B. Beck-Schimmer, R. C. Schimmer, T. Pasch (Auth.), Jean-Louis Vincent MD, PHD, FCCM, FCCP (Eds.) - Intensive Care Medicine - Annual Update 2003-Springer-Verlag New York (2003)

INTENSIVE
CARE
MEDICINE
2003
ANNUAL
UPDATE
JEAN~LOUIS VINCENT
Springer-Verlag Berlin Heidelberg GmbH
INTENSIVE
CARE
MEDICINE
ANNUAL
UPDATE
2003
Editor
Jean..-Louis Vincent
MD, PhD, FCCM, FCCP
Head, Department of Intensive Care

Erasme Hospital, Free University of Brussels
Brussels, Belgium
With 176 Figures and 96 Tables
~Springer
Jean-Louis Vincent, MD, PhD, FCCM, FCCP
Head, Department of Intensive Care
Erasme Hospital
Free University of Brussels
Route de Lennik 808
B-1 070 Brussels
Belgium
ISBN 978-1-4757-5550-3 ISBN 978-1-4757-5548-0 (eBook)

DOI 10.1007/978-1-4757-5548-0
Printed on acid-free paper.
©Springer-Verlag Berlin Heidelberg 2003

Softcover reprint of the hardcover 1st edition 2003
All rights reserved. This work may not be translated or copied in whole or in part without
the written permission of the publisher Springer-Verlag Berlin Heidelberg GmbH.
except for brief excerpts in connection with reviews or schol-
arly analysis. Use in connection with any form of information storage and retrieval, elec-
tronic adaptation, computer software, or by similar or dissimilar methodology now known or
hereafter developed is forbidden.
The use in this publication of trade names, trademarks, service marks, and similar terms,
even if they are not identified as such, is not to be taken as an expression of opinion as to
whether or not they are subject to proprietary rights.
While the advice and information in this book are believed to be true and accurate at the
date of going to press, neither the authors nor the editor nor the publisher can accept any
legal responsibility for any errors or omissions that may be made. The publisher makes no
warranty, express or implied, with respect to the material contained herein.
9 8 76 5 4 3 2 1 SPIN 10954263
www.springer-ny.com
Contents
Epithelial-Endothelial Alterations
Role of Epithelial ICAM-1 in Endotoxin-Induced Lung Injury 3

(B. Beck-Schimmer, R. C. Schimmer, and T. Pasch)
Pulmonary Endothelium-Bound Enzymes in the Normal

and the Diseased Lung . . . . . . . . . . . ......... .. ...
. 11 ..
(S.E. Orfanos, A. Kotanidou, and C. Roussos)
Endothelial Cell Replacement Therapy in the Critically Ill 21

(S. V. Baudouin)
Sepsis: Mechanisms and Therapy
Reconciling Clinical Criteria and the Use

of Genetically Engineered Animals in Sepsis Research . . . . . . 35
(G. Albuszies, C. Ince, and P. Radermacher)
Human Genetics and Human Sepsis:

Is the Tail Wagging the Dog? . . . . . . . . . . . ...
. . . . . . . . . . 46
(D. Burgner and M. Levin)
Microarray Technology in Sepsis: Tool or Toy . . . . . . . . . . . . 55

(S. Russwurm, H. P. Deigner, and K. Reinhart)
Update on Anti-Endotoxin Therapies 65

(R. Stephens and M. Mythen)
An Update of Childhood Meningococcal Sepsis . . . . . . . . . . . 76

(]. Ramet, N. Najafi, and A. Benatar)
The Effect of Alcohol Consumption on Risk of Sepsis

and ARDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
(E. L. Burnham, M. Moss, and G. S. Martin)
VI Contents
Supplementing Arginine during Sepsis:

from Theory to Clinical Practice . . . . . . . . . . . . . . . . . 97. . . . .
(M. Poeze and M.J. Bruins)
Coagulation Abnormalities
Severe Thrombotic Microangiopathy in Critically Ill Patients . 109

(F. Pene, Y. E. Claessens, and f. P. Mira)
Heparin in the Treatment of Critically Ill Patients

on the ICU Patients . . . . . . . . . . . . . . . . . ... . . .120
. .. ... ..
(M. Levi, A. Cornelie de Pont, and E. de Jonge)
Endogenous Anticoagulants and the Role of Heparin

in the Treatment of Severe Sepsis . . . . . . . . . . . . . . . .129
. . . . .
(C.J. Wiedermann and C. Pechlaner)
Is Recombinant Activated Factor VII a Universal Hemostatic? . 136

(P. Diprose, R. Gill, and M. Herbertson)
Infectious Challenges
Nasal Carriage of Staphylococcus aureus: Associated Risks

and Preventive Measures . . . . . . . . . . . . . . . . . . . . .149
.... ..
(H.F.L. Wertheim and J. A.J. W. Kluytmans)
Current Dilemmas in the Management of Adults

with Severe Community-Acquired Pneumonia . .. .... . .. .. 162
(J. Rello, f. A. Paiva, and C. S. Dias)
Evaluation of Non-Resolving and Progressive Pneumonia ... . 175

(R. Menendez and A. Torres)
Candida in Lung Specimens from Non-Neutropenic ICU

Patients: Infection or Colonization? . . . . . . ..... . . . . 188
... ..
(E. Azoulay and B. Schlemmer)
A Reappraisal of Selective Decontamination

of the Digestive Tract . . . . . . . . . . . . . . . . . . . . . 199
.. .... ..
(A. Heininger, W.A. Krueger, and K.E. Unertl)
Management of Catheter-Related Sepsis in the ICU ... ..... 209

(B. Mourvillier and f. F. Timsit)
Empiric Antibiotics in Critical Illness: Do they Help or Harm? 219

(M.A. Aarts and J. C. Marshall)
Contents VII
Acute Respiratory Failure
Mortality Rates in Patients with ARDS:

What Should be the Reference Standard? . . . . . . . . . . . . 231
.. .
(N.D. Ferguson, F. Frutos- Vivar, and A. Esteban)
Sigh in Acute Respiratory Failure . . . . . . . . . . . . . . . . 243

.. . ..
(N. Patroniti, G. Foti, and A. Pesenti)
The Conditioning of Medical Gases during Spontaneous

Breathing . . . . . . . . . . . . . . . . . . . . . . . . . . . . .255
. . . .. .. ..
(D. Chiumello, N. Bottino, and P. Pelosi)
Recent Innovations in Mechanical Ventilatory Support . . . . . 264

.
(N. Macintyre)
Expiratory Flow Limitation in Mechanically Ventilated Patients 272

(A. Koutsoukou, C. Roussos, and]. Milic-Emili)
Respiratory Muscle Unloading during Mechanical Ventilation . 280

(]. Beck, ]. Spahija, and C. Sinderby)
High Frequency Oscillation (HFO): Physiological Basis

for a Potentially 'Optimal' Protective Ventilatory Strategy . . . 288
(A. Rossi, T. E. Stewart, and V. M. Ranieri)
Withdrawal from Mechanical Ventilation in Patients

with COPD: The Issue of Congestive Heart Failure 295
(B. Cabello and]. Mancebo)
Inhalation Therapies
Inhalation Therapy during Mechanical Ventilation . . . . . . . 305

.
(E. Kondili, C. Alexopoulou, and D. Georgopoulos)
Trials of Surfactant Replacement Therapy in Patients

with ARDS . . . . . . . . . . . . . . . . . . . . . . . . . . .317
.... . . . . .
(M.]. Schultz,]. Kesecioglu, and B. Lachmann)
Surfactant Therapy: Beyond a Rescue Therapy for ARDS . . . . 331

(].]. Haitsma, R. A. Lachmann, and B. Lachmann)
VIII Contents
Perioperative Complications
High Risk Surgical Patients: Why We Should Pre-Optimize ... 341

(B. Vallet, G. Lebuffe, and E. Wiel)
Pain Control in the Intensive Care Unit . . . . . . . . . . . . . 348

. ...
(S. Brett and U. Waheed)
Respiratory Failure Post-Coronary Bypass Surgery ......... 355

(S. Yende and R. Wunderink)
Postoperative Respiratory Management . . . . ... . . . . . .366

....
(G.K. Albaugh and R.P. Dellinger)
Myocardial Ischemia or Cardiac Failure:

Which Constitutes the Major Perioperative Risk? . . . . ... . 377
. .
(P. Older and A. Hall)
Cardiac Crises
Acute Coronary Syndromes .... . .................... 391

(!.F. Coutts, S. R. Redwood, and A. Rhodes)
Pre-Hospital Reperfusion Strategies to Optimize Outcomes

in Acute Myocardial Infarction . . . . . . . . . . . . . . . . . 412
. .. ...
(P. Goldstein)
Glucose, Free Fatty Acids, and Insulin Following

Acute Myocardial Ischemia . . . . . . . . . . . . . . .... . 427
. . . . .. .
(H. B. van Wezel and S. W. M. de ]on g)
Quantifying Left Ventricular Ejection Effectiveness . . . . . . . 436

..
(M. R. Pinsky)
Cardiogenic Shock ................................ 447

(S.M. Hollenberg)
Cardiopulmonary Resuscitation
Inhibition of the Sarcolemmal Sodium-Hydrogen Exchanger:

A Potential Treatment for Resuscitation from Cardiac Arrest .. 461
(R.]. Gazmuri, I.M. Ayoub, and]. Kolarova)
Contents IX
Immediate Defibrillation for Out-of-hospital Ventricular

Fibrillation . . . . . . . . . . . . . ............... 472. . . . . . . .
(P. E. Pepe, f. G. Wigginton, and R. L. Fowler)
Monitoring Systems
Cardiac Output Monitoring: Will New Technologies Replace

the Pulmonary Artery Catheter? . . . . . . . . . . . . . . . . . . 481. . . .
(J.A.L. Pittman and K.f. Gupta)
Assessment of Cardiac Preload and Volume Responsiveness

using Echocardiography . . . . . . . . . . . . . . . . . . . . . .491
.....
(M. Slama and f. L. Teboul)
Early Transesophageal Echo Doppler Approach in Trauma:

Emergence of a New Tool . . . . . . . . . . . . . . . . . . . . 499
. . ....
(0. Richard, f.M. Caussanel, and Y. Lambert)
Management of Circulatory and Respiratory Failure

Using Less Invasive Hemodynamic Monitoring . . . . . . . . . . . 508
(F. Michard and A. Perel)
Minimally Invasive Hemodynamic Monitoring . . . . . . . . . . . 521

(W. T. Peruzzi, R. Gould, and L. Brodsky)
Oxygen Availability
Microvascular Alterations in Patients with Circulatory Failure 535

(D. De Backer, f. Creteur, and M.f. Dubois)
Critical Tissue Oxygen Thresholds for the Induction

of Apoptosis in Critical Illness . . . . . . . . . . . . . . . . . . . . 545
..
(B. Venkatesh, G. Gobe, and T.f. Morgan)
Reflectance Spectrophotometry and Tissue Oxygenation

in Experimental and Clinical Practice . . . . . . . . . . . . . . 553
.. .
(M.P. Buise, f. van Rommel, and C. !nee)
The Case for Tissue Base Excess . . . . . . . .... . . . . . . 564

....
(T.f. Morgan and B. Venkatesh)
Clinical Use of Venoarterial PC0 2 Difference in Septic Shock . 574

(J. L. Teboul and X. Monnet)
X Contents
Fluid Therapy
Hypovolemia: An Integration of Organ System Physiology . . . 585

(D. L. Traber)
New Light on Volume Therapy in the Critically Ill? . . . . . . 594

..
(!.Boldt)
Ethyl Pyruvate: A Novel Anti-inflammatory Agent ... . ..... 604

(M.P. Fink)
Clinical Use of Artificial Oxygen Carriers 615

(N. Dettori, R. Kocian, and D. R. Spahn)
Is There a Role for Red Blood Cell Transfusion

in the Critically Ill Patient? . . . . . . . . . . . . . . . ... . 623
.... . ..
(H.L. Corwin, M.D. Hampers, and S.D. Surgenor)
Transfusion Triggers 630

(L. T. Goodnough)
Renal Failure
Use of Dopaminergic Agonists for Renal Protection in the ICU 637

(P.T. Murray)
Interpreting the Mechanisms of CRRT in Sepsis:

The Peak Concentration Hypothesis . . . . . . . . . . . . . . 649
.. . . .
(C. Tetta, R. Bellomo, and C. Ronco)
SLEDD and Hybrid Renal Replacement Therapies

for Acute Renal Failure in the ICU . . . . . . . . . . . . . . . . 663. . . .
(W. Van Biesen and N. Lameire)
Brain-lung Interactions
Advanced Airway Management

in the Neurologically Injured Patient . . . . . . . . . . . . . . 679
.. . .
(A. Gabrielli, L.J. Caruso, and A.]. Layon)
Treatment Conflicts between the Injured Brain and the Lung . 701
(T. Lescot, L. Abdennour, and L. Puybasset)
Contents XI
Ventilatory Management in Head Injured Patients . . . . . . . . 710

.
(P. Pelosi, G. Apostolou, and D. Chiumello)
Neurological Crises
Induction of Ischemic Tolerance in the Brain:

A Novel Neuroprotective Strategy? . . . . . . . . . . . . . . . 725
.. ...
(A.M. Brambrink and J.P. Korner)
Positron Emission Tomography:

Anticipated Usefulness in Critical Care Settings . . . . . . . . 737
..
(F. Lamontagne, F. Benard, and 0. Lesur)
Measurement of Regional Cerebral Blood Flow by Near Infrared

Spectroscopy and Indocyanine Green Dye Dilution . . . . . . . 747
.
(E. Keller, A. Nadler, and H. Alkadhi)
Invasive Multimodal Online Monitoring

in Severe Stroke Patients . . . . . . . . . . . . . . . . . . . . 758
.. . ....
(T. Steiner and F. Meisel)
Critical Care of Myasthenic Crisis . . . . . . . . . . . . . . . .765. . . .

(N. ]anjua and S. A. Mayer)
Neuromuscular Abnormalities in Critical Illness . . . . . . . . 776

. .
(T. Sharshar, H. D. Outin, and B. de ]onghe)
Emergency Medicine
Interhospital Pediatric Intensive Care Transport . . . . . . . . .791

.
(G. D. Vos and G. Ramsay)
Carbon Monoxide Poisoning 800

(]. Varon and P. E. Marik)
Club Drugs: A New Challenge in Clinical Toxicology . . . . . . 811

.
(P. Lheureux, A. Penaloza, and M. Gris)
XII Contents
Gl Crises
New Insights into the Pathophysiology and Severity Assessment

of Acute Pancreatitis . . . . . . . . . . . . . . . . . . . . . . 823
...... . .
(D.]. van Westerloo, M.]. Bruno, and T. van der Poll)
Necrosectomy for Severe Acute Pancreatitis 838

(A. Leppiiniemi)
Acute Liver Failure in the ICU .................. . .... 847

(E. Sizer, f. Wendon, and W. Bernal)
Metabolic Support
Critical Role of Hormones in Traumatic Injury and Outcome . 861

( T. S. A. Samy, L. W. Rue III, and I.H. Chaudry)
Hyperglycemia and the Lung . . . . . . . . . . . . . . . . . .873

... . ..
(R.f. Cusack, f. Ball, and B.]. Philips)
Glycolysis in Sepsis and other Stress Conditions . . . . . . . . 881

..
(S. Karyampudi and M. Singer)
Dehydroepiandrosterone (DHEA) and its Sulfate (DHEAS)

in Critical Illness . . . . . . . . . . . . . . . . . . . . . . . . 891
..... . .. .
(A. Beishuizen and A.B.]. Groeneveld)
Vasopressin and Hypothalamic-Pituitary-Adrenal Axis

Relationships . . . . . .. ........ . . . . . . . . . . . 901. . . . . ... .
(F. Lauzier, N. Gallo-Payet, and 0. Lesur)
Clinical Applications of Indirect Calorimetry

in the Intensive Care Setting . . . . . . . . . . . . . . . . . . . 912. . . . . .
(P. Singer and J.D. Cohen)
Management, Education, and Ethics
Can Nosocomial Infections and Iatrogenic Events Serve

as Quality-of-Care Indicators in the ICU? . . . . . . . . . . . 923
... .
(M. Garrouste Orgeas, L. Soufir, and f. F. Timsit)
Contents XIII
Hospital and ICU Organizational Structure

and Quality of Care for Surgical Patients . . . . . . . . . . . . . . . 934
(].B. Dimick, PJ. Pronovost, and P. A. Lipsett)
Volume and Outcome in Pediatric Critical Care:

How Much is Enough? • . . . . . . . . . . . . . . . . . . . . . . . . . . . 945
(R. S. Watson and M. E. Hartman)
Human Factors and ICU Outcomes . . . . . . . . . . . . . . . . . . . 953

(D. T. Huang, f.B. Sexton, and D.C. Angus)
The Risk of Nursing in an Error-Prone Environment . . . . . . . 963

(!. M. Binnekade, M. B. Vroom, and f. Kesecioglu)
Identifying the Patient-at-Risk:

Technology and ICU Outreach Services . . . . . . . . . . . . . . . . 971
(D. C. Scales, f. T. Granton, and W.J. Sibbald)
Multimedia Medical Education and E-Learning . . . . . . . . . . . 982

(M. Antonelli, G. Bello, and M.A. Pennisi)
End-of-Life Care in the ICU:

Toward a Newer Concept of Futility . . . . . . . . . . . . . . . . . . . 991
(D. Crippen)
Subject Index ................................... 1001

List of Contributors
Aarts MA Anantha Samy TS

Dept of Surgery Center for Surgical Research
EN 9-234 and Dept of Surgery
Toronto General Hospital University of Alabama
200 Elizabeth Street at Birmingham
Toronto, Ontario M5G 2C4 Volker Hall
Canada G094 1670 University Blvd
Birmingham, AL 35294-0019
Abdennour L USA
Unit of Neuroanesthesiology
Dept of Intensive Care Angus DC
Hopital de la Pitie-Salp~trierie Room 604 Scaife Hall
47-83 Bvd de l'hOpital The CRISMA Laboratory
75013 Paris Critical Care Medicine
France University of Pittsburgh
3550 Terrace Street
Albaugh GK Pittsburgh, PA 15261
Section of Critical Care Medicine USA
Cooper Health System
One Cooper Plaza-459 Kelemen Antonelli M
Camden, NJ 08103 Dept of Anesthesiology
USA and Intensive Care
Universita Cattolica del Sacro Cuore
Albuszies G Policlinico A. Gemelli
Dept of Anesthesiology Largo A. Gemelli 8
University Hospital 00168 Rome
SteinhovelstraBe 9 Italy
89070 U1m
Germany Apostolou G
Dept of Clinical
Alexopoulou C and Biological Science
Dept of Intensive Care Universita degli Studi dell'Insubria
University Hospital of Heraklion Varese
Heraklion Italy
71110 Crete
Greece Ayoub 1M
Medical Service (111F)
Alkadhi H North Chicago VA Medical Center
Institute of Neuroradiology 3001 Green Bay Road
University of Zurich North Chicago, IL 60064
FrauenklinikstraBe 10 USA
8091 Zurich
Switzerland
XVI List of Contributors
Azoulay E Bellomo C
Dept of Intensive Care Dept of Nephrology, Dialysis,
Hopital Saint-Louis and Transplantation
1 Av Claude Vellefaux St Bortolo Hospital
75010 Paris Viale Rodolfi 31
France Vicenza
Italy
Ball J
Intensive Care Unit Benard F
St James' Wing Dept of Nuclear Medicine
St George's Hospital and Radiobiology
Blackshaw Road Universiz of Sherbrooke
London SW17 OQT 3001, 12 Avenue Nord
UK Sherbrooke, Quebec J1H 3J5
Canada
Baudouin SV
Dept of Anesthesiology Benatar A
Leazes Wing Pediatric Intensive Care Unit
Royal Victoria Infirmary AZ-Vrije Universiteit Brussel
Newcastle-upon-Tyne NE1 4LP 101 Laarbeeklaan
UK 1090 Brussels
Belgium
Beck]
Dept of Medicine Bernal W
Sainte-Justine Hospital Liver Intensive Care Unit
3175 Chemin de la C6te Institute of Liver Studies
Ste-Catherine 7th floor King's College Hospital
Montreal, Quebec H3T 1C5 Bessemer Road
Canada London SE15 9RS
UK
Beck-Schimmer B
Institute of Anesthesiology Binnekade ]M
and Institute of Physiology Dept of Intensive Care
University of Zurich-Irchel Academic Medical Center
RaemistraEe 100 University of Amsterdam
8091 Zurich Mail stop G3-206
Switzerland PO Box 22700
1100 DE Amsterdam
Beishuizen A The Netherlands
Dept of Intensive Care
VU University Medical Center Boldt J
De Boelelaan 1117 Dept of Anesthesiology
1081 HV Amsterdam and Intensive Care Medicine
The Netherlands Klinikum der Stadt Ludwigshafen
BremserstraEe 79
Bello G 67063 Ludwigshafen
Dept of Anesthesiology Germany
and Intensive Care
Universita Cattolica del Sacro Cuore Bottino N
Policlinico A. Gemelli Dept of Anesthesiology
Largo A. Gemelli 8 and Intensive Care
00168 Rome Universita degli Studi di Milano
Italy Ospedale Policlinico-IRCCS
Via F. Sforza 35
20122 Milan
Italy
List of Contributors XVII
Brambrink AM Burgner D
Department of Anesthesiology Pediatric Infectious Diseases
Johannes Gutenberg-University School of Pediatrics
Mainz and Child Health
LangenbeckstraBe 1 University of Western Australia
55131 Mainz Princess Margaret Medical Center
Germany GPO Box D184
Perth WA 6840
Brett S Australia
Department of Anaesthesia
and Intensive Care Cabello B
Hammersmith Hospital Dept of Intensive Care
Du Cane Road Hospital de la Santa Creu I Sant Pau
London W12 OHS Av SAM Claret 167
UK 08025 Barcelona
Spain
Brodsky L
Section of Critical Care Medicine Caruso LJ
Northwestern University Dept of Anesthesiology and Surgery
Feinberg School of Medicine University of Florida
251 E. Huron College of Medicine
Feinberg 8-336 PO Box 100254
Chicago, IL 60611 Gainesville, FL 32610-0254
USA USA
Bruins MJ Caussanel ]M
Bioavailability Service d' Aide Medicale Urgente
Unilever Health Institute (SAMU 78)
Unilever Research Vlaardingen Service Mobile d'Urgence
PO Box 114 et de Reanimation
3130 AC Vlaardingen Versailles Hospital
The Netherlands 177 rue de Versailles
78150 Le Chesnay
Bruno MJ France
Division of Gastroenterology
and Hepatology Chaudry IH
Academic Medical Center Center for Surgical Research
Meibergdreef 9 and Dept of Surgery
C2-321 University of Alabama
1105 AZ Amsterdam at Birmingham
The Netherlands Volker Hall
G094 1670 University Blvd
Buise MP Birmingham, AL 35294-0019
Dept of Anesthesiology USA
Erasmus MC Rotterdam
Dr. Molewaterplein 40 Chiumello D
3000 CA Rotterdam Dept of Anesthesiology
The Netherlands and Intensive Care
Universita degli Studi di Milano
Burnham EL Ospedale Policlinico-IRCCS
Division of Pulmonary, Allergy, Via F. Sforza 35
and Critical Care 20122 Milan
Grady Memorial Hospital Italy
69 Jesse Hill Jr Drive SE
Suite 2D-004
Atlanta, GA 30303
USA
XVIII list of Contributors
Claessens YE Cusack R/
Medical Intensive Care Unit Intensive Care Unit
Cochin University Hospital St James' Wing
27 rue du Faubourg Saint-Jacques St George's Hospital
75679 Paris cedex 14 Blackshaw Road
France London SW17 OQT
UK
Cohen ]D
Department of General De Backer D
Intensive Care Dept of Intensive Care
Rabin Medical Center Erasme Hospital
Campus Beilinson Free University of Brussels
49100 Petah Tikva 808 Route de Lennik
Israel 1070 Brussels
Belgium
Cornelie de Pont A
Dept of Vascular Medicine/Internal Deigner HP
Medicine Clinics of Anesthesiology
Academic Medical Centre F-4 and Intensive Care
Meibergdreef 9 Friedrich Schiller University of Jena
1105 AZ Amsterdam BachstraBe 18
The Netherlands 07743 Jena
Germany
Corwin HL
Section Critical Care Medicine de]ongSWM
Dept of Anesthesiology Department of Anesthesiology
Dartmouth Hitchcock Medical Academic Medical Center
Center Meibergdreef 9
Dartmouth Medical School 1105 AZ Amsterdam
One Medical Center Drive The Netherlands
Lebanon NH 03756
USA de ]onge E
Dept of Vascular Medicine/
Coutts ]F Internal Medicine
Department of Cardiology Academic Medical Centre F-4
Guys & St Thomas' NHS Trust Meibergdreef 9
Lambeth Palace Rd 1105 AZ Amsterdam
London SE1 7EH The Netherlands
UK
de ]onghe B
Creteur / Dept of Intensive Care
Dept of Intensive Care Centre Hospitalier de Poissy
Erasme Hospital 10 rue du champ-Gaillard
Free University of Brussels 78300 Poissy
808 Route de Lennik France
1070 Brussels
Belgium Dellinger RP
Section of Critical Care Medicine
Crippen D Cooper Health System
Dept of Critical Care Medicine One Cooper Plaza-459 Kelemen
University of Pittsburgh Camden, NJ 08103
Medical Center USA
616 Scaife Hall
Pittsburgh, PA 15261 Dettori N
USA Dept of Anesthesiology
University Hospital Lausanne
1011 Lausanne
Switzerland
list of Contributors XIX
Dias CS Foti G
Critical Care Dept Institute of Anesthesia
Hospital Universitari Joan XXIII and Intensive Care Unit
Carrer Dr Mallafre Guasch 4 Department of Surgical Science
43007 Tarragona and Intensive Care
Spain Milano-bicocca University
San Gerardo Hospital
Dimick]B Via Donizetti 106
The John Hopkins Hospital Monza
600 N. Wolfe Street Milan
Blalock 685 Italy
Baltimore, MA 21287-4685
USA Fowler RL
Dept of Surgery
Diprose P University of Texas
Division of Cardiac Anesthesia Southwestern Medical Center
Dept of Anesthesia 5323 Harry Hines Blvd
E Level Dallas, TX 75490-8579
Center Block USA
Southampton University Hospital
Southampton S016 6YD Frutos-Vivar F
UK Unidad de Cuidados Intensivos
Hospital Universitario de Getafe
Dubois M] Carretera de Toledo Km 12,500
Dept of Intensive Care 28905 Getafe
Erasme Hospital Madrid
Free University of Brussels Spain
808 Route de Lennik
1070 Brussels Gabrielli A
Belgium Dept of Anesthesiology and Surgery
University of Florida
Esteban A College of Medicine
Unidad de Cuidados Intensivos PO Box 100254
Hospital Universitario de Getafe Gainesville, FL 32610-0254
Carretera de Toledo Km 12,500 USA
28905 Getafe
Madrid Gallo-Payet N
Spain Endocrinology Service
Dept of Medicine
Ferguson ND Universiz of Sherbrooke
Dept of Medicine 3001, 12 Avenue Nord
Division of Respirology/Critical Care Sherbrooke, Quebec JlH 3J5
University of Toronto Canada
200 Elizabeth Street
Toronto, Ontario M5G 2C4 Garrouste Orgeas M
Canada Dept of Intensive Care
St. Joseph Hospital
Fink MP Paris
Dept of Critical Care Medicine France
University of Pittsburgh
Medical School Gazmuri R]
3550 Terrace Street Medical Service (111F)
Room 616 Scaife Hall North Chicago VA Medical Center
Pittsburgh, PA 15261 3001 Green Bay Road
USA North Chicago, IL 60064
USA
XX List of Contributors
Georgopoulos D Gris M
Dept of Intensive Care Department of Emergency Medicine
University Hospital of Heraklion Acute Poisons Unit
Heraklion Erasme University Hospital
71110 Crete Route de Lennik 808
Greece 1070 Brussels
Belgium
Gill R
Division of Cardiac Anesthesia Groeneveld AB]
Dept of Anesthesia Dept of Intensive Care
E Level VU University Medical Center
Center Block De Boelelaan 1117
Southampton University Hospital 1081 HV Amsterdam
Southampton S016 6YD The Netherlands
UK
Gupta K]
Gobe G Dept of Anesthesia
Dept of Molecular and Intensive Care
and Cellular Pathology Royal United Hospital
University of Queensland Bath BA1 3NG
Herston, QLD 4006 United Kingdom
Australia
Haitsma]]
Goldstein P Department of Anesthesiology
Dept of Emergency Medicine Room EE 2393
Centre Hospitalier Regional Erasmus University Rotterdam
Universitaire de Lille Post Box 1738
Lille 59037 3000 DR Rotterdam
Lille Cedex The Netherlands
France
Hall A
Goodnough LT Dept of Intensive Care
Division of Laboratory Medicine Western Hospital
Washington University School Footscray 3011
of Medicine Melbourne
660 South Euclid Avenue Australia
St Louis, MO 63110
USA Hampers MD
Section Critical Care Medicine
Gould R Dept of Anesthesiology
Section of Critical Care Medicine Dartmouth Hitchcock Medical
Northwestern University Center
Feinberg School of Medicine Dartmouth Medical School
251 E. Huron One Medical Center Drive
Feinberg 8-336 Lebanon, NH 03756
Chicago, IL 60611 USA
USA
Hartman ME
Granton J Dept of Critical Care Medicine
Dept of Critical Care University of Pittsburgh
University of Toronto 606C Scaife Hall
Health Network 3550 Terrace Street
TGH-10EN-220 Pittsburgh, PA 15261
200 Elizabeth Street USA
Toronto, Ontario
Canada
List of Contributors XXI
Heininger A Karyampudi S
Dept of Anesthesiology Bloomsbury Institute
and Intensive Care Medicine of Intensive Care Medicine
University Hospital Tiibingen University College London
Hoppe-Seyler Str 3 Fifth Floor, Jules Thorn Building
72076 Ti.ibingen Middlesex Hospital
Germany Mortimer Street
London W1 T 3AA
Herbertson M UK
Division of Cardiac Anesthesia
Dept of Anesthesia Keller E
E Level Department of Neurosurgery
Center Block University Hospital
Southampton University Hospital FrauenklinikstraBe 10
Southampton S016 6YD 8091 Zi.irich
UK Switzerland
Hollenberg SM Kesecioglu MB
Section of Cardiology Dept of Anesthesiology,
Cooper Hospital/ Cardiothoracic and Neurosurgical
University Medical Center Intensive Care Unit
One Cooper Plaza Division of Perioperative Medicine
Room 404 and Emergency Care
Camden, NJ 08103 University Medical Center Utrecht
USA Mail stop E03-511
PO Box 85500
Huang DT 3508 GA Utrecht
Room 604 Scaife Hall The Netherlands
The CRISMA Laboratory
Critical Care Medicine Kluytmans ]A]W
University of Pittsburgh Department of Clinical Microbiology
3550 Terrace Street Amphia Hospital Breda
Pittsburgh, PA 15261 Location Langendijk
USA PO Box 90158
4800 RK Breda
!nee C The Netherlands
Dept of Anesthesiology
Academic Medical Center Kocian R
Meibergdreef 9 Dept of Anesthesiology
1105 AZ Amsterdam University Hospital Lausanne
The Netherlands 1011 Lausanne
Switzerland
]anjua N
Depts of Neurocritical Care Kolarova J
Columbia Presbyterian Medical Service ( 111 F)
Medical Center North Chicago VA Medical Center
710 W 1681h St, Box 119 3001 Green Bay Road
New York, NY 10032 North Chicago, IL 60064
USA USA
Kacion R Kondili E
Dept of Anesthesiology Dept of Intensive Care
University Hospital Lausanne University Hospital of Heraklion
1011 Lausanne Heraklion
Switzerland 71110 Crete
Greece
XXII List of Contributors
Korner IP Lameire N
Department of Anesthesiology Renal Division
Johannes Gutenberg-University University Hospital of Ghent
Mainz De Pintelaan 185
LangenbeckstraBe 1 9000 Ghent
55131 Mainz Belgium
Germany
Lamontagne F
Kotanidou A Medical Intensive Care Unit
Department of Critical Care Dept of Medicine
& Pulmonary Medicine Universiz of Sherbrooke
University of Athens Medical School 3001, 12 Avenue Nord
Evangelismos Hospital Sherbrooke, Quebec J1H 3J5
45-47 lpsilandou Street Canada
10675 Athens
Greece Lauzier F
Medical Intensive Care Unit
Koutsoukou A Dept of Medicine
Critical Care Department Universiz of Sherbrooke
Evangelismos General Hospital 3001, 12 Avenue Nord
45-47 Ipsilandou Street Sherbrooke, Quebec J1H 3J5
10675 Athens Canada
Greece
Layon A]
Krueger WA Dept of Anesthesiology and Surgery
Dept of Anesthesiology University of Florida
and Intensive Care Medicine College of Medicine
University Hospital Tiibingen PO Box 100254
Hoppe-Seyler StraBe 3 Gainesville, FL 32610-0254
72076 Tiibingen USA
Germany
Lebuffe G
Lachmann B Dept of Anesthesiology
Dept of Anesthesiology and Intensive Care II
Erasmus Medical Center H6pital Claude Huriez
PO Box 1738 Centre Hospitalier Universitaire
3000 DR Rotterdam Lille
The Netherlands France
Lachmann RA Leppiiniemi A
Department of Anesthesiology Dept of Surgery
RoomE 2393 Meilahti Hospital
Erasmus University Rotterdam University of Helsinki
Post Box 1738 Haartmaninkatu 4
3000 DR Rotterdam PO Box 340
The Netherlands 00029 HUS
Finland
LambertY
Service d'Aide Medicale Urgente Lescot T
(SAMU 78) Unit of Neuroanesthesiology
Service Mobile d'Urgence Dept of Intensive Care
et de Reanimation H6pital de Ia Pitie-Salp~trierie
Versailles Hospital 47-83 Bvd de l'h6pital
177 rue de Versailles 75013 Paris
78150 Le Chesnay France
France
List of Contributors XXIII
Lesur 0 Marik PE
Medical Intensive Care Unit Dept of Medicine and Critical Care
Dept of Medicine University of Pittsburgh
Universi}l of Sherbrooke School of Medicine
3001, 12 Avenue Nord 3550 Terrace Street
Sherbrooke, Quebec JlH 3J5 Pittsburgh, PA 15261
Canada USA
Levi M Marshall ]C
Dept of Vascular Medicine/ Division of Intensive Care Medicine
Internal Medicine EN 9-234
Academic Medical Centre F-4 Toronto General Hospital
Meibergdreef 9 200 Elizabeth Street
1105 AZ Amsterdam Toronto, Ontario M5G 2C4
The Netherlands Canada
Levin M Martin GS
Pediatric Infectious Diseases Division of Pulmonary, Allergy,
Imperial College Faculty of Medicine and Critical Care
7th floor, QEQM Wing Grady Memorial Hospital
St Mary's Campus 69 Jesse Hill Jr Drive SE
London W2 1PG Suite 2D-004
UK Atlanta, GA 30303
USA
Lheureux P
Department of Emergency Medicine Mayer SA
Erasme University Hospital Depts of Neurology
Route de Lennik 808 and Neurosurgery
1070 Brussels Columbia Presbyterian Medical
Belgium Center
710 W 168th St, Box 39
Lipsett PA New York, NY 10032
The John Hopkins Hospital USA
600 N. Wolfe Street
Blalock 685 Meisel F
Baltimore, MA 21287-4685 Dept of Neurology
USA University of Heidelberg
Im Neuenheimer Feld 400
Macintyre N 69120 Heidelberg
Dept of Respiratory Care Services, Germany
Pulmonary Function Laboratory,
Pulmonary Rehabilitation Program Menendez R
Duke University Medical Center Dept of Pulmonary Medicine
Box 3911, Room 7451 Duke North Hospital Universitario La Fe
Durham, NC 27710 Valencia
USA Spain
Mancebo J Michard F
Dept of Intensive Care Medical ICU
Hospital de Ia Santa Creu I Sant Pau Bictre Hospital
Av SAM Claret 167 78 rue du General Leclerc
08025 Barcelona 94275 Le Kremlin Bicetre cedex
Spain France
XXIV List of Contributors
Milic-Emili JM Nadler A
Meakins-Christie Laboratories Dept of Biomedicine
McGill University University Hospital
Montreal, Quebec FrauenklinikstraEe 10
Canada 8091 Ziirich
Switzerland
Mira]P
Medical Intensive Care Unit Najafi N
Cochin University Hospital Pediatric Intensive Care Unit
27 rue du Faubourg Saint-Jacques AZ-Vrije Universiteit Brussel
75679 Paris cedex 14 101 Laarbeeklaan
France 1090 Brussels
Belgium
Monnet X
Medical Intensive Care Unit Older P
CHU Bicetre Dept of Intensive Care
Universite Paris XI Western Hospital
94275 Le Kremlin-Bicetre Footscray 3011
France Melbourne
Australia
Morgan TJ
Dept of Intensive Care Orfanos SE
Mater Misericordiae Hospital Department of Critical Care
Queensland & Pulmonary Medicine
Australia University of Athens Medical School
Evangelismos Hospital
MossM 45-47 Ipsilandou Street
Division of Pulmonary, Allergy, 10675 Athens
and Critical Care Greece
Grady Memorial Hospital
69 Jesse Hill Jr Drive SE Outin HD
Suite 2D-004 Dept of Intensive Care
Atlanta, GA 30303 Centre Hospitalier de Poissy
USA 10 rue du champ-Gaillard
78300 Poissy
Mourvillier B France
Dept of Intensive Care
Hllpital Bichat Claude Bernard Paiva fA
Rue Henri Huchard 46 Hospital San Joao
75018 Paris Porto
France Portugal
Murray PT Pasch T
Section of Nephrology, MC 5100 Institute of Anesthesiology
University of Chicago Hospitals University of Zurich-Irchel
5841 South Maryland Avenue RaemistraEe 100
Chicago, IL 60637 8091 Zurich
USA Switzerland
Mythen M
Portex Unit
6th Floor Cardiac Wing
Institute of Child Health
30 Guilford Street
London WC1N IEH
UK
List of Contributors XXV
Patroniti N PereZ A
Institute of Anesthesia Dept of Anesthesiology
and Intensive Care Unit and Intensive Care
Department of Surgical Science Sheba Medical Center
and Intensive Care Tel Aviv University
Milano-bicocca University 52621 Tel Hashomer
San Gerardo Hospital Israel
Via Donizetti 106
Monza Peruzzi WT
Milan Section of Critical Care Medicine
Italy Northwestern University
Feinberg School of Medicine
Pechlaner C 251 E. Huron
Medizinische Klinik Feinberg 8-336
University of Innsbruck Chicago, IL 60611
AnichstraBe 35 USA
6020 Innsbruck
Austria Pesenti A
Institute of Anesthesia
Pelosi P and Intensive Care Unit
Dept of Intensive Care Department of Surgical Science
Ospedale di Circolo Fondazione and Intensive Care
Macchi Milano-bicocca University
Via Borri 57 San Gerardo Hospital
2100 Varese Via Donizetti 106
Italy Monza
Milan
Penaloza A Italy
Department of Emergency Medicine
Acute Poisons Unit Philips B]
Erasme University Hospital Department of Anaesthetics
Route de Lennik 808 and Intensive Care
1070 Brussels St George's Hospital Medical School
Belgium Cranmer Terrace
London SW17 ORE
Pene F UK
Medical Intensive Care Unit
Cochin University Hospital Pinsky MR
27 rue du Faubourg Saint-Jacques Dept of Critical Care Medicine
75679 Paris cedex 14 University of Pittsburgh
France Medical Center
606 Scaife Hall
Pennini MA 3550 Terrace Street
Dept of Anesthesiology Pittsburgh, PA 15261
and Intensive Care USA
Universita Cattolica del Sacro Cuore
Policlinico A. Gemelli Pittman ]AL
Largo A. Gemelli 8 Dept of Anesthesia
00168 Rome and Intensive Care
Italy Royal Devon and Exeter Hospital
Exeter
Pepe PE Devon EX2 5DW
Dept of Emergency Medicine UK
University of Texas
Southwestern Medical Center
5323 Harry Hines Blvd
Dallas, TX 75490-8579
USA
XXVI List of Contributors
Poeze M Redwood SR
Department of Surgery Department of Cardiology
and Intensive Care Medicine King's College London
University Hospital Maastricht The Rayne Institute
P. Debyelaan 25 Guy's and St. Thomas' Hospitals
6202 AZ Maastricht London SE1 7EH
The Netherlands UK
Pronovost P] Reinhart K
The John Hopkins Hospital Clinics of Anesthesiology
600 N. Wolfe Street and Intensive Care
Blalock 685 Friedrich Schiller University of Jena
Baltimore, MA 21287-4685 BachstraBe 18
USA 07743 Jena
Germany
Puybasset L
Unit of Neuroanesthesiology Rello]
Dept of Intensive Care Critical Care Dept
Hopital de Ia Pitie-Salpetrierie Hospital Universitari Joan XXIII
47-83 Bvd de l'hOpital Carrer Dr Mallafre Guasch 4
75013 Paris 43007 Tarragona
France Spain
Radermacher P Rhodes A
University Hospital St George's Hospital
SteinhovelstraBe 9 Blackshaw Rd
89070 Ulm London SW17 OQT
Germany
Richard 0
Ramet] Service d' Aide Medicale Urgente
Pediatric Intensive Care Unit (SAMU 78)
AZ-Vrije Universiteit Brussel Service Mobile d'Urgence
101 Laarbeeklaan et de Reanimation
B-1 090 Brussels Versailles Hospital
Belgium 177 rue de Versailles
78150 Le Chesnay
Ramsay G France
Dept of Surgery and Intensive Care
University Hospital Maastricht Ronco C
PO Box 5800 Dept of Nephrology, Dialysis,
6202 AZ Maastricht and Transplantation
The Netherlands St Bortolo Hospital
Viale Rodolfi 31
Ranieri VM Vicenza
University of Turin Italy
Dipartimento di discipline Medico-
Chirurgiche Rossi A
Sezione di Anestesiologia University of Turin
e Rianimazione Dipartimento di discipline Medico-
Ospedale S. Giovanni Battista Chirurgiche
Corso Dogliotti 14 Sezione di Anestesiologia
10126 Turin e Rianimazione
Italy Ospedale S. Giovanni Battista
Corso Dogliotti 14
10126 Turin
Italy
List of Contributors XXVII
Roussos C Sexton ]B
Critical Care Department The University of Texas
Evangelismos General Hospital Team Research Project
45-47 lpsilandou Street Department of Psychology
10675 Athens The University of Texas at Austin
Greece Austin TX
USA
Rue LW III
Center for Surgical Research Sharshar T
and Dept of Surgery Respiratory Muscle Laboratory
University of Alabama Royal Brompton Hospital
at Birmingham Fulham Road
Volker Hall London SW3 6NP
G094 1670 University Blvd UK
Birmingham, AL 35294-0019
USA Sibbald W]
Dept of Critical Care
Russwurm S Sunnybrook & Women's College
Clinics of Anesthesiology Health Sciences Center
and Intensive Care 2075 Bayview Avenue Suite D474
Friedrich Schiller University of Jena Toronto, Ontario M4N 3M5
BachstraBe 18 Canada
07743 Jena
Germany Sinderby C
Dept of Pediatrics
Scales DC Sainte-Justine Hospital
Dept of Critical Care 3175 Chemin de la Cote
Sunnybrook & Women's College Ste-Catherine 7th floor
Health Sciences Center Montreal, Quebec H3T 1C5
2075 Bayview Avenue Suite D474 Canada
Toronto, Ontario M4N 3M5
Canada Singer M
Bloomsbury Institute
Schimmer RC of Intensive Care Medicine
Dept of Surgery University College London
University of Zurich Fifth Floor, Jules Thorn Building
RaemistraBe 100 Middlesex Hospital
8091 Zurich Mortimer Street
Switzerland London W1 T 3AA
UK
Schlemmer B
Dept of Intensive Care Singer P
Hopital Saint-Louis Dept. of General Intensive Care
1 Av Claude Vellefaux Rabin Medical Center
75010 Paris Campus Beilinson
France 49100 Petah Tikva
Israel
Schultz M]
Dept of Intensive Care Medicine Slama M
C3-326 Dept of Intensive Care,
Academic Medical Center Nephrology Service
Meibergdreef 9 CHU Sud
1105 AZ Amsterdam Avenue Rene Laennec.
The Netherlands 80054 Amiens Cedex 1
France
XXVIII List of Contributors
Soufir L Tetta C
Dept of Anesthesiology Dept of Nephrology, Dialysis,
St. Joseph Hospital and Transplantation
Paris St Bortolo Hospital
France Viale Rodolfi 31
Vicenza
Spahija] Italy
Dept of Medicine
Sainte-Justine Hospital Timsit ]F
3175 Chemin de Ia Cote Dept of Intensive Care
Ste-Catherine 7th floor Hopital Bichat Claude Bernard
Montreal, Quebec H3T 1C5 Rue Henri Huchard 46
Canada 75018 Paris
France
Spahn DR
Dept of Anesthesiology Torres A
University Hospital Lausanne Dept of Pulmonary Medicine
1011 Lausanne Institut Clinic de Pneumologia
Switzerland i Cirugia Tonicica
Hospital Clinic
SteinerT Villarroel 170
Dept of Neurology 08036 Barcelona
University of Heidelberg Spain
Im Neuenheimer Feld 400
69120 Heidelberg Traber DL
Germany Investigative Intensive Care Unit
University of Texas Medical Branch
Stephens R 610 Texas Avenue
Portex Unit Galveston, TX 77555-0833
6th Floor Cardiac Wing USA
Institute of Child Health
30 Guilford Street Unertl KE
London WC1N IEH Dept of Anesthesiology
UK and Intensive Care Medicine
University Hospital Tiibingen
Stewart TE Hoppe-Seyler StraBe 3
University of Toronto 72076 Tiibingen
Department of Medicine Germany
Mount Sinai Hospital
Toronto Vallet B
Canada Dept of Anesthesiology
and Intensive Care II
Surgenor SD Hopital Claude Huriez
Section Critical Care Medicine Centre Hospitalier Universitaire
Dept of Anesthesiology Lille
Dartmouth Hitchcock Medical Center France
Dartmouth Medical School
One Medical Center Drive Van Biesen W
Lebanon, NH 03756 Renal Division
USA University Hospital of Ghent
De Pintelaan 185
Teboul ]L 9000 Ghent
Medical Intensive Care Unit Belgium
CHU Bicetre
Universite Paris XI
94275 Le Kremlin-Bid~tre
France
List of Contributors XXIX
van Bommel] Vroom MB

Erasmus MC Rotterdam Academic Medical Center
Dr. Molewaterplein 40 University of Amsterdam
3000 CA Rotterdam Mail stop G3-206
The Netherlands PO Box 22700
llOO DE Amsterdam
van der Poll T The Netherlands
Dept of Infectious Diseases,
Tropical Medicine and AIDS Waheed U
Academic Medical Center Department of Anaesthesia
Meibergdreef 9 and Intensive Care
C2-321 Hammersmith Hospital
ll05 AZ Amsterdam Du Cane Road
The Netherlands London W12 OHS
UK
van Westerloo D]
Division of Gastroenterology Watson RS
and Hepatology Dept of Critical Care Medicine
Academic Medical Center University of Pittsburgh
Meibergdreef 9 606C Scaife Hall
C2-321 3550 Terrace Street
ll05 AZ Amsterdam Pittsburgh, PA 15261
The Netherlands USA
van Wezel HB Wendon]

Department of Anesthesiology Liver Intensive Care Unit
Academic Medical Center Institute of Liver Studies
Meibergdreef 9 King's College Hospital
ll05 AZ Amsterdam Bessemer Road
The Netherlands London SE15 9RS
UK
Varon]
Pulmonary and Critical Care Section Wertheim HFL
University of Texas University Hospital Erasmus MC
Health Science Center Dr. Molewaterplein 40
2219 Derrington Rotterdam
Houston, TX 77030 The Netherlands
USA
Wiedermann C]
Venkatesh B Medizinische Klinik
Dept of Intensive Care University of lnnsbruck
Royal Brisbane Hospital AnichstraBe 35
Herston, QLD 4029 6020 Innsbruck
Australia Austria
Vas GD WielE
Dept of Pediatrics Dept of Anesthesiology
Division of Pediatric Intensive Care and Intensive Care II
University Hospital Maastricht Hopital Claude Huriez
PO Box 5800 Centre Hospitalier Universitaire
6202 AZ Maastricht Lille
The Netherlands France
XXX List of Contributors
Wigginton ]G Yende S
Dept of Surgery Division of Pulmonary
University of Texas and Critical Care
Southwestern Medical Center The University of Tennessee
5323 Harry Hines Blvd Health Science Center
Dallas, TX 75490-8579 Memphis, TN 38104
USA USA
Wunderink R
Physicians Research Network
University of Tennessee
1265 Union Ave-501 Crews
Memphis, TN 38104
USA
Common Abbreviations
AIDS Acquired immunodeficiency syndrome

ALI Acute lung injury
APACHE Acute physiology and chronic health evaluation
APC Activated protein C
ARDS Acute respiratory distress syndrome
ATP Adenosine triphosphate
BAL Bronchoalveolar lavage
BiPAP Bilevel positive airway pressure
CBF Cerebral blood flow
CNS Central nervous system
COPD Chronic obstructive pulmonary disease
CPAP Continuous positive airway pressure
CPP Cerebral perfusion pressure
CRP C-reactive protein
CSF Cerebrospinal fluid
CT Computerized tomography
DIC Disseminated intravascular coagulation
DNA Deoxyribonucleic acid
D02 Oxygen delivery
EEG Electroencephalogram
EKG Electrocardiogram
EVLW Extravascular lung water
FRC Functional residual capacity
GCS Glasgow coma scale
G-CSF Granulocyte-colony stimulating factor
HIV Human immunodeficiency virus
ICAM Intercellular adhesion molecule
ICH Intracranial hypertension
ICP Intracranial pressure
ICU Intensive care unit
IFN Interferon
IL Interleukin
XXXII Common Abbreviations
1/R Ischemia-reperfusion
IV Intravenous
LPS Lipopolysaccharide
MAP Mean arterial pressure
MOF Multiple organ failure
MRI Magnetic resonance imaging
NAD Nicotinamide adenine dinucleotide
NF-KB Nuclear factor kappa-B
NO Nitric oxide
NOS Nitric oxide synthase
PAC Pulmonary artery catheter
PAl Plasminogen activator inhibitor
PAOP Pulmonary artery occlusion pressure
PEEP Positive end-expiratory pressure
pHi Gastric intramucosal pH
PSV Pressure support ventilation
RBC Red blood cell
RNA Ribonucleic acid
ROS Reactive oxygen species
SIRS Systemic inflammatory response syndrome
SVR Systemic vascular resistance
TBI Traumatic brain injury
TLC Total lung capacity
TNF Tumor necrosis factor
VAP Ventilator-associated pneumonia
VILI Ventilator-induced lung injury
vo2 Oxygen consumption
WBC White blood cell
ZEEP Zero end-expiratory pressure
Epithelial-Endothelial Alterations
Role of Epithelial ICAM-1
in Endotoxin-Induced Lung Injury
B. Beck-Schimmer, R. C. Schimmer, and T. Pasch
I Introduction
Distal airway epithelial cells, alveolar epithelial cells, are vital for maintenance of
the pulmonary air-blood barrier. Gaseous diffusion occurs across alveolar type I
cells, large thin cells that cover the majority of the alveolar surface. Type II cells
are cuboidal cells, which produce pulmonary surfactant. They are also progenitor
cells capable of proliferating and differentiating into type I cells [1]. Recent evi-
dence suggests that airway epithelial cells might also act as immune effector cells
in response to noxious endogenous or exogenous stimuli. Several studies have
shown that airway epithelial cells express and secrete various immune molecules
such as adhesion molecules, cytokines and chemokines. Through the expression
and production of these inflammatory mediators, the airway epithelium is thought
to play an important role in the initiation and exacerbation of inflammatory re-
sponse within the airway.
Leukocyte homing to sites of acute inflammation is a crucial step during an
inflammatory response. Adhesion molecules such as intercellular adhesion mole-
cule-1 (ICAM-1) play a major part in the inflammatory process by mediating ad-
herence of leukocytes to endothelium and initiating extravasation of these cells [2].
ICAM-1, a member of the immunoglobulin superfamily, is a cell surface glyco-
protein and a ligand for the P2 integrins CD1la/CD18 (LFA-1) and CD11b/CD18
(Mac-1) on leukocytes. Under normal conditions, ICAM-1 is present at low levels
on endothelial cells. It is up-regulated by a variety of inflammatory stimuli such as
endotoxin and different cytokines. It appears that the up-regulation of ICAM-1 is
important in both adhesion and migration of circulating neutrophils into inflamed
tissue. While endothelial ICAM-1 has been explored in detail, epithelial ICAM-1,
however, has been characterized much less and its functional role might be differ-
ent from endothelial ICAM-1.
In acute lung injury (ALI) and acute respiratory distress syndrome (ARDS},
ICAM-1 probably plays a crucial role although the great complexity of these immu-
nological processes is incompletely understood. In septic ARDS, the interaction be-
tween pathogens and macrophages or leukocytes results in a release of cytokines
causing lung damage [3]. This process is believed to be mediated through proteases
and oxidative metabolites of neutrophils that adhere to pulmonary endothelium
[4]. The role of adherence processes to alveolar epithelium in the pathogenesis of
ALI, and accordingly the role of ICAM-1 in this context, has still to be defined.
This chapter reviews insights into the role of ICAM-1 in alveolar epithelial cells in
vitro and in vivo in the inflammatory process of endotoxin-induced lung injury.
4 B. Beck-Schimmer et al.
In Vitro Studies on ICAM-1 Expression in Alveolar Epithelial Cells

It has been a general belief for many years that endothelial cells are the main
source of inflammatory mediators being produced during exposure of the lung to
an endotoxin such as lipopolysaccharide (LPS}. In the early 1990s, experimental
work from in vitro studies provided direct evidence that ICAM-1 is expressed on
alveolar epithelial cells [5, 6]. It was reported that rat alveolar epithelial cells in pri-
mary culture express ICAM-1, as determined by immunofluorescence staining and
Western blot analysis [5]. Immediately after isolation of type II cells, ICAM-1 was
not detected, but appeared after 48 hours when cells had changed their phenotype
towards type I cells. Therefore, it was assumed that ICAM-1 expression was a dif-
ferentiation-related feature of the type I cell phenotype. In addition, ICAM-1 ex-
pression was influenced by spatial interactions of the cells with the basement mem-
brane and other epithelial cells [6]. Constitutive ICAM-1 expression was not only
detected in isolated alveolar epithelial cell but also in the alveolar epithelium in
whole lung tissue [7].
A very surprising finding was the fact that, on stimulation with tumor necrosis
factor-a (TNF-a) and interferon-y (IFN-y), ICAM-1 was not found to be up-regu-
lated on alveolar epithelial cells in vitro [8]. The striking lack of a response of
ICAM-1 expression by alveolar epithelial cells to inflammatory cytokines was in
contrast to virtually all other epithelial cell studies. Years later, Fakler et al. demon-
strated a clear up-regulation of ICAM-1 on a transformed human cell line of alveo-
lar epithelial cells upon LPS-stimulation [9]. In addition, Dentener et al. described
a human alveolar epithelial cell line producing LPS-binding protein in response to
interleukin-1/1 (IL-1/1) and TNF-a [10]. The results of this group also implicated
that these cells were involved in inflammatory processes. On 12 cells, a cell line of
rat alveolar epithelial cell, enhanced ICAM-1 expression was seen as well after en-
dotoxin exposure [11]. In a recent study, ICAM-1 expression was assessed by stim-
ulating primary culture of alveolar epithelial cells with TNF-a, IFN-y and LPS [12].
All these experiments clearly showed up-regulation of ICAM-1 mRNA and protein
after stimulation with any of these three agonists, whereby LPS caused the strongest
up-regulation. These newer data imply that epithelial ICAM-1 is involved in the in-
flammatory response in endotoxin-induced lung injury.
In order to obtain more insight into the biological function of ICAM-1 expres-
sion, several studies aimed at the localization of ICAM-1 on alveolar epithelial cells.
Guzman et al. showed ICAM-1 to be expressed just on one side of the surface of
freshly isolated human type II cells [13]. Similar results were obtained when con-
focal microscopy was used to localize ICAM-1 [11]. Again, ICAM-1 was found to
be exclusively expressed on the apical part of the cell membrane. These results were
supported by previous immunohistological examinations of mouse lungs, where
ICAM-1 was only detected on the luminal surface of alveolar epithelial cells on
stimulation with cytokines and LPS [14, 15]. On endothelial cells, the apical expres-
sion of ICAM-1 is well known to be essential for the migration of white blood cells
(WBCs) out of the blood stream in direction of the site of inflammation [16]. If
these principal processes of inflammation were applied to the anatomy of the lung,
one would rather expect a more basolateral expression of ICAM-1 on alveolar
epithelial cells in order to enable WBCs to immigrate from the pulmonary intersti-
tium into the alveolar space.
Recent data from adherence assays with target cells (alveolar epithelial cells) and
effector cells (neutrophils, alveolar macrophages) have indicated that epithelial
ICAM-1 is of great importance concerning target cell-effector cell interaction. The
results of these adherence assays clearly demonstrated a functional role for ICAM-1
in the adhesion of neutrophils and macrophages to stimulated alveolar epithelial
cells (Fig. 1) [11, 12]. Adherence of neutrophils to LPS-stimulated alveolar epithelial
cells was much more robust when compared to the adhesion of macrophages. In
stimulated alveolar epithelial cells, adhesion of neutrophils increased by 100% as
compared to macrophages with an increase of only 40%. However, it appears that
other adhesion molecules are also involved in this process, since only about 40% of
neutrophil adherence could be attributed to ICAM-1 as assessed by anti-ICAM-1
antibody studies [12]. Increased adhesiveness between pneumocytes and neutro-
phils or macrophages in the setting of an inflammatory response would be ex-
pected to lead to increased injury of the alveolar cell-lining barrier. This theory was
supported by cytotoxicity assays [17]: Non-stimulated alveolar epithelial cells were
incubated with neutrophils and cytotoxicity was determined. It could be demon-
strated that tight adherence of stimulated neutrophils to epithelial cell monolayers
promoted epithelial cell killing. Furthermore, in vitro studies with alveolar epithe-
lial cells previously exposed to LPS and incubated with stimulated neutrophils
showed enhanced cytotoxicity [12] (Fig. 2). This finding would suggest that the
susceptibility of epithelial cells to injury were related to alveolar epithelial cell stim-
ulation by LPS. All these data underline the fact that similar mechanisms in the
epithelial compartment can be assumed as analyzed in endothelial cells, where neu-
trophils induce endothelial cell killing [18-20] (Fig. 3}.
Another interesting aspect of the functional role of ICAM-1 was recently ex-
plored [21]. Focusing on ICAM-1-mediated interaction involving alveolar epithelial
cells and alveolar macrophages, it was shown that ICAM-1 promoted mobility of al-
veolar macrophages in the alveoli. In addition, it appeared that ICAM-1 was critical
for the efficient phagocytosis of particulates by alveolar macrophages.
I In Vivo Studies on ICAM-1 in the Respiratory Compartment
The presence of endotoxin within the distal airspace of the lung induces an inflam-
matory response that results in the accumulation of neutrophils and the formation
of edema within 24 hours [22-24]. The response is attributed to the effect of endo-
toxin on epithelial cells, alveolar macrophages and endothelial cells to induce the
production of cytokines, whereby alveolar epithelial cells are known to play a major
role in the regulation of immune responses in the lung [25, 26].
Many studies have identified requirements for adhesion molecules and leuko-
cytes in the lung vascular compartment in several models of ALI [27-29]. In the
vascular compartment, /32 integrin molecules, reacting with the endothelial cell
'counter-receptors' such as ICAM-1, mediate firm adhesion of the leukocytes to the
endothelium [30]. Thereby, neutrophils migrate through the endothelial layer to-
wards the inflammatory foci [31]. Furthermore, previous studies hypothesized that
neutrophils penetrate the alveolar epithelial barrier from the extravascular space to
reach the alveolar space, where they interact with alveolar epithelial cells [32]. In a
large number of inflammatory and antigen-induced models of lung diseases such as
asthma [33], reperfusion-induced lung injury [34], lung damage caused by im-
100 0 unstimulated
• stimulated
Cll
:; 80
"'cr
.....
VI
..!!! 60
Qj
...c
v
40
~
cu
.c
"0 20
<
0
a control Ab anti-ICAM-1 Ab
0 unstimulated • p < 0.001

60
~ 50
:J
"'
.....~ 40
..!!!
Qj
...cv 30
~ 20
cu
.s::.
"0
< 10
0
b control Ab anti-ICAM-1
Fig. 1. a Neutrophil adhesion to alveolar epithelial cell monolayers previously stimulated with f. coli LPS
(1 00 J.Lg/ml) overnight. Alveolar epithelial cells were blocked with monoclonal mouse anti-rat ICAM-1 anti-
body (1A29) (10 J.Lg/ml) for 30 min or with a control antibody. At the same time, neutrophils were prein-
cubated with antibodies against FcyRIII (CD16) and FcyRII (CD32). Neutrophils were then added to alveo-
lar epithelial cells. Neutrophil adherence to stimulated cells increased by 100% in monolayers of LPS-stim-
ulated alveolar epithelial cells. Blocking ICAM-1 protein on alveolar epithelial cells with ICAM-1 antibody
resulted in a decreased adherence of neutrophils to alveolar epithelial cells (40% less on stimulated cells).
Values are means± standard error of mean (SEM). Statistical comparison was made between LPS-stimulat-
ed group with control antibody and LPS-stimulated group with anti-ICAM-1 antibody (p < 0.001).
b Adherence of alveolar macrophages to monolayers of alveolar epithelial cells. Confluent alveolar epithe-
lial cells were stimulated overnight with LPS (100 J.Lg/ml) in DMEM/1% FBS. Alveolar macrophages were
harvested from rat lungs and placed into the wells. Blocking studies with ICAM-1 antibody were per-
formed as described above. Adherence of macrophages to LPS-$timulated alveolar epithelial cells increased
by 40% compared to adhesion to non-stimulated alveolar epithelial cells. Modest decrease in adherence
of macrophages to stimulated alveolar epithelial cells (30% decrease) occurred in the presence of anti-
ICAM-1 antibody. All values are expressed as means± SEM. Statistical comparison was made between
LPS-stimulated group with control antibody and LPS-stimulated group with ICAM-1 antibody (p < 0.001)
munocomplexes [35], hyperoxia [15, 36] and endotoxin and cytokine exposure
[37, 38], a possible relevance of up-regulated epithelial ICAM-1 could be shown.
An interesting finding was the fact that ICAM-1 expression on type II cells could
not be shown by immunostaining in whole lungs after LPS-injury [12]. The stain-
ing demonstrated an exclusively type !-located ICAM-1 expression. These data sup-
100
Oco
• LPS
*
80
~
~ 60
·o
'§
0 40
u>-
20
0
1 h 2h 3h 4h 5h 6h
Fig. 2. Alveolar epithelial cell killing by phorbol-myristate-acetate (PMA)-stimulated neutrophils. Cytotoxici-

ty assay was performed by measuring lactate dehydrogenase (LDH) release. Alveolar epithelial cells were
stimulated with PBS or LPS overnight, followed by incubation with PMA-stimulated neutrophils for 1 to 6
hours. Cytotoxicity was calculated based on total content of LDH and spontaneous release of LDH. LPS-
stimulated alveolar epithelial cell had significant higher cytotoxicity values compared to control (CO)
alveolar epithelial cells between 4 and 6 hours (* p < 0.05). Values are shown as means± SEM
Respiratory compartment
I 7° I
Oi Oi + H202 =OH
·fo 2
Prote\es
~
E---~~----J
Alveolar Epithelium
• VCAM-1 ~LPS @ Alveolar macrophage
AICAM-1 ~ Neutrophil
Fig. 3. Schematic diagram of effector cell interaction (neutrophils, alveolar macrophages) and target cells
(alveolar epithelial cells) in the respiratory compartment of the lung after intratracheal accumulation of
lipopolysaccharide (LPS)
port previous in vitro results [8]. Type II cells have mainly two functions: surfac-
tant expression and conversion into type I cell. This mitotic and secretory activity
might be one reason for a lack of immunoreactivity of these cells.
The problem of the definition of the role of epithelial ICAM-1 in ARDS patients
remains unsolved. In a study of patients with ALI it could be shown that high ede-
ma fluid levels of soluble ICAM-1 were correlated with a longer duration of me-
chanica! ventilation and were associated with impaired alveolar fluid clearance [39].
These data imply that soluble ICAM-1 is released from the damaged alveolar epi-
thelium and might potentially serve as a biological marker for the severity of ALI.
I Therapeutic Options
Blockade of the activity of a pro-inflammatory cytokine is an effective approach to
an anti-adhesive therapy in LPS-induced lung injury. This strategy was tested in an
in vitro setup with human airway epithelial cells [40]. ICAM-1 surface- as well as
gene expression in epithelial cells was attenuated under blockade with antibody
against the TNF-a receptor p55. These results could be validated in an in vivo sys-
tem, where intratracheal application of antibodies against TNF-a decreased epithe-
lial ICAM-1 expression [41].
Another interesting approach in inhibiting epithelial ICAM-1 expression is the
use of inhibitors of nuclear factor kappa-B (NF-KB). In a transformed human cell
line of alveolar epithelial cells it was demonstrated that ICAM-1 expression was in
part mediated by NF-KB [9].
The direct blockade of the expression or the function of epithelial ICAM-1 may
be a potent target for inhibiting the inflammatory response. However, only sparse
data exist about airway blockade of ICAM-1 in endotoxin-induced lung injury. Air-
way instillation of anti-rat ICAM-1 antibody resulted in protective effects in a mod-
el of LPS-induced lung injury in rats [12]. Similar results were seen with an intra-
venous blockade of ICAM-1 in mice after intratracheal instillation of LPS [24]. A
protective effect of intratracheally applied anti-ICAM-1 was also found in an IgG
immune complex-mediated lung injury model [35]. In Klebsiella pneumoniae-in-
duced lung injury, however, epithelial blockade of ICAM-1 resulted in an impaired
ability to clear K. pneumoniae from the lungs, implicating that ICAM-1 also plays
an important role in host defense [42]. These findings were striking and implied
that ICAM-1 might show pleiotropic effects, potentially depending on the time
point of the response to injury. For instance, at an early time point of injury it
might have a pro-inflammatory character, while at a later time point enhanced
ICAM-1 expression might be protective. In another study, anti-CDlla- or ICAM-1
antibodies were given intravenously after intratracheal instillation of endotoxin
[38]. Evaluation of bronchoalveolar lavage (BAL) fluid showed a 30 to 70% dimin-
ished neutrophil accumulation. These data were very promising, and will be further
extended to intratracheal blockade.
I Conclusion
Several studies have demonstrated the up-regulation of epithelial ICAM-1 on alveo-
lar epithelial cells in vitro and in vivo in the respiratory compartment following
LPS-stimulation. The increased expression of ICAM-1 leads to enhanced adherence
of neutrophils and macrophages, clearly demonstrating a biological function of
ICAM-1 on alveolar epithelial cells. ICAM-1 mediated neutrophil adherence to LPS-
stimulated alveolar epithelial cells triggered alveolar epithelial cell injury with in-
creased cytotoxicity. All these experiments indicated that the lower airway compart-
ment plays an important role in endotoxin-induced inflammation. The respiratory
compartment offers the unique advantage of easy accessibility in case of therapeu-

tic interventions compared to other organs. Therefore, in view of promising results
in attenuating lung injury by blocking epithelial ICAM-1, further investigations will
explore the potential for therapeutic interventions targeting the respiratory com-
partment of the lung.
References
1. Evans MJ, Cabral LJ, Stephens RJ, Freeman G (1975) Transformation of alveolar type 2 cells
to type I cells following exposure to N0 2 • Exp Mol Path 22:142-150
2. Bevilacqua MP (1993) Endothelial-leukocyte adhesion molecules. Annu Rev Immunol
11:767-804
3. Strieter RM, Kunkel SL (1994) Acute lung injury: the role of cytokines in the elicitation of
neutrophils. J Investig Med 42:640-651
4. Tsuji C, Minhaz MU, Shioya S, Fukahori M, Tanigaki T, Nakazawa H (1998) The impor-
tance of polymorphonuclear leukocytes in lipopolysaccharide-induced superoxide anion
production and lung injury: ex vivo observation in rat lungs. Lung 176:1-13
5. Christensen PJ, Kim S, Simon RH, Toews GB, Paine R (1993) Differentiation-related expres-
sion of ICAM-1 by rat alveolar epithelial cells. Am J Respir Cell Mol Bioi 8:9-15
6. Paine III R, Christensen P, Toews GB, Simon RH (1994) Regulation of alveolar epithelial
cell ICAM-1 expression by cell shape and cell-cell interactions. Am J Physiol 266:1476-
1484
7. Cunningham AC, Milne DS, Wilkes J, Dark JH, Tetley TD, Kirby JA (1994) Constitutive ex-
pression of MHC and adhesion molecules by alveolar epithelial cells (type II pneumocytes)
isolated from human lung and comparison with immunocytochemical fmdings. J Cell Sci
107:443-449
8. Barton WW, Wilcoxen S, Christensen PJ, Paine R (1995) Disparate cytokine regulation of
ICAM-i in rat alveolar epithelial cells and pulmonary endothelial cells in vitro. Am J Phys-
iol 269:Ll27-L135
9. Fakler CR, Wu B, McMicken HW, Geske RS, Welty SE (2000) Molecular mechanisms of
lipopolysaccharide induced ICAM-1 expression in A549 cells. Inflam Res 49:63-72
10. Dentener MA, Vreugdenhil AC, Hoet PH, et al (2000) Production of the acute-phase pro-
tein lipopolysaccharide-binding protein by respiratory type II epithelial cells: implications
for local defense to bacterial endotoxins. Am J Respir Cell Mol Bioi 23:146-153
11. Madjdpour C, Oertli B, Ziegler U, Bonvini JM, Pasch T, Beck-Schimmer B (2000) Lipopoly-
saccharide induces functional ICAM-1 expression in rat alveolar epithelial cells in vitro.
Am J Physiol 278:L572-L579
12. Beck-Schimmer B, Madjdpour C, Kneller S, et al (2002) Role of alveolar epithelial ICAM-1
in lipopolysaccharide-induced lung inflammation. Eur Respir J 19:1142-1150
13. Guzman J, Izumi T, Nagai S, Costabel U (1994) ICAM-1 and integrin expression on isolated
human alveolar type II pneumocytes. Eur Respir J 7:736-739
14. Burns A, Takei F, Doerschuk C (1994) Quantitation of ICAM-1 expression in mouse lung
during pneumonia. J Immunoll53:3189-3198
15. Kang BH, Crapo JD, Wegner CD, Letts LG, Chang LY (1993) Intercellular adhesion mole-
cule-! expression on the alveolar epithelium and its mpdification by hyperoxia. Am J Res-
pir Cell Mol Bioi 9:350-355
16. Wawryk SO, Novotny JR, Wicks IP, et al (1989) The role of the· LFA-1/ICAM-1 interaction
in human leukocyte homing and adhesion. Immunol Rev 108:135-161
17. Simon RH, DeHart PD, Todd RF 3rd (1986) Neutrophil-induced injury of rat pulmonary
alveolar epithelial cells. J Clin Invest 78:13 75-1386
18. Varani J, Fligiel SEG, Till GO, Kunkel RG, Ryan US, Ward PA (1985) Pulmonary endothelial
cell killing by human neutrophils. Lab Invest 53:656-663
19. Varani J, Dame MD, Gibbs DF, et al (1992) Human umbilical vein endothelial cell killing
by activated neutrophils. Lab Invest 66:708-714
20. Murphy HS, Warner RL, Bakopoulos N, Dame MK, Varani J, Ward PA (1999) Endothelial
cell determinants of susceptibility to neutrophil-mediated killing. Shock 12:111-117
10 B. Beck-Schimmer et al.: Role of Epithelial ICAM-1 in Endotoxin-Induced Lung Injury
21. Paine R, 3rd, Morris SB, Jin H, Baleiro CE, Wilcoxen SE (2002) ICAM-1 facilitates alveolar
macrophage phagocytic activity through effects on migration over the AEC surface. Am J
Physiol 283:Ll80-Ll87
22. Ulich TR, Watson LR, Yin S, et a! (1991) The intratracheal administration of endotoxin
and cytokines. Characterization of LPS-induced IL-l and TNF mRNA expression and the
LPS-, IL-, and TNF-induced inflammatory infiltrate. Am J Pathol 138:521-524
23. Watson RW, Redmond HP, Bouchier-Hayes D (1994) Role of endotoxin in mononuclear
phagocyte-mediated inflammatory responses. J Leukoc Bioi 56:95-103
24. Kumasaka T, Quinlan WM, Doyle NA, et a! (1996) Role of the intercellular adhesion mole-
cule-1 (ICAM-1) in endotoxin-induced pneumonia evaluated using ICAM-1 antisense oligo-
nucleotides, anti-ICAM-1 monoclonal antibodies and ICAM-1 mutant mice. J Clin Invest
97:2362-2369
25. Simon RH, Paine III R (1995) Participation of pulmonary alveolar epithelial cells in lung
inflammation. J Lab Clin Med 126:108-118
26. Shanley TP, Warner RL, Ward PA (1995) The role of cytokines and adhesion molecules in
the development of inflammatory injury. Mol Med Today 1:40-45
27. Mulligan MS, Smith CW, Anderson DC, et a! (1993) Role of leukocyte adhesion molecules
in complement-induced lung injury. J Immunol 150:2401-2406
28. Mulligan MS, Varani J, Warren JS, et a! (1992) Roles of {12 integrins of rat neutrophils in
complement- and oxygen radical-mediated acute inflammatory injury. J Immunol 148:
1847-1857
29. Mulligan MS, Vaporciyan AA, Miyasaka M, Tamatani T, Ward PA (1993) Tumor necrosis fac-
tor a regulates in vivo intrapulmonary expression of ICAM-1. Am J Patho\142:1739-1749
30. Albelda SM, Smith SW, Ward PA (1994) Adhesion molecules and inflammatory injury.
FASEB J 8:504-512
31. Gonzalez-Amaro R, Diaz-Gonzalez F, Sanchez-Madrid F (1998) Adhesion molecules in in-
flammatory diseases. Drugs 56:977-988
32. Sibille Y, Reynolds HY (1990) Macrophages and polymorphonuclear neutrophils in lung
defense and injury. Am Rev Respir Dis 141:471-501
33. Miao H, Xue QF, Hu QH, et a! (1997) In situ expression of ICAM-1 and its mRNA in the
lung tissue of asthmatic rats. Clin Hemorheol Microcirc 17:325-331
34. Horgan MJ, GeM, Gu J, Rothlein R, Malik AB (1991) Role of ICAM-1 in neutrophil-mediated
lung vascular injury after occlusion and reperfusion. Am J Physiol 26l:Hl578-H1584
35. Mulligan MS, Vaporciyan AA, Warner RL, et a! (1995) Compartmentalized roles for leuko-
cytic adhesion molecules in lung inflammatory injury. J Immunol 154:1350-1363
36. Piedboeuf B, Frenette J, Petrov P, Welty SE, Kazzaz JA, Horowitz S (1996) In vivo expres-
sion of intercellular adhesion molecule 1 in type II pneumocytes during hyperoxia. Am J
Respir Cell Mol Bioi 15:71-77
37. Kang BH, Manderschied BD, Huang YC, Crapo JD, Chang LY (1996) Contrasting response
of lung parenchymal cells to instilled TNF alpha and IFN gamma: the inducibility of
specific cell ICAM-1 in vivo. Am J Respir Cell Mol Bioi 15:540-550
38. Tang WW, Yi ES, Remick DG, et a! (1995) Intratracheal injection of endotoxin and cyto-
kines. IX. Contribution of CDlla/ICAM-1 to neutrophil emigration. Am J Physiol 269:
L653-L659
39. Conner ER, Ware LB, Modin G, Matthay MA (1999) Elevated pulmonary edema fluid con-
centrations of soluble intercellular adhesion molecule- I in patients with acute lung injury:
biological and clinical significance. Chest 116 (1 suppl):83S-84S
40. Krunkosky TM, Fischer BM, Martin LD, Jones N, Akley NJ, Adler KB (2000) Effects of
TNF-alpha on expression of ICAM-1 in human airway epithelial cells in vitro. Signaling
pathways controlling surface and gene expression. Am J Respir Cell Mol Bioi 22:685-692
41. Beck-Schimmer B, Schimmer RC, Warner RL, et a! (1997) Expression of lung vascular and
airway ICAM-1 after exposure to bacterial lipopolysaccharide. Am J Respir Cell Mol Bioi
17:344-352
42. O'Brien AD, Standiford TJ, Bucknell KA, Wilcoxen SE, Paine III R (1999) Role of alveolar
epithelial cell intercellular adhesion molecule- I in host defense against Klebsiella pneumo-
niae. Am J Physiol 276:L961-L970
Pulmonary Endothelium-Bound Enzymes
in the Normal and the Diseased Lung
S. E. Orfanos, A. Kotanidou, and C. Roussos
I Introduction
The most intimal layer covering all blood vessels is composed of a single, continu-
ous sheet of simple squamous epithelial cells of mesenchymal origin, which are
called endothelial cells. Endothelial cells possess numerous important metabolic
properties. In the human lung, endothelial cells constitute over 40o/o of all cell types
and occupy an area with a surface of approximately 130 m2 [1]. The strategic loca-
tion of the lungs, and the tremendous surface area of the pulmonary capillary en-
dothelium allow the latter to filter the entire circulating blood volume before it en-
ters the systemic circulation. Healthy pulmonary endothelium, among other fea-
tures, promotes anti-aggregation and hemofluidity; synthesizes and/or degrades
several hormones and vasoactive peptides such as angiotensin II, nitric oxide
(NO}, endothelins, and prostaglandins (regulating both pulmonary and systemic
vascular tones); processes lipids; and interacts with blood components such as neu-
trophils, monocytes, and platelets [2, 3]. Consequently, the pulmonary endothelium
is a major metabolic organ necessary for the adequate homeostasis of both the pul-
monary and systemic circulations.
I Endothelium-Bound Enzymes
Many of the above-mentioned metabolic functions are catalyzed by enzymes that

are bound on the luminal endothelial surface, with their catalytic sites exposed to
the blood stream. These plasma membrane-bound enzymes are also known as ec-
toenzymes; they are able to interact with blood-borne substrates and inhibitors,
without the time and energy expenses required for interactions with cytosolic en-
zymes. Two such ectoenzymes are angiotensin converting enzyme (ACE) and 5' -nu-
cleotidase (NCT) [3].
ACE is a monomeric zinc dipeptidyl carboxypeptidase. It is present in most
mammalian tissues, particularly found on endothelial cells, on the surface of ab-
sorptive epithelia, and in the central nervous system (CNS) [4]. ACE catalyzes the
conversion of angiotensin I to angiotensin II (Ang II}, and the degradation of bra-
dykinin [5]. Ang II is an octapeptide with vasoconstrictive properties; it acts on
vascular smooth muscle cells, interacts with the nervous system and induces aldo-
sterone release. Bradykinin is a nonapeptide with vasodilatory and pro-inflamma-
tory properties. ACE appears, thus, to regulate the balance between the vasodilatory
properties of bradykinin and the vasoconstrictive properties of Ang II, promoting
12 S. E. Orfanos et al.
vascular tone. NCT is responsible for the dephosphorylation of extracellular adeno-

sine-5'-monophosphate (5'-AMP) to adenosine, a molecule with vasodilatory and
anti-thrombogenic properties [6]. Both ectoenzymes are uniformly distributed
along the luminal pulmonary endothelial surface area, although NCT appears to be
localized preferentially within the membrane caveolae [7].
Other pulmonary endothelial ectoenzymes, found in different species, include:
various nucleotidases; aminopeptidase P, which contributes to the break down of
bradykinin; lipoprotein lipase, which hydrolyzes triglycerides to fatty acids; carbo-
nic anhydrase, which acts on the release of carbon dioxide; the ECE-1a and ECE-1c
isoforms of endothelin converting enzyme (ECE), which are involved in the produc-
tion of endothelins (ETs) from their precursors big ETs [2, 3, 8, 9].
I Assessment of Pulmonary Metabolism

Pulmonary metabolism (i.e., pulmonary endothelial function) may be altered in
several acute or chronic lung pathologies, therefore pulmonary metabolism studies
may offer valuable insights into the pathophysiology and the clinical development
or outcome of certain lung diseases. Assessment of pulmonary endothelial function
can be made in vivo, ex vivo, or in situ, mainly by means of two methodologies:
1) by estimating the transpulmonary gradient of a substrate or an inhibitor from
measurements of its inflow and outflow concentrations in mixed venous and aor-
tic blood; and
2) by applying radioisotopic indicator-dilution type techniques.
Both methods provide information on the metabolism or extraction from the pul-
monary circulation of a certain compound; the indicator-dilution technique how-
ever provides more specific information as well as blood flow estimations [3, 4].
The former method, although 'crude', is often used especially in human studies. In
this respect, patients with acute lung injury (ALI) and acute respiratory distress
syndrome (ARDS) had abnormal pulmonary ET-1 metabolism, expressed by an
early decrease of the net balance between pulmonary ET-1 clearance and release, a
phenomenon that was reversed in patients who subsequently recovered [10].
Indicator-dilution techniques were initially used in order to study the removal of
several biologically active compounds from the pulmonary circulation. These are
processes that require energy and, therefore, a metabolically healthy pulmonary en-
dothelium. Such compounds include the biogenic amines, norepinephrine and sero-
tonin, prostaglandin E1 (PGE 1 ) and, more recently, ET-1. Studies may be performed
in the normal and the diseased lung, providing different types of information: Un-
der normal conditions, norepinephrine and serotonin pulmonary uptake in the dog
allow estimations oflung capillary recruitment with exercise [11, 12], while the hu-
man pulmonary circulation appears to be an important site for both clearance and
production of ET-1, resulting in a normal physiological ET-1 balance across the
pulmonary circulation [13]. Under pathological conditions, human studies have
shown a correlation between decreased pulmonary clearance of serotonin and PGE 1
and ARDS, although they failed to predict which patients at risk will develop the
syndrome [14, 15]. It is worth noting that data interpretation from this type of
study is quite complex, since it needs to take into consideration endothelial trans-
port properties, possible release of metabolites into the blood stream, and correct
for changes in blood flow.
Pulmonary Endothelium-Bound Enzymes in the Normal and the Diseased Lung 13
I Assays of Pulmonary Capillary Endothelium-Bound Enzyme Activity,

In Vivo
During the last twenty years increasing attention has been focused on the monitor-
ing of pulmonary capillary endothelial ectoenzyme activity in several animal mod-
els in vivo and in situ [16]. The pulmonary capillary bed provides an ideal environ-
ment for the function of these enzymes because it offers very high enzyme concen-
trations resulting from the combination of low plasma volume and high surface
area (i.e., high enzyme mass available for reaction). Additionally, it accepts the
highest possible substrate delivery, since 100% of the cardiac output passes through
the lungs. We and other investigators have studied the function of these enzymes
under physiological conditions in several animal models [17-20] and, more recently
in humans [21]. We have used the information obtained to provide insights into
the pulmonary vascular physiology, while we have in addition studied how these
enzymes are affected by various lung pathologies.
Indicator-Dilution Technique
The most common assay to estimate in vivo the activity of pulmonary endotheli-
um-bound ectoenzymes is a modification of the indicator-dilution technique, origi-
nally introduced for cardiac output estimations. Briefly, trace amounts of a radiola-
beled substrate are injected as a rapid bolus into a central vein. Simultaneously, ar-
terial blood is withdrawn by means of a peristaltic pump into a fraction collector,
for the duration of a single transpulmonary pass. Blood samples are then collected,
and the amount of radioactivity associated with both the substrate that survived
the single transpulmonary pass, and with the formed product, is quantified in each
sample [3, 4]. This technique allows estimations of very rapid interactions between
substrate and the endothelium-bound enzyme, thus minimizing the contribution of
the corresponding plasma soluble enzyme, provided that the latter is in low con-
centrations relative to the former. This is the case for both ACE and NCT [18]. In
addition, capillaries with a diameter of < 20 11m (i.e., alveolar capillaries) appear to
be responsible for the great majority of the product formed, due to the very high
local enzyme concentration. Thus in this type of study, measurement of pulmonary
ACE and NCT activity represents in practical terms pulmonary capillary endotheli-
um-bound ACE and NCT activity [6]. For a more detailed description of this proce-
dure the reader is referred to [18] and [21].
ACE Synthetic Substrates
In the mid-1970s, synthetic radiolabeled substrates highly specific for ACE sub-
strates were introduced by JW Ryan [22]. Contrary to the natural ACE substrates
Ang I and bradykinin which are also substrates for other naturally occurring en-
zymes, these synthetic substrates could be quantified easily and rapidly. Further-
more, they were adequately reactive to allow measurable hydrolysis during a single
transpulmonary pass in vivo. The first and more widely used to date synthetic sub-
strate is benzoyl-Phe-Ala-Pro (BPAP). Other synthetic ACE substrates include ben-
zoyl-Ala-Gly-Pro (BAGP), benzoyl-Phe-Gly-Pro (BPGP) and benzoyl-Phe-His-Leu
(BPHL). There is a wide range of reactivity O<cat1Km) among them, with BPAP
being the more reactive [22]. From all the aforementioned substrates only 3H-BPAP
has been used in human studies thus far.
One or more ectoenzymes can be assayed simultaneously, provided that sub-
strates are radiolabeled with different isotopes. In this respect, ACE and NCT activ-
ity can be measured during a single indicator-dilution experiment using 14C-la-
belled 5'-AMP (the natural substrate of NCT) and a 3 H-labelled ACE substrate.
More recently estimations of transpulmonary binding of radiolabeled ACE inhibi-
tors were introduced. While the use of substrates provides information on the cata-
lytic properties of the enzymes, inhibitors provide information on their binding
characteristics. Simultaneous use of a substrate and an inhibitor provides addi-
tional information on the functional status of pulmonary capillary endothelium-
bound-ACE and the perfused pulmonary vascular bed [23].
I Calculations of Pulmonary Capillary Endothelium-Bound

Enzyme Activity
Calculations under First-Order Reaction Conditions
(Substrate Concentrations « K.n)
When trace amounts of a substrate are injected, substrate hydrolysis proceeds un-
der first-order reaction conditions. Substrate transpulmonary utilization is then
measured by applying the integrated Henri-Michaelis-Menten equation [24], and
expressed as either o/o metabolism (o/oM), or hydrolysis (v= [E]xtcXk.:atiKm), with
[E], te> k.:at and Km being the capillary enzyme concentration, reaction time (capil-
lary mean transit time), catalytic rate constant and Michaelis-Menten constant re-
spectively [24]. [S 0 ] and [S] reflect the initial and final substrate concentrations in
the effluent arterial plasma estimated in dpm/ml.
Both v and o/oM are reflections of pulmonary capillary endothelium-bound en-
zyme activity per capillary. While v has the advantage of being directly propor-
tional to all three factors that determine product formation, percent substrate meta-
bolism is a term that investigators are more familiar with.
The modified kinetic parameter Amax1Km (=EXk.:atiKm; where E is total enzyme
mass) may be additionally calculated [18]. Amax1Km reflects enzyme activity per
vascular bed. Under physiological conditions, as long as the catalytic properties of
the enzyme remain unchanged, Amax1Km is an index of pulmonary capillary endo-
thelium-bound-enzyme mass and, for ACE or NCT that are evenly distributed along
the luminal endothelial surface, an index of dynamically perfused (i.e., accessible to
substrate) capillary surface area (DPCSA). Under toxic conditions, when alterations
of enzyme expression and/or kinetic constants may exist, AmaxiKm should be
viewed as an index of functional capillary surface area (FCSA) related to the en-
zyme mass available for reaction (the product of DPCSA and the enzyme mass ex-
pressed on the endothelial surface), and the enzyme kinetic constants.
More detailed information on the derivation of the above-mentioned equations,
as well as representative arterial outflow curves of indicator-dilution studies per-
formed in humans with normal and diseased lungs may be found in [21] and [25].
Calculations under Mixed-Order Reaction Conditions

Under mixed-order reaction conditions (i.e., data obtained under both first- and
zero-order reaction determinations) the apparent Amax and Km may be estimated
separately by applying the Hanes-Wolf transformation of the integrated Michaelis-
Menten equation [24, 26]:
1/ln([So]/[S]) = (Fp/ Amax) x {([So]) - [S]/ln([So]/[S])} + Fp x (Km/ Amax)
where Fp=pulmonary plasma flow, y-intercept= Fpx(Km/Amax) andx-intercept = -Km.
Under these conditions, it is possible to differentiate if an observed decrease of

FCSA is due to decreased enzyme mass available for reaction (i.e., decreased Amax)
or decreased enzyme-substrate affinity (i.e., increased Km). These studies include
the co-administration of an amount of non-radioactive 'cold' substrate, and have
been performed thus far only in animals.
Pulmonary Capillary Endothelium-bound Enzyme Activity

in the Normal Lung
Effect of Flow
In vivo assays under normal conditions have established the normal range of pul-
monary capillary endothelium-bound ACE and NCT activity values in several ani-
mal models, and more recently in man (only for ACE). Multiple determinations
performed in several animal models, at various controlled pulmonary blood flows
ranging from "'0.5 to "'3.5 times the normal flow, revealed a proportional and
parallel increase in Amax1Km denoting its validity as a DPCSA index [4, 25]. In all
these studies, transpulmonary hydrolysis of all substrates used was independent of
pulmonary blood flow implying that higher pulmonary blood volumes are accom-
modated mainly through parallel recruitment of capillaries with similar enzyme
concentrations and capillary transit times [3, 19, 20, 23]. When pulmonary blood
flow was increased beyond full recruitment no additional changes in AmaxiKm were
observed, as expected, while substrate hydrolysis decreased mainly due to de-
creased transit times through the fully recruited capillary bed [3, 19, 20, 25].
A similar study was more recently performed in four mechanically ventilated
brain-dead adult subjects, with normal chest x-rays and Pa0 2 /Fi0 2 > 300 mmHg
(absence of ALI [27]). Pulmonary capillary endothelium-bound ACE activity was
assessed at 3 different cardiac output values in each subject, ranging from 3.2 to
14.1 1/min. BPAP %M varied between 47 and 64%, showing no correlation with car-
diac output, and implying recruitment of capillaries with similar enzyme concen-
trations and substrate transit times (Fig. 1, top). Contrary to BPAP %M, Amax1Km
(normalized to body surface area) increased linearly with cardiac output (Fig. 1,
bottom; r = 0.85, p < 0.01). This pattern is similar to the one observed in animal
studies and further supports the validity of Amax1Km as a DPCSA index in humans.
100
E
.!!! 80
0
.0 0
vE"' 60 0 0 0
~0 0
40
~
0..
~ 20
al
0
0 3 6 9 12 15
Cardiac output (I/ min)
7000
"'e
..... 6000 r = 0.85
c
·e
::::, 5000
.s
<(
4000
Vl 3000
.....
al
E 2000
:.::
.....
e 1000
)(
<(
0
0 3 6 9 12 15
Cardiac output (I/ min)
Fig. 1. Effect of cardiac output elevations on the o/o metabolism of the ACE substrate BPAP (top), and on
the dynamically perfused capillary surface area index Amax1Km normalized to body surface area (BSA; bot-
tom), in four brain-dead subjects with normal chest x-rays and Pa0 2/Fi0 2 > 300 mmHg. Substrate metabo-
lism was independent of cardiac output, whereas a positive linear relationship between Amax /Km and car-
diac output was noted (p < 0.01 by Pearson's r). Symbols represent individual values
Pulmonary Capillary Endothelium-Bound ACE Activity Estimations

for Inhibition Studies, In Vivo
A new interesting application of pulmonary capillary endothelium-bound enzyme
activity assessment has been introduced recently. Ryan and coworkers provided evi-
dence that sequential pulmonary capillary endothelium-bound ACE activity deter-
minations, prior- and post-administration of an inhibitor, and the obtained hydro-
lysis (v) values allow estimations of the dissociation constant (k_ 1) of the inhibitor-
enzyme reaction, in vivo [28]. Pulmonary capillary endothelium-bound ACE ap-
pears to be the main locus where most circulating Ang II synthesis and bradykinin
breakdown occur [29, 30]; therefore, pulmonary capillary endothelium-bound ACE
should be the primary locus where ACE inhibitors act. Consequently, this type of
study might provide accurate information on inhibitory potency and duration. In
this respect, the ACE inhibitor, trandaloprilat, exhibited ~ threefold lower k_ 1 than
enalaprilat, consistent with the longer lasting ACE inhibition of the former [31].
Future application of these studies in the injured lung might also detect potential
alterations of pulmonary capillary endothelium-bound ACE-inhibitor reactions.
I Pulmonary Capillary Endothelium-Bound Enzyme Activity

in the Diseased Lung
Pulmonary endothelial injury may begin as a subtle metabolic dysfunction and
then progress to overt structural alterations and cell death. Reduced pulmonary
capillary endothelium-bound enzyme activity appears to be among the earliest
signs of lung injury, preceding alterations of numerous clinical, physiological, and
pathological parameters. For more details the reader is referred to [3] and [25]. In
most studies where pulmonary capillary endothelium-bound ACE and NCT activ-
ities were simultaneously assessed, they were both reduced. This is the case in lung
injury occurring in rabbits after lung radiation or phorbol myristate acetate (PMA)
administration [32-34].
Interestingly, different results were obtained in an animal model of chronic sys-
temic vascular disease, namely the Watanabe heritable hyperlipidemic rabbit
(WHHL). WHHL lacks low-density lipoprotein (LDL) receptors, being the animal
model of human homozygous familial hypercholesterolemia [35]. WHHL exhibited
decreased pulmonary capillary endothelium-bound ACE activity and no differences
in pulmonary capillary endothelium-bound NCT activity, as compared to control
New Zealand white rabbits (Fig. 2, top & middle). The presence of such a different
pattern in pulmonary capillary endothelium-bound enzyme activities, besides its
biological significance, facilitates the interpretation of the observed alterations. In
this respect, the observed decreases in BPAP v and AmaxiKm should be related to
either decreased expression of pulmonary capillary endothelium-bound ACE mass
and/or differences in ACE kinetic constants, and not to alterations in capillary tran-
sit times or perused vascular bed surface, phenomena that would also alter pulmo-
nary capillary endothelium-bound NCT kinetic parameters. Indeed, further studies
performed under mixed-order reaction conditions revealed a decrease in BPAP
Amax> denoting lower pulmonary capillary endothelium-bound ACE mass available
for reaction. No differences were observed in Km between the two animal strains,
suggesting similar enzyme-substrate affinities (Fig. 2, bottom) [35].
Pulmonary capillary endothelium-bound enzyme studies have been recently in-
troduced in humans and have already provided evidence for pulmonary endothelial
dysfunction, as assessed by pulmonary capillary endothelium-bound ACE activity
depression, in acute pathologies such as ALI/ARDS [36], as well as in chronic vas-
cular diseases such as systemic sclerosis [37]. Preliminary data already suggest that
subtle pulmonary endothelial dysfunction, as indicated by mild but significant de-
creases of pulmonary capillary endothelium-bound ACE activity, might be present
in mechanically ventilated patients [38] and brain-dead subjects [39], in the ab-
sence of any clinical or radiological sign of lung injury. It is possible that this tech-
nique might provide a means of detecting sub-clinical pulmonary endothelial dys-
function in humans, but this remains to be determined.
I Conclusion
The pulmonary vascular endothelium participates in various important physiologic
and pharmacokinetic processes, essential for the maintenance of cardiovascular
homeostasis. Assessing pulmonary capillary endothelium-bound enzyme activity by
means of indicator dilution techniques has been validated for many years in animal
4
• New Zealand 0 WHHL
> 2
0
BPAP 5' -AMP
1400
1200
'2
·E 1000
....
l 800
E 600
....
~
E 400
< 200
0
BPAP 5' - AMP
14
'2
12 •
.E 10
....
0 8
E
::l.
6
6
~ 4
3-
2
0
Fig. 2. Hydrolysis (v) and Amax1Km of the ACE substrate BPAP were reduced in Watanabe heritable hyper-
lipidemic rabbits (WHHL) as compared to control New Zealand White rabbits (top & middle), denoting de-
creased pulmonary capillary endothelium-bound ACE activity. There were no differences in pulmonary cap-
illary endothelium-bound NG activity between the two animal strains (top & middle). The observed ACE
activity reduction in WHHL appears to be related to decreased pulmonary capillary endothelium-bound
ACE mass expression, as shown by the Amax reduction (bottom). Values are means± SEM *p < 0.05 be-
tween the two groups by Student's t-test. (Modified from [35] with permission)
models and has been recently introduced in man. One might say that this is an
'old' method in a new application. This procedure is relatively simple, highly repro-
ducible in both animals and humans and can be safely applied at the bedside. In
addition, it offers accurate and quantifiable information on pulmonary endothelial
function and the perfused pulmonary vascular bed, in health and disease. Future
studies should determine the utility of this method in: i) predicting either the onset
or the outcome from pathologies such as ALI and ARDS, ii) unmasking sub-clinical
pulmonary vascular injury, and iii) monitoring the results of related medical inter-
ventions.
References
1. Simionescu M (1991) Lung endothelium: Structure-function correlates. In: Crystal RG,
West JB (eds) The Lung: Scientific Foundations. Raven Press, New York, pp 301-312
2. Hassoun PM, Fanburg BL, Junod AF (1991) Metabolic functions. In: Crystal RG, West JB
(eds) The Lung: Scientific Foundations. Raven Press, New York, pp 313-327
3. Orfanos SE, Catravas JD (1993) Metabolic Functions of the ~ulmonary endothelium. In:
Yacoub M, Pepper J (eds) Annual Review of Cardiac Surgery, 6 h edn. Current Science Lon-
don, pp 52-59
4. Catravas JD, Orfanos SE (1997) Pathophysiologic functions of endothelial angiotensin-con-
verting enzyme. In: Born GVR, Schwartz CJ (eds) Vascular Endothelium: Physiology,
Pathology and Therapeutic Opportunities. Schattauer Stuttgart, pp 193-204
5. Ryan JW, Ryan US (1982) Processing of endogenous polypeptides by the lung. Annu Rev
Physiol44:241-255
6. Ryan JW, Smith US (1971) Metabolism of adenosine-5'-monophosphate during circulation
through the lungs. Trans Assoc Am Physicians 84:297-306
7. Ryan US, Ryan JW (1977) Correlations between the fine structure of the alveolar-capillary
unit and its metabolic activities. In: Bakhle YS, Vane JR (eds) Metabolic Functions of the
Lung. Marcel Dekker, New York, pp 197-232
8. Chen XL, Orfanos SE, Ryan JW, et al (1991) Species variation in pulmonary endothelial
aminopeptidase P activity. J Pharmacol Exp Ther 259:1301-1307
9. Battistini B, Dussault P (1998) Biosynthesis, distribution and metabolism of endothelins in
the pulmonary system. Pulm Pharmacol Ther 11:79-88
10. Langleben D, Demarchie M, Laporta D, et al (1993) Endothelin-1 in acute lung injury and
the adult respiratory distress syndrome. Am Rev Respir Dis 148:1646-1650
11. Dupuis J, Goresky CA, Junear C (1990) Use of norepinephrine uptake to measure lung
capillary recruitment with exercise. J Appl Physiol 68:700-713
12. Dupuis J, Goresky CA, Rouleau JL, Simard A, Schwab AJ (1996) Kinetics of pulmonary up-
take of serotonin during exercise in the dog. J Appl Physiol 80:30-46
13. Dupuis J, Stewart DJ, Cernacek P, Gosselin G (1996) Human pulmonary circulation is an
important site for both clearance and production of endothelin-1. Circulation 94:1578-1584
14. Gillis CN, Pitt BR, Wiedemann HP, et al (1986) Depressed prostaglandin E1 and 5-Hydroxy-
tryptamine removal in patients with adult respiratory distress syndrome. Am Rev Respir
Dis 134:739-744
15. Morel DR, Dargent F, Bachmann M, et al (1985) Pulmonary extraction of serotonin and
propranolol in patients with adult respiratory distress syndrome. Am Rev Respir Dis
132:479-484
16. Pitt BR, Lister G, Gillis CN. (1987) Hemodynamic effects on lung metabolic function. In:
Ryan US (ed) Pulmonary Endothelium in Health and Disease. Marcel Dekker, New York,
pp 65-87
17. Ryan JW, Catravas JD (1991) Angiotensin converting-enzyme as an indicator of pulmonary
microvascular funtion In: Hollinger MA (ed). Focus on Pulmonary Pharmacology & Toxi-
cology. CRC Press, Boca Raton, pp 183-210
18. Catravas JD, White RE. (1984) Kinetics of pulmonary angiotensin-converting enzyme and
5'-nucleotidase in vivo. J Appl Physiol 57:1173-1181
19. Toivonen HJ, Catravas JD (1991) Effects of blood flow on lung ACE kinetics: Evidence for
microvascular recruitment. J Appl Physiol 71:2244-2254
20. Orfanos SE, Ehrhart IC, Barman S, Hofman WF, Catravas JD (1997) Endothelial ectoen-
zyme assays estimate perfused capillary surface area in the dog lung. Microvasc Res
54:145-155
21. Orfanos SE, Langleben D, Khoury J, et al (1999) Pulmonary capillary endothelium-bound
angiotensin-converting enzyme activity in humans. Circulation 99:1593-1599
20 S. E. Orfanos et al.: Pulmonary Endothelium-Bound Enzymes in the Normal and the Diseased Lung
22. Ryan JW (1987) Assay of pulmonary endothelial surface enzymes in vivo. In: Ryan US
(ed) Pulmonary Endothelium in Health and Disease. Marcel Dekker, New York USA,
pp 161-188
23. Orfanos SE, Chen XL, Ryan JW, Chung AYK, Burch SE, Catravas JD (1994) Assay of pul-
monary microvascular endothelial angiotensin-converting enzyme in vivo: comparison of
three probes. Toxicol Appl Pharmacol124:99-111
24. Segel IH (1975) Enzyme Kinetics. Wiley, New York
25. Orfanos SE, Kotanidou A, Roussos C (2002) Pulmonary endothelial angiotensin converting
enzyme activity in lung injury. In: Vincent JL (ed) 2002 Yearbook of Intensive Care and
Emergency Medicine. Springer, Heidelberg, pp 100-110
26. Catravas JD (1986) Michaelis-Menten kinetics of pulmonary endothelial angiotensin con-
verting enzyme in the conscious rabbit. In: Greenbaum LM, Magnolius HS (eds) Kinins IV.
Plenum, New York, pp 445-451
27. Bernard GR, Artigas A, Brigham KL, et al (1994) The American-European consensus con-
ference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trial coordina-
tion. Am J Respir Crit Care Med 49:818-824
28. Ryan JW, Falido MJ, Sequeira MJ, et al (1994) Estimation of rate constants for reactions of
pulmonary microvascular angiotensin converting enzyme with an inhibitor and a substrate
in vivo. J Pharmacol Exp Ther 270:260-268
29. Chen I, Pitt BR, Moalli R, Gillis CN (1984) Correlation between lung and plasma angioten-
sin converting enzyme and the hypotensive effect of captopril in conscious rabbits. J Phar-
macol Exp Ther 229:649-653
30. Esther CR, Marino EM, Howard TE (1997) The critical role of tissue angiotensin-convert-
ing enzyme as revealed by gene targeting in mice. J Clin Invest 99:2375-2385
31. Orfanos SE, Parkerson J, Fisher E, Catravas JD (1998) Estimation of dissociation constants
for pulmonary endothelial angiotensin converting enzyme reactions with trandolaprilat
and enalaprilat in vivo. Drug Dev Res 44:80-86
32. Catravas JD, Burch SE, Sprulock BO, Mills LR, et al (1988) Early effects of ionising radia-
tion on pulmonary endothelial angiotensin converting enzyme and 5'-nucleotidase, in vivo.
Toxicol Appl Pharamacol 94:342-355
33. Orfanos SE, Chen XL, Burch SE, Ryan JW, Chunk AYK, Catravas JD (1994) Radiation-in-
duced early pulmonary endothelial ectoenzyme dysfunction in vivo: effect of indomethacin.
Toxicol Appl Pharmacol124:112-122
34. Chen XL, Orfanos SE, Catravas JD (1992) Effects of indomethacin on PMA-induced pul-
monary endothelial enzyme dysfunction, in vivo. Am J Physiol 262:1153-1162
35. Orfanos SE, Parkerson JB, Chen XL, et al (2000) Reduced lung endothelial angiotensin-con-
verting enzyme activity in Watanabe hyperlipidemic rabbits in vivo. Am J Physiol 278:
11280-11288
36. Orfanos SE, Armaganidis A, Glynos C, et al (2000) Pulmonary capillary endothelium-
bound angiotensin converting enzyme activity in acute lung injury. Circulation 102:2011-
2018
37. Orfanos SE, Psevdi E, Stratigis N, et al (2001) Pulmonary capillary endothelial dysfunction
in early systemic sclerosis. Arthritis Rheum 44:902-911
38. Kaltsas P, Korovesi I, Mavrommati I, et al (2002) Pulmonary endothelial ACE dysfunction
in mechanically ventilated patients. Intensive Care Med 28 (suppl1):S89 (abst)
39. Orfanos SE, Glynos C, Mavrommati I, et al (2002) Pulmonary capillary endothelium-bound
angiotensin converting enzyme activity reduction in brain-dead subjects: potential cyto-
kine involvement. Am J Respir Crit Care Med 165:A102 (abst)
Endothelial Cell Replacement Therapy
in the Critically Ill
S. V. Baudouin
I Introduction
One of the long-standing goals of medical research is to find methods of regenerat-

ing damaged and destroyed tissues and vital organs. Solid organ transplantation is
well established in the treatment of irreversible single organ failure. However, it is
severely limited by lack of suitable organs, the problems of tissue rejection, and the
need for significant and long-term immunosuppressive treatment. Although the oc-
casional patient with critical illness will benefit from single organ transplantation,
it remains extremely unlikely that solid organ transplantation for multi-organ fail-
ure (MOF) will ever become a realistic clinical prospect.
Recent research in the field of stem cell biology has raised the possibility of a
different, and more physiological, approach to tissue regeneration [1-3]: the excit-
ing concept of using pluri-potential stem cells or multi-potential progenitor cells to
re-colonise and regenerate injured organs and tissue beds.
A variety of strategies are currently under intense investigation and a few, early
clinical trials have been performed. Approaches include the use of drugs to enhance
the natural release of progenitor cells and their incorporation into tissues; agents
which cause selective differentiation of progenitor cells into mature cells and the ex
vivo expansion of progenitor cells, collected either from the recipient or from fetal
cord blood and re-infused therapeutically into the patient at the time of illness.
This chapter will focus on one specific area of progenitor cell research - the endo-
thelial progenitor cell (EPC) [4-6].
There is good evidence that widespread vascular endothelial cell injury occurs in
the critically ill [7]. This, in turn, leads to the development of multi-organ dysfunc-
tion and ultimately failure. Agents that promote endothelial cell repair and regen-
eration are, therefore, attractive therapeutic targets in the critically ill. Most thera-
peutic trials in septic shock, the paradigm condition causing MOF, have attempted
to prevent organ damage. These studies have usually investigated anti-inflammatory
agents and most have been negative [8]. Alternate research strategies examining
the role of tissue repair may ultimately be more useful therapeutically. This chapter
will review the cell biology of EPCs and place this in the context of future applica-
tions of EPC therapy in the critically ill.
22 S. V. Baudouin
1 Endothelial Cell Damage in Sepsis

There is both direct and indirect evidence of widespread endothelial cell injury in
sepsis [7]. Anatomical damage to the endothelium has been described in several ex-
perimental studies. Reidy and Schwartz observed endothelial cell detachment asso-
ciated with an increase in endothelial cell replication in endotoxic rats [9]; Young
an co-workers found endothelial cell detachment in septic guinea pigs [10], and Re-
idy and Schwartz reported areas of complete endothelial cell loss in rats injected
with lipopolysaccharide [11]. The endothelial damage during sepsis may be pro-
longed. Leclerc and co-workers observed endothelial cell loss in aortas from endo-
toxic rabbits that took approximately 21 days to recover [12]. The de-endothelia-
lized surface also accounted for approximately 25o/o of the total endothelial surface
area.
Circulating endothelial-like cells have been detected in both septic animals and
man, supporting the hypothesis that significant endothelial damage is occurring.
Our group has reported increasing numbers of circulating cells expressing endothe-
lial surface markers (von Willibrand factor and the vascular endothelial growth fac-
tor [VEGF] receptor) in patients with sepsis and septic shock [13]. Mortality corre-
lated with the number of circulating cells detected, suggesting that endothelial cell
loss may be causal in producing MOE Circulating markers of endothelial cell dam-
age have also been detected in a number of studies of sepsis [14]. These include
raised levels of von Willibrand factor and platelet endothelial cell adhesion mole-
cule (PECAM)-1.
A number of complementary approaches, therefore, strongly suggest that diffuse
endothelial cell damage occurs in sepsis and contributes to the development of
MOF and poor outcome.
I Angiogenesis, Vasculogenesis, and Endothelial Repair

Angiogenesis is the process by which new blood vessels form in the adult and ma-
ture fetus (Fig. 1) [15], and involves the budding and sprouting of existing blood
Traditional mechanism - Angiogenesis

Damaged endothelium
CJ CJ CJ j/1/ICJ CJ
Cel l division and migration
Endothelial repair
Fig. 1. Schematic diagram of the traditional view of endothelial cell repair and regeneration. Endothelial
cell division occurs at the edge of the damaged area. Repair then occurs by endothelial cell migration
Table 1. Major angiogenic and vasculogenic factors
Name Functions
Vascular endothelial growth factor (VEGF) Vessel hyper-permeability: EC proliferation and

migration
Angiopoietin-2 (Ang-2) Vessel destabilization
Transforming growth factor beta (TGF-Pl Matrix remodeling; vessel stabilization: pericyte
differentiation
Fibroblast growth factor (FGF) EC proliferation and migration: tube formation
Epidermal growth factor (EGF) EC proliferation
Platelet-derived growth factor (PDGF) Tube formation: vessel stabilization: mesenchymal
proliferation and migration
Tumor necrosis factor alpha (TNF-a) Tube formation
Angiopoietin-1 (Ang-1) Vessel stabilization: mesenchymal proliferation
and migration
vessels. Physiological angiogenesis occurs during the ovarian cycle and in repair
processes such as wound healing. The angiogenic process requires the co-ordina-
tion of several complex factors [16]. In order for new vessel formation to occur,
pericytes, which are the mural cells of microvascular vessels, are first removed
from branching vessels. Matrix metalloproteinases then re-model the basement
membrane and extra-cellular matrix. A number of soluble growth factors/cytokines
and the matrix then induce the division and migration of existing mature endothe-
lial cells.
Once sufficient endothelial cells have been recruited to the neo-vessel, migration
arrest occurs and a tube-like structure is formed. Recruitment of mural cells
(smooth muscle cells in large vessels, pericytes in micro-vessels) occurs with subse-
quent formation of mature blood-carrying vessels.
A large number of soluble angiogenesis-promoting factors are involved in this
process (Table 1). These include VEGF, fibroblast growth factor (FGF), epidermal
growth factor (EGF), and transforming growth factor beta (TGF-p). Both VEGF and
FGF are particularly important in endothelial cell proliferation.
The VEGFs are a family of glycoproteins and include five members identified by
serial letters A to E [ 17]. Their principle target is the endothelial cell and they bind
to specific surface receptors. The VEGF receptor-2 or KDR receptor is expressed on
endothelial-like cells, some vascular smooth muscle cells and macrophages, while
the VEGF receptor-1 or flt-1 is more ubiquitous. Animals with gene 'knockouts' for
both VEGF and the KDR receptor demonstrate the central role of this cytokine in
vascular development. VEGF specifically stimulates endothelial cell proliferation.
Numerous studies implicate VEGF in angiogenesis including corneal and healing
bone graft models. Its production is regulated by local tissue oxygen concentra-
tions. The VEGF gene has a promoter region that binds hypoxia-inducible factor
(HIF) and hypoxia also promotes stability of VEGF mRNA, thereby prolonging its
translation.
Basic fibroblast growth factor (bFGF) and acidic fibroblast growth factor (aFGF)
are also important in endothelial cell regeneration and angiogenesis [18]. FGFs
24 S. V. Baudouin
Hematological - Neutrophils
stem cells
~ Lymphocytes
Platelets
Hemangioblast Endothelial Mature

CD34+ progenitor cells - endothelial cells
VEGF-Rl(KDR)+
(0133+
Fig. 2. A pluri-potential hemangioblast is the likely precursor of both mature endothelial and blood cells. An
intermediate stage of differentiation, the progenitor cell, signifies commitment to one or other cell line
stimulate endothelial cell proliferation and migration and bFGF induces the pro-
duction of tube-like structures from endothelial cells embedded in 3d collagen ma-
trices. FGFs also induce sprouting of blood vessels towards an implanted bolus in
experimental models of angiogenesis. However, vascular development in FGF gene-
deleted animals is normal although wound healing is impaired.
The process of blood vessel development in the fetus differs from that in the
adult. This process, called vasculogenesis, involves the differentiation of a proposed
multi-potential cell called the hemangioblast (Fig. 2) [19]. This cell subsequently
differentiates to form both endothelial and blood cells. Initial support for the exis-
tence of the hemangioblast came from microscopy studies of fetal blood islands.
These blood islands are the primitive precursors of blood vessels. Observations of
the simultaneous formation of endothelial lining cells and central hemapoietic stem
cells within the islands suggested the existence of a common precursor. More recent
in vitro differentiation studies and studies in the zebra fish strongly support the ex-
istence of the hemangioblast.
A further key observation supporting a common precursor is the fact that both the
endothelial and hematopoietic stem cells share common surface markers [6]. These
include the VEGF-receptor 2 (KDR), CD34 and the angiopoietin receptor Tie-2. The
factors promoting angioblast differentiation are still not fully defined, but both VEGF
and FGF have been implicated in the process. Studies in quail/chick chimeras show
that FGF-2 mediates the induction of angioblasts from the mesoderm [20]. Embryonic
angioblasts also divide and migrate in response to VEGF [20].
I Adult Vasculogenesis
The absolute separation of fetal vasculogenesis and adult angiogenesis has been
challenged by recent work suggesting that a circulating population of immature
EPCs exists in adults (Fig. 3). In 1997, Asahara and co-workers published a land-
mark paper which raised the possibility of post-natal vasculogenesis [21]. Using la-
belled magnetic beads, they isolated mononuclear cells from human blood which
were either CD34+ or positive for the VEGF receptor KDR. CD34 is expressed by
hematopoietic stem cells, but also by adult endothelial cells. KDR is also expressed
by some mature endothelial cells, but is strongly expressed on angioblasts.
Damaged endothelium
EPC recruitment
! •
Endothelial regeneration
Fig. 3. Post-embryonic vasculogenesis is an alternate model of blood vessel repair. Circulating endothelial
progenitor cells (EPCs), derived from the bone marrow, are recruited to areas of endothelial damage
where they subsequently differentiate to mature endothelial cells
Table 2. Comparison of surface markers of endothelial progenitor (EPC) and mature endothelial cells (EC)
Surface marker EPC Mature EC
VEGFR-2 (KDR) + +
VE-<adherin + +
(034 + +
PECAM-1 (CD31) + +
com +
The group demonstrated that when cultured in angiogenic-promoting medium,

both sets of selected cells differentiated to mature endothelial-like cells. This was
judged morphologically and by expression of characteristic endothelial surface mar-
kers, mRNA and protein expression. In addition, they labelled CD34+ cells and re-
ported incorporation into areas of neovascularization in animals with experimental
hindlimb ischemia. These results have since been replicated and extended by other
groups. For example, Shi and co-workers obtained CD34+ cells from both human fetal
cord blood and granulocyte colony stimulating factor (G-CSF) mobilized peripheral
blood which differentiated into mature endothelial cells in culture [22].
The CD34+ surface antigen is also expressed on hematological progenitor cells
[23]. Many groups have been searching for more specific markers of the proposed
EPC (Table 2). CD133 is expressed on a sub-set of CD34+ cells and a number of re-
ports have found that these cells have the potential to differentiate into mature en-
dothelial cells [24]. Surface expression of VEGF R2 (KDR) also appears to be a
marker of an EPC sub-set of hematological cells. Peichev and colleagues identified
CD34+ cells expressing both KDR and CD133 that produced endothelial colony-
forming units in semi-solid growth medium [24]. These colonies were similar to
the hematology colony forming units observed with cultured hematopoietic stem
cells.
26 S. V. Baudouin
Despite the substantial body of evidence supporting the existence of circulating

EPC, a number of difficulties and issues remain. The presence of mature circulating
endothelial cells has been found in both animals and man with vascular trauma
[25], myocardial infarction [26], sickle cell crisis [27], and infection [13]. These re-
ports mostly pre-date the work on circulating EPCs and it is possible that some of
these supposedly mature cells were in fact EPCs. In our study on human septic
shock, we identified an increased number of circulating mononuclear cells with the
VEGF KDR surface receptor [13]. We also successfully cultured mature endothelial
cells from a number of purified mononuclear cell preparations from our patients. It
is likely that at least some of the circulating endothelial cells that we detected were
in fact EPCs rather than apoptotic mature endothelial cells shed from the damaged
vasculature.
Lin's group have assessed the relative contribution that EPCs and shed mature en-
dothelial cells make to the circulating pool of endothelial-like cells [28]. These authors
examined the endothelial growth potential of enriched mononuclear cells obtained
from gender mismatched bone marrow transplant recipients. EPCs are derived from
bone marrow cells (see below) and the gender mismatched transplants allow a distinc-
tion to be made between donor (bone marrow-derived) and recipient cells. They
found evidence of a mixed population, both donor and recipient, of circulating cells
with endothelial growth potential. In the short term (9 days), most cells were of recip-
ient origin, but in the longer term (28 days) it was donor cells that predominated. The
researchers concluded that most circulating endothelial cells originate from mature
blood vessels, but have a poor growth population. A smaller population of bone mar-
row-derived cells, presumed to be EPCs, has a much higher growth potential with an
approximately 1000-fold expansion at 28 days.
Despite this type of evidence, it still remains difficult to distinguish between
EPCs and mature endothelial cells at the cellular level [6]. EPCs, mature endothelial
cells and sub-sets of hematopoietic cells all share the same surface markers includ-
ing CD34, PECAM (CD31), Tie-l, Tie-2, von Willibrand factor and VEGF R-2.
Other methods of detecting the endothelial origin of cells e.g. the incorporation of
acetylated low density lipoproteins (LDL) or the binding of lectins may also occur
in hematopoietic cells. The finding of one or more surface markers/antigens that
uniquely identify the proposed EPC would represent a major advance in the field.
I The Bone Marrow Origin of EPCs
Several studies have shown that EPCs originate in the bone marrow [29-31]. Most
involved experimental bone marrow transplantation and used the genetic differ-
ences between transplant and recipient cells to identify the origin of potential
EPCs. Asahara and co-workers used transgenic mice constitutively expressing P-ga-
lactosidase under the transcriptional regulation of an endothelial cell-specific pro-
moter [29]. Bone marrow cells from these donors were transplanted into irradiated
non-transgenic recipients. Endometrial neovascularization contained cells of donor
origin, as did areas of neovascularization in ischemic hindlimbs, ischemic hearts,
cutaneous wounds and sub-cutaneous tumors. In anther study of experimental
ischemic stroke in mice, areas of neovascularization in the brain incorporated mar-
row-derived cells from genetically-modified donors expressing green fluorescent
protein [32].
There is evidence that a similar bone marrow-derived population exists in man.

