate, with both mainstream and sidestream capnometry, measurement is continuous invasive measurement following
because there is a loss of expired gas. catheterization of a peripheral artery. However, because of the
risks involved, especially in small children, this procedure is
PORTABLE COLORIMETRIC PETco2 Detectors: Portable devices reserved for critically ill patients or major surgical procedures.
allow detection and estimation of expired CO2. They can be used Noninvasive methods are used during routine procedures.
in emergency situations when a capnograph is not readily available Normal values for BP according to age should be known in order
(e.g., prehospital setting) or during transport of the patient. to correctly interpret the measured data (see Chapter 7).
The Statcap (Nellcor) is a small, battery-operated capnograph
that provides a semiquantitative measurement of PETCO2 using
colored bars that range from purple (PETCO2 0–6 mmHg) to NIBP Measurement
yellow (>20 mmHg). The device is not designed for use in children
younger than 3 years or weighing less than 10 kg. Its disposable DESCRIPTION: Many noninvasive techniques are available to
airway sensor has a deadspace of 4 mL. measure BP using a BP cuff. Selection of a BP cuff of appropriate
The Pedi-cap (Nellcor) is a 5-gauge clear plastic device to be size is critical to obtain reliable results. Too narrow a BP cuff results
connected between the TT and the breathing system. It contains in overestimation of BP whereas a too large cuff underestimates
filter paper impregnated with a pH-sensitive chemical indicator it. As a rule, the width of the inflatable bladder of the cuff should
the color of which changes on exposure to CO2. It provides a be approximately 40% of the arm circumference. This usually
breath-to-breath estimation of PETCO2 through a range of colors corresponds to a BP cuff that is two thirds or three fourths of the
from purple (<4 mmHg) to yellow (15–38 mmHg). Because of its distance between the child’s axilla and the antecubital fossa.
small deadspace volume (3 mL), it can be used in children less But, in fact, when using the upper arm length criterion, one usually
than 15 kg. For bigger children, another version of the same chooses a BP cuff that is larger than when using the arm circum-
device, called Easy-capII (deadspace 25 mL), is used. All these ference criterion. Commercially available BP cuffs rarely corres-
devices are, however, easily damaged by excessive humidity pond to the chosen criterion for an individual child. As a rule, there
(e.g., humidified gases, pulmonary edema, drugs administered is a mild underestimation of systolic BP when compared with a
intratracheally), which can result in permanent color changes. radial arterial line if BP is measured with a cuff chosen according
to the child’s arm length.52 The basic working principle is observing
the return of arterial flow during deflation of the BP cuff. The
Measurement of Volatile Anesthetics pressure at which flow reappears is considered as systolic BP.
The measurement of volatile anesthetics is useful to assess the The various methods are (1) observation of a flush of the limb or
function of the vaporizer in use, detect agent error, and perform (2) palpation, auscultation, or Doppler location of the pulse distal
low-flow anesthesia. The technology and the limits are the same as to the cuff. The major drawback of all these methods is that they
for sidestream capnometry. Potential sources of transient erroneous are dependent on the speed of cuff deflation. The use of the
measurements when mass spectrometry or infrared analysis are Doppler method is difficult in the operating room because it
used are depends on the accurate placement of the probe and is subject to
● The presence of ethanol, as in some fruit-flavored extracts used motion and electrosurgical interferences.
to scent facemasks.48 Conversely, automated oscillometry allows the measurement
● The presence of halogenated propellants, when metered-dose of systolic, diastolic, and mean BP. Monitors using the oscillo-
bronchodilators are introduced into the breathing circuit.49 metric principle are easy to use and accurate and are, therefore,
the most popular nowadays. The cuff of the automated oscillo-
metry monitors (e.g., Dinamap) NIBP acts as the actuator and
Inspired and End-Tidal Oximetry transducer. Because the whole cuff acts as a signal sensor, place-
The measurement of inspired and expired O2 concentration is ment of the cuff directly over an artery is not necessary, although
achieved either with two different sensors (one being placed on strongly recommended. The cuff is automatically inflated above
the inspiratory limb of the anesthesia machine) or using the same systolic pressure and slowly deflated in steps by a microprocessor.
sampling system and technology as that used to measure volatile At each stage, both mean cuff pressure and oscillations resulting
agents concentration. This second approach is especially useful from the arterial pulse wave in the limb are sensed and stored.
when the FGF outlet used to supply the breathing circuit (e.g., Systolic BP corresponds to the cuff pressure where the oscillations
Mapleson D or F) does not pass through the oximeter of the rapidly increase, mean BP to the lowest cuff pressure at which
anesthesia machine. maximum oscillations are recorded, and diastolic BP to the cuff
A less known application of the measurement of expired pressure where the oscillations fade. A specific artifact rejection
O2 (FEO2) is the accurate assessment of preoxygenation before strategy requires that identical oscillations are measured at
induction of anesthesia in clinical situations at high risk for two consecutive times at each deflation step before the mon-
hypoxia such as rapid-sequence induction, anticipated difficult itor deflates the cuff to the next step. In case of motion artifact
intubation, pulmonary disease, obesity, or high altitude. This is potentially caused by the patient, surgeon, nurse, and/or leak in
provided that a snug mask seal is obtained to prevent entrainment the tubings, dysrhythmias, important variations of BP with
of ambient air.50 The aim is to obtain an FEO2 of 0.9 because the respiration or poor peripheral perfusion, determination of BP will
remaining 0.1 of exhaled gas consists of CO2 and N2.51 be slower or even unreliable because successive cardiac pulsations
will be compared until the rejection criterion is no longer met. Finger Blood Pressure and Arterial Tonometry
Many studies have shown a good correlation of systolic and mean Some devices were designed to monitor BP continuously in a
BP measured with NIBP with the same measurements made noninvasive way.
invasively. However, diastolic BP is much less precise. In neonates
and premature infants, noninvasive systolic BP is falsely elevated FINGER BLOOD PRESSURE: The Finapress device uses a small
if mean BP is less than 40 mmHg. When BP is measured in the pneumatically inflated cuff applied to the middle phalanx of a
lower limb (BP cuff placed on the calf with its upper edge at the finger. This cuff contains an infrared photoplethysmograph the
level of the tibial tuberosity), in children younger than 4 years wavelength of which is absorbed by hemoglobin, allowing arterial
old the mean BP is lower (mean 10 mmHg) than the pressure pulsations to be sensed. The finger-cuff pressure is continuously
measured in the upper limb.53 adjusted by a servocontrolled loop to keep the infrared signal and,
hence, the finger blood volume constant over the arterial pressure
QUALITY CONTROL: Guidelines to obtain accurate results when cycle. The fluctuations of pressure in the cuff are the same as in the
using NIBP to measure BP are summarized in Table 38–11. patient’s artery, which allows a continuous reading of BP. Accuracy
Because NIBP devices provide discontinuous data and are mainly and reliability of data vary widely in adult studies; although the
accurate as trend recorders, the anesthetic management should mean difference between Finapress and oscillometric or intra-
not be modified only on the basis of a single measurement. In case arterial data is small, there is a large variability in the difference
of difficulty with NIBP, the measurement should be repeated after between individual values.55 This device is, therefore, not a reliable
verifying that the patient’s condition is not deteriorating (presence alternative to direct BP monitoring. Although part of these
of a good peripheral pulse), that there are no leaks in the tubing differences is caused by difficult application of the cuff, variable
and connections, and that the cuff is correctly applied. Because levels of peripheral vasoconstriction explain the reduction
the presence of residual air in the BP cuff causes damping of the of accuracy related to time. The use of this device is limited to
oscillations and thus spurious low BP measurements, all air should children older than 5 years. A prototype pediatric finger cuff
be squeezed out of the cuff before positioning on the child’s arm. and software are currently under investigation. There is a large
Care should be taken to use tubing and cuffs that are adapted bias between finger arterial pressure and invasive BPs, but it gives
to the specific NIBP monitor in use, otherwise improper func- results similar to NIBP.56
tioning of the internal monitor algorithms could ensue.54 If the
NONOCCLUSIVE ARTERIAL TONOMETRY: When using arterial
NIBP and ECG are measured with independent devices, the BP tonometry (Vasotrac), the tonometer sensor is positioned over
measurements are valid if the heart rates displayed by both devices the skin and produces cyclical nonocclusive compression and
are similar. decompression of the radial artery between the sensor and the
POSSIBLE COMPLICATIONS: During placement of the BP cuff, care radius bone. Some variables are measured over three beats at a
should be taken to ensure that its tubing and cuff do not compress time and BP is calculated using an algorithm. If used in a “conti-
a nerve path and the skin is properly protected. Care should be nuous” mode, the device provides an arterial BP reading every
taken to avoid pinching the skin when closing the cuff, which 12 to 15 beats. In stable cardiac children in whom an adult sensor
could result in skin avulsion. was used, mean differences between systolic and diastolic BP as
measured invasively and with tonometry was 4.0 ± 4 mmHg and
3.4 ± 3.2 mmHg, respectively.57 Further studies are necessary to
TABLE 38-11. Guidelines to Obtain Accurate Data With evaluate the accuracy and reliability of these devices in small
an NIBP Device children and infants.
1. Use a BP cuff of proper size, i.e., it covers at least two thirds
of the distance between the axilla and the antecubital fossa. Intra-arterial Measurement
2. Squeeze all the residual air out of the BP cuff before
INDICATIONS: Intra-arterial BP measurement gives precise and
connecting it to the tubings
instantaneous information about BP changes; it allows sampling
3. Wrap the BP cuff snugly around the limb.
blood to measure parameters such as arterial blood gases,
4. Keep the BP cuff and heart at the same horizontal level. electrolytes, and blood glucose. Indications are the same as in
5. If the NIBP and ECG are measured with independent adults undergoing similar procedures and are mainly based on
devices, the BP measurements are valid if the heart rates hemodynamic or pulmonary considerations, taking into account
displayed by both devices are similar. the child’s preoperative condition, the invasiveness of the planned
6. In case of malfunction of the apparatus, check the child’s procedure, and the importance of the anticipated changes in blood
condition first! volume or fluid shifts. In small infants and neonates, the technical
● Peripheral pulse: shock? pulsus paradoxus?
feasibility and the risk/benefit ratio of the technique should be
● Hypovolemia causing major respiratory variations in BP?
evaluated on an individual basis. The techniques of insertion of a
● ECG: dysrhythmias?
catheter into an artery and the analysis of the hemodynamic
7. Common causes of malfunction are information provided are described in Sites of Measurements.
● BP cuff of inappropriate size.
Computerized analysis of the pulse pressure contour (PiCCO)
● Leak in the cuff, tubings, or connections.
allows the continuous measurement of cardiac output through a
● Extrinsic (surgeon, nurse) or intrinsic (movement) cuff
4-French arterial thermodilution catheter inserted in the femoral
compression. artery (see “Monitoring Mechanical Ventilation,” later).
BP = blood pressure; ECG = electrocardiogram; NIBP = noninvasive blood A few cases of deliberate intra-arterial injection of anesthetic
pressure. drugs have been published. In all cases, a femoral artery had been
inadvertently punctured in infants with no venous access and a flow-regulating device. An adult flow-regulating device requires
only drugs in an aqueous solvent (e.g., fentanyl, midazolam, that the solution be pressurized at 300 mmHg to provide a conti-
vecuronium) or normal saline were used. Although those reports nuous flow of approximately 3 mL/h. However, large differences in
are reassuring, this route of administration is risky and is not the infusion pressure effectively delivered to the flow-regulating
recommended.58 device are observed. This pressure is influenced by the volume of
the infusion bag (less if 250 mL compared with 500 mL) and by
SITES OF MEASUREMENT: Virtually all peripheral arteries can be the vertical position of the pressurized infusion according to the
used for intra-arterial monitoring. However, the use of the flow-regulating device. The pressure increases when the bag is
temporal artery is no longer recommended because it carries a above the device and vice versa.62 These variations in pressure can
risk of cerebral embolization during flushing of the line. The radial have important consequences because the flow rate and the fast
and femoral arteries are the most commonly used. Cannulation bolus flush performed through the flow-regulating device are
of the ulnar artery should be avoided when cannulation of the closely correlated. Insufficient flow can lead to catheter obstruc-
radial artery has already been attempted on the same wrist because tion, whereas excessive flow can produce fluid overload or
this could result in total occlusion of the arterial supply to the
retrograde embolization of flush solution in small infants. The
hand. Although it is recommended to perform Allen’s test to check
tubing connecting the cannula to the transducer should be rigid
the collateral circulation to the hand before attempting to insert a
and as short as possible to avoid discrepancies caused by high-
catheter in the radial or ulnar artery,59 this is often difficult to
frequency harmonics and resonance within the tubing.
perform in small children. Although its catheterization in a large
series of cardiac neonates and infants was not associated with PRACTICAL ASPECTS: Before inserting an arterial catheter, the
more complications than the radial artery, the brachial artery tubing and transducer are carefully flushed with the heparinized
should be used with caution because there is no collateral blood solution, taking care to eliminate any bubble of air. The pressure
flow at its level and the median nerve runs close to it.60 The axillary transducer is placed level with the child’s midaxillary line and
artery can be used because there is collateral flow at this level, but zeroed. In case of procedures in a head-up or sitting position
because it is surrounded by terminal nerves of the brachial plexus, (e.g., neurosurgery), the transducer should be placed at the level
it must be used with caution. The femoral artery is usually easy to of the brain (i.e., outer canthus of the eye) to allow more precise
locate and cannulate. Although there is a theoretical increased risk measurement of brain perfusion pressure. During use of the
of contamination owing to the proximity of the perineum, the arterial monitoring, the position of the zero baseline of the
incidence of infection is no greater than with radial catheters but transducer should be checked regularly because a slow drift
the incidence of perfusion-related complications is greater.61 When sometimes occurs.
using one of the pedal arteries, one should keep in mind that The limb in which the catheter will be inserted is gently
because of pressure-wave amplification in the vascular tree, peak immobilized. This will make arterial puncture and catheterization
systolic pressure may exceed aortic values. The umbilical artery is easier and probably less traumatic. Strict asepsis is essential to
accessible for monitoring purpose during the first 3 days of life. avoid infectious complications. To avoid damaging the tip of the
The position of the catheter tip should be monitored by x-ray to catheter when piercing the skin, make a small nick in the skin with
make sure it is either below the origin of the renal arteries or in the a 19-gauge needle before inserting the arterial catheter In neonates
midthoracic aorta. The use of an umbilical catheter is not suitable and small infants, in whom precise localization of the artery by
in cases of intra-abdominal surgery because it will be mobilized palpation alone is difficult, the peripheral arteries can be located
during the procedure. In surgery in which it is critical to know the using a Doppler probe, transillumination with a cold fiberoptic
brain perfusion pressure (neurosurgery) or the preductal PaO2 to light, or ultrasound.63 Three different techniques can be used
prevent retinopathy of prematurity or assess shunting through a to catheterize the artery: direct catheterization, transfixion, or
patent ductus arteriosus (diaphragmatic hernia repair), preductal Seldinger technique.
placement (into the right upper limb) of the arterial catheter is Once inserted into the artery, the cannula is carefully fixed in
necessary. order to avoid both accidental removal and kinking at the skin
DESCRIPTION: Small-gauge nontapered over-the-needle cannulas entry site. Connections should be secure in order to avoid blood
are used to catheterize peripheral arteries. They are 24 gauge for loss by disconnection. In neonates and small infants, the dressing
infants weighing less than 3 kg, 22 gauge for infants 3 to 20 kg, should allow visual control of the skin proximal and distal to the
and 20 gauge for bigger children. These cannulas are made of catheter in order to detect its blanching or cyanotic discoloration
Teflon or polyurethane. The latter are less rigid and potentially as soon as possible. These are considered early signs of a throm-
less traumatic but sometimes more difficult to insert. Catheters botic complication. The stopcocks of the arterial line should be
with a built-in atraumatic guidewire (e.g., BD Insyte-A) that can clearly identified in order to avoid the accidental intra-arterial
be introduced into the arterial lumen as soon as blood flows back injection of anesthetic agents, antibiotics, and other agents.
into the needle are available. The fluid used to maintain arterial Blood sampling should be performed slowly to avoid collapsing
line patency is a heparinized solution of normal saline, 0.45% the vessel and damaging its endothelium. After blood sampling,
saline, or 5% dextrose. The saline solutions have the advantage of the tubing should be flushed gently, especially in neonates and
allowing blood glucose measurements and to be less susceptible to infants. Too rapid or forceful flushing results in blanching of the
bacterial growth in case of contamination. The concentration of skin proximal to the cannula and transmission of the iatrogenic
heparin is 0.5 (neonates) or 1 IU/mL. The heparinized solution pressure wave to distal sites such as the cerebral or splanchnic
is flushed at a constant rate through an automatic disposable circulation. Flushing no more than 0.5 mL with a syringe over
pressurized system at a rate of 1 (neonates) to 3 mL/h (children a period of 5 seconds is recommended in neonates. In case of
and adults). The pressurized system consists of a syringe pump damping of the arterial waveform, the tubing and stopcocks
(neonates) or an externally pressurized infusion bag connected to should be inspected to eliminate bubbles of air; however, gentle
flushing is sometimes necessary to obtain a satisfactory waveform small changes in temperature. A thermocouple is an electrical
from a partially blocked cannula. circuit made of two different metals welded at their ends. The
end in contact with the body area produces a voltage difference
POSSIBLE COMPLICATIONS: The most common complication of proportional to temperature of the site of measurement. It is
arterial cannulation is a local hematoma that usually resolves
accurate with a quick response time and is sensitive to small
quickly. The incidence of arterial thrombosis varies according to
changes in temperature. The energy radiated from an object is
the child’s age. One prospective study in which the radial artery
proportional to its temperature. Infrared sensors measure the
was cannulated with a Teflon cannula and Doppler flow measure-
infrared radiation emitted by any surface without touching it.
ment was used to assess vessel patency is worth mentioning. In
Liquid crystal thermometers are adhesive strips attached to the
60 children, the incidence of total arterial thrombosis was of 7.4%
patient’s skin. The liquid crystals change in color with changes
but recanalization usually occurred within the following days.64 The
in skin temperature. It measures only skin temperature and is
most important predisposing factors were a cannula–to–artery
sensitive to humidity, air movement, or external sources of heat
diameter ratio in excess of 0.7, transfixion of the artery during
(e.g., heating lamps).
insertion, and presence of a hematoma at the site of cannulation.
Partly because of a greater cannula-to-artery ratio, thrombosis was
more common in neonates. Although permanent ischemic damage Sites of Measurement
after arterial catheterization is rare, removal of the cannula using The interpretation of the temperature measured depends on the
negative pressure to aspirate as much of the thrombus as possible site of measurement: rectal temperature is usually 0.5 to 1.0°C
is recommended in case of increasing difficulties with blood sam- greater than oral temperature, which is 0.5 to 1.0°C greater than
pling or appearance of cyanotic discoloration of the skin distal to axillary temperature. These differences are not constant and
the entry site. Ischemic damage is more likely in case of low cardiac depend on various factors such as environmental tempera-
output and/or use of vasopressors agents and can lead to dramatic ture, local blood supply, and rate of change in temperature.69 In
consequences such as amputation.65 anesthetized infants and children undergoing superficial surgery,
Embolization can occur distally or proximally. Distal embo- there is no significant difference between tympanic membrane
lization results from propagation of a thrombus formed near the and esophageal, rectal, or axillary temperature measurements.70
cannula; proximal embolization of air or debris occurs in case of Conversely, in children undergoing cardiac surgery, esophageal
aggressive flushing. Careful inspection of the skin proximal and temperature readings are the closest to those in the pulmonary
distal to the cannula entry site and gentle flushing by hand are artery (mean difference 0.1°C ± 0.5°C) compared with tympanic
mandatory to avoid these complications. (mean difference 0.6 °C ± 1.0°C), rectal (mean difference 0.7°C ±
Local infection is rare if the rules of asepsis are observed and if 1.7°C), bladder (mean difference 0.9°C ± 1.4°C), and axillary
the cannula is left in place less than 4 days. However, colonization temperature (1.3°C ± 1.3°C).69 Similarly, nasopharyngeal temper-
of the cannula is more frequent when multiple attempts have been ature measurements show the most rapid response during cooling
required for its insertion. This is probably caused by unnoticed and rewarming, whereas tympanic measurements vary in an
breaks in the rules of asepsis when dealing with technical dif- unpredictable way and rectal measurements lag behind.71
ficulties. Other complications described include nerve damage The site for the intraoperative measurement of temperature
by the exploring needle or by a compressive hematoma, tendon should be chosen according to the child’s age and the procedure
sheath injury,66 accidental intra-arterial injection of anesthetic undertaken. For example, core temperature can be monitored with
drugs, formation of an arteriovenous fistula, and occurrence of a good accuracy in the distal esophagus, nasopharynx, or tympanic
compartment syndrome.67 membrane for superficial procedures, but measuring temperature
at two sites, usually esophageal and rectal or vesical, is critical
during procedures in which large and/or rapid changes in temper-
Temperature Monitoring68 ature occur (e.g., cardiac bypass, trauma, spinal instrumentation)
Goal and Indications because large gradients are indicative of nonuniform heat
distribution or poor cardiac output. The specific advantages and
Intraoperative monitoring of body temperature is necessary to disadvantages of each site are described hereafter and summarized
detect hypo- and hyperthermia, manipulate body temperature in Table 38–12.
(e.g., to provide brain protection during hypothermic cardiac
surgery), and prevent complications associated with variations T YMPANIC MEMBRANE: Tympanic membrane temperature as
from normal. It is mandatory during pediatric anesthesia because measured with a thermistor or thermocouple placed in contact
the mechanisms of thermoregulation are less efficacious. Both the tympanic membrane is very close to core temperature because
hypothermia and hyperthermia are more frequently observed in the tympanic membrane is vascularized through a branch
children than in adults. Body temperature should be monitored of the internal carotid artery. Correct placement of the probe is
during any anesthetic lasting more than 30 minutes.68 sometimes difficult (risk of bending into the aural canal),
and some authors recommend otoscopic examination before
insertion. Cases of tympanic perforation have been described.
Technology After placement of the probe, it is important to block the aural
The temperature probes used in the operating room are either canal with some cotton wool to prevent cooling of the probe by
thermistors, thermocouples, infrared sensors, or liquid crystals. A air movement. The infrared tympanic thermometer allows only
thermistor is a metal semiconductor, the resistance of which varies intermittent measurement of temperature. The disposable cover
with temperature. Placed at the tip of the probe, it is generally of these portable otoscope-like probes is large and can be entered
incorporated in soft plastic tubing, an esophageal stethoscope, or only a few millimeters into the aural canal. The temperature
urinary catheter. It has a quick response time and is sensitive to recorded can be influenced by improper positioning of the probe
TABLE 38-12. Sites of Temperature Monitoring