Gunsilus and co-workers studied six leukemic patients carrying the BCR/ABL fu-
sion gene in their bone marrow-derived cells [30]. Endothelial cells were success-
fully cultured from blood and bone marrow-derived mononuclear cells and carried
the BCR/ABL fusion gene. This observation supports a common origin of hemato-
poietic and endothelial cells in man from a bone marrow-derived cell. In addition,
in one patient the presence of BCR/ABL expressing endothelial cells in the endothe-
lium of myocardial blood vessels was shown. It is therefore likely that marrow-de-
rived EPCs can contribute to vascular formation in man in vivo.
1 The Control of EPC Release and Differentiation

If EPCs are involved physiologically in the process of vascular regeneration and re-
pair, then their regeneration in bone marrow, release, migration to areas of vascular
damage and subsequent differentiation to mature endothelial cells must be under
precise control. Investigations of this sequence of events are currently being carried
out in several laboratories and some progress has been made. It is becoming clear
that many of the soluble growth factors/cytokines which control classical angiogen-
esis are also important in adult vasculogenesis [33, 34]. A number of studies have
focused on the role of VEGF in EPC mobilization. Asahara's group injected mice
with VEGF. They found a significant increase in a population of circulating mono-
nuclear cells which expressed endothelial surface markers and incorporated low
density lipoprotein (LDL) [35]. These cells were negative for macrophage markers.
VEGF also increased the proliferation of EPCs in a culture assay. A dose dependent
chemotactic effect on bone marrow-derived mononuclear cells was also demon-
strated.
Other cytokines can also mobilize EPCs from the bone marrow. Takahashi and
colleagues demonstrated increased numbers of circulating EPC following treatment
of rabbits with granulocyte macrophage colony-stimulating factor (GM-CSF) [36].
Pre-treatment with GM-CSF also enhanced neovascularization in animals with
hindlimb ischemia and in a mouse corneal micro-pocket assay of angiogenesis.
The relevance of these observations to the critically ill lies in the fact that tissue
ischemia and hypoxemia have been strongly implicated in the mobilization of EPCs
from the bone marrow. In animals, hindlimb ischemia mobilizes EPCs from a bone
marrow population as demonstrated in bone marrow transplanted recipients of
transgenic donor marrow [36].
In man there is also good evidence that ischemia and hypoxemia increase the
number of circulating EPCs. Shintani and colleagues reported an increased number
of CD34+ circulating mononuclear cells, following acute myocardial infarction in 16
patients which peaked on day 7 [37]. These cells formed endothelial-like cells in
culture. The number of cell clusters formed in ,vitro were greater at day 7 than day
1 correlating with circulating numbers of CD34+ cells. Plasma levels of VEGF also
increased with a peak on day 7. This again correlated with circulating numbers of
CD34+ cells and colonies of endothelial cells grown from these cells in vitro.
Gill and co-workers reported similar findings in patients with burn injury and
following elective coronary artery bypass [38]. VEGF plasma levels rapidly in-
creased after injury/operation and correlated with an increase in peripheral mono-
nuclear cells expressing mRNA and surface protein for VEGFR-2 and VE-cadherin.
The number of circulating cells then gradually decreased over a number of days.
28 S. V. Baudouin
These cells also expressed CD133 and in culture produced colonies of mature endo-
thelial cells.
The lipid lowering statin agents promote neovascularization in ischemic tissue
of animals with normal cholesterol levels. In a study of 15 patients with stable cor-
onary artery disease, statin therapy was shown to mobilize EPCs in peripheral
blood [39]. This action appeared independent of changes in circulating angiogenic
cytokine levels.
Septic shock causes tissue ischemia and hypoxemia and both these stimuli cause
the release of EPCs. Circulating levels of numerous cytokines and growth factors,
including VEGF and IL-8, are extremely high and many of these have the potential
to mobilize EPCs. Mutunga and colleagues detected a population of VEGFR-2 posi-
tive circulating mononuclear cells in patients with both sepsis and septic shock
[13]. These cells differentiated into mature endothelial cells in culture and circulat-
ing numbers correlated with the severity of sepsis. It is likely that these cells were
EPCs although their contribution, if any, to vascular repair in sepsis remains un-
known.
I The Functional Role of EPCs
Incorporation of bone marrow-derived EPCs into areas of neovascularization has

been demonstrated in animals with bone marrow transplants from donors with ge-
netically-modified cells [40-43]. These modifications, which persist following cell
division, are then used as markers for the incorporation of bone marrow-derived
cells into the recipient's vasculature. However, these findings, alone, are not a com-
plete proof of principle. It remains possible that the cells incorporated into the vas-
culature are not true EPCs, but are hematological (e.g., macrophage) in origin.
However, recent work has demonstrated the creation of whole functional blood ves-
sels from EPCs that are, therefore, unlikely to be of purely hematological origin
[44].
The relative contribution that EPCs make to vascular repair has been estimated
in one study [41]. New vessel formation was studied in granulation tissue from he-
matopoietic chimeric mice. In control animals, 0.2 to 1.4% of endothelial cells in
control tissues were derived from hematopoietic cells. By contrast, 8.3 to 11.2% of
endothelial cells in granulation tissue vessels were derived from circulating hemato-
poietic progenitors. These cells may, therefore, make a significant contribution to
neovascularization.
A functional role of EPC in vascular repair was shown by Kocher and collabora-
tors [40]. Human CD34+ cells were collected following G-CSF-induced mobilization.
A sub-group of immature blast-like cells was subsequently identified on the basis
of CD133 and Tie-2 expression with the addition of transcription factor expression
characteristic of primitive hemangioblasts (GATA-2 and 3). These cells differen-
tiated into mature endothelial cells in endothelial-promoting culture medium.
In a further series of experiments, human CD34+ cells were injected into rats
with experimental myocardial ischemia. These cells were incorporated into both
new vessels in the infarct-bed and proliferation of existing vasculature. The blast-
like nature of these cells was confirmed by finding increased expression of human
GATA-2 mRNA in the rat hearts. The CD34+ recipients also demonstrated signifi-
cant functional improvement in terms of reduced myocyte apoptosis and improved
left ventricular contractility.
EPCs may also contribute to regeneration in other vascular beds. Following ex-
perimental focal cerebral ischemia in the adult mouse, EPCs contributed to neovas-
cularization [42]. Similar changes have been described in retinal [43] and limb vas-
cular beds [21].
Therapeutic Uses of EPCs
A number of therapeutic uses of EPCs are currently being investigated. These in-
clude:
1 The use of EPCs to provide a physiological coating for implantable grafts and
stents [45].
I The use of growth factors/chemokines to enhance angiogenesis [46].
I The direct injection of EPCs to enhance vascular repair [47].
I The ex vivo expansion ofEPCs and therapeutic re-introduction into the donor [44].
The use of EPCs as vectors for gene transfer [48].
Some of these approaches are more applicable to the elective situation although the
chronicity of organ failure in some severely ill patients makes the investigation of
these approaches worthwhile in the critically ill.
The thrombosis of prosthetic grafts remains a major problem. The endothelium
has an important anti-coagulant role and successful endothelialization of prosthetic
grafts has been reported in animals [45]. These studies mostly used CD34+ positive
cells with in vitro pre-implantation graft coating.
Several experimental studies and two randomized, controlled trials (RCTs) in
man have investigated the use of prolonged growth factor/cytokine supplements in
promoting angiogenesis [46]. Despite reported success in animals with ischemia,
RCTs of both VEGF and TGF were negative in patients with myocardial ischemia.
However, local concentration of these growth factors may have been inadequate to
induce angiogenesis. There is also some suggestion that EPC mobilization is less ef-
fective in older animals. This may explain the differences between the human and
animal trials.
The use of EPCs as vectors for gene therapy is attractive. In theory, these cells
would localize to areas of vascular damage, thereby delivering relevant genes to the
critically ischemic area. Iwaguro et al. introduced EPCs transduced with adenovirus
encoding VEGF to athymic mice with hindlimb ischemia [48]. They found a signif-
icant functional improvement in limb ischemia in recipients and reported a 30
times reduced requirement for transduced EPCs compared to non-modified cells.
Similar approaches in man may be possible.
A clinical trial of the direct administration of CD34+ cells with EPC potential
has recently been performed in patients with critical limb ischemia. Tateishi-Yuya-
ma and colleagues injected autologous bone marrow-derived mononuclear cells into
one leg of 23 patients with bilateral lower limb ischemia [47]. The cells were a mix-
ture of CD34+ and CD34- sub-sets. The CD34+ sub-set contained cells of endotheli-
al lineage as assessed by expression of VEGFR-2, Tie-2 and FGF receptor mRNA ex-
pression. Significant clinical and physiological improvement occurred in the treated
limb compared to the control one.
A further therapeutic strategy is ex vivo expansion of EPCs [44]. Two different
approaches are possible. In the first, true EPCs could be selected and maintained in
30 S. V. Baudouin
vitro in order to generate further progenitor cells. In the second method, EPCs
would be selected and then differentiated ex vivo into mature endothelial cells.
These could be further expanded ex vivo and re-injected for therapy. Both these
methods have already been investigated by hematologists with an interest in thera-
peutic bone marrow transplantation for hematological disease and some successes
have been reported [49]. However, a self-renewing endothelial 'stem cell' has yet to
be identified. The peripheral EPCs may already be irreversibly committed to differ-
entiation and not possess any self-renewal capability. Further proof of self-renewal
requires the identification of true immature EPCs. These cells are likely to be very
rare and will only be identified by single cell studies and the discovery of novel
surface markers.
I Conclusion
The existence of both pluripotential stem cells and progenitor cells with more lim-
ited differentiation potential is now well established in adult animals and man. In
suitable environments, some of these cells can differentiate into mature, functional
endothelial cells. The cells are incorporated into areas of vascular repair and appear
to contribute to the vascular healing process. Widespread vascular dysfunction and
damage is common in the critically ill and endothelial progenitor replacement ther-
apy could be beneficial. Both the basic science and clinical aspects of such an
approach are currently under investigation in a number of laboratories.
References
1. Vander Kooy D, Weiss S (2000) Why stem cells? Science 287:1439-1441
2. Watt FM, Hogan BLM (2000) Out of Eden: Stem cells and their niches. Science 287:1427-
1430
3. Fuchs E, Segre JA (2000) Stem cells: A new lease on life. Cell100:143-155
4. Moore MA (2002) Putting the neo into neoangiogenesis. J Clin Invest 109:313-315
5. Luttun A, Carmeliet G, Carmeliet P (2002) Vascular progenitors: from biology to treatment.
Trends Cardiovasc Med 12:88-96
6. Rafii S (2000) Circulating endothelial precursors: Mystery, reality, and promise. J Clin In-
vest 105:17-19
7. Vallet B, Wiel E (2001) Endothelial cell dysfunction and coagulation. Crit Care Med
29:S36-S41
8. van der Poll T (2001) Immunotherapy of sepsis. Lancet Infect Dis 1:165-174
9. Reidy MA, Schwartz SM (1983) Endothelial injury and regeneration. IV. Endotoxin: a non-
denuding injury to aortic endothelium. Lab Invest 48:25-34
10. Young JS, Headrick JP, Berne RM (1991) Endothelial-dependent and -independent re-
sponses in the thoracic aorta during endotoxic shock. Circ Shock 35:25-30
11. Reidy MA, Bowyer DE (1997) Scanning electron microscopy: Morphology of aortic en-
dothelium following injury by endotoxin and during subsequent repair. Atherosclerosis
26:319-328
12. Leclerc J, Pu Q, Corseaux D, et al (2000) A single endotoxin injection in the rabbit causes
prolonged blood vessel dysfunction and a procoagulant state. Crit Care Med 28:3672-3678
13. Mutunga M, Fulton B, Bullock R, et al (2001) Circulating endothelial cells in patients with
septic shock. Am J Respir Crit Care Med 163:195-200
14. Reid PT, Donnelly SC, Haslett C (1995) Inflammatory predictors for the development of
the adult respiratory distress syndrome. Thorax 50:1023-1026
15. Henry TD (1999) Therapeutic angiogenesis. Br Med J 318:1536-1539
16. Papetti M, Herman IM (2002) Mechanisms of normal and tumor-derived angiogenesis. Am

J Physiol 282:C947-C970
17. Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z (1999) Vascular endothelial growth factor
(VEGF) and its receptors. FASEB J 13:9-22
18. Cross MJ, Claesson-Welsh L (2001) FGF and VEGF function in angiogenesis: signalling
pathways, biological responses and therapeutic inhibition. Trends Pharmacal Sci 22:201-
207
19. Choi K (1998) Hemangioblast development and regulation. Biochem Cell Bioi 76:947-956
20. Poole TJ, Finkelstein EB, Cox CM (2001) The role of FGF and VEGF in angioblast induc-
tion and migration during vascular development. Dev Dyn 220:1-17
21. Asahara T, Murohara T, Sullivan A, et al (1997) Isolation of putative progenitor endothelial
cells for angiogenesis. Science 275:964-967
22. Shi Q, Rafii S, Wu MH, et al (1998) Evidence for circulating bone marrow-derived en-
dothelial cells. Blood 92:362-367
23. Krause DS, Fackler MJ, Civin Cl, May WS (1996) CD34: structure, biology, and clinical uti-
lity. Blood 87:1-13
24. Peichev M, Naiyer AJ, Pereira D, et al (2000) Expression of VEGFR-2 and AC133 by circu-
lating human CD34+ cells identifies a population of functional endothelial precursors.
Blood 95:952-958
25. Mahdy Z, Otun HA, Dunlop W, Gillespie JI (1998) The responsiveness of isolated human
hand vein endothelial cells in normal pregnancy and in pre-eclampsia. J Physiol 508:609-
617
26. Mutin M, Canavy I, Blann A, Bory M, Sampol J, Dignat-George F (1999) Direct evidence of
endothelial injury in acute myocardial infarction and unstable angina by demonstration of
circulating endothelial cells. Blood 93:2951-2958
27. Solovey A, Lin Y, Browne P, Choong S, Wayner E, Hebbel RP (1997) Circulating activated
endothelial cells in sickle cell anemia. N Engl J Med 337:1584-1590
28. Lin Y, Weisdorf DJ, Solovey A, Hebbel RP (2000) Origins of circulating endothelial cells
and endothelial outgrowth from blood. J Clin Invest 105:71-77
29. Asahara T, Masuda H, Takahashi A, et al (1999) Bone marrow origin of endothelial pro-
genitor cells responsible for postnatal vasculogenesis in physiological and pathological neo-
vascularization. Circ Res 85:221-228
30. Gunsilius E, Duba HC, Petzer AL, et al (2000) Evidence from a leukaemia model for main-
tenance of vascular endothelium by bone-marrow-derived endothelial cells. Lancet
355:1688-1691
31. Reyes M, Dudek A, Jahagirdar B, Koodie L, Marker PH, Verfaillie CM (2002) Origin of en-
dothelial progenitors in human postnatal bone marrow. J Clin Invest 109:337-346
32. Hess DC, Hill WD, Martin-Studdard A, Carroll J, Brailer J, Carothers J (2002) Bone marrow
as a source of endothelial cells and NeuN-expressing cells after stroke. Stroke 33:1362-1368
33. Isner JM, Asahara T (1999) Angiogenesis and vasculogenesis as therapeutic strategies for
postnatal neovascularization. J Clin Invest 103:1231-1236
34. Flamme I, Frolich T, Risau W (1997) Molecular mechanisms of vasculogenesis and em-
bryonic angiogenesis. J Cell Physiol173:206-210
35. Asahara T, Takahashi T, Masuda H, et al (1999) VEGF contributes to postnatal neovascular-
ization by mobilizing bone marrow-derived endothelial progenitor cells. EMBO J 18:3964-
3972
36. Takahashi T, Kalka C, Masuda H, et al (1999) Ischemia- and cytokine-induced mobilization
of bone marrow-derived endothelial progenitor cells for neovascularization. Nat Med 5:
434-438
37. Shintani S, Murohara T, Ikeda H, et al (2001) Mobilization of endothelial progenitor cells
in patients with acute myocardial infarction. Circulation 103:2776-2779
38. Gill M, Dias S, Hattori K, et al (2001) Vascular trauma induces rapid but transient mobili-
zation ofVEGFR2(+)AC133(+) endothelial precursor cells. Circ Res 88:167-174
39. Vasa M, Fichtlscherer S, Adler K, et al (2001) Increase in circulating endothelial progenitor
cells by statin therapy in patients with stable coronary artery disease. Circulation 103:
2885-2890
32 S. V. Baudouin: Endothelial Cell Replacement Therapy in the Critically Ill
40. Kocher AA, Schuster MD, Szabolcs MJ, et al (2001) Neovascularization of ischemic myocar-
dium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, re-
duces remodeling and improves cardiac function. Nat Med 7:430-436
41. Crosby JR, Kaminski WE, Schatteman G, et al (2000) Endothelial cells of hematopoietic
origin make a significant contribution to adult blood vessel formation. Circ Res 87:728-
730
42. Zhang ZG, Zhang L, Jiang Q, Chopp M (2002) Bone marrow-derived endothelial progenitor
cells participate in cerebral neovascularization after focal cerebral ischemia in the adult
mouse. Circ Res 90:284-288
43. Grant MB, May WS, Caballero S, et al (2002) Adult hematopoietic stem cells provide func-
tional hemangioblast activity during retinal neovascularization. Nat Med 8:607-612
44. Kaushal S, Amiel GE, Guleserian KJ, et al (2001) Functional small-diameter neovessels cre-
ated using endothelial progenitor cells expanded ex vivo. Nat Med 7:1035-1040
45. Bhattacharya V, McSweeney PA, Shi Q, et al (2000) Enhanced endothelialization and micro-
vessel formation in polyester grafts seeded with CD34+ bone marrow cells. Blood 95:581-
585
46. Freedman SB, Isner JM (2002) Therapeutic angiogenesis for coronary artery disease. Ann
Intern Med 136:54-71
47. Tateishi-Yuyama E, Matsubara H, Murohara T, et al (2002) Therapeutic angiogenesis for
patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot
study and a randomised controlled trial. Lancet 360:427-435
48. Iwaguro H, Yamaguchi J, Kalka C, et al (2002) Endothelial progenitor cell vascular endothe-
lial growth factor gene transfer for vascular regeneration. Circulation 105:732-738
49. Emerson SG (1996) Ex vivo expansion of hematopoietic precursors, progenitors, and stem
cells: the next generation of cellular therapeutics. Blood 87:3082-3088
Sepsis: Mechanisms and Therapy
Reconciling Clinical Criteria and the Use of Genetically
Engineered Animals in Sepsis Research
G. Albuszies, C. Ince, and P. Radermacher
1 Introduction
A powerful method for identifying the in vivo molecular mechanisms that underlie
pathophysiologic conditions seen in sepsis and septic shock is the utilization of ge-
netically engineered mice in a clinically relevant experimental setting. Various as-
pects of preclinical study design, including the type of model, have to be consider-
ed carefully according to current understandings of the cause and course of clinical
sepsis. The implementation of recommended therapeutic strategies in experimental
sepsis is crucial to obtain meaningful data and, therefore, achieve a proper level of
relevance. Ongoing and rapid progress in the development of microsurgical tech-
niques and methods of measurements applicable in such a small-sized species facil-
itate the acquisition and evaluation of objective criteria and physiological parame-
ters, respectively. The transformation of a typical clinical setting in intensive care
units (ICUs), including mechanical ventilation and invasive monitoring of organ
function into experiments on mice, may become routine maneuvers.
Taken together, the increasing number of commercially available as well as indi-
vidually gene-modified mice and modern micro-technologies have widened the
spectrum of in vivo experiments in preclinical sepsis research.
This chapter will review an appropriate model of murine sepsis and suggest
practical guidelines for 'intensive care' of mice.
I Murine Models of Sepsis
Various types of animal models of sepsis have been described over the past decades
with a wide variety of pathogens and technical approaches for induction of experi-
mental sepsis as outlined in Table 1. When considering an appropriate model of
sepsis, the basic characteristics of clinical sepsis should be regarded. Sepsis, severe
sepsis, and septic shock represent progressive stages of the same illness in which a
systemic response to an infection mediated by endogenous mediators leads to a
generalized inflammatory reaction and concomitant dysfunction and/or failure in
organs remote from the initial insult. Although the most common cause of septic
shock is secondary to Gram-negative infections, invasion of Gram-positive organ-
isms accounts for an increasing percentage of cases {30-SOo/o of all incidences) with
a small number of cases due to viruses, fungi and parasites. However, many pa-
tients do not have documented infection at all [1]. Pathogenetic mechanisms that
underlie Gram-positive sepsis differ from Gram-negative sepsis, e.g., interaction be-
36 G. Albuszies et al.
Table 1. Sepsis models in mice
Sepsis model Pathogen Administration References

Endotoxicosis Lipopolysaccharide: Intravenous [4]
Escherichia coli, Klebsiella pneumonia, intraperitoneal
Pseudomonas aeruginosa, Salmonella species oral
Bacterial challenge Escherichia coli, Pseudomonas aeruginosa, Intravenous [3, 39]
Klebsiella pneumoniae, Staphylococcus aureus intraperitoneal
I Abscess formation Staphylococcus species, Bacteroides fragilis Intramuscular [40, 41]
subcutaneous
intraabdominal
Pneumonia/ARDS Streptococcus pneumoniae, Intranasal [42-44]
Klebsiella pneumoniae intraperitoneal
intratracheal
intravenous
I Peritonitis Autologous or heterologous feces Feces [12, 16, 20]
Indigenous gut flora: cecal ligation
Escherichia coli, Klebsiella, Proteus species, and perforation
Pseudomonas aeruginosa, Enterococcus
species, anaerobic streptococci
ARDS: acute respiratory distress syndrome
tween the host immune response and microbial organisms, whereas clinical features
of sepsis caused by Escherichia coli resemble those induced by Klebsiella or Proteus
species [2]. Thus, animal models in which single pathogens or bacterial cell wall
components, e. g., lipopolysaccharide (LPS, endotoxin) from Gram-negative bacte-
ria, are solely used, therefore, rather reflect a unique immune response to one sin-
gle agent provided an appropriate choice of challenge strain or derived LPS, respec-
tively [3, 4]. The route of administration, galenic preparation as well as preference
of strain, number and combination of bacteria may be individually chosen accord-
ing to investigator's needs and experimental settings. Yet, as with endotoxemia, the
decision for single bolus injection, intermittent or continuous administration sub-
stantially determine the kinetics of bacterial challenge [3]. Moreover, the systemic
administration of viable bacteria or LPS lacks typical septic features, i.e., complex
interaction of local and systemic pro- and antiinflammatory systems. Therefore, im-
munotherapy based on cytokine production after LPS challenge may be misdirected
since the LPS model has not always accurately reproduced the cytokine profile of
sepsis [5]. Consequently, agents such as steroids or anti-tumor necrosis factor
(TNF) antibody could only indicate beneficial effects on LPS-treated mice whereas
this concept was not borne out in experimental polymicrobial sepsis and well con-
trolled clinical trials, respectively [6-9]. Since most patients have a septic focus that
continually seeds the body with bacteria over time, models such as soft tissue ab-
scess formation, intraperitoneal inoculation and endobronchial instillation of live
pathogens, respectively, might therefore be advantageous in many instances.
Septic patients frequently suffer from peritonitis due to disturbances of the gas-
tro-intestinal or gall bladder wall integrity, e.g., ischemia, perforation and tissue
necrosis. An integral part of the septic focus in these patients lies in the presence
of a micro-environment. The content of perforated abdominal organs such as gas-
Reconciling Clinical Criteria and the Use of Genetically Engineered Animals in Sepsis Research 37
tric fluid, bile or stool, leak into the abdominal cavity. The peritoneal reaction is
the formation of fibrin clots. This micro-environment interferes with selection,
growth and elimination of bacteria and finally influences the local inflammatory re-
sponse [10]. The intraperitoneal implementation of bacteria together with adju-
vants, fibrin clots or fecal material may provide such a micro-environment. How-
ever, the entity of ischemic and necrotic tissue still needs to be realized in such
models. Moreover, the use of one single strain or even a combination of various
species does not mirror the typical clinical scenario in patients confronted with a
mixed bacterial flora. The polymicrobial nature of abdominal sepsis in the presence
of ischemic and necrotic tissue and concomitant realistic micro-environment is
constituted in experiments utilizing a cecal ligation and perforation (CLP) proce-
dure [11].
1 Cecal Ligation and Puncture

The CLP model first described by Wichterman et al. and adapted for mice by Baker
et al. appears to be a straightforward procedure in order to induce sepsis and septic
shock [11, 12]. In anesthetized and spontaneously breathing mice a laparotomy is
performed by a 1-2 em midline incision, sufficient to expose the cecum and ad-
joining intestine. With a 3- or 4-0 silk suture, the cecum is tightly ligated at its
base distal to the ileocecal valve without interrupting the continuation of the small
bowel and colon. The cecum is then punctured once or twice with an appropriate
needle size. To ensure that puncture holes are open and allowing the contained
stool to spill into the peritoneal cavity the cecum is gently squeezed and feces ex-
truded. The abdominal incision is subsequently closed in two layers, i.e., perito-
neum with musculature and cutis with a 6-0 and 4-0 suture respectively.
I Factors Affecting Septic Course after CLP

Major determinants of the septic course in CLP models are the number of puncture
holes and needle size that may be chosen according to the desired severity of sepsis
and septic shock with respect to predefined physiological and immunological pa-
rameters [13]. The influence of needle size in a two puncture model on mortality
rate over time according to Baker et al. is given in Fig. 1. Some authors prefer to
puncture three times or even make a 5-mm· incision .at the antimesenteric border
[14]. However, as with endotoxemia or bacterial challenge the fast onset and rapid
development of overwhelming sepsis due to high dosage of administered agent, a
CLP model with a considerably high mortality rate within the first 6-12 h after in-
sult may not provide enough time to develop the full manifestations of a true clini-
cal septic response. On the contrary, cecal ligation without puncture does not lead
to lethal septic shock although marked changes in macrophage cytokine release ca-
pacity are similar as with CLP [11]. Regarding the balance of inflammatory cyto-
kines, a decrease in puncture diameter is associated with delayed and decreased ex-
pression of the pro-inflammatory mediators TNF-a and interleukin (IL)-6 whereas
concentration of the anti-inflammatory IL-10 increases [15]. At first sight, most
studies do not reveal linearity of survival rate in dependence on the size of the ce-
cal lesions. A two puncture model with a 19-gauge needle led to a 50-60% mortal-
100
/
/
/>/
80
£ 60 / / / Needle size
~ ,"' ./ / (gauge)
;:;; / /, / --18
t: / ,/
0
::E
40
/
,"',/ ./ / '
,•
- - - 19
- ·-20
20
//
///
.· - ..-21
........ 22
"'/;/ ···············
~··
.,~r;-::--' ··•······
-·····
0~~.--.--.---.--.---.--,--.
0 12 24 36 48 60 72 84 96
Time after CLP (h)
Fig. 1. Mortality rate over time after CLP with different-sized needles. Modified from Baker et al. [12]
ity rate at 48 hours in CBA/J mice whereas in C57/Bl6 mice after one puncture with
a 18-gauge needle survival was 0% [12, 16]. Several reasons might explain the ham-
pered interlaboratorial control of mortality rates in relation to the CLP model used.
First, the genetic background determines susceptibility during murine sepsis [17].
BALB/c mice demonstrated a reduced ability to survive after CLP compared to
Swiss Webster mice. In addition, Stewart et al. reported a significant higher mortal-
ity in C57BL/6J (B6) than A/J mice [18]. Therefore, one cannot rule out that B6
mice have a higher susceptibility than CBA/J leading to different survival rates. Sec-
ond, Baker et al. stated that gender did not influence the outcome and therefore
data for males and females were pooled for purposes of analysis. However, C3H/
HeN mice have shown gender differences in the inflammatory response and surviv-
al after CLP, e.g., female C3H/HeN mice had a higher survival rate and lower plas-
ma levels of IL-6, TNF-a and prostaglandin E2 (PGE2 ) as compared to males [19].
Third, the increased sensitivity of aged mice to invasive bacterial infection accord-
ing to human epidemiologic experience has already been documented by Hyde et
al. in C57Bl/6Nnia mice [20]. In addition, factors such as pregnancy, sociophysiolo-
gic conditions, circadian rhythms, and state of health potentially modulate an indi-
vidual mouse's sensitivity to CLP. Hence, further studies need to be undertaken in
order to clarify the contribution of distinct factors to overall performance and time
course in experimental murine sepsis.
I Polymicrobial Sepsis: Clinical Criteria and Therapeutic Strategies

Guidelines for the treatment of sepsis in patients include surgical intervention in
the form of debridement of infected, devitalized or necrotic tissue [21]. In fact,
when CLP was followed at 16 hours by excision of the cecum and saline peritoneal
lavage, the mortality rate decreased from 100 to 20% versus CLP alone [12].
Retrospective studies have shown that early administration of appropriate anti-
biotics reduces the mortality in patients with bloodstream infections caused by
Gram-negative bacteria. By analogy with the observations made in these patients

and despite the lack of substantial clinical data in the literature, it is likely that the
same is true for Gram-positive sepsis [22). The CLP model is considered to induce
sepsis by the animal's indigenous gut flora. Consequently, blood cultures from mice
after CLP were positive for multiple organisms including Enterobacteriacea (e.g.,
Escherichia coli, Klebsiella and Proteus species), Pseudomonas aeruginosa, Entero-
coccus species and anaerobic streptococci [12, 16). Furthermore, one study revealed
a shift from predominantly Gram-positive to Gram-negative as well as anaerobic to
aerobic Gram-negative bacteria with progressing sepsis. Finally, at the time of
death, aerobic coliform bacteria predominated [20). The authors also proved that
the cecum was the primary focus, i.e., a strong correlation was demonstrated be-
tween bacterial species in the cecum and those found in other tissues such as liver
and spleen as well as blood cultures. Given the polymicrobial nature of this model,
antibiotic treatment with ceftriaxone (30 J.Lg/g) and clindamycin (30 J.Lg/g) injected
intramuscularly every 6 hours significantly increased survival in B6 mice [16).
Comparing the broad spectrum imipenem (25 J.Lg/g) with triple antibiotic mixture
of gentamicin, clindamycin, and ciprofloxacin (10, 325 and 50 J.Lg/g respectively)
given every 12 hours for a total of six injections, both approaches proved to be ef-
fective in eliminating positive blood cultures following CLP and revealed a higher
survival rate for the imipenem group [7, 23). Interestingly, kinetic appearance of
IL-l, IL-6, TNF-a, and neutrophil chemoattractant KC (a murine homolog of hu-
man IL-8) as well as LPS in plasma and peritoneum at 24 h post-CLP were not dif-
ferent.
Volume repletion in patients· with septic shock produces significant increases in
cardiac output and systemic oxygen delivery, and fluids alone are sometimes suffi-
cient to reverse hypotension and restore hemodynamic stability [24). Although vol-
ume resuscitation is mostly integrated into experimental models, the amount, com-
position, and timing still remain a matter of debate. Most frequently normal saline
(1 to 1.5 ml or 50 J.Lllg respectively) is injected subcutaneously at the time of sur-
gery. An early hyperdynamic and late hypodynamic state (5 and 24 h post-CLP, re-
spectively) has been observed in C3H/HeN in a two puncture model applying a 22-
gauge needle with single injection of saline (1 ml) [25]. Cardiac output, blood flow
in liver, small intestine, spleen, and kidneys as well as oxygen utilization were con-
comitantly increased in the hyperdynamic phase whereas these parameters together
with mean arterial pressure significantly decreased at 24 h after onset of sepsis. Re-
peated fluid administration (50 J.Ll!g normal saline) every 6 h for 2 days in B6 mice
after CLP with one 18-gauge needle puncture yielded an increased cardiac output
and sustained hyperdynamic state for the entire observation period [16). Hence, in
order to maintain a hyperdynamic condition during sepsis repeated or continuous
fluid administration should be provided. However, continuous infusion of fluid in
mice by means of intravascular catheters or mini-osmotic pumps has only been
performed in non-septic animals. The differentiated evaluation of intravascular
fluid support for 3 h, i.e., 50 J.Llfg/h normal saline versus 20 J.Ll/g!h polyhydroxyethyl
starch solution and no fluids, respectively, on hemodynamic parameters of anesthe-
tized and mechanically ventilated mice indicated beneficial effects for either fluid
regimen on mean arterial pressure, albeit at the cost of changes in organ water and
blood hemoglobin content [26). Although volume depletion in septic animals is ex-
pected to vary significantly, the above mentioned infusion rates might serve as
rough estimates of required fluid resuscitation. To circumvent the more accentuated
blood acidosis in the saline group the use of balanced electrolyte solution, e. g., lac-
tated Ringers solution and possibly the simultaneous administration of a synthetic

colloid should be beneficial. Yet, in order to provide adequate volume resuscitation
it is crucial to evaluate and deliver individual fluid needs as characterized by var-
ious hemodynamic parameters. Sophisticated methods for intermittent or perma-
nent evaluation of macrocirculatory function in closed-chest models such as two-
dimensionally directed M-mode echocardiography and conductance-micromano-
meter volumetry are readily available and applicable to mice, with the latter also
implying estimation of intraventricular filling pressures as guideline for fluid ad-
ministration [27]. In addition to improving hemodynamic variables, optimization
of intravascular volume status during sepsis may have important effects on immune
responses [28]. Moreover, the comparison of different types of fluid with this re-
spect revealed a more potent attenuation of early cytokine expression, i.e., hepatic
TNF-a messenger RNA (mRNA) and IL-1/l mRNA as well as intestinal IL-1/l mRNA
at 3 and 6 h post-CLP for saline rather than serum administration. Interestingly,
survival rate was higher in mice receiving a combination of 1 ml saline plus 0.1 ml
serum s.c. The choice of whether to favor one specific type or combination of fluids
with respect to the diversity of clinically applied substances and multiple parame-
ters in sepsis, should be more closely addressed in the future.
Acute lung injury (ALI) is a frequent extra-abdominal complication of bacterial
peritonitis. In fact, edematous lung tissue and bronchoalveolar lavage (BAL) fluid
from mice subjected to CLP contained elevated levels of macrophage cytokines,
pulmonary myeloperoxidase, 8-isoprostane, and protein, with concomitant aug-
mented neutrophil recruitment [29, 30]. In order to prevent severe hypoxemia and
hypercarbia at the level of the whole organism, early placement of an endotracheal
tube and institution of mechanical ventilation is required. Airway assessment in
mice is mainly achieved by two methods: direct laryngoscopy for orotracheal intu-
bation or, alternatively, tracheotomy according to investigator's preference and ex-
perimental settings [31]. Physiological values for murine respiratory parameters
and operation specifications of current mouse ventilators have been reviewed else-
where [32]. Briefly, to maintain normal gas exchange pressure-limited and time-
cycled ventilation with a respiratory rate of 100-150/min and airway pressure of 8-
15 em H2 0 yielding tidal volumes of 8-12 J.tllg may serve as general recommenda-
tion in otherwise healthy animals. However, some authors have reported differential
control of spontaneous breathing patterns among inbred strains and therefore sug-
gesting need for individually configured respirator settings [33]. Evaluation of ade-
quate mechanical ventilation may best be performed by means of mainstream cap-
nography or cutaneous COrelectrodes [32]. Pneumotachygraphs for direct airway
gas flow measurements and sidestream COrmonitors, respectively, integrated in
the ventilatory circuit are suspected to increase dead space depending on the site of
sampling and subsequently leading to partial rebreathing with hypercarbia and
eventually hypoxia. Sampling for intermittent blood gas analysis requires substan-
tial volume of arterial blood (0.1-0.2 ml), i.e., 5-10o/o of the total blood volume of a
25 g mouse, adding new sources of hemodynamic instability to the experiment. To
our knowledge, mechanical ventilation of septic mice has not been performed yet,
and current literature still lacks data concerning gas exchange and oxygen kinetics
in restrained and closed-chest models of murine sepsis. Clinical guidelines for pro-
vision of supplemental oxygen include the use of positive end-expiratory pressure
(PEEP) to reduce concentrations of inspired oxygen and small tidal volumes with
the goal to maintain end-inspiratory plateau pressures at levels less than 30 em
H2 0 with minimal risk for barotrauma or volutrauma [34]. Therefore, the imple-
mentation of 3-5 em H2 0 PEEP and 0.5-0.6 Fi0 2 in mechanically ventilated septic

mice should provide sufficient alveolar respiration during sepsis.
Laparotomy and CLP as well as tracheostomy and continuous mechanical venti-
lation require short- and long-term anesthesia, respectively. Arras et al. compared
eight different anesthetic protocols consisting of combinations of dissociative anes-
thetics (ketamine, tiletamine), aragonists (xylazine, medetomidine) and/or seda-
tives (acepromazine, azaperone, zolazepam) for their safety and efficacy [35]. Reflex
tests, physiological measurements such as respiratory rate, electrocardiogram, arte-
rial blood pressure, body temperature, blood gas tensions, and acid-base balance
were used to characterize the quality of anesthesia. The authors recommend a mix-
ture of ketamine, xylazine, and acepromazine (100 !lg/g, 20 11g/g and 3 11g/g i.p., re-
spectively) with respect to safety margins and time of surgical tolerance. They also
remark a wide range of appropriate dose levels arising from factors such as strain,
sex, age, and mutation and, therefore, suggest titrating the dose of anesthetic in a
preliminary trial. Limitations of virtually all different regimens reside within ad-
verse effects on multiple physiologic variables as indicated by hypoxia, hypercap-
nia, acidosis, hypothermia and decreased heart rate with diminished blood pres-
sure. Although most of the healthy mice were able to overcome the acid-base and
blood gas imbalance this might not be valid for severely diseased animals. Continu-
ous intraperitoneal administration of anesthetics is considered to be obsolete in
peritonitis since pharmacokinetic and pharmacodynamic parameters may vary con-
siderably under such conditions. Following initial induction, maintenance of an-
esthesia in mechanically ventilated mice may best be performed by use of inhala-
tional anesthetics [26]. Isoflurane at concentrations of 1.5-2% yielded acceptable
values for mean arterial pressure and heart rate in Swiss, CD-1, BalbC, and C57Bl/6
mice. Moreover, volatile anesthetics are related to easy titration to the desired level
of anesthesia and negligible perioperative mortality. However, Imai et al. observed
a time-varying influence of halothane inhalation on immunocytes in septic mice
[36]. According to the authors, a two-hour halothane exposure appears to be the
optimum for macrophage and leukocyte suppression, while a six-hour exposure
may suppress immunocytes and other functions to such a degree that CLP survival
declines when compared to a two-hour halothane exposure. Whether the intrave-
nous infusion of common anesthetics for long-term measurements and mechanical
ventilation of restrained mice will be superior to volatile or intraperitoneally adm-
inistered narcotics still needs to be tested.
After the CLP procedure and in particular with onset of peritonitis and subse-
quent sepsis, mice are expected to experience pain of varying degree. Pain control
is aimed at preventing an interfering reduction in food and water intake and nor-
malizing stress hormone levels. Gades et al. recommend the use of buprenorphine
(2 11g/g s.c.) for mild to moderate pain of increased duration at dosing intervals of
3 to 5 h [37]. Several aspects need to be considered prior to administering opioids
in the CLP model. Anesthetics for operation will interfere with postoperatively ap-
plied opioids with increased risk of hypoventilation and apnea. Furthermore, septic
mice are more prone to overdosage of depressant drugs. Last but not least, as with
anesthetics, pilot studies to titrate the optimum dose for the given strain, sepsis de-
gree, etc., are mandatory.
Similar to patients, mice develop either hyperthermia or hypothermia due to
sepsis [38]. Ebong et al. reported a relationship between severity of sepsis and de-
gree of hypothermia in BALB/c mice [13]. Therefore, the implementation of heating
devices such as infrared lamp or heating pads seems to be useful to maintain nor-
Table 2. Practical guidelines for experimental murine sepsis
IProcedure Guidelines References
Anesthesia short-term Ketamine : 100 119/9 [35)

+
Xylazine: 20 1-lg/9
+
Acepromazine: 3 ~tg/9
i.p.
Cecal ligation and puncture Two puncture: 19-9au9e needle [12, 16)
Alternatively:
One puncture: 18-9au9e needle
Antibiotics Ceftriax one: 30 119/9 [16, 23)
+
Clindamycin: 30 ~tg/g
i.m. every 6 h
Alternatively:
lmipenem: 25 119/9
s.c. every 12 h
Fluid resuscitation 0.9 N saline: 50 ~-tl/g [16)
s.c. every 6 h
Analgesia Buprenorphine: 2 119/9 [37)
s.c. every 3 to 5 h
Anesthesia long-term lsoflurane: 1.5-2% (26)
Mechanical ventilation Pressure-limited and time-cyded [32)
Fi02: 0.5- 0.6
Respiratory rate: 100-150/min
Airway pressure: 8-15 em H20
Tidal volumes: 8-12 ~tl/9
PEEP: 3-5 em H20
Fi0 2: inspir atory oxygen concentration; PEEP: positive end expiratory pressure
mal body temperature in hypothermic mice. A summary of the above mentioned

practical guidelines is given in Table 2. A proposal of a mouse ICU experimental
setup for studies on macro- and micro-circulatory function as well as oxygenation
and substrate metabolism during sepsis is illustrated in Fig. 2.
I Conclusion
With the advent of transgenic technology, genetically altered mice have contributed
remarkably to the characterization of molecular mechanisms and identification of
related genes participating in human sepsis. The appropriate choice of the animal
model and implementation of various septic features are crucial to insure clinical
relevance of study results. The CLP procedure may serve as a platform for induc-
tion of polymicrobial sepsis of varying degrees in a pre-clinical experimental set-
ting. The application of standard therapeutic strategies such as surgical revision,
Expiratory gas: Liver, small intestine: Portal vein,

mesenteric artery,
• Reflectance- renal artery:
• Respiratory spectrophotometrl
• Laser - Dopfler - • Perivascular
flowmetry volume flow
• Orthogonal polarization measurement8
• Capnograph
spectral (OPS) imaging 6
Femoral artery:
• NO-
• Blood pressure
chemi-
luminescence 1 • Acid base
status
• nCOz- • Substrate
infrared- concentration
spectometryl • Isotope
enrichment9
Carotid artery:
Rectum:
• Left ventricular -
pressure -volume • Closed-loop -
conductance temperature -
micromanometrl control
Fig. 2. Mouse intensive care unit (MICU) setup for studies on macro- and micro-circulatory function,
tissue oxygenation and substrate metabolism during sepsis. References: 1: [45); 2: [46); 3: [47); 4, 5: [48);
6: [49); 7, 9: [SO); 8: [51)
antibiotics and fluid resuscitation is now considered to be state-of-the-art. With on-

set of mechanical ventilation in anesthetized mice and use of miniaturized tech-
niques to monitor organ function, the transformation of a typical clinical ICU set-
ting to the mouse model is facilitated. Yet, as with clinical everyday occurrence, on-
going development in sepsis research has also to be integrated in such experiments.
Therefore, practical guidelines for 'intensive care' in mice need to be updated in a
continuous fashion to replicate, as well as progress, understanding of human sepsis.
References
1. Bahar MA, Kilani RT, Ghahary A (2000) The spectrum of pathogenic bacteria in positive
blood cultures. Microbios 103:107-117
2. Opal SM, Cohen J (1999) Clinical gram-positive sepsis: does it fundamentally differ from
gram-negative bacterial sepsis? Crit Care Med 27:1608-1616
3. Cross AS, Opal SM, Sadoff JC, Gemski P (1993) Choice of bacteria in animal models of
sepsis. Infect Immun 61:2741-2747
4. Red! H, Bahrami S, Schlag G, Traber DL (1993) Clinical detection of LPS and animal mod-
els of endotoxemia. Immunobiology 187:330-345
5. Remick DG, Newcomb DE, Bolgos GL, Call DR (2000) Comparison of the mortality and in-
flammatory response of two models of sepsis: lipopolysaccharide vs. cecal ligation and
puncture. Shock 13:110- 116
6. Evans GF, Snyder YM, Buder LD, Zuckerman SH (1989) Differential expression of interleu-
kin-1 and tumor necrosis factor in murine septic shock models. Circ Shock 29:279-290
7. Remick D, Manohar P, Bolgos G, Rodriguez J, Moldawer L, Wollenberg G (1995) Blockade

of tumor necrosis factor reduces lipopolysaccharide lethality, but not the lethality of cecal
ligation and puncture. Shock 4:89-95
8. Abraham E, Anzueto A, Gutierrez G, et a! (1998) Double-blind randomised controlled trial
of monoclonal antibody to human tumour necrosis factor in treatment of septic shock.
NORASEPT II Study Group. Lancet 351:929-933
9. Bone RC, Fisher CJ Jr, Clemmer TP, Slotman GJ, Metz CA, Balk RA (1987) A controlled
clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic
shock. N Eng! J Med 317:653-658
10. Freise H, Bruckner UB, Spiegel HU (2001) Animal models of sepsis. J Invest Surg 14:195-
212
11. Wichterman KA, Baue AE, Chaudry IH (1980) Sepsis and septic shock- a review of la-
boratory models and a proposal. J Surg Res 29:189-201
12. Baker CC, Chaudry IH, Gaines HO, Baue AE (1983) Evaluation of factors affecting mortal-
ity rate after sepsis in a murine cecal ligation and puncture model. Surgery 94:331-335
13. Ebong S, Call D, Nemzek J, Bolgos G, Newcomb D, Remick D (1999) Immunopathologic
alterations in murine models of sepsis of increasing severity. Infect Immun 67:6603-6610
14. Lush CW, Cepinskas G, Sibbald WJ, Kvietys PR (2001) Endothelial E- and P-selectin ex-
pression in iNOS-deficient mice exposed to polymicrobial sepsis. Am J Physiol 280:G291-
G297
15. Walley KR, Lukacs NW, Standiford TJ, Strieter RM, Kunkel SL (1996) Balance of inflamma-
tory cytokines related to severity and mortality of murine sepsis. Infect Immun 64:4733-
4738
16. Hollenberg SM, Dumasius A, Easington C, Colilla SA, Neumann A, Parrillo JE (2001) Char-
acterization of a hyperdynamic murine model of resuscitated sepsis using echocardiogra-
phy. Am J Respir Crit Care Med 164:891-895
17. Godshall CJ, Scott MJ, Peyton JC, Gardner SA, Cheadle WG (2002) Genetic background de-
termines susceptibility during murine septic peritonitis. J Surg Res 102:45-49
18. Stewart D, Fulton WB, Wilson C, et a! (2002) Genetic contribution to the septic response
in a mouse model. Shock 18:342-347
19. Diodato MD, Knoferl MW, Schwacha MG, Bland KI, Chaudry IH (2001) Gender differences
in the inflammatory response and survival following haemorrhage and subsequent sepsis.
Cytokine 14:162-169
20. Hyde SR, Stith RD, McCallum RE (1990) Mortality and bacteriology of sepsis following ce-
cal ligation and puncture in aged mice. Infect Immun 58:619-624
21. Jimenez MF, Marshall JC (2001) Source control in the management of sepsis. Intensive Care
Med 27 (suppl 1):S49-S62
22. Bochud PY, Glauser MP, Calandra T (2001) Antibiotics in sepsis. Intensive Care Med 27
(suppl1):S33-S48
23. Newcomb D, Bolgos G, Green L, Remick DG (1998) Antibiotic treatment influences out-
come in murine sepsis: mediators of increased morbidity. Shock 10:110-117
24. Vincent JL (2001) Hemodynamic support in septic shock. Intensive Care Med 27 (suppl
1):S80-S92
25. Yang S, Chung CS, Ayala A, Chaudry IH, Wang P (2002) Differential alterations in cardio-
vascular responses during the progression of polymicrobial sepsis in the mouse. Shock
17:55-60
26. Zuurbier CJ, Emons VM, Ince C (2002) Hemodynamics of anesthetized ventilated mouse
models: aspects of anesthetics, fluid support, and strain. Am J Physiol 282:H2099-H2105
27. Hoit BD (2001) New approaches to phenotypic analysis in adult mice. J Mol Cell Cardiol
33:27-35
28. Wilson MA, Chou MC, Spain DA, et a! (1996) Fluid resuscitation attenuates early cytokine
mRNA expression after peritonitis. J Trauma 41:622-627
29. Razavi HM, Werhun R, Scott JA, et a! (2002) Effects of inhaled nitric oxide in a mouse
model of sepsis-induced acute lung injury. Crit Care Med 30:868-873
30. Tsujimoto H, Ono S, Mochizuki H, et a! (2002) Role of macrophage inflammatory protein
2 in acute lung injury in murine peritonitis. J Surg Res 103:61-67
31. Hastings RH, Summers-Torres D {1999) Direct laryngoscopy in mice. Contemp Top Lab
Anim Sci 38:33-35
32. Schwarte LA, Zuurbier CJ, Ince C {2000) Mechanical ventilation of mice. Basic Res Cardiol
95:510-520
33. Tankersley CG, Fitzgerald RS, Kleeberger SR {1994) Differential control of ventilation
among inbred strains of mice. Am J Physiol 267:R1371-R1377
34. Martin GS, Bernard GR {2001) Airway and lung in sepsis. Intensive Care Med 27 (suppl1):
S63-S79
35. Arras M, Autenried P, Rettich A, Spaeni D, Rulicke T (2001) Optimization of intraperito-
neal injection anesthesia in mice: drugs, dosages, adverse effects, and anesthesia depth.
Comp Med 51:443-456
36. Imai T, Takahashi K, Masuo F, Goto F {1998) Anaesthesia affects outcome of sepsis in mice.
Can J Anaesth 45:360-366
37. Gades NM, Danneman PJ, Wixson SK, Tolley EA {2000) The magnitude and duration of
the analgesic effect of morphine, butorphanol, and buprenorphine in rats and mice. Con-
temp Top Lab Anim Sci 39:8-13
38. Kluger MJ, Kozak W, Leon LR, Conn CA (1998) The use of knockout mice to understand
the role of cytokines in fever. Clin Exp Pharmacal Physiol 25:141-144
39. Silva AT, Bayston KF, Cohen J {1990) Prophylactic and therapeutic effects of a monoclonal
antibody to tumor necrosis factor-alpha in experimental gram-negative shock. J Infect Dis
162:421-427
40. Noble WC (1965) The production of subcutaneous staphylococcal skin lesions in mice. Br J
Exp Pathol 46:254-262
41. McConville JH, Snyder MJ, Calia FM, Hornick RB {1981) Model of intraabdominal abscess
in mice. Infect lmmun 31:507-509
42. Strand TA, Briles DE, Gjessing HK, Maage A, Bhan MK, Sommerfelt H {2001) Pneumococ-
cal pulmonary infection, septicaemia and survival in young zinc-depleted mice. Br J Nutr
86:301-306
43. Kim MK, Zhou W, Tessier PR, et al {2002) Bactericidal effect and pharmacodynamics of
cethromycin (ABT-773) in a murine pneumococcal pneumonia model. Antimicrob Agents
Chemother 46:3185-3192
44. Wang E, Ouellet N, Simard M, et al {2001) Pulmonary and systemic host response to Strep-
tococcus pneumoniae and Klebsiella pneumoniae bacteremia in normal and immunosup-
pressed mice. Infect lmmun 69:5294-5304
45. Weicker S, Karachi TA, Scott JA, McCormack DG, Mehta S (2001) Noninvasive measure-
ment of exhaled nitric oxide in a spontaneously breathing mouse. Am J Respir Crit Care
Med 163:1113-1116
46. Ishihara K, Oyaizu S, Mizunoya W, Fukuchi Y, Yasumoto K, Fushiki T {2002) Use of 13C-la-
beled glucose for measuring exogenous glucose oxidation in mice. Biosci Biotechnol Bio-
chem 66:426-429
47. Nemoto S, Vallejo JG, Knuefermann P, et al {2002) Escherichia coli LPS-induced LV dys-
function: role of toll-like receptor-4 in the adult heart. Am J Physiol282:H2316-H2323
48. Kragh M, Quistorff B, Horsman MR, Kristjansen PE {2002) Acute effects of vascular modi-
fying agents in solid tumors assessed by noninvasive laser Doppler flowmetry and near in-
frared spectroscopy. Neoplasia 4:263-267
49. Biberthaler P, Langer S, Luchting B, Khandoga A, Messmer K (2001) In vivo assessment of
colon microcirculation: comparison of the new OPS imaging technique with intravital mi-
croscopy. Eur J Med Res 6:525-534
50. Hallemeesch MM, Soeters PB, Deutz NE {2002) Renal arginine and protein synthesis are
increased during early endotoxemia in mice. Am J Physiol282:F316-F323
51. Baykal A, Kavuklu B, !skit AB, Guc MO, Hascelik G, Sayek I {2000) Experimental study of
the effect of nitric oxide inhibition on mesenteric blood flow and interleukin-10 levels with
a lipopolysaccharide challenge. World J Surg 24:1116-1120
Human Genetics and Human Sepsis:
Is the Tail Wagging the Dog
D. Burgner and M. Levin
Introduction
In almost every area of clinical practice, individuals respond very differently to the
same infectious pathogen. Although humans are repeatedly exposed to potentially
life-threatening pathogens, only a minority will succumb to clinical infection and
fewer still will die from sepsis. Infectious complications often seen in intensive care,
such as septic shock following intestinal perforation or ventilator-associated pneu-
monia (YAP) occur only in a minority of those potentially at risk [1]. Outside the
hospital setting, the inter-individual differences in susceptibility and outcome when
confronted with a potentially lethal infection are more dramatic still. This is espe-
cially true in children, who globally bear most of the infectious disease burden.
For example, an estimated two thirds of the world's population is infected with My-
cobacterium tuberculosis, but the lifetime risk of succumbing to clinically apparent
disease is thought to be about one in ten. Of the estimated 500-million falciparum
malaria infections per year, only about 20% are symptomatic and the overall mor-
tality is probably only 1-2%. Approximately 10% of people carry Neisseria meningi-
tidis in their nasopharynx, yet only 1 in 40 000 develop invasive meningococcal dis-
ease. What factors determine why one individual develops a life-threatening infec-
tion, while another carries the same organism as a harmless commensal, or limits
the infection to a clinically trivial episode?
The huge variation in clinical response to identical infecting pathogens is the re-
sult of the combined effects of virulence of the infecting organism and the immune
response of the infected host. In this chapter, we concentrate on aspects of the host
response and in particular the naturally occurring human genetic variability that
underpins the inter-individual differences in disease susceptibility and outcome.
These genetic determinants of infectious disease resistance are potentially very in-
formative about the pathways involved in pathogenesis and outcome in sepsis and,
therefore, will ultimately guide the development of targeted preventative strategies,
such as vaccines and focused interventions.
Infection, Selection and Variation in the Human Genome
The recent completion of the sequencing of the human genome has led to an esti-
mate of the total number of genes, with the 3 billion nucleotides (or base pairs)
thought to constitute about 30-50000 genes. In fact, most of the genome - about
97% of the total sequence - is non-coding and does not contribute to protein syn-
Human Genetics and Human Sepsis: Is the Tail Wagging the Dog 47
Coding regions
~Ill
3'UTR
'
mRNA
Protein
Fig. 1. A highly simplified caricature of a typical human gene (see text for explanation)
thesis in a direct way. Although this intergenic sequence has been called 'junk or
selfish DNA', it clearly will have important roles, probably in regulation of gene ex-
pression [2]. Our genomes are largely identical, but even so genetic variation be-
tween individuals is common, with difference in sequence of relatively high popula-
tion frequency arising approximately every 3-500 base pairs [3]. Different types of
sequence variation exist, including deletions or insertions of relatively large seg-
ments of sequence, repetitive sequences that vary in the number of repeating ele-
ments (mini- or microsatellites) and single base changes (single nucleotide poly-
morphisms or SNPs). SNPs are particularly useful for analysis of genetic basis of
disease, as they are generally stable, numerous and can be identified by automated
techniques [4].
The site of variation in a gene has implications for its effects on gene function
(Fig. 1). In the 'typical' human gene, transcription is regulated in part by proteins
known as transcription factors that bind to specific sequences in the promoter re-
gion of the gene. The promoter is usually situated upstream (or 5') to the coding
regions of the gene and can be thought of in its simplest form as a complex tightly
regulated 'on-off' switch for gene transcription. Transcription factors facilitate the
binding of RNA polymerase II, the enzyme that leads to the formation of messen-
ger RNA [5]. The central portion of the gene contains regions known as introns
and exons. Only exons contain sequence that directly contributes to protein se-
quence. Intronic sequence is removed during RNA processing and this 'splicing'
process is involved in gene regulation and tissue specificity of gene expression. The
downstream (3') region of the gene is involved in mRNA stability and degradation.
mRNA is transcribed into protein, which is further modified prior to assembly of
the mature polypeptide.
Genetic variation can occur anywhere in a gene and its location determines its
effects. Promoter variants may prevent or facilitate binding of transcription factors
and so alter transcriptional efficiency. Intronic variants may also have effects of
regulation of gene expression. Polymorphisms within the 3' region may affect RNA
stability. Finally exonic variants may be synonymous (the base change does not al-
ter protein structure), or they may result in a non-synonymous amino acid change,
resulting in altered protein structure or even in a stop codon, which leads to a
48 D. Burgner and M. Levin
truncated and functionally compromised protein. On average, each human gene will
contain twelve relatively common variant sites, but in practice these polymorphisms
are not distributed evenly through the genome and 'hot-spots' of variation occur in
certain regions [3, 6]. Polymorphisms have been reported to be rarer in coding re-
gions [7] although other studies suggest that only non-synonymous coding SNPs
are less frequent [8]. In non-coding regions, the 5' untranslated region (UTR) is
generally less diverse than the 3'-UTR, reflecting functional conservation of se-
quence [3]. In the case of genes involved in the immune response, there may clearly
be an evolutionary advantage in maximizing genetic variation and mechanisms to
generate such diversity may have been actively selected for in evolution [9].
The genes involved in the immune response are amongst the most numerous
and the most diverse in the genome [10]. This has long been suggested to reflect
the powerful evolutionary selection pressure exerted by infectious diseases [11], as
the ability to mount an effective immune response to infection is clearly advanta-
geous. An efficient response to one infectious outbreak is only as good - in evolu-
tionary terms - as the response to the next, but different, epidemic which afflicts a
population. There is clearly no advantage in having a top-of-the-range response to
influenza, if the entire population then succumbs to tuberculosis. In practice, sup-
portive data for the evolutionary selective effects of infection on the genome has
proved remarkably difficult to substantiate and it is only recently that convincing
evidence of this phenomenon has surfaced [12].
The marked variation in sequence of the genes involved in the immune response
is most obvious within the human leukocyte antigen (HLA) region, where genetic
variation directly affects the antigen-presenting function of HLA molecules and
thus the efficiency of the subsequent immune response. This functional variation
has, therefore, developed as a strategy to counter the diversity of pathogenic anti-
gens. These evolutionary changes are not merely of historical interest, but continue
to shape our responses to infections. Individuals with human immunodeficiency
virus (HIV) - a relatively 'recent' infection - progress to acquired immunodefi-
ciency syndrome (AIDS)-defining illnesses at markedly different rates. Maximal
HLA variation seems to offer a direct protective effect, as those with the most dif-
ferent alleles at class I HLA loci have the slowest HIV disease progression and low-
est mortality (a so-called 'heterozygote advantage') [13]. In hepatitis B infection,
there is a similar heterozygote advantage within the HLA class II region [14]. Con-
versely, lack of HLA diversity, resulting from a relatively small gene pool, may in-
crease susceptibility to infection amongst isolated communities [15].
Linkage, Association, and the Whole Damn Genome

The genetic basis underpinning infectious disease resistance is rarely the effect of a
single polymorphism at a single gene, but results from the interaction of relatively
subtle effects generated by variation at a number of different loci. In keeping with
other human diseases, infections are described as 'complex', meaning that the ge-
netic contribution to them is not inherited in a simple Mendelian manner and a
number of genes (or loci) are involved. Identifying the important genetic variation
that determines susceptibility or outcome can, therefore, be difficult and requires
an approach that can detect subtle increases in risk (often in the range of 2-5-fold)
at a population level.
There are two broad types of studies that are employed to address the contribu-
tion and identify the genes involved in human diseases. Classical whole genome
screens or linkage studies study families with more than one affected member, of-
ten those where two siblings suffer from the same disease. This can be a distinct
disadvantage when studying less common diseases, such as meningococcal sepsis
or severe pneumonia. Linkage studies have the advantage of making no supposition
about which genes might be involved in a disease, as they merely identify stretches
of chromosome that are inherited more commonly than expected by chance by af-
fected relatives. However, linkage studies can detect only large genetic effects and
are relatively insensitive to the more subtle contributions from a variety of loci that
probably characterize many infectious and other diseases. Thus, convincing linkage
data for human infection is scarce. There are however notable exceptions, with sig-
nificant linkage found for hepatitis C [16], schistosomiasis [17], and intracellular
infections such as Leishmania, leprosy, and tuberculosis [18, 19]. Further associa-
tion studies (see below) then allow more precise identification of genes of interest.
Association studies differ from linkage studies in that they look for a relation-
ship between polymorphism at a gene of interest (called the 'candidate gene') and
the disease phenotype. Such studies are widely employed to investigate inflamma-
tory and infectious diseases and generally rely on stable variants, such as SNPs. As-
sociation studies typically use a case-control design, comparing frequencies of
polymorphisms in cases and controls. However, hidden population artefacts, such
as ethnic differences, can lead to spurious results (a type I error), where there ap-
pears to be a genetic association between the gene and the disease but this merely
reflects poor matching between cases and controls. Increasingly, family-based stud-
ies, where the parents act as genetic controls for their affected (or infected) child
are employed. This approach, particularly useful for childhood diseases, circum-
vents this issue, but is statistically more conservative than a case-control study
[20]. Recently, statistical methods have allowed association studies to be extended
to the entire genome ('whole genome association studies'), which may allow the de-
tection of common but more subtle effects than would be amenable to linkage anal-
ysis [21].
All genetic association studies have potential pitfalls that are pertinent to bear in
mind. As discussed, the genetic effects they detect are relatively subtle and studies
are often underpowered to reveal such modest increases in risk, leading to type II
errors. It is also vital that the study population all have the same disease. For ex-
ample, although septic shock is often considered as a single clinical entity, the mo-
lecular determinants and responses to Gram-positive, Gram-negative, and toxin-
mediated shock may be very different. It is also important to correct for multiple
statistical comparisons, either by using a staged approach, or seeking to replicate
findings in a second independent population. Finally, one of the most important is-
sues is the selection and optimal use of the genetic variants in the candidate locus.
In almost all instances, the position of the genetic variant having a biological ef-
fect is unknown and association studies are used to home in (or 'map') the disease
locus. Most genetic variants therefore serve as 'markers', identifying genetic regions
of potential biological interest. The power of association mapping is increased by
exploiting the fact that polymorphisms occur together in clusters on chromosomes
to form 'haplotypes' - rather like stations on a railway line. The non-random rela-
tionship between different polymorphisms - i.e., the fact that some polymorphisms
occur together more frequently than expected by chance- is called linkage disequi-
librium. Haplotypic association studies are generally more powerful in identifying
the disease locus than using individual SNPs or other markers in isolation. The
converse is also true, so that a lack of a genetic association between a single mar-
ker and a disease may well reflect an inadequate and underpowered study, rather
than a lack of involvement of that gene in the disease process.
I Microarrays - Chips with Everything?

Until recently, candidate gene studies were limited by the imagination of the re-
searcher in choosing a plausible gene and science is not a discipline classically as-
sociated with imagination. Recent and spectacular advances in genetic technology
now allow automated analysis of gene expression of all human genes contempora-
neously potentially within a single cell. The technology relies on mRNA isolated
from cells hybridizing to complementary sequences arranged (or 'arrayed') on glass
slides (microarrays). The hybridization results in a fluorescent colour change whose
presence and magnitude is detected and analyzed. This gives a real-time measure
of gene expression across the whole genome [22]. Although microarrays have a
number of important uses, one of the most exciting developments will be to com-
pare the gene expression of those with very different outcomes from the same in-
fection, or compare the response to different infections. This will allow the identifi-
cation of genetic loci that might be central to determining protection or outcome
that would not have been identified through classical candidate gene association
studies. Preliminary studies of genes activated in peripheral lymphocytes in re-
sponse to diverse bacteria indicate that much of the innate immune response is
stereotypical - effectively identical irrespective of the stimulus, although certain re-
sponses are unique to the infecting organism [23]. Studies of this type are likely to
be highly informative about the immediate innate response to infection [24].
I Genetic Association Studies of Sepsis - Some Examples

The HLA region has been the focus of many of the initial genetic association stud-
ies of infectious diseases. These genes are highly polymorphic and also clearly cen-
tral to the recognition of foreign antigens. HLA associations with infections such
as HIV, tuberculosis, leprosy, malaria, and persistence of both hepatitis B and C
virus are well described [16, 25]. The extensive linkage disequilibrium across some
HLA regions makes it difficult to localize specific disease-associated polymorph-
isms, although for some diseases, the HLA allelic association has allowed identifica-
tion of critical pathogenic epitopes, which in turn might act as potential vaccine
candidates. In falciparum malaria, the protective association of HLA-B53 in West
Africans has allowed the identification of an HLA-restricted parasite epitope as a
potential pre-erythrocytic vaccine candidate [26]. This 'reverse immunogenetics'
has also been used to identify HLA-restricted epitopes in HIV [27] and hepatitis C
[28].
Other non-HLA disease associations have also been informative about identify-
ing the genetic basis underlying infectious disease resistance and have identified
critical pathways in disease resistance. This in turn has opened up exciting poten-
tial new avenues for interventions. For example, HIV employs various chemokine
receptors as cofactors for CD4 binding to gain entry into human leukocytes. A
functional polymorphism of the chemokine receptor CCRS, which is essential for
HIV entry into macrophages, results in a truncated non-functional protein that con-
fers highly significant protection against HIV susceptibility in the homozygous

state and slows disease progression in heterozygotes [29]. Subsequently, other poly-
morphisms in other chemokine receptors have been shown to alter the rate of dis-
ease progression and the risk of HIV transmission from mother to child [30].
These studies not only provide basic information about HIV biology but also iden-
tify potential treatments. For example, CCR5 antibodies, which could be generated
by vaccination, are able to prevent HIV entry into lymphocytes and are thus of
great potential in the development of HIV vaccines [31].
Another example of the potential of genetic studies to illuminate fundamental
biological processes in infection is provided by the role of an erythrocyte surface
protein in protecting from infection by vivax malaria. Although relatively benign
when compared to P. falciparum, vivax malaria causes morbidity in thousands of
infected individuals each year. Certain West Africans, and their descendents never
become infected with P. vivax. The disease resistance stems from a SNP in the Duf-
fy antigen/chemokine receptor (DARC) gene promoter, which prevents gene tran-
scription in erythrocytes but not other cell types. P. vivax utilizes the Duffy antigen
to invade erythrocytes [32]. This again provides a potential therapeutic target for
preventing infection.
Variation in genes may have implications far beyond a single disease or infec-
tious agent. For example, although increased susceptibility to meningococcal infec-
tion in those with deficiency of either the terminal component of complement or
properdin is well recognized [33], these genetic variations are rare. Recently, varia-
tion in the mannose binding lectin (MBL) pathway of complement activation has
also been associated with increased susceptibility to meningococcal infection [34].
Unlike the extremely rare defects in the terminal complement pathways, homozy-
gous mutations in the MBL gene are relatively common in the general population
and appear to be important risk factors for susceptibility to a variety of infections,
including infection in patients with cystic fibrosis [35], severe sepsis in oncology
patients [36, 37], and possibly infection of any cause that is severe enough to war-
rant hospital admission [38]. MBL variants are also associated with the response to
interferon therapy for hepatitis C [39]. These studies beg the question as to why
such a seemingly adverse genetic variant is found at such a high frequency in the
population. Presumably MBL deficiency has had (or continues to have) a powerful
- but unknown - evolutionary selective advantage.
Genetic variation may influence outcome as well as susceptibility to sepsis. For
example, polymorphisms in the regulatory regions of the TNF gene are associated
with poor outcome from meningococcal sepsis [40], cerebral malaria [41], septic
shock [42], Helicobacter pylori [43], and meliodosis [44]. Furthermore, genetically
controlled differences in the coagulation response are also associated with throm-
botic complications of meningococcal disease, with patients heterozygous for the
Factor V Leiden gene having an increased risk of severe purpura fulminans [45].
I The Clinical Relevance of Genetic Studies of Infection

Studies of the genetic determinants to infectious disease susceptibility can tell us
much about the responses of the immune system to infection and how we might
harness or augment these responses to prevent or treat infectious diseases. In pur-
pura fulminans, the finding that a polymorphism in the plasminogen activator in-
hibitor (PAl) gene, which results in higher plasma concentrations of PAI-l during
sepsis, also affects outcome, suggests that the plasminogen pathway is an important
regulator of the inflammatory response to meningococcal infection. This pathway
might thus be a potential therapeutic target in future trials.
In infectious and other diseases, it may ultimately be possible to identify pa-
tients whose risk factors make them candidates for targeted therapies. For example,
understanding the genetic determinants that underpin poor outcome in sepsis,
combined with rapid genotyping technology, might allow more intensive therapies
for those patients known to be at greatest risk of poor outcome and death. Similar-
ly, it may be possible selectively to vaccinate those individuals known to be at in-
creased risk of specific infections. In fact, this is already done with vaccines against
encapsulated organisms in those with sickle cell disease. The potential to target
drug treatment, both in terms of identifying patients most likely to benefit clini-
cally and in terms of predicting those susceptible to either favorable or adverse
pharmacological outcome is of great importance and intense interest [46]. It is con-
ceivable that in the future our understanding of host genetics will largely influence
our therapeutic response to an infected patient, determining our choice of both
preventative and curative interventions.
I Conclusion
Genetic studies have the potential to revolutionize the way in which we understand,
prevent and treat infectious and other diseases. These are relatively early days and
this potential to date is largely unrealized. Some have suggested that there is an ele-
ment of the 'emperor's new clothes' about some of the claims made for the field
[47] and although these criticisms are possibly unfair, a healthy scepticism is advis-
able. It is becoming apparent that modern technology is evolving faster than our
ability to analyze the data it produces and we are also struggling to keep pace with
the ethical implications of the 'new genetics'. Ultimately, understanding the genetic
basis of human infection should prove invaluable in the development of new inter-
ventions. This is of great importance, as our current antibiotic-based approach is
struggling to keep pace with increasing resistance and other approaches will be
needed in combating the continuing onslaught from infectious pathogens.
References
1. Angus DC, Wax RS (2001) Epidemiology of sepsis: an update. Crit Care Med 29:5109-116
2. Makalowski W (2000) Genomic scrap yard: how genomes utilize all that junk. Gene
259:61-67
3. Halushka MK, Fan JB, Bentley K, et al (1999) Patterns of single-nucleotide polymorphisms
in candidate genes for blood-pressure homeostasis. Nat Genet 22:239-247
4. Chakravarti A (1998) It's raining SNPs, hallelujah? Nat Genet 22:216-217
5. Young BA, Gruber TM, Gross CA (2002) Views of transcription initiation. Cell 109:417-420
6. Clark AG, Weiss KM, Nickerson DA, et al (1998) Haplotype structure and population ge-
netic inferences from nucleotide- sequence variation in human lipoprotein lipase. Am J
Hum Genet 63:595-612
7. Nickerson DA, Taylor SL, Weiss KM, et al (1998) DNA sequence diversity in a 9.7-kb region
of the human lipoprotein lipase gene. Nat Genet 19:233-240
8. Cargill M, Altshuler D, Ireland J, et al (1999) Characterization of single-nucleotide poly-
morphisms in coding regions of human genes. Nat Genet 22:231-238
9. Ackerman H, Udalova I, Hull J, Kwiatkowski D (2002) Evolution of a polymorphic regula-

tory element in interferon-gamma through transposition and mutation. Mol Biol Evol
19:884-890
10. Murphy PM (1993) Molecular mimicry and the generation of host defense protein diver-
sity. Cell 72:823-826
11. Haldane JBS (1950) Disease and evolution. La Ricerca Scientifica, pp 68-75
12. Sabeti PC, Reich DE, Higgins JM, et al (2002) Detecting recent positive selection in the hu-
man genome from haplotype structure. Nature 419:832-837
13. Carrington M, Nelson GW, Martin MP, et al (1999) HLA and HIV-1: heterozygote advan-
tage and B*35-Cw*04 disadvantage. Science 283:1748-1752
14. Thursz MR, Thomas HC, Greenwood BM, Hill AV (1997) Heterozygote advantage for HLA
class-11 type in hepatitis B virus infection. Nat Genet 17:11-12
15. Black FL, Schiffman G, Pandey JP (1995) HLA, Gm, and Km polymorphisms and immu-
nity to infectious diseases in South Amerinds. Exp Clin Immunogenet 12:206-216
16. Mangia A, Gentile R, Cascavilla I, et al (1999) HLA class II favors clearance of HCV infec-
tion and progression of the chronic liver damage. J Hepatol 30:984-989
17. Marquet S, AbelL, Hillaire D, et al (1996) Genetic localization of a locus controlling the in-
tensity of infection by Schistosoma mansoni on chromosome 5q31-q33. Nat Genet 14:181-
184
18. Blackwell JM (1998) Genetics of host resistance and susceptibility to intramacrophage
pathogens: a study of multicase families of tuberculosis, leprosy and leishmaniasis in
north-eastern Brazil. Int J Parasitol 28:21-28
19. Bellamy R, Beyers N, McAdam KP, et al (2000) Genetic susceptibility to tuberculosis in
Africans: a genome-wide scan. Proc Natl Acad Sci USA 97:8005-8009
20. Spielman RS, Ewens WJ (1996) The TDT and other family-based tests for linkage disequili-
brium and association [editorial]. Am J Hum Genet 59:983-989
21. Ardlie KG, Kruglyak L, Seielstad M (2002) Patterns of linkage disequilibrium in the human
genome. Nat Rev Genet 3:299-309
22. Cook SA, Rosenzweig A (2002) DNA microarrays: implications for cardiovascular medi-
cine. Circ Res 91:559-564
23. Boldrick JC, Alizadeh AA, Diehn M, et al (2002) Stereotyped and specific gene expression
programs in human innate immune responses to bacteria. Proc Natl Acad Sci USA 99:972-
977
24. Reiman DA (2002) Genome-wide responses of a pathogenic bacterium to its host J Clin In-
vest 110:1071-1073
25. Hill AV (1998) The immunogenetics of human infectious diseases. Annu Rev Immunol
16:593-617
26. Hill AV, Elvin J, Willis AC, et al (1992) Molecular analysis of the association of HLA-B53
and resistance to severe malaria. Nature 360:434-439
27. Ikeda-Moore Y, Tomiyama H, Miwa K, et al (1997) Identification and characterization of
multiple HLA-A24-restricted HIV-1 CTL epitopes: strong epitopes are derived from V re-
gions of HIV-1. J Immunol 159:6242-6252
28. Ibe M, Sakaguchi T, Tanaka K, et al (1998) Identification and characterization of a cyto-
toxic T cell epitope of hepatitis C virus presented by HLA·B*3501 in acute hepatitis. J Gen
Virol 79:1735-1744
29. Martin MP, Dean M, Smith MW, et al (1998) Genetic acceleration of AIDS progression by a
promoter variant of CCR5. Science 282:1907-1911
30. John GC, Rousseau C, Dong T et al (2000) Maternal SDF1 3'A polymorphism is associated
with increased perinatal human immunodeficiency virus type 1 transmission. J Virol
74:5736-5739
31. Wang Y, Underwood J, Vaughan R, Harmer A, Doyle C, Lehner T (2002) Alto-immuniza-
tion elicits CCR5 antibodies, SDF-1 chemokines, and COS-suppressor factors that inhibit
transmission of R5 and X4 HIV-1 in women. Clin Exp Immunol129:493-501
32. Tournamille C, Colin Y, Cartron JP, Le Van Kim C (1995) Disruption of a GATA motif in
the Duffy gene promoter abolishes erythroid gene expression in Duffy-negative individuals.
Nat Genet 10:224-228
54 D. Burgner and M. Levin: Human Genetics and Human Sepsis: Is the Tail Wagging the Dog
33. Wurzner R, Orren A, Lachmann PJ (1992) Inherited deficiencies of the terminal compo-
nents of human complement. Immunodefic Rev 3:123-147
34. Hibberd ML, Sumiya M, Summerfield JA, Booy R, Levin M (1999) Association of variants
of the gene for mannose-binding lectin with susceptibility to meningococcal disease.
Meningococcal Research Group. Lancet 353:1049-1053
35. Turner MW (1998) Mannose-binding lectin (MBL) in health and disease. Immunobiology
199:327-339
36. Neth 0, Hann I, Turner WM, Klein NJ (2001) Deficiency of mannose-binding lectin and
burden of infection in children with malignancy: a prospective study. Lancet 358:614-618
37. Peterslund NA, Koch C, Jensenius JC, Thiel S (2001) Association between deficiency of
mannose-binding lectin and severe infections after chemotherapy. Lancet 358:637-638
38. Summerfield JA, Sumiya M, Levin M, Turner MW (1997) Association of mutations in man-
nose binding protein gene with childhood infection in consecutive hospital series. Br Med
J 314:1229-1232
39. Matsushita M, Hijikata M, Ohta Y, et al (1998) Hepatitis C virus infection and mutations of
mannose-binding lectin gene MBL. Arch Virol 143:645-651
40. Nadel S, Newport MJ, Booy R, Levin M (1996) Variation in the tumor necrosis factor-alpha
gene promoter region may be associated with death from meningococcal disease. J Infect
Dis 174:878-880
41. McGuire W, Hill AV, Allsopp CE, Greenwood BM, Kwiatkowski D (1994) Variation in the
TNF-alpha promoter region associated with susceptibility to cerebral malaria. Nature
371:508-510
42. Mira JP, Cariou A, Grall F, et al (1999) Association of TNF2, a TNF-alpha promoter poly-
morphism, with septic shock susceptibility and mortality: a multicenter study. JAMA
282:561-568
43. Kunstmann E, Epplen C, Elitok E, et al (1999) Helicobacter pylori infection and poly-
morphisms in the tumor necrosis factor region. Electrophoresis 20:1756-1761
44. Nuntayanuwat S, Dharakul T, Chaowagul W, Songsivilai S (1999) Polymorphism in the pro-
moter region of tumor necrosis factor-alpha gene is associated with severe meliodosis.
Hum Immunol 60:979-983
45. Kondaveeti S, Hibberd ML, Booy R, Nadel S, Levin M (1999) Effect of the Factor V Leiden
mutation on the severity of meningococcal disease. Pediatr Infect Dis J 18:893-896
46. Cariou A, Chiche JD, Charpentier J, Dhainaut JF, Mira JP (2002) The era of genomics: im-
pact on sepsis clinical trial design. Crit Care Med 30:S341-348
47. Weiss KM, Terwilliger JD (2000) How many diseases does it take to map a gene with SNPs?
Nat Genet 26:151-157
Microarray Technology in Sepsis: Tool or Toy?
S. Russwurm, H. P. Deigner, and K. Reinhart
I Introduction
Sepsis is a result of highly heterogeneous processes characterized by an involve-

ment of multiple components and their interactions at each organizational level of
the human body: genes, cells, tissues, organs. The complexity of the underlying
biological and immunological processes has encouraged multiple types of research
studies comprising a broad panel of clinical aspects. One of the lessons learned to
date is that evaluation of new sepsis therapies has been hampered by fairly unspeci-
fic, clinically-based inclusion criteria which insufficiently reflect the molecular
mechanism.s [1].
Therefore, there is an urgent need for innovative biosensors that could provide
us with a molecular 'fingerprint' of this threat to public health and, thus, improve
our ability to characterize and stratify septic patients. Technological progress, in
particular the development of microarray technology, now enables researchers to
compare ten thousand or more genes and their products simultaneously. Applica-
tion of such microarray technologies can now provide clues about health status,
regulatory mechanisms, biochemical links, and signaling networks. Improving the
understanding of how an organism responds to infection should facilitate the devel-
opment of enhanced detection, diagnosis, and treatment modalities for sepsis. This
chapter gives a short characterization of current, mainly DNA-based technological
options, highlights their limitations, and summarizes present and upcoming appli-
cations, in particular in the field of diagnosis.
I Microarray Technology
Microarrays are defined as a group of more than two characterized, addressable

probes immobilized to a flat solid support or substrate. They are composed of
many microscopic spots, each of them typically containing numerous identical
probes with the ability to bind a tagged matching partner, e.g., carrying a comple-
mentary sequence. After the binding reactions, microarrays are analyzed based on
the known architecture and the amount of tag acquired by spots. They might have
different characteristics (see Table 1 for classification) but share the ability to ac-
complish hybridization/binding assays that can be analyzed due to the knowledge
of the microarray architecture.
Microarrays originate from Southern blotting [2], which represents the first
approach to immobilizing DNA molecules on a solid support in a spatially addres-
56 S. Russwurm et al.
Table 1. Classification of microarray technology according to the type of arrayed probes
Type Probes Analyzed matching Analyze using

partner
DNA array Oligonucleotides, eDNA, RNA, Fluorescence dyes,
eDNA oligonucleotides gold particles,
radioactivity
RNA array RNA eDNA, RNA, Fluorescence dyes,
oligonucleotides gold particles,
radioactivity
Protein array Proteins, antibodies Proteins, antibodies, Fluorescence dyes,
organic compounds gold particles,
radioactivity
Cell/tissue array Histological material DNA, RNA, proteins, Fluorescence dyes,
antibodies radioactivity
sable manner. The early microarrays consisted of fragments of DNA, often with un-
known sequence, and were spotted on a porous membrane (usually nylon). Routi-
nely eDNA, genomic DNA, or plasmid libraries were used and the hybridized mate-
rial was labeled with a radioactive group [3-5]. Recently, the use of glass as a sub-
strate and fluorescence for detection, together with the development of new tech-
nologies for synthesizing or depositing nucleic acids at very high densities, have al-
lowed the miniaturization of nucleic acid arrays with a concomitant increase in ex-
perimental parallelism/throughput and information content [6-8].
DNA microarrays can be distinguished by the size of arrayed fragments, the
methods of arraying, the surface chemistry, the structure of linkers for attaching
probes, the hybridization and the detection methods. Immobilized sequences cover
a length from ten or twenty bases up to several thousand (eDNA arrays). The hy-
bridization reaction can be driven, for example, by an electric field [9]; other detec-
tion methods [10] besides fluorescence may be used. The surfaces can contain ma-
terials other than glass, such as plastic, silicon, gold, a gel or a membrane, or may
even be comprised of beads at the ends of fibre-optic bundles [ 11-13]. In addition,
there is alternative probe coupling chemistry (Fig. 1). Nonetheless, the key element
is always the process of a parallel hybridization to localized, surface-bound nucleic
acid probes with subsequent counting of bound molecules.
Usually, arrays are designed on specific sequence information, a process some-
times referred to as "downloading the genome onto a chip" [14].
Two DNA chip formats are currently in wide use:
I the in situ synthesized oligonucleotide arrays [7], and
I that of the eDNA array format [8].
In the former case, a company called Affymetrix has established a method of combin-
ing an oligonucleotide synthesis and photolitographic computer chip synthesis to
generate DNA chips carrying 65 000-400 000 different oligonucleotides; these repre-
sent up to 9000 genes on a 1.6 cm 2 glass surface. In this process, UV light is shone
through holes in a mask in order to direct a parallel, stepwise synthesis of oligonu-
cleotides [14]. At each step in the synthesis, oligonucleotides requiring, for example,
guanine in the next position within the probe sequence, are deprotected by light di-
Microarray Technology in Sepsis: Tool or Toy? 57
Aldehyde
~~A ~DNA
NHz
~DNA
~~H-C
N- H
II)
H-C-OH
N
II
H-C
~
I Covalent
coupling
I I
Schiff
base by I
I
Substrate dehydration
Substrate
Amine
DNA
ffi:lfX/ DNA DNA
+ + +
11\:iXY/
.....- .....,... - .... {A0YI
NH3 NH3 NH3 NH3 NH3 NH3 NH3 NH NH3
I
Ill~
I static
Ill~
I coupling
I I II
I «
coupling with heat
Substrate orUV
Fig. 1. Principles of aldehyde (top) and amine (bottom) coupling chemistry. (From http://arrayit.com/Prod-
ucts/Substrates/substrates.html). Top: A six carbon linear (aliphatic) amine is added to each DNA molecule
(double-stranded PCR products or single-stranded oligonucleotides). DNA attachment proceeds via an un-
stable intermediate that converts quickly to a Schiff's base. Bottom: Surface amines carrying a positive
charge allow attachment of native DNA through the formation of ionic bonds with the negatively charged
phosphate backbone of DNA. Electrostatic attachment is supplemented by treatment of the printed sub-
strate with ultraviolet light, which induces free radical-based coupling between thymidine residues on the
DNA and carbons on the alkyl amine
rected to the appropriate positions by a mask. The chip is then flooded with activated
guanine nucleotides which couple to the deprotected positions; uncoupled guanines
are then washed away. In the next step, another mask is applied and the deprotection
and coupling steps are carried out with cytosine, for example. Repetition of this cycle
approximately 70 times, with 70 different masks, allow synthesis of a complete array
comprising thousands of 25-mer oligonucleotides in parallel. eDNA microarrays re-
present array format developed at Stanford University. These arrays are made by ro-
botic deposition of DNA spots that are approximately 50-250 f.Lm in diameter onto a
coated glass surface. Usually, polymerase chain reaction (PCR)-amplified inserts from
eDNA libraries are arrayed, but long synthetic oligonucleotides can also be used. An
average density of this type of array is 10 000 spots deposited on microscopic glass
which represents up to 10 000 genes on an area of 3.6 cm2 •
A typical differential expression monitoring experiment using eDNA arrays
shown in Figure 2 comprises isolation of two RNAs to be compared, for example,
from the sample material of interest (i.e., blood cells/tissues from a patient) and a
corresponding control/reference sample (i.e., those from a healthy individual); then
their subsequent labeling by different dyes (usually Cy3 and Cy5) via reverse tran-
Control SIRS Sepsis Control Sepsis
RNA separation
RT-PCR and
labeling with
fluorescent
dyes
Nylon membrane
l
Identification of relevant e-DNA
clones
~
Hybridization
l
Propagation and !
quality management ""''lj
~r:;<;r:
I
...
l
Laser scanning
Robotic printing of final microarrays Raw data
Fig. 2. Development and application of customized eDNA microarrays. Relevant eDNA clones are identified
using high density nylon membranes. After propagation and quality management robotic printing of final
customized microarrays is performed (left side). Total RNA from both the test and sepsis sample is fluor-
escently labeled. The fluorescent targets are pooled and allowed to hybridize. Laser excitation yields an
emission, which is measured using a scanning confocal laser microscope. Monochrome images from the
scanner are imported into software in which the images are pseudo-colored and merged (right side).
SIRS ... systemic inflammatory response syndrome
scription into eDNA; cohybridization of obtained cDNAs with the same array; ac-
quisition of raw hybridization data (usually using confocal epifluorescence micro-
scope scanners or CCD-based systems); and finally their analysis and mining.
Down-scaling of the assay (miniaturization), its multistep proceeding, and cohybri-
dization of two differentially-labeled targets make gene expression data subject to
cumulative error. This cumulative nature comes from a contribution of every ex-
perimental factor of microarray experiment using spotted arrays: DNA deposition,
slide heterogeneity, pin geometry, RNA preparation, reverse transcription, fluores-
cence labeling, hybridization conditions, scanning conditions, and image analysis
method [15]. These facts put strong requirements for standardization and quality
control at each step of the experimental performance. In addition, in order to re-
move aforementioned systemic and random errors introduced at various stages of
experimental performance, a data normalization process has to be performed. Data
interpretation after finishing an experimental series is a highly sophisticated pro-
cess. Analysis of the vast amount of data requires appropriate software. At present,
unfortunately, the solutions are still far from optimal.
I Microarrays in Differential Gene Expression

A rationale for the applicability of microarray technology was initially substantiated
by clinical investigations in the field of cancer research. Here, expression profiling
has shown its usefulness in identifying single/groups of gene activities correlating
with distinct clinical phenotypes [16]. By analyses of multiple samples obtained
from individuals with or without acute leukemia or diffuse large B-cell lymphoma,
gene expression (mRNA) markers were discovered and applied to the classification
of these cancers [16, 17]. Golub and colleagues found that reliable predictions could
not be made based on any single gene, but predictions based on the expression lev-
els of 53 genes (selected from more than 6000 monitored on the arrays) were
highly accurate [16]. Alizadeh et al. [17] studied diffuse large B-cell lymphoma
(DLBCL). The authors performed gene-expression profiling with a 'Lymphochip', a
micro array carrying 18 000 clones of complementary DNA designed to monitor
genes involved in normal and abnormal lymphocyte development. Using clustering
analysis, they were able to separate DLBCL into two categories, which had marked
differences in overall survival of the patients. The gene-expression signatures of
these subgroups corresponded to distinct stages in the differentiation of B cells.
The potential value of only limited changes in gene activities is supported by re-
cent data. Varambally and colleagues [18] applied gene expression profiling to pros-
tate cancer and found that the polycomb group protein enhancer of zeste homolo-
gue 2 (EZH2), a transcriptional suppressor of a number of genes, is over-expressed
in hormone-refractory, metastatic prostate cancer. Therefore, EZH2 may have po-
tential as a molecular marker to discriminate indolent localized forms of prostate
cancer from lethal progressive metastatic forms.
These studies indicate that even with limited initial data it may be possible to
identify unusual cases (e.g., classic leukemia with atypical morphology) that will
help guide clinical decision making. In the future, DNA arrays will assist in the for-
mation of information databases which will be able to correlate genetic variation
and gene expression with clinically based phenotypes such as patient status, prog-
nosis and responsiveness to treatment. However, cancer treatment prognoses based
on gene-expression patterns and single nucleotide polymorphism (SNP) analysis
also have their limitations [19] and it remains to be clarified how much 'noise'
from tumor heterogeneity and genetic instability affect the process.
It appears reasonable to use multi-parallel devices to investigate multi-factorial
diseases in light of the complexity of the mechanisms and changes involved. In this
context, expression analyses by microarrays should be perfectly suited to explore
diseases such as sepsis where information about events on the molecular level and
their relation to common clinical phenotypes is very limited. Recent reports sup-
port the notion that microarray technology in fact revolutionizes research, diagno-
sis and treatment in this field. Using broad transcriptional profiling, Joyce and col-
leagues [20] reported on novel links between coagulation, inflammation, and cell
death. They showed that rhAPC, a recombinant activated form of human protein C,
directly modulates patterns of endothelial cell gene expression clustering into anti-
inflammatory and cell survival pathways. Microarray analyses revealing the re-
sponses of human mononuclear [21] or endothelial cells [22] to lipopolysaccharides
(LPS) were performed in order to identify new potential molecular markers of sys-
temic inflammation, its progression/outcome, and to select drug targets for new,
beneficial treatment opportunities. When analyzing organ-specific expression,
Chinnaiyan and colleagues elucidated highly complex transcriptional responses
during sepsis [23]. We agree with their statement that this global perspective of the
host response should provide a molecular framework for future research into the
pathophysiology of systemic inflammation. Such information will allow a broader,
more complete and less biased view on molecular events during sepsis, help to de-
termine possible associations between candidate gene polymorphisms and outcome
of severe sepsis, and thereby aid the development of novel diagnostics, treatment
surveillance and therapeutic options. Finally, gene-expression profiling can be used
to identify the genes and pathways that really matter for the process, thereby re-
vealing new targets for therapy.
I Microarrays in SNP Mapping and Sequencing
In diseases caused by a single gene defect with high penetrance, a linkage mapping
within afflicted families has led to the identification and cloning of hundreds of
disease genes. In the past, this was accomplished by relatively low-throughput tech-
niques, such as restriction fragment length polymorphism (RFLP) or microsatellite
mapping. However, single-gene related Mendelian diseases are relatively rare. By
contrast, most diseases are thought to be caused by several genes, each of them af-
fecting or interacting with others to cause the disease. This suggestion has been
supported by studies demonstrating high incidence in twins or relatives of afflicted
individuals. At present there is general agreement that high-throughput, robust and
cost-effective genotyping of large numbers of individuals at a large number of sites
in the genome, is a prerequisite for success.
The advancements that microarrays have brought into the analysis of enormous
amounts of sequencing data can be illustrated by an example: an array of 65 536
spots of all possible eight-mer oligonucleotides could be constructed and a fairly
short piece of DNA (e.g., 1000 bases) then tagged and applied to the array. The
spots that glow could then be detected. Each eight-mer sequence is decoded from
its location and, from an analysis of the overlapping short sequences, the original
long sequence could be reconstructed. The principles of SNP detection by microar-
ray hybridization is shown in Figure 3.
Researchers quickly realized, however, that if a given short sequence appeared
more than once in encompassing long sequence analyses, one would have a branch
point in the reconstruction diagram and could not assign an overall sequence with-
out ambiguity. This application has thus largely fallen out of favor, although re-se-
quencing in order to look for mutations or polymorphisms in a region whose 'nor-
mal' sequence is already known, is still considered to be a worthwhile goal. There-
fore, arrays are widely applied to genomic studies, including re-sequencing. Such
studies primarily involve the search for single nucleotide polymorphisms, which
may have considerable importance regardless of whether they overtly cause a dis-
ease [24].
Starting from these factors, one can use analytical techniques such as genetic-
linkage mapping or association analysis to discover genetic predispositions to dis-
eases, to classify diseases according to the respective defects, and to choose treat-
ment options. Some prognostic indicators (genetic, allelic differences) for disease
development might escape detection by expression profiling, as this approach is de-
pendent on which gene set probes are arrayed and is cell/tissue/organ specific.
Minimally altered sequences may encode proteins with a different activity or stabil-
I G- homozygote II G/A-heterozygote I
0 0
0 • •• 0• ••
0 0
[2] [2]• ••
I A- homozygote I
0
0
0 ••
[2] • ••
Fig. 3. Principle of SNP detection by microarray hybridization. An example is given for the detection of
TNF-alpha promotor mutation (position-308). DNA was isolated from whole blood and PCR amplification
of 160 bp fragment comprising the mutation locus was performed. On the left side, a tailing strategy
based on the presence of oligonucleotide probes carrying all possible nucleotide substitutions at SNP po-
sition is shown. Amplified fragments were labeled and simultaneously converted to single strands. Result-
ing CyS labeled targets were hybridized; raw data are depicted on the right side
ity that affects disease progression or response to treatment. In this respect, moni-
toring of SNP appears as an appealing complementary approach [25]. Microarray-
based sequencing by hybridization (SBH) can rapidly determine short DNA se-
quences for the detection and definition of mutations present in oncogenes, tumor
suppressors, and other genes in order to optimize their diagnosis, prognosis and
treatment. In the future, microarrays that detect the most prominent mutations af-
fecting sepsis (to be identified in large scale clinical studies) may be feasible.
I Microarrays in Drug Development/Toxicology

Microarrays can be used in all aspects of pharmaceutical development, from target
identification (see above) and drug discovery/optimization to toxicology studies.
This technique enables profile-based comparison of structures and the deduction
of relevant mechanisms of drug/toxin actions; the simultaneous screening of thou-
sands of genes can identify multiple potential drug effectors (Fig. 4).
Expression analyses may identify sentinel genes that exhibit altered expression
in a given cell or tissue type in response to a drug or toxin. Conversely, the identi-
fication of signature genes, biomarkers, or expression patterns indicative of a dis-
ease process may offer candidate targets for drug screening and lead compound se-
lection.
Discovery Early Full

development development
,.-------"----------...., ,-------"'----'"" ~
Hit lead lead Preclinical Clinical

10 10 OP Evaluation Poe
\
Discovery genetics System- based research Clinical genetics
Discovery genomics Combinatorial high - speed Pharmacogenetics
Functional genomics Lead ID, optimiziation Individual responses
Toxicology
Fig. 4. Microarray technology in drug discovery. Potential applications of microarrays during all steps of
drug development. ID: identification; OP: optimization; PoC: proof of concept. For further details see text
Drug development is hampered by inherited differential responses of people to

most drugs. An array-based analysis of SNPs and other genetic markers can be
used to 'type' individuals as to their drug susceptibility. It will further help to select
genes that are involved in individual drug action, metabolism or resistance, all pre-
conditions of an individualized therapy. Microarrays thus will enable clinicians to
distinguish between responders and non-responders and help to identify indivi-
duals at risk for adverse reactions to a drug. The genetic profiles of individual pa-
tients and the individual response to a drug or toxin are thus addressable by phar-
macogenomic and toxicogenomic studies that provide the basis for rational individ-
ual drug therapy.
I Conclusion
Microarray technologies offer rapid and cost-effective methods of monitoring dif-
ferential gene expression and analyzing genetic variations. These technologies have
revolutionized our ability to monitor molecular changes during disease progression
and will lead to improved molecular characterization and stratification of patients
with multi-factorial diseases such as sepsis. Such technologies will help in thera-
peutic decision-making by bridging the gap between current, mainly clinical diag-
nosis, and a more individualized approach. These technologies, however, are still
far from point of care application. At present, the main reason for mRNA tran-
scripts, though they do represent intermediates on the way to final protein prod-
ucts, is that protein-based approaches are generally more difficult, less sensitive,
and give a lower throughput than RNA-based ones. However, there is no question
that protein- and RNA-based measurements are complementary, and that protein-
based techniques are important as they measure variables that are not readily de-
tected otherwise (i.e., post-translational modifications or changes in intracellular

localization). The next breakthrough will be when protein-based measurements can
be performed with a microarray format.
Acknowledgements. This publication was partly supported by the Thuringian and

German Ministry of Science. Contributions by Andriy Ruryk, Marc Lehmann,
Hans-Peter Saluz, and Don Bredle are gratefully acknowledged.
References
1. Vincent JL, Angus D, Annane D, et al (2001) Clinical expert round table discussion (ses-
sion 5) at the Margaux Conference on Critical Illness: outcomes of clinical trials in sepsis:
lessons learned. Crit Care Med 29:S136-137
2. Southern EM (1974) An improved method for transferring nucleotides from electrophor-
esis strips to thin layers of ion-exchange cellulose. Anal Biochem 62:317-318
3. Gillespie D, Spiegelman S (1965) A quantitative assay for DNA-RNA hybrids with DNA im-
mobilized on a membrane. J Mol Bioi 12:829-842
4. Lennon GG, Lehrach H (1991) Hybridization analyses of arrayed eDNA libraries. Trends
Genet 7:314-317
5. Kafatos FC, Jones CW, Efstratiadis A (1979) Determination of nucleic acid sequence homo-
logies and relative concentrations by a dot hybridization procedure. Nucl Acid Res 7:1541-
1552
6. Fodor SP, Read JL, Pirrung MC, Stryer L, Lu AT, Solas D (1991) Light-directed, spatially
addressable parallel chemical synthesis. Science 251:767-773
7. Pease AC, Solas D, Sullivan EJ, Cronin MT, Holmes CP, Fodor SP (1994) Light-generated
oligonucleotide arrays for rapid DNA sequence analysis. Proc Natl Acad Sci USA 91:5022-
5026
8. Schena M, Shalon D, Davis RW, Brown PO (1995) Quantitative monitoring of gene expres-
sion patterns with a complementary DNA microarray. Science 270:467-470
9. Edman CF, Raymond DE, Wu DJ, et al (1997) Electric field directed nucleic acid hybridiza-
tion on microchips. Nucleic Acid Res 25:4907-4914
10. Gray DE, Case-Green SC, Fell TS, Dobson PJ, Southern EM (1997) Ellipsometric and inter-
ferometric characterization of DNA probes immobilised on a combinatorial array. Lang-
muir 13:2833-2842
11. Ferguson JA, Boles TC, Adams CP, Walt DR (1996) A fiber-optic DNA biosensor microarray
for the analysis of gene expression. Nat Biotechnol14:1681-1684
12. Michael KL, Taylor LC, Schultz SL, Walt DR (1998) Randomly ordered addressable high-
density optical sensor arrays. Anal Chern 70:1242-1248
13. Walt DR (2000) Bead-based fiber-optic arrays. Science 287:451-452
14. Lockhart DJ, Winzeler EA (2000) Genomics, gene expression and DNA arrays. Nature
405:827-836
15. Wu W, Wildsmith SE, Winkley AJ, Yallop R, Elcock FJ, Bugelski PJ (2001) Chemometric
strategies for normalization of gene expression data obtained from eDNA microarrays.
Analytica Chimica Acta 446:451-466
16. Golub TR, Slonim DK, Tamayo P, et al (1999) Molecular classification of cancer: class dis-
covery and class prediction by gene expression monitoring. Science 286:531-537
17. Alizadeh AA, Eisen MB, Davis RE, et al (2000) Distinct types of diffuse large B-celllym-
phoma identified by gene expression profiling. Nature 403:503-511
18. Varambally S, Dhanasekaran SM, Zhou M, et al (2002) The polycomb group protein EZH2
is involved in progression of prostate cancer. Nature 419:624-629
19. Bakay M, Chen Y-W, Borup R, Zhao P, Nagaraju K, Hoffman EP (2002) Sources of variabil-
ity and effect of experimental approach on expression profiling data interpretation. BMC
Bioinformatics 3:4
20. Joyce DE, Gelbert L, Ciaccia A, DeHoff B, Grinnell BW (2001) Gene expression profile of
antithrombotic protein c defines new mechanisms modulating inflammation and apoptosis.
J Bioi Chern 276:11199-11203
64 5. Russwurm et al.: Microarray Technology in Sepsis: Tool or Toy?
21. Fillion I, Ouellet N, Simard M, Bergeron Y, Sato S, Bergeron MG (2001) Role of chemo-
kines and formyl peptides in pneumococcal pneumonia-induced monocyte/macrophage re-
cruitment. J lmmunol 166:7353-7361
22. Zhao B, Bowden RA, Stavchansky SA, Bowman PD (2001) Human endothelial cell response
to gram-negative lipopolysaccharide assessed with eDNA microarrays. Am J Physiol Cell
Physiol 281:Cl587-C1595
23. Chinnaiyan AM, Huber-Lang M, Kumar-Sinha C, et al (2001) Molecular signatures of sep-
sis. Multiorgan gene expression profiles of systemic inflammation. Am J Pathol 15:1199-
1209
24. Drmanac S, Kita D, Labat I, et a! (1998) Accurate sequencing by hybridization for DNA di-
agnostics and individual genomics. Nat Biotechnol 16:54-58
25. Cargill M, Altshuler D, Ireland J, et a! (1999) Characterization of single-nucleotide poly-
morphisms in coding regions of human genes. Nat Genet 22:231-238
Update on Anti-Endotoxin Therapies
R. Stephens and M. Mythen
I Introduction
Endotoxin is part of the Gram-negative bacterial cell wall and can start some of the
processes that lead in the end to organ failure and death. Higher levels during criti-
cal illness, surgery and trauma have been associated with a worse outcome.
Several natural endogenous substances are thought to be able to neutralize endo-
toxin. Many anti-endotoxin trials have failed to show a mortality reduction in sep-
sis, and this may be due to the difficulty in intervening once the inflammatory cas-
cade has started.
Current approaches are aimed at reducing endotoxin release, binding free endo-
toxin, or altering the cellular response to endotoxin. Elucidation of the endotoxin
receptor, Toll-like receptor 4 (TLR4), along with the factors that associate with it
may lead to new theraputic approaches.
I What is Endotoxin and What Can it do?
Endotoxin, or lipopolysaccharide ('LPS'), is part of the outer cell wall of Gram-neg-

ative bacteria. It consists of 3 parts: a lipid-A region, inner and outer core sugars
(both of which have similar structures in most Gram-negative bacteria) and a dis-
tinct 0 polysaccharide side chain (which varies, acting as the 'fingerprint' of a par-
ticular bacterial species). Whilst our own gastrointestinal tracts are sterile when we
are born [1], once colonized with normal bowel flora, they overwhelmingly repre-
sent the largest store of endotoxin. Endotoxin has also been measured at sites of
Gram-negative infection, in cardiopulmonary bypass circuits and in sterilized drugs
and fluids. Bacteria can shed endotoxin spontaneously and this process can be ac-
celerated by antibiotics ('antibiotic-induced endotoxin release') [2].
Endotoxin can Initiate Inflammation

Endotoxin can initiate many of the pathways thought to cause the changes seen in
multiple organ dysfunction syndrome (MODS). When given to volunteers in small
doses (2-4 ng/kg), its effects are similar to those seen in sepsis, but less pro-
nounced. These effects include symptoms (headache, chills, myalgia, nausea,
fatigue, and general malaise) [3] and cardiovascular, respiratory, gastrointestinal,
immune and hematologic alterations. On a cellular level, these changes in the im-
66 R. Stephens and M. Mythen
Cardiovascular
e.g., Hr l BPI (diastolic > systolic)
SVR I
Cardiac depression
Respiratory
e.g., Bronchoconstriction (inhaled endotoxin)
Gastrointestinal
e.g., Nausea
Hepatic acute phase reactants (e.g. CRP)
Neurological
e.g., Headache
I REM sleep
Immune
e.g., Fever
Monocytes-activated; release cytokines
Neutrophils-activated; release superoxide
Complement activation
Tolerance
Hematological
e.g., Endothelium-activated - nitric oxide, ICAM
Coagulation -activated fibrinolysis
Metabolic
e.g., Glucose/cortisoi/ACTHl
Fig. 1. The actions of endotoxin found when human volunteers receive 2-4 ng/kg i.v. BP: blood pressure;
SVR: systemic vascular resistance; REM: rapid eye movement; CRP: (-reactive protein; ICAM: intercellular
adhesion molecule
mune system alert the body to the presence of a foreign substance and activate our
defense mechanisms (Fig. 1).
Endotoxin and Organ Failure
Endotoxin has been found in the blood of surgical patients, patients with pancrea-
titis and during Gram-negative, Gram-positive, and fungal sepsis. Several studies
have found that the degree of trauma is associated with the endotoxin level [4].
Many studies have found elevated levels are associated with a greater degree of or-
gan dysfunction or other measurements of outcome, although this is not a consis-
tent finding [5]. According to one theory of organ failure, during critical illness
and surgery, underperfused gut mucosa becomes permeable allowing bacteria or
endotoxin contained within the lumen to leak out into the circulation with conse-
quent effects [6]. Thus gut-derived endotoxin enters the portal venous and lym-
phatic systems, where in health, presumably, much of it is taken up by the liver
and neutralized by hepatic Kuppfer cells.
0- Polysaccharide Outer Core Inner Core lipid- A
Fig. 2. A schematic representation of the endotoxin molecule
Endotoxin Induces Natural Anti-Endotoxin Defenses

Being a 'foreign' substance, endotoxin induces natural antibodies to the 0-polysac-
charide chain, core or lipid-A portions (Fig. 2). As well as antibodies, several blood
borne substances such as high density lipoprotein cholesterol (HDL-C) and bacteri-
cidal permeability increasing protein (BPI, released from neutrophils) bind endo-
toxin. Concurrent infusion of these substances reduces the effect of endotoxin in
volunteers. On the other hand, lipopolysaccharide binding protein (LBP) removes
endotoxin from HDL-C and presents it to CD14, part of the 'endotoxin receptor
complex' (including TLR4, MD-2, CD14) on the cell surface, increasing the effect of
endotoxin [7]. Blocking this pathway reduced endotoxin responsiveness in endotox-
in-challenged volunteers [8]. Albumin also binds endotoxin but does not appear to
reduce its effect: it may facilitate the actions of CD14 and LBP.
I Endotoxin Receptors
For a long time, the link between immune stimulation by microorganisms and the
initiation of host defense was unknown. Recently, a receptor family, homologous to
the defense receptors called 'Toll' in the fruit fly Drosophila, have been character-
ized in mammals [9]. One of these, TLR4, along with the accessory protein MD-2,
appears to mediate most of the effects of bacterial endotoxin in humans [10]. Two
TLR4 polymorphisms (Asp299Gly and Thr399Ile) appear to alter endotoxin's effects
and have been associated with susceptibility to and severity of Gram-negative
shock [11], urological infections [11, 12] but not meningococcal disease [13]. Fasci-
natingly, the Asp299Gly TLR4 polymorphism is associated with a decreased risk of
atherosclerosis: what you get in one hand is taken away from the other [14].
I Previous Anti-Endotoxin Therapies

The only study that has shown a mortality reduction with a specific anti-endotoxin
therapy in sepsis was Zeigler's groundbreaking trial [15]. In it, she and her col-
leagues took 'control' plasma from young men in San Diego before vaccinating
them with a mutant JS E. coli endotoxin core-lipid-A preparation. Two weeks later
they removed more plasma that was used as the 'treatment' plasma. Next, 304 pa-
tients were randomized to receive either the 'treatment' or the 'control' antiserum
for a variety of indications considered to be indicative of Gram-negative sepsis. The
'treatment' plasma was given to 109 patients with Gram-negative bacteremia whilst
103 patients had the 'control'; the treatment group mortality was 22% compared to
39% in the controls. The main criticism made of this study, published in 1982, was
that no intention to treat analysis was performed: the outcome data were given only
for the group subsequently . found to have Gram-negative bacteraemia. In another
study, the JS E. coli antiserum was reported to lower the rate of Gram-negative
shock in a surgical ICU population [16].
Lipid-A Monoclonal Antibodies HA-1A and ES

After the JS trials came the anti-lipid-A monoclonal antibodies HA-lA (Centoxin)
and ES (Xoma). These studies failed to show a reduction in mortality on an 'inten-
tion to treat' basis in sepsis. Another monoclonal antibody, T88 (Chiron}, directed
against the common enterobacterial antigen also showed no overall benefit. Some
of this may be because HA-1A and ES have little specific endotoxin-binding ability,
but it might also show the difficulties of attempting to intervene once the inflam-
matory cascade has been started [17].
Natural Anti-Endotoxin Antibodies are Associated with a Better Outcome

All humans have endogenous serum antibodies directed against the endotoxin core
(EndoCAb) the number of which varies between people by over three hundred-fold
[18]. Several studies have noted that those patients with higher natural levels of an-
tibodies to endotoxin 'core' have a better outcome. This finding, in cardiac and
general surgery, sepsis, and pancreatitis has led to a renewed interest in anti-endo-
toxin therapies [19-21]. One of these studies involving 1056 patients undergoing
major non-cardiac surgery, found low IgM EndoCAb to be a predictor of postoper-
ative complications, independent of the patients' general immune status (total IgG
and total IgM levels) and the Physiological and Operative Severity Score for the
enUmeration of Mortality and morbidity (POSSUM) surgical risk score [21]. This
is consistent with the theory that these antibodies are capable of neutralizing endo-
35
l30
~ 25
0
~ 20
a.
E 15
0
u
5 10
·;o
~ 5
0
<74 75-138 139-264 > 265
Preoperative lgM EndoCAb level (MU/ml)
Fig. 3. Association of preoperative lgM EndoCAb levels with postoperative complications following major
surgery (adapted from [21])
toxin. However, it is not really known if they act to reduce endotoxin-induced in-
flammation or if they are markers of an otherwise healthy immune system (Fig. 3).
I How can we Intervene: Now and in the Future?

Once endotoxin is released into the circulation, it can initiate the events outlined
above. Some investigators have attempted to reduce the gastrointestinal tract's en-
dotoxin content with selective digestive decontamination (SDD) [22]. Others, in the
belief that inadequate gut perfusion increases endotoxin 'leak', have used guided
pre-operative fluid therapy to improve gastrointestinal perfusion [23]. For planned
events such as elective surgery, we are able, in theory, to give anti-endotoxin thera-
pies before endotoxin exposure. However in patients with sepsis, who present after
endotoxin exposure when the inflammatory cascade has started, this is not possible
in the same way.
Limit Endotoxin Release

Inhibitors of Lipid-A Synthesis. As lipid-A is integral to endotoxin's function, altering
the enzymes involved in its manufacture could leave the bacterium more prone to
lysis and immune cell killing. This can be achieved by either infection with a bac-
teriophage (a virus that infects a bacteria) that in turn alters the DNA or RNA en-
coding the enzyme, or by direct enzyme inhibition of the lipid-A manufacturing
enzymes. These approaches are at the pre-clinical stage [24].
Reducing Antibiotic-induced Endotoxin Release. As many antibiotics cause bacterial cell

wall breakdown, they can also release endotoxin into the circulation. One group that
bind to penicillin-binding protein 2 (PBP-2), a protein in the bacterial cell wall, caus-
ing rapid cell death is associated with less endotoxin release compared to those anti-
biotics that bind to penicillin-binding protein 3 (PBP-3). This group (which includes
cefotaxime, piperacillin, ceftazidime and aztreonam) generate long filamentous forms
that release larger amounts of unbound endotoxin, both in vitro and in vivo. However,
there is no good prospective trial examining the use of the 'low endotoxin releasing
group' of antibiotics on a clinical outcome. In one study of 334 trauma patients with
sepsis [25], the authors examined the effect of PBP-3-specific versus non-PBP-3-spe-
cific antibiotics on overall in-hospital mortality. In 78 patients receiving PBP-3-specif-
ic antibiotics (aztreonam, cefotaxime, or ceftazidime), mortality was 17% compared
to 8% in the 256 patients receiving other antimicrobials (p=0.02). But whilst the ini-
tial study (designed to test the effect of interferon [IFN]-y in trauma patients) was
prospective, the analysis of the effects of antibiotic treatment was performed by a post
hoc examination of patient notes.
Remove Free Endotoxin

The observation that elevated endotoxin levels have been associated with a worse
outcome has give rise to the idea that removing 'free' endotoxin may be beneficial.
In theory, this could be done by raising the level of 'endogenous' endotoxin-neu-
tralizing substances (antibodies, HDL-Cholesterol, BPI) or by novel methods such
as endotoxin-binding columns.
------"~~-~~". c
Antibodies: 0-Polysaccharide vs Core. Antibodies to endotoxin occur naturally and act

to neutralize endotoxin, facilitate endotoxin clearance and complement-dependent
anti-bacterial activities, and are thought to offer in vivo protection against Gram-
negative infection [26]. Antibodies against the 0-polysaccharide portion will be
more specific to that species of bacteria: protection is in general limited to that or-
ganism [27]. Antibodies to the core or lipid-A components, however, being con-
served across a range of Gram-negative bacteria show more cross reactivity to a
greater range of endotoxins [28].
Passive or Active. There are two ways to increase antibody levels: passively (giving
antibodies) or actively. Vaccination requires the patient to be able to mount an
antibody response, but if successful, levels are sustained for a greater time than
that acquired by passive immunity.
Commercial gammaglobulin. Many commercial gammaglobulins have unknown

quantities of antibodies to endotoxin but some have been found to be useful in
both prevention [29] and early treatment of sepsis [30]. A Cochrane Systematic
Review of intravenous immunoglobulin for treating sepsis and septic shock con-
cluded that polyclonal gammaglobulin has a promising role as adjuvant therapy
to reduce mortality in sepsis, but stopped short of recommending its routine use
in adult practice [31].
'Natural' hyperimmune plasma. Plasma can be removed from healthy individuals
who happen to have high levels of antibodies to endotoxins. One study found
the resulting hyperimmune gammaglobulin protective in a sheep model of Es-
cherichia coli sepsis [32]. Using this approach, a small study in patients with low
levels of antibodies to endotoxin core having surgery found that length of hospi-
tal stay was shortened. This approach is currently being investigated, although
there are concerns about transfer of prions and other unidentified agents in
blood products [33].
I Vaccinated volunteer serum. Volunteers have been vaccinated with various
'smooth type' species (endotoxin lacking an 0-polysaccharide tail) to provide
serum rich in antibodies to that bacteria's endotoxin. As mentioned earlier, one
mutant, Escherichia coli J5 has been used in both prevention [34] and treatment
[15] of sepsis.
Monoclonal antibodies. In theory, monoclonal antibodies would yield a plentiful
source of infection free anti-endotoxin antibodies, which could be used as study
agents and potential therapies. However as described above, the trials of anti-
lipid A monoclonal antibodies E5 and HA-1A in sepsis failed prospectively to
show a reduction in mortality.
Endotoxin Vaccines. Vaccines from parts of the 0-polysaccharide or core [34] com-
ponents have been given to both patients and potential plasma donors. One endo-
toxin 'core' vaccine that included E. coli. J5 mutant [35] was able to protect against
endotoxin injection and Gram-negative infection in the vaccinated animals. A non-
pyrogenic liposomal vaccine consisting of complete-core endotoxins from four
Gram-negative bacterial strains elicited cross-reactive antibodies to a large panel of
endotoxins and was protective in mice against a lethal challenge with E. coli 018
endotoxin [28].
High Density Lipoprotein Cholesterol. Recombinant HDL-C binds to endotoxin, lowers

cytokine levels and improves survival in animal models of sepsis. In patients un-
dergoing surgery, low HDL-C levels are associated with more IL-6 release [36] and
more surgical infections, mainly attributable to Gram-negative organisms [37].
When volunteers are challenged with endotoxin, recombinant HDL-C greatly re-
duces the release of tumor necrosis factor (TNF), interleukin (IL)-6, and IL-8, while
only modestly attenuating the secretion of proinflammatory cytokine inhibitors IL-
l receptor antagonist (IL-lra), soluble TNF receptors and IL-10 [38]. No interven-
tional clinical studies have yet been published.
Bactericidal Permeability Increasing Protein. BPI is apart of our innate immune sys-
tem. Released from activated neutrophils [39], it neutralizes soluble and mem-
brane-bound endotoxin and is cytotoxic for Gram-negative bacteria [40]. It is pro-
tective in animal models of sepsis whilst in human volunteers it reduces the cardio-
vascular changes and cytokine levels associated with endotoxin [41]. A recombi-
nant version has been the subject of 2 large studies. One of these, enrolled 393 chil-
dren with a 'clinical picture suggestive of meningococcal sepsis, and with evidence
of severe disease' to receive either rBPI or placebo. Unfortunately, the study showed
only a trend towards fewer deaths and multiple amputations, but a significant re-
duction in functional deterioration. For practical, logistical reasons the rBPI was
not given until 6 h after the first antibiotic; most seriously ill children would have
deteriorated and died leaving a group with a much lower mortality (8.7%) to be
enrolled [42]. Once again this also shows the ·difficulty of blocking endotoxin when
the cascade is in full flow. The other large study, in adult trauma, also showed only
a trend in outcome improvements but a significant reduction (in a post hoc analy-
sis) of pneumonia and acute respiratory distress syndrome (ARDS) [43].
Endotoxin-binding Columns. Polymyxin B, a synthetic antibiotic is one of the most

potent endotoxin-binding substances. Renal toxicity prevents its systemic use, but
it can be complexed to immunoglobulins or bound to a hemoflltration circuit.
Treatment with immobilized polymyxin fibers lowers endotoxin and cytokine levels
[44]. In a small prospective, open and randomized trial of 98 septic patients, pa-
tients treated with immobilized polymyxin fibers had a better 28-day survival rate
compared to controls {41 vs 11%) (p=0.002). This was most effective in patients
with APACHE II scores less than 20 (65% survival in the treatment group vs 19%
in the controls) than in patients with higher APACHE II scores [45].
Stop Endotoxin Action at the Cell Surface

Anti-CD14 and LBP Monoclonal Antibodies. Endotoxin, when bound to LBP, activates
the target cell via cell surface receptors, including CD14, the TLR4 and MD-2.
Whilst monoclonal antibodies against CD14 reduce cell responses to endotoxin in
animal models of sepsis [46], and in endotoxin-challenged human volunteers [8],
this approach has not been tried in human clinical trials.
Lipid-A Analogs. Although lipid-A is thought to impart most of the pathological

effects of endotoxin, there are both natural and synthetically altered forms of lipid-
A that are much less pathogenic than can act as lipid-A antagonists. In animals
these substances such as MPLA, DPLA, E5531 and E5564 reduce the effects of
administered endotoxin and improve survival in experimental sepsis [47]. Phase 1

trials showed that most of the responses to endotoxin could be reduced or abol-
ished (in a dose-dependent manner) in humans given both endotoxin and the lip-
id-A antagonist E5531 [48].
Stop Endotoxin Action Inside the Cell

The sequence of events once endotoxin reaches its target cell is not fully known.
Interest has focused on the endotoxin receptor complex, which in turn alters activ-
ity in gene promoters such as (e.g., nuclear factor kappa B [NF-KB]) via myeloid
differentiation factor 88 (MYD-88), an essential adaptor molecule used as a signal
transduction pathway by the TLR family [49]. Therapies aimed at this level are at a
preclinical stage.
'Neutralize' Products of the Target Cell

Endotoxin initiates changes once it reaches its 'target cell'. Whilst outside the scope
of this chapter, therapies directed at the products of endotoxin-induced cell activa-
tion are in some ways 'anti-endotoxin therapies'.
I Conclusion
Endotoxin is associated with organ failure and death during critical illness, after
surgery and after trauma. Most anti-endotoxin substances have failed to show a re-
duction in mortality in sepsis: this may be due to the difficulty in intervention
once the inflammatory cascade has started compared to preventing endotoxin-in-
duced inflammation.
~::------------ Reduce release

'4 E d . Antibiotics. Gl , Bind endotoxin
dotoxin n otoxm Manipulation ,.- Anti-endotoxin antibodies
Endotoxin Lipid·A synthesis ,..- HDL·C and BPI
,
Endotoxin ~ inhibitors ,-' Endotoxin · binding columns
,-• Soluble endotoxin receptors
,/
,
Endotoxin
+LBP
Altered target effect .,.
Lipid · A antagonists ---------------
Anti·CD14mAb
Cytokine antagonists
Fig. 4. Possible anti-endotoxin approaches

There is no commercial anti-endotoxin agent available for clinical use either in

sepsis or for before situations where we might expect endotoxin release to occur.
Experimental approaches have been aimed at reducing endotoxin release, binding-
free endotoxin (with anti-endotoxin antibodies, HDL-cholesterol, BPI protein, or
endotoxin-binding columns) or interfering with the cellular response to endotoxin
(Fig. 4). Discovery of the endotoxin receptor TLR4 may lead to new therapeutic
agents.
References
1.. Boike E, Jehle PM, Trautmann M, et al (2002) Different acute-phase response in newborns
and infants undergoing surgery. Pediatr Res 51:333-338
2. Trautmann M, Zick R, Rukavina T, Cross AS, Marre R (1998) Antibiotic-induced release of
endotoxin: in-vitro comparison of meropenem and other antibiotics. J Antimicrob Chemo-
ther 41:163-169
3. Suffredini AF, Fromm RE, Parker MM, et al (1989) The cardiovascular response of normal
humans to the administration of endotoxin. N Engl J Med 321:280-287
4. Boike E, Jehle PM, Storck M, et al (2001) Endovascular stent-graft placement versus con-
ventional open surgery in infrarenal aortic aneurysm: a prospective study on acute phase
response and clinical outcome. Clin Chim Acta 314:203-207
5. Hurley JC (1995) Reappraisal with meta-analysis of bacteremia, endotoxemia, and mortal-
ity in gram-negative sepsis. J Clin Microbial 33:1278-1282
6. Pastores SM, Katz DP, Kvetan V (1996) Splanchnic ischemia and gut mucosal injury in sep-
sis and the multiple organ dysfunction syndrome. Am J Gastroenterol 91:1697-1710
7. Dobrovolskaia MA, Vogel SN (2002) Toll receptors, CD14, and macrophage activation and
deactivation by LPS. Microbes Infect 4:903-914
8. Verbon A, Dekkers PE, ten Hove T, et al (2001) IC14, an anti-CD14 antibody, inhibits en-
dotoxin-mediated symptoms and inflammatory responses in humans. J Immunology 166:
3599-3605
9. Medzhitov R, Preston-Hurlburt P, Janeway CA Jr (1997) A human homologue of the Droso-
phila Toll protein signals activation of adaptive immunity. Nature 388:394-397
10. Mancek M, Pristovsek P, Jerala R (2002) Identification of LPS-binding peptide fragment of
MD-2, a toll-receptor accessory protein. Biochem Biophys Res Commun 292:880-885
11. Lorenz EP, Mira JPMD, Frees KL, Schwartz DAMD (2002) Relevance of mutations in the
TLR4 receptor in patients with Gram-negative septic shock. Arch Intern Med 162:1028-
1032
12. Svanborg C, Frendeus B, Godaly G, et al (2001) Toll-like receptor signaling and chemokine
receptor expression influence the severity of urinary tract infection. J Infect Dis 183:S61-
S65
13. Bjerre A, Brusletto B, Mollnes TE, et al (2002) Complement activation induced by purified
Neisseria meningitidis lipopolysaccharide (LPS), outer membrane vesicles, whole bacteria,
and an LPS-free mutant. J Infect Dis 185:220-228
14. Kiechl S, Lorenz E, Reindl M, et al (2002) Toll-like receptor 4 polymorphisms and athero-
genesis. N Engl J Med 347:185-192
15. Ziegler EJ, McCutchan JA, Fierer J, et al (1982) Treatment of gram-negative bacteremia and
shock with human antiserum to a mutant Escherichia coli. N Engl J Med 307:1225-1230
16. Baumgartner JD, Glauser MP, McCutchan JA, et al (1985) Prevention of gram·negative
shock and death in surgical patients by antibody to endotoxin core glycolipid. Lancet
2:59-63
17. Wisniewski MA, Kazemi M, Fang IS, et al (1994) Comparison of binding specificity and
the function of two human IgM anti-lipid A monoclonal antibodies. Circ Shock 44:230-237
18. Barclay GR (1990) Antibodies to endotoxin in health and disease. Rev Med Microbial
1:133-142
19. Bennett-Guerrero E, Ayuso L, Hamilton-Davies C, et al (1997) Relationship of preoperative
antiendotoxin core antibodies and adverse outcomes following cardiac surgery. JAMA
277:646-650
20. Hamilton-Davies C, Barclay GR, Cardigan RA, et al (1997) Relationship between pre-opera-
tive endotoxin core antibody levels, gut perfusion and outcome following cardiac valve sur-
gery. Chest 112:1189-1196
21. Bennett-Guerrero E, Panah MH, Barclay GR, et al (2001) Decreased endotoxin immunity is
associated with greater mortality and/or prolonged hospitalization after surgery. Anesthe-
siology 94:992-998
22. Nathens AB, Marshall JC (1999) Selective decontamination of the digestive tract in surgical
patients: a systematic review of the evidence. Arch Surg 134:170-176
23. Mythen MG, Webb AR (1995) Perioperative plasma volume expansion reduces the inci-
dence of gut mucosal hypoperfusion during cardiac surgery. Arch Surg 130:423-429
24. Heath RJ, White SW, Rock CO (2001) Lipid biosynthesis as a target for antibacterial agents.
Prog Lipid Res 40:467-497
25. Mock CN, Jurkovich GJ, Dries DJ, Maier RV (1995) Clinical significance of antibiotic endo-
toxin-releasing properties in trauma patients. Arch Surg 130:1234-1240
26. Di Padova FE, Mikol V, Barclay GR, et al (1994) Anti-lipopolysaccharide core antibodies.
Prog Clin Bioi Res 388:85-94
27. Cryz SJ Jr, Lang A, Rudeberg A, et al (1997) Immunization of cystic fibrosis patients with
a Pseudomonas aeruginosa 0-polysaccharide-toxin A conjugate vaccine. Behring lnst Mitt
Feb:345-349
28. Bennett-Guerrero E, Mcintosh TJ, Barclay GR, et al (2000) Preparation and preclinical eval-
uation of a novel liposomal complete-core lipopolysaccharide vaccine. Infect Immun 68:
6202-6208
29. Cafiero F, Gipponi M, Bonalumi U, et al (1992) Prophylaxis of infection with intravenous
immunoglobulins plus antibiotic for patients at risk for sepsis undergoing surgery for col-
orectal cancer: results of a randomized, multicenter clinical trial. Surgery 112:24-31
30. Schedel I, Dreikhausen U, Nentwig B, et al (1991) Treatment of gram-negative septic shock
with an immunoglobulin preparation: a prospective, randomized clinical trial. Crit Care
Med 19:1104-1113
31. Alejandria MM, Lansang MA, Dans LF, Mantaring JB (2001) Intravenous immunoglobulin
for treating sepsis and septic shock. Cochrane Database Syst Rev CD001090
32. Hodgson JC, Barclay GR, Hay LA, Moon GM, Poxton IR (1995) Prophylactic use of human
endotoxin core hyperimmune gammaglobulin to prevent endotoxaemia in colostrum-de-
prived gnotobiotic lambs challenged orally with Escherichia coli. FEMS Immunol Med Mi-
crobiol11:171-180
33. Smith A, Bawa P, Royston D, Barclay R, Hamilton-Davies C (1999) Peak preoperative Anti-
Endotoxin core Antibody concentration is inversely related to hospital stay in high risk
cardiac surgical patients. Anesthesiology 91:A88 (abst)
34. Baumgartner JD, Heumann D, Calandra T, Glauser MP (1991) Antibodies to lipopolysac-
charides after immunization of humans with the rough mutant Escherichia coli J5. J Infect
Dis 163:169-772
35. Bhattacharjee AK, Opal SM, Taylor R, et al (1996) A noncovalent complex vaccine prepared
with detoxified Escherichia coli J5 (Rc chemotype) lipopolysaccharide and Neisseria me-
ningitidis Group B outer membrane protein produces protective antibodies against gram-
negative bacteremia. J Infect Dis 173:1157-1163
36. Fujita T, Hara A, Yamazaki Y (2001) Relationship between circulating high density lipopro-
tein concentrations and interleukin-6 release during abdominal operations. Eur J Surg
167:347-350
37. Delgado-Rodriguez M, Medina-Cuadros M, Martinez-Gallego G, Sillero-Arenas M (1997)
Total cholesterol, HDL-cholesterol, and risk of nosocomial infection: a prospective study in
surgical patients. Infect Control Hosp Epidemiol18:9-18
38. Pajkrt D, Doran JE, Koster F, et al (1996) Antiinflammatory effects of reconstituted high-
density lipoprotein during human endotoxemia. J Exp Med 184:1601-1608
39. Giroir BP, Quint PA, Barton P, et al (1997) Preliminary evaluation of recombinant amino-
terminal fragment of human bactericidal/permeability-increasing protein in children with
severe meningococcal sepsis. Lancet 350:1439-1443
40. Elsbach P, Weiss J {1998) Role of the bactericidal/permeability-increasing protein in host
defence. Curr Opin Immunol10:45-49
----- Update on Anti-Endotoxin Therapies
41. Von der Mohlen MAM, Kimmings AN, Wedel Nl, et a! (1995) Inhibition of endotoxin-in-
75
duced cytokine release and neutrophil activation in humans by use of recombinant bacteri-
cidal/permeability-increasing protein. J Infect Dis 172:144-151
42. Levin M, Quint PA, Goldstein B, et a! (2000) Recombinant bactericidal/permeability-in-
creasing protein (rBPI21) as adjunctive treatment for children with severe meningococcal
sepsis: a randomised trial. rBPI21 Meningococcal Sepsis Study Group. Lancet 356:961-967
43. Demetriades D, Smith JS, Jacobson LE, et a! (1999) Bactericidal/permeability-increasing
protein (rBPI21) in patients with hemorrhage due to trauma: results of a multicenter phase
II clinical trial. rBPI21 Acute Hemorrhagic Trauma Study Group. J Trauma 46:667-676
44. Tani T, Hanasawa K, Endo Y, et a! (1998) Therapeutic apheresis for septic patients with or-
gan dysfunction: hemoperfusion using a polymyxin B immobilized column. Artif Organs
22:1038-1044
45. Nemoto H, Nakamoto H, Okada H, et a! (2001) Newly developed immobilized polymyxin B
fibers improve the survival of patients with sepsis. Blood Purif 19:361-368
46. Schimke J, Mathison J, Morgiewicz J, Ulevitch RJ (1998) Anti-CD14 mAb treatment pro-
vides therapeutic benefit after in vivo exposure to endotoxin. Proc Nat! Acad Sci USA
95:13875-13880
47. Hawkins LD, Ishizaka ST, McGuinness P, et a! (2002) A novel class of endotoxin receptor
agonists with simplified structure, toll-like receptor 4-dependent immunostimulatory ac-
tion, and adjuvant activity. J Pharmacol Exp Ther 300:655-661
48. Christ WJ, Asano 0, Robidoux AL, et a! (1995) E5531, a pure endotoxin antagonist of high
potency. Science 268:80-83
49. Janssens S, Beyaert R (2002) A universal role for MyD88 in TLR/IL-1R-mediated signaling.
Trends Biochem Sci 27:474-482
An Update of Childhood Meningococcal Sepsis
J. Ramet, N. Najafi, and A. Benatar
I Introduction
In 1805, Vieusseux reported the first identification of meningococcal disease [1]

while the causative organism, Neisseria meningitidis, was first isolated in 1887 [2].
In 1919 Herrick stated with respect to meningococcal infections "no other infection
so quickly slays" [3], a statement that still holds true 80 years later.
Despite the advances in high-level intensive care, the mortality and morbidity in
patients with meningococcal disease still remains high. The clinical presentation
may include a wide spectrum, progressing within a few hours to septic shock and
multiorgan system failure (MOP). Swift institution of therapy is of utmost impor-
tance, and consists of aggressive cardiovascular and ventilatory support once the
diagnosis is suspected and should on no account be delayed. Prevention and con-
trol of meningococcal disease, partially achieved by vaccination and chemoprophy-
laxis, still remains a public health challenge.
This chapter summarizes current knowledge of the pathogenesis, therapy, and
prevention of meningococcal disease, with emphasis on meningococcal sepsis.
I Epidemiology
Meningococcal disease occurs worldwide as endemic infections. Its incidence, dur-

ing the last 30 years, has remained relatively stable at 1-3 per 100000 in most in-
dustrialized countries [4], with the majority of cases occurring during the winter
and early spring. The highest incidence is in children under the age of 5 years,
with a secondary peak during adolescence and early adulthood.
There are at least 13 serogroups of N. meningitidis, of which five serogroups, de-
signated A, B, C, Y and W135, account for virtually all disease-causing cases [5]. In
Europe, at least 50% of cases are attributable to serogroup B, and most of the re-
mainder to serogroup C, whereas serogroups A and C predominate throughout Asia
and Mrica [6]. Currently, in certain areas of the United States, serogroup Y is re-
sponsible for approximately one-third of the cases, serogroup C for another one-
third, and serogroup B, W135, and uncommon serogroups for the remainder of
cases [7]. In all countries, the incidence of group B disease is highest in infants less
than a year of age, whereas group C disease frequently causes localized outbreaks
amongst teenagers and young adults. Epidemics are usually characterized by a pre-
dominance of a single meningococcal serotype, higher incidence rates, and a shift
of cases toward older age groups.
An Update of Childhood Meningococcal Sepsis 77
I Pathogenesis
N. meningitidis are Gram-negative, aerobic diplococci. They are classified into sero-
groups according to the immunologic reactivity of their capsular polysaccharides,
which are the basis for meningococcal vaccines. They are further classified accord-
ing to their outer membrane proteins and lipo-oligosaccharides [8] (Fig. 1).
The only natural reservoir of N. meningitidis is the human nasopharyngeal mu-
cosa from which transmission to others occurs by aerosol or secretions. Approxi-
mately 5 to 10% of adults are asymptomatic carriers of N. meningitidis strains [9],
most of which are not pathogenic. Although invasive disease is relatively rare, it
can occur under the following conditions: exposure to a pathogenic strain, coloni-
zation of the nasopharyngeal mucosa, passage through that mucosa, survival, and
eventually outgrowth of meningococci into the bloodstream [8]. These processes
are influenced by bacterial properties, climatologic and social conditions, alcohol
consumption, smoking [10], preceding or concomitant viral (influenza A virus),
and Mycoplasma pneumoniae infections, immunosuppressive drugs, autoimmune
diseases [11], hyposplenia, deficiency of terminal complement components [12],
and probably human immunodeficiency virus (HIV) seropositivity [13].
_,__,, r- - - - -- - Cytoplasmic membrane

Periplasmic space
Outer membrane
---- Pilus
Outer-membrane proteins
Phospholipid
Fig. 1. Cross-sectional view of the meningococcal cell membrane. (From [8] with permission)
78 J. Ramet et al.
I Clinical Presentations
Patients with invasive meningococcal disease can fall into one of four groups: pa-
tients with bacteremia without shock, patients with bacteremia with shock but no
meningitis, patients with shock and meningitis, and patients with meningitis alone.
The beginning of the bacteremia phase is often marked by the onset of chills,
acute fever, or generalized muscle aches, and may be indistinguishable from any
other infection. Within a few hours, fulminant meningococcal sepsis may develop
without signs of meningitis, characterized by an abrupt onset of a petechial or pur-
puric rash. This may progress to hypotension; diffuse intravascular coagulopathy
(DIC, Fig. 2), acute adrenal hemorrhage (Waterhouse-Friederichsen syndrome),
MOF, small vessel thrombosis, tissue necrosis, and death [14] .
Meningitis occurs in about 50% of patients and is marked by a sudden onset of
headache, fever, and neck stiffness, often accompanied by nausea, vomiting, photo-
phobia, and an altered mental status. In infants, meningitis may present with non-
specific signs such as feeding difficulties and without neck stiffness. A bulging fon-
tanel is occasionally noted. Other reported presentations associated with meningo-
coccal disease are pneumonia in 5 to 15% of cases [15], conjunctivitis, otitis media,
epiglottitis, arthritis, urethritis, and pericarditis.
Endothelial cell Neutropl1il Loss of nuld with

coagulation factors
I. Vascular injury and capillary leak I.
and protein:§;
..
Endotoxin Tissue factor
leinines (procoagulant surface)
cytoklnes
......·
l complement
Excess of PAI·l
!
Cell adhesion mole<ule< Adhesion of platelets Fibrin deposition
Formation of microthrombi
Fig. 2. Disseminated intravascular coagulation characterized by microvascular thrombosis and bleeding

diathesis (PAl plasminogen activator inhibitor, PAF platelet activating factor). (From [14) with permission)
Pathophysiology
It has been shown that the release of lipo-oligosaccharide from the outer membrane
of N. meningitidis stimulates the patient's inflammatory pathway [16] while, menin-
gococcal endotoxin, activates, in particular, the complement system [17]. These ef-
fects result in an increase in both pro- and anti-inflammatory cytokines such as tu-
mor necrosis factor {TNF)-a, interleukin (IL)-1, IL-6, IL-8, IL-10 and IL-12, causing
the generalized dysregulation of the inflammatory pathway seen with meningococ-
cal sepsis [18]. Activated protein C {APC}, is an endogenous protein, which has an-
tithrombotic, anti-inflammatory, and fibrinolytic properties. It is converted from its
inactive precursor, protein C, by thrombin coupled to thrombomodulin [19]. This
conversion may be impaired during sepsis as a result of the down-regulation of
thrombomodulin by inflammatory cytokines. During sepsis, an excess of nitric ox-
ide (NO) reduces vascular resistance and, in turn, a drop in the systemic and pul-
monary blood pressures, associated with myocardial dysfunction, and increases in
oxygen consumption and endothelial permeability [20]. Fibronectin is another in-
flammatory mediator, found in cryoprecipitate, which also stimulates platelet aggre-
gation and the clotting cascade in DIC [21]. Once meningococci invade the subar-
achnoid compartment, where the basic humoral and cellular host defense mecha-
nisms are absent, they proliferate uncontrolled, but the inflammatory response re-
mains localized resulting in increased cytokine concentration in the cerebrospinal
fluid (CSF) of these patients [22].
I Diagnosis
Early diagnosis suspected on clinical signs and symptoms is crucial and life-saving,
as meningococcal disease can be fatal within a few hours. Hematological findings
include low concentrations of fibrinogen, clotting factors, and platelets as a result
of their consumption, and prolonged prothrombin and partial thromboplastin
times, elevated fibrinogen degradation products, and reduced concentration of pro-
tein C, S and antithrombin III. The classic laboratory diagnosis has relied on bac-
teriologic culture of blood or CSF. Other methods not affected by prior antibiotic
administration are antigen detection or polymerase chain reaction (PCR) on me-
ningococcal DNA in blood or CSF. Finally, adrenal hemorrhages as identified at
postmortem examination may indicate an underlying Waterhouse-Friderichsen syn-
drome [23].
Predictors of Meningococcal Disease Severity

Multiple scoring systems have been published, all based on quickly available clinical
and laboratory parameters. In summary, predictors of a poor prognosis are: the ex-
tremes of age, a short period between onset of disease and admission, the absence
of meningitis, progressive or widespread skin lesions, shock, hypotension, metabolic
acidosis, a moderately elevated or normal C-reactive protein (CRP) concentration in
serum, the absence of leukocytosis, the presence of thrombocytopenia, DIC, low con-
centration of factor VII, X, V, VIII, and hypofibrinogenemia [24, 25].
80 J. Ramet et al.
Data from recent publications have suggested a correlation between the levels of
the following mediators and the severity of meningococcal disease; high concentra-
tions of cytokines [26], procalcitonin [27], NO [28] and fibronectin [29], high
ACTH and low cortisol concentration [30], high meningococcal bacterial DNA load
at presentation [31], increased levels of plasminogen activator inhibitor (PAl) I
[32], low concentrations of anti-thrombin III, protein S and protein C [33], and de-
letion variant of the angiotensin-converting-enzyme (ACE) gene [34]. Although the
levels of these mediators are a direct reflection of the inflammatory process, long
laboratory turnaround times make them unsuitable for prognostic evaluation in
daily practice.
I Outcome
Recovery from meningococcal disease may be complicated by hemorrhages, acute
respiratory distress syndrome (ARDS), anuria, MOF, long lasting myocardial de-
pression, life-threatening bradyarrhythmias, cardiac tamponade, and sterile pericar-
ditis. Skin and limb necrosis, secondary tissue infection requiring amputation or
plastic surgery may occur. Despite improved supportive intensive care, mortality
rates under 5 years remain high at 9 to 12%, and up to 40% in meningococcal sep-
sis [4]. The neurological sequelae after meningococcal meningitis include sensori-
neural deafness, mental retardation, spasticity, seizures and concentration distur-
bances [35]. The mortality seen in 1 to 5% of these patients is often caused by ce-
rebral edema and brain stem herniation. The outcome should be improved by pre-
vention, early recognition, and improvements in early management and transport.
I Treatment
Aggressive early treatment of meningococcal disease consists of supportive care of
shock and specific treatment of septicemia.
Supportive Care
The recommendations for hemodynamic support of pediatric patients with septic
shock have been outlined recently [36]. The diagnosis of septic shock is made clini-
cally and is based on a suspected infection manifested by hypo- or hyperthermia
and clinical signs of decreased perfusion and altered mental status. Cold shock is
defined as prolonged capillary refill of > 2 s, diminished peripheral pulses and
mottled cool extremities whereas warm shock is characterized by flash capillary re-
fill and bounding peripheral pulses.
The immediate supportive care of pediatric septic shock consists of maintaining
airway, breathing and circulation to restore normal mental status and peripheral
perfusion. Airway and breathing should be rigorously monitored .and maintained.
The decision to intubate and ventilate is made on a clinical diagnosis of increased
work of breathing, poor airway reflexes, and impaired mental status. Waiting for
confirmatory laboratory tests is discouraged. Volume loading may be required dur-
ing intubation because of hypovolemia and use of induction agents.
Pediatric septic shock is associated with severe hypovolemia, and children fre-
quently respond well to aggressive fluid resuscitation. Therefore, in these patients,
reliable venous access should be rapidly established, followed by administration of
fluid boluses of 20 ml/kg of colloids or crystalloids titrated to clinical monitors of
cardiac output. Large fluid deficits may exist with initial requirements of 40-60 mU
kg but can be as much as 200 mUkg. The presence of meningitis does not justify
limited fluid resuscitation, as large volumes of fluid for acute stabilization in chil-
dren have not been shown to increase cerebral edema [37]. In children with fluid-
responsive shock, observation in a pediatric intensive care unit (ICU) with mini-
mally invasive monitoring is necessary.
lnotropesNasopressors
Invasive hemodynamic monitoring should be considered in patients who do not re-
spond rapidly to initial fluid boluses. A second catheter, preferably a central cathe-
ter in the femoral vein, should be established for administration of vasoactive
drugs. Dobutamine or mid-dosage dopamine can be used as the first-line drug for
inotropic support. However, children < 12 months can be less responsive. Dobuta-
mine or dopamine refractory shock must be quickly recognized and epinephrine
used.
In catecholamine-resistant hypotensive shock, adrenal insufficiency, caused by
adrenal hemorrhages and adrenocortical insufficiency syndrome, should be sus-
pected. In this setting, the use of stress doses of corticoids seems appropriate and
is potentially life-saving in the reversal of shock [38]. To maintain metabolic home-
ostasis in children, hypoglycemia, hypokalemia, and hypocalcemia must be rapidly
diagnosed and promptly treated. Beyond the first hours, fluid losses and persistent
hypovolemia secondary to diffuse capillary leak can continue for days. Ongoing
fluid replacement should be directed at clinical endpoints.
Hemodynamic support may be required for days in children with fluid-refrac-
tory shock:
I Patients with low cardiac output and dobutamine/dopamine resistant shock will
require epinephrine.
I Low cardiac output state with high systemic vascular resistance. Mortality in pe-
diatric septic shock is strongly associated with low cardiac output state [39]. In
this group of epinephrine-resistant shock patients, milrinone or amrinone (ino-
tropic and vasodilating agents) can be considered. Use of these vasodilators is
best reserved for patients where detailed cardiac output monitoring can be con-
ducted and not for use in the resuscitation phase.
I NormaUhigh cardiac output state with low systemic vascular resistance. In these
patients, persistence of hypotension despite dopamine and epinephrine adminis-
tration will require norepinephrine as the next choice of inotropic agent.
I In children with refractory shock, associated pathology needs to be excluded
such as pericardia! effusion or hypoadrenalism.
I Occasionally a child will demonstrate severe refractory low cardiac output unre-
sponsive to escalating inotropes in maintaining adequate systemic perfusion. At
this stage, extracorporeal membrane oxygenation (ECMO) becomes an alterna-
tive to consider, even though the expected survival does not exceed SOo/o [40 ].
82 J. Ramet et al.
Specific Treatments
Antibiotics. Effective antibiotics should be administered as early as possible and

must not be delayed by the diagnostic procedures. Given the increasing resistance
to penicillin, broad-spectrum cephalosporins (e.g., cefotaxime, ceftriaxone) are re-
commended.
Blood- and blood product infusion. Coagulopathy and low fibrinogen concentration
should be corrected by fresh frozen plasma and cryoprecipitate. Hemoglobin should
be maintained at a minimum of 10 g/dl. Platelet transfusion should be considered
only in the presence of thrombocytopenia and clinical bleeding.
Plasmapheresis, hemofiltration. In the acute phase, meningococcal disease may be

complicated by renal failure due to acute tubular or cortical necrosis. At this stage,
filtration should be started to help limit edema and fluid overload when excessive
volumes of blood products are needed. Data have shown a reduced mortality asso-
ciated with the early therapeutic filtration for presumed meningococcal disease
[41]. The benefits of filtration to remove inflammatory cytokines and mediators re-
main controversial.
Recombinant human APC. APC is an endogenous protein with antithrombotic, antiin-

flammatory and profibrinolytic properties. The serum level of protein C, as well as
its activation by thrombomodulin appears to be reduced in meningococcal sepsis.
Controlled trials have shown the efficacy of protein C concentrate in meningococcal
disease [42] and the efficacy of recombinant activated protein C in patients with se-
vere sepsis in terms of reduced mortality [43]. However, the additional risk of se-
vere bleeding with use of these needs to be weighed by the clinician.
Adjuvant Treatments
I Heparin: inhibits thrombus formation and consumption of coagulation factors.
Its use, however, remains controversial because of the tendency for hemorrhage
and no beneficial effect on survival in the few limited trials [44].
I Anti-thrombin III: may be reduced in meningococcal disease and replacement
has been shown to normalize levels and reverse coagulopathy.
I Recombinant tissue plasminogen activator: induces clot specific fibrinolysis
without any direct hemodynamic effect [44]. Hemorrhagic complications tend to
limit its use.
1 Immunomodulating therapies, such as antiserum to E. coli JS and human anti-
lipid A monoclonal antibodies, have not significantly altered the mortality rate
of meningococcal disease in experimental models [45] and anticytokine treat-
ments appear to offer no protection. These therapies need further evaluation of
their safety and efficacy in meningococcal disease.
I Primary Prevention
The polysaccharide capsules of N. meningitidis are important determinants of viru-
lence and basis of vaccination. Recently, the quadrivalent polysaccharide vaccines
against groups A, C, Y, and W135 have become available. These vaccines are safe
but arouse poor immunogenic response in young children [46], who are at highest
risk of disease. They are, therefore, not recommended for routine childhood vacci-
nation.
The immunogenicity of polysaccharide vaccines can be improved by chemical
conjugation to carrier proteins. The resulting polysaccharide-protein conjugated
vaccines are safe, immunogenic in young infants, induce long-term protection, and
also reduce nasopharyngeal carriage and transmission of the organism. Conjugated
vaccines for group C disease have been licensed and recommended in childhood
vaccination schedules.
Despite nearly 25 years of work, there is no effective vaccine against group B
strains. Efforts to use the capsular polysaccharide as a group B vaccine have been
discouraged by its poor immunogenicity and developing a group B conjugated vac-
cine has led to the potential for induction of autoantibodies [47].
The new generation group B vaccines, using a chemically modified E. coli K1
polysaccharide capsule which is structurally identical to the group B polysaccharide
or using Nad.A, a novel surface antigen of N. meningitidis [48], or vaccines against
commensal Neisseria spp. particularly with N. lactamica [49] seem promising.
Large clinical studies with extensive follow-up will be required to prove their safety
and efficacy.
1 Secondary Prevention
Chemoprophylaxis should be administered as soon as possible to close contacts of
patients including household members, day care, and medical personnel in close
contact with oral secretions. The recommended antibiotics in this setting are: ci-
profloxacin for adults in a single dose of 500 mg orally, rifampicin 5 mglkg twice a
day for 2 days orally for children < 1 month, and rifampicin 10 mglkg twice a day
for 2 days orally for children <::1 mo. [8]. Other chemoprophylaxis regimens in chil-
dren include the use of azithromycin 10 mg/kg once only.
I Conclusion
Despite the significant progress in our understanding of the epidemiology and
pathogenesis and, in our intensive care management, the mortality of meningococ-
cal disease has not changed in recent years. Early recognition of subtle signs
should lead the clinician to the early management of meningococcal disease. Effec-
tive antibiotic treatment, aggressive hemodynamic support including ventilatory
and inotropic support remains the cornerstone of therapy and invasive monitoring
is recommended in high-risk patients. Reasonable hope to improve the outcome
lies upon several experimental treatment modalities such as the use of recombinant
human APC, plasmapheresis, and immunomodulating treatments. Efforts to find an
effective and safe meningococcal vaccine covering the various meningococcal
strains must be continued.
84 J. Ramet et al.
References
1. Vieusseux M (1805) Memoire sur la maladie qui a regne a Geneve au printemps de 1805. J
Med Chir Pharmacol11:163
2. Weichselbaum A (1887) Ueber die aetiologie der akuten meningitis cerebrospinalis. Fortsch
Med 5:573-583
3. Herrick WW (1919) Extrameningeal meningococcus infections. Arch Intern Med 23:409-418
4. Rosenstein NE, Perkins BA (2000) Update on Haemophilus influenzae serotype b and me-
ningococcal vaccines. Pediatr Clin North Am 47:337-352
5. Jodar L, Feavers IM, Salisbury D, Granoff DM (2002) Development of vaccines against me-
ningococcal disease. Lancet 359:1499-1508
6. Connolly M, Noah N (1999) Is group C meningococcal disease increasing in Europe? A re-
port of surveillance of meningococcal infection in Europe 1993-6. European Meningitis
Surveillance Group. Epidemiol Infect 122:41-49
7. Stephens DS (1999) Uncloaking the meningococcus: dynamics of carriage and disease.
Lancet 353:941-942
8. Rosenstein NE, Perkins BA, Stephens DS, Popovic T, Hughes JM (2001) Meningococcal dis-
ease. N Engl J Med 344:1378-1388
9. Sim RJ, Harrison MM, Moxon ER, Tang CM (2000) Underestimation of meningococci in
tonsillar tissue by nasopharyngeal swabbing. Lancet 356:1653-1654
10. Kriz P, Bobak M, Kriz B (2000) Parental smoking, socioeconomic factors, and risk of inva-
sive meningococcal disease in children: a population based case-control study. Arch Dis
Child 83:117-121
11. Lin VH, Parekh RS, McQuillan MA, Braun DK, Markovitz DM (1995) Meningococcal endo-
carditis presenting as cellulitis. Clin Infect Dis 21:1023-1025
12. Hoare S, El-Shazali 0, Clark JE, Fay A, Cant AJ (2002) Investigation for complement defi-
ciency following meningococcal disease. Arch Dis Child 86:215-217
13. Garcia-Lechuz JM, Alcala L, Gijon P, San Juan R, Bouza E (1998) Primary meningococcal con-
junctivitis in a human immunodeficiency virus-infected adult. Clin Infect Dis 27:1556-1557
14. de Kleijn ED, Hazelzet JA, Kornelisse RF, de Groot R (1998) Pathophysiology of meningo-
coccal sepsis in children. Eur J Pediatr 157:869-880
15. Racoosin JA, Whitney CG, Conover CS, Diaz PS (1998) Serogroup Y meningococcal disease
in Chicago, 1991-1997. JAMA 280:2094-2098
16. Braun JM, Blackwell CC, Poxton IR, et al (2002) Proinflammatory responses to lipo-oligo-
saccharide of Neisseria meningitidis immunotype strains in relation to virulence and dis-
ease. J Infect Dis 185:1431-1438
17. Bjerre A, Brusletto B, Mollnes TE, et al (2002) Complement activation induced by purified
Neisseria meningitidis lipopolysaccharide (LPS), outer membrane vesicles, whole bacteria,
and an LPS-free mutant. J Infect Dis 185:220-228
18. Hatherill M, Tibby SM, Turner C, Ratnavel N, Murdoch IA (2000) Procalcitonin and cyto-
kine levels: relationship to organ failure and mortality in pediatric septic shock. Crit Care
Med 28:2591-2594
19. Bernard GR, Vincent JL, Laterre PF, et al (2001) Efficacy and safety of recombinant human
activated protein C for severe sepsis. N Engl J Med 344:699-709
20. Symeonides S, Balk RA (1999) Nitric oxide in the pathogenesis of sepsis. Infect Dis Clin
North Am 13:449-463
21. Riordan FA, Bestwick K, Thomson AP, Sills JA, Hart CA (1997) Plasma fibronectin levels
in meningococcal disease. Eur J Pediatr 156:451-453
22. van Deuren M, Brandtzaeg P, van der Meer JW (2000) Update on meningococcal disease
with emphasis on pathogenesis and clinical management. Clin Microbiol Rev 13:144-166
23. Hardman JM, Earle KM (1967) Meningococcal infections: a review of 200 fatal cases. J
Neuropathol Exp Neurol 26:119
24. Riordan FA, Marzouk 0, Thomson AP, Sills JA, Hart CA (2002) Prospective validation of
the Glasgow Meningococcal Septicaemia Score. Comparison with other scoring methods.
Eur J Pediatr 161:531-537
25. Idrissi S, Corne L, Ramet J (1998) Evaluation of scoring systems in acute meningococce-
mia. Eur J Emerg Med 5:225-230
26. Braun JM, Blackwell CC, Poxton IR, et al (2002) Proinflammatory responses to lipo-oligo-
saccharide of Neisseria meningitidis immunotype strains in relation to virulence and dis-
ease. J Infect Dis 185:1431-1438
27. Van der Kaay DC, De Kleijn ED, De Rijke YB, Hop WC, De Groot R, Hazelzet JA (2002)
Procalitonin as a prognostic marker in meningococcal disease. Intensive Care Med
28:1606-1612
28. Baines PB, Stanford S, Bishop-Bailey D, et al (1999) Nitric oxide production in meningo-
coccal disease is directly related to disease severity. Crit Care Med 27:1187-1190
29. Riordan FA, Bestwick K, Thomson AP, Sills JA, Hart CA (1997) Plasma fibronectin levels
in meningococcal disease. Eur J Pediatr 156:451-453
30. De Kleijn ED, Joosten KF, Van Rijn B, et al (2002) Low serum cortisol in combination with
high adrenocorticotrophic hormone concentrations are associated with poor outcome in
children with severe meningococcal disease. Pediatr Infect Dis 21:330-336
31. Hackett SJ, Guiver M, Marsh J, et al (2002) Meningococcal bacterial DNA load at presenta-
tion correlates with disease severity. Arch Dis Child 86:44-46
32. Hermans PW, Hibberd ML, Booy R, et al (1999) 4G/5G promotor polymorphism in the
plasminogen-activator-inhibitor-1 gene and outcome of meningococcal disease. Meningo-
coccal Research Group. Lancet 354:556-560
33. Faust SN, Levin M, Harrison OB, et al (2001) Dysfunction of endothelial protein C activa-
tion in severe meningococcal sepsis. N Engl J Med 345:408-416
34. Harding D, Baines PB, Brull D, et al (2002) Severity of meningococcal disease in children
and the angiotensin-converting enzyme insertion/deletion polymorphism. Am J Respir Crit
Care 165:1103-1106
35. Erickson L, De Wals P (1998) Complications and sequelae of meningococcal disease in
Quebec, Canada, 1990-1994. Clin Infect Dis 26:1159-1164
36. Carcillo JA, Fields AI, American College of Critical Care Medicine Task Force Committee
Members (2002) Clinical practice parameters for hemodynamic support of pediatric and
neona~al patients in septic shock. Crit Care Med 30:1365-1378
37. Powell KR, Sugerman Ll, Eskenazi AE, et al (1990) Normalization of plasma arginine vaso-
pressin concentrations when children with meningitis are given maintenance plus replace-
ment fluid therapy. J Pediatr 117:515-522
38. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR (2001) Epide-
miology of severe sepsis in the United States: analysis of incidence, outcome, and asso-
ciated costs of care. Crit Care Med 29:1303-1310
39. Ceneviva G, Paschall JA, Maffei F, Carcillo JA (1998) Hemodynamic support in fluid-refrac-
tory pediatric septic shock. Pediatrics 102:e 19
40. Goldman AP, Kerr SJ, Butt W, et al (1997) Extracorporeal support for intractable cardiore-
spiratory failure due to meningococcal disease. Lancet 349:466-469
41. Pearson G, Khandelwal PC, Naqvi N (2000) Early filtration and mortality in meningococcal
septic shock? Arch Dis Child 83:508-509
42. Clarke RC, Johnston JR, Mayne EE (2000) Meningococcal septicaemia: treatment with pro-
tein C concentrate. Intensive Care Med 26:471-473
activated protein C for severe sepsis. N Eng! J Med 344:699-709
44. Leclerc F, Leteurtre S, Cremer R, Fourier C, Sadik A (2000) Do new strategies in meningo-
coccemia produce better outcomes? Crit Care Med 28(9 suppl):S60-63
45. J5 Study Group (1992) Treatment of severe infectious purpura in children with human
plasma from donors immunized with Escherichia coli J5: a prospective double-blind study.
J Infect Dis 165:695-701
46. Campagne G, Garba A, Fabre P, et a! (2000) Safety and immunogenicity of three doses of a
Neisseria meningitidis A+C diphtheria conjugate vaccine in infants from Niger. Pediatr In-
fect Dis J 19:144-150
47. Jodar L, Feavers IM, Salisbury D, Granoff DM (2002) Development of vaccines against
meningococcal disease. Lancet 359:1499-1508
48. Comanducci M, Bambini S, Brunelli B, et al (2002) NadA, a novel vaccine candidate of
Neisseria meningitidis. J Exp Med 195:1445-1454
49. Oliver KJ, Reddin KM, Bracegirdle P, et al (2002) Neisseria lactamica protects against ex-
perimental meningococcal infection. Infect immune 70:3621-3626
The Effect of Alcohol Consumption on Risk
for Sepsis and ARDS
E. L. Burnham, M. Moss, and G. S. Martin
I Introduction
Alcohol is the most frequently abused drug throughout the world, and alcohol-re-
lated problems are a common occurrence among patients admitted to hospitals and
intensive care units (ICUs). Alcohol affects all tissues of the body. Its effects on im-
mune function and the systemic inflammatory response syndrome (SIRS) remain
topics of active investigation. In regard to immune function, alcohol consumption
alters the response at several points along the inflammatory cascade. Due to these
potent modulating effects on immune function, alcoholic patients have an increased
incidence and severity of infection, particularly in the lung. This association be-
tween alcohol use and infection is especially evident in the post-operative setting.
Among patients with sepsis, a prior history of chronic alcohol abuse confers a sig-
nificant increase in the likelihood of respiratory dysfunction and development of
acute respiratory distress syndrome (ARDS). Chronic alcohol abuse similarly in-
creases the mortality from ARDS. One possible mechanism by which chronic alco-
hol abuse may increase susceptibility to acute lung injury (ALI} is through altera-
tions in pulmonary glutathione homeostasis. This chapter discusses the immuno-
modulatory effects of alcohol and the epidemiological and experimental evidence
associating chronic alcohol abuse, sepsis, and the development of ARDS.
I Background
Alcohol is the most commonly abused drug in the world, with approximately half the
US population consuming alcohol regularly. Fifteen to twenty million individuals
meet the criteria for alcoholism [1]. The economic cost of alcohol in the USA is
around $100 billion (USD), with > 10% of this cost directly attributable to medical
services [2]. Alcohol is a leading cause of preventable mortality, and is associated with
100 000 deaths per year.
Up to 40% of all hospitalized patients have alcohol-related disorders [3]. Alco-
holism is a problem of particular concern in the ICU, where the morbidity and
mortality in all alcoholic patients admitted to ICU is many-fold times higher than
the rate in non-alcoholics [4]. To further illustrate this point, one study examined
435 patients admitted to the ICU of a tertiary referral center [5]. Of these admis-
sions, 9% were alcohol-related, which generated 13% of overall costs for this ICU.
Alcohol is often associated with major injuries, and nearly 50% of trauma deaths
are related to alcohol ingestion [6]. The prevalence of chronic alcoholics among pa-
tients with trauma admitted to the ICU ranges from 23-68%, and these alcoholics
The Effect of Alcohol Consumption on Risk for Sepsis and ARDS 87
will often have a prolonged ICU stay due to infectious complications, including sep-
sis [4].
Alcohol can adversely affect all tissues of the body. The liver appears to be the
organ most susceptible to the effects of alcohol; early changes of fatty liver may
progress to hepatitis and ultimate fibrosis with hepatic cirrhosis [ 1]. Alcohol can
also affect other parts of the gastrointestinal system, causing acute erosive gastritis,
diarrhea, and pancreatitis. Heavy alcohol consumption can lead to a myriad of car-
diac abnormalities, including cardiomyopathies, arrhythmias, and possibly coro-
nary disease. Alcohol has a potent vasopressor effect, which could explain the asso-
ciation between its use and hypertension [1]. In the central nervous system (CNS),
protracted alcohol use has been associated with cerebellar degeneration.
The effect of chronic alcoholism in the lung is relatively unexplored. In the
1960s, a high incidence of pulmonary disorders among alcoholics was observed,
believed to be attributable to these patients' coincident poor overall health [7]. Re-
cently, the effects were described of chronic alcohol abuse on the development of
ARDS, a common complication of sepsis. Given the combination of the increased
incidence of sepsis [8] and the extremely high prevalence of alcohol as a drug of
abuse, the effect of alcohol on sepsis bears closer examination.
I Alcohol and Immune Function

Mechanisms by which infections in alcoholics can lead to sepsis include an in-
creased risk of aspiration, malnutrition, and alterations in the gut/liver/lung/inflam-
matory axis [9]. More importantly, alcohol is a potent immunosuppressive drug
that impairs immunity, independent of a patient's nutritional status [6].
The abnormalities seen in the immune function of alcoholics are protean and in-
clude suppression of neutrophil chemotaxis, spleen cell mitogenesis, and serum im-
munoglobulin production [6]. The effect of alcohol on the immune system varies
depending on whether the ingestion is acute or chronic (Tables 1 and 2). In acute
alcohol abuse, neutrophil adhesion and chemotaxis are impaired, whereas in
chronic alcohol abuse, these activities are unaffected. However, in chronic alco-
holics, the marrow production of neutrophils is diminished, and these cells have re-
duced superoxide production [2].
Table 1. Effects of acute alcohol abuse on immune function
Immune component Effects

Neutrophil function Diminished adhesion and chemotaxis
Normal phagocytosis
Normal intracellular killing
Pulmonary clearance Decreased ciliary activity
Decreased bacterial clearance
Macrophage function Decreased production of tumor necrosis factor
Decreased production of granulocyte colony
stimulating factor
Decreased superoxide activity
88 E. L. Burnham et al.
Table 2. Effects of chronic alcohol abuse on immune function
Immune component Effects

Neutrophil function Decreased marrow production
Decreased superoxide production
Normal adherence and chemotaxis
Surfactant function Reduced anti-pneumococcal activity
Macrophage function Decreased superoxide production
After exposure to bacterial toxins, macrophages secrete tumor necrosis factor

(TNF) and reactive oxygen intermediates. In a rat model of sepsis, lipopolysaccha-
ride (LPS) was demonstrated to induce a dramatic release of TNF [10]. When these
study animals were given alcohol shortly before an LPS infusion (to simulate acute
ingestion), the release of TNF was markedly attenuated. Additionally, in another
model of acute alcohol abuse [11], septic rats exhibited diminished alveolar macro-
phage hydrogen peroxide production. In contrast, animals chronically fed ethanol
do not exhibit reductions in their TNF production [10]. However, isolated alveolar
macrophages from chronic alcoholic patients release less TNF in response to stimu-
lation than alveolar macrophages from normal individuals [12].
Alcohol has been reported to have direct suppressive effects on the bone mar-
row, and can inhibit neutrophilic granulopoiesis through inhibition of granulocyte
colony stimulating factor (G-CSF) release from T cells [13]. Leukopenia appears to
be a phenomenon of chronic alcoholics, and is not observed in acute ethanol inges-
tion [14].
Surfactant has a demonstrated, potent bactericidal activity against invading pul-
monary pathogens, which is believed to be secondary to the detergent-like activity
of surfactant long-chain free fatty acids {FFAs) [15]. Chronic alcohol abuse causes
deficiencies in the amount of these FFAs produced by alveolar type II cells [16,. 17],
and induces the release of surfactant inhibitors, thus preventing optimal surfactant
function [17]. These abnormalities lead to decreased opsonization of microorgan-
isms and reduced bactericidal activity.
Alcohol has been reported to enhance intestinal permeability, leading to abnor-
malities in intestinal epithelial barrier function [18]. Increased intestinal permeabil-
ity can facilitate bacterial translocation, a process by which gut flora or bacterial
products traverse the abnormal intestinal barrier and ultimately reach mesenteric
lymph nodes and the portal circulation. The translocation of bacteria can ulti-
mately lead to sepsis and provoke the release of inflammatory cytokines such as
TNF-a. Chronic low-grade immune system stimulation, such as this, is believed to
decrease the efficacy of the defenses necessary to ward off secondary infectious
challenges [9].
I The Relationship between Alcohol and Infectious Diseases

The recognition of alcohol as a contributing factor for infectious diseases has been
noted since the 1700s [19]. The prototypic infection of alcoholics is pneumonia and
many investigations have been performed examining the association between alco-
holism and pneumonia. In 1905, Sir William Osler postulated that the single most
important predisposing condition for bacterial pneumonia was alcohol abuse [20].
Typically, 25-50% of all general hospital patients admitted with pneumonia will
carry a concomitant diagnosis of alcoholism. One study examined the hospital dis-
charge data of all adults hospitalized with a principal diagnosis of pneumonia dur-
ing 1992 in Massachusetts, USA [21]. Over 23000 cases of pneumonia were identi-
fied. Although the patients who carried an alcohol-related diagnosis were younger
and had fewer co-morbid illnesses (such as diabetes), hospital charges, length of
stay, and ICU utilization were significantly higher for this group.
The type of organisms causing pneumonia in alcoholics differs from those in the
general community, with a predominance of intracellular pathogens. These bacteria
include Listeria monocytogenes, Streptococcus pneumoniae, Klebsiella pneumoniae,
and Mycobacterium tuberculosis. In both animal and human models, alcohol ap-
pears to increase susceptibility to these types of infections, decrease the ability of
the host to clear organisms, and enhance the spread of these organisms to the
bloodstream, resulting in bacteremia [22, 23]. In addition, alcoholics typically have
a higher incidence of gingivodental disease and higher likelihood of aspiration, re-
sulting in a higher frequency of anaerobic lung infections [2].
Over 15 years ago, the association of alcoholism, leukopenia, and pneumococcal
sepsis was described as a distinct clinical entity [13]. This syndrome, known as
ALPS, occurred mainly in younger men and carried with it an extremely high mor-
tality. However, more recent data pertaining to mortality ascribable to pneumonia
among alcoholics are conflicting, with some reports in the literature showing no ef-
fect on mortality in the post-antibiotic era [24]. A meta-analysis attempting to elu-
cidate prognostic factors for increased mortality from community-acquired pneu-
monia (CAP) reviewed 120 studies of CAP, excluding those patients with nosoco-
mial pneumonia, non-infectious pneumonia, and human immunodeficiency virus
(HIV). In nine studies, alcoholism was listed as a co-morbid illness, and was found
in 1414 of the 33148 patients eligible for the study. The presence of alcohol abuse
was 1.6 times more likely to be associated with a fatal case of pneumonia than with
a non-fatal case [25].
Carbohydrate-deficient transferrin (CDT) has been demonstrated to be a poten-
tial biomarker of chronic alcohol abuse. Individuals who consume alcohol regularly
appear to have elevated levels of this transferrin isoform. In a group of 66 male
trauma patients, CDT measurements were taken on arrival to the emergency de-
partment. Patients were assigned a priori to either a high CDT group (> 20 U/1) or
a low CDT group (< 20 U/1). The high CDT group had a significantly prolonged
median ICU stay when compared with the low CDT group (13 days vs. 5 days).
Morbidity was also significantly higher in the elevated CDT group, with an increase
in complications, such as the alcohol withdrawal syndrome, pneumonia, and sepsis.
Importantly, 32 of the 36 patients with high CDT levels were classified as alcoholics
by Diagnostic and Statistical Manual (3rd ed., rev.) (DSM-III-R) criteria, compared
with 9 of the 30 low CDT level patients [26].
Alcoholism in individuals undergoing an operative procedure can also have dele-
terious consequences. In a group of 213 patients presenting for resection of upper
digestive tract tumors, 121 were diagnosed as being chronic alcoholics by DSM-III-
R criteria [27]. Although the patients had no significant differences between their
Acute Physiology and Chronic Health Evaluation (APACHE) III scores upon admis-
sion to the ICU, the incidence of pneumonia post-operatively was 38% in the alco-
holics compared with 7% in non-alcoholics. Moreover, 13% of the alcoholics devel-
Table 3. Differences in post-operative outcomes between alcoholic and non-alcoholic patients
ICU and major Chronic alcoholics Social drinkers Non-alcoholics p

intercurrent I II Ill
complications (n=121) (n=39) (n=61)
APACHE Ill score on admission* 40±11 39±8 36±10 0.3742

MOF score on admission* 2.3±2.0 2.1 ±1.4 1.9±1.3 0.2322
Cases of mechanical ventilation 118 {98%) 38 (97%) 59 (97%) 0.9880
on admission
Highest APACHE Ill 56±43 39±9 40±11 0.0134

score during stay* 1-11, 1-111
Highest MOF score 4±3 3±1 3±1 0.0000
during stay* 1-11, 1-111
Period of mechanical 6± 13 days 1±1 days 1± 1 days 0.0010
ventilation* 1-11, 1-111
Cases of pneumonia 46 {38%) 4 (10%) 4 (7%) 0.0000
1-11,1-111
Cases of sepsis 16 (13%) 0 (0%) 0 {0%) 0.0014
1-11, 1-111
ICases of death 9 (7%) 0 {0%) 0 {0%) 0.0438
1-11, 1-111
* mean± standard deviation; APACHE: Acute Physiology and Chronic Health Evaluation; ICU: intensive care
unit; MOF: multiple organ failure. Adapted from [27)
oped sepsis, and 7% of this group died. No sepsis or deaths were reported in the
non-alcoholic group (Table 3). In a prospective study of 106 patients with surgically
documented intra-abdominal infections, the effects of several variables on the inci-
dence of organ dysfunction and death were examined [28]. The prevalence of
chronic alcoholism in this group was approximately 20%, and these alcoholic pa-
tients had a 45% mortality rate. Consistently significant risk factors of death from
intra-abdominal sepsis in this study included old age, alcoholism, intestinal infarc-
tion, and malnutrition. If any of these risk factors occurred in conjunction with
shock, the likelihood of a patient developing death or organ dysfunction increased
substantially.
I Linking Alcohol Consumption and Lung Injury
ARDS results from a diverse group of biological insults, including trauma, pancrea-
titis, and sepsis. Sepsis remains the most common risk factor for the development
of ARDS, and is a major cause of mortality in trauma patients as well as in general
medical patients. The chronic use of alcohol may enhance a patient's susceptibility
to the development of sepsis, as evidenced by one study prospectively examining a
cohort of 2559 patients admitted after blunt or penetrating trauma [29]. It was
found that chronic, but not acute, alcohol abuse led to a two-fold higher risk for
the development of pneumonia and increased risk of infection of any kind. Another
study emphasizing the relationship between alcohol, sepsis, and ARDS prospec-
60
p < 0.001
• Alcohol abuse
l 50 0 No alcohol abuse
"'
Cl
a:
40
<:
0 30
41
u
c
<II 20
"0
·a
.!: 10
0
Sepsis (n = 109) Trauma (n = 175) Other (n = 67)
Fig. 1. The incidence of acute respiratory distress syndrome (ARDS) when stratified by the 'at risk' diag-
nosis and history of alcohol abuse. Adapted from [30]
tively followed a cohort of 351 critically ill individuals, all of whom had one of sev-
en 'at risk' diagnoses for ARDS, such as sepsis, pancreatitis, or severe trauma [30].
Ultimately, patients with a prior history of chronic alcohol abuse had an increased
incidence and severity of ARDS, regardless of the 'at risk' diagnosis, with a relative
risk (RR) of 1.98 for the development of this disorder in alcoholic patients. Ap-
proximately 50o/o of the patients developing ARDS carried a prior history of alco-
holism, making this a common association. In the subset of patients with sepsis,
the effects of chronic alcohol abuse on the development of ARDS were even more
striking, with a RR for developing ARDS of 2.59 (Fig. 1). It was also apparent from
these data that alcoholic patients had a higher mortality rate from ARDS (65o/o)
than those non-alcoholics who developed ARDS (36o/o). These observations distin-
guished chronic alcohol abuse as the first reported co-morbid variable that signifi-
cantly increased a patient's risk of developing ARDS. Further, it posed questions
about the pathophysiology and treatment of ARDS, and the effects of alcoholism
on the lungs.
In ARDS, the type II alveolar cell, while comprising only 5-10o/o of the total al-
veolar cell surface, is critical in the regeneration of a normally functioning lung.
Processes that delay alveolar repair will eventually lead to increased collagen de-
position from lung fibroblasts, and thus the progression of ARDS [31]. Glutathione
(GSH), a tripeptide predominantly synthesized in the liver, is involved in many im-
portant biological pathways, including:
I detoxification of reactive oxygen species (ROS)
I conjugation and excretion of toxic molecules
I control of inflammatory cytokine production.
Based on extensive evidence implicating the depletion of GSH in the pathogenesis of

alcohol-mediated liver disease [32], abnormal GSH homeostasis within the lungs of
chronic alcoholics may represent one mechanism contributing to these individuals'
susceptibility for ALI. The lung is unable to synthesize its own supply of GSH and
is dependent upon its importation from the liver. Alveolar type II cells normally main-
tain a concentration in the epithelial lining fluid > 80 times that found in the plasma.
400 p < 0.05

41
c
:s
0
300
~~
'O>::l.
cui'
0\Vl
200
"''-'
>-
..!2
en 100
c
::1
-'
0
Ethanol None
Fig. 2. levels of glutathione (GSH) in the lung lavage fluid of rats fed on a standard control diet with or
without ethanol (20% v/v in water). Adapted from [33]
p < 0.05
T
100
=
J:';;;'
Vl
u
-"' 41
~"0
u~
- ......
-; 0 so
c.E
~..s
Ethanol None
Fig. 3. levels of glutathione (GSH) in alveolar type II cells isolated from rats fed on a standard control
diet with or without ethanol (20% v/v in water). Adapted from [33]
ARDS is characterized by oxidant stress to the lung, and GSH represents an important
anti-oxidant in the human body. It follows that an inadequate supply of GSH to the
lung may render these patients more likely to develop ALI.
To support this hypothesis, we examined the effects of chronic alcohol consump-
tion on an in vivo rat model. When rats were fed a diet containing 20% v/v etha-
nol, GSH levels in the plasma, lung tissue, and lung lavage fluid were significantly
decreased, with a large percentage of the remaining GSH present in its oxidized
form (Fig. 2). Additionally, the chronic alcohol diet appeared to deplete alveolar
type II cell GSH concentration (Fig. 3), and decrease the synthesis and secretion of
surfactant by these cells. Furthermore, the viability of alveolar type II cells was re-
duced [33].
A central feature of alcohol-induced liver disease is the inhibition of GSH trans-

port from the cytosol to the mitochondria within hepatocytes. GSH transport may
similarly be impaired in alveolar type II cells, as demonstrated in a study examin-
ing rats chronically fed alcohol. These animals exhibited depletion of their mito-
chondrial GSH within alveolar type II cells. Additionally, TNF-a induced generation
of mitochondrial ROS and apoptosis were enhanced. These activities could be nor-
malized by the addition of GSH replacement therapy when this was added to the
rats' die~ [31].
Additional investigation using an in vivo rat model of chronic alcohol abuse ex-
amined rats fed a liquid diet containing 36% of caloric intake from ethanol for 6
weeks. Net vectorial fluid transport across the alveolar epithelium decreased, while
bidirectional protein permeability increased in the alcoholic animals compared with
controls. These findings are indicative of impaired alveolar liquid clearance and in-
creased alveolar epithelial permeability to protein. Treatment of these alcoholic ani-
mals with the GSH precursor, L-2-oxothiaxolidine-4-carboxylate, normalized GSH
levels in alveolar epithelial cells and epithelial lining fluid, and appeared to help
maintain alveolar epithelial barrier function [34].
Examining the effects of chronic alcohol on sepsis in animal models has been
revealing. In the lungs of rats fed a diet of ethanol (20% in water for > 3 weeks)
then given endotoxin (2 mg/kg peritoneally), a significantly greater hydrostatic
weight gain was observed when compared to controls, indicating pulmonary edema
formation. When the septic, alcohol-fed rats were treated with the GSH precursors
S-adenosyl-L-methionine and N-acetylcysteine (GSH precursors) in the final week
of their ethanol ingestion, the development oflung edema was ameliorated [33].
Matrix metalloproteinases (MMPs) are enzymes that contribute to the develop-
ment of ALI through degradation of the extracellular matrix. The activity of MMPs
is influenced by GSH homeostasis. We hypothesized that the abnormal GSH
homeostasis seen in chronic alcoholics may increase MMP activity· within the
alveolar epithelial space [35], leading to damage of the extracellular matrix during
sepsis. In a septic rat model of chronic alcohol consumption [35], MMP-9 and
MMP-2 activity within the lungs was increased. Elevated levels of the 7S fragment
of type IV collagen were also present in the lung lavage fluid of the ethanol-fed
rats, suggesting increased degradation of the alveolar epithelium. The administra-
tion of a GSH supplement significantly increased lung GSH levels, blocked MMP-9
and MMP-2 activation, and decreased levels of the 7S fragment of type IV collagen
in these ethanol-fed septic animals. These findings in septic animal models suggest
that GSH may have a vital role in protecting the lung from the oxidative damage
associated with sepsis, and also allude to possible treatment modalities for ALI and
ARDS.
Mechanisms of Disease Related to Alcoholism
The effects of chronic alcohol abuse on pulmonary GSH homeostasis and alveolar
permeability have also been examined in humans. A recent study examined plasma
and bronchoalveolar lavage (BAL) fluid from otherwise healthy alcoholics (normal
liver function tests, spirometry, and chest radiographs). GSH in both its reduced
and oxidized (GSSG) forms were measured in blood and epithelial lining fluid (de-
termined from the BAL fluid). Although GSH levels were decreased only slightly in
plasma, the concentration of reduced GSH in epithelial lining fluid was dramati-
94 E.l. Burnham et al.
cally decreased in alcoholic patients compared with controls. In contrast to this,

the percentage of GSH present as GSSG was elevated, indicating increased utiliza-
tion of an already diminished store of GSH [36]. Recent data show that the de-
crease in GSH appears to persist in the alcoholic patients despite a week of absti-
nence from alcohol [37]. Additionally, increased levels of total protein present in
the epithelial lining fluid of the alcoholic patients are increased when compared
with controls. These findings may indicate a relationship between the abnormality
in GSH homeostasis and alveolar epithelial permeability in humans, and are consis-
tent with the observation that alcoholic ARDS patients have significantly greater ex-
travascular lung water than non-alcoholic ARDS patients [38].
ALI is characterized by neutrophil activation with the release of oxygen-free rad-
icals. The production of these compounds may play a role in the pathophysiology
of this disorder. As mentioned previously, the concentration of oxidized glutathione
is significantly elevated in individuals who abuse alcohol chronically, despite a peri-
od of abstinence, perhaps signifying on-going oxidative stress. We recently mea-
sured hydrogen peroxide levels from the lavage fluid of chronic alcoholic patients
and found the level of this oxygen-free radical to be significantly higher when com-
pared to the level measured in control patients, indicating the occurrence of oxida-
tive stress without overt disease (Burnham et al., unpublished data).
1 Conclusion
Alcohol is a common drug of abuse that can adversely alter the immune system
through a variety of mechanisms, causing an increased risk of infection among
individuals who abuse this substance. Its use has been implicated in injuries such
as trauma and burns, where it may exacerbate already abnormal immune function-
ing elicited by these injuries. Alcoholism is a contributing factor causally in sepsis,
and also leads to more adverse outcomes from sepsis. A variety of organs are af-
fected by this drug, including ones not usually thought of as being prone to alco-
hol's deleterious effects, such as the lung. Alcoholics are believed to be susceptible
to the development of ARDS secondary to their decreased levels of pulmonary
GSH. GSH replacement has been used therapeutically in ARDS patients with en-
couraging results. The role of GSH replacement in the treatment of alcohol-related
ARDS is presently not known. The mechanisms behind these abnormalities are
myriad, and have only recently begun to be elucidated, mostly in animal models.
Outcomes of sepsis in alcoholic patients remain poor; however, with new ap-
proaches to treating what are perhaps fundamental abnormalities on the cellular
level in these patients, there is hope for better therapy in the future.
References
1. Lieber CS {1995) Medical disorders of alcoholism. N Engl J Med 333:1058-1065
2. Moss M {2001) The role of alcohol in severe pneumonia and acute lung injury. In: Rello J,
Leeper KV (eds) Severe Community Acquired Pneumonia. Kluwer Publishers, Boston, pp
119-138
3. Adams WL, Yuan Z, Barboriak JJ, et al (1993) Alcohol-related hospitalizations of elderly
people. Prevalence and geographic variation in the United States. JAMA 270:1222-1225
4. Spies C, Neuner B, Neumann T, et al {1996) Intercurrent complications in chronic alcoholic
men admitted to the intensive care unit following trauma. Intensive Care Med 22:286-293
5. Baldwin WA, Rosenfeld BA, Breslow MJ, Buchman TG, Deutschman CS, Moore RD (1993}
Substance abuse-related admissions to adult intensive care. Chest 103:21-25
6. Napolitano LM, Koruda MJ, Zimmerman K, McKowan K, Chang J, Meyer AA (1995}
Chronic ethanol intake and burn injury: Evidence for synergistic alteration in gut and im-
mune integrity. J Trauma 38:198-207
7. Burch GE, DePasquale (1967) Alcoholic lung disease - an hypothesis. Am Heart J 73:147-148
8. Bone RC, Fisher CJ, Clemmer TP, Slotman GJ, Metz CA, Balk RA (1989) Sepsis syndrome:
A valid clinical entity. Methylprednisolone Severe Sepsis Study Group. Crit Care Med
17:389-393
9. Mason CM, Dobard E, Kolls J, Nelson S (1998} Effect of alcohol on bacterial translocation
in rats. Alcohol Clin Exp Res 22:1640-1645
10. Nelson S, Bagby G, Summer WR (1989} Alcohol suppresses lipopolysaccharide-induced tu-
mor necrosis factor activity in serum and lung. Life Sci 44:673-676
11. Nelson S, Bagby G, Andreson J, Nakamura C, Shellito J, Summer W (1991} The effects of
ethanol, tumor necrosis factor, and granulocyte-colony stimulating factor on lung antimi-
crobial defenses. Adv Exp Med Bioi 288:245-253
12. Omidvari K, Casey R, Nelson S, Olariu R, Shellito JE (1998} Alveolar macrophage release
of tumor necrosis factor alpha in chronic alcoholics without liver disease. Alcohol Clin
Exp Res 22:567-572
13. Perlino CA, Rimland D (1985} Alcoholism, leukopenia, and pneumococcal sepsis. Am Rev
Respir Dis 132:757-760
14. Spagnuolo PJ, MacGregor RR (1975) Acute ethanol effect on chemotaxis and other compo-
nents of host defense. J Lab Clin Med 86:24-31
15. Coonrod JD, Lester RL, Hsu LC (1984} Characterization of the extracellular bactericidal
factors of rat alveolar lining material. J Clin Invest 74:1269-1279
16. Baughman RP, Roselle GA (1987} Surfactant deficiency with decreased opsonic activity in
a guinea pig model of alcoholism. Alcohol Clin Exp Res 11:261-264
17. Rubins JB, Charboneau D, Prigge W, Mellencamp MA (1996} Ethanol ingestion reduced
anti-pneumococcal activity of rat pulmonary surfactant. J Infect Dis 174:507-512
18. Keshavarzian A, Fields J, Vaeth J, Holmes EW (1994} The differing effects of acute and
chronic alcohol on gastric and intestinal permeability. Am J Gastroenterol 89:2205-2211
19. Rush B (1943} An inquiry into the effects of ardent spirits upon the human body and
mind. Q J Stud Alcohol 4:321-341
20. Osler W (1905) The Principles and Practices of Medicine. Appleton, New York
21. Saitz R, Ghali W, Moskowitz M (1997} The impact of alcohol-related diagnoses on pneu-
monia outcomes. Arch Intern Med 157:1446-1452
22. Carpenter JL, Huang DY (1991} Community-acquired pulmonary infections in a public
municipal hospital in the 1980s. South Med J 84:299-306
23. Szabo G (1999} Consequences of alcohol consumption on host defense. Alcohol Alcohol
34:830-841
24. Mufson MA, Kruss DM, Wasil RE, Metzger WI (1974} Capsular types and outcome of bac-
teremic pneumococcal disease in the antibiotic era. Arch Intern Med 134:505-510
25. Fine MJ, Smith MA, Carson CA, et al (1996} Prognosis and outcomes of patients with com-
munity-acquired pneumonia: A meta-analysis. JAMA 275:134-141
26. Spies CD, Kissner M, Neumann T, et al (1998} Elevated carbohydrate-deficient transferrin
predicts prolonged intensive care unit stay in traumatized men. Alcohol Alcohol 33:661-
669
27. Spies CD, Nordmann A, Brummer G, et a! (1996) Intensive care unit stay is prolonged in
chronic alcoholic men following resection of the upper digestive tract. Acta Anaesthesiol
Scand 40:649-656
28. Pine RW, Wertz MJ, Lennard ES, Dellinger EP, Carrico CJ, Minshew BH (1983) Determi-
nants of organ malfunction or death in patients with intra-abdominal sepsis. A discrimi-
nant analysis. Arch Surg 118:242-249
29. Jurkovich GJ, Rivara FP, Gurney JG, et a! (1993} The effect of acute alcohol intoxication
and chronic alcohol abuse on outcome from trauma. JAMA 270:51-56
30. Moss M, Bucher B, Moore F, Moore EE, Parsons PE (1996} The role of chronic alcohol abuse
in the development of acute respiratory distress syndrome in adults. JAMA 275:50-54
96 E.l. Burnham et al.: The Effect of Alcohol Consumption on Risk for Sepsis and ARDS
31. Brown LA, Harris FL, Guidot DM (2001) Chronic ethanol ingestion potentiates TNF-alpha-
mediated oxidative stress and apoptosis in rat type II cells. Am J Physiol281:L377-386
32. Lieber CS (1993) Biochemical factors in alcoholic liver disease. Semin Liver Dis 13:136-153
33. Holguin F, Moss I, Brown LA, Guidot GM (1998) Chronic ethanol ingestion impairs alveo-
lar type II cell glutathione homeostasis and function and predisposes to endotoxin-
mediated acute edematous lung injury in rats. J Clin Invest 101:761-768
34. Guidot DM, Modelska K, Lois M, et al (2000) Ethanol ingestion via glutathione depletion
impairs alveolar epithelial barrier function in rats. Am J Physiol279:L127-135
35. Lois M, Brown LA, Moss IM, Roman J, Guidot DM (1999) Ethanol ingestion increases acti-
vation of matrix metalloproteinases in rat lungs during acute endotoxemia. Am J Respir
Crit Care Med 160:1354-1360
36. Moss M, Guidot DM, Wong-Lambertina M, Ten Hoor T, Perez RL, Brown LA (2000) The
effects of chronic alcohol abuse on pulmonary glutathione homeostasis. Am J Respir Crit
Care Med 161:414-419
37. Burnham EL, Brown LAS, Eaton S, et al (2001) Prolonged glutathione deficiency and in-
creased total protein concentrations in epithelial lining fluid of chronic alcoholics. Am J
Respir Crit Care Med 163:A816 (abst)
38. Eaton S, Moss IM, Martin GS (2002) Extravascular lung water correlates with oxygenation
and lung injury in patients with severe sepsis. Am J Respir Crit Care Med 165:A712 (abst)
Supplementing Arginine during Sepsis:
from Theory to Clinical Practice
M. Poeze and M. J. Bruins
I Introduction
Arginine has important roles in the transport, storage, and excretion of nitrogen by
disposition of ammonia via the urea cycle. Moreover, arginine is pivotal in
metabolic functions since it serves as a precursor of nitric oxide (NO}, polyamines,
and other molecules. Humans obtain arginine from dietary sources and by endo-
genous synthesis. In humans, arginine is considered a conditionally essential amino
acid since stress conditions with increased arginine demand such as sepsis and
inflammation indicate that exogenous arginine is required for a positive nitrogen
balance.
Although arginine was initially considered important with respect to its nitrogen
retaining capacity [1], renewed interest in supplementation of arginine during sep-
sis and inflammation was initiated with respect to its precursor function for NO
[2]. During sepsis and inflammation, profound changes are induced by excess for-
mation of NO from arginine by the inducible NO synthase enzyme (iNOS). This
excess production of NO is thought to contribute importantly to the systemic hypo-
tension and vascular hyporeactivity in sepsis [3]. Initially, promotion of NO by ar-
ginine supplementation was, therefore, assumed to worsen the hypotension during
sepsis and septic shock, whereas inhibition of NO synthesis by NOS inhibitors was
thought to improve the hemodynamics during sepsis.
Besides its function in vascular dilatation, NO is also pivotal for certain cellular
functions, such as neurotransmisson [4] and immune defense [5]. Recent trials
demonstrated disturbed hepatosplanchnic function and increased mortality during
inhibition of NO synthesis [6] in sepsis pointing to an important role of NO in
blood flow and splanchnic perfusion. Impaired NO synthesis was associated with
reduced splanchnic perfusion. Arginine may become rate limiting, as substrate for
the synthesis of NO and increased arginine availability (concentration) was found
to increase the NO production rate [7]. Reduced arginine levels have been found in
patients after trauma, surgery, and during sepsis [8].
By producing NO in the iNOS pathway, arginine is thought to exert an important
antimicrobial role during sepsis [9], not only as a precursor of NO, but also as a pre-
cursor of the polyamines putrescine, spermine, and spermidine. Whereas intracellular
polyamines are essential for cell activation and proliferation, exogenous polyamines
have been implicated in reducing the hyperinflammation during sepsis [10].
L-arginine administration has been found to be beneficial in improving repro-
ductive, cardiovascular, pulmonary, renal, gastrointestinal, liver, and immune func-
tions, and in facilitating wound healing [11]. This chapter will focus on the role of
arginine during sepsis and septic shock. It will address the effects of sepsis on the
98 M. Poeze and M. J. Bruins
metabolism of arginine and will discuss the effects of supplementing arginine dur-
ing sepsis and inflammation, both in experimental and clinical studies.
Arginine Requirements and Homeostasis
Arginine Requirements
Arginine is considered an indispensable amino acid in carnivores [12] and a condi-
tionally indispensable amino acid in omnivores [13]. A conditionally indispensable
amino acid is defined as an amino acid that becomes indispensable when de novo
capacities of synthesis are insufficient to cover increased needs occurring for exam-
ple during growth [14] or in response to stress conditions such as trauma and sep-
sis [15]. Arginine requirements also depend on species-related enzyme distribu-
tions. Dietary arginine is required for young growing species like dogs, cats, rab-
bits, guinea pigs, rats and pigs [16] because the biosynthesis of endogenous argi-
nine is not capable of meeting the arginine need. In humans with arginine-re-
stricted diets, intestinal citrulline production from glutamine is sufficient to pro-
vide enough arginine to sustain growth [17], although not enough for optimal
growth [16].
Arginine is an intermediate of the urea cycle and serves as a precursor for the
synthesis of proteins, NO, agmatine, creatine and polyamines, and as an intermedi-
ate in the detoxification of ammonia. Of these, protein, creatine and urea synthesis
are quantitatively most important. In growth and metabolic stress conditions, the
requirements for arginine as a precursor in these pivotal metabolic processes are
expected to be elevated.
Arginine Homeostasis
Whole body arginine derives from dietary intake, endogenous protein degradation
and de novo synthesis. The kidney plays a major role in the maintenance of argi-
nine homeostasis [18] by newly synthesizing arginine from citrulline [19] that, in
turn, is formed in the intestine from glutamine and proline [20]. The arginine bio-
synthesis capacity in humans only amounts to approximately 20% of the daily ex-
penditure [20]. In response to starvation and low arginine levels, the kidney is cap-
able of upregulating the arginine synthesizing enzymes, argininosuccinate synthase
and argininosuccinate lyase, as an adaptive response to maintain plasma arginine
levels in response to starvation and low arginine levels [21]. Although the rate of
citrulline to arginine transfer was initially thought to depend on arginine levels
[22], Castillo et al. postulated that the rate of de novo arginine synthesis was inde-
pendent of arginine content in the diet [23]. Under stress conditions such as trau-
ma and sepsis, the muscle becomes an important source of circulating arginine.
Under catabolic conditions, by definition more protein is degraded than synthe-
sized and, as a consequence, arginine appearance is increased providing an impor-
tant source of circulating arginine [24].
Maintenance of plasma arginine levels depends on the rate of protein degrada-
tion rather than on the rate of de novo synthesis [25]. When, under sustained stress
conditions, arginine utilization exceeds the endogenous production, the latter may
become insufficient to meet the elevated requirements and to maintain constant ar-
ginine levels. After liver transplantation for ornithine transcarbamoylase deficiency,
Supplementing Arginine during Sepsis: from Theory to Clinical Practice 99
plasma citrulline levels still remain low, whereas after transplantation for arginino-
succinate synthase deficiency, plasma citrulline levels remain high and arginine lev-
els low [26]. These findings indicate that endogenous routes for arginine produc-
tion cannot fully compensate arginine deficiency.
I Effects of Sepsis and Inflammation

Arginine Metabolism
During sepsis and inflammation, profound changes in metabolic and cardiovascular
function are induced by a variety of mediators, including endotoxin and various
cytokines, and secondary induction of hormones. One of the main features of sep-
sis is the rapid breakdown of protein, specifically in the muscle resulting in acceler-
ated arginine appearance at the whole-body level. Increased arginine appearance is
predominantly the result of increased protein catabolism in the skeletal muscle,
which is a prominent feature of the metabolic response to inflammatory stimuli
[27, 28]. Arginine derived from induced muscle breakdown was found to predomi-
nantly ("' 70-80%) account for the arginine appearing at the whole-body level un-
der normal and septic conditions. Accelerated arginine degradation also contributes
substantially to accelerated arginine turnover at the whole-body level under septic
conditions. Inflammatory stimuli such as endotoxin and cytokines contribute to
elevated arginine utilization under infectious conditions by accelerating the flux
through the urea cycle and NOS pathway [29, 30]. The increased flux through the
NOS and, to a larger extent, arginase pathways by inflammatory stimuli such as en-
dotoxin and cytokines may, in the long run, contribute to the frequently observed
arginine depletion of plasma arginine levels. In a previous study, we demonstrated
increased arginine utilization by the portal-drained viscera and liver during hyper-
dynamic endotoxemia. Moreover, unpublished results suggest that the renal argi-
nine utilization may be elevated as well under endotoxemic conditions. Increased
arginine utilization, ornithine efflux, and urea production by the kidneys is likely
to represent arginine degradation by the inducible non-hepatic arginase (arginase-
11) [31, 32]. The increased renal arginine utilization during endotoxemia may also
represent increased creatine synthesis from arginine and glycine, which is sup-
ported by the observation that renal glycine uptake increased. Creatine synthesis
accounts for a considerable portion of arginine catabolism [13]. In endo toxemic
pigs, the hindquarter (mainly muscle) was the main supplier of arginine deriving
from accelerated protein degradation. During recovery from endotoxemia, one and
five days after cessation of endotoxin challenge and during feeding, arginine release
from the hindquarter was still continued but arginine consumption by the hind-
quarter was even higher, resulting in net arginine influx into this organ.
In endotoxin-treated rats [33-35], pigs [24] (from 120 to 70 ~). and septic hu-
mans [36], reduced plasma concentrations of arginine were found indicating that,
despite increased whole-body arginine production, this arginine does not match
the increased whole-body arginine utilization.
Hemodynamic Effects
Sepsis-associated endotoxins and cytokines induce excess production of NO by
iNOS in a wide variety of cells resulting in high NO production rates. Expression
of iNOS mRNA occurs 2 to 6 hours after induction [37-40] while the iNOS protein
may still be present up to 24 h after stimulation [39]. The role of iNOS-mediated
NO production in the altered hemodynamics observed during sepsis and septic
shock has been a subject of intensive debate. The excessive production of NO by
iNOS has been attributed a harmful role in the development of septic shock by con-
tributing to the hypotension, cardiodepression, and vascular hyporeactivity (41]
through the mechanism of vascular smooth muscle relaxation and vasodilatation.
During episodes of shock, cardiac output tends to decrease to below the normal
range while systemic vascular resistance (SVR) remains abnormally low [42]. In
contrast, hyperdynamic or compensated sepsis is characterized by a hemodynamic
proflle with increased cardiac output and low SVR. In contrast to the impaired
blood flow to the myocardium and central organs characteristic of hypodynamic
sepsis, in hyperdynamic sepsis regional blood flow to these organs is maintained
or increased (43]. By mediating vasodilatation, NO synthesis may preserve organ
perfusion during endotoxemia or sepsis. Therefore, although excessive iNOS-in-
duced NO may cause hypotension in septic shock, it may be crucial in the mainte-
nance of microcirculatory blood flow to the pivotal organs in hyperdynamic sepsis.
In this respect, at a time of sufficient availability, arginine supplementation was
proposed to be detrimental, whereas at times of decreased availability, arginine
may protect against organ injury by controlling blood flow to the organs.
Immunologic Effects
In some cells, including macrophages, NO appears to be an important mediator in
immune defense against invading bacteria [44]. Macrophages effect their antimicro-
bial activity principally through induction of iNOS and the subsequent generation
of NO and oxidants (45, 46]. The radicals that are generated by the massive release
of NO in the cascade reaction have a cytotoxic effect and are responsible for bacte-
rial killing but also for tissue damage associated with inflammation. This cytotoxic
property of NO constitutes a primary mechanism of non-specific immune defense
against microorganisms [47, 48]. Moreover, the suppression by sustained NO pro-
duction on lymphocyte proliferation [45] contributes to an immunosuppressive ef-
fect of NO during sepsis. NO, therefore, occupies a key position in regulation of
immune function, thereby having a dual role by both limiting infection and induc-
ing tissue injury.
I Effects of Supplementing Arginine during Sepsis and Inflammation
Metabolic Effects
Addition of arginine in the diet has been shown to reduce or improve impaired
nitrogen balance in septic, surgical, and trauma patients [49-51]. In a study by Bar-
bul et al. trauma induced a significant negative cumulative nitrogen balance, while
arginine supplementation induced a highly positive balance [51]. Cerra et al.
showed that during arginine supplementation nitrogen retention could be achieved,
but this was also the case in the control ICU patients in this randomized clinical
trial [52]. However, arginine supplementation improved visceral protein status and
in vitro lymphocyte proliferative response. In another randomized trial in porcine
sepsis, arginine supplementation could not increase nitrogen balance [53]. In con-
trast Daly et al. demonstrated a positive nitrogen balance in the arginine supple-
mented group in surgical patients [54].
As mentioned above, beneficial effects of arginine supplementation on protein
synthesis have also been demonstrated. Our research group demonstrated that L-ar-
ginine supplementation during endotoxemia caused decreased protein turnover in
the liver [55]. Liver protein synthesis and breakdown were reduced without affect-
ing the protein net balance of the liver. This was confirmed by Frederick et al. who
demonstrated an inhibition of the increase in hepatic protein synthesis during en-
dotoxemia using a NO blocker [56]. Whole-body protein synthesis was significantly
increased during arginine feeding in protein-starved chicks [57].
Arginine supplementation also has significant effects on NO synthesis. Substan-
tial indirect evidence indicates that arginine supplementation can increase systemic
NO production, for example by measuring the metabolic stable end-products ni-
trite and nitrate (NOx). In kidney transplantation, L-arginine improved urinary
NOx excretion [58]. Moreover, L-arginine infusion in children increased plasma L-
citrulline levels, suggesting increased NO production [59]. Direct evidence of in-
creased NO production comes from our model of stable isotope infusion [60]. Argi-
nine infusion resulted in increased whole-body NO synthesis [61]. Moreover, the
arginine intervention significantly increased NO synthesis in the portal-drained vis-
cera, liver and kidneys.
Hemodynamic Effects
Endothelial production of NO in the vascular wall exerts important physiological
functions, such as vasodilatation, anticoagulation, leukocyte adhesion, smooth mus-
cle proliferation, and anti-oxidative capacity. The results indicating a vasoprotective
effect of NO were not primarily derived from arginine supplementation studies, but
from experiments studying the inhibition of NO synthesis. NO inhibition during
sepsis decreased hepatic [62] and renal [63] blood flow and reduced splanchnic tis-
sue perfusion [64]. In a study by Saetre et al. [65] the non-specific NOS inhibitor
N(G)-nitro-L-arginine-methyl-ester (L-NAME) reduced hepatic oxygen delivery and
liver blood flow. It was shown that arginine-induced vasodilatation, when restricted
to local, microvascular regions, may enhance local perfusion (microcirculation). Ac-
cordingly, Buwalda and Ince [66] found that infusing nitroglycerine increased the
microcirculatory flow, which was reduced during septic shock.
On the other hand, the release of large amounts of NO may cause systemic vaso-
dilatation. Preliminary data from our center indicate that systemic infusion of L-ar-
ginine {3 mglkg!h) as pretreatment during porcine endotoxemia did not lower
mean arterial pressure (MAP) significantly, although global oxygen delivery and
cardiac output were increased [Poeze, unpublished results]. In a study in septic pa-
tients, a single primed intravenous dose of arginine (200 mglkg) induced hypoten-
sion, although this effect of arginine ceased after 10-15 min [67]. Whether long-
term infusion is detrimental to the hemodynamics of septic patients remains to be
established.
During ischemia-reperfusion injury the beneficial role of arginine is less contro-
versial. Arginine as pre-treatment before intestinal ischemia is beneficial in reduc-
ing intestinal mucosal injury [68]. Moreover, the reperfusion damage after intestinal
ischemia-reperfusion injury is attenuated using arginine supplementation [69]. Ar-
ginine was also associated with an improved mucosal permeability of the gut after
massive intestinal resection [70]. Several experimental studies indicated improve-
ment of the glomera! filtration rate by arginine after renal ischemia-reperfusion in-
jury. Renal function may also be improved by arginine in human kidney transplan-
tation [57]. Arginine infusion during coronary bypass surgery significantly de-
creased troponin levels and tended to increase the cardiac index [71]. In a study by
Szabo et al. [72] arginine infusion significantly improved myocardial blood flow, re-
covery of systolic function and myocardial relaxation after coronary artery bypass
graft surgery. Moreover, arginine infusion improved endothelial dysfunction both
in the early and late phases after reperfusion [73]. Ischemia-reperfusion injury is
an important phenomenon during sepsis [74]. Ischemia-reperfusion in the micro-
circulation of the gut plays an important role in the development and deterioration
of the sepsis syndrome. These studies suggest that arginine supplementation may
improve ischemia-reperfusion injury in septic patients.
Immunological Effects
Current evidence indicates that arginine enhances the depressed immune response
of patients suffering from trauma, surgery, malnutrition or sepsis. In experimental
studies, arginine was shown to improve arginine concentrations in the jejunum.
During experimental inflammation of the intestine, iNOS expression induced re-
duced granulocyte infiltration [75]. A supply of arginine was found to increase the
thymic weight and the response of T-lymphocytes [76]. Rats receiving arginine-
supplemented nutrition showed an increased ability to synthesize acute-phase pro-
teins when challenged with endotoxin [77]. Although our study group did not find
an increased acute-phase response during arginine supplementation in porcine en-
dotoxemia, as indicated by unchanged a 1 antitrypsin, haptoglobin and fibrinogen
levels, the net hepatic protein synthesis was decreased [55]. In a study by Trepaske
et al. [78], oral arginine supplementation improved delayed-type hypersensitivity
response to recall antigens and lowered interleukin (IL}-6 concentrations. Carrier et
al. [79] found that arginine reduced the release of biochemical markers of myocar-
dial damage and tended to lower intensive care unit (ICU) and hospital stay.
Many clinical trials have evaluated the use of arginine as an immuno-modulating
agent in patients with trauma, cancer or critical illness. A number of meta-analyses
have been published regarding the so-called 'immunonutrition', which includes
arginine supplementation. The most recent meta-analysis by Heyland et al. [80]
found that the treatment effect of immuno-nutrition in surgical and trauma
patients was different than the treatment effect in septic patients. However, there
are several shortcomings in the designs of a large number of included studies.
Many trials did not compare arginine infusion with an isocaloric and isonitrogen-
ous control infusion. Interestingly, in this meta-analysis a tendency towards a lower
mortality was found on post-hoc analysis in the studies using these high-arginine
content formulas [80]. In addition, a significant lower infection rate and shorter
length of hospital stay were found in the high-arginine content groups [80]. How-
ever, these immuno-nutritions are usually a combination of .Qrunsaturated fatty
acids, glutamine, and arginine, making it difficult to distill the effect of arginine as
such.
I Conclusion
Results of all these studies indicate that arginine is required for a number of criti-
cal conditions and that arginine supplementation may even be beneficial under se-
vere and sustained stress conditions. Reduced arginine availability during stress
conditions such as surgery and ischemia-reperfusion is associated with increased
risk of infection and multiple organ failure, and may be treated by supplementing
arginine. On the other hand, also during conditions with excess NO production, ar-
ginine supplementation may be beneficial. Thus far, inhibition of NO production
during sepsis by using NOS inhibitors (both selective and non-selective) has pro-
duced conflicting results. Enhanced NO production during sepsis or septic shock
may protect the microcirculation from prolonged ischemia, induced by, e.g., hypo-
volemia or prolonged use of vasopressors during septic shock which are often ag-
gravated by reduced arginine availability. The effect of arginine in treating many
common diseases is unique among amino acids, and arginine supplementation of-
fers great promise with respect to its capacity to improve stress conditions such as
sepsis. However, further studies regarding the effects of arginine supplementation
during sepsis are necessary.
I References
1. Beaumier L, Castillo L, Yu YM, Ajami A, Young VR (1996) Arginine: new and exciting de-
velopments for an "old" amino-acid. Biomed Environ Sci 9:296-315
2. Kelly E, Morris SM Jr, Billiar TR (1995) Nitric oxide, sepsis, and arginine metabolism. J
Parent·Enteral Nutr 19:234-238 ·
3. Szabo C, Thiemermann C (1994) Invited opinion: role of nitric oxide in hemorrhagic, trau-
matic, and anaphylactic shock and thermal injury. Shock 2:145-155
4. Wiesinger H (2001) Arginine metabolism and the synthesis of nitric oxide in the nervous
system. Prog Neurobiol 64:365-391
5. Cifone MG, Cironi L, Meccia MA, et al (1995) Role of nitric oxide in cell-mediated tumor
cytotoxicity. Adv Neuroimmunol 5:443-461
6. Grover R, Lopez A, Lorente JA, et al (1998) Multi-center, randomized, placebo-controlled,
double blind study of the nitric oxide synthase inhibitor 546C88: effect on survival in pa-
tients with septic shock. Crit Care Med 27:A33 (abst)
7. Hattori Y, Kasai K, Gross SS (1999) Cationic amino acid transporter gene expression in
cultured vascular smooth muscle cells and in rats. Am J Physiol 276:H2020-2028
8. Freund H, Atamian S, Holroyde J, Fischer JE (1979) Plasma amino acids as predictors of
the severity and outcome of sepsis. Ann Surg 190:571-576
9. Hibbs JB Jr (1991) Synthesis of nitric oxide from L-arginine: a recently discovered pathway
induced by cytokines with antitumour and antimicrobial activity. Res Immunol142:565-569
10. Johnson ML, Billiar TR (1998) Roles of nitric oxide in surgical infection and sepsis. World
J Surg 22:187-196
11. Wu G, Meininger CJ, Knabe DA, Bazer FW, Rhoads JM (2000) Arginine nutrition in devel-
opment, health and disease. Curr Opin Clin Nutr Metab Care 3:59-66
12. Quemener V, Moulinoux JPH, Bergeron C, et al (1992) Tumour inhibition by polyamine
deprivation. In: Dowling RH, Folsch UR, Loser C (eds) Polyamines in the Gastrointestinal
Tract, 1st edn. Kluwer Academic Press, Lancaster, pp 375-385
13. Visek WJ (1985) Arginine and disease states. J Nutr 115:532-541
14. Visek WJ (1986) Arginine needs, physiological state and usual diets. A reevaluation. J Nutr
116:36-46
15. Hoogenraad N, Totino N, Elmer H, Wraight C, Alewood P, Johns RB (1985) Inhibition of
intestinal citrulline synthesis causes severe growth retardation in rats. Am J Physiol
249:G792-G799
16. Barbul A (1986) Arginine: biochemistry, physiology, and therapeutic implications. J Paren-
ter Enteral Nutr 10:227-238
17. Wakabayashi Y (1985) The glutamate crossway. In: Cynober L (ed) Amino acid metabolism
and therapy in health and nutritional disease. CRC Press, Boca Raton, pp 89-98
18. Jenkinson CP, Grody WW, Cederbaum SD (1996) Comparative properties of arginases.
Comp Biochem Physiol B Biochem Mol Biol114:107-132
19. Dhanakoti SN, Brosnan ME, Herzberg GR, Brosnan JT (1992) Cellular and subcellular loca-
lization of enzymes of arginine metabolism in rat kidney. Biochem J 282:369-375
20. Windmueller HG, Spaeth AE (1981) Source and fate of circulating citrulline. Am J Physiol
241:E473-E480
21. Morris SMJ (1992) Regulation of enzymes of urea and arginine synthesis. Annu Rev Nutr
12:81-101
22. Dhanakoti SN, Brosnan JT, Herzberg GR, Brosnan ME (1990) Renal arginine synthesis:
studies in vitro and in vivo. Am J Physiol 259:E437-E442
23. Castillo L, Ajami A, Branch S, et a! (1994) Plasma arginine kinetics in adult man: response
to an arginine-free diet. Metabolism 43:114-122
24. Bruins MJ, Lamers WH, Soeters PB, Meijer AJ, Deutz NEP (2002) In vivo measurement of
nitric oxide production porcine gut, liver and muscle during hyperdynamic endotoxemia.
Br J Pharmacol137:1225-1236
25. Castillo L, Chapman TE, Sanchez M, eta! (1993) Plasma arginine and citrulline kinetics in
adults given adequate and arginine-free diets. Proc Natl Acad Sci USA 90:7749-7753
26. Rabier D, Narcy C, Bardet J, Parvy P, Saudubray JM, Kamoun P (1991) Arginine remains
an essential amino acid after liver transplantation in urea cycle enzyme deficiencies. J In-
herit Metab Dis 14:277-280
27. Bruins MJ, Soeters PB, Deutz NE (2000) Endotoxemia affects organ protein metabolism dif-
ferently during prolonged feeding in pigs. J Nutr 130:3003-3013
28. Gore DC, Jahoor F, Hibbert J, DeMaria EJ (1995) Except for alanine, muscle protein catabo-
lism is not influenced by alterations in glucose metabolism during sepsis. Arch Surg
130:1171-1176
29. Mori M, Gotoh T, Nagasaki A, Takiguchi M, Sonoki T (1998) Regulation of the urea cycle
enzyme genes in nitric oxide synthesis. J Inherit Metab Dis 21:59-71
30. Wang WW, Jenkinson CP, Griscavage JM, et al (1995) Co-induction of arginase and nitric
oxide synthase in murine macrophages activated by lipopolysaccharide. Biochem Biophys
Res Commun 210:1009-1016
31. Chu SW, Nesheim MC (1979) The relationship of plasma arginine and kidney arginase
activity to arginine degradation in chickens. J Nutr 109:1752-1758
32. Gotoh T, Araki M, Mori M (1997) Chromosomal localisation of the human arginase II gene
and tissue distribution of its mRNA. Biochem Biophys Res Commun 233:487-491
33. Lortie MJ, Ishizuka S, Schwartz D, Blantz RC (2000) Bioactive products of arginine in sep-
sis: tissue and plasma composition after LPS and iNOS blockade. Am J Physiol 278:C1191-
1199
34. Desmukh DR, Ghole VS, Marescau B, De Deyn PP {1997) Effect of endotoxemia on plasma
and tissue levels of nitric oxide metabolites and guanidino compounds. Arch Physiol Bio-
chem 105:32-37
35. Roland CR, Nakafusa Y, Flye MW (1999) Gadolinium chloride inhibits lipopolysaccharide-
induced mortality and in vivo prostaglandin E2 release by splenic macrophages. J Gastro-
intest Surg; 3:301-307
36. Freund H, Atamian S, Holroyde J, Fischer JE (1979) Plasma amino acids as predictors of
the severity and outcome of sepsis. Ann Surg 190:571-576
37. Hecker M, Sessa WC, Harris HJ, Anggard EE, Vane JR (1990) The metabolism of L-argi-
nine and its significance for the biosynthesis of endothelium-derived relaxing factor: cul-
tured endothelial cells recycle L-citrulline to L-arginine. Proc Natl Acad Sci USA 87:8612-
8616
38. Morin MJ, Unno N, Rodin RA, Fink MP (1998) Differential expression of inducible nitric
oxide synthase messenger RNA along the longitudinal and crypt-villus axes of the intestine
in endotoxemic rats. Crit Care Med 26:1258-1264
39. Chen K, Inoue M, Okada A (1996) Expression of inducible nitric oxide synthase mRNA in
rat digestive tissues after endotoxin and its role in intestinal mucosal injury. Biochem Bio-
phys Res Commun 224:703-708
40. Tabuchi S, Gotoh T, Miyanaka K, Tomita K, Mori M (2000} Regulation of genes for induci-
ble nitric oxide synthase and urea cycle enzymes in rat liver in endotoxin shock. Biochem
Biophys Res Commun 268:221-224
41. Kirkeboen KA, Strand OA (1999) The role of nitric oxide in sepsis - an overview. Acta
Anaesthesiol Scand 43:275-288
42. Kreimeier U, Brueckner UB, Gerspach S, Veitinger K, Messmer K (1993} A porcine model
of hyperdynamic endotoxemia: pattern of respiratory, macrocirculatory, and regional blood
flow changes. J Invest Surg 6:143-156
43. Green SJ, Nacy CA (1993} Antimicrobial and immunopathologic effects of cytokine-in-
duced nitric oxide synthesis. Curr Opin Infect Dis 6:384-396
44. van der Veen RC (2001) Nitric oxide and T helper cell immunity. Int Immunopharmacol
1:11491-11500
45. Crawford RM, Leiby DA, Green SJ, Nacy CA, Fortier AH, Meltzer MS (1994} Macrophage
activation: a riddle of immunological resistance. Immunol Ser 60:29-46
46. Bastian NR, Hibbs JB Jr (1994) Assembly and regulation of NADPH oxidase and nitric
oxide synthase. Curr Opin Immunol 6:131-139
47. Hibbs JB Jr, Westenfelder C, Taintor R, et al (1992} Evidence for cytokine-inducible nitric
oxide synthesis from L-arginine in patients receiving interleukin-2 therapy. J Clin Invest
89:867-877
48. Chyun JH, Griminger P (1984} Improvement of nitrogen retention by arginine and glycine
supplementation and its relation to collagen synthesis in traumatized mature and aged rats.
J Nutr 114:1697-1704
49. Cui XL, Iwasa Y, Omori A, et al (1999} Effects of dietary arginine supplementation on pro-
tein turnover and tissue protein synthesis in scald-burn rats. Nutrition 15:563-569
50. Pui YM, Fisher H (1979} Factorial supplementation with arginine and glycine on nitrogen
retention and body weight gain in the traumatized rat. J Nutr 109:240-246
51. Barbul A, Wasserkrug HL, Yoshimura N, Tao R, Efron G (1984} High arginine levels in in-
travenous hyperalimentation abrogate post-traumatic immune suppression. J Surg Res
36:620-624
52. Cerra FB, Lehmann S, Konstantinides N, et al (1991} Improvement of immune function in
ICU patients by enteral nutrition supplemented with arginine, RNA and menhaden oil is
independent of nitrogen balance. Nutrition 7:193-219
53. Gonce SJ, Peck MD, Alexander JW, Miskell PW (1990) Arginine supplementation and its ef-
fect on established peritonitis in guinea pigs. J Parenteral Enteral Nutr 14:237-244
54. Daly JM, Lieberman MD, Goldfme J, Shou J, et al (1992} Enteral nutrition with supplemen-
tal arginine, RNA, and omega-3 fatty acids in patients after operation: immunologic, meta-
bolic, and clinical outcome. Surgery 112:56-67
55. Bruins MJ, Soeters PB, Lamers WH, Deutz NE (2002) L-arginine supplementation in pigs
decreases liver protein turnover and increases hindquarter protein turnover both during
and after endotoxemia. Am J Clin Nutr 75:1031-1044
56. Frederick JA, Hasselgren PO, Davis S, Higashiguchi T, Jacob TD, Fischer JE (1993} Nitric
oxide upregulate in vivo hepatic protein synthesis during endotoxernia. Arch Surg 128:152-
156
57. Muramatsu T, Kato M, Tasaki I, Okumura J (1986} Enhanced whole-body protein synthesis
by methionine and arginine supplementation in the protein-starved chicks. Br J Nutr
55:635-641
58. Schramm L, La M, Heidbreder E, et al (2002} L-arginine deficiency and supplementation
in experimental acute renal failure and human kidney transplantation. Kidney 61:1423-
1432
59. Nelin LD, Hoffman GM (2001} L-arginine infusion lowers blood pressure in children. J Pe-
diatr 139:747-749
60. Soeters PB, Hallemeesch MM, Bruins MJ, van Eijk HM, Deutz NE (2002} Quantitative in
vivo assessment of arginine utilization and nitric oxide production in endotoxernia. Am J
Surg 183:480-488
106 M. Poeze and M. J. Bruins: Supplementing Arginine during Sepsis: from Theory to Clinical Practice
61. Bruins MJ, Soeters PB, Lamers WH, Meijer AJ, Deutz NE (2002) L-arginine supplementa-
tion in hyperdynamic endotoxemic pigs: effect on nitric oxide synthesis by the different
organs. Crit Care Med 30:508-517
62. Dahm PL, Thorne J, Myhre E, Grins E, Martensson L, Blomquist S (1999) Intestinal and
hepatic perfusion and metabolism in hypodynamic endotoxic shock. Effects of nitric oxide
synthase inhibition. Acta Anaesthesiol Scan 43:56-63
63. Cohen RI, Hassell AM, Marzouk K, Marini C, Liu SF, Scharf SM (2001) Renal effects of
nitric oxide in endotoxemia. Am J Respir Crit Care Med 15:1890-1895
64. Nishida J, McCuskey RS, McDonnell D, Fox ES (1994) Protective role of NO in hepatic
microcirculatory dysfunction during endotoxemia. Am J Physiol 267:Gll35-1141
65. Saetre T, Gundersen Y, Smiseth OA, et al (1998) Hepatic oxygen metabolism in porcine
endotoxemia: the effect of nitric oxide synthase inhibition. Am J Physiol 275:Gl377-l385
66. Buwalda M, Ince C (2002) Opening the microcirculation: can vasodilators be useful in sep-
sis? Intensive Care Med 28:1208-1217
67. Lorente JA, Landin L, Renes R, et a! (1993) Role of nitric oxide in the hemodynamic
changes of sepsis. Crit Care Med 21:759-767
68. Schleiffer R, Raul F (1996) Prophylactic administration of L-arginine improves the intest-
inal barrier function after mesenteric ischaemia. Gut 39:194-198
69. Warnecke HB, Schirmeier A, Nussler AK, et al (2002) The combined treatment with L-argi-
nine and methylprednisolone improves graft morphology and mucosal barrier function.
Transplant Proc 34:996-998
70. Kubes P (1993) Ischemia-reperfusion in feline small intestine: a role for nitric oxide. Am J
Physiol 264:G143-149
71. Welters CF, Dejong CH, Deutz NE, Heineman E (1999) Effects of parenteral arginine sup-
plementation on the intestinal adaptive response after massive small bowel resection in the
rat. J Surg Res 85:259-266
72. Carrier M, Pellerin M, Perrault LP, et al (2002) Cardioplegic arrest with L-arginine im-
proves myocardial protection: results of a prospective randomized clinical trial. Ann Thor-
ac Surg 73:837-841
73. Szabo G, Biihrle S, Batkai S, et al (1998) L-arginine: effect on reperfusion injury after heart
transplantation. World J Surg 22:791-798
74. Vinten-Johansen J, Zhao ZQ, Nakamura M, et al (1999) Nitric oxide and the vascular en-
dothelium in myocardial ischemia-reperfusion injury. Ann NY Acad Sci 874:354-370
75. Hobbs AJ, Higgs A, Moncada S (1999) Inhibition of nitric oxide synthase as a potential
therapeutic target. Annu Rev Pharmacol Toxicol 39:191-220
76. Barbul A, Returra G, Levenson S (1977) Arginine: thymotropic and wound healing promot-
ing agent. Surg Forum 28:101-103
77. Leon P, Redmond HP, Stein TP, et al (1991) Arginine supplementation improves histone
and acute-phase protein synthesis during gram-negative sepsis in the rat. J Parenter Enteral
Nutr 15:503-508
78. Tepaske R, Velthuis H, Oudemans-van Straaten HM, et al (2001) Effect of preoperative oral
immune-enhancing nutritional supplement on patients at high risk of infection after cardi-
ac surgery: a randomised placebo-controlled trial. Lancet 358:696-701
79. Carrier M, Pellerin M, Perrault LP, et al (2002) Cardioplegic arrest with L-arginine im-
proves myocardial protection: results of a prospective randomized clinical trial. Ann Thor-
ac Surg 73:837-842
80. Heyland DK, Novak F, Drover JW, Jain M, Su X, Suchner U (2001) Should immunonutri-
tion become routine in critically ill patients? A systematic review of the evidence. JAMA
286:944-953
j Coagulation Abnormalities
Severe Thrombotic Microangiopathy
in Critically Ill Patients
F. Pene, Y. E. Claessens, and J.P. Mira
I Introduction
Thrombotic microangiopathies (TMA) are uncommon multisystemic microvascular
occlusive diseases combining various stages of hematological, renal, and neurologi-
cal disorders and characterized by a classical pentad: fever, peripheral thrombocy-
topenia, microangiopathic hemolytic anemia, acute renal failure, and neurological
abnormalities. Treatment with exogenous plasma, either through plasma exchange
or plasma infusion, has dramatically improved the outcome of the disease. How-
ever, most severe patients require monitoring and support in the intensive care unit
(ICU) for organ failures, mainly renal, and neurological disorders. This chapter
provides recent insights into the pathophysiology of the disease and focuses on
treatment management and prognosis of severe TMA.
Clinical Presentations and Etiologies

Two clinical forms of TMA have been described, depending on the predominant or-
gan failure associated with the thrombocytopenia and the hemolytic anemia: the
hemolytic uremic syndrome (HUS) with a predominant renal failure and the
thrombotic thrombocytopenic purpura (TTP) which is characterized by fluctuating
neurological abnormalities such as confusion, focal deficits, seizures, and coma.
However, both syndromes share common features, frequently overlap, and are often
clinically indistinguishable in adult patients. Hence, a prospective study reported
that the frequency and the severity of neurological symptoms are identical in TMA
patients with or without renal failure [1, 2). Recently, some authors proposed that
the classical classification be replaced by a single clinical entity, the TTP/HUS
disorder [3).
Clinical manifestations are the consequences of microvascular thrombotic occlu-
sions and laboratory analyses are necessary to diagnose TMA. These biological fea-
tures reflect hemolysis (decreased haptoglobin level, increased plasma bilirubin
concentration, and high reticulocyte count) with presence of schistocytes and nega-
tive antiglobulin test, and reveal platelet consumption with normal clotting times.
Increased lactate dehydrogenase (LDH) serum level is constant and reflects hemoly-
sis and tissue ischemia. Currently a dyad of both hematological criteria (hemolysis
and thrombocytopenia) without alternative explanation is sufficient to establish a
presumptive diagnosis of TMA and to initiate specific therapy [3).
Various conditions have been implicated in the precipitation of TMA (Table 1).
The classical childhood HUS is observed after a gastro-intestinal infection by a
110 F. Pene et al.
Table 1. Etiologies of thrombotic microangiopathy (TMA)
Infections
I Verotoxin-producing bacteria
- Escherichia coli 0157:Hl
- Shigella dysenteriae serotype 1
- Streptococcus pneumoniae
- Mycobacterium tuberculosis
I Various microorganisms {bacteria, virus, fungi, parasites)
HIV
Multisystemic diseases
I Lupus
I Scleroderma
I Antiphospholipid syndrome
Cancer
Bone marrow transplantation
Drugs
I Antiplatelet agents: ticlopidine, clopidogrel
I Chemotherapy: mitomycine C, gemcitabine, cisplatin
I Immunosuppressive agents: cyclosporin A, tacrolimus
I Quinine
Pregnancy/post-partum
Familial
Unknown
verotoxin-producing bacteria, mostly Escherichia coli 0157:H7, in a vast majority of

cases [4]. Children with diarrhoea-associated HUS spontaneously recover without
any specific TMA treatment and require only short-term renal support by hemodia-
lysis. Adult HUS has been occasionally associated with verotoxin-producing bacte-
ria infection, but the prognosis differs substantially from children, as the adult dis-
ease has a high mortality rate [5]. Besides verotoxin-producing bacteria, various
microorganisms (bacteria, virus, fungi and parasites) have been implicated in the
precipitation of TMA. As an example, TMA is particularly frequent in the context
of human immunodeficiency virus (HIV) infection, accounting for the increasing
incidence of TMA in the last two decades [6]. For all TMA diagnosed in an infec-
tious context, therapeutic modalities are similar and the prognosis is essentially
linked to the underlying disease.
During the course of all neoplastic diseases, TMA can occur either as an adverse
effect of chemotherapy or as a complication of end-stage disease [7]. The latter is
characterized by plasmatherapy resistance and a constant, rapidly fatal outcome.
During pregnancy, pathophysiological, therapeutic and prognostic characteristics
of specific TMA such as eclampsia and HELLP syndrome (acronym for HEmolysis,
Liver enzymes, Low Platelets) are radically different from TTP/HUS despite com-
mon features. Differential diagnosis is unclear and based on the time of onset and
on the improvement of the symptoms after delivery [8].
TMA following bone marrow transplantation (BMT) is often part of a complex
association of infection, graft-versus-host disease, conditioning regimen, and drug
Severe Thrombotic Microangiopathy in Critically Ill Patients 111
toxicity, or relapse of the underlying disease, making the diagnosis inconsistent.

Considering the frequent uncertainty of diagnosis, some authors consider this en-
tity as BMT-related TTP-like syndrome [9]. As for end-stage cancer TMA, and in
contrast to classical TTP/HUS, the outcome of TMA following BMT is poor because
of plasmatherapy resistance.
Finally, idiopathic forms are frequent in adults. Idiopathic TTP is often observed
in young women, as a single resolute episode or chronic relapsing TTP. Familial
cases of TTP are infrequent and appear in childhood, with recurrent evolution (re-
current TTP of children).
I Epidemiology
The incidence of HUS in children is 2.1/100 000/year and represents the most common
etiology of acute renal failure during childhood. In adults, the incidence of TMA is
poorly evaluated but seems to be increasing. Mortality registries in the United States
have provided useful data: between 1968 and 1991, the TMA-related mortality rate in-
creased from 0.4 to 1.1 per million, despite improvement in the prognosis, giving an
estimated incidence of approximately 3.7 cases per million per year [10]. The Amer-
ican and Canadian apheresis registries have also provided interesting data about epi-
demiology. The Canadian Apheresis Group reported a significant increase in the total
number of patients treated with plasma exchange for TMA between 1981 and 1997
(30 vs 206) [11]. Similarly the Oklahoma TTP/HUS registry, which includes about
211 patients with TMA, noted a 7-fold increase in the number ofTMA patients treated
with plasma exchange between 1989 and 2000 [3].
Pathophysiology
Despite the variability of their clinical presentations, TMAs are characterized by
identical histological findings in the microcirculation (arterioles and capillaries):
thickening of the vessel wall, swelling of endothelial cells from the basement mem-
brane in the microvasculature, and occlusion of the microvascular vessel lumina by
thrombi composed of platelets and von Willebrand factor (vWF), but without fi-
brin, in contrast to thrombi observed in disseminated intravascular coagulation
(DIC). Recent advances in the understanding of the pathophysiology of TMA have
highlighted the role of endothelial cell injury and of the vWF-cleaving protease in
triggering platelet aggregation.
Role of the Endothelium

Although histological studies have never found perivascular inflammation or patent
endothelial abnormalities, multiple data implicate endothelial cell injury in the
pathogenesis of TMA. Thus, enhanced endothelial cell apoptosis has been described
in splenic tissues of patients with TTP [12] and autoantibodies directed against en-
dothelial proteins have been detected in TMA plasma [13]. In vitro, plasma of TMA
patients exhibits particular properties towards cultured microvascular endothelial
cells: it can induce their apoptosis [14] and generate pro-coagulant endothelial mi-
croparticles [15].
112 F. Pene et al.
Various agents such as bacterial components, immune complexes or drugs,

known to be potentially responsible for TMA induction, can trigger endothelial cell
activation and injury. For instance, verotoxin, released by bacteria in the gut, gains
the systemic circulation and binds to its specific receptor mainly expressed on the
renal endothelial cell surface, leading to protein synthesis inhibition and cell apop-
tosis [16]. Similarly the Thomsen-Friedenreich antigen that is expressed on platelet
and endothelial cell membrane and usually covered by sialic acid, is exposed after
action of the bacterial neuraminidase produced by Streptococcus pneumoniae, a fre-
quent infectious cause of TMA, particularly in children. As a consequence, pre-
formed circulating IgM bind to the Thomsen-Friedenreich antigen, causing endo-
thelial damage and platelet aggregation [17].
The endothelium may be also injured by numerous anti-cancerous drugs through
the generation of free radicals [7] or by immune complexes through the cytotoxic ef-
fect of complement activation. Moreover, recent data suggest that enhanced activation
of complement may potentiate or sustain autoantibody- or immune complex-
mediated endothelial damage, as a consequence of deficiency of complement factor
H which normally inhibits alternative complement pathway [18].
Role of vWF and the vWF Cleaving Protease

A general consequence of endothelial injury is the release of unusually ultralarge
multimers of vWF, which is a multimeric glycoprotein, synthesized by platelets and
endothelial cells, with an essential role in adhesion and platelet aggregation. Circu-
lating vWF ranges from dimers to polymers of high molecular weight. However, in
normal plasma ultralarge multimers of very high molecular weight are absent due
to physiological cleavage by the recently purified vWF-cleaving protease
ADAMTS13, a member of the ADAMTS metalloprotease family (A Disintegrin And
Metalloproteinase with ThromboSpondin I motif) [19, 20]. Ultralarge vWF multi-
mers have been detected in TMA plasma [21] and their pathogenic role has been
suggested by their ability to induce platelet aggregation more efficiently than nor-
mal multimers, especially in high shear stress condition present in microcirculation
[22].
Deficiency of the protease activity, leading to the intravascular presence of ultra-
large vWF multimers, was initially described in TTP but not in HUS. This deficien-
cy was due to an inhibitory antibody against the enzyme in non-familial cases or
to a mutation within the gene of the protease in familial cases [23-25]. From these
observations, it would be very attractive to conclude that clinical presentations of
TMA, TTP, or HUS may be determined by distinct pathophysiological mechanisms
based on ADAMTS13 activity. However, even if a complete deficit of the protease
activity (< 5%) seems specifically involved in TMA [26], protease activity was
found normal in an important proportion of patients with TTP [23, 24] and in
TTP-like syndrome following BMT [27]. Moreover, recent studies have reported un-
detectable protease activity in patients with pure HUS [28, 29] and reduced levels
of protease activity are measured in various other physiological or pathological
conditions such as pregnancy, liver disease, chronic renal failure, inflammatory sta-
tus, surgery or metastatic cancer, independent of the presence of TMA [30]. In con-
clusion, although the protease activity is not a constant criteria to distinguish TTP
from HUS, it correlates with clinical syndromes in a large proportion of patients
and defines various pathophysiological entities of TMA, that would benefit from
targeted therapies in the future.
I Treatment
No randomized study has compared plasmatherapy and supportive treatment alone
in TMA patients. However, comparison of historical series of TMA patients treated
without or with plasma infusion provide strong evidence that exogenous plasma
leads to a dramatic improvement of the outcome of this pathology [1, 31, 32]. Plas-
matherapy, either through plasma exchange or plasma infusion, is actually the cor-
nerstone of treatment of TMA. Various alternative strategies have been proposed,
essentially when plasmatherapy fails, but no controlled studies support their use as
first-line therapy (Table 2).
Role of Plasma in the Treatment of Thrombotic Microangiopathy

The therapeutic effect of plasma remained unexplained until recently, when a 100%
vWF-cleaving protease activity was detected in fresh frozen plasma and solvent-de-
tergent-treated plasma [33]. Thus, plasma infusion may compensate protease deficit
and neutralize low titres of autoantibodies against ADAMTS13 protease. Consistent
with this explanation, plasma has to be used as a replacement fluid during plasma-
pheresis, as confirmed by the fact that plasma exchange substituted with albumin
and saline is inefficient to treat TMA [34]. Cryosupernatant plasma, which is rela-
tively depleted in high molecular weight vWF multimers, has also been investigated
as replacement fluid during plasma exchange. Remission and survival rates of 61
and 83%, respectively, were obtained in a pilot study of 18 patients refractory to
Table 2. Mechanisms of action and indications of therapies in TMA
Therapeutic modalities Mechanisms of action Indications
Plasma exchange Exogenous compensation First line therapy

of vWF-cleaving protease deficiency
Removal of toxic agents from plasma
Fresh frozen Exogenous compensation Reference therapy
plasma infusion of vWF-cleaving protease deficiency
Antiplatelet agents Inhibition of microthrombi formation Adjunctive therapy if platelet
count > 50000/mm3
Prevention of relapse?
I Corticosteroids Immunosuppressive Adjunctive therapy after
exclusion of evolving infection
I Intravenous Inhibition of platelet aggregation Second line therapy
immunoglobulins
Vinaistine Inhibition of platelet aggregation Second line therapy
Immunosuppressive
I Cydins Treatment of underlying Bortonnella Second line therapy
infection
I Splenectomy Removal of a major site of antibody Chronic relapsing TIP during
synthesis hematological remission
vWF =von Willebrand factor; TTP =thrombotic thrombocytopenic purpura

114 F. Pene et al.
plasma exchange substituted with fresh frozen plasma, and treated by PE replaced
with cryosupernatant. Subsequently, the use of cryosupernatant as a first line thera-
py in 40 patients led to a 75% remission rate and to a 95% survival rate at one-
month and represents a promising therapy in severe TMA [35]. These preliminary
results have to be confirmed by prospective studies.
Plasma Exchange or Plasma Infusion?

Whether the efficacy of plasma exchange is due to a better tolerance to large
amounts of infused plasma remains unclear. The modalities of plasmatherapy have
been evaluated in three comparative studies. A prospective randomized study com-
paring plasma exchange and plasma infusion in 102 patients showed a clear advan-
tage for plasma exchange in terms of clinical response {78 versus 49%, p = 0.002)
and 6-month survival {78 versus 63%, p=0.036) [1]. However, the volume of plas-
ma administered to the patients from the exchange group was 3-fold higher than
for the patients treated with plasma infusion. Results of studies using similar vol-
umes of plasma in plasmapheresis and infusion arms are inconsistent. A French
randomized study concluded that plasma exchange was superior to plasma infusion
[36], whereas a retrospective study showed no difference in terms of remission and
survival [37]. In a retrospective multicenter study including 63 critically ill patients
with severe TMA, we identified the use of plasma exchange as a prognostic factor
of survival in univariate and multivariate analysis [38]. Thus the efficacy and
superiority of plasma exchange in the treatment of TMA is probably mediated by
two distinct mechanisms, according to the pathophysiology of this syndrome: first,
plasmapheresis may remove pathogenic components present in TMA plasma such
as ultralarge multimers of vWF and autoantibodies directed against the ADAMTS13
protease and, second, the large amount of plasma infused during plasma exchange
may compensate the protease deficiency.
Whether plasmatherapy is beneficial during adult HUS remains debated, as re-
covery of renal function is often slow and incomplete. However, published observa-
tions suggested that plasma exchange improves survival in adult patients including
those with renal failure [2]. These reports have been confirmed by Dundas and coli.
who showed that in contrast with the spontaneous recovery of diarrhoea-associated
HUS in children, adult patients with E. coli 0157:H7-induced HUS have high mor-
tality rates and may also benefit from plasma exchange treatment [39, 40].
Currently, plasma exchange remains the reference therapy for TMA, especially in
the most severe cases. Apheresis groups recently edited recommendations for plas-
ma exchange treatment in TMA, consisting of 1 to 2 plasma volume daily plasma-
pheresis, with compensation by either fresh frozen plasma or cryosupernatant.
After improvement of the clinical and biological abnormalities, the frequency of
plasma exchange and/or the volume of plasma infusion must be gradually reduced
until withdrawal [3, 41]. When plasma exchange cannot be used, it has been re-
cently reported in a retrospective study that high-dose plasma infusion (30 mVkg
per day) may be a safe and efficacious treatment [42].
Anti-platelet Agents
Based on histological examinations that found occlusive platelet microthrombi in
small vessels, anti-platelet agents have been widely used in the treatment of TMA,
but their efficacy remains uncertain and seems particularly difficult to evaluate be-
cause of constant association with other TMA-specific therapies. An Italian ran-

domized trial reported a trend towards lower mortality rate in patients treated by
an association of plasma exchange with anti-platelet agents, as compared to pa-
tients treated by plasma exchange alone [43]. Some studies suggested a preventive
role of anti-platelet agents on relapse of TMA. Potential adverse effects of these
drugs, particularly severe hemorragic complications in thrombocytopenic patients,
limit their use to patients with a platelet count >50000/mm3 • Furthermore, some
anti-platelet agents such as ticlopidine and clopidogrel have been implicated in the
precipitation of TMA [44, 45].
Corticosteroids
Steroids have been extensively used in the treatment of TMA and recent advances
in the comprehension of the pathophysiology of TMA have identified a subgroup of
TMA due to immune disorder, providing a rationale for their use. However, in the
absence of randomized study, their place in TMA therapy remains unclear. In a
prospective study, Bell and colleagues demonstrated that prednisone (200 mg per
day) led to a complete remission in 55% (30 of 54) of TMA patients without neuro-
logical symptoms [31] and some authors recommend to add steroids in patients
who respond poorly to plasma exchange [3].
Treatment of Underlying Infections

In our retrospective study of severe TMA patients treated in the ICU, proved sys-
temic infections were present in half of the population [38]. Accordingly, extensive
research of underlying infection should be systematically performed in the context
of TMA, to initiate appropriate anti-microbial therapy besides TMA-specific treat-
ment. In a previous report, the discovery of Bartonnella-like erythrocyte inclusions
in 5 patients with TTP led to the use of cyclins, achieving a remission in 4 of them
[46]. However, antibiotic therapy in cases of diarrhoea-associated HUS deserves
caution. In a prospective study of 71 children with diarrhoea caused by E. coli
0157:H7, antibiotic treatment increased the risk of HUS, potentially by a large re-
lease of verotoxin [47]. A recent meta-analysis however did not confirm these data
and this question remains open [48].
Other Therapeutic Modalities

Alternative agents, which inhibit platelet aggregation (vincristine, intravenous im-
munoglobulins) or decrease the titre of autoantibodies (rituximab, cyclophospha-
mide, immunoadsorption on staphylococcal protein A column, splenectomy), have
been reported as salvage therapies in refractory or recurrent TTP, but their respec-
tive roles remain largely unknown [41]. Anticoagulation therapy is definitely ineffi-
cient and dangerous in these thrombocytopenic patients, despite the presence of
coagulation abnormalities in some subgroups of patients and should be avoided
[49, 50].
Platelet transfusions have been implicated in the worsening of neurological
symptoms of TMA [51]. In a large prospective study, nine patients experienced rap-
id and severe clinical deterioration after platelet transfusion [31]. In another study
on 55 patients with TTP, mortality was significantly higher in the group of patients
116 F. Pene et al.
who received platelets (52% [13 of 25] versus 7% [2 of 30]) [52]. Hence, platelet
transfusion should be strictly limited to patients with active bleeding or requiring
invasive procedures.
I Evolution and Prognosis

Before the demonstration of the efficacy of plasmatherapy, the mortality rate of his-
torical series of TIP was 95%. Plasmatherapy, mainly through plasma exchange,
has dramatically improved the prognosis of this syndrome, with survival rates of
78 to 90% and remission rates of 70% [1, 31, 32]. Relapses occur frequently, com-
monly during the weaning of plasmatherapy, but their incidence is highly variable
from 13 to 64% according to the definitions used for remission and relapse [1, 31,
32, 53, 54].
The outcome from TMA is very unpredictable. Recent advances in the patho-
physiology will probably contribute to a better classification of the diseases and a
better definition of their prognosis. Rose and Eldor proposed a clinical severity
score (CSS) including the four main features of the disease, with a total score rang-
ing from 0 to 8 (Table 3) [53]. In their study, all patients who died, had a score
above 6, whereas all patients with a score of 5 or less survived. This score has been
recently validated in a large retrospective study, where a high score at presentation
(6 or more) was associated with a high risk of death [32]. According to both stud-
ies, a CSS of 6 or above clearly identifies a poor prognosis subgroup of TMA. In a
large retrospective study of severe TMA in the ICU, we included only patients with
CSS ;:::: 6, or a neurological or renal score of 2. In this population, we identified neu-
rological failure as the main prognostic factor of TMA, whereas neither renal failure
nor hemodialysis requirement influenced the outcome [38]. The normalization of
the platelet count and of the LDH rate after 72 hours of plasma exchange has been
reported to be the best predictive factor of long-term remission in a sample of 30
patients with TTP/HUS [55]. In another study, relapse was more frequent in late re-
sponders than in early responders [54]. All these data emphasize the critical role of
early therapy during the first 72 hours, confirming the fact that a long delay in ini-
tiation of plasma exchange is a poor prognostic factor [56].
Table 3. Clinical Severity Score of thrombotic microangiopathy [53)
Score Neurologk Renal abnormalities Platelet count Hemoglobin level

symptoms (per mm3) (g/dl)
0 None None > 100000 >12

Confusion Serum creatinine 120- 250 Jlmol/1 20000-100000 9-12
Proteinuria
Hematuria
2 Seizures Serum creatinine > 250 Jlmol/1 <20000 <9
Coma Hemodialysis
Focal deficits
I Conclusion
Thrombocytopenia is a frequent disorder among critically ill patients, especially in
patients with severe infections. In this context, TMA should be systematically sus-
pected in order to perform appropriate investigations and to promptly initiate spe-
cific therapy besides treatment of underlying condition. Plasmatherapy, either
through plasma exchange or plasma infusion, is the reference treatment of TMA
and alternative therapeutics have to be considered as second-line therapy. The mo-
dalities of plasma exchange concerning volume and frequency of plasma exchanges
as well as weaning strategy remain empirical and based on each patient's particular
course. Despite frequent profound thrombocytopenia, platelet transfusions must be
avoided in TMA patients, because of potential worsening of symptoms. Recent ad-
vances in the comprehension of the mechanisms of the disease will probably lead
to the definition of new prognostic factors and may provide improved treatment
strategies.
References
1. Rock GA, Shumak KH, Buskard NA, et al (1991) Comparison of plasma exchange with
plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian
Apheresis Study Group. N Engl J Med 325:393-397
-2. Rock G, Shumak KH, Kelton J, et al (1992) Thrombotic thrombocytopenic purpura: out-
come in .24 patients with renal impairment treated with plasma exchange. Canadian Apher-
esis Study Group. Transfusion 32:710-714
3. George JN (2000) How I treat patients with thrombotic thrombocytopenic purpura-hemo-
lytic uremic syndrome. Blood 96:1223-1229
4. Mead PS, Griffin PM (1998) Escherichia coli 0157:H7. Lancet 352:1207-1212
5. Carter AO, Borczyk AA, Carlson JA, et al (1987) A severe outbreak of Escherichia coli
0157:H7-associated hemorrhagic colitis in a nursing home. N Engl J Med 317:1496-1500
6. Hymes KB, Karpatkin S (1997) Human immunodeficiency virus infection and thrombotic
microangiopathy. Semin Hematol34:117-125
7. Gordon 11, Kwaan HC (1999) Thrombotic microangiopathy manifesting as thrombotic
thrombocytopenic purpura/hemolytic uremic syndrome in the cancer patient. Semin
Thromb Hemost 25:217-221
8. McCrae KR, Cines DB (1997) Thrombotic microangiopathy during pregnancy. Semin He-
matol 34:148-158
9. Roy V, Rizvi MA, Vesely SK, George JN (2001) Thrombotic thrombocytopenic purpura-like
syndromes following bone marrow transplantation: an analysis of associated conditions
and clinical outcomes. Bone Marrow Transplant 27:641-646
10. Torok TJ, Holman RC, Chorba TL (1995) Increasing mortality from thrombotic thrombo-
cytopenic purpura in the United States - analysis of national mortality data, 1968-1991.
Am J Hematol 50:84-90
11. Clark WF, Rock GA, Buskard N, et al (1999) Therapeutic plasma exchange: an update from
the Canadian Apheresis Group. Ann Intern Med 131:453-462
12. Dang CT, Magid MS, Weksler B, Chadburn A, Laurence J (1999) Enhanced endothelial cell
apoptosis in splenic tissues of patients with thrombotic thrombocytopenic purpura. Blood
93:1264-1270
13. Tandon NN, Rock G, Jamieson GA (1994) Anti-CD36 antibodies in thrombotic thrombocy-
topenic purpura. Br J Haematol88:816-825
14. Laurence J, Mitra D, Steiner M, Staiano-Coico L, Jaffe E (1996) Plasma from patients with
idiopathic and human immunodeficiency virus-associated thrombotic thrombocytopenic
purpura induces apoptosis in microvascular endothelial cells. Blood 87:3245-3254
15. Jimenez JJ, Jy W, Mauro LM, Horstman LL, Ahn YS (2001) Elevated endothelial microparti-
cles in thrombotic thrombocytopenic purpura: findings from brain and renal microvascu-
lar cell culture and patients with active disease. Br J Haematol112:81-90
118 F. Pene et al.
16. Morigi M, Galbusera M, Binda E, et al (2001) Verotoxin-1-induced up-regulation of adhe-

sive molecules renders microvascular endothelial cells thrombogenic at high shear stress.
Blood 98:1828-1835
17. Novak RW, Martin CR, Orsini EN (1983) Hemolytic-uremic syndrome and T-cryptantigen
exposure by neuraminidase-producing pneumococci: an emerging problem? Pediatr Pathol
1:409-413
18. Noris M, Ruggenenti P, Perna A, et al (1999) Hypocomplementemia discloses genetic pre-
disposition to hemolytic uremic syndrome and thrombotic thrombocytopenic purpura:
role of factor H abnormalities. Italian Registry of Familial and Recurrent Hemolytic Uremic
Syndrome/Thrombotic Thrombocytopenic Purpura. JAm Soc Nephrol10:281-293
19. Fujikawa K, Suzuki H, McMullen B, Chung D (2001) Purification of human von Willebrand
factor-cleaving protease and its identification as a new member of the metalloproteinase fa-
mily. Blood 98:1662-1666
20. Gerritsen HE, Robles R, Lammle B, Furlan M (2001) Partial amino acid sequence of puri-
fied von Willebrand factor-cleaving protease. Blood 98:1654-1661
21. Moake JL, Rudy CK, Troll JH, et al (1982) Unusually large plasma factor VIII: von WIDe-
brand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura. N
Engl J Med 307:1432-1435
22. Moake JL, Turner NA, Stathopoulos NA, Nolasco LH, Hellums JD (1986) Involvement of
large plasma von Willebrand factor (vWF) multimers and unusually large vWF forms de-
rived from endothelial cells in shear stress-induced platelet aggregation. J Clin Invest
78:1456-1461
23. Furlan M, Robles R, Galbusera M, et al (1998) Von Willebrand factor-cleaving protease in
thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl J Med
339:1578-1584
24. Tsai HM, Lian EC (1998) Antibodies to von Willebrand factor-cleaving protease in acute
thrombotic thrombocytopenic purpura. N Engl J Med 339:1585-1594
25. Levy GG, Nichols WC, Lian EC, et al (2001) Mutations in a member of the ADAMTS gene
family cause thrombotic thrombocytopenic purpura. Nature 413:488-494
26. Bianchi V, Robles R, Alberio L, Furlan M, Lammle B (2002) Von Willebrand factor-cleaving
protease (ADAMTS13) in thrombocytopenic disorders: a severely deficient activity is
specific for thrombotic thrombocytopenic purpura. Blood 100:710-713
27. van der Plas RM, Schiphorst ME, Huizinga EG, et al (1999) von Willebrand factor proteoly-
sis is deficient in classic, but not in bone marrow transplantation-associated, thrombotic
thrombocytopenic purpura. Blood 93:3798-3802
28. Veyradier A, Obert B, Houllier A, Meyer D, Girma JP (2001) Specific von Willebrand fac-
tor-cleaving protease in thrombotic microangiopathies: a study of 111 cases. Blood
98:1765-1772
29. Remuzzi G, Galbusera M, Noris M, et al (2002) Von Willebrand factor cleaving protease
(ADAMTS13) is deficient in recurrent and familial thrombotic thrombocytopenic purpura
and hemolytic uremic syndrome. Blood 100:778-785
30. Mannucci PM, Canciani MT, Forza I, Lussana F, Lattuada A, Rossi E (2001) Changes in
health and disease of the metalloprotease that cleaves von Willebrand factor. Blood
98:2730-2735
31. Bell WR, Braine HG, Ness PM, Kickier TS (1991) Improved survival in thrombotic throm-
bocytopenic purpura-hemolytic uremic syndrome. Clinical experience in 108 patients. N
Engl J Med 325:398-403
32. Lara PN Jr, Coe TL, Zhou H, Fernando L, Holland PV, Wun T (1999) Improved survival
with plasma exchange in patients with thrombotic thrombocytopenic purpura-hemolytic
uremic syndrome. Am J Med 107:573-579
33. Allford SL, Harrison P, Lawrie AS, Liesner R, MacKie IJ, Machin SJ (2000) Von Willebrand
factor-cleaving protease activity in congenital thrombotic thrombocytopenic purpura. Br J
Haematol111:1215-1222
34. Ruggenenti P, Galbusera M, Cornejo RP, Bellavita P, Remuzzi G (1993) Thrombotic throm-
bocytopenic purpura: evidence that infusion rather than removal of plasma induces remis-
sion of the disease. Am J Kidney Dis 21:314-318
35. Rock G, Shumak KH, Sutton DM, Buskard NA, Nair RC (1996) Cryosupernatant as replace-
ment fluid for plasma exchange in thrombotic thrombocytopenic purpura. Members of the
Canadian Apheresis Group. Br J Haematol 94:383-386
36. Henon P (1991) [Treatment of thrombotic thrombopenic purpura. Results of a multicenter
randomized clinical study]. Presse Med 20:1761-1767
37. Novitzky N, Jacobs P, Rosenstrauch W (1994) The treatment of thrombotic thrombo-
cytopenic purpura: plasma infusion or exchange? Br J Haematol 87:317-320
38. Pene F, Heshmati F, Moreau D, et al (2001) [Thrombotic microangiopathy in ICU: a retro-
spective multicenter study). Reanimation 10 (suppl 1):SP 269 (abst)
39. Dundas S, Murphy J, Soutar RL, Jones GA, Hutchinson SJ, Todd WT (1999) Effectiveness
of therapeutic plasma exchange in the 1996 Lanarkshire Escherichia coli 0157:H7 out-
break. Lancet 354:1327-1330
40. Dundas S, Todd WT, Stewart AI, Murdoch PS, Chaudhuri AK, Hutchinson SJ (2001) The
Central Scotland Escherichia coli 0157:H7 Outbreak: Risk factors for the hemolytic uremic
syndrome and death among hospitalized patients. Clin Infect Dis 33:923-931
41. Rock G, Porta C, Bobbio-Pallavicini E (2000) Thrombotic thrombocytopenic purpura treat-
ment in year 2000. Haematologica 85:410-419
42. Coppo P, Busse! A, Adrie C, Alberti C, Le Gall J, Schlemmer B (2001) Early high dose plas-
ma infusion versus plasmapheresis as an emergency treatment of thrombotic microangio-
pathy. Transf Apher Sci 24:163-164a (abst)
43. Bobbio-Pallavicini E, Gugliotta L, Centurioni R, et al (1997) Antiplatelet agents in throm-
botic thrombocytopenic purpura (TTP). Results of a randomized multicenter trial by the
Italian Cooperative Group for TTP. Haematologica 82:429-435
44. Bennett CL, Weinberg PD, Rozenberg-Ben-Dror K, Yarnold PR, Kwaan HC, Green D (1998)
Thrombotic thrombocytopenic purpura associated with ticlopidine. A review of 60 cases.
Ann Intern Med 128:541-544
45. Bennett CL, Connors JM, Carwile JM, et a! (2000) Thrombotic thrombocytopenic purpura
associated with clopidogrel. N Eng! J Med 342:1773-1777
46. Tarantolo SR, Landmark JD, Iwen PC, Kessinger A, Chan WC, Hinrichs SH (1997)
Bartonella-like erythrocyte inclusions in thrombotic thrombocytopenic purpura. Lancet
350:1602
47. Wong CS, Jelacic S, Habeeb RL, Watkins SL, Tarr PI (2000) The risk of the hemolytic-
uremic syndrome after antibiotic treatment of Escherichia coli 0157:H7 infections. N Engl
J Med 342:1930-1936
48. Safdar N, Said A, Gangnon RE, Maki DG (2002) Risk of hemolytic uremic syndrome after
antibiotic treatment of Escherichia coli 0157:H7 enteritis: a meta-analysis. JAMA 288:996-
1001
49. Chandler WL, Jelacic S, Boster DR, et al (2002) Prothrombotic coagulation abnormalities
preceding the hemolytic-uremic syndrome. N Engl J Med 346:23-32
50. Raife TJ, Lentz SR, Atkinson BS, Vesely SK, Hessner MJ (2002) Factor V Leiden: a genetic
risk factor for thrombotic microangiopathy in patients with normal von Willebrand factor-
cleaving protease activity. Blood 99:43 7-442
51. Harkness DR, Byrnes JJ, Lian EC, Williams WD, Hensley GT (1981) Hazard of platelet
transfusion in thrombotic thrombocytopenic purpura. JAMA 246:1931-1933
52. McCarthy LJ, Danielson CF, Graves V (1994) Do platelet transfusions to patients with TTP
influence their survival? Blood 84 (suppl 1):669a (abst)
53. Rose M, Eldor A (1987) High incidence of relapses in thrombotic thrombocytopenic pur-
pura. Clinical study of 38 patients. Am J Med 83:437-444
54. Sarode R, Gottschall JL, Aster RH, McFarland JG (1997) Thrombotic thrombocytopenic
purpura: early and late responders. Am J Hematol 54:102-107
55. Patton JF, Manning KR, Case D, Owen J (1994) Serum lactate dehydrogenase and platelet
count predict survival in thrombotic thrombocytopenic purpura. Am J Hematol 47:94-99
56. Pereira A, Mazzara R, Monteagudo J, et al (1995) Thrombotic thrombocytopenic purpura/
hemolytic uremic syndrome: a multivariate analysis of factors predicting the response to
plasma exchange. Ann Hematol 70:319-323
Heparin in the Treatment of Critically Ill Patients
on the ICU
M. Levi, A. Cornelie de Pont, and E. de Jonge
I Introduction
Not all physicians will realize that, when they inject 1 ml of heparin in a patient,
they in fact inject a cocktail of more than 100 different molecules. Heparin consists
of a large number of glycosaminoglycans of various molecular size (4-20 kDa)
(Fig. 1) that are isolated from the intestines or lungs of pig or cow [1]. Heparin is
able to bind to antithrombin III, thereby more than 1000-fold potentiating the
inhibitory effect of antithrombin III on coagulation factors Ila (thrombin) and Xa.
Besides this anticoagulant effect, heparin (and in particular its high molecular
weight constituents) may also inhibit platelet function [2] . Although the subject of
some controversy in the past, heparin does not appear to exert thrombolytic activ-
ity. The weight of evidence suggests that heparin has no direct effect on clot lysis,
but strongly inhibits the recurrent formation of thrombotic deposits during the
process of endogenous fibrinolysis [3].
Heparin is usually administered parenterally. Since the intramuscular adminis-
tration is associated with local bleeding complications, this route is regarded as un-
acceptable. After subcutaneous administration, heparin has a highly variable bio-
availability, with a maximum effect three hours after the injection. Intravenous ad-
ministration should be executed by continuous infusion in view of the relatively
short half-life of heparin and because it has been shown that intermittent intrave-
nous bolus injections are associated with an excess of bleeding complications as
compared to continuous intravenous administration. Heparin has a dose-dependent
half-life: After the intravenous administration of a bolus dose of 5000 units, the
mean half life is approximately 60-90 minutes. Heparin is cleared from the circula-
tion by a number of mechanisms involving uptake by endothelial receptors and
Fig. 1. Schematic representation of heparin. Un-

fractionated heparin is a glycosaminoglycan com-
posed of D-glucuronate-2-sulfate alternating with
N-sulfo-D-glucosamine-6-sulfate. Each unit con-
tains a pentasaccharide, with a high-affinity bind-
ing site to antithrombin
Heparin in the Treatment of Critically Ill Patients on the ICU 121
mononuclear cells, internalization, depolymerization, metabolism and {urinary) ex-

cretion [2]. The anticoagulant effect of heparin may be highly variable between
individuals but also intraindividually, and therefore frequent laboratory monitoring
is required. Usually the activated partial thromboplastin time (aPTT) is used to tai-
lor heparin treatment. In special conditions, such as extracorporeal cardiopulmon-
ary bypass the whole blood activated clotting time (ACT) may be applied.
The most important side effect of heparin is bleeding, which may be life threat-
ening or result in life-long morbidity. Another serious side effect is heparin-in-
duced thrombocytopenia, an immunological phenomenon resulting in the aggrega-
tion and subsequent consumption of platelets, leading to bleeding and paradoxical
widespread arterial thrombotic occlusions (see further). Heparin-induced osteo-
porosis may occur in particular in patients receiving heparin at high doses for per-
iods longer than 3-6 months, for example during pregnancy. Heparin can be safely
administered to pregnant patients since it does not cross the placental barrier. Im-
mediate neutralization of the heparin-induced anticoagulant activity may be
achieved by the intravenous administration of protamine sulphate or protamine
chloride.
About 20 years ago, low molecular weight (LMW) heparins were introduced,
with an average molecular weight between 4 and 6 kDa [4, 5]. These heparin frac-
tions have shown a somewhat more favorable antithrombotic effect and induce less
bleeding complications at therapeutic doses as compared to unfractionated heparin.
In addition, LMW heparins have a highly predictable inter- and intra-individual
bioavailability and clearance, thereby precluding the need for frequent laboratory
monitoring and frequent dose-adjustments, which highly facilitates its clinical use.
The much longer half-life of LMW heparins as compared to unfractionated heparin
is advantageous in situations that require stable anticoagulation over a longer peri-
od of time, however, may be a complicating factor in situations that require easily
adjustable anticoagulation, such as in ICU patients at high risk for bleeding. The
antithrombin activity and not the anti-Xa activity of LMW heparin may be neutral-
ized by protamine, hence the reversion is not as complete as the protamine-induced
neutralization of unfractionated heparin.
I Use of Heparin to Prevent Thrombosis in Critically Ill Patients
In clinical medicine, the use of low dose heparin to prevent venous thromboembo-
lism has become common practice [6]. In particular, in patients undergoing ortho-
pedic or general surgery, the use of heparin is associated with a considerable re-
duction in the incidence of postoperative venous thrombosis and pulmonary embo-
lism [7]. Also in medical and neurological patients low dose heparin or LMW hep-
arin results in a reduced occurrence of venous thromboembolism, in particular in
bedridden patients. The use of low dose heparin is relatively safe, also in periopera-
tive patients, and the incidence of major bleeding complications is low [8]. It is not
clear to what extent these data, mainly derived in patients at the general ward, can
be translated to the intensive care unit {ICU). The absolute risk of developing
venous thromboembolism in ICU patients is not precisely known. This is due to
the fact that venous thromboembolism may clinically present with highly variable
manifestations, which in critically ill patients can be easily missed or confused for
other intercurrent complications. In addition, clinically important venous throm-
122 M. levi et al.
boembolism may be present with remarkably few symptoms. A recent survey of

published clinical studies on the objective diagnosis of deep vein thrombosis
(DVT) in critical care patients revealed an incidence of venous thrombosis of 13 to
31 o/o [9, 10]. This same study noted that many ICU patients were not receiving
thrombosis prophylaxis at all. In addition, patients on mechanical ventilation were
3-fold less likely to receive thrombosis prophylaxis as compared to patients that
were weaned from the ventilator. The authors concluded that use of preventive mea-
sures for venous thromboembolism is very dependent on the patient situation but
also on physician preference. In conclusion, venous thromboembolism is common
in the ICU and probably underdiagnosed.
The question is whether prophylactic measures are effective in ICU patients.
There are a number of trials specifically addressing this issue [11]. In medical ICU
patients the (non-randomized) use of heparin prophylaxis was associated with a
lower incidence of thrombosis [12]. One randomized controlled trial of heparin
versus placebo in medical and surgical ICU patients demonstrated an incidence of
venous thrombosis of 29% in placebo-treated patients as compared with 13% in pa-
tients receiving low dose heparin [13]. Thromboprophylaxis with unfractionated
heparin lowers the risk for DVT by 20%, whereas LMW heparins seem to reach a
risk reduction of SOo/o [ 11, 14]. In trauma patients on the ICU the use of prophylac-
tic heparin is still associated with a 30% incidence of venous thrombosis [15].
Nevertheless, these figures are much higher than incidences of venous thromboem-
bolism in non-ICU medical or surgical patients [14]. An explanation for this may
be that critically ill ICU patients are more immobilized than non-ICU patients and
therefore have a higher risk of thrombosis. In addition, the severity of disease on
the ICU (e.g., sepsis) may predispose to a procoagulant state and, therefore, may
increase the risk of thrombosis [16]. Lastly, the pharmacokinetics and pharmacody-
namics of heparin may be different in ICU patients than in non-ICU patients. In a
recent study, we hypothesized that the relative lack of efficacy of subcutaneous hep-
arin might be due to vasopressor medication causing impaired peripheral circula-
ICU patients ICU patients non-ICU

on vasopressor medication not on vasopressor medication patients
p = 0.0001
p = 0.0001
'......E o.4
::>
::. 0.3
X"'
....0v 0.2
~
·;:;
0.1
c
c(
3 6 9 12 15 0 3 6 9 12 15 0 3 6 9 12 15
Hours Hours Hours
Fig. 2. Anti-factor Xa levels in three groups of patients after a single subcutaneous injection of the lMW
heparin nadroparin at a dose of 2850 international anti-Xa units [17). The p-values represent overall re-
peated measures ANOVA and post-hoc Newman-Keuls test
tion and inadequate systemic bioavailability of the anticoagulant agent [17]. Three
consecutive patient groups were investigated: 15 ICU patients receiving vasopressor
medication; 15 ICU patients not receiving vasopressor medication; and 15 postop-
erative patients from a general surgical ward (8 patients after major orthopedic sur-
gery and 7 patients after abdominal surgery). Mean plasma anti-factor Xa activity
in the ICU group on vasopressor medication was significantly lower at all time-
points following subcutaneous injection of LMW heparin as compared to the ICU
patients not on vasopressor medication and the non-ICU patients (Fig. 2). In all
three groups, peak levels of anti-factor Xa were found 3 hours after LMW heparin
injection with mean values of 0.23 (95o/o confidence interval 0.18-0.27) and 0.28
(95o/o confidence interval 0.23-0.31) IU/ml for ICU patients not on vasopressor
medication and non-ICU patients, respectively, whereas the peak level for ICU pa-
tients receiving vasopressor treatment was only 0.09 (95o/o confidence interval 0.05-
0.1) IU/ml. Similar findings were recently reported in another study in intensive
care patients [18]. ln this study, high bodyweight and presence of multiple organ
dysfunction were identified as risk factor for subtherapeutic heparin levels.
I Other Indications for Heparin in Intensive Care Patients

There are a number of other reasons to use heparin in critically ill patients. These
reasons frequently encompass the prevention of clotting in extracorporeal circuits,
such as hemofiltration or dialysis equipment. For these reasons, higher (therapeu-
tic) doses of heparin are generally used, aiming at a doubling of the aPTT when
unfractionated heparin is used [19, 20]. Despite this approach, clotting in the extra-
corporeal circuits is common and requires change of machine, which is associated
with less effective dialysis time, loss of patient's blood, and considerable costs. Si-
multaneously, the risk of bleeding while using therapeutic anticoagulation is rela-
tively high (see further) in particular in patients with renal failure [21]. There is
not much difference in the incidence in these complications between unfractionated
heparin and LMW heparin [22]. In fact, the use of LMW heparin is generally not
advocated in ICU patients because of its long half-life and the difficulty in immedi-
ately and completely reversing its anticoagulant effect, which renders it a less favor-
able drug in unstable patients at risk for bleeding.
Another frequently occurring indication for heparin use is to prevent clotting in
central lines. Catheter-thrombosis frequently occurs in ICU patients (in particular
when catheters are not removed for a long period) and is related to central vein
thrombosis and catheter infections [23, 24]. For this reason, in some ICUs the prac-
tice of administering low dose heparin via indwelling catheters has become routine.
However, randomized controlled trials did not show a clinically significant differ-
ence between the use of heparin or sodium chloride [25-27]. Also, a meta-analysis
of 26 trials comparing heparin and saline flush to maintain patency of indwelling
catheters did not find any differences, hence this practice is not effective [28].
An increasing use of heparin, and in particular LMW heparin, occurs in patients
with acute coronary artery syndromes, such as unstable angina or acute myocardial
infarction. Although most of these patients are treated out of the ICU, unstable pa-
tients may be admitted to an ICU ward. This indication, however, falls somewhat
outside the scope of this review and will not be discussed further.
124 M. Levi et al.
Bleeding Associated with the Use of Heparin in Critically Ill Patients
Heparin increases the risk of bleeding. In patients treated with low dose unfrac-
tionated or LMW heparip the bleeding risk is relatively low, although perioperative
patients may experience major bleeding complications [29]. In randomized con-
trolled trials on the treatment of venous thromboembolism with unfractionated
heparin or LMW heparin, bleeding rates range from 7-15% and the incidence of
major bleeding is 1-4% [30]. ICU patients who receive heparin because of an acute
coronary event experience even higher rates of bleeding. Patients on the intensive
care frequently have thrombocytopenia [31], which may increase the risk of bleed-
ing when treated with heparin [32]. The most frequent localization of bleeding in
ICU patients on heparin is from the gastro-intestinal tract, which complication may
be associated with considerable morbidity, prolongation of ICU stay and increased
mortality [33].
The risk of bleeding in ICU patients with disseminated intravascular coagulation
(DIC) is also a matter of concern, especially since heparin is often contemplated in
these patients because of the ongoing intravascular clotting, which may contribute
to organ dysfunction. Although severe bleeding may dominate the clinical picture
in a patient with DIC and may even be the attributable cause of death, major bleed-
ing is not a frequent manifestation of this disorder [34, 35]. Heparin has been used
as treatment for DIC since 1959 [36]. Animal studies have shown that heparin can
inhibit the activation of coagulation in experimental septicemia but does not affect
mortality [37]. Studies of heparin for treatment of DIC in humans claimed to be
successful, but were not controlled. A retrospective analysis of cases of DIC re-
ported in the literature found similar survival for patients treated with heparin and
those not treated with heparin [38]. Interestingly, from this analysis it seems that
the use of heparin in patients with DIC and often thrombocytopenia does not in-
crease the incidence of bleeding complications. The effect of the LMW heparin, dal-
teparin, as an anti-DIC treatment has been studied in a multi-center double-blind
randomized trial [39]. The underlying cause of DIC in most of these patients was
malignancy and only 13% of patients suffered from infectious disease. In this study,
dalteparin showed superior efficacy as compared with unfractionated heparin in
improving bleeding symptoms and in improving a subjective organ failure score.
The improvement in survival in the dalteparin group was not significant.
Interaction Between Heparin and Anticoagulant Factor Concentrates
The successful results with recombinant human activated protein C (APC) in trials
of patients with sepsis [40] and the subsequent registration of this product in many
countries will prompt the use of this type of treatment in critically ill patients. An-
other anticoagulant factor concentrate is antithrombin III, which has been available
for many years and, although the most recent multicenter trial in patients with sep-
sis did not show a reduction in mortality [41], is still used in many ICUs. An im-
portant concern with the use of anticoagulant factor concentrates is the concomi-
tant use of heparin, which may increase the risk of bleeding.
In the Recombinant Human Protein C Worldwide Evaluation in Severe Sepsis
(PROWESS) study, the incidence of major bleeding in patients receiving APC was
3.5% as compared with 2.0% in placebo-treated patients [40]. Use of therapeutic
Table 1. Incidence of bleeding complications in the PROWESS (activated protein C (APC)) and the Kyber-
sept (antithrombin Ill (ATIII)) trials [40, 41]. The effect on bleeding events by administration of APC or
ATIII with or without heparin is compared
n Minor Major/ Intracranial

bleeding serious hemorrhage
bleeding
Placebo± heparin 840 2.0% 0.1%
APC +heparin
APC-heparin
634
216
3.7%
3.5% } 0.2%
Placebo+ heparin
Placebo- heparin
810
345
8.2%
7.1%
6.2%
4.6% } 0.4%
ATill+ heparin 807 15.0% 10.9% } 0.7%

AT Ill - heparin 354 12.7% 7.9%
doses of anticoagulant agents, including heparin, was not allowed in this trial. In-
terestingly, the concomitant use of prophylactic heparin in patients that were ran-
domized to receive APC did not increase the risk of major bleeding (Table 1). In
addition, mortality rates were not different between patients who received APC
with or without prophylactic heparin. Since there is a theoretical concern that there
might be an interaction between the use of heparin and APC, which is partly based
on in vitro studies showing an effect of heparin on APC binding to protein C in-
hibitor [42, 43], the manufacturer of APC has committed to an additional clinical
study comparing APC with or without concomitant heparin in patients with sepsis.
The interaction between heparin and antithrombin III concentrate appears to be
more important. The recently published large multicenter trial of antithrombin con-
centrate versus placebo in patients with sepsis did not show any effect of this treat-
ment on mortality [41]. However, when analyzing a subgroup of patients that did
not receive heparin, antithrombin treatment resulted in a non-significant reduction
of mortality from 43.6 to 37.8% at day 28, a trend that became statistically signifi-
cant after 90 days. It should be stressed, however, that assignment to heparin treat-
ment was not random and was likely to be influenced by patient characteristics
and subject to bias. Nevertheless, this observation raises the hypothesis that anti-
thrombin without concomitant heparin might be of benefit in patients with sepsis,
although this needs confirmation in a prospective randomized trial. Of importance,
minor and major bleeding was much more common in the antithrombin III trial as
compared with the APC trial, although a formal comparison is difficult since differ-
ent definitions of bleeding were used. Nevertheless, the data suggest that bleeding
is a more serious complication when using antithrombin III in combination with
heparin than when using APC with or without heparin.
I Heparin-Induced Thrombocytopenia
Apart from bleeding, one of the most frequent adverse events of heparin use is the
development of heparin-induced thrombocytopenia [44]. The incidence of heparin-
induced thrombocytopenia is estimated at 1-5% in patients using heparin. In ICU
126 M. Levi et al.
patients the incidence of heparin-induced thrombocytopenia is probably higher

than in the general ward, since patients receive higher doses of heparin (e. g., dur-
ing extracorporeal by-pass surgery) and for a longer period of time (e.g., during
continuous veno-venous hemofiltration). The incidence of heparin-induced throm-
bocytopenia is indeed influenced by the type of heparin and its dose. The use of
LMW heparin has been shown to be much less frequently complicated by the oc-
currence of heparin-induced thrombocytopenia than the administration of fraction-
ated heparin [45]. Also, the source of the heparin is thought to affect the incidence
of heparin-induced thrombocytopenia (more frequent with bovine versus porcine
heparin), although this view has been contested [46]. Heparin-induced thrombocy-
topenia is diagnosed by a low or rapidly decreasing platelet count in a patient re-
ceiving heparin in combination with a positive test for anti-heparin/platelet factor
4 antibodies. The clinical manifestation of heparin-induced thrombocytopenia is
characterized by the occurrence of arterial and venous thrombosis, which at first
sight may be considered paradoxical in view of the low platelet count [47]. The
pathophysiology of heparin-induced thrombocytopenia, however, can readily ex-
plain this clinical presentation. Antibodies towards the complex of heparin and
platelet factor 4 strongly induce platelet aggregation, leading to platelet consump-
tion and formation of platelet aggregates, resulting in clinically important throm-
botic manifestations. Immediate cessation of heparin therapy leads to a rapid re-
covery of platelet count, which may be another helpful feature to establish the diag-
nosis [48]. Alternative anticoagulant strategies may consist of danaparoid (a syn-
thetic heparin analog) or administration of hirudin or hirudin analogs [49, 50].
However, the use of hirudin in critically ill patients is complicated by its exclusive
renal clearance, which dramatically prolongs the half-life of this agent in the pres-
ence of renal failure and may lead to bleeding that is difficult to manage.
I Conclusion
Heparin is a frequently used drug in critically ill patients admitted to the ICU. Pa-
tients on the ICU are at high risk for venous thromboembolism and prophylactic
unfractionated or LMW heparin significantly reduced this risk. Nevertheless, in
contrast to general surgical or medical patients, a substantial number of patients
who receive prophylaxis for thrombosis will still develop this complication, which
might be caused by different characteristics of ICU patients and by a reduced bio-
availability of subcutaneous low dose heparin in critically ill patients. The bleeding
risk associated with prophylactic heparin is low but therapeutic doses of heparin
may cause serious complications in ICU patients. The combined use of anticoagu-
lant factor concentrates (such as APC or antithrombin concentrate) and prophylac-
tic heparin in patients with sepsis may increase the risk of bleeding, although this
occurs in particular with antithrombin III treatment whereas the risk when using
APC seems to be low. Besides bleeding, the most frequently occurring side-effect of
heparin in ICU patients is the development of heparin-induced thrombocytopenia
with paradoxical thrombosis.
References
1. Hirsh J (1991) Heparin. N Engl J Med 324:1565-1574
2. Hirsh J, Warkentin TE, Raschke R, Granger C, Ohman EM, Dalen JE (1998) Heparin and
low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing considera-
tions, monitoring, efficacy, and safety. Chest 114:489S-510S
3. Biemond BJ, Friederich PW, Levi M, Vlasuk GP, Buller HR, ten Cate JW (1996) Compari-
son of sustained antithrombotic effects of inhibitors of thrombin and factor Xa in experi-
mental thrombosis. Circulation 93:153-160
4. Weitz JI (1997) Low-molecular-weight heparins. N Engl J Med 337:688-698
5. Hirsh J (1993) Low molecular weight heparin. Thromb Haemost 70:204-207
6. Bijsterveld NR, Hettiarachchi R, Peters R, Levi M, Buller HR (1999) Low-molecular weight
heparins in venous and arterial thrombotic disease. Thromb Haemost 82 (suppl1):139-147
7. Hirsh J, Warkentin TE, Raschke R, Granger C, Ohman EM, Dalen JE (1998) Heparin and
low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing considera-
tions, monitoring, efficacy, and safety. Chest 114:489S-510S
8. Agnelli G, Sonaglia F (2000) Prevention of venous thromboembolism. Thromb Res 97:V49-
V62
9. Geerts W, Cook D, Selby R, Etchells E (2002) Venous thromboembolism and its prevention
in critical care. J Crit Care 17:95-104
10. Cook D, Attia J, Weaver B, McDonald E, Meade M, Crowther M (2000) Venous thromboem-
bolic disease: an observational study in medical-surgical intensive care unit patients. J Crit
Care 15:127-132
11. Attia J, Ray JG, Cook DJ, Douketis J, Ginsberg JS, Geerts WH (2001) Deep vein thrombosis
and its prevention in critically ill adults. Arch Intern Med 161:1268-1279
12. Marik PE, Andrews L, Maini B (1997) The incidence of deep venous thrombosis in ICU pa-
tients. Chest 111:661-664
13. Cade JF (1982) High risk of the critically ill for venous thromboembolism. Crit Care Med
10:448-450
14. Samama MM, Cohen AT, Darmon JY, et al (1999) A comparison of enoxaparin with place-
bo for the prevention of venous thromboembolism in acutely ill medical patients. Prophy-
laxis in Medical Patients with Enoxaparin Study Group. N Engl J Med 341:793-800
15. Geerts WH, Jay RM, Code Kl, et al (1996) A comparison of low-dose heparin with low-mo-
lecular-weight heparin as prophylaxis against venous thromboembolism after major trau-
ma. N Engl J Med 335:701-707
16. ten Cate JW, van der Poll T, Levi M, ten Cate H, van Deventer SJ (1997) Cytokines: triggers
of clinical thrombotic disease. Thromb Haemost 78:415-419
17. Dorffier-Melly J, de Jonge E, Pont AC, Meijers J, Buller HR, Levi M (2002) Bioavailability of
subcutaneous low-molecular-weight heparin to patients on vasopressors. Lancet 359:849-850
18. Mayr AJ, Dunser M, Jochberger S, et al (2002) Antifactor Xa activity in intensive care pa-
tients receiving thromboembolic prophylaxis with standard doses of enoxaparin. Thromb
Res 105:201-204
19. Ward DM (1997) The approach to anticoagulation in patients treated with extracorporeal
therapy in the intensive care unit~ Adv Ren Replace Ther 4:160-173
20. Martin PY, Chevrolet JC, Suter P, Favre H (1994) Anticoagulation in patients treated by
continuous venovenous hemofiltration: a retrospective study. Am J Kidney Dis 24:806-812
21. Prentice CR (1985) Acquired coagulation disorders. Clin Haematol14:413-442
22. Lai KN, Ho K, Li M, Szeto CC (1998) Use of single dose low-molecular-weight heparin in
long hemodialysis. Int J Artif Organs 21:196-200
23. Timsit JF, Farkas JC, Boyer JM, et al (1998) Central vein catheter-related thrombosis in in-
tensive care patients: incidence, risks factors, and relationship with catheter-related sepsis.
Chest 114:207-213
24. Hentschel R, Wiescholek U, von Lengerke J, Harms E, Jorch G (1999) Coagulation-asso-
ciated complications of indwelling arterial and central venous catheters during heparin
prophylaxis - a prospective study. Eur J Pediatr 158 (suppl3):S126-S129
25. Heilskov J, Kleiber C, Johnson K, Miller J (1998) A randomized trial of heparin and saline
for maintaining intravenous locks in neonates. J Soc Pediatr Nurs 3:111-116
128 M. Levi et al.: Heparin in the Treatment of Critically Ill Patients on the ICU
26. Epperson EL (1984) Efficacy of 0.9% sodium chloride injection with and without heparin
for maintaining indwelling intermittent injection sites. Clin Pharm 3:626-629
27. Hanrahan KS, Kleiber C, Berends S (2000) Saline for peripheral intravenous locks in neo-
nates: evaluating a change in practice. Neonatal Netw 19:19-24
28. Randolph AG, Cook DJ, Gonzales CA, Andrew M (1998) Benefit of heparin in peripheral
venous and arterial catheters: systematic review and meta-analysis of randomised con-
trolled trials. Br Med J 316:969-975
29. Geerts WH, Heit JA, Clagett GP, et al (2001) Prevention of venous thromboembolism. Chest
119:132S-175S
30. Levine MN, Raskob G, Landefeld S, Kearon C (2001) Hemorrhagic complications of anti-
coagulant treatment. Chest 119:108S-121S
31. Akca S, Haji Michael P, de Medonca A, Suter PM, Levi M, Vincent JL (2002) The time
course of platelet counts in critically ill patients. Crit Care Med 30:753-6
32. Strauss R, Wehler M, Mehler K, Kreutzer D, Koebnick C, Hahn EG (2002) Thrombocytope-
nia in patients in the medical intensive care unit: bleeding prevalence, transfusion require-
ments, and outcome. Crit Care Med 30:1765-1771
33. Cook DJ, Griffith LE, Walter SD, et al (2001) The attributable mortality and length of in-
tensive care unit stay of clinically important gastrointestinal bleeding in critically ill pa-
tients. Crit Care 5:368-375
34. Levi M, ten Cate H (1999) Disseminated intravascular coagulation. N Engl J Med 341:586-592
35. Levi M, van Gorp E, ten Cate H (2003) Disseminated intravascular coagulation. In: Handin
RI (ed) Blood: Principles and Practice of Hematology. Lippincott, Williams and Wilkins,
Philadelphia (in press)
36. Little JR (1959) Purpura fulminans treated successfully with anticoagulation: report of a
case. JAMA 169:36-40
37. Corrigan JJ Jr, Kiernat JF (1975) Effect of heparin in experimental gram-negative septice-
mia. J Infect Dis 131:138-143
38. Corrigan JJ Jr (1977) Heparin therapy in bacterial septicemia. J Pediatr 91:695-700
39. Sakuragawa N, Hasegawa H, Maki M, Nakagawa M, Nakashima M (1993) Clinical evalua-
tion of low-molecular-weight heparin (FR-860) on disseminated intravascular coagulation
(DIC) - a multicenter co-operative double-blind trial in comparison with heparin. Thromb
Res 72:475-500
activated protein C for severe sepsis. N Engl J Med 344:699-709
41. Warren BL, Eid A, Singer P, et al (2001) Caring for the critically ill patient. High-dose an-
tithrombin III in severe sepsis: a randomized controlled trial. JAMA 286:1869-1878
42. Aznar J, Espana F, Estelles A, Royo M (1996) Heparin stimulation of the inhibition of acti-
vated protein C and other enzymes by human protein C inhibitor - influence of the mole-
cular weight of heparin and ionic strength. Thromb Haemost 76:983-988
43. Friedrich U, Blom AM, Dahlback B, Villoutreix BO (2001) Structural and energetic character-
istics of the heparin-binding site in antithrombotic protein C. J Biol Chern 276:24122-24128
44. Kelton JG (2002) Heparin-induced thrombocytopenia: an overview. Blood Rev 16:77-80
45. Warkentin TE, Levine MN, Hirsh J, et al (1995) Heparin-induced thrombocytopenia in pa-
tients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med
332:1330-1335
46. Konkle BA, Bauer TL, Arepally G, et al (2001) Heparin-induced thrombocytopenia: bovine
versus porcine heparin in cardiopulmonary bypass surgery. Ann Thorac Surg 71:1920-1924
47. Baglin TP (2001) Heparin induced thrombocytopenia thrombosis (HIT/T) syndrome: diag-
nosis and treatment. J Clin Pathol 54:272-274
48. Warkentin TE, Kelton JG (2001) Temporal aspects of heparin-induced thrombocytopenia.
N Engl J Med 344:1286-1292
49. Ibbotson T, Perry CM (2002) Danaparoid: a review of its use in thromboembolic and coag-
ulation disorders. Drugs 62:2283-2314
50. Lubenow N, Greinacher A (2002) Hirudin in heparin-induced thrombocytopenia. Semin
Endogenous Anticoagulants and the Role of Heparin
in the Treatment of Severe Sepsis
C.J. Wiedermann and C. Pechlaner
I Introduction
New treatments for severe sepsis have yielded disappointing results in numerous
trials conducted in the past 20 years. The interventions tested improved survival
only marginally, if at all. Some were associated with unexpected toxicities. Not a
single new agent had been introduced into clinical practice until recently [1-4].
The majority of trials tested strategies aimed at suppressing inflammation. The
focus has shifted to treatment strategies aimed at inhibiting excessive blood coagu-
lation. Three large multicenter trials with human anticoagulant proteins have been
completed recently in adults with severe sepsis. One of the three shows a clinically
relevant reduction of mortality, by treatment with activated protein C. The other
two anticoagulants, with similar preclinical proflles, have failed in large clinical
trials, as did other drugs with both anti-inflammatory and anticoagulant effects
(ibuprofen, antagonists of platelet-activating-factor receptor) [2-4].
I Clinical Trials with Endogenous Anticoagulants
Protein C in the PROWESS Study

The PROWESS (recombinant human protein C worldwide evaluation in severe sep-
sis) study [5] reported significantly lower mortality in patients with severe sepsis
treated with activated protein C (drotrecogin alfa activated) as compared to placebo
infusion. Total mortality at day 28 was 24.7% of 850 patients in the study group ad-
ministered recombinant human protein C that was pre-activated with bovine
thrombin. Mortality of the 840 patients in the placebo group was 30.8%. This trans-
lates into an absolute risk reduction of 6% {95% confidence interval 2-10%), rela-
tive risk reduction 19%, number needed to treat 16, and p=0.006. Post-hoc analy-
sis of long term effects of drotrecogin alfa (activated) suggests that the survival ad-
vantage previously demonstrated at 28 days continues for more than 12 months of
follow-up [6]. Severe bleeding within 28 days was observed in 3.5% of the active
treatment group, as compared to 2.0% in the placebo group (p=0.06). In subse-
quent open-label and compassionate use studies, higher rates of serious bleeding
were reported that were frequently associated with invasive procedures [7].
After 20 years of disappointing sepsis trials, PROWESS was the first large ran-
domized trial reporting a meaningful mortality reduction with an innovative drug.
Protein C is a human anticoagulant protein. Experimental data suggest additional
anti-inflammatory and pro-fibrinolytic effects. Activated protein C prevented sepsis
130 C. J. Wiedermann and C. Pechlaner
in animal models, and was associated with non-significant mortality benefit in a

human phase-II-study [8].
Post-hoc analyses revealed that 28-day mortality differences were not consistent
in subgroups. Significant differences in mortality in favor of activated protein C
were only seen in more severely ill patients, e.g., patients in the upper half of
APACHE-II score [9, 10]. Most recent results of the open-label ENHANCE trial in
the United States [11] with inclusion and exclusion criteria identical to that of
PROWESS (after the amendment) support a positive benefit-risk profile.
In summary, activated protein C reduces mortality in high risk patients with
severe sepsis but there remains some uncertainty regarding the identification of pa-
tients particularly likely to benefit from activated protein C. Activated recombinant
human Protein C (Xigris; Eli Lilly Corp., Indianapolis, IN) for severe sepsis was ap-
proved by the FDA and EMEA, the European regulatory agency. The approval was
granted under exceptional circumstances. This means Lilly and the Regulatory
Agencies have to agree/agreed upon postapproval clinical trial commitments includ-
ing an 11 000 patient trial in less severe sepsis and an obligation for Lilly to provide
the agency with an annual update regarding its trials in order to allow answers to
the questions raised in the critical appraisal.
Antithrombin in the KyberSept Study
High-dose antithrombin treatment was not associated with an effect on 28-day

mortality in patients with severe sepsis in KyberSept [12]. Mortality in the anti-
thrombin group was 38.9% of 1157 patients, as compared to 38.7% of 1157 patients
in the placebo group. Of 10 subgroup analyses, none yielded significant 28-day-
mortality differences. Treatment with antithrombin was associated with increased
28-day-risk of severe bleeding (10.0% with antithrombin, 5.7% with placebo; bleed-
ing definition different to the one in PROWESS). Mortality at 56 and 90 days and
survival time in the intensive care unit (ICU), did not differ between the antithrom-
bin and placebo groups. As a secondary end point, in the subgroup of patients who
did not receive concomitant heparin during the 4-day treatment phase (n=698),
there was a statistical trend for lower 28-day mortality in the antithrombin group
{37.8%) compared with the placebo group (43.6%) (p = 0.08). This trend became
significant after 90 days (n = 686; 44.9% for antithrombin group vs 52.5% for place-
bo group; p=0.03). In patients receiving antithrombin and concomitant heparin, a
significantly increased bleeding incidence was observed (23.8% for antithrombin
group vs 13.5% for placebo group; p < 0.001), whereas bleeding was only moder-
ately increased in patients who did not receive heparin concomitantly [12]. Over a
90-day period, survivors of severe sepsis receiving antithrombin experienced signif-
icant improvements as compared with placebo on several attributes of quality of life
[13).
Antithrombin is a broad-spectrum plasma serine protease inhibitor affecting the
intrinsic, extrinsic, and common coagulation pathways [14-16]. Evidence suggests
additional anti-inflammatory mechanisms of action [17-19]. The results of the Ky-
berSept trial contrast to that of a meta-analysis of the previously collected clinical
experience derived from 122 European patients with high-dose antithrombin in
three double-blind, placebo-controlled Phase 2 trials that employed similar entry
criteria and dosing strategies [20]. However, it should be noted that in two of these
trials no heparin was used [20].
Endogenous Anticoagulants and the Role of Heparin in the Treatment of Severe Sepsis 131
In summary, the results of the KyberSept trial indicate that high-dose antithrom-
bin, at least when combined with heparin therapy, is not beneficial in severely sep-
tic patients but may have beneficial effects without concomitantly administered
heparin. Results of the post-hoc analyses of the activated protein C trial [9] sug-
gested that in the development of multiple organ failure (MOF) early use of endoge-
nous anticoagulants as a treatment of severe sepsis may be crucial. The potential
importance of this inclusion criterion is supported by beneficial effects of early
goal-directed intervention in severe sepsis [21]. Due to the KyberSept trial's criteria
for patient enrolment, in particular the acceptance of patients with late stage organ
failure, this study does not answer the question of the therapeutic value of antith-
rombin in patients with early severe sepsis.
Tissue Factor Pathway Inhibitor in the OPTIMIST Trial

Chiron Corporation announced in November 2001 that recombinant tissue factor
pathway inhibitor failed to reduce 28-day-mortality in a multicenter randomized
controlled trial in 2000 patients with severe sepsis. More details have not yet been
presented or published.
1 Does Anticoagulant Treatment Benefit Sepsis Patients?