Site Advantages Disadvantages
Tympanic membrane Closest to hypothalamus Rare: risk of perforation via internal carotid artery
Nasopharyngeal Close to internal carotid artery Affected by temperature of inspired gases
Risk of epistaxis
Esophageal Close to great vessels and heart Affected by temperature of inspired gases if placed in distal
third! if thoracic surgery
Rectal Traditional Inaccurate if temperature changes are rapid
Guide to uniform rewarming affected by feces, peritoneal after
induced hypothermia lavage, cystoscopy.
Risk of perforation in infants
Bladder Better reflector of central temperature High urine output necessary
than rectal
Oral Convenient Probe must be placed over axillary artery; affected by blood
Axillary Convenient pressure cuff and ipsilateral I.V. infusion
Needs 10–15 min equilibration time
Skin Useful to indicate temperature Affected by peripheral perfusion, gradient between core and
vasoconstriction, sweating, and periphery environmental
temperature
Swan-Ganz catheter Measures mixed venous Affected by cardiac bypass blood temperature or thoracic
surgery
and the temperature of the aural canal. It is atraumatic and is the arm tightly adducted. It requires a few minutes of equilibration
often used in the recovery room. A tug on the ear and application before giving accurate results. In order to avoid displacement
of gentle pressure on the probe during the measurement could of the probe, the BP cuff should not be placed on the same arm.
improve the correlation with core temperature. No fluids should be administered intravenously in the same limb
because their temperature affects the performance of the probe. It
NASOPHARYNX: Nasopharyngeal measurement is close to hypo-
is a commonly used site of measurement in nonintubated children
thalamic temperature when the probe is placed in the naso-
undergoing short procedures.
pharynx. It is influenced by the temperature of inspired gases if
there is a leak around the TT or supraglottic airway and there is a SKIN: Because skin temperature is under the influence of many
risk of epistaxis during its insertion. factors such as cardiac output, anesthetic technique, environ-
mental temperature and, therefore, shows great variability in
ESOPHAGUS: Esophageal measurement (e.g., within an esophageal
correlation with core temperature, its intraoperative monitoring
stethoscope or with a temperature probe) rapidly reflects changes
is of little use during anesthesia. The core-to-forehead temperature
in core temperature if it is located in the distal third of the
gradient is rather stable when ambient temperature varies between
esophagus, between the heart and the great vessels. There is a
small influence of the inspired gases temperature because it is 18° and 26°C. Core temperature can be inferred from forehead
approximately 0.25°C lower than tympanic temperature in the skin temperature as long as a correction factor of +2°C is added.68
absence of humidification and 0.35°C higher when inspired gases TEMPORAL ARTERY: The temporal artery infrared skin temper-
are actively or passively humidified and warmed.70 ature probe records the highest temperature across the forehead
RECTUM: Although a good index of core temperature, rectal including the site of the temporal artery. The temporal artery
temperature measurement may show some delay in case of rapid temperature is theoretically very close to core temperature,
changes in temperature because the rectum is less well vascu- but this monitoring is not sufficiently accurate in clinical circum-
larized than the other central sites of measurement. It is often stances.72
considered as an intermediate site of measurement.69 The presence PULMONARY ARTERY: The temperature of mixed venous blood,
of feces may insulate the probe and the temperature of the fluids as measured with a probe incorporated in a pulmonary artery
used during peritoneal lavage or cystoscopy may interfere with catheter, is the closest to core temperature and is used to measure
the measurement. Because of fear of trauma or perforation, a rectal cardiac output by thermodilution.
probe should not be inserted in small infants nor in children who
have undergone previous anorectal surgery.
Possible Complications
BLADDER: Bladder temperature measurement, through a probe The probe should be checked before use to detect any defect in its
incorporated in the urinary catheter (e.g., silicone Foley catheters insulation because this could lead to local electrical burns during
with a thermocouple), could be a better index of core temperature
the use of diathermy. In order to avoid cross-contamination
than rectal measurement, but its performance depends on the
between patients, the reusable temperature probe should be
presence of a high urine output.
covered with a plastic protective sleeve before insertion into the
AXILLA: Axillary measurement is easy, but placement of the probe patient. In case of nasopharyngeal probes, care should be taken
is critical. It should be placed directly over the axillary artery with to retrieve the sleeve before extubating the patient. A case of
postoperative airway obstruction caused by a sheath lost in the shifts or blood loss (scoliosis repair, organ transplantation, and
patient’s nasopharynx has been described. Intraoperative airway major laparotomy), cardiac surgery, and procedures carrying a
obstruction caused by inadvertent intratracheal insertion of high risk of venous air embolism (neurosurgery) or in which the
an esophageal probe has also been described.73 Last, a case of acci- infusion of inotropes could be necessary.
dental extubation when removing an oropharyngeal temperature Normal CVP is approximately 2 to 6 mmHg (3–12 cmH2O). In
probe has also been described.74 children with normal right ventricle function, its value is well
correlated with intravascular volume and left ventricle preload.
However, as in adults, the trend of successive measurements is
Urine Output more useful in therapeutic management than an absolute value.
Goal and Indications The CVP value is rarely the sole basis of therapeutic action. It
should be interpreted in accordance with the other hemodynamic
The presence of an adequate urine output is a sign of good renal parameters and interfering events such as compression of the
perfusion and an indirect sign of adequate volume loading and inferior vena cava by retractors or cross-clamping by the surgeon.
peripheral perfusion of the patient. Urine output should be
measured during procedures in which large shifts of fluids are
anticipated. Cardiopulmonary bypass, transplant surgery, neu- Quality Control
rosurgery, anticipated blood loss in excess of 1 effective blood The pressure transducer should be at a level with the child’s
volume are good examples. Bladder drainage is also performed midaxillary line and the position of the zero baseline of the
before long procedures to prevent bladder distention, for anorectal transducer should be checked regularly because a slow drift
or urogenital surgery to avoid intra- and postoperative surgical sometimes occurs. The measurement should ideally be made at the
wound contamination by urine, or to ensure vesical emptiness end of expiration to avoid any respiratory interference and after
during some laparoscopic surgery. verifying that a CVP waveform is present on the monitoring screen.
In case of difficult access to the child’s neck or contraindication to
Description the catheterization of the superior vena cava, the venous pressure
measured in the abdominal inferior vena cava or common iliac
Either a urinary Foley catheter or a percutaneous cystostomy
vein is identical with CVP, provided the measurement is made
catheter can be used. In both cases, great care should be taken to
at end-expiration and there is no obstruction to flow from the
avoid trauma to the fragile urethral mucosa or the neighboring
inferior vena cava to the right atrium such as in patients present-
organs, respectively. The catheter should be connected to a drain-
ing with an abdominal tumor.75 In the same way, there is a good
age system allowing the precise measurement of the hourly urine
correlation between CVP and pressure from a peripheral I.V.
output. The color of the urine produced should also be noted, for
catheter (peripheral venous pressure [PVP]) (mean difference 2 ±
example, the apparition of red or brown urine should alert for the
1 mmHg), provided there is a continuity with the central venous
presence of hematuria, myoglobinuria, or hemolysis.
compartment as shown by an increase in PVP in response to a
Valsalva maneuver or following occlusion of the limb above the site
Limits and Caution of the catheter.76 However, the measurement is less valid if PVP is
Beyond the neonatal period, a urine output of 0.5 to 1 mL/kg/h measured through an I.V. catheter placed on the dorsum of the
indicates adequate renal perfusion. However, it should be inter- hand or the lateral aspect of the foot.77
preted cautiously in case of use of diuretics (mannitol, dopamine,
and I.V. contrast media) or in the presence of glycosuria. Large
amounts of diluted urine are produced in case of diabetes insipidus
Neuromuscular Block
(see Chapter 93), postobstructive diuresis, salt-losing nephropathy, Neuromuscular blockade (NMB) following the administration of
or metabolic disorder (e.g., absence of or resistance to aldosterone). a muscle relaxant varies in both depth and duration, especially in
Conversely, the patency of the urinary catheter and/or the absence neonates and infants. It is important to monitor not only the depth
of a huge bladder should be checked before establishing the of NMB but also, most importantly, recovery from it whenever a
diagnosis of anuria or oliguria. In neonates younger than 1 week, muscle relaxant is administered. The pharmacology and clinical
urine output alone is not a good index of changes in intravascular use of NMB are described in Chapter 27.
volume or cardiac output because the neonatal kidney has a limited
capacity to concentrate and dilute urine.
Description and Limits
The basic principle of neuromuscular monitoring is to stimulate a
Central Venous Pressure peripheral motor nerve and to observe/measure the resultant
CVP is the venous BP measured at the junction of the right atrium motor response of the corresponding muscle. This method is
and the vena cavae, and it represents the filling pressure of the independent of the patient’s effort, unlike head lift or eye opening,
right ventricle. The type of catheters used is described later in but is dependent on many other factors such as the pattern of
this chapter, whereas the routes of insertion and the possible stimulation used, the sensitivity of the muscle tested, the age and
complications are described in Chapter 70. body temperature of the patient, the method used to assess the
evoked muscular response, and the pharmacodynamic properties
of the muscle relaxant administered. Most of these factors are
Indications considered later. Moreover, when evaluating recovery from NMB,
The indications of CVP measurement are the same as for insertion one should always bear in mind that incomplete recovery is
of a central venous line: major surgery involving massive fluid possible despite normal evoked motor responses and ventilatory
movements and that the upper airway muscles are more sensitive underlying tissue while decreasing the risk of direct muscle
to the muscle relaxants than the muscle tested. The following stimulation. The negative electrode should be placed closest to
clinical indices of recovery should also be present when spon- the nerve to be stimulated and distally. This reduces the current
taneous breathing has resumed and before extubating the child: required to depolarize the nerve.81 Careful attention to the details
listed herein can significantly reduce the skin-electrode impedance
● Absence of a “rocking” pattern of breathing (i.e., upward move-
and allow supramaximal stimulation to be achieved at a lower
ment of the abdominal wall and sinking of the chest during in-
current:
spiration, owing to the contraction of the diaphragm in the
presence of residual paralysis of the other respiratory muscles). ● Cleaning the skin with an alcohol swab.
● Sustained wide opening of the eyes. ● Sealing the edges of the electrode before applying pressure to its
● Lifting both legs (in neonates and infants).78 central area. Otherwise, gel will be lost and the quality of current
● Swallowing. conduction will deteriorate,
● Protrusion of the tongue. ● Avoiding contact between electrodes, which is sometimes diffi-
● Ability to perform purposeful movements (e.g., catching the na- cult to achieve in neonates and small infants.
sogastric tube).
Needles are almost never used as stimulating electrodes in
Neuromuscular monitoring is not widely used in routine children.
pediatric anesthesia owing to the complexity of setting up the
monitoring devices available at present in small patients. Because
Sites of Stimulation: Pharmacologic Differences
of immaturity of their neuromuscular junction, neonates may
show abnormal evoked responses to nerve stimulation in the Several “nerve-muscle units” can be used to monitor NMB. The
absence of any NMB.79,80 ulnar nerve + adductor pollicis (thumb), the posterior tibial nerve
+ flexor hallucis brevis (big toe), and the facial nerve + corrugator
supercilii (eye) are the most commonly used because these motor
Equipment nerves are superficially placed and their evoked muscular response
Accurate monitoring of NMB requires the precise and constant is easily observable. However, differences in sensitivity to NMB
delivery of the minimum current that produces supramaximal exist between the muscle evaluated by the monitor and the
nerve stimulation. A reliable peripheral nerve stimulator and muscles that are of special interest to the anesthesiologist (i.e., the
carefully placed stimulating electrodes are necessary.81 The diaphragm, intercostal, laryngeal, and upper airway muscles).
peripheral nerve stimulator must have the characteristics described Muscles that are the most resistant to nondepolarizing muscle
in Table 38–13. relaxants are the diaphragm, the vocal cords and abdominal wall
Most peripheral nerve stimulators available at present have muscles, and the corrugator supercilii.82 The muscles that are more
the characteristics just discussed. Neuromuscular transmission sensitive to muscle relaxants are the upper airway muscles (tongue,
monitors that include both a stimulating and a recording system pharynx), masseter, adductor pollicis, and flexor hallucis brevis.
(e.g., TOF-Guard; TOF-Watch, Relaxograph) also carry most of Thus, stimulation of the facial nerve to observe the response of
those features. The stimulating electrodes are pediatric ECG the corrugator supercilii is most useful to monitor the relaxation
silver/silver chloride electrodes. Their small size allows accurate of the laryngeal muscles and the diaphragm (e.g., before intu-
anatomic positioning and increases the current density in the bation), whereas stimulation of the ulnar or posterior tibial nerve
allows the evaluation of the relaxation of the upper airway muscles
(e.g., during recovery).
TABLE 38-13. Ideal Properties of a Nerve Stimulator Used The time course of NMB is not simultaneous in all muscles: in
to Monitor Neuromuscular Blockade children, onset of blockade is faster at the masseter than at the
Delivery of a monophasic square wave of 0.2–0.3 ms adductor pollicis.83 This is probably because the masseter muscles
● Longer stimulation time favors repetitive nerve stimulation
are closer to the central circulation and receive a larger blood flow
and direct muscle stimulation. than the muscles of the hand and because of small differences in
● Shorter stimulation time depolarizes only part of the nerve
muscle composition.
and could lead to overestimation of the NMB.
Delivery of a constant current despite a varying impedance Modes of Stimulation
(drying of electrodes, cooling of the limb): if stimulation of
the nerve becomes submaximal, changes in the muscular SINGLE-TWITCH STIMULATION: Single-twitch stimulation of the
response are observed that are not caused by NMB. motor nerve at a frequency of 0.1 to 1 Hz is of limited usefulness
Adjustable current output with a digital readout of the current during pediatric anesthesia because the size of the evoked
delivered. response must be compared with a control response obtained
Digital readout of the current delivered to detect a weak battery before the administration of any muscle relaxant. Sufficient
or a bad contact with the skin. accuracy is achieved if the response is precisely measured (see
Clearly labeled output polarity to avoid errors when connecting “Modes of Evaluation of the Motor Response,” later).
the electrodes. TRAIN OF FOUR: The train of four (TOF) is the sequence of four
Audible pulse indicator to warn when stimuli are delivered. equal stimulations at 2.0 Hz. This allows an easy identification of
Possibility of delivering all stimulus patterns: single-twitch, TOF, the individual responses and measurement of fading of the fourth
tetanus, DBS. response. Successive TOF stimuli should be separated by at least
DBS = double-burst stimulation; NMB = neuromuscular blockade; TOF = train a 12-second interval to avoid fade of one sequence interfering with
of four. the following sequence. The evoked response can be quantified
either as the number of muscular twitches obtained (TOF count) the Motor Response) as the control value, the clinical fade was no
or as the ratio of the force of the fourth and the first responses longer detected by TOF when the TOF ratio was 0.44 ± 0.03, but
(TOF ratio). A TOF ratio less than 0.5 is an indicator of important remained detectable by DBS until the TOF ratio was 0.67 ± 0.04
residual NMB, whereas a TOF ratio greater than 0.9 indicates (P = .00002).85 This is because the two DBS-elicited contractions
adequate “monitored” (as opposed to clinical) recovery. However, are stronger and probably easier to compare than the first and
a TOF ratio greater than 0.9 was associated with some visual fourth responses to TOF.
disturbance in adult volunteers who had received mivacurium.84
In neonates, the fourth response to TOF is lower even in the
absence of NMB.79 If a depolarizing muscle relaxant (succinyl-
Modes of Evaluation of the Motor Response
choline) is used, the responses after TOF stimulation remain VISUAL OR TACTILE EVALUATION: Although commonly used to
equal in height and the appearance of some fade is associated with assess the evoked motor response, both visual and tactile
the appearance of a phase II block. This mode of stimulation has evaluations usually overestimate recovery of NMB even when
become the gold standard in NMB monitoring because of its using DBS.85 In the same way, when visual evaluation of the
simplicity and ease of interpretation. It is not necessary to establish response to TOF stimulation was compared with accelerography
a control response, and failure to deliver supramaximal nerve or electromyography (EMG) in children, full recovery by clinical
stimulation does not affect the monitoring of the TOF ratio
evaluation alone was reported, although a TOF ratio of 0.4 was
because all responses are affected proportionally.
still measured.86 Visual and tactile evaluations are most useful only
TETANUS: Tetanus consists of a repetitive high-frequency when they detect fade because this indicates the presence of
stimulation in which the responses to individual stimuli summate significant residual NMB.
and produce a sustained muscle contraction. A rate of stimulation
of 50 Hz during 5 seconds is considered as the maximum physiol-
MECHANICAL RECORDING: The motor response of the thumb can
be accurately measured using a force transducer. Both the hand
ogic rate because the evoked muscle response is similar to the
maximal tension developed during voluntary muscle contraction. and the forearm are immobilized on an armboard and the thumb
The response to tetanic stimulation (i.e., the presence or absence of is attached to the force transducer that is preloaded with 100 to
fading of the contraction obtained) is mainly used to assess the 300 g of tension. Although this system is the gold standard for
adequacy of recovery. Tetanic stimulation is painful and should research purposes, it is very cumbersome to use in everyday
not be performed in awake patients. Following tetanic stimulation practice.
in the presence of a nondepolarizing muscle relaxant, increased ELECTROMYOGRAPHY: EMG measures the electrical activity of
mobilization and release of acetylcholine occur at the neuro- the muscle. The biphasic action potentials obtained in response
muscular junctions tested. This causes posttetanic facilitation (i.e., to nerve stimulation are summated as a single compound action
an increased response to the following stimulus). To avoid this potential recorded between an electrode placed on the belly of the
conditioning effect of previous tetanic stimulation from interfering muscle studied, a reference electrode placed on the tendon of
with the assessment of NMB recovery, it is necessary to delay any the same muscle, and a ground electrode. The most widely used
type of stimulation for 2 minutes after a tetanic stimulation. device is the Relaxograph that delivers only TOF stimuli and
POSTTETANIC COUNT: Posttetanic count (PTC) stimulation takes automatically calibrates current output to obtain supramaximal
advantage of posttetanic facilitation to evaluate a deep level of stimulation. It also displays TOF ratio, TOF count, and the height
NMB, when responses to single-twitch and TOF have been of the first twitch as a percentage of the control value. In children,
abolished. PTC is the number of responses to 1 Hz stimulation a good-quality EMG recording can be obtained when the record-
starting 3 seconds after 5-second 50-Hz tetanus. The number of ing electrode is placed on the adductor pollicis or the hypothenar
posttetanic responses is inversely related to the depth of NMB. The muscles and the ground electrode is placed on the second or
deeper the block, the smaller the PTC. However, to avoid any fifth finger.87 The hypothenar muscles are probably best avoided
conditioning effect from the preceding tetanic stimulation, this in infants and small children because the onset latency between
stimulus pattern should not be repeated more often than every the stimulus and the compound action potential is often shorter
6 minutes! than the 3 ms internal delay from the stimulus used in the
Relaxograph to avoid stimulus artifact.87 Careful positioning of
DOUBLE-BURST STIMULATION: Double-burst stimulation (DBS)
the electrodes and immobilization of the limb on a splint, with the
consists of two short bursts of 60 ms, 50-Hz tetanus separated
hand in the open position, is very important to obtain successful
by 0.75 second. This time interval allows the muscle to relax
recordings. The initial calibration sequence is painful and should
completely between the tetanic stimuli, so that the responses
be done after induction of anesthesia in children. Difficulties
are perceived as two twitches. These tetanic bursts fatigue the
with calibration are unfortunately not uncommon. A drift of the
neuromuscular junction more than single twitches, so that fade
baseline recording or a progressive decrease of the height of
is exaggerated. This type of stimulation is mainly used to detect
the first twitch in the absence of NMB is also not uncommon. The
residual NMB. An interval of at least 12 to 15 seconds should
final baseline of the EMG trace can be used to calculate recovery
separate DBS to avoid any conditioning effect from previous
times from NMB,88 and it does not affect calculation of the
stimulation. The DBS ratio (i.e., the ratio of the height of the
TOF ratio.
second response to that of the first) is numerically similar to the
TOF ratio. The DBS is more sensitive than TOF for the clinical ACCELEROGRAPHY: Accelerography measures the accelera-
assessment of recovery from NMB in children. With the TOF ratio tion produced by the evoked muscle contraction using a small
measured with mechanomyography (see Modes of Evaluation of piezoelectric wafer with electrodes on both sides placed on the
TABLE 38-14. Monitoring of Neuromuscular Blockade Plateau Pressure

With a Nondepolarizing Agent The plateau pressure is the end-inspiratory pressure (i.e., the
distending pressure of the lungs used to calculate dynamic
1. Before intubation: first choice TOF count ⇒ 0 at the
compliance).
orbicularis oculi
Otherwise: TOF count ⇒ 0 at the ulnar nerve, but
diaphragm and vocal cords are more resistant! Positive End-Expiratory Pressure
2. During maintenance: deep block: posttetanic count < 10 at PEEP is used to prevent atelectasis. PEEP is set at a value just
the ulnar nerve greater than the lower inflection point of the PV loop and/or with
Moderate block: TOF count 1⇔ 3 reference to the dynamic compliance (see Chapter 42).
3. During recovery: first choice: adductor pollicis
Orbicularis oculi may underestimate residual block
I:E Ratio
Either TOF ratio or DBS ratio
Measurement: visual but absence of fade is unreliable! The I:E ratio must allow adequate time for the lungs to deflate or
Electromyography air-trapping will occur. The typical adult (and default) value is 1:2.
Accelerography In neonates and infants, values of 1:1 to 1:1.5 are often used.
DBS = double-burst stimulation; TOF = train of four.
VT, Minute Volume, and Respiratory Rate
distal phalanx of the thumb or big toe. The setup is easy because Inspiratory and expiratory VTs are obtained by integrating the flow
the only requirement is that the thumb or toe must be able to move signal with time. A difference between the inspiratory and the
freely and no preload is required. Both the TOF-Guard and the expiratory VTs indicates a leak around the TT or in the breathing
system. Expiratory minute volume is obtained by multiplying the
NMT Monitor use this technology. Very small acceleration
expired VT by the respiratory rate.
transducers (0.5 × 1 cm, weighing only 20 g) are available that can
be placed on an infant’s thumb or big toe.89 In children, when using
TOF stimulation, accelerography provides similar estimations Respiratory Rate
of recovery of NMB as observed with EMG but is easier to use.86 The respiratory rate is greater in infants and children than in
When determining the dose-response curve of rocuronium in adults because of their increased metabolic rate per kilogram.
children, the curve determined by accelerography was steeper and Typical values are 10 to 12 breaths/min for adults, 12 to 20 for
shifted to the right compared with that obtained with mechano- children, and 20 to 30 for infants.
myography.90 The neuromuscular block was consistently under-
estimated by accelerometry with a bias of –25%! Compliance
A summary of the best choice of stimulation and evaluation
Dynamic compliance reflects the distensibility of the lung-thoracic
techniques according to whether curarization or decurarization is
system. It is calculated as
evaluated is proposed in Table 38–14.
Compliance = Expired VT (mL)/
Plateau pressure – PEEP (cmH2O)
Possible Complications
Care should be taken to avoid pressure injury from the electrodes Typical values during mechanical ventilation are 5 to 15 mL/
or their leads when setting up the neuromuscular monitor device. cmH2O for infants, 15 to 50 for children, and 50 to 100 for adults.
A decreased compliance may indicate suboptimal values of
PEEP or PIP, increased intra-abdominal pressure (e.g., during
Monitoring Mechanical Ventilation laparoscopy), or decreasing neuromuscular blockade. When
compliance decreases, the slope of the PV loop moves toward the
The latest ventilators are equipped with electronic devices and horizontal axis and more pressure is needed to maintain constant
screens to monitor real-time values of respiratory mechanics lung inflation.
during anesthesia and in the PICU. This helps not only monitor
the adequacy of ventilation but also minimize lung injury (baro-
and volutrauma) and prevent atelectasis. The following respiratory Resistance
parameters and gas values can be displayed on the anesthetic Airway resistance expresses the relationship between the pressure
machine monitor: difference across the airway (i.e., between the mouth and the
alveoli) and the rate at which gas is flowing through the airway.
Peak Inspiratory Pressure An increase in airway resistance (e.g., because of a kinked tracheal
tube, bronchospasm, or airway secretions) is most easily detected
The PIP is of special significance in pediatric anesthesia because as a reduction in the size of the flow-volume loop.
the potential leak around the tracheal tube and high compliance
of standard breathing systems dictate the use of pressure-
controlled ventilation. The PIP must initially be set at a value that Pressure-Volume and Flow-Volume Loops
ensures an adequate VT (e.g., 20 cmH2O) or chest expansion. After PV and flow-volume loops illustrate on-line the relationship
this, it can be adjusted with reference to the upper inflection between pressure and volume and flow and volume, respectively
point (UIP) of the pressure-volume (PV) loop and the dynamic (Figure 38–6). It allows changes in these relationships to be
compliance. directly visualized and thus easier to perceive than using numbers
those monitors in clinical practice. Both CO2 and O2 consump-

tion increase with age and body weight but actually decrease
if indexed according to body weight or surface. This makes inter-
pretation of data even more delicate. The measurement made
should be interpreted according to the child’s clinical status and
to other parameters such as BP, hemoglobin level, and SpO2. Their
changes according to therapy are probably more relevant to
clinical care than their absolute value.
Pulmonary Artery Pressure and

Central Venous O2 Saturation
In children as in adults, insertion of a pulmonary artery cath-
eter allows measurement of right atrial, right ventricular, and
pulmonary pressures, and when occluding a distal pulmonary
artery during balloon inflation, the measurement of the pulmonary
wedge pressure. If the compliance of the left ventricle is normal,
there is no mitral valve disease, the pulmonary and tricuspid valves
Figure 38-6. Pressure-volume loop measured in a 9-kg child as well as right ventricule function are normal, pulmonary wedge
undergoing pressure-controlled ventilation with a laryngeal pressure is close to left atrial pressure and reflects left ventricular
mask airway (LMA). preload. The insertion of a flow-directed pulmonary catheter (PC)
is indicated in the presence or anticipation of left ventricular
or pressure or flow versus time curves. Loop recognition is helpful dysfunction, to monitor pulmonary artery pressure (e.g., after
for an early diagnosis of several adverse events such as TT kinking, corrective cardiac surgery or to make the diagnosis of cardiac vs.
bronchospasm, bronchial intubation, and reduced compliance. noncardiac pulmonary edema), to monitor mixed venous oxygen
It helps to detect the development of auto-PEEP (e.g., when venti- saturation (SvO2) or to measure cardiac output either by thermo-
lation frequency is too high) when the expiratory loop no longer dilution or by using the Fick principle (via measure of SvO2).
reaches the baseline. Moreover, analysis of the PV waveform can Guidelines for adequate catheter size according to the child’s body
be used to optimize patient ventilation. weight are given in Table 38–16.
In the author’s experience, the occlusion pressure measured
Special Hemodynamic Monitoring: with a PC in an infant or small child often overestimates left atrial
pressure because the fast heart rate does not allow enough time
Measurement of Cardiac Output and for equilibration of the pressures across the pulmonary bed.
Related Parameters Regarding cardiac output measurement, interpretation of the
Different monitoring tools are available to measure cardiac output data is also difficult because it varies with age and it is influenced
in children. Thermodilution or dye dilution or applying the Fick by associated pathologies such as presence of an intracardiac
principle to O2 metabolism is considered the gold standard. The defect or end-stage liver disease. SvO2 is measured by withdrawing
different tools usable are based on different physiologic principles a blood sample through the nonwedged pulmonary artery catheter
and technologies (Table 38–15). The latter should be understood or by fiberoptic oximetry. In the absence of cyanotic cardiac
to ensure the safe, effective, and appropriate use of the results of disease, the normal value is close to 75%. The risks and contrain-
TABLE 38-15. Devices to Assess Carbon Monoxide in Children

Reliability
Name (Manufacturer) Technology Invasiveness in children Remarks
PiCCO (Pulsion, TPTD + APCCO +++ +++ Multiple hemodynamic parameters,
Germany) continuous, gold standard in children.
LidCO (LidCO, UK) TPLD + APCCO ++ +++ Continuous, requires injection of lithium,
not for young children.
Flowtrac/Vigileo APCCO + ? Uses existing arterial catheter, continuous,
Edwards, US) calibration not possible.
Cardio QP Esophageal Doppler +/– + No intravascular catheters needed, velocity
(Deltex, UK) in descending aorta.
Difficult in small children.
NICO (Respironics, NL) CO2 Fick +/– ? Noninvasive, only in intubated patients with
rebreathing) VT > 300 mL.
Aesculon (Cardiotronic, Electrical (impedance) – +/– Noninvasive, continuous, no calibration.
Germany) cardiometry
APCCO = arterial pressure–based continuous cardiac output; TPLD = lithium dilution; TPTD = transpulmonary thermodilution; USTD = transpulmonary
ultrasound dilution; VT = tidal volume.
TABLE 38-16. Pediatric Pulmonary Artery Catheters: line should be checked regularly because a slow drift sometimes
Recommended Sizes occurs. The waveform displayed should be regularly checked
to ensure that the PC is not permanently wedging. It reduces
Distance From pulmonary perfusion in small children and is a significant risk
Introducer Catheter Right Atrium factor for pulmonary infarction or pulmonary artery perforation.
Weight, kg Size, Fr Size, Fr Port to Tip, cm If thermodilution is used to measure cardiac output, the volume of
<15 5 4 10 cold injectate used should be measured to avoid fluid overload.
15–40 6 5 10 or 15
>40 8.5 7 20 Pulse Contour Analysis
The basic principle of pulse contour analysis is that the area under
dications are similar to those for to the placement of any central the curve of the arterial waveform correlates with cardiac stroke
venous catheter (see Chapter 70). There are, however, specific volume (Figure 38–7). However, the arterial waveform is the
complications of the insertion of a PC: combination of an incident pressure wave (proportional to stroke
volume) and a reflected wave created by the reflection of the
● Pulmonary artery rupture or thrombosis. preceding pressure wave from the periphery, which is influenced
● Pulmonary infarction. by arterial compliance and systemic resistances. Pulse contour
● Dysrhythmias: ventricular or supraventricular arrhythmias, analysis should be used to estimate changes in stroke volume and
rarely acute right bundle-branch block. cardiac output rather than to measure them precisely.
● Cardiac valve damage. The PiCCO system incorporates both a transpulmonary
● Intracardiac knotting. thermodilution (through a thermistor at the tip of the catheter) and
● Thrombocytopenia.. a computerized analysis of the pulse pressure contour to continu-
The risk-benefit ratio of the technique should be carefully ously measure the cardiac output. It is a 3- (7 cm) or 4-French
evaluated on an individual basis. (8 cm) catheter inserted in the femoral artery (or radial artery in
Because of all those risks and limitations, noninvasive tech- older children and adolescents). Transpulmonary thermodilution is
niques such as transesophageal/transthoracic echocardiography/ used first to calibrate the system by injecting cold saline in a central
Doppler are, therefore, increasingly used to monitor cardiac venous catheter (5–15 mL depending on the patient’s weight) and
output, heart function, and filling in children. Central venous pulse contour analysis is used to measure stroke volume and
oxygen saturation (ScvO2) in the superior vena cava reflects O2 calculate cardiac output, cardiac function index, intrathoracic
extraction from the upper part of the body and can be used as a blood volume, and extravascular lung water. The system has to be
surrogate for SvO2. In the absence of cardiac pathology, its normal recalibrated every 4 hours (or earlier in case of brisk hypovolemia
value is 70 to 85%. A multilumen central venous catheter allowing or hypotension). Pulse contour analysis is much more reliable in
continuous ScvO2 (one lumen contains a fiberoptic filament) is children without intracardiac shunts92 than in the presence of
now available in pediatric sizes (Pediasat Oximetry catheter): two unrepaired congenital heart disease.93
lumens 4.5 French (5 or 8 cm) and three lumens 5.5 French (8 and Another equipment using pulse contour analysis is the FloTrac
15 cm). It needs in vivo calibration (blood sample analyzed with sensor, which has to be used with a Vigileo monitor. The sensor is
a co-oximeter) after insertion and includes a signal quality index connected to a peripheral arterial catheter and the cardiac output
from 1 to 4; a value of 4 means unreliable measure.91 is continuously calculated using a secret algorithm without any
Changes in SvO2/ScvO2 usually precede modifications of other need for calibration. It has been designed for adults; its reliability
hemodynamic parameters and excellent tools to evaluate the in children is not established.
adequacy of cardiac output and tissue perfusion. They are very
useful in the management of congenital heart disease, shock, and
resuscitation.
Quality Control
To prevent air embolism, all the ports of the PC should be carefully
flushed with saline before insertion. Fluoroscopy is useful during
insertion of the PC because it allows proper orientation of the
balloon tip, which helps accurate placement and reduces insertion
time. The tip of the PC should be placed in an area of the lung
where pulmonary venous pressure exceeds pulmonary alveolar
pressure (i.e., in a dependent part of the lung [West zone 3]).
Otherwise, the pressure measured in the PC, whether pulmonary
or occlusion pressure, will be influenced by airway pressure.
The measurement should be made at the end of expiration to
avoid any respiratory interference. When using a 5-French PC to
measure cardiac output, the distance between the atrial and the
distal ports should be adapted to the child’s height to obtain Figure 38-7. PICCO tracing (and derived hemodynamic values)
reliable results. The pressure transducer should be at a level with obtained from a 20-gauge catheter inserted in the femoral artery
the child’s midaxillary line and the position of the zero base- of a 12-kg child.
Esophageal Doppler (CardioQP) Partial CO2 Rebreathing

Esophageal Doppler measures beat-to-beat blood flow velocity in The NICO (Novametrix Medical Systems) is a noninvasive
the descending aorta via a Doppler transducer at the tip of a flexible monitor that uses partial rebreathing of CO2 to determine cardiac
probe introduced in the esophagus. The probe should be greased output via the Fick principle in mechanically ventilated patients.
with lubricant jelly before being carefully inserted in the esophagus. The monitor includes a mainstream CO2 sensor, a special valve
It should be rotated in order to obtain the best Doppler signal able to direct the flow of expired gas to a rebreathing tubing added
possible. Aortic blood flow is calculated from the product of flow to the ventilator circuit, an airflow sensor (to measure minute
(average of five cycles) times the aortic diameter as obtained from ventilation), and a pulse oximeter. The change in PETCO2 is meas-
a normogram based on age, weight, and height. Blood flow in ured during a short period of rebreathing and is used to estimate
the descending aorta is only about 70% of total cardiac output: a the change in PaCO2. It is assumed that cardiac output, carbon
correction factor of 30% is automatically added to the measured dioxide production (VCO2), and physiologic deadspace remain
value. Cardiac output can be calculated from the area under the the same during the measurement period: thus cardiac output =
velocity-time waveform (called stroke distance, i.e., the distance ΔVCO2/ΔPETCO2. The pulmonary shunt fraction is calculated to
traveled by a column of blood during one systole). By multiplying correct the measurement.
stroke-distance by heart rate, one obtains minute-distance. Multi- NICO has been validated in adults but the correlation with
plying the latter times the aortic diameter as obtained from a thermodilution becomes poor when cardiac output is high. A
normogram based on age, weight, and height gives an estimation pediatric study has shown that NICO, using the shortest position
of the rebreathing tubing (125 mL), provides clinically “acceptable”
of cardiac output. Recent research suggests that measuring the
results (mean percentage difference between NICO and thermo-
child’s aortic diameter or cross-sectional area in M mode instead
dilution: 3, 2% ± 17.2%) in children with no intracardiac shunt
of using the normogram would improve the accuracy of the
lesions nor pulmonary hypertension, a body surface area greater
measurements.94
than 0.6 m2 and a VT greater than 300 mL.97 The system is difficult
Systolic flow time corrected for heart rate reflects preload
to use in the operating room.
(it is shorter in case of hypovolemia) but is also influenced
by systemic vascular resistances whereas peak velocity is an index
of left ventricular contractility. This monitor is relatively easy Neurophysiologic Monitoring
to use and should be use to follow the trends in cardiac output
or other derived values rather than to accurately measure Electroencephalography Monitoring
cardiac output. The electroencephalogram (EEG) recorded from the scalp is
generated by electrical activity in the cerebral cortex (see Chapter
74). Subcortical activity is not recorded by surface EEG. EEG
Echocardiography consists of waves of various frequencies and amplitudes. The
The indications and use of transesophageal echocardiography frequencies are divided in four categories: α (8–13 Hz), β1 (13–30
are described in Chapter 73. In addition to the visualization of the Hz), θ (4–8 Hz), and δ (0.5–4 Hz). To facilitate its quick inter-
cardiac chambers, valves, and flows, echocardiography can be used pretation by nonspecialists, EEG is mathematically transformed by
to measure cardiac output. The operator needs to measure the Fourier analysis. The latter is based on the hypothesis that each
diameter of the ascending aorta. Its surface (in square centimeters) waveform of the raw EEG is the summation of various sinus waves
can be calculated and cardiac output is estimated by multiplying with different frequencies and amplitudes. The EEG can be
this surface by the blood velocity (in centimeters per second) analyzed by spectral analysis and displayed as a power spectrum of
measured in the ascending aorta using the Doppler function of the four categories of frequencies. By definition, median frequency
the monitor. The main advantage of echocardiography, whether divides the power spectrum (i.e., area under the curve on a graph
transthoracic or esophageal, in the context of cardiac output evalu- with frequency in Hz on the x-axis and power in μV2 on the y-axis)
ation is that it also allows direct visualization of cardiac contrac- in half and spectral edge frequency (SEF) is the frequency under
tility and preload. It should be kept in mind that interpretation of which 95% of the EEG is registered (Figure 38–8).
echocardiography needs training and experience and that trans- Different devices using continuous EEG monitoring are
esophageal echocardiography (the easiest to use in the operating currently used to measure depth of anesthesia. However, because
room) can cause complications such as tracheal, bronchial, or the EEG measures only the cortical activity, only the hypnotic
great vessel compression and esophageal injury.95 component of general anesthesia or sedation is evaluated. EEG
monitoring is unable to predict the absence of motor response to
a noxious stimulus that is mediated by subcortical and spinal
Electrical Velocimetry structures. The relationship between EEG under anesthesia and
This noninvasive technique uses the changes in electrical consciousness is imprecise and drug-dependent. Some anesthesia-
conductivity of aortic blood flow in the thorax, as measured via related influences on EEG are reported in Table 38–17. Last, there
skin electrodes, to calculate stroke volume and cardiac output. are age-related differences in EEG: for example, the dominant
Standard ECG electrodes are placed side to side in a vertical frequency is 5 Hz at 6 months, 6 to –7 Hz from 9 to 18 months,
direction (two at the left middle and lower neck level and two on 7 to 8 Hz at 2 years, and 9 Hz at 7 years and reaches the adult value
the thorax, on the midaxillary line and at the level of the xyphoid of 10 Hz around 15 years.98,99 Finally, the relationship between
process). The signal is correct if an ECG signal and an impedance arousal and consciousness as well as the transition from the awake
waveform are seen on the monitor. This system does not correlate to the asleep state are very different in infants. All the EEG-derived
well with thermodilution in cardiac children but can be used to monitors can be reliably used in children older than 2 years, but
evaluate changes in cardiac output.96 their use in infants cannot be recommended at present.
TABLE 38-17. Factors Influencing Electroencephalography

and Bispectral Index Under Anesthesia
Agent or Environmental
Change Effect on BIS
Halogenated agents BIS higher under halothane than
under equipotent doses of
isoflurane or sevoflurane
N2O Moderate increase (70%)
Propofol Dose-dependent diminution
Opiates No influence except in very high
doses
Ketamine Increases BIS
Xenon Unreliable
Hypocapnia Increases total EEG power
Hypothermia Decreases brain metabolism and,
thus, EEG and BIS
BIS = bispectral index; EEG = electroencephalogram.
Figure 38-8. Power spectrum of the awake electroencephalogram
(EEG). Median frequency and SEF are shown on the graph with
frequency in Herz on the x-axis and power in μV2 on the y-axis. hydrogel is present on the electrodes to reduce impedance. When
placed on the skin, each electrode needs to be pressed with the
finger for 5 seconds to ensure optimal conductance. The electrodes
BISPECTRAL INDEX MONITOR: The bispectral index (BIS) monitor are applied as follows: the first in the center of the forehead, the
uses an algorithm based on changes of EEG in adults undergoing second above the eyebrow, and the last on the temple. They are
sedation. This algorithm is regularly adapted according to ongoing connected to a recording system in which the signal is processed.
research. A one-channel EEG undergoes Fourier transformation The device requires no calibration but is subject to interference
and bispectral analysis to give a single number called BIS. It ranges from electric equipment present in the operating room.
from 0 (isoelectric EEG) to 100 (awake). A value between 40 and The underlying pathology of the child and its treatment must
60 is considered satisfactory for general anesthesia (sedation be kept in mind when interpreting BIS. For example, although
65–85). The monitor provides the BIS value, the real-time unproc- BIS monitoring changes during anesthesia were similar, abso-
essed EEG waveform (to enable the user to detect burst suppression lute BIS values were lower than in normal children in pro-
or electric silence), the amount of EEG suppression (suppres- foundly delayed noncommunicating children with quadriplegic
sion ratio: percentage of time over the last 60 s when EEG was cerebral palsy under antiepileptic therapy.100 In the same way, even
isoelectric), a facial electromyogram in decibels (a potential source awake low BIS values are not unexpected in the presence of
of artifact), and a signal quality index (SQI bar graph) to give an an abnormal cerebral cortex.101 The pharmacology of the EEG
indication of the amount of interference from EMG as a bar graph effects of sevoflurane also explains the paradoxical increase
(Figure 38–9). The adult disposable sensor presents with four in BIS during induction with sevoflurane.102 In children, BIS is
electrodes, and the pediatric sensor has only three electrodes. Some probably more useful to avoid too deep maintenance of general
A B
Figure 38-9. A: Pediatric bispectral index (BIS) electrodes. B: Signal obtained during induction. Note that the BIS value increased
when the child was switched from a Mapleson D circuit to the circle circuit. This short period of time is at risk for awareness because
the alveolar concentration of the halogenated agent decreases transiently.
TABLE 38-18. Narcotrend Stages and Index SPECTRAL ENTROPY: Spectral Entropy is a measure of the degree
of disorder in the EEG (see Chapter 75). It quantifies the
Level of Narcotrend Narcotrend EEG randomness of distribution of the frequencies of the EEG after
Consciousness Stage Index Activity removing artifacts, normalizing amplitudes, and applying Fourier
Awake A 100–95 α transformation. The working principle is that frequency disorder
Sedated B0–B2 94–80 B decreases with increasing depth of anesthesia. The Datex-Ohmeda
Light anesthesia C0–C2 79–65 β➪␾ Entropy module measures state entropy (0–91), a slow response to
General anesthesia D2–D2 64–37 ␾ changes computing the EEG-dominant frequencies (0.8–32 Hz),
Deep general E0–E2 36–13 ␾➪δ and response entropy (0–100), a quicker response to changes
anesthesia computing the EMG-dominant frequencies (0.8–47 Hz). If there
General anesthesia F0–F1 12–0 Isoelectric, is no electromyographic activity, both values are the same.
with burst suppression Adequate depth of anesthesia is achieved when both parameters
suppression burst vary from 40 to 60. Because it is independent of amplitude and
frequency, this monitoring could be less age-specific than the
EEG = electroencephalogram. other EEG processing monitors. Preliminary studies have shown
that, in the same way as BIS, it is less reliable in infants.106
anesthesia (BIS < 20) and to avoid awareness in at-risk situations103
(see Chapter 77). Monitoring Brain Oxygenation
This monitoring is mostly used during cardiac surgery to monitor
NARCOTREND: Narcotrend is an automatic EEG analysis system brain oxygenation during surgery and in the PICU (Figure 38–
using an algorithm based partially on a sleep classification. This 10). There are two main systems.
algorithm includes age-related changes of the EEG and helps The INVOS by Somanetics uses two wavelengths of near-
differentiate 6 EEG stages (A–F) and 15 substages (Table 38–18). infrared light to measure the brain concentrations of HbO2 and Hb
It provides a Narcotrend index ranging from 100 (awake) to 0. and calculate the SaO2 of the part of the brain (frontal cortex)
Other EEG parameters are provided such as power spectrum, under the electrodes. The numerical value displayed (called rSO2i
relative power (percentage) of frequencies of waveforms, and SEF. [regional cerebral saturation index]) is the ratio of HbO2 to total
The system uses a single-channel lead with three standard ECG Hb (15–95%) measured in the electrode light path. The INVOS
electrodes placed on the patient’s forehead (two lateral and one probe is placed on the forehead, below the hairline. The probe
central reference electrode). Comparative studies in adults have contains one diode emitting 15 times/s two wavelengths of near-
shown that, although BIS and Narcotrend index are very close, infrared (730 and 810 nm) light that passes through a small part of
both measures are not linearly scaled and equal numbers do not brain tissue before being detected by two detectors placed 3 and
represent similar hypnotic states. Pediatric studies have shown 4 cm from the emitting diode. The proximal detector measures
a negative correlation between end-tidal halogenated agent light absorbed by extracranial tissue and the distal one light ab-
and Narcotrend index.104 However, even if the Narcotrend index sorbed by all tissues. The algorithm subtracts proximal absorption
follows changes in sedation level, there is such a high probability from distal absorption to obtain cranial tissue absorption and
of incorrect prediction of changes that its clinical usefulness in calculates rSO2i on the mean of 50 consecutive measures. The
pediatric patients is still doubtful.105 INVOS 5100 model can be used in children 4 to 40 kg. It uses a
A B
Figure 38-10. A: INVOS electrodes on the infant’s forehead. This infant undergoing open heart surgery is also equipped with a
transesophageal echocardiography probe and a 4.5-Fr ScvO2 (central venous oxygen saturation) catheter (Pediasat) inserted in the
right internal jugular vein (dressing removed for picture). B: Monitor and values measured.
specific algorithm taking into account the thinner skull and and flow are generally correlated, the status of the cerebral vascular
extracranial tissues present at that age. resistances (e.g., according to PaCO2) must be taken into account.
The NIRO300 by Hamamatsu measures absolute values
of HbO2 and Hbtot by spatially resolved spectrophotometry. Laser- Auditory Evoked Potentials
emitting diodes generate light at 775, 825, 850, and 904 nm.
Absorption of those wavelengths is measured by detectors placed Only the middle latency evoked potentials (MLAEPS) are briefly
at a distance of 4 cm, and a specific algorithm allows the measure- described here: sensory and motor evoked potentials as used
ment of absolute concentrations of HbO2, Hbtot and calculation of during scoliosis surgery are described in Chapter 76. The
a tissue oxygenation index (TOI). MLAEPS are extracted from the EEG 10 to 100 ms after an
Because they measure tissue oxygenation, both rSO2i and TOI auditory signal delivered through headphones. They represent the
correlate only moderately with either venous bulb saturation earliest cortical response to this stimulus. It is an active measure of
(venous blood drainage from the brain) or ScvO2 (total venous brain activity, contrary to the previously described EEG monitor-
ing devices. Both their amplitude and their latency are influenced
drainage).107 No standard values are available. Ideally, these
by anesthesia. Different algorithms have been elaborated but
monitors should be placed on the child’s forehead when awake
even the latest one (AAI-1.6 of the AEP Monitor by Danmeter
and used as a trend monitoring of brain oxygenation. For example,
Neurosensor) is a poor predictor of sevoflurane concentration in
when using the INVOS system, normal rSO2i values of 68% ± 10%
infants and children.111
are obtained in healthy children but are much lower in case of
cyanotic cardiac disease (57% ± 12% in tetralogy of Fallot). This
individual reference value can be used to determine a threshold Special Monitoring
value that is usually a decrease of 20% or more of the initial rSO2i
or an rSO2i lower than 50%. Ideally, one probe should be placed Blood Chemistry112
over each cerebral hemisphere. This allows detecting quickly bad The presence of an arterial or central venous catheter allows
positioning of an arterial or venous bypass cannula.108 sampling of blood to measure blood gases, electrolytes, and
The INVOS device is also used to monitor splanchnic (kidney, glucose level as well as coagulation tests.
liver) tissue oxygenation in infants. The probe is positioned on the Continuous intra-arterial blood-gas monitoring is presently
skin surface closest to the organ (lumbar area for the kidney). available. The Paratrend 7+ is a 0.48-mm diameter heparin-coated
Splanchnic oxygenation is normally 10 to 20% higher than the sensing element that can be introduced in a 20–gauge arterial
cerebral one. It seems that a difference of less than 10% between cannula without interfering with the invasive measurement of BP.
splanchnic and cerebral rSO2i is a predictive sign of tissue The sensor in fact consists of three separate optodes to measure
hypoperfusion and an increase in anaerobic metabolism. It could PaO2, PaCO2, and pH and a thermocouple to measure temperature.
thus be used to quickly detect hypoperfusion and low cardiac A pediatric version (Neotrend) can be inserted via the femoral or
output.109 The latest version of INVOS includes this simultaneous umbilical artery. No interference from anesthetic agents (halogen-
multisite monitoring option. ated agents, propofol) has been described so far. It should be kept
in mind that the measurement system becomes unreliable if
blood flow around the catheter decreases or stops (vasospasm,
Monitoring Brain Perfusion: Transcranial Doppler resuscitation) and that the sensing probe should be inserted for a
A 2-MHz pulsed-wave ultrasound probe (different sizes are sufficient distance (10 cm in children and adults, 23 mm in
available) placed at the level of the temporal window (i.e., above the neonates and infants) over the distal end of the arterial cannula to
zygoma just anterior to the tragus of the ear) can be used to measure avoid contamination with the arterial flush solution. Both the
cerebral blood flow velocity in the middle cerebral artery in real- monitor and the disposable sensor are very expensive. The use of
time. This measurement can also be made through the anterior this monitoring device is reserved for situations in which the
fontanelle in small infants. The monitor displays and measures peak patient’s clinical condition can change rapidly (acute respiratory
systolic velocity and mean flow velocity (in centimeters per second). failure, major acidosis). The system requires 30 minutes warm-up
Moreover, it calculates the pulsatility index: time for calibration before being used.
Peak systolic velocity – Peak diastolic velocity/mean velocity
Nitric Oxide and Its Byproducts
Normal values in awake children are given in Table 38–19.110
When interpreting these measurements, keep in mind that GOAL AND INDICATIONS113: Nitric oxide (NO) is sometimes used
transcranial Doppler measures velocity, not flow. Although velocity in the operating room or cardiac catheterization unit to continue
TABLE 38-19. Normal Transcranial Velocities in Awake Infants and Children

Mean Velocity, Peak Systolic End-diastolic
Age Depth, mm cm/s Velocity, cm/s Velocity, cm/s
0–3 mo 25 24–42 ± 10 46–75 ± 15 12–24 ± 8
3–12 mo 30 74 ± 14 114 ± 20 46 ± 9
1–3 y 35–45 85 ± 10 124 ±10 65 ±11
3–6 y 40–45 94 ± 10 147 ±17 65 ± 9
6–10 y 45–50 97 ± 9 143 ±13 72 ± 9
10–18 y 45–50 81 ± 11 129 ±17 60 ± 8
From reference 100.
a therapy initiated in the PICU (e.g., in neonates with pulmonary neonatal intensive care in conjunction with SpO2 and arterial
hypertension or congenital diaphragmatic hernia) or to allow blood gases when available. However, better design of electrodes
weaning from cardiopulmonary bypass in infants with complex nowadays permits their use in children and even adults.
cardiac pathologies. NO delivery is more complicated with anes-
thesia machines than with PICU ventilators because some re-
DESCRIPTION AND LIMITS: Heating of the skin between 42° and
44°C induces local hyperperfusion. PtcO2 is measured with a
breathing of exhaled gases occurs. The true inspired concentration
miniaturized Clark electrode whereas PtcCO2 is measured with a
of NO depends on the NO concentration added to the system, the
modified Severinghaus electrode (pH-sensitive glass electrode).
FGF, the I:E ratio, the patient’s minute ventilation, and NO uptake.
NO can be delivered accurately with an anesthesia machine using Both measurements are under the influence of all variables that
either a nitrous oxide (N2O) flowmeter or a special device (e.g., affect skin perfusion such as
INOvent, INOmax, OPTI-NO), provided FGF is greater than the ● Skin thickness. They are, therefore, more often used in neonates
patient’s minute volume. It is important to accurately measure in- (less keratinized skin). The presence of edema impedes the dif-
spired NO but also nitrogen dioxide (NO2), which is produced in fusion of O2.
the presence of O2 and can cause pulmonary edema. The concen- ● Peripheral perfusion: for example, hypovolemia, hypothermia,
tration unit used to measure NO is parts per million in volume increased peripheral vascular resistance, hyperventilation, and
(1 ppm = 1 mol NO/106 mol gas) or even parts per billion (1 ppb vasoactive drugs.
= 1 mol NO/109 mol gas). ● Electrode temperature, but are also appropriate for use by
DESCRIPTION: Mass spectrometry, electrochemical sensing, or experienced personnel:
chemoluminescence reaction devices can be used to measure NO.
● Careful calibration and maintenance of the electrode (intact
NO and NO2 levels are measured in the inspiratory limb of the membrane).
ventilator. ● Proper placement of the probe on the skin.
The electrochemical analyzer (e.g., Noxbox) consists of ● Avoidance of air bubbles being trapped between the membrane
analyzing gases through an oxidoreduction reaction. The potential and the skin.
difference produced by the transfer of electrons is proportional to Transcutaneous measurements should be regularly validated
the each gas concentration. Separate cells measure NO and NO2. against an arterial sample. Other technical limitations make this
These devices are mainly used as security sensors to warn when equipment difficult to use in the operating room:
NO or NO2 concentrations are above a fixed limit or when the NO
cylinder is empty. ● Warm-up time of 5 to 10 minutes.
Chemoluminescence is based on the reaction of NO with ozone ● Need for calibration (5–10 min).
in a chamber. This produces energized NO2 molecules which emit ● A low response time. It is of little usefulness in acute situations.
photons. The amount of light emitted is proportional to the ● Interference of electrosurgical apparatus.
concentrations of NO + NO2 initially present in the chamber. To ● Halothane and N2O can produce falsely high PtcO2 values unless
measure the original NO2 level, a molybdenum converter reduces a Teflon membrane or an electrode with a low polarization volt-
NO2 to NO in a parallel system. This allows the exact measure- age is used.
ment of NO concentration by subtracting NO2 of the parallel
system from (NO + NO2) measured in the chamber. Although POSSIBLE COMPLICATIONS: Care should also be taken to change
widely used in the clinical setting, this method is susceptible to the measuring site regularly to avoid local skin injury (erythema,
several artifacts such as blisters, burns).
● The presence of a high O2 concentration. PTCo2: Ptco2 is an indirect measurement of PaO2 and does not
● The presence of water (3.5% of the signal is lost for each per- reflect O2 delivery nor O2 content. Their assessment requires the
cent of humidity present); a water trap or a heated sampling line measurement of hemoglobin and its saturation. Although PtcO2
is thus mandatory. monitoring is usually recommended in premature infants to avoid
● The presence of halogenated agents. NO2 monitoring is tem- hyperoxemia and lessen the risk of retinopathy of prematurity, the
porarily affected by a sudden change in inspired concentration correlation between PaO2 and PtcO2 becomes less good when PaO2
of a halogenated agent.114 is greater than 100 mmHg.
● The composition of the tubing used to sample the gas. De-
pending in part on its nature and in part on the NO concen- PTCco2: The PtcCO2 is usually slightly higher than PaCO2 owing
tration present in the tubing, molecules of NO may be either to local skin metabolism producing CO2. In the presence of an in-
absorbed or released and the measurement will be affected creased deadspace and/or shunt fraction, which increase the dif-
accordingly. ference between PaCO2 and PETCO2 (e.g., infants with respiratory
failure), PtcCO2 provides a more accurate estimation of PaCO2 than
POSSIBLE COMPLICATION: Because NO therapy can cause does PETCO2.115 A monitor integrating in the same ear probe a
methemoglobinemia, MetHb levels should be checked regularly pulse oximeter and a PtcCO2 Severinghaus electrode (Tosca mon-
when NO is administered. itor) is successfully used in children14 and very low birthweight
infants116 (see Figure 38–2). It can be used to evaluate PaCO2 when
Transcutaneous Blood Gas Measurement115 PETCO2 is unreliable or unmeasurable (e.g., during laparoscopic
surgery, high-frequency jet ventilation [HFJV],117 noninvasive
GOAL: Transcutaneous monitoring is used to measure skin- ventilation, or sedation). However, it is not substitute for PETCO2
surface PtcO2 and transcutaneous arterial carbon dioxide pressure monitoring because the latter has a shorter response time, can
(PtcCO2) and to estimate PaO2 and PaCO2. It is mostly used in act as a deconnection alarm in intubated patients, and helps to
diagnose pulmonary embolism. The analysis of the capnogram seconds instead of advancing the catheter farther will allow blood
gives useful information. to appear at the needle hub. A good trick to detect immediate
entering the vein in children whose veins are poorly filled is
to prime the catheter with some saline. Red blood cells will be
Peripheral I.V. Cannulas seen “running” up to the catheter hub as soon as the vein wall is
Access to the venous circulation should be obtained for every pierced.
anesthesia. The techniques and sites of venous access are described Small polyurethane cannulas sometimes adhere to their needle,
in Chapter 69. which can make venous catheterization difficult. Gentle mobili-
zation before the use of the cannula over the needle is useful. To
avoid damaging the cannula or peelback of its tip when entering
Description the skin, a small nick in the skin can be made with a 19-gauge
Nontapered Teflon or polyurethane over-the-needle cannulas are needle before inserting the venous catheter is useful. Because there
currently available. The diameter of the I.V. cannula is related to is a risk of shearing or piercing the shaft of the catheter, the needle
the child’s size, chosen vein, and the importance of the procedure should not be re-inserted into the cannula blindly, that is., beyond
to be performed: 22-gauge cannulas can be used from the neonatal the point of entry in the skin. The cannula should be carefully
period up to 4 to 5 years, whereas 24-gauge cannulas are used in fixed to the skin in order to avoid losing venous access at critical
premature infants, and 26 gauge in very small premature infants. moments (e.g., in case of agitation during recovery) or to have to
The design of these cannulas is still improving. For example, stick the child again.
Vialon cannulas have a thinner wall and are able to deliver greater
fluid flow than Teflon cannulas of the same gauge size. These
Complications
cannulas are better fitted on their inner needle, which results in a
lesser incidence of cannula damage when puncturing the skin. In addition to a small tender hematoma at the site of skin
Some cannulas are designed with a build-in silicone injection valve penetration, the main possible complications of peripheral venous
(e.g., Venflon or Adsyte). cannulation are phlebitis and extravasation. Phlebitis is caused by
Whenever a medication (e.g., a muscle relaxant) is injected, mechanical and chemical irritation of the venous endothelium.
care should be taken to flush the injection site and catheter in It depends on the material of the cannula (polyurethane is less
order to avoid the retention of part of the dose and its delayed phlebogenic than Teflon), the duration of catheterization, the
administration when another injection is performed.118 In order nature of the solution injected (pH, tonicity, composition), and
to prevent needlestick injuries, I.V. cannulas are now designed the site of insertion (veins of the upper limb are less prone to
with either a spring-loaded mechanism (e.g., Insyte or Angiocath phlebitis than the lower limb).
Autoguard; pushing a button retracts the needle into a plastic Delayed diagnosis of extravasation can have dramatic conse-
safety barrel when it is taken out of the cannula) or a protective quences: for example, skin necrosis (Figure 38–11), compartment
shield that automatically (no active maneuver needed) retracts the syndrome, and delayed limb deformation.121 It should be pre-
needle point when it is withdrawn from the catheter (Introcan vented by a careful insertion technique and surveillance of the
Safety). The efficient use of these catheters needs some experience peripheral venous line. At the time of insertion of the catheter, it
and training. Although the number of needlesticks is dramatically is sometimes difficult, in the absence of blood return, to make sure
reduced, an increased incidence of blood splashes of the environ- the cannula is truly in the vein. A simple way to confirm the I.V.
ment can be observed, especially with the active systems.119 Some placement of the cannula is to allow the infusion to drip by gravity
devices are designed to improve peripheral vein visualization and alone. The obtained flow rate is observed and compared with the
cannulation. For example, flow rate obtained when the anesthesiologist’s hand occludes the
limb (like a tourniquet) well above the tip of the I.V. cannula. If
● Transillumination with a portable light source and a light-emit- the flow stops quickly, the cannula is in the lumen of the vein; if the
ting diode (LED; e.g., Vein-Locator-Universal, Wee Sight).120 flow does not change, extravascular placement of the cannula
● Using a movable system that includes a near-infrared light should be strongly suspected.122
source, a digital video camera, and a digital image projector. It
provides a real-time image of the subcutaneous veins onto the
surface of the overlying skin (Veinviewer).
Practical Aspects
Strict asepsis should be observed during venous cannulation.
Because the inner needle of the catheter is slightly longer than the
cannula, it may be located in the vein (with blood running back in
its hub) while the cannula is still outside it. Therefore, as soon as
a venous flashback is observed at the needle hub, which means
that it is in the vein, the needle should be advanced a few
millimeters farther to make sure the cannula has also entered the
venous lumen. The needle is then slightly withdrawn and kept
immobile while the cannula is gently advanced over it into the
vein. However, the venous flashback is sometimes not immediate.
Some experience is required to recognize entering the vein by
feeling a “click” when the venous wall is pierced. Waiting a few Figure 38-11. Extravasation of I.V. fluids in the lower right leg.
I.V. Administration Sets TABLE 38-20. Properties of a volumetric infusion device.

The amount of I.V. fluids administered during the perioperative Ideal Properties of a Volumetric Pump for Pediatric Use
period needs to be carefully measured. The use of a microdrip 1. Accuracy of flow rate: <5% difference at 25 mL/h
infusion set (e.g., 150-mL Burette or Soluset) allows the accurate 2. Detection of air in the tubing
delivery of small volumes of infusate and also prevents accidental 3. Time to alarm after occlusion: <10 min at 5mL/h
volume overload if care is taken to fill it with a volume of fluid not 4. Volume of bolus administered after relief of occlusion:
exceeding the calculated hourly infusion rate. Conversely, for <0.9 mL
procedures in which the rapid administration of fluid is neces- Ideal Properties of a Syringe Pump for Pediatric Use
sary (e.g., major abdominal surgery), it is wise to place a large 1. Accuracy of flow rate: <5% difference at 5 mL/h
(adult) extension between the stopcock and the I.V. cannula to 2. Effective delivery of syringe content < 1 min after starting
lessen the resistance to injection. A standard adult infusion set is (without priming)
used in children older than 10 years. Extension tubing is often 3. Time to alarm after occlusion: <10 min at 2 mL/h
necessary, especially if the I.V. cannula has been placed in the foot. 4. Volume of bolus administered after relief of occlusion:
Many textbooks recommend using a short T-connector as the last <0.5 mL
extension, to reduce the deadspace to be flushed. However, using 5. Alarm to warn that the syringe is nearly empty
this injection port carries a risk of embolization of part of its 6. Firm grip on the syringe plunger to prevent undesired
material (latex or elastomere) and of needle injury to the caregiver. movements of it (risk of siphoning, see text)
The author prefers using short Luer-Lok extension tubing (10 cm 7. Simple to operate, lightweight, operating with chargeable
long, 0.1 mL capacity). The use of non–Luer-Lok fitting extension batteries (for transport)
carries a risk of accidental and possibly unnoticed disconnection
with its risks of hemorrhage or air embolism.
The whole I.V. administration set should be carefully flushed to These mechanical systems should not be used for the admin-
eliminate any bubble of air both when prepared and immediately istration of potent agents such as vasopressors or opiates.
before connection to the I.V. cannula. Cases of air embolism
caused by the presence of air in the I.V. administration set do Volumetric Pumps
occur.123 and even small bubbles should be eliminated because A photoelectric drop-counting system is combined with a
there is a risk of paradoxical embolism in children with any microprocessor controlling the intermittent occlusion of the
intracardiac shunt or a patent foramen ovale. An air filter can be infusion tubing. The system is usually able to detect air in the
added in the I.V. fluid administration set but it increases resist- tubing and occlusion of the infusion line. The ideal properties of
ance to injection, which may be deleterious when rapid volume a volumetric infusion device for use in children are summarized
loading is necessary. When blood is administered, a standard in Table 38–20. If a peristaltic pump is used to run the infusion,
“adult-type” 170-μm filter is sufficient to trap leucocytes micro- special, more expensive, precision silicone tubing is necessary.
aggregates, and the use of smaller pore (20–40 μm) filters is no These pumps are appropriate to administer large volumes of fluids
longer recommended. (e.g., maintenance fluids), but syringe pumps perform better if
If an I.V. patient-controlled analgesia (PCA) device or a small volumes of potent medications are to be administered.
continuous infusion of an opiate is used to control postoperative
pain, a special I.V. administration set, equipped with an antisiphon
and antireflux valve, should be connected to the I.V. administration Syringe Pumps
set in order to avoid the retrograde accumulation of the infused Syringe pumps are often used in pediatric anesthesia because they
drug in case of occlusion of the I.V. cannula. If no such valve is allow the continuous administration of small volumes of I.V. fluids
used, the occlusion will be detected at a later time and the drug or a local anesthetic solution. However, owing to the potential
accumulated in the I.V. set will be rapidly administered when the dramatic consequences of accidental over- or underdosage of
occlusion is relieved. potent medications (e.g., inotropes, vasopressors, opiates) in small
children, the syringe pump should have the properties summarized
in Table 38–20.124 Most problems of accidental bolus or delayed
Infusion Devices drug administration are caused by the overall compliance of the
Mechanical Devices syringe, connecting tubing, and syringe-pump combination. As a
rule of thumb,
These simple systems function by gravity alone and with an
adjustable mechanical occlusion system; the user must control the ● The time to trigger the occlusion alarm is shorter when using
rate of infusion by drop counting. More controllable systems such small syringes and/or high infusion rates.
as Dosicair or Dial-a-Flo have been calibrated under very precise ● The volume of the bolus injected when the occlusion is released
conditions of use and are, therefore, reliable only if: increases with the infusion rate and the compliance of the ad-
ministration system.125
● The I.V. fluid container is approximately 80 cm above the mi-
daxillary line of the patient. These problems should be prevented by establishing operating
● The I.V. cannula is larger than 21 gauge. procedures. For example, when a slow infusion rate (e.g., 1 mL/h)
● The fluid infused is a normal parenteral solution and does not is foreseen, a small-size syringe with low-compressibility plunger
contain blood or blood products, lipid emulsion, or glucose in should be preferred to avoid start-up delays that can be clinically
a concentration above 10%. important (e.g., 3.6 ± 0.9 min with a 10-mL BD syringe at 1 mL/h
with a Alaris Asena syringe pump) and the time required to