Anticoagulant treatment very likely benefits sepsis patients, based on indirect evi-
dence and current understanding of severe infectious disease, the associated pro-
thrombotic state and the close links between inflammation and coagulation in gen-
eral [22-24].
Heparin
Heparin and low-molecular-weight heparin are anticoagulants with anti-inflamma-
tory properties, however, heparin improved inflammatory diseases, e.g., in inflam-
matory bowel disease, asthma, rhinitis and glomerulonephritis, only in small stud-
ies [25]. Coalson et al. [26] reported that the use of heparin decreased endotoxin-
related clotting, but was ineffective in preventing organ failure and death in the ba-
boon model. Heparin is recommended for prophylaxis against thromboembolism
in patients with sepsis [27]. Low-dose heparin is standard care in most ICUs even
though heparin treatment in severe sepsis has never been examined in an ade-
quately powered rigorous clinical trial. Heparin has been studied extensively in the
past for the treatment of sepsis-induced disseminated intravascular coagulation
(DIC) [28, 29].
Both PROWESS and KyberSept lend indirect support for a benefit of anticoagu-
lant treatment at mild doses. In the two trials, 75 and 70% of the patients, respec-
tively, received prophylactic heparin or low-molecular-weight heparin. Among 1995
pooled placebo recipients from the two trials, the odds of survival for the patients
who received heparin, as compared with those who did not, was 1.45 (95 percent
confidence interval, 1.18 to 1.78; P<0.001} [30]. In each trial, heparin use was asso-
ciated with improved survival among placebo recipients. The primary limitation of
such analysis is that the administration of heparin was not randomly assigned, and
selection bias is therefore possible, i.e., heparin might have been withheld from pa-
132 C. J. Wiedermann and C. Pechlaner
tients at higher risk for bleeding and also for death, the heparin dosage was not
controlled, and the heparin effect may be a post-randomization bias as patients dy-
ing early in the study are not available to be treated with heparin at a later point of
time [31]. The efficacy of heparin remains controversial.
Interaction of Heparin and Activated Protein C

In the report of the PROWESS trial, results of a retrospective subgroup analysis
showed that the administration of low-dose heparin, in addition to activated pro-
tein C, had no effect on safety [5]. In the subgroup of patients co-medicated with
heparin during study drug infusion, however, mortality differed by only 3%,
whereas in patients without additional heparin the placebo group mortality was
15% higher than that of the treatment group (Table 1) [9]. Whether this difference
is related to randomization or post-randomization bias regarding the uncontrolled
administration of heparin or if it is due to beneficial effects of heparin in the treat-
ment of severe sepsis and/or adverse effects of heparin on activated protein C is
unknown and is currently being studied in a 2000 patient trial.
Interaction of Heparin and Antithrombin

Antithrombin has been used for septic shock complicated by DIC for nearly 25
years [29]. As is known in clinical use, antithrombin contains a heparin-binding
domain and its anticoagulation activity is enhanced several orders of magnitude
after binding with heparin in the blood stream or glycosaminoglycans on the vas-
cular endothelium; the anticoagulant activity of antithrombin is reported to be
maximized through the conformational changes after the binding with heparin or
glycosaminoglycans on endothelium [17]. The drug interaction between high-dose
antithrombin and heparin was principally responsible for the increased bleeding
events seen in KyberSept [12]. The trial also reported a significant reduction in 90-
day mortality by antithrombin exclusively in the subgroup of patients without si-
multaneous heparin prophylaxis. Patients additionally receiving heparin did not
benefit from antithrombin treatment {Table 2) [12].
Binding of antithrombin to glycosaminoglycans of endothelium and leukocytes
via its heparin-binding site elicits anti-inflammatory responses including prostacy-
clin release and deactivation of chemokine receptor responses in vitro and in vivo
[17, 18]. Heparin adversely affects these anti-inflammatory mechanisms of anti-
thrombin by blocking its binding to cellular glycosaminoglycans at prophylactic
Table 1. Effect of prophylactic heparin administration on day 28 mortality of patients with severe sepsis
in the PROWESS trial. Data obtained from [9]. ArhPC: activated recombinant human protein C; n: number
of patients
Heparin Study drug n Mortality day 28
Yes ArhPC 634 158 (25%)

Yes Placebo 637 179 (28%)
No ArhPC 216 52 (24%)
No Placebo 203 80 (39%)
Table 2. Effect of prophylactic heparin administration on mortality of patients with severe sepsis in the
KyberSept trial. Data obtained from [12]. AT, antithrombin; n.a., not available
Subgroup by drug Mortality (%)
AT Heparin Day 28 Day 90
I~
+ 36.6 n.a.
37.8 44.9
+ 39.4 n.a.
43.6 52.2
concentrations [32]leading to the loss of antithrombin's anti-inflammatory proper-

ties within the microcirculation [33].
I Conclusion
Two contemporaneous sepsis trials with comparable endogenous human anticoagu-
lants, i.e., activated protein C and antithrombin, concluded with different results.
Mortality differences between placebo groups suggest that the patient populations
in the two studies were different. The entry criteria may have selected populations
that were in different phases of sepsis; early (reversible) versus late (irreversible)
sepsis. Heparin interferes with the anti-inflammatory properties of antithrombin
and promotes its systemic anticoagulant activities that may explain the efficacy of
antithrombin in the absence of heparin. Whether a heparin interaction with acti-
vated protein C is responsible for reduced efficacy of activated protein C when
combined with heparin as seen in post-hoc analyses is currently unknown. The
drug interaction between antithrombin and heparin was principally responsible for
the increased bleeding events, and the loss of antithrombin's anti-inflammatory
properties within the microcirculation. Continued study in basic research should
lead to a better understanding of the mechanistic differences between activated
protein C and antithrombin. Current trials with activated protein C will provide
further data on how to use activated protein C in daily practice whereas trials of
antithrombin may show a more positive outcome if concomitant heparin therapy is
avoided.
References
1. Graf J, Doig GS, Cook DJ, Vincent JL, Sibbald WJ (2002) Randomized, controlled clinical
trials in sepsis: has methodological quality improved over time? Crit Care Med 30:461-472
2. Marshall JC (2000) Clinical trials of mediator-directed therapy in sepsis: what have we
learned? Intensive Care Med 26(suppll):S75-S83
3. Natanson C, Esposito CJ, Banks SM (1998) The sirens' songs of confirmatory sepsis trials:
selection bias and sampling error. Crit Care Med 26:1927-1931
4. Opal SM, Cross AS (1999) Clinical trials for severe sepsis. Past failures, and future hopes.
Infect Dis Clin North Am 13:285-297
5. Bernard GR, Vincent JL, Laterre PF, et a! (2001) Efficacy and safety of recombinant human
activated protein C for severe sepsis. N Eng! J Med 344:699-709
134 c.J. Wiedermann and C. Pechlaner
6. Angus DC, Laterre P-F, Helterbrand J, Ball D, Garg R, Bernard G (2002) The effects of dro-
trecogin alfa (activated) on long-term survival after sepsis. Annual Meeting of the Ameri-
can College of Chest Physicians, November 2-7, 2002, San Diego, CA, Abstract S144
7. Bernard GR, Macias WL, Vincent J-L (2002) Drotrecogin alfa (activated) cumulative safety
update. Annual Meeting of the American College of Chest Physicians, November 2-7, 2002,
San Diego, CA, Abstract S141
8. Bernard GR, Ely EW, Wright TJ, et al (2001) Safety and dose relationship of recombinant
human activated protein C for coagulopathy in severe sepsis. Crit Care Med 29:2051-2059
9. Warren HS, Suffredini AF, Eichacker PQ, Munford RS (2002) Risks and benefits of acti-
vated protein C treatment for severe sepsis. N Eng! J Med 347:1027-1030
10. Anti-Infective Advisory Committee. FDA briefing document: drotrecogin alfa (activated)
[recombinant human activated protein C (rhAPC)] Xigris. BLA #125029/0. Rockville, Md.:
Food and Drug Administration, September 12, 2001. (Accessed November 30, 2002, at
http://www.fda.gov/ohrms/dockets/ac/01/briefing/3797b1_02_FDAbriefing.pdf
11. Bernard GR, Margolis B, Shanies H, et al (2002) Efficacy and safety of drotrecogin alfa (ac-
tivated) in the treatment of adult patients with severe sepsis: Report from a single-arm
open-label trial in the United States. Annual Meeting of the American College of Chest
Physicians, November 2-7, 2002, San Diego, CA, Abstract S142
12. Warren BL, Eid A, Singer P, et al (2001) Caring for the critically ill patient. High-dose an-
tithrombin III in severe sepsis: a randomized controlled trial. JAMA 286:1869-1878
13. Rublee D, Opal SM, Schramm W, Keinecke HO, Knaub S (2002) Quality of life effects of an-
tithrombin III in sepsis survivors: results from the KyberSept trial. Crit Care 6:349-356
14. Vervloet NG, Thijs LG, Hack CE (1998) Derangements of coagulation and fibrinolysis in
critically ill patients with sepsis and septic shock. Semin Thromb Hemostas 24:33-34
15. Levi M, ten Cate H (1999) Disseminated intravascular coagulation. N Eng! J Med 341:586-
592
16. Bock SC, Harris JF, Balazs I, et al (1985) Assignment of the human antithrombin III struc-
tural gene to chromosome 1q 23-25. Cytogenet Cell Genet 39:67-74
17. Opal SM, Kessler CM, Roemisch J, Knaub S (2002) Antithrombin, heparin, and heparan
sulfate. Crit Care Med 30(suppl):S325-S331
18. Wiedermann CJ, Romisch J (2002) The anti-inflammatory actions of antithrombin - a re-
view. Acta Med Austriaca 29:89-92
19. Iba T, Kidokoro A (2002) High-dose antithrombin therapy for sepsis: mechanisms of ac-
tion. Shock 18:389-394
20. Eisele B, Lamy M, Thijs LG, et al (1998) Anti-thrombin III in patients with severe sepsis:
a randomized, placebo-controlled, double-blind, multicenter trial plus a meta-analysis on
all randomized-placebo-controlled, double-blind trials with antithrombin III in severe sep-
sis. Intensive Care Med 24:663-672
21. Rivers E, Nguyen B, Havstad S, et al (2001) Early goal-directed therapy in the treatment of
severe sepsis and septic shock. N Eng! J Med 345:1368-1377
22. Levi M (2001) Pathogenesis and treatment of disseminated intravascular coagulation in the
septic patient. J Crit Care 16:167-177
23. Opal SM (2001) Clinical impact of novel anticoagulation strategies in sepsis. Curr Opin
Crit Care 7:347-353
24. Healy DP (2002) New and emerging therapies for sepsis. Ann Pharmacother 36:648-654
25. Ahmed T, Gonzalez BJ, Danta I (1999) Prevention of exercise-induced bronchoconstriction
by inhaled low-molecular-weight heparin. Am J Respir Crit Care Med 160:576-581
26. Coalson JJ, Benjamin B, Archer LT, et al (1978) Prolonged shock in the baboon subjected
to infusion of E. coli endotoxin. Circ Shock 5:423-437
27. Wheeler AP, Bernard GR (1999) Treating patients with severe sepsis. N Eng! J Med
340:207-214
28. Corrigan JJ (1977) Heparin therapy in bacterial septicemia. J Pediatr 91:695-700
29. Schipper HG, Jenkins CSP, Kahl LH, et al (1978) Antithrombin III transfusion in dissemi-
nated intravascular coagulation. Lancet 1:854-856
30. Davidson BL, Geerts WH, Lensing AW (2002) Low-dose heparin for severe sepsis. N Eng! J
Med 347:1036-1037
31. Langer M, Riccardi F, Piovella F, et al (2002) Use of anticoagulants in patients with sepsis.
JAMA 287:448-449
32. Kaneider NC, Reinisch CM, Dunzendorfer S, Romisch J, Wiedermann CJ (2002) Syndecan-
4 mediates antithrombin-induced chemotaxis of human peripheral blood lymphocytes and
monocytes. J Cell Sci 115:227-236
33. Hoffmann JN, Vollmar B, Laschke MW, et al (2002) Adverse effect of heparin on anti-
thrombin action during endotoxemia: microhemodynamic and cellular mechanisms.
Thromb Haemost 88:242-252
Is Recombinant Activated Factor VII
a Universal Hemostatic?
P. Diprose, R. Gill, and M. Herbertson
Introduction
Advances in resuscitation, surgical, anesthetic, and critical care management have
significantly improved outcomes after trauma or major surgery in the past two de-
cades. However, morbidity and mortality still occur due to a wide variety of com-
plications in the setting of trauma and major surgery. One of the foremost of these
complications is continued blood loss [1, 2]. Despite best surgical practice ongoing
bleeding from sites of major trauma and surgery frequently occurs due to coagulo-
pathy [3, 4]. With laboratory testing, some of the deficits in the coagulation process
can be identified and with blood bank supplies patients' hemoglobin concentrations
can be maintained and some deficits in the pathways of blood coagulation can be
rectified. However, our understanding of coagulation processes is still incomplete
and our ability to intervene in the setting of inadequate coagulation is limited.
Furthermore, the use of large volumes of blood bank supplies, in the setting of on-
going major hemorrhage, carries its own list of complications, in particular on-
going organ damage and iatrogenic infection. Taking a broader view of the provi-
sion of health care in the context of limited resources, increasing demand for blood
bank components makes ever increasing inroads into scarce supplies.
It has become a matter of urgency given the above considerations to find a bet-
ter appreciation of the physiology of the coagulation process and its pathophysiolo-
gical disturbances around the time of those disease processes associated with major
hemorrhage. Along with a better understanding of the pathophysiology we need a
more comprehensive range of rapidly available tests of all aspects of the coagula-
tion process. Finally, and crucially, to improve treatment and outcomes for individ-
ual patients and to allow optimal utilization of blood bank resources we need treat-
ments which go beyond those traditionally used for coagulopathic bleeding; these
coagulopathic bleeding states being predominantly associated with the congenital
defecits in coagulation and the acquired defecits around times of major trauma
and surgery.
In the last decade we have gained new understandings of the physiology of the co-
agulation process and its pathological disturbance. We also have some further capac-
ity to measure important disturbances in coagulation function using thrombo-
elastography and measures of platelet function [5]. In terms of making a difference
in the direct treatment of major coagulopathic states we may have an agent whose role
in the treatment of congenital coagulation problems is well defined but which now can
be used in a novel manner for a variety of the acquired conditions as well.
Recombinant activated factor VII (rFVIIa, Novoseven, Novo Nordisk, Bagsvaerd,
Denmark), has been demonstrated to have an important role in the management of
Is Recombinant Activated Factor VII a Universal Hemostatic? 137
bleeding for patients with congenital hemophilia who have inhibitors [6-8] and in
the uncommon acquired hemophilias [9]. There is now a scientific understanding
of the central role of factor VII (FVII),. in other acquired coagulopathic states.
These include uremia, hepatic failure, and treatment with anti-coagulants but over-
ridingly from most critical care perspectives these are the coagulopathies associated
with major hemorrhage in the setting of trauma and surgery. In these clinical con-
ditions the role of FVII may translate into a treatment benefit from the use of
rFVIIa for severe hemorrhage secondary to coagulopathy acquired due to major
trauma or surgery. Focusing for critical care physicians it is in these areas of clini-
cal practice for which we review the treatment role of rFVIIa.
I The Role of Factor VII in Physiological Coagulation

Present understanding of normal processes of coagulation in response to vessel in-
jury puts tissue factor (TF) in a central role (Fig. 1) [10]. TF is not usually exposed
to the circulation, being linked to fibroblasts and smooth muscle cells deep to the
endothelium within the blood vessel wall. After injury, this TF becomes exposed to
the coagulation proteins of the plasma as an initiating event to the process of fibrin
clot formation.
The next step in this process is the complexing of TF with FVII or its activated
form (FVIIa); this is usually with FVII since only 1o/o is normally circulating al-
ready activated. Thus, complexed FVII bound to TF on cells becomes activated.
This leads to conversion of prothrombin to thrombin locally, a process also involv-
ing activated forms of factors IX and X [11].
X II
\ \. Vlll/vWF
vua""-xa~..._____ I
lla -----• ~
I
TF - Bearing Cell ) _,-'' \ VIlla

'--.,.G==---------...J , II
.
1
VIla IX v-va "
~X ~
II
II a
Fig. 1. The normal coagulation pathways based on a cellular model. Exposed tissue factor (TF) interacts
with FVII and via interaction with FX and FV leads to an initial thrombin burst. This is amplified to a full
thrombin burst by the role of activated platelets and factors V, VII, VIII, IX, X. The process occurs locally
at the site of vessel and tisue injury. From [1 0] with permission
138 P. Diprose et al.
In order to achieve a normal hemostatic response to vessel trauma, an amplified

production of thrombin is necessary in the presence of activated platelets. This
platelet activation results from the initial production of thrombin. The activated
platelets bind active forms of coagulation factors IX, VIII, V, and X with resultant
activation of further factor VIII, V, and XI so leading to the production of maximal
levels of thrombin.
This thrombin burst is central to fibrin production, aetivation of further plate-
lets, and equally importantly in aiding stabilization of the fibrin plug. The fibrin
plug stabilizing effect is mediated by the production of thrombin-activatable fibri-
nolysis inhibitor along with FXIII and possible other fibrinolysis controlling com-
pounds [12, 13].
Therefore, for coagulation to proceed normally towards the formation of a stable
hemostatic plug at the site of vessel injury, FVII must be present in the plasma at
levels close to the normal range. Furthermore, in evaluating the role of FVII it is
apparent that it contributes to a very local activation of the coagulation process
since it interacts with cellular bound TF to cause a local generation of thrombin
rather than a systemic reaction.
I Coagulation Abnormalities in Trauma or Major Surgery
A broad range of adverse changes to the endogenous processes for achieving he-
mostasis may occur with trauma and around the time of major surgery. Dilution of
coagulation factors leads to a reduction in the initial and sequential thrombin
bursts. This is further damaged by the reduction in platelet count available for acti-
vation. A lowered level of fibrinogen then reduces the generation of fibrin, and
along with the thrombocytopenia, the lessening of initial clot production.
The clot that is generated is weakened by the lack of stabilization from throm-
bin-activatable fibrinolysis inhibitor and FXIII both of which will be reduced. Ac-
tive fibrinolysis due to released tissue plasminogen activator further damages what
hemostasis has been achieved.
These disturbances of the pathways to hemostasis are clearly multi-factorial in
origin. The complex causative events including dilution of coagulation proteins and
platelets by resuscitation fluids [14], direct effects of some resuscitation fluids such
as hydroxyethyl starches [15,16], hypothermia [17], acidosis and direct trauma to
tissues [18, 19].
While no single therapy will reverse all these causative processes, returning
thrombin generation as a central event in coagulation to normal will be very pro-
ductive in returning hemostasis overall towards normal.
I Pharmacology of Recombinant Activated FVII

Recombinant FVIIa acts similarly to endogenous FVII in binding to TF and stimu-
lating a local coagulation process involving factor X. This leads to an initial throm-
bin burst and fibrin production. Recombinant FVIIa also activates factor IX. There-
fore, overall there is activation of factors IX, X, and II with fibrin production [20].
Recombinant FVIIa can also bind with the platelet surface and give rise to a full
thrombin burst independent of factor VIII or IX (Fig. 2) [21]. This is very predomi-
X II
VII~Xa~" ' - - l l a
TF -Bearing Cell I ,,,''\
'------,Q=TF=----------' ,.-' \
~ V--+Va "
Fig. 2. The ability of rFVIIa to promote full thrombin burst generation independently from the roles of
FVIII and FIX. FVIIa interacts with TF, and FV and FX. This involves TF bearing cells and activated platelets
and can lead to optimal thrombin generation. From [1 0] with permission
nantly a local phenomenon at the site of vessel injury, therefore, limiting the degree
of systemic activation and so decreasing the likelihood of systemic fibrin forma-
tion.
Therapy with rFVIIa, therefore, has the ability to normalize local thrombin gen-
eration in response to vessel injury where thrombin generation has been disturbed
by a variety of pathologies. This thrombin can then normalize both production of
fibrin and its stabilization into a functional hemostatic clot [20].
The published indications for use of rFVIIa are bleeding or required surgery in
patients with inherited or acquired hemophilia in the presence of inhibitors to face
tors VIII or IX [6-8]. Its use in coagulopathic bleeding due to trauma or surgery is
at present unlicensed but has been extensively used on a named patient basis at the
judgement of the responsible physician [22-24].
The pharmacodynamic effect of rFVIIa in leading to thrombin generation is
dose dependant. A dose of rFVIIa of 120 meg/kg body weight leads to a plasma lev-
el of 2-3 mcg!ml [20]. This produces a level of FVII functional clotting ability of
60-90 units/ml that leads to thrombin generation equivalent to that of normal indi-
viduals [21]; however, this should be put in the context of considerable individual
patient variability [25] and, therefore, this dose may not generate normal amounts
of thrombin in some individuals. In addition, pharmacokinetic data from hemophi-
liac patients shows that pediatric patients may have a substantially greater clear-
ance, and a shorter plasma half-life, than adults [26]. Therefore, in some patients,
adult or pediatric, an adjusted dosing schedule with higher initial dose or shorter
interval before considering repeat dosing may be appropriate.
The appropriate treatment interval is uncertain in the hemorrhage around time
of trauma-surgery population. While in hemophiliac patients a dosing interval of 2
hours is often necessary [27], in the non-hemophiliac population an observation of
response to the initial dose is more commonly used. A single initial dose is often
all that is required to return hemostasis to that adequate to control major coagulo-
pathic bleeding. However, clearly a repeating schedule along the lines of that used
for the hemophiliac population may be considered.
Monitoring of the Effects of rFVIIa
In this population, the clinical effect on rate of hemorrhage once optimal surgical
control has been achieved is critical. However, in an attempt to make our assess-
ment of the effects of rFVIIa more scientific, testing the coagulation pathways dur-
ing treatment is important.
While activated partial thromboplastin and prothrombin times may reflect to
some extent improvements in coagulation [22], these may be variable between pa-
tient groups [28]. Some other measures of coagulation may not be readily available
but they may provide a more meaningful window on the effects of rFVIIa on coag-
ulation. FVII levels may be assayed [22] or the one stage clotting assay of FVII
functional clotting ability may be utilized. However, a measure of thrombin genera-
tion may be the more appropriate test to look at, this being obtained via modified
thromboelastography, a measure of endogenous thrombin generation [29], or
through a measure of whole blood coagulation [30].
Laboratory Results from Clinical Models using rFVIIa

The experimental evidence for the efficacy of rFVIIa in the trauma setting has
rested on a series of papers describing the effects of its administration on the man-
agement of a massive liver injury in a pig model. There is evidence that if pigs are
rendered both hypothermic and coagulopathic rFVIIa can reverse the abnormal co-
agulation function and significantly reduce blood loss [31]. Subsequent work by
Schreiber et al. [32] confirmed these initial findings but also showed that the more
often quoted dose of 120 meg/kg was as effective at reducing blood loss as a con-
siderably larger dose of 720 meg/kg. Finally, in a recent paper there appeared to be
a trend towards showing a decreased mortality in pigs with severe liver injury
(avulsion of the left median lobe) of 0 versus 43% in the placebo group but with
small numbers not quite reaching statistical significance (p = 0.08) [33].
Clinical Experience with Recombinant Activated FVII

We shall review the evidence from the use of rFVIIa in the clinical settings of hem-
orrhage around the times of accidental trauma or surgery. Although there is already
an extensive body of literature demonstrating efficacy in inherited and also ac-
quired hemophila, in the critical care field the major sources of coagulopathy asso-
ciated major hemorrhage are from trauma and surgery.
Trauma
Much of the evidence for the efficacy of rFVIIa in the trauma setting comes from
the work of Martinowitz and others from Israel. Martinowitz' group initially de-
scribed in 1999 the successful management of a 19 year old soldier who had sus-
tained a gunshot wound tearing through the inferior vena cava (34]. The patient
had continued to bleed in spite of massive blood product transfusion and surgical
attempts at hemostasis including repeated packing of the trauma site. A total dose
of 120 meg/kg of rFVIIa was administered with a good hemostatic effect.
Following this, a further series of 7 patients who had received rFVIIa for adjunc-
tive hemorrhage control in trauma (both blunt and penetrating) was reported [22].
All seven patients had conventional attempts to achieve hemostasis and had re-
ceived a median of 40 units of red blood cells (RBCs, range of 25-49 units) prior
to the administration of rFVIIa. Four patients survived with the three deaths being
attributed to reasons unrelated to rFVIIa administration. The dose of rFVIIa re-
quired to achieve effective hemostasis was variable with the total ranging from 120
to 212 meg/kg.
Cardiac Surgery
The cardiac surgical population are at high risk of coagulopathic bleeding peri-op-
eratively for reasons including thrombocytopathy, thrombocytopenia, fibrinolysis,
and sometimes dilution of coagulation proteins (Fig. 3). The published use of
rFVIIa for severe intractable cardiac surgical bleeding is limited to a number of
case reports and clinical series although at least one clinical trial is ongoing. Al
Douri et al. reported the use of rFVIIa in an open-label study for 5 cardiac patients
all of whom had excessive and uncontrollable bleeding [24]. Effective hemostasis
was achieved in all 5 patients at a dose of 30 jlg/kg, although one patient subse-
quently died of right ventricular failure. In 2001, another case report of a patient
with severe intractable bleeding after tricuspid and mitral valve repair documented
120
c
0
·.;::;
~
~'
c-
v:::i!
100
''
''
v UJ
CV"I
0
v '
.....
"'
+ 80 ''
2~ '' ... ..-!
V::::>
~.:::::.
60 ' ... ...
' ...
/
c
"'
Cll
:::1! ' 'r ...
40
Pre Bypass Post
Fig. 3. Coagulopathy may be present after cardiopulmonary bypass because of loss of coagulation pro-
teins. Factor VII plasma levels pre-cardiopulmonary bypass (pre), on bypass (bypass), and after cardiopul-
monary bypass (post) (n = 18). Unpublished data from Southampton University Hospital
1600
1400
1200
'2
..... 1000
I 800
"'
"'
.2 600
"00 400
a:;
200
0 ·~
Fig. 4. Blood loss (ml/hour) before and after
Before After administration of rFVIIa in the first 5 patients
at Southampton University Hospital
Table 1. Administration of homologous blood coagulation products to patients bleeding post cardiac
surgery before and after administration of rFVIIa. Data (n = 10) Southampton University Hospital. Data in
units of products, or units of Beriplex, which is a prothrombin complex product
Product BefoR! rFVlla After rFVIIa

I Fresh-frozen plasma 2 (0-12) 0
I Platelets 2 (2-4) 0 (0-3)
I Cryoprecipitate 10 (0-10) 0
I Beriplex411 1000 (0-1000) 0
the successful use of rFVIIa at a dose of 90 Jlg/kg, with marked reduction in blood
loss and improvement in most coagulation parameters [35].
In our adult cardiac unit, since 2001, we have used rFVIIa for 16 patients with
severe intractable coagulopathic bleeding [28]. Ten patients have survived to hospi-
tal discharge. Administration of rFVIIa was accompanied in the majority of patients
by a dramatic reduction in blood loss (Fig. 4) and concomitant reduction in need
for further red cell and coagulation product transfusion (Table 1). Of the 6 deaths,
four patients died from continued hemorrhage peri-operatively and other two died
from causes believed to be unrelated directly to bleeding or rFVIIa administration.
These are promising results although a note of caution exists on the use of
rFVIIa in patients with active coronary artery disease who as a result of the expres-
sion of tissue factor on coronary artery plaques may be at increased risk of coro-
nary thrombosis [36].
Hepatic Surgery and Hepatic Failure

Treatment with rFVIIa in coagulopathic cirrhotic patients prior to laparoscopic liv-
er biopsy appears to be safe and effective in terms of normalization of prothrombin
time, speed of hemostasis and no requirement for blood transfusion in a total of
71 patients [37]. Results of a pilot study of the use 80 jlg/kg of rFVIIa for 6 patients
undergoing orthotopic liver transplantation were reported in 2001 [38]. The investi-
gators found that there were significant reductions in the transfusion of homolo-
gous RBCs and coagulation products and in the quantity of blood lost from these
patients as compared to matched controls. Of note, however, was the development
in one patient of hepatic vein thrombosis. In a subsequent study by the same
group, the coagulation parameters of another six patients undergoing liver trans-
plantation who received 80 J..lg/kg of rFVIla were compared with matched controls
[39]. The results showed significantly improved prothrombin and activated partial
thromboplastin times together with improvement of the majority of thromboelasto-
graphy parameters.
Abdomino-pelvic Surgery
Recombinant FVIIa has also been used in abdomino-pelvic surgery. Both in the set-
ting of intractable bleeding during complex abdominal surgery [40, 41), and when
used prospectively for retro-pubic prostatectomy [23], rFVIIa has shown significant
efficacy.
I Safety of rFVIIa
Infection
Recombinant FVIIa is produced, without exposure to human plasma, in hamster re-
nal cells with the cooperation of fetal calf serum. Therefore, there should be a zero
risk of transmission of human based pathogens. Theoretical risks of transmitting
agents causing encephalopathies remains, but realistically this should be only theo-
retical.
Thrombotic Episodes
The vast majority of rFVIIa usage has been in patients with hemophilia so although
we are principally reviewing its use in acquired non-hemophiliac coagulopathic
bleeding these are important safety data to include in our considerations. During
the last six years, over 200 000 doses of rFVIIa have been utilized, but only 24
thrombotic events have been reported [42]. The majority have been in the elderly
where known or covert vascular disease will be more common. Furthermore, other
risk factors were present in all patients other than the use of rFVIIa, and no dose
relationship was present in relation to the occurrence of thrombotic events. These
results demonstrate an excellent risk-benefit profile for the use of rFVIIa overall.
However, in the context of trauma and major surgery, it may be a balanced view in
patients with significant vascular disease to only use rFVIIa if there is serious hem-
orrhage with a coagulopathic basis, rather than using it in a prophylactic manner
to try to avoid a coagulopathy developing. This balance clearly requires decision
making on a case-by-case basis and ideally backed by some experience in the use
of rFVIIa.
This safety record is backed up by data from administration of rFVIIa to healthy
volunteers [43]. No adverse effects have been noted in this setting and although
there have been markers of increased extravascular coagulation this does not seem
to have been accompanied by increased intra-vascular coagulation [44).
Immunological
No inhibitor production should follow from the use of rFVIIa since it contains no
factors VIII or IX.
I Conclusion
The management of patients with severe hemorrhage due to coagulopathy in the

setting of accidental trauma or major surgery is a challenge for all clinicians in-
volved. These clinical scenarios carry high risks of morbidity and mortality for pa-
tients while there are intense pressures for clinicians to husband the finite resources
of our blood banks. It is crucial both for reasons of patient outcome and resource
utilization that we progress the treatment options in these problematic states.
Whilst scientific understanding of the coagulation process and laboratory monitor-
ing of its dysfunction are important, the crux in improving clinical outcome is real-
ized by novel treatments which are shown to be effective. In rFVIIa we have a drug
that is well recognized in the management of congenital coagulation deficits and in
the treatment of the rare acquired hemophilias. Beyond this, in the field of other
more nebulous acquired deficits in coagulation function, rFVIIa is receiving intense
interest. The preliminary findings of sporadic clinical experience and now some
evidence from clinical trials are very positive in a range of trauma and surgical set-
tings. Following on from this fledgling experience there are many new studies on
the horizon offering the potential of an exciting treatment opportunity for these
difficult to manage patients [42].
Although it may be premature to answer the question embedded in the title of
this review in the affirmative, there are a remarkably diverse range of inherited and
acquired coagulopathic conditions in which rFVIIa has been demonstrated to carry
benefit in reducing hemorrhage and improving outcome. The basic science under-
standing we have at present also backs this up by pointing to a wide range of con-
ditions where rFVIIa might be expected to be beneficial. The new studies being un-
dertaken at present will hopefully eventually answer this question with positive evi-
dence.
References
1. Gofrit ON, Leibovici D, Shapira SC, Shemer J, Stein M, Michaelson M (1997) The trimodal
death distribution of trauma victims: military experience from the Lebanon War. Mil Med
162:24-26
2. Sauaia A, Moore FA, Moore EE, et al (1995) Epidemiology of trauma deaths: a reassess-
ment. J Trauma 38:185-193
3. Cosgriff N, Moore EE, Sauaia A, Kenny-Moynihan M, Burch JM, Galloway B (1997) Pre-
dicting life-threatening coagulopathy in the massively transfused trauma patient: hypother-
mia and acidoses revisited. J Trauma 42:857-861
4. Attar S, Boyd D, Layne E, McLaughlin J, Mansberger AR, Cowley RA (1969) Alterations in
coagulation and fibrinolytic mechanisms in acute trauma. J Trauma 9:939-965
5. Kaufmann CR, Dwyer KM, Crews JD, Dols SJ, Trask AL (1997) Usefulness of thrombelasto-
graphy in assessment of trauma patient coagulation. J Trauma 42:716-720
6. Diness V, Bregengaard C, Erhardtsen E, Hedner U (1992) Recombinant human factor VIla
(rFVIIa) in a rabbit stasis model. Thromb Res 67:233-241
7. Hedner U, Glazer S, Pingel K, et al (1988) Successful use of recombinant factor VIla in pa-
tient with severe haemophilia A during synovectomy. Lancet 2:1193
8. Glazer S, Redner U, Falch JF (1995) Clinical update on the use of recombinant factor VII.
Adv Exp Med Biol386:163-174
9. Green D, Lechner K {1981) A survey of 215 non-hemophilic patients with inhibitors to Fac-
tor VIII. Thromb Haemost 45:200-203
10. Hoffman M, Monroe DM, III, Roberts HR {1998) Activated factor VII activates factors IX
and X on the surface of activated platelets: thoughts on the mechanism of action of high-
dose activated factor VII. Blood Coagul Fibrinolysis 9 (suppl1):S61-S65
11. Hoffman M, Monroe DM, Oliver JA, Roberts HR {1995) Factors IXa and Xa play distinct
roles in tissue factor-dependent initiation of coagulation. Blood 86:1794-1801
12. Bajzar L, Manuel R, Nesheim ME {1995) Purification and characterization of TAFI, a
thrombin-activable fibrinolysis inhibitor. J Bioi Chern 270:14477-14484
13. Bouma BN, Meijers JC (1999) Fibrinolysis and the contact system: a role for factor XI in
the down-regulation of fibrinolysis. Thromb Haemost 82:243-250
14. Gubler KD, Gentilello LM, Hassantash SA, Maier RV (1994) The impact of hypothermia on
dilutional coagulopathy. J Trauma 36:84:7-851
15. Jamnicki M, Zollinger A, Seifert B, Popovic D, Pasch T, Spahn DR (1998) Compromised
blood coagulation: an in vitro comparison of hydroxyethyl starch 130/0.4 and hydroxyethyl
starch 200/0.5 using thrombelastography. Anesth Analg 87:989-993
16. Jarnnicki M, Zollinger A, Seifert B, Popovic D, Pasch T, Spahn DR (1998) The effect of po-
tato starch derived and corn starch derived hydroxyethyl starch on in vitro blood coagula-
tion. Anaesthesia 53:638-644
17. Bergstein JM, Slakey DP, Wallace JR, Gottlieb M {1996) Traumatic hypothermia is related
to hypotension, not resuscitation. Ann Emerg Med 27:39-42
18. Gando S, Tedo I, Kubota M {1992) Post-trauma coagulation and fibrinolysis. Crit Care
Med 20:594-600
19. Kapsch DN, Metzler M, Harrington M, Mitchell FL, Silver D {1984) Fibrinolytic response
to trauma. Surgery 95:473-478
20. Redner U, Erhardtsen E {2002) Potential role for rFVIIa in transfusion medicine. Transfu-
sion 42:114-124
21. Monroe DM, Hoffman M, Oliver JA, Roberts HR (1997) Platelet activity of high-dose factor
VIla is independent of tissue factor. Br J Haematol 99:542-547
22. Martinowitz U, Kenet G, Segal E, et al {2001) Recombinant activated factor VII for adjunc-
tive hemorrhage control in trauma. J Trauma 51:431-438
23. Friederich PW, Geerdink MG, Spataro M, et al (2000) The effect of the administration of
recombinant activated factor VII (NovoSeven) on perioperative blood loss in patients un-
dergoing transabdominal retropubic prostatectomy: the PROSE study. Blood Coagul Fibri-
nolysis 11 (suppl 1):S129-S132
24. AI Douri M, Shafi T, AI Khudairi D, et al {2000) Effect of the administration of recombi-
nant activated factor VII (rFVIIa; NovoSeven) in the management of severe uncontrolled
bleeding in patients undergoing heart valve replacement surgery. Blood Coagul Fibrinolysis
11 (suppl1):S121-S127
25. Sumner WT, Monroe DM, Hoffman M {1996) Variability in platelet procoagulant activity
in healthy volunteers. Thromb Res 81:533-543
26. Erhardtsen E {2000) Pharmacokinetics of recombinant activated factor VII (rFVIIa). Semin
27. Redner U, Ingerslev J (1998) Clinical use of recombinant FVIIa (rFVIIa). Transfus Sci
19:163-176
28. Diprose P, Herbertson MJ, O'Shaughnessy D, Gill R {2002) Recombinant factor VIla for se-
vere cardiac surgical bleeding - A review of our first seven patients (abstract presented at
Rome NATA meeting)
29. Dam-Mieras MC, Muller AD, van Deijk WA, Hemker HC (1985) Clotting factors secreted
by monocytes and macrophages: analytical considerations. Thromb Res 37:9-19
30. Melton LG, Thompson CM, Ezban M {1999) Response of rFVIIa concentrate on hemostasis
in hemophilia (abstract). Blood 94 (Suppl1):228
31. Martinowitz U, Holcomb JB, Pusateri AE, et al {2001) Intravenous rFVIIa administered for
hemorrhage control in hypothermic coagulopathic swine with grade V liver injuries. J
Trauma 50:721-729
146 P. Diprose et al.: Is Recombinant Activated Factor VII a Universal Hemostatic?
32. Schreiber MA, Holcomb JB, Hedner U, Brundage SI, Macaitis JM, Hoots K (2002) The ef-
fect of recombinant factor VIla on coagulopathic pigs with grade V liver injuries. J Trauma
53:252-257
33. Lynn M, Jerokhimov I, Jewelewicz D, et al (2002) Early use of recombinant factor VIla im-
proves mean arterial pressure and may potentially decrease mortality in experimental he-
morrhagic shock: a pilot study. J Trauma 52:703-707
34. Kenet G, Walden R, Eldad A, Martinowitz U (1999) Treatment of traumatic bleeding with
recombinant factor VIla. Lancet 354:1879
35. Hendriks HG, van der Maaten JM, de Wolf J, Waterbolk TW, Slooff MJ, van der Meer J
(2001) An effective treatment of severe intractable bleeding after valve repair by one single
dose of activated recombinant factor VII. Anesth Analg 93:287-289
36. Dietrich W, Spannagl M (2002) Caveat against the use of activated recombinant factor VII
for intractable bleeding in cardiac surgery. Anesth Analg 94:1369-1370
37. Jeffers L, Chalasani N, Balart L, Pyrsopoulos N, Erhardtsen E (2002) Safety and efficacy of
recombinant factor VIla in patients with liver disease undergoing laparoscopic liver biopsy.
Gastroenterology 123:118-126
38. Hendriks HG, Meijer K, de Wolf JT, et al (2001) Reduced transfusion requirements by re-
combinant factor VIla in orthotopic liver transplantation: a pilot study. Transplantation
71:402-405
39. Hendriks HG, Meijer K, de Wolf JT, et al (2002) Effects of recombinant activated factor VII
on coagulation measured by thromboelastography in liver transplantation. Blood Coagul
Fibrinolysis 13:309-313
40. White B, McHale J, Ravi N, et al (1999) Successful use of recombinant FVIIa (Novoseven)
in the management of intractable post-surgical intra-abdominal haemorrhage. Br J Haema-
tol107:677-678
41. Vlot AJ, TonE, Mackaay AJ, Kramer MH, Gaillard CA (2000) Treatment of a severely bleed-
ing patient without preexisting coagulopathy with activated recombinant factor VII. Am J
Med 108:421-423
42. Erhardtsen E (2002) Ongoing NovoSeven((R)) trials. Intensive Care Med 28 (Suppl
2):S248-S256
43. Friederich PW, Levi M, Bauer KA, et al (2001) Ability of recombinant factor VIla to gener-
ate thrombin during inhibition of tissue factor in human subjects. Circulation 10:2555-
2559
44. Bauer KA, Kass BL, ten Cate H, Hawiger JJ, Rosenberg RD (1990) Factor IX is activated in
vivo by the tissue factor mechanism. Blood 76:731-736
I Infectious Challenges
Nasal Carriage of Staphylococcus aureus:
Associated Risks and Preventive Measures
H.F.L. Wertheim and J.A.J.W. Kluytmans
1 Introduction
Humans are a natural reservoir for Staphylococcus aureus. This micro-organism is a

frequent cause of clinically important infections, including bacteremia, metastatic
abscesses, septic arthritis, pneumonia, osteomyelitis, and wound infections [1].
Many of these infections are nosocomial and lead to increased hospital stay, anti-
biotic use, costs, and mortality [2]. Due to an increasing number of infections
caused by methicillin-resistantS. aureus (MRSA) strains, which are now most often
multi-resistant, therapy has become problematic. Even more worrying is the fact
that recently the first vancomycin-resistant S. aureus has been cultured in the Unit-
ed States [3]. Therefore, prevention of staphylococcal infections is of the uttermost
importance.
Nasal carriage of S. aureus plays a central role in the development of S. aureus
infections [4]. This chapter will mainly focus on the latest developments in research
on determinants of S. aureus nasal carriage, the risks for infection associated with
S. aureus nasal carriage, and strategies for prevention.
Epidemiology of S. aureus Nasal Carriage
S. aureus colonizes the skin and mucosal surfaces of humans and also of several
animal species.
Studies have shown that the anterior nares are the most consistent site from
which this organism can be cultured [5]. In longitudinal studies, three types of S.
aureus nasal carriers can be distinguished: persistent carriers, intermittent carriers,
and non-carriers [5]. Between 10 and 35% of healthy individuals almost always car-
ry one strain and are called persistent carriers. A larger proportion (20 to 75%)
harbors S. aureus intermittently, and are called intermittent carriers. Finally, be-
tween 5 and 50% almost never carry S. aureus and are called non-carriers [5].
Genotyping data reveal that persistent carriers usually carry only one identical S.
aureus strain over time and that intermittent carriers commonly carry different
strains over time [5]. The load of S. aureus is higher in persistent carriers com-
pared to intermittent carriers, resulting in more dispersal and higher risk of infec-
tion [5]. Persistent carriage is more common in children than in adults and many
people shift from persistent carriage to intermittent or non-carriage between the
age of 10 and 20 years [5]. The reasons for these differences in colonization pat-
terns are not yet known.
150 H. F.L. Wertheim and J. A. J. W. Kluytmans
Cross-sectional studies yield a prevalence of approximately 35o/o in the general

population, which is actually a mix of persistent and intermittent carriers at that
time point [6]. Increased carriage rates are found in hospitalized patients. Sub-
groups of patients with significantly increased carriage rates include those with in-
sulin-dependent diabetes mellitus, on hemodialysis or continuous ambulatory peri-
toneal dialysis (CAPD), intravenous drug use, S. aureus skin infections, liver dys-
function, and human immunodeficiency virus (HIV) [6]. The reasons for the high-
er carriage rates are largely unclear, however repeated puncturing of the skin seems
to play a role.
Mechanisms of S. aureus Nasal Carriage

The mechanisms that may lead to S. aureus nasal carriage are multifactorial, and it
is the net result of repellent and attracting forces that decide whether an individual
is a carrier at a certain time point. Only S. aureus strains that are capable of with-
standing host defenses (innate immunity) and that can reach the site to which they
can adhere, will result in a carrier state. The different mechanisms that play a role
in S. aureus nasal carriage are summarized in Table 1.
The anterior nares are anatomically a mixture of fully keratinized epidermis
with hairs, sebaceous glands and sweat glands, squamous epithelium and ciliated
mucosal membrane. A recent study has demonstrated that S. aureus predominantly
colonizes the moist squamous epithelium on the septum adjacent to the nasal os-
tium. This area is devoid of cilia and relatively absent of nasal mucous secretions
that contain antimicrobial peptides [7]. It has been suggested that S. aureus nasal
carriers have deficiencies in their innate immune response, but recent data do not
support this [8]. These data show that S. aureus nasal colonization induces a neu-
trophil-mediated inflammatory response, which fails to clear the colonizing bacteria
[7]. Twin studies and family studies are not conclusive as to whether there is evi-
dence for genetic determinants [9]. One study, where persistent carriers and non-
carriers were inoculated with a mix of different S. aureus strains, including the resi-
dent strain of carriers, showed that most non-carriers expel the S. aureus strains
and persistent carriers usually select their resident strain out of the mix [6]. This
proves that host determinants are important, but still remain to be elucidated. In
addition, behavior, like nosepicking, is a risk factor for S. aureus nasal carriage,
probably by making lesions in the nose [10].
S. aureus adherence may be non-specifically mediated via physicochemical forces
including hydrophobic interactions. Alternatively, adherence may more specifically
be accomplished through binding of certain bacterial cell surface moieties (adhe-
sins) to defined structural receptors in the membrane of the host cell [5]. Recent
experiments have shown that clumping factor B, a S. aureus virulence factor, is cap-
able of adhering to human cytokeratin type 10 (O'Brien L.M., et al., Poster presen-
tation, lOth ISSSI Conference, 2002). Polymorphisms in the genes coding for either
keratin or clumping factor and many other putative adhesins and receptors may be
a clue to carriership of S. aureus, but research in this field is lacking.
Nasal Carriage of Staphylococcus aureus: Associated Risks and Preventive Measures 151
Table 1. Overview of mechanisms influencing 5. aureus nasal carriage
Mechanism Host S. aurws
General Age Virulence

Sex Bacterial interference by coagu-
Race lase negative staphylococci and
corynebacteria.
Nosepicking
Nasal abnormalities
Immune status
HLA type
Underlying illness•
Antibiotic use
Adherence Keratin type 10 Clumping factor B
Epithelial membrane Lipoteichoic acid
Teichoic acid
Collagen Collagen binding protein
Vitronecti n Vitronectin binding protein
Fibronectin Fibronectin binding protein
Fibrinogen Fibrinogen binding protein
La minin Laminin binding protein
Mucins Capsular polysaccharides
(Extracellular) matrix proteins MSCRAMMsb
Charge Charge
Hydrophobicity Hydrophobicity
(Evading) immune Clearance in mucus by microvilli Protein A (binds Fe of lgG)
response Lysozyme, lactoferrin, Host cell internalization
antimicrobial peptides Resistance to antimicrobial
peptides
• insulin-dependent diabetes mellitus, HIV-positive patients, dialysis patients, intravenous drug use
b microbial surface components recognizing adhesive matrix molecules
I Clinical Impact of S. aureus Nasal Carriage
In the late 1950s there was a pandemic of serious staphylococcal infections in both
community and hospitals, which involved strains resistant to many available anti-
biotics at that time [5]. The spread and virulence of S. aureus in the hospital was
considered to be enhanced by resistance. In 1959, several reports were published
that investigated the relation between nasal carriage of S. aureus and the develop-
ment of surgical wound infections. A clonal relation between nasal strains and in-
fectious strains was often found, as determined in those days by phage typing.
Further studies showed a significantly increased risk for development of a wound
infection by nasal carriers. The causal relationship is emphasized by a correlation
between the colonization density of S. aureus at the carriage site and the risk for
the development of infection [5].
Since then, carriage of S. aureus has been identified as a risk factor for the de-
velopment of infections in various setting. This has been studied extensively in sur-
152 H. F.L. Wertheim and J.A.J. W. Kluytmans
gical patients (general, orthopedic, and thoracic surgery), in patients on hemodialy-

sis, in patients on CAPD, HIV-infected patients, and in patients in intensive care
units (ICUs). Von Eiff et al. have elegantly illustrated in a prospective study that
nasal strains and subsequent bacteremic strains have the same genotype in more
than 80% of cases, by pulsed field gel electrophoresis [11]. Wertheim et al. [12],
studied the incidence of bacteremia in carriers as well as non-carriers in a non-sur-
gical patient population (n=14014}. This study found a significantly increased risk
for S. aureus nasal carriers to acquire a nosocomial S. aureus bacteremia, compared
to non-carriers, relative risk of 2.9 (95% CI: 1.9-4.3) [12]. The bacteremic strain of
the carriers had the same genotype as the nasal strain in approximately 80% of
cases.
A contradictory study found that the presence of a central venous catheter (odds
. ratio 6.9), anemia (odds ratio 3.3), or hyponatremia (odds ratio 3.3} was associated
with hospital acquired S. aureus bacteremia [13]. Nasal carriage of S. aureus was
not an independent risk factor for nosocomial S. aureus bacteremia, but the design
of this study was not adequate to study this association. Nasal carriers among pa-
tients in surgery (odds ratio 4.0) did have a higher risk for nosocomial S. aureus
bacteremia compared to controls. The presence of S. aureus bacteremia significantly
increased the mortality (2.4- fold). Anemia and hyponatremia are probably proxies
for severity of disease and should not be considered as risk factors.
In hemodialysis patients, S. aureus is the most frequently found pathogen in in-
fections at the vascular access site and in bacteremia [5]. The infection rate is high-
er in carriers on hemodialysis, with relative risks varying from 1.8 to 4.7 [5]. S.
aureus isolates are usually identical to that previously isolated from the patient's
nares. In patients treated with CAPD, S. aureus is the leading cause of exit site- and
tunnel-infection, often leading to catheter loss. The observed relative risks for car-
riage are even higher than those in hemodialysis patients (range: 1.8 to 14.0} [5].
Also, in CAPD patients, the nasal strain and the infectious strain are clonally re-
lated in most cases [5].
In HIV-positive patients, increased rates of S. aureus bacteremia and deep soft
tissue infections have been observed, which frequently recur. Even higher rates are
found in patients with acquired immunodeficiency syndrome (AIDS) compared
with HIV-positive, asymptomatic patients. Nguyen et al. found that nasal carriage
is an important risk factor in this patient population (odds ratio 5.1) [14]. Other
risk factors for infection in this study were presence of a vascular catheter (odds
ratio 4.9}, low CD4 cell count (< 100 cells/mm3 ; odds ratio 3.5) and neutropenia.
The risk for developing a S. aureus infection was approximately 10% for every six
months in patients who were nasal carriers of S. aureus and had CD4 cell counts of
less than 100/cells/mm3 • It should be noted that nasal carriage was more common
in patients who were not receiving trimethoprim-sulfamethoxazole prophylaxis.
After coagulase-negative staphylococci, S. aureus is the most prevalent organism
causing intravascular device-associated bacteremia [5]. However, no study has been
performed with the primary aim of establishing the role of S. aureus nasal carriage
in this setting. Pujol et al. looked at bacteremia in an ICU. Most of the S. aureus
bacteremias had an intravascular device as a source. In this study, carriers of S.
aureus had a relative risk of 12.4 for the development of S. aureus bacteremia [15].
Carriage of MRSA constitutes a special problem with regard to prevention and
treatment of infection. Studies show that nasal MRSA carriers have a higher risk of
nosocomial infection with this microorganism, and more morbidity and mortality
compared to carriers of susceptible strains [15, 16].
I From Nose to Infection

The nose is regarded as the ecological niche from where S. aureus can spread to
other parts of the body. Elimination of nasal carriage by using topical mupirocin
also eliminates hand carriage [17]. These observations suggest that, from the nose,
the skin becomes colonized, which can cause subsequent colonization of impaired
skin sites, like surgical wounds and catheter exit sites. Whether colonization at an
impaired site leads to infection and whether it is contained or spreads from there,
depends on a complex interplay between S. aureus virulence factors and host de-
fense mechanisms [1]. The risk of infection is increased by the presence of foreign
material. This can be explained by the impaired phagocytic function in the pres-
ence of foreign material and coating of these materials with human serum proteins
to which S. aureus can adhere and where it can propagate [1].
In surgical patients, other routes to infection may be considered, which have not
been studied yet. Intubation prior to surgery traumatizes the epithelial lining of the
throat, which may cause hematogenous spreading of S. aureus to the surgical site.
However, most surgical procedures include the use of antimicrobial prophylaxis,
which should protect against this route of infection. Another possibility is that S.
aureus is dispersed from the nose into the air of the operating room and then con-
taminates the surgical site during or soon after surgery. Antimicrobial prophylaxis
is usually not sufficient to eliminate strains at the surgical site, and a few days after
the surgical procedure a surgical site infection may occur. As already mentioned,
the skin of nasal carriers of S. aureus is often concomitantly colonized by this
pathogen. Preoperative disinfection may not be effective in the deeper layers of the
skin where S. aureus can reside, or may not be effective for S. aureus colonies inter-
nalized in host cells. These colonies can become a source of infection during sur-
gery. The above described pathogenic mechanisms are only hypotheses and ought
to be confirmed in further studies. Studies are needed because an optimal preven-
tive strategy can be developed only when the pathogenesis is fully understood.
I Decolonization Strategies
In populations in which S. aureus nasal carriage is identified as a risk factor for infec-
tion it is conceivable that elimination of carriage would reduce the infection rate.
Three approaches for elimination of carriage are available:
1) local with nasal ointments or sprays,
2) systemic antibiotics, and
3) bacterial interference.
The available options are summarized in Table 2.
For the first option, mupirocin nasal ointment has shown to be efficacious in
eliminating S. aureus carriage. Mupirocin is well tolerated and, when used appro-
priately (application to the nose twice daily for 5 days), development of resistance
is minimal. An extensive review of the literature on mupirocin has been published
by Hudson [18]. Doebbeling et al. found that when mupirocin was applied to the
nose twice daily for 5 consecutive days, this resulted in elimination of carriage in
91 o/o of stable nasal carriers [19]. Four weeks post-treatment, 87o/o of the subjects
remained free of nasal carriage, at six months 48o/o, and at 12 months 53o/o. In pa-
154 H. F.L Wertheim and J. A. J. W. Kluytmans
Table 2. Strategies a for eliminating 5. aureus from the nose

I
Strategy Frequency Efficacy Remark
Topicalb
Mupirocin nasal ointment 2% 2-3 times daily Very good Beware of resistance
Polysporin 2-3 times daily Good Use when therapy failure
Bacitracin 3 times daily Moderate Anaphylaxis reported
Chlorhexidine 4 times daily Poor Anaphylaxis reported
lysostaphin nasal cream not registered Potential Trial expected soon
Povidone-iodine cream unclear Potential Needs more evaluation
Tea tree oil 4% unclear Potential Needs more evaluation
Systemic
Rifampicin 600 mg/day Good Don't use as single therapy
Clindamycin 1200 mg/day Potential Needs more evaluation.
Combinations
Fusidic acid 2% and oral cotrimoxazole 3 times daily Very good As effective as mupirocin
Rifampicin and other oral or topical depends on Very good
drug combination
I Interference
5. aureus 502A not registered Good Prevents (re)colonization
Needs more evaluation
Corynebacteria not registered Potential Eliminates 5. aureus
Needs more evaluation
a most strategies are effective after 5 to 10 days. Always be aware of the possibility of resistant micro-or-
ganisms. Short-course therapies prevent resistance formation
b for MRSA decolonization, most strategies are combined with antiseptic skin scrub with chlorhexidine,
which is the most effective for 5. aureus decolonization
tients on hemodialysis, mupirocin is less effective. Apparently, in this group of pa-

tients other sites exist where S. aureus can maintain itself [20].
Although development of resistance to mupirocin was not observed in the clini-
cal studies for eradication of carriage, it has been reported repeatedly in the litera-
ture [21]. Generally, it has been found in cases of prolonged and extensive use,
such as in the form of skin-preparation. The resistance mechanism is transmissible
and causes concern about the future spread of mupirocin resistance, if it is used on
a large scale. Therefore, restricted usage of this antimicrobial agent is recom-
mended. 'Appropriate' means in selected groups of patients and for short courses
only.
Polysporin ointment (containing bacitracin, polymixin B, and gramicidin) was
shown to be successful in 82% of 11 cases who had previously failed a 1 week
course of topical mupirocin [22]. This ointment should be reserved for resistant or-
ganisms and/or treatment failure. Topical bacitracin is half as effective as mupiro-
cin for nasal decolonization and is, therefore, not considered an option for the pur-
pose of decolonization [23] . Acomparative study of mupirocin and oral cotrimoxa-
zole plus topical fusidic acid, both in conjunction with a chlorhexidine soap bath,
are equally effective and safe for the eradication of MRSA from nasal and extra na-
sal sites [24]. Novel strategies that may be helpful in the future are lysostaphin, tea
tree oil, and povidone-iodine cream. Lysostaphin is a rapid bactericidal anti-staph-
ylococcal agent that hydrolyzes the cell wall and old studies show elimination rates
of 90o/o [25]. Recently an intranasal lysostaphin cream has been developed and clin-
ical trials are expected in the near future. Tea tree oil has a wide spectrum of anti-
microbial activity and is relatively non-toxic when applied topically [26]. A con-
trolled trial should be performed with tea tree oil, to measure its efficacy in com-
parison with other regimes. In vitro studies with povidone-iodin cream indicate
that this ointment has potential and is suitable for clinical trials (27].
The second approach to eliminate S. aureus nasal carriage by administrating sys-
temic antibiotics, has been disappointing for most agents. Rifampicin has proven to
be an effective agent [28]. When prescribing rifampin, one must be aware of its
side effects and the prevalence of rifampin-resistant S. aureus isolates. It is advised
to combine rifampin with another oral drug or a topical drug, like bacitracin or
mupirocin. A potential effective drug is clindamycin, a bacteriostatic agent that
achieves high tissue concentrations. In a small study of seven carriers, clindamycin
was able to decolonize all these carriers [28]. This drug should be studied more ex-
tensively for the indication of nasal decolonization. Also quinolones achieve eradi-
cation rates of up to 70o/o and warrant further evaluation [28].
The third strategy is bacterial interference. This method is based upon the find-
ing that when two competing microorganisms fight for an ecological niche, the or-
ganism arriving first will usually prevail. This microorganism can accomplish this
by blocking receptor sites and/or quorum sensing. However, the exact mechanism
for bacterial interference has not been clarified. Colonization with a virulent strain
of S. aureus can be prevented by active colonization with a non-virulent strain of S.
aureus (502A) and other bacterial species. This strategy was used successfully in
nurseries during outbreaks of S. aureus infections in the 1960s and to treat patients
with recurrent furunculosis. However, due to a fatal infection with S. aureus 502A,
this strategy has been abandoned. Nevertheless, the benefits of the S. aureus 502A
interference program outweighed the hazards at that time. Recently S. aureus 502A
has been used in a trial with CAPD patients. S. aureus 502A is able to colonize the
nares after eliminating the resident strain and colonizes the exit sites after some
time (oral communication, Nouwen J., Erasmus M.C., The Netherlands). A recent
Japanese study in healthy volunteers has shown successful eradication by applica-
tion of corynebacteria in the nose [29]. More studies are needed to see if these
strategies are practical for daily clinical use and beneficial to the patient in terms
of clinical outcome.
For all strategies, recolonization or colonization with new S. aureus strains has
been described. Therefore, follow-up of individual patients by nasal culturing is
warranted and treatment should be given when these cultures are positive. Staying
ahead of antibiotic resistance by developing alternative effective eradication strate-
gies stresses the point that the exact mechanism of S. aureus carriership needs to
be elucidated.
I Prophylaxis
To prevent S. aureus infection, elimination of S. aureus nasal carriage seems to be
the most straightforward strategy. The introduction of mupirocin ointment in the
late 1980s led to several intervention studies. One study compared cardio-thoracic
surgery patients who received mupirocin prophylaxis (n = 868) with a historical

control group (n=928) [5]. The surgical wound infection rate in the control group
was 7.3% and was 2.8% in the treated group (p<0.001) [5].
Recently, two randomized controlled trials have been published, studying the ef-
ficacy of mupirocin in a general surgical and an orthopedic patient population [30,
31]. Perl et al. included 3 864 patients in their study, both carriers and non -carriers,
who were randomized to either mupirocin or placebo. Overall, 2.3% of mupirocin
recipients, and 2.4% of placebo recipients had S. aureus infections at the surgical
site. Nasal carriage of S. aureus was eliminated in 83.4% of patients who received
mupirocin, versus 27.4% of those who received placebo. Among the S. aureus nasal
carriers (n=891), 4.0% of those who received mupirocin had overall nosocomial S.
aureus infections, as compared with 7.7% of those who received placebo (odds ratio
for infection, 0.49 [0.25-0.92]). Kalmeijer et al. also included carriers and non-car-
riers, before an orthopedic surgical intervention [30]. A total of 315 and 299 pa-
tients were randomized to receive mupirocin or placebo, respectively. The preopera-
tive nasal carriage rate was approximately 30%. Eradication of nasal carriage was
significantly more effective in the mupirocin group (eradication rate, 83.5 versus
27.8%). In this study, mupirocin nasal ointment did not reduce the S. aureus surgi-
cal site infection rate significantly (3.8% in the mupirocin group and 4.7% in the
placebo group) nor the duration of hospital stay. In the mupirocin group, the rate
of endogenous S. aureus infections (i.e., the strain that causes the infection has the
same genotype as the strain previously cultured from the nose) was 5 times lower
than in the placebo group (not significant).
Wertheim et al. performed a randomized placebo-controlled study in a non-sur-
gical patient population of S. aureus carriers [12]. Patients were either assigned to
a short course ofmupirocin (n=805) or placebo (n=822) after a nasal culture grew
S. aureus. No differences were observed in the rates of nosocomial S. aureus infec-
tions, in-hospital mortality, or in duration of hospitalization, between the mupiro-
cin and the placebo group. Survival analysis showed that mupirocin prophylaxis
significantly delayed the time to the occurrence of nosocomial S. aureus infection,
from 16.7 to 30 days (p = 0.013), indicating that repetitive mupirocin application
may be effective.
Several oral and topical antibiotics have been studied for eradication of S. aureus
nasal carriage in hemodialysis patients and are summarized by Chow and Yu [28].
Rifampicin in conjunction with nasal bacitracin can result in a significant reduc-
tion of the S. aureus infection rate in hemodialysis patients. Emergence of rifampi-
cin-resistant strains has been observed. Short course therapies and combination
therapies may prevent the emergence of resistant isolates.
Mupirocin has also been evaluated extensively in hemodialysis patients. See also
the review by Boelaert [32]. In a randomized, double-blind placebo-controlled trial,
stable nasal carriers were treated with mupirocin for two weeks three times daily,
and then thrice weekly for a total of 9 months [33]. A significant reduction in the
S. aureus infection rate (1/104 patient-months among treated and 6/147 patient-
months among non-treated) was observed. The administration of mupirocin to na-
sal carriers was later adjusted to an initial course of 5 days, 3 times per day, and
thereafter once a week during the remaining period on hemodialysis. Using this
schedule a highly effective elimination of carriage was achieved and this was ac-
companied by a four- to six-fold reduction in the S. aureus-bacteremia rate [5].
The effect of decolonizing the nares from S. aureus has also been studied in
peritoneal dialysis patients. The effects of intermittent administration of rifampicin
in patients on CAPD was studied in a randomized controlled trial [34]. No signifi-

cant difference in the S. aureus peritonitis rates was found. Until now two reports
have been published studying the effects of mupirocin on the infection rate in
CAPD patients. A case-control study in a CAPD patient population found that the
S. aureus peritonitis rate was significantly reduced in S. aureus nasal carriers who
were given mupirocin [35]. There was a significant lower catheter loss due to exit-
site infections in the treated group. The overall peritonitis rate was not reduced,
mainly due to a significantly higher rate of peritonitis caused by Gram-negative
bacteria in the treated group compared to the not-treated group. Recolonization oc-
curred frequently, especially after three months. A randomized controlled study
was performed also in this patient population. Nasal carriers were treated with mu-
pirocin or placebo ointment twice daily for five days and this was repeated every
four weeks. In 1144 patients screened, 267 carriers were identified (23.3%). The S.
aureus exit-site infection rate was significantly lower in the treated group (1 in 99.3
patient-months versus 1 in 28.1 patient-months, p = 0.006). There was no significant
increase in Gram-negative infections and development of resistance to mupirocin
was not observed. The possibility of development of resistance should be accounted
for when using mupirocin for prolonged periods such as in CAPD patients. It can
be concluded that elimination of S. aureus nasal carriage in patients on CAPD de-
creases the exit-site infection rate. The effect on the peritonitis rates remains un-
clear.
I Costs of Prophylaxis
Cost-effectiveness studies have been performed for mupirocin prophylaxis in hemo-
dialysis patients, peritoneal dialysis patients, and thoracic surgery patients [2, 36, 37].
Bloom et al. evaluated three management strategies:
1) all patients are screened by a nasal culture every three months and those carry-
ing S. aureus are treated with mupirocin, twice daily for five consecutive days,
2) all patients are treated, irrespective of their carrier state, with mupirocin weekly
for 3 days, twice daily, or
3) no preventive measures are taken, only infections are treated.
It was assumed that 75o/o of S. aureus infections are attributable to nasal carriage in
hemodialysis patients and eliminating nasal carriage of S. aureus reduces the num-
ber of infections by 45 to 55o/o. The annual savings of the first strategy were
$ 784 000 per thousand dialysis patients and of the second strategy the savings were
$ 1117000 per thousand dialysis patients. Both strategies prevented death and im-
proved the quality of life. Since the risk of development of resistance with wide-
spread use of mupirocin is increased, the first strategy would be preferred.
Davey et al. also performed a cost-effectiveness study in peritoneal dialysis pa-
tients, on the basis of a randomized placebo-controlled trial described earlier [37,
38]. Patients in the mupirocin group had lower antibiotic and hospitalization costs.
However, overall antibiotic costs, including mupirocin, were significantly higher in
the mupirocin group. Mupirocin prophylaxis would have been cost neutral if the
exit-site infection rate in the placebo group increased to 75o/o, or if the costs of
screening were reduced from £ 15 to £ 3, or if the costs of mupirocin treatment
were reduced from £ 93 to £40 per patient-year. This study did not take the pa-
tient's quality of life or the long-term effects of S. aureus infection into considera-
tion. One may conclude that short-term savings of mupirocin prophylaxis in dialy-
sis patients in health care costs are unlikely to be sufficiently great to offset the cost
of mupirocin.
Vandenbergh et al. assessed the cost-effectiveness of perioperative intranasal ap-
plication of mupirocin calcium ointment in cardiothoracic surgery, based on results
of an intervention study with historical controls [2]. Postoperative costs were in-
creased significantly in patients with a surgical-site infection, in comparison with
uninfected patients. The mean attributable costs of these surgical site infections
were estimated at $ 16 878. The incidence of surgical site infections was 7.3% in the
control group and 2.8% in the mupirocin group. The costs of mupirocin were $ 11
per patient, which results in savings per surgical site infection prevented of
$ 16633. A sensitivity analysis showed that of the four variables that could influ-
ence the resulting cost-effectiveness (the cost of mupirocin, the effectiveness of the
intervention, the cost of a surgical site infection, and the incidence of surgical site
infection without using mupirocin), only the costs of a surgical site infection had a
major influence on the model. Therefore, the authors concluded that, provided that
perioperative mupirocin reduces the surgical site infection rate, mupirocin prophy-
laxis in patients undergoing cardiothoracic surgery is highly cost-effective.
I Vaccination
Over the past 100 years many attempts have been made to develop a vaccine to
control staphylococcal disease in humans and cattle. The fact that an infection with
S. aureus does not protect against a new infection with S. aureus, illustrates that
vaccine development is not going to be easy. Some recent advances in vaccine de-
velopment do show some protective action. Recently, a double-blind trial in pa-
tients receiving hemodialysis has evaluated the use of a conjugate vaccine with S.
aureus type 5 and 8 capsular polysaccharides [39]. These two types account for ap-
proximately 85% of all clinical isolates and can induce a type-specific opsonopha-
gocytic killing by neutrophils in vitro and confer protection in animals. The study
has shown that this vaccine can confer partial immunity against S. aureus bactere-
mia for approximately 40 weeks, after which protection wanes as antibody levels
decrease. Nearly 90% of the patients had a response to the vaccine and the decrease
in vaccine efficacy paralleled the decrease in levels of specific antibodies. It would
be interesting to study the efficacy of this vaccine or an improved version of this
vaccine in other patient populations at risk for S. aureus bacteremia.
1 Discussion
The increased risk of S. aureus nasal carriers for acquiring S. aureus infection and
the introduction of mupirocin in the '80s with reported high elimination rates of S.
aureus nasal carriage, has raised hope that S. aureus nosocomial infections would
be something of the past. Unfortunately, these hopes could not be met. S. aureus is
present as ever at the very top of the list of causative organisms of nosocomial in-
fections and has become more resistant than ever. Prevalence rates of MRSA strains
in blood cultures have rocketed sky-high, to more than 50% in many countries.
Also mupirocin resistance is on the rise due to increased usage, and the first two
Table 3. Summary of randomized controlled intervention studies
Ref. Intervention Population Outcome
[31) Mupirocin Surgical Two-fold reduction in nosocomial 5. aureus infections

[30) Mupirocin Orthopedic Non-significant 1.7-fold reduction in surgical site infection rate
Five-fold reduction in endogenous 5. aureus infection
[39) Vaccine Hemodialysis Two-fold reduction for approximately 40 weeks in development

of 5. aureus bacteremia
1121 Mupirocin Medicine Non-significant two-fold reduction in nosocomial 5. aureus

bacteremia. Development of nosocomial 5. aureus infection
delayed by 13 days
[33) Mupirocin Hemodialysis Four-fold reduction in 5. aureus infection
[38) Mupirocin CAPo• Three-fold decrease in exit-site 5. aureus infection
Not cost effective
• chronic ambulatory peritoneal dialysis
vancomycin-resistant S. aureus strains have been cultured from two different pa-
tients in the United States in 2002.
The first trials studying the efficacy of mupirocin in preventing S. aureus noso-
comial infection, used historical controls. These studies may have resulted in an
overestimation of the efficacy of mupirocin. The randomized trial in general sur-
gery showed a significant two-fold decrease in overall nosocomial S. aureus infec-
tion in S. aureus nasal carriers, but not in S. aureus surgical site infection (Table 3).
Two other studies in orthopedic surgery and an internal medicine patient popula-
tion showed a two-fold reduction rate in S. aureus infections, but the incidence of
these infections was too low to show significance. Both the incidence of S. aureus
infections and the effect of mupirocin on this incidence were lower than expected.
There are several explanations for this phenomenon. The effect of the study itself
on the incidence may have been stronger than the effect of the intervention studied.
The fact that recolonization occurs, and that patients in the placebo arm also show
a reduction in the carriage rate, contributes to this phenomenon.
The randomized trials in hemo- and peritoneal dialysis patients show three- to
four-fold reductions in S. aureus infections, that are statistically significant. For he-
modialysis patients, mupirocin prophylaxis is cost-effective, but for peritoneal dial-
ysis patients this may not be the case. Moreover, prolonged use in this population
has caused resistance to mupirocin.
Future studies should target on patients at risk for S. aureus infection, who may
benefit from eliminating S. aureus from the nose. Further targeting of prophylaxis
will lead to more cost-effectiveness and less resistance. Also the efficacy of other
strategies than mupirocin on reducing the S. aureus carriage rates should be stud-
ied more carefully in different patient populations. Eliminating S. aureus carriage
from extra-nasal sites may also contribute to more effective strategies in the future.
The ability to control S. aureus infections will depend on many factors, includ-
ing development of new antibiotic agents, development of new prophylactic regimes
(vaccines, topical agents), and optimization of infection control measures (espe-
cially handwashing).
I Conclusion
This chapter has summarized the clinical impact of S. aureus nasal carriage and
the effect of several prophylactic measures on these infections. Mupirocin has not
been as effective as hoped for. There is no evidence that this topical agent should
be used on a large scale. So far there is only hard evidence that mupirocin prophy-
laxis is efficacious for hemo- and peritoneal dialysis patients, and patients under-
going surgery. For this last category, the profile of patients that are most at risk
should be identified in more detail to make this strategy more effective. More stud-
ies should be performed to identify other patient categories that may benefit from
prophylaxis. Since mupirocin resistance is rising, more effort should be put into
elucidating the mechanisms leading to S. aureus nasal carriage and infection, to be
able to develop new and better, effective prophylactic strategies.
References
1. Lowy F (1998} Staphylococcus aureus infections. N Eng! J Med 339:520-532
2. Van den Bergh MF, Kluytmans JA, van Hout BA, et a! ( 1996} Cost-effectiveness of peri o-
perative mupirocin nasal ointment in cardiothoracic surgery. Infect Control Hosp Epide-
miol17:786-792
3. Anonymous (2002} Public Health Dispatch: Vancomycin-resistant Staphylococcus aureus;
Pennsylvania, 2002. MMWR Morb Mortal Wkly Rep 51:902
4. Kluytmans JA, Mouton JW, Van den Bergh MF, eta! (1996} Reduction of surgical-site infec-
tions in cardiothoracic surgery by elimination of nasal carriage of Staphylococcus aureus.
Infect Control Hosp Epidemiol17:780-785
5. Kluytmans JA, van Belkum A, Verbrugh HA (1997} Nasal carriage of Staphylococcus aur-
eus: epidemiology, underlying mechanisms, and associated risks. Clin Microbiol Rev
10:505-520
6. Nouwen JL, van Belkum A, Verbrugh HA (2001} Determinants of Staphylococcus aureus
nasal carriage. Neth J Med 59:126-133
7. Cole AM, Tahk S, Oren A, et a! (2001) Determinants of Staphylococcus aureus nasal car-
riage. Clin Diagn Lab Immunol 8:1064-1069
8. Cole AM, Dewan P, Ganz T (1999} Innate antimicrobial activity of nasal secretions. Infect
Immun 67:3267-3275
9. Peacock SJ, de Silva I, Lowy FD (2001} What determines nasal carriage of Staphylococcus
aureus? Trends Microbiol 9:605-610
10. Wertheim HFL, Kleef M, Vos MC, Verbrugh H, Fokkens W (2002} Nosepicking and nasal
carriage of Staphylococcus aureus. ICAAC Abstract Book. ASM Press, Herndon K456
(abst)
11. von Eiff C, Becker K, Machka K, Stammer H, Peters G (2001} Nasal carriage as a source of
Staphylococcus aureus bacteremia. Study Group. N Eng! J Med 344:11-16
12. Wertheim HFL, Vos MC, Ott A, et a! (2002) Mupirocin prophylaxis for nosocomial Staphy-
lococcus aureus infections in non-surgical patients. ICAAC Abstract Book. ASM Press,
Herndon, K-460 (abst)
13. Jensen AG, Wachmann CH, Poulsen KB, et a! (1999} Risk factors for hospital-acquired
Staphylococcus aureus bacteremia. Arch Intern Med 159:1437-1444
14. Nguyen MH, Kauffman CA, Goodman RP, et a! (1999} Nasal carriage of and infection with
Staphylococcus aureus in HIV- infected patients. Ann Intern Med 130:221-225
15. Pujol M, Pena C, Pallares R, et a! (1996} Nosocomial Staphylococcus aureus bacteremia
among nasal carriers of methicillin-resistant and methicillin-susceptible strains. Am J Med
100:509-516
16. Selvey LA, Whitby M, Johnson B (2000} Nosocomial methicillin-resistant Staphylococcus
aureus bacteremia: is it any worse than nosocomial methicillin-sensitive Staphylococcus
aureus bacteremia? Infect Control Hosp Epidemiol 21:645-648
17. Doebbeling BN (1994) Nasal and hand carriage of Staphylococcus aureus in healthcare
workers. J Chemother 6 (suppl) 2:11-17
18. Hudson IR (1994) The efficacy of intranasal mupirocin in the prevention of staphylococcal
infections: a review of recent experience. J Hosp Infect 27:81-98
19. Doebbeling BN, Breneman DL, Neu HC, et al (1993) Elimination of Staphylococcus aureus
nasal carriage in health care workers: analysis of six clinical trials with calcium mupirocin
ointment. The Mupirocin Collaborative Study Group. Clin Infect Dis 17:466-474
20. Bommer J, Vergetis W, Andrassy K, et al (1995} Elimination of Staphylococcus aureus in
hemodialysis patients. Asaio J 41:127-131
21. Cookson BD (1998) The emergence of mupirocin resistance: a challenge to infection con-
trol and antibiotic prescribing practice. J Antimicrob Chemother 41:11-18
22. Fung S, O'Grady S, Kennedy C, et al (2000) The utility of polysporin ointment in the eradi-
cation of methicillin-resistant Staphylococcus aureus colonization: a pilot study. Infect
Control Hosp Epidemiol 21:653-655
23. Soto NE, Vaghjimal A, Stahl-Avicolli A, et al (1999) Bacitracin versus mupirocin for Staph-
ylococcus aureus nasal colonization. Infect Control Hosp Epidemiol. 20:351-353
24. Parras F, Guerrero MC, Bouza E, et al (1995} Comparative study of mupirocin and oral co-
trimoxazole plus topical fusidic acid in eradication of nasal carriage of methicillin-resistant
Staphylococcus aureus. Antimicrob Agents Chemother 39:175-179
25. Quickel KE Jr, Selden R, Caldwell JR, Nora NF, Schaffner W (1971) Efficacy and safety of
topical lysostaphin treatment of persistent nasal carriage of Staphylococcus aureus. Appl
Microbiol 22:446-450
26. Carson CF, Cookson BD, Farrelly HD, Riley TV (1995) Susceptibility of methicillin-resistant
Staphylococcus aureus to the essential oil of Melaleuca alternifolia. J Antimicrob Chemo-
ther 35:421-424
27. Hill RL, Casewell MW (2000) The in-vitro activity of povidone-iodinecream against Staph-
ylococcus aureus and its bioavailability in nasal secretions. J Hosp Infect 45:198-205
28. Chow JW, Yu VL (1989) Staphylococcus aureus nasal carriage in hemodialysis patients. Its
role in infection and approaches to prophylaxis. Arch Intern Med 149:1258-1262
29. Uehara Y, Nakama H, Agematsu K, et al (2000) Bacterial interference among nasal inhabi-
tants: eradication of Staphylococcus aureus from nasal cavities by artificial implantation of
Corynebacterium sp. J Hosp Infect 44:127-133
30. Kalmeijer MD, Coertjens H, Van Nieuwland-Bollen PM, et al (2002) Surgical site infections
in orthopedic surgery: the effect of mupirocin nasal ointment in a double-blind, random-
ized, placebo-controlled study. Clin Infect Dis 35:353-358
31. Perl TM, Cullen JJ, Wenzel RP, et al (2002) Intranasal mupirocin to prevent postoperative
Staphylococcus aureus infections. N Engl J Med 346:1871-1877
32. Boelaert JR (1994} Staphylococcus aureus infection in haemodialysis patients. Mupirocin
as a topical strategy against nasal carriage: a review. J Chemother 6 (suppl 2):19-24
33. Boelaert JR, De Smedt RA, De Baere YA, et al (1989} The influence of calcium mupirocin
nasal ointment on the incidence of Staphylococcus aureus infections in haemodialysis pa-
tients. Nephrol Dial Transplant 4:278-281
34. Zimmerman SW, Ahrens E, Johnson CA, et al (1991} Randomized controlled trial of pro-
phylactic rifampin for peritoneal dialysis-related infections. Am J Kidney Dis 18:225-231
35. Perez-Fontan M, Garcia-Falcon T, Rosales M, et al (1993) Treatment of Staphylococcus au-
reus nasal carriers in continuous ambulatory peritoneal dialysis with mupirocin: long-term
results. Am J Kidney Dis 22:708-712
36. Bloom BS, Fendrick AM, Chernew ME, Patel P (1996} Clinical and economic effects of mu-
pirocin calcium on preventing Staphylococcus aureus infection in hemodialysis patients: a
decision analysis. Am J Kidney Dis 27:687-694
37. Davey P, Craig AM, Hau C, Malek M (1999} Cost-effectiveness of prophylactic nasal mupiro-
cin in patients undergoing peritoneal dialysis based on a randomized, placebo-controlled
trial. J Antimicrob Chemother 43:105-112
38. Mupirocin Study Group (1996} Nasal mupirocin prevents Staphylococcus aureus exit-site
infection during peritoneal dialysis. J Am Soc Nephrol 7:2403-2408
39. Shinefield H, Black S, Fattom A, et al (2002} Use of a Staphylococcus aureus conjugate vac-
cine in patients receiving hemodialysis. N Engl J Med 346:491-496
Current Dilemmas in the Management of Adults
with Severe Community-Acquired Pneumonia
J. Rella, J. A. Paiva, and C. S. Dias
Introduction
Severe community-acquired pneumonia (CAP) is generally regarded as pneumonia

requiring a specific clinical approach in an intensive care unit (ICU) [1-15]. Be-
tween 10 and 36o/o of patients with CAP who are hospitalized need ICU treatment
[3, 16, 17], and mortality ranges from 20 to 50o/o [5-11].
The first guidelines published by the American Thoracic Society (ATS) classified
patients according to estimated pneumonia severity. This allowed a risk-adapted
approach, and there is general agreement that severe CAP requires a specific proce-
dure [18, 22]. Other national organizations have produced guidelines for CAP [19-
21]. New guidelines such as those of the European Study on Community-Acquired
Pneumonia (ESOCAP) committee [19], and the recently updated ATS and IDSA
guidelines for CAP, contain evidence-based information [20-22]. The cost-effective-
ness of CAP guidelines in an individual hospital depends on the system that is
available [26-28], but there is solid evidence that compliance with the recommen-
dations of the CAP guidelines does in fact improve the cost-effectiveness of care
[29].
A meeting was attended by physicians from Spain, Portugal, and the United
Kingdom, aimed at evaluating the variances in the diagnosis and treatment of se-
vere CAP. This document reports the conclusions of this meeting. The primary ob-
jective was to define the panel members' current policies for the management of
patients with severe CAP. A secondary objective was to identify the reasons for
variance; the discussion aimed to prompt physicians to reflect on their own man-
agement of patients with CAP, and to establish whether the variance in their prac-
tices could be justified on clinical grounds.
I Methodology
The participants voted on and discussed the reasons for current practices in the
management of severe CAP. In contrast with other documents that had aimed to
provide a rationale for pneumonia treatment, participants discussed whether a con-
sensus could be reached. Discrepancies were admitted and reported.
The meeting was held on 16 March 2001, in Porto, Portugal. The format chosen
followed broadly the International Conference for the development of consensus on
the diagnosis and treatment of ventilator-associated pneumonia [30]. The panel
consisted of twelve physicians - one from the UK, five from Spain, and six from
Current Dilemmas in the Management of Adults with Severe Community-Acquired Pneumonia 163
Portugal. All the participants had at least five years of experience in the field and
currently devote at least 50% of their time to the study and treatment of severe in-
fections. Jordi Rello, co-chairman, and Jose Artur Paiva, co-chairman and host, se-
lected the peers and prepared the questions for discussion during the meeting.
Questions were put simultaneously to all participants and answers were given inde-
pendently and anonymously, without discussion. Abstentions were permitted. The
results obtained were communicated to all participants. A discussion followed, and
reasons for individual answers were stated and debated. Participants were allowed
to change their votes. A first draft of the text was prepared by the conference secre-
tary, C.S. Dias, including references reported in the literature up to June 2001. This
draft was mailed to all participants for comments and suggestions. It was then re-
vised and a second draft was re-sent for further suggestions. The final text was
then written and approved by all participants.
Terminology
Pneumonia was defined as reported elsewhere [18]. Nursing home episodes were
excluded. Severe CAP was considered as the requirement of intensive care admis-
sion for respiratory failure, severe sepsis, or nursing care. 'Invasive sampling' was
defined as the use of fiberoptic bronchoscopy for respiratory secretion sampling.
I Background Data and Questions
Criteria for Admission to the ICU

1. What Criteria do you Use for Admission to the ICU?
a) Fine's; b) ESOCAP; c) ATS; d) BTS; e) A patient-based selection.
Background data: Exact criteria for admission of patients with CAP to the ICU re-
main undetermined [7-13], even though prognostic factors associated with death
have been extensively studied [31-34]. Some important areas of severity assessment
remain unclear [35, 36]. The clinical prediction rule developed by Fine et al. [32]
aimed to identify low risk patients who could be safely treated on an outpatient ba-
sis. It provides a rational basis for the decision to hospitalize a patient.
The British Thoracic Society (BTS) has proposed two sets of guidelines to detect
patients at risk of death from pneumonia [37], including three simple clinical or
laboratory parameters. These rules have been validated repeatedly in the general
population [38-45]. The second set of guidelines tends to be more specific but less
sensitive than the first, particularly in elderly patients [38-40, 42].
The ten ATS criteria from the original 1993 statement [18] are grouped into
baseline 'minor' criteria assessed at admission and 'major' criteria assessed at ad-
mission or during the clinical course. In a preliminary communication, Gordon et
al. [45] reported a validation of these severity criteria. Ewig et al. [46] showed that
the use of a single criteria for severe CAP, as suggested by the ATS guidelines, was
very sensitive, but had a low positive predictive value (24%) for ICU admission.
The updated ATS guidelines [22] provide the following criteria: at least two of
six minor criteria (respiratory rate > 30/min, Pa0 2 /Fi0 2 < 250, systolic arterial blood
pressure < 90 mm Hg, BUN > 7 mmol/1, mental confusion, and multilobar involve-
164 J. Rello et al.
ment) or one of the three major criteria (acute renal failure, septic shock and re-
quirement of mechanical ventilation). The European guidelines for lower respirato-
ry tract infections provided by ESOCAP [19] have proposed similar criteria.
Multivariate analyses of prognostic factors of severe CAP have shown that the
prognosis depends on the baseline characteristics of patients, the initial severity of
pneumonia and the evolution during ICU stay, as well as ineffective initial antimi-
crobial therapy, radiographic spread of pneumonia, and the occurrence of non-
pneumonia-related complications [7, 11, 47]. The majority of patients with severe
CAP have chronic underlying diseases [7, 8, 10, 13, 48, 49]. The impact of age on
CAP mortality has been a matter of debate [13, 50]. Host factors such as previous
health state or comorbid conditions may have a greater impact on the prognosis of
CAP than age [13, 50].
Responses: The criteria suggested by the ESOCAP and by the original 1993 ATS
statement were each followed by one peer. Another abstained. The remaining nine
participants used a patient-based selection. The predominant opinion was that the
decision of admission to the ICU must be individualized and should be based on
severity of illness. Acute respiratory failure, shock and host factors including im-
mune status and comorbid conditions are frequently associated with severity and
poor outcome and were widely accepted as important factors in the decision to ini-
tiate early intensive care. Fine's score includes age and comorbid condition, but age
has a high score and its influence on the decision may therefore be excessive. It
should be remembered that Fine's rule was developed to assess low risk patients
and therefore may underestimate the severity of illness [42, 51].
The majority of participants preferred to use a patient-based approach, consider-
ing that the reasons for intensive care admission may not be reflected in prognostic
scoring rules alone. Many rules have low sensitivity and low specificity, and the de-
cision needs to be individualized. Each hospital has different systems (step-down
units, specific ICUs, organization of emergency departments) and these differences
may also affect the decision-making process. Peers agreed on laying special empha-
sis on severity of illness, comorbidity, and biological age. They also stated that it is
important to assess signs of clinical deterioration and give early intensive care sup-
port to patients who do not meet severity criteria on admission but may neverthe-
less be at high risk of developing severe CAP.
Microbiological Diagnosis in Severe Community-Acquired Pneumonia

The usefulness of diagnostic testing in the management of CAP is a subject of con-
troversy [37, 52]. There are many advantages in determining a specific etiological
pathogen: it can improve care of some individual patients, allowing for a rational
basis for selection or change of therapy, and improve the care of other patients by
broadening our knowledge and defining local antimicrobial policies. The arguments
reported against microbiological studies include the limitations of these techniques,
the fact that bacteriological results seldom change therapy, and the lack of con-
firmed benefit in terms of cost or outcome [3, 6, 54].
1. What is the Role of Gram Stain in Treatment of Severe CAP?
a) I use it to streamline initial empirical regimen; b) I use it to broaden first-line
empirical regimen; c) I use it for both purposes; d) I do not use it; e) I use it,
but it does not influence my first-line regimen.
Background Data: Several studies suggest that the sputum Gram stain is an insensi-
tive but specific early guide to diagnosis and treatment of CAP when interpreted by
a skilled observer [53, 55-59]. A specimen with fewer than 10 squamous epithelial
cells and more than 25 neutrophils per low power field, and evidence of a predomi-
nant bacterial morphotype of a likely pulmonary pathogen when examined under
high power field is a reliable guide for initial antibiotic therapy [57, 60]. Many
studies have reported the Gram stain to be highly specific in identifying pneumo-
cocci in sputum [51, 61-63]. The presence of a multitude of diverse bacteria in a
neutrophilic exudate could suggest oropharyngeal aspiration. In the 1993 ATS
guidelines, the sputum Gram stain was not recommended for routine performance,
but the 2001 update acknowledges that the sputum Gram stain is helpful for focus-
ing initial empiric therapy. However, the microbiological data obtained from the
Gram stain may prove to be unreliable, due to misinterpretation by inexperienced
observers, poor-quality specimens [59, 60, 65-68] or reduced sensitivity in patients
who have taken antibiotics prior to specimen collection [69].
Responses: Two peers did not use it. One used the Gram stain to streamline therapy
and four to broaden the spectrum of therapy. Finally, 5 participants used the direct
staining but did not take decisions on therapy.
There was general consensus about the indication of a sputum Gram stain. Even
the two peers who reported that they did not use Gram stains stated that they fa-
vored it and would perform it if technical facilities at their institution allowed.
However, no clear agreement emerged on its role in the decision on treatment. Few-
er than half used the Gram stain to guide empirical therapy; five of the twelve par-
ticipants did, but stated that it did not influence their choice of initial antibiotic
choices. They acknowledged that the Gram stain could be used to guide the initial
treatment, but its results are frequently of limited value because many patients re-
ceive antibiotics prior to admission and because a good quality sample and a
skilled microbiologist are not always available. In any case, the sputum Gram stain
will aid the decision whether to perform a culture, how to interpret the culture re-
sult and subsequently how to decide on empirical antibiotic prescriptions. This
limitation is not applicable for Legionella cultures.
The other five participants reported using Gram's stain to decide the first-line
regimen; four of them used it to limit or broaden the empirical antibiotic therapy
and one of them to streamline. However, all agreed on the importance of starting
empirical therapy without delay even if microbiologic tests are not available.
2. When do you Perform Blood Cultures?

a) Always; b) Sometimes.
Background Data: The cost-effectiveness of blood cultures in CAP has been ques-
tioned, for three reasons: the low percentage of patients with CAP who have bacter-
emia, the bacteria that are commonly identified, and the clinical relevance of the
culture for either modifying antibiotic therapy or predicting outcome [54, 70-74].
Obtaining blood samples for culture within 24 h of admission to hospital for
CAP has been associated with a statistically significant reduction in 30-day mortal-
ity [70]. When positive, blood cultures can provide useful information on both the
causative agent and antibiotic sensitivity. The incidence of positive blood cultures
in hospitalized patients with CAP was lower than 20o/o [16, 73, 75-80], with pneu-
mococci accounting for half of the positive cultures [9, 78, 81, 82]. The mortality
166 J. Rello et al.
rate reported in patients with pneumococcal bacteremia is high and increases with
age [83-85]. Finally, blood cultures have been recognized as an indicator of quality
[19-22].
Responses: All the twelve peers perform blood cultures. This consensus is due to
the fact that blood culture results can provide useful information on both the caus-
ative agent and antibiotic sensitivity. All peers admitted altering therapy - or at
least streamlining it - on the basis of blood culture results.
3. When do you Perform Urinary Antigen Detection?

a) Always; b) Sometimes; c) when microbiological results are unknown.
Background Data: A negative urinary antigen test does not rule out legionellosis
but a positive test is highly specific. In both the IDSA and the Canadian guidelines
the urine test for Legionella antigen is recommended in patients with severe CAP.
A rapid and sensitive immunochromatographic assay (Binax Now, Portland, Maine)
is now commercially available, as there is an available test to detect urinary anti-
gens for Streptococcus pneumoniae.
Responses: All twelve peers advocated searching for Legionella pneumophila and all
attempt to detect urinary antigens if the microbiologic etiology is unknown at ICU
admission (50% always perform the urinary antigen detection test in all episodes
and the other half when there are no microbiological findings). Only a minority of
the participants had experience with urinary pneumococcal or Pneumocystis carinii
antigen detection tests and these options were excluded from consideration.
4. When do you Perform Invasive Sampling?

a) If the patient is intubated; b) Only in immunocompromised patients; c) Only in
refractory cases; d) In the immunocompromised patient plus refractory cases; e)
Only if there is a bilateral diffuse radiological pattern.
Background Data: There is considerable controversy about the role and use of inva-
sive testing in the diagnosis of CAP. The use of bronchoscopy for diagnostic assess-
ment of CAP patients who have failed initial management has identified an infec-
tious agent in <30% of patients [10, 89-92]. In non-resolving pneumonia, BAL
helps to diagnose opportunistic infections [64].
In the most recent guidelines for CAP management [19-22] the use of broncho-
scopic sampling is recommended for particularly severe, selected cases but not for
all patients under mechanical ventilation. Some authors also favor the use of this
technique in patients with a fulminant course [20, 95].
Responses: Bronchoscopy and adequate processing of samples requires technical ex-
pertise and is impractical for routine use, but it is quite important to have an early
accurate etiological diagnosis in patients with severe illness. The majority of parti-
cipants (10 out of 12) prefer to use invasive sampling only for immunosuppressed
patients, in whom suspicion of atypical agents is higher, or in refractory cases,
although the sensitivity of protected specimen brush (PSB) and bronchoalveolar
(BAL) fluid cultures is likely to be lower in patients under antibiotics. In fact, inva-
sive diagnostic techniques have been previously recommended for patients with
CAP unresponsive to antimicrobial therapy and for patients at risk for uncommon
pathogens. Only two out of the twelve participants perform invasive sampling in all
intubated patients. All the participants considered that the availability of a skilled
bronchoscopist and an experienced microbiologist is a key factor in the decision of
whether to perform invasive sampling on admission. Therefore, therapeutic deci-
sions should not be delayed.
Antibiotic Therapy
1. Which Patients Should be Treated as Possible Pseudomonas aeruginosa Pneumo-
nia Cases?
a) All patients; b) All patients who need intubation; c) Those who have received P-
lactam therapy within the past 3 months; d) Those who have received recent steroid
therapy; e) Those with chronic obstructive pulmonary disease (COPD) or other
structural lung disease; f) None.
Background Data: Pseudomonas aeruginosa is a possible agent in CAP only in cer-
tain settings and needs specific therapy [31]. The 2001 update of the ATS guidelines
recommends that this pathogen should be considered only when specific risk fac-
tors are present. Pseudomonas aeruginosa should definitely be a concern in patients
with structural lung diseases (bronchiectasis), but other risk factors have also been
reported [7, 10, 11, 15, 34].
Responses: Only one of the peers considered that all patients with severe CAP
should be treated as possible cases of Pseudomonas aeruginosa pneumonia, but all
agreed that therapy should cover this pathogen in patients with severe COPD or
other structural lung disease. None of the twelve participants considered recent ste-
roids or P-lactam therapy within 3 months as risk factors for Pseudomonas aerugi-
nosa infection. It was also stressed that coverage of Pseudomonas infection should
not preclude coverage of the most common pathogens.
2. When would you Consider Aspergillus as a Possible Pathogen?

a) COPD; b) Use of steroids; c) Granulocytes below 500/mm3 ; d) COPD and granu-
locytes below 500/mm3 ; e) Use of steroids and granulocres below 500/mm3 ; f)
COPD and use of steroids and granulocytes below 500/mm.
Background Data: Aspergillus is a well-recognized pathogen among immunocom-
promised patients [96]. Aspergillus can also cause pneumonia in immunocompetent
hosts with underlying lung disease but is infrequent in healthy patients. The major
risk factors for invasive aspergillosis reported are neutropenia (neutrophil
count< 500/mm3 ), immunosuppressive therapy including steroids, and underlying
lung disease. Several cases of invasive aspergillosis have been reported in patients
with COPD and most of these patients had received steroids.
Responses:
I COPD and use of steroids and granulocytes below 500/mm3 7
I Use of steroids and granulocytes below 500/mm3 4
I Use of steroids 1
All the participants acknowledged the importance of using steroids as a risk factor
for Aspergillus infection. The great majority also mentioned both neutropenia and
COPD as important risk factors.
168 J. Rello et al.
3. Which Patients Should be Treated as Possible Cases of penicillin-resistant S. pneu-

moniae (PRSP)?
a) All those admitted to the ICU; b) Beta-lactam therapy within 3 months or hospi-
talization within 6 months; c) HIV patient; d): b) + c); e) Resident in or traveller
to an endemic area; f) Never.
Background Data: The susceptibility of S. pneumoniae to penicillin is usually
grouped in three categories. The association between penicillin resistance and ad-
verse clinical outcome has been well documented for meningitis but is not well de-
fined for pneumonia [97]. Despite some reports of poor outcome among patients
infected with intermediate-susceptibility strains, most of the current available evi-
dence indicates that standard treatment with adequate doses of P-lactams is effec-
tive against pneumococcal pneumonia caused by strains with MIC $; 1 J..Lg/ml.
Multiple comorbidities have been identified as risk factors for infection with
PRSP. Recent studies have reported a higher rate of antibiotic-resistant pneumococ-
ci in human immunodeficiency virus (HIV)-infected patients. The major risk fac-
tors reported in the literature are the use of P-lactam within the previous 3 months,
prior hospitalization, and immunocompromise. Not all patients who are exposed in
an endemic area will be infected with these organisms.
Responses:
I P-lactam therapy within 3 months, hospitalization within 6 months, HIV patients 5
I All patients admitted to the ICU 4
I Residents in or travellers to an endemic area 2
I P-lactam therapy within 3 months or hospitalization within 6 months 1
Consensus was not reached. The panel considered beta-lactam therapy within 3
months or hospitalization within 6 months the most important factors, as half of
the participants answered that patients with these characteristics should be treated
as potential cases of PRSP. Five of these six peers also included HIV infection as a
risk factor. One third of the peers would treat all patients admitted to the ICU as
possible PRSP infections. A debate followed about the relevance of pneumococcal
resistance level and the site of infection, but no consensus was achieved.
4. Which Patients with Severe CAP Should be Treated for Legionella?

a) All patients with an episode of severe CAP; b) Only when the clinical picture is
suggestive.
Background Data: The true prevalence of atypical agents in CAP remains controver-
sial. However, Legionnaire's disease is associated with a high mortality. A number
of studies have concluded that Legionella pneumonia cannot be distinguished from
other etiologies on clinical grounds [78] whereas a diagnostic scoring system for
Legionnaire's disease has been developed. Delay in the onset of appropriate treat-
ment is the crucial factor related to poor outcome.
Responses: The fear of atypical pathogens and specifically Legionella differed sharp-
ly between participants, a reflection of the fact that incidence varies in the three
countries represented in the Conference. Two participants include effective antibio-
tics against Legionella only when the clinical picture is suggestive, whereas the re-
maining ten always did so. The high prevalence of Legionella in the Iberian penin-
sula [13], the lack of confidence in the syndromic approach, and the recognition of
the vital importance of the adequacy of the initial antibiotic regimen leads most of
the participants to start empirical coverage for Legionella in all cases.
5. Should a Macrolide be Used for the Empirical Treatment of Severe CAP?
Background Data: Macrolides are very active against intracellular organisms. In-
deed, initial therapy with a macrolide has been associated with shorter hospital
stay and the association of a macrolide plus a second- or third-generation cepha-
losporin has been associated with decreased mortality [98].
Other investigators suggested that a macrolide-based therapy is not advisable as
first-line therapy of CAP if the prevalence of 'atypical' pathogens is low. New fluoro-
quinolones emerged as an alternative to macrolides; they cover both typical and
atypical respiratory pathogens and are active against PRSP.
Responses: Six of the peers answered affirmatively and the other six negatively. Fifty
percent of the peers do not use a macrolide but nearly all use another antibiotic for
the same purpose, either a tetracycline or a new fluoroquinolone.
6. What is the Role of New Fluoroquinolones in the Treatment of Severe CAP?
a) As first-line treatment for severe CAP, as single agent; b) as first-line treatment
for severe CAP, combined with a beta-lactam; c) only for proved PRSP cases; d)
only for patients at special risk for PRSP pneumonia; e) only for refractory cases
and for beta-lactam allergic patients; f) for proven PRSP cases, refractory cases,
and for beta-lactam allergic patients; g) for patients at special risk of PRSP pneu-
monia, refractory cases and beta-lactam allergic patients.
Background Data: The range of therapeutic options available to clinicians has broad-
ened with the licensure of new fluoroquinolones. There is good evidence that newer
fluoroquinolones are effective and achieve results comparable to those of beta-lac-
tam with or without macrolides in treatment of mild to moderate CAP. Gleason et
al. [98] have also reported that initial treatment with a fluoroquinolone alone was
associated with lower mortality rates than treatment with a non-pseudomonal
third-cephalosporin alone.
In fact, the use of fluoroquinolones in patients with severe CAP admitted to the
ICU had not been studied when the Conference was held, and the number of criti-
cally ill patients included in clinical trials using fluoroquinolones is small. In severe
CAP, initial therapy with fluoroquinolones has been recommended in association
with /1-lactams as a first-choice or as an alternative to macrolides [19-22]. There
have been emerging reports of resistance. This fact and the broad spectrum of
these agents raise concerns that their generalized use may promote the outgrowth
of more resistant strains [97].
Responses:
First-line treatment for severe CAP, as single-agent 0
First-line treatment for severe CAP, combined with a beta-lactam 1
Only for proven PRSP cases 0
I Only for patients at special risk for PRSP pneumonia 0
I Only for refractory case and for /1-lactam allergic patients 3
I For proven PRSP cases, refractory cases, P-lactam allergic patients 5
I For patients at risk for PRSP, refractory cases, P-lactam allergic patients 1
I None 1
Abstension 1
170 J. Rello et al.
Most participants restricted the use of new fluoroquinolones for P-lactam allergic
patients, refractory cases, or proven cases of severe pneumonia caused by PRSP.
None considered the newer fluoroquinolones appropriate as first-line monotherapy
for severe CAP due to the fact that no studies had been carried out in the critically
ill population of CAP patients at the time the meeting was held. The real question
for clinicians is how long the susceptibility of pathogens such as S. pneumoniae to
quinolones will persist. In this connection, all peers agreed with the CDC recom-
mendations [97] that the use of these drugs should be more restrictive in order to
avoid early development of resistances.
I Conclusion
In summary, the conference format is unique as disagreements between partici-
pants were permitted and no consensus was mandatory. The participants have
clearly shown important divergences regarding clinical practice. The ICU admission
decision for severe CAP should be customized to each institution and patient. Prog-
nostic scoring rules are adjunctive tools, but should not be applied to individual
patients to guide ICU admission. It would be important to assess whether the prog-
nostic scoring system will perform in specific settings. Although substantial diver-
gences were found regarding the policy of diagnostic testing, at least 10 partici-
pants performed blood cultures, Gram stains and urinary detection of antigens.
The data from this report indicate that prescriptions recommended by guidelines
may not be reflected in everyday local practice. Geographical variations in inci-
dence, clinical practices and experience may explain the variability. This important
variability underlines the limitations of the ATS, IDSA or ESOCAP consensus re-
ports. This report suggests that a patient-based selection is often used in taking di-
agnostic or therapeutic decisions.
Acknowledgement. This work was supported in part by CIRIT grant (2001-SGR-441)

and Distinci6 a Ia Promoci6 de Ia Recerca Universitaria.
Appendix: Affiliation of Participants

From the Hospital Universitario Joan XXIII, Universitat Rovira and Virgili, Tarrago-
na, Spain (Dr. Rello); Hospital Universitario Arnau de Vilanova, Lleida, Spain (Dr.
Barcenilla); Hospital Universitario de Valme, Seville, Spain (Dr. Leon); Unitat de Di-
agnostic i Alta Tecnologia, Sabadell, Spain (Dr. Mariscal); Corporacio Sanitaria Pare
Tauli, Sabadell, Spain (Dr. Valles); Hospital San Joao, Porto, Portugal (Dr. Paiva, Dr.
Sousa & Dr. Rios), Hospital Sto. Antonio, Porto, Portugal (Dr. Carneiro), Hospital
Santo Antonio dos Capuchos, Lisbon, Portugal (Dr. Estrada), and The Lothian Uni-
versity Hospitals NHS Trust, Edinburgh, UK (Dr. Bell).
References
1. Garibaldi RA (1985) Epidemiology of community-acquired respiratory tract infections in
adults. Am J Med 78 (suppl 6B):32-37
2. Woodhead MA, Macfarlane JT, McCracken JS, Rose DH, Finch RG (1987) Prospective study
of the aetiology and outcome of pneumonia in the community. Lancet 1:671-674
3. Ewig S, Torres A (1999) Severe community-acquired pneumonia. Clin Chest Med 20:575-587
4. Leeper KV, Torres A (1995) Community-acquired pneumonia in the intensive care unit.
Clin Chest Med 16:155-171
5. Woodhead MA, Mcfarlane JT, Rodgers FG, Laverick A, Pilkington R, Macrae AD (1985) Ae-
tiology and outcome of severe community-acquired pneumonia. J Infect 10:204-210
6. Pachon J, Prado MD, Capote F, Cuello JA, Garnacho J, Verano A (1990) Severe community-
acquired pneumonia. Am Rev Respir Dis 42:369-373
7. Torres A, Serra-Batlles J, Ferrer A, et al (1991) Severe community-acquired pneumonia.
Epidemiology and prognostic factors. Am Rev Respir Dis 114:312-318
8. British Thoracic Society Research Committee and the Public Health Laboratory Service
(1992) The aetiology, management and outcome of severe community-acquired pneumonia
on the intensive care unit. Respir Med 86:7-13
9. Rello J, Quintana E, Ausina V, Net A, Prats G (1993) A three-year study of severe commu-
nity-acquired pneumonia with emphasis on outcome. Chest 103:232-235
10. Moine P, Vercken JB, Chevret S, Chastang C, Gajdos P (1994) Severe community-acquired
pneumonia. Etiology, epidemiology, and prognosis factors. Chest 105:1487-1495
11. Leroy 0, Santre C, Beuscart C, et al (1995) A 5-year study of severe community-acquired
pneumonia with emphasis on prognosis in patients admitted to an intensive care unit. In-
tensive Care Med 21:24-31
12. Feldman C, Ross S, Mahomed AG, Omar J, Smith C (1995) The aetiology of severe commu-
nity-acquired pneumonia and its impact on initial, empiric, antimicrobial treatment. Respir
Med 89:187-192
13. Rello J, Rodriguez R, Jubert P, Alvarez B (1996) Severe community-acquired pneumonia in
the elderly. Epidemiology and prognosis. Clin Infect Dis 23:723-728
14. Hirani NA, Macfarlane JT (1997) Impact of management guidelines on the outcome of se-
vere community-acquired pneumonia. Thorax 52:17-21
15. Ruiz M, Ewig S, Marcos MA, et al (1999) Etiology of community-acquired pneumonia. Am
J Resp Crit Care Med 160:397-405
16. Marrie T J, Durant H, Yates L (1989) Community-acquired pneumonia requiring hospitali-
zation: 5-year prospective study. Rev Infect Dis 11:586-599
17. Sorensen J, Forseberg P, Hakanson E, et al (1989) A new diagnostic approach to the patient
with severe pneumonia. Scand J Infect Dis 21:33-41
18. Niederman MS, Bass J, Campbell GD, Torres A, Yu VL (1993) American Thoracic Society
Guidelines for the initial management of adults with community-acquired pneumonia: di-
agnosis, assessment of severity and initial antimicrobial therapy. Am Rev Respir Dis
148:1418-1426
19. European Study on Community-acquired pneumonia (ESOCAP) Committee (1998) Guide-
lines for management of adult community-acquired lower respiratory tract infections. Eur
Respir J 11:986-991
20. Bartlett J G, Dowell SF, Mandell LA, File TM Jr, Musher DM, Fine MJ (2000) Practice
guidelines for the management of commmunity-acquired pneumonia in adults. Guidelines
from the Infectious Diseases Society of America. Clin Infect Dis 31:347-382
21. Mandell LA, Marrie TJ, Grossman RF, Chow AUJ, Hyland RH (2000) Canadian guidelines
for the initial management of community-acquired pneumonia: an evidence-based update
by the Canadian Infectious Diseases Society and the Canadian Thoracic Society. Clin Infect
Dis 31:383-421
22. American Thoracic Society (2001) ATS Guidelines for the management of adults with com-
munity-acquired pneumonia. Diagnosis, assessment of severity. Antimicrobial therapy and
prevention. Am J Respir Crit Care Med 163:1730-1754
23. SPILF, Societe de Pathologie Infectieuse de Langue Franyaise (1991) Infections des voies re-
spiratoires: conference de concensus en therapeutique anti-infectieuse. Rev Med Infect
21:1s-8s
24. Gialdroni GG, Bianchi L (1995) Guidelines for the management of community-acquired
pneumonia in adults. Monaldi Arch Dis Chest 50:21-27
25. SEPAR, Spanish Thoracic Society (1992) National Recommendations for Diagnosis and
Treatment of Community Acquired Pneumonia. Ediciones Doyma, Barcelona
26. British Thoracic Society (1993) Guidelines for the management of community-acquired
pneumonia in adults admitted to hospital. Br J Hosp Med 49:349-350
172 J. Rello et al.
27. Huchon GJ, Gialdroni GG, Leophonte P, Manresa F, Schaberg T, Woodhead M (1996) Initial
antibiotic therapy for lower respiratory tract infection in the community: a European sur-
vey. Eur Respir J 9:1590-1595
28. Ortqvist A (1995) Antibiotic treatment of community-acquired pneumonia in clinical prac-
tice: a European perspective. J Antimicrob Chemother 35:205-212
29. Nathwani D, Rubinstein E, Barlow G, Davey P (2001) Do guidelines for community-ac-
quired pneumonia improve the cost-effectiveness of hospital care? Clin Infect Dis 32:728-
741
30. Rello J, Paiva JA, Baraibar J, Rios M, Rodriguez A, Sole-Violan J (2001) International con-
ference for the development of consensus on the diagnosis and treatment of ventilator-as-
sociated pneumonia. Chest 120:955-970
31. Fine MJ, Smith MA, Carson CA, et al (1996) Prognosis and outcomes of patients with com-
munity-acquired pneumonia. JAMA 275:134-141
32. Fine MJ, Auble TE, Yealy DM, et al (1997) A prediction rule to identify low-risk patients
with community-acquired pneumonia. N Engl J Med 336:243-250
33. Gilbert K, Fine MJ (1994) Assessing prognosis and predicting patients outcomes in com-
munity-acquired pneumonia. Sernin Respir Infect 9:140-152
34. Ruiz M, Ewig S, Torres A, et al (1999) Severe community-acquired pneumonia. Risk factors
and follow-up epidemiology. Am J Respir Crit Care Med 160:923-929
35. Ewig S, Schafer H, Torres A (2000) Severity assessment in community-acquired pneumo-
nia. Eur Respir J 16: 1193-1201
36. Houston MS, Silverstein MD, Suman VJ (1997) Risk factors for 30-day mortality in elderly
patients with lower respiratory tract infection: a community-based study. Arch Intern Med
157:2190-2195
37. British Thoracic Society and the Public Health Laboratory Service (1987) Community-ac-
quired pneumonia in adults in British hospitals in 1982-1983: a survey of aetiology, mor-
tality and prognostic factors and outcome. QJM 239:195-120
38. Parr BM, Sloman AJ, Fisch MJ (1991) Predicting death in patients hospitalized for commu-
nity-acquired· pneumonia. Ann Intern Med 115:428-436
39. Karalus NC, Cursons RT, Leng RA, Coleman L (1991) Community-acquired pneumonia: ae-
tiology and prognostic index evaluation. Thorax 46:413-418
40. Neil AM, Martin IR, Weir R, Frampton C, Hutton S, Chambers ST, Town GI (1996) Com-
munity-acquired pneumonia: aetiology and usefulness of severity criteria on admission.
Thorax 51:1010-1016
41. Lim WS, Lewis S, Macfarlane JT (2000) Severity prediction rules in community-acquired
pneumonia: a validation study. Thorax 55:219-223
42. Ewig S, Kleinfeld T, Bauer T, Seifert K, Schafer H, Goke N (1999) Comparative validation
of prognostic rules for community acquired pneumonia in an elderly population. Eur Re-
spir J 14:370-375
43. Conte HA, Chen YT, Mehal W, Scinto JD, Quagliarello VJ (1999) A prognostic rule for el-
derly patients admitted with community-acquired pneumonia. Am J Med 106:20-28
44. Woodhead M (1996) Predicting death from pneumonia. Thorax 51:970-971
45. Gordon G, Throop D, Berberian L (1996) Validation of the American Thoracic Society
Guidelines for community-acquired pneumonia in hospitalized patients. Am J Respir Crit
Care Med 153:A257 (abst)
46. Ewig S, Ruiz M, Mensa J, et al (1998) Severe community-acquired pneumonia-assessment
of severity criteria. Am J Respir Crit Care Med 158:1102-1108
47. Leroy 0, Devos P, Guery B, et al (1999) Simplified prediction rule for prognosis of patients
with severe community-acquired pneumonia in ICUs. Chest 116:157-165
48. Dean NC (1999) Use of prognostic scoring and outcome assessment tools in the admission
decision for the community-acquired pneumonia. Clin Chest Med 20:521-529
49. Almirall J, Mesalles E, Klamburg J, Parra 0, Agudo A (1995) Prognostic factors of pneumo-
nia requiring admission to the intensive care unit. Chest 107:511-516
50. Riquelme R, Torres A, El-Ebiary M, Hernandez C, Rodriguez-Roisin R (1996) Community-
acquired pneumonia in the elderly: etiology, risk, and prognosis factors. Am J Respir Crit
Care Med 154:1450-1455
51. Atlas SJ, Benzer TI, Borowsky LH, et al (1998} Safely increasing the proportion of patients
with community-acquired pneumonia treated as outpatients: an interventional trial. Arch
Intern Med 158:1350-1356
52. San Pedro GS, Campbell GD Jr (1997} Limitations of diagnostic testing in the initial man-
agement of patients with community-acquired pneumonia. Semin Respir Infect 12:300-307
53. Gleckman R, Devita J, Hibert D, Pelletier C, Martin R (1988} Sputum Gram stain assess-
ment in community-acquired bacteremic pneumonia. J Clin Microbial 26:846-849
54. Theerthakarai R, El-Ha).ees W, Ismail M, Solis RA, Khan MA (2001} Non value of initial
microbiological studies in the management of non severe community-acquired pneumonia.
Chest 119:181-184
55. Benner EJ, Munzinger JP, Chan R (1974} Superinfections of the lung. An evaluation by se-
rial transtracheal aspirate. West J Med 121:173-178
56. Potgieter PD, Hammond JMJ (1992} Etiology and diagnosis of pneumonia requiring ICU
admission. Chest 101:199-203
57. Rein MF, Gwaltney JM, O'Brien WM, Jennings RH, Mandell GL (1978} Accuracy of Gram's
stain in identifying pneumococci in sputum. JAMA 239:2671-2673
58. Thorsteinsson SB, Musher DM, Fagan T (1975} The diagnostic value of sputum culture in
acute pneumonia. JAMA 233:894-895
59. Park DR, Skerrett SJ (1995} The usefulness of the sputum Gram stain in the diagnosis of
pneumonia. Clin Pulm Med 2:201-212
60. Dans PE, Charache P, Fahey M (1996) Management of pneumonia in the prospective pay-
ment era. Arch Intern Med 144:1392-1397
61. Boerner DF, Zwadyk P (1982} The value of the sputum Gram's stain in community-ac-
quired pneumonia. JAMA 247:642-645
62. Ort S, Ryan JL, Barden G, D'Esopo N (1983} Pneumococcal pneumonia in hospitalized pa-
tients. JAMA 249:214-248
63. Ortqvist A, Jonsson I, Kalin M, Krook A (1989} Comparison of three methods for detec-
tion of pneumococcal antigen in sputum of patients with community-acquired pneumonia.
Eur J Clin Microbiol Infect 8:956-961
64. Skerrett SJ (1999} Diagnostic testing for community-acquired pneumonia. Clin Chest Med
Sept 20:531-548
65. Reed WW, Byrd GS, Gates RH Jr, Howard RS, Weaver MJ (1996} Sputum Gram's stain in
community-acquired pneumonia: a meta-analysis. West J Med 165:197-204
66. Fine MJ, Orloff JJ, Rihs JD, et al (1991} Evaluation of housestaff physicians preparation and
interpretation of sputum Gram stains for community-acquired pneumonia. J Gen Intern
Med 6:189-198
67. Merill CW, Gwaltney JM, Hendley JO (1973} Rapid identification of pneumococci Gram
stain vs the Quellung reaction. N Engl J Med 288:510-512
68. Perlino CA (1984} Laboratory diagnosis of pneumonia due to Streptococcus pneumonia. J
Infect Dis 150:139-144
69. Kalin M, Lindberg AA (1983) Diagnosis of pneumococcal pneumonia. A comparison be-
tween microscopic examination of expectorate antigen detection and cultured procedures.
Scand J Infect Dis 15:247-255
70. Arbo MDJ, Snydman DR (1994} Influence of blood cultures results on antibiotic choice in
treatment of bacteremia. Arch Intern Med 154:2641-2645
71. Waterer GW, Jenning SG, Wunderink RG (1999) The impact of blood cultures on antibiotic
therapy in pneumococcal pneumonia. Chest 116:1278-1281
72. Bryan CS (1999} Blood cultures for community-acquired pneumonia. No place to skimp.
Chest 116:1153-1155
73. Chalasani NP, Valdecanas MA, Gopal AK, McGowan JE Jr, Jurado RL (1995} Clinical utility
of blood cultures in adult patients with CAP without defined underlying risks. Chest
108:932-936
74. Woodhead MA, Arrowsmith J, Chamberlain-Webber R, Wooding S, Williams I (1991} The
value of routine microbial investigation in community-acquired pneumonia. Respir Med
85:313-317
75. Bartlett JG, Mundy LM (1995} Community-acquired pneumonia. N Engl J Med 333:1618-
1624
174 J. Rello et al.: Current Dilemmas in the Management of Adults
76. Marston BJ, Plouffe JF, File TM Jr, et al (1997) Incidence of community-acquired pneumo-
nia requiring hospitalization: results of a population-based active surveillance study in
Ohio. Arch Intern Med 157:1709-1718
77. Porath A, Schlaeffer F, Lieberman D (1997) The epidemiology of community-acquired
pneumonia among hospitalized adults. J Infect 34:41-48
78. Fang GD, Fine M, Orloff J, et al (1990) New and emerging etiologies for community-ac-
quired pneumonia with implications for therapy: a prospective multicenter study of 359
cases. Medicine 69:307-316
79. Mundy LM, Auwaerter PG, Oldach D, Gopalan R, Moore RD (1995) Community-acquired
pneumonia: impact of immune status. Am J Respir Crit Care Med 152:1309-1315
80. Ewig S, Bauer T, Hasper E, Pizzulli L, Kubini R, Luderitz B (1996) Value of routine micro-
bial investigation in community-acquired pneumonia treated in a tertiary care center. Re-
spiration 63:164-169
81. Marrie TJ (1994) Community-acquired pneumonia. Clin Infect Dis 18:501-513
82. Moine P, Vercken JB, Chevret S, Gajdos P (1995) Severe community-acquired pneumococ-
cal pneumonia. The French Study Group of Community-Acquired Pneumonia in ICU.
Scand J Infect Dis 27:201-206
83. Plouffe JF, Breiman RF, Facklam RR (1996) Bacteremia with Streptococcus pneumoniae: im-
plications for therapy and prevention. JAMA 275:194-198
84. Lippmann ML, Goldberg SK, Walkenstein MD, Herring W, Gordon M (1995) Bacteremic
pneumococcal pneumonia: a community hospital experience. Chest 108:1608-1613
85. Watanakunakorn C, Bailey TA (1997) Adult bacteremic pneumococcal pneumonia in a
community teaching hospital, 1992-1996: a detailed analysis of 108 cases. Arch Intern Med
157:1965-1975
86. Souto JE, Yu VL (1997) Legionellosis. N Engl J Med 337:682-687
87. Marston BJ, Lipman HB, Breiman RF (1994) Surveillance for legionnaires' disease: risk fac-
tors for morbidity and mortality. Arch Intern Med 154:2417-2422
88. Edelstein PH (1993) Legionnaires's disease. Clin Infect Dis 16:741-749
89. Glanville AR, Marlin GE, Hartnett BJS (1995) The use of fiberoptic bronchoscopy with ster-
ile catheter in the diagnosis of pneumonia. Aust NZ J Med 15:309-319
90. Wimberly NW, Bass JB Jr, Boyd BW, Kirkpatrick MB, Serio RA, Pollock HM (1982) Use of
a bronchoscopic protected catheter brush in the diagnosis of pulmonary infections. Chest
81:556-562
91. Shelhamer JH, Gill VJ, Quinn TC, et al (1996) The laboratory evaluation of opportunistic
pulmonary infections. Ann Intern Med 124:585-599
92. Feinsilver SH, Fein AM, Niederman MS, Schultz DE, Faegenburg DH (1990) Utility of fiber-
optic bronchoscopy in non-resolving pneumonia. Chest 98:1322-1326
93. Pollock HM, Hawkins EL, Bonner JR, Sparkman T, Bass JB Jr (1983) Diagnosis of bacterial
pulmonary infections with quantitative protected catheter cultures obtained during
bronchoscopy. J Clin Microbiol 17:255-259
94. Teague RB, Wallace RJ, Awe RJ (1981) The use of quantitative sterile brush culture and
Gram stain analysis in the diagnosis of lower respiratory tract infection. Chest 79:15 7-161
95. Jimenez P, Saldias F, Meneses M, Silva ME, Wilson MG, Otth L (1993) Diagnostic fiberoptic
bronchoscopy in patients with community-acquired pneumonia: comparison between
bronchoalveolar lavage and telescoping plugged catheter cultures. Chest 103:1023-1027
96. WaldA, Leisenring W, van Burik JA, Bowden RA (1997) Epidemiology of Aspergillus infec-
tions in a large cohort of patients undergoing bone marrow transplantation. J Infect Dis
175:1459-1466
97. Heffelfinger JD, Dowell SF, Jorgensen JH, Schuchat A, Whitney CG (2000) Management of
community-acquired pneumonia in the era of pneumococcal resistance: a report from the
drug-resistant streptococcus pneumoniae therapeutic working group. Arch Intern Med
160:1399-1408
98. Gleason PP, Meehan TP, Fine JM, Galusha DH, Fine MJ (1999) Associations between anti-
microbial therapy and medical outcomes for hospitalized elderly patients with pneumonia.
Arch Intern Med 159:2562-2572
Evaluation of Non-Resolving
and Progressive Pneumonia
R. Menendez and A. Torres
I Introduction
The concepts of non-resolving and progressive pneumonia are difficult to define
and have led to various reports that have been modified over time. In both cases,
these concepts refer to a bad therapeutic response of pneumonia and, in the case
of progressive pneumonia, may cause a medical emergency with vital implications
for the patient requiring very rapid changes in diagnostic and therapeutic attitude.
The initial difficulty for a clinician is to decide precisely whether the patient has
non-resolving or progressive pneumonia, since different authors have arbitrarily
used time for definition [1]. The knowledge of the natural clinical manifestations
of community-acquired pneumonia (CAP), the evolution of its symptoms, and the
speed of radiographic resolution have provided the basis for defining these terms.
Thus, in 1987, Fein and colleagues used clinical criteria to define non-resolving
pneumonia as a clinical syndrome in which focal infiltrates clearly begin with some
clinical association of acute pulmonary infection (that is fever, expectoration, mal-
aise and/or dyspnea) and do not resolve in the expected time. In 1991, Kirtland
and Winterbauer [2] added radiographic criteria and slowly resolving pneumonia
was defined as a clearing of the radiographic image of less than 50% in two weeks
or incomplete at 4 weeks. Another criteria includes a minimum of 10 days of anti-
biotic therapy and a radiographic infiltrate that has not resolved in an expected
period of time based on the presumed diagnosis.
There are fewer definitions for the concept of progressive pneumonia. In the re-
cent recommendations of the American Thoracic Society (ATS) for the manage-
ment of CAP [3], the following clinical criteria were used for its identification: clin-
ical deterioration after 24 hours of treatment with an increase of 50% in the radio-
graphic images. In the same guidelines, therapeutic failure or non-responding
pneumonia was defined as the absence of clinical stability on the third day with no
known coexisting factors of slow response or response on day 7. Ortqvist et al. [4]
observed progressive pneumonia in 6.5% of the patients showing intrahospital anti-
biotic treatment failure within the first 48-72 hours. Arancibia et al. [5] defined
progressive pneumonia as clinical deterioration with respiratory insufficiency re-
quiring mechanical ventilation or septic shock after 72 hours of treatment, and
non-responding pneumonia when there is persistent fever (> 38 °C) with clinical
symptoms after at least 72 hours of treatment.
The incidence of non-resolving pneumonia has not been clearly established.
Approximately 10% of hospitalized patients do not adequately respond to empiric
treatment and another 6% may evolve to progressive pneumonia [4, 6]. In the
group of CAP patients with non-resolving pneumonia, Arancibia et al. [5] found
176 R. Menendez and A. Torres
that 39% evolved to progressive pneumonia. The incidence of non-resolving noso-

comial pneumonia is higher. Alvarez Lerma et al. [7] found values of 36% with a
lack of clinical response and Crouch et al. [8] observed up to 60% in ventilator-as-
sociated pneumonia (VAP).
The mortality of patients with CAP and non-responding pneumonia was 43%
[5] in one study, a value that is three-fold higher than the global mortality reported
in hospitalized patients (5-15%). Moreover, when the cause of therapeutic failure
was the consequence of nosocomial infection, mortality was 88%. In fact, this cause
was an independent predictive factor of death with a relative risk of 16 (RR 16.7;
CI 95%: 1.4-1.94). This increased mortality did not occur if the cause of failure
was due to primary or persistent infection or for other reasons. In another study of
non-responding nosocomial pneumonia in patients admitted to a medical intensive
care unit (ICU), Pereira et al. [9] found a similar global mortality (43.4%), although
this study was not adjusted for other risk variables. In a recently finished study,
the mortality was five-fold greater in a group of patients with nosocomial pneumo-
nia (M. Ionas and A. Torres, personal communication).
I Factors Associated with the Resolution of Pneumonia

Factors related to the host and the causal microorganism are implicated in the dis-
appearance of symptoms and radiographic resolution of pneumonia.
Host Factors
The expected therapeutic response in pneumonia is the disappearance of fever within
3-5 days, improvement in leukocytosis by day 4, while the crackling on pulmonary
auscultation persists for more than 7 days. With regard to the resolution of radio-
graphic condensation, at 4 weeks up to 40% of the patients still present images [3].
In classical studies, most of which were performed in hospitalized subjects, it is
known that advanced age, alcoholism and comorbidity such as diabetes mellitus, cor-
onary artery disease and other diseases delay the resolution of CAP [1, 2, 10, 11].
The initial severity of the presentation of pneumonia influences the posterior
evolution and prognosis. Thus, the initial severity measured as PSI or Fine risk
scale, graded in five classes (I-V) [13], including 20 combined prognostic variables
such as age, comorbidity, and analytical and radiological alterations is associated
with the resolution of signs and symptoms. Halm et al. [14] found that the number
of days until disappearance of fever, respiratory insufficiency, and normalization of
vital signs (heart and respiratory rate, and blood pressure) depended on the class
of initial risk. Thus, the more severe, the higher the number of days necessary to
achieve clinical stability, ranging from 5-7 days according to the different conserva-
tive cut offs chosen.
In the latest ATS recommendations [3], three periods of clinical response have
been proposed to orient the clinician in the evaluation of therapeutic response: the
first on initiation of treatment, the second begins at day 3 when the patient is
expected to achieve clinical stability, and the third period is that of recovery and
resolution of previous alterations.
In a cohort of immunocompetent individuals, including hospitalized and ambu-
latory patients, it was found that radiographic resolution is obtained in 67% of the
Evaluation of Non-Resolving and Progressive Pneumonia 177
cases within 4 weeks and in 73% at 6 weeks [14]. The resolution was rapid in non-
smokers and in those with ambulatory CAP [1, 10, 11], and an inverse correlation
was observed with the number of lobes involved on radiography and age [14]. Pre-
vious studies have demonstrated the influence of some factors on clinical resolution
such as bacteremic CAP with multilobar involvement.
Host inflammatory response versus infection with local and systemic production
of proinflammatory cytokines has been correlated with initial severity of pneumo-
nia and mortality. Cytokines participate in response to infection with activation of
the immune cells and recruitment of monocytes and neutrophils. Although these
mediators have a beneficial effect on host response, excessive production may have
a deleterious effect [15-17]. Thus, high plasma levels of interleukin (IL-)6 and
tumor necrosis factor (TNF)-a have been correlated with higher mortality in CAP
and acute respiratory distress syndrome (ARDS) [18]. Some recent studies in
patients with sepsis have suggested that the balance between proinflammatory and
antiinflammatory cytokines has a role in patient outcome [17]. To date, the implica-
tion of local and systemic response of cytokines in non-responding and/or progres-
sive pneumonia remains not very well known. Preliminary studies, in patients
receiving empiric treatment for ICU-acquired pneumonia, have found that high
serum levels of IL-6 on the first day represent an independent risk factor and pre-
dictor of non-responding pneumonia (A. Torres, personal communication). An ade-
quate, balanced response to cytokines may be a key factor contributing to the lack
of response despite adequate initial antibiotic treatment. In a pilot study, Monton
et al. [19] found that the use of glucocorticoids in the treatment of severe pneumo-
nia was able to reduce inflammatory response with a decrease in IL-6 and TNF-a
and lower observed mortality.
Factors Related to the Causal Microorganism
The causal microorganism plays an important role in the natural evolution of CAP.
The most frequent causal microorganisms of CAP are Streptococcus pneumoniae,
Mycoplasma pneumoniae, Legionella pneumophila, Chlamydia pneumoniae and en-
teric Gram-negative microorganisms, and the relationship established with the host
determines peculiarities in the resolution of the symptoms and radiographs. S.
pneumoniae is the most frequent causal microorganism producing the most deaths
by CAP. Its evolution largely depends on the interrelation with the host characteris-
tics, therefore weak elderly patients with comorbidity and immunodepression have
the worse prognosis and slowest resolution. Classical studies have shown that from
8-10 weeks the disappearance of radiographic images is complete in 90% of the pa-
tients. However, this resolution is also delayed in CAP with bacteremia and multilo-
bar involvement. The risk factors associated with delay in resolution are advanced
age, chronic obstructive pulmonary disease (COPD}, alcoholism and multilobar
pneumonia. On the contrary, in individuals under the age of 50 years, the resolu-
tion of infiltrates takes place within 12 weeks in 94% of the cases.
Legionella spp. is the cause of 1-8% of CAP and is somewhat higher in patients
requiring admission to an ICU. The evolution of the symptoms of CAP by Legionel-
la spp. is slower than that with other typical microorganisms, and may even lead to
progressive pneumonia, triggering severe respiratory insufficiency and radiographic
progression [20]. The radiographic evolution of this type of pneumonia may show
worsening in condensation and dissemination to the contralateral lung in one third
of the patients [21], particularly in mixed infection by more than one species of
Legionella; normalization of the images within 4 weeks is only achieved in 12o/o,
and in up to 40o/o residual lesions may be present at three months [11]. In previous
studies it has been shown that the percentage of patients presenting resolution in
the first 4 weeks (29-52%) is lower than for S. pneumoniae. In immunosuppressed
patients, cavitation may appear during the evolution of CAP.
Mycoplasma pneumoniae is the most frequent causal microorganism in youths,
although it may affect patients of all ages. Although it may evolve, with progression
in radiologic lesions in some cases, its evolution normally shows resolution of
radiographic lesions in 98o/o of patients within 8 weeks [1, 22]. Nonetheless, if
Mycoplasma pneumoniae causes CAP in a patient with alterated defenses, it may
evolve with a more severe clinical course and worse prognosis.
Fewer studies have been performed in patients with CAP by Chlamydia pneumo-
niae but its course is more benign than that of S. pneumoniae and Legionella and
radiographic lesions are cleared within 4-6 weeks. In a study comparing different
parameters of CAP by Chlamydia alone or in association with S. pneumoniae,
Kauppinen et al. [23] reported worse prognosis, a greater number of days of hospi-
talization, and slower radiographic resolution when CAP is caused by mixed organ-
isms. Less information is available on the natural evolution and rate of radio-
graphic resolution for other organisms, less commonly involved in CAP.
The interaction between the causal microorganism, bacterial load, and the host
may trigger a determined inflammatory response with a fundamental role in clini-
cal response and resolution. Some authors have demonstrated differences in the
production of cytokines according to the causal microorganism. Lieberman et al.
[24] found higher serum concentrations of IL-1P and IL-6 in CAP caused by S.
pneumoniae than that caused by Mycoplasma. From another perspective, some hy-
potheses have indicated the possibility that persistent levels of cytokines may favor
the growth of nosocomial bacteria. Thus, in in vitro studies with different concen-
trations of cytokines, Meduri et al. [25] found a higher concentration-dependent
growth of S. aureus, Acinetobacter spp. and Pseudomonas aeruginosa.
I Causes of Non-Resolving and Progressive Pneumonia

The causes of non-resolving and progressive pneumonia are classified in two
groups: infectious and non-infectious origin [3].
Infectious Causes
When the clinical and/or radiographic evolution of the patient does not follow the
normal previously mentioned parameters this may be due to an etiology of CAP by
microorganisms resistant to antibiotics, unusual pathogens or a complicated evolu-
tion of the pneumonia itself [3, 5]. Arancibia et al. [5] found that nearly 70o/o of
causes of treatment failure were for infectious reasons. Concerning resistance, the
normal treatment schedules in CAP adequately cover resistant S. pneumoniae.
Nevertheless, therapeutic failure has been observed due to resistance to third gen-
eration cephalosporins or the new fluoroquinolones, specifically levofloxacin [26],
and, thus, surveillance is necessary since resistance may even develop during treat-
ment.
Initial empiric treatment may fail when the etiology is due to infrequent or un-
usual CAP microorganisms; S. aureus and P. aeruginosa are microorganisms which
are not adequately covered with the usual empiric therapeutic schedules recom-
mended in CAP. Although these microorganisms are infrequent, their mortality,
particularly with P. aeruginosa, is high and, thus, the risk factors for this microor-
ganism have been reported in detail in the latest ATS recommendations with the
aim of selecting the ideal initial treatment [3]. Arancibia et al. [5] found five cases
of Pseudomonas in 49 (10.2%) cases of non-responding pneumonia due to persis-
tent infection in three patients and the later appearance of nosocomial infection in
two cases. In non-responding ventilator-associated pneumonia (YAP), multiple re-
sistance of the microorganisms to the usual antibiotic treatments is responsible for
the lack of resolution in 50% of episodes and the most frequent microorganisms
were methicillin-resistant S. aureus (MRSA), P. aeruginosa and Acinetobacter spp.
[27].
Mycobacteria, Nocardia spp., Pneumocystis carinii, anaerobes, leptospires, and
endemic fungi are included within the group of unusual microorganisms requiring
a specific antibiotic treatment other than that recommended in the norms of initial
empiric treatment for CAP. Tuberculosis may be suspected in concrete environ-
ments or in subjects from risk-related groups or countries with a high incidence of
this disease. Although infrequent and with a subacute course, environmental myco-
bacteria may lead to middle lobe syndromes or lesions in the pulmonary apex with
cavitation. Nocardia spp. is a microorganism which may be an etiological agent in
patients treated with steroids and/or immunosuppressive therapies, such as those
with COPD, systemic diseases, transplant recipients, and others [28]. Contact with
animals for work, leisure, and/or housepets may lead to infection by leptospires,
psittacosis, tularemia, and hantavirus.
Complications may produce a slower resolution or progression of CAP with the
appearance of shock or respiratory distress or multiorgan failure (MOF). Pleural ef-
fusion is a frequent cause of lack of response requiring radiography and/or com-
puted tomography (CT) for its exclusion since thoracocentesis and analysis of
pleural fluid is necessary. Metastatic infections such as endocarditis, arthritis, and
peritonitis are more frequent in bacteremic CAP.
Non-Infectious Causes
Other diseases with acute involvement of the pulmonary parenchyma may simulate
CAP and therapeutic failure. This group includes: neoplasms, pulmonary hemor-
rhage, inflammatory diseases such as bronchiolitis obliterans and organizing pneu-
monia (BOOP), acute interstitial pneumonitis, eosinophilic pneumonia, hypersensi-
tivity pneumonitis, and others. The frequency of non-infectious etiologies is not
well established. Neoplasms are the most frequent, with Feinsilver et al. [29] ob-
serving 10% of lung cancers in adults with non-resolving pneumonia. Ortqvist et
al. and Arancibia et al., however, found a lower percentage of neoplasms (around
1-6%) [4, 5].
1 Evaluation of Non-Resolving and Progressive Pneumonia
Clinical Evaluation
In a patient with non-responding or progressive pneumonia a complete reevalua-
tion of the anamnesis and a full physical examination are required in order to rule
out infectious and non-infectious causes. This evaluation includes important epide-
miologic keys, which may reveal unusual microorganisms (Table 1), risk factors for
resistant microorganisms, or infection by the human immunodeficiency virus
(HIV).
Microbiologic investigation (Table 2) may begin with studies of non invasive
samples such as sputum (with special conventional and modified Ziehl staining for
M. tuberculosis and Nocardia, methenamine silver for P. carinii), urinary antigens
detection, blood cultures and serum antibody studies. More recent techniques in-
clude blood and urine PCR (polymerase chain reaction) which allow identification
of S. pneumoniae, Legionella and C. pneumoniae and M. pneumoniae in pharyngeal
swabs [30] . The use of these techniques, however, is not completely standardized
and is still being developed.
Role of Fibrobronchoscopy
Respiratory samples may be obtained with fibrobronchoscopy (Table 2) and, at the
same time, the permeability of the airway may be examined at the same site in
which pneumonia is located. The diagnostic yield for some bacterial microorgan-
isms may be reduced because of previous antibiotic administration thereby de-
creasing their usefulness, being around 41 [4] to 42% [5] in non-responding pneu-
monia, and 72% [9] in nosocomial pneumonia in the ICU.
Table 1. Possible causal microorganism according to epidemiologic data
I Coxiella burnetii Cats

Goats
Sheep
Cattle
Tularemia Rabbits
Ticks
Leptospirosis Rats
Plague
Psittacosis Birds
Anaerobes Nursing-home
Reduction in level of consciousness
Alcoholism
Steroid treatment Nocardia
Aspergillus
Recent journeys Dimorphic fungi
Burkho/deria pseudomallei
Tuberculosis
Table 2. Microbiologic studies indicated in non-resolving or progressive pneumonia
Sputum Gram stain and conventional bacterial cultures

DFA Legionella
Giemsa staining
Normal and modified Ziehl staining
Staining for fungi
Blood cultures 2 sets
Urine Antigen for Legionella and 5. pneumoniae
Bronchoalveolar lavage (BAL) fluid Gram stain and intracellular bacteria
Bacterial cultures (colony counts)
Normal and modified Ziehl
Giemsa stain
Staining for fungi
DFA Legionella
Protected specimen brush (PSB) Gram stain and intracellular bacteria
Bacterial cultures (colony counts)
Giemsa stain
Staining for fungi
DFA Legianella
PCR
Pleura Cultures for anaerobes
Bacterial cultures
DFA: direct fluorescent antibody
Bronchoalveolar lavage (BAL) fluid and protected specimen brush (PSB) are re-
commended prior to changes in therapy in order to avoid the masking of unusual
microorganisms, which are persistent or resistant. False negative cultures may be
found in bacteria such as S. pneumoniae, H. influenza or anaerobes although these
microorganisms are not the most frequently found in non-responding pneumonia.
If possible, respiratory samples should be obtained by both, complementary, tech-
niques. Nonetheless, BAL fluid is the most complete sample since it analyzes an
anatomical pulmonary area corresponding to around 106 alveoli, in contrast to
PSB, which collects airway secretions at the level of subsegmentary bronchi. BAL
fluid therefore provides valuable information for differential diagnosis and a suffi-
cient quantity of respiratory sample for studying the cellular component and the
fluid [31].
A simple differential cell count from BAL fluid provides useful diagnostic data
(Table 3): the predominance of neutrophils is suggestive of infectious disease; the
presence of eosinophils > 20% of eosinophilic pneumonia, fungal infection, drugs
or others (Table 4); the presence of blood or > 20% hemosiderin macrophages (Ta-
ble 5) are suggestive of pulmonary bleeding [32]; and an increase in lymphocytes
due to hypersensitivity pneumonitis, sarcoidosis or pulmonary fibrosis. In patients
with delayed-resolution pneumonia after 2 weeks of treatment, the persistence of
an inflammatory cell pattern has been demonstrated in the BAL fluid with higher
percentages of lymphocytes, neutrophils and eosinophils than in patients with com-
plete resolution [33].
Table 3. Possible diseases depending on differential cell count in BAL fluid
i Polymorphonuclear leukocytes
Bacterial infection
BOOP (bronchiolitis obliterans and organizing pneumonia)
1 Lymphocytes
Tuberculosis
Hypersensitivity pneumonitis
Sarcoidosis
Idiopathic pulmonary fibrosis
1 Hemosiderin-laden maaophages
Alveolar hemorrhage
l Eosinophils
Eosinophilic pneumonia
Fungal infection
P. carinii
Systemic diseases
Drug-induced disease
Table 4. Studies recommended for eosinophilia in BAL fluid
Parasite infection Mycobacteria

Previous drugs P. carinii
Fungi Neoplasms
Table S. Studies recommended for macrophages with hemosiderin or blood in BAL fluid
Autoantibodies: pANCA, cANCA, antibodies against basement membrane

Renal function with biochemical and sediment tests
I Bronchial and/or transbronchial biopsy
In a group of pneumonias with bad therapeutic response in ICUs, Jacobs et al.