achieve steady-state flow.126 In practice, flushing an initial bolus
of 2 mL before actually connecting the infusion line to the patient
reduces the delay in effective fluid delivery.127
The height of the pump should not be changed relative to the
patient. For example, when the infusion rate is 1 mL/h, elevating
the syringe pump 1 m above the child results in a bolus admin-
istration of 0.19 to 2.28 mL in less than 1 minute (depending on
the model of the pump and on the size of the syringe) and
returning the pump to its original level results in the aspiration
of 0.06 to 0.34 mL into the syringe!125 After such an up-down
maneuver, the syringe pump does not actually deliver any volume
at all during the following 8 to 105 minutes. This is caused by the
presence of the small gap that facilitates fitting the syringe wings
onto the pump. This gap allows some internal motion between
the plunger and the syringe cylinder and some siphoning to Figure 38-12. Transesophageal echocardiography through the
occur by gravity alone. Only the syringe(s) recommended by the central movable opening of an airway endoscopy mask. The
manufacturer of the pump should be used to avoid problems with breathing circuit is connected to the flexible lateral extension.
calibration of the pump.
Very sophisticated electronic syringe pumps are currently ● The Patil-Syracuse mask has an endoscopic port with a silicone
available that make the use of target-controlled total intravenous
diaphragm. In small children, a similar system may be created
anesthesia (TIVA) reliable in children (see Chapter 41).
by connecting a swivel bronchoscopy adapter to the appropri-
ately sized facemask. The fiberoptic bronchoscope is passed
STANDARD AIRWAY EQUIPMENT through the suction port of the adapter.
● The airway endoscopy mask.129 The center of a regular facemask
The various techniques of airway management is described in is removed and replaced by a removable distensible silicone
Chapter 72. membrane. The latter is equipped with a movable opening al-
lowing direct access of the fiberoptic bronchoscope to the nares
or mouth. An airtight flexible extension is inserted in a second
The Pediatric Facemask hole in the lateral part of the mask and connected to the anes-
Description thesia circuit. It can also be used for upper airway or esopha-
The two most common types of pediatric masks used currently gogastric endoscopy or transesophageal echocardiography.
are the Rendell-Baker-Soucek (RBS) mask and a variety of When a TT has been inserted into the trachea over the bron-
cushioned masks. The RBS masks have a low-deadspace, and the choscope, the silicone membrane is pushed inside to allow re-
cushioned masks have a cushion rim inflatable with air that makes moval of the mask over the TT. This device is available in three
achieving a good seal easier. The larger deadspace created by the sizes and may be used in newborns (airway endoscopy mask,
presence of the cushion is clinically of little consequence. Pediatric VBM) (Figure 38–12). However, handling of the fiberoptic
masks may be scented with the child’s preferred flavor. In case of bronchoscope in the oropharynx is somewhat impaired and
application of fruit-flavored extracts onto the inside surface of the may lead to an increased intubation time when compared with
mask, transient erroneous measurement of end-tidal vapors may fiberoptic intubation without a facemask.
be observed if ethanol is added in these extracts (see Respiratory When holding a facemask in neonates and small children, care
Gas Monitoring).128 When selecting a facemask for a child, should be taken to avoid digital pressure in the submental triangle
consider its dead space and the ease of its application to the child’s because this could push the child’s tongue on its palate and aggra-
face to fit over the bridge of the nose, cheeks, and chin. It should vate airway obstruction. Care should also be taken to avoid eye
be transparent to facilitate detection of cyanosis, secretions, or injury (e.g., corneal abrasion) or compression with the rim of the
regurgitated material. mask. During mask ventilation, it is sometimes easier to maintain
a good airway by tilting the child’s head slightly on one side. This
Indications moves the tongue laterally and usually provides a clear airway with
less jaw-thrust.
The facemask is used to perform inhalation induction of
anesthesia, preoxygenate the patient before rapid-sequence
I.V. induction, assist or control ventilation, and administer O2 at Cleaning and Sterilization
any time during anesthesia. A special double-mask has been Reusable facemasks are usually made from different materials
developed to allow scavenging of gases leaking around the inner (rubber, silicone, plastic) that deteriorate rapidly when autoclaved
mask (see “Scavenging,” later). The housing for the connection in high-pressure steam. Fortunately, decontamination and high-
to the breathing circuit and the exhaust tube is unfortunately level disinfection are sufficient to avoid cross-contamination. The
large and heavy, and this system did not achieve much popularity. masks should be immersed in a soap solution immediately after
Several endoscopic masks have been designed to allow fibero- use. They may be cleaned automatically in a washing machine or
ptic intubation in an anesthetized patient breathing spontaneously soaked in a liquid chemical. Phenolic compounds should not be
or receiving positive-pressure ventilation by mask. used because they are absorbed by many materials and could result
in dermatitis in the area of contact between the child’s face and forward with a Magill forceps while the airway is inserted in the
the mask. Whatever the cleaning method used, the masks should mouth and advanced into the pharynx. The “classic method,” in
be thoroughly rinsed and carefully dried before being used in which the airway is inserted with its concave side toward the upper
another patient. lip and rotated 180 degrees when its tip has passed the uvula,
should be avoided in children to prevent trauma to the oral tissue.
When using an oral airway, take care to avoid the avulsion of loose
Oral and Nasopharyngeal Airways or decayed teeth or to catch the child’s lip between the airway and
Oral Airways the child’s teeth.
Oral airways are used either to maintain an open oropharyngeal
airway (as during induction of anesthesia) or to prevent a patient Nasopharyngeal Airways
from biting and occluding an orally inserted TT. Choosing its A nasopharyngeal airway is used to provide a conduit for gas
appropriate size is crucial. If the airway is too small, it will push the flow between the tongue and the posterior pharyngeal wall. Its
tongue backward and obstruct the oropharynx. If it is too large, it pharyngeal end should be above the epiglottis and below the base
could push the epiglottis down into the laryngeal inlet. The correct of the tongue. It offers an alternative to an oral airway and is better
size is estimated by placing the oral airway along the child’s tolerated in awake or semiawake patients. It can be used only in a
face. When the flange is at the child’s lips, the tip should be at the spontaneously breathing patient. Either the Robertazzi nasal
angle of the mandible (Figure 38–13). Using MRI to measure the airway (Rüsh) or the Wendl nasal airway (with an adjustable flange
distance between the teeth or lips and the prevertebral tissues, it at its nasal end) may be used. Although nasal airways are available
was found that the distance varies with age, weight, and gender in 12- to 36-French sizes (ID in millimeters), they can be made
and that the location of the tip of the epiglottis varies widely as
from a cut TT. A safety pin or a tube connector should be inserted
well.130 Standards for manufacturing oral airways probably need
at the nasal end of the airway to prevent its migration into the
to be adapted accordingly. The most commonly used oral airways
nasopharynx. The proper diameter of the nasal airway is usually
are the Guedel airway (with a central lumen) and the Berman
the same or even 0.5 mm larger than the TT that is appropriate
airway that consists of two horizontal plates joined by a median
ridge. A suction catheter can be passed down either side of the for the child’s age (see “Standard Tracheal Tubes,” later). The
ridge. These oral airways may be modified to facilitate oral fiber- proper length of the nasal airway is estimated by measuring the
optic intubation. They help keep the fiberscope in the midline, distance between the nose tip and the tragus of the ear (Figure
maintain an open airway, and expose the laryngeal opening while 38–14). However, especially in cases of orofacial dysmorphism,
preventing the patient from biting the fiberscope. The Guedel the actual length of a nasal airway is the one that provides good
airway can be modified by cutting out a strip of its convex surface; entry of air without stridor and/or a capnogram. The indications
however, in order to allow adequate visualization of the hypoph- for insertion of a nasopharyngeal airway are listed in Table
arynx, it is recommended to use an airway device slightly smaller 38–21.131 Contraindications to the use of a nasopharyngeal airway
than if it had been used only to maintain the airway patent. The include hemorrhagic disorders, a basilar skull fracture, and any
median ridge of the original model of the Berman airway is pathology of the nose or nasopharynx. The nasal airway is
displaced to one side, providing a longitudinal opening on the lubricated with water, a local anesthetic ointment, or a silicone
other side. These modified oral airways are rarely used since the spray and gently inserted through a nostril in a posterior direction,
LMA became available. perpendicular to the coronal plane along the floor of the naso-
To avoid laryngospasm or vomiting, pharyngeal and laryngeal pharynx. During insertion, it is sometimes necessary to turn or
reflexes should be depressed before attempting the insertion of an twist the airway to follow the path of least resistance, but the
oral airway. Various methods of insertion have been described. passage should never be forced to avoid mucosal damage and/
The tongue may be depressed with a tongue blade or gently pulled or epistaxis. The patency of the small nasopharyngeal airways
Figure 38-13. Estimation of the correct size of an oral airway. Figure 38-14. Estimation of the length of a nasopharyngeal
When the flange is at the child’s lips, the tip should be at the airway by measuring the distance between the tip of the nose
angle of the mandible. and the tragus of the ear.
TABLE 38-21. Indications of Nasopharyngeal Airway breathing. If the air flow is laminar, resistance is proportional to
the length of the tube and inversely proportional to the fourth
● To provide some postoperative CPAP power of its radius (Hagen-Poiseuille law). For example, resistance
● To maintain a patent airway in neonates and infants with to airflow increases by 50% when the ID of the TT decreases from
obstructive apnea (e.g., Pierre Robin anomalad, Treacher- 3.5 to 3.0 mm. Luminal changes between the 15-mm connector
Collins syndrome, sleep apnea syndrome) and the TT favor turbulent flow, which further increases resist-
● To maintain a patent airway following cleft palate, ance. These considerations led the anesthesiologist to use the
palatopharyngeal, or choanal atresia surgery largest TT possible that will enter the child’s larynx (cricoid ring)
● To allow insufflation of O2 and halogenated agents during without force and without compressing the tracheal mucosa.
upper airway endoscopy (e.g., fiberoptic intubation, laser Additional reasons to use a large TT are
surgery on the larynx)
● To allow insufflation of O2 and halogenated agents during ● The lesser likelihood of its occlusion by secretions.
chair dental anesthesia. ● The ability to use a larger suction catheter if suction is neces-
sary.
CPAP = continuous positive airway pressure. ● A relative protection against regurgitation of foreign material
into the lungs.
should be checked frequently because they can easily become ● Less leakage around the TT, which has implications for the qual-
obstructed by blood or secretions. Possible complications of the ity of ventilation and monitoring of PETCO2 and halogenated
use of a nasopharyngeal airway are epistaxis and submucosal agents as well as for the use of closed circle ventilation.
insertion. Gentle insertion is mandatory. It produces sometimes
hypersalivation. Conversely, whereas resistance to breathing is linked to the ID
and length of the TT, the potential for laryngeal or tracheal injury
is related to its OD, the gentleness applied during its insertion, and
Standard Tracheal Tubes the duration of intubation. Mild trauma to the airway causing as
little as 1 mm edema can result in significant airway narrowing at
Description the level of the cricoid cartilage in infants137: avoiding traumatic
The TTs in common use today are made of polyvinylchloride intubation is essential. Ischemia of the tracheal mucosa occurs
(PVC) and disposable. They should bear markings showing that when the pressure from the TT exceeds the capillary pressure of
they comply with the American Society for Testing and Materials the tracheal mucosa. In the absence of pediatric data in the
standards, such as IT or Z79, that specifies that the material has literature, this pressure is unknown but believed to be close to
not shown tissue toxicity both in vivo and in vitro. They are 25 to 35 mmHg or 20 to 25 cmH2O, as in adults. Until recently,
calibrated according to their ID (millimeters), outer diameter uncuffed TTs were almost exclusively used in pediatric patients
(OD; mm), and length (cm), and are beveled ± 40 degrees off to up to 8 to 10 years of age, essentially because it was believed, based
the left when viewed with the tube curved up. Most TTs contain a on cadaver studies, that the child’s larynx was funnel-shaped with
radio-opaque line in their wall that allows easy evaluation of their its apex (i.e., smallest portion) at the level of the round cricoid ring
position by x-ray. Some TTs are designed with a hole in their wall and, subsequently, that a TT whose OD is close to the ID of the
on the side opposite to the bevel and just above the tip—they are cricoid would seal the trachea without applying dangerous pres-
called Murphy-type tubes, in contrast to the others, which are sure on the tracheal mucosa. In fact, both MRI138 and videobron-
called Magill-type. The purpose of the Murphy hole is to provide choscopy139 have demonstrated that the glottis is the narrowest
an alternate pathway for airflow if the bevel becomes occluded or portion of the pediatric airway and that the trachea as an elliptic
the TT is inserted too far into the trachea, but it makes pulmo- section at the cricoid level. However, the vocal cords are mobile
nary auscultation less reliable to detect bronchial intubation.132 and can distend when a TT is inserted through them. This
Although the TTs are categorized according to their ID, their wall explains damage to the vocal cords after traumatic or prolonged
thickness and also their OD vary from one manufacturer to intubation and the cricoid ring remains functionally the narrowest
another. For example, the OD of a 4.5-ID TT is 6.0, 6.2, 6.2, or part of the larynx.
6.6 mm when it is made by Mallinckrodt, Rüsch, Sheridan, or When using an uncuffed TT, the pressure applied against the
Portex-Sims, respectively. The smallest uncuffed TT available is tracheal wall by the tube can be estimated by slowly inflating the
2.0-mm ID. TTs are usually supplied from the manufacturer with breathing bag of the anesthetic circuit and listening for a leak over
their connector loosely attached. Care should be taken to insert the neck (stethoscope) or mouth. A properly sized TT is the one
the connector tightly into the tube before its use to minimize the that, once in place, allows leakage at an insufflation pressure
risk of accidental disconnection. Conversely, the connector should ranging from around 18 to 20 cmH2O. However, many other
be inserted gently, especially if the TT has been cut, taking care to factors may affect the pressure at which the leak occurs and should
avoid buckling it. Any inward deformation of the connector can be borne in mind when performing the leak test. For example, the
result in total or partial occlusion of the TT.133 depth of insertion of the TT and the FGF do not influence leak
pressure, but measuring the leak when the child’s head is turned
to one side or when she or he is not paralyzed increases the
Size pressure required to cause the leak.140 This could lead to a leak
When choosing a TT for use in a child, consider its influence on occurring at a much lower pressure, with a risk of hypoventilation,
airway deadspace,134 resistance during spontaneous breathing,135 when the child’s head is straight or when she or he is paralyzed.
and potential tracheal or laryngeal injury136 (see Chapter 43). Last, most data on postoperative croup were collected at a time
Tracheal intubation actually decreases the deadspace of the natural when rubber reusable TTs were used. They were confirmed in
extrathoracic airway but dramatically increases resistance to a study with modern PVC TTs.141 Children who had no leak at
TABLE 38-22. Recommended Uncuffed Tracheal Tube Sizes

Age Size, mm ID
premature < 1000 g 2
>1000 g 2.5
Term neonate ≥ 3 mo 3.0–3.5
3–9 mo 3.5–4.0
9–18 mo 4.0–4.5
>2 y Age + 16
4
25 cmH2O pressure presented with 2.8 times more adverse respi-

ratory events than those with an audible leak. But it also high-
lighted the role of trauma because intubation by an inexperience
anesthesiologist increased the risk of adverse events 3.7 times.141 Figure 38-15. Palpation of the tip of the tracheal tube in the
Several methods are available to aid selecting the appropriate TT. suprasternal notch.
Measuring the diameter of the external nares, the distal joint of
the index finger, or the tip of the little finger or even the child’s
Other methods to position the TT in the mid-trachea are
height (Broselow tape) have been proposed.142 The most accurate
estimation can usually be obtained by using an age-based 1. Suprasternal palpation of the tip of the tube. With the child’s
formula143,144 and results in the recommendations shown in Table head in the neutral position and his or her neck mildly
38–22. However, they represent estimates that should be confir- hyperextended with a roll under the shoulders, the pad of
med in each patient by testing the leak pressure. They are not the palpator’s index finger may feel the TT when it is gently
usable with ticker-walled TTs such as reinforced TTs. In practice, moved in the trachea and position its tip just within the
three sizes of TT should always be available during induction of suprasternal notch. This should be done gently to avoid local
anesthesia: the size calculated from the formula, one size larger, trauma and stimulating the lower airway (Figure 38–15).
and one size smaller. Palpation of the TT tip in the suprasternal notch is very reliable
The depth to which the TT should be advanced past the glottis in children between 2 and 8 years of age to prevent accidental
varies with the length of the trachea (i.e., the child’s age). Many extubation and endobronchial intubation during neck
uncuffed TTs have a black area or a line printed near their tracheal movement.149
end. The aim is that advancing the tube through the cords up to 2. Deliberate gentle bronchial intubation followed by withdrawal
the line or the end of the black area places the tip of the TT of the TT until breath sounds become symmetrical (i.e., near
approximately in the midtrachea. However, the length of this black the carina). The TT is withdrawn a further 2 cm.150 This tech-
area varies from one manufacturer to another. For example, it is nique carries a risk of bronchospasm and is not recommended.
2.5 cm long in the 4.5 to 6.0 ID Portex Ivory TT and the 3.5 to 6.5 Whatever the method or formula used, the correct positioning
ID Vygon plain TT, whereas it increases progressively with tube of the TT should be verified by careful auscultation of all the
size in the Sheridan TT.145 Several formulas are available to lung fields. The position of the TT should be verified each time
calculate the approximate length at which a TT can be inserted the patient’s head is moved because the distal tip of the tube
into the trachea with a low risk of unexpected extubation or moves toward the carina during flexion and toward the vocal
bronchial intubation, However, they are accurate only in children cords during extension of the neck.151
whose airway dimensions do not differ significantly from those
of children of the same age or size (e.g., not in children with We recommend disconnecting the TT from the breathing
dwarfism). The approximate length at which an oral uncuffed TT circuit each time the child’s position is changed in order to prevent
has to be at the alveolar ridge to have its tip in the midtrachea is both accidental extubation and laryngotracheal trauma. The TT
should be secured using tape or a gauze band. Many different
Length (cm) = 3 × ID (mm) techniques can be used to achieve this goal. If the TT has been
or inserted nasally, care should be taken to avoid applying too
Age (y) + 13 older than1 year of age146 much pressure on the alae nasi or septum to prevent pressure
Length (cm) = necrosis. If the TT has been inserted orally, an oropharyngeal
2
airway is placed along it (except in case of oral surgery!) to pre-
For a nasal tube, the formulas are vent occlusion (e.g., the child biting on her or his TT during
awakening) or displacement in the oropharynx. Before perform-
Length (cm) = 3 × ID (mm) + 2147
ing nasotracheal intubation, a suction catheter should be inserted
or into the TT to avoid plugging it with secretions or debris accu-
Age (y) + 15 older than 1 year of age146 mulated during its passage through the nasopharynx. A close-
=
2 fitting suction catheter is carefully lubricated with a silicone
spray and placed in the TT. They are inserted together through the
or, more practically, setting the following mark at the level of nares and carefully slipped into the posterior pharynx; the suction
the cords: 3 cm for the 3 and 3.5 ID TT, 4 cm for the 4 and 4.5 ID catheter is then withdrawn from the TT, which is introduced into
TT, and 5 cm for the 5 and 5.5 TT.148 the trachea.
Cuffed Pediatric Endotracheal Tubes Last, the incidence of postintubation stridor is not a good
indicator of the presence and severity of airway injury. Stridor can
Description indeed be a sign of early benign edema or severe obstruction, but
The design of pediatric TTs with low pressure-high volume cuffs large areas of mucosal necrosis do not cause stridor until later,
led to their use in infants and children with poor lung compliance when scarring narrows the airway by more than 50%.156 The pilot
in order to maintain adequate ventilation (see Chapter 43). In balloon of cuffed TTs usually contains a stainless steel spring that
several series, there was no increased incidence of postintubation may cause signal interference during MRI.157
stridor in children intubated with a cuffed TT, but they were
intubated with a TT 0.5-mm ID smaller than calculated with
the usual formulas and a minimal leak was maintained at the Precautions
current PIP needed by the child.152,153 However, most TTs with a The use of cuffed TTs in small children is becoming a more
PVC cuff available at present are poorly designed for use in common practice in the operating room, especially when
pediatric patients. Their OD varies considerably for the same ID, prevention of aspiration or possible intraoperative changes in lung
most of these cuffs do truly show low-pressure, high-volume compliance is of concern. Other advantages of using cuffed TTs in
properties when tested, and, the length and position of their cuff children are a more reliable monitoring of end-tidal gases and
are inadequate. If the tip of the TT is in the middle of the trachea, expired volumes, a reduction in contamination of the operating
the cuff of most TTs less than 5 mm ID lies in the subglottic area room atmospheres, and a lesser need for repeated laryngoscopy
or between the cords. Conversely, if the cuff is adequately placed (and its own traumatic risk) to replace an initially too small TT.153
in the trachea, endobronchial intubation ensues.154 TTs specially The following points should, however, be kept in mind when using
designed for pediatric use with a low-compliance, thin-walled, a cuffed TT in a pediatric patient:
short polyurethane cuff placed distally and marks allowing
positioning their tip in the middle of the trachea and their cuff 1. The presence of a cuff, especially a high-volume, low-pressure
at the tracheal level (to avoid any pressure on the subglottic cuff, increases the OD of the tube by approximately 0.5 mm.158
mucosa) are now available (Microcuff) (Figure 38–16). The major A TT 0.5 mm smaller than calculated with the usual formulas
companies will probably adapt their products accordingly. In should be inserted or the following rule should be used:
vitro studies using a tracheal model in which parietal pressure ID (mm) = age (y)/4 +3 or 3.5.153,159
measurements were made have demonstrated that, regardless of
whether the cuff had a low or high compliance when tested in an An air leak should be present at 20 cmH2O around the TT with
unrestricted environment, cuff compliance decreased considerably its cuff uninflated. If not, a smaller TT should be inserted.156,160
when placed in the model. More important, this study also showed Table 38–23 shows the size recommendations for the Microcuff
that tracheal wall pressure increased with cuff pressure if the latter TT. The ensuing reduced ID of all cuffed TTs increases both
was sufficiently large when inflated to drape the inner tracheal airway resistance and the work of breathing during spontaneous
wall. Accordingly, even the use of high-volume, low-pressure cuffs ventilation.
does not avoid high intratracheal pressures being generated,
2. Cuff pressure should be monitored, even if no N2O is used, to
and cuff pressure monitoring (and limitation to 20 cmH2O) is,
avoid tracheal mucosa damage. The increase in temperature of
therefore, mandatory.155
the air used to inflate the cuff will raise the pressure within it
and may be responsible for tracheal edema.
3. Active deflation of the cuff must be avoided (except during the
process of tracheal intubation and extubation) because it
usually results in sharp folds and edges at the external surface
of the cuff and leads to mucosal damage.156,160
4. The cuff should be carefully positioned below the cricoid area
because the majority of endoscopy-proven postintubation
laryngeal injuries were caused by folds and malposition of
the cuff.156
TABLE 38-23. Recommended Size of Microcuff Tracheal

Tube According to Age
ID of the Cuffed TT, mm Child’s Body Weight or Age
3.0 Term ≥3 kg to <8 mo
3.5 8 mo to <2 y
4.0 2 to <4 y
4.5 4 to <6 y
Figure 38-16. Comparison of the distal part of a Microcuff tra-
5.0 6 to <8 y
cheal tube with a Mallinckrodt tube of the same size. The cuff of
5.5 8 to <10 y
the Microcuff tube is shorter, cylindrical, closer to the tip, and
6.0 10 to <12 y
made of polyurethane. When the large black mark is at the level
6.5 12 to <14 y
of the vocal cords, the cuff is theoretically in the middle of the
7.0 14 to <16 y
trachea, below the cricoid area.
Preformed Tubes TABLE 38-24. Supraglottic Airways: Indications

TTs with a special configuration may be useful during certain ● In place of a facemask: any peripheral or superficial surgery
surgical procedures. The most commonly used are the RAE tubes Laser treatment of the face
(designed by Ring, Adair, and Elwyn) for cleft palate surgery and ● In place of a TT: ophthalmic examination or surgery
any head and neck surgery in which the surgeon needs to have ENT, anterior dental surgery
intraoral access. The preformed tubes are made of PVC and Neonatal resuscitation, administration of surfactant
available in oral and nasal versions. The oral version is bent toward ● For remote control of the airway: radiotherapy
the concavity of the curve of the tube so that, when in place, it rests MRI
● For diagnostic examination of the airway: fiberoptic
on the patient’s chin. The nasal version is bent away from the
curvature of the tube and rests on the patient’s forehead when laryngoscopy or bronchoscopy
● For difficult intubation: as the sole airway or to help
in place. These acute nasal or oral curves make tracheal suction
difficult. Uncuffed preformed TTs are available from 3.0 to endotracheal intubation (introduction of fiberoptic
7.0 mm ID. Most uncuffed preformed TTs have two Murphy holes laryngoscope or bougie)
(distal lateral wall orifices). However, in neonates and small infants, ENT = ear, nose, and throat; MRI = magnetic resonance imaging; TT = tracheal
the presence of a Murphy hole can make the diagnosis of bronchial tube.
intubation more difficult or even hinder adequate ventilation if it
encroaches into the glottis following head movement. The main distal end of the tube prevent the epiglottis from obstructing the
disadvantage of the preformed TTs is that their flexion point (bend) lumen. When the CLMA is correctly placed, its tip rests against
is fixed. Their intratracheal length may be inappropriate in children the upper esophageal sphincter, the sides of the cuff face the
whose cricoid diameter is larger or smaller than usual for their age pyriform fossae, and the epiglottis and esophagus are outside the
and results in either bronchial intubation,161 especially when a bowl. A black line along the posterior aspect of the tube is used to
mouth gag is inserted, or accidental extubation. An easy way to ensure proper positioning of the LMA. When this black line is in
prevent bronchial intubation if the TT is too long is to place a pad the midline and facing cephalad, the mask faces the larynx.
(e.g., piece of gauze) between the chin and the tube. If the bend is Fiberoptic bronchoscopy performed through a clinically well-
placed inside or outside the oral cavity, kinking of the TT is more positioned CLMA revealed a clear laryngeal opening in only 27%
likely after insertion of a mouth gag. of children and the epiglottis was either impinged in the bars of
Oral cuffed TTs range in size from 4.0 to 9.0 mm ID and the the CLMA 1 or downfolded by the CLMA 2 in 57% and 38% of
nasal cuffed TTs from 6.0 to 8.0 mm ID. Their design, especially children, respectively.163 In other words, clinical airway patency
the bend–to–tracheal tube tip distance, varies according to does not guarantee ideal anatomic positioning of the CLMA in
the manufacturer.161 Even with the newly designed oral cuffed infants and children. The cuff around the mask is inflated via a
pediatric TTs (high-volume, low-pressure polyurethane cuff close pilot balloon and a valve. Reusable CLMAs are made of silicone
to the TT tip), it is not unusual that the cuff moves toward the (and are thus latex-free) and, therefore, able to withstand auto-
cricoid area during head extension.162 Whatever the type of TT claving and repeated use. Because careful washing and sterilization
used, insertion of a mouth gag moves it caudally and auscultation do not eliminate protein deposits from reusable LMAs,164 single-
should be checked afterward. use PVC LMAs should be preferred. Different companies pro-
duce LMAs (e.g., Portex Soft Seal, Intersurgical Solus, or Ambu
AuraOnce). They vary slightly in shape, tube diameter, maximum
Supraglottic Airways volume of inflation, presence of bars, and flexibility, which can
Based on their shape and presence of a sealing device, supraglottic influence their easiest mode of insertion165
airways can be classified as The Flexible reinforced version of the LMA allows its use for
head, neck, and oral surgery. The mask is connected to a flexo-
● Cuffed perilaryngeal sealers: all LMAs.
● Cuffed pharyngeal sealers: laryngeal tube, CobraPLA.
● Uncuffed preshaped sealer: Igel. TABLE 38-25. Contraindications to the Use of a
Supraglottic Airway
Some of them are equipped with a drain tube to allow escape of
gastric fluid and gases. Their common indications and contra- Increased risk of aspiration/regurgitation (except Proseal LMA,
indications are reported in Tables 38–24 and 38–25. The naso- Supreme, LTD, Igel, which are equipped with a gastric drain
pharyngeal airway is in fact an uncuffed nonsealer supraglottic tube)
● Any full stomach situation
airway.
● Presence of a gastroesophageal reflux disease
● Obesity
The LMAs ● Upper abdominal surgery
Initially designed to be an alternative to the face mask and the TT, ● Laparoscopic surgery
the LMA quickly became an essential tool in the management of Need for high inflation pressures: lungs with low compliance,
the difficult airway. thoracotomy
Oral, laryngeal, or pharyngeal pathology
DESCRIPTION: The classic laryngeal mask airway (CLMA) Difficult control of the airway in case of dislodgment: e.g., prone
consists of a bowl-shaped mask with an inflatable cuff, connected
position
to a large-bore tube attached to the back of the mask. It provides
Too small mouth opening
a low-pressure seal around the laryngeal inlet. Vertical bars at the
TABLE 38-26. Specifications of the Laryngeal Mask Airways

Max. Cuff Volume ID, mm, Largest Fiberoptic Largest Gastric
Patient’s Max. Pressure, Standard/ Bronchoscope Usable, Tube in
Size, # Weight, kg 60 cmH2O, mL Reinforced mm, With Reusable LMA Proseal LMA
1 >5 <4 5.3 2.7 NA
1.5 5–10 <7 6.1 3.0 10 Fr
2 10–20 <10 7.0/5.1 4.7 10 Fr
2.5 20–30 <14 8.4/6.1 5.3 14 Fr
3 >30 <20 10.0/7.6 7.3 16 Fr
4 Adult <30 10.0/7.6 7.3 16 Fr
5 Large adult <40 11.5/8.7 8.7 18 Fr
ID = inner diameter; LMA = laryngeal mask airway.
metallic tube that can be bent without kinking. In the reinforced respectively.171 Although the sizes of all models are recommended
version, the mask and the ID of the tube are smaller, and the tube according to the child’s body weight, in case of malnutrition or
is longer, than in the standard version (Table 38–26). It is available obesity, another method can be used. The child’s hand is extended
in sizes 2 to 4 only. with the palm facing up and the three middle fingers kept together.
The Proseal laryngeal mask airway (PLMA) is a single-use An LMA with its cuff inflated with the maximum volume recom-
LMA to which an esophageal drain tube is added. This tube passes mended is placed with its anterior aspect facing the palmar side of
parallel to the flexible wire–reinforced airway tube and across the the child’s three middle fingers. The widest part of the LMA that
floor of the mask to open at its distal end, at the level of the upper matches the widest part of those three fingers is the most appro-
esophageal sphincter. The drain tube gives access to the digestive priate size for the child.172
tract and allows escape of gastric fluid and gases. This tube can Both the silicone-made classic and the reinforced version of the
also be used to place a temperature probe or even a small gastro- LMA have been shown to be more resistant to a CO2, KTP
scope or a transesophageal echocardiography probe.166 The airway (potassium titanyl phosphate), or Nd:YAG (neodymium:yttrium-
tube of the PLMA is 0.6 mm smaller than the conduit of the aluminum-garnet) laser beam than PVC TT. The most vulnerable
CLMA of the same size and its cuff is different in sizes greater than parts are the black marks on the shaft, the places where the LMA
2. It does not contain distal bars, and a rear part has been added is blood-stained, the metal wires of the reinforced LMA, and the
to improve the seal at the pharyngeal level. The different sizes of cuff, but filling the latter with saline has a protective effect.173
PLMA available and the sizes of gastric tube insertable in their When compared with the TT that could be inserted in the same
drain tube are reported in Table 38–26. The PLMA can be inserted child, a CLMA has a lower resistance to flow. A reinforced LMA
using the operator’s finger, a special introducer tool, a gum elastic has a similar resistance to flow. Spontaneous ventilation through
bougie placed in the drain tube (the distal extremity of the bougie a CLMA is associated with a high incidence of hypercarbia. It is
protruding out of the distal end of the tube is introduced in the better to use controlled ventilation, and in this setting, pressure-
esophageal inlet during direct pharyngoscopy before railroading controlled ventilation is more efficient than volume-controlled
the PLMA over it),167 or a Trachlight placed in the drain tube.168 ventilation,174 unless pressure-support ventilation is available.175
The LMA Supreme is similar to the PLMA, but its shaft is
more curved, which makes it easier to insert.169 The smallest PRESSURES IN AND AROUND THE LMA CUFF: The LMA sealing
model available is #3 for children weighing more than 30 kg. or leak pressure is the pressure measured in the breathing system
An intubating laryngeal mask (Fastrach) has been designed when air can first be heard to escape around the LMA. It usually
to allow blind tracheal intubation through it. It consists of an varies between 15 and 25 cmH2O. The leak pressure is usually
anatomically curved stainless steel tube bonded to a standard LMA higher around a PLMA than around the same size CLMA. This
cuff (sizes 3, 4, or 5) and a handle. This allows manipulation of the makes the PLMA more suitable for controlled ventilation.176
device within the patient’s airway. Moreover, the ID of the airway The LMA cuff inflation pressure or intracuff pressure is meas-
tube is larger and the tube is shorter than that of the CLMA, ured by connecting a pressure transducer to the LMA pilot balloon
whereas the distal bars are replaced by an epiglottic elevating bar to valve. Measurement of cuff inflation pressure gives only indirect
keep the epiglottis from obstructing the glottic opening. The size 3 information about the pressure applied by the LMA to the pha-
Fastrach can be used in children weighing more than 25 kg.170 The ryngeal mucosa because the latter is determined by cuff pressure
LMACTrach is equipped with a small video camera that allows and volume, the muscular activity and/or elasticity of the pharyn-
visual control of correct positioning of the airway tube in front of geal wall, and the elastic recoil from the curved tube. Using strain
the glottis and intubation through it. gauge microchip sensors placed between the LMA and the
The air-Q ILA intubating LMA is specially designed to facilitate pharyngeal mucosa, Brimacombe and Keller were able to directly
intubation using fiberoptic laryngobronchoscopy. It has a shorter, measure pharyngeal mucosal pressures in anesthetized adults.
more curved shaft than a CLMA, a removable airway adapter, and They found that mucosal pressure increases with increasing
no grills in the bowl. It can be removed when the TT is in place intracuff pressure and cuff volume,177 and there is no correlation
without the need a stabilizing device. It is available in single-use between mucosal pressures and leak pressure. Pharyngeal damage
(1–4.5) and reusable (2–4.5) models. Their size is based on the caused by excessive mucosal pressure is unlikely if intracuff
same weights as the CLMA. Sizes 1, 1.5, 2, and 2.5 can be used to pressure is kept below 60 cmH2O. The maximum volumes of air to
intubate the trachea with cuffed TTs up to 4.0, 5.0, and 5.5 mm ID, be injected according to CLMA size are given in Table 38–26,
keeping in mind that intracuff pressure should not exceed 60 cm is maintained. Bronchoalveolar lavage and fiberoptic removal of
H2O. In vitro studies have shown that injecting the maximum bronchial foreign bodies can also be performed while securing the
recommended cuff filling volumes in pediatric LMAs, as is usually upper airway with an LMA. In adults, tracheal or pharyngeal laser
done by many teams, results in hyperinflation in almost all models surgery has been performed while airway patency was secured
tested.178 This has been confirmed by measuring their cuff PV with an LMA.
relationship in vivo; injecting approximately 50% of the maximum Finally, any model of LMA is an important tool in the manage-
volume recommended resulted in intracuff pressure in excess ment of the difficult airway and during the “cannot intubate, cannot
of 60 cmH2O.179 Because a higher intracuff pressure can result ventilate” situation, in which it is a safe alternative to cricothyro-
in pharyngeal morbidity and increased leakage of air around the tomy. It is usually inserted after induction of anesthesia, but it can
LMA, monitoring intracuff is now strongly recommended.180 be inserted in awake infants with an abnormal upper airway186 or
Diffusion of N2O into an air-filled LMA cuff causes a signifi- to administer surfactant in neonates.187 Although blind passage of
cant increase in intracuff pressure and much more if the cuff is in the TT or a bougie through the CLMA has been described in adults
silicone rather than in PVC.181 To minimize the risk of cuff and children,188 it is not recommended. A fiberoptic bronchoscope
overinflation of the LMA cuff, we recommend should be used to confirm proper position of the epiglottis within
the LMA and/or to guide the TT into the trachea either directly or
1. Careful inspection of the LMA cuff before each use.
after inserting a guide under direct vision.189
2. Inflating the cuff with the lowest effective volume and meas-
uring intracuff pressure; if volumes of air greater than 50% of CONTRAINDICATIONS: The contraindications to the use of an
those indicated in Table 38–26 or an intracuff pressure greater LMA are (see Table 38–25)
than 60 cmH2O are needed to obtain a leak pressure of ● Except for the Proseal and the Supreme versions, any situ-
10 cmH2O or lower, the LMA should be re-inserted or a larger
ation in which there is an increased risk for aspiration or
size used.
regurgitation (emergency, obesity) because the seal between the
3. If N2O is used, periodic measurement of intracuff pressure
should be performed. larynx and the LMA is not watertight and does not protect the
patient from aspirating gastric contents. In children with no
esophagogastric pathology, use of the LMA could be associated
INDICATIONS: The indications for the use of LMAs are sum-
with a greater incidence of gastroesophageal reflux up to the
marized in Table 38–24. LMAs can be used in place of a facemask
middle third of the esophagus, especially at the time of its
for any peripheral or superficial surgery. They free the hands of
removal and during the following 30 minutes.190 This could be
the anesthesiologist and reduce environmental pollution with
caused by lowering of the lower esophageal sphincter pressure
inhaled agents. For example, in case of laser treatment of facial
by the presence of the LMA cuff in the pharynx. Last but not
port-wine stains, the O2 concentrations measured around the
least, the esophagus is within the lumen of the LMA in up to
lips in children breathing spontaneously 100% O2 were lower than
10% of the cases!
when a facemask was used.182 The reinforced LMA can be used ● In patients with a low-compliance respiratory system when pos-
instead of a TT to perform ophthalmic surgery or examination
itive airway pressures greater than 20 cmH2O are required to
under anesthesia because the insertion of an LMA does not
ventilate the lungs, major air leak and/or gastric inflation can
increase intraocular pressure as is often observed with a face-
occur.
mask.183 The reinforced LMA is an alternative to tracheal ● The presence of an oral, laryngeal, or pharyngeal pathology, al-
intubation in children undergoing adenotonsillectomy. When
though the airway of children with mild or severe subglottic
compared with an oral Ring-Adair-Elwyn (the name of the
stenosis can be successfully managed with an LMA.191
inventors [RAE]) preformed TT, it provides as good surgical ● Situations in which the airway would be difficult to control
access and no more postoperative complications. Care should be
quickly if the LMA becomes dislodged (e.g., prone position,
taken when the surgeon inserts and opens the mouth gag because
complex oral surgery).
this could displace or obstruct the LMA. The LMA seems to ● A small mouth opening that hinders the introduction of the
protect the lower airway better than an uncuffed TT against
LMA into the mouth.
inhalation of blood. Minor oral and dental surgery can also be
performed using a reinforced LMA. The LMA is also useful when
remote control of the airway is necessary, such as during Quality Control
radiotherapy, avoiding repeated tracheal intubation in children The LMA should be checked before each use for discoloration
undergoing daily anesthetics for several weeks, and MRI or CT (yellow), kinking when flexed to 180 degrees, or any damage of its
scan. When the LMA is used for MRI, care should be taken to outer aspect. The cuff should be inflated with a volume of air 50%
place the LMA valve away from the coil because it generally greater than the maximum volume recommended (see Table 38–
contains a metallic spring that interferes with the quality of the 26) to check whether there is any herniation or leak either at the
image.184 Only a few companies (e.g., Medis) produce LMAs with cuff or at the valve level. The cuff should be fully deflated and, if
an MRI-compatible nonferrous valve. A reusable LMA should spontaneous re-inflation occurs, it indicates failure of the valve.
not be used for 13C spectroscopy of the head because silicone- The connection between the mask and the cuff should be inspected
containing material has a resonance similar to that of the sur- to detect any disconnection. The inside of the LMA should be
rounding tissue.185 The LMA is also useful when performing inspected to make sure it does not contain a foreign body and that
diagnostic fiberoptic examination of the larynx, trachea, and the distal bars are intact. Last, whatever the technique of insertion
bronchi. It provides effective oxygenation and ventilation while of the LMA used, only its posterior aspect should be lubricated,
providing excellent views of these structures and allowing their taking care to avoid using silicone-containing solution if the cuff is
examination under dynamic conditions if spontaneous ventilation made of silicone.
CLEANING AND STERILIZATION: Careful washing and sterilization

do not eliminate protein deposits from reusable LMAs.164 If a
single-use LMA is unavailable, the following steps should be taken
to ensure the safest possible repeated use of a reusable LMA. The
LMA is washed immediately after use with warm water and a mild
detergent. Glutaraldehyde should not be used because any residue
could cause supraglottic edema. Ethylene oxide, formaldehyde,
iodine-containing solutions, or even chlorhexidine should be
avoided because they may damage the LMA. After cleaning, the
LMA is sterilized in an autoclave at a temperature of maximum
134°C for 18 minutes. The cuff and the pilot tube should be Figure 38-17. Reusable laryngeal tube size 1 with two cuffs
completely deflated before autoclaving to prevent damage to the fully inflated.
cuff and the inflation valve.
PRACTICAL POINTS: The different techniques of insertion of drainage tube. Different sizes are available: 0 for neonates and
the different versions of the LMA in a child are described in infants less than 5 kg, 1 from 5 to 12 kg, 2 from 15 to 25 kg, and 3
Chapter 72. However, some points related to the safe use of the for small adults (<155 cm tall). The device is available as a silicone
LMA need to be emphasized. autoclavable model (LT and LTS II) or as a PVC single-use model
(LTD and LTSD).
● During insertion of the LMA, the patient should be deeply anes- The LT should be lubricated and its cuffs fully deflated before
thetized in order to avoid coughing, laryngospasm, and vomiting. insertion. It is introduced into the mouth with the flat edge of its
Whatever the technique used (standard, rotational, lateral), the in- tip placed against the hard palate. It is slid along the palate in the
sertion should be performed gently to avoid pharyngeal trauma.192 midline of the pharynx until some resistance is felt or the depth
If the LMA has to be placed in a child in whom cricoid pressure is marker on the tube is at the level of the upper teeth. The company
applied, for example, in a “cannot intubate and full stomach” situ- recommends deflating the tubes before removing the LT.
ation, cricoid pressure could hinder correct positioning of the The ventilation orifices of the pediatric LTS II are small, and a
LMA and should be temporarily relieved during its insertion. fiberoptic bronchoscope cannot be inserted through them in case
● The shaft of the LMA should not be held during inflation of the of difficult intubation. A case has nevertheless been published in
cuff because this will prevent the slight outward movement that which a flexible bronchoscope introduced nasally was passed
usually occurs at that time and could result in misplacement of alongside the LTS to intubate an infant.195 The insertion success
the LMA. This could result in a higher incidence of regurgita- rate of the LT II version (with no drainage tube) is similar to that
of the LMA, but its leak pressure is higher than that of a CLMA.196
tion because stretching of the upper esophageal sphincter by
the tip of the LMA decreases the tone of the lower esophageal
sphincter. Inflation of the cuff above 60 cmH2O should be The CobraPLA
avoided because it increases both leak pressure and morbidity.180 The CobraPLA is a cuffed, disposable, and latex-free pharyngeal
Cases of lingual edema could have been caused by prolonged sealing supraglottic airway (Figure 38–18). It is available in eight
use of an overinflated LMA obstructing the lingual venous sizes (Table 38–27) and presents three parts:
drainage.193 The position of the LMA in the middle of the mouth
1. a silicone distal part that broadens distally into the shape of the
should be secured by using two lateral bite blocks (e.g., rolled-
head of a cobra snake. It is equipped with slotted openings to
up gauze swabs). To prevent dislodgment of the LMA, it should
allow the passage of air and to keep soft tissues and the
be disconnected from the breathing circuit each time the pa-
epiglottis away from the glottic opening. This part is flatter and
tient’s position is changed, and unnecessary traction from
larger than the distal part of the cuff of an LMA.
breathing systems should be avoided. Whether the LMA should 2. A circumferential low-pressure pharyngeal at the junction of
be removed with the child fully awake or still deeply anes- the distal one fourth and the proximal three fourths of the
thetized and with the cuff inflated or deflated are matters of con-
troversy (see Chapter 58).
The Laryngeal Tube

The laryngeal tube (LT) is a short J-shaped tube equipped with
two low-pressure cuffs separated with two ventilation holes
oriented toward the laryngeal aperture (Figure 38–17). The
proximal cuff is bigger and designed to stabilize the tube in the
pharynx and to achieve proper seal. The distal cuff is smaller and
intended to block the esophageal inlet. Both cuffs are inflated via
a single inflation tube; a maximum intracuff pressure of 60 cmH2O
is recommended. Sealing pressure should be checked when the
child’s head position is modified. Neck flexion has been shown to
compromise ventilation with the LTS II.194 The latest version (LTS
II or LTS D) is longer than the first ones, has a more ovoid distal Figure 38-18. CobraPLA size 11/2 supraglottic airway with its
cuff, and is equipped with a posteriorly placed esophageal pharyngeal cuff fully inflated.
TABLE 38-27. Sizes of Pediatric CobraPLA

Max. Volume of Max. ID of Uncuffed
Patient Air Injectable TT Insertable
Size Child’s Age Weight, kg Tube ID, mm in the Cuff, mL Through CobraPLA
1
/2 Neonate 2.5–7.5 5 <8 ≤3
1 Infant 7.5–15 6 <10 ≤4.5
11/2 Child 16–30 6 <25 ≤4.5
2 Child 31–60 1.5 <40 ≤6.5
ID = inner diameter; TT = tracheal tube.
breathing tube. It is inflated with air to a cuff pressure that There are straight and curved blades; most textbooks recommend
should not exceed 40 cmH2O. using a straight blade in neonates and infants and a curved blade
3. A breathing tube, the distal part of which is curved anteriorly in children and adolescents. In theory, a straight blade is used
(toward the base of the tongue) to avoid kinking. It is larger to lift the epiglottis anteriorly to see the vocal cords and a curved
than the breathing tube of an LMA and can be connected to a blade is placed in the vallecula, anterior to the epiglottis. In
standard 15-mm ID connector. practice, however, a straight blade can be used in the same way as
a curved blade.
To insert this device, slightly extend the child’s head. Lubricate
the head and cuff of the CobraPLA. Open the mouth with the
nondominant hand and advance the CobraPLA with its cuff Description
totally deflated into the pharynx until moderate resistance is met. The Miller blade is straight with a slight curve near the tip,
Pull back slightly before inflating the cuff. The cuff should not be whereas the Wisconsin, Wis-Foregger, and Wis-Hipple blades
visible in the mouth after proper insertion. The CobraPLA have no curve at all. In cross-section, as seen from the handle
provides a higher airway seal pressure and a better endoscopic connection, they are C-shaped, which gives enough room to
view of the glottis and is more stable during anesthesia than perform oral intubation but does not always prevent the child’s
a single-use LMA.197 A new model, CobraPLAPLUS, is equipped tongue from slipping underneath the spatula. The Robertshaw
with a thermistor temperature probe on the posterolateral part of blade is curved near the tip, but its cross-section presents a
the cuff (to measure hypopharyngeal temperature) and a gas C-shape, which is extended to the left (as seen by the intubator) to
sampling line. Video assessment of the airway through the initial give more room to use a Magill forceps.
(not bent) version of the CobraPLA showed that the laryngeal Other straight blades have a reverse-Z shaped cross-section,
view was nearly or completely obstructed in 76.9% of the children which keeps the patient’s tongue away and facilitates the use a
weighing 10 kg or less. It was caused by downfolding of the epi-
Magill forceps. They are easier to use during nasotracheal intu-
glottis. The bars of the grill were apposed against the supraglottic
bation. They are the Soper (straight) and the Seward, Cardiff,200 or
structures. It is recommended to remove the CobraPLA under
Heine (curve near the tip) blades. The Macintosh blade is the only
deep anesthesia to avoid laryngospasm.198 If the glottic opening is
curved blade. In cross-section, as seen from its handle connection,
not obstructed by the epiglottis, a TT can be inserted through the
CobraPLA (see Table 38–27).197 it has a reverse-Z shape. In the improved vision modification of the
Macintosh blade, the midportion of the spatula of the blade is
concave. One disadvantage of the small Macintosh blades equipped
Uncuffed Preshaped Sealer: Igel with a light bulb is the excessive height of their connection to the
Igel, a single-use supraglottic airway, contains an airway and an handle, which is smaller in the fiberoptic curved blades.
esophageal drainage tube equipped with a noninflatable cuff made The McCoy levering laryngoscope allows mechanical
in a gel-like thermoplastic elastomer that softens when warming manipulation of the blade tip in order to improve the glottic view
to body temperature. There are no bars inside the distal part of without applying excessive force on the pharyngeal structures.
the airway tube, but a small ridge is present at the proximal end of A pediatric levering laryngoscope with a Seward blade (size 1
the bowl to prevent epiglottis downfolding. The posterior part or 2) has been introduced in practice, but it does not provide any
of the device should be well lubricated before insertion. Place the advantage over the classic Miller blade.201
child’s head in the sniffing position and introduce the device, By contrast to a fiberoptic laryngoscope, a light bulb laryn-
grasped at the level of its integral bite block, into the mouth against goscope blade can fall out during laryngoscopy202 and can reach
the hard palate until resistance is felt. Correct position is con- temperatures that could result in burns to the oropharynx.
firmed by adequate chest expansion when ventilation is assisted, It should be switched on for less than 1 minute before use or
the presence of a capnogram, absence of gastric insufflation, and its temperature should be checked with the hand before use.203
the presence of an air leak. At the time of writing, the pediatric Both the Miller and the Macintosh blades have a built-in tube
experience with this new device is limited.199 The size 3 Igel can be that allows administration of oxygen or anesthetic gases during
used in children weighing more than 30 kg. laryngoscopy and intubation: they are called oxiport versions. They
are both also available in plastic, single-use, fiberoptic versions
that are especially useful in infected cases. Their quality (flexibility,
Laryngoscopes and Blades brightness, and direction of light) varies according to the manu-
The choice of pediatric laryngoscope blades is extensive and their facturer.204 They usually make laryngoscopic view a little worse
selection is largely a matter of user preference and familiarity. than a reusable blade of the same size and shape.
TABLE 38-28. Disinfection of Airway Equipment After

Use in a Patient With Known or Suspected Prion Disease
Whenever possible, use disposable equipment, which should be
destroyed after use for reusable items:
1. Aluminum- or zinc-containing tools: chemical disinfection
with sodium hypochlorite for 1 h
2. Stainless steel tools: chemical disinfection with sodium
hydroxide 1 N for 1 h followed, in both cases, by autoclaving
at 134°C for 1 h (or two cycles of 18 min each at 134°C)
suggested that the light output should be at least 700 lux at a

distance of 20 mm for a minimum of 10 minutes, but this level of
illumination seemed too bright in a study.207
Figure 38-19. Correct way to hold the laryngoscope handle