[34] were able to orient the diagnosis towards a non-infectious etiology in 19% of
cases, with the study of cytocentrifuged BAL fluid. The suspected diagnosis was
achieved with May-Griinwald Giemsa staining for the identification of cells and
Perls' staining for haemosiderin visualization and was confirmed by other diagnos-
tic methods in 77% of cases.
Gram staining performed in cytocentrifuged BAL fluid is also useful in the iden-
tification of the microorganism and has a predictive value of bacterial growth. This
method is rapid and may aid in decision making regarding changes in antimicro-
bial therapy. The process of microbiologic study should include conventional bacte-
ria, normal and modified Ziehl staining for Nocardia, fungi and opportunistic bac-
teria [31]. The investigation of Legionella should be performed with direct immu-
nofluorescence and posterior cultures. Recent PCR techniques with a greater sensi-
tivity for the detection of microorganisms may increase the diagnostic yield,
although careful interpretation is required because of their capacity to detect mo-

lecular components or incomplete microorganisms. To identify conventional bacte-
ria with the aim of separating contamination from infection, quantitation of cul-
tures is necessary. Bacterial cultures should be interpreted together with clinical
data and other tests since previous antibiotics may reduce the counts below the
established cut offs (103 for PSB and 104 for BAL fluid).
Ortqvist et al. [4] found that BAL fluid and PSB provided diagnostic information
in 79% of patients, with 50% showing positive findings and 29% negative findings
including another diagnosis or adequate treatment due to the lack of demonstration
of the microorganism. Arancibia et al. [5] isolated microorganisms in 40% of the
BAL carried out in patients with prior therapeutic failure and in 42% of the PSB
samples. In the same study, the most frequent causes of therapeutic failure were de-
termined corresponding to primary, persistent or nosocomial infections and 18.3%
were due to non-infectious illness.
Pereira et al. [9] studied the impact of BAL fluid on nosocomial pneumonia with
previous therapeutic failure in a medical ICU with a diagnostic yield of 75% (> 103
cfu/ml if receiving treatment or > 104 cfu/ml) and found resistant nosocomial mi-
croorganisms despite previous antibiotic treatment. These findings allowed modifi-
cation of antibiotic treatment in more than half of the patients (54.8%), which,
however, was not accompanied by a reduction in mortality.
In non-resolving pneumonia, BAL fluid allows identification of resistant micro-
organisms (generally P. aeruginosa). Confirmation of the high concentrations of
these microorganisms with levels of> 104 cfu/ml is useful for predicting bad prog-
nosis. However, the therapeutic changes carried out with the information obtained
do not reduce the probability of mortality. Likewise, Luna et al. [35] found that the
results of BAL fluid analysis confirmed the adequacy or inadequacy of initial treat-
ment and determined the difference in mortality in these two groups, 35 versus
91%. In a review of the role of serial bronchoscopy in non-resolving nosocomial
pneumonia, Niederman [36] concluded that, although this technique provides use-
ful information in regard to etiology, its possible impact on reducing mortality has
not been demonstrated.
The diagnostic yield of bronchial and trans bronchial biopsy in non-resolving or
progressive pneumonia has not been established and depends on the probability of
other suspected etiologies. Arancibia et al. [5] made a diagnosis in up to 57% of
cases when transbronchial biopsy was performed in non-resolving pneumonia, de-
spite this sample only being obtained in 25% of cases. In this study, in which 18%
of the causes of therapeutic failure were of non-infectious origin, the authors con-
cluded that this technique is particularly useful in the diagnosis of this group
which includes neoplasms, BOOP, and histiocytosis X.
Role of Radiologic Studies
The follow-up by chest radiograph in pneumonia, when clinical evolution is ade-

quate, is not required to indicate sequential treatment or hospital discharge and
one control after 4 weeks of discharge is sufficient [3]. In progressive pneumonia,
the clinical deterioration and the extension of the chest radiograph lesions may
even appear prior to the 72 hours after initiation of treatment. In non-resolving
pneumonia, conventional chest radiographs, posteroanterior and lateral, may show
pleural effusion, the appearance of cavitation and/or new infiltrates. These findings
are more evident on CT scan that also allows detailed study of the parenchyma, the
interstitium, the pleura, and the mediastinum.
Pulmonary CT findings may be characteristic of some microorganisms although
not being pathognomonic [37]. The appearance of nodular images with a halo sign
(nodules surrounded by a halo of ground-glass attenuation) or pleura-based
wedge-shaped areas of consolidation is suggestive of pulmonary aspergillosis and/
or mucor. Nodular images of a similar appearance have also been described in
Candida, cytomegalovirus (CMV) infection, Wegener's granulomatosis, Kaposi's
sarcoma, and hemorrhagic metastases. The finding of ground-glass opacity or
images of interstitial pneumonia are characteristic features of pneumonia by P. cari-
nii. Bacterial infection with nodules or multiple masses with or without cavitation
may be caused by Nocardia spp., M. tuberculosis or Q fever. Diffuse or mixed inter-
stitial infiltrates may be due to virus or M. pneumoniae.
High-resolution CT (HRCT) is useful for differential diagnosis between an infec-
tious and non-infectious etiology, although it does not specifically identify the dis-
ease. In a recent study on the usefulness of HRCT in acute parenchymatous lung
disease, Tomiyama et al. [38] found that this technique correctly classified the in-
fectious or non-infectious etiology in 90% of the subjects. This study, which was
carried out in non-immunosuppressed patients without the aid of clinical data, also
showed that the identification of the diagnosis was correct in 90% of the acute in-
terstitial pneumonias, in 72% of the hypersensitivity pneumonias, and, to a lesser
extent, pulmonary hemorrhages and eosinophilic pneumonia. Although the study
was not undertaken in similar conditions to those of real practice, the key finding
of identifying an image as infectious or not is interesting and hopeful.
Other Studies
Other imaging studies are performed according to the initial suspicion such as per-
fusion ventilation scintigraphy to exclude pulmonary embolism, which should be
suspected in the absence of microorganisms and in patients with risk factors, such
as recent surgery, prolonged immobilization or signs of deep vein thrombosis or
right ventricular failure. Spiral CT and pulmonary angiography complement this
diagnosis.
An echocardiogram should be performed if endocarditis, pericarditis or conges-
tive cardiac failure are suspected.
Open biopsy is indicated when other diagnostic methods have been given no re-
sults. However, in immunocompetent patients, Dunn et al. [39] reported that rele-
vant information for improving prognosis is seldom provided with this technique.
I Empiric Therapeutic Changes in Non-Responding Pneumonia
Infectious causes are the most frequently observed in non-responding pneumonia

and the results of microbiologic studies may be delayed up to 48 hours. Thus, after
obtaining the samples, an empiric therapeutic change is indicated. To carry out this
change, all the initial microbiologic results should be reviewed and treatment
should be adjusted with the determination of positive results. However, the initial
results will probably provide little information. In these circumstances, the empiric
therapeutic change should be aimed at extending the bacteriologic spectrum
including the possibility of resistant or unusual microorganisms. In the study by

Arancibia et al. [5], the most frequent microorganisms found in non-responding
pneumonia were S. pneumoniae and P. aeruginosa.
The treatment of non-responding CAP patients should include combined therapy
and coverage should be extended to cover anerobes, P. aeruginosa and S. aureus
and maintain therapy towards usual microorganisms such as S. pneumoniae and
Legionella, with antipseudomonal betalactamic drugs (piperacillin/tazobactam, imi-
penem, meropenem, cefepime) and intravenous antipneumococcal fluoroquinolones
(trovafloxacin or levofloxacin) or an intravenous macrolide (azithromycin or clari-
thromycin). If suspicion of Pseudomonas aeruginosa is very high (the risk factors
are defined in the latest ATS guidelines [3]}, the antimicrobial therapy should in-
clude at least two antipseudomonal agents: antipseudomonal betalactam (piperacil-
lin/tazobactam, imipenem, meropenem, cefepime) plus intravenous ciprofloxacin or
aminoglucosides and intravenous macrolide (azithromycin or clarithromycin).
In non-responding nosocomial pneumonia, combinations occasionally including
up to three antibiotics may be required to cover P. aeruginosa, MRSA, and, accord-
ing to the local flora of each hospital, Acinetobacter spp. or others. The most fre-
quent causes of treatment failure are inappropriate initial treatment with resistant
microorganisms and superinfections by the flora of the hospital (Ionas M., Torres
A., personal communication). The evaluation of the empiric therapeutic changes
must, therefore, take into account the patterns of resistance themselves. The asso-
ciations in these cases should include antipseudomonal betalactamic drugs (pipera-
cillin-tazobactam, imipenem, meropenem) or antipseudomonal quinolones, amino-
glucosides and vancomycin until MRSA is safely eliminated.
I Conclusion
The concepts of non-resolving and progressive pneumonia are difficult to define:
both refer to a failure in the therapeutic response, which in the case of progressive
pneumonia may cause a medical emergency even in the first 72 hours after empiric
treatment. The incidence of non-resolving pneumonia in CAP is approximately
10%, and > 30% in nosocomial pneumonia. Mortality in non-responding pneumo-
nia increases three-fold in CAP and five-fold in nosocomial pneumonia compared
to global mortality in hospitalized patients. Factors associated with the resolution
of pneumonia are related to host, microorganisms and the relationship between
them, which may modulate the cytokine response that plays a key role in resolu-
tion. Causes of non-resolving or progressive pneumonia may be infectious or non-
infectious. Management of non-responding patients requires a reevaluation of epi-
demiological data, a complete microbiologic investigation, with conventional and
invasive respiratory samples, and performance of a new radiographic study. Em-
piric therapeutic changes are aimed at broadening the bacteriologic spectrum in
order to cover resistant or unusual microorganisms.
References
1. Kuru T, Lynch JP 3rd (1999) Nonresolving or slowly resolving pneumonia. Clin Chest Med
20:623-651
2. Kirtland SH, Winterbauer RH (1991) Slowly resolving, chronic, and recurrent pneumonia.
3. Niederman MS, Mandell LA, Anzueto A, et al (2001) Guidelines for the management of
adults with community-acquired pneumonia. Diagnosis, assessment of severity, antimicro-
bial therapy, and prevention. Am J Respir Crit Care Med 163:1730-1754
4. Ortqvist A, Kalin M, Lejdeborn L, Lundberg B (1990) Diagnostic fiberoptic bronchoscopy
and protected brush culture in patients with community-acquired pneumonia. Chest
97:576-582
5. Arancibia F, Ewig S, Martinez JA, et al (2000) Antimicrobial treatment failures in patients
with community-acquired pneumonia: causes and prognostic implications. Am J Respir
6. Ruiz M, Ewig S, Marcos MA, et al (1999) Etiology of community-acquired pneumonia: im-
pact of age, comorbidity, and severity. Am J Respir Crit Care Med 160:397-405
7. Alvarez-Lerma F (1996) Modification of empiric antibiotic treatment in patients with pneu-
monia acquired in the intensive care unit. ICU-Acquired Pneumonia Study Group. Intensive
Care Med 22:387-394
8. Crouch Brewer S, Wunderink RG, Jones CB, et al (1996) Ventilator-associated pneumonia
due to Pseudomonas aeruginosa. Chest 109:1019-1029
9. Pereira Gomes JC, Pedreira WL Jr, Araujo EM, et al (2000) Impact of BALin the manage-
ment of pneumonia with treatment failure: positivity of BAL culture under antibiotic ther-
apy. Chest 118:1739-1746
10. Fein AM, Feinsilver SH, Niederman MS (1993) Nonresolving and slowly resolving pneumo-
nia. Diagnosis and management in the elderly patient. Clin Chest Med 14:555-569
11. Johnson JL (2000) Slowly resolving and nonresolving pneumonia. Questions to ask when
response is delayed. Postgrad Med 108:115-122
12. Fine MJ, Auble TE, Yealy DM, et al (1997) A prediction rule to identify low-risk patients
with community-acquired pneumonia. N Engl J Med 336:243-250
13. Halm EA, Fine MJ, Marrie TJ, et al (1998) Time to clinical stability in patients hospitalized
with community-acquired pneumonia: implications for practice guidelines. JAMA
279:1452-1457
14. Mittl RL Jr, Schwab RJ, Duchin JS, Gain JE, Albeida SM, Miller WT (1994) Radiographic
resolution of community-acquired pneumonia. Am J Respir Crit Care Med 149:630-635
15. Nelson S (2001) Novel nonantibiotic therapies for pneumonia: cytokines and host defense.
Chest 119:419S-425S
16. Skerrett SJ, Park DR (2001) Anti-inflammatory treatment of acute and chronic pneumonia.
Semin Respir Infect 16:76-84
17. Bonten MJ, Froon AH, Gaillard CA, et al (1997) The systemic inflammatory response in
the development of ventilator-associated pneumonia. Am J Respir Crit Care Med 156:1105-
1113
18. Manton C, Torres A, El-Ebiary M, Fillela X, Xaubet A, de la Bellacasa JP (1999) Cytokine
expression in severe pneumonia: a bronchoalveolar lavage study. Crit Care Med 27:1745-
1753
19. Manton C, Ewig S, Torres A, et al (1999) Role of glucocorticoids on inflammatory response
in nonimmunosuppressed patients with pneumonia: a pilot study. Eur Respir J 14:218-220
20. Domingo C, Roig J, Planas F, Bechini J, Tenesa M, Morera J (1991) Radiographic appear-
ance of nosocomial legionnaires' disease after erythromycin treatment. Thorax 46:663-666
21. Muder RR, Yu VL, Parry MF (1987) The radiologic manifestations of Legionella pneumo-
nia. Semin Respir Infect 2:242-254
22. Kim CK, Chung CY, Kim JS, Kim WS, Park Y, Koh YY (2000) Late abnormal findings on
high-resolution computed tomography after Mycoplasma pneumonia. Pediatrics 105:372-
378
23. Kauppinen MT, Saikku P, Kujala P, Herva E, Syrjala H (1996) Clinical picture of commu-
nity-acquired Chlamydia pneumoniae pneumonia requiring hospital treatment: a compari-
son between chlamydia! and pneumococcal pneumonia. Thorax 51:185-189
24. Lieberman D, Livnat S, Schlaeffer F, Porath A, Horowitz S, Levy R (1997) IL-1beta and IL-6
in community-acquired pneumonia: bacteremic pneumococcal pneumonia versus Myco-
plasma pneumoniae pneumonia. Infection 25:90-94
25. Meduri GU, Kanangat S, Stefan J, et al (1999) Cytokines IL-1beta, IL-6, and TNF-alpha en-
hance in vitro growth of bacteria. Am J Respir Crit Care Med 160:961-967
26. Chen DK, McGeer A, de Azavedo JC, Low DE (1999) Decreased susceptibility of Strepto-
coccus pneumoniae to fluoroquinolones in Canada. Canadian Bacterial Surveillance Net-
work. N Eng! J Med 341:233-239
27. Ferrer M, Ioanas M, Torres A (2001) The evaluation of the non-responding patients with
ventilator-associated pneumonia. Clin Pulm Med 8:290-295
28. Menendez R, Cordero PJ, Santos M, Gobernado M, Marco V (1997) Pulmonary infection
with Nocardia species: a report of 10 cases and review. Eur Respir J 10:1542-1546
29. Feinsilver SH, Fein AM, Niederman MS, Schultz DE, Faegenburg DH (1990) Utility of fiber-
optic bronchoscopy in nonresolving pneumonia. Chest 98:1322-1326
30. Menendez R, Cordoba J, de Ia Cuadra P, et a! (1999) Value of the polymerase chain reac-
tion assay in noninvasive respiratory samples for diagnosis of community-acquired pneu-
monia. Am J Respir Crit Care Med 159:1868-1873
31. Mares DC, Wilkes DS (1998) Bronchoscopy in the diagnosis of respiratory infections. Curr
Opin Pulm Med 4:123-129
32. De Lassence A, Fleury-Feith J, Escudier E, et a! (1995) Alveolar hemorrhage. Diagnostic
criteria and results in 194 immunocompromised hosts. Am J Respir Crit Care Med
151:157-163
33. Fujimura M, Yasui M, Nishi K, et a! (1999) Comparison of bronchoalveolar lavage cell find-
ings in complete-resolution pneumonia and delayed-resolution pneumonia. Am J Med Sci
317:222-225
34. Jacobs JA, De Brauwer EI, Ramsay G, et a! (1999) Detection of non-infectious conditions
mimicking pneumonia in the intensive care setting: usefulness of bronchoalveolar fluid cy-
tology. Respir Med 93:571-578
35. Luna CM, Vujacich P, Niederman MS, et a! (1997) Impact of BAL data on the therapy and
outcome of ventilator-associated pneumonia. Chest Ill :676-685
36. Niederman MS (2000) Bronchoscopy in nonresolving nosocomial pneumonia. Chest
117:212S-218S
37. Franquet T (2001) Imaging of pneumonia: trends and algorithms. Eur Respir J 18:196-208
38. Tomiyama N, Muller NL, Johkoh T, et a! (2000) Acute parenchymal lung disease in immu-
nocompetent patients: diagnostic accuracy of high-resolution CT. Am J Roentgenol 174:
1745-1750
39. Dunn IJ, Marrie TJ, MacKeen AD, Bhan V, Janigan DT (1994) The value of open lung
biopsy in immunocompetent patients with community-acquired pneumonia requiring hos-
pitalization. Chest 106:23-27
Candida in Lung Specimens from Non-Neutropenic
ICU Patients: Infection or Colonization ?
E. Azoulay and B. Schlemmer
I Introduction
Candida is an opportunistic yeast normally found in the oral cavity and gastroin-
testinal tract. Its ability to multiply and to invade the bloodstream and deep tissues
is increasing. This has produced new clinical patterns of systemic disease whose ex-
pression is dependent on the immune status .of the host. Thus, presence of Candida
is intimately linked to the effects of chemotherapy and radiation therapy for cancer,
hematological malignancies, human immunodeficiency virus (HIV) infection, mal-
nutrition, corticosteroid therapy, and broad-spectrum antibiotics.
New definitions have been developed for classifying invasive fungal infections in
cancer patients and/or bone marrow transplant (BMT) recipients as 'proven', 'prob-
able', or 'possible', with the goal of improving the cross-study comparability of clin-
ical and epidemiological data [ 1]. A diagnosis of proven invasive candidiasis re-
quires a positive blood culture, a positive culture from a normally sterile site (other
than the urine and sinuses), or a histologically positive biopsy specimen.
The 'probable' and 'possible' categories are defined based on three groups of cri-
teria:
I host factors: duration of neutropenia longer than 10 days, persistent fever de-
spite broad-spectrum antibiotic therapy, recent use of immunosuppressants, his-
tory of definite or probable candidiasis, acquired immunodeficiency syndromes
(AIDS), clinical evidence of graft-versus-host disease;
I microbiological criteria: positive blood culture, positive urine culture in a pa-
tient without a urinary catheter;
I Clinical criteria indicating lower respiratory tract infection, sinonasal infection
or central nervous system (CNS) infection, with major and minor criteria; crite-
ria for disseminated infection (extensive skin lesions, enophthalmos) or chronic
infection (abscesses of the liver or spleen, alkaline phosphatase elevation).
'Probable' invasive· candidiasis is defined as the combination of one host factor, one
microbiological factor, and either one major or two minor clinical factors. 'Possible'
invasive candidiasis is the presence of one host factor and either one major or two
minor clinical factors. A positive blood culture should be interpreted according to
host factors, neutrophil counts, whether the patient has a central line, and whether
the blood was sampled from a peripheral vein or a catheter.
Many intensive care unit (ICU) patients have pulmonary specimens containing
Candida counts above the significant 'thresholds' validated for distinguishing coloni-
zation from nosocomial pneumonia [2]. Candida colonization in ICU patients reflects
Candida in Lung Specimens from Non-Neutropenic ICU Patients: Infection or Colonization? 189
acquired immunodepression with alterations in both neutrophil function (killing of

bacteria, production of oxidants) and alveolar macrophage function [3-:;].
We will focus on the interpretation of specimens yielding Candida in non-neu-
tropenic ICU patients. After reviewing the clinical and experimental literature, we
will critically appraise this issue, taking care to separate the questions that have
been answered from those that remain open. Finally, we will suggest a research
agenda for improving our understanding of the continuum that extends from colo-
nization to infection of the lower respiratory tract by Candida in non-neutropenic
ICU patients.
I Candida Infection in the ICU: Epidemiological Studies
We will consider two groups of epidemiological studies, those addressing nosoco-

mial pneumonia in general and those focusing specifically on fungal infections in
the ICU. In the former, an approach similar to the standard diagnostic strategy for
bacterial nosocomial pneumonia revealed a high prevalence of respiratory tract
specimens yielding Candida in concentrations above the threshold used to distin-
guish colonization from infection. The latter used a more specific approach to the
diagnosis of Candida pneumonia and found that the incidence of this condition,
although low, is on the rise.
The European Prevalence of Infection in Intensive Care (EPIC) study, a 1995 pre-
valence survey of nosocomial infection in European ICUs, found that pneumonia
contributed 46.9% of all ICU-acquired infections and that 17% of ICU-acquired in-
fections were related to yeasts, primarily Candida [2]. The National Nosocomial In-
fections Surveillance (NNIS) system in the United States showed that Candida spe-
cies were responsible for 10.1% of all ICU-acquired infections between 1980 and
1990 [6]. Furthermore, the incidence of Candida infection in hospital patients in-
creased steadily over the study period, 5-fold for candidemia, 2-fold for urinary
tract infections, and 1.6-fold for pneumonia [6]. Other studies have reported noso-
comial Candida pneumonia in patient subgroups sharing factors such as ICU ad-
mission or postoperative status [7-9]. Candida pneumonia has. also been described
in patients with diabetes mellitus or alcohol abuse; pharyngeal colonization by
yeasts is also common in these patients [10, 11].
In a study of fungal pneumonia conducted at the National Taiwan University
Hospital, a 27-fold increase in nosocomial candidemia occurred between 1980 and
1994 [12]. The diagnosis of fungal pneumonia was based on examination of lung"·
biopsies obtained by thoracotomy or thoracoscopy, percutaneous pleural or lung
biopsies obtained under ultrasound guidance, or transbronchial biopsies. The num-
ber of cases of fungal pneumonia increased from 5 in 1988 to 30 in 1997. Over the
10-year study period, 140 cases of fungal pneumonia were identified, including 20
due to Candida. Candida was associated with 70% mortality, the highest rate
among causes of fungal pneumonia; mortality was 40% for Aspergillus and 6.7%
for Cryptococcus.
In patients with cancer, neutropenia, anticancer chemotherapy, hematological
malignancies, or organ transplants, Candida pneumonia is a marker for severe im-
mune system impairment accompanied with selective vulnerability to opportunistic
infections [13-15]. In most patients, pneumonia occurs as a metastatic complica-
tion of candidemia, often at the terminal stage of a malignant disease with pro-
190 E. Azoulay and B. Schlemmer
found immunodepression [16]. Positive specimens for Candida in these patients

raise specific issues, which will not be discussed here.
I Candida Colonization: Considerations Specific to ICU Patients
Studies in ICU and surgery patients have confirmed that a continuum exists from
colonization to infection with Candida: colonization is an independent risk factor
for systemic candidiasis [17-20]. Pittet et al. found that Candida colonization was
an independent risk factor for deep-seated candida! infection and that routine seri-
al testing for colonization at multiple sites (trachea, urine, skin, stool, surgical
wounds, and drainage fluids) can be used to define a colonization index (number
of positive sites/number of tested sites) [8]. A colonization index greater than 0.5
was associated with an increased risk of deep-seated candida! infection. This risk
increase may, in theory, indicate systemic antifungal treatment [21]. Evidence from
several studies indicates that candidemia carries a poor prognosis and, conse-
quently, requires early diagnosis or prophylactic measures [19, 22-25]. The benefi-
cial effects of prophylactic treatment have been documented in hematology patients
[26-28] and suggested by several ICU studies [29-32]. Work is ongoing to validate
pre-emptive antifungal treatment in patients with Candida colonization.
At the respiratory tract, the colonization/infection dichotomy is supported by
evidence from autopsy studies (which are older) and clinical studies. Three autopsy
studies in 91 cancer patients led to the same conclusions. In immunocompromised
patients with systemic candidiasis and pulmonary manifestations, lung pathology
consists of necrotizing vasculitis, where the vessels are lined with pus cells contain-
ing yeasts. In contrast, in patients without systemic candidiasis, the pulmonary le-
sions are more likely to consist of pneumonia with intra-alveolar involvement but
no vasculitis [16, 33, 34]. Thus, candida! 'pneumonia' seems to exist as two vari-
ants. One is secondary to hematogenous dissemination with selective tropism for
the blood vessels; this is probably true pulmonary candidiasis. In the other variant,
Candida colonizing the oropharynx and gastrointestinal tract spreads along the res-
piratory tract, ultimately filling the alveoli, so that endobronchial specimens are
positive but no clinical or pathological evidence of pneumonia is detectable (Fig. 1)
[35, 36].
Clinical studies consistently support this distinction. We will focus on two stud-
ies that investigated the clinical relevance of 'positive' tracheal or protected distal
specimens, bronchoalveolar lavage (BAL) fluid, or bronchial or transbronchial biop-
sies. Both studies included ICU patients who received mechanical ventilation for
longer than 3 days [37, 38] and had no evidence of systemic candidiasis. In most
patients, lung biopsies or lung autopsy specimens found tracheobronchial coloniza-
tion without evidence of invasive candidiasis despite positive respiratory specimens.
Thus, the usual diagnostic criteria for nosocomial pneumonia do not seem valid
for pulmonary candidiasis. Among clinical studies, we will discuss the immediate
postmortem study by El-Ebiary et al. [37] in 25 non-neutropenic ICU patients who
received mechanical ventilation for longer than 72 hours and died in the ICU. The
objective was to investigate correlations between qualitative or quantitative cultures
positive for Candida and a diagnosis of pulmonary candidiasis. Immediately after
death, endotracheal aspirate, protected specimen brush (PSB), BAL, blind trans-
bronchial biopsies, and bronchoscopically guided biopsies were performed. Ten
Spread along the lower Spread from the

respiratory tract bloodstream
= Colonization = Infection
Fig. 1. Pathophysiological concept of Candida pneumonia. Candida pneumonia seems to exist as two vari-
ants. Even when Candida concentrations in respiratory specimens are greater than the cuts-off separating
colonization from infection, the most likely diagnosis is lower respiratory tract colonization related to
spread of Candida colonization from the digestive tract to the tracheobronchial tree [58). Histology shows
no evidence of infectious vasculitis related to Candida invasion. Conversely, when candidemia is suspected,
pulmonary involvement can reflect invasive candidiasis of the lungs secondary to hematogenous dissemi-
nation of the organism
(40%) of the 25 patients had at least one biopsy yielding Candida, and Candida
contributed 9% of isolates from biopsies. However, only two (8%} of these patients
had definite pulmonary candidiasis. Alveolitis was found in several patients, but
there was no evidence of a causal relation with Candida since other organisms were
usually present also. Furthermore, Candida colonization seemed uniform through-
out the tracheobronchial tree. Although the small number of patients is a limitation
of this study, the data provide a description of Candida colonization in ventilated
ICU patients and emphasize the poor correlation between respiratory samples
yielding Candida (colonization) and invasive pulmonary candidiasis.
I Experimental Models of Pulmonary Candidiasis

Host defence mechanisms against Candida albicans have been investigated in sev-
eral animal models, which are summarized in Table 1.
Knockout Mice for the Interferon Gamma Gene

Evidence for a key role of phagocytic cells stimulated by interferon (IFN)-y has
been obtained in knockout mice for the IFN-y gene. As early as the second day
after an intraperitoneal injection of C. albicans, a lymphoid infiltrate was seen
~
\0
IV
Table 1. Experimental models of Candida pneumonia !""'

:»
N
0
Refer- Year of Experimental model Route of Pulmonary involvement c::
Qj'"
ence publi- Candida administration '<
cation "':::>0..
!="
59) 1976 Mice Intravenous C. albicans multiplies at a faster pace in the kidneys V>
,..,
:::r
than in the lungs ;;;-
3
60] 1991 Rats with obstructive jaundice Intravenous Increased pulmonary localiz.ation of C. albicans 3 weeks 3
~
following ligation and division of the distal common bile duct
61) 1992 Neutropenic rats (cyclophosphamide} Intraperitoneal Compartmentalized TNF production in the lower respiratory
tract. Increased mortality, shock and All
[62] 1993 Rats with dual infection Intravenous in association Increased lung distribution of E. coli following dual injection
(E coli and C albicans) with E. coli injection
63) 1994 Neutropenic rats (cyclophosphamide) Intraperitoneal Reduced incidence of shock and ADRS in GM-CSF treated rats.
treated with GM-CSF Decreased mortality. No hemorrhage, alveolar disruption,
or fungi in lung parenchyma
64) 1994 Murine SAL fluid was tested Ex vivo experiments Heat-stable, soluble factor(s) suppress candida! colonization
for anti-candida! activity of the lower respiratory tract
[39) 1998 Mice KO for interferon y-gene Intraperitoneal Extensive perivascular lymphoid infiltrate by day 3, diffuse
pneumonia by day 28. Excess mortality
[41] 1999 Wild mice (control group) Intratracheal Normal lungs, normal clearance of C. albicans
[41] 1999 Mice deficient in MPO Intratracheal Delayed clearance of viable C. albicans. Edema and massive
(homozygous mutant) infiltration of alveolar and peribronchiolar spaces with
neutrophils by 120 hours. Excess mortality
[41] 1999 Mice deficient in MPO Intraperitoneal Increased Candida dissemination
(homozygous mutant) (high dose) All animals dead by 2 days
'[42] 2001 Alveolar macrophage-depleted mice Intravenous Increased cfu numbers of C. albicans, reduced pulmonary
edema, SAL neutrophilia, MPO activity and MIP-2 expression
in lung homogenates. Reduced mortality
KO: Knockout; SAL: bronchoalveolar lavage; MPO: myeloperoxidase; ALl: acute lung injury; cfu: colony forming unit; ARDS: acute respiratory distress syndrome
around the pulmonary blood vessels. Subsequently, the infiltrate cleared and diffuse
pneumonia developed, without necrotizing vasculitis in the lungs, although necro-
tizing vasculitis was found in other organs (spleen, liver, heart, and brain). Mortal-
ity was considerably higher in the knockout mice than in the controls [39].
Myeloperoxidase-deficient Mice
Although mononuclear phagocytes are important in combating C. albicans, neutro-
phils also play a crucial role. Myeloperoxidase is an enzyme found mainly within
neutrophils. It converts hydrogen peroxide (H 2 0 2 ) to hypochlorite (HOCl), a highly
cytotoxic compound involved in the neutrophil respiratory burst that releases reac-
tive oxygen species (ROS), which are the key to the antimicrobial effects of neutro-
phils. Aratani et al. reported increased susceptibility to C. albicans in myeloperoxi-
dase-deficient mice. Although Staphylococcus aureus clearance was normal in these
mice, after instillation of C. albicans pneumonia was more likely to develop, and
once developed to be fatal [40, 41].
Role of the Alveolar Macrophage in Defence Mechanisms against Candida

Another study established a role for alveolar macrophages in neutrophil recruit-
ment induced by Candida instillation. This role is mediated by the cytokine macro-
phage inflammatory protein (MIP)-2, which is a chemoattractant for neutrophils.
Mice deficient in alveolar macrophages were less likely to die than control mice
during candidemia. [42] Yet, Candida concentrations were higher in the deficient
mice. Neutrophil counts in BAL fluid were lower in the deficient mice than in the
controls. Neutrophil recruitment was related to secretion of MIP-2 by alveolar
macrophages [42].
In general, experimental models for invasive candidiasis have been developed
only in immunocompromised animals [43, 44]. Defence mechanisms against Candi-
da albicans and the pathophysiology of systemic candidiasis have been only partly
elucidated [45-47]. Phagocyte dysfunction is associated with susceptibility to sys-
temic fungal infections. Phagocytosis of C. albicans is optimal after opsonization,
which is required for phagocytosis by mononuclear cells [45-47], via a mechanism
strongly dependent on nitric oxide (NO) [48]. The pivotal role for dendritic cells in
the phagocytosis of C. albicans has been established recently [49]. Experimental
models have been used to develop agents that are active on C. albicans yet have
limited toxicity to the patient; efforts have also been made to enhance the antifun-
gal effects of the immune system [50, 51]. Thus, human recombinant myeloperoxi-
dase, IFN-y, or granulocyte/macrophage colony-stimulating factor (GM-CSF) stimu-
late mononuclear phagocytes and enhance C. albicans phagocytosis and killing
[50-52]
I Conclusion of the Literature Review
Positive specimens for Candida are common in patients with immunodepression or

prolonged broad-spectrum antibiotic therapy [37, 38]. Invasive pulmonary candi-
diasis is an exceedingly rare entity that seems to represent the pulmonary expres-
sion of hematogenous dissemination. It is intimately linked to profound immuno-
depression, generally systemic (bone marrow failure, chemotherapy, HIV infection)

but occasionally local (prolonged intubation in the ICU), and occurring mainly in
terminally ill patients with several interlinked conditions (host factors, treatments,
risk factors) [16]. Nevertheless, endobronchial specimens yielding Candida in
counts above or below positivity thresholds remain clinically relevant: they indicate
'relative' immunodepression, particularly in ICU patients or after surgery (postag-
gression immunodepression). In this situation, curative antifungal treatment should
be discussed. Because a respiratory specimen yielding Candida indicates bronchial
colonization, a search for colonization at other sites is in order, to allow estimation
of the colonization index, which is known to correlate well with secondary emer-
gence of systemic candidiasis [8, 21, 30, 31].
Although we will not review the details of antifungal treatment, we will point
out that treatment decisions depend on patient-related factors, the nature and se-
verity of clinical manifestations, blood culture results, whether bone marrow failure
is present, and whether other sites are colonized (colonization index). The recom-
mendations issued by the British Society for Antimicrobial Chemotherapy Working
Party can be used to select the antifungal agent [53, 54]; however, it should be
borne in mind that the experts who developed these recommendations did not in-
clude the lungs among the targets of deep-seated candidal infection.
Suggested Research Agenda
Below is a suggested research agenda designed to help clinicians interpret pulmo-

nary specimens yielding Candida in non-neutropenic ICU patients.
Epidemiological Questions
I What is the epidemiology of lower respiratory tract colonization by Candida in
the ICU (host factors, Candida species involved)?
I What are the risk factors for acquiring Candida colonization of the lower respi-
ratory tract? Identification of these risk factors would define a patient subset
likely to benefit from prophylactic antifungal treatment strategies.
Impact of Lower Respiratory Tract Colonization

by Candida in ICU Patients
What are the morbidity and mortality attributable to Candida colonization of
the lower respiratory tract?
I Is it possible to create, under experimental conditions, a model of invasive sys-
temic candidiasis developing from lower respiratory tract Candida colonization
in immunocompetent animals?
I How specific is lower respiratory tract Candida colonization? Does colonization
at this site provide additional information over colonization at other sites? Does
it have specific meaning in mechanically ventilated patients, given the described
risk of translocation of bacteria colonizing the lower respiratory tract [55-57]?
Does Lower Respiratory Tract Candida Colonization per se Indicate

Pre-emptive Antifungal Treatment in Patients on Mechanical Ventilation?
The value of pre-emptive or preventive treatment has been established in high-risk
ICU patients [30] and is being evaluated in patients with multiple-site Candida col-
onization. The problem here is to discuss pre-emptive antifungal treatment in non-
neutropenic patients with lung specimens yielding Candida, adjusting on the colo-
nization index. The variable of interest will not necessarily be the mortality rate or
incidence of candidemia; treatment efficacy could be evaluated based on criteria
such as morbidity (ICU length of stay, mechanical ventilation duration), acquisition
of bacteria with multiple drug resistance, emergence of resistance to the antifungal
agent used, or selection of resistant Candida species.
References
1. Ascioglu S, Rex JH, de Pauw B, et al (2002} Defining opportunistic invasive fungal infec-
tions in immunocompromised patients with cancer and hematopoietic stem cell trans-
plants: an international consensus. Clin Infect Dis 34:7-14
2. Vincent JL, Bihari DJ, Suter PM, et al (1995} The prevalence of nosocomial infection in in-
tensive care units in Europe. Results of the European Prevalence of Infection in Intensive
Care (EPIC) Study. EPIC International Advisory Committee. JAMA 274:639-644
3. Stephan F, Yang K, Tankovic J, et al (2002) Impairment of polymorphonuclear neutrophil
functions precedes nosocomial infections in critically ill patients. Crit Care Med 30:315-
322
4. Nakos G, Malamou-Mitsi VD, Lachana A, et al (2002} Immunoparalysis in patients with se-
vere trauma and the effect of inhaled interferon-gamma. Crit Care Med 30:1488-1494
5. Kox WJ, Volk T, Kox SN, Volk HD (2000} Immunomodulatory therapies in sepsis. Intensive
Care Med 26:S124-128
6. Jarvis WR (1995) Epidemiology of nosocomial fungal infections, with emphasis on Candi-
da species. Clin Infect Dis 20:1526-1530
7. Eggimann P, Francioli P, Bille J, et al (1999} Fluconazole prophylaxis prevents intra-abdom-
inal candidiasis in high-risk surgical patients. Crit Care Med 27:1066-1072
8. Pittet D, Monod M, Suter PM, Frenk E, Auckenthaler R (1994} Candida colonization and
subsequent infections in critically ill surgical patients. Ann Surg 220:751-758
9. Vincent JL, Anaissie E, Bruining H, et al (1998} Epidemiology, diagnosis and treatment of
systemic Candida infection in surgical patients under intensive care. Intensive Care Med
24:206-216
10. Fernandez-Sola J, Junque A, Estruch R, Monforte R, Torres A, Urbano-Marquez A (1995}
High alcohol intake as a risk and prognostic factor for community-acquired pneumonia.
11. Wheat LJ (1980} Infection and diabetes mellitus. Diabetes Care 3:187-197
12. Chen KY, Ko SC, Hsueh PR, Luh KT, Yang PC (2001} Pulmonary fungal infection: emphasis
on microbiological spectra, patient outcome, and prognostic factors. Chest 120:177-184
13. von Eiff M, Roos N, Fegeler W, et al (1994} Pulmonary fungal infections in immunocom-
promised patients: incidence and risk factors. Mycoses 37:329-335
14. von Eiff M, Zuhlsdorf M, Roos N, Hesse M, Schulten R, van de Loo J (1995) Pulmonary
fungal infections in patients with hematological malignancies - diagnostic approaches.
Ann Hematol 70:135-141
15. Bodey GP (1984) Candidiasis in cancer patients. Am J Med 77:13-19
16. Masur H, Rosen PP, Armstrong D (1977) Pulmonary disease caused by Candida species.
Am J Med 63:914-925
17. Wey SB, Mori M, Pfaller MA, Woolson RF, Wenzel RP (1989} Risk factors for hospital-ac-
quired candidemia. A matched case-control study. Arch Intern Med 149:2349-2353
18. Wey SB, Mori M, Pfaller MA, Woolson RF, Wenzel RP (1988} Hospital-acquired candide-
mia. The attributable mortality and excess length of stay. Arch Intern Med 148:2642-2645
19. Petri MG, Konig J, Moecke HP, et al (1997) Epidemiology of invasive mycosis in ICU pa-
tients: a prospective multicenter study in 435 non-neutropenic patients. Paul-Ehrlich So-
ciety for Chemotherapy, Divisions of Mycology and Pneumonia Research. Intensive Care
Med 23:317-325
20. Eubanks PJ, de Virgilio C, Klein S, Bongard F (1993) Candida sepsis in surgical patients.
Am J Surg 166:617-619
21. Eggimann P, Pittet D (2001) [Candidiasis among non-neutropenic patients: from coloniza-
tion to infection]. Ann Fr Anesth Reanim 20:382-388
22. Trick WE, Fridkin SK, Edwards JR, Hajjeh RA, Gaynes RP (2002) Secular trend of hospi-
tal-acquired candidemia among intensive care unit patients in the United States during
1989-1999. Clin Infect Dis 35:627-630
23. Leleu G, Aegerter P, Guidet B (2002) Systemic candidiasis in intensive care units: A multi-
center, matched-cohort study. J Crit Care 17:168-175
24. BlotS, Vandewoude K, Hoste E, Poelaert J, Colardyn F (2001) Outcome in critically ill pa-
tients with candida! fungaemia: Candida albicans vs Candida glabrata. J Hosp Infect 47:
308-313
25. Rangel-Frausto MS, Wiblin T, Blumberg HM, et al (1999) National epidemiology of my-
coses survey (NEMIS): variations in rates of bloodstream infections due to Candida species
in seven surgical intensive care units and six neonatal intensive care units. Clin Infect Dis
29:253-258
26. Goodman JL, Winston DJ, Greenfield RA, et al (1992) A controlled trial of fluconazole to
prevent fungal infections in patients undergoing bone marrow transplantation. N Engl J
Med 326:845-851
27. MacMillan ML, Goodman JL, DeFor TE, Weisdorf DJ (2002) Fluconazole to prevent yeast
infections in bone marrow transplantation patients: a randomized trial of high versus re-
duced dose, and determination of the value of maintenance therapy. Am J Med 112:369-
379
28. Winston DJ, Chandrasekar PH, Lazarus HM, et al (1993) Fluconazole prophylaxis of fungal
infections in patients with acute leukemia. Results of a randomized placebo-controlled,
double-blind, multicenter trial. Ann Intern Med 118:495-503
29. Pelz RK, Hendrix CW, Swoboda SM, et al (2001) Double-blind placebo-controlled trial of
fluconazole to prevent candida! infections in critically ill surgical patients. Ann Surg
233:542-548
30. Garbino J, LewD, Romand J-A, Hugonnet S, Auckenthaler R, Pittet D (2002) Prevention of
severe Candida infections in non-neutropenic, high-risk, critically ill patients. A rando-
mized, double-blind, placebo-controlled trial in patients treated by selective digestive de-
contamination. Intensive Care Med 28:1708-1717
31. Calandra T, Marchetti 0 (2003) Antifungal prophylaxis for intensive care unit patients: let's
fine tune it. Intensive Care Med (in press)
32. Rex JH, Sobel JD (2001) Prophylactic antifungal therapy in the intensive care unit. Clin In-
fect Dis 32:1191-1200
33. Haron E, Vartivarian S, Anaissie E, Dekmezian R, Bodey GP (1993) Primary Candida
pneumonia. Experience at a large cancer center and review of the literature. Medicine (Bal-
timore) 72:137-142
34. Rose HD, Sheth NK (1978) Pulmonary candidiasis. A clinical and pathological correlation.
35. Azoulay E, Limal N, Mayaud C, Schlemmer B (2001) Bronchial specimens positive to can-
dida: infection or colonization. Reanimation 10:323-328
36. Azoulay E, Mayaud C (1999) [Candida pneumopathy: fact or fiction?]. Rev Pneumol Clin
55:349-351
37. el-Ebiary M, Torres A, Fabregas N, et al (1997) Significance of the isolation of Candida
species from respiratory samples in critically ill, non-neutropenic patients. An immediate
postmortem histologic study. Am J Respir Crit Care Med 156:583-590
38. Rello J, Esandi ME, Diaz E, Mariscal D, Gallego M, Valles J (1998) The role of Candida sp
isolated from bronchoscopic samples in nonneutropenic patients. Chest 114:146-149
39. Kaposzta R, Tree P, Marodi L, Gordon S (1998) Characteristics of invasive candidiasis in

gamma interferon- and interleukin-4-deficient mice: role of macrophages in host defense
against Candida albicans. Infect Immun 66:1708-1717
40. Aratani Y, Kura F, Watanabe H, et al (2000) Differential host susceptibility to pulmonary
infections with bacteria and fungi in mice deficient in myeloperoxidase. J Infect Dis
182:1276-1279
41. Aratani Y, Koyama H, Nyui S, Suzuki K, Kura F, Maeda N (1999) Severe impairment in
early host defense against Candida albicans in mice deficient in myeloperoxidase. Infect
Immun 67:1828-1836
42. Kubota Y, Iwasaki Y, Harada H, et al (2001) Role of alveolar macrophages in Candida-in-
duced acute lung injury. Clin Diagn Lab Immunol 8:1258-1262
43. Fulurija A, Ashman RB, Papadimitriou JM (1996) Early inflammatory responses to Candi-
da albicans infection in inbred and complement-deficient mice. FEMS Immunol Med Mi-
crobiol 14:83-94
44. Fulurija A, Ashman RB, Papadimitriou JM (1996) Neutrophil depletion increases suscep-
tibility to systemic and vaginal candidiasis in mice, and reveals differences between brain
and kidney in mechanisms of host resistance. Microbiology 142:3487-3496
45. Marodi L, Forehand JR, Johnston RB Jr (1991) Mechanisms of host defense against Candi-
da species. II. Biochemical basis for the killing of Candida by mononuclear phagocytes. J
Immunol 146:2790-2794
46. Marodi L, Korchak HM, Johnston RB Jr (1991) Mechanisms of host defense against Candi-
da species. I. Phagocytosis by monocytes and monocyte-derived macrophages. J Immunol
146:2783-2789
47. Marodi L (1997) Local and systemic host defense mechanisms against Candida: immuno-
pathology of candida! infections. Pediatr Infect Dis J 16:795-801
48. Blasi E, Pitzurra L, Puliti M, et al (1994) Different events involved in the induction of
macrophage tumor necrosis factor by Candida albicans and lipopolysaccharide. Cell Immu-
nol 157:501-509
49. Newman SL, Holly A (2001) Candida albicans is phagocytosed, killed, and processed for
antigen presentation by human dendritic cells. Infect Immun 69:6813-6822
50. Marodi L, Tournay C, Kaposzta R, Johnston RB Jr, Moguilevsky N (1998) Augmentation of
human macrophage candidacidal capacity by recombinant human myeloperoxidase and
granulocyte-macrophage colony-stimulating factor. Infect Immun 66:2750-2754
51. Marodi L, Johnston RB Jr (1993) Enhancement of macrophage candidacidal activity by in-
terferon-gamma. Immunodeficiency 4:181-185
52. Marodi L, Schreiber S, Anderson DC, MacDermott RP, Korchak HM, Johnston RB Jr (1993)
Enhancement of macrophage candidacidal activity by interferon-gamma. Increased phago-
cytosis, killing, and calcium signal mediated by a decreased number of mannose receptors.
J Clin Invest 91:2596-2601
53. British Society for Antimicrobial Chemotherapy Working Party (1994) Management of
deep Candida infection in surgical and intensive care unit patients. Intensive Care Med
20:522-528
54. Rex JH, Walsh TJ, Sobel JD, et al (2000) Practice guidelines for the treatment of candidia-
sis. Infectious Diseases Society of America. Clin Infect Dis 30:662-678
55. Cakar N, Akinci 0, Tugrul S, et al (2002) Recruitment maneuver: does it promote bacterial
translocation? Crit Care Med 30:2103-2106
56. Murphy DB, Cregg N, Tremblay L, et al (2000) Adverse ventilatory strategy causes pulmo-
nary-to-systemic translocation of endotoxin. Am J Respir Crit Care Med 162:27-33
57. Nahum A, Hoyt J, Schmitz L, Moody J, Shapiro R, Marini JJ (1997) Effect of mechanical
ventilation strategy on dissemination of intratracheally instilled Escherichia coli in dogs.
58. Torres A, El-Ebiary M, Soler N, Monton C, Fabregas N, Hernandez C (1996) Stomach as a
source of colonization of the respiratory tract during mechanical ventilation: association
with ventilator-associated pneumonia. Eur Respir J 9:1729-1735
59. Rogers T, Balish E (1976) Experimental Candida albicans infection in conventional mice
and germfree rats. Infect Immun 14:33-38
198 E. Azoulay and B. Schlemmer: Candida in Lung Specimens from Non-Neutropenic ICU Patients
60. Katz S, Merkel GJ, Folkening WJ, Rosenthal RS, Grosfeld JL (1991) Impaired clearance and
organ localization of Candida albicans in obstructive jaundice. J Pediatr Surg 26:904-906
61. Lechner AJ, Tredway TL, Brink DS, Klein CA, Matuschak GM {1992) Differential systemic
and intrapulmonary TNF-alpha production in Candida sepsis during immunosuppression.
Am J Physiol 263:1526-535
62. Katz S, Merkel GJ, Folkening WJ, Rosenthal RS, Grosfeld JL (1993) Blood clearance and or-
gan localization of Candida albicans and E coli following dual infection in rats. J Pediatr
Surg 28:329-332
63. Lechner AJ, 1amprech KE, Potthoff 1H, Tredway T1, Matuschak GM (1994) Recombinant
GM-CSF reduces lung injury and mortality during neutropenic Candida sepsis. Am J Phy-
siol 266:1561-568
64. Samaranayake LP, Tobgi RS, MacFarlane TW (1994) Anti-candida activity of murine
bronchoalveolar lavage fluid. J Med Microbiol 40:350-357
A Reappraisal of Selective Decontamination
of the Digestive Tract
A. Heininger, W. A. Krueger, and K. E. Unertl
I Introduction
Nosocomial infections are associated with an increased risk of death as well as pro-
longed hospitalizations and additional costs [1-4]. Patients in intensive care units
(ICUs) are at particular risk; nosocomial infection rates there are 5 to 10 times higher
than on general wards [5]. Pneumonias are the most frequent ICU-acquired infections
and are also associated with the highest attributable mortality [2, 3, 6]; their preven-
tion represents a major challenge for intensivists. Meticulous hygiene and surveillance
measures can reduce the infection rate by about one third. Such efforts are mainly di-
rected against the transmission of pathogens. However, the majority of cases arise
from endogenous sources which we are still far from controlling adequately, particu-
larly the patients' own microflora in the oropharnyx or the gut.
Selective decontamination of the digestive tract (SDD) was developed to prevent
nosocomial infections, especially pneumonias, by selectively eliminating aerobic
Gram-negative potentially pathogenic microorganisms and yeasts while preserving
the indigenous anaerobic flora [7]. SDD consists of the topical administration of
nonabsorbable antibiotics in the mouth and the gut and is optionally combined
with systemic antimicrobial prophylaxis during the patient's first few days in the
ICU. The topical component, usually including tobramycin, polymyxin E, and am-
photericin B, is directed against colonization of the aerodigestive tract; in most
cases the systemic component consists of a third-generation cephalosporin, which
is added to prevent early infections. Since the introduction of the SDD concept in
the early 1980s, different combinations of topical agents have been administered to
various mucosal sites with or without the additional use of intravenous antibiotics.
Ten years ago, the members of the first European consensus conference on SDD
came to the conclusion that "the available information does not permit an unequiv-
ocal recommendation for the use of SDD in any particular population of patients"
[8]. They based their statement on the lack of evidence that mortality can be de-
creased with SDD. Moreover, the experts conceded that SDD appeared to reduce the
incidence of respiratory tract infections, but they emphasized that further studies
were needed to verify this effect in well-defined homogenous patient populations.
In particular they stressed that it was still unclear which specific groups of patients
might benefit, which components should be applied and whether the emergence of
resistant microorganisms is promoted by the use of SDD.
Since this statement was issued, several controlled trials and meta-analyses have
been published [9-18]. This research work confirmed that SDD can cut the rate of
ventilator-associated pneumonia (YAP) by one half on average [9, 10, 12, 14-17].
More importantly, two meta-analyses [15, 16] calculated a significant survival bene-
200 A. Heininger et al.
fit in patients receiving combined topical and systemic prophylaxis [15, 16]. Never-
theless, SDD has not yet gained acceptance as a routine treatment concept, mainly
because of persisting doubts about a true survival benefit as well as major concerns
about the risk of increasing resistance [11, 13]. Now, two large randomized clinical
trials show an improved survival rate in SDD patients [19, 20]. Since equally effec-
tive, alternative preventive measures are not available at present, the time seems to
be ripe to reconsider the SDD concept for the management of ICU patients.
SOD for the Prevention of Pneumonia
Aspiration of contaminated secretions from the oropharynx into the lower airways
is a common event in critically ill patients and has been recognized as the crucial
mechanism for the emergence of VAP [21, 22]. In approximately 50o/o of ICU pa-
tients the upper respiratory tract is already colonized at the time of admission by
potentially pathogenic microorganisms [23]; during hospitalization the initially co-
lonizing microorganisms are usually replaced, mainly by Gram-negative bacteria.
The topical component of SDD is directed against this colonization to counterba-
lance the pathogenic effect of microaspiration. The additional elimination of poten-
tially pathogenic microorganisms from the gut was assumed to augment the effect,
since the stomach is considered to be an internal reservoir for pathogens entering
the oropharynx and finally the bronchial tree [24]. Parenteral antibiotics are usual-
ly added to eradicate pathogens already present in the lower airways, thereby pro-
tecting against early-onset pneumonia [25, 26]. Since the hazard of contracting
VAP is highest within the first week after intubation ( ~ 3o/o/day), the prevention of
these infections represents a crucial part of the overall protective effect [27]. Pneu-
monia of exogenous origin can hardly be prevented with SDD. This type of pneu-
monia can occur when contaminated aerosols are inhaled. Such events are usually
due to improper handling of nebulizers or ventilator equipment and can be best
avoided by appropriate hygienic measures aimed at interrupting the transmission
of pathogens.
The results obtained with SDD in controlled trials are consistent with these hy-
potheses about the pathomechanisms of VAP. Many individual studies [28-32] and
all meta-analyses indicated a significantly reduced incidence of VAP with SDD [9,
10, 12, 14-17]. A recent calculation on the basis of 32 trials showed that the inci-
dence of pneumonia was 57o/o lower in patients receiving SDD [17]. The strongest
effects were observed with regard to Gram-negative and mixed infections and when
patients received topical plus intravenous prophylaxis. A meta-analysis of 16 studies
enrolling 2,883 patients delivered an odds ratio (OR) of 0.35 (95o/o CI, 0.29-0.41)
for a combined regimen versus no antibiotics [15]. Similarly, in the meta-analyses
of Nathens and colleagues [16] and Van Nieuwenhoven and coworkers [17], the
best results were obtained with combined topical and parenteral prophylaxis. The
risk reduction observed in trials which tested topical antibiotics alone versus no
prophylaxis was still remarkable {OR 0.39; 95o/o CI 0.30-0.52) [15]. On the other
hand some trials, including one large randomized double-blind trial enrolling 15
French medical ICUs, showed no significant beneficial effect [33-35]. Potential rea-
sons for these negative findings include a high prevalance of Gram-positive or a
priori resistant Gram-negative potentially pathogenic microorganisms. Negative trial
results have also been attributed to a stricter study design. It was suspected that
the more favorable results in other SDD trials reflected a bias in evaluating treat-
A Reappraisal of Selective Decontamination of the Digestive Tract 201
ment effects rather than a true reduction in VAP rates. In fact, the lack of a gold
standard for the diagnosis of pneumonia makes it difficult to assess the true effect
of SDD on VAP rates. A bias in favor of the SDD group is likely whenever the isola-
tion of pathogens in respiratory samples is part of the diagnosis, since the applica-
tion of antibiotics interferes with microbiological culturing. Non-blinded and/or
non-randomized trial designs can introduce additional bias.
A recent meta-analysis specifically addressed the relationship between the meth-
odological aspects of trials and the reported effects on pneumonia and mortality
[17]. The quality of the included studies was rated by a score designed to assess
the method of diagnosing VAP and other methodological criteria (patient selection,
matching of patient characteristics, allocation sequence, concealment of allocation,
and blinding). This analysis indicated that low-quality studies tend to overestimate
the protective effect of SDD against VAP, since the risk reduction decreased by
5.8o/o for each additional quality score point (9So/o CI, 2.4-9.3). However, a remark-
able reduction in the VAP incidence by 46o/o (9So/o CI 0.35-0.56) was still obtained
even when only the 12 highest-quality studies (cutoff point >7) were analyzed. In
comparison, when all 32 studies were evaluated together, irrespective of their meth-
odological quality, the relative risk reduction was 0.57 {95o/o CI, 0.49-0.65) [17].
These data, gathered by Van Nieuwenhoven and colleagues, confirm that study de-
sign had a major influence on the observed effects but that even with strict study
criteria the beneficial effects of SDD were still remarkable.
In most studies, the topical component of SDD was administered to the orophar-
ynx as well as the stomach. However, in recent work the relative impact of gastric
colonization on the development of VAP has been considered less important [36].
Moreover, while exclusive administration of antibiotics into the stomach was shown
to reduce colonization in the gastrointestinal tract, it had no impact on infection
rates [37]. To elucidate the relative roles of oropharyngeal and intestinal coloniza-
tion in the pathogenesis of VAP, Bergmans et al. treated a mixed group of medical
and surgical patients with a 2o/o solution of gentamicin, colistin and vancomycin
exclusively administered to the oropharynx and compared its effects with placebo
[28]. They achieved a significant reduction in VAP incidence without influencing
gastrointestinal colonization and without employing systemic prophylaxis. When
the study group {87 patients) was compared with the two control groups {78 and
61 patients, respectively) relative risk reductions of 0.67 and 0.55 were found. Com-
parable results were obtained in a smaller group of surgical ICU patients [29]. Sim-
ilarly, oral rinse with 0.12o/o chlorhexidine decreased the rate of pneumonia in pa-
tients undergoing cardiac surgery to 3o/o, compared to 9o/o in controls [38]. When
oropharyngeal decontamination was applied in combination with systemic prophy-
laxis, a significantly lower incidence of both primary {0 versus 33o/o, p < 0.001) and
secondary (22 versus 47o/o, p<O.OOl) pneumonia appeared in patients receiving
SDD [39]. The magnitude of the risk reduction observed in these studies is in the
range reported for the combined form of SDD [IS, 16]. Bergmans et al. have sug-
gested [28] that oropharyngeal application of non-antibiotic substances such as
chlorhexidine should be systematically tested for VAP prevention. However, the
long-term effects of chlorhexidine on the mucosa of severely ill patients are still
unknown, and the risk of promoting the emergence of antimicrobial resistance
against this substance is unclear.
Taken together, the results of the various trials have improved our understanding
of the relative contributions of the SDD components to the prevention of VAP. Oro-
pharyngeal decontamination appears to be the cornerstone of the regimen, whereas
202 A. Heininqer et al.
the effects of intestinal decontamination are questionable at the very least. The im-
pact of the systemic component might vary between groups of patients depending
on their baseline risk of colonization on admission and early-onset pneumonia.
Thus, since the first consensus conference some clarification has been achieved
with regard to the impact of SDD on the VAP rate and the relative importance of
the individual components for the observed effects.
I SDD for the Prevention of Non-Respiratory Infections

Several investigations have indicated that SDD can prevent non-respiratory infections
[16, 19, 30, 31, 40]. A large, prospective, double-blind study showed that surgical pa-
tients receiving topical plus systemic prophylaxis developed fewer blood stream infec-
tions than controls (risk ratio 0.384; 95% CI 0.177-0.836; p =0.007) [19]; the incidence
of urinary infections also decreased (risk ratio 0.593; 95% CI 0.357-0.985; p =0.042).
Moreover, fewer severe organ dysfunctions occurred in the SDD group (risk ratio
0.636; 95% CI 0.463-0.874; p=0.0051) [19]. Similarly, Sanchez Garda et al. achieved
a significant reduction of all non-respiratory infections with a combined SDD regi-
men [31]. These findings agree with those of a meta-analysis which demonstrated a
significant decrease in bacteremias and urinary tract infections in surgical patients,
while in medical patients only the rate of urinary tract infections declined [16]. In
a specific group of surgical patients undergoing esophageal resection, even postoper-
ative wound infections decreased from 35% in the control group to 11% in the SDD
group (p < 0.01) [40 ]. In contrast with these findings, one study encompassing 310
trauma patients found that the incidence of respiratory and non-respiratory infections
remained unchanged when topical decontamination plus intravenous ciprofloxacin
was administered compared with intravenous ciprofloxacin alone [35]. Possible expla-
nations for these findings include diminished effectiveness of a combined topical plus
systemic prophylaxis compared to systemic prophylaxis alone. Moreover, the reduc-
tion of intestinal Gram-negative bacteria was comparable in both groups, since cipro-
floxacin is secreted transmucosally into the intestinal lumen [41]. Finally, the low
baseline rates for VAP and mortality in this study population makes the detection
of a treatment effect more difficult.
How can the effects of SDD against non-respiratory infections be explained? Bac-
terial translocation, i.e., the passage of living pathogens or endotoxin from the lu-
men of the gut through mesenteric lymph nodes to the portal vein blood and final-
ly to distant organ systems, has been observed in animals models of hemorrhagic
shock, hypovolemia and thermal injury. This phenomenon was proposed as a cru-
cial pathomechanism for sepsis and multiple organ failure (MOP) [42]. Based on
this finding, intestinal decontamination was expected to reduce the incidence of
bacteremia and endotoxemia and possibly the incidence of MOP as well. Contrary
to this hypothesis on the pathogenic role of bacterial translocation, however, infec-
tion rates remained unchanged when decontamination was applied exclusively to
the gut [37]. Even oropharyngeal plus intestinal decontamination failed to decrease
non-respiratory infections when used without the additional administration of in-
travenous antibiotics [32, 33]. On the other hand, various individual trials [19, 30,
31, 40] and one meta-analysis [16] showed that non-respiratory infections could in-
deed be prevented when a systemic component was added to topical prophylaxis.
These findings suggest that parenteral antibiotics rather than intestinal decontami-
nation are the keys to preventing bacteremia and other non-respiratory infections.
Influence of SOD on Mortality

Two meta-analyses demonstrated significantly reduced mortality rates for a combined
systemic plus topical regimen [15, 16]. In one of them, enrolling a total of 5,727 sur-
gical and medical patients in 33 randomized trials, the subset of 1 779 patients receiv-
ing a combined regimen had a mortality rate of 24% compared with 30% in 1802 con-
trol patients. This equals a relative risk reduction of 20% (OR 0.8; 95% CI 0.69-0.93);
in other words, 23 patients would need to be treated with a combined SDD regimen to
prevent one death, assuming a baseline risk of 29% in controls [15]. Topical prophy-
laxis alone did not improve the chances of survival (OR 1.01; 95% CI 0.84-1.22) [15].
In a second meta-analysis comparing surgical and medical patients the risk reduction
for surgical patients was even more pronounced (OR 0.6; 95% CI 0.41-0.88}, whereas
the benefit in medical patients did not reach significance (OR 0.75; 95% CI 0.53-1.06}
[16]. Again, topical decontamination alone did not reduce mortality [16]. A beneficial
effect on mortality was also determined in the meta-analysis of Van Nieuwenhoven et
al. [17], who evaluated the possible correlation between methodological trial quality
and the effects of SDD; in the 32 trials surveyed, they observed a relative risk reduc-
tion of 0.12 (95% CI 0.03-0.21) in SDD patients. The relative risk reduction for mor-
tality - in contrast to VAP - was not associated with the methodological quality of the
evaluated studies [17].
For the first time, two individual trials [19, 20] have demonstrated lower mortal-
ity rates in patients treated with SDD. De Jonge et al. [20] observed a hospital mor-
tality of 24.2% in 468 surgical and medical patients receiving SDD, compared with
31.2% in the 466 control patients without antibiotics (OR 0.7; 95% CI 0.5-0.9;
p==0.02). In the study of Krueger et al. [19], the total study population of 546 surgi-
cal patients was stratified according to the severity of their illness. In the midrange
stratum with APACHE-II scores of 20-29 on ICU admission, 33.0% of the control
patients died; this figure dropped to only 16.4% when SDD was given (OR 0.508;
95% CI 0.295-0.875} (Table 1) [19]. That means that 12 patients have to be treated
with SDD to prevent one death; this improvement is more pronounced than the
beneficial effect obtained with pressure-limited ventilation in acute lung injury or
with activated protein C for severe sepsis [43].
The findings of both studies agree well with previous meta-analyses [16, 17] in
which the survival benefit was shown with a study design testing systemic plus top-
ical prophylaxis versus placebo [15, 16]. Moreover, the favorable effect was achieved
in patients with a baseline mortality of approximately one third. This is consistent
with the results of Sun et al. [14], who concluded that a survival benefit is most
likely in populations with a high mortality risk at study entry.
The data obtained within the last decade have also contributed to our understand-
ing of the mechanisms which might be relevant for outcome improvement. A central
target of SDD is the prevention of VAP and its sequelae. The mortality rates attribut-
able to VAP, however, vary and depend largely on the underlying disease, the severity
of illness [44], the causative pathogens [2, 45] and the quality of the antibiotic therapy
[4]. Consequently, certain investigators have calculated mortality rates attributable to
VAP of 24%, and even 43% for certain high-risk pathogens [2, 45], whereas others
have denied that pneumonia is an independent risk factor for death [46]. Given the
great variety of interdependent factors, it is not surprising that the prevention of
VAP does not translate into reduced mortality in all patients. Data from the meta-
analysis by Nathens and Marshall [16] suggest that surgical patients are more likely
to benefit from SDD than medical patients. Although this finding is not fully under-
Table 1. Survival in SDD patients and controls according to severity of illness on ICU admission [19)
APACHE-II Numbers of Fatalities in Relative risk p Fatalities Relative risk p

on admission patients the ICU of death after 1 year of death
n (%) 95% Cl n (%) 95% Cl
All patients soo•: 265 52 (19.6) 0.761 0.1321 102 (38.5) 0.856 0.2542
Placebo: 262 75 (28.6) 0.533-1 .086 113 (43.1) 0.655-1.118
Score S19 soo•: 120 17 (14.2) 0.885 0.7022 33 (27.5) 0.969 0.8961
Placebo: 121 23 (19.0) 0.472-1.659 34 (28.1) Q.600- 1.564
Score 20- 29 soo•: 122 20 (16.4) 0.508 0.0147b 51 (41.8) 0.720 0.0844
Placebo: 115 38 (33.0) 0.295-0.875 60 (52.2) 0.496-1.046
Score 2::30 soo•: 23 15 (65.2) 1.593 0.2118 18 (78.3) 1.316 0.4046

Placebo: 26 14 (53.8) 0.767- 3.306 19 (73.1) 0.690-2.508
•Topically applied polymyxin Band gentamicin were combined with intravenously administered ciprofloxacin.
bThe chance of survival increased in patients with severe but not fatal disease (APACHE-II Score 20-29) when
SOD was given.
stood, it might be assumed that the outcome in medical patients may depend more
strongly on the underlying disease process than on additional infection.
The prevention of non-respiratory infections, particularly bloodstream infec-
tions, also seems to be of relevance for the reduction of mortality. This is suggested
by the findings of Krueger et al., who observed substantial mortality reduction as-
sociated with a considerably lower incidence of bloodstream infections, circulatory
failure and severe organ dysfunctions [19]. The available studies do not allow us to
assess the exact relative contributions of the topical and the parenteral components
to the beneficial effect of SDD on survival. However, it should be noted that topical
prophylaxis alone, despite its protective effect against pneumonia, failed to improve
survival either in meta-analyses or in individual trials [15, 16]. A reduction in mor-
tality was achieved only when a combined SDD regimen was applied [15, 16, 19,
20], suggesting that maximum protection is essential for improvement of outcome.
I Influence of SDD on Antimicrobial Resistance

Antibiotics are widely used in critically ill patients, thereby contributing to the
emergence of more resistant pathogens, which in turn are more difficult to treat.
Since resistance poses a major threat to patients and appears to be steadily on the
rise there is deep concern that the routine use of SDD could result in a further in-
crease in selection pressure and resistance. Early studies in the 1960s demonstrated
an association between the use of topical polymyxin for the prevention of pneumo-
nia, the emergence of resistant pathogens, and higher mortality; since then such an
approach has been discouraged [43].
The reports on the influence of SDD on the development of resistance are con-
tradictory. New resistance is rarely reported, but severe problems have been en-
countered in hospitals with endemic resistant bacteria (especially methicillin-resis-
tant Staphylococcus aureu [MRSA], Serratia ssp. and Acinetobacter). Emergence of
tobramycin resistance was reported by Verwaest et al. [30], who used the standard
SDD protocol (cefotaxime plus topical polymyxin, tobramycin and amphotericin B).
However, 17o/o of the patients were already colonized on admission by Morganella
morganii and Serratia; the latter is frequently resistant to tobramycin and both are
usually resistant to polymyxin. Misset et al. [47], who used a regimen of gentami-
cin, polymyxin E and amphotericin B, reported an increase of resistant Gram-nega-
tive rods by up to 50o/o, but again, 15-26o/o of the colonizing pathogens were al-
ready resistant to polymyxin E and gentamicin on admission. Other investigators
reject the further use of SDD, because they have observed increasing rates of infec-
tions with resistant Gram-positive bacteria [11, 48, 49].
On the other hand Sanchez Garcia et al. calculated a reduction of the overall use
of antibiotics in their institution [31] with the use of SDD. They did not observe an
increase in infections due to resistant microorganisms in the 10+ years that SDD
had been used there [50]. Moreover, a 4-year study on the long-term effect of SDD
on antimicrobial resistance found no change in resistance patterns [51]. Similarly,
in a report on surveillance cultures taken over a 2-year period no increased resis-
tance was observed in isolates of Enterobacteriaceae, Pseudomonads and other
non-fermenters, and only a small increase in isolates of Proteus, Morganella, and
Providencia spp. at the end of the surveillance period [52].
Moreover, Krueger et al. [19] reported a trend towards decreased resistance in
SOD-treated patients and DeJonge and coworkers [20] even found a significant de-
crease.
It is difficult to interpret the conflicting findings, but it seems that the differ-
ences reflect mainly the substantial variations in the distribution of pathogens and
their resistance pattern in different ICUs. In a setting with a high prevalence of re-
sistance against the various components of the SDD regimen, efficacy is reduced or
lost and SDD can even promote the selection and further spread of these patho-
gens. The use of SDD is therefore not advisable under such circumstances. On the
other hand, SDD may be safely used in an environment with a favorable resistance
pattern. The variations in the distribution of pathogens and resistance also speak
against the universal application of a single SDD regimen. One solution might be
to tailor the regimen to fit the local resistance patterns, but as yet insufficient data
are available for such a targeted approach.
I Conclusion
SDD is an effective strategy for the prevention of VAP and possibly also bacteremia.
More importantly, survival was improved when combined topical and systemic anti-
biotics were applied, especially in surgical patients with a high mortality risk. The
prerequisite for obtaining these favorable results was a low prevalence of multiresis-
tant pathogens. A selective approach seems to be the key - selecting those patients
who might be expected to benefit most and those ICUs where the endemic resis-
tance pattern allows the use of SDD.
To optimize the concept, it will be necessary to address the question of whether
the intestinal component is necessary. Another issue is the influence of the long-
term use of SDD on the overall bacterial ecology. Finally, it remains to be investi-
gated whether tailored regimens - better covering Gram-positive bacteria for in-
stance - might add further benefit.
References
1. Vincent JL, Bihari DJ, Suter PM, et al ( 1995) The prevalence of nosocomial infection in in-
tensive care units in Europe: results of the European Prevalence of Infection in Intensive
Care (EPIC) Study. JAMA 274:639-644
2. Fagon JY, Chastre J, Vuagnat A, Trouillet JL, Novara A, Gibert C (1996) Nosocomial pneu-
monia and mortality among patients in intensive care units. JAMA 275:866-869
3. Pittet D, Tarara D, Wenzel RP (1994) Nosocomial blood stream infection in critically ill pa-
tients: excess length of stay, extra costs and attributable mortality. JAMA 271:1598-1601
4. Kollef MH, Sherman G, WardS, Fraser VJ (1999) Inadequate antimicrobial treatment of in-
fections. Chest 115:462-474
5. Craven DE, Kunches LM, Lichtenberg DA, et al (1988) Nosocomial infection and fatality in
medical and surgical intensive care unit patients. Arch Intern Med 148:1161-1168
6. Anonymous (2000) Monitoring hospital-acquired infections to promote patient safety- Uni-
ted States 1990-1999. MMWR Morb Mortal Wkly Rep 49:149-153
7. Stoutenbeek ChP, Van Saene HKF (1992) Prevention of pneumonia by selective decontami-
nation of the digestive tract (SDD). Intensive Care Med 18:S18-S23
8. Loirat P, Johanson WG, Van Saene HKF, et al (1992) Selective decontamination in intensive
care unit patients. Intensive Care Med 18:182-188
9. Vandenbroucke-Grauls CMJE, Vandenbroucke JP (1991) Effect of selective decontamination
of the digestive tract on respiratory tract infections and mortality in the intensive care
unit. Lancet 338:859-862
10. Selective Decontamination of the Digestive Tract Trialists' Collaborative Group (1993)
Meta-analysis of randomised controlled trials of selective decontamination of the digestive
tract. Br Med J 307:525-532
11. Kollef MH (1994) The role of selective digestive tract decontamination on mortality and re-
spiratory tract infections. Chest 105:1101-1108
12. Heyland DK, Cook DJ, Jaeschke R, Griffith L, Lee HN, Guyatt GH (1994) Selective deconta-
mination of the digestive tract. Chest 105:1221-1229
13. Potgieter PD, Hammond JMJ (1995) Selective decontamination of the digestive tract. Curr
Opin Anaesthesia! 8:114-118
14. Sun X, Wagner DP, Knaus WA (1996) Does selective decontamination of the digestive tract
reduce mortality for severely ill patients? Crit Care Med 24:753-755
15. D'Amico R, Pifferi S, Leonetti C, Torri V, Tinazzi A, Liberati A (1998) Effectiveness of anti-
biotic prophylaxis in critically ill adult patients: systematic review of randomised con-
trolled trials. Br Med J 316:1275-1285
16. Nathens AV, Marshall JC (1999) Selective decontamination of the digestive tract in surgical
patients. Arch Surg 134:170-176
17. Van Nieuwenhoven CA, Buskens E, Van Tiel FH, Bonten MJM (2001) Relationship between
methodological trial quality and the effects of selective digestive decontamination on pneu-
monia and mortality in critically ill patients. JAMA 286:335-340
18. Krueger WA, Unertl KE (2002) Selective decontamination of the digestive tract. Curr Opin
Crit Care 8:139-144
19. Krueger WA, Lenhart FP, Neeser G, et a! (2002) Influence of combined intravenous and to-
pical antibiotic prophylaxis on the incidence of infections, organ dysfunctions, and mortal-
ity in critically ill surgical patients. Am J Respir Crit Care Med 166:1029-1037
20. De Jonge E, Schultz M, Spanjaard L, et al (2002) Effects of selective decontamination of the
digestive tract on mortality and antibiotic resistance. Intensive Care Med 28 (suppl l):S12
(abst)
21. Kollef MH (1999) The prevention of ventilator-assoociated pneumonia. N Eng! J Med
340:627-634
22. Bauer TT, Ferrer R, Angrill J (2000) Ventilator-associated pneumonia: incidence, risk fac-
tors, and microbiology. Semin Respir Infect 15:272-279
23. Drakulovic M, Bauer TT, Torres A, et a! (2001) Initial bacterial colonization in patients ad-
mitted to the intensive care unit: Bacteriological pattern and risk factors. Respiration
68:58-66
------ A Reappraisal of Selective Decontamination of the Digestive Tract
24. Craven DE, Daschner FD (1989) Nosocomial pneumonia in the intubated patient: role of
207
gastric colonization. Eur J Clin Microbiol Infect Dis 8:40-50

25. Akca 0, Koltka K, Uzel S, et al (2000) Risk factors for early-onset, ventilator-associated
pneumonia in critical care patients. Anesthesiology 93:638-645
26. Sirvent JM, Torres A, El-Ebiary M, Castro P, de Battle J, Bonet A (1997) Protective effect of
intravenously administered cefuroxime against nosocomial pneumonia in patients with
structural coma. Am J Respir Crit Care Med 155:1729-1734
27. Cook D (2000) Ventilator associated pneumonia: perspectives on the burden of illness. In-
tensive Care Med 26:S31-S37
28. Bergmans DCJJ, Bonten MJM, Gaillard CA, et a! (2001) Prevention of ventilator-associated
pneumonia by oral decontamination: a prospective, randomized, double-blind, placebo-
controlled study. Am J Respir Crit Care Med 164:382-388
29. Pugin J, Auckenthaler R, Lew DP, Suter PM (1991) Oropharyngeal decontamination de-
creases incidence of ventilator-associated pneumonia: a randomized, placebo-controlled,
double-blind clinical trial. J Am Med Assoc 265:639-644
30. Verwaest C, Verhaegen J, Ferdinande P, et a! (1997) Randomized controlled trial of selective
digestive decontamination in 600 mechanically ventilated patients in a multidisciplinary in-
tensive care unit. Crit Care Med 25:63-71
31. Sanchez Garcia M, Cambronero Galache JA, Lopez Diaz J, et a! (1998) Effectiveness and
cost of selective decontamination of the digestive tract in critically ill intubated patients.
Am J Respir Crit Care Med 158:908-916
32. Quinio B, Albanese J, Bues-Charbit M, Viviand X, Martin C (1996) Selective decontamina-
tion of the digestive tract in multiple trauma patients. Chest 109:765-772
33. Gastinne H, Wolff MD, Deflatour F, Faurisson F, Chevret S (1992) A controlled trial in in-
tensive care units of selective decontamination of the digestive tract with nonabsorbable
antibiotics. N Eng! J Med 326:594-599
34. Hammond J, Potgieter PD, Saunders GL, Forder AA (1992) Double-blind study of selective
decontamination of the digestive tract in intensive care. Lancet 340:5-9
35. Lingnau W, Berger J, Javorsky F, Lejeune P, Mutz N, Benzer H (1997) Selective intestinal
decontamination in multiple trauma patients: prospective controlled trial. J Trauma
42:687-694
36. Bonten MJM, Gaillard CA, de Leeuw PW, Stobberingh EE (1997) Role of colonization of
the upper intestinal tract in the pathogenesis of ventilator-associated pneumonia. Clin In-
fect Dis 24:309-319
37. Brun-Buisson C, Legrand P, Rauss A, et a! (1989) Intestinal decontamination for control of
nosocomial multiresistant Gram-negative bacilli: study of an outbreak in an intensive care
unit. Ann Intern Med 110:873-881
38. DeRiso AJ II, Ladowski JS, Dillon TA, Justice JW, Peterson AC (1996) Chlorhexidine gluco-
nat 0.12% oral rinse reduces the incidence of total nosocomial respiratory infection and
nonprophylactic systemic antibiotic use in patients undergoing heart surgery. Chest
109:1556-1561
39. Abele-Horn M, Dauber A, Bauernfeind, A, Russwurm W, Seyfarth-Metzger I, Gleich P,
Ruckdeschel G (1997) Decrease in nosocomial pneumonia in ventilated patients by selective
oropharyngeal decontamination (SOD). Intensive Care Med 23:187-195
40. Tetteroo GWM, Wagenvoort JHT, Castelein A, Tilanus HW, Ince C, Bruining HA (1990) Se-
lective decontamination to reduce gram-negative colonisation and infections after oesopha-
geal resection. Lancet 335:704-707
41. Krueger WA, Ruckdeschel G, Unertl K (1997) Influence of intrvenously administered cipro-
floxacin on aerobic intestinal microflora and fecal drug levels when administered simulta-
neously with sucralfate. Antimicrob Agents Chemother 41:1725-1730
42. Deitch EA (1992) Multiple organ failure; pathophysiology and potential future therapy.
Ann Surg 216:117-133
43. Aarts MA, Marshall JC (2002) In defense of evidence: the continuing saga of selective de-
contamination of the digestive tract. Am J Respir Crit Care Med 166:1014-1015
44. Rello J, Rue M, Jubert P, et a! (1997) Survival in patients with nosocomial pneumonia: im-
pact of the severity of illness and the etiologic agent. Crit Care Med 25:1862-1867
208 A. Heininger et al.: A Reappraisal of Selective Decontamination of the Digestive Tract
45. Fagon JY, Chastre J, Hance AJ, Montravers P, Novara A, Gibert C (1993) Nosocomial pneu-
monia in ventilated patients: a cohort study evaluating attributable mortality and hospital
stay. Am J Med 94:281-288
46. Bregeon F, Ciais V, Carret V, et al (2001) Is ventilator-associated pneumonia an indepen-
dent risk factor for death? Anesthesiology 94:554-560
47. Lingnau W, Berger J, Javorsky F, Pille M, Allerberger F, Benzer H (1998) Changing bacterial
ecology during a five-year period of selective intestinal decontamination. J Hosp Infect
39:195-206
48. Misset B, Kitzis MD, Conscience G, Goldstein FW, Fourrier A, Carlet J (1994) Mechanism
of failure to decontaminate the gut with polymyxin E, gentamicin and amphotericin B in
patients in intensive care. Eur J Clin Microbial Infect Dis 13:165-170
49. Webb CH (2000) Selective decontamination of the digestive tract, SDD: a commentary. J
Hosp Infect 46:106-109
50. Sanchez Garcia M (2001) Influence of methodological quality on study conclusions. JAMA
286:2545-2546
51. Hammond JMJ, Potgieter PD (1995) Long-term effects of selective decontamination on
antimicrobial resistance. Crit Care Med 23:637-645
52. Lance Saunders G, Hammond JMJ, Potgieter PD, Plumb HA, Forder AA (1994) Microbio-
logical surveillance during selective decontamination of the digestive tract. I Antimicrob
Chemother 34:529-544
Management of Catheter-Related Sepsis in the ICU
B. Mourvillier and J. F. Timsit
I Introduction
Catheter-related infections (CRI) are the second most common cause of nosocomial
infection and are associated with a substantial morbidity. Suspicion of CRI is a fre-
quent problem in the ICU and frequently leads to unnecessary removal of the cath-
eter. The management of suspected CRI relates to the underlying illness (cardiac
prosthesis, immunosuppression), the severity of the acute illness, and the micro-or-
ganisms involved or suspected.
I Epidemiology
Central venous catheters (CVCs) are a leading source of bacteremia in intensive
care units (ICUs) [1].
The so-called primary bacteremias, most of which are actually secondary to
catheter infection, are responsible for about 10-20% of nosocomial infections in
ICUs in the United States. CRis occur in about 5-10% of catheter use. The reported
ICU incidence of catheter-related bacteremia is variable ranging from 0.28 to 1.28
per 100 catheter-days for all ICU types and average rates of 0.45 per 100 catheter-
days for medical-surgical ICUs [2].
The most common organisms causing catheter-related blood stream infections
(BSis) are staphylococci, Candida spp. and Gram negative rods. However, Coagu-
lase negative staphylococci are frequently recovered from systematic culture of ca-
theters no longer needed [3, 4]. On the contrary, positive quantitative catheter cul-
ture with S. aureus, P. aeruginosa, A. baumannii are more frequently associated
with bacteremia, severe sepsis and complications (Table 1) [5-7], such as septic
shock occurred in 12% of cases, suppurative thrombophlebitis in 7% of cases, and
metastatic infection in 5% of cases with 2 episodes of right side endocarditis [5].
Mechanisms of Infection
Colonization of the catheter may occur by two main pathways: the extra-luminal
route or the intra-luminal route. Colonization of the catheter from its cutaneous en-
try site is the predominant route of colonization for short-term eves (< 15-20
days) whereas colonization via the endoluminal route resulting from a hub contam-
ination predominates for prolonged catheterization [8]. In both cases, the source of
microorganisms was from the patient's own skin commensal bacteria. The extra-lu-
minal route is far more frequent in ICU CRI.
~
""'
0
Table 1. Micro-organisms involved in primary bacteremia, catheter-related bloodstream infections, and catheter colonization !"'
s::
0
CCLIN CCLIN c:
CCLIN CCLIN NNIS
France (S. ouest) Paris-Nord Paris-Nord Paris-Nord USA ~
;;;·
~
2000 20Q0-2001 20Q0-2001 20Q0-2001 (n= 4394) Q>
(n= 760) [39) (n= 307) [40) (n= 180) [40) :::>
(n= 95/22/63 a) [40) [2) 0.
~
Significant Significant CRI :-n

CRI Primary -i
catheter catheter Total Locai/BC-/ bacteremia ~-
colonization colonization BC+a ;::;:
Coagulase negative 302 (39.7%) 161 (52.4%) 64 (35.5%) 33/4/27 38.7%

staphylococci
5. oureus 80 (10.5%) 15 (4.8%) 39 (21.1%) 16/4/19 11.5%
Enterococcus sp. 22 (2.9%) NO NO NO 11.3%
Other Gram+ 5 (0.7%) 24 (6.2%) 2 (1%) 0/0/2 7.0%
P. oeruginoso 92 (12.1%) 51 (16.6%) 39 (21.6%) 24/7/8 3.7%
Enterobacteriaceae 182 (23.9%) 76 (25.0%) 54 {30%) 35/9/10 10.3%
Acinetobacter sp. 15 (2.0%) NO NO NO 1.5%
Other Gram - 15 (2.0%) NO NO NO 4.0%
Candido sp. 25 (3.3%) 12 (3.9%) 4 (2%) 2/2/0 12.2%
Other indetermined 22 (2.9%) 6 (2%) 3 (1.5%) 2/1/0
CRI: catheter-related infection; •: local: local infection, BC -: catheter-related sepsis without positive blood cultures, BC +: catheter-related sepsis with positive blood cultures
Management of Catheter-Related Sepsis in the ICU 211
I Diagnosis of Catheter-Related Infections
Establishing the diagnosis of CRI is often difficult. Diagnosis is typically based on

clinical and/or laboratory criteria, with each having significant diagnostic limits.
Value of Clinical Criteria

Fever or erythema at the catheter entry site are non specific and usually of little
help in diagnosing CRI. Usually, when CRI is suspected, common practice is to re-
move the CVC and to replace it at a new site. However, only about 15 to 25o/o of
CVCs so removed actually prove infected upon quantitative tip culture. Moreover,
in our experience, erythema is not associated with an increased risk of the catheter
origin of a new sepsis [9].
CRI can be subdivided into local and bacteremic infections. Superficial infec-
tions are defined by inflammation or presence of pus at the eve entry site or
along the catheter tunnel. These signs of deep venous inflammation may have a
high diagnostic value and must lead to CVC removal. Most often, local signs are
minor and the suspicion of CRI is based on the occurrence of an unexplained sep-
sis and/or positive blood culture in a patient with a eve.
Diagnostic Tests for Catheter-Related BSis

Diagnostic tests after removal of the catheter: Qualitative broth culture has a high
sensitivity and a very low specificity and is unable to distinguish contamination
from infection. Therefore, Maki et al. proposed a semi-quantitative culture tech-
nique whereby the external surface of the catheter segment is rolled on a blood
agar plate. A threshold of 15 cfu/ml was found to be associated with local signs of
inflammation, and corresponded to catheter colonization [10]. This method could
only explore the external surface of the catheter and endoluminal infection may be
undetected. Quantitative culture techniques have been tested also. The most cost-ef-
fective technique [11] is that of Brun-Buisson et al. [12]. The distal 5 em catheter
segment is vortexed vigorously in a tube containing 1 ml sterile water, and 0.1 ml
of this solution is cultured. Using a 10 3 colony forming units (cfu)/ml threshold,
this technique exhibited a sensitivity of 88o/o and a specificity of 97o/o in predicting
catheter-related sepsis with or without bacteremia.
Diagnosis of infection with the catheter in place: In severe sepsis, the treatment of
catheter-related BSI requires catheter removal in most cases. In these cases, the di-
agnosis of catheter-related BSI should be performed as previously described.
However, most of the situations in which CRI are suspected are not life-threaten-
ing. Assuming that the catheter is still needed, diagnostic techniques allowing an
accurate diagnosis while keeping the catheter still in place would be attractive,
especially when insertion of a new catheter would be hazardous:
1 Quantitative culture of the catheter exit site: Quantitative culture using a thresh-
old of 15-50 cfu/ml reflects the extra-luminal contamination pathway, which pre-
dominates for short term catheters. Culture of the skin insertion site appears to
be very sensitive in detecting colonization, but since all colonized patients will
not develop CRI, it may not be systematically indicated in the absence of local
signs of thrombophlebitis [13-15]. Nevertheless, the absence of micro-organisms
212 B. Mourvillier and J. F. Timsit
at the insertion site might have a good negative diagnostic value. In case of sus-
picion of CRI, it allows the diagnosis of CRI to be excluded and avoids unneces-
sary catheter replacement.
I Quantitative blood culture: Simultaneous samples, drawn through the catheter
and a peripheral vein without removal or exchange of the catheter, are more ac-
curate in predicting catheter-related BSI. A differential colony count of 5:1 is in-
dicative of CRI [16, 17]. The major limitation of the technique is that organisms
are retrieved from the internal surface of the catheter. Consequently, it is prob-
ably more accurate for diagnosis of long-term catheter-related BSI. However,
Quilici et al. found a very good diagnostic accuracy of this technique using a 8:1
threshold in ICU patients [18]. Overall, this technique is very specific but is lim-
ited by its complexity and cost.
An attractive alternative of this technique is to measure the differential time to po-

sitivity between hub-blood and peripheral blood cultures [19]. Using a cut off of
120 minutes, sensitivity and specificity was greater than 90%. However, this result
needs to be confirmed with short-term catheters [20].
Guidewire Exchange of the Catheter

The catheter may be changed using guidewire exchange in the case of catheter mal-
function, positive blood culture obtained since the catheter was last changed, septic
clinical pattern when there is no other likely source of sepsis in the absence of skin
site infection (purulent drainage at the skin puncture site, cellulitis (erythema, ten-
derness and edema) at the skin puncture site or the association of erythema at the
skin puncture site and a positive qualitative skin culture at 24 hours). Guidewire
exchange is associated with fewer mechanical complications (RR 0.48, 95% CI:
0.12-1.91), but, compared to new-site replacement, guidewire exchange is asso-
ciated with a trend toward a higher rate of catheter colonization (RR 1.26, 95% CI:
0.87-1.84). Guidewire exchange is also associated with a trend toward a higher rate
of catheter exit site infection (RR 1.52, 95% CI [0.34-6.73]) and catheter-related
bacteremia RR= 1.72, 95% CI: [0.89-3.33]) [21].
I Management of Catheter-Related Sepsis (Fig. 1)
Catheter Removal or a More Conservative Attitude?

If suspicious of catheter infection, the diagnostic strategy must be to change the
catheter or a more conservative strategy. The physician's attitude must be guided
by the ease of insertion of a new catheter, the immune status, the severity of the
underlying illness of the patient, and the severity of the clinical sepsis. In this field,
relevant data are very rare as there are very few randomized studies, and because
of uncontrolled biases of most of the cohort studies. Cautious decisions about cath-
eter removal and type and length of antibiotic therapy should be made after each
case is examined in light of these variables.
In septic shock or severe sepsis of undetermined origin, or when frank local
signs of infection are found, the catheter should be removed.
In the absence of severe sepsis or local signs, two conservative strategies might be
proposed, especially when new catheter insertion is hazardous: 1) to change the cath-
Suspicion of CR-BSI
/~
Shock. severe
sepsis or pus
(tunnelitis) at
th entry site
I
I GWX I
Culture of the eve
exit site
+
Appropriate antimicrobials:
Vancomycin± ~-lactams
~ \
Surveillance
other septic sites
(orGWX)
+ aminoglycosides
Consider candida! infection risk Peripheral + central blood
/ i '::"'=''"'::'
r -_ _::__:__--, culture
Catheter culture Quantitative ratio > 5:1
,------;
Other infection
lfGWX :eve removal \
Blood cultures results
~I~---., Other infection
- +
r---:------:-----,
/ "--1Certain
/
CR-BSIJ
.........
Partial recovery after ¥ "'-.
P
I
eve remova.
Yes S. Au reus (TEE mandatory} CNS, other GNB
I
Pseudomonas, eve removal + ATB < 7 d
A. baumannii or eve in place + ATB 14-21 d
Yeast
eve removal + ATB
IProbable CR -BSI I
/ Persistence of sepsis > 3 days
Positive blood cultures > 3 days
- S. aureus, Pseudomonas: ATB: 7 d?
- CNS, GNB, Candida: Yes No
No ATB unless immunocompromized
or valvular heart diseases ~
Alternative: TEE is always mandatory .b;-T-B1-0-
i-1 - 14-d'l
No ATB but monitor closely septic signs Endocarditis: ATB 4-6 weeks
and repeat blood cultures Deep seated infection?
Thrombophlebitis: ATB 4-6 weeks
Osteomyelitis: ATB 6-8 weeks
Fig. 1. Management of catheter-related bloodstream infection (CR-BSI). CVC: central venous catheter;
GWX: guidewire exchange; GNB: Gram-negative bacilli; ATB: antibiotic; CNS: coagulase negative staphylo-
cocci; TEE: transesophageal echocardiography
eter over a guidewire; 2) to perform catheter exit site culture (high negative predictive
value) with or without paired blood cultures (high positive predictive value).
When conservative strategies have been decided on, the decision to remove the
catheter mainly depends on micro-organisms and on the evolution of the patient's
state during the first 48 hours.
214 B. Mourvillier and J.F. Timsit
For Candida spp. catheter-related BSI, Rex et al [22] in a subgroup analysis,

showed that failure to remove the catheter resulted in a prolonged duration of can-
didemia (5.6±0.8 days vs 2.6± 0.5 days, p<0,001). However, in this study the
APACHE II of the patients with catheters left in place was higher than that of the
patients with removed catheters. Nevertheless, another prospective cohort study
suggested that catheter removal is associated independently with a lower rate of
complications and a better survival [23] and the expert consensus conference from
the Infectious Disease Society of America (IDSA) argued for a systematic change of
the catheters in case of candidemia [24] although studies were not designed to al-
low definite conclusions to be drawn [25].
For CRI due to S. aureus, catheter maintenance is associated with persisting pos-
itive blood cultures and with an over-risk of death in observational studies [26,
27]. The attitude should be similar for catheter-related BSI with S. maltophilia,
Pseudomonas spp., A. baumannii, and multiresistant Gram-negative bacilli [28, 29].
Overall, a conservative strategy is always risky in critically ill patients. For ex-
ample, in 62 episodes of catheter-related BSI in hemodialyzed patients, the relative
risk of persistent bacteremia was 4-fold higher when the catheters were left in place
[30]. The risk was more important for Gram positive infections. When the decision
is made for a conservative approach, patients must be cautiously monitored. The
catheter must be removed if the course is complicated as suggested by persistent fe-
ver or bacteremia> 3 days [31].
Results from studies mainly performed in cancer patients, suggest that coagulase
negative staphylococci might be treated successfully without catheter removal. How-
ever, if the CVC is not removed, there is a 20% chance of bacteremia recurrence
(as compared to 3% if the CVC is removed) [32].
If guidewire exchange is performed in the setting of an infection, the newly
placed catheter should be removed. The timing of antimicrobial therapy in this case
has not been studied. Antimicrobials instituted just before guidewire exchange
might decrease the risk of infection of the new eve.
Antimicrobial Therapy
When catheter-related BSI is associated with severe sepsis or shock, antimicrobial
therapy must be administered immediately, together with catheter replacement.
Empiric treatment should include vancomycin, a broad spectrum beta-lactamase
with activity against P. aeruginosa and an aminoglycoside. In case of Candida, pre-
vious colonization, or high risk patients, antifungal therapy should be started.
Treatment must be adapted according to the result of catheter tip culture and
blood culture. In case of catheter-related BSI with positive blood cultures, the dura-
tion of treatment should be at least 14 days for uncomplicated (regression of septic
signs and bacteremia <3 days, no persistent infectious site) S. aureus, Pseudomonas
spp., A. baumanni, and Candida spp.
For other microorganism-uncomplicated CRI, antimicrobial therapy should not
exceed one week if the catheter has been removed.
In some rare circumstances, catheter salvage therapy might be proposed in the
ICU, especially for long-term catheters inserted before the ICU stay. This treatment
should only be discussed in the absence of severe sepsis and when Candida spp., S.
aureus (and probably; Pseudomonas spp., A. baumanni) are not the responsible mi-
croorganisms. Recent studies have demonstrated that antibiotic concentrations must
be more than 100 times greater to kill sessile bacteria present in the biofilm at-
tached to the catheter than to kill planktonic (in solution) bacteria [33]. This fact
has prompted investigators to try filling the catheter lumen with pharmacological
concentrations of antibiotics and leaving them there for hours or days, the so-
called antibiotic lock technique. Compared with parenteral therapy alone, therapy
including antibiotic lock was significantly more likely to result in catheter salvage
(RR= 1.24, 95o/o CI: 1.13-1.36, p = 0.0001). Although this technique is more and
more used outside the ICU, the fact that the catheter needs to be unused during
the antibiotic lock process limits its potential usefulness in the ICU.
There are no data in the literature to guide clinicians regarding the use of anti-
microbial therapy for patients whose catheter tip cultures reveal significant growth
in the absence of culture proven bacteremia or fungemia. In this setting, a febrile
patient whose catheter reveals a significant growth of S. aureus, P. aeruginosa or C.
albicans, especially in immunocompromised patients or patient with heart valve
disease, might receive a short (7 days) course of antimicrobials [34]. When the
catheter tip culture grows coagulase negative staphylococci, enterococci and entero-
bacteriaceae, catheter removal with no antimicrobial treatment might be sufficient.
On the contrary, when a conservative attitude has been decided on, and a blood
culture drawn through the catheter is positive, antimicrobial therapy should be
given.
Complicated Courses
Relapse, continuous fever, or bacteremia, despite removal of the catheter is consis-

tent with the persistent focus of infection. This implies prolonged or modified anti-
microbial treatment and an active search for a CRI of another vascular line, meta-
static abscess, septic thrombophlebitis or endocarditis [5].
Failures due to the phamacokinetic-pharmacodynamic properties of the antimi-
crobial are mainly encountered when treating methicillin resistant S. aureus
(MRSA) with glycopeptides. Dopamine, dobutamine, and furosemide use in pa-
tients with shock may enhance vancomycin clearance by inducing an improvement
in cardiac output and/or renal blood flow, and/or by interacting with the renal an-
ion transport system, and thus causing an increased glomerular fll.tration rate and
renal tubular secretion. Clinicians must be aware of possible subtherapeutic serum
vancomycin concentrations when these drugs are coadministered. Therefore, thera-
peutic drug monitoring for the pharmacokinetic optimization of vancomycin thera-
py is strongly recommended in these situations [35]. Trough levels of vancomycin
of 15-20 mg/1 (or even 20-25 mg/1 with S. aureus endocarditis) should be reached
to obtain a minimum concentration/minimum inhibitory concentration (Cmin/
MIC) ratio of more than 5. Even higher concentrations may be necessary in the
near future, due to the increase of MRSA strains with high MIC of 4-8 mglml [36].
Endocarditis was diagnosed in 16 (23o/o) of 69 patients with catheter related bac-
teremia. Among patients considered to have endocarditis on the basis of the Dukes
criteria, the sensitivity of transthoracic echocardiography was only 27o/o [37]. Con-
sequently, transesophageal echocardiography (TEE) is mandatory in this setting.
Such patients must be treated with antimicrobial therapy for >4 weeks.
An infected intravascular thrombus after catheter removal may explain the per-
sistence of severe sepsis despite adequate antibiotic therapy. In general the most
216 B. Mourvillier and J. F. Timsit
common infecting organism is S. aureus. Less common pathogens include Candida

species and Gram-negative bacilli.
The optimal choice and duration of therapy is based on retrospective studies
[38] and expert recommendations [34]. Antibiotic treatment for 4-6 weeks, asso-
ciated with heparin, should be given; surgical excision is rarely needed.
Conclusion
Catheter-related infection is a frequent problem in the ICU. Severe infections are

mostly due to S. aureus, Pseudomonas sp. and candida! infections. In case of severe
infections, catheter removal is the rule and must be associated with an effective
antimicrobial treatment. The optimal duration of antimicrobial therapy is more
based on expert consensus than on strong scientific evidences. The optimal strategy
for patients with positive results of quantitative or semi-quantitative catheter cul-
ture (with negative blood culture) and no other obvious site of infection needs fu-
ture research.
References
1. Edgeworth JD, Treacher DF, Eykyn SJ (1999) A 25-year study of nosocomial bacteremia in
an adult intensive care unit. Crit Care Med 27:1421-1428
2. Anonymous (1999) National Nosocomial Infections Surveillance (NNIS) System report,
data summary from January 1990-May 1999, issued June 1999. Am J Infect Control 27:520-
532
3. Raad I, Darouiche R, Dupuis J, et a! (1997) Central venous catheters coated with minocy-
cline and rifampin for the prevention of catheter-related colonization and bloodstream in-
fections. A randomized, double-blind trial. The Texas Medical Center Catheter Study
Group. Ann Intern Med 127:267-274
4. Maki DG, Stolz SM, Wheeler S, et a! (1997) Prevention of central venous catheter-related
bloodstream infection by use of an antiseptic-impregnated catheter. A randomized, con-
trolled trial. Ann Intern Med 127:257-266
5. Arnow PM, Quimosing EM, Beach M (1993) Consequences of intravascular catheter sepsis.
Clin Infect Dis 16:778-784
6. Souflr L, Timsit JF, Mahe C, et a! (1999) Attributable morbidity and mortality of catheter-
related septicemia in critically ill patients: a matched, risk-adjusted, cohort study. Infect
7. Timsit JF, Bruneel F, Cheval C, et a! (1999) Use of tunneled femoral catheters to prevent
catheter-related infection. A randomized, controlled trial. Ann Intern Med 130:729-735
8. Sitges-Serra A, Puig P, Linares J, et a! (1984) Hub colonization as the initial step in an out-
break of catheter-related sepsis due to coagulase negative staphylococci during parenteral
nutrition. JPEN J Parenter Enteral Nutr 8:668-672
9. Timsit JF, Sebille V, Farkas JC, eta! (1996) Effect of subcutaneous tunneling on internal ju-
gular catheter-related sepsis in critically ill patients: a prospective randomized multicenter
study. JAMA 276:1416-1420
10. Maki DG, Weise CE, Sarafin HW (1977) A semiquantitative culture method for identifying
intravenous-catheter-related infection. N Eng! J Med 296:1305-13099
11. Siegman-Igra Y, Anglim AM, Shapiro DE, et a! (1997) Diagnosis of vascular catheter-re-
lated bloodstream infection: a meta-analysis. J Clin Microbiol 35:928-936
12. Brun-Buisson C, Abrouk F, Legrand P, et a! (1987) Diagnosis of central venous catheter-re-
lated sepsis. Critical level of quantitative tip cultures. Arch Intern Med 147:873-877
13. Fan ST, Teoh-Chan CH, Lau KF (1989) Evaluation of central venous catheter sepsis by dif-
ferential quantitative blood culture. Eur J Clin Microbiol Infect Dis 8:142-144
14. Guidet B, Nicola I, Barakett V, et al (1994) Skin versus hub cultures to predict colonization
and infection of central venous catheter in intensive care patients. Infection 22:43-48
15. Raad II, Baba M, Bodey GP (1995) Diagnosis of catheter-related infections: the role of sur-
veillance and targeted quantitative skin cultures. Clin Infect Dis 20:593-597
16. Flynn PM, Shenep JL, Stokes DC, et al (1987) In situ management of confirmed central ve-
nous catheter-related bacteremia. Pediatr Infect Dis J 6:729-734
17. Mosca R, Curtas S, Forbes B, et al (1987) The benefits of Isolator cultures in the manage-
ment of suspected catheter sepsis. Surgery 102:718-723
18. Quilici N, Audibert G, Conroy MC, et al (1997) Differential quantitative blood cultures in
the diagnosis of catheter-related sepsis in intensive care units. Clin Infect Dis 25:1066-1070
19. Blot F, Nitenberg G, Chachaty E, et a! (1999) Diagnosis of catheter-related bacteraemia: a
prospective comparison of the time to positivity of hub-blood versus peripheral-blood cul-
tures. Lancet 354:1071-1077
20. Blot F (2002) Why should paired blood cultures not be useful for diagnosing catheter-re-
lated bacteremia in critically ill patients? Crit Care Med 30:1402-1403
21. Cook D, Randolph A, Kernerman P, et al (1997) Central venous catheter replacement stra-
tegies: a systematic review of the literature. Crit Care Med 25:1417-1424
22. Rex JH, Bennett JE, Sugar AM, et al (1995) Intravascular catheter exchange and duration
of candidemia. NIAID Mycoses Study Group and the Candidemia Study Group. Clin Infect
Dis 21:994-996
23. Nguyen MH, Peacock JE Jr, Tanner DC, et a! (1995) Therapeutic approaches in patients
with candidemia. Evaluation in a multicenter, prospective, observational study. Arch Intern
Med 155:2429-2435
24. Rex JH, Walsh TJ, Sobel JD, et al (2000) Practice guidelines for the treatment of candidia-
sis. Infectious Diseases Society of America. Clin Infect Dis 30:662-678
25. Nucci M, Anaissie E (2002) Should vascular catheters be removed from all patients with
candidemia? An evidence-based review. Clin Infect Dis 34:591-599
26. Malanoski GJ, Samore MH, Pefanis A, et al (1995) Staphylococcus aureus catheter-asso-
ciated bacteremia. Minimal effective therapy and unusual infectious complications asso-
ciated with arterial sheath catheters. Arch Intern Med 155:1161-1166
27. Fowler VG Jr, Sanders LL, Sexton DJ, et al (1998) Outcome of Staphylococcus aureus bac-
teremia according to compliance with recommendations of infectious diseases specialists:
experience with 244 patients. Clin Infect Dis 27:478-486
28. Benezra D, Kiehn TE, Gold JW, et a! (1988) Prospective study of infections in indwelling
central venous catheters using quantitative blood cultures. Am J Med 85:495-498
29. Elting LS, Bodey GP (1990) Septicemia due to Xanthomonas species and non-aeruginosa
Pseudomonas species: increasing incidence of catheter-related infections. Medicine (Balti-
more) 69:296-306
30. Marr KA, Sexton DJ, Conlon PJ, et al (1997) Catheter-related bacteremia and outcome of
attempted catheter salvage in patients undergoing hemodialysis. Ann Intern Med 127:275-
280
31. Raad I, Narro J, Khan A, eta! (1992) Serious complications of vascular catheter-related Sta-
phylococcus aureus bacteremia in cancer patients. Eur J Clin Microbial Infect Dis 11:675-
682
32. Raad I, Davis S, Khan A, et al (1992) Impact of central venous catheter removal on the re-
currence of catheter-related coagulase-negative staphylococcal .bacteremia. Infect Control
Hosp Epidemiol13:215-221
33. Dunne WM (2002) Bacterial adhesion: Seen any good biof!lm lately? Clin Microbial Rev
15:155-166
34. Mermel LA, Farr BM, Sherertz RJ, et al (2001) Guidelines for the management of intravas-
cular catheter-related infections. Infect Control Hosp Epidemiol 22:222-242
35. Pea F, Porreca L, Baraldo M, et al (2000) High vancomycin dosage regimens required by
intensive care unit patients cotreated with drugs to improve haemodynamics following car-
diac surgical procedures. J Antimicrob Chemother 45:329-335
36. Smith TL, Pearson ML, Wilcox KR, et a! (1999) Emergence of vancomycin resistance in
Staphylococcus aureus. Glycopeptide-Intermediate Staphylococcus aureus Working Group.
N Engl J Med 340:493-501
218 B. Mourvillier and J.F. Timsit: Management of Catheter-Related Sepsis in the ICU
37. Fowler VG Jr, Li J, Corey GR, et al (1997) Role of echocardiography in evaluation of pa-
tients with Staphylococcus aureus bacteremia: experience in 103 patients. J Am Coll Cardi-
ol 30:1072-1078
38. Verghese A, Widrich WC, Arbeit RD (1985) Central venous septic thrombophlebitis - the
role of medical therapy. Medicine (Baltimore) 64:394-400
39. Ayzac L, Callat-Vallet E, Savey A, et al (2001) CCLIN Sud Est. Rapport annuel du n!seau de
surveillance des infections nosocomiales en nianimation.2001; http://cclinsudest.univlyonl.fr/
surveillance/Reseaux/REA/Outil00rea/rap2000rea.pdf:
40. REACAT (2001) Reseau de surveillance des infections liees au catheters veineux centraux dans
les services de reanimation adulte: donnees de surveillance REACAT. http://www.ccr.jussieu.fr/
cclin/welcomebis.htm
Empiric Antibiotics in Critical Illness:
Do they Help or Harm?
M.A. Aarts and J.C. Marshall
I Introduction
Empiric antibiotic therapy - the administration of antibiotics before a microbiolo-
gical diagnosis of infection is established - is a widely-used, but unproven practice
in contemporary intensive care units (ICUs). The perceived need for pre-emptive
antibiotic therapy stems from factors unique to infection in the critically ill. Noso-
comial infection is common, occurring in up to one third of all patients admitted
to an ICU [1]. The diagnosis is challenging. Clinical manifestations are non-specific
[2-5], culture data are unreliable because of concomitant antibiotic use [6], and the
differentiation of colonization from invasive infection is notoriously difficult [7, 8].
Infecting organisms are commonly resistant to first-line antibiotics [9, 10]. ICU-ac-
quired infections develop in the sickest patients, for whom maximal therapeutic in-
tervention is the norm, and clinicians are frequently reluctant to stop therapy, even
when cultures are negative [11, 12].
On the other hand, indiscriminate use of broad-spectrum coverage is associated
with the emergence of multi-resistant organisms, an increased rate of superinfec-
tions in exposed patients, and substantial cost for the health care system [13-16].
Individual clinicians vary in their approach to the indications for empiric therapy,
and attitudes, though divergent, are strongly held. Although the benefits of antibio-
tics as specific anti-infective therapy for community-acquired infection are well-ac-
cepted, those of empiric broad-spectrum coverage for suspected nosocomial infec-
tion in the ICU are not, and available research does not permit firm conclusions
about whether such empiric therapy helps, harms, or yields no net benefit.
I Diagnosis and Treatment of Suspected ICU-Acquired Infection

Empiric antibiotic therapy is therapy that is given when an infection is suspected
but not microbiologically proven. This differs from directed therapy that is targeted
to a specific known pathogen, or prophylactic therapy that is given to prevent the
development of infection. The goal of empiric antibiotic therapy is to provide effec-
tive therapy, prior to the availability of the results of cultures and radiological in-
vestigations, with the expectation that early treatment of infection will result in im-
proved patient survival [8]. While the merits of empiric therapy for community ac-
quired infection are generally well-accepted, nosocomial infections developing in
the ICU present a much more complex challenge.
Infection is difficult to diagnose in the ICU, because fever, leukocytosis, and he-
modynamic instability can be the result not only of infection, but also of such com-
220 M.A. Aarts and J.C. Marshall
mon non-infectious triggers as tissue ischemia, iatrogenic insult, drug toxicity, and
multiple organ failure (MOF) [17]. Ventilator associated pneumonia (YAP) is the
most common ICU-acquired infection, but also the most difficult to diagnose [1,
18]. The signs and symptoms of YAP are non-specific and a gold standard diagnos-
tic test is not available. Moreover antibiotic treatment of YAP has not been con-
vincingly demonstrated to improve outcomes. We recently completed a systematic
review evaluating the effectiveness of all antibiotic regimens for clinically suspected
YAP. We searched both Medline and Embase and further sought unpublished arti-
cles by contacting all authors of reviewed studies, identifying 35 appropriate trials.
No placebo-controlled trials were found, nor was there a proven beneficial therapy
(or gold standard antibiotic) against which alternative regimens could be com-
pared. Only two studies were double blind and most studies reviewed were under-
powered to show equivalence, were of low quality, and excluded patients without
microbiologically proven infection from the efficacy analysis. Although 30 different
regimens have been compared, no significant difference in mortality was observed
in any of these 'equivalence trials'. While intuition suggests that antibiotics may be
beneficial for the critically ill patient with nosocomial pneumonia, evidence from
well-designed clinical trials is lacking.
All the antibiotic trials evaluated in our systematic review used a clinical diagno-
sis of infection to determine study entry and treatment with antibiotics. Sterling
and colleagues created a decision analysis to estimate the impact of antibiotics on
mortality in patients with YAP [19]. They found that if the diagnosis of YAP was
based on a clinical diagnosis or suspicion of infection alone, the probability of sur-
viving was higher if antibiotic therapy was withheld than if it was given (68.2 vs
66.3% if treated). However, if the diagnosis was based on quantitative culture re-
sults obtained by bronchoalveolar lavage (BAL), the probability of survival was
greater with antibiotic therapy (57.3 vs 42.4%). Withholding antibiotics was asso-
ciated with a greater probability of survival if the mortality rate of treated YAP ex-
ceeded 70o/o, or the mortality rate of untreated YAP was less than 54o/o. In this deci-
sion analysis, the potential toxic side effects of antibiotics were not a significant
risk factor; excess mortality reflected the combined impact of excessive antibiotic
use in ventilated patients without pneumonia, based on an estimate that 77o/o of pa-
tients will needlessly be given antibiotics [19, 20]. Because of the significant prob-
ability that ventilated patients will eventually develop pneumonia, the principle risk
associated with antibiotic therapy is that subsequent infections will be caused by
drug-resistant organisms, a circumstance which is associated with a high likelihood
of death regardless of therapy.
I The Prevalence of Antibiotic Therapy

for Suspected ICU-Acquired Infection
The frequency of use and indications for broad spectrum empiric antibiotic thera-
PY in the ICU have been extensively studied. A European point prevalence study of
more than 10000 ICU patients found that 62.3% of ICU patients are receiving anti-
biotics on any given day [ 1]. A large cohort study in a single American institution
found that antibiotics were initiated for suspected infection in 42o/o (1557/3708) of
consecutive patients, both in the ICU and on the wards, based on a diagnosis of
suspected sepsis, severe sepsis, or septic shock. Only 41 o/o of these patients subse-
quently had an infection documented by a positive culture result [4]. Similar anti-
biotic prescribing practice patterns have been observed in Australian and New
Zealand ICUs. In a multicenter observational study of patients receiving antibiotics,
suspected infection was the second most common indication for antibiotics after
surgical prophylaxis [21]. Of 183 patients who received empiric therapy, only 46
(25.1o/o) were subsequently confirmed to have infection. We recently completed a
multicenter international study of 529 ICU patients with suspected infection to eval-
uate a novel assay for endotoxin. The diagnosis of infection was established by cri-
teria of the Centers for Disease Control (CDC), and through a detailed retrospective
review by a clinical evaluation committee of clinicians with expertise in infection
in the critically ill. Only 26% of patients met CDC criteria for infection, and only
17% were adjudicated as being infected by the clinical evaluation committee. On
the other hand, 80% of these patients were prescribed antibiotics, and this percent-
age did not change over the seven days of the study [Marshall et al, unpublished
data].
I The Risks of Broad-Spectrum Antibiotics

for Suspected ICU-Acquired Infections
The adverse consequences of indiscriminate antibiotic use are well-recognized, and

the ICU has been identified as a particularly important site for the emergence of
bacterial resistance [22]. The Society for Healthcare Epidemiology of America/In-
fectious Diseases Society of America (SHEA/IDSA) guidelines for the prevention of
antimicrobial resistance note that antimicrobial resistance is more common in no-
socomial than in community-acquired bacterial strains. Areas within the hospital
with the highest use of antibiotics also have the highest rates of resistance. Changes
in antimicrobial usage are paralleled by changes in the prevalence of resistance,
and patients who have been infected with resistant strains are more likely than
controls to have received previous antibiotics [16].
Antibiotics alter patterns of microbial colonization of the respiratory and gastro-
intestinal tracts, and are thought to play a pivotal role in the selection of opportu-
nistic species. For instance, the most important risk factors for colonization with
antibiotic resistant enterococci, and methicillin-resistant Staphylococcus aureus
(MRSA) include treatment with more than three antibiotics, empiric use of antibio-
tics, and the use of third generation cephalosporins [23, 24]. Previous antibiotic
use is also a significant risk factor for the development of superinfection with or-
ganisms such as Clostridium difficile or Candida, and for infection with multi-resis-
tant organisms [14, 25-27]. Trouillet and colleagues in a retrospective cohort study
of patients with YAP found that prior antibiotic use (OR= 13.5) and prior use of
broad spectrum antibiotics (0 R =4.1) were associated with the development of sub-
sequent YAP caused by resistant bacteria, including MRSA, Pseudomonas aerugino-
sa, Acinetobacter baumannii, and Stenotrophomonas maltophilia [14]. This finding
was replicated by Rello et al. who found that rates of Pseudomonas infection were
higher in patients who had previously received antibiotics, and that these patients
had a higher risk of death as compared to patients who had not received previous
antibiotics [13].
Because of a growing awareness of the risks involved with the indiscriminate ad-
ministration of broad spectrum antibiotics, recent guidelines recommend treating
222 M.A. Aarts and J. C. Marshall
infection early when it is first clinically suspected and then de-escalating therapy
when culture results become available, usually 24-48 hours later [28]. This recom-
mendation is based on the assumption that early treatment of infection with broad
spectrum agents will maximize patient survival, while discontinuing therapy or
narrowing antibiotic selection based on eventual culture results will minimize the
attendant risks of antibiotics. In reality, however, de-escalation of therapy when cul-
tures are negative is inconsistently practiced, and there is no evidence to evaluate
the impact of even 48 hours of unnecessary broad spectrum therapy on the venti-
lated patient.
When culture results become available, empiric therapy is frequently found to
be inadequate. In 4 studies reviewed by Kollef [9], rates of inadequate empiric ther-
apy for suspected VAP ranged from 27 to 73o/o because of the prevalence of resis-
tant Gram-negative bacteria (Pseudomonas aeruginosa, Acinetobacter species, Kleb-
siella pneumoniae and Enterobacter species) or MRSA. In a study of 530 patients
with clinically diagnosed VAP, 214 empiric antibiotic regimens were later modified
because of the isolation of an organism not covered by the empiric regimen
(62.1%}, lack of clinical response (36%}, or the development of resistance (6.6%)
[29]. On the other hand, when culture results are negative or inconclusive, empiric
antibiotics are rarely discontinued [11, 12, 30, 31]. Failure to stop empiric therapy
may reflect a fear of missing occult infection, or the perception that clinical im-
provement implies a therapeutic response, while a worsening clinical course implies
a new infection [7, 8]. In a study of a protocol for suspected sepsis based on em-
piric prescription of imipenem and gentamicin with a policy to discontinue therapy
if cultures were negative, 123/157 evaluable patients had negative cultures but only
37o/o of these had their antibiotics discontinued [11].
I The Evidence in Support of Broad-Spectrum Empiric Antibiotic Therapy
Support for a policy of liberal and broad spectrum antibiotic use in critically ill pa-
tients with clinically suspected infection derives from cohort studies comparing pa-
tients who received adequate initial antimicrobial therapy with patients for whom
the initial choice of antibiotics was deemed inadequate [29, 32-36]. Each of these
studies considers antimicrobial therapy to be inadequate when an organism is sub-
sequently isolated that was not sensitive to the initial prescribed antibiotic regimen,
either because the therapy is inappropriate for the class of organism identified, or
the identified pathogen is resistant to the agents administered. For example, Kollef
and colleagues reported a prospective cohort study of 2000 ICU patients, 655 of
whom were thought to be infected. They found that patients whose initial therapy
had been 'inadequate' had a significantly higher mortality rate than those who had
received 'adequate therapy' (42 vs 17.7%) [32]. However, patients in this study who
had received inadequate therapy also had a higher rate of infection with resistant
organisms, and were more likely to have acquired their infection while in the ICU.
Thus factors other than antibiotic selection may have confounded the increased
mortality risk. In a similar study of Argentinean patients with VAP, Luna and col-
leagues reported that patients whose empiric antibiotic regimen had been inade-
quate had a mortality of 90%, compared to a mortality of 38o/o for patients whose
initial empiric regimen had been considered adequate. Intriguingly, however, pa-
tients who received no antibiotics at all had an intermediate mortality of 60%, a
value that was not significantly different from that of patients receiving adequate
antibiotics in this small study [36]. Moreover, no cohort studies provide informa-
tion on the outcomes of patients who received empiric antibiotic therapy but in
whom no pathogen was ever identified.
In addition, the mortality associated with nosocomial infection is unclear. Some
case control studies suggest that nosocomial infections are associated with an in-
creased risk of morbidity and mortality [1, 13, 37, 38]. However, others have found
that when patients are matched by severity of illness, length of ICU stay and degree
of multiple organ dysfunction, nosocomial infection is no longer independently as-
sociated with mortality [39-42). It is unclear, therefore, whether mortality is attrib-
utable to infection or alternatively, whether the development of nosocomial infec-
tion is a marker of illness severity and an increased risk of death. If it is difficult
to prove that the development of nosocomial infection is an important determinant
of survival, it would not be surprising that even adequate and early antimicrobial
therapy may not significantly impact patient survival.
1 The Evidence for More Restrictive Antimicrobial Regimens
Recent evidence suggests that more restrictive initial antimicrobial regimens may
reduce the development of subsequent superinfections and infections with resistant
organisms. Singh et al. in an unblinded controlled trial randomly assigned 81 pa-
tients with a low suspicion of VAP to either standard therapy as decided by the at-
tending ICU physician or a restrictive antibiotic regimen [43]. Patients in the re-
strictive arm received ciprofloxacin for 48 hours, to be discontinued if cultures
were negative. Patients randomized to the restrictive regimen received fewer anti-
biotics, developed significantly fewer superinfections, and showed a trend toward
increased survival. Indeed this study was discontinued early because participating
physicians perceived it to be unethical for some patients to be denied the benefits
of the restrictive regimen. The use of more specific diagnostic tests has also been
shown to increase survival. Fagon et al. randomized 413 patients with suspected
VAP to either an invasive diagnostic strategy with bronchoscopy or a clinical strat-
egy, with the use of endotracheal aspirate specimens for culture [44]. Patients un-
dergoing bronchoscopy received fewer initial empiric antibiotics (52 vs 91 %), had
more antibiotic free days, and had fewer subsequent fungal infections (11.3 vs
22.6%); their survival at 14 days was significantly better (84 vs 75%).
I Proposed Strategy for Reducing the Unnecessary Use

of Broad-Spectrum Antibiotics
Withholding antibiotic therapy until culture results are available may be a reason-
able approach to avoid the unnecessary administration of antibiotics in the ICU.
Previous observational studies suggest that a delay in the initiation of antibiotic
therapy does not alter outcomes. Pelletier and colleagues found that the time from
fever onset to initiation of antibiotic therapy (0-12 hours, 12-24 hours, > 24 hours)
was not associated with adverse outcome in a cohort of surgical patients with noso-
comial infections stratified by APACHE-II score [45]. In Kollef's study of patients
with both community-acquired and nosocomial infections, there was no significant
224 M.A. Aarts and J. C. Marshall
difference in mortality between patients who received empiric therapy and those
who did not, although the size of the latter group was small [32]. And finally, in a
prospective study of 72 patients with microbiologically confirmed VAP, a delay in
starting antibiotics pending bronchoscopic culture results did not influence out-
come [46]. The observational designs of these studies do not allow us to infer a
cause and effect relationship as there may have been unmeasured differences be-
tween patients who did and those who did not receive empiric therapy. However,
these studies contribute to the hypothesis that withholding of antibiotic therapy
until there is microbiological evidence of infection is safe.
Clinical Scenarios from a Survey on Approaches to Empiric Antibiotic Therapy

SCENARIO 1. A 30-year-old man sustained motor vehicle trauma and was admitted
to the ICU with multiple rib fractures and bilateral pulmonary contusions, a liver
laceration and a fractured right femur. Early operative interventions included inter-
nal fixation of his femur and an exploratory laparotomy. Post-operatively he was
admitted to the ICU. He was intubated and had a right internal jugular central ve-
nous line, and a Foley catheter in place. His admission chest x-ray revealed bilateral
infiltrates. Cefoxitin has been continued since his admission.
On post-operative day 5 he develops a new temperature of 38.5 °C with a
white blood cell count of 18000 cells/mm3 • He requires ongoing mechanical ven-
tilation. He remains hemodynamically stable. On physical exam there is no ob-
vious source of infection. Chest x-ray is unchanged from admission. CT scan of
his chest and abdomen reveal no evidence of an abscess or fluid collection.
SCENARIO 2. A 70-year-old woman was hospitalized with congestive heart failure

and started on levofloxacin for suspected concomitant pneumonia. The next day
she required intubation and admission to the ICU. Her chest x-ray revealed bilat-
eral interstitial markings. Levofloxacin was continued and metronidazole was
added upon transfer.
On day 3 of her ICU admission her WBC has increased to 18000 cells/mm3
and her temperature is 38.5 °C. Her ventilatory requirements have increased and
she is now oliguric with a urine output of 10 cc/hour. She was started on dopa-
mine earlier today and is now requiring 10 IJ,g/kglmin. On physical exam there
is no obvious source of infection. A repeat chest x-ray is unchanged with diffuse
bilateral airspace disease. Blood and urine cultures from ICU admission are neg-
ative.
SCENARIO 3. An obese, diabetic 62-year-old male undergoes a Hartmann proce-

dure for perforated sigmoid diverticulitis. Post-operatively he is admitted to the
ICU, ventilated and treated with ongoing IV ciprofloxacin and metronidazole.
By post-operative day 7 he has made little improvement. He remains intu-
bated and has repeatedly failed to wean from the ventilator. His creatinine is 220
IJ.mol!L (2.4 mgldL) and rising, and his urine output is borderline despite suffi-
cient fluid administration. Today he develops a temperature of 38.5 °C and a
WBC of 18000. Abdominal CT scan is completed and is non-contributory. On
CXR he has a new diffuse bilateral infiltrate.
Although there are significant risks, toxicity and costs associated with empiric
antibiotic use and little rigorous evidence of benefit, no randomized controlled
trials (RCTs) comparing empiric antibiotics to delayed infection directed, narrow
spectrum therapy have been conducted. Clearly there is no incentive for pharma-
ceutical companies to undertake studies that might reduce the market for antimi-
crobial agents. Equally potent, however, is the fear of some clinicians that such a
study may be ethically difficult since it would deny patients the potential benefits
of antibiotics. However, there is clear-cut evidence of equipoise in the community
of clinicians who most commonly treat these patients. We recently conducted a sce-
nario-based survey of 113 surgical infectious disease specialists (113/383 surveyed
response rate 29.5%), the majority of whom were Americans with an academic
practice, and found that 62% of respondents agreed that overuse of antibiotics is a
significant problem in their own ICU [47]. Approaches to the use of empiric anti-
biotics were evaluated using three scenarios describing hypothetical patients with
new fever and leukocytosis, in whom physical exam and clinical investigations did
not reveal an obvious source of infection (see text box). Considerable variability in
approach was found. For example in a stable trauma patient (Scenario 1), 59.3% of
physicians were 'very unlikely' or 'unlikely' to add empiric antibiotics, while 32.7%
were 'very likely' or 'likely' to add antibiotics. With evidence of increasing clinical
deterioration significantly more physicians would prescribe empiric antibiotics,
however even in the face of hypotension or worsening MOF (Scenario 3), 30% were
still 'very unlikely' or 'unlikely' to add empiric therapy. Significantly, few respon-
dents voiced neutral opinions, although their approaches were variable (Fig. 1). De-
pending on the scenario, respondents who would administer empiric therapy re-
commended 19 to 26 different antibiotic regimens. Physicians have strong, but di-
vergent opinions regarding empiric antibiotics .
• Very unlikely or unlikely 0 Neutral • Very likely or likely

70
60
l so
~ 40
c:
g.
Qj
30
~
u.. 20
10
0
Scenario 1 Scenario 2 Scena rio 3
Fig. 1. Likelihood of prescribing empiric antibiotics. Proportion of physicians who would add empiric anti-
biotic therapy across 3 typical ICU patient scenarios. Severity of illness increases across the three scenarios
(see text box). Scenario 1 - Stable trauma patient, ICU day 5, with new fever and leukocytosis; scenario
2 - patient with CHF, ICU day 2, ongoing fever, negative cultures and hemodynamic instability; scenario
3 - post sigmoid resection for perforated diverticulitis, post-op day 7, new fever and progressive organ
failure
226 M.A. Aarts and J.C. Marshall
I Conclusion
Antibiotic overuse is a serious problem that contributes to the growing prevalence
of resistant organisms in critical care units and an increased risk of superinfections
in individual patients. Clinicians are divided on the merits of empiric therapy, as
there is no rigorous evidence to guide treatment decisions. Given the potential risks
associated with unrestrained antibiotic use, on the one hand, or of inadequate or
delayed treatment of nosocomial infection on the other, the effectiveness and safety
of delayed narrow spectrum antibiotic therapy directed by culture results merits
formal and rigorous evaluation in a randomized controlled trial. Such a trial is not
only ethically justified, it is desperately needed to ensure that we are improving the
survival of patients rather than promoting the selection of resistant organisms in
our ICUs.
References
1. Vincent JL, Bihari DJ, Suter PM, et al (1995) The prevalence of nosocomial infection in in-
Care (EPIC) Study. JAMA 274:639-644
2. Salvo I, de Cian W, Musicco M, et al (1995) The Italian SEPSIS study: Preliminary results
on the incidence and evolution of SIRS, sepsis, severe sepsis and septic shock. Intensive
Care Med 21:S244-S249
3. Pittet D, Rangel-Frausto S, Li N, et al (1995) Systemic inflammatory response syndrome,
sepsis, severe sepsis and septic shock: incidence, morbidities and outcomes in surgical ICU
patients. Intensive Care Med 21:302-309
4. Rangel-Frausto MS, Pittet D, Costigan M, Hwang T, Davis CS, Wenzel RP (1995) The natur-
al history of the systemic inflammatory response syndrome (SIRS). A prospective study.
JAMA 273:117-123
5. Fagan JY, Chastre J, Hance AJ, Domart Y, Trouillet JL, Gibert C (1993) Evaluation of clini-
cal judgment in the identification and treatment of nosocomial pneumonia in ventilated
patients. Chest 103:547-553
6. Darby JM, Linden P, Pasculle W, Saul M (1997) Utilization and diagnostic yield of blood
cultures in a surgical intensive care unit. Crit Care Med 25:989-994
7. Wunderink RG (1995) Ventilator-associated pneumonia. Failure to respond to antibiotic
therapy. Clin Chest Med 16:173-193
8. Kim JH, Gallis HA (1989) Observations on spiraling empiricism: its causes, allure, and
perils, with particular reference to antibiotic therapy. Am J Med 87:201-206
9. Kollef MH (1999) Antimicrobial therapy of ventilator-associated pneumonia: how to select
an appropriate drug regimen. Chest 115:8-11
10. McGowan JE (1983) Antimicrobial resistance in hospital organisms and its relation to anti-
biotic use. Rev Infect Dis 5:1033-1048
11. Namias N, Harvill S, BallS, et al (1998) Empiric therapy of sepsis in the surgical intensive
care unit with broad-spectrum antibiotics for 72 hours does not lead to the emergence of
resistant bacteria. J Trauma 45:887-891
12. Heyland DK, Cook DJ, Marshall J, et al (1999) The clinical utility of invasive diagnostic
techniques in the setting of ventilator-associated pneumonia. Canadian Critical Care Trials
Group. Chest 115:1076-1084
13. Rello J, Ausina V, Ricart M, Castella J, Prats G (1993) Impact of previous antimicrobial
therapy on the etiology and outcome of ventilator-associated pneumonia. Chest 104:1230-
1235
14. Trouillet JL, Chastre J, Vuagnat A, et al (1998) Ventilator-associated pneumonia caused by
potentially drug-resistant bacteria. Am J Respir Crit Care Med 157:531-539
15. Weber DJ, Raasch R, Rutala WA (1999) Nosocomial infections in the ICU: the growing im-
portance of antibiotic-resistant pathogens. Chest 115:34S-41S
16. Shlaes DM, Gerding DN, John JF, et al (1997) Society for Healthcare Epidemiology of
America and Infectious Diseases Society of America Joint Committee on the Prevention of
Antimicrobial Resistance: guidelines for the prevention of antimicrobial resistance in hos-
pitals. Clin Infect Dis 25:584-599
17. Bone RC, Balk RA, Cerra FB, et al (1992) Definitions for sepsis and organ failure and
guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Con-
ference Committee. American College of Chest Physicians/Society of Critical Care Medi-
cine. Chest 101:1644-1655
18. Bergmans DC, Bonten MJ, Gaillard CA, et al (1997) Indications for antibiotic use in ICU
patients: a one-year prospective surveillance. J Antimicrob Chemother 39:527-535
19. Sterling TR, Ho EJ, Brehm WT, Kirkpatrick MB (1996) Diagnosis and treatment of ventila-
tor-associated pneumonia - impact on survival. A decision analysis. Chest 110:1025-1034
20. Fagon JY, Chastre J, Hance AJ, et al 1988) Detection of nosocomial lung infection in venti-
lated patients. Use of a protected specimen brush and quantitative culture techniques in
147 patients. Am Rev Respir Dis 138:110-116
21. Bellomo R, Bersten AD, Boots RJ, et al (1998) The use of antimicrobials in ten Australian
and New Zealand intensive care units. The Australian and New Zealand Intensive Care
Multicentre Studies Group Investigators. Anaesth Intensive Care 26:648-653
22. Archibald L, Phillips L, Monnet D, McGowan JE Jr, Tenover F, Gaynes R (1997) Antimicro-
bial resistance in isolates from inpatients and outpatients in the United States: increasing
importance of the intensive care unit. Clin Infect Dis 24:211-215
23. Weinstein JW, Roe M, Towns M, et al (1996) Resistant enterococci: a prospective study of
prevalence, incidence, and factors associated with colonization in a university hospital. In-
fect Control Hosp Epidemiol 17:36-41
24. Hershow RC, Khayr WF, Smith N (1992) A comparison of clinical virulence of nosocomi-
ally acquired methicillin-resistant and methicillin-sensitive Staphylococcus aureus infec-
tions in a university hospital. Infect Control Hosp Epidemiol 13:587-593
25. Dean DA, Burchard KW (1996) Fungal infection in surgical patients. Am J Surg 171:374-
382
26. Schwaber MJ, Simhon A, Block C, Roval V, Ferderber N, Shapiro M (2000) Factors asso-
ciated with nosocomial diarrhea and Clostridium difficile-associated disease on the adult
wards of an urban tertiary care hospital. Eur J Clin Microbiol Infect Dis 19:9-15
27. Barbut F, Petit JC (2001) Epidemiology of clostridium difficile-associated infections. Clin
Microbiol Infect 7:405-410
28. American Thoracic Society (1995) Hospital-acquired pneumonia in adults: diagnosis, as-
sessment of severity, initial antimicrobial therapy, and preventive strategies. A consensus
statement. Am J Respir Crit Care Med 153:1711-1725
29. Alvarez-Lerma F (1996) Modification of empiric antibiotic treatment in patients with pneu-
monia acquired in the intensive care unit. ICU-Acquired Pneumonia Study Group. Intensive
Care Med 22:387-394
30. Ruiz M, Torres A, Ewig S, et al (2000) Noninvasive versus invasive microbial investigation
in ventilator- associated pneumonia: evaluation of outcome. Am J Respir Crit Care Med
162:119-125
31. Sole VJ, Fernandez JA, Benitez AB, Cardenosa Cendrero JA, Rodriguez DC (2000) Impact
of quantitative invasive diagnostic techniques in the management and outcome of me-
chanically ventilated patients with suspected pneumonia. Crit Care Med 28:2737-2741
32. Kollef MH, Sherman G, WardS, Fraser VJ (1999) Inadequate antimicrobial treatment of in-
fections: a risk factor for hospital mortality among critically ill patients. Chest 115:462-474
33. Leibovici L, Shraga I, Drucker M, Konigsberger H, Samra Z, Pitlik SD (1998) The benefit
of appropriate empirical antibiotic treatment in patients with bloodstream infection. J In-
tern Med 244:379-386
34. Ibrahim EH, Sherman G, Ward S, Fraser VJ, Kollef MH (2000) The influence of inadequate
antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting.
Chest 118:146-155
35. Celis R, Torres A, Gatell JM, Almela M, Rodriguez-Roisin R, Agusti-Vidal A (1988) Noso-
comial pneumonia. A multivariate analysis of risk and prognosis. Chest 93:318-324
228 M.A. Aarts and J.C. Marshall: Empiric Antibiotics in Critical Illness: Do they Help or Harm?
36. Luna CM, Vujacich P, Niederman MS, et al (1997} Impact of BAL data on the therapy and
outcome of ventilator-associated pneumonia. Chest 111:676-685
37. Girou E, Stephan F, Novara A, Safar M, Fagon JY (1998} Risk factors and outcome of noso-
comial infections: results of a matched case-control study of ICU patients. Am J Respir Crit
Care Med 157:1151-1158
38. Soufir L, Timsit JF, Mahe C, Carlet J, Regnier B, Chevret S (1999} Attributable morbidity
and mortality of catheter-related septicemia in critically ill patients: a matched, risk-ad-
justed, cohort study. Infect Control Hosp Epidemiol 20:396-401
39. Heyland DK, Cook DJ, Griffith L, Keenan SP, Brun-Buisson C (1999} The attributable mor-
bidity and mortality of ventilator-associated pneumonia in the critically ill patient. The Ca-
nadian Critical Trials Group. Am J Respir Crit Care Med 159:1249-1256
40. Marshall J, Sweeney D (1990} Microbial infection and the septic response in critical surgi-
cal illness. Sepsis, not infection, determines outcome. Arch Surg 125:17-22
41. Brun-Buisson C (2000} The epidemiology of the systemic inflammatory response. Intensive
Care Med 26:S64-S74
42. Bonten MJ, Froon AH, Gaillard CA, et al (1997} The systemic inflammatory response in
the development of ventilator-associated pneumonia. Am J Respir Crit Care Med 156:1105-
1113
43. Singh N, Rogers P, Atwood CW, Wagener MM, Yu VL (2000} Short-course empiric antibio-
tic therapy for patients with pulmonary infiltrates in the intensive care unit. A proposed so-
lution for indiscriminate antibiotic prescription. Am J Respir Crit Care Med 162:505-511
44. Fagon JY, Chastre J, Wolff M, et al (2000} Invasive and noninvasive strategies for manage-
ment of suspected ventilator-associated pneumonia. A randomized trial. Ann Intern Med
132:621-630
45. Pelletier SJ, Crabtree TD, Gleason TG, et al (1999) Waiting for microbiologic data to direct
therapy against nosocomial infections in febrile surgical patients: are outcomes worsened?
Arch Surg 134:1300-1307
46.· Bonten MJ, Bergmans DC, Stobberingh EE, et al (1997) Implementation of bronchoscopic
techniques in the diagnosis of ventilator-associated pneumonia to reduce antibiotic use.
47. Aarts MA, Granton J, Cook D, Bohnen J, Marshall JC (2002) Empiric antimicrobial therapy
in critical illness: Results of an SIS Survey. Surg Infect 3:91 (abst)
I Acute Respiratory Failure
Mortality Rates in Patients with ARDS:
What should be the Reference Standard?
N.D. Ferguson, F. Frutos-Vivar, and A. Esteban
I Introduction
Acute respiratory distress syndrome (ARDS) was first described by Ashbaugh and
colleagues in 1967 [1]. These authors reported a syndrome characterized by acute
onset of tachypnea, hypoxemia, and loss of lung compliance after a variety of stim-
uli, such as pneumonia and multiple trauma. Since this original description, ARDS
has become a disease entity of significant importance to intensivists because of its
incidence, its high mortality rate, and the management challenges that it presents.
Estimates of the incidence of this disorder vary widely (a problem that will be dis-
cussed further below) from 1.5 to 70 per 100000 population [2-7]. The reported
mortality from ARDS ranges from 31-74% depending on the specific patient mix,
with most deaths occurring as a consequence of multiple organ failure (MOP) and
sepsis. Determining a reference mortality rate would be useful, as it would help put
results from studies in clinical context, as well as being helpful in areas of quality
assessment assurance. This chapter will explore two main issues in determining the
mortality from ARDS. First, what is the best way to define ARDS and how will this
affect mortality? Second, from which available studies should we draw our reference
standard for the ARDS mortality rate?
I Classification, Diagnosis and Measurement
Before a true mortality rate for ARDS can be discovered, some agreement must be
reached regarding the question of "What is ARDS?'' [8, 9]. As alluded to above,
ARDS is an extremely heterogeneous entity, potentially affecting patients from the
previously healthy young involved in major trauma, to the elderly with significant
co-morbidities and now presenting with septic shock. Similarly, individual patients
may have relatively mild single-organ respiratory failure or they may develop severe
MOP that ultimately leads to their demise. The underlying cause of ARDS is also
extremely complex and to date is incompletely understood, and may be triggered
by a diverse range of clinical situations [10]. ARDS seems to involve the initiation
of an inflammatory cascade involving the alveolar-capillary barrier's endothelium
and/or epithelium, and a wide range of inflammatory cells, cytokines and chemo-
kines have been implicated [11]. This diversity has prompted some authors to call
for a separation of ARDS into different disorders based either on the inciting event
(direct vs indirect) [12], the clinical duration of the illness [13, 14], the timing of
onset (responsible for intensive care unit (ICU) admission vs developing in an ICU
232 N.D. Ferguson et al.
patient) [15], or the type of inflammatory markers present [16, 17]. These issues of
heterogeneity have caused pessimism in some authors, claiming that until ARDS is
better understood and characterized, clinical trials are destined to fail [18], while
others take a more optimistic approach [19].
Although a valid formal working definition of ARDS has proved challenging,
many experts seem to agree on the theoretical concept of ARDS as a disorder or
pathophysiologic entity. Numerous review articles have been published on this topic
in the last 10 years [11, 20-23] and the majority which address pathophysiology
concur that, at least in its early stages, ARDS represents the pathological state of
diffuse alveolar damage (DAD) [11, 20, 21]. There is damage to both endothelial
and epithelial layers of the alveolar-capillary membrane, with resultant alveolar
flooding and hyaline membrane formation [11, 21, 24]. These changes evolve over
hours to days and result in a loss of the barrier and gas exchange functions of the
lung [20, 21]. The exact mechanisms and pathways through which these changes
occur are clearly very complex, not fully described, and beyond the scope of this
chapter. It is generally agreed that an inflammatory process is involved, often stim-
ulated by a specific inciting event, but the exact mechanisms remain elusive and
may vary between patients and inciting causes [21].
One aspect of measurement that should be clarified when considering any mea-
surement instrument or definition is the purpose of the measurement. Two broad
categories of purpose exist that could capture ARDS definitions. These categories
are termed discriminative and evaluative [25, 26]. Discriminative instruments are
designed with the purpose of distinguishing among groups of patients at a given
point in time, for example separating patients by the presence or absence of a dis-
ease, or by the severity of a disease or symptom. The key properties of a discrimi-
native instrument are reliability and validity (including face and content validity)
[25, 26]. In contrast, evaluative instruments are designed for the purpose of mea-
suring change over time in an individual or group [25, 26]. The key properties of
an evaluative instrument are therefore responsiveness (the ability to detect small
but clinically significant differences over time) and validity [25, 26]. These catego-
ries, discriminative and evaluative, are not mutually exclusive, and an instrument
can sometimes be designed to satisfy more than one purpose if desirable or neces-
sary. Most ARDS definitions in use today function as discriminative instruments.
In addition to the general purpose of an instrument outlined above, it is often
important to consider the specific purpose for which the definition is intended. It
is not difficult to imagine that a definition or other measurement tool examining a
certain entity may need to have very different forms, depending whether it is to be
used as a routine tool in clinical practice, as a screening test, as a diagnostic test
to evaluate the incidence of a disease in a population, or as an inclusion criteria or
endpoint in clinical trials. The screening tool would ideally be a sensitive measure,
while specificity would be demanded in clinical trials. Ease of use and a lack of
specialized skills required would be best for routine use in clinical practice and in
incidence determination, but these properties might not be so important in the ex-
perimental research setting. These different demands placed on an instrument may
require differences in construction and content in order to be able to aptly satisfy
the purpose.
Mortality Rates in Patients with ARDS: What should be the Reference Standard 233
I Previous Definitions of ARDS