during laryngoscopy in neonates and infants. Hold it at the level
Cleaning and Sterilization
of the hook-on connection to allow the intubator to use the little The laryngoscope blade should be considered as contaminated
finger to push on the child’s trachea and improve the vision of after use and stored away from clean surfaces to avoid contami-
the glottic aperture. nation of other items. Because laryngoscopy and insertion of any
airway device can cause mucosal abrasion and bleeding, increasing
the risk of spread of blood-borne pathogens, the reusable blades
Laryngoscope blades of different shapes and sizes should be
available before induction of anesthesia. Usually, the blade is should be washed and scrubbed between cases before undergoing
introduced at the right side of the mouth and passed on the side autoclaving (which progressively damages fiberoptic bundles), gas
of the tongue to displace it to the left and reach the vallecula. sterilization, or immersion in a disinfectant solution (e.g., 70%
A modified technique, the retromolar or paraglossal approach, alcohol solution). Although transmission of prion disease by blood
is useful in case of micrognathia. The straight blade is inserted or airway secretions is unlikely, the patient’s tonsils are a possible
source. Because of the high resistance of this infectious agent to
through the corner of the mouth, posterior to the molar teeth, and
ordinary sterilizing procedures, the use of a disposable laryngo-
directed in the groove between the tongue and the ipsilateral tonsil
scope or special sterilization techniques is recommended. Five
until the epiglottis is seen. The endotracehal is then inserted
minutes’ immersion in a potassium permanganate solution
through the ipsilateral corner of the mouth and directed into the
(8 mg/L) at 50°C to remove all protein deposits208 (Table 38–28) is
glottis with the help of external laryngeal manipulation and a stylet
suggested.209 The laryngoscope handle must be considered as
or an intubation guide.205,206 During laryngoscopy, care should be
a potential source of contamination and should be cleaned
taken to avoid crushing the child’s lip between the blade and the
between cases.
teeth and to avoid applying force on the neonate’s upper gum
because this could result in damage to future teeth. In case of cleft
lip and palate, inserting a roll of gauze into the gap in the gum Aids for Intubation
helps prevent the laryngoscope blade from slipping into it, which
prolongs laryngoscopy and could result in tissue damage. Laryn- This is equipment designed to make oral or nasal intubation easier.
goscope handles are also available in several sizes: a lightweight
narrow handle is useful in neonates and infants. In this population, Bougies or Intubation Guides
the laryngoscope should be held at the level of the hook-on Bougies or intubation guides are used as an atraumatic guide over
connection instead of at the handle itself to allow the intubator to which the TT is advanced
use his or her left little finger to push on the cricoid cartilage and
bring the glottis into view without applying too much force on the ● When the tip of the TT cannot be directed easily into the glot-
infant’s mandible (Figure 38–19) (see Chapter 86). tis during direct laryngoscopy.
● To facilitate the insertion of a Flexible LMA, but their tip
should not protrude beyond the distal extremity of the airway
Quality Control tube.
The blade is equipped with a light bulb, a fiberoptic bundle, or ● When oral intubation is difficult but an LMA has already been
LEDs that transmit light from a source in the handle. The position inserted.210
of this light should be near the tip of the blade. If it is too proximal, ● During retrograde intubation after the guidewire has been
the pharyngeal soft tissues or the distal part of the tongue can passed in the oropharynx.
come in front of it and obstruct the light. The light bulb is screwed ● When an already placed TT has to be changed in difficult
into a socket with a metallic contact. This area is subject to soiling circumstances or when mobilization of the neck has to be
and oxidation, which can affect the quality of the light; the avoided.
adequate screwing of the bulb to its socket should be verified
The following devices can be used for those purposes:
before each use. The brightness and steadiness of the light as well
as the proper contact between handle and blade should be checked ● An exchange catheter such as the Cook airway exchanger (four
before use by placing the blade in working position. It has been sizes, the smallest being usable with endotracheal tubes of
ID ≥ 3 mm), the Sheridan T.T.X., and Tracheal tube guide, both intraoral maneuvers (intubation, insertion of an oral or supr-
available in 5-French size). aglottic airway or a rigid bronchoscope), a single-use PVC
● A suction catheter. device can be inserted (e.g., Ortho Plus Junior). This will either
● A nasogastric tube can also be used for that purpose. support and protect a loose tooth or bridge the gap of an already
lost one.
The use of a hollow device allows the delivery of O2 during the
procedure and/or the measurement of CO2 to confirm its
intratracheal position before inserting the TT over it. Tracheal Topical Anesthesia of the Upper Airway
trauma is possible when using a bougie, especially in neonates and Topical application of a lidocaine solution (benzocaine should be
infants. It should be used very gently and force should never be avoided to prevent methemoglobinemia) to the larynx and trachea
applied if any resistance is met. is used before endoscopy of the upper airway or even before
routine endotracheal intubation. When deep inhalational
Stylets induction is used, this allows the evaluation of the depth of
Stylets are pliable but firm devices (usually plastic-coated metal anesthesia before intubation and reduces the incidence of
rods) used to modify the curvature of the TT and impose a laryngospasm, coughing, and bucking after intubation. Either a
predetermined shape to it. This is mandatory when using the multiuse sprayer with disposable nozzles or a needle connected to
retromolar approach or most videolaryngoscopes (Glidescope or a Luer-Lok syringe (to avoid dropping the needle into the pharynx
Airtraq). They are often used for routine intubation. The stylet or trachea) can be used. The use of a needle carries a risk of injury
should resist chipping and breaking, and its distal end should be to the oral and pharyngeal mucosa. Because its absorption from
smooth to avoid trauma to the pharyngeal and laryngeal tissues. mucosal surfaces is rapid and may lead to high blood levels, the
Before inserting the stylet into the TT, it should be well lubricated dose of lidocaine should not exceed 3 mg/kg.212
with silicone or another water-soluble lubricant and the TT
connector should be removed to make withdrawal of the stylet
easier. The stylet is inserted into the TT until its distal end is just ANESTHETIC CIRCUITS
inside the tip of the TT. Bending the stylet at the proximal end of Numerous anesthetic breathing systems are described in the
the TT or an adjustable stop should prevent the stylet from literature and large differences of practice exist around the world,
advancing past the end of the TT during the intubation procedure. based more on local habits, imprinting by initial teaching, and
The stylet and TT are bent to the desired shape, usually a “hockey- local availability of components than on scientific grounds.
stick” configuration (distal end bent sharply). The laryngeal inlet A simple and easily understandable functional classification of the
is exposed with a laryngoscope or videolaryngoscope and the breathing systems usable in children is based on the presence or
styletted TT is directed into it. The stylet should be removed as absence of a CO2 absorption device and on the direction of flow
soon as the extremity of the TT has passed the vocal cords. in the system (bidirectional vs. unidirectional)213:
Possible complications are difficult removal of the stylet after
intubation, shearing off of part of the stylet during its difficult ● The nonabsorber bidirectional circuit: Mapleson classification.
removal and subsequent TT obstruction,211 and tracheal trauma. ● The unidirectional circuits: presence of a nonrebreathing
Many brands and sizes of stylets are available that can be used in valve.
TTs as small as 2 mm ID. If reused, stylets should be washed and ● The absorber unidirectional circuit: the “circle” system.
scrubbed between cases before undergoing autoclaving, gas
sterilization, or immersion in a disinfectant solution. A detailed description of all these circuits can be found in
Understanding Anesthesia Equipment (5th edition by Dorsch JA &
Dorsch SE, published by Wolters Kluwer, Lippincott, Williams &
Forceps Wilkins 2008).
The Magill forceps can be used to guide a TT in the trachea or a
nasogastric tube in the esophagus, to pull out the patient’s tongue,
or to retrieve foreign objects from the pharynx or larynx. During Nonabsorber Bidirectional Circuits
endotracheal intubation, the forceps is used to place the distal part (e.g., Mapleson’s Circuits)
of the TT between the arytenoids. It should not be used to further The Mapleson circuits were invented to reduce deadspace and
advance the TT into the trachea because the “feel” of the force work of breathing. These circuits have no unidirectional valves
applied to it is less precise and forceful insertion could result in
and no CO2 absorber, but a high FGF is needed to flush the
laryngeal trauma. Care should also be taken to avoid traumatizing
expired CO2 out of the circuit and avoid rebreathing. They
the uvula when picking up the TT or a nasogastric tube in the
are listed from A to F (Figure 38–20) in order of increased
nasopharynx. When intubating with a cuffed TT, care should be
requirement of FGF to prevent rebreathing during spontaneous
taken to avoid picking it up at the cuff level because this could
ventilation and described according to the place of the reservoir
result in cuff damage. The Magill forceps is available in a small
size to be used in neonates and infants. bag and of an adjustable pressure-limiting (APL) valve. The major
The Magill forceps should be cleaned in the same way as the advantages of these circuits are a low compression volume and
laryngoscope blade. allowance of rapid changes in the inspired gas concentration.
Their common drawbacks are loss of heat and humidity, waste of
anesthetic gases, and difficult scavenging, leading to increased
Teeth Protector pollution of the working environment. They are mainly used for
The presence of loose deciduous teeth is not uncommon in induction and emergence of anesthesia, but also for transport, in
children 4 to 11 years old. To prevent their dislodgment during neonates and small infants.
Mapleson C
In the Mapleson C circuit, there is almost no corrugated tubing
between the FGF inlet and the reservoir bag (see Figure 38–20C).
This allows complete mixing of FGF and exhaled gases during
expiration. An FGF of three times the patient’s minute ventilation
is necessary to prevent rebreathing.
Reusable systems are commercially available that combine an
FGF inlet and an APL valve connected to a scavenging tubing.
These systems, which can be used in the Mapleson B or C configu-
ration, are cumbersome to use during surgery and carry a risk of
reverse connection of the FGF and scavenging tubing.
Mapleson D, E, and F
In the Mapleson D circuit, the FGF inlet is close to the patient’s
Figure 38-20. Mapleson’s classification of nonabsorber bidirec-
airway and the APL valve is placed just before the reservoir bag
tional breathing systems: A = Magill circuit; A’ = coaxial version
of Lack circuit; A” = parallel version of Lack circuit; D’ = coaxial (see Figure 38–20D). It also exists in a coaxial version, the Bain
version of D = Bain circuit; E = Ayre’s T-piece; F = Jackson-Rees circuit (see Figure 38–20D’), in which the FGF supply runs inside
modification of Ayre’s T piece; F’ = Kuhn’s circuit (lateral hole in the corrugated tubing through which expired gases are eliminated.
the reservoir bag). This is supposed to allow heating of FGF. The major drawback
Adapted from Cazalaà JB, Murat I, Servin F, et al. Pour ou contre of this coaxial circuit is that major rebreathing occurs if the
les circuits anesthésiques accessoires: arguments pour leur utili- inspiratory tubing disconnects or cracks within the expiratory
sation. Ann Fr Anesth Réanim 1998;17:372–384, with permission limb, which can be difficult to detect during the preanesthetic
of the authors and publishers. check. The Mapleson E circuit is the Ayre’s T-piece, in which
neither a reservoir bag nor an APL valve is present. The Mapleson
F circuit is the Jackson-Rees’ modification of Ayre’s T-piece; a
Mapleson A double-ended reservoir bag is added to the end of the reservoir
In the Mapleson A (or Magill) circuit, FGF enters the circuit near limb. To control ventilation manually, the open end of the
the reservoir bag and the APL valve is placed close to the patient’s reservoir can be squeezed between two fingers or partially closed
face. This system is very efficient during spontaneous ventilation, with a tap. Another version, Kuhn’s circuit (see Figure 38–20F’), is
because the FGF needs to be only 0.7 to 1.0 times the patient’s available in Western Europe. The reservoir bag has no open end
minute ventilation (~150 mL/kg/min in children) to avoid but a lateral hole that can be occluded with one finger to control
rebreathing. It is less efficient in case of rapid respiratory rate (such ventilation. In fact, the Mapleson D, E, and F circuits are func-
as in small children) because the end-expiratory pause that allows tionally the same because the same factors influence the gas
the elimination of the alveolar gas that has entered the tubing content of the expired limb and, thus, of the inspired gas mixture
during exhalation becomes too short. It is even less efficient during of the subsequent inspiration. They are
controlled ventilation, because an FGF of two or more times the 1. The patient’s CO2 production, which is related to both body
patient’s minute ventilation is necessary to avoid rebreathing. size and metabolic status (body temperature, catabolism).
Close proximity of the APL valve to the patient’s face is incon- 2. The capacity of the reservoir limb. Its volume should be greater
venient during surgery. A version of the Mapleson A circuit exists than the patient’s tidal volume to avoid entrainment of air
in which the APL valve is away from the patient’s face. It is called during inspiration if FGF is low. If a reservoir bag is present,
the Lack circuit and exists in coaxial and parallel versions (see its volume should be similar to the child’s vital capacity (i.e.,
Figure 38–20A’ and A”). The Magill circuit should not be used 0.5 L in neonates, 1 L in infants, and 2 L in children).
in children less than 20 kg because of the important appa- 3. The respiratory rate. If the expiratory pause is too short, such
ratus deadspace (40 mL without the facemask). The Lack and as during rapid ventilation, time is insufficient for FGF to flush
Humphrey A Hybrid Systems circuits deliver FGF much closer to alveolar gas out of the reservoir limb, unless FGF is increased.
the patient’s airway and are therefore more efficient (deadspace of 4. The VT. If the VT increases, the volume of alveolar gas filling
apparatus 1.8 mL). the reservoir limb increases. Therefore, if the FGF or the
expiratory pause is insufficient to flush it, rebreathing will
Mapleson B occur and PaCO2 may not change, although minute ventilation
increases.
The FGF enters the circuit close to the patient, just distal to the 5. The FGF. As soon as FGF is sufficient to flush alveolar gas from
APL valve (see Figure 38–20B). During expiration, both FGF and the reservoir limb, any further increase in FGF does not change
exhaled gases accumulate in the reservoir tubing and bag to the PaCO2. Conversely, if FGF is too low, rebreathing increases
point at which the pressure in the circuit is sufficient to open the with respiratory rate and PaCO2 remains stable despite
APL valve. The patient inhales FGF and a mixture of retained FGF increased minute ventilation. Different formulas have been
and exhaled gases. FGF greater than twice the patient’s minute recommended for FGF and minute ventilation when using
volume is necessary to reduce rebreathing to acceptable levels Mapleson D, E, or F circuits for spontaneous or controlled
during both spontaneous and controlled ventilation. It is seldom ventilation in children. However, whatever the formula used,
used today. the safest and most accurate means to determine the FGF and
minute ventilation requirements is to continuously monitor children larger than 8 kg.218 It is very efficient during spontaneous
PETCO2,214 bearing in mind the limitations described in ventilation in the A mode and allows an FGF of 3 L/min to be used
“Capnography,” earlier. with no rebreathing in children less than 25 kg. During controlled
ventilation in the E mode, it behaves similar to a T-piece circuit.
For spontaneous ventilation:
Despite its advantages, this system has not gained much popularity
FGF (mL/min) = 15 × weight (kg) × in pediatric anesthesia.
respiratory rate (breaths/min)
e.g.: 10 kg ⇒ FGF is 4500 mL/min if RR is 30 breaths/min Nonabsorber Unidirectional Circuits
FGF (mL/min) = 2.5 to 3 times the child’s theoretical (Nonrebreathing Valves)
minute ventilation These breathing systems are those in which the inspired and
(~150 mL/kg/min) expired gases are completely separated by a nonrebreathing (one-
way) valve. The expired gases are directly eliminated to the
For controlled ventilation: atmosphere. Various valves are available that can be used for that
FGF (mL/min) = 1000 + (200 × weight in kg)215 purpose: for example, the Ruben valve, the Ambu valve, the
Laerdal valve, and the Digby-Leigh valve. The valve is inserted
if a VT of 10 mL/kg and a respiratory rate of 20 breaths/min between the patient and the reservoir bag into which the FGF inlet
are chosen and the expiratory limb of the T-piece is connected to is connected. Controlled ventilation is achieved either by
a Nuffield Ventilator 200 with a Newton valve occluding the expiratory port of the valve (Digby-Leigh) or by
e.g.: 10 kg ⇒ FGF is 3000 mL/min squeezing the reservoir bag (Ruben, Ambu). These valves may also
be used with a self-inflating reservoir bag for resuscitation or
FGF (mL/min) = 250 mL/kg/min transport, for the administration of 50% N2O in O2 (Entonox,
If a PETCO2 of 38 mmHg is aimed at and the expiratory limb of Kalinox) for conscious sedation, or as part of a draw-over circuit
a Mapleson F circuit is connected to a Sechrist ventilator (expired (see Chapter 56). Because there is no mixing of inspired and
VT of 10–15 mL/kg, I:E ratio of 1:2, PIP 15–25 mmHg)214 expired gases, the exact composition of the inspiratory gases
is known but FGF needs to be much greater than the patient’s
e.g.: 10 kg ⇒ FGF is 2500 mL/min minute ventilation to keep the reservoir bag filled during both
FGF (mL/min) = 1000 mL/min + 100 mL/kg/min216 spontaneous and controlled ventilation. This results in loss of heat
and humidification and in a waste of anesthetic gases. Although
and minute ventilation is set at twice the FGF the nonrebreathing valves used have a low resistance, they increase
e.g.: 10 kg ⇒ FGF is 2000 mL/min and apparatus deadspace (e.g., 7 mL, 9 mL, and 0.8 mL for the Digby-
minute ventilation is 4000 mL/min Leigh, Ruben, and Ambu Paedi valves, respectively), which
can result in significant hypercarbia in spontaneously breathing
The D, E, and F circuits are more efficient during controlled small infants. The risks associated with the use of nonrebreathing
than during spontaneous ventilation. The shape of the FGF inlet, valves are219
the T-piece, is important, especially for neonates and infants. If it
is at an angle pointing toward the patient rather than at right ● Bad connection or misassembly after cleaning. They should be
angles to the inspiratory and expiratory limbs, it provides some checked before each use.
continuous positive airway pressure (CPAP) during expiration, ● Overdistention of the reservoir bag, causing barotrauma, if the
which could be beneficial in reducing the fall in functional valve becomes blocked by moisture or if FGF is too high.
residual capacity during anesthesia. The good functioning of these ● Hypoventilation and rebreathing in case of malfunction of the
breathing systems (especially the expiratory valve) should be valve. The easiest way to check the good functioning of a non-
checked before each use, and care should be taken to avoid any rebreathing valve before use is to breathe oneself through it
obstruction of the expiratory limb because this may cause while wearing a mask or through a bacterial filter.
barotrauma.217
Absorber Unidirectional Circuits (Circle)

Hybrid Systems
Some hybrid breathing systems have been proposed as the Description
universal breathing system because they incorporate the features The circle circuit incorporates unidirectional valves, a CO2
of the Mapleson A, D, and E circuits. The most recent is the absorber, an FGF inlet, a reservoir bag, an APL valve, and a
Humphrey ADE circuit. It consists of a manifold that has to be Y-piece to connect its inspiratory and expiratory limbs to the
connected to the FGF outlet of the anesthesia machine. A lever patient. All those components are part of the modern ventilators.
switch rotates a cylinder within the manifold and converts Although all these components increase the volume of the circuit,
the system from the A (Lack version) to the D/E mode. The its resistance during spontaneous ventilation, and the risk of leaks,
Humphrey system can be used for spontaneous ventilation in the circle systems are increasingly used in pediatric anesthesia in order
A mode (lever up) and for controlled ventilation in the D/E mode to decrease operating room pollution, because scavenging is easy;
(lever down) and is connected to a mechanical “bag-squeezer” minimize loss of heat and water through the respiratory system;
ventilator. It is easy to scavenge from the manifold. A version reduce the consumption of anesthetic vapors by using less FGF;
supplied with 15 mm smooth-bore nonkinking breathing hose and standardize the equipment used by pediatric and adult
and a low-resistance special APL valve has been evaluated in anesthesiologists.
Although the circle system is usually presented with two parallel concentrations of CO and a significant rise in absorbent
limbs joining at the Y-piece, coaxial versions have also been temperature. Those with calcium hydroxide-based CO2
designed (Universal F or PedF2, especially for children 3–0 kg, absorbents such as Amsorb do not produce CO. The anesthetic
Mera F)220 in which the inspiratory gases are delivered through the agent used may, at equipotent concentrations, show a dif-
inner tubing. As with any coaxial circuit, care should be taken to ferent degree of degradation and production of CO. Desflurane
avoid kinking or obstruction of the inner tube, reverse attachment and enflurane produce more CO than isoflurane, whereas
of the inspiratory and expiratory limbs to the absorber, and halothane and sevoflurane produce negligible amounts. The
displacement of the inner tube into the outer one, which results in higher the absorbent temperature, the greater the production
increased deadspace. Another breathing circuit that can be adapted of CO.
to a circle system is the Limb-θ. It is made of one corrugated tube, 3. Compounds A and B are produced when sevoflurane passes
22 mm in diameter, with a septum extruded down its middle sepa- through soda lime. Compound A is a known nephrotoxic agent
rating the inspiratory from the expiratory passage. Its compliance in rats, but its toxic threshold in human beings is not known.
and its expiratory resistance are less than with the Universal F2 The use of low-flow sevoflurane anesthesia (FGF 600 mL/min),
coaxial circuit; it can be used in children down to 5 kg body weight. with soda lime as CO2 absorbent, is safe in healthy pediatric
Stand-alone disposable circle circuits are available at present patients because the mean highest concentration of compound
(Universal F, PedF2, Clear Flo Circle) that can be connected to the A obtained after up to 7 hours of anesthesia is only 12.2 ±
inspiratory outflow of the anesthesia machine or used during 3.8 ppm.222 The calcium hydroxide-based CO2 absorbent
transport or in remote locations anesthesia. (Amsorb) produces no compound A when in contact with
volatile anesthetic agents. The exhaustion of the absorbent is
indicated by the color change of the indicator added to it.
Quality Control
However, the color may revert back to its pre-exhaustion status
The adequate functioning of the unidirectional valves is if the absorbent is left to stand for a few hours because
mandatory when using a circle system. The presence of moisture, exchange of hydroxide ions coming from the inside of the
electrostatic charges, or foreign material can impair normal absorber occurs. The color of an already used absorber is not
seating of the disk of the valve and allow reverse flow through it. a reliable index of its efficacy except if Amsorb is in use.
For example:
For all these reasons, it is safer to use an absorber with no KOH.
● An expiratory valve that does not close properly at the end of ex-
halation causes reverse flow in the expiratory limb during in-
spiration and thus rebreathing, which can be detected by Circle Circuit for Spontaneous Ventilation
capnography. Pediatric circle circuits (i.e., made of 15-mm diameter tubings
● A leaking inspiratory valve allows reverse flow in the inspira- connected to a standard adult CO2 absorber) have been shown to
tory limb during exhalation and rebreathing during the begin- be efficient for spontaneously breathing infants and children.223
ning of the next inspiration, which is difficult to detect. These studies were done with equipment less efficient than
● An inspiratory valve that does not open easily increases the currently available and their results are difficult to compare. In
child’s work of breathing and can result in the absence of venti- brief, expiratory resistance increases with FGF in both systems.
lation if it remains stuck in the closed position. This should be borne in mind during inhalational induction of
● If the expiratory valve is stuck in the closed position, exhalation anesthesia, when a high FGF is used in the circle circuit to increase
is impossible, leading to lung overinflation and barotrauma. the uptake of volatile anesthetics. When using an FGF of 6 L/min,
the Jackson-Rees circuit is more efficient in terms of work of
The circuit should be checked carefully for leaks and for correct breathing than the pediatric circle circuit, which is more efficient
functioning of its unidirectional valves before use. A simple way to than the coaxial Mera F circuit (Table 38–29).220 However, the use
check the valves is to breathe while wearing a mask through the of higher than usual FGF in both circle circuits might have
circuit or through each limb of it separately and to observe the influenced the observed differences. In conclusion, there is no
movement of the valves and the reservoir bag during inhalation great problem letting an infant or child breathe spontaneously
and exhalation. through a circle system for a limited period of time, except perhaps
for the coaxial version that increases the work of breathing.
The CO2 Absorber
Although often considered as an “inert” part of the circle circuit, Circle Circuit for Controlled Ventilation:
the absorbent used to remove the CO2 from the re-inhaled gases The Compression Volume Issue
has possible interactions with the volatile anesthetic used.221 During positive-pressure ventilation, whether mechanical or
1. the CO2 absorbent can absorb the volatile anesthetic at the manual, with a circle system, pressure increases within the circuit
beginning of inhalational induction. This occurs when the and leads to important changes to its gas content.224 A reduction
absorbent is very dry, the absorber is placed between the FGF in ventilation actually delivered to the patient may result from
inlet and the patient, and FGF is low. This can result in a slow ● Compression of the gas in the circuit, which is directly related
inhalation induction.
to the volume of the circuit, is called the compression volume.
2. Carbon monoxide (CO) can be produced from the degradation ● Distention of the breathing circuit itself, which is influenced by
of volatile anesthetics by the CO2 absorbent. The importance of
the material of the tubing, is called the compliance volume.
CO production depends upon the type of absorbent, that
is, those containing high amounts of potassium hydroxide These volumes are usually combined and called compression
(KOH) and or lye (NaOH) can produce clinically important volume. This lost volume of ventilation, which does not enter or
TABLE 38-29. Comparison of the Jackson-Rees circuit, the Pediatric Circle Circuit, and the MERA F Coaxial Breathing
System in Spontaneously Breathing Childrena
Criterion Jackson-Rees Pediatric Circle MERA F
Minute ventilation 226 ± 50 mL/kg 213 ± 58 239 ± 70
Respiratory rate (breaths/min) 39 ± 9 39 ± 9 39 ± 8
Inspired airway resistance (cmH2O/L/s) 27.7 ± 10.4 31.8 ± 10.5b 30.5 ± 8.4c
Expired airway resistance (cmH2O/L/s) 14.8 ± 6.0 23.0 ± 6.6b 22.6 ± 6.1c
Work of breathing (J/L) 0.48 ± 0.16 0.52 ± 0.14b 0.56 ± 0.16b,c
PaCO2 (mmHg) 35.0 ± 3.5 42.9 ± 5.9b 42.1 ± 3.7b
PaCO2 = arterial carbon dioxide pressure; sd = standard deviation.
a
Values are mean ± sd.
b
P < .05 vs Jackson-Rees Circuit.
c
P < .05 vs pediatric circle.
leave the patient’s airway, is a function of airway pressures and may illustrated clinically in infants with normally compliant lungs who
be quite large. Its effects are comparatively more important in were adequately ventilated using an Ohmeda 7800 ventilator, the
small patients. For example, VT being set to provide appropriate chest expansion and PIP.226
The safe use of circle circuits with a large compression volume is
● To deliver a 10-mL/kg VT to a 5-kg infant with a PIP of
easier and safer with modern ventilators that measure their own
18 cmH2O using an adult circle circuit with adult bellows
total compliance during their pressure test and have a system of
(compression volume 4 mL/cmH2O), 122 mL will have to be de-
continuous compensation of compression losses and changes in
livered within the circuit (72 mL for the circuit + 50 mL for the
FGF. Last, whenever possible, small-bore noncompliant tubing
patient),
and a small reservoir bag should be used when using a circle
● Conversely, if a low-compliance pediatric circle circuit (com-
circuit for controlled ventilation in small infants.
pression volume 0.7 mL/cmH2O) is used; only 63 mL will have
The majority of children can be anesthetized using a standard
to be delivered within the circuit (13 mL for the circuit only).
adult circle circuit, with modification of the size of the reservoir
● If the child weighs 20 kg, 272 mL and 213 mL will have to be bag and, if possible, of the connecting tubing in order to reduce as
delivered within the adult and pediatric circuits, respectively. much as possible the volume of the circuit. Even a neonate can be
The compression volume of a circuit can be estimated as anesthetized with an adult circle system provided the anesthe-
follows: siologist understands how its PV characteristics (compression
volume) alter the clinical estimation of the adequacy of ventilation,
1. occlude the patient’s end of the circuit and fill the reservoir bag ventilation is controlled, and adequate monitoring (PETCO2, SpO2,
with some fresh gas. and PIP) is used.
2. Stop the FGF and compress of the reservoir bag up to a
predetermined pressure (e.g., 20 cmH2O).
3. Release the reservoir bag and measure the volume of gas Scavenging227
displaced within the circuit with a spirometer connected on the Occupational exposure to waste anesthetic gases is more impor-
expiratory limb of the circle circuit. tant during pediatric anesthesia than in adults because of the
4. Divide the volume so measured by the predetermined pressure frequent use of mask or steal induction, uncuffed TTs, supraglottic
obtained. It gives the compliance of the breathing system. airways, and breathing systems requiring high FGF and that are
Usual values are 0.78, 0.74, 2, and 1.6 mL/cmH2O for the difficult to scavenge.228 Effective scavenging of excess gases, non-
pediatric circle, pediatric coaxial, adult circle, and adult recirculating air-conditioning, and the use of low-flow anesthesia
coaxial systems, respectively, but values up to 5 mL/cmH2O are can reduce pollution.
considered acceptable with the ventilators that compensate for The optimal scavenging system is made of five components:
circuit compliance.
● A gas collecting assembly: a 30- or 19-mm connection to the
In an in vitro study, the Mapleson D circuits had the smallest APL valve of the breathing system or to the ventilator pressure
compression volume and were more efficient than all the circle relief valve.
circuits tested.224 The addition of a humidifier to any circle system ● A transfer tubing: a wide-bore, kink-resistant tubing that can be
(pediatric or adult, rubber or plastic) increased their compression easily disconnected in case of malfunction and that should be as
volume further. More recent studies have been performed to better short as possible to avoid it being crushed by the wheels of the
understand which ventilator setup parameters are required when anesthesia machine.
using an adult circle system during infant anesthesia.225 They ● An interface that acts as a reservoir to accommodate for changes
demonstrated that, when an adult circle is used for controlled in flow rate and to prevent pressure changes in the scavenging
ventilation in infants and small children, the PIP achieved, system from being transmitted into the breathing system.
the respiratory rate chosen, and the compliance of the infant’s It contains either pressure-relief valves (“closed interface”) or a
lungs are the main determinants of the ventilation delivered. system allowing escape of excess gases in case of overpressure
But in infants with poorly compliant lungs, a very high PIP may and air entrainment in case of excessive negative pressure (“open
be needed to provide an adequate VT. This concept has been interface”).
● A gas disposal tubing. and the circuit. Although disposable breathing circuits are avail-
● A gas disposal assembly that is either passive (pressure is raised able, their cost is high. The best way to achieve a more cost-
above atmospheric by the patient’s expiratory flow or by the ven- effective acceptable standard of hygiene with breathing systems is
tilator) or active (suction from the hospital vacuum system gen- a subject of research.
erates a small negative pressure in the tubing). The filters currently available are classified into two groups. The
pleated hydrophobic filters are made of an extremely compact fiber
An absorption system made of activated charcoal stored in
matrix membrane with very small pores. Resistance to airflow is
special canisters can be used instead of the gas disposal assembly
significant but is compensated for by pleating that increases the
in nonventilated remote locations. This system is expensive, does
exchange surface. The electrostatic or “electret” filters have a small
not absorb N2O, and is effective for only a limited period of time.
flat surface and incorporate a feltlike material with a high polarity.
Nonrecirculating air-conditioning is another way to reduce
Their network of fibers is less dense and they have a greater pore
personnel exposure to waste gases. A frequency of air change of
size. The use of filters is controversial in pediatric anesthesia
20 cycles/h reduces high concentrations of anesthetic vapors in
because they tend to have a poorer filtration performance than
10 minutes. Some devices have been designed to scavenge the
filters used for adults. They increase work of breathing by adding
pediatric breathing systems, especially during facemask induction.
deadspace and resistance to flow. The ideal pediatric breathing
For example, scavenging around the facemask with a double
filter should have a good filtration performance, a low-pressure
facemask (Medicvent) is designed to evacuate gases leaking
drop when gases flow through it, and a small internal volume. In
around the silicone inner mask through a slot between it and a
vitro studies have shown that
rigid plastic outer mask.229 The inner mask is connected to any
breathing system, whereas the gas escaping between the two masks ● The filtration performance of pleated filters is generally better
is evacuated through a housing connected to a fan unit that but pressure drop across them is greater.
aspirates 25 to 40 L/min. The same coupling housing could also be ● The greater the gas flow through the filter, the more particles
connected to an uncuffed TT to scavenge gas escaping around it. pass through it. This can be a concern because flow can be
Another system to scavenge gases around an uncuffed TT is to greater than 15 L/min during cough.235
place a gas-impermeable plastic bag around the child’s face. Its ● Desflurane reduces the filtration performance of some filters
exhaust port is connected to a vacuum source via multiperforated when administered at 2 minimum alveolar concentration
suction tubing placed inside into this flexible hood.227 (MAC) during at least 1 hour.236
In fact, scavenging of waste anesthetic gases is rather easy
The solutions usable for each type of breathing circuit are
as soon as an APL valve is present in the breathing circuit, as in
described hereafter.
the circle, Mapleson A, B, C, and D systems. The 19- or 30-mm
collecting assembly system can be connected to it. However, this
often makes the Mapleson A, B, C, and D systems more awkward Bacterial/Viral Precautions When Using a
to use. Many home-made systems have been designed to scavenge Nonabsorber Bidirectional Circuit (Mapleson)
the Mapleson F system in which no APL valve is present. For ● Use a disposable breathing system for each patient.
example, ● Wash-disinfection (pasteurization) of a reusable circuit after
● Scavenging through the reservoir limb. A second T-piece is each use. The treated equipment must be dried and packaged,
placed proximal to the reservoir bag and is connected to a large and its adequate functioning should be rechecked before use
tubing leading the expired gases to a control valve on the anes- ● Insert a filter at the circuit connector. This increases resistance
thesia machine and so to the collecting system.230 in the inspiratory limb and diverts some FGF into the expiratory
● Scavenging at the bag level. For example, different valves to be limb. In the presence of a filter, the FGF actually delivered
fixed at the open tail of the bag,231,232 a silicone tail placed through the inspiratory limb of a T-piece in which the FGF inlet
through the end of the bag,233 and a big bag enclosing the reser- is at right angles to the inspiratory and expiratory limbs is ± 50%
voir bag.234 less than the total FGF dialed on the rotameters.237 Once a tight
fit with the facemask is achieved, the child’s inspiratory effort
Unfortunately, all these devices make the Mapleson F system can inhale gas from the expiratory limb, but this is obviously
more awkward to use and can result in overinflation of the not possible for neonates and infants. If a filter has to be used,
reservoir bag, and barotrauma, if the outflow becomes obstructed. these authors recommend closing the open tail of the Mapleson
Even when appropriate equipment is used, scavenging is difficult F circuit as long as no tight fit with the facemask is obtained, in
during mask induction in children. Chronic exposure of the order to direct all the FGF to the inspiratory limb. In children in
personnel to sevoflurane in excess of 2 ppm is important, espe- whom the trachea is intubated, weighing 3 to 8 kg, adding a dry
cially when working outside the operating room, in a poorly 12-mL HME between the TT and a Mapleson D circuit in-
ventilated postanesthesia care unit (PACU) or when performing creased their work of breathing by a median of 43% (95% con-
facemask induction or rigid bronchoscopy.228 fidence interval [CI] 25–138%).238 This should be kept in mind
when anesthetizing spontaneously breathing infants.
Cleaning and Disinfection
Breathing systems can become contaminated and act as a reservoir Bacterial/Viral Precautions When
for a wide variety of infectious agents. Possible solutions to prevent Using a Nonabsorber Unidirectional
patient cross-contamination are complete replacement of the Circuit (Nonrebreathing Valves)
breathing circuit between cases or introducing a mechanical The whole circuit (including the valve) should be disinfected
barrier such as a bacterial/viral filter between the patient’s airway except if a filter has been placed on the TT or mask connector
(which is not recommended in case of spontaneous breathing ● A self-inflating bag that is expanded in the resting state and con-
because it increases deadspace and resistance to breathing). tains a bag refill valve.
● A fresh gas inlet for O2, with or without a reservoir at one end.
● A nonrebreathing valve (Ambu, Ruben, Laerdal) at the
Bacterial/Viral Precautions When Using an
patient end.
Absorber Unidirectional Circuit (Circle)
● Use a disposable circuit. These manual resuscitators should always be used with a
● Place a filter either at the Y-piece connection or on both the inlet reservoir, which is either long tubing or a large-capacity bag, because
and the outlet valves of the circle. The outlet filter also prevents it stores O2 that cannot enter the self-inflating bag during its
soda lime dust from entering the circuit. The parts of the cir- compression and provides a greater FIO2 during the next filling cycle.
cuit that are placed between the bacterial filter and the patient If a reservoir bag is used, it should be equipped with an overpressure
should be disposable or disinfected between cases. It should be and an entrainment valve to avoid both barotrauma (excessive O2
kept in mind that, in a clinical study, 9% of filters were contam- supply, inspiratory jamming of the nonrebreathing valve) and
inated on the machine side after use. The breathing circuit collapse of the bag (interruption of O2 supply). Many pediatric
should be changed if there were episodes of coughing while the manual resuscitators are also equipped with an overpressure safety
filter was in use.239 valve fitted on the nonrebreathing valve. This safety valve has an
opening pressure at 30 or 45 cmH2O, but it can be overridden by
placing a finger on it when higher inflation pressures are needed.
VENTILATORS Care must be taken not to use these resuscitators in a spontaneously
breathing child, because they increase deadspace and because the
Only the working principles of the different types of ventilators inspired gas may come from the exhalation port as well as from the
available at present and the essential points that need to be under- self-inflating bag, depending on the design of the nonrebreathing
stood when using them in pediatric patients are described here- valve and on the relative resistance of its inspiratory and expiratory
after. For more details, the reader is invited to consult specialized limbs. The proper functioning of the bag and the nonrebreathing
textbooks (e.g., Al-Shaikh B, Stacey S. Essentials of Anaesthetic valve should be carefully checked every day in the morning and
Equipment. 3rd edition, Churchill Livingstone/Elsevier; 2007; or before use.219 The whole manual resuscitator should be carefully
Dorsch JA, Dorsch SE: Understanding Anesthesia Equipment, 5th disinfected after each use.
ed. Baltimore, Wolters Kluwer and Lippincott Williams & Wilkins;
2008) and the instruction manual of the ventilator(s) in use in your
hospital. The principles and modes of mechanical ventilation are Mechanical Ventilators
described in Chapter 42. The ideal properties of the pediatric
Many classifications of the mechanical ventilators have been
anesthesia ventilator are summarized in Table 38–30.
proposed. In pediatric anesthesia, the two main working principles
used are (1) the intermittent occlusion of the expiratory limb of a
Manual Resuscitators (Self-inflating Bag) T-piece: the “mechanical thumb” and (2) squeezing the reservoir
bag, the “mechanical or pneumatic bag squeezer.” The latter is
Manual resuscitators are used for patient transport, for emergency more frequently used.
resuscitation, or as a part of draw-over anesthesia. A manual
resuscitator should be immediately available in every place where
anesthesia is administered to allow emergency ventilation in case Mechanical Thumbs
of failure of the breathing system, accidental intravascular The most popular ventilators of this type are the Sechrist, Babylog,
injection of local anesthetics in awaken patients, and other and Bear Cub. The ventilator is connected to the expiratory limb
situations. They have three components: of the T-piece and the FGF enters the anesthesia breathing system
at the usual place. Cycling of the intermittent occlusion of the
expiratory limb of the T-piece is determined by the settings of the
TABLE 38-30. Ideal Properties of a Pediatric ventilator control panel, which adjusts PIP, respiratory rate, I:E
Anesthesia Ventilator ratio, and PEEP. In some cases (e.g., Sechrist 100 and 200), the
1. Easy and quick change-over to manual ventilation. FGF coming from the anesthesia machine can be connected
2. Ability to deliver tidal volumes ranging from 20 to 500 mL directly to the inspiratory limb of the ventilator in place of the
in the volume or pressure-controlled mode. air/O2 mixture as when used in intensive care. Because the FGF is
3. Ability to deliver respiratory rates ranging from 10 to diverted to the infant’s/child’s lung, it must be equal to the
60 breaths/min. inspiratory flow rate. The calculation of FGF is described in
4. Ability to deliver PEEP. “Mapleson D, E, and F,” earlier. This results in very high FGF
5. Ability to provide pressure-support ventilation. requirements in large patients; this mode of ventilation is usually
6. Adjustable I:E ratio. restricted to children less than 20 kg.
7. Ability to deliver an air/O2 mixture. A similar ventilation system is very popular in the United
8. Accurate pressure and volume monitoring and alarms. Kingdom and among UK-trained pediatric anesthesiologists. It is
9. Compensation of the compression volume of the breathing the Penlon Nuffield 200 ventilator connected to the expiratory
circuit. limb of a T-piece via the Newton valve.240 This valve has four ports:
10. Interruption or buffering of FGF during inspiration. ● An input port, connected to the outlet of the low-compliance
FGF = fresh gas flow; I:E ratio = inspired-to-expired ratio; PEEP = positive ventilator. Inspiratory time, expiratory time, and flow rate are
end-expiratory pressure. determined on the ventilator control panel.
● A fixed-orifice gas outlet. alarm and could result in the patient being not ventilated, un-
● A patient port, connected to the expiratory limb of the T-piece derventilated, or ventilated with a mixture of circuit gas and en-
in place of the reservoir bag. trained room air. However, it is important to mention that the
● A safety pressure relief valve set at 40 cmH2O. “falling bellows” is also an early warning sign of disconnection.
The FGF is set as recommended for controlled ventilation with The mechanical bag squeezers use a motor or a piston to
a T-piece (see “Mapleson D, E, and F,” earlier). The system actually mobilize the bellows. These ventilators usually have a lower
functions as a partial thumb occluder if the ventilator gas flow is compliance than the pneumatic bag squeezers and, thus, more
lower than FGF, as a thumb occluder if ventilator gas flow is equal accurately deliver very small VTs. Most of these anesthesia venti-
to FGF and as a bag squeezer if ventilator gas flow exceeds FGF. In lators use the portion of FGF coming into the breathing circuit
order to avoid dilution of the inspired anesthetic gases by the when the inspiratory valve is open and add it to the VT delivered
ventilator driving gas (usually O2), the ventilator circuit deadspace by the ventilator bellows. Changes in FGF may modify the
(i.e., volume of tubing interposed between the patient port of the delivered VT even if no change is made to the ventilator settings.241
valve and the expired limb of the T-piece + internal volume of the This may have serious consequences in small patients. For example,
last) should be at least equal to the delivered VT. The pressure- if the ventilator is set to provide a 2-L/min minute ventilation with
limited nature of the ventilation provided by these “mechanical an I:E ratio of 1:2 and an FGF of 6 L/min, the child actually receives
thumbs” is potentially dangerous in the operating room where a VE of 2 L/min + 1/3 6 L/min = 4 L/min. If the FGF is reduced to
events may lead to a fall in VT or even in the absence of ventilation 2 L/min, the child receives a VE of 2 L/min + 1/3 2 L/min = 2.7
without any changes in the ventilator display unless volume and L/min, that is, a reduction of 32% of delivered minute ventilation
pressure alarms are added close to the patient. These events are (VE)! Careful monitoring of oxygenation, ventilation, and PIP, and
adaptation of the ventilator settings, is mandatory when FGF is
● Brisk intraoperative changes in lung compliance caused by re- altered in order to avoid both hypo- and hyperventilation. This
tractors, the surgeon leaning on the infant’s thorax, pneumoth- effect of FGF on delivered VT is no longer present in modern
orax, bronchospasm, and other factors. ventilators in which changes in FGF are electronically compensated
● Kinking or blockade of the TT. by its interruption or storage in a reservoir bag during inspiration.
● Obstruction of the expiratory limb of the T-piece. For example, when using the Ohmeda 7900 ventilator, inspired and
● Disconnection of the anesthesia system or interruption of FGF. expired minute ventilation as well as PETCO2 are not affected by
Continuous monitoring of ventilation (chest movement, changes in FGF from 1.5 to 6 L/min.242
stethoscope, PETCO2, and SpO2) is mandatory. As far as cleaning All these ventilators are equipped with pressure and volume
and disinfection is concerned, only the T-piece, its expiratory limb, alarms. However, it is very important to correlate the monitor
and the connection to the ventilator (e.g., the Newton valve) have information with the clinical patient observation (i.e., chest
to be changed between cases unless a bacterial filter has been placed movement, auscultation, oximetry, and capnography). For
on the TT connection. The availability of electronic ventilators able example, if a large leak is present around the TT, insufficient
to more precisely ventilate small infants makes the use of those expired volume goes back to the ventilator, which leads to
ventilators less and less popular in the operating room. sounding of the low-volume alarm despite adequate ventilation.
The low-pressure alarm may not be triggered in case of accidental
extubation when small infants are ventilated with an adult-size
Bag Squeezers ventilator and a large FGF because small TTs add a great resistance
Most of these ventilators use semiclosed circuit anesthesia to the circuit.243 A bacterial filter should be placed either at
(i.e., they include a circle breathing system and re-administer the the inlet and outlet valve connectors of the circle circuit or at the
expired gases to the patients). patient connection (Y-piece) to prevent contamination of the
The pneumatic bag squeezers use a double-circuit system in ventilator and cross-contamination between patients. The parts of
which a separate gas supply (O2, air, or a mixture of both) provides the breathing system that are not isolated from the patient should
the driving pressure to compress the reservoir bag (“bag-in bottle”) be either single-use or disinfected between cases.
or the bellows of the breathing system. When the bellows are
compressed, these ventilators are further classified according to
the direction of bellows movement during expiration: descending
Electronically Controlled Ventilators
(or hanging) bellows fall during expiration whereas ascending (or The most recent ventilators are bag squeezers (pneumatic:
standing) bellows rise during expiration. Ideally, the movement of Smartvent 7900, Aisys, Julian, Titus, Kion; or mechanical: Primus,
the bellows should be visible so that any abnormality (e.g., Apollo, Zeus) equipped with electronic sensors and microproc-
insufficient FGF) can be rapidly detected. essors. Two main techniques are used to match the VT actually
The descending bellows design has potentially two disad- delivered to the lungs with the desired VT during volume-
vantages controlled ventilation:
● The effect of gravity creates a negative pressure that can be 1. The total compliance of the breathing system is measured
transmitted to the breathing circuit and to the patient. At the during the preuse test and provides continuous compensation
beginning of expiration, this is prevented in the most recent of FGF (which is either stored in a reservoir or interrupted
ventilators by adding a reservoir bag into which FGF is stored during inspiration) and of volume losses caused by com-
during inspiration or by providing FGF during expiration only. pression and leaks.
● In case of disconnection in the breathing circuit, the bellow falls 2. A special flow sensor placed between the TT and the
with gravity and room air is entrained through the disconnec- Y-connector of the breathing circuit compares the delivered VT
tion site. This may hinder triggering of the low–airway pressure to the desired VT and adjust the difference (caused by leaks and
TABLE 38-31. Usual Settings for Pressure-Support There is no entrainment of gas; the FIO2 delivered is the same as the
Ventilation in Children FIO2 provided by the ventilator.
PEEP: +3 cmH2O
Flow: 2.5 L/min HFJVs (Frequency: 100–150 Breaths/min)
Trigger: ⫺2 cmH2O decrease in airway pressure HFJVs are used in the PICU for the treatment of acute respiratory
Max PIP: 10 cmH2O above PEEP distress syndrome (ARDS) or the management of an air leak (e.g.,
Rescue breathing rate: according to age pulmonary interstitial emphysema, bronchopleural fistula); and in
the operating room for laryngotracheal surgery, bronchoscopy, or
PEEP = positive end-expiratory pressure; PIP = peak inspiratory pressure.
laser surgery of the airway, or as an alternative to one-lung
ventilation during thoracic surgery.249 Short bursts of a high-
changes in FGF) within the following 5 to 6 breaths.242 Control velocity jet of fresh gas are delivered in the airway using a TT with
and safety functions are fully integrated in those ventilators, a special port or through a special cannula used either alone250,251 or
enabling them to ventilate small infants (VT < 20 mL) in the within a laryngoscope or rigid bronchoscope. During bronchos-
volume- and pressure-controlled mode244 and to provide low- copy, intermittent jet ventilation can be performed through the
flow anesthesia. suction channel of a fiberoptic bronchoscope. Because of the
The Zeus ventilator is a closed circuit machine equipped with Venturi effect, a large volume of air or gas contained in a parallel
a servocontrolled valve system to control different ventilation and continuous-flow circuit is entrained. The jet is produced with a
FGF feedback modes and a compressor turbine in the inspiratory special ventilator (e.g., Mistral, Monsoon ) or, for short cases, with
limb. It can be used as a conventional ventilator (fresh gas control a manual system (e.g., the Manujet III by VBM). Because expiration
mode: anesthetic vapor is mixed with the fresh gas before injection is passive, relying on the passive recoil of the lungs and chest wall,
in the circuit), in the autocontrol mode (fresh gas and vapors are there should be no obstruction to expiration. Expired airway
injected separately aiming at a target end-tidal concentration), or pressure is monitored in all jet ventilators to avoid barotrauma and
in the uptake mode (same as autocontrol but with feedback control the jet is automatically interrupted as soon as a threshold end-
of FGF, FIO2, and anesthetic delivery). The latter mode is the most expiratory pressure is achieved. As a rule, oxygenation depends on
economical.245 mean airway pressure, which is a function of driving pressure and
The most recent ventilators are able to provide pressure- I:E ratio and on FIO2, whereas ventilation depends on VT, which is
support ventilation175 (Table 38–31). Some teams even use the also a function of driving pressure and I:E ratio but is inversely
pressure-support mode to perform target-controlled inhalation related to respiratory rate. In clinical practice, the following
induction in infants and children.246 The recommendations parameters are adapted to the patient’s response:
regarding the prevention of contamination of the ventilator are ● Driving pressure. In infants and children with normal lung
similar to those given in “Bag Squeezers,” earlier. The “preuse test,”
compliance, the starting pressure should be 0.1 bar (= 1.5 psi =
which calculates the compliance of the breathing circuit, should be
10 kPa). Increasing the driving pressure (maximum 3.5 bar in
performed after connection of the bacterial filters.
adults) increases VT and, thus, both CO2 elimination and oxy-
genation. The usual value in children is between 0.5 and 1 bar
High-frequency Ventilators ● Respiratory rate. Increasing the respiratory rate reduces VT and
CO2 elimination. PaCO2 usually increases above 150 breaths/min.
High-frequency ventilation refers to the different modes of venti- ● I:E ratio. The I:E ratio is usually set between 25 and 33%, in
lation characterized by supraphysiologic ventilatory frequencies order to avoid gas trapping and barotraumas.
and low VTs (less than or equal to physiologic dead space). The ● FIO2. No more than 40% should be administered if CO2 laser
main advantage is that it ensures adequate transport of CO2 with is used.
small VTs at a near-constant airway pressure, avoiding both high ● If a multilumen central venous catheter or a special tube is used
and low extremes of lung volumes. When using such ventilators in
to deliver jet ventilation, one of its lumens can be connected to
the operating room, the different problems are
a sidestream capnometer to monitor PETCO2 and FEO2 when
● Inhalational agents are not usable because special vaporizers ventilation is temporarily slowed to more physiologic rates.
are not available. The Venturi effect produced by the jet venti-
If a manual jet injector system is used, a high-pressure source
lators has a diluting effect. A total I.V. anesthesia technique is
mandatory. of gas is connected to a reducing valve, a pressure gauge, and a
● Measurement of expired volumes is not possible. manual on-off trigger valve. The anesthesiologist controls the
● Monitoring PETCO2 is not possible unless a special port is used duration of the injection with the manual valve by watching the
and connected to a sidestream capnometer.247 Measuring PtcCO2 movement of the chest. Care should be taken to avoid barotrauma
is a good alternative.117,248 by using a purpose-made device such as the Manujet III (by VBM
● To avoid necrotizing tracheitis, a special humidification system, with color-coded range of insufflation pressures according to
usually adapted to the ventilator, must be used during utilization child’s size). The Enk O2 Flow Modulation set can also be used. It
lasting more than 3 hours. is a short connector with five side holes, a distal Luer-Lok fitting,
and a side syringe connector (for nebulizing drugs) placed
between the O2 tubing and the airway connection. It can be totally
High-frequency Positive-Pressure Ventilation or partially occluded by the operator’s fingers during bursts
(Frequency: 60–100 Breaths/min) of insufflation. However, it has been experimentally shown that
A conventional pressure-controlled ventilator with low- it should be totally occluded to allow effective insufflation.252
compliance tubing is used to produce these high respiratory rates. Whatever the manual injector system used, an I:E ratio of 1/3 to 1/4
should be used along with a slow ventilation rate (12 breaths/min) foot-operated spring-loaded bellows with unidirectional valves).
to avoid overinsufflation and barotrauma. Whatever the injection The suction nozzle or catheter should include a limiting pressure
system used, the peak inflation pressures produced in the child’s valve that admits air and reduces the vacuum when opened (e.g.,
lung are influenced not only by the driving pressure and the the Yankauer handheld suction to clear pharyngeal secretions)
diameter of the jet injector but also by the diameter and shape of and/or have two or more holes at its end to avoid performing a
the device in which jet ventilation is performed, that is, much mucosal suction biopsy. The shape of the tip of these suction
higher inflation pressures are measured when the jet injector catheters should be smooth to prevent tissue damage. When
enters 3 to 5 mm Storz bronchoscopes at an angle of 20 degrees performing tracheal suctioning, take care to minimize the negative
than when it is placed coaxially in same-size Pilling broncho- pressure generated within the tracheobronchial tree by using a
scopes.253 Partial obstruction of the lumen of these bronchoscopes suction catheter the diameter of which does not exceed the two
by instruments (e.g., forceps, aspiration) will further increase thirds of the ID of the TT. For the same purposes, suction should
the inflation pressure. Manual jet injection should be used very not be applied when the suction catheter is introduced in the
cautiously in pediatric patients because small changes in the TT but only during its withdrawal. Vacuum should, however,
system can produce large changes in the patient.254 be maintained until the suction catheter has been completely
removed in order to retrieve solid debris that cannot pass through
the lumen of the catheter.
HFOs255 (Frequency: 400–2400 Breaths/min)
HFOs are mainly used in neonatal intensive care for the treatment
of respiratory failure (e.g., hyaline membrane disease, meconium DEVICES DESIGNED TO
aspiration syndrome) and the preoperative stabilization of con- MAINTAIN NORMOTHERMIA
genital diaphragmatic hernia (see Chapter 86). Gas is delivered to
the patient by the to-and-fro movement of a reciprocating piston These devices are used either to maintain normothermia or to
or diaphragm that moves the same volume of fresh gas into a warm up a hypothermic patient. Their use is mandatory in
standard TT. Expiration is active, which is an important anesthetized neonates and infants because their heat balance is
characteristic of HFOs, but air trapping may still occur. V T and more affected by environmental factors than that of older children
CO2 elimination are adjusted by changing the peak-to-peak and adults, because of their higher surface area–to–weight ratio,
pressure generated by the piston, whereas oxygenation is their increased thermal conductance (thin skin and subcutaneous
controlled with the FIO2 and the mean airway pressure. If tissue), and their thermoregulatory mechanisms being more
ventilation is interrupted (e.g., for patient transport), the alveoli affected by general anesthesia (see Chapter 14). In order to main-
tain perioperative normothermia, all mechanisms of heat loss (i.e.,
collapse and a sustained inflation (a “sigh”) are necessary to recruit
radiation, convection, evaporation, and conduction) must be
them and reestablish adequate ventilation. The most popular HFO
addressed. Approximately 90% of metabolic heat is lost via the skin
in use is the Sensormedics 3100A,256 but it lacks the means to pro-
surface and less than 10% is lost via the respiratory system.
vide a conventional mode of ventilation when weaning from HFO.
Radiation and convection are the main mechanisms of heat loss,
Other oscillatory-type ventilators are the Baby Log 8000 and the
accounting for approximately 60% and 25%, respectively, but the
Humming V, which are able to provide conventional ventilation contribution of evaporation increases dramatically when a large
either alone or superimposed on oscillations. According to a wound (peritoneum, small bowel) is exposed to air. The different
comparative study in rabbits, the mean airway pressure displayed methods to prevent hypothermia are summarized in Table 38–32.
on the control screen of neonatal oscillators can be lower, similar,
or higher than the mean alveolar pressure in the lung, depending
on the oscillator used. The mean pressure dial should be adjusted Cutaneous Warming
to achieve the desired degree of alveolar recruitment on the chest
Cutaneous warming may be obtained by several methods.
x-ray and according to arterial blood gas measurements.
High-frequency Flow Interrupters TABLE 38-32. Prevention of hypothermia

The Infant Star and Infant Star 950 are not true “oscillators” ● Keep operating room warm (>21°C in children, ≥ 24°C for
because they use a mechanical valve to very frequently interrupt neonates and small infants).
a continuous flow of gas into a low-compression delivery system. ● Use an overhead radiant warmer until completion of skin
This produces low VTs at high rates. They are able to produce preparation.
the entire range of respiratory rates used in high-frequency ● Use warmed skin preparation solution and irrigation fluids
ventilation. (e.g., cystoscopy, open abdominal surgery).
● Cover as much as possible of the child’s body surface with a
warmed cotton blanket (before surgery) or sterile drapes, and
SUCTION APPARATUS put a hat on the neonates’ and infants’ head.
A good functioning suction apparatus is essential to the safe
● Use an HME.
practice of anesthesia. It is used to clear mucus, blood, secretions,
● Use a forced-air warming device.
or debris from the pharynx, trachea, main bronchi, or stomach.
● Use a fluid warming device if large volumes of I.V. fluids or
The power source that generates the necessary subatmospheric blood is to be administered.
pressure may be an electric motor or a pneumatically driven
● Monitor body temperature to avoid both hypothermia and
pump, which usually uses the Venturi principle and is driven by overheating.
compressed air, O2, or water, or even human energy (hand- or HME = heat and moisture exchanger.
Increasing the Operating Room Temperature weighing more than 30 kg, pressure-heat lesions or skin burns can
Ideally, this temperature should be close to the neutral temperature occur where the patient is lying on the warming area.259 Thermal
(i.e., the temperature at which the child’s O2 consumption and injuries have been described owing to malfunction or a fault in
metabolic rate are minimal, related to the child’s age and/or the insulation.260
birthweight). For a newborn baby lying naked in a draught-free
incubator with 50% relative humidity, neutral temperature is Using Forced-air Warming Devices
± 33°C at term and±36°C if preterm or low birthweight. This Forced-air warming devices are a very effective method of pre-
temperature range is lower and wider if the newborn is covered venting intraoperative hypothermia because they provide con-
with a layer of clothing. The recommended optimal operating vective warming by passing heat over the skin. This heat is
room temperature during induction of anesthesia varies with the transferred from the warmed skin surface to the body core by
child’s age and is 24 to 26°C for a newborn or small infant and 21°C convection. Environmental air entrained through a microbial filter
for an older child. Maintaining the operating room warm until is heated and blown through a detachable hose into a specialized
skin preparation is completed will prevent the drop in tem- disposable cover with perforations. Special pediatric covers have
perature observed after induction of anesthesia (see Chapter 14).
been designed in a tubular configuration to allow easy access to
In addition, this initial heat loss can be prevented or lessened by
the child while providing sufficient contact with the body surface
● Using a overhead radiant warmer during both induction and for heat transfer. In fact, the covers designed to direct the warm air
recovery reduces cutaneous heat loss by 77%.257 stream mainly toward body areas where major blood vessels are
● Covering the child with a warmed blanket. close to the skin (chest, abdomen, axilla) are more efficacious than
● Using prewarmed skin preparation fluids. the others. In practice and for economical reasons, these devices
● Using waterproof paper drapes. are frequently used without their cover with warm air blowing
directly onto the patient, under the surgical drapes. This practice
The use of an overhead radiant-warmer is mandatory when
is not recommended because it carries a risk of burn if the patient’s
anesthetizing children in situations in which the room temper-
skin is to close to the exit of warm air.261
ature cannot be controlled (e.g., the radiology suite). Ideally, the
overhead radiant-warmer should be servocontrolled with a skin
probe placed on the child to avoid skin burns. However, ambient Airway Heating and Humidification
temperatures greater than 21°C and radiant warmers are uncom-
fortable for the operating personnel and are rarely maintained Airway heating and humidification is more effective in infants and
during surgery. Other means should be used to maintain small children than in adults because of their higher minute
intraoperative normothermia. ventilation per kilogram of body weight. Humidification of the
inspired gases is more important than heating because 65 to 85%
of the respiratory heat loss is insensible and caused by the high
Covering the Skin with Passive Insulators latent heat of vaporization of water. Only a small amount of heat
Insulation of the skin with cotton blankets, drapes, plastic com- is needed to warm gases from ambient to body temperature, and
posites, or even aluminum foil can decrease heat loss by approxi- maintaining a relative humidity of at least 50% in the respiratory
mately 30%. Differences among insulators are minimal, the most system is sufficient to maintain normal cilia function in the
important factor being the amount of surface isolated to reduce trachea.262 Airway heating and humidification may be active
heat loss. Cotton-made wrapping may become counterproductive or passive.
if it becomes wet with surgical preparation or irrigation fluid.
In neonates and infants, in whom the head is a great proportion of ● Active heater-humidifiers warm and humidify inspired gases
total body surface area, covering their head with cotton or foil hat using a water bath with a controlled temperature. They are ex-
significantly reduces heat loss. pensive and bulky and are sometimes difficult to clean and ster-
ilize, which increases the risk of bacterial contamination. There
is a risk of overhydration or overheating if the airway tempera-
Using a Warming Mattress, ture probe is either misplaced or omitted. Water condensation
either Electric or Circulating Hot Water in the inspired gases tubing requires regular drainage or instal-
The old models used to reduce conductive heat loss were lation of a water trap to avoid obstruction of gas flow or patient
poorly effective to warm the patient owing to the small area of the aspiration. Last, adding a humidifier may change the breathing
body they were in contact with. New systems (e.g., Thermowrap system compression volume.
by Allon, Thermamed, Klimamed, or Kimberly-Clark Patient ● Passive HMEs conserve some of the water and heat of the
Warming System) consist of a microprocessor heating/cooling expired gases and return them to the inspired gases. Their
unit connected to a modular and flexible garment or gel pads efficiency is reduced in the presence of a large leak around the
placed on the nonoperated parts of the patient. One or two body TT. They should be placed as close to the patient’s airway as
temperature sensors (nasopharyngeal or rectal and cutaneous possible. Ideally, respiratory gases should be sampled between
temperature) provide feedback data to the microprocessor, the breathing circuit and the HME in order to prevent ingress
which is preset to the desired body temperature.258 The surface of water and infectious agents into the sampling system, but
temperature should not exceed 39°C in order to avoid burnlike sampling on the machine side of the HME results in an under-
tissue injuries caused by the combination of heat and pressure. estimation of PETCO2.263 End-tidal gases are, therefore, best
The risk of injury is increased when skin preparation fluid is sampled distal to or within the HME (Figure 38–21; see also
allowed to run between the patient’s skin and the mattress. In case Figure 38–5). When used with nonabsorber breathing circuits,
of intense cutaneous vasoconstriction, especially in a patient the HMEs provide 50% relative humidity after a few minutes
the blood bag is immersed in a 37°C water bath.268 Most in-line

fluid warmers incorporate an optional gas eliminator at the patient
end to eliminate microbubbles. Care should be taken when a gas
eliminator is not in use because the decreasing solubility of gases
in liquid as they warm leads to the formation of bubbles that are
a potential source of air embolism.269 Unfortunately, both the
warming device and its disposable tubing are expensive.
Warming of Irrigation Fluids