Although experts may agree about the concept of ARDS, translating this under-
standing into a working definition that is valid and reliable has proved challenging.
Specific criteria for the diagnosis of ARDS have changed significantly over the
years. As stated above, the first investigators to coin the term "acute respiratory dis-
tress syndrome" were Ashbaugh and colleagues in 1967 [1]. These authors identi-
fied twelve patients with acute respiratory failure who had similar clinical and
pathologic findings. The clinical aspects that their patients had in common were:
1) severe dyspnea; 2) tachypnea; 3) cyanosis refractory to oxygen therapy; 4) loss
of lung compliance; 5) diffuse alveolar infiltration seen on chest x-ray; and 6) no
previous history of significant respiratory disease [1]. It seems clear that this dis-
ease entity did not materialize in the late 1960s, and in fact in their discussion the
authors point out similarities to disease descriptions dating back as far as the 1918
influenza epidemic. At the time of their description, however, dedicated ICUs and
positive pressure ventilation were being widely introduced, and from this point on
the disease became increasingly recognized. For the next ten to twenty years, ARDS
remained very loosely defined. Definitions such as a "worsening picture on analysis
of arterial blood gas levels and increasing amounts of bilateral diffuse infiltrates on
chest x-ray films" were used [27]. Many authors seemed to view ARDS as a gestalt
diagnosis, where no specific definition was needed. When performing a systematic
overview of ARDS incidence and risk factors, Garber et al. found that 51% of the
83 articles identified did not give any specific definition for ARDS [6]. When ARDS
was defined in clinical trials from the early-mid 1980s, more restrictive definitions
tended to be used than definitions in use today [28]. Several studies from this era
required that all of the following be present to diagnose ARDS: 1) a known risk
factor for ARDS; 2) a low static respiratory compliance (generally <50 ml/cm
H2 0); 3) a non-increased pulmonary artery wedge pressure (PAWP) (generally
< 12-18 mmHg, and thereby mandating the insertion of a PA catheter); 4) diffuse
bilateral infiltrates on chest radiograph; and 5) a decreased arterial to alveolar par-
tial pressure of oxygen ratio (variable but generally equivalent to a Pa0 2/Fi0 2 ratio
of approximately 150 or less) [28, 29].
In 1988, Murray and coworkers introduced the first attempt at creating a uni-
form definition of ARDS, the Lung Injury Score (LIS) [30]. This score has four do-
mains (chest x-ray, hypoxemia, positive end-expiratory pressure [PEEP] and respi-
ratory system compliance) and assigns a score of 0-4 to each domain that is avail-
able. The individual domain scores are then summed and divided by the number
of domains used to give the final LIS. The authors recommend that a diagnosis of
ARDS be made when the LIS > 2.5 [30]. Although the reliability and validity of this
instrument have never been established, its use remains relatively common, as in
recent epidemiologic and therapeutic studies of ARDS [4, 31, 32].
In 1992, the American-European Consensus Conference (AECC) on ARDS was
formed, meeting twice that year to "bring clarity and uniformity to the definition
of acute lung injury and ARDS" [24]. The definition of ARDS reached by the AECC
will be discussed in some detail in the following section.
234 N. D. Ferguson et al.
I American-European Consensus Conference ARDS Definition
The AECC definition of ARDS is a multi-item instrument used for the diagnosis of
ARDS [24]. Published in 1994, it was designed for use in many settings including
research, epidemiology, and individual patient care. The target population of the
AECC ARDS definition includes patients with actual or impending respiratory fail-
ure and includes both intubated patients in the ICU and others. The definition con-
sists of the four criteria listed here with their corresponding operational defini-
tions:
I timing - acute onset
1 oxygenation- Pa02 /Fi0 2 $;200 (regardless of PEEP level)
I chest radiograph - bilateral infiltrates seen on frontal chest radiograph
I pulmonary artery wedge pressure - PAWP :-: :; 18 mmHg when measured, or no
clinical evidence of left atrial hypertension.
The outcomes of each of these criteria are binary (yes/no). All of the four criteria
must be present in order to arrive at a diagnosis of ARDS. The AECC definition
was designed to be administered by clinicians or researchers or both, depending
upon the setting in which it is being employed.
In addition to defining ARDS, this first AECC also defined a clinical entity
termed acute lung injury (ALI) [24]. ALI is a disorder that encompasses ARDS (a
subset of patients with a severe form of ALI), but also includes patients with less
severe forms of the same pathologic entity. ALI is defined in an identical way to
ARDS, except for a difference in the operational definition for the oxygenation cri-
teria, which in ALI is Pa0 2/Fi0 2 $;300 (regardless of PEEP level). ARDS and ALI
were, therefore, designed simply to represent different severities of the same dis-
ease, with the only difference between them being an arbitrary oxygenation cutoff.
Since the publication of the ALI criteria in 1994, however, a number of studies have
found that the majority of patients with ALI go on to meet criteria for ARDS [7,
33, 34], and other studies have demonstrated similar mortality rates in both ALI
and ARDS patients [7, 33, 35-37]. Thus, the separation between ARDS and ALI,
originally designed to be an arbitrary severity division, may be even more indis-
tinct than intended. In this chapter, therefore, largely for the sake of clarity, the
novel term ALI will not be addressed and we will instead focus on the more tradi-
tional clinical entity of ARDS.
Reliability of the AECC Definition

Reliability is an important issue for the AECC definition of ARDS when it is used
as an inclusion criterion in clinical trials. If an unreliable definition were used, this
might lead to a given patient being either included or excluded inappropriately be-
cause of error in the measurement rather than reflecting their clinical condition.
This in turn has obvious yet unpredictable effects on mortality estimation.
The reliabilities of some of the individual components of the definition have
been assessed. The chest x-ray criterion, 'bilateral infiltrates on frontal chest x-ray',
has recently been examined in two studies [38, 39]. The first study examined 21 ex-
perts who were shown 28 randomly selected chest radiographs taken from critically
ill hypoxemic (Pa0 2 /Fi0 2 <300) patients [39]. These investigators demonstrated
only moderate agreement among these experts when they were asked if the chest
x-ray met AECC criteria for ARDS, with an overall kappa of 0.55 (95% C.I. 0.52-
0.57). The second study [38] demonstrated similar findings. The authors examined
the inter-observer reliability of bilateral infiltrates seen on frontal chest radiograph
by examining chest x-rays of patients with or at high risk of ARDS who were en-
rolled in a randomized controlled trial (RCT) of a ventilation strategy to reduce
barotrauma. Comparisons of the chest x-ray interpretations were made between the
intensivists and a radiologist, blinded to each other's interpretation. Only moderate
agreement between the study intensivists and the radiologist was found, and also
between the study intensivists and a second central intensivist, with raw percent
agreement of 69-80% and a kappa of 0.40-0.56. A strategy to improve reliability of
the chest x-ray interpretation was also tested. The radiologist and one intensivist
each reviewed a sample of the films independently, and then met to discuss their
different interpretations and produce guidelines for handling films where the out-
come of interest was questionable. They then individually reviewed the entire set of
films and compared their results. After this pilot training they showed a significant
improvement in inter-observer reliability with a raw percent agreement of 89-92%
and a kappa of 0.75-0.85. The accuracy and validity of their interpretations remain
unknown, but clearly they were able to improve the reliability considerably.
The oxygenation criterion has also been studied, but the focus has been on the
effect that within patient variability has on its validity. Gowda and Klocke used
data from ARDS patients and performed computer modeling on them to estimate
the stability and reliability of the Pa0 2/Fi0 2 ratio [40]. Despite being designed to
standardize the Pa0 2 for changes in the Fi0 2 , there was considerable variability in
the Pa0 2 /Fi0 2 ratio for varying levels of Fi0 2 within patients. This was more pro-
nounced at a lower Fi0 2 and in patients with lower (< 30%) shunt fractions. An-
other recent publication is informative about the stability of the Pa0 2/Fi0 2 ratio
[41]. In this study, patients meeting the AECC definition of ARDS were placed on
standardized ventilator settings, including an Fi0 2 of 1.0 and a PEEP of 10 em
H2 0. Of the 21 patients screened, all of whom had an initial Pa0 2/Fi0 2 $;200, 12
patients were found to have a Pa0 2 /Fi0 2 > 200 after 30 minutes on the standardized
ventilator settings [41]. These data do not allow the calculation of an intraclass cor-
relation coefficient, but both studies discussed above clearly suggest that in many
situations the Pa0 2/Fi0 2 ratio may not be reliable, as one could raise or lower it by
simply adjusting the Fi0 2 and/or other ventilator parameters.
Diagnosis and Construct Validity
There is no clear gold standard for the diagnosis of ARDS, which raises issues re-
garding the validation of this (or any) ARDS definition. In the absence of a gener-
ally accepted reference standard some diagnostic tests are accepted on the basis of
consensus alone. In fact, even a gold standard by definition requires consensus
agreement that it behaves as such. An alternate or adjunctive approach to gold
standard testing is to create and test a series of theories about the instrument's re-
sults in a number of settings, thereby judging its construct validity. In the case of
ARDS, however, this is also not without its concerns. ARDS never exists in isola-
tion. At the very least there is the predisposing condition that led to ARDS to con-
sider, and frequently it is seen in the setting of sepsis and MOE In fact, despite se-
vere impairment of pulmonary function, most of the patients who die with ARDS
do so as a result of MOF rather than from hypoxemia or other pulmonary compli-
cations. This makes constructing hypotheses regarding mortality and the presence
or absence of ARDS difficult, as MOP may also occur in critically ill patients with-
out ARDS.
Another theory to be tested for construct validity is to compare the patients
identified as having ARDS by the new definition, with those identified as having
ARDS by preexisting definitions. This can also help increase generalizability and
acceptance if it is found that the new defmition is easier to use and still identifies
similar patients. The concern again, though, is that by comparing a new instrument
to older, poorly validated and potentially flawed instruments, incorrect inferences
may be made. This comparison has been made in at least two studies. Moss et al.
[28] compared the AECC definition to the reference standard of a more restrictive
older definition of ARDS that included a documented decreased thoracic compli-
ance and a more severe oxygenation criterion. In a university hospital setting and
examining ICU patients with specific predisposing factors for ARDS, they found
that the AECC definition had a sensitivity of 100% and a specificity of 96%, refer-
enced against their more restrictive historical definition [28]. Another study [42]
compared the AECC definition with the Murray LIS [30]. In 118 university hospital
ICU patients at high risk for ARDS enrolled in a clinical trial they found an overall
raw percent agreement of 73% and a kappa of 0.46. The incidence of ARDS was
55.1% using the AECC definition and 61.9% using the lung injury score (p=0.07).
No significant differences were noted in the baseline characteristics or mortality
outcome of patients classified as having ARDS by one definition or the other [42].
Again, however, interpretation of both of these studies is problematic because one
cannot be sure which of the two definitions is correct in cases of disagreement.
I Importance of ARDS Definitions
A uniform definition of ARDS is of vital importance in clinical research, both ob-

servational and interventional. As in many areas of medicine the number of papers
studying this disease has grown exponentially in recent years, and studies are
being performed in many different countries. Before the publication of the AECC
definition, many studies did not explicitly define ARDS [6]. Others used different
combinations and permutations of clinical criteria derived from the original paper
[1], and still others used the multi-item score derived by Murray and colleagues
[30]. Without a universally accepted definition of the disease process being as-
sessed, comparison between studies becomes impossible. One striking example is
simply estimating the incidence of ARDS. Initially estimated at approximately 70
per 100000 population by an expert panel [2], several studies have now been pub-
lished on this topic [3-7] with their estimates of incidence ranging from 1.5 to 13.5
per 100 000 inhabitants. These wide variations likely are due in large part to the
use of different definitions and the performance of those definitions [6, 24, 34].
Similarly, when comparing studies of treatment efficacy, the likelihood of discre-
pancies between study results being explained by differences in patient populations
becomes much higher if investigators do not use the same criteria to decide which
subjects have the disease of interest. Additionally, as outlined above for the AECC
definition, even when investigators do apply the same definition in different studies
they may not be recruiting similar patients, depending on the reliability and valid-
ity of the definition used, the perceptions and biases of the individuals involved,
and the makeup of the general ICU population being studied. All of these problems
make estimating a current 'true' or reference mortality rate a task fraught with dif-
ficulty and potential for error.
Observational vs lnterventional Studies
Large multi-center RCTs are being published with increasing frequency in the study
of ARDS. Because of their potentially important implications in terms of patient
therapeutics, as well as for other reasons, these studies often are among the most
talked about and well known among clinicians and researchers alike. When one
starts to consider a baseline mortality rate for ARDS, therefore, a logical place to
start would often seem to be the examination of the mortality rates in the control
arms of recent ARDS RCTs. This may not, however, be the best approach. There
are a number of reasons why the findings of a RCT may not be exactly applicable
to a 'real-life' situation. RCTs are often performed in specialized centers and en-
rolled patients may receive additional time and attention compared to non-enrolled
patients. In addition, and perhaps more importantly, RCTs typically enroll a very
select group of patients, hoping to maximize the potential effect of the treatment
being studied. These issues all may lead to significantly lower mortalities being
seen in RCTs (even in the control groups) when compared to those recorded in ob-
servational studies (which by their nature tend to be much less selective regarding
their patient population). To illustrate this point we show a convenient sample of
six recent RCTs in ARDS in Table 1 [31, 32, 43-46]. The mortality rates among
these studies vary widely; a result not only of the use of different definitions and
their inherent measurement properties (see discussion above), but also because of
the use of different exclusion criteria. On preliminary inspection one can see that
the two studies with the lowest mortality rates [32, 44] also appear to be those with
the most exclusion criteria. In addition, on closer observation, it can be seen that
while many of the criteria are quite objective (e.g., age, duration of ventilation},
every study contains at least one subjective criteria that effectively gives the attend-
ing physician or research team a 'veto' regarding that patient's participation, on the
basis of unlikely survival. These escape clauses can be phrased directly (as in Stew-
art et al. [43]} or may be more indirect (such as the presence of a do-not-resusci-
tate [DNR] order [44] or of unlikely underlying 6 month survival [31, 32, 44, 46]}.
Excluding patients with little chance for survival may be appropriate for therapeu-
tic trials (although the accuracy of these estimates by physicians is not well estab-
lished), but is certainly not desirable when estimating a reference mortality rate for
any disease.
The populations studied in these trials are highly selected patients and, just as
this affects the generalizability of their therapeutic results, it also affects the inter-
pretation of their control mortalities. Clinicians working in an 'average' ICU should
not expect to see the 40% mortality achieved in the ARDS Network control arm
when they audit their own ICU outcomes. Underscoring this point is an important
study by Suchyta and colleagues [47]. The authors report on information from
three recent ARDS Network studies that is not available in most studies, namely
the outcomes of patients who met the inclusion criteria, but then also met one or
more exclusion criteria and were not randomized. They report two striking find-
ings. The first is that of 7454 patients screened, 6552 (88%) met one or more exclu-
,......
......
00
Table 1. Control group mortality in recent ARDS Ras I~

!='
....,
Amato et al [31) Stewart et al [43) 11>
Brochard et al [32) ARDSNet [44) Gattlnoni et ~I [45) Derdak et al [46)
J .ac:
V>
0
I Year 1998 1998 1999 2000 2001 2002 ::I
11>
I Number of control patients 24 60 58 429 152 73
~
I Oxygenation aiteria LIS>2.5 P/F <250 LIS>2.5 P/F <300 P/F <300 P/F <200
-
I Control mortality 71% 47% 38% 40% 48% 52%
I Major Exduslon Criteria:
Unlikely survival ijudged by MD) y
Underlying terminal illness y y y y
Age >70 >76
Severe underlying lung disease y y y y
Intracranial hypertension or neuro y y y y y
disease
Underlying hepatic/renal failure y y
Acute coronary disease or CHF y y y y y
Prolonged ventilation >1 wk PIP>30 >72 hrs >36 hrs Fi0 2>0.8
x 2 hrs x48 hrs
Previous barotrauma/airleaks y y y
Pregnancy y y
Morbid obesity y y
Burns (>50% BSA) y
Lung or bone marrow transplant y y
Presence of DNR Order y
Severe hemodynamic instability y y y
'
LIS: lung injury score; CHF: congestive heart failure; DNR: do not resuscitate; P/F: peak flow
Table 2. Mortality in recent observational ARDS studies
Study Author Year Number Patients Mortality Rate
Doyle et al [37] 1995 123 58%

Monchi et al [48] 1998 259 65%
Zilberberg and Epstein [36] 1998 81 58%
Luhr et al [7] 1999 lll 42%
Roupie et al [33] 1999 61 60%
Esteban et al [1 5] 2002 231. 52%
Esteban et al [15] 2002 218b 63%
• ARDS present at onset of ventilation; bARDS developed during ventilation
sion criteria [47]. In other words only 12% of an average ARDS population would
be eligible for one of these ARDS Network studies. The other main finding is that
across all different predisposing conditions for ARDS the mortality rate was signifi-
cantly higher in excluded patients, with overall mean estimates of 34% (included)
vs 44% (excluded) [47].
Results of recent observational studies are in keeping with the findings of higher
mortality rates in non-selected ARDS patients. A convenient sample of these obser-
vational studies is shown in Table 2. As can be seen the published mortality rates
are generally between 50 and 60% with one or two exceptions on either side of this
range [7, 15, 33, 36, 37, 48]. Although a few studies have suggested that mortality
from ARDS may be decreasing [7, 49], others have observed a similar mortality to
previous decades [33, 35, 48].
It is important to remember that the same problems with ARDS definitions that
affect the RCT results will also affect the mortality rates seen in observational stud-
ies. Thus their results are also open to question because of the use of different defi-
nitions and the uncertainty regarding the reliability and validity of those defini-
tions. One final point that should be made is the importance of the makeup of the
ICU population pool from which ARDS patients are identified. Because different
mortality rates have been seen depending on the inciting event of ARDS (particu-
larly trauma vs others), the patient population that an ICU usually treats could af-
fect their estimate of the ARDS mortality rate. This is particularly problematic in
single-center or small studies. For example an observational study performed in the
ICU of a regional trauma center might find a significantly lower ARDS mortality
than one done in a medical ICU, even if the same ARDS definition was applied in
an identical way in each study. The best way around this problem is to rely on large
multi-center observational studies with a mix of ICUs representative of that seen in
the community.
I Conclusion
In conclusion, significant difficulties exist in estimating a reference mortality rate.
First we must agree about the clinical entity that we are trying to measure (i.e.,
ARDS as a concept). Then a method to capture that entity in a practical fashion
suitable for clinical use is needed (such as the LIS, the AECC definition, or other
clinical ARDS definitions). Subsequently we need to know the reliability and valid-
ity of these defmitions. Finally we need to agree to use the same definition (hope-
fully the one that is shown to be most reliable, valid, and easy to use), thereby al-
lowing us to make comparisons across studies and to generalize the results of stud-
ies with more confidence. At the present time only the first two of these four prob-
lems above have been even reasonably well addressed.
Using the currently available definitions our best estimate of a reference mortal-
ity for ARDS comes from large observational studies that, because of their non-se-
lective and multi-centered nature, are probably the best estimates available regard-
ing the average mortality rate for a usual ARDS patient in a typical ICU. As such,
we can estimate that the current reference ARDS ICU mortality rate is still around
50%. More work is needed as outlined above to further refine this figure.
References
1. Ashbaugh DG, Bigelow DB, Petty TL, Levine BE (1967) Acute respiratory distress in adults.
Lancet 2:319-323
2. Murray JF, and the staff of the Division of Lung Diseases NHLBI (1977) Mechanisms of
acute respiratory failure. Am Rev Respir Dis 115:1071-1078
3. Villar J, Slutsky AS (1989) The incidence of the adult respiratory distress syndrome. Am
Rev Respir Dis 140:814-816
4. Lewandowski K, Metz J, Deutschmann C, et al (1995) Incidence, severity, and mortality of
acute respiratory failure in Berlin, Germany. Am J Respir Crit Care Med 151:1121-1125
5. Thomsen GE, Morris AH (1995) Incidence of the adult respiratory distress syndrome in
the State of Utah. Am J Respir Crit Care Med 152:965-971
6. Garber BG, Hebert PC, Yelle JD, Hodder RV, McGowan J (1996) Adult respiratory distress
syndrome: a systemic overview of incidence and risk factors. Crit Care Med 24:687-695
7. Luhr OR, Antonsen K, Karlsson M, et al (1999) Incidence and mortality after acute respira-
tory failure and acute respiratory distress syndrome in Sweden, Denmark, and Iceland.
The ARF Study Group. Am J Respir Crit Care Med 159:1849-1861
8. Brochard L, Brun-Buisson C (1999) Clinical trials in acute respiratory distress syndrome:
what is ARDS? Crit Care Med 27:1657-1658
9. Schuster DP (1995) What is acute lung injury? What is ARDS? Chest 107:1721-1726
10. Hudson LD, Milberg JA, Anardi D, Maunder RJ (1995) Clinical risks for development of
the acute respiratory distress syndrome. Am J Respir Crit Care Med 151:293-301
11. Ware LB, Matthay MA (2000) The acute respiratory distress syndrome. N Engl J Med
342:1334-1349
12. Lyons WS (2000) Advancing the concept of two distinct ARDSs. J Trauma 48:188
13. Croce MA, Fabian TC, Davis KA, Gavin TJ (1999) Early and late acute respiratory distress
syndrome: two distinct clinical entities. J Trauma 46:361-366
14. Gattinoni L, Bombino M, Pelosi P, et al (1994) Lung structure and function in different
stages of severe adult respiratory distress syndrome. JAMA 271:1772-1779
15. Esteban A, Anzueto A, Frutos F, et al (2002) Characteristics and outcomes in adult patients
receiving mechanical ventilation. A 28-Day International Study. JAMA 287:345-355
16. Abraham E, Matthay MA, Dinarello CA, et al (2000) Consensus conference definitions for
sepsis, septic shock, acute lung injury, and acute respiratory distress syndrome: Time for a
reevaluation. Crit Care Med 28:232-235
17. Abraham E (1999) Toward new definitions of acute respiratory distress syndrome. Crit
Care Med 27:237-238
18. Fuhrman BP, Abraham E, Dellinger RP (1999) Futility of randomized, controlled ARDS
trials - a new approach is needed. Crit Care Med 27:431-433
19. Bernard GR (1999) Research in sepsis and acute respiratory distress syndrome: are we
changing course? Crit Care Med 27:434-436
20. Hudson LD, Steinberg KP (1999) Epidemiology of acute lung injury and ARDS. Chest
116:74S-82S
21. Lesur 0, Berthiaume Y, Blaise G, et al (1999) Acute respiratory distress syndrome: 30 years
later. Can Respir J 6:71-86
22. Marini JJ, Evans TW (1998} Round table conference: acute lung injury, 15th-17th March
1997 Brussels, Belgium. Intensive Care Med 24:878-883
23. Anonymous (1998} Round table conference. Acute lung injury. Am J Respir Grit Care Med
158:675-679
24. Bernard GR, Artigas A, Brigham KL, et al (1994} The American-European Consensus Con-
ference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordina-
tion. Am J Respir Grit Care Med 149:818-824
25. Guyatt GH, Kirshner B, Jaeschke R (1992} Measuring health status: What are the necessary
properties? J Clin Epidemiol45:1341-1345
26. Lacasse Y, Wong E, Guyatt G (1997} A systematic overview of the measurement properties
of the Chronic Respiratory Questionnaire. Can Respir J 4:131-139
27. Rotman HH, Lavelle TF, Dimcheff DG, Vandenbelt RJ, Weg JG (1977} Long-term physiolo-
gic consequences of the adult respiratory distress syndrome. Chest 72:190-192
28. Moss M, Goodman PL, Heinig M, Barkin S, Ackerson L, Parsons PE (1995) Establishing
the relative accuracy of three new definitions of the adult respiratory distress syndrome.
Grit Care Med 23:1629-1637
29. Montgomery AB, Stager MA, Carrico CJ, Hudson LD (1985) Causes of mortality in patients
with the adult respiratory distress syndrome. Am Rev Respir Dis 132:485-489
30. Murray JF, Matthay MA, Luce JM, Flick MR (1988} An expanded definition of the adult re-
spiratory distress syndrome. Am Rev Respir Dis 138:720-723
31. Amato MB, Barbas CS, Medeiros DM, et al (1998) Effect of a protective-ventilation strategy
on mortality in the acute respiratory distress syndrome. N Engl J Med 338:347-354
32. Brochard L, Roudot-Thoraval F, Roupie E, et al (1998} Tidal volume reduction for prevention
of ventilator-induced lung injury in acute respiratory distress syndrome. The Multicenter
Trail Group on Tidal Volume reduction in ARDS. Am J Respir Grit Care Med 158:1831-1838
33. Roupie E, Lepage E, Wysocki M, et al (1999} Prevalence, etiologies and outcome of the
acute respiratory distress syndrome among hypoxemic ventilated patients. SRLF Collabora-
tive Group on Mechanical Ventilation. Societe de Reanimation de Langue Francaise. Inten-
sive Care Med 25:920-929
34. Lewandowski K (1999} Epidemiological data challenge ARDS/ALI definition. Intensive Care
Med 25:884-886
35. Krafft P, Fridrich P, Pernerstorfer T, et al {1996} The acute respiratory distress syndrome:
definitions, severity and clinical outcome. An analysis of 101 clinical investigations. Inten-
36. Zilberberg MD, Epstein SK (1998} Acute lung injury in the medical ICU: comorbid condi-
tions, age, etiology, and hospital outcome. Am J Respir Grit Care Med 157:1159-1164
37. Doyle RL, Szaflarski N, Maclin GW, Wiener-Kronish JP, Matthay MA (1995} Identification
of patients with acute lung injury. Predictors of mortality. Am J Respir Grit Care Med
152:1818-1824
38. Meade MO, Cook RJ, Guyatt GH, et al (2000} Interobserver variation in interpreting chest
radiographs for the diagnosis of acute respiratory distress syndrome. Am J Respir Grit
Care Med 161:85-90
39. Rubenfeld GD, Caldwell E, Granton JT, Hudson LD, Matthay MA (1999} Interobserver
variability in applying a radiographic definition for ARDS. Chest 116:1347-1353
40. Gowda MS, Klocke RA (1997} Variability of indices of hypoxemia in adult respiratory dis-
tress syndrome. Grit Care Med 25:41-45
41. Ferguson ND, Kacmarek RM, Mehta S, Stewart TE, Hallet D (2001} Influence of standard
ventilatory settings on enrollment and mortality in trials of ARDS/ALI. Am J Respir Grit
42. Meade MO, Guyatt GH, Cook RJ, et al (2001} Agreement between alternative classifications
of acute respiratory distress syndrome. Am J Respir Grit Care Med 163:490-493
43. Stewart TE, Meade MO, Cook DJ, et al (1998} Evaluation of a ventilation strategy to pre-
vent barotrauma in patients at high risk for acute respiratory distress syndrome. Pressure-
and Volume-Limited Ventilation Strategy Group. N Engl J Med 338:355-361
242 N.D. Ferguson et al.: Mortality Rates in Patients with ARDS: What should be the Reference Standard
44. The Acute Respiratory Distress Syndrome Network (2000} Ventilation with lower tidal vo-
lumes as compared with traditional tidal volumes for acute lung injury and the acute re-
spiratory distress syndrome. N Eng! J Med 342:1301-1308
45. Gattinoni L, Tognoni G, Pesenti A, et a! (2001} Effect of prone positioning on the survival
of patients with acute respiratory failure. N Eng! J Med 345:568-573
46. Derdak S, Mehta S, Stewart TE, et a! (2002} High frequency oscillatory ventilation for acute
respiratory distress syndrome: A randomized controlled trial. Am J Respir Crit Care Med
166:801-808
47. Suchyta MR, Morris AH, Thompson BT, for the NIH/ARDS Network (2000} Attributes and
outcomes of randomized vs excluded patients in ALI/ARDS clinical trials. Am J Respir Crit
48. Monchi M, Bellenfant F, Cariou A, et a! (1998} Early predictive factors of survival in the
acute respiratory distress syndrome. A multivariate analysis. Am J Respir Crit Care Med
158:1076-1081
49. Milberg JA, Davis DR, Steinberg KP, Hudson LD (1995} Improved survival of patients with
acute respiratory distress syndrome (ARDS): 1983-1993. JAMA 273:306-309
Sigh in Acute Respiratory Failure
N. Patroniti, G. Foti, and A. Pesenti
I Introduction
Mechanical ventilation, a cornerstone in the management of patients affected by
acute respiratory failure, has undergone progressive and profound changes through
the last 30 years. In the '70s, tidal volumes (VT) as high as 10-15 ml/kg and ele-
vated plateau pressures were routinely applied in patients with acute lung injury/
acute respiratory distress syndrome (ALI/ARDS); apart from hypocapnia, no other
major side effect was recognized at that time [1). Positive end-expiratory pressure
(PEEP) was already in use to enhance alveolar recruitment, targeted to optimize
respiratory mechanics, gas exchange, and hemodynamics [2). High VT could help
in providing adequate arterial oxygenation at the lowest PEEP and inspired oxygen
fraction (Fi0 2 ), considered to be the most important damaging factor for diseased
lungs [3). By the late '80s, many authors had described animal models of ventila-
tor-induced lung injury (VILI), showing how high airway pressure could induce se-
vere lung injury [4) and histopathological findings strikingly similar to those of pa-
tients treated by injurious ventilation (ventilator lung) [5). Subsequent studies iden-
tified the high transalveolar distending pressure (volu-barotrauma) [6) as a possible
mechanism for lung rupture, fractures of epithelium and basement membrane [7).
More recent trials suggested that an intense inflammatory response (biotrauma)
could be elicited by parenchymal stretching, and that high levels of cytokines could
be found both in plasma and bronchoalveolar (BAL) fluid during high volume ven-
tilation [8), though other studies applying similar experimental settings found that
a lung injured by high VT ventilation does not cause, per se, a significant release of
pro-inflammatory cytokines into the airspaces or the systemic circulation [9].
Hickling et al. suggested that low volume, pressure limited ventilation could im-
prove survival and that hypercapnia should be tolerated to foster the healing of dis-
eased lungs [10). Thus, a series of randomized controlled trials [11-15), investigat-
ing the effects of a low VT strategy on mortality, culminated in the groundbreaking
study of the ARDS Network [14) which showed that in patients ventilated at 6 mU
kg, mortality was 22o/o lower than in patients ventilated with high VT (12 mUkg).
Beside lung injury deriving from high transalveolar distending pressure, the
other major determinant of VILI is the cyclical alveolar opening and closing caused
by an end expiratory pressure lower than the critical closing pressure [8, 16, 17).
To this end, the worst type of ventilation proved to be that associating high VT and
low PEEP.
Mead et al. estimated that the application of a transpulmonary pressure (P1p) of
30 cmH2 0 would raise distending pressure to very dangerous levels (up to
140 cmH2 0) in collapsed regions completely surrounded by expanded air spaces
244 N. Patroniti et al.
[18]. Lachmann suggested that shear (tangential) forces exerted on collapsed alveoli
by cyclic re-opening approximate this value and cause barotrauma [19].
Based on these findings, the use of low VT to limit plateau pressure to 30-
35 cmH 2 0, while maintaining the lung open by means of sufficient levels of PEEP
has been recommended [20]. To this purpose, Amato and colleagues first intro-
duced and applied the concept of the lung protective ventilatory strategy, by com-
bining low VT ventilation with high PEEP (16.4±0.4 cmH 20), and sustained pres-
sure recruitment maneuvers [10]. Interestingly, apart from the ARDSNet trial,
Amato's study was the only one showing a significant reduction in mortality by re-
ducing VT· Moreover, although the ARDSNet study seems to demonstrate that the
use of low VT alone may be effective in reducing mortality, a recent analysis
showed that intrinsic PEEP (PEEPi) derived from the use of high respiratory rates
in the low VT group could have affected the results [21].
The two most frequent approaches to perform recruiting maneuvers are the use
of high sustained airway pressure commonly employed by application of high con-
tinuous positive airways pressure (CPAP) levels (30-60 cmH2 0) for 20-40 s [22-26]
and the periodical increase in peak airway pressure (sigh) [27-29]. This chapter
will mainly focus on the latter approach.
1 Sigh in the High Tidal Volume Era
Periodic deep breathing in young, healthy adults is the first example of sigh re-
ported in the literature. Bendixen et al. [30], studying spontaneously breathing nor-
mal volunteers, described spontaneous sighs as breaths larger than three times the
average Vn occurring 9 to 10 times per hour. As stated in a previous animal study
[31], sigh was identified as a possible physiological mechanism to recruit atelectatic
lung regions, given that pulmonary compliance showed a downward trend when
periodic hyperinflation were stopped. Also in human volunteers undergoing reduc-
tion of chest volume and FRC, the decrease in arterial oxygenation was promptly
reversed by passive deep inflations [32].
The clinical application of sigh was tested, in 1963, in sedated and paralyzed pa-
tients undergoing general anesthesia, with low VT ventilation. Deep breaths approx-
imating vital capacity, with sustained pressure of 20-30 cmH2 0, intermittently ap-
plied every 5 to 10 minutes, proved effective in improving both compliance and gas
exchange, presumably by reversal of atelectasis [33]. In a subsequent study, Housley
et al. [34] performed sighs by holding airway pressure at the level of 30 cmH 20 as
much as possible and removing it before the patient could show discomfort (aver-
age 15 s). The goal of this study was to investigate whether intermittent re-expan-
sion could improve respiratory compliance and arterial oxygenation in patients un-
dergoing long term ventilation. Sigh showed no beneficial effects, although the
authors suggested that larger volumes and more elevated plateau pressures (e.g.,
50 cmH 2 0) would probably have resulted in atelectasis reversal.
In 1976, Fairley, in an editorial provocatively entitled "The mechanical ventila-
tion sigh is a dodo", reviewed the evidence available at the time on the application
of sigh during intermittent positive pressure ventilation (IPPV) in ALI patients,
and concluded: "I believe there is no longer any place for sigh. In patients with
normal lungs, each tidal volume should be large. In those with acute pulmonary
failure, PEEP (to maximum compliance) should be used. Sighs, superimposed upon
Sigh in Acute Respiratory Failure 245
this, are likely to damage lungs. Perhaps I will relent a little and say that, in appro-
priate cases, a single manually activated sigh may be a useful physical therapy ad-
junct, e.g., artificial coughing. Our newer ventilators would be both cheaper and
safer if we could all reach agreement on this issue. The sigh is dead. May it be per-
mitted to rest in peace!" [35] . Nevertheless, 15 years later, Davies et al. investigated
the possible benefits of sigh (12 ml/kg, delivered every 10 minute) during pressure
support ventilation (PSV) [36]. The authors concluded that, regardless of the mode
of ventilation, deep breaths did not improve oxygenation or lung mechanics, thus
suggesting that, in agreement with Fairley's Editorial statement [35], sigh was still a
"dodo", for the ICU patient.
I Sigh in the Low Tidal Volume Era
Several authors have investigated the relationship between alveolar recruitment,

PEEP, and VT. It is now widely accepted that recruitment occurs progressively and
continuously throughout the inspiratory limb of the respiratory cycle [37-39].
Thus, for any given PEEP level, higher VT determining more elevated opening pla-
teau pressures, result in increased alveolar recruitment [40, 41]. On the other hand,
a reduction in VT may result in progressive alveolar derecruitment as demonstrated
during general anesthesia in healthy lungs [42], and in ARDS patients [41, 43].
Cereda et al. demonstrated that alveolar derecruitment, associated with low VT ven-
tilation, could be prevented by higher PEEP levels [41].
The use of sigh stems from the need to avoid high-volume, high-pressure lung
injury, while preventing the damage associated with alveolar cyclical opening and
closing, by maintaining a condition of stable alveolar recruitment by the periodical
application of intermittent high distending pressure.
Different groups have investigated the use of periodical sighs as an approach to
alveolar recruitment in ARDS patients (Table 1) [27-29].
In a study by Pelosi et al. [27], on 10 ARDS patients, sigh consisted of the appli-
cation of three consecutive high pressure VT (45 cmH 2 0) per minute. Normal VT
ranged between 6 and 8 ml!kg. They found that after a one-hour sigh period, Pa0 2
increased, while PaC0 2 , venous admixture CQvaiQ), and elastance of respiratory
system and lung decreased compared to baseline (Fig. 1). Resumption of baseline
Table 1. Studies investigating use of periodical sigh in ALI/ARDS: Main characteristics of sigh
Baseline Sigh Sigh Plateau Sigh rate PEEP

ventilation maneuver duration pressure (bpm) (cmH20)
(s) (cmH 20)
Pelosi et al. [27] CPPV CPPV 2.5±1.1 45± 1.1 3 consecutives 14±2
Foti et al. [28) CPPV Increases Two 24.8±6.4 2 9.4±3
of PEEP consecutive
breaths
Patroniti et al. [29) PSV BiPAP/APRV 3.6±0.7 38± 3.2 10±4
CPPV: continuous positive pressure ventilation; PSV: pressure support ventilation; BiPAP: bilevel positive
airway pressure; APRV: airway pressure release ventilation
OvalO
38 ± 12 29± 12* 28 ± 14* 41 ± 15 37± 15
180
*
150
Ol 120
:I:
E
.s... 90
0,
~
60
30
0
Baseline 30 min 60min 30min 60min
'--v--1 '--v--1
Sigh No Sigh
Fig. 1. Pa0 2 (open bars) and venous admixture !Ova /Q) at end of baseline period, at 30 and 60 minutes
of sigh period, and at 30 and 60 minute of no sigh period. * p < O.Dl compared to baseline period. Modi-
fied from [27]
ventilation was characterized by progressive alveolar derecruitment and deteriora-

tion of gas exchange and respiratory mechanics.
Foti et al. [28] applied periodical recruitment maneuvers (sighs) by intermit-
tently increasing the PEEP level for two consecutive breaths. These investigators
studied 15 ARDS patients ventilated in continuous positive pressure ventilation
(CPPV, VT average 7.9 ± 1.8 ml!kg), testing three different mechanical ventilatory
approaches applied for 30 minute each:
1) low PEEP CPPV (9.4±3 cmH 2 0);
2) high PEEP CPPV (16±2 cmH 2 0k
3) low PEEP CPPV witil interposition of sighs (two breatils at high PEEP) every 30 s.
Use of periodical sighs resulted in higher Pa0 2 , and lower shunt fractions com-
pared to low PEEP CPPV. However, oxygenation was best during high PEEP CPPV,
suggesting that despite its effectiveness in obtaining alveolar recruitment, sighs in
the form of a periodic increase in PEEP did not reach tile full effect of a constantly
applied high PEEP.
The main results of these studies may be summarized as follows:
1) the use of intermittent sighs during low VT ventilation promotes alveolar recruit-
ment, improving gas exchange and respiratory mechanics
2) tile positive physiological effects of sigh are maintained as long as sigh is deliv-
ered but they are lost in most patients after restoring standard ventilation
3) sigh may be exploited to employ low VT ventilation at lower inspiratory oxygen
fraction or PEEP levels while maintaining adequate gas exchange.
Despite tilese preliminary positive physiological studies, application of sigh during
controlled ventilatory modes in tile clinical setting will be limited by the need for
dedicated hardware and software. However in modern ventilators, which are soft-
ware driven, implementation of some form of sigh should be easy.
I Sigh in Assisted/Spontaneous Breathing

In the last 10 years, an increasing number of studies have shown that gas exchange
[44], hemodynamics [44], length of intubation and of ICU stay [45], are beneficially
affected by preserving spontaneous respiratory activity during mechanical ventila-
tion. In order to enhance spontaneous activity, relatively low levels of pressure sup-
port (PS) should be used [46]. It was shown however that ARDS patients with
higher ventilatory needs and worse respiratory mechanics [47] were more prone to
fail a PSV trial, although a higher PS level could probably have improved the suc-
cess rate of the trial. Moreover the low VT associated with the use of a low PS level,
may lead, as in CPPV, to alveolar derecruitment and worsening of gas exchange.
Encouraged by the successful application of sigh during CPPV, Patroniti et al.
[29] tested the use of sigh in ARDS patients undergoing PSV. They combined PSV
(VT average 7.2 ± 1.4 ml!kg) with airway pressure release ventilation/bilevel positive
airway pressure (APRV/BiPAP) and delivered sigh by applying the higher CPAP
level of APRV/BIPAP ventilation at pressures of 38 ± 3.2 cmH 2 0 for at least 3 s once
per minute. Use of sigh produced an increase in Pa02 (Fig. 2), lung volumes, and
respiratory system compliance. The introduction of sigh resulted in a decreased
respiratory drive as indicated by the significant decrease in P0 . 1• This result may
depend on peripheral chemoreceptor or lung mechanoreceptor inhibition on the
breaths immediately following sighs; this effect has been shown during propofol
general anesthesia [48] and in healthy subjects with artificially reduced lung vol-
umes [32]. The respiratory drive could also be normalized by the positive effect of
improved gas exchange [49]. In a study by Pelosi et al. [SO], on 16 ALI patients, ap-
plication of periodic hyperinflation during CPAP improved respiratory function
250
*
200
c;;
::r 150
E
5
....
0 100
"'
<>.
50
0
Base 1 SIGH Base2
Fig. 2.• Changes in arterial tension of oxygen (Pa02} during baseline ventilation with pressure support
ventilation (PSV, Base 1}, sigh ventilation with PSV+sigh (Sigh}, and return to baseline ventilation with
PSV (Base 2}. Solid lines represent changes in each patient between different steps. Solid horizontal bars
represent the mean values, and open vertical columns indicate SO. * p < 0.001 compared to base 1. Modi-
fied from [29]
and reduced work of breathing. Thus, the introduction of sigh during spontaneous
breathing may enhance feasibility and tolerability of partial ventilatory techniques,
even in ARDS patients. Use of sigh during PSV may have also two major advan-
tages compared to IPPV: 1) while no modern ventilators implement the possibility
of delivering sighs at desired pressure or rate during controlled mode of ventila-
tion, sigh can be easily performed during PSV by means of synchronized intermit-
tent mandatory ventilation (SIMV) or APRV/BiPAP breaths; 2) use of periodical hy-
perinflations to obtain lung recruitment could be preferable in conscious patients
who could not tolerate prolonged high inspiratory pressure commonly needed for
sustained pressure recruitment maneuvers.
1 Sigh: Which Modality, Pressure, Duration, Rate?
The effectiveness of a recruitment maneuver depends on two major factors: the

pressure applied and how long this pressure is held [51-54].
First, it is important to underline that despite most studies reporting the values
of plateau or peak airway pressures applied during the recruitment maneuver, the
effective opening pressure is the transpulmonary pressure (P 1p), which is a function
of the chest wall to respiratory system elastance ratio.
At any given airway pressure, patients affected by primary ARDS, characterized
by elevated lung elastance, but quite normal chest wall elastance, present higher
Ptp that minimally affects intrathoracic pressure, while secondary ARDS patients,
with both lung and chest wall elastance impairment, present lower Ptp but in-
creased intrathoracic pressure. However, it has been shown that patients with pri-
mary ARDS are less responsive to recruitment or require higher recruiting pressure
than patients with secondary ARDS [23, 27, 55]. Thus, adequate and effective pres-
sure, as well as hemodynamic and barotraumatic drawbacks, greatly depends on
the patient's own characteristics.
Provided that a certain sigh pressure has induced opening of a collapsed lung,
complete filling and stabilization of the newly recruited alveoli may greatly depend
on the duration of the recruitment maneuver [51]. Time is particularly critical dur-
ing periodically administered sighs, in which the recruiting pressure is effectively
applied only during the inspiratory plateau pressure period. This may partially ex-
plain why in the study by Patroniti et al., which applied sigh pressure for 3-5 s, a
lower rate of sighs proved effective than in the study by Pelosi et al. To maximize
the time during which the recruiting pressure is applied, volume-controlled sigh
breaths should be delivered at high inspiratory flow rates. However, sighs adminis-
tered as pressure-controlled breaths, which allow also the direct setting of plateau
pressure, may be preferable. Moreover, if alveolar recruitment takes place during a
pressure-controlled breath, more gas is delivered to maintain the plateau pressure
that may favour filling of recruited alveoli. Finally, in view of the potential draw-
backs of high distending pressures, sigh should be delivered at the lowest possible
rate, determined probably by the opposite effects of factors promoting and factors
opposing collapse. Beside natural mechanisms such as surfactant, lung unit inter-
dependency, and collateral ventilation, the level of PEEP is, independent of the
approach used (sustained pressure recrutiment maneuver or periodical sighs), the
major factor opposing lung collapse [22, 24, 40, 41, 43, 51, 53]. On the other side,
surfactant depletion [52], gravitational forces [56], absorptive atelectasis occurring
at high inspiratory fractions of oxygen [57], and the degree of hypoventilation are
all identified factors favoring lung collapse. Pelosi et al. have nicely shown that ten-
dency to derecruitment was a function of ventilation; patients with more severe hy-
poventilation showed greater derecruitment [27].
I Periodical Sighs versus Sustained Pressure Recruitment Maneuvers
There are no studies up to now comparing sustained pressure recruitment maneu-

vers versus periodical sighs. Several studies, separately employing both approaches,
found similar results on gas exchange and respiratory mechanics. Theoretical con-
siderations suggest that the use of sustained pressure recruitment maneuvers
should result in a more effective and longer lasting recruitment. As reported above,
the duration of effects greatly depends on the PEEP levels applied in the post-
recruitment manuever period. This should apply also to periodical sighs, but no
study has specifically investigated this issue. The duration of the sigh-dependent
recruitment effect should be the main determinant for the selection of its rate of
administration. In this perspective, sigh may be seen as a tool to prevent derecruit-
ment of alveoli that have been open by a sustained recruitment manuever or by the
sigh itself, that acting synergically with PEEP, may contribute to maintain recruit-
ment effects. In this perspective sustained pressure recruitment maneuvers, periodi-
cal sighs, and PEEP may be all parts of a unique protective ventilatory strategy
approach. Finally, periodical sighs may be preferable on conscious patients who
might not tolerate high inspiratory pressures held for too long.
Conclusion
Application of periodical sighs has proved effective in inducing alveolar recruitment
and improving gas exchange, with no hemodynamic impairment in patients with
ALI/ARDS during both controlled and assisted ventilation. Sighs may be used as a
unique recruitment approach, or in association with sustained high pressure to
prevent re-collapsing. However, up to now, only short term physiological effects
have been investigated, and further studies are necessary to investigate the possible
role of periodical sigh in ventilatory management of ALI/ ARDS patients. Future
studies should address the definition of safer and more effective ways to administer
sighs, the comparison of the sigh approach with other recruitment strategies, and
the possible benefits on outcome.
References
1. Pontoppidan H, Geffin B, Lowentin (1972) Acute respiratory failure in the adult. N Engl J
Med 287:799-806
2. Suter PM, Fairley HB, Isenberg MD (1978) Effect of tidal volume and end-expiratory pres-
sure on compliance during mechanical ventilation. Chest 73:158-162
3. Nash G, Bowen JA, Langlinais PC (1971) Respirator lung: a misnomer. Arch Path 21:234-240
4. Kolobow T, Moretti MP, Fumagalli R, et a! (1987) Severe impairment in lung function in-
duced high peak airway pressure during mechanical ventilation: an experimental study.
Am Rev Respir Dis 135:312-315
5. Rouby JJ, Lherm T, Martin de Lassal E, et al (1993) Histologic aspects of pulmonary baro-
traumas in critically ill patients with acute respiratory failure. Intensive Care Med 19:383-
389
6. Dreyfuss D, Basset G, Soler P, Saumon G (1985) High inflation pressure pulmonary edema:
respective effects of high airway pressure, high tidal volume and positive end-expiratory
pressure. Am Rev Respir Dis 137:1159-1164
7. Parker CJ, Hernandez LA, Peevy KJ (1993) Mechanisms of ventilator-induced lung injury.
8. Trembley L, Valenza F, Ribeiro S, et al (1997) Injurious ventilatory strategies increases
cytokines and c-fos m-RNA expression in an isolated rat lung model. J Clin Invest 99:944-
952
9. Ricard JD, Dreyfuss D, Saumon G (2001) Production of inflammatory cytokines in ventila-
tor-induced lung injury: a reappraisal. Am J Respir Crit Care Med 163:1176-1180
10. Hickling KG, Henderson SJ, Jackson R (1990) Low mortality associated with low volume
pressure limited ventilation with permissive hypercapnia in severe adult respiratory dis-
tress syndrome. Intensive Care Med 16:372-377
11. Amato MBP, Barbas CSV, Medeiros DM, et al (1998) Effect of a protective-ventilation strat-
egy on mortality in the acute respiratory distress syndrome. N Engl J Med 338:347-354
12. Brochard L, Roudot-Thorval F, Roupie E, et al (1998) Tidal volume reduction for preven-
tion of ventilator-induced lung injury in acute respiratory distress syndrome. Am J Respir
13. Stewart TE, Meade MO, CooK DJ, et al (1998) Evaluation strategy to prevent barotrauma
in patients at high risk for acute respiratory distress syndrome. N Engl J Med 338:355-361
14. The Acute Respiratory Distress Syndrome Network (2000) Ventilation with lower tidal
volume tidal volumes for acute lung injury and the acute respiratory distress syndrome.
N Engl J Med 342:1301-1308
15. Brower RG, Shanholtz CB, Fessler HE, et al (1999) Prospective, randomised, controlled
clinical trial comparing traditional versus reduced tidal volume ventilation in acute respira-
tory distress syndrome patients. Crit Care Med 27:1492-1498
16. Taskar V, John J, Evander E, Robertson B, Jonson B (1997) Surfactant dysfunction makes
lung vulnerable to repetitive collapse and re-expansion. Am J Respir Crit Care Med 155:
313-320
17. Muscedere JG, Mullen JBM, Gan K, Slutsky AS (1994) Tidal ventilation at low airway pres-
sures can augment lung injury. Am J Respir Crit Care Med 149:1327-1334
18. Mead J, Takishima T, Leith D (1970) Stress distribution in lungs: a model of pulmonary
elasticity. J Appl Physiol 28:596-608
19. Lachmann B (1992) Open up the lung and keep the lung open. Intensive Care Med 18:319-
321
20. International Consensus Conference in intensive care medicine (1999) Ventilator-associated
lung injury in ARDS. Am J Respir Crit Care Med 160:2118-2114
21. de Durante G, del Turco M, Rustichini L, et al (2002) ARDSNet lower tidal volume ventila-
tory strategy may generate intrinsic positive end-expiratory pressure in patients with acute
respiratory distress syndrome. Am J Respir Crit Care Med 165:1271-1274
22. Lapinski SE, Aubin M, Metha S, Boiteau P, Slutsky AS (1999) Safety and efficacy of sus-
tained inflation for alveolar recruitment in adults for respiratory failure. Intensive Care
Med 25:1297-1301
23. Grasso S, Mascia L, Del Turco M, et al (2002) Effects of recruitment maneuvers in patients
with acute respiratory distress syndrome ventilated with protective ventilatory strategy. An-
esthesiology 96:795-802
24. Rirnensberger PC, Cox PN, Frova H, et al (1999) The open lung during small tidal volume
ventilation: concepts of recruitment and optimal PEEP. Crit Care Med 27:1946-1952
25. Van der Kloof TE, Blanch L, Youngblood AM (2000) Recruitment maneuvers in three ex-
perimental models of acute lung injury, Am J Respir Crit Care Med 161:1485-1494
26. Medoff BD, Harris RS, Kesselman H, et al (2000) Use of recruitment maneuvers and high
positive end expiratory pressure in patient with acute respiratory distress syndrome. Crit
Care Med 28:1210-1216
27. Pelosi P, Cadringher P, Bottino N, et a! (1999) Sigh in acute respiratory distress syndrome.
28. Foti G, Cereda M, Sparacino ME, De Marchi L, Villa F, Pesenti A (2000) Effects of periodic
lung recruitment maneuvers on gas exchange and respiratory mechanics in mechanically
ventilated acute respiratory distress syndrome (ARDS) patients. Intensive Care Med 26:
501-507
29. Patroniti N, Foti G, Cortinovis B, et a! (2002) Sigh improves gas exchange and lung volume
in patients with acute respiratory distress syndrome undergoing pressure support ventila-
tion. Anesthesiology 96:788-794
30. Bendixen HH, Smith GM, Mead J (1964) Pattern of ventilation in young adults. J Appl Phy-
siol 19:195-198
31. Mead J, Collier C (1959) Relation of volume history of lungs to respiratory mechanicsin
anesthetized dogs. J Appl Physiol14:669-678
32. Mcilroy MB, Butler J, Finley TN (1962) Effects of chest compression on reflex ventilatory
drive and pulmonary function. J Appl Physiol17:701-705
33. Egbert LD, Laver MB, Bendixen HH (1963) Intermittent deep breaths and compliance dur-
ing anesthesia in man. Anesthesiology 24:57-60
34. Housley E, Louzada N, Becklake MR (1970) To sigh or not to sigh. Am Rev Respir Dis
101:611-614
35. Fairley HB (1976) The mechanical ventilation sigh is a dodo. Respir Care 21:1127-1130
36. Davies K, Branson RD, Campbell RS, Perembka DT, Johnson DJ (1993) The addition of
sighs during pressure support ventilation. Is there a benefit? Chest; 104:867-870
37. Pelosi P, Golden A, Mckihbemn A, et a! (2001) Recruitment and derecruitment during
acute respiratory failure. An experimental study. Am J Respir Crit Care Med 164:122-130
38. Crotti S, Mascheroni D, Caironi P (2001) Recruitment and derecruitment during acute
respirtaory failure. A clinical study. Am J Respir Crit Care Med 164:131-140
39. Hickling KG (1998) The pressure volume curve is greatly modified by recruitment: a math-
ematical model of ARDS lungs. Am J Respir Crit Care Med 158:194-202
40. Dambrosio M, Roupie E, Mollet JJ, et a! (1997) Effects of positive end-expiratory pressure
and different tidal volumes on alveolar recruitment and hyperinflation. Anesthesiology
87:495-503
41. Cereda M, Foti G, Musch G, Sparacino ME, Pesenti A (1996) Positive end-expiratory pres-
sure prevents the loss of respiratory compliance during low tidal volume ventilation in
acute lung injury patients. Chest 109:480-485
42. Rothen HU, Sporre B, Engberg G, Wegenius G, Hedenstierna G (1995) Re-expansion of
atelectasis during general anesthesia: a computed tomography study. Acta Anaesthesia!
Scand 39:118-125
43. Richard JC, Maggiore SM, Jonson B, Mancebo J, Lemaire F, Brochard L (2001) Influence of
tidal volume on alveolar recruitment: respective role of PEEP and a recruitment maneuver.
44. Putensen C, Rasanen J, Lopez FA (1994) Ventilation-perfusion distributions during me-
chanical ventilation with superimposed spontaneous breathing in canine lung injury. Am J
Respir Crit Care Med 150:101-108
45. Putensen C, Zech S, Wrigge H, et a! (2001) Long-term effects of spontaneous breathing
during ventilatory support in patients with acute lung injury. Am J Respir Crit Care Med
164:43-49
46. Brochard L ( 1994) Pressure support ventilation. In: Tobin MJ (ed) Principles and Practice
of mechanical ventilation, 1st edn. McGraw, NewYork, pp 239-257
47. Cereda M, Foti G, Marcora B, et a! (2000) Pressare support ventilation in patients with
acute lung injury. Crit Care Med 28:1269-1275
48. Goodman NW, Dow AC (1993) Effect of active and passive sighs in normoxia and hyperxia
on the breathing of patients anesthetized with infusion of propofol. Br J Anaesth 70:536-
541
49. Pesenti A, Rossi N, Calori A, Foti G, Rossi GP (1993) Effects of short-term oxygenation
changes on acute lung injury patients undergoing pressare support ventilation. Chest 103:
1185-1189
252 N. Patroniti et al.: Sigh in Acute Respiratory Failure
50. Pelosi P, Chiumello D, Calvi E, et al (2001) Effects of different continuous positive airway
pressure devices and periodic hyperinflations on respiratory function. Grit Care Med
29:1683-1689
51. Marini JJ, Amato MB (1998) Lung recruitment during ARDS. In: Marini JJ, Evans TW
(eds) Acute Lung Injury. Berlin, Springer, pp 288-295
52. Gaver DP III, Samsel RW, Solway J (1990) Effects of surface tension and viscosity on air-
way reopening. J Appl Physiol 69:74-85
53. Day R, Goodfellow AM, Apgar V, et al (1952) Pressure-time relations in the safe correction
of atelectasis in animal lungs. Pediatrics 10:593-602
54. Neumann P, Berglund JE, Mondejar EF, et al (1998) Effect of different pressure levels on
the dynamics of lung collapse and recruitment in oleic-acid-induced lung injury. Am J Re-
spir Grit Care Med 158:1636-1643
55. Gattinoni L, Pelosi P, Suter PM, et al (1998) Acute respiratory distress syndrome caused by
pulmonary and extrapulmonary disease: different syndromes? Am J Respir Grit Care Med
158:3-11
56. Pelosi P, d'Andrea L, Vitale G, et al (1994) Vertical gradient of regional lung inflation in
adult respiratory distress syndrome. Am J Respir Grit Care 149:8-13
57. Dantzker DR, Wagner PD, West JB (1975) Instability of lung units with low Va/Q ratios
during 0 2 breathing. J Appl Physiol 38:886-895
I Ventilatory Support
Conditioning of Medical Gases during
Spontaneous Breathing
D. Chiumello, N. Bottino, and P. Pelosi
I Introduction
The humidification and heating (i.e., the conditioning) of medical gases is now well
established clinical practice in intubated patients receiving invasive ventilatory sup-
port [1]. Under normal circumstances, room air is only partially humidified, with
a relative humidity around 50%, absolute humidity of 19.4 mgH 2 0/l and room tem-
perature (22 °C). Through the nose and upper airways, the inspired air is filtered
for particles and microorganisms, warmed to body temperature (37 °C), and fully
saturated [2]. This can ensure optimal gas exchange and respiratory function,
maintaining the gas mixture constant, at 37 oc with absolute humidity of 44
mgH 2 0/l (i.e., relative humidity 100%), within the lower airways and alveoli. Nasal
mucosa and turbinate bones in the nose, are mostly involved in these mechanisms.
The nasal mucosa is always moist, due to its high vascularization and high concen-
tration of mucous glands [3]. The surface area of turbinates, covered by the muco-
sa, can increase the turbulence of gas flow due to the convoluted surface. Both
these factors increase the contact between the gas and mucosa [4]. As a result, in-
spiratory flow arriving in the oropharynx is already heated to 30-32 °C and almost
fully saturated (absolute humidity 28-34 mgH 2 0/l, corresponding to 90-100% rela-
tive humidity) [5]. During the passage in the trachea, the gas is further heated to
body temperature and charged of water vapor until the isothermic saturation
boundary [6].
During the expiratory phase, heat and water are in part recovered by the muco-
sal membrane, although this recovery is not complete and the expired air is hotter
and more humidified than the inspired air, resulting in a physiologic net loss of
heat and water [3, 7].
The recommendations for conditioning in non intubated spontaneously breath-
ing patients who need oxygen therapy or non-invasive positive pressure ventilation
(NPPV), are lacking [8]. In non-intubated, spontaneously breathing patients receiv-
ing oxygen therapy or NPPV, we have to consider that we are delivering com-
pressed medical gases to the nose and mouth. The temperature of medical gases
depends on hospital storage locations and room temperature while the humidifica-
tion is always low. Consequently, compressed medical gases will remain excessively
dry until delivered to patients.
On the other hand, the indiscriminate use of humidification devices, currently
used in intubated mechanical ventilated patients, can lead to inappropriate overhu-
midification and excessive air heating, which can result in severe patient discomfort
with possible premature interruption of NPPV. Both these situations (deficit in or
excess conditioning) can worsen a precarious clinical status, resulting in a failure
256 D. Chiumello et al.
of NPPV with the necessity of endotracheal intubation and invasive ventilatory sup-
port.
In this chapter we will discuss the optimal way to condition medical gases in non-
intubated, spontaneously breathing patients who need oxygen therapy or NPPV.
1 Oxygen Therapy
In clinical practice oxygen therapy is usually administered in pulmonary or cardiac
respiratory failure [9]. Data regarding the ability of sick patients (especially with
pulmonary disease) to condition inspired gases are scanty. Walker et al. speculated
that patients with pulmonary disease might have a reduction in the ability to con-
dition [7], and, similarly, Green and Nesarajah found a reduction in the water pres-
sure of the expired gases in three patients with chronic bronchitis [10]. On the con-
trary, Caldwell et al. did not find any difference in water loss in healthy volunteers
and patients with chronic airway obstruction [11]. Primiano et al. measured the
water vapor pressure and temperature at different sites of the upper airways in a
group of healthy subjects and in a group of patients with cystic fibrosis while
breathing room air [12]. They found no difference between the two groups regard-
ing the temperature and water vapor pressure, measured at pharynx or airway
opening, during mouth or nose breathing. However, when the cystic fibrosis group
inspired hot air, the temperature in the pharynx was similar compared to the
healthy group, while the water vapor partial pressure was lower. This suggests a
lower ability of the airway to humidify due to the disease that affects the airway
epithelium.
Hence, we investigated the ability of different commonly used humidification de-
vices, setting the medical gas flow as usually adopted in clinical practice. We mea-
sured the temperature and absolute and relative humidity of the medical gases, di-
rectly at the pipeline, before applying any form of conditioning. The hygrometric
measurements were computed by a psychometric method [13], based on two ther-
mal probes, a dry one and a wet one. The two probes were placed at the exit of the
gases from the pipeline. The temperatures were measured and displayed on a chart
recorder (Yokogawa, Tokyo, Japan). The mean temperatures were recorded and
used for the following computation. The psychometric method calculates the abso-
lute humidity and relative humidity based on the temperatures obtained by the two
probes. The dry probe measures the actual gas temperature. The wet probe is
coated with cotton wet with sterile water. The evaporation of the sterile water is
proportional to the dryness of the gas, so the difference of temperature between
the dry and wet probe is related to the gas dryness.
The relative humidity was obtained by a reference to a psoriometric diagram
considering the differences of temperature between the two probes.
The absolute humidity at a saturation point (AHs) was obtained from the follow-
ing formula:
AHs = 16.451563- 0.731 T + 0.03987 T2 (mgH 2 0/l)
where T (0 C) is the dry probe temperature.

Absolute humidity was obtained with the following formula:
Absolute humidity= relative humidity* AHs/100 (mgH2 0/l).

Conditioning of Medical Gases during Spontaneous Breathing 257
Table 1. Temperature, absolute and relative humidity of gases from 21 to 100% oxygen
Fi02 Temperature Absolute humidity Relative humidity

(%) co (mgH 2011) (%)
21 24.0 3.9 18
30 23.6 3.9 18
40 23.5 2.8 13
50 23.3 2.5 12
60 23.2 2.4 12
70 23.0 2.4 12
80 23.0 2.5 12
90 22.9 2.8 14
1100 22.7 2.9 14
As shown in Table 1, the medical gases present a low absolute humidity while the
temperature is within acceptable ranges. When dry gases are inspired, a humidity
deficit (the difference between the alveolar and ambient air water content) is gener-
ated [2, 6]. This deficit may lead to a moisture depletion of the mucosa, a reduction
in the ciliary activity, and functional alteration in the upper airway epithelium
[2, 6].
Low Gas Flow Rates (< 4 1/min)

Low gas flows during oxygen therapy are usually administered in less severe pa-
tients. The ACCP-NHLBI national conference on oxygen therapy stated that: "the
routine humidification of oxygen (using a flow lower than 4 1/min) delivered by a
nasal canula, is not necessary when the environmental humidity is adequate"
[14, 15]. Despite this recommendation, routine humidification when using low flows
of oxygen remains common practice [16]. Using such low gas flows, only a minimal
part of the patient's minute ventilation (room air) is mixed with the oxygen deliv-
ered [17]. In this case, the patient continues to breath through the nose, maintaining
an adequate conditioning capability, so the only possible consequence would be
discomfort and not a real humidity deficit [16].
Considering a patient with a total minute ventilation of 9 1/min composed of 6 1
of room air and 3 1 of pure oxygen delivered by a canula, the temperature and ab-
solute humidity will be 22 oc and 13.9 mgH 2 0/l, respectively.
In a small study, it was showed that patients receiving oxygen at low flow rates re-
ported discomfort without any benefit from oxygen humidification [18]. Campbell et
al. studied, in a large prospective randomized study, the administration of humidified
(using a simple bubble humidifier) and dry oxygen in sick patients [16]. The dry nose,
dry mouth, chest discomfort, and headache were evaluated by a dedicated scale. The
complaints of dry nose and throat were mild and similar in both the treatment groups
(42.9 vs 43.9%) and did not change during the study period. No differences were
found in frequency or in severity for the other symptoms.
These data suggest that the discomfort frequently reported by patients receiving
oxygen at low flow rates is mainly due to direct contact of the gas on the nose and
throat epithelium and is not ameliorated by humidification.
High Gas Flow Rates (6-12 1/min)
Several types of humidification devices (usually employed with gas flows less than
10/15 l!min) have been developed with different abilities to condition medical gases
in spontaneously breathing patients. In our opinion, the goal of these devices, when
delivering high flows of medical gases in non-intubated and non-tracheostomized
patients, is simply to add water moisture to reach an absolute humidity above 10
mgH 2 0/l.
The most simple and common device is the bubble humidifier. In this device,
the gas flow passes through a stem beneath the water surface to produce gas bub-
bles that mix with the water, increasing the amount of absolute humidity in the
gas. The water is contained in a reservoir, which is periodically refilled. The ability
of conditioning is limited by the surface area of the gas water interface and the
water temperature. Several factors can alter the performance:
1) the gas flow affects the time of contact with the water: increasing the gas flow
decreases the time contact and the absolute humidity
2) the bubble sizes: the lower the size, the higher is the surface contact between the
gas and water increasing the absolute humidity
3) the temperature of the gases: when gases pass through the water the evaporation
cools the water reducing the efficiency of the device
4) the room temperature: the higher the temperature, the higher the absolute hu-
midity.
In clinical practice these humidifiers carry a low risk of infection and do not need
to be changed between patients [19].
To increase efficiency, a diffuser was added to the bottom of the stem of a bub-
ble humidifier to produce a bubble diffuser humidifier. The goal of the diffuser is
to decrease the size of the bubbles increasing the total gas water interface and in-
creasing the absolute humidity.
Another common device is the RESPIFLO (Tyco Healthcare, Italy) in which there
is direct contact between gas and water without any bubble formation. The gas flow
passes through a small orifice of the tube and the water is aspirated laterally (Ber-
noully principle) from a prefilled water reservoir. Moreover the RESPIFLO can heat
the gases by an internal electrical resistance.
We evaluated the performance in terms of temperature, absolute humidity and
relative humidity of these two devices at two different gas flows (6 and 12 l!min)
using 100% oxygen.
Table 2. Efficiency of conditioning of different bubble humidification devices
Bubbles RESPIFLO Active RESPIFLO
6 Vmin 12 Vmin 6 Vmin 12 Vmin 6 Vmin 121/min
Temperature (0 () 21 .0 20.6 21.3 20.7 35.0 34.8

Absolute humidity 15.0 12.6 12.8 10.5 37 37
(mgH 20/I)
Relative humidity 82 70 68 58 93 95
I (%)
As showed above the simple bubble humidifier and the RESPIFLO humidifier
were able to adequately condition the medical gases. The heated RESPIFLO further
increased the temperature and humidity of the gases well above a temperature of
30°C.
The hot water humidifiers, commonly used in mechanically ventilated patient
with a range of temperature of 32-28 oc, should not be used during oxygen therapy
for several reasons: 1) the bubble humidification devices are able to adequately
condition the medical gases; 2) the gases heated and humidified by hot-water humi-
difiers can cause discomfort to the patient and create water deposition in the in-
spiratory line and face mask.
A possible disadvantage of the reusable bubble humidifiers, due to the possible
contamination from the external environment (nurses, doctors) and to the produc-
tion of microaerosols, could be the transmittion of bacterial infection [20]. Based
on these concepts a prefilled, single use, water humidifier, has been developed to
exclude any contact with the environment. Golar et al. did not find any difference
in the bacteriological cultures in the water of a prefilled or a reusable humidifier
[19]. In the 60 cultures from reusable humidifiers they found only 6 bacterical
growths compared to 0 in the prefilled, and these were coagulase negative Staphylo-
coccus, suggesting a contamination from the medical staff. More importantly, the
prefilled humidifiers were kept in place for a maximum of 30 days or until the
water was consumed, suggesting a possible long term use and avoiding routine
changes between patients.
In conclusion, during oxygen therapy we have to consider the gas flow required
for the patient. With low gas flows, it appears that it is not necessary to apply any
humidification system while with high gas flows we recommend simple bubble hu-
midification systems that work well and are cheaper compared to the hot-water hu-
midification systems.
Non-invasive Positive Pressure Ventilation
Since the first application of NPPV in chronic pulmonary disease patients, this
form of ventilation is now broadly applied in any kind of acute respiratory failure
from acute respiratory distress syndrome (ARDS) to cardiogenic pulmonary edema
[8]. The last consensus conference on NPPV stated that: "inadequate humidification
may cause patient distress, especially if pipeline or cylinder gas is used"; based on
the paucity of the available data no specific recommendations were made [8]. How-
ever, life threatening inspissated secretions due to inadequate conditioning were re-
ported in a patient during NIPPY [21]. In patients with obstructive sleep apnea
(OSA) treated with continuous positive airway pressure (CPAP), a possible compli-
cation due to the air leaks is formation of a high unidirectional flow that passes
through the nose. If this high gas flow is not conditioned, it may cause an increase
in inflammatory mediators [22] and in nasal airway resistance [23]. Richards et al.
showed that during CPAP with mouth leaks, the active conditioning of the inspired
gases, using a heat and water bath humidifier, attenuated the increase in the airway
resistance [24]. This study confirms that mucosal dryness due to a high gas flow
can cause an increase in nasal resistance. Similarly, Martins de Araujo et al. evalu-
ated the impact on relative humidity of heated and humidified gases compared to
dry gases during CPAP in OSA patients [25]. Compared to spontaneously breathing
Table 3. Performance of face mask during NPPV
Temperature Absolute Relative

(OC) humidity humidity
(mgH20/I) (%)
Ventilator CPAP with hot humidifier

Quiet breathing 35.2±0.2 39.1 ±0.2 98±1
Maximal voluntary ventilation 35.2±0.1 39.1±0.3 97±1
Ventilator CPAP without hot humidifier
Quiet breathing 28.7±1.1 19.9±1.6 71±3
Maximal voluntary ventilation 28.0± 1.4 18.1 ±2.6 68±6
Low flow CPAP with hot humidifier
Quiet breathing 31.7± 1.0 31.7 ±3.0 95±4
Maximal voluntary ventilation 31.8±2.2 32.5 ±2.7 97±3
Low flow CPAP without hot humidifier
Quiet breathing 27.2±1.1 17.3±5.8 63±22
Maximal voluntary ventilation 28.5±0.7 19.0±3.9 68± 11
High flow CPAP with hot humidifier
Quiet breathing 31.2 ± 1.5 31.2±4.1 96±5
High flow CPAP without hot humidifier
Quiet breathing 28.3 ±0.4 14.8±0.2 54±1
Maximal voluntary ventilation 28.0±2.1 13.5 ± 3.5 49±7
patients without CPAP, the relative humidity was significantly reduced when CPAP
was started (80 vs 63%) and further decreased when patients simulated air leaks
(39%). The conditioning of gases significantly increased the relative humidity to
similar values as spontaneous breathing (82%). Most importantly, the authors also
evaluated the relative humidity when CPAP was delivered by a face mask. Using the
face mask and dry gases the relative humidity was similar to spontaneous breath-
ing. The face mask is able to mix the inspired dry gases with the heated and humi-
dified expired gases, establishing an optimal humidity gradient so avoiding the
need for additional conditioning.
However, dyspneic patients often breath through their mouths, causing airleak-
age and decreasing efficacy of NPPV when the nasal mask is used [26]. NPPV may
fail in a significant number of cases due to technical problems, such as gas leaks
around the mask [26, 27], skin lesions [28], and mask discomfort [29, 30]. Recently
a new device, the 'helmet' has been introduced into clinical practice to deliver
NPPV [31]. The 'helmet' is a transparent plastic hood with an internal volume of
12-15 1 depending on the size, originally used to deliver the desired oxygen frac-
tion during hyperbaric oxygen therapy. The helmet, due to the absence of any con-
tact with the patient's face, avoids skin lesions and may increase patient comfort,
compared to the facial mask, with the possibility of a longer NPVV delivery. In ad-
dition, the helmet can be used in difficult situations such as in edentulous patients
or in patients with facial trauma. A recent report describing the use of the helmet
Table 4. Performance of helmet during NPPV
Temperature Absolute Relative

(oq humidity humidity
(mgH20/I) (%)
Ventilator CPAP with hot humidifier

Quiet breathing 31.7±1.1 32.7± 1.8 98±1
Maximal voluntary ventilation 33.5±1.0 35.0± 1.7 97±1
Ventilator CPAP without hot humidifier
Quiet breathing 27.2± 1.3 18.1±71 71±30
Maximal voluntary ventilation 29.0±1.9 19.1 ±5.6 67±28
I Low flow CPAP with hot humidifier
Quiet breathing 30.7± 1.2 27.1±4.1 86±8
I Low flow CPAP without hot humidifier
Quiet breathing 28.5± 1.4 12.1± 2.7 43±7
Maximal voluntary ventilation 29.7±1 .8 19.7±3.2 66±5
High flow CPAP with hot humidifier
Quiet breathing 30.6±1.1 27.5±3.0 87±4
Maximal voluntary ventilation 31.1 ± 1.0 31.0±3.7 96±6
High flow CPAP without hot humidifier
Quiet breathing 27.2± 1.6 8.8±0.3 34±5
Maximal voluntary ventilation 27.8 ±0.9 13.3 ±0.6 49±5
in the delivering NPPV in a group of patients with acute respiratory failure, found
that no patients failed NPVV due to the discomfort of the interface [31].
Due to the higher internal volume (see above), compared to 0.3 1 for a face
mask, the mix of moisture inside the helmet from the expired gas will be diluted in
a higher gas volume and the resulting inspired humidity will be lower than with a
face mask.
We measured the temperature, relative humidity and absolute humidity during
NPPV with CPAP inside a face mask or helmet in a group of healthy subjects. CPAP
was delivered using: a low (40 1/min) or a high (80 1/min) flow system and a me-
chanical ventilator with dry gas, and with conditioned gas (100% of oxygen) using
a hot-water humidifier that was set at 34 °C. The measurements were done during
normal quiet breathing (S-8 1/min) and during maximal voluntary ventilation (25-
30 1/min) (Tables 3 and 4).
Using face mask or helmet with dry gas, during normal quite breathing or maxi-
mal voluntary ventilation, the absolute humidity was always above 10 mgH 2 0/l; ex-
cept with the helmet during high flow CPAP, when the absolute humidity was lower.
Using the helmet, the conditioned gases caused patient discomfort due to water
deposition on the helmet wall.
Two recent studies evaluated the impact of a heat and moisture exchanger
(HME) or a hot-water humidifier during NPPV delivered by a face mask [32, 33] .
The HME induced a significant increase in the indexes of patient effort compared
to the hot-water humidifer. The HME due to its high dead space also generated an
increase in carbon dioxide, partially compensated by higher minute ventilation.

Unfortunately, there was no evaluation of patient comfort. In our opinion, using
the hot-water humidifier for a longer period can cause patient intolerance due to
the high temperature of the gases that reach the face. This might cause a premature
interruption of NPPV. We must remember that it is not possible to use the HME
with the helmet because there is no expiratory flow passing the HME.
From these data it appears that, at least during short term use, it is not neces-
sary to apply any conditioning to the medical gases.
I Conclusion
The conditioning of medical gases is a common practice in intubated patients dur-
ing oxygen therapy and NPPV, yet there are no defmed guidelines. During oxygen
therapy using high gas flows bubble humidification devices are sufficient, while
during low gas flows or NPPV no conditioning seems to be necessary.
Acknowledgements. The authors would like to thank Dr. A Candiani and Dr. A Car-
lesso for their useful suggestions and collaboration.
References
1. Cook D, Ricard JD, Reeve B (2000) Ventilator circuit and secretion management strategies:
A Franco-Canadian survey. Crit Care Med 28:3547-3554
2. Shelly MP, Lloyd GM, Park GR (1988) A review of the mechanisms and methods of humi-
dification of inspired gases. Intensive Care Med 14:1-9
3. Negus VE (1952) Humidification of the air passages. Thorax 7:148-151
4. Cole P (1954) Respiratory mucosal vascular responses, air conditioning and thermoregula-
tion. J Laryngeal Tool 68:613-622
5. Chatburn RL, Primiano FP Jr (1987) A rational basis for humidity therapy. Respir Care
32:249-254
6. Shelly MP (1992) Conditioning of inspired gases. Respir Care 37:1070-1080
7. Walker JEC, Wells RE, Merril EW (1961) Heat and water exchange in the respiratory tract.
Am J Med 30:259-264
8. American Thoracic Society (2001) International Consensus Conferences in intensive care
medicine: noninvasive positive pressure ventilation in acute respiratory failure. Am J Respir
9. Kallstrom TJ (2002) AARC Clinical practice guidelines: oxygen therapy for adults in the
acute care facility-2002 revision and update. Respir Care 47:717-720
10. Green ID, Nesarajah MS (1968) Water vapor pressure of end tidal air of normals and
chronic bronchitis. J Appl Physiol 24:229-231
11. Caldwell PRB, Gomez DM, Fritts HW (1969) Respiratory heat exchange in normal subjects
and in patients with pulmonary disease. J Appl Physiol 26:82-88
12. Primiano FP Jr, Saidel GM, Montague FW Jr, Kruse KL, Green CG, Horowitz JC (1988)
Water vapor and temperature dynamics in the upper airways of normal and CF patients.
Eur Respir J 1:407-414
13. Jackson C, Webb A (1992) An evaluation of the heat and moisture performance of four
ventilator circuit filters. Intensive Care Med 12:975-977
14. Anonymous (1984) American College of Chest Physicians - National Heart Lung and
Blood Institute- National conference on oxygen therapy. Chest 86:234-237
15. American Association for Respiratory Care and Clinical Practice Guideline (1991) Oxygen
therapy in the acute care. Respir Care 36:1410-1413
16. Campbell EJ, Baker D, Silver PC (1988) Subjective effects of humdification of oxygen for
delivery by nasal cannula. A prospective study. Chest 2:289-293
17. Lasky MS (1982) Bubble humidifiers are useful-Fact or myth? Respir Care 27:735-736
18. Estey W (1980) Subjective effects of dry versus humidified low flow oxygen. Respire Care
25:1143-1144
19. Golar SD, Sutherland LLA, Ford CT (1993) Multipatient use of prefilled disposable oxygen
humidifiers for up to 30 days: Patient safety and cost analysis. Respir Care 38:343-347
20. Ahlgren EW, Chapel JF, Dorn GL (1977) Pseudomonas aeruginosa infection potential of
oxygen humidifier devices. Respir Care 22:383-385
21. Wood KE, Flaten AL, Backes WJ (2000) Inspissated secretions. A life threatening complica-
tion of prolonged noninvasive ventilation. Respir care 45:491-493
22. Togias AG, Naclerio RM, Proud D, et al (1985) Nasal challenge with cold, dry air results in
released of inflammatory mediators. Possible mast cell involvement. J Clin Invest 76:1375-
1381
23. Takayagi Y, Proctor DF, Salman S, Evering S (1969) Effects of cold air and carbon dioxide
on nasal air flow resistance. Ann Otol Rhino Laryngol 78:40-48
24. Richards GN, Cistulli PA, Ungar RG, Berthon-Jones M, Sullivan CE (1996) Mouth leak with
nasal continuos positive airway pressure increases nasal airway resistance. Am J Respir
Crit Care 154:182-186
25. Martins de Araujo MT, Vieira SB, Vasquez EC, Fleury B (2000) Heated humidifcation or
fac mask to prevent upper airway dryness during continuous positive airway pressure ther-
apy. Chest 117:142-147
26. Navalesi P, Fanfulla F, Frigerio P, Gregoretti C, Nava S (2000) Physiologic evaluation of
noninvasive mechanical ventilation delivered with three types of masks in patients with
chronic hypercapnic respiratory failure. Crit Care Med 28:1785-1790
27. Antonelli M, Conti G (2000) Noninvasive ventilation in intensive care unit patients. Curr
Opin Crit Care 6:11-16
28. Meduri GU, Turner RE, Abou-Shala N, Wunderink R, Tolley E (1996) Non invasive positive
pressure ventilation via face mask. First line intervention in patients with acute hypercap-
nic and hypoxemic respiratory failure. Chest 109:179-193
29. Criner G, Travaline JM, Brennan KJ, Kreimer D (1994) Efficacy of a new full face mask for
noninvasive positive pressure ventilation. Chest 106:1109-1115
30. Kramer N, Meyer TJ, Meharg J, Cece RD, Hill N (1995) Randomized prospective trial of
non-invasive positive pressure ventilation in acute respiratory failure. Am J Respir Crit
Care Med 151:1799-1806
31. Antonelli M, Conti G, Pelosi P, et al (2002) New treatment of acute hypoxemic respiratory
failure: Non invasive pressure support ventilation delivered by helmet. A pilot controlled
trial. Crit Care Med 30:602-608
32. Lellouche F, Maggiore SM, Deye N (2002) Effect of the humidification device on the work
of breathing during noninvasive ventilation. Intensive Care Med 28:1582-1589
33. Jaber S, Chanques G, Matecki S, et al (2002) Comparison of the effects of heat and moist-
ure exchangers and heated humdifiers on ventilation and gas exchange during non-invasive
ventilation. Intensive Care Med 28:1590-1594
Recent Innovations in Mechanical Ventilatory Support
N. Macintyre
Introduction - The Need for Innovations

Mechanical ventilation has been used successfully for decades to support gas ex-
change in patients with respiratory failure. The technology, however, is not without
risks and innovations in our use of mechanical ventilation are needed. Among the
most serious problems is the risk of ventilator-induced lung injury (VILI) from
both mechanical processes and oxygen toxicity [1]. Other significant problems as-
sociated with mechanical ventilatory support are ventilator-associated pneumonias
(VAP}, patient-ventilator synchrony, iatrogenic weaning delays, and costs [2].
Over the last few years, a number of innovations have been introduced to ad-
dress these issues. Some appear to have real value, some are theoretically attractive
but need further investigation, and some have been little more than a marketing-
driven innovation with little real clinical utility. In the sections below, a number of
these innovations are reviewed and their clinical utility assessed.
I Innovative Strategies for 'Lung Protection'

There are a number of recently introduced approaches to the management of acute
respiratory failure that are designed to reduce VILI. Some are available on conven-
tional ventilators (airway pressure release ventilation, pressure-regulated volume
control, volume support) and some require special equipment (tracheal gas insuf-
flation [TGI]) or a special ventilator (high frequency ventilation [HFV]).
Airway Pressure Release Ventilation - APRV (Also Known as Biphasic

Ventilation, Bilevel Ventilation and Bilevel Positive Airways Pressure [BiPAP])
APRV is a time-cycled, pressure-targeted form of ventilatory support [3, 4]. It dif-
fers from conventional pressure control in that a pressure release mechanism allows
spontaneous breathing to occur during both the inflation and deflation phases
(Fig. 1). Generally, APRV is used in a strategy of long inspiratory time ventilation
and has sometimes been termed 'continuous positive airways pressure (CPAP) with
release' or 'upside down intermittent mandatory ventilation (IMV)'. The putative
advantages of this approach are that:
the long inflation phase recruits more slowly filling alveoli and raises mean air-
way pressure without increasing applied positive end-expiratory pressure (PEEP,
although intrinsic PEEP can develop with short deflation periods) - in this sense
it is similar in concept to older forms of inverse ratio ventilation (IRV) [5-7].
Recent Innovations in Mechanical Ventilatory Support 265
~
::>
"'"'~
a..
k=
Ventilator
triggered
L/ \ "
Patient
triggered
~
Qj
E
::>
~~
g
;:
0
u::
Fig. 1. Airway pressure, flow and volume tracings over time during APRV. Note that spontaneous breaths
can occur during the long inflation phase of this mode.
I the additional spontaneous efforts during inflation may enhance both recruit-
ment and cardiac filling as compared to other controlled forms of support [8].
I the availability of spontaneous breath may make APRV more tolerable to pa-
tients than pressure- or volume-controlled IRV. Although IRV strategies are
usually reserved for very severe forms of respiratory failure in which airway
pressures and Fi0 2 levels are approaching potentially injurious levels, the com-
fort and recruitment potential associated with APRV may prompt consideration
of its use in less severe forms of lung injury.
Good gas exchange, often with lower maximal airway pressures than control venti-
lation, has been demonstrated with APRV in several small observational clinical
trials [3]. However, the end inspiratory lung distention in APRV may not be neces-
sarily less than that provided during other forms of support (and, indeed, could be
substantially higher) since spontaneous tidal volumes can occur while the lung is
fully inflated with the APRV set pressure. Outcomes have not been routinely as-
sessed in most of these trials although the most recent suggested benefit of APRV
compared to a pressure control mode strategy [4]. However, this observation is
open to criticism because of small patient numbers, the fact that the control pa-
tients were 'sicker' (i.e., had more acute respiratory distress syndrome [ARDS]),
and different patient management strategies (e.g., routine paralysis was given for
three days in the control group). Perhaps more importantly, the control group was
not ventilated with settings consistent with the current standard of care - the ARDS
Network trial [9] .
266 N. Macintyre
Pressure-Regulated Volume Control (PRVC)

This mode is pressure-targeted, time-cycled ventilation which uses tidal volume
(VT) as a feedback control for continuously adjusting the pressure limit [10]. The
clinician is required to set a VT target and the ventilator will then automatically set
the inspiratory pressure within a clinician set range to achieve these goals. The
ventilator will alarm if the tidal volume and maximum pressure limit settings are
incompatible.
These breaths conceptually combine the enhanced gas mixing and patient venti-
lator synchrony effects of a pressure targeted breath with a certain volume guaran-
tee. Moreover, PRVC will automatically reduce applied inspiratory pressure as respi-
ratory system mechanics improve. However, it is important to realize that providing
a volume guarantee negates the absolute pressure limiting feature of a clinician set
pressure control level (i.e., worsening respiratory system mechanics will drive ap-
plied pressures up). Another potential problem with PRVC is that during assisted
breaths, if the patient's demand increases and produces a larger VT> the pressure
level will diminish, a change that may not be appropriate for a patient in respira-
tory failure.
True randomized controlled trials with PRVC using the ARDS Network protocol
[9] as the gold standard do not exist. At the present time, then, PRVC use is based
primarily on the physiologic concepts and theoretical advantages noted above.
Tracheal Gas Insufflation

TGI is the use of a catheter placed at the distal end of the endotracheal tube to pro-
vide fresh gas to flush the endotracheal tube free of C0 2 during exhalation [11].
The concept is that the next delivered breath will effectively be free of endotracheal
tube C0 2 and thus will have an effectively reduced dead space. This approach has
particular appeal during lung protective ventilatory strategies in which the PaC0 2
is rising. A number of studies have shown that the TGI concept accomplishes this
physiologic goal (i.e., reduced dead space) but there is the potential for an inadver-
tent PEEP to build up [11].
TGI catheters can deliver fresh gas either continuously or just during exhalation.
The former approach is easier to implement but the latter reduces the potential for
excessive end-inspiratory over inflation. TGI catheters can also be designed to deli-
ver gas directly into the lung or in a retrograde fashion back up the endotracheal
tube. The former enhances gas mixing but the latter reduces inadvertent PEEP
buildup. At the present time it is unclear what the best way to deliver TGI is or
whether TGI can significantly affect outcome. Clearly, however, TGI systems need to
have safeguards to protect the lung from inadvertent overdistention [11].
High Frequency Ventilation

HFV uses very high breathing frequencies (120-300 breaths per minute in the
adult) coupled with very small VT (often less than anatomic dead space) to provide
gas exchange in the lungs [12]. Gas transport under these seemingly unphysiologic
conditions involves such mechanisms as Taylor dispersion, coaxial flows, and aug-
mented diffusion [13]. HFV can be supplied by either jets or oscillators. Jets inject
high frequency pulses of gas into the airways. Oscillators literally vibrate a fresh
bias flow of gas delivered at the tip of the endotracheal tube [14].
The putative advantages to HFV are two-fold. First, the high gas flow provides
for considerable intrinsic PEEP (iPEEP) and thus alveolar recruitment. This is par-
ticularly effective following recruitment maneuvers. Second, the very small tidal
pressure swings keep the lung well below the overdistention thresholds. Because of
these features, HFV has sometimes been considered the 'ultimate' lung protection
strategy [14, 15].
Clinical experience with HFV has been most extensive in the neonatal and pe-
diatric literature [12, 16]. Recent studies have suggested that in neonates at risk for
overdistention injury, HFV improves outcome [14]. Adult experience is less as only
recently have HFV devices been available to adequately support gas exchange in
this setting [17]. A recently completed study using HFV in adults with severe ARDS
showed a borderline improvement in mortality over conventional ventilation [18].
Automated Weaning Strategies
Over the years, a number of attempts have been made to 'automate' the weaning
process [19]. An example is minimum minute ventilation (MMV) which adjusts the
intermittent mandatory breath rate according to the level of spontaneous ventila-
tion. The concept underlying these attempts was that significant clinician time
could be saved and appropriate ventilatory support reductions based on simple
ventilator measurements could be done in a timely fashion. Good clinical data sup-
porting this notion, however, do not exist [19].
Volume support is the latest of these strategies with the potential for automatic
support reduction [10]. Volume support is a dual control breath-to-breath-pressure
support mode that uses VT as a feedback control for continuously adjusting the
pressure support level. All breaths are patient triggered, pressure limited, and flow
cycled but clinicians select a target VT. Depending on the specific algorithm em-
ployed, automatic adjustments in inspiratory pressure are made by the ventilator
within a clinician prescribed range.
Proponents claim that this approach could 'automatically' wean a patient by
reducing pressure support as patient effort increases and respiratory system
mechanics improve. Conversely, pressure support would increase if patient effort
diminished or respiratory system mechanics worsened. Similarly, it has also been
suggested that volume support may be a useful way to maintain a more constant
level of partial support in patients with fluctuating levels of effort related to drugs
or neurological conditions. All of these effects have been demonstrated in small
studies focused on patients with rapidly recovering respiratory failure [10].
Unfortunately, the simplicity of volume support may produce problems. For in-
stance, if the clinician set volume is excessive for patient demand, a recovering pa-
tient may not attempt to take over the work of breathing for that volume and thus
support reduction and weaning may not progress. In addition, if the pressure level
increases in an attempt to maintain an inappropriately high set VT in the patient
with airflow obstruction, iPEEP may result. On the other hand, a patient may re-
ceive inadequate support if the clinician set VT is not adequate for patient demand.
Under these conditions, a patient will perform excessive work to maintain a certain
VT all the while the inspiratory pressure is being reduced because it exceeds the
clinician setting.
Although no outcome studies have been performed using volume support, there
are specific clinical situations where there may be some utility (e.g., fluctuating pa-
268 N. Macintyre
tient demand, rapidly recovering patient). However, clinicians need to be aware of

the behavior of volume support under a variety of circumstances to properly use
this mode.
I Optimizing Synchrony During Interactive Breaths
Interactive breaths are commonly used during mechanical ventilatory support to im-
prove comfort (and reduce sedation), especially during the recovery phase of respira-
tory failure. Interactive breaths need to be synchronous with patient efforts during all
three phases of breath delivery: trigger, flow delivery, and cycle [20]. To this end, a
number of recent innovations have been introduced and are reviewed below.
It must be realized that while all of these innovations have conceptual appeal
and have been shown to perform as designed in both bench testing and small clini-
cal observational trials, patient outcomes including sedation needs, ventilator days,
or patient comfort assessments have not been done. Nevertheless, their straightfor-
ward designs, ease of operation, and safety make them appropriate to consider in
patients receiving interactive breaths.
Automatic Tube Compensation (ATC)

The endotracheal tube provides a measurable resistance to flow during both in-
spiration and expiration. During the inspiratory phase, this means that pressure
buildup in the airways 'lags' behind the pressure buildup in the ventilator circuity.
Thus, the 'square' wave of pressure in the circuitry provided by a pressure-targeted
breath is distorted to a slower linear rise to pressure in the airways. This may
create significant initial flow dys-synchrony in patients with vigorous inspiratory
efforts. During expiration, a similar gradient between airway pressures and set cir-
cuit PEEP can develop.
One way to address this is to target ventilator pressures to a measured tracheal
pressure beyond the endotracheal tube. Unfortunately, the reliability of intra-airway
pressure sensors over prolonged periods is not good. Another approach is to math-
ematically account for endotracheal tube resistance in the ventilator flow delivery
pattern [19, 21]. This tends to create a decelerating pattern of delivered inspiratory
airway pressure and an initial expiratory airway pressure below the set PEEP. A
squarer wave pattern of inspiratory and expiratory tracheal pressures is the result.
Applying ATC is relatively straightforward. Clinicians must initially input endo-
tracheal tube characteristics. Thereafter, the ventilator automatically provides the
appropriate circuit pressure profile during both inspiration and expiration to create
the desired square wave pattern in the trachea. Although outcome studies using
ATC have not been done, the conceptual appeal should make it a consideration in
virtually all patients receiving assisted/supported pressure-targeted breaths - espe-
cially those with vigorous inspiratory efforts.
Pressure-Targeted Inspiratory Pressure Slope Adjusters

The original design for pressure targeted-breaths (pressure support and pressure
assist-control) had a programmed flow delivery algorithm that attempted to reach
the target inspiratory pressure quickly, without causing a discomforting overshoot.
Newer ventilators, however, have developed the ability for clinicians to adjust this
pressure rate of rise (slope adjusters) and clinical studies have suggested that this
could significantly enhance flow synchrony in many patients [22]. Specifically, these
studies found that a rapid rate of rise was often desired in a patient with vigorous
flow demands while a much slower rate of rise was often preferable in patients with
less vigorous demands.
There are several approaches to setting the slope adjuster. The most direct way
is to use the airway pressure graphic and adjust the slope to create a 'smooth
square wave' appearance to the airway pressure profile. Studies have also shown
that an optimal slope setting correlates with the greatest VT for a given pressure
setting [22]. Patient comfort should always be considered in determining optimal
slope settings.
Pressure Support Cycle Adjusters

Cycle dys-synchrony has recently been recognized as an issue with the flow cycling
mechanism of pressure support. On earlier machines, a set flow criteria was usually
manufacturer determined (e.g., 25-35% of peak flow). While this was often effective
in most patients, it could sometimes terminate breaths too early in patients with
long inspiratory demands, or too late, typically in patients with obstructive airway
disease. In this latter situation, air trapping could also be made worse because of
the resulting shorter expiratory time.
There are several approaches to improving cycle synchrony with pressure sup-
port. One is to switch from pressure support to a pressure assist breath (patient
triggered, pressure targeted, time-cycled breath - usually available on most ma-
chines providing pressure ACV if the set rate is turned low or off). This breath pro-
vides direct clinician control of inspiratory time and thus cycling. Another strategy
is to adjust the pressure slope setting described above on pressure support breaths.
A very rapid peak initial flow will have a correspondingly high flow cycle variable
(and thus short inspiratory time); a very slow peak initial flow will have a corre-
spondingly low flow cycle variable (and thus long inspiratory time).
A newer, more direct approach, however, is to actually allow adjustments of the
pressure support cycle flow criteria to assure appropriate synchrony of the cycle
with the end of patient effort. As with other adjustments of interactive breaths, air-
way pressure graphics and assessments of patient comfort should guide adjust-
ments. Proper breath synchrony is characterized by a comfortable patient and no
evidence on the airway pressure graphic of expiratory effort during inspiration (de-
layed cycle) or continued inspiratory effort after cycling (premature cycling).
Although no outcome studies have been performed using these cycle adjusters,
their physiological appeal, ease of use, and apparent safety should make them a
consideration in virtually every patient receiving pressure support.
Proportional Assist Ventilation (PAV)

PAV is a novel approach to assisted ventilation that uses a clinician set 'gain' on pa-
tient-generated flow and volume [23]. It, thus, does not apply a set pressure, flow,
or volume. Instead, it boosts the sensed patient effort according to a clinician set
proportion. The greater the patient effort, the greater the delivered pressure, flow,
and volume. This contrasts with volume assist where flow and volume are not af-
270 N. Macintyre
fected by effort and where, in fact, applied pressure may be 'pulled down' by effort.
PAV also contrasts with pressure assist/support where flow and volume are affected
by effort but pressure is not.
PAV has been compared to other forms of assisted ventilation and has been
found to be comparable in terms of muscle unloading and patient comfort in clini-
cally meaningful settings [24]. An invasive and non-invasive (i.e., mask ventilator)
version of PAV will be available shortly. Whether PAV improves clinical outcomes
remains to be determined.
I Conclusion
Mechanical ventilatory support is a critical component of the management of pa-
tients with respiratory failure. It must always be remembered, however, that this
technology is supportive - not therapeutic. It cannot cure lung injury. Indeed, the
best we can hope for is that it will 'buy time' by supporting gas exchange without
harming the lungs.
There are exciting innovations on the horizon. They must be assessed properly,
however. This is particularly important for innovations with significant risks and!
or costs. Only with properly conducted studies with such clinically relevant out-
comes as mortality, ventilator-free days, barotrauma, and costs can we properly
assess the sometimes bewildering array of new approaches to this vital life support
technology.
References
1. Dos Santos CC, Slutsky AS (2000) Mechanisms of ventilator induced lung injury: a per-
spective. J Appl Physiol 89:1645-1655
2. Fulkerson W, Macintyre NR (1991) Complications of Mechanical Ventilation. Problems in
Respiratory Care, Vol 4. Lippincott, Philadelphia
3. Stock MC, Downs JB, Frolicher DA (1987) Airway pressure release ventilation. Crit Care
Med 15:462-466
4. Putensen C, Zech S, Wrigge H, et al (2001) Long term effects of spontaneous breathing
during ventilatory support in patients with ALI. Am J Respir Crit Care Med 164:43-49
5. Armstrong BW, Macintyre NR (1995) Pressure controlled inverse ratio ventilation that
avoids air trapping in ARDS. Crit Care Med 23:279-285
6. Cole AGH, Weller SF, Sykes MD (1984) Inverse ratio ventilation compared with PEEP in
adult respiratory failure. Intensive Care Med 10:227-232
7. Tharratt RS, Allen RP, Albertson TE (1988) Pressure controlled inverse ratio ventilation in
severe adult respiratory failure. Chest 94:755-762
8. Kuhlen R, Rossaint R (2002) The role of spontaneous breathing during mechanical ventila-
tion. Respir Care 47:296-303
9. NIH ARDS Network (2000) Ventilation with lower tidal volumes as compared with tradi-
tional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N
Engl J Med 342:1301-1308
10. Branson RD, Macintyre NR (1996) Dual control modes of mechanical ventilation. Respir
Care 41:294-305
11. Hess DR, Macintyre NR (2001) Tracheal gas insuftlation: overcoming obstacles to clinical
implementation. Respir Care 46:198-199
12. Froese AB, Bryan C (1987) High frequency ventilation. Am Rev Respir Dis 135:1363-1374
13. Chang HK (1984) Mechanisms of gas transport during high frequency ventilation. J Appl
Physiol 56:553-563
14. Macintyre NR (1994) High frequency ventilation. In: Tobin M (ed) Mechanical Ventilation:
Principles and Practice. McGraw-Hill, New York, pp 455-460
15. Froese AB (1998) High frequency oscillatory ventilation for ARDS: let's get it right this
time. Grit Care Med 25:906-908
16. Keszler M, Donn SM, Bucciarelli RL, et al (1991) Multicenter controlled trial comparing
HFJV and conventional mechanical ventilation in newborns with PIE. J Pediatr 119:85-93
17. Mehta S, Lapinsky SE, Hallett DC, et al (2001) Prospective trial of high frequency oscilla-
tion in adults with acute respiratory distress syndrome. Grit Care Med 29:1360-1369
18. Derdak S, Mehta S, Stewart TE, Smith T, et al (2002) High frequency oscillatory ventilation
for ARDS; a randomized controlled test. Am J Respir Grit Care Med 166:801-808
19. ACCP/AARC/SCCM Task Force (2001) Evidence based guidelines for weaning and discon-
tinuing mechanical ventilatory support. Chest 120 (suppl 6}:375S-395S
20. Macintyre NR (1997) Patient ventilator interactions: dys-synchrony and imposed loads. In:
Marini J, Slutsky A (eds) Physiologic Basis of Ventilatory Support. Marcel Dekker, New
York, pp 183-188
21. Fabry B, Zappe D, Guttman J (1997) Breathing pattern and additional work of breathing in
spontaneously breathing patients with different ventilatory demand during inspiratory
pressure support and automatic tube compensation. Intensive Care Med 23:545-552
22. Ho L, Macintyre NR (1991) Effects of initial flow rate and breath termination criteria on
pressure support ventilation. Chest 99:134-138
23. Younes .M (1992) Proportional assist ventilation, a new approach to ventilatory support.
24. Grasso S, Ranieri VM (2001) Proportional assist ventilation. Respir Care Clin N Am 7:465-
473
Expiratory Flow Limitation
in Mechanically Ventilated Patients
A. Koutsoukou, C. Roussos, and J. Milic-Emili
I Introduction
The highest pulmonary ventilation that a subject can achieve is ultimately limited
by the highest flow rates that can be generated. Most normal subjects and endur-
ance-trained athletes do not exhibit expiratory flow limitation even during maximal
exercise [1, 2]. In contrast, patients with chronic obstructive pulmonary disease
(COPD) may exhibit expiratory flow limitation even at rest, as first reported by
Hyatt [1]. This is based on the observation that, even at rest, many patients with
severe COPD often breathe tidally along their maximal expiratory flow-volume
(MEFV) curve (Fig. 1) [3]. The presence of expiratory flow limitation during tidal
breathing promotes dynamic hyperinflation with a concurrent increase in inspira-
tory work, functional impairment of inspiratory muscles, and adverse effects on he-
modynamics and dyspnea [4, 5]. It also plays a central role in causing acute ventila-
tory failure.
Normal Airways obstruction
400
t 300
."
ci
200
100
!:£
_gE 0
u..6
100
~ 200
.s
! 300
400
r--1
t
Full expir" 0.51 Full inspir"
Volume
Fig. 1. Flow-volume curves obtained from a normal subject and a COPD patient at rest (- - - -) and max-
imal exercise (····) are compared with maximum flow-volume loops (-). Positive values of flow indicate
expiration and negative values inspiration. (From [3] with permission)
However, recent studies have shown that expiratory flow limitation may be pre-
sent not only in patients with acute exacerbation of COPD but also in intensive
care unit (ICU) patients without airway obstruction [6], especially those with the
acute respiratory distress syndrome (ARDS) [7, 8].
I Dynamic Hyperinflation
In normal subjects at rest, the end-expiratory lung volume (functional residual ca-
pacity, FRC) corresponds to the relaxation volume (Vr) of the respiratory system,
i.e., the lung volume at which the overall elastic recoil pressure of the respiratory
system is zero [9]. Pulmonary hyperinflation is defined as an increase in FRC
above the predicted normal value, which may be due to: a) increased Yr as a result
of loss of lung recoil (e.g., emphysema) and b) dynamic hyperinflation, which is
said to be present when FRC exceeds Yr [5]. Dynamic hyperinflation exists when
the duration of expiration is insufficient to allow the lungs to deflate to Yr prior to
the next inspiration. In mechanically ventilated patients this tends to occur under
conditions in which expiratory flow is impeded because of increased respiratory
system resistance and/or the high resistance offered by the endotracheal tubes and
expiratory circuit of the ventilator [10], or when the expiratory time is short (e.g.,
increased breathing frequency or liE ratio), or when ventilation is increased [6]. In
patients with airway obstruction, however, dynamic hyperinflation is in general
due mainly to expiratory flow limitation [5, 11, 12].
I Expiratory Flow Limitation

Definition
The term expiratory flow limitation should be used only for describing a condition
in which the expiratory flow cannot augment by increasing the transpulmonary
pressure at a given lung volume [5, 11]. Thus, expiratory flow limitation is axiomat-
ically present in normal subjects, as well as patients with respiratory disorders,
during a correctly performed forced expiratory vital capacity maneuver in which,
after the peak flow, the flow can not be increased by greater expiratory effort and,
thus, is maximal (Vmax) [13]. Expiratory flow limitation implies dynamic compres-
sion of the airways which during a forced vital capacity maneuver is initially con-
fined to the trachea and main bronchi but at low lung volume extends into the
peripheral airways [14].
While in normal subjects expiratory flow limitation is absent even during maxi-
mal exercise, in patients with respiratory disorders it may be present at rest. The
presence of expiratory flow limitation during tidal breathing implies cyclic com-
pression and re-expansion of peripheral airways with concurrent shear stresses in
the peripheral airway which may cause low lung volume injury [7, 8]. Furthermore,
because of surface tension phenomena and lack of structural support (cartilage),
the dynamically compressed peripheral airways may close with a liquid plug and
reopen again on inflation at a considerably higher transmural pressure than at
which closure occurred [15]. If this is valid, tidal expiratory flow limitation should
promote peripheral airway closure, and, therefore, expiratory flow limitation and
"closing volume" should reflect closely related phenomena [7].
274 A. Koutsoukou et al.
Pathophysiology of Expiratory Flow Limitation

Several mechanisms may contribute to the occurrence of tidal expiratory flow lim-
itation: a) decreased lung volume; b) decreased Ymax; and c) increased ventilatory
demand. As shown in Fig. 1, Vmax decreases with decreasing lung volume. As a re-
sult, any reduction in FRC, as observed for example in gross obesity, is axiomati-
cally associated with a decrease of Vmax in the tidal volume range, which promotes
presence of expiratory flow limitation during tidal breathing [16]. Similarly, shifting
from sitting to decubitus position also promotes expiratory flow limitation, as a
result of the concurrent decrease in FRC [5, 11, 17].
As shown in Fig. 1 (right), a decrease in Vmax is a characteristic feature of
COPD. Indeed, stable COPD patients exhibit a high prevalence of tidal expiratory
flow limitation, particularly in the supine position [5]. In acute exacerbation, most
mechanically ventilated COPD patients exhibit tidal expiratory flow limitation,
which indeed is the main cause of dynamic hyperinflation and concurrent ventila-
tory failure [6, 10, 18].
As in COPD, the maximal expiratory flows available in the tidal volume range
are also decreased in ARDS because of a reduction in functional lung units due to
flooding with edema fluid, atelectasis, and peripheral airway closure [7, 8]. In fact,
Gattinoni et al. [19] have aptly stated that ARDS patients have "baby lungs": as a
result, normal adult ventilatory requirements are necessarily associated with tidal
expiratory flow limitation in these patients.
Increased ventilation promotes expiratory flow limitation both during sponta-
neous breathing [11] and mechanical ventilation because of greater flow require-
ments.
I Assessment of Expiratory Flow Limitation during Mechanical Ventilation
Recently, the negative expiratory pressure method has been introduced to detect
expiratory flow limitation in mechanically ventilated patients [10]. It consists of
applying a small negative pressure (about -5 cmH 2 0) during tidal expiration, thus
widening the pressure gradient between the alveoli and the airway opening. In ab-
sence of expiratory flow limitation, with negative expiratory pressure there is an in-
crease in expiratory flow compared to the preceding control breath (Fig. 2). In con-
trast, in the presence of expiratory flow limitation the expiratory flow does not in-
crease throughout the entire or part of the tidal expiration over that of the preced-
ing control expiration. The negative expiratory pressure method, which has been
validated using iso-volume flow-pressure curves, does not require cooperation from
the subjects [10]. A ventilator with an in-built negative expiratory pressure device,
which allows on-line assessment of expiratory flow limitation, has been constructed
by Draeger, Lubeck, Germany [6-8].
I Clinical Implications of Expiratory Flow Limitation
Although it is well known that expiratory flow limitation promotes dynamic hyper-
inflation and intrinsic positive end-expiratory pressure (PEEPi) with concomitant
increase in work of breathing, impairment of inspiratory muscle function, dyspnea
100
r-..
"'-.. #2 ...... ....... #1 1
r--.
so ..._
' "' -...... "
- "' '\.
~ Exp.
'2
·......e ......
0
;::
0
EFL = 35 % Vr non EFL -
u::
Insp.
-50
-100
Volume 0.51
Fig. 2. Flow-volume loops of negative expiratory pressure (NEP) test breath and preceding control breath
for two representative ARDS patients on ZEEP, one with expiratory flow limitation (EFL) exceeding 35% of
control Vr {left) and the other without EFL (right). Thin lines: control breaths; heavy lines: NEP breaths. In
the EFL patient, onset of EFL is heralded by an inflection point on the expiratory flow-volume curve (ar-
row). On-line records from an Evita 2 screen (Draeger, Lubeck, Germany). (From [7] with permission)
and adverse effects on hemodynamics, tidal expiratory flow limitation is seldom as-
sessed in mechanically ventilated patients because the conventional method to de-
tect expiratory flow limitation based on comparison of maximal and tidal expira-
tory flow-volume curves is not feasible in the ICU. As a result, therapy that may re-
duce expiratory flow limitation (e.g., bronchodilators) is not always administered to
the appropriate patients [20]. Patients who have expiratory flow limitation are diffi-
cult to wean because of high values of PEEPi [21]. In such patients, administration
of external PEEP has been suggested as a therapeutic modality to reduce the work
of breathing [22, 23]. External PEEP, however, is beneficial in offsetting PEEPi only
in patients with significant airway obstruction [24, 25], and should not be applied
without evidence of expiratory flow limitation [4].
The presence of tidal expiratory flow limitation promotes regional inequality of
PEEPi within the lung because expiratory flow limitation implies non-homogeneous
lung emptying because during expiration dynamic compression of peripheral air-
ways is preferential in dependent lung zones as a result of the vertical pleural pres-
sure gradient. As a result, ARDS patients who have expiratory flow limitation have
significantly higher PEEPi inhomogeneity than ARDS patients who do not have
expiratory flow limitation, based on measurement of PEEPi inequality index (8].
Administration of external PEEP sufficient to balance static PEEPi to expiratory
flow limitation patients not only reduces the regional PEEPi inequality but may also
improve the arterial oxygenation in the absence of a significant increase in end-
expiratory lung volume and alveolar recruitment [8].
Measurement of expiratory flow limitation and PEEPi is also useful in assessing
the effects of bronchodilators and changes in body posture on dynamic hyperinfla-
tion and PEEPi inequality index [18, 26, 27].
I Low Lung Volume Injury

In 1984, Robertson [28) suggested that ventilation at low lung volumes may cause
lung injury as a result of shear stresses caused by cyclic opening and closing of
peripheral airways. Using an ex-vivo model of lavaged rat lung Muscedere et al.
[29] showed that ventilation with physiologic tidal volumes at zero end-expiratory
pressure (ZEEP) resulted in a significant increase of injury scores in the respiratory
(RIS) and membranous bronchioles (MIS) relative to ventilation from PEEP above
the lower inflection point (LIP) on the static inflation volume-pressure curve of the
lung. Significant increases in RIS and MIS, as well as increased airway resistance,
have been found recently in normal open-chest rabbits ventilated with constant
flow inflation mode at ZEEP for 3-4 hours [30]. Since in these rabbits there was no
evidence of atelectasis, the airway injury was probably due entirely to cyclic open-
0.00 Integ P = Inspect
0.00
0~-.--~~~-r~r==T~~~~
0 2 3 4 5 6 7 8 9
0.00 Integ F (ml): Inspect
--"'3:
0
u::
0 2 3 4 s 6 7 8 9
0.00 Integ V = Inspect

800 ~--------------------------------
~ 600 +--..,.-~---------j=;------F"'\-----
l
~ 400 +--7-~---.r-r-----r-~---
:::J
g 200 +-~--~--r--~----+--~-~0.00
0 2 3 4 5 6 7 8 9
Fig. 3. Recordings of pressure at airway opening (Pawl. flow, and volume in an ARDS patient with zero
PEEP. At the onset of inflation there is a rapid increase in Paw to 30 em H20
ing and closing of peripheral airways. The authors of this study also suggested that
the low-volume ventilator induced lung injury (VILI) observed in the rabbits was
related to the rapid swing in pressure delivered by the ventilator at the onset of
constant flow inflation, with concurrent increase in shear stresses caused by peri-
pheral airway compression and closure. In this connection it should be noted that
while low-volume VILI elicits peripheral airway damage, high-volume VILI causes
parenchymal pulmonary damage similar to ARDS (i.e., non-cardiogenic pulmonary
edema) [31, 32].
Cyclic peripheral airway closure and reopening probably also occurs in ARDS
patients because they breathe at low lung volume. This, together with the reduction
of functional lung units ("baby lung"), promotes tidal expiratory flow limitation
which implies cyclic compression and re-expansion of the peripheral airways with
concurrent inhomogeneous filling of airspaces. In fact, using the negative expira-
tory pressure technique, it has been recently shown that at ZEEP many ARDS pa-
tients exhibit expiratory flow limitation with concurrent PEEPi [7, 8]. In the inho-
mogeneous ARDS lungs, expiratory flow limitation entails development of high
shear forces with risk of low-volume VILI [29, 30]. In this connection it should be
noted that, during mechanical ventilation with constant inflation flow, the rapid in-
crease in airway pressure at the onset of lung inflation is, in general, in the order
of 25- 50 cmH 20 (Fig. 3), which must enhance the shear forces developed within
the lung. With decelerating inflation flow, the increase in airway pressure at the on-
set of lung inflation should be even greater than with constant-flow inflation, with
greater risk of VILI. In contrast, with a sinusoidal inspiratory flow profile, the pres-
sure applied by the ventilator should increase more gently and hence there is possi-
ble reduction of risk of barotrauma. It should be noted, however, that the actual
pressure transients applied at the periphery of the lung depend not only on the
pressure delivered at the airway opening but also on the transmission of these pres-
ZEEP PEEP 10
100
'-
so " ,' _.,. _ '-
'-
~Exp. -....;."',.
.........
'"' '
FL =36%Vr NFL -
h
f-lnsp.
-SO
No.2
-100
Volume 0.51
Fig. 4. Flow-volume loops of control and negative expiratory pressure (NEP) test breaths of an ARDS pa-
tient on zero end-expiratory pressure (ZEEP, left) and positive end-expiratory pressure (PEEP) of 10 cmH 20
(right). On ZEEP, expiratory flow limitation (EFL) amounted 36% of tidal volume (V1) and is heralded by
an inflection point (arrow). With PEEP, EFL is abolished. On-line records from .Evita 2 screen. NFL, nonflow-
limited; INSP. inspiration. (From [8] with permission)
sure impulses to the lung periphery, i.e., on the time constant of transmission
which depends both on the resistance offered by the airways and endotracheal tube
and the regionally inhomogeneous pulmonary mechanics [33]. This difficult aspect
of VILI requires further studies.
To avoid low-volume VILI, external PEEP has to be applied in order to increase
the end-expiratory lung volume above the expiratory flow limitation volume
(Fig. 4). Such therapeutic levels of PEEP can be readily determined by on-line in-
spection of the effect of negative expiratory pressure on the expiratory flow-volume
loops: PEEP should be increased until tidal expiratory flow limitation disappears
[7]. Risk of low-volume VILI may not be confined to ARDS but could be present in
all patients who exhibit expiratory flow limitation during mechanical ventilation,
such as morbidly obese subjects [16, 26]. In such individuals, administration of ex-
ternal PEEP may not only abolish expiratory flow limitation but also improve gas
exchange [34].
I Conclusion
Detection of expiratory flow limitation in mechanically ventilated patients provides
useful information concerning both respiratory mechanics, gas exchange and risk
of low-volume VILI. Accordingly, ventilators allowing on-line assessment of expira-
tory flow limitation appear to be mandatory.
References
1. Hyatt RE (1961) The interrelationship of pressure, flow and volume during various respira-
tory maneuvers in normal and emphysematous patients. Am Rev Respir Dis 85:676-83
2. Mota S, Casan P, Drobnic F, et al (1999) Expiratory flow limitation during exercise in com-
petition cyclists. J Appl Physiol 86:611-616
3. Leaver DG, Pride NB (1971) Flow-volume curves and expiratory pressures during exercise
in patients with chronic airways obstruction. Scand J Respir Dis 77 (suppl):23-27
4. Gottfried SB (1991) The role of PEEP in the mechanically ventilated COPD patient. In:
Roussos C, Marini JJ (eds) Ventilatory Failure. Springer, Berlin, pp 392-418
5. Eltayara L, Becklake MR, Volta CA, Milic-Emili J (1996) Relationship of chronic dyspnea
and flow limitation in COPD patients. Am J Respir Crit Care Med 154:1726-1734
6. Armaganidis A, Stavrakaki-Kallergi K, Koutsoukou A, et al (2000) Intrinsic PEEP in me-
chanically ventilated patients with and without tidal expiratory flow limitation. Crit Care
Med 28:3837-3842
7. Koutsoukou A, Armaganidis A, Stavrakaki-Kallergi K, et al (2000) Expiratory flow limita-
tion and intrinsic positive end-expiratory pressure at zero positive end-expiratory pressure
in patients with adult respiratory distress syndrome. Am J Respir Crit Care Med 161:1590-
1596
8. Koutsoukou A, Bekos V, Sotiropoulou C, et al (2002) Effects of positive end-expiratory
pressure on gas exchange and expiratory flow limitation in adult respiratory distress syn-
drome. Crit Care Med 30:1941-1949
9. Agostoni E, Mead J (1964) Statics of the respiratory system. In: Macklem PT, Mead J (eds)
Handbook of Physiology - Section 3. Vol I The Respiratory System: Mechanics of Breath-
ing. American Physiological Society, Bethesda, pp 387-409
10. Valta P, Corbeil C, Lavoie A, et al (1994) Detection of expiratory flow limitation during
mechanical ventilation. Am J Re~pir Crit Care Med 150:1131-1137
11. Koulouris NG, Dimopoulou I, Valta P, et al (1997) Detection of expiratory flow limitation
during exercise in COPD patients. J Appl Physiol 82:723-731
12. Diaz 0, Villafranca C, Ghezzo H, et al (2000) Exercise tolerance in COPD patients with
and without tidal expiratory flow limitation at rest. Eur Respir J 16:269-275
13. Volta CA, Ploysongsang Y, Eltayara L, et al (1996) A simple method to monitor perfor-
mance of forced vital capacity. J Appl Physiol 80:693-698
14. Macklem P, Mead J (1968) Factors determining maximum expiratory flow in dogs. J Appl
Physiol 25:159-169
15. Macklem PT, Proctor DF, Hogg JC (1969) The stability of peripheral airways. Respir Phys-
iol 8:191-203
16. Ferretti A, Gampiccolo P, Cavalli A, et al (2001) Expiratory flow limitation and orthopnea
in massively obese subjects. Chest 119:1401-1408
17. Castile R, Mead J, Jackson A, et al (1982) Effect of posture on flow-volume curve config-
uration in normal humans. J Appl Physiol; 53:1175-1183
18. Volta CA, Alvisi R, Marangoni E, et al (2001) Responsiveness to intravenous administration
of salbutamol in chronic obstructive pulmonary disease patients with acute respiratory fail-
ure. Intensive Care Med 27:1949-1953
19. Gattinoni L, Pesenti A, Avalli L, et al (1987) Pressure-volume curve of total respiratory sys-
tem in acute respiratory failure. Am Rev Respir Dis 136:730-736
20. Reinoso MA, Gracey DR, Hubmayr RD (1993) Interrupter mechanics of patients admitted
to a chronic ventilator dependency unit. Am Rev Respir Dis 148:127-131
21. Kimball WR, Leith DE, Robins AG (1982) Dynamic hyperinflation and ventilator depen-
dence in chronic obstructive pulmonary disease. Am Rev Respir Dis 126:991-995
22. Smith TC, Marini H (1988) Impact of PEEP on lung mechanics and work of breathing in
severe airflow obstruction. J Appl Physiol 65:1488-1499
23. Petrof BJ, Legare M, Goldberg P, et al (1990) Continuous positive airway pressure reduces
work of breathing and dyspnea during weaning from mechanical ventilation in severe
chronic obstructive pulmonary disease. Am Rev Respir Dis 141:281-289
24. Van den Berg B, Starn H, Bogaard JM (1991) Effects of PEEP on respiratory mechanics in
patients with COPD on mechanical ventilation. Eur Respir J 4:561-567
25. Tan IKS, Bhatt YH, Oh TE (1993) Effects of PEEP on dynamic hyperinflation in patients
with airflow limitation. Br J Anaesth 70:267-272
26. Koutsoukou A, Armaganidis A, Papakonstantinou K, et al (2000) Expiratory flow limitation
and intrinsic positive end-expiratory pressure in sedated paralyzed morbidly obese pa-
tients. Am J Respir Crit Care Med 161:390a (abst)
27. Koutsoukou A, Milic-Emili J, Armaganidis A, et al (2000) Effect of bronchodilators on
PEEPi and respiratory mechanics in mechanically ventilated morbidly obese postoperative
patients with expiratory flow limitation. Eur Respir J 16:155s (abst)
28. Robertson B (1984) Lung Surfactant. In: Robertson B, Van Golde L, Batenburg J (eds) Pul-
monary Surfactant. Elsevier, Amsterdam, pp 384-417
29. Muscedere JM, Mullen JB, GunK, et al (1994) Tidal ventilation at low airway pressures can
augment lung injury. Am J Respir Crit Care Med i49:1327-1334
30. D'Angelo E, Pecchiari M, Baraggia P, et al (2002) Low volume ventilation induces periph-
eral airways injury and increased airway resistance in normal open-chest rabbits. J Appl
Physiol 92:949-956
31. Dreyfuss D, Soler P, Basset F, Saumon G (1988) High inflation pressure pulmonary edema.
Respective effects of high airway pressure, tidal volume, and positive end-expiratory pres-
sure. Am Rev Respir Dis 137:1159-1164
32. Dreyfuss D, Basset F, Soler P, Saumon G (1985) Intermittent positive-pressure hyperventila-
tion with high inflation pressures produces pulmonary microvascular injury in rats. Am
33. Mead J, Takishima T, Leith D (1970) Stress distribution in lungs: a model of pulmonary
elasticity. J Appl Physiol 28:596-608
34. Pelosi P, Ravagnan I, Giurati PG, et al (1999) Positive end-expiratory pressure improves
respiratory function in obese but not in normal subjects during anesthesia and paralysis.
Anesthesiology 91:1221-1231
Respiratory Muscle Unloading
during Mechanical Ventilation
J. Beck, J. Spahija, and C. Sinderby
Introduction
Mechanical ventilation is aimed at unloading the respiratory muscles and maintain-

ing adequate ventilation. Webster's dictionary states that 'unloading' is "to remove
or discharge a load"; however, the aim in mechanical ventilation may just be to
reduce the load. Unloading can be complete, as with controlled ventilation where
the ventilator assumes all work and the respiratory muscles are inactive, or partial,
where the ventilator assumes a portion of the workload and the respiratory muscles
are active and contribute to the work performed. The 'load' to the respiratory mus-
cles can be quantified as the force (pressure) that is required to displace the respi-
ratory system in order to generate flow and volume. In patients with respiratory
failure, this load is usually increased due to abnormal respiratory mechanics and
intrinsic positive end-expiratory pressure (PEEPi) [1]. Also in such patients, the
force generating capacity can be severely reduced [2], and therefore, what may
appear to be a 'normal' load may actually represent an increased relative load.
I Inspiratory Effort
According to Webster's dictionary, 'mechanical effort' is defined as "the force or en-

ergy that is applied to a machine for the accomplishment of useful work". With re-
spect to breathing, 'inspiratory effort' is frequently associated with measurements
of changes in respiratory muscle pressure, which are either measured directly or
predicted by using the equation of motion. The work of breathing and the pres-
sure-time product have also been suggested as useful indices of respiratory muscle
effort [3]. Paradoxically, the same measures are used to describe the degree of res-
piratory muscle unloading promoted by mechanical ventilation [4]. Although, me-
chanical effort does not always represent the neural effort (i.e., respiratory drive)
[S-7], the two are often used interchangeably when referring to inspiratory effort.
Figure 1 shows that diaphragm activation increases progressively during incremen-
tal, symptom-limited, maximum bicycle exercise in patients with chronic obstruc-
tive pulmonary disease (COPD) and reaches high values at the end of exercise. In
contrast, transdiaphragmatic pressure increases only modestly and reaches a pla-
teau shortly after onset of exercise. These results indicate that the lack of increase
in Pdi during incremental exercise cannot be attributed to a central inhibition of
the diaphragm but rather to the diaphragm's inability to generate pressure at in-
creasing lung volumes (Fig. 2).
Respiratory Muscle Unloading during Mechanical Ventilation 281
100 30
0 • "Rest"
• 0-33% exercise
E
9
• 33-66% exercise 25
80 0
:>
E
<> • 66-99 % exerdse 0
·;c 6 • 100 'Mt exerdse
20 £
"'
E 60
~
E
~ 15
'5
-----r-------~-- ---1
1---------
r:l.
'5 40 c
~ 10
LLJ
"'IV
""'"'<II 20 5
:2
r:l. - PeakEAdi
----MeanPdi
0 0
10 15 20 25 30 35
Minute ventilation (1/min)
Fig. 1. Graph showing the group mean values of peak diaphragm electrical activity (EAdi, dosed symbols,
left y axis) and mean transdiaphragmatic pressure (Pdi, open symbols, right y axis) plotted against minute
ventilation iiE, x axis) during resting breathing (circles), as well as 0 to 33% (triangle with base up), 33 to
66% (squares), 66 to 99% (diamond), and 100% (triangle with base down) of exercise time. Values are
means± SO. From [6] with permission
100 -
95
g 90
1-
~ 85
"'IV
E 80
:>
0
> 75
C\
r:
:> 70
-'
60
60
•Rest• 0 - 33% 33 - 66% 66-100%
Exercise time (%maximum)
Fig. 2. Operational lung volumes during quiet breathing and incremental exercise. Vr=tidal volume
(shaded area), EELV =end-expiratory lung volume; EILV =end-inspiratory lung volume. Values are
means± SO. From [6] with permission
Another definition found for 'effort' is 'deliberate exertion of physical or mental

power'. In psychophysics, effort is often used to refer to a perceived sensation that
is distinct from the perception of load and perception of force. We previously dem-
onstrated that perceived respiratory effort is at least in part related to diaphragm
membrane excitability, which is regulated by both diaphragm activation (neural ef-
282 J. Beck et al.
fort) and pressure generation (mechanical effort) [7]; hence, the difficulty of separ-
ating the nuances of the term 'effort'.
For the purpose of clarity 'respiratory muscle activation' will hereafter be used
when referring to neural effort and 'respiratory muscle pressure generation' when
referring to mechanical effort.
1 Neuromechanical Coupling and Neuroventilatory Coupling
Simplified, the act of breathing constitutes the transformation of the central ner-
vous system respiratory drive into:
I neural activity (electrical nerve activity) and muscle excitation (electrical muscle
activity); in turn followed by
I respiratory muscle contraction (development of mechanical tension); which re-
sults in
1 pleural pressure generation (esophageal, transdiaphragmatic pressures); and fi-
nally
I expansion of the lungs (inspiratory flow).
The transformation of neural activity into muscle mechanical output, which can be
assessed in humans by relating the transdiaphragmatic pressure to a given dia-
phragm electrical activity [5-7], is referred to as the neuromechanical coupling.
The pressure generating capacity of the diaphragm is determined by:
1 its three-dimensional shape, radius of curvature and tension according to the
Laplace law
I the relative degree to which it is apposed to the rib cage (zone of apposition)
and lungs, and
I its length force properties [8].
The transformation of neural activity into flow and volume can be referred to as
the neuroventilatory coupling, measured as the amount of volume generated for a
given maximal or submaximal diaphragm electrical activity [6, 9, 10], which addi-
tionally takes into consideration the transformation of pressure into flow and vol-
ume (influenced by the respiratory mechanics).
In non-ventilated subjects, it has been shown that for a given amount of dia-
phragm activation, transdiaphragmatic pressure is reduced with increasing lung
volume, during phrenic nerve stimulation [11, 12] or voluntary contractions [5, 13,
14]. Therefore, increasing lung volume causes neuromechanical uncoupling and the
respiratory muscles become progressively weaker. With respect to the effect of in-
spiratory flow rates on neuromechanical coupling of the diaphragm, Goldman et al.
[15] and Pengelly et al. [16] described that increasing inspiratory flow rates reduces
diaphragm pressure generating capacity. Corne et al. [17] showed that the un-
coupling effect due to flow is negligible below peak flow rates below 1.65 Us. Using
validated methodology to measure diaphragm electrical activity, while controlling
inspiratory flow rate, airway pressure, and chest wall configuration during inspira-
tions to total lung capacity (TLC), we could not find evidence for loss of dia-
phragm pressure generating capacity with increasing mean inspiratory flow rates
up to 1.4 1/s [18]. Hence, the effect of clinically observed flow rates on neuromecha-
nical uncoupling seems to be minimal.
I Respiratory Muscle Unloading during Partial Ventilatory Assist

In a review on control of breathing during mechanical ventilation, Georgopoulos
and Roussous [19] summarized three possible ways in which a patient could re-
spond to partial ventilatory assist:
1 "respiratory muscle activation is down-regulated, so that the same ventilation as
before unloading is obtained",
I "respiratory muscle activation remains unchanged and, therefore, ventilation in-
creases according to the degree of unloading", and
I "there may be an intermediate response, whereby ventilation is higher at a lower
level of respiratory muscle activity".
From this information, one can conclude that mechanical ventilation improves neu-
roventilatory coupling (in all circumstances ventilation increases for a given level of
muscle activation). However, in general, the underlying mechanisms of the actual
unloading are poorly described. A major reason for the uncertainty surrounding
the mechanisms of respiratory muscle unloading during partial ventilatory assist is
the fact that most published studies only report measured or predicted respiratory
muscle pressures, i.e., they do not measure respiratory muscle activation directly.
Moreover, it is frequently stated that measurements of respiratory muscle pressure
actually represent respiratory muscle activation, when in fact mechanical ventila-
tion alters the relative contribution of the rib cage and abdomen to volume [20-23]
and thus likely changes the neuromechanical coupling of the diaphragm (i.e., the
relationship between neural input and mechanical output). It is imperative to mea-
sure/control for chest wall configuration, since a given lung volume may be asso-
ciated with different diaphragm lengths [24].
Studies that have reported both measures of respiratory muscle activity and
pressure generation during application of partial ventilatory assist, have shown that
partial ventilatory assist reduces respiratory muscle electrical activity and pressure
generation within a matter of minutes [25-29]. The study of Viale et al. [29]
showed that the transdiaphragmatic pressure decreased on the first breath, whereas
the decrease in diaphragm electrical activity required at least 6-8 breaths (corre-
sponding to approximately 20-28 s) before it stabilized. During synchronized inter-
mittent mandatory ventilation (SIMV), in both infants [30] and adults [31], delivery
of a mandatory breath was found not to alter diaphragm electrical activity relative
to the preceding and subsequent breaths, whereas the esophageal pressure was re-
duced and tidal volume increased during the mandatory breath [31]. In a breath-
by-breath analysis, Viale et al. [29] reported similar findings for diaphragm electri-
cal activity and transdiaphragmatic pressure between unassisted and assisted
breaths during delivery of biphasic positive airway pressure (BiPAP). Recently, it
was demonstrated that the application of positive pressure pulses, delivered by a
mechanical ventilator, causes graded facilitation of electrical activity of the dia-
phragm, which serves to counteract a negative effect of the force-length relation-
ship on transdiaphragmatic pressure [17]. These studies suggest that neuromecha-
nical uncoupling of the diaphragm occurs following the application of partial venti-
latory assist.
A common critique of studies that specifically evaluate respiratory muscle activa-
tion by measuring electrical activity of the respiratory muscles is that this method-
ology is sensitive to artifacts and prone to measurement errors. Recently, standardi-
zation of the electrode design and methodology for signal acquisition and proces-
284 J. Beck et al.
sing have overcome problems associated with measurement of diaphragm electrical

activity [32, 33]. Another recurring criticism is that the measurement of diaphragm
electrical activity can be artifactually affected by changes in lung volume. However,
recent studies have clearly demonstrated that this artifact is unique to evoked po-
tentials and does not apply to spontaneous breathing when signals are obtained
with standardized esophageal recordings of diaphragm electrical activity and signal
quality is controlled for [5]. Moreover, diaphragm electrical activity represents the
temporo-spatial summation of muscle motor unit recruitment and/or firing rate
[34, 35], correlates to phrenic nerve activity [36], and when measured with an eso-
phageal electrode array has been shown to represent both costal and crural dia-
phragm activity [5, 10].
Impact of Patient-ventilator Interaction

on Respiratory Muscle Unloading
To optimize unloading during partial ventilatory assist the ventilator needs to be
synchronized with the patient's inspiration and deliver assist in response to the
neural drive [37, 38]. The general consensus [39-43) is that there are three impor-
tant components to control with respect to patient-ventilator interaction:
initiation, i.e., triggering of the ventilatory assist
I termination i.e., cycling-off of the ventilatory assist,
I the profile of assist delivered within a breath.
Conventional airway pressure, flow, and volume controlled modes of mechanical

ventilation are limited in maintaining patient-ventilator synchrony since they are
influenced by respiratory system mechanics, PEEPi, mechanical response of the
ventilator, and the level of ventilator assist [44-54]. It has been demonstrated that
there can be significant delays between the onset of electrical activity of the dia-
phragm and the onset of ventilatory assist, as well as between the termination of
electrical activity of the diaphragm and the termination of ventilatory assist [25,
33, 55, 56).
In general, a ventilator-assisted breath can be divided into at least three phases:
1 pre-trigger period where diaphragm electrical activity and pressure are present,
however no assist is delivered. This occluded contraction period will add to in-
spiratory load [48, 57].
A period when the ventilator assist coincides with the respiratory muscle activa-
tion. This is the only period when the instantaneous effect of ventilator assist on
neuromechanical coupling can be studied.
I A period after diaphragm electrical activity has ceased, where the ventilator pas-
sively causes the lungs to inflate. This period will add to tidal volume; however,
in absence of respiratory muscle activity and pressure generation.
Unless triggering and cycling-off are optimized, it becomes difficult to evaluate the
mechanisms by which partial ventilatory assist unloads the respiratory muscles. It
was recently demonstrated in healthy subjects, that neurally adjusted ventilatory
assist [33], which optimizes patient-ventilatory synchrony, could almost totally
unload the diaphragm, while only decreasing diaphragm electrical activity by half
[58], indicating that significant diaphragm unloading is achieved by neuromechani-
cal uncoupling.
I Conclusion
Despite the fact that partial ventilatory assist has been applied for decades, how it un-
loads the respiratory muscles remains unclear. The literature appears to show that
partial ventilatory assist reduces pressure generation more than it reduces diaphragm
activation, suggesting that neuromechanical coupling may play an important role in
explaining how partial ventilatory assist unloads respiratory muscle. Incorporation of
direct and valid measurements of respiratory muscle activation and optimization of
patient-ventilator interaction would be worthwhile in future studies.
Acknowledgement. The authors wish to thank Dr. Paolo Navalesi for his useful com-
ments. Dr. Sinderby and Dr. Beck received support from the FRSQ.
References
1. Aldrich TK, Prezant DJ (1994) Indications for mechanical ventilation. In: Tobin MJ (ed)
Principles and Practice of Mechanical Ventilation. McGraw Hill, New York, pp 155-189
2. Goldstone J, Moxham J (1991) Weaning from mechanical ventilation. Thorax 46:56-62
3. Tobin M, Brochard L, Rossi A (2002) Assessment of respiratory muscle function in the
intensive care unit. ATS/ERS statement on respiratory muscle testing. Am J Respir Crit
Care Med 166:518-624
4. Banner MJ, Kirby RR, Gabrielli A, Blanch PB, Layon AJ (1994) Partially and totally unload-
ing respiratory muscles based on real-time measurements of work of breathing. Chest
106:1835-1842
5. Beck J, Sinderby C, Lindstrom L, Grassino A (1998) Effects ·of lung volume on diaphragm
EMG signal strength during voluntary contractions. J Appl Physiol 85:1123-1134
6. Sinderby C, Spahija J, Beck J, Kaminski D, Yan S, Sliwinski P (2001) Diaphragm activation
during exercise in chronic obstructive pulmonary disease. Am J Respir Crit Care Med
163:1637-1641
7. Sinderby C, Spahija J, Beck J (2001) Changes in respiratory effort sensation over time are
linked to the frequency content of diaphragm electrical activity. Am J Respir Crit Care
Med 163:905-910
8. Gauthier AP, Verbanck V, Estenne M, Segebarth C, Macklem PT, Paiva M (1994) Three-di-
mensional reconstruction of the in vivo diaphragm shape at different lung volumes. J Appl
Physiol 76:495-506
9. Spahija J, Beck J, Comtois N, et al (1999) Use of diaphragm activation in the assessment of
neuro-ventilatory coupling. Am J Respir Crit Care Med 159:A365 (abst)
10. Sinderby C, Beck J, Weinberg J, Spahija J, Grassino A (1998) Voluntary activation of the
human diaphragm in health and disease. J Appl Physiol 85:2146-2158
11. Hubmayr RD, Litchy WJ, Gay PC, Nelson SB (1989) Transdiaphragmatic twitch pressure.
Effects of lung volume and chest wall shape. Am Rev Respir Dis 139:647-652
12. Smith J, Bellemare F (1987) Effect of lung volume on in vivo contraction characteristics of
the human diaphragm. J Appl Physiol 62:1893-1900
13. Agostini E, Rahn H (1960) Abdominal and thoracic pressures at different lung volumes.
J Appl Physiol 15:1087-1092
14. Hershenshorn MB, Kikuchi Y, Loring S (1988) Relative strengths of the chest wall muscles.
15. Goldman M, Grassino A, Mead J, Sears T (1978) Mechanics of the human diaphragm dur-
ing voluntary contractions: dynamics. J Appl Physiol 44:840-848
16. Pengelly LD, Anderson AM, Milc-Emili J (1971) Mechanics of the diaphragm. J Appl Phy-
siol 30:797-805
17. Corne S, Webster K, Younes M (2000) Effects of inspiratory flow on diaphragmatic motor
output in normal subjects. J Appl Physiol 89:481-492
18. Beck J, Sinderby C, Lindstrom L, Grassino A (1998) Crural diaphragm activation during
dynamic contractions at various inspiratory flow rates. J Appl Physiol 85:451-458
286 J. Beck et al.
19. Georgopoulos D, Roussos C (1996) Control of breathing in mechanically ventilated pa-

tients. Eur Respir J 9:2151-2160
20. Aliverti A, Dellaca R, Pelosi P, Chiumello D, Pedotti A, Gattinoni, L (2000) Optoelectric
plethysmography in intensive care patients. Am J Respir Care Med 161:1546-1552
21. Froese A, Bryan AC (1974) Effects of anaesthesia and paralysis on diaphragmatic me-
chanics in man. Anesthesiology 41:242-255
22. Grimby G, Hedenstierna G, Lofstrom B (1975) Chest wall mechanics during artificial venti-
lation. J Appl Physiol 38:576-580
23. Krayer S, Rehder K, Vetterman J, Didier E, Ritman E (1989) Position and motion of the
human diaphragm during anaesthesia paralysis. Anesthesiology 75:891-898
24. Grassino A, Goldman M, Mead J, Sears T (1978) Mechanics of the human diaphragm dur-
ing voluntary contractions: statics. J Appl Physiol 44:829-839
25. Beck J, Gottfried SB, Navalesi P, et al (2001) Electrical activity of the diaphragm during
pressure support ventilation in acute respiratory failure. Am J Respir Crit Care Med 164:
419-424
26. Belman, MJ, Soo Hoo GW, Kuei JH, Shadmehr R (1990) Efficacy of positive vs negative
pressure ventilation in unloading the respiratory muscles. Chest 98:850-856
27. Brochard L, Pluwska F, Lemaire F (1987) Improved efficacy of spontaneous breathing with
inspiratory pressure support. Am Rev Respir Dis 136:411-415
28. Brochard L, Harf A, Lorino H, Lemaire F (1989) Inspiratory pressure support prevents dia-
phragmatic fatigue during weaning from mechanical ventilation. Am Rev Respir Dis 139:
513-521
29. Viale JP, Duperret S, Mahul P, et al (1998) Time course evolution of ventilatory responses
to inspiratory unloading in patients. Am J Respir Crit Care Med 157:428-434
30. Beck J, Tucci M, Millotte B, et al (2002) Synchronized intermittent mandatory ventilation
elicits the Hering-Breuer reflex in mechanically ventilated infants. Am J Respir Crit Care
Med 165:A789 (abst)
31. lmsand C, Feihl F, Perret C, Fitting JW (1994) Regulation of inspiratory neuromuscular
output during synchronized intermittent mechanical ventilation. Anesthesiology 80:13-22
32. Aldrich T, Sinderby C, McKenzie D, Estenne M, Gandevia S (2002) Electrophysiologic tech-
niques for the assessment of respiratory muscle function. ATS/ERS Statement on Respira-
tory Muscle Testing. Am J Respir Crit Care Med 166:518-624
33. Sinderby C, Navalesi P, Beck J, et al (1999) Neural control of mechanical ventilation in
respiratory failure. Nature Med 5:1433-1436
34. Beck J, Sinderby C, Weinberg J, Grassino A (1995) Effects of muscle-to-electrode distance
on the human diaphragm electromyogram. J Appl Physiol 79:975-985
35. Beck J, Sinderby C, Lindstrom L, Grassino A (1996) Influence of bipolar esophageal elec-
trode positioning on measurements of human crural diaphragm EMG. J Appl Physiol 81:
1434-1449
36. Lourenco RV, Cherniack NS, Malm JR, Fishman AP (1966) Nervous output from the re-
spiratory centers during obstructed breathing. J Appl Physiol21:527-533
37. Ranieri VM, Giuliani R, Mascia L, et al (1996) Patient-ventilator interaction during acute
hypercapnia: pressure-support vs. proportional-assist ventilation. J Appl Physiol. 81:425-
436
38. Slutsky A (1993) Mechanical ventilation. American College of Chest Physicians' Consensus
Conference. Chest 104:1833-1859
39. Ranieri VM (1997) Optimization of patient-ventilator interactions: closed-loop technology
to turn the century. Intensive Care Med 23:936-939
40. Rossi A, Appendini L (1995) Wasted efforts and dyssynchrony: is the patient-ventilator bat-
tle back? Intensive Care Med 21:867-870
41. Sassoon CSH, Foster GT (2001) Patient-ventilator asynchrony. Curr Opin Crit Care 7:28-33
42. Tobin M (2001) Advances in mechanical ventilation. N Engl J Med 344:1986-1996
43. Tobin M, Jubran A, Laghi F (2001) Patient-ventilator interaction. Am J Respir Crit Care
Med 163:1059-1063
44. Appendini L, Purro A, Patessio A, et al (1996) Partitioning of inspiratory muscle workload
and pressure assistance in ventilator-dependent COPD patients. Am J Respir Crit Care Med
154:1301-1309
45. Calderini E, Confalonieri M, Puccio PG, Francavilla N, Stella L, Gregoretti C (1999) Pa-
tient-ventilator asynchrony during non-invasive ventilation: the role of the expiratory trig-
ger. Intensive Care Med 25:662-667
46. Imanaka H, Nishimura M, Takeuchi M, Kimball W, Yahagi N, Kumon K (2000) Autotrigger-
ing caused by cardiogenic oscillation during flow-triggered mechanical ventilation. Crit
Care Med 28:402-407
47. Jubran A, Van de Graaff, Tobin MJ (1995) Variability in patient-ventilator interaction with
pressure support ventilation in patients with COPD. Am J Respir Crit Care Med 152:129-
136
48. Leung P, Jubran A, Tobin MJ (1997) Comparison of assisted ventilator modes on trigger-
ing, patient effort, and dyspnea. Am J Respir Crit Care Med 155:1940-1948
49. Macintyre NR, Ho LH (1991) Effects of initial flow rate and breath termination criteria on
pressure support ventilation. Chest 99:134-138
SO. Tobin MJ (1994) Management of the patient who is "fighting the ventilator". In: Tobin MJ
(ed) Principles and Practice of Mechanical Ventilation. McGraw Hill Inc, New York,
pp 1149-1162
51. Yamada Y, Du HL (1998) Effects of different pressure support termination on patient-venti-
lator synchrony. Respir Care 43:1048-1057
52. Yamada Y, Du HL (2000) Analysis of the mechanisms of expiratory asynchrony in pressure
support ventilation: a mathematical approach. J Appl Physiol 88:2143-2150
53. Yamada Y, Du HL (2002) Expiratory asynchrony during proportional assist ventilation. Am
J Respir Crit Care Med 165:972-977
54. Schulze A, Rich W, Schellenberg L, Schaller P, Heldt GP (1998) Effects of different gain set-
tings during assisted mechanical ventilation using respiratory unloading in rabbits. Pediatr
Res 44:132-138
55. Parthasarathy S, Jubran A, Tobin MJ (1998) Cycling of inspiratory and expiratory muscle
groups with the ventilator in airflow limitation. Am J Respir Crit Care Med 158:1471-1478
56. Parthasarathy S, Jubran A, Tobin MJ (2000) Assessment of neural inspiratory time in venti-
lator-supported patients. Am J Respir Crit Care Med 162:546-552
57. Aslanian P, Atrous S, lsabey D, et al (1998) Effects of flow triggering on breathing effort
during partial ventilatory assist. Am J Respir Crit Care Med 157:135-143
58. Beck J, Spahija J, DeMarchie M, Comtois N, Sinderby C (2002) Unloading during neurally
adjusted ventilatory assist (NAVA). Eur Resp J 20:637s (abst)
High Frequency Oscillation (HFO):
Physiological Basis· for a Potentially
'Optimal' Protective Ventilatory Strategy
A. Rossi, T. E. Stewart, and V. M. Ranieri
I Introduction
Acute respiratory distress syndrome (ARDS) is a primary cause of death in ICUs
with a reported mortality ranging between 30-60% [1, 2]. Intrapulmonary shunt,
increased dead space, and reduced lung compliance are the main pulmonary
patho-physiological alterations leading to multiple organ failure (MOF) and ulti-
mately death. Conventional mechanical ventilation is effective in delivering oxygen
and providing adequate carbon dioxide clearance, both in volume-cycled and pres-
sure-limited modes. However experimental and clinical data show that conventional
ventilation may stress the alveolar wall resulting in further pulmonary injury (ven-
tilator induced lung injury [VILI]) [3, 4]. Tidal volume (VT), positive end-expira-
tory pressure (PEEP), and inspiratory oxygen fraction (Fi0 2 ) are the three key ven-
tilator settings during conventional ventilation. Strong evidence suggests that re-
ducing VT and optimizing PEEP prevents VILI, providing a lung protective strategy
[5, 6]. However, 'conventional' protective ventilatory strategies are usually accompa-
nied by side effects such as use of high respiratory rate, hypercapnia, hemody-
namic impairment, etc. [7].
The delicate balance between sufficient gas exchange and safe ventilatory settings
may be achieved using ventilatory strategies that deviate from the common concept
of delivering flow and volume similar to those occurring during spontaneous
breathing. High frequency oscillation (HFO) is an open ventilator system that main-
tains continuous exchange with the atmosphere and escape of ventilated gases
through an open port. A bulk flow provides fresh air to the circuit and small VT
delivered by the strokes of the device sustain alveolar ventilation. This chapter will:
I review the physiological mechanisms involved in the alveolar stress caused by
conventional mechanical ventilation;
I describe the main physiological and technological characteristic of HFO; and
1 describe the physiological background supporting the use of HFO as an 'opti-
mal' protective ventilatory strategy.
I Conventional Ventilation and Mechanical Stress

According to the current models, VILI can be caused by extra-alveolar air (baro-
trauma), alveolar damage due to overdistension (volutrauma), shear stress from
repetitive opening and closure of alveoli (atelectrauma) [3, 4, 8-10].
High Frequency Oscillation (HFO} 289
Barotrauma
This term defines the presence of air in the extrapulmonary space due to high
transpulmonary pressure generated between the internal (alveolar pressure} and
the external (intra-thoracic pressure) sides of the alveoli. Alveolar pressure is deter-
mined by the VT and PEEP level and by the elastic properties of the lung. Intra-
thoracic pressure is determined by the elastic properties of the chest wall including
the abdomen [11].
Volutrauma
Volutrauma describes the damage caused by the delivered VT per se, due to the me-
chanical stretch of the alveolar surface of the reduced number of open alveoli that
receive the entire amount of tidal inflation leading to diffuse alveolar damage, pul-
monary edema, increased fluid filtration, increased epithelial permeability, and in-
creased microvascular permeability [12].
Atelectrauma
Atelectrauma refers to the repeated recruitment/derecruitment that is responsible
for mechanical stress on the alveolar surface of both healthy and atelectatic alveoli
due to tangential shear forces [13-14].
I Physiology and Technology of HFO
The application of basic principles of respiratory physiology to conventional me-

chanical ventilation means that when VT is higher than alveolar dead space (V 0 },
alveolar ventilation can be described by the following equation:
fV A= f(VT- Vo)
where VT is the total volume inspired, VA the alveolar volume, V0 the dead space
volume and f the frequency. This equation predicts that the minute alveolar volume
is a positive value if VT is higher than dead space. Conventional ventilation uses
VT higher than this value; HFO relies on the principle of delivering a VT lower than
the anatomical dead space (1-3 ml/kg), but at a very high frequency (3-15 Hz)
(Fig. 1).
Several alternative ventilatory strategies use respiratory frequencies higher than
the physiologic respiratory rates with constant flowing through the lung [15-17].
Unique of HFO is that a minimal amount of gas volume 'oscillates' through the
complex alveolar structure causing the small successive movements of a single col-
umn of air inside the lung. A sequence of very small volumes (lower than V0 )
given a set amplitude promote the movement of this column without interfering
with VA. Hence, the oscillatory technique should be considered as a 'vibrating
column of gas' that brings fresh gas into the alveolar space without affecting the
expansion since, during each short breath, a parabolic core of fresh gas enters the
alveoli activating convective and diffusive mechanism that affect gas transportation
since small amounts of energy are intermittently provided to the static column of
290 A. Rossi et al.
,-----,
I
I
I
I
.-----.
I
I
I
I
I
I I
I I
I I HFOV
I I
I I I
I I I I
I I
I I : I
------·
, _____ .!I _____ ,.!I : CMV:
Time
Fig. 1. In high frequency oscillatory ventilation (HFOV) the alveolar pressure changes for negligible values,
while in controlled mechanical ventilation (CMV) the ~ P is higher and corresponds to the set values of
PEEP and PrLAT. From [6] with permission
gas, and are responsible for the gas mixing [18]. Under these circumstances, if a
VT < VD is given and VT is close to zero, the total alveolar volume inside the lung is
equal to the first volume of air delivered during the first inspiration. This volume
depends on the level of constant applied pressure and on the elastic characteristic
of the respiratory system.
An important concept in HFO is that it provides an active expiration mode and
no derecruitment is required to eliminate C0 2 • In other words, during HFO, in-
spiration and expiration are independent of the level of applied pressure, and C0 2
removal and oxygenation are not coupled to the inflation/deflation of the lung. Al-
veolar gas exchange is therefore entirely due to the bulk flow of fresh air delivered
through the circuit through different mechanisms including:
I direct ventilation by low VT of those alveoli located more proximally;
I pendelluft occurring between nearby lung units with different time constants;
I streaming of inspiratory/expiratory flow in diverging alveolar ducts;
I axial convection and lateral mixing [19, 20].
High respiratory frequencies may substantially influence the resistive, inertial and
elastic behavior in a non-homogenous system such as the lung of patients with
ARDS influencing the overall distribution of flow, pressure and volume. Besides,
complicated pulmonary anatomy, fractal distribution of distal terminations, poorly
defined pulmonary physical properties and complex local fluid dynamics may
further influence regional distribution since during oscillation the inertial compo-
nents dominate the overall pulmonary compliance.
I Is HFO the 'Ideal' Protective Ventilatory Strategy?