Using a cold irrigation fluid to wash the wound, peritoneum, or
thorax or to perform a cystoscopy may cause rapid hypothermia,
especially in infants and small children. All these fluids should be
prewarmed to body temperature before use. The use of cold gas to
inflate the abdomen or thorax during laparoscopic surgery also
exposes the child to the risk of hypothermia in case of prolonged
surgery.
Figure 38-21. Special infant capnometry connector placed
between the HME and the tracheal tube in a 3-kg neonate.
Warming During Transportation
of use and become nearly as effective as active systems in terms Transportation to and from the operating theater is another
of relative humidification after 80 minutes of use262 even though opportunity to lose heat, especially in neonates and small infants.
the absolute inspired humidity achieved does not meet the re- Neonates should be transported in a prewarmed transport
quirements of the International Standards Organization (i.e., 30 incubator and infants well covered with a warm blanket.
mgH2O/L). They are useful even in short-lasting procedures.264
An HME is less expensive than active systems and most of them
are also efficient bacterial and viral filters. Their main disad- FRAMES USED TO
vantage is the increase in deadspace and in resistance to respi- POSITION THE PATIENT
ration when used in small children breathing spontaneously.
Patient positioning for anesthesia and surgery is described in
The use a circle anesthetic circuit is another way to humidify detail in Chapter 80. The basic equipment for child positioning is
and rewarm inspired gases.
● A roll to be placed underneath the child’s shoulders to help
maintain airway patency during induction of anesthesia and re-
Warming of I.V. Fluids and Blood covery, especially in cases in which positioning the child’s large
head in a neutral position would result in flexion of the neck
Heat loss caused by the administration of large amounts of cold
(e.g., premature infants, neonates, and those with hydrocephaly
I.V. fluids or blood can be prevented by using an I.V. warming
or macrocephaly), increasing the risk of upper airway obstruc-
device. Conventional devices warming the solution by circulating
tion. The height of the roll should be adapted to the child’s size
it through a sleeve or coil in contact with a heat exchanger perform
to avoid hyperextension of the neck. It is, however, often useful
poorly in children because, at slow infusion rates, the warmed
to remove the shoulder roll for laryngoscopy in neonates and
fluid cools to room temperature because of heat loss from the
small infants. Similarly, the roll must be placed under the iliac
tubing connecting the warmer and the patient.265 They have a high
spines and the thorax to avoid abdominal compression when
resistance to flow and warm inadequately at high flow rates.
the child is placed in the prone position.
A similar method to warm I.V. fluids consists of placing the tubing ● A head ring to stabilize the child’s head when lying supine or in
around a special holder into the hose of a forced-air warming
the lateral position. In the latter case, the hollow part of the ring
device (241 Fluid warming set for Bair Hugger). The immersion of
provides free space to the child’s downside ear and prevents
the tubing of the bottle of albumin solution or of the bag of blood
its compression. This sort of device can be used to position
in a container filled with warm water or placing most of the I.V.
neonates with meningomyelocele to protect their fragile zone
tubing under a warming mattress are frequently used to warm
of defect during induction of anesthesia (see Chapter 93). This
fluids.266 The efficacy of the former method is variable, depending
device can be homemade with short remnants of disposable
on the volume of fluid present in the immersed part of the tubing
ventilator tubing covered with foam padding or tissue, but soft
and on the gradient of temperature between the two solutions,
models made of a viscoelastic polymer or carboxyvinyl are com-
and carries a risk of contamination. In-line warming devices, in
mercially available.
which warm water circulates around the delivery tubing, deliver ● Sandbags to maintain positioning (e.g., lateral decubitus position).
adequately warmed I.V. fluids or blood at rates ranging from ● Different sizes of foam padding to protect potential pressure
10 to 6000 mL/h (e.g., Hotline, System 250, Medi-Temp II,
points (e.g., heels, elbows, head of fibula).
Thermocyl, or Ranger).267 When using the Hotline, 20 mL of 4°C ● Small and adaptable armboards and stirrups.
packed red blood cells injected over 60 seconds reaches an average
temperature of 34.6°C at the patient’s end of the tubing, whereas A very useful tool during pediatric anesthesia is the anesthetic
it needs 15 minutes to obtain a mean temperature of 32.7°C when screen. It divides the operating table into two areas, a sterile
working area for the surgeon and a “clean” working area for the in the superior vena cava, the catheter is withdrawn 2 to 3 cm
anesthesiologist. Ideally, the anesthetic screen should be rigid from the place where the size of P-wave started to increase. This
enough to support the surgical drapes and the surgeon’s elbow system does not work in case of dysrhythmias or if the
but flexible enough to adapt to the procedure and to the child’s guidewire has followed an aberrant intravascular pathway.
size. During any positioning maneuver, the TT or supraglottic 3. The use of a Doppler system connected to a special exploratory
airway should always be disconnected from the breathing system needle (e.g., 22-, 20-, or 18-gauge SmartNeedle) is not easy to
to prevent accidental tracheal extubation and/or mucosal trauma use because the exploratory needle needs to be flushed regularly
caused by movement of the artificial airway. (air bubbles or particulate matter result in loss of Doppler
signal) and because the presence of the probe into the needle
slows the return of blood flow.274
SPECIAL CONSIDERATIONS
IMPLANTABLE CATHETERS (HICKMAN, BROVIAC, IMPLANTABLE
Special I.V. Access Devices PORT): Implantable catheters are polyurethane or silicone
catheters that are either fixed to the subcutaneous tissue with a
Central Venous Catheters Dacron cuff or equipped with a clampable reinforced extravascular
The indications, technique of insertion, and early complications of section or connected to a subcutaneous implanted injection
central venous catheters are described in Chapter 70. chamber. They are inserted for long-term but intermittent use,
PERCUTANEOUSLY INSERTED CENTRAL VENOUS CATHETERS: mainly chemotherapy or parenteral nutrition. They are usually
Central venous catheters are polyurethane or silicone single— or inserted surgically. The child’s parents should be carefully informed
about the care of the catheter injection site; a specific protocol
multiple-lumen catheters. Polyurethane softens at body temper-
for catheter flushing with a heparin or saline solution should be
ature and becomes more flexible, which reduces the risk of per-
followed. These catheters can also be used for anesthesia, but strict
foration. They are inserted in a central vein using the Seldinger
asepsis should be observed to avoid bacterial contamination.
technique. The metallic guidewire should be atraumatic and
equipped with a J-tip. In neonates and infants, the radius of PERIPHERALLY INSERTED CENTRAL VENOUS CATHETERS: To
curvature of the J-tip is close to the size of or larger than the vessel avoid the immediate complications associated with the insertion
to be cannulated. It is important, in those cases, to use a relatively of a central venous catheter (e.g., pneumothorax, arterial puncture,
stiff introducing catheter rather than a needle to enter the vein and hematoma), these especially designed venous catheters are
and to introduce it completely into the vein before using the J-wire inserted in a peripheral vein (upper or lower limb) to gain access
for the Seldinger technique.270 Ideally, these catheters should to the central circulation. They are rarely used for surgical pro-
be radio-opaque, making x-ray visualization easier. Also, they cedures. Their main indications are access for prolonged I.V.
should provide length marks that help to diagnose an eventual therapy (e.g., antibiotics, parenteral nutrition). Cases of cardiac
decannulation or partial embolization. The tip of the catheter dysrhythmias,275 myocardial perforation and tamponade have
should be atraumatic and slightly tapered to facilitate its insertion been described with these devices because movements of the arm
through tissue and vein wall. The catheter fixation system should affect the position of the tip of the catheter (e.g., the tip of a catheter
be secured and easy to handle in order to prevent both premature inserted in the basilic or axillary vein migrates toward the heart
exit and kinking of the catheter. Adjustable wings that can be fixed when the arm is adducted).276 The catheter tip should be positioned
to the catheter and to the skin are probably the best system. The outside the pericardial reflection line (i.e., above the second
size of the catheter should be adapted to the child’s size: 22 gauge thoracic rib on the chest x-ray while the arm is in the position that
(or 2 French) if body weight is less than 2 kg and 20 gauge (or 3 or leads to the maximum migration toward the heart). When the
4 French) when it is above 2 kg. Over 10 kg body weight, 18 gauge catheter is inserted in the cephalic vein, abduction of the arm will
(or 5 French) catheters can be used. New equipment for central advance the catheter toward the heart whereas adduction will cause
venous catheterization that uses adjunct technologies to facilitate the same displacement when the basilic or axillary vein is used.
either localization of the vein or precise positioning of the catheter Cases of pleural effusion or catheter rupture with migration into a
without x-ray is available: pulmonary artery with subsequent hemorrhage have also been
reported.277 The peripherally inserted central venous catheters
1. A portable two-dimensional ultrasound machine with a (PICCs) are made of polyurethane, silicone, or Silastic. They are
7.5- or 9-MHz probe that allows high-resolution imaging either radio-opaque or provided with a radio-opaque guidewire to
of structures up to 40 mm deep to the skin surface before facilitate insertion and radiologic control of the position of their
(screening the vascular anatomy, vessel position and patency) distal tip. Their length can be adapted to the patient’s size. They
and/or during the procedure.271 Its use results in a higher suc- either are through-the-needle catheters (with a metallic “split-able”
cess rate for internal jugular vein cannulation and a lower introductory needle) or can be placed under echographic control
incidence of complications than the classic landmark tech- using the Seldinger technique.
niques.272 It can also be used to catheterize the femoral and PICCs are used in small premature infants in place of centrally
subclavian vein, deep brachial veins, and the axillary vein. inserted venous catheters. They are also used in ambulatory
Ultrasound imaging allows quick diagnosis of early compli- patients with cystic fibrosis for prolonged antibiotic treatments.
cations such a hemo- or pneumothorax. Its learning requires Their lumen is narrow, which makes rapid infusion of fluid
supervision and training to correctly interpret the ultrasound difficult and withdrawal of blood often problematic. There is a
images and to coordinate the hand movement with the two- risk of rupture and intravascular migration of the distal part of
dimensional pictures on the screen.273 the catheter: 11 cases were observed in a series of 1650 PICCs.
2. An endocavitary ECG (with a special connection of the Forceful attempts to flush a blocked line (e.g., with a syringe
guidewire to the ECG monitor via an adapter). In order to be < 5 mL) is an important risk factor for rupture.278
Intraosseous Needles279 vasation, the intraosseous route should not be attempted in a

The intraosseous access is a last resort for vascular access to be broken bone or after previous intraosseous administration in the
used in life-saving circumstances, when no other venous access is same bone. The needle should be properly secured and its site of
possible and only as a temporary measure. Although it can be used insertion regularly inspected.
in adults, this access is usually used only in children younger than
5 to 6 years because later the bone becomes too hard to allow Intraoperative Autotransfusion Devices
insertion. The preferred insertion sites are the proximal or distal
end of the tibia and the distal end of the femur. Any bone marrow Indications and Contraindications
aspiration needle can be used, but special needles have been The salvage and re-infusion of blood lost during major surgery is
designed that are shorter, preventing deep insertion, and easier the most common form of autologous blood transfusion in
to secure. They are available with different lengths (2.5, 3.0, or children because predeposited autologous blood transfusion is
4.0 cm), different needle design (lancet, trochar, or pencil-point often difficult for technical and organizational reasons. Blood
end), or even lateral sideports near the distal tip of the needle to salvage techniques are used in surgical procedures known to be
ensure flow in case the distal end is obstructed (Dieckmann modi- associated with important blood loss such as scoliosis surgery,
fication). Other models of intraosseous needles are the Sussman- cardiac surgery, or liver transplantation. Even in these circum-
Raszynski needle, which includes a fine screw needle cannula tip stances, the main indication for the use of a blood cell processor in
to facilitate needle insertion and stabilization, and the Sur-Fast a child larger than 10 kg is an anticipated blood loss greater than
needle, which is shorter and includes both a screw needle cannula 20% of its estimated blood volume. Blood salvage techniques are
and lateral sideports. Some brands have an adjustable flange to rarely used in children less than 10 kg because a minimum of 100
allow better control of needle insertion depth. to 300 mL of shed blood is needed to fill the currently available
The Bone Injection Gun is a small trochar needle (18 gauge pediatric-size centrifuge bowls (e.g., 55 mL bowl of Dideco
for children < 6 y) that is incorporated in a specially designed Compact A, 100 mL bowl of HaemoLite 2 Plus, 70 mL for CellSaver
insertion device. The depth of insertion is predetermined and 5) before the processing phase. Homologous blood transfusion is
insertion is automatic after triggering a spring-loaded system. unavoidable in these cases, and most of the advantages of auto-
The EZ-I0 (Vidacare) device is a 15-gauge stainless steel needle
transfusion are then lost. In the author’s experience, the centri-
(pink,15 mm long for patients 3–39 kg; blue, 25 mm long for those
fugation and washing system of the autotransfusion apparatus can
weighing = 40 kg; and yellow, 45 mm long for adults) adapted to
be successfully used to avoid hyperkalemia during massive
a battery-powered driver that allows the insertion of the needle in
transfusion (see Chapter 54), especially in small children and
less than 30 seconds. The needle is equipped with a Luer-Lok
infants. The blood bank blood is processed through the autotrans-
connection and can be adapted to any I.V. line (Figure 38–22). It
fusion system, as if it was shed blood, before being warmed and
can be easily removed by connecting the hub to a Luer-Lok syringe
administered to the patient. The contraindications to intraoperative
moved counterclockwise.
blood salvage are
Possible complications of the intraosseous route are cellulitis,
osteomyelitis, bone fracture, fat or bone marrow embolism, and ● Suspected or confirmed contact with bowel contents.
extravasation of fluid into the extraosseous tissue that can lead to ● Suspected or confirmed contamination with malignant cells.
compartment syndrome if not recognized early. To avoid extra- ● Shed blood from an infected wound.
● Shed blood from a wound irrigated with a wound-sterilizing
solution or in which hemostatic substances have been used (e.g.,
thrombin, microfibrillar collagen glue).
● Hemolysis.
Some teams use intraoperative blood salvage in patients with
sickle cell disease.
Description
Most autotransfusion devices are discontinuous systems in which
shed blood is aspirated from the surgical field through a double-
lumen suction designed to allow immediate mixing with an
anticoagulant solution (usually acid-citrate-dextrose [ACD] or
citrate-phosphate-dextrose [CPD] solution) and stored in a special
reservoir until a sufficient amount has been collected. Shed
blood is pumped into a spinning centrifuge bowl that separates
blood components on the basis of their density. Red blood cells
accumulate progressively in the bowl, starting from its base,
whereas all other components are evacuated into a waste container.
When the bowl is totally filled with red blood cells, a washing cycle
rinses away all contaminants and residual anticoagulants before
resuspending the washed red blood cells in a normal saline
solution. The final hematocrit varies from 50 to 70%. It should be
Figure 38-22. EZ-10 intraosseous access device. kept in mind that the centrifugation process virtually eliminates
all the plasma components of the salvaged blood. Its potassium Devices for Laser Airway Surgery
content is very low but plasma proteins, including coagulation During laser endoscopic surgery, the anesthesiologist shares the
factors, and platelets are eliminated. When large volumes of airway with the surgeon and must ensure optimal operator’s view
salvaged blood are re-infused, dilutional coagulopathy can occur. and proper laser beam path. All equipment in contact with the
Another autotransfusion system has recently been designed laser beam must be nonflammable, and the gas mixture should
that allows continuous washing and separation of collected blood not support combustion. The other safety aspects of endoscopic
(C.A.T.S.). It is based on the principle of the separation chamber laser surgery, such as avoidance of N2O, aspiration of smoke, eye
used in cell separators or plasmapheresis devices. Shed blood protection of the patient and all the personnel present in the
and normal saline directly enter the rotating separation chamber operating room, must be done.
(15–30 mL volume) so that the red blood cells are washed during
the centrifugation/separation process. An optical sensor guar- ● Apneic ventilation, in which the TT is removed at regular
antees that the washed red blood cells do not leave the chamber intervals.
before a hematocrit of at least 65% is reached. This continuous
● Spontaneous ventilation with a nasopharyngeal airway.
processing system is preferable for intraoperative autotransfusion
● Positioning a metal (e.g., the Andrews anterior commissure
in pediatric surgery because it guarantees a hematocrit level retractor or a Benjamin proximal injection cannula by Storz)282
greater than 60% independent of the volume of shed blood to be or Teflon cannula above the glottis through a suspension laryn-
processed.280 Some of these autologous transfusion systems goscope or a bronchoscope. Either spontaneous ventilation or
(e.g., BRAT 2 or C.A.T.S.) are equipped with a special “plasma Venturi jet ventilation may be used. If jet ventilation is used,
sequestration program,” which allows the separation of the care should be taken to maintain the cannula aligned in the
laryngotracheal axis at a proper distance above the glottis to
patient’s blood taken before the start of surgery into plasma, red
avoid gastric inflation and barotrauma.
cells, and platelets. ● Positioning a metal cannula into the trachea (e.g., stainless steel
Holinger aspiration cannula # 507055, 3 mm OD and 1.5 mm
Ultrafiltration281 ID283 or pediatric cannula 2.5 mm OD and 1.7 mm ID250)
In case of cardiac surgery, a hemofilter can be added to the through the surgeon’s microlaryngeal laryngoscope and using
extracorporeal circuit to remove excess circulating blood volume HFJV. Proper alignment with the tracheal axis and free egress of
at the end of bypass. Ultrafiltration is a technique in which fluids expired gas are mandatory.
pass through a semipermeable membrane filter. Water, electrolytes, ● Positioning a Teflon double-lumen tube (Hunsaker Mon Jet
and other substances of small molecular weight (depending on ventilation tube) into the trachea. One lumen (3.5 mm OD) is
the size of the pores in the membrane) are removed following used for HFJV and the other (1 mm ID) for end-tidal gases or
transmembrane pressure gradient. Red blood cells from the extra- pressure monitoring. When the inner stylet is removed from the
corporeal circuit can then be concentrated to the desired hemat- tube, distal flanges open out and maintain the tube in a central
ocrit without losing platelets or plasma proteins but at the expense position in the trachea, avoiding any lashing of the tube caused
of increased plasma free hemoglobin concentration (hemolysis by HFJV. This tube is very flexible and nonflammable, even in
caused by bypass) and prolonged activated clotting time (recircu- 100% ambient O2, when struck with a CO2, KTP, or Nd:YAG
lation of heparin). laser beam. However, because of its size, this device is usable
only in big children and adolescents.284 The author nevertheless
uses it routinely in infants after cutting off the distal flanges of
Special Airway Equipment the device (Figure 38–23).
● Transtracheal ventilation through a radio-opaque Teflon
Reinforced or Anode Tubes transtracheal catheter (Ravussin 16 gauge, ID 0.8 mm, length
Most standard PVC TTs kink when they are bent at an acute angle 37 mm, VBM), which can be used in neonates and children up
or when compressed. In situations when this could occur, for to 12 years of age.251 The catheter is inserted percutaneously
example, during intraoral or neurosurgery, kinking-resistant tubes through the cricothyroid membrane and its correct position is
should be used. They are made by embedding a reinforcing spiral verified by endoscopy. The cannula has two lateral holes at its
of metal or nylon into the wall of the tube, which is often made of distal end, and two lateral attachments allow its secure fixation
material that is more elastic than usual (silicone, rubber; e.g.: around the neck with a Velcro band. Care must be taken to avoid
Safety-Flex, Spiral-Flex). These TTs are flexible and more difficult damage to the tracheal wall and the esophagus.
to insert without the use of a stylet. They are also more susceptible
A TT can also be used:
to accidental extubation. The TT with a metallic spiral should not
be used for MRI. ● A standard rubber or PVC TT wrapped with an adhesive
laminate of silver foil and sponge material (Merocel Laser-
Guard). This adhesive material, which adds almost 2.5 mm to
Tubes With Additional Lumens the OD of the TT, has to be carefully applied around it and
The PVC uncuffed TTs have been developed with one or more soaked with water or saline. The smallest TT that can be covered
additional small channels to allow tracheal administration of gases with Merocel Laser Guard is 5.0 mm ID. If this special material
(high-frequency ventilation) or drugs (e.g., surfactant), or airway is not available, either an aluminum #425 (3M) or a copper Ven-
monitoring (pressure and/or PETCO2; Boussignac, Edgar tube, ture foil (Venture Tape) tape may be used to wrap the TT.285
Sheridan EtCO2; all starting from size 2.0 ID). The OD of these However, foil wrapping reflects only the energy of the laser
TTs is larger than the standard TTs of the same ID. These small beam and does not protect a combustible TT from indirect
sampling channels are easily obstructed by secretion. combustion owing to sparks or high temperature owing to tis-
TABLE 38-33. Internal and External Diameter of the

Smallest “Laser” Tracheal Tubes
Tube ID, mm OD, mm
Xomed Laser-Shield II 4.0 6.6
4.5 7.3
5.0 8.0
5.5 8.6
Laser-Trach cuffed 4.0 8.2
5.0 9.5
Laser-Flex uncuffed 3.0 5.2
3.5 5.7
4.0 6.1
Cuffed 4.5 7.0
5.0 7.5
5.5 7.9
Bivona Laser tube 3.0 5.5
4.0 6.5
5.0 7.5
Lasertubus 4.0 8.0 (wrapped area)
Figure 38-23. High-frequency jet ventilation in a 4-year-old indication of cuff rupture and to extinguish any small ignition.
child. Suspension laryngoscopy is used and the Hunsaker is Care should be taken to avoid overfilling the cuff with saline
connected to the high-frequency jet ventilation source. because this could cause a dramatic increase in tracheal mucosal
pressure. Because of the special composition of their wall, all
sue combustion. Lastly, if a cuff if present, it cannot be wrapped “laser-tubes” have an outer diameter that is greater than the
with the protective foil and should be covered by wet cottonoids. standard TT of the same ID (Table 38–33). If the child has already
● A silicone-made TT with an overlapping spiral aluminum wrap a tracheostomy tube in place before surgery, this should be
and a smooth Teflon outer coating of the Laser-Shield II series. replaced with a metal cannula before using the laser. Special
There is 1 cm of unprotected silicone proximal to the cuff that standard PVC TTs can be used for microlaryngeal surgery when
has to be protected by wet cottonoids during the procedure. The no laser is used. They are available with an ID of 4, 5, and 6 mm
smallest tube available has an ID of 4.0 mm. but with the same length and cuff as a standard 8-mm ID tube.
● A metallic tube with a silicone covering (Bivona Laser tube).
This tube is also equipped with a polyurethane self-inflating
Devices for One-lung Ventilation
foam cuff from which air has to be actively aspirated before its
insertion into or removal from the larynx. The pilot tube of the In children, one-lung ventilation is used either to prevent the
cuff is located at the outer surface of the tube and is susceptible contamination of one lung by blood, pus, or secretions coming
to damage by the laser beam. This could result in the cuff being from the other or to improve surgical access during thoracotomy
undeflatable and laryngeal damage during removal of the TT. or thoracoscopic procedures (see Chapters 96 and 97).
This tube may ignite when high-power laser is applied. DOUBLE-LUMEN TTS: In children older than 8 to 10 years, 26-,
● A stainless-steel flexible tube (Laser-Flex). Pediatric uncuffed 28-, or 32-French double-lumen TTs may be used (Table 38–34
Laserflex tubes are available from 3.0 mm ID (OD 5.2 mm). The provides sizes). As a rule, the largest double-lumen tube that can
smallest cuffed version is 4.5 mm ID. It has two PVC cuffs that be introduced atraumatically through the glottis and passed into
are inflated by separate inflation tubes, so that the distal cuff can the appropriate bronchus should be used. Less air is required to
be used if the proximal one is damaged by the laser beam. It is seal the bronchial airway, and this reduces the risk of mucosal
compatible with CO2 and KTP but not with Nd:YAG lasers. trauma from overinflation and bronchial cuff herniation into the
● A red rubber TT covered with an embossed copper foil and carina. Whether the dependent or the operated lung should be
overwrapped with Teflon (Laser-Trach). The smallest version is selectively intubated is a matter of controversy.
4.0 mm ID and cuffed. It has to be soaked with water or saline For neonates and infants, a special uncuffed double-lumen tube
before use but may ignite if an Nd:YAG laser is used.
initially designed by Marraro for separate lung ventilation can be
● A rubber foam (Merocel) and silver foil–wrapped Lasertubus.
used.286 It consists of two separate radio-opaque Portex blue line
Before use, it has to be soaked in water or saline to help absorb
PVC tubes, of different length and attached laterally to each other.
the laser energy. It has a Murphy hole and a double cuff (one
The bronchial tube is longer and usually larger than the tracheal
inside the other). The smallest ID available is 4.0 mm.
one; has a bevel and a Murphy hole, which both face outward; and
All those special laser tubes are laser-resistant, not laser-proof. is bent at an angle of±5 degrees a few millimeters proximal to the
They can ignite if laser intensity is high or if they are directly Murphy hole to facilitate bronchial entry. The Marraro Paediatric
exposed to the beam for a prolonged period of time. Bilumen tube is inserted orally and rotated to the right or the left
The cuffs of the TT used for laser surgery should be filled with after passing the vocal cords, according to the bronchus to be
methylene blue–tinged saline to give an immediate visual intubated. A tricky aspect of the use of this tube is its connection
TABLE 38-34. Tracheal Tube Dimensions of Devices TABLE 38-36. Characteristics of Fogarty Thru-Lumen
Used for One-lung Ventilation (Baxter) Arterial Embolectomy Catheters
ID of Each Catheter size, Fr 3 4 5 6
Devicea Lumen, mm Total OD, mm Diameter of inflated balloon, mm 5 9 11 13
Max. liquid capacity, mL 0.15 0.5 0.9 1.4
26 Ch Bronchopart 3.4 9.0–8.0
Max. gas capacity, mL 0.4 1.2 1.7 2.3
28 Ch Bronchopart 3.7 10.2–8.6
Broncho-Cathb 3.5–5.4 9.3 According to the manufacturer’s data sheet.
32 Ch Broncho-Cathb 3.8–6.7 10.7
35 Ch Bronchopart 4.2 12.5–10.8 lumen that allows suctioning or administration of O2 to the
Broncho-Cathb 4.7–8.7 11.7 blocked lung. They are equipped with a stylet that allows gentle
Univent 3.5 3.5 7.5–8.0 curving of the catheter about 2 cm from the tip to facilitate its
Univent 4.5 4.5 8.5–9.0 introduction into the mainstem bronchus. However, the high
Univent 6.0 6.0 10–11 pressures generated in these balloons when they are inflated
Univent 6.5 6.5 10.5–11.5 above the recommended volume to completely occlude the
Univent 7.0 7.0 11–12 bronchial lumen might induce localized ischemic damage to the
ID = inner diameter; OD = outer diameter. airway or even bronchial rupture.292 The balloon should be care-
a
Bronchopart by Rüsch; Broncho-Cath by Mallinckrodt; Univent by Fuji/Vitaid. fully inflated according to the manufacturer’s recommendations.
b
For the Broncho-Cath: both lumens are D-shaped and the dimensions given are The characteristics of the 3-, 4-, 5-, and 6-French Fogarty
the largest and the smallest width for each lumen. catheters made by Baxter are given in Table 41.36. The 3-French
Fogarty catheter is used in infants weighing 5 to 10 kg, whereas
to two breathing systems. The recommended sizes are shown in the 4 French is used in 11- to 15-kg children.
Table 38–35. Recently, the use of a homemade assembly of two ● Balloon atrioseptostomy catheters. their tip is angled at 35 de-
small cuffed TTs connected together via the Y-connector of a grees, which may help manipulation into the bronchus, and have
standard double-lumen TT has been described to perform lung a central lumen for suction or administration of O2 to the
lavage in a child.287 blocked lung.291 A 5-French Edwards atrioseptostomy catheter
BRONCHIAL BLOCKERS: Selective mainstem bronchial intubation has a 19-mm diameter when fully inflated with 4 mL of fluid.
of the nonoperative lung with a standard288 or slightly modified289 ● Swan-Ganz pulmonary artery flotation catheters. These are easy
TT can ensure one-lung ventilation. The appropriate TT is usually to insert and have a central lumen for suction or administration
ID 0.5 mm smaller than would normally be used for tracheal of O2 to the blocked lung. No more than the recommended vol-
intubation. To perform selective bronchial intubation, the child’s ume of air should be injected in the balloon.
head should be turned to the side opposite to the bronchus to be All these devices may be inserted either inside or outside the
intubated. The orientation of the bevel of the TT seems critical. standard TT. It is usually better to insert them outside the
Ideally, the TT should be turned so that its bevel faces the TT because this makes fiberoptic confirmation of position
bronchus opposite to the one to be intubated to guide the tip of the
and fixing easier. It also eliminates the risk of leaks across the
tube down into the bronchus.288 If a cuffed TT is used, the distance
swivel connector. If fibroscopy is not used, the position should be
from the tip of the TT to the proximal edge of the cuff must be
controlled by x-ray (if necessary with contrast dye in the catheter
shorter than the length of the mainstem bronchus to ensure that
the cuff will be entirely in the bronchus. balloon). To prevent bronchial injury, the largest balloon whose
Another way to achieve one-lung ventilation in children is catheter will pass beside the TT at the cricoid level should be used
to perform tracheal or selective bronchial intubation and to and the balloon should be inflated to the smallest volume that seals
block the mainstem bronchus of the operated lung. Several the bronchus, under bronchoscopic control.292
devices have been described to achieve bronchial blockade290 and The best bronchial blocker is the pediatric version of the
consist of Arndt catheter. It consists of a 50-cm-long 5-French double-lumen
catheter (ID 0.7 mm; maximum OD 2.5 mm) with a high-volume,
● Balloon-tipped catheters (Fogarty arterial embolectomy cathe- low-pressure elliptical silicone balloon (maximum capacity 3 mL;
ters).291 However, only the Thru-lumen Fogarty has an internal length 1 cm) near the end. One lumen allows inflation of the
balloon. A nylon guideloop is inserted through the second
TABLE 38-35. Marraro Pediatric Bilumen Tube lumen and exits at the end of the blocker (Figure 38–24). The tip
of a pediatric fiberoptic bronchoscope is passed into this loop
Age Tracheal ID Bronchial ID to help insert the blocker into the bronchus. When the guide is
Premature 1400–2500 g 2 2 withdrawn, this lumen can be used for suction or administration
Neonate 2500–4000 g 2 2.5 of O2. A special multiport airway adapter, with a bronchoscopy
2.5 2.5 port, a ventilation port, and a blocker port, needs to be connected
1 mo 2.5 2.5 to the TT. This system can be used in children older than
6 mo 2.5 3.0 2 years.293 In infants, the blocker can be placed within the TT
12 mo 3.0 3.5 under fibroscopic control if the connector is slightly modified or
ID = inner diameter; OD = outer diameter.
fluoroscopic guidance can be used to place it into the selected
According to Marraro G. Selective endobronchial intubation in paediatrics: the bronchus before tracheal intubation. In the latter case, the blocker
Marraro Paediatric Bilumen tube. Paediatr Anaesth. 1994;4:255–258. is placed outside the TT.294,295
easy and quick to perform because the cricothyroid membrane is

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Illustrator: Danny Aguilar - Canada

PEOPLE’S MEDICAL PUBLISHING HOUSE—USA

People’s Medical Publishing House-USA

© 2011 PMPH-USA, Ltd.

Printed in China by People’s Medical Publishing House

Library of Congress Cataloging‐in‐Publication Data

Sales and Distribution

To All the Children of the World We Care For

Mette M. Berger, MD, PhD [124] Gilles Boulay, MD [1]

Pierre Carli, MD [68] Brian Chanpong, DDS, MSc [126]

Neroli Chadderton, BHB, MBChB, FANZCA [23] Olivier Choquet, MD [45]

Patrick T. Farrell, MD [97] Steven Ganzberg, DMD, MS [126]

Mohamed El-Gammal, MD [115] Marie Granier, MD [103]

Jean-Claude Granry, MD [11] Brendan O’Hare, MB [119]

Renée Krivosic-Horber, MD [81] Martin Jöhr, MD [31]

Brenna L. Jacobson, MD [59] Cassandra M. Kelleher, MD [107]

Sonia ben Khalifa, MD [90] Wai-Ching Lam, MD, FRCS(C) [102]

Vincent P. Laudenbach, MD, PhD [19]

Patricia A. McGrath, PhD [16] Isabelle Murat, MD, PhD [127]

Hawa Keïta-Meyer, MD, PhD [19] Sif-Eddine Nejmi, MD [79]

Gregory Moloney, MBBS, FANZCA [43] David G. Nykanen, MD [118]

Dalia Mohamed Tohlob, MD [82] Polina Voronov, MD [50]

Anne Laffargue Vetter, MD [52] Robert Whitty, FCARCSI [33]

William Wisden, MA, PhD [5] Myron Yaster, MD [66]

CHAPTER 92 CHAPTER 105

CHAPTER 93 CHAPTER 106

CHAPTER 94 CHAPTER 107

CHAPTER 118 CHAPTER 126

CHAPTER 121 CHAPTER 128

CHAPTER 124 CHAPTER 132

Prenatal Normal and Abnormal

INTRODUCTION following birth, have specific implications for the perioperative

2 PART 1 ■ Developmental Considerations

Figure 1-1. Formation of the blastocyst.

Figure 1-2. Formation of the trilaminar germ disk. (1) Amniotic

CHAPTER 1 ■ Prenatal Normal and Abnormal Development 3

Figure 1-4. Formation of the heart

4 PART 1 ■ Developmental Considerations

Figure 1-5. Herniation and

TABLE 1-1. Normal Embryonic Development and Malformation

7–14 (0.1) Yolk sac

19 (1) Enlargement of Allantois

6 PART 1 ■ Developmental Considerations

TABLE 1-2. Relative Timing and Developmental Pathology of Some Malformations

Abnormal Development6–9 (incomplete separation of fingers), cleft palate (incomplete closure

CHAPTER 1 ■ Prenatal Normal and Abnormal Development 7

8 PART 1 ■ Developmental Considerations

CHAPTER 1 ■ Prenatal Normal and Abnormal Development 9

10 PART 1 ■ Developmental Considerations

CHAPTER 1 ■ Prenatal Normal and Abnormal Development 11

12 PART 1 ■ Developmental Considerations

CHAPTER 1 ■ Prenatal Normal and Abnormal Development 13

14 PART 1 ■ Developmental Considerations

CHAPTER 1 ■ Prenatal Normal and Abnormal Development 15

16 PART 1 ■ Developmental Considerations

CHAPTER 1 ■ Prenatal Normal and Abnormal Development 17

18 PART 1 ■ Developmental Considerations

CHAPTER 1 ■ Prenatal Normal and Abnormal Development 19

General Growth and Tissue

Ruth Oelhafen Luginbuehl

CHAPTER 2 ■ General Growth and Tissue Development Throughout Childhood 21

Figure 2-1. Growth percentiles for preterm neonates.

22 PART 1 ■ Developmental Considerations