Established protective ventilatory strategies during 'conventional' ventilation [18-
22] target a low end-inspiratory plateau pressure (PPLAT) based on the assumption
that the atelectatic regions should not be involved in the dynamic cycling of venti-
lation while the inflating volume is evenly distributed in healthy or partially healthy
alveoli without risk of mechanical stretch. As a consequence of the VT reduction,
High Frequency Oscillation (HFO) 291
permissive hypercapnia must be implemented unless high respiratory rates are used
to increase minute ventilation potentially leading to the development of consider-
able levels of auto-PEEP. On the other hand, high PEEP levels have been proven to
effectively provide better oxygenation since PEEP reduces intrapulmonary shunt.
The adverse effects of PEEP include decreased cardiac output, increased dead space,
and resistance of the bronchial circulation. When PEEP is not effective in recruiting
collapsed alveoli, such as in patients with pneumonia and severely compromised
parenchyma, these adverse effects may be more pronounced and alveolar overdis-
tension may occur increasing the risk of mechanical stress.
Several elements may theoretically affect the efficacy of conventional ventilation
to guarantee the optimal setting able to protect the lung from mechanical stress
providing adequate gas exchange and minimal hemodynamic impairment: a) the
relative non homogeneous distribution of atelectatic vs normal alveolar units may
change with the natural evolution of the disease, with patient position, with medi-
cal treatment, nursing maneuvers etc. This implies that a 'ventilator prescription'
may be safe or stressful based on the particular mechanical condition of the lung;
b) in case of severe ARDS the use of low volumes and pressures may induce unac-
ceptable levels of hypercapnia and/or hypoxemia. Therefore, violation of the 'safe'
limits must be accepted [23]. Under these circumstances, HFO may represent an
optimal theoretical protection since:
a constant pressure is initially applied to recruit the collapsed lung and then
maintaining the lung open and accessible to the oscillating small volumes;
1 stretch due to overinflation should be avoided providing that the initial increase
in lung volume brings the respiratory system to oscillate around the deflating
limb of the static volume-pressure curve of the respiratory system allowing high-
er mean airway pressure values than in conventional ventilation but well above
the lower inflection point and immediately below the upper inflection point;
a VT close to zero oscillates minimizing tidal alveolar recruitment/derecruitment
while keeping alveolar pressure relatively constant because of the absence of per-
iodical tidal inflations;
the high rate of oscillations activates the physical mechanisms related to the os-
cillating gas column in a homogeneous lung providing optimal oxygenation and
C0 2 removal [24, 25].
I Clinical Investigations
Although many experimental data were produced about HFO in the '80s and '90s,
few clinical trials in adult patients have been run so far. Interest for this technique
increased in the early '90s, when evidence for lung protective strategies was proved.
Recent studies focused on the importance of lung recruitment for better oxygena-
tion, new strategies for oxygenation improvement and carbon dioxide removal, and
limitation of delivered Fi0 2 • In particular, general attention was paid for lung
recruitment maneuvers, application of high levels of PEEP, use of low VT and mod-
erate values of peak and mean airway pressures. In patients with severe ARDS these
limits can be problematic since the lungs cannot provide adequate oxygenation and
C0 2 exchange with low levels of applied pressure, volume and oxygen and/or the
patients cannot tolerate the hemodynamic impairment due to high levels of PEEP
and recruitment maneuvers. In addition, protective approaches during conventional
292 A. Rossi et al.
ventilation may result in hypercapnia with potentially adverse consequences [26].

New modes of ventilatory support could have application when conventional venti-
lation fails in maintaining protective settings, and the clinical trials run so far test
the hypothesis of high frequency ventilation as a rescue technique. This concept it-
self implies that only severely ill patients might be eligible for such a non-standard
technique, due to practical and ethical issues of switching to new protocols. The
first trials in humans involved pediatric units [27-29] and showed no differences in
terms of survival in the HFO arm, but demonstrated some benefits in terms of oxy-
genation without increasing barotrauma when infants were exposed at lower Fi0 2 ,
and lower incidence of chronic lung diseases at 30 days. Published data on the clin-
ical experience with HFO in adults are limited to observational studies and case re-
ports evaluating its use in patients failing conventional mechanical ventilation.
These studies report significant improvements in oxygenation using an open lung
strategy.
These observational results have been confirmed in more recent trials with a
suggestion of better outcome when HFO is applied in early stages of the course of
ARDS [30-32]. In all these studies, survival was significantly better when HFO was
used after evident failure of conventional mechanical ventilation, and secondary
outcome measurements, such as mucus plugs and hemodynamic stability, were sat-
isfactory. Physiological improvements were obtained 8-16 hours after HFO was in-
itiated. Carbon dioxide levels in the blood were constant during all the time of the
investigation, but at higher values than during conventional mechanical ventilation
and within the ranges of permissive hypercapnia. Hemodynamic stability was not
affected by HFO, and there was no increase in air leaks (pneumothorax, pneumo-
mediastinum). Most recent results show that cumulative experience in using HFO
may help in choosing the most appropriate ventilator setting when HFO is started:
initial lung recruitment maneuver at 40 cmH 2 0, gradual Fi0 2 withdrawn from 100
to 50%, allowance of cuff air leaks in case of hypercapnia may be crucial for out-
come improvement. Adjunctive therapies such as use of nitric oxide (NO), prone
positioning [33, 34] and high-dose corticosteroids may be used in life-threatening
conditions that do not respond to ventilation.
Conclusion
This physiological review suggests HFO as a potentially effective method of venti-
lating patients with ARDS as the determinants for gas transportation are compati-
ble with maintaining a lung protective strategy while providing optimal gas ex-
change. The lack of oscillatory forces may minimize the risk of mechanical stress
even in the presence of non-homogeneous and unstable alteration of the mechani-
cal properties. The most recent clinical investigations suggest that early use of HFO
may be effective in the treatment of patients with ARDS.
References
1. Sloane PJ, Gee MH, Gottlieb JE, et al (1992) A multicenter registry of patients with acute
respiratory distress syndrome. Physiology and outcome. Am Rev Respir Dis 146:419-426
2. Zilberberg MD, Epstein SK (1998) Acute lung injury in the medical ICU: comorbid condi-
tions, age, etiology, and hospital outcome. Am J Respir Crit Care Med 157:1159-1164
High Frequency Oscillation (HFO) 293
3. Slutsky AS, Tremblay LN (1998) Multiple system organ failure. Is mechanical ventilation a
contributing factor? Am J Respir Crit Care Med 157:1721-1725
4. Slutsky AS (1999) Lung injury caused by mechanical ventilation. Chest 116:9S-15S
5. Slutsky AS (1993) Mechanical ventilation. American College of Chest Physicians' Consensus
Conference. Chest 104:1833-1859
6. Ferguson ND, Stewart TE (2001) The use of high-frequency oscillatory ventilation in adults
with acute lung injury. Respir Care Clin N Am 7:647-661
7. Brower RG, Ware LB, Berthiaume Y, Matthay MA (2001) Treatment of ARDS. Chest
120:1347-1367
8. Tremblay LN, Slutsky AS (1998) Ventilator-induced injury: from barotrauma to biotrauma.
Proc As soc Am Physicians 110:482-488
9. Ranieri VM, Giunta F, Suter PM, Slutsky AS (2000) Mechanical ventilation as a mediator of
multisystem organ failure in acute respiratory distress syndrome. JAMA 284:43-44
10. Tremblay LN, Miatto D, Hamid Q, Govindarajan A, Slutsky AS (2002) Injurious ventilation
induces widespread pulmonary epithelial expression of tumor necrosis factor-alpha and in-
terleukin-6 messenger RNA. Crit Care Med 30:1693-1700
11. Boussarsar M, Thierry G, Jaber S, Roudot-Thoraval F, Lemaire F, Brochard L (2002) Rela-
tionship between ventilatory settings and barotrauma in the acute respiratory distress syn-
drome. Intensive Care Med 28:406-413
12. Dreyfuss D, Soler P, Basset G, Saumon G (1988) High inflation pressure pulmonary edema.
Respective effects of high airway pressure, high tidal volume, and positive end-expiratory
pressure. Am Rev Respir Dis 137:1159-1164
13. Chiumello D, Pristine G, Slutsky AS (1999) Mechanical ventilation affects local and sys-
temic cytokines in an animal model of acute respiratory distress syndrome. Am J Respir
14. Tremblay L, Valenza F, Ribeiro SP, Li J, Slutsky AS (1997) Injurious ventilatory strategies
increase cytokines and c-fos m-RNA expression in an isolated rat lung model. J Clin Invest
99:944-952
15. Slutsky AS, Drazen FM, Ingram RH Jr, et a! (1980) Effective pulmonary ventilation with
small-volume oscillations at high frequency. Science 209:609-671
16. Slutsky AS, Brown R, Lehr J, Rossing T, Drazen JM (1981) High-frequency ventilation:
a promising new approach to mechanical ventilation. Med Instrum 15:229-233
17. Rimensberger PC, Pristine G, Mullen BM, Cox PN, Slutsky AS (1999) Lung recruitment
during small tidal volume ventilation allows minimal positive end-expiratory pressure
without augmenting lung injury. Crit Care Med 27:1940-1945
volumes as compared with traditional tidal volumes for acute lung injury and the acute
respiratory distress syndrome. N Eng! J Med 342:1301-1308
19. Stewart TE, Meade MO, Cook DJ, et a! (1998) Evaluation of a ventilation strategy to pre-
vent barotrauma in patients at high risk for acute respiratory distress syndrome. Pressure-
and Volume-Limited Ventilation Strategy Group. N Engl J Med 338:355-361
20. Brochard L, Roudot-Thoraval F, Roupie E, et a! (1998) Tidal volume reduction for preven-
tion of ventilator-induced lung injury in acute respiratory distress syndrome. The Multi-
center Trail Group on Tidal Volume reduction in ARDS. Am J Respir Crit Care Med 158:
1831-1838
21. Amato MB, Barbas CS, Medeiros CM, et a! (1998) Effect of a protective-ventilation strategy
on mortality in the acute respiratory distress syndrome. N Eng! J Med 338:347-354
22. Ranieri VM, Suter PM, Tortorella C, eta! (1999) Effect of mechanical ventilation on inflam-
matory mediators in patients with acute respiratory distress syndrome: a randomized con-
trolled trial. JAMA 282:54-61
23. Hubmayr RD (2002) Perspective on lung injury and recruitment: a skeptical look at the
opening and collapse story. Am J Respir Crit Care Med 165:1647-1653
24. dos Santos CC, Slutsky AS (2001) Overview of high-frequency ventilation modes, clinical
rationale, and gas transport mechanisms. Respir Care Clin N Am 7:549-575
25. Oberg PA, Sjostrand U (1969) Studies of blood-pressure regulation. I. Common-carotid-
artery clamping in studies of the carotid-sinus baroreceptor control of the systemic blood
pressure. Acta Physiol Scand 75:276-286
294 A. Rossi et al.: High Frequency Oscillation (HFO)
26. Stewart TE, Slutsky AS (1995) Mechanical ventilation: A shifting philosophy. Curr Opin
Crit Care 1:49-56
27. HIFI Study Group (1989) High frequency oscillatory ventilation compared with conven-
tional mechanical ventilation in the treatment of respiratory failure in preterm infants.
N Engl J Med 320:88-93
28. Arnold JH, Hanson JH, Toro-Figuero LO, Gutierrez J, Berens RJ, Anglin DL (1994) Prospec-
tive, randomized comparison of high-frequency oscillatory ventilation and conventional
mechanical ventilation in pediatric respiratory failure. Crit Care Med 22:1530-1539
29. Gerstmann DR, Minton SD, Stoddard RA, et al (1996) The Provo multicenter high-fre-
quency oscillatory ventilation trial improved pulmonary and clinical outcome in respira-
tory distress syndrome. Pediatrics 98:1044-1057
30. Fort P, Farmer C, Westerman J, et al (1997) High-frequency oscillatory ventilation for adult
respiratory distress syndrome-a pilot study. Crit Care Med 25:937-947
31. Mehta S, Lapinsky SE, Hallett DC, et al (2001) A prospective trial of high frequency oscil-
latory ventilation in adults with acute respiratory distress syndrome. Crit Care Med 29:
1360-1369
32. Derdak S, Mehta S, Stewart TE, et al (2002) High-frequency oscillatory ventilation for acute
respiratory distress syndrome in adults: a randomized, controlled trial. Am J Respir Crit
Care Med 166:801-808
33. MacDonald R, Stewart TE, Lapinsky S, Aubin M, Hallett D, Mehta S (2000) Oxygenation re-
sponse to inhaled nitric oxide (INO) when combined with high frequency oscillatory venti-
lation (HFOV). Am J Respir Crit Care Med 161:A47 (abst)
34. Varkul MD, Stewart TE, Lapinsky SE, Ferguson ND, Mehta S (2001) Successful use of com-
bined high-frequency oscillatory ventilation, inhaled nitric oxide, and prone positioning in
the acute respiratory distress syndrome. Anesthesiology 95:797-799
Withdrawal from Mechanical Ventilation in Patients
with COPD: The Issue of Congestive Heart Failure
B. Cabello and J. Mancebo
I Introduction
Weaning or liberation from mechanical ventilation in patients with respiratory fail-

ure begins when the precipitating cause is partially or totally reversed. The aim of
this process is to induce spontaneous breathing and, ultimately, extubation.
Several difficulties can appear during the weaning process, prolonging the time
of intubation with a consequent increase in morbidity, including bronchopulmo-
nary and systemic infections, barotrauma, tracheal injury and a longer stay in the
intensive care unit (ICU), and also in mortality [1]. Early identification and treat-
ment of causes leading to weaning failure can, thus, improve clinical outcome.
This process will fail in about 25% of patients meeting weaning criteria. In these
cases, time of withdrawal from the ventilator can be a substantial fraction of total
mechanical ventilation time. In. clinical practice, the possible liberation from me-
chanical ventilation should be evaluated daily. Once the patient is considered able
to breathe without mechanical assistance a spontaneous breathing trial (SBT) can
be carried out using a t-tube or low pressure support levels for between 30 and
120 minutes [2-5]. This process is particularly difficult in patients with chronic ob-
structive pulmonary disease (COPD) [4]. The most frequent cause of failure in a
SBT is respiratory pump failure. Other causes include gas exchange abnormalities,
psychological dependence on the ventilator, and congestive heart failure [6].
I Mechanical Derangements in COPD Patients
The most important finding in COPD patients is airflow obstruction with a high air-
way resistance and dynamic airway collapse during expiration. In COPD patients,
particularly during exacerbations, the inspiratory muscles are burdened due to an in-
crease in the total mechanical load of the respiratory system [7]. Moreover, passive
lung emptying is slow because of the airway obstruction and the expiratory flow lim-
itation. Consequently, the relaxation volume is not achieved at the end of expiration,
and dynamic hyperinflation ensues. The contributing factors include increases in:
respiratory rate, as less time is available for expiration; minute ventilation, because
mean expiratory flow increases; and airway resistance. The increase in airway resis-
tance includes the expiratory circuit in the ventilator and the endotracheal tube, con-
tributing to increasing the time constant of the respiratory system.
The product of resistance times compliance is the time constant. The lung needs
three time constants to passively empty 96% of the total insuflated volume. There-
296 B. Cabello and J. Mancebo
fore, if resistance and/or compliance increase, the lung will need a longer expira-
tory time to exhale the entire tidal volume before achieving the relaxation volume.
In COPD exacerbations, because of the previously described factors, there is not
sufficient time to reach the relaxation volume of the respiratory system. The pulmo-
nary volume continues to increase above the functional residual capacity (FRC)
and then, when a new equilibrium situation is reached, the entire tidal volume is
exhaled. This occurs when the volume at end-inspiration (the sum of tidal volume
and trapped volume) develops a sufficiently high recoil pressure to exhale the tidal
volume [8].
Dynamic Pulmonary Hyperinflation
Dynamic pulmonary hyperinflation is defined as an increase in the end-expiratory

lung volume (EELV) above relaxation volume (Vr), usually referred to as FRC [9].
Dynamic hyperinflation occurs whenever the time available to exhale the tidal vol-
ume is shorter than the time required to decompress the lungs to Yr. Nevertheless,
flow limitation during tidal expiration, due to dynamic compression of the small
airways, is a major mechanism determining dynamic pulmonary hyperinflation
and intrinsic positive end-expiratory pressure (PEEPi) in patients with COPD. In
mechanically ventilated patients, the ventilator settings as well as the added resis-
tance due to the endotracheal tube and/or ventilator tubing and circuits can play a
role in magnifying the degree of dynamic pulmonary hypertension.
Intrinsic Positive End-Expiratory Pressure (PEEPi)
In the presence of dynamic pulmonary hypertension, alveolar pressure (Pa~v) can

remain positive throughout expiration because of the persistent inward elastic
recoil of the total respiratory system (Pel,rs>· The positive end-expiratory Pel,rs
(above external PEEP as set in the ventilator) due to incomplete expiration has
been termed auto-PEEP or intrinsic PEEP (PEEPi). Direct measurement of PEEPi
can be performed by means of the end-expiratory airway occlusion at the expira-
tory port of the ventilator in passively ventilated patients. During spontaneous
breathing, PEEPi can also be measured by simultaneous recordings of esophageal
pressure and flow from the change in esophageal pressure preceding the start of in-
spiratory flow. This is true when expiratory muscles are relaxed. When expiratory
muscle recruitment exists, then a correction needs to be made to take into account
the amount of abdominal pressure transmitted to the thorax [10].
This measure of PEEPi reflects the minimum amount of pressure required to
counterbalance PEEPi in the fast time constant units, that is, the lowest PEEPi,
which has been termed PEEPidyn• because it is measured during dynamic breathing
[11]. Therefore, in patients with advanced COPD, PEEPidyn may be significantly
lower than the mean end-expiratory static recoil pressure of the total respiratory
system (PEEPi,st) measured with the end-respiratory occlusion technique [12].
Although PEEPi usually implies dynamic hyperinflation, the two are not synon-
ymous. Lung volume can be normal in the setting of persistent flow at the end of
exhalation caused by the recruitment of the expiratory muscles. As a consequence,
the Palv will be positive and the gradient of alveolar to central airway pressure will
produce a PEEPi effect.
Withdrawal from Mechanical Ventilation in Patients with COPD: The Issue of Congestive Heart Failure 297
When a COPD patient begins a SBT, an increase in mechanical load and in work
of breathing can occur. This scenario is characterized by a rapid shallow breathing
pattern: the patient develops an increase in respiratory frequency and a decrease in
tidal volume [13]. This strategy, however, may increase the degree of pulmonary
dynamic hyperinflation because of the reduction in expiratory time. Unresolved
respiratory failure leads to an increase in respiratory rate, dynamic hyperinflation,
dead space ventilation, respiratory acidosis as a consequence of the increase in
dead space ventilation and geometrical disadvantage of the respiratory muscles,
particularly when dynamic hyperinflation is important [14].
In addition, when dynamic pulmonary hyperinflation is sufficiently high, the
respiratory muscles, in particular the diaphragm, are at a geometrical disadvantage
because of an increase in the radius of curvature [2, 14].
In patients with acute exacerbation of COPD under assisted mechanical ventila-
tion, the presence of PEEPi increases the work of spontaneous breathing and can
even cause hemodynamic disturbances [15]. When patients start inspiration during
spontaneous breathing they must first generate a sufficiently high negative pressure
to counterbalance PEEPi before inspiratory airflow begins [16]. This generates an
increase in the work of breathing, which is the product of tidal volume and the
PEEPi level.
In patients on assisted ventilatory modes, the application of external PEEP has a
major impact on the breathing workload [17, 18]. Indeed, the application of addi-
tional external PEEP to compensate for PEEPi and flow limitation, frequently de-
creases the inspiratory effort to initiate an assisted breath. Nevertheless, if the ex-
ternal PEEP level is excessive (above the intrinsic PEEP level) the dynamic hyperin-
flation can increase [19]. External PEEP per se, when adjusted at or below the level
of PEEPi, does not modify the degree of dynamic pulmonary hyperinflation at all.
During assisted ventilatory modes external PEEP titration is difficult because it in-
volves the measurement of esophageal and gastric pressures to estimate the amount
of PEEPidyn·
During assisted breathing, the airway occlusion pressure, measured from airway
pressure during the phase of ventilator triggering {P0.u), has been proposed to as-
sess the effects of external PEEP in patients with PEEPi. Therefore, a decrease in
P0 . 1 with PEEP could indicate a decrease in PEEPi and a decrease in the inspiratory
work of breathing. Even more important, the changes in P0. 1 which may appear
when external PEEP is modified, are related to changes in work of breathing. Sig-
nificant correlations were found between work of breathing per min and P0 . 1 at the
three levels of PEEP, and between changes in P0 .1 versus the changes in work of
breathing per min, indicating that P0 . 1 and work of breathing changed in the same
direction. A decrease in P0 . 1 with PEEP indicated a decrease in PEEPi with a speci-
ficity of 71 o/o and a sensitivity of 88o/o and a decrease in work of breathing with a
specificity of 86o/o and a sensitivity of 91 o/o [18].
The effect of PEEP may well depend upon the severity and homogeneity of the
obstructive process, the minute ventilation requirement, the activity of expiratory
muscles, and the existence of dynamic airway collapse. In COPD patients the me-
chanical derangements described above will jeopardize weaning from mechanical
ventilation. Moreover, the weaning phase is a stress test for these patients, and this
may be a relevant issue not only because of its respiratory effects but also because
of its cardiovascular effects (Fig. 1).
'] ,<;=-;-.r>,.
53
'~~ lc;:-r-,. I <'r=r-- lc;=---;--., s---r-- I {'; I
83
-1 nme (s)
Fig. 1. Tracing from top to bottom of airway pressure (Pawl. airflow (Flow), esophageal pressure (P.,),
gastric pressure (Pgal, transdiaphragmatic pressure (P dil and tidal volume (volume) in COPD patient exhi-
biting overt cardiac failure during a spontaneous breathing trial (SBT). In this patient SBT was done with
PEEP 6 and pressure support of 8 cmH 20. This patient showed a major dynamic pulmonary hyperinfiltra-
tion (average corrected PEEPi dyn 8 cmH 20), a huge recruitment of expiratory muscles (as reflected by
the raising P9• during expiration), probably induced by both pulmonary edema and COPD. Note the pres-
ence of wasted inspiratory efforts (ventilator respiratory rate was about 18 breaths/minute and patient's
respiratory rate was about 28 breaths/minute)
I The Issue of Congestive Heart Failure in Weaning COPD Patients
The transition from full mechanical ventilatory support to spontaneous breathing

may be considered as exercise, thus increasing the oxygen demand, in particular of
the respiratory muscles [20]. The patient, depending on his/her hemodynamic sta-
tus will respond in different ways, augmenting the cardiac output or increasing the
oxygen extraction across the capillary beds in those situations without an adequate
cardiac response.
In normal conditions, oxygen consumption of the respiratory muscles is about
So/o of total body consumption. In a situation of increased oxygen demand, such as
weaning, the oxygen consumption of the respiratory muscles can increase up to
50% [21] . Thus, if the hemodynamic function is not well preserved, weaning can
fail [22, 23]. Patients with impaired cardiovascular function will not be able to gen-
erate a cardiac output suitable to the demand; oxygen transport will not be suffi-
cient to meet the metabolic needs of the respiratory muscles. Moreover, hypoxemia
will increase if'weaning induces left ventricular failure (due to ischemia and/or in-
crease in preload and/or afterload). Congestive heart failure leads the patient to
acute cardiogenic pulmonary edema, which in turn generates hypoxemia and in-
creases the mechanical load of the respiratory system.
In ICU patients, congestive heart failure may be diagnosed for the first time or
worsen as a consequence of an increase in venous return, hyperhydration or stress
with catecholamine release, such as weaning [24-26]. These factors determine nega-
tive effects in cardiac function, and together with hypoxemia, can favor the devel-
opment of acute pulmonary edema [6, 24, 25, 27].
One cause of acute pulmonary edema is diastolic cardiac dysfunction, frequently
associated with systemic hypertension [25]. In this setting, echocardiography has a
low sensitivity because most patients have a normal systolic function with a normal
ejection fraction [28]. Consequently, in intubated and mechanically ventilated pa-
tients the diagnosis is frequently made by a thermodilution catheter documenting
left ventricular failure. Although invasive, a thermodilution catheter allows a per-
manent monitoring of pulmonary artery pressure and frequent monitoring of pul-
monary capillary wedge pressure.
Lemaire et al. described the hemodynamic response during weaning in fifteen
COPD patients. They observed an increase in the pulmonary artery occlusion pres-
sure (PAOP} during the shift from a positive (mechanical ventilation) to a negative
(spontaneous breathing) intrathoracic pressure} [24].
In this scenario, many factors contribute to the increase in PAOP: an increased
preload includes an increased venous return as a consequence of decrease in pleur-
al pressure and sympathetic discharge, and also reduced left ventricular compliance
due to: 1) the myocardial ischemia (oxygen supply reduced, because of low Pa0 2
and/or increased oxygen demand, due to increased oxygen consumption of the res-
piratory muscles}; 2) left ventricular enlargement (due to augmentation in left ven-
tricular filling pressures and end-diastolic volumes); 3} right ventricular enlarge-
ment (ventricular interdependence); 4} compression of the heart chambers by re-
gionally hyperintlated lungs. Other factors are ischemia, which induces further de-
creases in cardiac contractility, and an increase in the afterload, with high systolic
blood pressure and disminished pleural pressure.
Lemaire et al. [24) concluded that the left ventricular dysfunction made the
weaning process even more difficult in COPD patients. Richard et al. [29] also
showed a decrease in left ventricular ejection fraction without coronary artery dis-
ease during weaning from mechanical ventilation; they hypothesized that this was
secondary to a increase in left ventricular afterload.
More recently, Jubran et al. [27] studied the hemodynamic changes during wean-
ing in a series of patients, most of them having COPD. One group of patients failed
to be weaned, while the other group was successfully weaned. During full mechani-
cal ventilatory support there were no significant differences between the success
and failure groups in terms of cardiac output or mixed venous oxygen saturation
{Sv02 }. When a SBT was initiated, successfully weaned patients showed an increase
in both cardiac output and oxygen transport in comparison with the values re-
corded during mechanical ventilation. These phenomena were not observed in un-
successfully weaned patients. Moreover, in this latter group, a decrease in Sv0 2
(secondary to the higher oxygen extraction from the capillary beds) and a decrease
in the oxygen transport (due in part to an increase in the preload and afterload)
was documented. Futhermore, an increase in arterial blood pressure was observed

in these patients.
Conclusion
When withdrawal from mechanical ventilation fails in COPD patients, the co-exis-
tence of cardiovascular disease must be ruled out. The most frequent clinical mani-
festations of cardiovascular disease during weaning are dyspnea, anxidy, tachyp-
nea, tachycardia and systemic hypertension. In both COPD decompensation and
left ventricular failure wheezing, hypoxemia and hypercapnia are common. As these
signs and symptoms are not specific, they are difficult to differentiate from respira-
tory pump failure alone. Clinical diagnosis of cardiac failure during weaning and
SBT may be challenging. Congestive heart failure diagnosis is crucial since the
treatment is not mechanical ventilation alone but includes specific therapy with
vasodilators and diuretics.
Cardiovascular disease must be ruled out in COPD patients because there is one
major common risk factor for both diseases: tobacco smoking. COPD patients also
have a severe derangement in gas exchange and in the mechanical properties of the
respiratory system. The shift from mechanical ventilation to spontaneous breathing
is a stressful test which may precipite overt cardiac failure if cardiovascular func-
tion is already impaired. In this scenario it is crucial to rule out congestive heart
failure or to treat it when it already exists.
References
1. Ely EW, Baker AM, Evans GW, Haponik EF (1999) The prognostic significance of passing a
daily screen of weaning parameters. Intensive Care Med 25:581-587
2. Mancebo J (1996) Weaning from mechanical ventilation. Eur Respir J 9:1923-1931
3. Kress JP, Pohlman AS, O'Connor MF, Hall JB (2000) Daily interruption of sedative infu-
sions in critically ill patients undergoing mechanical ventilation. N Engl J Med 342:1471-
1477
4. Vallverdu I, Calaf N, Subirana M, Net A, Benito S, Mancebo J (1998) Clinical characteris-
tics, respiratory functional parameters, and outcome of a two-hour T-piece trial in patients
weaning from mechanical ventilation. Am J Respir Crit Care Med 158:1855-1862
5. Ely EW, Baker AM, Dunagan DP, et al (1996) Effect on the duration of mechanical ventila-
tion of identifying patients capable of breathing spontaneously. N Engl J Med 335:1864-
1869
6. Jubran A (2002) Weaning induced cardiac failure. In: Mancebo J, Net A, Brochard L (eds)
Mechanical Ventilation and Weaning. Springer, Heidelberg, pp 184-192
7. Derenne P, Fleury B, Pariente R (1988) Acute respiratory failure of chronic obstructive pul-
monary disease. Am Rev Respir Dis 138:1006-1033
8. Tuxen DV (1994) Permissive hypercapnic ventilation. Am J Respir Crit Care Med 150:870-
874
9. Decramer M (1997) Hyperinflation and respiratory muscle interaction. Eur Respir J
10:934-941
10. Lessard MR, Lofaso F, Brochard L (1995) Expiratory muscle activity increases intrinsic po-
sitive end-expiratory pressure independently of dynamic hyperinflation in mechanically
ventilated patients. Am J Respir Crit Care Med 151:562-569
11. Rossi A, Polese G, Brandi G, Conti G (1995) Intrinsic positive end-expiratory pressure
(PEEPi). Intensive Care Med 21:522-536
12. Petrof BJ, Legare M, Goldberg P, Milic-Emili J, Gottfried SB (1990} Continuos positive air-
way pressure reduced work of breathing and dyspnea during from mechanical ventilation
in severe chronic obstructive pulmonary disease. Am Rev Respir Dis 141:281-289
13. Jubran A, Tobin MJ (1997) Pathophysiologic basis of acute respiratory distress in patients
who fail a trial of weaning from mechanical ventilation. Am J Respir Crit Care Med
155:906-915
14. De Troyer A (1997} Effect of hyperinflation on the diaphragm. Eur Respir J 10:708-713
15. Ranieri VM, Giuliani R, Cinnella G, et al (1993} Physiologic effects of positive end-expira-
tory pressure in patients with chronic obstructive pulmonary disease during acute ventila-
tory failure and controlled mechanical ventilation. Am Rev Respir Dis 147:5-13
16. Broseghini C, Brandolese R, Poggi R, et al (1988} Respiratory mechanics during the first
day of mechanical ventilation in patients with pulmonary edema and chronic airway ob-
struction. Am Rev Respir Dis 138:355-361
17. Smith TC, Marini JJ (1988} Impact of PEEP on lung mechanics and work of breathing in
severe airflow obstruction. J Appl Physiol 65:1488-1499
18. Mancebo J, Albaladejo P, Touchard D, et al (2000} Airway occlusion pressure to titrate posi-
tive end-expiratory pressure in patients with dynamic hyperinflation. Anesthesiology
93:81-90
19. Ranieri VM, Dambrosio M, Brienza N (1996) Intrinsic PEEP and cardiopulmonary interac-
tion in patients with COPD and acute ventilatory failure. Eur Respir J 9:1283-1292
20. Pinsky MR (2000) Breathing as exercise: the cardiovascular response to weaning from me-
chanical ventilation. Intensive Care Med 26:1164-1166
21. Mir6 M, Pinsky MR (1994) Heart-lung interactions. In: Tobin MJ (ed) Principles and Prac-
tice of Mechanical Ventilation. McGraw-Hill, New York, pp 647-671
22. Jones NL, Killian KJ (2000} Exercise limitation in health and disease. N Engl J Med 343:
632-641
23. O'Donnell DE, Revill SM, Webb KA (2001} Dynamic hyperinflation and exercise intoler-
ance in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 164:770-777
24. Lemaire F, Teboul JL, Cinotti L, et al (1988) Acute left ventricular dysfunction during un-
successful weaning from mechanical ventilation. Anesthesiology 69:171-179
25. Gandhi SK, Powers JC, Nomeir AM, et al (2001) The pathogenesis of acute pulmonary ede-
ma associated with hypertension. N Engl J Med 344:17-22
26. Poppas A, Rounds S (2002) Congestive heart failure. Am J Respir Crit Care Med 165:4-8
27. Jubran A, Mathru M, Dries D, et al (1998) Continuous recordings of mixed venous oxygen
saturation during weaning from mechanical ventilation and the ramifications thereof. Am J
28. Scharf SM, Iqbal M, Keller C, et al (2002} Hemodynamic characterization of patients with
severe emphysema. Am J Respir Crit Care Med 166:314-322
29. Richard C, Teboul JL, Archambaud F, et al (1994) Left ventricular function during weaning
of patients with chronic obstructive pulmonary disease. Intensive Care Med 20:181-186
j Inhalation Therapies
Inhalation Therapy during Mechanical Ventilation
E. Kondili, C. Alexopoulou, and D. Georgopoulos
I Introduction
Aerosol medications are commonly used in mechanically ventilated patients. Sev-

eral classes of drugs with different properties and indications may be given by in-
halation. In all cases, compared to the systemic route, inhaled therapy has the ad-
vantage that for a given therapeutic response, the drug dose is several-fold lower,
while systemic absorption is negligible, thus, greatly minimizing the side effects. In
addition, for some medications the systemic route either causes non-acceptable side
effects or results in considerably inferior therapeutic response, rendering the in-
haled route the method of choice of drug administration. Bronchodilators, corticos-
teroids, vasoactive drugs, surfactant, antibiotics, helium, and perfluorocarbons are
the medications that can be given by inhalation during mechanical ventilation.
I Bronchodilators
Bronchodilator agents are mainly administered in order to relax the airway smooth
muscle and, thus, to decrease the resistance to airflow. Adrenergic and anticholiner-
gic agents are the two main categories of bronchodilator that may be given by in-
halation (Table 1). It is well known that, especially in patients with obstructive lung
Table 1. Bronchodilator drugs that may be administered by inhalation
lDrug Recommended Initial Dose
Adrenergic agents MDI (J.ig) Nebulizer (mg)

(JJ2-agonists)
Fenoterol 200-400 0.5-2.0
Salbutamol 200-400 2.5-5.0
Terbutaline 500-100
Formoterol 24-48
Salmeterol 100-200
Anticholinergic agents
lpratropium bromide 80-160 0.25-0.5
Oxitropium bromide 400
306 E. Kondili et al.
MDI
Space chamber
l
To patient
Expiratory line
Fig. 1. Schematic representation of the metered dose inhaler (MDI) adapted to the spacer devise in the
inspiratory limb of the ventilator circuit. Notice that the MDI flume is directed away from the patient.
(From [2) with permission)
disease (COPD or asthma) or acute lung injury (ALI), inhaled bronchodilator

drugs administered with nebulizer or metered dose inhaler (MDI) during mechan-
ical ventilation, significantly decrease the resistance to airflow and dynamic hyper-
inflation [1, 2]. Although the use of MDis has several advantages over the nebulizer,
such as, ease of administration, reduced cost, less personnel time, reliability of dos-
ing, and a lower risk of contamination, the delivery of bronchodilators with MDI is
considered to be relatively ineffective due to drug deposition in the ventilator cir-
cuit and endotracheal tube. This consideration, however, is not supported by recent
data. Studies using a high volume spacer devise instead of elbow adapter did not
confirm these findings; bronchodilator delivery using an MDI and a spacer devise
results in a significant decrease in airflow resistance as well as in dynamic hyperin-
flation [3-6] (Fig. 1). In addition, the use of nebulizers may lead to patient ventila-
tor asynchrony especially with assisted modes due to increased ineffective efforts
[2].
Significant bronchodilation may be achieved without modification of the com-
monly used ventilator settings making the bronchodilator therapy using MDI and a
spacer a rather simple procedure [3- 6]. The optimal dose of bronchodilators deliv-
ered in mechanically ventilated patients is not clearly established. It seems that in
stable mechanically ventilated patients, 2-6 puffs of a short acting P2 -agonist may
achieve maximum or near maximum bronchodilation with no side effects. However,
patients with acute bronchospasm (i.e., status asthmaticus) may require higher
doses. An alternative strategy is the individual titration of the dose such as to
achieve the best bronchodilation with the minimum acceptable side effects [2]. The
optimal dose of other bronchodilators such as anticholinergic or long acting P2 -
agonists is not known. In addition, the optimal dose of bronchodilators adminis-
tered with nebulizer is also unknown.
The duration of the bronchodilator response is an important issue, which, sur-
prisingly, has not been adequately studied. In a recent study we observed that, in
patients with COPD, 6 puffs of salbutamol resulted in significant bronchodilation
Inhalation Therapy during Mechanical Ventilation 307
lasting approximately 3 hours [7]. Duarte et al. [8] in COPD patients compared the
duration of bronchodilation of 4 and 10 puffs of albuterol administered with MDI
and a spacer with that achieved with 2.5 mg of albuterol given via nebulizer. The
duration of bronchodilation ranged between 90 and 120 min without any depen-
dence on the dose and the mode of drug delivery. The findings of the above studies
indicate that the duration of bronchodilation in mechanically ventilated patients is
decreased compared to that in ambulatory patients, in line with the systemic bio-
availability data of inhaled albuterol obtained by Duarte et al. [8]. It follows that
the dose interval when bronchodilator drugs are given either with MDI or with
nebulizer in mechanically ventilated patients might be shorter than that in ambula-
tory patients.
,8-adrenergic agonists are commonly administered to patients with acute pulmo-
nary edema, particularly when auscultation reveals rhonchi, rales, or expiratory
wheezes on physical examination. In addition, in patients with ALI or hydrostatic
pulmonary edema the delivery of adrenergic bronchodilators might be beneficial
because this class of medications enhances the epithelial fluid clearance via several
mechanisms involving the function of the Na +-K+-ATPase pump and the amiloride
sensitive epithelial Na channel [9]. It has been shown recently that alveolar fluid
clearance is impaired in the majority of patients with acute respiratory distress syn-
drome (ARDS)/ ALI, particularly in sepsis, and that decreased clearance is asso-
ciated with higher morbidity and mortality [10]. Therefore, in these patients,
adrenrgic bronchodilators may accelerate the resolution of pulmonary edema and
improve the outcome. Interestingly, several animal studies have demonstrated that
the fluid clearance rate from the alveolar space can be markedly increased by .Br
adrenergic agonists that have been instilled or aerosolized to the distal airspaces
[11-13]. Among the ,82 -agonists, the inhaled lipid-soluble agent salmeterol seems to
have the more potent effect [12]. In sheep, 5 mg of salmeterol delivered by simple
nebulizer resulted in a high concentration (10- 6 M) in alveolar edema fluid even 3
h after administration [12]. Studies in ex vivo human lung indicate that this con-
centration elicits a maximal or near maximal response [14]. Frank et al. showed
that nebulized salmeterol resulted in a 60% increase in alveolar liquid clearance in
sheep with hydrostatic pulmonary edema [12]. Studies in humans and animal mod-
els with hydrostatic pulmonary edema or ALI show that ,82 -agonists can accelerate
the resolution of alveolar edema [12, 13, 15]. The dose-response curve for the effect
of .Bragonists on up-regulating the rate of alveolar fluid clearance has been defined
in the ex vivo human lung [14]. Most studies have indicated that only a small
fraction of aerosolized particles are delivered to the proximal airway, with an even
smaller proportion reaching distal airways. However, it is not known whether aero-
solization of ,82 -agonists in intubated, ventilated patients delivers therapeutic levels
to the distal airways and alveoli, the primary sites of reabsorption of pulmonary
edema. If therapeutic concentrations of an aerosolized ,8-adrenergic agonist could
be delivered to the alveoli in patients with acute pulmonary edema, the resolution
of alveolar edema might be accelerated.
Data on the pharmacokinetics of albuterol are limited primarily to studies of
plasma concentrations measured after inhaled, oral, or intravenous administration.
In a recent study, Atabai et al. measured edema fluid and plasma concentrations of
a commonly used ,82 -agonist, albuterol, in samples obtained from patients with
acute pulmonary edema, either hydrostatic or of high permeability form [16]. The
authors reported that administration of standard doses of albuterol (4.2 ± 3.2 mg)
through a mechanical ventilator circuit resulted in pulmonary edema fluid drug
levels that are sufficient to augment alveolar fluid clearance based on ex vivo hu-
man lung studies.
I Corticosteroids
It is now well established that high doses of systemic corticosteroids should be part
of the standard therapy in patients with acute exacerbation of COPD or asthma, de-
creasing the possibility of treatment failure and the time of lung function restora-
tion. In addition, Rubini et al. have shown in mechanically ventilated COPD pa-
tients that systemic administration of methylprednisolone resulted in an acute im-
provement of respiratory system mechanics [17]. The use of high doses of systemic
corticosteroids, however, is associated with significant side effects and inhaled ste-
roids might be an alternative. Indeed, Nava et al. [18] have shown recently in stable
COPD patients on long-term mechanical ventilatory support that inhaled flutica-
sone propionate for 5 days significantly decreased airway resistance and intrinsic
positive airway pressure (PEEPi). If these results are applicable in mechanically
ventilated patients with acute exacerbation of COPD or in patients with status asth-
maticus then inhaled steroids combined with bronchodilators might be used to de-
crease the airway wall inflammation as well as the dynamic hyperinflation, with
minimal side effects. Surprisingly, there are no data on this important topic.
Antibiotics
In order for an antimicrobial agent to be effective, it must fulfil two requirements.
First, the agent must reach the site of infection and remain in the vicinity for an
adequate length of time. Second, it must bind to a target site and remain bound
for a length of time sufficient to disrupt the life cycle of the cell. Once these re-
quirements are met, the drug is able to exert its antimicrobial activity against the
cell. Knowledge and application of pharmacodynamic principles can assist clini-
cians in optimizing antimicrobial therapy by allowing them to maximize the anti-
microbial activity of an agent while minimizing patient exposure and thus reducing
the likelihood of toxicity.
The use of aerosolized antibiotics for lung infections has the advantage over the
systemic administration of the drug in providing a high concentration directly to
the site of infection. Aminoglycosides, pentamidine, polymixin, ribavarin, and am-
photericin B are some of the anti-infective drugs that have been given by inhalation
in patients prone to colonization with potential pathogens, such as patients with
cystic fibrosis, chronic ventilator dependence, bronchiectasis, and acquired immu-
nodeficiency syndrome (AIDS) [2]. Ventilator-associated pneumonia (VAP) is the
most frequent nosocomial infection in the critically ill, and Gram-negative bacilli
are the causative microorganisms in more than 60% of cases. Because of the sever-
ity of these infections and the increasing incidence of multiresistant causative or-
ganisms, intravenous aminoglycosides are commonly used in association with beta-
lactam antibiotics. The tissue concentration at the site of infection is the main de-
terminant of bactericidal efficiency, whereas toxicity depends on the trough plasma
concentration [19]. Intravenous aminoglycosides easily penetrate in lung parenchy-
ma and bronchial secretions according to the plasma-tissue concentration ratio.
However, lung tissue concentrations remain small because plasma levels are kept
low deliberately to avoid toxicity [20]. Aerosol administration offers the theoretical
advantage of high concentrations of antibiotics at the site of infection together with
a low systemic absorption resulting in reduced renal toxicity. It has been previously
demonstrated that the intratracheal administration of colistin significantly reduced
the incidence of YAP in a large series of critically ill patients [21]. On the other
hand, little information exists on the deposition of aerosolized antibiotics into the
pulmonary parenchyma during mechanical ventilation. A number of human studies
have measured concentrations of inhaled aminoglycosides in bronchial secretions
and demonstrated that these concentrations are more indicative of the deposition
of the antibiotic in the central airways than in the alveolar compartment [22, 23].
Because of methodological limitations regarding tissue sampling in humans, an an-
imal model is required to assess the quantitative deposition of inhaled aminoglyco-
sides in the whole lung parenchyma. According to previous studies that identified
parameters required for an optimal delivery of aerosols, an ultrasonic nebulizer
equipped with a large reservoir was selected to administer amikacin in a previously
validated experimental model of mechanically ventilated piglets [24]. In conclusion,
a substantial penetration of aerosolized amikacin into the distal lung of mechani-
cally ventilated piglets was demonstrated using an optimized ultrasonic nebulizer.
The lung concentrations of inhaled amikacin were more than 10-fold higher than
that achieved with intravenous amikacin, reaching levels considerably higher than
the minimal inhibitory concentrations (MIC) of the most resistant strains. Because
this first study dealt with healthy lungs, the main clinical implications may be the
prevention of pulmonary infections as previously reported for intratracheal colistin
and the treatment of early stages of bronchopneumonia where the lung remains
well aerated [21]. The clinical relevance of the present data for treating confluent
bronchopneumonia complicating mechanical ventilation is uncertain, as tissue con-
centrations of amikacin in infected and poorly aerated lung parenchyma may be
lower. Further studies are required to investigate the lung deposition of nebulized
amikacin in severely infected lung parenchyma.
Data in stable mechanically ventilated patients with tracheobronchitis indicate
that therapy with aerosolized aminoglycosides might decrease the risk of YAP, while
preserving the oral and gut flora with limited bacterial resistance [25]. However,
the clinical significance of these findings is uncertain and further carefully de-
signed studies are needed.
The emergence of resistant bacteria is a potential major disadvantage of inhaled
antibiotics. This issue is highly controversial and the reported incidence of resis-
tance rates is variable [25, 26]. In patients with bronchiectasis, tobramycin resistant
P. aeruginosa strains developed in 11 o/o of patients treated with inhaled tobramycin
and 3o/o of patients receiving placebo [25]. Bronchospasm is another side effect of
inhaled antibiotic therapy, mainly observed with aerosolized polymyxin.
I Vasoactive Drugs
The vasoactive drugs are classified as vasodilators or vasoconstrictors. In general,

vasodilators are vasoactive medications commonly used during mechanical ventila-
tion in order to modulate the tone of pulmonary vasculature when severe derange-
ment of gas exchange properties of the lung and pulmonary hypertension ensue
tr::::=:::=:::r l (··
..............
..···r
t·.--
······-·--·
-:·l
--~·······
t l
Fig. 2. Schematic diagram showing the rationale of administering inhaled vasodilators with short-half life.
During intravenous infusion of a vasodilator drug which is not deactivated through the first pass from
the lung the amount of blood passing through poorly or non-ventilated lung regions increases due to
non-selective vasodilation. This may result in deterioration of oxygenation. Hypotension may also occur
due .to vasodilation of systemic circulation. Administering a vasodilator with short half-life by inhalation
the vasodilation is restricted to lung regions with relatively preserved ventilation, thereby reducing the
shunt and improving the ventilation/perfusion ratio, without systemic effects. Alv: Alveolus. RH: Right
heart. LH: Left heart. (From [2) with permission)
[27). The ideal vasodilator should have short biological life and act on vessels
subserving open alveoli that contribute to ventilation. These features should limit
the side effects associated with an action on systemic circulation and increase in
right to left shunt (Fig. 2). Obviously, the inhaled route is the mode of choice of
drug administration when modulation of the tone of pulmonary vasculature is
desirable.
Nitric oxide (NO) is an endothelium-derived relaxing factor, which can be deliv-
ered only by inhalation and, thus, vasodilates vessels adjacent to well-ventilated
lung regions. In humans with ARDS or pulmonary hypertension inhaled NO causes
an acute decrease in pulmonary arterial pressure, intrapulmonary right to left
shunt, and dead-space volume, changes associated with an improvement in arterial
P0 2 [28]. Negative predictors of response to NO are sepsis and the inability to re-
cruit the lung and low baseline pulmonary vascular resistance [29]. Most patients
respond at doses from 5 to 40 PPM [28] . Although NO is close to being an ideal
pulmonary vasodilator, complex and expensive technology is needed, to insure safe
and effective use. The other major problem is the risk of methemoglobinemia, even
with therapeutic doses and the rebound vasoconstriction upon treatment disconti-
nuation. Older age, multi-system organ failure (MOF) and initial blood pressure in-
crease in response to NO are factors independently associated with significant he-
modynamic deterioration after abrupt therapy withdrawal [30].
Inhaled prostacyclin (PGI 2 ) and prostaglandin E2 (PGE 1 ) are other vasodilators
that have been used to dilate the pulmonary vasculature during conventional or
partial liquid mechanical ventilation [28, 31]. In general, comparable effects on gas
exchange have been reported for both agents, although the time to reach the peak
effect on Pa0 2 is much slower with PGI 2 and PGE 1 [28]. As with NO, the response
to inhaled PGI2 and PGE 1 is variable and difficult to predict. Although a recent
study suggested that patients with secondary ARDS might respond better to in-
haled PGI 2 than those with primary ARDS, others have shown that inhaled PGI2 in
primary ARDS is also effective [31]. Iloprost is a stable prostacyclin analog with
strong vasodilatory and antithrombotic properties [32]. Inhaled iloprost decreases
pulmonary artery pressure and increases cardiac output without affecting mean
systemic arterial pressure in severe primary and secondary pulmonary hyperten-
sion. In addition, evidence of long-term beneficial effects of daily repetitive iloprost
inhalation has been reported [32]. In comparison with the duration of inhaled
prostacyclin (10-20 min), the pulmonary vasodilatory response to nebulized ilo-
prost lasts significantly longer (45-90 min). Nevertheless, patients need multiple
daily inhalation maneuvers to achieve substantial alleviation of pulmonary hyper-
tension when employing inhaled iloprost for long-term treatment. The relatively
simple technique of PGI 2 and PGE 1 administration using commercial nebulizers
makes these substances an attractive and possibly better alternative to NO. How-
ever, it is an expensive therapy, particularly as there is much wastage of active drug
even with efficient delivery systems. Neither NO nor inhaled PGI2 and PGE2 are in-
dicated as standard treatment in mechanically ventilated patients with ARDS [28].
However, inhaled vasodilator therapy could be useful as a rescue therapy in an in-
dividual patient with refractory hypoxemia or with severe pulmonary hypertension
and impeding right heart failure.
I Surfactant
Since the first description of ARDS, disturbances of the alveolar surfactant system
have been proposed as a major determinant of the pathophysiology of the syn-
drome. Studies in animal models and patients with ARDS have demonstrated sur-
factant deficiency and dysfunction [33, 34]. Functional abnormalities of surfactant
promote alveolar collapse and decrease lung compliance, necessitating higher air-
way pressures and inspired oxygen concentration to provide adequate oxygenation
[28]. It follows that exogenous administration of surfactant in patients with ALI is
a reasonable choice and surfactant replacement therapy might be considered for
restoration of gas exchange and improvement in lung mechanics. Furthermore,
studies in ARDS animal models have shown that surfactant replacement therapy
may exhibit a favorable effect on inflammatory response and ventilator-induced
lung injury (VILI) [35, 36].
Several small non-randomized studies of surfactant therapy suggest that admin-
istration of artificial surfactant in selected patients with ARDS may be beneficial in
terms of gas exchange and lung mechanics. In these studies, surfactant was given
in large doses (ranging between 50 and 500 mg!Kg of phospholipids) via direct in-
tratracheal or bronchoscopic application and resulted in oxygenation improvement
and reduction of mortality [37]. Nevertheless, with this route the cost of therapy, at
least in adults, is extremely high, whereas the large volume of liquid may cause re-
gional obstruction and instantaneous gas-exchange deterioration. These shortcom-
ings make the aerosolization of surfactant using a nebulizer a much more attractive
technique. Data in animals indicate that inhaled is equally or even more effective
than bronchial instilled surfactant therapy, despite the considerably lower drug dose
[38].
Although inhaled surfactant therapy is attractive and supported by data in ani-
mals and humans, a large randomized trial in patients with sepsis-induced ARDS
failed to demonstrate a significant effect of continuous administration of aeroso-
lized synthetic surfactant (Exosurf, 112 mg/Kg!day) on 30 day survival, length of
ICU stay, or duration of mechanical ventilation [39]. The inadequate drug delivery
to alveoli and the lack of a protein component of the used artificial surfactant may
be responsible for the negative results. Furthermore, it has been shown that the ef-
ficacy of exogenous surfactant may be influenced by ventilatory strategies, such as
recruitment maneuvers or PEEP application [40]. Nevertheless, despite these disap-
pointing results, the administration of aerosolized surfactant in ARDS patients
deserves further study. Currently, aerosolized surfactant is not recommended as a
part of the standard therapy of ARDS.
I Helium
Helium is an inert gas with unique physical properties, which might be useful for
various respiratory emergencies. In mechanically ventilated patients, by substituting
the air-oxygen with an oxygen-helium mixture (heliox) - which has considerably
lower gas density - a decrease in airflow resistance ensues [41]. Tassaux et al. have
shown in mechanically ventilated COPD patients that the use of He-oxygen mixture
reduces dynamic hyperinflation and lowers peak, mean, and intrinsic PEEP [41].
No side effects have been observed with heliox breathing. It appears that heliox is
an attractive and safe treatment for dynamic hyperinflation due to high airflow re-
sistance Heliox breathing has been applied also during non-invasive ventilation
(NIV) [42]. Jabber et al. demonstrated in patients with acute exacerbation of COPD
that substituting heliox (78:22) for air-oxygen enhanced the efficacy of non-invasive
pressure support ventilation [42]. These results indicate that the use of heliox dur-
ing NIV may further increase the effectiveness of this therapy to avoid intubation.
Furthermore the use of heliox has been shown to be beneficial in the postextuba-
tion period [43]. Jaber et al. used a helium-oxygen mixture in non-COPD patients
during the postextubation period and observed a decreased inspiratory effort asso-
ciated with an improvement in patient comfort [43]. These findings might have
clinical application in selected patients by decreasing the reintubation rate. Finally,
the use of heliox in the ventilator circuit may improve aerosol delivery. Goode et
al. [44] in an in vitro lung model of mechanical ventilation demonstrated that
heliox (80:20) increased significantly the albuterol delivery from both MDI and
nebulizer by as much as 50%. Whether this increase is associated with better clini-
cal outcome remains to be determined.
The use of heliox presents some problems, mainly related to the interference of
ventilator function by helium. Discrepancies have been found between the actual
volume of oxygen delivered by the ventilator and that set by the operator [45]. The
relationship between the actual and dialed ventilator settings depends on the type
of the ventilator used. This should be taken into account and, when heliox is used,
correction factors should be applied in order to avoid false readings from the venti-
lator.
I Perfluorocarbon
Perfluorocarbons are biologically inert compounds characterized by high-density,
low surface tension, and high respiratory gas solubility. Perfluorocarbon has been
used to partially fill the lungs, which are mechanically ventilated with conventional
or high frequency modes, a strategy termed partial liquid ventilation (PLY) [46].
During PLY, perfluorocarbon is distributed primarily to the dorsal atelectatic lung
regions. This results in recruitment of collapsed areas, increase in functional resi-
dual capacity (FRC) and compliance, improvement of gas exchange and decrease in
shunt flow. PLY, however, is associated with significant side effects and requires
considerable respiratory care. Because of these drawbacks, aerosolized and vapor-
ized perfluorocarbons have been used as an alternative mode of administration.
Both methods have the advantage of a more uniform distribution of the medica-
tion. Kandler et al. in a surfactant-depleted piglet lung model compared aerosolized
perfluorocarbon with PLY and showed that aerosolized perfluorocarbon resulted in
an improvement in oxygenation and lung mechanics that was sustained much long-
er [47]. It is of interest to note that 6 hours after the aerosol treatment the Pa0 2
and dynamic compliance were at near maximal values [47]. Hubler et al. in an ex-
perimental ALI animal model studied the effect of vaporized perfluorocarbon ad-
ministration on ventilator-perfusion matching and demonstrated that treatment
with vaporized perfluorocarbon improved gas exchange by increasing ventilation/
perfusion metching [48]. In a lung model of oleic-acid-induced ARDS, Bleyl et al.
showed that vaporized perfluorocarbon resulted in a significant improvement in
peak inspiratory pressure and compliance as well as in a decrease in alveolar-arteri-
al oxygen difference [49]. However, vaporized administration of perfluorocarbon,
similar to heliox, has some disadvantages related to errors in measurement of ven-
tilatory parametrs. In a recent study, Davies and Dunster showed that the presence
of perfluorocarbon vapor during PLY resulted in .overestimation of the delivered
tidal volume [SO]. At present, aerosolized perfluorocarbon remains an experimental
therapy and further clinical studies are necessary.
I Conclusion
Bronchodilators, corticosteroids, vasoactive drugs, surfactant, antibiotics, helium,
and perfluorocarbons are the medications that can be given by inhalation during
mechanical ventilation. Although this mode of therapy has several advantages over
the systemic route, only inhaled bronchodilators are recommended as standard
practice in patients with obstructive lung disease. The role of the other inhaled
drugs in mechanically ventilated patients is not well established. Some, such as cor-
ticosteroids, vasoactive drugs, surfactant, antibiotics, and helium may be used in
selected patients, whereas the use of others (perfluorocarbons) remains experimen-
tal. Further studies are needed to clarify the indications and the groups of patients
that will benefit more from this form of therapy.
References
1. Dhand R, Tobin MJ (1997) Inhaled bronchodilator therapy in mechanically ventilated pa-
tients. Am J Respir Crit Care Med 156:3-10
2. Kondili E, Georgopoulos D (2002) Aerosol medications. Respir Care Clin 8:309-334
3. Mouloudi E, Katsanoulas K, Anastasaki M, Hoing S, Georgopoulos D (1999) Bronchodilator
delivery by metered-dose inhaler in mechanically ventilated COPD patients: influence of
tidal volume. Intensive Care Med 25:1215-1221
4. Mouloudi E, Katsanoulas K, Anastasaki M, Askitopoulou E, Georgopoulos D (1998)
Bronchodilator delivery by metered-dose inhaler in mechanically ventilated COPD patients:
influence of end-inspiratory pause. Eur Respir J 12:165-169
5. Mouloudi E, Prinianakis G, Kondili E, Georgopoulos D (2000) Bronchodilator delivery by
metered-dose inhaler in mechanically ventilated COPD patients: influence of flow pattern.
Eur Respir J 16:263-268
6. Mouloudi E, Prinianakis G, Kondili E, Georgopoulos D (2001) Effect of inspiratory flow
rate on beta2-agonist induced bronchodilation in mechanically ventilated COPD patients.
Intensive Care Med 27:42-46
7. Mouloudi E, Malliotakis Ch, Kondili E, Kafetzakis A, Georgopoulos D (2001) Duration of
salbutamol-induced bronchodilation delivered by meter-dose inhaler in mechanically venti-
lated patients with chronic obstructive pulmonary disease. Monaldi Arch Chest Dis 56:
189-194
8. Duarte AG, Momi K, Bidani A (2000) Bronchodilator therapy with metered-dose inhaler
and spacer versus nebulizer in mechanically ventilated patients: comparison of magnitude
and duration of response. Respir Care 45:817-823
9. Crandall ED, Matthay MA (2001) Alveolar epithelial transport. Basic science to clinical
medicine. Am J Respir Crit Care Med 163:1021-1029
10. Ware LB, Matthay MA (2001) Alveolar fluid clearance is impaired in the majority of pa-
tients with acute lung injury and the acute respiratory distress syndrome. Am J Respir Crit
Care Med 163:1376-1383
11. Berthiaume Y, Staub NC, Matthay MA (1987) Beta-adrenergic agonists increase lung liquid
clearance in anesthetized sheep. J Clin Invest 79:335-343
12. Frank JA, Wang Y, Osorio 0, Matthay MA (2000) Beta-adrenergic agonist therapy the reso-
lution of hydrostatic pulmonary edema in sheep and rats. J Appl Physiol 89:1255-1265
13. Garat C, Meignan M, Matthay MA, Luo DF, Jayr C (1997) Alveolar epithelial fluid clearance
mechanisms are intact after moderate hyperoxic lung injury in rats. Chest 111:1381-1388
14. Sakuma T, Folkesson HG, Suzuki S, Okaniwa G, Fujimura S, Matthay MA (1997) Beta-
adrenergic agonist stimulated alveolar fluid clearance in ex vivo human and rat lungs. Am
J Respir Crit Care Med 155:506-512
15. Verghese GM, Ware LB, Matthay BA, Matthay MA (1999) Alveolar epithelial fluid transport
and the resolution of clinically severe hydrostatic pulmonary edema. J Appl Physiol 87:
1301-1312
16. Atabai K, Ware LB, Snider ME, et a! (2002) Aerosolized P2 -adrenergic agonists achieve
therapeutic levels in the pulmonary edema fluid of ventilated patients with acute respira-
tory failure. Intensive Care Med 28: 705-711
17. Rubini F, Rambulla C, Nava S (1994) Acute effect of corticosteroids on respiratory
mechanics in mechanically ventilated patients with chronic airflow obstruction and acute
respiratory failure. Am J Respir Crit Care Med 149:306-310
18. Nava S, Compagnoni ML (2000) Controlled short-term trial of fluticasone propionate in
ventilator-dependent patients with COPD. Chest 118:990-999
19. Moore RD, Smith CR, Lietman PS (1984) Association of aminoglycoside plasma levels with
therapeutic outcome in gram-negative pneumonia. Am J Med 77:657-662
20. Pennington JE (1981) Penetration of antibiotics into respiratory secretions. Rev Infect Dis
3:67-73
21. Rouby JJ, Poete P, Martin de Lassale E, et a! (1994) Prevention of Gram negative noso-
comial bronchopneumonia by intratracheal colistin in critically ill patients. Histologic and
bacteriologic study. Intensive Care Med 20:187-192
22. Klastersky J, Geuning C, Mouawad E, Daneau D (1972) Endotracheal gentamicin in bron-

chial infections in patients with tracheostomy. Chest 61:117-120
23. Ilowite JS, Gorvoy JD, Smaldone GC (1987) Quantitative deposition of aerosolized gentami-
cin in cystic fibrosis. Am Rev Respir Dis 136:1445-1449
24. Goldstein I, Wallet F, Robert J, et al (2002) Lung tissue concentrations of nebulized amika-
cin during mechanical ventilation in piglets with healthy lungs. Am J Respir Grit Care Med
165:171-175
25. Palmer LB, Smaldone GC, Simon SR, O'Riordan TG, Cuccia A (1998) Aerosolized antibio-
tics in mechanically ventilated patients: delivery and response. Grit Care Med 26:31-39
26. Barker AF, Couch L, Fie! SB, et al (2000) Tobramycin solution for inhalation reduces
sputum Pseudomonas aeroginosa density in bronchiectacis. Am J Respir Grit Care Med
162:481-485
27. Zimmerman JL, Hanania NA (1998) Vasodilators in mechanical ventilated patients. Grit
Care Clin 14:611-627
28. Mcintyre RC, Pulido EJ, Bensard DD, Gotfriedet MA, Ilowite J, Meyer KC (2000) Thirty
years of clinical trials in acute respiratory distress syndrome. Grit Care Med 28:3314-3331
29. Puybasset L, Roudyt JJ, Mourgeon E, et al (1995) Factors influencing cardiopulmonary ef-
fects of inhaled nitric oxide in acute respiratory failure. Am J Respir Grit Care 152:318-328
30. Christenson J, Lavoie A, O'Connor M, Bhorade S, Pohlman A, Hall JB (2000) The incidence
and pathogenesis of cardiopulmonary deterioration after abrupt withdrawal of inhaled
nitric oxide. Am J Respir Grit Care Med 161:1443-1449
31. Domenighetti G, Stricker H, Waldispuehl B (2001) Nebulized prostacyclin in acute respira-
tory distress syndrome: impact of primary (pulmonary injury) and secondary (extrapul-
monary injury) disease on gas exchange response. Grit Care Med 29:57-62
32. Muller B, Schmidtke M, Witt W (1987) Action of the stable prostacyclin analogue iloprost
on microvascular tone and permeability in the hamster cheek pouch. Prostaglandins Leu-
kat Med 29: 187-198
33. Gregory TJ, Longmore WJ, Moxley MA, et al (1991) Surfactant chemical composition and
biophysical activity in acute respiratory distress syndrome. J Clin Invest 88:1976-1981
34. Lewis JF, Jobe AH (1993) Surfactant in adult respiratory distress syndrome. Am Rev Respir
Dis 147:218-233
35. Vazquez de GF, Lachmann RA, Gammers D, Verbrugge SJ, Haitsma J, Lachmann B (2001)
Treatment of ventilation-induced lung injury with exogenous. Intensive Care Med 27:559-
565
36. Haitsma JJ, Uhlig S, Lachmann U, Verbrugge SJ, Poelma DL, Lachmann B (2002) Exoge-
nous surfactant reduces ventilator-induced decompartmentalization of tumor necrosis fac-
tor alpha in absence of positive end - expiratory pressure. Intensive Care Med 28:1131-
1137
37. Frerking I, Gunther A, Seeger W, P Ison U (2001) Pulmonary surfactant: functions ab-
normalities and therapeutic options. Intensive Care Med 27: 1699-1717
38. Schermuly R, Gunther F, Weissmann N, et al (2000) Differential impact of ultrasonic
nebulized versus instilled surfactant on ventilation perfusion mismatch V A/Q) in a model
of acute lung injury. Am J Respir Grit Care Med 16:152-159
39. Anzueto A, Baughman RP, Kalpalatha K, et al (1996) Aerosolized surfactant in adults with
sepsis- induced acute respiratory distress syndrome. N Engl J Med 334:1417-1422
40. Kerr CL, Ito Y, Manwell SE, et al (1998) Effects of surfactant distribution and ventilation
strategies on the efficacy of exogenous surfactant. J Appl Physiol 85:676-684
41. Tassaux D, Jolliet P, Roeseler J, Chevrolet JC (2000) Effects of helium-oxygen on intrinsic
positive end-expiratory pressure in intubated and mechanicalventilated patients with severe
chronic obstructive pulmonary disease. Grit Care Med 28:2721-2728
42. Jaber S, Fodil R, Carlucci A, et al (2000) Noninvasive ventilation with helium-oxygen in
acute exacerbation of chronic obstructive pulmonary disease. Am J Respir Grit Care Med
161:1191-1200
43. Jaber S, Carlucci A, Boussarsar M, et al (2001} Heliox - oxygen in the postextubation
period decreases inspiratory effort. Am J Respir Grit Care Med 164:633-637
316 E. Kondili et al.: Inhalation Therapy during Mechanical Ventilation
44. Goode ML, Fink JB, Dhand R, Tobin MJ (2001) Improvement in aerosol delivery with
helium-oxygen mixtures during mechanical ventilation. Am J Respir Grit Care Med 163:
109-114
45. Tassaux D, Jolliet P, Thouret JM, Roeseler J, Dorne R, Chervolet JC (1998) Calibration of
seven ICU ventilators for mechanical ventilation with helium-oxygen mixtures. Grit Care
Med 26:290-295
46. Hirschi R, Pranikoff R, Wise C, et al (1996) Initial experience with partial liquid ventila-
tion in adult patients with the acute respiratory distress syndrome. JAMA 275:383-389
47. Kandler M, von der Hardt I, Schoof E, Dotsch J, Rascher W (2001) Persistent improvement
of gas exchange and lung mechanics by aerosolized perfluorocarbon. Am J Respir Grit
Care Med 164:31-35
48. Hubler M, Souders JE, Shade ED, Polissar NL, Schimmel C, Hlastala MP (2001) Effects of
vaporized perfluorocarbon on pulmonary blood flow and ventilation /perfusion distribu-
tion in a model of acute respiratory distress syndrome. Anesthesiology 95:1414-1421
49. Bleyl J, Ragaller M, Tscho U, et al (1999) Vaporized perfluorocarbon improves oxygenation
and pulmonary function in an ovine model of acute respiratory distress syndrome. An-
SO. Davis MW, Dunster KR (2002) Effect of perfluorocarbon (perflurooctyl bromide) vapor on
tidal volume measurement during partial liquid ventilation. Grit Care Med 30:1123-1125
Trials on Surfactant Replacement Therapy in Patients
with ARDS
M. J. Schultz, J. Kesecioglu, and B. Lachmann
I Introduction
Surfactant is synthesized by alveolar type II cells, stored in the lamellar bodies, and
secreted to the alveolar space where it covers the epithelial surface [1]. Surfactant
consists of phospholipids (85%), different proteins, lipids, and carbohydrates [2].
Surfactant proteins (SP}-B and SP-C are small, extremely hydrophobic proteins that
are important in surfactant dynamics within the terminal air spaces and are an
essential part in the reduction of surface tension [3]. The composition of surfactant
changes in various disease states [4], which leads to alveolar instability, alveolar
flooding and alveolar collapse. Initially, surfactant abnormalities were found in in-
fant respiratory distress syndrome (IRDS); later on, changes in the surfactant sys-
tem were also demonstrated in acute respiratory distress syndrome (ARDS) [5, 6].
Both qualitative and quantitative changes of surfactant have been described in pa-
tients with established ARDS [6-8], and in patients at risk for ARDS [8].
In neonates, Fujiwara et al. reported exogenous surfactant therapy for the first
time in 1980 [9]. Thereafter, several studies showed a clear reduction of mortality
and morbidity in neonates after surfactant therapy [10]. Surfactant replacement
therapy is now well established in the management of IRDS, and represents stan-
dard care for neonates requiring mechanical ventilation [11, 12]. Use of the natural
surfactant of Fujiwara in an adult surfactant deficiency model indicated that exoge-
nous surfactant might be a potential therapy for ARDS to improve gas exchange
and outcome [9]. Indeed, numerous animal models with ARDS lungs have demon-
strated that exogenous surfactant improves gas exchange and lung mechanics [13].
To date, clinical ARDS trials have produced diverse results [14-18], and the Federal
Drug Administration (FDA) has not yet approved the use of surfactant preparations
in patients with ARDS. However, data from recent studies show that surfactant
replacement therapy may prove to be an important adjunctive therapy in patients
with ARDS.
Here we discuss the published and unpublished studies on surfactant replace-
ment in ARDS. Special attention is paid to the composition of the exogenous sur-
factant used in these studies, as well as to the mode of delivery of the surfactant,
since we consider the differences in composition and the way of administration to
be important for the effectiveness of surfactant replacement in patients with ARDS.
Furthermore we will discuss the safety of this therapy.
318 M. J. Schultz et al.
Rationale for Surfactant Replacement Therapy in ARDS
Since there are many similarities between IRDS and ARDS, Ashbaugh and collea-
gues postulated that the surface-active material of the lung is abnormal in patients
with ARDS [5]. It is well established that abnormalities of the surfactant system
occur in ARDS and that these abnormalities contribute to the pathophysiology of
ARDS. Whereas in IRDS a deficiency of surfactant is the initiating problem, in
ARDS both deficiency of surfactant and biophysical/biochemical abnormalities of
the pulmonary surfactant system have been observed (reviewed in [3]).
The rationale for surfactant replacement therapy in patients with ARDS is both
to restore the normal composition of the surfactant system, and to overcome the
(ongoing) inactivation of present surfactant (i.e., by plasma proteins). It is clear
that higher doses of surfactant are needed in ARDS then in IRDS because of the
presence of inactivating factors in the pulmonary compartment during ARDS. Stud-
ies have shown that surfactant replacement can normalize the composition of the
surfactant system [19, 20], restore its surface activity [20], and thereby restore gas
exchange [17, 19, 21, 22].
I Studies on Surfactant Replacement in ARDS
In 1987, a child with near drowning and superimposed pneumonia was treated with
exogenous surfactant, resulting in a dramatic improvement of gas exchange [23].
This was the first report on the treatment of an ARDS patient with exogenous sur-
factant. Richman et al. described their initial experience with surfactant replace-
ment in three patients in 1989 [24], and Haslam et al. described 4 patients that
were treated with surfactant in 1994 [25]. Since then several pilot studies, four
phase-II studies, and two phase-III studies have been performed to investigate the
efficacy of surfactant replacement therapy in patients with ARDS (Table 1).
Pilot and Phase-1 Studies on Surfactant Replacement Therapy

Walmrath et al. and Gunther et al. investigated the impact of bronchoscopic instilla-
tion of a natural bovine surfactant extract (Alveofact) on the biochemical and bio-
physical properties of surfactant in patients with severe and early ARDS and septic
shock [20, 22]. In the same group of patients they investigated the efficacy of
bronchoscopic surfactant instillation on gas exchange [20]. A total of 27 patients
were described in three reports in this pilot study, which contained no control
group (i.e., there were no patients with ARDS not receiving surfactant). Severe sur-
factant abnormalities were demonstrated in the ARDS patients, compared to
healthy subjects. Surfactant replacement resulted in a near normalization of the
surfactant properties and, within 12 hours, gas exchange improved in most pa-
tients. Patients with a relapse received a second instillation of surfactant, which
again resulted in improved arterial oxygenation.
Wiswell et al. performed an open label phase-! trial to assess the safety and tol-
erability of sequential bronchopulmonary segmental lavage with a diluted synthetic
surfactant (Surfaxin) in 12 adults with ARDS [26]. Patients received one of three
dosing regimens in which aliquots of Surfaxin were administered in each of all
bronchopulmonary segments via a wedged bronchoscope. Similar to the studies
Table 1. Trials on surfactant replacement therapy in patients with Acute Respiratory Distress Syndrome
Author/study name Surfactant Type of surfactant Instillation technique Study details No of pts Main results
[ref) name
No control group 10/27 Improvement in gas
Walmrath; Gunther Alveofact Natural surfactant Bronchoscopic Study with ARDS 27 + 12 controls exchange, restoration of
[19, 20, 22) (Bovine) instillation patients and healthy composition and surface
controls activity of surfactant
Wiswell [26) Surfaxin Synthetic surfactant Sequential segmental No control group 12 Improvement in gas
including lipids and lavage via a wedged exchange after
surfactant proteins bronchoscope instillation of surfactant
(SP-8)
Spragg [21) Curosurf Natural surfactant Sequential segmental No control group 6 Restoration of compo- ~
(Poractant) (Porcine) lavage via a wedged sition of surfactant "'v;-
bronchoscope after instillation of 0
:::>
surfactant '-"'
Phase-It study: =;
~
~
Weg [14) Exosurf Lipid-based synthetic Aerosolization Prospective, 51 Surfactant "'%
surfactant multi-center, administration was safe :::0
randomized placebo Trend in reduction of "'C
"';;:;-
controlled trial mortality n
Phase-It study: "'3

:::>
"'.....
Kesecioglu [1 5) HL 10 Natural surfactant Intratracheal Prospective, 36 Surfactant -I
(Porcine) randomized, administration was safe ::r
Q.l
"'
open-label trial Decreased mortality :s1
Phase-It study: :r
Walmrath (16] Venticute Synthetic surfactant Intratracheal Prospective 41 Surfactant -o
~
including lipids and multi-center, administration was safe ;;;·
surfactant proteins randomized trial Decreased ventilator- a
(SP-C) free days ::E
;::;:
I ::r
:>
:::0
0
'-"'
w
~
\.0
w
N
0
Table 1 (continued) I~
V'O
...,
.uthor/study name Surfactant Type of surfactant Instillation technique Study details No of pts Main results ~
c:
[ref) name f;f
~
Phase-11 study: ~
Gregory [1 7] Survanta Natural surfactant Intratracheal Prospective, 59
(Bovine) '"'""'" •d m;,;'"'""
randomized, was safe
open-label trial
Phase-Ill study:
Anzuetto [18] Exosurf Lipid-based Aerosolization Prospective, 725 No beneficial effects of
synthetic surfactant multi-center, surfactant administration!
randomized
placebo controlled
trial
Phase-Ill study:
·VITAL Venticute Synthetic surfactant Intratracheal Prospective, 227 No improvement in gas
(unpublished data) including lipids and multi-center, exchange,
surfactant proteins randomized trial Decreased ventilator-free
(SP-Q days in subgroup
(trauma/surgery)
compared with controls I
RCT, randomized placebo controlled trial; SP, surfactant protein; AU, acute lung injury
Trials on Surfactant Replacement Therapy in Patients with ARDS 321
discussed above, there was no control group. Patients received: 1) one 30-ml aliquot
of a 2.5-mglml concentration of Surfaxin in each segment followed by a second
30-ml aliquot with a 10-mg/ml concentration (N = 3}, 2) two 30-ml aliquots of the
2.5-mg/ml concentration followed by a third lavage with the 10-mg/ml concentra-
tion (N =4}; or 3) similar treatment as in (2), plus a possible extra dosing 6 to 24 h
later (N = 5}. Suctioning was performed 10-30 s after instillation of individual ali-
quots. In the 96 h after treatment initiation, Fi02 decreased from 0.80 to 0.52 and
positive end-expiratory pressure (PEEP) decreased from 10.3 to 7.6 cmH 2 0.
In another study, six patients with ARDS were treated with a single dose of por-
cine surfactant (Curosurf) [21]. Surfactant delivered via a bronchoscope in aliquots
to each of the lobar bronchi was well tolerated and caused a modest transient im-
provement in gas exchange. Bronchoalveolar lavage (BAL) phospholipid concentra-
tions were elevated 3 h after surfactant administration relative to pre-administration
levels and fell by 24 h. In addition, in two patients a reduced inhibition of surfac-
tant function in BAL after surfactant replacement was found.
Phase-11 Studies
Gregory et al. performed a randomized, prospective, controlled, open-label clinical
study of intratracheal administration of a natural bovine surfactant (Survanta) in
patients with ARDS to obtain information about its safety and efficacy [17]. Pa-
tients received surfactant by endotracheal instillation in addition to standard thera-
py (n=43} or standard therapy alone (n= 16}. Three different surfactant regimes
were studied: patients received either: up to eight doses of 50 mg phospholipids/kg
(n=8}; up to eight doses of 100 mg phospholipids/kg (n= 19); or up to four doses
of 100 mg phospholipids/kg (n= 16}. The Fi02 at 120 h after instillation of surfac-
tant was significantly decreased only for patients who received up to four doses of
100 mg phospholipids/kg surfactant, compared with control patients (p = 0.011).
Mortality in the same group of patients was 18.8%, compared with 43.8% in the
control group (p = 0.075}. The investigators concluded that surfactant might have
therapeutic benefit for patients with ARDS.
Kesecioglu et al. determined the efficacy and safety of intratracheal instillation
of a natural porcine surfactant (HL 10) in patients with acute lung injury (ALI) or
ARDS in a prospective, randomized, multi-center, open label, phase-11 study in
Europe [15]. Patients were randomized to receive standard therapy plus surfactant
(n=22} or standard therapy alone (n= 14}. Dosage was from 200 mg phospholi-
pids/kg ideal body weight (up to 4 doses in case of relapse). Efficacy variables were
changes in Pa02 /Fi02 , length of hospital stay, and 28-day mortality. Measures of
oxygenation, duration of mechanical ventilation, and length of stay in the intensive
care unit (ICU) did not differ significantly between the two groups. However,
28-day mortality in the surfactant group was 2/22 (9%) versus 6/14 (43%) in the
control group (p = 0.036). Based on these promising results, they concluded that
surfactant therapy improved survival significantly.
To evaluate the safety and potential efficacy of aerosolized lipid-based synthetic
surfactant (Exosurf) in patients with ARDS, Weg et al. performed a prospective,
double-blind, placebo-controlled, randomized, parallel, multicenter pilot-dose clini-
cal trial [14]. Fifty-one patients with sepsis-induced ARDS that entered into this
phase-II study were randomly assigned to four treatment groups: 1) 12 h of surfac-
tant per day (n= 17}; 2) 24 h of surfactant per day (n= 17}; 3) 12 h of 0.6% saline
per day; and 4) 24 h of 0.6% saline per day (controls combined: n= 17). Surfactant
or saline was aerosolized continuously for up to 5 days using an in-line nebulizer.
Surfactant administration was safe. Although there were no differences in any phys-
iological parameters between the treatment groups, there was a dose-dependent
trend in reduction of mortality from 47% in the placebo group to 41 and 35% in
the groups treated with 12 h and 24 h of surfactant per day, respectively. A phase-
III study was initiated to determine the efficacy of aerosolized surfactant in patients
with ARDS (see below) [18].
In another phase-II study, Walmrath et al. randomized patients with ARDS tore-
ceive standard therapy alone, or standard therapy plus a synthetic surfactant in-
cluding surfactant protein (SP)-C (Venticute) [16]. In this multicenter, parallel
group, controlled trial in Europe and South Africa, 41 patients received standard
therapy, or standard therapy plus surfactant. Two different treatment groups were
investigated: one group received a low dose of surfactant; a second group received
a high dose of surfactant. Intratracheal instillation of surfactant resulted in a better
arterial oxygenation, compared with the control group 24 h after instillation.
Furthermore, more patients were weaned off the ventilator by day 28, compared
with the patients in the control group. From these results it was concluded that sur-
factant instillation may offer a safe approach for replacement of surfactant in pa-
tients with ARDS, and a phase-III trial was initiated (see below) (Seeger, unpub-
lished data).
Phase-Ill Studies
As mentioned, until now only the last two phase-II studies, the ones with Exosurf
and Venticute [14, 16], have been followed by a large phase-III study.
Anzueto et al. described the results from the prospective, multicenter, double-
blind, randomized, placebo-controlled trial with 725 patients suffering from sepsis-
induced ARDS [18]. Patients were randomly assigned to receive either continuously
administered Exosurf or placebo in aerosolized form for up to five days. Hemody-
namic measures, changes in oxygenation, duration of mechanical ventilation, and
length of ICU stay did not differ significantly between the two groups. Survival at
30 days was 60% for both groups. Survival was similar in the groups when ana-
lyzed according to APACHE III score, cause of death, time of onset, severity of
ARDS, presence or absence of documented sepsis, and underlying disease. The in-
vestigators concluded that the continuous administration of aerosolized synthetic
surfactant to patients with sepsis-induced ARDS had no beneficial effects.
The last, not yet published, phase III randomized controlled trial on the efficacy
of surfactant instillation is the VITAL-study (Venticute In the Treatment of Acute
Lung Injury) (Seeger, presentation of data at the annual meeting of the American
Thoracic Society, San Francisco, May 2001). In this prospective, double-blinded,
randomized phase-III trial on 189 patients with ARDS, patients were randomized
to receive standard therapy or standard therapy plus intratracheal Venticute for up
to four doses within 24 h after start of therapy. There was a significant overlap be-
tween patient categories: in the control group 66% met the criteria of sepsis, 39%
suffered from pneumonia, and 35% had developed ARDS after trauma or surgery
(64, 47 and 28%, respectively, in the treatment group). The difference in overall
mortality at 28 days between groups was not significant (42 and 37% in control
group and treatment group, respectively). However, analysis of mortality in one
subgroup (trauma or surgery) demonstrated a remarkably lower mortality rate for

patients that were treated with surfactant compared with standard therapy alone
(30 vs 51 o/o). The number of ventilator-free days at 28 days after initiation of thera-
PY was significantly higher in this subgroup {11.0 days vs 3.1 days, p<O.OS). Inter-
estingly, in accordance with another study demonstrating improved survival after
surfactant replacement therapy [15], in this study changes in Pa0 2/Fi0 2 were simi-
lar in the treatment group and control group. The data of the VITAL study as pre-
sented here are from the European/South African arm of the study. Data from the
American arm are not yet available.
1 What can be Learned from Studies on Surfactant Replacement Therapy?
Data from the phase-II and phase-III studies on surfactant replacement in patients
with ARDS are contradictory. What is the explanation for the differences in results
of the phase-II and phase-III studies on surfactant therapy in patients with ARDS?
There are some important differences between the studies that have been per-
formed in the last decade, such as differences in types of surfactant used, the way
surfactant is instilled, the amount of surfactant applied, timing of therapy, patient
selection and, possibly, applied ventilation strategies.
Surfactant Composition
In studies on surfactant replacement therapy, different types of surfactant have been
used. One can roughly divide the studies into those using natural surfactants (bovine
or porcine), containing the SP-B and SP-C [15, 17], and those using a synthetic sur-
factant without any surfactant proteins [14, 18], or only containing SP-C [16].
Although synthetic surfactants can be produced in larger quantities, both experi-
mental and clinical data have demonstrated the superiority of natural surfactant
preparations over synthetic products. Natural surfactants have been found to be
more effective in increasing arterial oxygenation and alveolar stability [27].
Furthermore, use of natural surfactants results in a more rapid improvement and
natural surfactants are less sensitive to inhibition by serum proteins and other in-
flammatory mediators. Indeed, a recent study on premature neonates comparing a
natural surfactant with a synthetic surfactant demonstrated a significant lower mor-
tality when treated with the natural surfactant (Fig. 1} [28].
Synthetic surfactants failed to show any improvement in survival in the two
studies using a synthetic surfactant (Fig. 2) [18, Seeger, unpublished data]. In the
two studies with a natural surfactant [15, 17], as well as in the studies with a
(semi-}synthetic surfactant [18, Seeger, unpublished data], mortality rates in the
control groups were approximately 40%. Whereas in the studies using natural sur-
factant mortality in the treatment groups dropped significantly (to 9o/o in the study
by Kesecioglu et al. [15]}, in the studies with a (semi-}synthetic surfactant mortal-
ity in the treatment groups was comparable to that in the control groups.
Mode of Delivery of Surfactant

Different techniques have been used to instill surfactant in patients with ARDS. In
two studies surfactant was instilled by means of aerosolization [14, 18], in other
40
30
l
.~ 20
Iii
t
0
::?!
10
Fig. 1. In premature neonates, lower mortality
has been found with natural surfactant com-
0 pared with synthetic surfactant. Neonatal mor-
(N) 100 99 100 99 tality and pre hospital-discharge mortality in
Neonatal Predischarge neonates treated with a natural surfactant (Por-
mortality mortality tactant, closed bars), and a synthetic surfactant
(Punactant, open bars). Data from [8]
Natural surfactant Synthetic surfactant

50 so
40 40
l 30
l 30
.~ .~
Iii ~
t 20
0 0 20
::?! ::?!
10 10
0 0
(N) 16 35 14 12 (N) 361 364 94 95
Survanta HL 10 Exosurf Venticute
Gregory et al. Kesecioglu et al. Anzuetto et al. Seeger et al.
Fig. 2. Mortality in phase-11 and phase-Ill studies on surfactant in ARDS. In studies on surfactant replace-
ment therapy in patients with ARDS, lower mortality has been found with the use of natural surfactant,
compared with synthetic surfactant. Left panel: mortality in patients treated with natural surfactant
(closed bars) and controls (open bars). Right panel: mortality in patients treated with synthetic surfactant
(closed bars) and controls (open bars). Data from [15, 17, 18] and Seeger et al. (umpublished data)
studies surfactant instillation was achieved by means of a bronchoscope [19-22,

26]. Most of the reviewed studies used intratracheal instillation [15-17].
Although aerosolizing surfactant is a promising technique, its inadequacy to de-
liver sufficient amounts of surfactant to the terminal airways precludes this tech-
nique from being used nowadays. The aerosol system used in the studies by Weg et
al. [14] and Anzueto et al. [18] allowed the investigators to instill less than 5 mg/kg
of the dose of 112 mg/kg per day (i.e., only 4.5%) [18]. The amount of surfactant
delivered with this technique is only 1/16 of the dose delivered in the studies by
Kesecioglu et al. and Gregory et al. [15, 17], which is an insufficient amount to
Fig. 3. Distribution of surfactant in sheep lungs after whole lung lavage. Surfactant is installed as a bolus
through a syringe connected to the endotracheal tube. A: CT-scan image of lungs before lavage; B: directly
after lavage; C: directly after instillation of surfactant. The excellent distribution of surfactant is shown by the
homogenous spreading of the radio-opaqueness of contrast medium+ surfactant throughout the lungs
overcome the inhibiting activities of plasma proteins present in the airways of pa-
tients with ARDS [29].
Other studies used bronchoscopic lavage to instill surfactant into the lungs [20-
23, 27]. Investigators claimed that this instillation technique provides both 'cleans-
ing' of the airways, and the instillation of surfactant to all segments of the lungs.
Bronchoscopic lavage is expected to be efficient in patients with direct lung injury,
because during the procedure inflammatory mediators are removed from the lung
(27]. However, this procedure is very time consuming; in the study by Wiswell et
al. the median duration of the lavage procedure was > 90 minutes [27], and in other
reports, the bronchoscopic procedure lasted 45 minutes [20, 21]. This time-consum-
ing aspect may prohibit the treatment of many patients with ARDS who are in one
clinic at the same time.
326 M.J. Schultz et al.
In most of the studies, surfactant is instilled as a bolus, either by means of a

catheter installed via the endotracheal tube and advanced up to some centimeters
above the carina [16, 17], or by means of a bolus through a syringe connected to
the endotracheal tube [15]. Instillation of surfactant by this means is very simple
to perform and less time-consuming than instillation via a bronchoscope. Impor-
tantly, distribution of surfactant in this way is excellent (Fig. 3).
Although it has been argued that this way of instillation may pose a problem
with respect to the volume that is instilled into the lungs, it has been demonstrated
that the volume of fluid that has to be instilled is rapidly absorbed [30].
Surfactant Dosing
Because of the presence of strong surfactant inhibitors in the alveoli, approximately
1 mg of surfactant is needed to overcome the inhibitory effect of 1 mg of plasma
proteins [29]. Thus, the dosage of exogenous surfactant needs to be large enough
to overcome all the inhibitors present in the lung. Gregory et al. studied four differ-
ent dosing strategies in 48 adults with ARDS. Maximum improvement in oxygena-
tion, minimum ventilatory requirements, and lowest mortality rate were obtained
by using four doses of 100 mg/kg of a natural surfactant (total amount of 400 mgt
kg) [17].
It is clear that in the studies with aerosolized surfactant, the amount of surfac-
tant that was delivered was too low (25 mg/kg) [14, 18]. The dosing protocol used
in the study by Kesecioglu et al. [15], and the study by Seeger et al. [unpublished
data] allowed the investigators to repeat surfactant instillation until improvement in
oxygenation was achieved. Furthermore, in these two studies, on each instillation
sufficient amount of surfactant was instilled to allow an optimal effectiveness of the
surfactant therapy.
Timing of Therapy
Timing of therapy has been shown to be of importance (Table 2). In the studies in
which surfactant replacement had to be achieved within 48-60 hours after the diag-
nosis of ARDS, reduced mortality was demonstrated [15], or a trend towards re-
duced mortality was found [14, 17]. By contrast, in the VITAL study, in which sur-
factant therapy could be given up to 96 hours after the diagnosis of ARDS, no re-
duction in mortality was seen [unpublished data]. An early change in the local situ-
ation from a pathophysiological state to a more physiological state during ARDS
may make sense. When the normal physiology of the lung is achieved earlier (by
normalization of the surfactant system), less serum proteins will be able to accu-
mulate (preventing further inhibition of the surfactant system) [32].
Patient Selection
The reviewed studies on surfactant replacement therapy are at no point uniform
with respect to the recruitment of patients (Table 2). Some studies included only
patients with sepsis-related ARDS [14, 18, 22], while in other studies patients with
all-cause ARDS were recruited [15, 16, 19, 20, 26].
Although ARDS is a state of insufficiency of active surfactant, the mechanisms
involved in the development of ARDS are complex. ARDS associated with sepsis is
Table 2. Study-details
Author/study Timing of therapy* Diagnosis, P/F Instillation technique Duration of instillation/number of

name [ref) doses
Walmrath; Gunther <96 h ARDS+sepsis, P/F <100 [23), Bronchoscopic instillation 45 ± 11 min (mean± SO), one dose
[19, 20, 22) All-cause ARDS, P/F < 200 only
[20, 21)
Wiswell [26) <72 h Pulmonary and extra-pulmonary Bronchoscopic instillation 92.5 min (median), up to two dose~
ARDS (P/F <200)
Spragg [21) <48 h ?-ARDS Bronchoscopic instillation ?, one dose only
Weg [141 < 18 h of ARDS/All + Sepsis, P/F < 300 Aerosolisation 12 or 24h/day, up to 5 days ~
sepsis diagnosis ~
0
:::>
Kesecioglu [15) <60 h Pulmonary and extra pulmonary Intratracheal instillation 5-10 min, up to four doses V>
ARDS/All, P/F < 300 ~

C!'
,...
Walmrath [16) ARDS-? Intratracheal instillation ?, ? s
~
Gregory [17) <48 h ARDS-? Intratracheal instillation ? , up to eight doses 11>
'C
""
Qj"
,...
11>
Anzuetto [18) <48 h and ARDS/All + Sepsis, P/F < 250 Aerosolisation 24 h/day, up to 5 days 3
11>
< 96 h of ~
sepsis diagnosis -f
::r
11>
VITAL < 120 h Pulmonary and extra pulmonary Intratracheal instillation ?, up to four doses (within 24 h) 0::
~
(unpublished data) ARDS, P/F < 200 :r
AROS, acute respiratory distress syndrome; ALl, acute lung injury; P/F, Pa0 2/Fi0 2 ratio; *, after diagnosis of ARDS, unless stated otherwise; ?, indicates information not ~
;;;·
given or not available a::;:
;::;:
::r
)>
0
""
V>
w
N
o,J
caused by increased permeability of the endothelium and epithelium, and an asso-

ciated inflammatory response. From this it can be speculated that in case of sepsis-
related ARDS more surfactant is required to normalize the surfactant system. In-
deed, applying higher dosages of surfactant in sepsis-related ARDS patients does
improve oxygenation [22]. Furthermore, in the study by Wiswell et al. patients with
sepsis demonstrated a smaller decline in ventilator support than the non-septic pa-
tients [26]. Similarly, in the study by Seeger et al., in patients with sepsis this pa-
rameter was not different between the treatment group and the control group, while
patients with trauma/surgery related ARDS showed an increase in ventilator free
days after treatment with surfactant [unpublished data].
Mechanical Ventilation Strategies

The contradictory data from the randomized clinical trials, especially between
phase-11 and phase-III studies, may in part be caused by differences in the applied
ventilation strategy. Introduction of a more lung-protective ventilation strategy
could have improved patient outcome in the last decade [32, 33]. In this respect,
newer studies may have been underpowered to demonstrate a clear effect of surfac-
tant replacement therapy.
I Safety Aspects
All reviewed studies have shown that instillation of surfactant is safe. Although
synthetic surfactants are considered to be safer with respect to the transmission
risks of diseases or allergic sensitization to animal proteins than natural surfac-
tants, there have been no reports on these side effects so far. Until now, both syn-
thetic and natural surfactants have been safely used in large numbers of neonates.
I Conclusion
Data from several studies indicate that surfactant therapy may be an important tool
in the treatment of ARDS in the future. Since only studies with a natural surfactant
have demonstrated an improved survival in ARDS patients, we support the use of
natural surfactant, containing both SP- B and SP-C. Furthermore, the amount of sur-
factant instilled should be large enough, and repeated doses should be given, to
overcome the ongoing inactivation of surfactant. We favor surfactant administration
by means of a bolus through a syringe connected to the endotracheal tube, because
excellent distribution has been demonstrated with this technique, and it is less time
consuming than administration by bronchoscope. Timing of surfactant therapy is
important, since early application of exogenous surfactant will prevent accumula-
tion of more surfactant inhibitors, which blocks the vicious circle of inhibition and
further progression of the disease. Finally, surfactant administration is a safe thera-
py.
In the next few years, the on-going phase-III studies will provide more informa-
tion on the future of surfactant replacement therapy in ARDS.
References
1. King RJ, Clements JA (1972) Surface active materials from dog lung. II. Composition and
physiological correlations. Am J Physiol 223:715-726
2. Jobe A, Ikegami M (1987) Surfactant for the treatment of respiratory distress syndrome.
3. Frerking I, Gunther A, Seeger W, Pison U (2001) Pulmonary surfactant: functions, abnorm-
alities and therapeutic options. Intensive Care Med 27:1699-1717
4. Hallman M, Spragg R, Harrell JH, Moser KM, Gluck L (1982) Evidence of lung surfactant
abnormality in respiratory failure. Study of bronchoalveolar lavage phospholipids, surface
activity, phospholipase activity, and plasma myoinositol. J Clin Invest 70:673-683
5. Ashbaugh DG, Bigelow DB, Petty TL, Levine BE (1967) Acute respiratory distress in adults.
Lancet 2:319-323
6. Lewis JF, Jobe AH (1993) Surfactant and the adult respiratory distress syndrome. Am Rev
7. Petty TL, Silvers GW, Paul GW, Stanford RE (1979) Abnormalities in lung elastic properties
and surfactant function in adult respiratory distress syndrome. Chest 75:571-574
8. Gregory TJ, Longmore WJ, Moxley MA, et al (1991) Surfactant chemical composition and
biophysical activity in acute respiratory distress syndrome. J Clin Invest 88:1976-1981
9. Fujiwara T, Maeta H, Chida S, et al (1980) Artificial surfactant therapy in hyaline-mem-
brane disease. Lancet 1:55-59
10. Morley CJ (1997) Systematic review of prophylactic vs rescue surfactant. Arch Dis Child
Fetal Neonatal Ed 77:F70-74
11. Jobe AH (2000) Which surfactant for treatment of respiratory distress syndrome. Lancet
355:1380-1381
12. Jobe AH, Ikegami M (2000) Lung development and function in preterm infants in the sur-
factant treatment era. Annu Rev Physiol 62:825-846
13. Lachmann B (1989) Animal models and clinical pilot studies of surfactant replacement in
adult respiratory distress syndrome. Eur Respir J Suppl 3:98s-103s
14. Weg JG, Balk RA, Tharratt RS, et al (1994) Safety and potential efficacy of an aerosolized
surfactant in human sepsis-induced adult respiratory distress syndrome. JAMA 272:1433-
1438
15. Kesecioglu J, Schultz MJ, Lundberg D, Lauven PM, Lachmann B (2001) Treatment of acute
lung injury (ALI/ARDS) with surfactant. Am J Respir Crit Care Med 163:A819 (abst)
16. Walmrath D, De Vaal JB, Bruining HA, et al (2000) Treatment of ARDS with rSP-C surfac-
tant. Am J Respir Crit Care Med 161:A379
17. Gregory TJ, Steinberg KP, Spragg R, et al (1997) Bovine surfactant therapy for patients
with acute respiratory distress syndrome. Am J Respir Crit Care Med 155:1309-1315
18. Anzueto A, Baughman RP, Guntupalli KK, et al (1996) Aerosolized surfactant in adults
with sepsis-induced acute respiratory distress syndrome. Exosurf Acute Respiratory Dis-
tress Syndrome Sepsis Study Group. N Engl J Med 334:1417-1421
19. Walmrath D, Grimminger F, Pappert D, et al (2002) Bronchoscopic administration of bo-
vine natural surfactant in ARDS and septic shock: impact on gas exchange and haemody-
namics. Eur Respir J 19:805-810
20. Gunther A, Schmidt R, Harodt J, et al (2002) Bronchoscopic administration of bovine nat-
ural surfactant in ARDS and septic shock: impact on biophysical and biochemical surfac-
tant properties. Eur Respir J 19:797-804
21. Spragg RG, Gilliard N, Richman P, et al (1994) Acute effects of a single dose of porcine
surfactant on patients with the adult respiratory distress syndrome. Chest 105:195-202
22. Walmrath D, Gunther A, Ghofrani HA, et al (1996) Bronchoscopic surfactant administra-
tion in patients with severe adult respiratory distress syndrome and sepsis. Am J Respir
23. Lachmann B (1987) The role of pulmonary surfactant in the pathogenesis and therapy of
ARDS. In: Vincent J-L (ed) Update in Intensive Care and Emergency Medicine. Springer,
Berlin, pp 123-134
24. Richman PS, Spragg RG, Robertson B, Merritt TA, Curstedt T (1989) The adult respiratory
distress syndrome: first trials with surfactant replacement. Eur Respir J Suppl3:109s-111s
330 M. J. Schultz et al.: Trials on Surfactant Replacement Therapy in Patients with ARDS
25. Haslam PL, Hughes DA, MacNaughton PD, Baker CS, Evans TW (1994) Surfactant replace-
ment therapy in late-stage adult respiratory distress syndrome. Lancet. 343:1009-1011
26. Wiswell TE, Smith RM, Katz LB, et a! (1999) Bronchopulmonary segmental lavage with
Surfaxin (KL( 4)-surfactant) for acute respiratory distress syndrome. Am J Respir Crit Care
Med 160:1188-1195
27. Gommers D, van't Veen A, Verbrugge SJC, Lachmann B (1998) Comparison of eight differ-
ent surfactant preparations on improvement of blood gases in lung-lavaged rats. Appl Car-
diopulm Pathophysiol 7:95-102
28. Ainsworth SB, Beresford MW, Milligan DW, et a! (2000) Pumactant and poractant alfa for
treatment of respiratory distress syndrome in neonates born at 25-29 weeks' gestation: a
randomised trial. Lancet 355:1387-1392
29. Lachmann B, Eijking EP, So KL, Gommers D (1994) In vivo evaluation of the inhibitory
capacity of human plasma on exogenous surfactant function. Intensive Care Med 20:6-11
30. Gilliard N, Richman PM, Merritt TA, Spragg RG (1990) Effect of volume and dose on the
pulmonary distribution of exogenous surfactant administered to normal rabbits or to rab-
bits with oleic acid lung injury. Am Rev Respir Dis 141:743-747
31. Eijking EP, Gommers D, So KL, et a! (1993) Prevention of respiratory failure after hydro-
chloric acid aspiration by intratracheal surfactant instillation in rats. Anesth Analg 76:472-
477
32. Amato MB, Barbas CS, Medeiros DM, eta! (1998) Effect of a protective-ventilation strategy
on mortality in the acute respiratory distress syndrome. N Eng! J Med. 338:347-354
volumes as compared with traditional tidal volumes for acute lung injury and the acute
respiratory distress syndrome. N Eng! J Med 342:1301-1308
Surfactant Therapy:
Beyond a Rescue Therapy for ARDS
J. J. Haitsma, R. A. Lachmann, and B. Lachmann
I Introduction
In acute respiratory distress syndrome (ARDS) the deficiency of (active) surfactant
leads to the progressive deterioration of lung function. If one can reverse the sur-
factant deficiency one can expect also to improve lung function and ultimately this
may reduce the mortality rates in ARDS patients. Therefore, it would be logical to
supplement the ARDS lung with exogenous surfactant. Because ARDS is associated
with a high mortality rate (> 40o/o) current investigation on surfactant therapy in
adults is focused on reducing mortality in these patients by using exogenous sur-
factant as a rescue therapy. However, in light of the unique properties of surfactant
as a rate-limiting factor in the transfer across the alveolo-capillary membrane, as
well as its surface tension lowering properties and the critical role of surfactant in
pulmonary host defense, in this chapter we present an outline for future applica-
tions of exogenous surfactant.
Properties of Surfactant
The normal physiological functions of the pulmonary surfactant system include:
Mechanical stabilization of lung alveoli: during deflation of the lung a high sur-
face tension would tend to promote alveolar collapse, however, the dynamic sur-
face tension behavior of surfactant prevents this.
I Transport of mucus and inhaled particles: surfactant acts as an anti-glue factor,
preventing the development of large adhesive forces between mucus and the
bronchial wall [1].
I Protection against lung edema: another important function of surfactant is stabi-
lization of the fluid balance in the lung, especially across the alveolo-capillary
membrane. Figure 1 presents a diagram of fluid balance across the lung. The
normal plasma oncotic pressure of 37 cmH 2 0 is opposed by the capillary hydro-
static pressure of 15 cmH 2 0, by the oncotic pressure of interstitial fluid proteins
of 18 cmH 2 0, and by the surface tension conditioned suction pressure of
4 cmH2 0. In general, alveolar flooding will not occur when the surfactant system
is functioning properly. However, when the surface tension rises above a critical
level, alveolar flooding will occur, leading to influx of proteins into the alveolar
space, which results in further inactivation of surfactant. Besides stabilizing the
fluid balance across the alveolo-capillary membrane, surfactant is also rate limit-
ing in the transfer of several other molecules across the alveolo-capillary mem-
brane [2].
332 J. J. Haitsma et al.
;_....---Pulmonary capillary
Base layer
·:....-<1'\l!:::llr-- Superficial layer
Air space
- - -
Plasma
oncotic
pressure
Capillary
blood
pressure
Tissue nuid
oncotic
pressure
-
Surface
tension
pressure
(radius, tension)
Normal values (cmH20) 37 15 + 18 + 4
Respiratory distress 37 < 15 + 18 + 410 30
Syndrome (crnH 10)
Fig. 1. Diagram showing the factors influencing fluid balance in the lung
1 Local defense against infection: it has been demonstrated that surfactant, in par-
ticular surfactant protein A (SP-A) and probably SP-D, enhances the antibacterial
and antiviral defense properties of alveolar macrophages [3] .
I Preventive Treatment with Exogenous Surfactant

Our group showed that respiratory failure induced by aspiration of hydrochloric
acid could be prevented when exogenous surfactant was given before deterioration
of lung function (i.e., within 10 min after acid aspiration), whereas after develop-
ment of respiratory failure exogenous surfactant served only to prevent further de-
cline of lung function but did not restore gas exchange [4]. When treatment starts
in a later stage of lung injury, the amount of inhibitory proteins that have accumu-
lated in the lung require larger amounts of surfactant, or several consecutive ad-
ministrations, to improve lung function.
If surfactant can prevent aspiration-induced lung injury, we speculated that treat-
ment with surfactant could diminish the lung injury observed by ventilation, venti-
lator-induced lung injury (VILI). Therefore, using a standard model of VILI, we in-
vestigated whether administration of exogenous surfactant has any beneficial
effects. In the animals ventilated with high peak inspiratory volumes and low levels
of positive end-expiratory pressure (PEEP), inducing VILI, we demonstrated that
surfactant prevented impairment of oxygenation and deterioration of lung me-
chanics, and reduced the permeability to Evans blue [5].
When patients are ventilated for even short periods, this can result in the release
of lung injury markers [6]. Verbrugge and colleagues showed that mechanical ven-
tilation for only 7 minutes resulted in release of purines [6]. Instillation of exoge-
nous surfactant before the start of mechanical ventilation reduced this release of
this lung injury marker [6].
Surfactant Therapy: Beyond a Rescue Therapy for ARDS 333
1000
e......
en
E:
~ 500
a.
lji
LL
z
r-
0
No-surf Surf Control
Fig. 2. Tumor necrosis factor (TNF)-a concentration in the broncho-alveolar lavage (BALl fluid of animals
which had a compartmentalized systemic activation of the pro-inflammatory mediator TNF-a. After
20 min of ventilation increased levels of TNF-a are found in the BAL fluid of the animals who did not
receive surfactant (no-Surf) indicating loss of compartmentalization. In the animals pre-treated with sur-
factant (Surf) there is a significant reduction in loss of compartmentalization. Control animals had no sys-
temic inflammation activation. Adapted from [9)
Mechanical ventilation of a healthy lung can activate the inflammatory cascade.

In ARDS lungs, characterized by increased inflammatory activation, mechanical
ventilation will augment this activation of the inflammatory process. Although pro-
duction of the inflammatory mediators is compartmentalized, mechanical ventila-
tion can lead to loss of compartmentalization [7]. This loss of compartmentaliza-
tion induces a shift of inflammatory mediators across the alveolo-capillary mem-
brane [7], increasing the risk of patients to develop multi-organ failure (MOF) [8].
We have recently demonstrated that this loss of compartmentalization is largely de-
pendent on the function of surfactant, especially its rate-limiting function in the
transfer of inflammatory mediators across the alveolo-capillary membrane [9]. In-
creasing the amount of active surfactant in a lung significantly reduced the decom-
partmentalization of pro-inflammatory mediators [9] (Fig. 2).
We therefore speculate that the early use of exogenous surfactant as an adjuvant
therapy during mechanical ventilation could help reduce the incidence of VILI in
patients, diminish the occurrence of MOF due to ventilation, and, thus, help to im-
prove the outcome of patients requiring mechanical ventilation. Finally preventive
application of surfactant requires lower amounts of surfactant and could help to re-
duce overall costs by shortening the ICU stay.
I Surfactant and Pneumonia

Surfactant (especially SP-A) and alveolar macrophages have a synergistic effect in
the defense against bacteria [3]. Studies in patients have shown that, following a
decrease in lung compliance (thus, surfactant deficiency), pneumonia will often de-
velop. There are, however, several pathways along which an jmpairment of surfac-
tant might develop in pneumonia (Fig. 3). Pathogens can directly interact with the
extracellular surfactant pool or cause surfactant impairment through interactions
Surfactant impairment by:
1. Direct
interactions
2. synthesis
changes
3. inflammatory
mediators
4.High
permeability
edema
Fig. 3. Pathways along which surfactant impairment may develop into pneumonia. Pathogens can direct-
ly interact with the extracellular surfactant pool or cause surfactant impairment through interactions with
type II cells, through induction of an inflammatory cell response, or by damaging the integrity of the
alveolo capillary membrane
with type II cells, through induction of an inflammatory response, or by destroying

the integrity of the alveolar-capillary membrane. Bacteria, bacterial toxins, oxygen
radicals, viruses, phospholipases, and proteinases released from inflammatory cells
interact directly with the surfactant film. Furthermore, type II cell function may be
affected by virus replication, bacterial cytotoxic agents, or oxygen radicals and
interleukins (IL) released by inflammatory cells leading to alterations in surfactant
composition and/or a decreased surfactant synthesis. Endothelial and epithelial cell
lysis and/or proteolytic activity derived from microorganisms or inflammatory cells
can, finally, damage the alveolar-capillary membrane leading to high permeability
edema. The plasma proteins of the edema will inactivate the surfactant film. Sur-
face tension at the alveolar walls increases, leading to increased suction forces
across the alveolo-capillary membrane. This finally results in a vicious circle. De-
pendent on the pathogen involved, one or more of the above-mentioned mecha-
nisms may contribute to a surfactant dysfunction. Thus, with the proven deficiency
of active exogenous pulmonary surfactant in patients with pneumonia, it is rational
to assume that replenishment with active surfactant could halt or even reverse the
disease process.
We demonstrated the effectiveness of surfactant therapy in different animal
models suffering from viral pneumonia or Pneumocystis carinii pneumonia [10,
11] . In viral pneumonia, tracheal administration of exogenous surfactant led to im-
proved lung compliance and improved functional residual capacity (FRC), as well
as restoration of gas exchange. Similarly, in rats with Pneumocystis carinii pneumo-
nia, surfactant instillation led to improvement of arterial oxygenation [10] .
In humans suffering from infectious lung diseases, data on treatment with exo-
genous surfactant are scarce. Lachmann treated a four-year-old patient with bacte-
rial pneumonia and acute respiratory failure. Surfactant was instilled in three doses,
in succession (150; 100; 50 mglkg) and after the last dose of surfactant, gas
exchange improved dramatically. Chest X-ray taken four hours after treatment
showed nearly 'normal' lungs. The results of first multi-patient studies with surfac-
tant are now being published. Walmrath et al. studying patients with sepsis and
established severe ARDS, showed that bronchoscopic application of a natural sur-
factant (300 mglkg) improved arterial oxygenation in all patients; in half of the pa-
tients a second dose (200 mglkg) was required [12]. Surfactant can also restore or
diminish lung injury due to infections; however, surfactant and surfactant produc-
ing alveolar type II cells are susceptible to bacteria and viruses. Nowadays, the
interest in improving surfactant therapy while simultaneously preventing and/or
treating lung infections is growing.
I Surfactant as a Carrier
It has been proposed that the spreading properties and the inherent therapeutic
potential of surfactant could be used to deliver antimicrobial agents to the lung
parenchyma [13]. Direct application of antibiotics to the airway offers many poten-
tial advantages in the treatment and prevention of pneumonia. Delivery direct to
the airways should increase the local effectiveness and reduce the risk for systemic
toxicity caused by antibiotics, e.g., aminoglycosides [14]. Locally administered anti-
biotics for prevention and/or treatment of lower respiratory tract infection have
been extensively studied [13]. However, despite the high antibiotic dose delivered
to the lung, the question of efficacy remains controversial; explanations for this in-
clude failure of the antibiotic to reach the infected lung area. When delivered as an
aerosol, only a small amount of nebulized antibiotic (around 10%) is actually de-
posited 'in the lung. Moreover, with increased airway obstruction, atelectasis and
lung damage, the amount of aerosol deposited will be even lower. Lung distribution
of intratracheally instilled antibiotic solutions is poorly studied. It is known, how-
ever, that distribution of intratracheally-instilled saline is largely limited to the cen-
tral regions of the lung [15]. Due to the small diameter of peripheral airways, fluid
with a high surface tension (such as saline or water) requires high pressures for
passage through these airways [16]. Studies have shown that pulmonary surfactant
is superior to saline in distributing a radioactive colloid within healthy lungs, as
indicated by the more homogenous and peripheral lung distribution; the effective-
ness of surfactant as a carrier was even more evident at lower volumes of fluid
[15]. Furthermore, surfactant re-expands atelactatic areas, which are most likely to
be the infected areas. It is, therefore, expected that intratracheally-instilled antibio-
tics are more effective when the distribution within the lung is optimized by using
pulmonary surfactant as a carrier.
I Experimental Studies
Although the idea to use surfactant as a carrier agent was proposed several years
ago, data from in vivo experimental studies are scarce. Our group was the first to
study the effect of a surfactant-tobramycin mixture on mice suffering from respira-
tory infection with Klebsiella pneumoniae [17]. It was demonstrated that intratra-
cheal instillation of a surfactant-tobramycin mixture is more effective in protecting
mice from death due to a respiratory Klebsiella pneumoniae infection than intratra-
cheal instillation of tobramycin alone or of surfactant alone [17]. These results were
the first to indicate that exogenous surfactant is an effective carrier agent. It is sug-
gested that one of the advantages of locally administered drugs is the minimization
of systemic side-effects of the drugs.
Various surfactant preparations are already commercially available and are being
used in the treatment of RDS in neonates. Studies performed in animal models un-
der standardized conditions showed marked differences between several natural
and synthetic surfactant preparations in their ability to improve lung function [18].
Natural surfactants containing the hydrophobic proteins SP-B and SP-C (which are
more able to withstand inactivation by plasma proteins) are more effective in im-
proving lung function than artificial surfactants, or natural surfactants with low
amounts of SP-B and SP-C.
I Conclusion
Although use of surfactant as a rescue therapy in ARDS is supported by a large body
of evidence, the unique properties of surfactant give rise to other application areas.
Exogenous surfactant therapy can be used to prevent injury caused by mechani-
cal ventilation and help diminish the occurrence of VILI. Thus, when patients re-
quire mechanical ventilation the use of surfactant as an adjuvant therapy should be
considered. Because surfactant is also rate limiting in transfer of several substances
(including inflammatory mediators) across the alveolo-capillary membrane, appli-
cation of surfactant could reduce the incidence of MOF due to translocation of in-
flammatory mediators from the lung to the systemic circulation.
Furthermore, we present information on the critical role surfactant plays in the
development of pneumonia. Using the low surface tension properties combined
with the excellent spreading potential of surfactant, we have outlined the use of a
combination of surfactant and antibiotic mixture to improve the effectiveness of
antimicrobial therapy. Experimental data show very promising results and warrant
future clinical application of the potent combination of antibiotics and surfactant
in patients with pnaumonia.
References
l. Lachmann B (1985) Possible function of bronchial surfactant. Eur J Respir Dis (suppl)
142:49-61
2. Bos JA, Wollmer P, Bakker W, Hannappel E, Lachmann B (1992) Clearance of 99mTc-DTPA
and experimentally increased alveolar surfactant content. J Appl Physiol 72:1413-1417
3. van Iwaarden F, Welmers B, Verhoef J, Haagsman HP, van Golde LM (1990) Pulmonary
surfactant protein A enhances the host-defense mechanism of rat alveolar macrophages.
Am J Respir Cell Mol Bioi 2:91-98
4. Eijking EP, Gommers D, So KL, Vergeer M, Lachmann B (1993) Surfactant treatment of
respiratory failure induced by hydrochloric acid aspiration in rats. Anesthesiology 78:
1145-1151
5. Verbrugge SJ, Vazquez de Anda G, Gommers D, et al (1998) Exogenous surfactant pre-
serves lung function and reduces alveolar Evans blue dye influx in a rat model of ventila-
tion-induced lung injury. Anesthesiology 89:467-474
6. Verbrugge SJ, de Jong JW, Keijzer E, Vazquez de Anda G, Lachmann B (1999) Purine in
bronchoalveolar lavage fluid as a marker of ventilation-induced lung injury. Crit Care Med
27:779-783
7. Haitsma JJ, Uhlig S, Goggel R, Verbrugge SJ, Lachmann U, Lachmann B (2000) Ventilator-
induced lung injury leads to loss of alveolar and systemic compartmentalization of tumor
necrosis factor-alpha. Intensive Care Med 26:1515-1522
8. Ranieri VM, Giunta F, Suter PM, Slutsky AS (2000) Mechanical ventilation as a mediator of
multisystem organ failure in acute respiratory distress syndrome. JAMA 284:43-44
9. Haitsma JJ, Uhlig S, Lachmann U, Verbrugge SJ, Poelma DL, Lachmann B (2002) Exogen-
ous surfactant reduces ventilator-induced decompartmentalization of tumor necrosis factor
alpha in absence of positive end-expiratory pressure. Intensive Care Med 28:1131-1137
10. Eijking EP, van Daal GJ, Tenbrinck R, et al (1991) Effect of surfactant replacement on
Pneumocystis carinii pneumonia in rats. Intensive Care Med 17:475-478
11. van Daal GJ, So KL, Gommers D, et al (1991) Intratracheal surfactant administration
restores gas exchange in experimental adult respiratory distress syndrome associated with
viral pneumonia. Anesth Analg 72:589-595
12. Walmrath D, Grimminger F, Pappert D, et al (2002) Bronchoscopic administration of
bovine natural surfactant in ARDS and septic shock: impact on gas exchange and haemo-
dynamics. Eur Respir J 19:805-810
13. van 't Veen A, Gommers D, Lachmann B (1997) Rationale for surfactant therapy in pneu-
monia. In: Vincent JL (ed) Yearbook in Intensive Care and Emergency Medicine. Springer,
Berlin Heidelberg, pp 638-653
14. Touw DJ, Brimicombe RW, Hodson ME, Heijerman HG, Bakker W (1995) Inhalation of
antibiotics in cystic fibrosis. Eur Respir J 8:1594-1604
15. Kharasch VS, Sweeney TD, Fredberg J, et al (1991) Pulmonary surfactant as a vehicle for
intratracheal delivery of technetium sulfur colloid and pentamidine in hamster lungs. Am
16. Enhorning G, Duffy LC, Welliver RC (1995) Pulmonary surfactant maintains patency of
conducting airways in the rat. Am J Respir Crit Care Med 151:554-556
17. van 't Veen A, Mouton JW, Gommers D, Lachmann B (1996) Pulmonary surfactant as vehi-
cle for intratracheally instilled tobramycin in mice infected with Klebsiella pneumoniae. Br
J Pharmacol119:1145-1148
18. Gommers D, van 't Veen A, Verbrugge SJC, Lachmann B (1998) Comparison of eight dif-
ferent surfactant preparations on improvement of blood gases in lung-lavaged rats. Appl
Cardiopulm Pathophysiol 7:95-102
Perioperative Complications
High-Risk Surgical Patients:
Why We Should Pre-Optimize
B. Vallet, G. Lebuffe, and E. Wiel
I Introduction
In the United Kingdom, a recent analysis of an intensive care unit (ICU) database
reported that surgical patients represented 45o/o of total ICU admissions with an im-
portant mortality rate since 20.1 o/o of them died [1]. A surgical patient is consider-
ed at high risk if their preoperative status is altered or if the surgical procedure is
prolonged and/or associated with heavy blood loss. Many attempts have been made
to identify such patients early and to evaluate the impact of perioperative therapeu-
tic optimization on outcome. In 1979, Shoemaker et al. [2] defined criteria for high
surgical risk. These included:
I patient history: age more than 70 years with evidence of limited major physio-
logic function, previous severe cardiopulmonary or vascular illness, severe nutri-
tional disorders
I critical factors: severe multiple trauma, massive acute blood loss, shock, septi-
cemia or septic shock, respiratory failure, acute abdominal catastrophe, acute
intestinal or renal failure
I surgical procedure factors: extensive surgery for cancer or prolonged surgery
more than 8 hours.
In their particular series of high-risk surgical patients, Shoemaker and his group
observed that the mortality rate was around 25o/o [2]; these authors also observed
that the ability of the patients to adapt their cardiopulmonary function dramati-
cally influenced their prognosis. In survivors, peri-operative values for cardiac in-
dex (CI) >4.5 Vmin.min 2, oxygen delivery (D0 2 ) >600 ml/min.m2, and oxygen up-
take (V0 2 ) > 170 ml/min.m2 were significantly higher than in non-survivors. These
values were qualified as "supranormal" by Shoemaker and his colleagues who pos-
tulated, therefore, that the observed increase in CI and D02 might account for cir-
culatory compensation secondary to increased postoperative oxygen demand. Their
conclusions confirmed previous observations demonstrating the major role played
by hemodynamic and metabolic responses on outcome in patients after cardiopul-
monary bypass (CPB) [3] or in patients after surgery for peritonitis [4]. In those
previous observations it was reported that the larger CI was associated with a bet-
ter outcome in the perioperative period. In high-risk surgical patients, the limita-
tion of cardiac output function may compromise regional perfusion in organs such
as the gastrointestinal tract or kidney leading to ischemia and reperfusion injuries.
The subsequent release of reactive oxygen species (ROS) or inflammatory mediators
might participate in activation of immune cells, leukocyte-to-endothelial cell inter-
342 B. Vallet et al.
action and distant organ injury (lung, liver) resulting in multiple organ failure
(MOF).
Because the gut is particularly sensitive to ischemia, a methodology based on
early detection of gastrointestinal hypoperfusion has been proposed to limit the oc-
currence of multiple organ dysfunction. Recently, several studies have demonstrated
that gastrointestinal hypoperfusion is associated with more severe MOF, longer in-
tensive care unit (ICU) length of stay, and larger mortality in surgical [5, 6] and in
trauma patients [7]. After cardiac surgery, we reported that patients who developed
circulatory failure were those in whom the postoperative-induced high vo2 was not
associated with an increase in D0 2 • Gastrointestinal hypoperfusion as detected by
air-automated gastric tonometry represented an early indicator of subsequent circu-
latory failure and was prognostic of increased morbidity in these patients [5].
Supranormal Hemodynamics
That spontaneous higher D02 could be associated with increased survival was re-
cently demonstrated by Pittet et al. [8] in an elegant, sustained endotoxic shock
sheep model. In the absence of any therapeutic attempt to increase D02 , surviving
animals were those that were able to increase their cardiac output and D0 2 • By
contrast, in animals that ultimately died, D02 was not different from that measured
in animals which did not receive endotoxin infusion. These results illustrate quite
convincingly the above conclusions formed by Shoemaker and colleagues [2] from
their own observations in high-risk surgical patients. Shoemaker et al. [9] went one
step further and hypothesized that survival in high-risk surgical patients could be
improved by using fluid or inotropes in order to therapeutically achieve supra-
physiologic CI, D0 2 , and consequently V0 2 • Shoemaker and colleagues were the
first to carry out a clinical trial in which 88 high-risk surgical patients were ran-
domized into three groups: two groups with normal hemodynamic targets (with or
without Swan-Ganz inserted) and one group with "supranormal" hemodynamic tar-
gets. In the "supranormal" group, a significant reduction in complications was ob-
served when compared to the two other groups (11 vs 39 and 31; p <0.00 1) along
with a lower percentage of patients having one or more complications (28 vs 50
and 50%, respectively; p < 0.05). The use of supraphysiologic values as a therapeutic
goal led to a significant reduction in postoperative mortality (4 vs 23 and 33%, re-
spectively).
It is important to emphasize, however, that many subsequent trials of hemody-
namic 'optimization' applied to other patient groups, such as septic shock patients
did not show improved outcome. Even worse, in a heterogeneous group of 109 cri-
tically ill patients, Hayes et al. reported higher mortality in the treatment group
(54 vs 34%, p=0.04) as compared with classical treatment [10]. The authors con-
cluded that the use of dobutamine to deliberately boost CI and D0 2 in order to
raise V0 2 failed to improve outcome, and that in some cases, the aggressive efforts
to increase V0 2 may have been seriously detrimental. In those particular cases, ino-
tropes were used at very high dose (17 patients received dobutamine at a dose
~50 f.lg/kg/min) and this was associated with the subsequent need for vasocon-
stricting agents (68% of the total group received norepinephrine).
These results clearly suggest that some critically ill patients do not adapt to me-
tabolic stress. In this context, pushing the hemodynamic reserve too far provides
High-Risk Surgical Patients: Why We Should Pre-Optimize 343
an "energy crisis" in patients who do not self-generate increased CI, D0 2 , or V0 2 •

Several groups demonstrated that patients who were able to increase both D0 2 and
V0 2 in response to dobutamine infusion presented a much higher survival rate
than those who could not [11, 12]. In fact, an increased VOz-D0 2 profile with do-
butamine infusion is very similar to what is observed in a healthy volunteer who
receives an infusion of this inotrope [13] suggesting that in critically ill patients
the best prognostic profile is associated with the presence of a larger physiologic
reserve. Consequently, a recent French prospective, multicenter, randomized trial
reported that responders to a 1 hour dobutamine infusion (as defined by an in-
crease in V0 2 of> 15%} were younger, had less chronic disease, and had much low-
er mortality (13.7 vs 40%, p<0.05) [14]. These factors are all consistent with great-
er physiologic reserve. In the same trial, after the "dobutamine test", patients were
randomized to receive dobutamine or not for a maximal period of 9 days. In re-
sponders, the lower mortality rate was not modified by prolonged dobutamine in-
fusion and in non-responders who received dobutamine the mortality rate was
much higher (47.4%} than in non-responders who did not receive dobutamine
(20.7%}. These results confirmed data reported by Hayes and colleagues [10].
While the V0 2 -to-D0 2 relationship may be used to test the ability of a patient to
respond to catecholamines and to endure metabolic stress, it is certainly important
to emphasize that the timing of a therapeutic intervention by an inotrope may
largely influence outcome. Most of the previous studies on hemodynamic optimiza-
tion in critically ill patients were performed up to 72 hours after admission to the
ICU, and can therefore be considered as post-optimization trials. Recently, Rivers et
al. [15] published the efficacy of early goal-directed therapy in the emergency room
before admission to the ICU, in patients with severe sepsis or septic shock. Patients
were randomized to receive or not 6 hours of early goal-directed therapy which
aimed to maintain a central venous oxygen saturation (Scv0 2 ) greater than 70% by
using mechanical ventilation, fluid loading, red blood cells (hematocrit ;::::30%) and/
or inotropic agents. The mortality rate appeared significantly lower in the group
assigned to early goal-therapy than in the group assigned to standard therapy. Until
this study, the notion that early hemodynamic optimization improves patient out-
come had only been observed in high-risk surgical patients. In 1996, Heyland et al.
grouping studies on optimization of D0 2 already stated that patients might benefit
from it when therapy was initiated pre-operatively [16].
I Peri-Operative Optimization of Oxygen Delivery
In high-risk surgical patients, several studies published in the last few years
demonstrated in general that increased D0 2 in the perioperative period reduces
both morbidity and mortality. In a randomized trial, Boyd et al. [17] used dopexa-
mine to obtain a perioperative D0 2 greater than 600 ml/min.m 2 in a population of
severe trauma patients. The high-risk criteria were intraoperative blood loss of
2000 ml or more with transfusion of 4 units or more of packed red cells during
the first 6 hours of admission in order to maintain hemoglobin level greater than
10 g/dl. The mean dose of dopexamine infused was 1.18 f.lg/kg/min during the pre-
operative course and 1.32 f.tg/kg/min during the postoperative course. The mortality
rate at 28 days was 5.7% in the protocol group and 22.2% in the control group.
These data were confirmed a few years later by Wilson et al. [18]. High-risk pa-
tients were randomized into 3 groups. One group considered as control received
routine perioperative care. Two groups were considered as "preoptimized": optimi-
zation consisted of invasive hemodynamic monitoring, fluid loading to achieve pul-
monary artery occlusion pressure (PAOP) of 12 mmHg, red blood cell transfusion
to maintain hemoglobin concentration more than 11 gfdl, oxygen support to keep
arterial oxygen saturation greater than 94%, and either epinephrine (initial rate at
0.025 !lglkglmin) or dopexamine (initial rate at 0.125 !lg/kglmin) to increase D0 2
to 600 ml/min.m2 or more. Inotropic support was continued during surgery and
for at least 12 hours afterwards. Seventy per cent of patients had more than two
Shoemaker entry criteria. The mortality rate was reduced in both the epinephrine
and dopexamine treatment groups (2 and 4%) compared to the control group
(17%, p=0.007). Dopexamine administration (30%) significantly decreased post-
operative morbidity when compared with both the epinephrine (52%) and the con-
trol groups (61%).
Much more recently, a randomized, double-blind, multicenter trial [19] tested
the effects on mortality rate of a dopexamine-infusion given in 412 high-risk pa-
tients undergoing major abdominal surgery with an expected duration of at least
1.5 hours. The patients were divided into 3 groups: placebo (n= 140), dopexamine
at 0.5 !lglkg/min (n = 135), or dopexamine at 2.0 !lg/kg/min (n = 137). The 28-day
mortality, which was the primary outcome variable registered in this study, did not
appear different between the placebo group (13%) and either the low-dose dopexa-
mine group (7%) or the high-dose group (15%). These data led to a discussion of
the clinical interest of hemodynamic optimization strategies in high-risk surgical
patients. Compared with the previous studies published, several differences might
explain, at least in part, the results observed by Takala et al. [19]:
I dosages of dopexamine were relatively fixed and were not chosen on any D0 2
criterion as was the case in the two above cited-studies; dopexamine at a dose of
2.0 !lg/kglmin might have caused harm which might explain the lack of any
trend for benefit;
I more importantly, patients selected by Takala et al. seemed to be less seriously
ill than patients from the previous studies of Boyd et al. [17] and Wilson et al.
[18] in which mortality rates of 23 and 17%, respectively, were observed in the
control groups (for a mortality of 13% in the one from Takala et al.);
I furthermore, only 41% of the patients included had more than two Shoemaker
entry criteria whereas a strong proportion of patients (82%) had major cancer
surgery compared with only 21% in Boyd's study who reported 54% emergency
cases in their patients.
In this context, it is worth noting that a post hoc analysis of the data from the
study by Takala et al. [19] showed a 50% reduction in mortality in patients with
two or greater Shoemaker entry criteria who received dopexamine at a rate of
0.5 !lg/kglmin. The same trend toward a benefit has been reported also with fixed
doses of dopexamine (0.5 !lg/kg/min or 2.0 !lg/kglmin) infused perioperatively in
high-risk surgical patients who had a low preoperative gastric intramucosal pH
(pHi <7.35) (20). Day 28 mortality was 20.5% (8/39) in patients with low pHi re-
ceiving placebo, whereas it was 10.8% (4/37) and 18.9% (7/37) in patients with 0.5
and 2.0 !lg/kg/min, respectively. There was no difference between the treated or the
placebo subgroups in patients with pHi of more than 7.35, the overall mortality
rate being significantly higher in the low preoperative pHi group ("' 18 vs -4%,
p=0.0001). Interestingly, dopexamine increased pHi but not D0 2 in low pHi pa-
Unoptimized hemodynamics
(low flow, inflammation)
~ p,. -opt;m;,,.;,"
Tissue
Distant organ injury -------+ MOF hypoperfusion
.
j
I
I
I
\
Bacterial and/ or endotoxin Tissue
translocation ischemia- reperfusion
,............. .."""
------, 2"" hit --- ----
'
Gut hyperpermeability
,- Post - optimization
Fig. 1. Proposed targets of "pre-" and "post-"optimization strategies. MOF; multiple organ failure
tients while in normal pHi patients, dopexamine induced increase in D0 2 without

any effect on pHi.
Clearly, improvement of global perfusion is not sufficient by itself to improve
outcome in the most severe, high-risk surgical patients, Their inability to raise D0 2
in response to the metabolic demand threatens gastrointestinal perfusion, which, by
intestinal microcirculatory disturbances and mucosal ischemia-reperfusion injury
with subsequent oxidant stress, may lead to the development of increased intestinal
permeability. The loss of gastrointestinal integrity has been hypothesized to play a
central role in the development and maintenance of MOF.
The exact target of "pre-optimization strategy" is still not understood. It may be
suggested that goal-directed therapy applied at the earliest stages in either high-risk
surgical or septic patients may prevent tissue hypoperfusion with both systemic
and regional balance between oxygen delivery and oxygen demand being restored
(Fig. 1). Conversely, a delayed hemodynamic optimization, the so-called "post-opti-
mization", would be less effective on patient outcome. In this latter case, the strat-
egy is performed when tissue ischemia-reperfusion, oxygen free radicals, and the
subsequent inflammatory cascade have already been activated; increasing D0 2
could even fuel peroxidation and systemic inflammation leading to further and
more severe distant organ injury.
I Conclusion
Hemodynamic optimization has been associated with reduced mortality in 4 out of
6 studies performed in surgical and trauma patients [9, 17-19, 21, 22]. This finding
was particularly observed in patients who had 2 or more Shoemaker entry criteria.
Furthermore, this strategy did not provide any beneficial effect on critically ill pa-
tient outcomes unless performed at the early stages of the critical illness. Periopera-
tively, dopexamine infused at a rate of 0.5 to 1.5 J.Lg/kglmin induces an increase in

D0 2 that may be beneficial if the hemodynamic reserve is not pushed too far. Fluid
and red cell administration, as well as inotrope infusion, will be best adjusted by
either monitoring of D02 or by gastrointestinal perfusion assessment.
References
1. Grounds RM, Rhodes A, Bennett ED (2001) Reducing surgical mortality and complications.
In: Vincent JL (ed) Yearbook of Intensive Care and Emergency Medicine: Springer, Heidel-
berg, pp 57-67
2. Shoemaker WC, Czer LS (1979) Evaluation of the biologic importance of various hemody-
namic and oxygen transport variables: which variables should be monitored in postopera-
tive shock? Crit Care Med 7:424-431
3. Boyd A, Tremblay R, Spencer F (1959) Estimation of cardiac output soon after intracardiac
surgery with cardiopulmonary bypass. Ann Surg 150:613-625
4. Clowes GJ, Vucinic M, Weidner M (1966) Circulatory and metabolic alterations associated
with survival or death in peritonitis: clinical analysis of 25 cases. Ann Surg 163:866-885
5. Lebuffe G, Decoene C, Pol A, Prat A, Vallet B (1999) Regional capnometry with air-auto-
mated tonometry detects circulatory failure earlier than conventional hemodynamics after
cardiac surgery. Anesth Analg 89:1084-1090
6. Bennett-Guerrero E, Panah MH, Bodian CA, et al (2000) Automated detection of gastric lu-
minal partial pressure of carbon dioxide during cardiovascular surgery using the Tonocap.
7. Miller PR, Kincaid EH, Meredith JW, Chang MC (1998) Threshold values of intramucosal
pH and mucosal-arterial C02 gap during shock resuscitation. J Trauma 45:868-872
8. Pittet JF, Pastor CM, Morel DR (2000) Spontaneous high systemic oxygen delivery increases
survival rate in awake sheep during sustained endotoxemia. Crit Care Med 28:496-503
9. Shoemaker WC, Appel PL, Kram HB, Waxman K, Lee TS (1988) Prospective trial of supra-
normal values of survivors as therapeutic goals in high-risk surgical patients. Chest
94:1176-1186
10. Hayes MA, Timmins AC, Yau EH, Palazzo M, Hinds CJ, Watson D (1994) Elevation of sys-
temic oxygen delivery in the treatment of critically ill patients. N Engl J Med 330:1717-
1722
11. Vallet B, Chopin C, Curtis SE, et al (1993) Prognostic value of the dobutamine test in pa-
tients with sepsis syndrome and normal lactate values: a prospective, multicenter study.
12. Rhodes A, Lamb FJ, Malagon I, Newman PJ, Grounds RM, Bennett ED (1999) A prospec-
tive study of the use of a dobutamine stress test to identify outcome in patients with sep-
sis, severe sepsis, or septic shock. Crit Care Med 27:2361-2366
13. Bhatt SB, Hutchinson RC, Tomlinson B, Oh TE, Mak M (1992) Effect of dobutamine on
oxygen supply and uptake in healthy volunteers. Br J Anaesth 69:298-303
14. Vallet B, Chopin C (2000) The supranormal oxygen delivery trials controversy. Dobutamine
in Sepsis Study Group. Crit Care Med 28:1257-1258
15. Rivers E, Nguyen B, Havstad S, et al (2001) Early goal-irected therapy in the treatment of
severe sepsis and septic shock. N Engl J Med 345:1368-1377
16. Heyland DK, Cook DJ, King D, Kernerman P, Brun-Buisson C (1996) Maximizing oxygen
delivery in critically ill patients: a methodologic appraisal of the evidence. Crit Care Med
24:517-524
17. Boyd 0, Grounds RM, Bennett ED (1993) A randomized clinical trial of the effect of delib-
erate perioperative increase of oxygen delivery on mortality in high-risk surgical patients.
JAMA 270:2699-2707
18. Wilson J, Woods I, Fawcett J, et al (1999) Reducing the risk of major elective surgery:
randomised controlled trial of preoperative optimisation of oxygen delivery. Br Med J
318:1099-1103
19. Takala J, Meier-Hellmann A, Eddleston J, Hulstaert P, Sramek V (2000) Effect of dopexa-
mine on outcome after major abdominal surgery: a prospective, randomized, controlled
multicenter study. European Multicenter Study Group on Dopexamine in Major Abdominal

Surgery. Crit Care Med 28:3417-3423
20. Poeze M, Takala J, Greve JW, Ramsay G (2000) Pre-operative tonometry is predictive for
mortality and morbidity in high-risk surgical patients. Intensive Care Med 26:1272-1281
21. Berlauk JF, Abrams JH, Gilmour IJ, O'Connor SR, Knighton DR, Cerra FB (1991) Preopera-
tive optimization of cardiovascular hemodynamics improves outcome in peripheral vascu-
lar surgery. A prospective, randomized clinical trial. Ann Surg 214:289-297
22. Bishop MH, Shoemaker WC, Appel PL, et a! (1995) Prospective, randomized trial of survi-
vor values of cardiac index, oxygen delivery, and oxygen consumption as resuscitation end-
points in severe trauma. J Trauma 38:780-787
Pain Control in the Intensive Care Unit
S. Brett and U. Waheed
I Introduction
Analgesia is defined as the absence of sensibility to pain or noxious stimuli in the
conscious patient. Patients admitted to the intensive care unit (ICU) commonly
have pain and physical discomfort from a number of factors, which include pre ex-
isting disease, invasive procedures, and trauma. Pain and discomfort can also be
caused by monitoring, routine nursing care (airway suctioning, physiotherapy, pa-
tient mobilization and dressing changes) and therapeutic devices such as drains,
non-invasive ventilation, and endotracheal tubes. Inadequate analgesia can contrib-
ute to inadequate sleep leading to exhaustion, disorientation and agitation. Pain
evokes a stress response characterized by tachycardia, increased myocardial oxygen
consumption, hypercoagulability, immunosuppression, and persistent catabolism
[1]. Poorly controlled analgesia may be associated with pulmonary dysfunction due
to guarding of muscles around areas of pain leading to restrictive movements of
the chest wall and diaphragm.
Pain assessment within the ICU may be difficult, a fact reinforced by the limited
amount of literature currently available. The most reliable indicator of pain is the
patient's self report [2]. A number of assessment scoring systems have been identi-
fied, including the verbal rating scale (VRS) and the numeric rating scale (NRS)
[3]. The NRS consists of a visual analog scale ranging from 0 to 10. The VRS in-
volves a scale between "no pain" and "worst pain''. The patient is asked to highlight
where they perceive their pain to be at that time on the scale. However, critically ill
patients are often unable to communicate their level of pain if sedated, anesthetized
or paralyzed. Both scoring systems mentioned, and many others, rely on the pa-
tients' ability to communicate with their carers.
The use of behavioral and physiological indicators to infer the presence of pain
has been advocated for uncommunicative critical care patients [4-6]. However little
research has examined the appropriateness or the accuracy of these measures. A re-
cent study showed that restlessness, sweating, tachycardia, lacrimation, pupil dilata-
tion and hypertension were signs of inadequate analgesia in 24 critically ill patients
[7]. In a study by Puntillo [8], patients reported that they had attempted to use eye
signals, facial expressions, and limb movements to let ICU staff know they were in
pain. However, such nonspecific signs might be misinterpreted or affected by ob-
server bias, leading to an underestimation of the degree of pain experienced by the
patient [9].
Because accurate and systematic pain assessment is a necessary step in the suc-
cessful management of a patient's pain, healthcare professionals need to use all
methods at their disposal to perform such an assessment. When patients are able
Pain Control in the Intensive Care Unit 349
to communicate, their subjective report should be the most important guide, and
when patients are unable to report their pain, comprehensive assessments using
systematic observations of behavioral and physiological indicators should be per-
formed.
I Treatment
Non-pharmacological
Non-pharmacological interventions are important to maintain patient comfort. Sim-
ple measures including attention to positioning of patients, stabilization of fractures
and eliminating irritating physical stimuli (ventilator tubing pulling on endotra-
cheal tubes) can make a significant difference. Music therapy has been shown tore-
lax patients and reduce their pain, decreasing heart rate, respiratory rate and systo-
lic blood pressure in surgical patients [10]. In mechanically ventilated patients, mu-
sic therapy was shown to decrease anxiety and promote relaxation [11].
Pharmacological
Opioids. Opioid analgesics are the drugs of choice for pain relief in the critically ill.
They have activity at a variety of receptors and although the J.l and K receptors are
most important for analgesia, interaction at other receptors may contribute to ad-
verse effects. The analgesic agents most commonly used in ICU patients include
morphine, fentanyl, alfentanil, sufentanil and, more recently, remifentanil. Desirable
attributes of an opioid include rapid onset, ease of titration, lack of accumulation
of the parent drug and its active metabolites, and low cost.
The major dose limiting side effect of opioid analgesics is respiratory depression,
which is especially important in spontaneously breathing patients or those weaning
from ventilatory support. Some opioids especially morphine may cause histamine
release resulting in hypotension, smooth muscle contraction and pruritis. Opioids
blunt the cough reflex. This effect in the ICU setting is of benefit to patients who
are mechanically ventilated, and is important in patients who require frequent suc-
tioning with irritable airways, e.g., asthmatics. Chest wall rigidity is seen with all
opioids but more so with the phenyl piperidines and this may result in reduced
chest wall compliance [12]. Hypotension has been seen when associated with hypo-
volemia or in patients with elevated sympathetic tone [13]. Opioid related hypoten-
sion in normovolemic patients is related to a combination of sympatholysis, vagally
mediated bradycardia and histamine release [14]. Reduced gut motility results in
nausea, vomiting and often an ileus. Jejunal feeding tubes may be needed for ent-
eral nutrition because of gastric hypomotility [15]. Smooth muscle contraction may
result in bladder sphincter dysfunction and urinary retention.
Historically, morphine has been the drug of choice in ICUs. It has a slow onset
of action owing to its lipid solubility with a longer duration of action (half-life 3-7
hr), so intermittent doses maybe given. It is metabolized in the liver by glucuroni-
dation and a potent metabolite, morphine-6-glucuronide, can accumulate in renal
failure and cause prolonged sedation.
The phenyl piperidines are more potent than morphine and have a faster onset
of action. Fentanyl is the opioid of choice in patients with hemodynamic instability
[16]. Intravenous fentanyl has a relatively short half-life of 30-60 minutes due to
350 S. Brett and U. Waheed
100
c
0
jI Fentanyl
·;:;
~
I
~~ 75
~ .; j Alfentanil
o E i ···································
i ...···
u ~
·=a. ·v;~ 50
eu /~---·······
---
... ,.. Sufentanyl
"0~
;§1 01
o ...
"' "' 25
/J..{ _____ . .
s
01 it'"
E Remifentanil
i=
o¥===~==~==~==~==~~
0 100 200 300 400 500 600
Duration of infusion (min)
Fig. 1. A simulation of the time necessary to achieve a 50% decrease in drug concentrations in the blood
(or plasma) after variable-length intravenous infusions of remifentanil, fentanyl, alfentanil, and sufentanil.
(From [19] with permission)
rapid distribution into peripheral tissues. However, when given as an infusion it

tends to accumulate in these peripheral compartments with a resultant rise in its
half-life to 9-16 hours. Fentanyl has no active metabolite, although its major meta-
bolite norfentanyl may accumulate in renal failure and has been associated with
toxic delirium.
Alfentanil also has no active metabolite and is commonly used in patients with
renal insufficiency; however, in patients with impaired hepatic function the plasma
clearance may be reduced and recovery prolonged.
Remifentanil is an ultra short acting agent that is well established for use during
anesthesia. When compared to the other phenyl piperidines it has a unique phar-
makokinetic profile. It undergoes rapid metabolism by non-specific esterases in
blood and tissue, independent of organ function [17]. This ensures that it has a
short duration of action and rapid recovery even when given as a continuous infu-
sion [18], and does not accumulate (Fig. 1 [19]). The short duration of action could
be beneficial in selected patients requiring interruptions for neurological examina-
tion [20]. The main metabolite is remifentanil acid and this is excreted renally. It is
inactive and even in renal insufficiency where it accumulates; it is not associated
with any adverse effects [21). Of all the opioids mentioned, remifentanil is the near-
est to the ideal agent (mentioned above) and a promising step forward in optimiz-
ing the provision of analgesia in ICU patients.
Sufentanil is another selective f.1 agonist that is not commonly used in the ICU
setting. It is an analog of fentanyl and has ten times its potency. Sufentanil causes
little hemodynamic disturbance though has been associated with orthostatic hypo-
tension secondary to venous pooling. The duration of action is short when given in
small doses but increases with larger or repeated doses. The use of sufentanil in
the ICU has not been well described, though interest has been shown in post-neu-
rosurgical patients. Boluses of sufentanil have been shown to increase intracranial
pressure (ICP) and hence reduce cerebral perfusion pressure (CPP) [22].
Pethidine is a synthetic compound and was originally developed as an anticholi-

nergic agent. It tends to cause anticholinergic effects, such as dry mouth, blurred
vision and tachycardia. It is claimed that pethidine induces less constriction of the
biliary sphincter than morphine, and perhaps the only indication for its use is in
biliary pathology. It is metabolized in the liver and the metabolites are excreted by
the kidney. In renal failure significant amounts of norpethidine may accumulate,
leading to grandma! convulsions. Its use in the ICU is limited.
Patients exposed to high doses of opioid during their stay in the ICU may devel-
op physiological dependence [23]. A regime which involves rapid discontinuation
could lead to symptoms of withdrawal. These signs include pupillary dilatation,
sweating, lacrimation, and rhinorrhea. Other physiological signs include tachycar-
dia, hypertension, fever, and tachypnea. Length of stay, mechanical ventilation, and
opioid dose have all been associated with withdrawal [24]. It has been shown that a
5 mglday dose of fentanyl or its equivalent, given for seven days or more puts pa-
tients at high risk [24]. Recommendations for opioid weaning include; 5-10% daily
dose decrements [25], or an initial 20-40% reduction followed by 10% reductions
every 12-24 hours [26]. If the drug is administered intermittently, converting to a
longer acting agent has been shown to reduce the effects of withdrawal [27].
Non-steroidal Anti-Inflammatory Drugs. Non-steroidal anti-inflammatory drugs

(NSAIDs) are mild analgesics that inhibit prostaglandin and thromboxane synthesis
via the non selective competitive inhibition of cyclo-oxygenase (COX). In addition
to having anti-inflammatory activity, NSAIDs are antipyretic and inhibit platelet
aggregation. They do not cause sedation, respiratory depression or hypotension, ad-
verse effects that are more common with opioid analgesics. Administration of
NSAIDs has been shown to reduce opioid requirement by 30-50% [28], although
the analgesic benefit of NSAIDs has not been systemically studied in ICU patients.
NSAIDs have the potential to cause significant adverse effects, including gastro-
intestinal bleeding, bleeding secondary to platelet inhibition, and the development
of renal impairment. The elderly, hypotensive, and hypovolemic patients are more
susceptible to induced renal injury [29], as are patients with congestive heart fail-
ure, chronic renal disease, cirrhosis, and hypertension [30]. Interestingly, studies
have shown that it is the duration of treatment with NSAIDs rather than NSAIDs
per se that is associated with renal impairment, with or without the presence of
risk factors [30]. Ketorolac when given intravenously for less than 5 days was
shown to have the same incidence of renal impairment as opioids. However, after 5
days it was associated with a two-fold increase in creatinine [30]. The renal impair-
ment is attributed to, in theory, the inhibition of prostaglandins (PGI 2 enhances
Na+, Cl- and water excretion; PGE2 causes vasodilatation of the afferent arteriole to
maintain the glomerular filtration rate), especially in clinical states characterized
by high circulating levels of norepinephrine and angiotensin II [31].
The role of the more selective COX-2 inhibitors in the critically ill remains un-
known. It is hypothesized that they may have a lower risk of gastrointestinal com-
plications (bleeding, perforation, or obstruction) than traditional NSAIDs [32-33].
The Celecoxib Long term Arthritis Safety Study (CLASS) [34] initially showed un-
equivocal benefit over traditional NSAIDs but was later criticized for many discre-
pancies [35]. Interestingly both CLASS and VIGOR [33] (compared rofecoxib and
naproxen) showed an increased incidence of serious adverse effects related to spe-
cific cardiovascular events (myocardial infarction and thrombotic events) [36]. The
COX-1 isoform is constitutively expressed in most cells, which results in the pro-
352 S. Brett and U. Waheed
duction of homeostatic prostaglandins that maintain gastrointestinal mucosal integ-

rity and renal blood flow. The COX-1 isoform is also expressed in platelets and
mediates production of thromboxane A2 , a potent platelet activator and aggregator.
The COX-2 isoform inhibitors have no effect on thromboxane A2 production, but
by decreasing PGI 2 production may tip the natural balance between prothrombotic
thromboxane A2 and anti thrombotic PGI 2 , potentially leading to an increase in
thrombotic cardiovascular events [37]. The lack of intravenous formulations and
the slow onset of action of some agents may decrease their utility for acute pain
management in the ICU setting.
Acetaminophen. Acetaminophen (paracetamol) is a non-narcotic analgesic which is

used in the ICU for mild to moderate pain or discomfort. Its analgesic effects are
caused by inhibition of prostaglandin within the central nervous system. It has no
anti-inflammatory effects (due to minimal effects on peripheral prostaglandin syn-
thesis) and although hypersensitivity has been reported, it is very rare. It has few
adverse effects although an association with hypotension post administration has
been noted [38].
Acetaminophen is also an effective antipyretic. The mechanism of action is
thought to be two fold: a direct effect on the hypothalamus leading to peripheral
vasodilatation and sweating, and an inhibitory effect to pyrogens on the hypothala-
mic heat-regulating centers.
In combination with an opioid, paracetamol produces a greater analgesic effect
than higher doses of the opioid alone [39]. When compared with NSAIDs as ad-
juncts to opioids, paracetamol was found to be more effective [40), thus avoiding
the potential adverse effects of NSAIDs as previously stated. Care must be taken,
however, to avoid excessive and potentially hepatotoxic doses, especially in patients
with depleted glutathione stores resulting from hepatic dysfunction or malnutrition.
Studies have shown that paracetamol can increase the anticoagulant effects of war-
farin to the same extent as NSAIDs. Patients taking 1 gram per day for more than
one week are ten times more likely to have an international normalized ratio (INR)
of greater than six [41]. This feature is important especially in ICUs where patients
require analgesia for heart valve replacements and have been anticoagulated. Para-
cetamol as a single agent lacks analgesic potency, however when used as an adjunct
with other analgesics it becomes a very useful aid.
Alpha 2 Agonists. The alpha 2-agonist, dexmedetomidine is a new class of sedative/

analgesic drug that is being investigated in ICU settings. It is an effective agent for
the management of sedation and analgesia in the post operative period [42]. Paren-
teral, epidural, and intrathecal placement causes analgesia and synergistically en-
hances the effects of opioids. Its analgesic effects are thought to' be associated with
the stimulation of the locus coerulus and, hence, activation of the descending
noradrenergic antinociceptive system. It also has an effect within the spinal cord
by stimulating the alpha 2a receptors in the substantia gelatinosa of the dorsal horn
and preventing the activation of nociceptive neurones. Because of its remarkable
cardiovascular stability and its lack of respiratory depression [43], there is currently
great interest in the use of this agent. Clonidine has been used for many years as
an adjunct to sedation and analgesia in intensive care practice. It is used commonly
in the ICU to augment the effects of opioids and to treat drug withdrawal syn-
dromes [44].
I Conclusion
Virtually all mechanically ventilated patients will require some form of analgesia
during their stay in the ICU. Proper use can enhance patient comfort, but misuse
through a lack of understanding may lead to side effects and adverse reactions.
The goal for the intensivist regarding the use of analgesics is to provide comfort
and safety without increased cost, morbidity, and mortality.
References
1. Lewis KS, Whipple JK, Michael KA, Quebbeman EJ (1994) Effect of analgesic treatment on
the physiological consequences of acute pain. Am J Hosp Pharm 51:1539-1554
2. Acute Pain Management Guideline Panel {1992) Acute Pain Management: Operative or
Medical Procedures and Trauma. Clinical Practice Guideline. AHCPR Publication No. 92-
0032. Agency For Health Care Policy and Research, Rockville
3. Puntillo KA, Miaskowski C, Kehrle K, Stannard D, Gleeson S, Nye P (1997) Relationship
between behavioral and physiological indicators of pain, critical care patients' self reports
of pain, and opioid administration. Crit Care Med 25:1159-1166
4. Christoph SB (1987) Pain assessment: The problem of pain in the critically ill patient. Crit
Care Nurse Clin North Am 3:11-16
5. Harrison M, Contach P (1987} Pain: Advances and issues in critical care. Crit Care Nurse
Clin North Am 22:691-697
6. Les D (1990) Monitoring pain control and charting. Crit Care Clinician 6:283-294
7. Rawal N, Tandon B {1985) Epidural and intrathecal morphine in intensive care units. In-
8. Puntillo KA {1990) The pain experiences of intensive care unit patients. Heart Lung
19:526-533
9. Ferguson J, Gilroy D, Puntillo K {1997) Dimensions of pain and analgesic administration
associated with coronary artery bypass in an Australian intensive care unit. J Adv Nurs
26:10654-10672
10. Byers JF, Smyth KA (1997) Effect of music intervention on noise annoyance, heart rate,
and blood pressure in cardiac surgery patients. Am J Crit Care 6:183-191
11. Chlan L {1998) Effectiveness of a music therapy intervention on relaxation and anxiety for
patients receiving ventilatory assistance. Heart Lung 27:169-176
12. Bonnet F, Kergrohen F, Lafosse JE, Loriferne JF, Salvat A, Debras C (1986) Postoperative
rigidity after fentanyl administration. Eur J Anesthesiol 3:413-416
13. McArdle P (1999} Intravenous analgesia. Crit Care Clin 15:89-105
14. Grossmann M, Abiose A, Tangphao 0, et al {1996) Morphine-induced venodilation in hu-
mans. Clin Pharmacal Ther 60:554-560
15. Placke JW, Placke WE, Bloor BC, Van Etten AP, Kripke BJ {1987) Histamine release by four
narcotics: A double blind study in humans. Anaesth Analg 66:723-730
16. Shapiro BA, Warren J, Egol AB, et al {1995) Practice parameters for intravenous for intra-
venous analgesia and sedation for adult patients in the intensive care unit: An executive
summary. Crit Care Med 23:1596-1600
17. Egan TD (1995) Remifentanil pharmakokinetics and pharmacodynamics. A preliminary
appraisal. Clin Pharmakokinet 29:80-94
18. Westmoreland CL, Hoke JF, Sebel PS, Hug CC Jr, Muir KT (1993) Pharmakokinetics of re-
mifentanil and its major metabolite in patients undergoing elective implant surgery. Anaes-
thesiology 79:893-903
19. Egan TD, Lemmens HJM, Fiset P, et al (1993) The pharmacokinetics of the new short-act-
ing opioid remifentanil (g187084B) in healthy adult volunteers. Anesthesiology 79:881-892
20. Tipps LB, Coplin WM, Murry KR, et al {2000) Safety and feasibility of continuous infusion
of remifentanil in the neurosurgical intensive care unit. Neurosurgery 46:596-602
21. Breen D, Wilmer A, Bodenham A, et al {2001) The offset of pharmacodynamic effects of
remifentanil in ICU patients is not affected by renal impairment. Intensive Care Med
27:S207 (abst)
354 S. Brett and U. Waheed: Pain Control in the Intensive Care Unit
22. Albanese J, Viviand X, Potie F, Rey M, Alliez B, Martin C (1999) Sufentanil, fentanyl, alfen-
tanil in head trauma patients: A study on cerebral hemodynamics. Crit Care Med 27:407-
411
23. Jacobi J, Fraser GL, Coursin DB, et al (2002) Task force of the American college of critical
care medicine (ACCM) of the society of critical care medicine (SCCM), American society
of health-system pharmacists (ASHP), american college of chest physicians. Clinical prac-
tice guidelines for the sustained use of sedatives and analgesics in the critically ill adult.
24. Cammarano WB, Pittet JF, Weitz S, Schlobohm RM, Marks JD (1998) Acute withdrawal
syndrome related to the administration of analgesic and sedative medications in adult in-
tensive care unit patients. Crit Care Med 26:676-684
25. Buck M, Blumer J (1991) Opioids and other analgesic: Adverse effects in the intensive care
unit. Crit Care Clin 7:615-637
26. Anand KJS, Ingraham J (1996) Tolerance, dependence, and strategies for compassionate
withdrawal of analgesics and anxiolytics in the pediatric ICU. Crit Care Nurse 16:87-93
27. Stokie IL (1992) Principles of Analgesic Use in the Treatment of Acute Pain and Cancer
Pain, 3rd edition. American Pain Society, Glenview.
28. Wall PD (1995) Inflammatory and neurogenic pain: new molecules, new mechanisms. Br J
Anaesth 75:123-124
29. Schlondorff D (1993) Renal complications of nonsteroidal anti-inflammatory drugs. Kidney
Int 44:643-653
30. Feldman HI, Kinman JL, Berlin JA, et al (1997) Parenteral Ketorolac: The risk for acute re-
nal failure. Ann Intern Med 126:193-199
31. Clive DM, Stoff JS (1984) Renal, syndromes associated with nonsteroidal anti-inflammatory
drugs. N Engl J Med 310:563-572
32. Warner TD, Giuliano F, Vojnovic I, et al (1999) Nonsteroid drug selectivities for cyclo-oxy-
genase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity:
a full in vitro analysis. Proc Natl Acad Sci USA 96:7563-7568
33. Bombardier C, Laine L, Reicin A, et al (2000) Comparison of upper gastrointestinal toxicity
of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR study group. N
Engl J Med 343:1520-1528
34. Silverstein FE, Faich G, Goldstein JL, et al (2000) Gastrointestinal toxicity with celecoxib
versus non steroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis.
The CLASS study: A randomized control trial. JAMA 284:1247-1255
35. Juni P, Rutjes A, Dieppe P (2002) Are selective COX 2 inhibitors superior to traditional
non steroidal anti-inflammatory drugs?: Adequate analysis of the CLASS trial indicates that
this may not be the case. Br Med J 324:1287-1288
36. Cleland LG, James MJ, Stamp LK, Penglis PS (2001) COX-2 inhibition and thrombotic ten-
dency: a need for surveillance. Med J Aust 175:214-217
37. Mukherjee D, Nissen SE, Topol EJ (2001) Risk of cardiovascular events associated with se-
lective cox-2 inhibitors. JAMA 286:954-959
38. Mackenzie IM, Forest K, Thompson F, et al (1999) Hypotension following acetaminophen
administration to critically ill patents. Crit Care Med 27:33a (abst)
39. Pedutta VA, Ballabio M, Stefanini S, et al (1998) Efficacy of propacetamol in the treatment
of postoperative pain. Morphine sparing effect in orthopaedic surgery. Italian Collabora-
tion Group on Proparacetamol. Acta Anaesthesiol Scand 42:293-298
40. Schug SA, Sidebotham DA, McGuinnely M, et al (1998) Acetaminophen as an adjunct to mor-
phine by PCA in the management of acute post-operative pain. Anaesth Analg 87:368-372
41. Hylek EM, Heiman H, Skater SJ, Sheenan MA, Singer DE (1998) Acetaminophen and other
risk factors for excessive warfarin anticoagulation. JAMA 279:657-662
42. Venn RN, Bradshaw CJ, Spencer R, et al (1989) Preliminary UK experience of dexmedeto-
midine, a novel agent for post operative sedation in the intensive care unit. Anaesthesia
54:1136-1142
43. Furst SR, Weinger MB (1990) Dexmedetomidine A selective alpha 2-agonist, does not potenti-
ate the cardiorespiratory depression of alfentanil in the rat. Anaesthesiology 72:882-888
44. Gold MS, Redmond DE Jr, Kleber HD (1978) Clonidine blocks acute opiate-withdrawal
symptoms. Lancet 2:599-601
Respiratory Failure Post-Coronary Bypass Surgery
S. Yende and R. Wunderink
I Introduction
Coronary artery bypass graft (CABG) surgery is the most common cardiac surgery
performed in the United States and around the world. In 1999, approximately
571000 CABG surgeries were performed in the United States alone [1, 2]. Over the
past decade the number of bypass operations has declined, especially when com-
pared to other revascularization procedures, such as balloon angioplasty. However,
the average age and associated comorbid conditions of patients who undergo CABG
surgery has increased. The cardiopulmonary bypass (CPB) circuit is also used for
valve repair, heart transplantation, and heart lung transplantation.
A number of respiratory complications occur after CABG surgery, such as acute
respiratory distress syndrome (ARDS) [3], cardiogenic pulmonary edema [4], ex-
acerbation of chronic obstructive pulmonary disease (COPD), pneumonia [5], pul-
monary embolism [6], atelectasis [7], and pleural effusion [8]. These complications
often manifest as difficulty extubating patients from mechanical ventilation. Failure
to be extubated may occur due to the above mentioned pulmonary causes as well
as non-pulmonary causes, such as cerebral vascular accident (CVA) or excess post-
operative bleeding. These patients are also termed failure to wean or experiencing
prolonged mechanical ventilation.
In order to define "prolonged mechanical ventilation", one must decide what is
an acceptable duration of mechanical ventilation after CABG surgery. Anesthesiolo-
gists, cardiovascular surgeons, and critical care physicians may answer this ques-
tion differently. For example, studies examining outcomes of fast track cardiac an-
esthesia have used different endpoints within the first twelve hours to define unsuc-
cessful extubation [9]. Other studies use the percentage of patients who are not ex-
tubated at 24 or 48 h as an endpoint [10]. This chapter examines epidemiology,
etiology, risk factors and outcomes of patients with prolonged mechanical ventila-
tion after CABG surgery, including how these are affected by the different endpoint
times.
Incidence
The overwhelming majority of patients are extubated within twenty-four hours
after CABG surgery. However, the median duration of mechanical ventilation after
CABG varies from 4-20 h in different studies [10, 11]. In one study, the majority
were extubated in the operating room itself [12], whereas another study reported a
median duration of forty eight-hours [13]. This wide variability in the duration of
356 5. Yende and R. Wunderink
mechanical ventilation post-CABG surgery may be attributable to differences in

baseline comorbid conditions of patients, surgical techniques, anesthetic techni-
ques, and varying proportions of patients receiving repeat CABG or associated
valve repair surgery.
Based on the Society of Thoracic Surgeons (STS) database, prolonged mechanical
ventilation greater than twenty-four hours occurs in 5.6% and 10.3% of patients
undergoing first and repeat CABG surgery, respectively [2]. This appears to be a
reasonable definition of prolonged mechanical ventilation since the incidence of
prolonged mechanical ventilation for time points prior to 24 h is so variable that
no consensus on incidence can be achieved.
Pathogenesis
Several factors in the pathogenesis of post-CABG respiratory failure are important

to understand the risk factors for prolonged ventilation.
Post-CABG Surgery Inflammatory Cascade

CABG is followed by release of proinflammatory and antiinflammatory cytokines,
which is an important cause of postoperative complications [14]. This inflammatory
cascade may contribute to various postoperative complications that cause prolonged
mechanical ventilation, including ARDS, acute lung injury (ALI), postoperative de-
lirium, and even excessive postoperative bleeding. Various stimuli have been sug-
gested to initiate cytokine release after CABG, including exposure of blood to the
foreign surface of the bypass machine, complement activation [15], ischemia-reper-
fusion injury [16], and endotoxin released due to gastrointestinal tract hypoperfu-
sion [17]. Release of tumor necrosis factor (TNF), interleukin (IL)-1, IL-6, IL-8, an-
giotensin converting enzyme (ACE), adhesion molecules, such as CD18 and CDllb,
neutrophil elastase and arachidonic acid metabolites follows this trigger.
TNF is a crucial proinflammatory cytokine in the post CABG inflammatory cas-
cade and stimulates other proinflammatory mediators, such as IL-1/], IL-6 and IL-8
[17, 18]. Gilliland et al. found that elevated levels of TNF in bronchial secretions in
patients undergoing CABG surgery correlated with lung dysfunction [19]. Similarly,
postoperative IL-6 and IL-8 levels are associated with pulmonary and cardiac com-
plications after CABG surgery [20, 21]. Wan and coworkers showed that the release
of inflammatory mediators is lower after off-pump coronary artery bypass surgery
compared to conventional CABG surgery [22]. Patients undergoing off-pump coro-
nary artery bypass surgery have lower incidence of prolonged mechanical ventila-
tion compared to those undergoing conventional CABG surgery [23]. These find-
ings further emphasize the role of inflammatory mediators in prolonged mechanical
ventilation in patients post-CABG surgery.
Genetic Factors
Although part of the variability in duration of ventilation post CABG can be ex-
plained by the heterogeneity of causes of prolonged mechanical ventilation, genetic
factors may also have a role in post-CABG surgery complications. Population based
gene association studies have been used to examine the role of genetic factors in
Respiratory Failure Post-Coronary Bypass Surgery 357
post CABG surgery complications. This approach assesses the frequency of specific
genetic factors, often single nucleotide polymorphisms (SNP), in patients with and
without specific clinical outcomes [24].
Genetic variation in cytokines that are important in the post-CABG surgery in-
flammatory cascade, such as TNF, IL-l, IL-6, ACE, have been described extensively
[25, 26]. Therefore, these genes are excellent candidate genes for association stud-
ies. A haplotype formed by the +250 site within the LTa gene and the -308 site
within the TNF gene is associated with prolonged mechanical ventilation after
CABG surgery [27]. A polymorphism within the ACE gene consists of either inser-
tion or deletion (I/D) of a 250-base pair fragment. The D allele is associated with
higher levels of ACE compared to the I allele [28]. In a recent study, patients with
the D allele had higher mortality and restenosis rates after CABG surgery compared
to the I allele [29]. The D allele is also associated with susceptibility to, and prog-
nosis of, ARDS [30], an important cause of prolonged mechanical ventilation post-
CABG at the 24 and 48 h time points [5]. Chew et al. have also reported associa-
tions between the apolipoprotein E polymorphisms and complications after cardiac
surgery [31]. Preoperative genotyping may not only improve pre-operative risk
stratification, but pharmacologic manipulation based on genotype also represents a
potential therapeutic strategy.
I Etiology
The causes of prolonged mechanical ventilation are heterogeneous and vary with
time. In a prospective study, we examined early (within 24 h) and late (24-48 h)
causes of prolonged mechanical ventilation after CABG surgery (Table 1). In this
study, patients failed to be extubated for a variety of causes and, at each time point,
an individual patient could have more than one cause of prolonged mechanical
ventilation. In a small subgroup of patients, the causes may change over time. For
example, a patient may initially fail to be extubated due to excessive postoperative
bleeding and may later require mechanical ventilation for ARDS secondary to mul-
tiple transfusions. Once ARDS has occurred, prolonged mechanical ventilation may
be due to hypoxemia and tachypnea (secondary to agitation or metabolic acidosis).
At the eight hour time point, depressed respiratory drive due to prolonged ef-
fects of anesthetic agents was the most common cause of unsuccessful extubation,
occurring in a third of the patients. The frequency of this cause is likely to have
the most variability between institutions based on local surgical and anesthesia
techniques. The effect of different anesthesia protocols on prolonged mechanical
ventilation has been studied extensively, and randomized clinical trials using short
acting anesthetic techniques have shown reduced duration of mechanical ventila-
tion, as well as cost [9, 32]. Therefore, prolonged effect of anesthesia is likely to
also be the cause most amenable to intervention.
In contrast, hypoxemia was the most common reason for prolonged mechanical
ventilation at the 24 and 48 h time points. The common causes of hypoxemia were
ARDS and cardiogenic pulmonary edema. However, many patients had significant
hypoxemia with a normal or near normal chest radiograph. Excess postoperative
bleeding was also a common cause of prolonged mechanical ventilation in the early
and late group of patients. Bleeding may delay extubation due to hypotension, car-
diogenic pulmonary edema, noncardiogenic pulmonary edema secondary to blood
Table 1. Early (< 24 h) and late causes (> 24 h) of prolonged mechanical ventilation
Early causes (n= 167) Late causes (n = 27)

Depressed respiratory drive
Prolonged anesthesia 51 (2) 0
I Neurologic insult 6 4
Others 1 0
Hypoxemia
Unknown etiology 23 (1) 4
ARDS 10 7
Pulmonary edema 7 (3) 4 (1)
Pneumonia 2 0
lnaeased respiratory rate
Metabolic acidosis 6 (2) 0
I Respiratory alkalosis (agitation) 8 1
I Respiratory acidosis 10 0
Mixed acid base disorders 3 (2) 2
Cardiovascular instability 3 (6) 1 (2)
Postoperative bleeding 17 (1) 2
Physician choice
Cause not determined 4 0
Sleep apnea 2 0
I Tracheal stenosis 1 0
Poor NIF or FVC 13 0
Others
Diaphragmatic paralysis 0 (1) 0 (1)
Laryngeal edema 0 (1) 1
Right main stem intubation 0 (1) 1
Parentheses represent number of patients with cause as secondary significant factor.

FRC: functional residual capacity; NIF: negative inspiratory force
transfusions and additional exposure to anesthetic agents if exploratory surgery is

required to identify the source of bleeding. Cardiovascular instability was a surpris-
ingly uncommon primary cause of inability to extubate. Tachypnea due to meta-
bolic disorders, agitation, and obstructive lung disease were uncommon causes of
prolonged mechanical ventilation. Other causes of prolonged mechanical ventilation
included sleep apnea, tracheal stenosis, laryngeal edema and diaphragmatic paraly-
sis due to phrenic nerve paralysis.
Finally, the delayed causes of prolonged mechanical ventilation, especially for pa-
tients requiring mechanical ventilation more than three days, remain unclear. The
majority of these patients may still have ARDS. However, complications of chronic
mechanical ventilation, such as nosocomial pneumonia and sepsis, may complicate
the hospital course in these patients [33].
I Risk Factors for Prolonged Mechanical Ventilation

Epidemiologic Approach
Various preoperative and intraoperative factors increase the risk of prolonged me-
chanical ventilation after CABG surgery. Table 2 enumerates some of the studies
that have examined risk factors for prolonged mechanical ventilation > 24 h after
CABG surgery.
Cardiovascular factors are probably the most important risk factor for prolonged
mechanical ventilation after CABG surgery. Patients undergoing CABG surgery are
at increased risk for reduced ejection fraction secondary to coronary artery disease
or concomitant hypertension. Numerous investigators have investigated the role of
cardiovascular factors, such as unstable angina, congestive heart failure (CHF) and
reduced pre-operative ejection fraction on prolonged mechanical ventilation post
CABG [10, 34-36]. A higher incidence of postoperative CHF or postoperative hypo-
tension increase the duration of mechanical ventilation in patients with a history of
CHF or reduced left ventricular ejection fraction [34, 35]. Hypotension during the
postoperative period may require vasopressors or intra-aortic balloon pump (IABP)
Table 2. Studies examining risk factors for prolonged mechanical ventilation
Patients Study Risk factors identified •

(n) endpoint
Branca et al. [13) 4863 Society of thoracic surgeons score, mitral valve disease,
age, renal failure, operative urgency, pre-operative need
for mechanical ventilation, prior CABG, female gender,
acute myocardial infarct, previous 0/A
Sando et al. l341 586 NA' Operative urgency, congestive heart failure,
perioperative bleeding, coma, reduced cardiac output,
stroke and postoperative CKMB release.
Thompson et al. [38) 139 7 days COPD, bypass time, operation duration, urban residence
Spivack et al. [10) 513 48h CHF, angina, current smoking, diabetes
Habib et al. [37) 507 NA' Age, weight, NYHA class IV, number of anastomoses, fluid
balance, perioperative IABP. PRBC transfusions
Miyamoto et al. [44) 78 NA' Reduced FEV1, post operative cardiac index, post operative
use of temporary pacemakers
Cohen et al. [39) 66 48h Elevated creatinine, reduced FEV1, longer cardiopulmonary
bypass time, positive post operative fluid balance
Legare et al. [36] 1829 24 h Unstable angina, ejection fraction, COPD, renal failure,
female gender, age> 70, post operative stroke, bleeding
or Ml during intraoperative period
Suematsu et al. [35] 167 24 h Age, duration of surgery, perioperative glucose, periopera-
tive CHF, postoperative transfusion, postoperative hypox-
emia (Pa02/Fi02 ratio)
• Includes multivariable analysis only; b multiple linear regression; 'cox proportional hazards model;
CHF: congestive heart failure; CVA: cerebrovascular accident; COPD: chronic obstructive airways disease;
Ml: myocardial infarction; PRBC: packed red blood cell; lAB: intra-aortic balloon pump
360 S. Yende and R. Wunderink
[37], which are also independent risk factors for prolonged mechanical ventilation
[5, 34].
Smoking is an important risk factor for coronary artery disease. Therefore, pa-
tients undergoing CABG surgery have higher prevalence of smoking as well as of
COPD. COPD [13, 36, 38] smoking [10], and the role of spirometry or pulmonary
function tests [39] have been studied extensively in these patients. Smoking is an
independent risk for prolonged mechanical ventilation in various studies and pre-
operative discontinuation of smoking is associated with better outcome [40]. The
role of COPD as a risk factor for prolonged mechanical ventilation is controversial.
Most patients with COPD will extubate successfully [41] and the role of routine
preoperative pulmonary function tests remains controversial [42]. Cardiovascular
factors, especially low ejection fraction, are probably more important risk factors
for prolonged mechanical ventilation than pre-operative pulmonary status.
Similar to cardiovascular factors and smoking, patients undergoing CABG sur-
gery have a higher prevalence of renal failure. In a large prospective Veteran's Asso-
ciation co-operative study, Anderson and coworkers demonstrated that renal failure
is an independent risk factor for prolonged mechanical ventilation after CABG sur-
gery [43], and other studies have confirmed this association [34, 36, 39]. These pa-
tients may be at higher risk for prolonged mechanical ventilation due to an in-
creased incidence of postoperative bleeding and volume overload.
Age has been identified as an important risk factor for prolonged mechanical
ventilation in various studies [13, 34-37, 44]. Age may increase the risk of pro-
longed mechanical ventilation by various mechanisms. First, age may be a surro-
gate marker for comorbid risk factors, such as CHF, which are important risk fac-
tors for prolonged mechanical ventilation. Second, aging is associated with reduced
total lung capacity, which may increase the risk of prolonged mechanical ventila-
tion. Third, elderly patients may require longer duration to recover from anesthe-
sia, thereby delaying extubation [9]. Finally, the risk of postoperative bleeding,
which is an important cause of prolonged mechanical ventilation [5], is higher in
older patients [45].
Surgical technique is an important and modifiable risk factor for prolonged me-
chanical ventilation after CABG surgery. In various observational studies, patients
undergoing off-pump coronary artery bypass surgery compared to conventional
CABG surgery have a lower incidence of prolonged mechanical ventilation, and
randomized clinical trials are underway to assess whether off pump surgery may
reduce duration of mechanical ventilation [46]. Other intraoperative risk factors
such as bypass time or aortic cross clamp time are also important risk factors for
prolonged mechanical ventilation [38]. Patients who require emergent surgery, re-
peat CABG surgery, or associated valve repair also have higher risk of prolonged
mechanical ventilation [34]. Most surgical factors alter risk of prolonged mechani-
cal ventilation by modulating the post-CABG surgery inflammatory cascade [13].
Pitfalls in Studies Examining Risk Factors

for Prolonged Mechanical Ventilation
The epidemiologic approach to risk factors for prolonged mechanical ventilation
has several pitfalls. While most studies examined preoperative and intraoperative
risk factors, a few studies also included postoperative complications. Postoperative
complications, such as bleeding and hypoxemia, are probably best viewed as causes
of prolonged mechanical ventilation, whereas pre-operative and intra-operative

variables should be regarded as risk factors.
Use of various endpoints to study prolonged mechanical ventilation after CABG
surgery can lead to a systematic bias. Use of total duration of mechanical ventilation
or "time to be extubated" as an endpoint [13] is unlikely to yield valuable information
regarding risk factors, since causes of unsuccessful extubation are heterogeneous and
vary over time [5]. Combining all the causes of prolonged mechanical ventilation and
then examining risk factors may not be an appropriate method to understand mech-
anisms for different causes of prolonged mechanical ventilation. Analysis of only a
specific time point, such as number of patients extubated at 10, 24 or 48 h may also
not be ideal [10, 32, 36]. Analyzing different endpoints often yields conflicting results
based on underlying etiology. For example, the most common etiology of failure to
exacerbate within the initial12 h period is delayed recovery from anesthesia and stud-
ies that examine risk factors at this time point will identify risk factors for delayed
recovery from anesthetic agents, such as total time of anesthesia or cross clamp time.
Conversely, a third of patients with prolonged mechanical ventilation at the 48 h time
point have ARDS and studies that examine risk factors using this later time point are
more likely to identify risk factors for ARDS.
Mechanistic Approach
Given the problems with an epidemiologic approach, an alternative is a mechanistic
analysis, which would identify risk factors for specific causes of prolonged mechan-
ical ventilation after CABG. This approach avoids misclassification bias by separate-
ly analyzing patients with prolonged mechanical ventilation due to a single cause
or clinical presentation. For example, patients who fail to wean from ventilation be-
cause of persistent hypoxemia could be studied together or patients who meet the
classic definition of ARDS could be specifically studied.
Only a few studies have examined risk factors for specific causes of prolonged
mechanical ventilation after CABG surgery. Christenson et al. studied risk factors
for ARDS in 3848 patients who underwent CABG and valve repair surgery [3].
Although, ARDS occurred in only 1o/o of patients, the mortality approached 70%.
Risk factors for ARDS in multivariable analysis included low ejection fractipn
(< 40%), emergency surgery, hypertension, current smoking, New York Heart Asso-
ciation (NYHA) class 3 and 4 status, and postoperative hypotension. Other studies
on the risks for specific causes included risk factors for prolonged effects of an-
esthesia [32] or for bleeding [45].
Surrogate endpoints may be needed to examine risk factors for relatively uncom-
mon specific causes. For example, studies examining lung injury after CABG have
used different measures of hypoxemia, such as Pa0 2/Fi0 2 ratio, P(A-a)0 2 gradient
or degree of shunting to define lung injury after CABG. Although hypoxemia is a
good surrogate marker of lung injury following CABG surgery, this endpoint may
also include patients with cardiogenic pulmonary edema, major atelectasis, pulmo-
nary embolism, and severe chronic obstructive lung disease. In our study, approxi-
mately three fourths of patients who were diagnosed with hypoxemia (Pa0 2/
Fi0 2 < 300) had either ARDS or 'hypoxemia of unknown etiology' [5]. Therefore,
the use of surrogate endpoints also has potential for misclassification bias.
Clearly, further work is needed on risk factors for specific syndromes or compli-
cations post-CABG. However, the true risk factors are more likely to be found using
a mechanistic approach rather than combining widely disparate causes into a single
362 S. Yende and R. Wunderink
group of weaning failures. More importantly, defining risk factors for specific com-
plications causing prolonged ventilation is more likely to result in appropriate pre-
vention strategies and a clearer understanding of which patients are most likely to
benefit from those interventions.
I Outcomes of Prolonged Mechanical Ventilation
Patients with prolonged mechanical ventilation have longer duration of intensive

care unit (ICU) and hospital stay [5, 13, 39]. These patients develop complications
related to long term ventilator dependence, such as ventilator associated pneumonia
(VAP), sepsis and multiorgan failure (MOF). Although the overall mortality follow-
ing CABG surgery is 2%, the mortality for those requiring mechanical ventilation
more than 48 h or ~7 days was reported to be 20% and 40%, respectively [33]. In
addition, patients who develop ARDS after CABG surgery had a mortality of 68%.
Cohen et al. showed that patients with prolonged mechanical ventilation after
CABG surgery were also more likely to require rehabilitation and had poor quality
of life [39] . These results are consistent with our study where patients who required
mechanical ventilation for more than 8 h after CABG surgery were more likely to
require discharge to a rehabilitation facility [5].
The outcome of patients with prolonged mechanical ventilation is related to the
underlying cause. Although, ARDS occurs in fewer than 2o/o of patients undergoing
CABG surgery, these patients have the worst outcomes. Figure 1 describes the med-
ian duration of mechanical ventilation and length of stay for different causes of un-
successful extubation after CABG surgery in our study. Patients with ARDS had the
longest median duration of mechanical ventilation and length of stay compared to
those with prolonged mechanical ventilation secondary to depressed respiratory
drive due to anesthetic agents. Therefore, prolonged mechanical ventilation is a
marker for worse outcomes after CABG surgery.
300 30
• Median duration
;;; 250 • Length of stay 25
u
·c:
"'~
~~
u~
200
"'
"'
>.
20 ::!:!.
<11 c: >.
E.Q
150 "'
t;
15 .....
0~ 13 0
gc ~
·;:; ~ 100 10 0,
~ c:
:::J
<11
a
_J
so 5
0 0
ARDS Bleeding Hypoxemia Pulmonary
of unknown edema
etiology
Fig. 1. Impact of individual causes on duration of mechanical ventilation and length of stay
I Conclusion
Prolonged mechanical ventilation is an important complication after CABG surgery.
The causes of prolonged mechanical ventilation are heterogeneous and individual
causes have variable outcomes. In order to understand the mechanism of prolonged
mechanical ventilation, risk factors for specific causes should be identified. Current
epidemiological approaches may not identify risk factors for rare causes of pro-
longed mechanical ventilation, such as ARDS, which has a major impact on post
CABG surgery outcomes.
References
1. American Heart Association. http://www.americanheart.org
2. Society of Thoracic Surgeons (STS) National Database. http://www.ctsnet.org
3. Christenson JT, Aeberhard JM, Badel P, et al (1996) Adult respiratory distress syndrome
after cardiac surgery. Cardiovasc Surg 4:15-21
4. Milot J, Perron J, Lacasse Y, Letourneau L, Cartier PC, Maltais F (2001) Incidence and pre-
dictors of ARDS after cardiac surgery. Chest 119:884-888
5. Yende S, Wunderink RG (2002) Causes of prolonged mechanical ventilation after coronary
artery bypass surgery. Chest 122:245-252
6. Shammas NW (2002) Pulmonary embolus after coronary artery bypass surgery: a review
of literature. Clin Cardiol 23:637-644
7. Gale GD, Teasdale SJ, Sanders DE, et al (1979) Pulmonary atelectasis and other respiratory
complications after cardiopulmonary bypass and investigation of aetiological factors. Can
Anaesth Soc J 26:15-21
8. Lee YC, Vaz MA, Ely KA, et al (2001) Symptomatic persistent post-coronary artery bypass
graft pleural effusions requiring operative treatment: clinical and histologic features. Chest
119:795-800
9. Wong DT, Cheng DC, Kustra R, et al (1999) Risk factors of delayed extubation, prolonged
length of stay in the intensive care unit and mortality in patients undergoing coronary ar-
tery bypass graft surgery with fast track cardiac anesthesia. Anesthesiology 91:936-944
10. Spivack SD, Shinozaki T, Albertini JJ, Deane R (1996) Preoperative prediction of postopera-
tive respiratory outcome: coronary artery bypass grafting. Chest 109:1222-1230
11. Silbert BS, Santamaria JD, O'Brien JL, Blyth CM, Kelly WJ, Molnar RR (1998) Early extuba-
tion following coronary artery bypass surgery. Chest 113:1481-1488
12. Royse CF, Royse AG, Soeding PF (1999) Routine immediate extubation after cardiac opera-
tion: a review of our first 100 patients. Ann Thorac Surg 68:1326-1329
13. Branca P, McGaw P, Light RW (2001) Factors associated with prolonged mechanical ventila-
tion following coronary artery bypass surgery. Chest 119:537-546
14. Wan S, LeClerc J, Vincent J (1997) Inflammatory response to cardiopulmonary bypass.
Chest 112:676-692
15. Kirklin JK, Westaby S, Blackstone EH, Kirklin JW, Chenoweth DE, Pacifico AD (1983)
Complement and the damaging effects of cardiopulmonary bypass. J Thorac Cardiovasc
Surg 86:845-857
16. Lindal S, Gunnes S, Lund I, Straume BK, Jorgensen L, Sorlie D (1995) Myocardial and mi-
crovascular injury following coronary surgery and its attenuation by mode of reperfusion.
Eur J Cardiothorac Surg 9:83-89
17. Jansen NJ, van Oeveren W, Gu YJ, van Vliet MH, Eijsman L, Wildevuur CR (1992) Endo-
toxin release and tumor necrosis factor formation during cardiopulmonary bypass. Ann
Thorac Surg 54:744-748
18. Haeffner-Cavaillon N, Roussellier N, Ponzio 0, et al (1989) Induction of interleukin-1 pro-
duction in patients undergoing cardiopulmonary bypass. J Thorac Cardiovasc Surg 98:
1100-1106
19. Gilliland HE, Armstrong MA, McMurray TJ (1998) Tumor necrosis factor as predictor for
pulmonary dysfunction after cardiac surgery. Lancet 352:1281-1282
20. Rothenburger M, Soeparwata R, Deng MC, et al (2002) The impact of anti-endotoxin core
antibodies on endotoxin and cytokine release and ventilation time after cardiac surgery. J
Am Coli Cardiol 38:124-130
21. Hennein HA, Ebba H, Rodriguez JL, et al (1994) Relationship of the proinflammatory cyto-
kines to myocardial ischemia and dysfunction after uncomplicated coronary revasculariza-
tion. J Thorac Cardiovasc Surg 108:626-635
22. Wan S, Izzat MB, Lee TW, Wan I, Tang N, Yim AP (1999) Avoiding cardiopulmonary by-
pass in multivessel CABG reduces cytokine response and myocardial injury. Ann Thorac
Surg 68:52-57
23. Cremer J, Martin M, Red! H, et al (1996) Systemic inflammatory response syndrome after
cardiac operations. Ann Thorac Surg 61:1714-1720
24. Tardiff BE, Newman MF, Saunders AM, et a! (1997) Preliminary report of a genetic basis
for cognitive decline after cardiac operations. Ann Thorac Surg 64:715-720
25. Abraham LJ, Kroeger KM (1999) Impact of the -308 TNF promoter polymorphism on the
transcriptional regulation of the TNF gene: relevance to disease. J Leukoc Bioi 66:562-566
26. Majetschak M, Flohe S, Obertacke U, et al (1999) Relation of a TNF gene polymorphism to
severe sepsis in trauma patients. Ann Surg 230:207-214
27. Yende S, Quasney MW, Tolley EA, Qing Z, Wunderink RG (2002) Association of TNF gene
polymorphisms and prolonged mechanical ventilation after coronary artery bypass surgery.
Crit Care Med (in press)
28. Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvo! P, Soubrier F (1990) An insertion/
deletion polymorphism in the angiotensin I converting enzyme gene accounting for half
the variance of serum enzyme levels. J Clin Invest 86:1343-1346
29. Volzke H, Engel J, Kleine V, et al (2002) Angiotensin !-converting enzyme insertion/dele-
tion polymorphism and cardiac mortality and morbidity after coronary artery bypass graft
surgery. Chest 122:31-36
30. Marshall RP, Webb S, Bellingan GJ, et al (2002) Angiotensin converting enzyme insertion/
deletion polymorphism is associated with susceptibility and outcome in acute respiratory
distress syndrome. Am J Respir Crit Car Med 166:646-650
31. Chew ST, Newman MF, White WD, et a! (2000) Preliminary report on the association of
apolipoprotein E polymorphisms, with postoperative peak serum creatinine concentrations
in cardiac surgical patients. Anesthesiology 93:325-331
32. Cheng DC, Karski J, Peniston C, eta! (1996) Early tracheal extubation after coronary artery
bypass graft surgery reduces costs and improves resource use. Anesthesiology 85:1300-
1310
33. Kollef MH, Wragge T, Pasque C (1995) Determinants of mortality and multiorgan dysfunc-
tion in cardiac surgery patients requiring prolonged mechanical ventilation. Chest 107:
1395-1401
34. Bando K, Sun K, Binford RS, Sharp TG (1997) Determinants of longer duration of endo-
tracheal intubation after adult cardiac operations. Ann Thorac Surg 63:1026-1033
35. Suematsu Y, Sato H, Ohtsuka T, Kotsuka Y, Araki S, Takamoto S (2000) Predictive risk fac-
tors for delayed extubation in patients undergoing coronary artery bypass grafting. Heart
Vessels 15:214-220
36. Legare JF, Hirsch GM, Buth KJ, MacDougall C, Sullivan JA (2001) Preoperative prediction
of prolonged mechanical ventilation following coronary artery bypass grafting. Eur J
Cardiothorac Surg 20:930-936
37. Habib RH, Zacharias A, Engoren M (1996) Determinants of prolonged mechanical ventila-
tion after coronary artery bypass grafting. Ann Thorac Surg 62:1164-1171
38. Thompson MJ, Elton RA, Mankad PA, et a! (1997) Prediction of requirement for, and out-
come of, prolonged mechanical ventilation following cardiac surgery. Cardiovasc Surg
5:376-381
39. Cohen AJ, Katz MG, Frenkel G, Medalion B, Geva D, Schachner A (2000) Morbid results of
prolonged intubation after coronary artery bypass surgery. Chest 118:1724-1731
40. Warner MA, Offord KP, Warner ME, Lennon RL, Conover MA, Jansson-Schumacher U
(1989) Role of preoperative cessation of smoking and other factors in postoperative pul-
monary complications: a blinded prospective study of coronary artery bypass patients.
Mayo Clin Proc 64:609-616
41. Powell CA, Caplan CE (2001) Pulmonary function tests in preoperative pulmonary evalua-
tion. Clin Chest Med 22:703-714
42. Zibrak JD, Marton K (1990) Preoperative pulmonary function testing: position paper. Ann
43. Anderson RJ, O'Brien M, MaWhinney S, et al (1999) Renal failure predisposes patients to
adverse outcome after coronary artery bypass surgery: VA cooperative study. Kidney Int
5:1057-1062
44. Miyamoto T, Kimura T, Hadama T (2000) The benefits and new predictors of early extuba-
tion following coronary artery bypass grafting. Ann Thorac Cardiovasc Surg 6:39-45
45. Dacey LJ, Munoz JJ, Baribeau YR, et al (1998) Reexploration for hemorrhage following
coronary artery bypass grafting. Arch Surg 133:442-447
46. Kshettry VR, Flavin TF, Emery RW, Nicoloff DM, Arom KV, Petersen RJ (2000) Does multi-
vessel, off-pump coronary artery bypass reduce postoperative morbidity? Ann Thorac Surg
69:1725-1731
Postoperative Respiratory Management
G. K. Albaugh and R. P. Dellinger
Introduction
Optimal postoperative respiratory management relies on adequate preoperative risk

reduction and medical optimization if necessary in patients undergoing elective
procedures. The goals of management in elective patients is to reduce the risk of
postoperative pulmonary complications including: nosocomial pneumonia, atelecta-
sis, prolonged ventilatory support, and acute respiratory distress syndrome (ARDS).
With adequate screening of patients along with emphasis on smoking cessation
and vigilant pulmonary care in the postoperative period the risk of these complica-
tions can be reduced.
A particularly problematic population of patients occurring in significant num-
bers is those presenting with an acute abdominal catastrophe. These patients do
not have the luxury of preoperative evaluation and must be taken to the operating
room with little more than fluid resuscitation. Invariably these patients require a
large midline abdominal incision from xiphoid to pubis to allow a potentially life-
saving surgical procedure. Massive blood replacement may be initially required and
intraabdominal sepsis may occur as a postoperative complication. Risk for pulmo-
nary complications is high. The intensivist is faced with a most demanding situa-
tion in managing these patients through their postoperative course. These patients
will be emphasized in these chapter.
Perioperative risk reduction
The major goals of preoperative screening are to identify patients who are at risk
for postoperative complications and, if possible, to optimize chronic underlying
disease with medical interventions. Identified risk factors for postoperative pulmo-
nary complications are advancing age, chronic obstructive pulmonary disease
(COPD), smoking, impaired cognitive function, nasogastric tube placement, thorac-
ic or upper abdominal incision, history of cancer, chronic cardiac or renal disease,
and an American Society of Anesthesiologists Physical status scale (ASA class) des-
ignation higher than 2 [1-9].
With the exception of patients undergoing lung resection [10], controversy exists
in regard to preoperative pulmonary function testing in patients undergoing elec-
tive surgery. Spirometry prediction of postoperative pulmonary complications has
been shown to be inferior to abnormal findings on chest examination. The primary
utility of spirometry rests in the ability to objectively document improvement in
Postoperative Respiratory Management 367
airflow obstruction after medical therapy for pulmonary dysfunction. Some authors
recommend pulmonary function testing in patients who are smokers with dyspnea
and in the presence of uncharacterized lung disease. In patients with symptomatic
lung disease a preoperative arterial blood gas may be useful in setting goals for
postoperative respiratory management [11]. In a case control study by Lawrence et
al. [12] in patients undergoing abdominal surgery, the risk of pulmonary complica-
tions was predicted by abnormal results on chest examination, abnormal chest
radiographs, a high score on the Goldman Cardiac Risk Index, and a high score on
the Charlson co-morbidity index.
Smoking is a risk factor for postoperative pulmonary complications. This risk is
present even without the clinical findings of COPD. To significantly reduce the risk
of postoperative pulmonary complications it is necessary that patients abstain from
smoking for 8 weeks prior to surgery. Pharmacological therapy (nicotine replace-
ment gum or patches) or anti-depression medication may be useful to aid in smok-
ing cessation.
In patients with asthma and COPD, symptomatic airflow obstruction should be
aggressively treated with inhaled ipratopium and short-acting beta adrenergic re-
ceptor agonists 4 times a day [13]. In patients who continue to have symptoms on
this therapy, a course of corticosteroids for 2 weeks prior to elective surgery may
be helpful. Improvement can be documented with spirometry. In individuals who
have COPD and a change in the character of their sputum (thicker, color change,
or increased quantity), a course of antibiotics (for example: doxycycline, trimetho-
prim/sulfamethoxazole, amoxicilln/clavulanate, or floroquinolone) may be prudent.
There is no evidence that routine use of antibiotics in other patient groups reduces
the risk of postoperative pulmonary complications.
Preoperative lung expansion training and education on the importance of pre-
venting atelectasis should be emphasized prior to surgery. Observations at our in-
stitution have shown that when patients are educated as to the importance of lung
expansion, they seem more motivated to breath deeply and ambulate.
Operative factors which reduce the risk of postoperative pulmonary complica-
tions are surgery time 3 hours or less, avoiding long acting neuromuscular block-
ade, use of spinal or epidural anesthesia, laparoscopic approach instead of open
procedure, and minimizing upper abdominal and thoracic manipulation [7]. The
surgical time can be difficult to control and can be either procedural based or sur-
geon based.
I Influence of Type of Surgical Procedure on Pulmonary Complications

The surgical incision site has a predictable impact on the development of pulmo-
nary complications. It has been known for over 30 years that thoracic and upper
abdominal incisions impart a higher risk of postoperative pulmonary complications
[14]. Influence on the amount of postoperative physiological derangement varies
with the type of incision. Upper abdominal incisions have a 30% incidence of pul-
monary complications as opposed to lower abdominal incisions that have a 10-15%
of pulmonary complications. After upper abdominal surgery there is a 70% de-
crease in maximal transdiaphagmatic pressure that impairs inspiration for the first
postoperative week [15].
Esophagectomy imparts a 25-50% pulmonary complication rate and determines
40 to 60% of the mortality seen associated with this procedure. Complications
368 G. K. Albaugh and R. P. Dellinger
occur in 30% of thoracotomy patients and if cardiac surgery the rate is higher
(40%). Thoracotomy surgically traumatizes the intercostal muscles and chest wall
leading to ventilation/perfusion (V/Q) mismatching and hypoventilation from 'in-
spiratory splinting'. After thoracic surgery it is necessary to leave at a minimum
one chest tube which further contributes to pain with inspiration. Adequate pain
control is essential to reduce splinting by the patient and resultant hypoventilation.
The increased pulmonary complication rate with cardiac surgery is largely due to
the use of cardiopulmonary bypass (CPB). After CPB, patients frequently show
some magnitude of pulmonary dysfunction thought to result from damage to pul-
monary vascular endothelium, increase in lung water and impairment of oxygen
transfer [16]. Accumulation of pleural fluid after cardiac surgery can impair pulmo-
nary function. Factors which predispose to symptomatic pleural effusion are:
COPD, insulin dependent diabetes mellitis, increased blood loss, and > 24 hours of
mechanical ventilation. Payne et al. [17] showed that placement of a closed suction
pleural drain to evacuate pleural effusion decreased symptomatic pleural effusion
from 11.9 to 3.5%. In another study, Douglas and Spaniol [18] demonstrated that
opening of the right pleural spaces after coronary artery bypass grafting (CABG)
reduced the occurrence of postoperative pneumothorax. This maneuver created a
communicating space between the mediastinum and both hemithorax to be drained
by the mediastinal tubes routinely used. The use of epidural anesthesia in CABG
patients, theoretically predicted to reduce postoperative respiratory dysfunction
failed to prove superior to general anesthesia alone [19].
When both the chest and the abdomen are opened, such as occurs with repair
of thoracoabdominal aortic aneurysm, the pulmonary complication rate increases
to 60%. In decreasing order of occurrence, the complications are: atelectasis, pleur-
al effusion, pneumonia, pneumothorax, and ARDS. Identified risk factors for post-
aneurysm repair complications include COPD, smoking, cardiac compromise, and
postoperative renal insufficiency or failure [20].
Emergent surgery is an independent risk factor for the development of post-
operative pulmonary complications, which include prolonged ventilatory support.
In these situations, concomitant sepsis or massive fluid replacement are frequent.
Disorders of the alimentary tract requiring emergent surgery include perforation,
abscess, bleeding, and trauma. The systemic inflammatory response syndrome
(SIRS) may produce pulmonary dysfunction. The inflammatory state may produce
increased lung water and resultant decrease in Pa0 2 and an increase in the A-a gra-
dient [21]. Emergent vascular intervention by nature predisposes to increased blood
loss and increased fluid replacement. Transfusion of more than two units of blood
is an independent risk factor for the development of postoperative pulmonary com-
plications including ARDS [9, 22]. All these factors lead to prolonged ventilatory
support.
I Atelectasis
The most common postoperative pulmonary complication is atelectasis. This is
caused by a variety of factors associated with the surgical procedure itself, the an-
esthesia and the underlying medical condition of the patient. Prior to intubation
and induction of general anesthesia it was previously common practice to pre-oxy-
genate patients with 100% oxygen. The absence of nitrogen in the inspired air leads
to rapid and total absorption of alveolar gas. The resultant high rate of atelectasis
can be avoided by using a mixture of 80o/o oxygen for pre-oxygenation [23]. The
splinting effect of the 20o/o nitrogen decreases the rate of absorption atelectasis. It
is also a common practice to ventilate patients in the operating room without posi-
tive end expiratory pressure (PEEP). With prolonged cases, the resultant loss of
functional residual capacity (FRC) and V/Q mismatch leads to hypoxemia. The sur-
gery itself decreases the FRC. In upper abdominal incisions and thoracotomy inci-
sions there is a 30o/o and 35o/o decrease in the FRC observed, respectively. In con-
trast, purely lower abdominal incisions incur a 10-15% decline in the FRC. Usually
the FRC comprises SOo/o of the total lung capacity (TLC). An additional 30o/o of the
TLC is the closing volume (CV), defined as the volume at which the flow from the
dependent portions of the lung stops during expiration due to airway closure. Fac-
tors leading to an increase in CV are fluid overload, advanced age, obesity, smok-
ing, bronchospasm, and airway secretions [15]. As the FRC declines the CV in-
creases with perioperative physiologic changes, the lung is subject to airway col-
lapse and atelectasis. The sequelae of atelectasis, trapping of secretions, and V/Q
mismatch may lead to respiratory insufficiency. Release of inflammatory mediators
in the presence of atelectasis may produce fever in the first 24 to 48 postoperative
hours.
Lung re-expansion is the treatment for atelectasis and periodic increased lung
expansion prevents atelectasis. In low risk patients this can be achieved with nurs-
ing intervention such as coughing, deep breathing exercises, and ambulation. In
higher risk patients various devices, typically incentive spirometry, have proven ef-
fective at a relatively low cost [24]. In patients requiring mechanical ventilation
postoperatively the routine use of low levels of PEEP (5-8 cmH2 0) help to reduce
the ill effects of atelectasis in high risk populations.
Although obesity has been linked to an increased risk of atelectasis, the data are
conflicting. Several authors have found that body mass index (BMI) of greater than
27 kglm2 predisposes patients to postoperative pulmonary complications [5, 25].
Certainly, the patient who is morbidly obese and displays clinical features of ob-
structive sleep apnea is at higher risk of postoperative pulmonary complications
and their abnormal physiology is not amenable to pharmacological manipulation.
Patients who use continuous positive airway pressure (CPAP) or non-invasive me-
chanical ventilator at home should also receive it during their hospital stay with
pressure adjustments as needed to accommodate any respiratory derangement im-
posed by the surgical intervention.
I Postoperative Pneumonia
In the operating room, several physiologic changes take place in the pulmonary
system that may predispose to development of postoperative pneumonia. The fac-
tors mentioned previously which lead to atelectasis, predispose patients to the de-
velopment of postoperative pneumonia. Approximately 90o/o of patients who under-
go anesthesia have postoperative collapsed lung tissue regardless of the anesthetic
agent used. This atelectasis can account for as much as 74o/o of the gas exchange
impairment seen in postoperative patients [23]. In healthy individuals who are ex-
tubated in the operating room and resume negative pressure ventilation, sponta-
neous coughing and aggressive pulmonary toilet, these changes are transient. In
patients who remain intubated, the normal physiologic processes are abated.
The second most common nosocomial infection and the most common cause of
death is nosocomial pneumonia. Approximately 50% of hospital acquired pneumo-
nias occur in surgical patients [25]. The reported mortality of nosocomial pneumo-
nia, depending on the source, ranges from 20 to 50% [26]. The financial conse-
quence of this complication is great but can be rectified with aggressive pulmonary
care.
Several retrospective studies have been performed to assess the risk factors for
developing postoperative pneumonia. The risk of pneumonia in the postoperative
period relies on factors described by Croce in a recent review [27]. The patient's
underlying medical condition prior to surgery includes advanced age, COPD dis-
ease and either absolute or relative immunosuppression. Environmental agents
which impact the occurrence of pneumonia include endotracheal intubation, gastric
intubation, and ICU admission. Prolonged mechanical ventilation and subsequent
impedance of adequate pulmonary toilet predispose to pneumonia.
The underlying medical conditions of at-risk patients are usually identified and
evaluated prior to elective surgery. Patients with documented COPD undergo opti-
mal conditioning with the goal of reducing the risk of postoperative pneumonia
and other postoperative pulmonary complications. The medical condition and the
general physiologic state of the patient is graded routinely by anesthesia personnel
prior to surgery and assigned an ASA class (Table 1). Those patients with an ASA
class greater then 2 are at increased risk for developing pneumonia [1]. Factors that
place these patients in higher categories (i.e., symptomatic COPD, obesity, etc.) are
usually self-evident. Obesity in general is linked to pulmonary complications. Pa-
tients with a BMI greater then 27 kg!m 2 show a propensity for pulmonary compli-
cations and as the BMI rises the patients are less able to clear secretions. Obstruc-
tive sleep apnea, often associated with obesity, may also be problematic. Chronic
bronchitis may not be clinically evident in patients with COPD and escape detec-
tion prior to elective surgery. This factor increases the risk of pneumonia. The el-
derly population is at risk for postoperative pulmonary complications including
postoperative pneumonia. It is suspected that impairment of mucocillary clearance
is at least partially responsible for this risk.
Environmental factors putting the patient at risk for development of postoperative
pneumonia are usually some mechanical impediment to the body's barrier to prevent
Table 1. American Society of Anesthesiologists physical status scale. Adapted from [1 0)
Class Patient status
1 No organic, physiologic, biochemical, or psychiatric disturbance; localized operation

2 Mild to moderate systemic disease caused by condition to be treated or other process
(hypertension, anemia, smoking, diabetes, obesity, asthma, chronic bronchitis, age
< 1 or > 70, pregnant)
3 Severe systemic disturbance of whatever cause (angina, poorly controlled hypertension
or diabetes, symptomatic COPD, prior Mil
4 Severe systemic disorder already life threatening and not correctable by operation
(unstable angina, CHF, debilitating COPD, hepato-renal failure)
S Moribund with little chance of survival (ruptured AAA with shock, major head trauma,
severe abdominal trauma)
aspiration of bacteria. Nasogastric or orogastric intubation was described by Mitchell

et al. as a significant risk factor for the development of respiratory complications and
pneumonia [6]. Admission to the ICU is an environmental risk factor but the impor-
tance is unclear. Certainly all surgical patients who require mechanical ventilation are
mandated admission to an ICU for monitoring and resuscitation. The nurse to patient
ratio may impact on postoperative pulmonary complications and was examined by
Dimick and co-workers [28] by evaluating all patients who underwent hepatectomy.
The study was designed to compare nursing ratios of one nurse for 1 or 2 patients
versus one nurse to 3 to 4 patients. The study showed that there was a lower incidence
of re-intubation and pulmonary failure in the lower acuity settings. There was a high-
er incidence of aspiration in the lower acuity group but these findings were not sig-
nificant [28]. Nursing has a pivotal role in the prevention of postoperative pneumonia.
Nurses need to be vigilant in assessing the patient's risk and avoiding oversedation
and confusion in postoperative patients which may lead to aspiration and atelectasis.
Nurses are usually charged with the responsibility of teaching proper use of incentive
spirometers, initiating early ambulation of the patients, and encouraging coughing
and deep breathing to promote lung expansion and clearing of secretions [29]. The
position of the patient in bed also has a impact on postoperative pulmonary compli-
cations. In surgical patients who have had some manipulation of their viscera the su-
pine position should be avoided. In one retrospective review by Kolle£ [30], supine
positioning of mechanically ventilated patients imparted a three-fold increase in no-
socomial pneumonia when compared to patients placed in the semi-recumbent posi-
tion (30° elevation of the head of the bed). Patient positioning is even more critical in
those receiving gastric feedings. Retrospective reviews of supine and semi-recumbent
feeding have given conflicting data, however it is the opinion of the authors that pa-
tients requiring gastric feeding with some impairment of their sensorium whether it
be organic or pharmacological should not be fed in the supine position.
Isolation procedures similar to those performed in patients with hematologic
diseases have been evaluated as a possible way to decrease the incidence of nosoco-
mial pneumonia. Koss et al. [31] compared the effects of sterile gowns, gloves and
hand washing to gloves and hand washing on the incidence of nosocomial pneumo-
nia. They found that there was no difference in the amount of airway colonization
between groups but the incidence of nosocomial pneumonia was higher in the iso-
lation group [31]. We interpret from this study that extra protection is not detri-
mental but the organisms causing nosocomial pneumonia are indigenous to the
particular patients and the benefit of addition of sterile gowns in this patient group
is unclear. The number of transports out of the ICU setting also has an influence
on the development of pneumonia in mechanically ventilated patients. Commonly
the more critically ill a patient is, the more likely the need for visits to radiology
or the operating room for studies and interventions. In a study by Kolle£ et al.,
transports out of the ICU imparted a four fold risk of developing pneumonia [32].
They determined in their study that the time from the first transport to appearance
of pneumonia was 4.1 ±4.8 days. Those patients who required more transports out
of the ICU tended to require longer ventilatory support, longer length of stay,
developed more multisystem organ failure (MOF), and had a higher mortality. The
authors note that a break in the ventilatory circuit, aspiration of secretions, move-
ment of the patient, and prolonged placement in the supine position collectively
constitute independent risk factors for the development of pneumonia.
Prolonged mechanical ventilation is not suprisingly a risk factor for development
of nosocomial pneumonia. Respiratory and nursing personnel intervene intermit-
tently in the mechanically ventilated patient to facilitate clearance of secretions.

The development of pneumonia requires contaminated secretions from the pharynx
and upper airway to reach the normally sterile lower airways. The goal is to discon-
tinue ventilatory support as soon as possible in order to restore the body's normal
modalities for secretion control and barrier protection. Timely weaning from me-
chanical ventilation has been described by various authors and is an integral edu-
cation component for most training programs in critical care. Data reported by the
OUTCOMEREA study group described the impact of re-intubation after weaning
(RAW) and unplanned extubation (UE) on the risk of pneumonia in ICU patients
[33]. This study showed there was a significantly increased risk of pneumonia in
both of these groups; however in those patients who self extubated there was no
association with developing pneumonia. In both RAW and UE patients, the study
showed an increased number of ventilator days and an almost four-fold increase in
tracheostomy. Interestingly, the mortality between the study group and the control
group was not significantly different. Conventional endotracheal tubes allow secre-
tions to pool in the subglottic area which can be aspirated in the lower airways
during tube manipulation. Recently endotracheal tubes have been developed which
allow intermittent drainage of subglottic secretions which should reduce the risk of
bacterial aspiration. These specialized endotracheal tubes have a suction port above
the balloon and are connected to intermittent suction. The suction is cycled on for
8 seconds and off for 20 seconds as described in [34]. Intermittent suction is re-
quired because the 100 mmHg suction can potentially injury the tracheal endotheli-
um. In a study by Kollef et al. [35] the investigators found a lower incidence of
pneumonia but the difference was not significant. They did notice a significant de-
lay in onset of pneumonia in patients with subglottic suctioning (5.6 ± 2.3 days ver-
sus 2.9 ± 1.2 days in the control group) [35].
The diagnosis of pneumonia has historically been made on the basis of purulent
sputum, fever, and new or progressive infiltrates on chest radiographs. It is com-
mon in clinical practice to culture sputum and gauge antibiotic coverage to the or-
ganisms recovered. In a review by Croce, the difficulty in obtaining accurate speci-
mens in surgical patients was illustrated [27]. After even a short period of intuba-
tion the upper airway or endotracheal tube in intubated patients is colonized with
potentially pathogenic organisms. Careful clinical correlation must be undertaken
to apply these results effectively to make the diagnosis of pneumonia. Autopsy
studies have shown that the clinical criteria for diagnosing pneumonia was incor-
rect in 29% of the cases evaluated when compared to histological examination of
the lungs. More specific modalities are present to make the diagnosis of pneumo-
nia, in particular protected specimen brushing (PSB) and bronchoalveolar lavage
(BAL). Both of these modalities require some skill in bronchoscopy and additional
equipment for completion. The major benefit of BAL over PSB is a larger sample
area in the lower airways. When quantitative cultures are done and the threshold
for positivity is 105 cfu/ml, this imparts low false negative reports and highest mor-
tality [36]. Obtaining bronchoscopic specimens for the diagnosis of postoperative
pneumonia in surgical patients does impart additional cost in the form of equip-
ment, sterilization, and personnel costs. Using these criteria to guide antibiotic
therapy may actually be cost effective when factoring in the cost of intravenous
antibiotics in those patients who do not have pneumonia. There is a risk of un-
needed antibiotic therapy to include nephrotoxicity, emergence of resistant strains,
and super infection with opportunistic organisms. Recently introduced mini-BAL
may be a more resource friendly approach to obtaining quantitative cultures
In patients that require prolonged oro tracheal intubation who are failing weaning
due to underlying disease or deconditioning, tracheostomy is a valuable tool. Tra-
cheostomy improves the ability to clear the airway of secretions and allow for better
oral care by the nursing staff and allows transfer to lower level of care. The American
College of Chest Physicians recommend that if someone requires greater than 21 days
of ventilatory support then a tracheostomy is indicated. If the expected duration of
ventilatory support is 10 days or less then orotracheal intubation is adequate. There
continues to be debate when the patients require 11 to 20 days of support. Prolonged
endotracheal intubation has been linked to dysfunction of the swallowing mechanism
which can lead to recurrent aspiration pneumonia after extubation. The cuff of the
endotracheal tube can also cause damage to the tracheal epithelium and may lead
to tracheomalacia. The best management is to extubate patients as soon as possible;
however in surgical patients who have had an abdominal catastrophe including severe
acute pancreatitis or had their postoperative course complicated by sepsis, prolonged
ventilation may be necessary. In these patients the clinical picture must be evaluated
and the decision for tracheostomy must be guided by those data.
Complications of postoperative pneumonia include ARDS, empyema, lung ab-
scess, and necrotizing pneumonia. Empyema may occur as a result of extension of
pneumatic infection into the previously sterile pleural fluid. There are 3 described
stages of empyema which are described in Table 2. The treatment objective for
early empyema is adequate drainage which can be accomplished with either serial
thorocentesis or tube thoracostomy. This along with focused antibiotic coverage is
usually successful. When the empyema progresses to the fibropurulent phase (Stage
2), surgical intervention is usually required in the form of video-assisted thora-
coscopy to clear the infected material. When the empyema becomes organized
(Stage 3) then formal decortication of the lung is usually required. Hemothorax is
a less frequent complication of thoracic surgery. In patients with retained hemo-
thorax routinely taking these patients to the operating room for videoscopic-as-
sisted techniques (VATS) 10 to 14 days later to directly evacuate the clot in the
hope of preventing fibrothorax and trapped lung, has been described [26].
Lung abscesses are uncommon in post surgical patients and usually are a sequel of
aspiration, commonly containing anaerobic organisms such as Bacteroides, Pepto-
streptococcus, and Prevotella sps. These are usually diagnosed and treated with chest
computed tomography (CT)-guided percutaneus catheter drainage and appropriate
antibiotic coverage. Clinical improvement should occur in 48 hours. If improvement
is not seen these patients may need open surgical drainage. Reported mortality has
ranged from 10 to 38% for all lung abscesses. Poorer outcome has been noted in pa-
tients with abscess in the right lower lobe, larger abscess size and abscess caused by
Staphylococcus aureus, Pseudomonas aeruginosa, or Klebsiella pneumonia.
Postoperative necrotizing pneumonia is a rare condition often caused by Kleb-
siella or Pneumococcus. The progressive infection results in devitalized lung tissue.
Table 2. Stages of empyema and pleural fluid findings. Adapted from [26]
Stage I (first few days): fluid is free flowing, pH >7.3, glucose >60 mg/dl, LOH <500 IU
2 Stage II (1-2 weeks): Fibropurulent fluid, pH < 7.2, glucose <40 mg/dl, LDH > 1000 IU
3 Stage Ill (after 2 weeks): Organized phase, thickened peel. pH < 7.1
LDH =lactate dehydrogenase

On occasion operative drainage is required to avoid the progression to mediastinitis

and its additive mortality risk [26].
I Acute Respiratory Distress Syndrome

Postoperatively either progression of pneumonia or systemic inflammation from
postoperative infection at any site may result in ARDS. This condition produces
capillary leak leading to V/Q mismatch and shunting induced severe hypoxemia.
There is an increase in interstitial lung water. Ventilatory support is required. The
diagnostic criteria for ARDS are described in Table 3. Bilateral infiltrates on chest
radiographs without other cause suggest the diagnosis. The differentiation between
ARDS and cardiogenic pulmonary edema may require placement of a pulmonary
artery catheter and evaluation of the patient's fluid status.
The physiologic changes in the lung are due to some combination of direct cap-
illary injury, microemboli, and platelet trapping. Postoperative clinical situations
associated with an increased incidence of ARDS include: severe infection, severe
trauma, major burns, ischemia/reperfusion, severe bone injury, severe pancreatitis
and transfusion of more than 5 units of blood. A systemic inflammatory response
illicited by cardiopulmonary bypass (CPB) imparts a 0.4% incidence of ARDS in
patients undergoing cardiac surgery. ARDS associated with CPB imposes a 15%
mortality in those patients involved [16].
The management of ARDS is primarily supportive although identification and
amelioration of a precipitating factor must be aggressively pursued. The differential
diagnosis of ARDS includes primarily congestive heart failure, massive aspiration,
smoke inhalation, and bilateral pulmonary contusion [37]. These conditions must
be excluded and appropriate management instituted.
The mainstay of treatment for ARDS is optimization of pulmonary and cardiac
function and aggressive identification and treatment of the underlying cause.
Patients with ARDS should be managed with low tidal volume and minimal PEEP
strategy according to ARDSnet published criteria [38]. Tidal volume is reduced to
6 ml!kg and PEEP is targeted to Fi0 2 requirements. Newer ventilatory interventions
such as inhaled nitric oxide, prone ventilation, and alveolar recruitment although
demonstating oxygenation improvement have not decreased morbidity and mortal-
ity [39-41] .
Table 3. Criteria for the diagnosis of acute respiratory distress syndrome (ARDS). Adapted from [16]
I Tachypnea (respiratory rate > 30 breaths/min)

Bilateral pulmonary infiltrates on chest radiographs
Severe hypoxemia (PaOzffraction of inspired oxygen ratio < 200)
I Requirement of positive-end-expiratory pressure > 5 cmH 20
I No evidence of left heart failure (pulmonary capillary wedge pressure < 18 mmHg)
I No other pathology to explain these findings
I Conclusion
Postoperative respiratory management for the majority of patients is focused on
techniques to facilitate deep breathing and adequate pain control. The decrease in
FRC in postoperative patients can be predicted and the presence of atelectasis
should be anticipated. Patients who are older, have chronic underlying medical
conditions, smoke with intermittent dyspnea, are obese, or have documented pul-
monary disease are at risk for postoperative pulmonary complications. Preoperative
smoking cessation, treatment of airway obstruction, and treatment of pulmonary
conditions such as chronic bronchitis with exacerbation significantly reduce the in-
cidence of these complications. In patients with postoperative fever and changes on
chest radiographs suggesting postoperative pneumonia, techniques allowing quanti-
tative culture may be useful. Drainage of infected pleural fluid may be necessary to
improve respiratory function in some patients with parapneumonic effusion. Tra-
cheostomy allows for better management of secretions and reduces the work of
breathing, which may aid marginal patients in weaning .from ventilatory support
but more importantly may allow transfer to a lower level of care. Finally, ARDS
management rests in supportive care, aggressive identification of the underlying
cause of the inflammatory state, and compliance with ARDSnet guidelines.
References
1. Hall JC, Tarala RA, Hall JL (1996) Respiratory insufficiency after abdominal surgery.
Respirology 1:133-138
2. Arozullah AM, Khuri SF, Henderson WG, et al (2001) Development and validation of a
multifactorial risk index for predicting post-operative pneumonia after major noncardiac
surgery. Ann Intern Med 135:847-857
3. Martin LF, Atnip RG, Holmes PA, et al (1994) Prediction of post-operative complications
after elective aortic surgery using stepwise logistic regression analysis. Am Surg 60:163-
168
4. Fisher BW, Majumdar SR, McAlister FA (2002) Predicting pulmonary complications after
nonthoracic surgery: a systematic review of blinded studies. Am J Med 112:219-225
5. Brooks-Brunn JA (1997) Predictors of post-operative pulmonary complications following
abdominal surgery. Chest 111:564-571
6. Mitchell CK, Smoger SH, Pfeifer MP, et al (1998) Multivariate analysis of factors associated
with post-operative pulmonary complications following general elective surgery. Arch Surg
133:194-198
7. Trayner E, Celli BR (2001) Postoperative pulmonary complications. Med Clin North Am
85:1129-1139
8. Engoren M, Buderer NF, Zacharias A, et al (1999) Variables predicting reintubation after
cardiac surgery. Ann Thorac Surg 67:661-665
9. Vaporciyan AA, Merriman KW, Bee F, et al (2002) Incidence of major pulmonary morbid-
ity after pneumonectomy: association with timing of smoking cessation. Ann Thorac Surg
73:420-426
10. Hayden SP, Mayer ME, Stoller JK (1995) Post-operative pulmonary complications: risk
assessment, prevention, and treatment. Cleve Clin J Med 62:401-407
11. Zibrak JD, O'Donnell CR (1993) Indications for pre-operative pulmonary function testing.
12. Lawrence VA, Dhanda R, Hilsenbeck SG (1996) Risk of pulmonary complications after elec-
tive abdominal surgery. Chest 110:744-750
13. Smetana GW (1999) Pre-operative pulmonary evaluation. N Engl J Med 340:937-944
14. No author listed (1968) The post-operative chest. Br Med J 2:713-714
15. Ferguson MK (1999) Pre-operative assessment of pulmonary risk. Chest 115:58S-63S
376 G. K. Albaugh and R. P. Dellinger: Postoperative Respiratory Management
16. Milot J, Perron J, Lacasse Y, et a! (2001) Incidence and predictors of ARDS after cardiac
surgery. Chest 119:884-888
17. Payne M, Magovern GJ, Benckart DH, et al (2002) Left pleural effusion after coronary
artery bypass decreases with a supplemental pleural drain. Ann Thorac Surg 73:149-152
18. Douglas JM, Spaniol S (2002) Prevention of post-operative pneumothorax in patients un-
dergoing cardiac surgery Am J Surg 183:551-553
19. Fillinger MP, Yeager MP, Dodds TM, et a! (2002) Epidural anesthesia and analgesia: effects
on recovery from cardiac surgery. J Cardiothorac Vase Anesth. 16:15-20
20. Svensson LG, Hess KR, Caselli JS, et al (1991) A prospective study of respiratory failure
after high-risk surgery on the thoracoabdominal aorta. J Vase Surg 14:271-282
21. Jayr C, Matthay MA, Goldstone J, eta! (1993) Pre-operative and intraoperative factors asso-
ciated with prolonged mechanical ventilation. A study in patients following major abdom-
inal vascular surgery. Chest 103:1231-1236
22. Dunne JR, Malone D, Tracy JK, et a! (2002) Peri-operative anemia: an independent risk
factor for infection, mortality, and resource utilization in surgery. J Surg Res 102:237-244
23. Hedenstierna G (2002) Airway closure, atelectasis and gas exchange during anaesthesia.
Minerva Anestesiol 68:332-336
24. Hall JC, Tarala RA, Tapper J, et al (1996) Prevention of respiratory complications after ab-
dominal surgery: a randomized clinical trial. Br Med J 312:148-152
25. Doyle RL (1999) Assessing and modifying the risk of post-operative pulmonary complica-
tions. Chest 115:77S-81S
26. Rowe S, Cheadle WG (2000) Complications of nosocomial pneumonia in the surgical pa-
tient. Am J Surg 179 (Suppl 2A):63S-68S
27. Croce MA (2000) Post-operative pneumonia. Am Surg 66:133-137
28. Dimick JB, Swoboda SM, Pronovost PJ, et a! (2001) Effect of nurse-to-patient ratio in the
intensive care unit on pulmonary complications and resource use after hepatectomy. Am J
Crit Care 10:376-382
29. Brooks JA (2001) Post-operative nosocomial pneumonia: nurse sensitive interventions.
AACN Clinical Issues 12:305-323
30. Kollef MH (1993)Ventilator associated pneumonia: a multivariate analysis. JAMA 270:1965-
1970
31. Koss WG, Khalili TM, Lemus JF, et a! (2001) Nosocomial pneumonia is not prevented by
contact isolation in the surgical intensive care unit. Am Surg 67:1140-1144
32. Kollef MH, Von Harz B, Prentice D, et a! (1997) Patient transport from intensive care in-
creases the risk of developing vetilator-associated pneumonia. Chest 112:765-773
33. de Lassence A, Alberti C, Azoulay E, et a! (2002) Impact of unplanned extubation and rein-
tubation after weaning on nosocomial pneumonia risk in the intensive care unit. Anesthe-
siology 97:148-156
34. Smulders K, van der Hoeven H, Weers-Pothoff I, et al (2002) A randomized clinical trial of
intermittent subglottic secretion drainage in patients receiving mechanical ventilation.
Chest 121:858-862
35. Kollef MH, Skubas NJ, Sundt TM (1999) A randomized clinical trial of continuous aspira-
tion of subglottic secretions in cardiac surgery patients. Chest 116:1339-1346
36. Montravers P, Veber B, Auboyer C (2002) Diagnostic and therapeutic management of noso-
comial pneumonia in surgical patients: results of the Eole study. Crit Care Med 30:368-375
37. Burchard KW, Gann DS, Wiles CE (2000) The Pulmonary System. In: The Clinical Hand-
book for Surgical Critical Care, Parthenon Publishing Group, New York, pp 103-159
38. The ARDS Network. Ventilation with lower tidal volumes as compared with traditional
tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Eng! J
Med 2000 342:1301-1308
39. Klinger JR (2002) Inhaled nitric oxide in ARDS. Crit Care Clin 18:45-68
40. Pelosi P, Brazzi L, Gattinoni L (2002) Prone positioning in acute respiratory distress syn-
drome. Eur Respir J 20:1017-1028
41. Grasso S, Mascia L, Del Turco M, et a! (2002) Effects of recruiting maneuvers in patients
with acute respiratory distress syndrome ventilated with protective ventilatory strategy.
Myocardial Ischemia or Cardiac Failure:
Which Constitutes the Major Perioperative Risk?
P. Older and A. Hall
I Introduction
That cardiac disease is a potent cause of postoperative morbidity and mortality is
not open to question. The question should be, is myocardial ischemia or cardiac
failure the greater threat to the surgical patient? It is our contention that cardiac
failure in the postoperative period, is the most important issue and that myocardial
ischemia, as an isolated finding, may not be as important as is often thought.
Historically, recent myocardial infarction [1] and congestive cardiac failure [2]
were recognized as being associated with high mortality. In 1987, the Confidential
Enquiry into Perioperative Deaths [3] highlighted, in a series of over 500000 pa-
tients, that the majority of postoperative deaths occurred in elderly patients, with
pre-existing cardiac or pulmonary disease, undergoing major surgery. In 1995, an-
other report from Finland [4] showed the same findings, this time in over 325000
patients. These articles served to highlight the work of Goldman et al. who pub-
lished one of the first indices for identification of cardiac risk in non-cardiac sur-
gery in 1977 [2]. Well before this, in 1960, Clowes and Del Guercio had related
operative mortality specifically to poor ventricular function [5].
Identification of high-risk patients is of value only if there is a change in the
management prompted by this finding. This is important for the effective use of in-
tensive care unit (ICU) beds for post surgical patients. The objective should be to
identify preoperatively the patients at risk and triage them for specialist manage-
ment in the ICU before they develop cardiopulmonary complications. The concept
of admitting patients to ICU postoperatively when they have deteriorated on the
ward results in poor outcomes due to the high severity of illness at the time of ICU
admission. The issues are: How do we identify high-risk patients, what specifically
do we look for, and what tests do we perform?
Are We Replacing Ignorance by Fallacy?
Much of the literature, particularly that targeting an anesthetic audience, empha-

sizes myocardial ischemia and myocardial infarction as the main concerns for sur-
gical patients [6, 7]. One of the consequences of this approach is that identification
of risk factors and preoperative screening tests for cardiac disease tend to concen-
trate solely on detection of myocardial ischemia and not its effect on ventricular
function. In fact, risk factors for cardiac disease in general, and for myocardial
ischemia in particular, have a common end point - impaired ventricular function.
378 P. Older and A. Hall
Other important consequences are that perioperative management is stratified only

according to risk of ischemia and infarction as identified from these tests. Therapy
is then directed to prevention of myocardial ischemia and not optimization of car-
diac performance.
Anesthesiologists accept this approach, as their problem is the management of
the patient during and immediately after surgery. During this period, global and
also myocardial oxygen demand are extremely low with oxygen consumption fig-
ures of less than 70 ml/min/m2 [8) (cf resting values 110-140 ml!min/m2 ). It is un-
likely that cardiac failure, in terms of oxygen delivery will manifest itself as a prob-
lem at that time. Most anesthesiologists are not directly involved in the postopera-
tive care of these patients and may not be aware of the high oxygen consumption
figures that occur in the first 48 hours following major surgery. Major intra-cavity
surgery, even in the elderly, is associated with an increase of over 40o/o in oxygen
consumption to 150 ml/min/m2 or higher necessitating a similar increase in cardiac
output [9). This response is neurohumoral and is not ablated by differing anes-
thetic techniques or adequate postoperative pain relief. It is a response to the im-
posed stresses of the postoperative period and, even now, is tacitly ignored
although Clowes and Del Guercio identified it 40 years ago [5).
Postoperative cardiac failure is difficult to identify in the absence of invasive
monitoring. It is a discussion of forward flow rather than elevation of the central
venous pressure or raJ.es in the chest, as found with the classical picture of conges-
tive cardiac failure. In 2000, we defined postoperative cardiac failure as the inability
of the heart to meet the demand of postoperative stress [10 ). It may only be appar-
ent postoperatively when oxygen demand is increased. It may occur independent of
both cardiac failure, in the traditional sense, and myocardial ischemia, although all
three may coexist.
I Current Preoperative Assessment

Various risk indices for non-cardiac surgery have been developed over the last
twenty years that emphasize the symptoms of chronic cardiac disease and inade-
quacy of myocardial perfusion [2, 11). It is noteworthy that preoperative tests for
myocardial ischemia are readily and frequently performed, whereas tests for assess-
ment of cardiac failure and evaluation of ventricular function are, in the main, less
frequently performed.
I Myocardial Ischemia
Bodenheimer [12) suggests that "if the patient has clinically stable angina or has
only risk factors for coronary artery disease, non-invasive testing adds little but
confusion''. He goes on to say that in the absence of unstable angina the patients'
cardiac status "does not warrant evaluation in and of itself". He bases this argu-
ment on the poor positive predictive value of non-invasive testing for postoperative
cardiac events. In fact these statements deny the role of cardiac failure as a risk fac-
tor. He poses the right question when he asks, "Why do patients experience adverse
events and how might these events be prevented?" Unfortunately 'adverse events' in
this context relate to myocardial ischemia and infarction, not post-operative cardiac
Myocardial Ischemia or Cardiac Failure: Which Constitutes the Major Perioperative Risk? 379
failure. He also makes the statement "If postoperative stress is accepted as the etio-
logic mechanism responsible for postoperative events then the optimal strategy be-
comes clear" and advocates reduction in postoperative oxygen consumption as a
possible management strategy. This latter statement clearly implies that he is dis-
cussing an increase in postoperative oxygen demand and the associated increase in
cardiac output. The focus should then be on ventricular function under conditions
of stress - not just a discussion of myocardial ischemia. Myocardial ischemia may
be a cause of ventricular dysfunction but as we have pointed out ventricular dys-
function may exist as a sole entity.
Our concept is that many patients, with or without ischemia, have impairment
of ventricular function that is not clinically detectable and that the preoperative de-
tection of such cardiac failure has major predictive value [13-15].
I Ventricular Function
In general, tests of ventricular function are little more than estimates based on clin-
ical history; examples include the American Society of Anesthesiologists Classifica-
tion of Physical Status published in 1963 [16] or the New York Heart Association
(NYHA) Classification of Functional Status as published in 1973 [17]. The latter is
a subjective evaluation of limitation of physical activity and was not intended as a
preoperative screening test. In 1988, Dunselman et al. [18], found in a study using
cardiopulmonary exercise testing, that there was considerable overlap of function
between Classes I and II and Classes III and IV. We consider that making distinc-
tions between these classes is crucial to management. The study also revealed a dis-
crepancy in one third of the cases between subjective and objective assessment of
severity of heart failure. Dunselman concluded that "only data from exercise studies
showed differences between the groups".
To overcome the subjectivity (or lack of objectivity) of assessment in the original
document of 1973, a revised version of the NYHA Classification was published in
1994 [19] and included what was termed an 'Objective Assessment'. This was based
on chest radiograph, resting electrocardiogram {EKG), EKG stress tests, echocar-
diograms and other radiological images. There was no reference to the use of data
from exercise studies. The 1994 document acknowledges, "grading is based on the
individual physician's judgment", and still uses imprecise terms, such as 'minimal',
'moderately severe' or 'severe'. In our view, these guidelines remain unsatisfactory
as they still fail to provide a truly objective assessment of cardiac function.
In 1996, the American College of Cardiology and the American Heart Associa-
tion (ACC/AHA) published a set of guidelines for preoperative evaluation of pa-
tients for non-cardiac surgery [20]. It was pointed out that the presence of coronary
artery disease in the presence of a good functional capacity was not a high-risk sit-
uation.
In 1993, our group had already published data showing that myocardial isch-
emia, in the absence of heart failure as defined by cardiopulmonary exercise test,
had little or no effect on postoperative outcome [13]. In the same study, we showed
that the combination of cardiac failure and EKG evidence of ischemia at low work
rates was associated with a high incidence of postoperative cardiac events. We also
showed that the incidence of an abnormal exercise EKG in patients over 65 without
any cardiovascular history is about 24% [14]. The 1996 Guidelines support this
finding and state that between 20 and 25% of patients with a normal resting EKG
will have an abnormal exercise EKG.
The ACC/AHA guidelines of 2002 [21] specifically state that myocardial ischemia
at high-levels of exercise (greater than 85% of age predicted) is a low risk situation.
However we take issue with the statement in "Recommendations: When and Which
Test", that "in most ambulatory patients, the test of choice is exercise EKG testing,
which can provide an estimate of functional capacity and detect myocardial isch-
emia through changes in the EKG and hemodynamic response". An EKG stress test
provides a very poor estimate of functional capacity; in addition the instantaneous
estimate of actual work rate is very inaccurate [22]. Measurement of blood pressure
and pulse rate change during exercise does not constitute measurement of the he-
modynamic response, i.e., adequacy of forward flow (cardiac output) and oxygen
delivery. In a study comparing invasive and non-invasive blood pressure measure-
ment during exercise, we showed that there was poor correlation between the two
techniques. In particular, the maximum values obtained were very much higher
with the invasive method. Blood pressure measurements made only 20 seconds after
exercise ceased, showed systolic readings 20-30 mm Hg less than those achieved at
end exercise (unpublished data, McGrath BP, Newman R, Older P 1989). EKG stress
tests should not be used for assessment of hemodynamic response.
In 1999, Lee et al. [23] published a validation of a clinical assessment for predic-
tion of cardiac risk in non-cardiac surgery. The Revised Cardiac Risk Index is an
enhancement of the original concept of Goldman et al. of 1977 [2]; Professor Gold-
man is a co-author of the revised index. The index is based on historical or simple
laboratory data and assigns scores to various factors, including history of conges-
tive cardiac failure and surgery specific risk - the latter was included in the 1996
ACC/AHA Guidelines [20]. According to the definitions of the Revised Cardiac Risk
Index, patients undergoing repair of abdominal aortic aneurysm, and thoracic and
abdominal procedures were excluded from Class 1 (low risk). In addition, there
was no relationship between risk class and major cardiac complications among
patients who underwent aortic aneurysm surgery. Although claiming superiority
over other published risk prediction indices, Lee acknowledges that the use of the
Revised Cardiac Risk Index "remains to be defined".
Other so-called objective measurements of ventricular systolic function including
radionuclide angiography, transthoracic echocardiography or dobutamine stress
echocardiography have been shown not to be reliable as screening tests for detec-
tion of operative risk in major surgery [10]. Both Higginbotham [24] and Cohen-
Solal [25] have shown that ejection fraction does not correlate with cardiac failure
as defined by aerobic capacity in patients with either coronary artery disease or
heart failure. In 1981, Franciosa et al. reported that no estimate of cardiac function
including left ventricular end-diastolic dimensions, ejection fraction or treadmill
time correlated well with measured exercised capacity [26]. This is not to decry the
potential value of these tests in the appropriate situation. It is, however, to say that
they are of doubtful value as screening tests for assessment of cardiac risk for non-
cardiac surgery.
Preoperative assessment of ventricular function is frequently made in terms of
the metabolic equivalent of common activities of daily living as described by the
Duke Activity Status Index published in 1989 [27]. A metabolic equivalent, or MET,
is the amount of oxygen consumed whilst sitting at rest by a 40 year old 70 kg male
and equates to 3.5 ml oxygen/min/kg. The energy costs of various activities, in
METs, are tabulated by many authorities [28].
In fact all of these 'tests of ventricular function' are actually surrogates of a true
cardiopulmonary exercise test as described by Sue and Wasserman in 1991 [29].
I Cardiopulmonary Exercise Testing: Measurement Versus Estimates
As objective measurement of ventricular function is readily performed it seems

pointless to use estimates. The most reliable and objective screening test for both
myocardial ischemia and ventricular function is the cardiopulmonary exercise test
[30, 31].
A cardiopulmonary exercise test using respiratory gas analysis and, of choice, a
bicycle ergometer, will give exactly the same EKG information as the treadmill test
and does not rely on estimates of METs. The workload of a bicycle ergometer is
known precisely and oxygen consumption is measured directly; thus estimates of
METs are rendered obsolete.
The ACC/ AHA Guidelines suggest that a patient unable to perform an estimated
4 METs has poor functional capacity and is likely to need further investigation.
They also suggest that a moderate functional capacity equates to 4-7 METs. They
urge that every effort must be made to detect unsuspected heart failure by careful
clinical history and examination. These statements themselves need examination.
In 1985, Weber and Janicki classified cardiac failure in terms of anerobic thresh-
old and peak aerobic capacity [32]. In this classification those patients with an
anerobic threshold greater than 14 ml!min/kg have no cardiac failure; those with
anerobic threshold between 11-14 ml/min/kg have mild cardiac failure; those with
anerobic threshold between 8-11 ml!min/kg have moderate cardiac failure and
those with anerobic threshold less than 8 ml!min/kg have severe cardiac failure.
The 4 METs exercise capacity quoted in the 2002 ACC/AHA Guidelines [21] equates
to a sustained work rate of 14 ml!min/kg (4x 3.5 ml/min/kg). Thus, using these
guidelines, any patient defined objectively with any degree of heart failure by
Weber and Janicki criteria, is high risk.
Our work measuring oxygen consumption directly via cardiopulmonary exercise
testing suggests a different situation. In our current series of 1240 consecutive pa-
tients over 50 years of age scheduled for major surgery, 1004 cases had an anerobic
threshold of less than 14 ml!min/kg, i.e., more than 80% (unpublished data Older
P, Hall A). We have found that elderly patients undergoing major surgery who have
an anerobic threshold of more than 11 ml!min/kg do not require ICU admission
and do not have postoperative cardiac events, i.e., postoperative myocardial infarc-
tion or cardiac failure, even if they have ischemia as detected during the cardiopul-
monary exercise test [15]. This anerobic threshold of 11 ml!min/kg equates to 3.1
METs or an average external workload of 50 watts. Only 383 cases of the 1240, i.e.
32%, had an anerobic threshold of less than 11 ml!min/kg and using our criteria
were classified as high risk. We do not believe it possible to make a clinical differ-
entiation between patients with an anerobic threshold in the range 11 ml!min/kg to
14 ml!min/kg. In our experience, validated by 2 published consecutive series total-
ing over 735 patients [13, 15], this distinction is of major and pivotal importance
in preoperative assessment and perioperative management.
The average anerobic threshold of the study population of 1240 consecutive pa-
tients is 12.4 ml/min/kg (3.5 METs), i.e., between 11 ml!min/kg and 14 ml!min/kg.
A sustained work rate of 7 METs, which is described as good functional capacity,
18
n = 1240
0,
-" 16
......
c:
·e
..... 14
].
-o
0 12
..t::.
~
.£u 10
1i
e
<II 8
c:
<t ""86 n = 105 n = 182 n = 265 n = 252 n = 218 n = 96 n=36
6
S0 - 54 55-59 60-64 65 -69 70-74 75-79 80 - 84 >85
Age (years)
Fig. 1. Comparison of anerobic threshold (mean and standard deviation) with age for 1240 elderly surgi-
cal patients
would be equivalent to an anerobic threshold of 25 ml/min/kg. This level of aerobic

capacity equates to an external workload on bicycle ergometry of over 140 watts
and would be unlikely in any patient over 60 years of age. In the series of 1240 pa-
tients to which we have referred, there were two patients with an anerobic thresh-
old of greater than 25 ml/min/kg. It is clear that we need something much more
accurate than estimates of functional capacity.
The Guidelines maintain that extremes of age are a minor clinical predictor of
perioperative risk. With this we concur. Figure 1 shows anerobic threshold versus
age for 1240 patients. Age is clearly not an adequate discriminator of ventricular
function in that one standard deviation of any age group embraces all the means of
the entire cohort! In 1993, Paty et al. [33] showed, in patients having surgery for
resection of abdominal aortic aneurysms, that mortality was 3% in patients over 80
(n= 116) and 2% in patients under 80 (n=622).
Professor Wasserman elegantly summarized this issue when he described the in-
herent dangers of using age as a discriminator of surgical risk. He pointed out that
"we all age at different rates; using age will deny surgery to potential survivors and
place younger patients with occult cardiopulmonary disease at great risk" [34]. We
believe that measurement of physiologic function is more important than chronolo-
gical age.
I The Basis For Cardiopulmonary Exercise Testing
During exercise up to the anerobic threshold, aerobic metabolism supplies the ma-
jority of ATP at a cellular level; after this there is an ever increasing need for sup-
plementation by anerobic means, with a consequent lactic acidosis. This situation
occurs not only in exercising muscle but also in any tissue where oxygen delivery
is inadequate to meet energy requirement.
It was shown by Clowes and Del Guercio in 1960 [5], that non-survivors of ma-
jor surgery failed to increase their cardiac output in the postoperative period and
succumbed with an increasing metabolic acidosis; whilst survivors did increase
their cardiac output. This was well before the era in which inotrope support was
used. Although the means of management have now changed, i.e., postoperative
monitoring with attention to optimization of oxygen delivery, the underlying phy-
siology relating to major surgery remains the same.
In 1996, we postulated the concept of a 'surgical anerobic threshold' [14], this
being the point where tissue oxygen delivery is unable to support aerobic genera-
tion of ATP. If aerobic metabolism is inadequate due to impaired ventricular func-
tion with consequent impairment of oxygen delivery, anerobic metabolism must
supplement ATP production, but at the cost of lactic acid production. This will re-
sult in acidosis and impaired cellular function that is manifested as postoperative
cardiac failure as described by Clowes and Del Guercio [5]. In our opinion the
presence of a rising lactate in postoperative patients should prompt immediate in-
vestigation of the adequacy of oxygen delivery and global oxygen extraction. We
have found that an elevated lactate is generally associated with inadequate cardiac
output and oxygen delivery in the presence of high oxygen consumption and an
oxygen extraction ratio of 30% or more.
I That Cardiac Failure is of More Serious Prognostic Significance

than Myocardial Ischemia
Del Guercio, in 1980 [35], showed that it is possible to predict operative mortality
by preoperative hemodynamic studies using a pulmonary artery catheter to evalu-
ate ventricular performance. He found that elevation of pulmonary artery occlusion
pressure at rest, intrapulmonary shunt greater than 20%, and low cardiac index all
had serious prognostic significance. He also found that inadequate oxygen trans-
port is more likely to be detected by desaturation of mixed venous gas samples
than by arterial desaturation. Patients with large arterio-venous oxygen differences
at rest were classed as having moderate or advanced functional deficits because
they were already using their mixed venous oxygen reserve. Changes in blood flow
or oxygen demand postoperatively were thus more likely to result in tissue hypoxia
in such patients.
Further, he showed that clinical evaluation was unable to identify high-risk pa-
tients. All patients in the study had been cleared for surgery by standard assess-
ment but only 13.5% had normal measured hemodynamic, respiratory and oxygen
transport function.
In a study in 1988 [9], we showed that 13% of patients evaluated in a similar
fashion to those of Del Guercio had serious cardiac problems with 11 o/o having a
resting cardiac index of less than 2.2 l!min/m 2 • These patients had already been
clinically evaluated and had been scheduled for major surgery. Seven of the one
hundred study patients had their operation postponed due to problems that could
not be rectified in the time available. Another six had their operations cancelled.
One patient opted for surgery despite the risks and died on day two; three others
identified as being in the high-risk group were in need of essential vascular surgery
but died following surgery of cardiovascular complications.
These studies also imply that ventricular function is of major importance in de-
termining postoperative morbidity and mortality and that methods relying solely
on clinical evaluation are doomed to failure. These lessons may well have been for-
gotten.
I Cardiopulmonary Exercise Testing Studies and Outcome
In a study of 548 consecutive elderly patients scheduled for major intracavity sur-
gery, published by our group in 1999 [15], we related outcome to cardiopulmonary
function as assessed preoperatively by cardiopulmonary exercise testing. The over-
all mortality rate for major intra-abdominal surgery in that study was 3.9% (21 of
548). The incidence of myocardial ischemia, on exercise EKG criteria, was 24%
(132 patients). Of the 21 deaths, twelve were unrelated to cardiopulmonary disease.
The remaining nine deaths were attributable solely to poor cardiopulmonary func-
tion, with only two of these patients having myocardial ischemia identified preop-
eratively. Only one of these nine patients died following a myocardial infarction.
Seven of the nine cardiovascular deaths had poor ventricular function identified
preoperatively i.e. poor ventricular function was a more potent discriminator of
death than myocardial ischemia. There were no deaths related to cardiopulmonary
causes in any patient with adequate ventricular function as previously defined on
cardiopulmonary exercise testing, i.e., an anerobic threshold greater than 11 ml/
min/kg; even if myocardial ischemia had been detected.
If myocardial ischemia were the dominant factor causing perioperative morbidity
then one would expect to see morbidity predominantly in the group with ischemia.
This is clearly not the case.
Myocardial ischemia is caused by a failure of oxygen delivery to support the
regeneration of high-energy phosphate in the myocardium needed to allow normal
ventricular contraction. In 1996 [14] and in 2002 [36], we published data showing
the relevance of the time of onset of myocardial ischemia during exercise testing.
The majority of our patients have normal resting EKGs and there appear to be two
major patterns of ST segment change during the exercise test. Ischemia with onset
early in exercise, i.e., before the anerobic threshold, is associated with a low anero-
bic threshold. In other patients the ischemia occurs late in exercise, i.e., after the
anerobic threshold. We have found that the average anerobic threshold for patients
who developed ischemia at low work rates was 10.4 ml/min/kg whereas the anero-
bic threshold averaged 13.9 ml/min/kg in those who developed ischemia late in ex-
ercise at higher work rates [14].
We contend that patients will reach their 'surgical anerobic threshold' when oxy-
gen demand and cardiac output rise postoperatively to the equivalent level where
'cardiac failure' requiring anerobic metabolism occurred during exercise, i.e., the
exercise anerobic threshold. This will result in impaired ventricular function mani-
festing as postoperative cardiac failure as defined above.
The clinical relevance of this is enormous. In patients with a lower anerobic
threshold, this postoperative ventricular dysfunction will be more likely and will
occur at lower levels of postoperative stress, with consequently higher risk of mor-
bidity and mortality. If myocardial ischemia develops and further impairs already
poor ventricular function then morbidity and mortality will be even higher.
As minor surgery does not induce this extent of stress response the same patient
may undergo lesser surgery without cardiovascular morbidity. In 1980, Backer et al.
[37] reported no cardiac complications in 288 ophthalmologic operations in pa-
tients with a previous myocardial infarction. This compared to a reinfarction rate
of 6.1 o/o in other surgery at the same hospital.
Significantly, in our studies [ 13-15], there has been no cardiovascular morbidity
in patients with adequate ventricular function as defined by an anerobic threshold
of greater than 11 ml!min/kg. These patients are managed without need for high
dependency or intensive care facilities. As a precautionary measure we have ad-
mitted patients to a high dependency unit who have late myocardial ischemia on
cardiopulmonary exercise testing but with an anerobic threshold of 11 ml/min/kg
or greater. Currently we are running a trial to allow all such patients with or with-
out ischemia to go to the ward. We still admit patients scheduled for intracavity
surgery where such surgery is likely to be prolonged or result in high oxygen de-
mand stress. This includes cases such as pancreatico-duodenectomy procedure,
total gastrectomy or esophagectomy; this equates to Surgery Specific Risk as de-
fined in the ACC/AHA Guidelines [21].
Conclusion
Postoperative outcome is mainly influenced by ventricular function. Tests to identi-
fy myocardial ischemia will fail to detect cardiac failure and are inadequate as a
screening test for identification of cardiac risk in non-cardiac surgical patients. We
use cardiopulmonary testing as the sole test to evaluate cardiopulmonary function
and myocardial ischemia, and modify perioperative management according to the
result. We find that the degree of cardiac failure is the most important predictor of
morbidity and mortality. This is independent of myocardial ischemia; however
myocardial ischemia combined with moderate to severe cardiac failure (anerobic
threshold <11ml/min/kg) is predictive of the highest morbidity and mortality.
References
1. Rao TK, Jacobs KH, El-Etr AA (1983) Reinfarction following anesthesia in patients with
myocardial infarction. Anesthesiology 59:499-505
2. Goldman L, Caldera DL, Nussbaum SR, et a! (1977) Multifactorial index of cardiac risk in
non-cardiac surgical procedures. N Eng! J Med 297:845-850
3. Buck N, Devlin HB, Lunn JN (1987) The report of a confidential enquiry into perioperative
deaths. The Nuffield Provincial Hospitals Trust and the Kings Fund, London
4. Tikkanen J, Hovi-Viander H (1995) Deaths associated with anaesthesia and surgery in Fin-
land in 1986 compared to 1995. Acta Anaesthesia! Scand 39:262-267
5. Clowes GHA, Del Guercio LRM (1960) Circulatory response to trauma of surgical opera-
tions. Metabolism 9:67-81
6. Fleisher LA (1992) Perioperative myocardial ischemia and infarction. In: Beattie C, Fleisher
LA (ed) International Anesthesiology Clinics, Volume 30 Number 1. Little, Brown and
Company, Boston, pp 1-17
7. Aitkenhead AR (1993) Postoperative ischemia: cardiac morbidity after non-cardiac surgery.
Lancet 341:731-732
8. Shoemaker WC, Thangathurai D, Wo CJC, et a! (1999) Intraoperative evaluation of tissue
perfusion in high-risk patients by invasive and noninvasive hemodynamic monitoring. Crit
Care Med 27:2147-2152
9. Older PO, Smith R (1988) Experience with the preoperative invasive measurement of
haemodynamic, respiratory and renal function in 100 elderly patients scheduled for major
abdominal surgery. Anaesth Intensive Care 16:389-395
10. Older P, Smith R, Hall A, French C (2000) Preoperative cardiopulmonary risk assessment
by cardiopulmonary exercise testing. Critical Care and Resuscitation 2:55-65
11. Detsky AS, Abrams HB, Forbath N, Scott JG, Hilliard JR (1986) Cardiac assessment in pa-
tients undergoing non-cardiac surgery. A multifactorial clinical risk index. Arch Intern
Med 146:2131-2134
12. Bodenheimer MM (1996) Noncardiac surgery in the cardiac patient: What is the question?
13. Older P, Smith R, Courtney P, Hone R (1993) Preoperative evaluation of cardiac failure and
ischaemia in elderly patients by cardiopulmonary exercise testing. Chest 104:701-704
14. Older PO, Hall AC (1996) The role of cardiopulmonary exercise testing for preoperative
evaluation of the elderly. In: Wasserman K (ed) Exercise Gas Exchange in Heart Disease.
Futura Publishing Company, New York, pp 287-297
15. Older P, Hall A, Hader R (1999) Cardiopulmonary exercise testing as a screening test for
perioperative management of major surgery in the elderly. Chest 116:355-362
16. American Society of Anesthesiologists (1963) New classification of physical status. An-
esthesiology 24:111
17. The Criteria Committee of the New York Heart Association (1973) Diseases of the heart
and blood vessels. In: Nomenclature and Criteria for Diagnosis of Diseases of the Heart
and Great Vessels, 7th edn. Little, Brown and Company, Boston, pp 286
18. Dunselman PH, Kuntze CE, Van Bruggen A, et al (1988) Value of New York Heart Associa-
tion classification, radionuclide ventriculography, and cardiopulmonary exercise tests for
selection of patients for congestive heart failure studies. Am Heart J 116:1475-1482
19. The Criteria Committee of the New York Heart Association (1994) Diseases of the heart
and blood vessels. In: Nomenclature and Criteria for Diagnosis, 9th edn. Little, Brown and
Company, Boston, pp 253-256
20. Eagle KA, Brunage BH, Chaitman BR, et al (1996) Guidelines for perioperative cardiovas-
cular evaluation for noncardiac surgery. Report of the American College of Cardiology/
American Heart Association Task Force on Practice Guidelines. Committee on Periopera-
tive Cardiovascular Evaluation for Noncardiac Surgery. Circulation 93:1278-1317
21. Eagle KA, Berger PB, Calkins H, et al (2002) ACC/AHA Guideline update for perioperative
cardiovascular evaluation for noncardiac surgery. Circulation 105:1257-1267
22. Wasserman K, Hansen JE, Sue DY, Whipp BJ, Casaburi R (1994) Protocols for exercise test-
ing. In: Wasserman K (ed) Principles of Exercise Testing and Interpretation, 2nd edn. Lea
and Febiger, Malvern Pennsylvania, pp 103
23. Lee TH, Marcantoniao ER, Mangione CM, et al (1999) Derivation and prospective valida-
tion of a simple index for prediction of cardiac risk of major noncardiac surgery. Circula-
tion 100:1043-1049
24. Higginbotham MB (1996) Diastolic dysfunction and exercise gas exchange. In: Wasserman
K (ed) Exercise Gas Exchange in Heart Disease. Futura Publishing Company, New York,
pp 39-54
25. Cohen-Solal A (1996) Cardiopulmonary exercise testing in chronic heart failure. In: Was-
serman K (ed) Exercise Gas Exchange in Heart Disease. Futura Publishing Company, New
York, pp 17-38
26. Franciosa JA, Park M, Levine TB (1981) Lack of correlation between exercise capacity and
indexes of resting left ventricular performance in heart failure. Am J Cardiol 47:33-39
27. Hlatky MA, Boineau RE, Higginbotham MB, et al (1989) A brief self administered ques-
tionnaire to determine functional capacity (the Duke Activity Status Index). Am J Cardiol
64:651-654
28. Park KW (2001) Tests of myocardial function. In: Park KW (ed) International Anesthesiol-
ogy Clinics, Volume 39 Number 4. Little, Brown and Company, Boston, pp 11-19
29. Sue DY, Wasserman K (1991) Impact of integrative cardiopulmonary exercise testing on
clinical decision making. Chest 99:981-992
30. Kleber FX, Sabin GV, Winter UJ, et al (1997) Angiotensin-converting enzyme inhibitors in
preventing in preventing remodeling and development of heart failure acute myocardial in-
farction: results of the German multicenter study of the effects of captopril on cardiopul-
monary exercise parameters (ECCE). Am J Cardiol 80:162A-167A
31. Lipkin DP (1987) The role of exercise testing in chronic heart failure. Br Heart J 58:559-
566
32. Weber KT, Janicki JS (1985) Cardiopulmonary exercise testing for evaluation of chronic
cardiac failure. Am J Cardiol 55:22A-31A
33. Paty PS, Lloyd WE, Chang BB, Darling RC, Leather RP, Shah DM (1993) Aortic replace-
ment for abdominal aortic aneurysm in elderly patients. Am J Surg 166:191-193
34. Wasserman K (1993) Preoperative evaluation of cardiovascular reserve in the elderly. Chest
104:663-664
35. Del Guercio LRM, Cohn JD (1980) Monitoring operative risk in the elderly. JAMA 243:
1350-1355
36. Older PO, Hall AC (2002) Preoperative assessment of elderly surgical patients. In: Wasser-
man K (ed) Cardiopulmonary Exercise Testing and Cardiovascular Health. Futura Publish-
ing Company, New York pp 119-133
37. Backer CL, Tinker JH, Robertson DM, Vlietstra RE (1980) Myocardial reinfarction follow-
ing local anesthesia for ophthalmic surgery. Anesth Analg 59:267-262
I Cardiac Crises
Acute Coronary Syndromes
J. F. Coutts, S. R. Redwood, and A. Rhodes
I Introduction
The term acute coronary syndromes describes a spectrum of conditions including

ST elevation or q wave myocardial infarction (also known as 'STEMI'), non-q wave
myocardial infarction (or 'NSTEMI') and unstable angina. Patients with these diag-
noses represent a significant proportion of acute admissions and have a high mor-
tality and morbidity. There have been significant developments recently in the un-
derstanding of these conditions, and a wide range of treatment strategies have been
proposed. In this chapter, we aim to overview the pathophysiological processes un-
derlying the conditions and to discuss how a practical approache to management
can be derived given the current evidence.
I Plaque Rupture
The grouping of conditions within the category of acute coronary syndromes de-
rives from the observation that the pathological process is essentially the same in
each case. The acute events are characterized by the disruption of coronary artery
plaques, exposing blood products to the thrombogenic lipid core. Subsequent
thrombosis on the underlying plaque results in varying degrees of obstruction to
flow.
Central to the process is the development of a vulnerable plaque. Coronary ar-
tery plaques can develop from early adult life, particularly in association with the
well-known risk factors for coronary disease [1). Mature plaques are characterized
by a lipid rich core encased by a fibrous plaque of structural proteins.
Plaques with a high lipid content, with foam cell infiltration, and with reduced
numbers of smooth muscle cells, are particularly prone to rupture [1]. Disruption
of the fibrous cap most frequently occurs at the peripheries where the cap tends to
be thinnest, with a high infiltration of foam cells [2). The precipitation of plaque
rupture is believed to be due to mechanical stresses as a result of movement of the
coronary arteries during the cardiac cycle and from the pulsatile arterial flow.
These stresses are believed to be concentrated on the fibrous cap [3).
The ruptured cap allows exposure of the plaque core: the thrombogenic gruel to
the components of circulating blood. Activation of platelets occurs, particularly by
lipid components of the gruel. Platelet surface proteins undergo constitutional
changes during activation, in particular the glycoprotein lib/lila receptor, which,
on activation, presents fibrinogen binding sites to allow the formation of bridges
392 J. F. Coutts et al.
between platelets with subsequent aggregation. The clotting cascade is initiated by

exposure of blood proteins to tissue factor, related to smooth muscle and macro-
phage cells in the gruel, and collagen. The process is enhanced by systemic tenden-
cies promoting thrombosis, as found in cigarette smokers. The activated platelet
mass releases further factors that promote continued platelet aggregation, vasocon-
striction and thrombus formation, which may be aggravated by reduction in arteri-
al flow and subsequent stasis [4].
Although plaque rupture probably accounts for the majority of acute coronary
syndromes, there is some evidence that thrombosis can be activated by a process
of plaque erosion [5]. In up to 30o/o of cases of intra-coronary thrombosis the pla-
que has a different constitution with a low lipid content and a large number of
smooth muscle cells. The endothelium appears to have been eroded in a process in-
volving inflammatory cells, thereby exposing blood proteins to tissue factor and
collagen. In these cases there is frequently a systemic clinical disorder of clotting.
The immediate consequences of the thrombosis depend on its site and severity.
Studies in cases of death from non-cardiovascular causes suggest that asymptomatic
plaque rupture is not uncommon, evidence of recent rupture being present in up
to So/o of cases [6]. A non-occlusive plaque rupture without distal embolization may
subsequently heal without immediate clinical sequelae, although the plaque would
be expected to remain unstable for a period of time. At the other end of the spec-
trum complete occlusion of a large epicardial vessel may result from the thrombus.
If there is inadequate collateralization, trans-mural ischemia develops, progressing
to trans-mural infarction, which may be associated with ST elevation and subse-
quent q waves electrocardiographically. Within this spectrum are cases of incom-
plete occlusion of large vessels, perhaps with distal embolization from the develop-
ing thrombus, and cases of occlusion of small vessels, which fail to damage suffi-
cient myocardium to give a full q wave myocardial infarction.
The underlying plaque lesion need not be unduly severe to result in a myocar-
dial infarction: in fact, lesions of < SOo/o vessel occlusion account for infarcts in over
75o/o of cases in some series [7].
Since the disease process is the same in each case, the different sub-types of
acute coronary syndrome will share many of the fundamental management strate-
gies. The treatment of the disease process should be similar for all cases, the strat-
egy for restoring flow being dependent on the site and severity of thrombosis.
I Management Options
In addition to supportive measures, specific therapies for acute coronary syn-
dromes should aim to:
I Restore/maintain coronary flow
I Treat the underlying disease process.
Maintaining Coronary Flow

A wide range of strategies can be undertaken to improve coronary flow. In each
case, the risks of the therapy need to be carefully assessed in terms of the potential
benefit to the patient. Evidence is accumulating in order for a risk benefit analysis
to be undertaken for each agent. Evidence is lacking regarding the combinations of
strategies.
Acute Coronary Syndromes 393
Medical Therapies
Fibrinolytic Therapy: Fibrinolytic agents include streptokinase, tissue plasminogen
activator (tPA) and anistrepalase. They act by dissolving fibrin within the develop-
ing arterial thrombus. The use of fibrinolytic agents in cases of ST elevation or new
left bundle branch block (LBBB) myocardial infarction is now well established
(Fig. 1) [8, 9]. When used appropriately there is an overall reduction in mortality
from approximately 10 to 7% at 30 days when given within 6 hours from the onset
of symptoms and to 8% when given between 7 and 12 hours [8]. The fibrinolytics
available have slightly different properties, tPA being associated with a higher initial
artery patency rate compared to streptokinase, but there is little evidence to sug-
gest a significant difference in survival benefit between the different agents [10].
Fibrinolytic agents carry a significant risk of hemorrhage; in particular there is
an excess hemorrhagic stroke rate of approximately 0.19% [8]. The risks of therapy
result in fibrinolytics being restricted to those patients at highest risk, i.e., where
there is clinical evidence of a recent major epicardial vessel occlusion: ST elevation
or new LBBB in the appropriate clinical context. This clinical categorization is nec-
essarily imperfect: there are some sub-groups of ST elevation myocardial infarction
where the risk benefit is more clearly in favor of fibrinolytic use; for example, ante-
rior infarction is associated with a higher mortality and a consequently greater
benefit/risk ratio than inferior infarction [8]. In contrast, cases of posterior infarc-
tion associated with widespread anterior ST depression in the absence of ST eleva-
tion at any site, perhaps due to proximal occlusion of a large dominant circumflex,
might benefit from fibrinolysis although the lack of clear differentiation with ante-
rior ischemia makes analysis more difficult.
Pre-hospital fibrinolysis has been advocated in order to maximize efficacy. Sig-
nificant improvements in survival have been demonstrated [11].
Where myocardial infarction occurs without evidence of major vessel occlusion,
i.e., non-ST elevation myocardial infarction, the risks of fibrinolysis are not war-
ranted. Several trials have failed to show a benefit in this group [8], and in the
Thrombolysis In Myocardial Infarction (TIMI) 111B trial there was evidence to
suggest such a strategy may be harmful [12].
Aspirin only
10
~ Streptokinase only
.~ Streptokinase and
Iii
t: Aspirin
0
5 8 % cumulative
~
mortality
0
0 2 3 4 5
Weeks after starting treatment
Fig. 1. Cumulative mortality of patients with ST elevation acute coronary syndromes (ACS). Results of ISIS
2. Adapted from [10)
Thrombin Inhibitors and Anticoagulants: Plaque rupture can trigger the extrinsic
pathway of coagulation by exposing tissue factor to plasma proteins. The activation
of the clotting cascade results in the cleavage of prothrombin to thrombin, which
can activate platelets and cleaves fibrinogen to form fibrin, strengthening the
thrombus. Thrombin inhibitors are an important component of treatment in acute
coronary syndromes.
I Heparin
Unfractionated Heparin: Traditionally infusion of unfractionated heparin has repre-
sented a central component of treatment in unstable angina. Its action on thrombin
is indirect, by binding to and accelerating the actions of antithrombin. Evidence
suggests benefit from unfractionated heparin in non-ST elevation acute coronary
syndromes, with significant reductions in subsequent myocardial infarction [13,
14]. There is evidence of an increased event rate shortly after cessation of unfrac-
tionated heparin infusion [15]. Control of the anticoagulant effect over a period of
time is, however, notoriously difficult due to the competitive binding of heparin to
plasma proteins resulting in periods of over and underdosage [16]. Long-term
treatment (>48 hours) appears to be associated with an increased rate of progres-
sion to death/myocardial infarction [17]. Furthermore, unfractionated heparin has
a significant risk of thrombocytopenia [18], and in the longer-term osteoporosis.
I Low Molecular Weight (LMW) Heparin
LMW heparins are short chain fragments of heparin, which act in concert with
antithrombin. Their dose-responses are more predictable, such that continued mon-
itoring is not required [19]. Thrombocytopenia is less common [20].
LMW heparins have been compared to unfractionated heparin in non-ST eleva-
tion acute coronary syndromes. Studies with different agents have produced vari-
able results. The FRIC (Fragmin in Unstable Coronary Artery Disease) study, for
example, found dalteparin to be equivalent in terms of safety and efficacy with un-
fractionated heparin, with no benefit from a protracted treatment (up to 45 days)
with dalteparin and aspirin vs aspirin alone [21]. The Efficacy and Safety of Sub-
cutaneous Enoxaparin in Non-Q-Wave Coronary Events (ESSENCE) and TIMI liB
studies, however, found reductions with enoxaparin vs. unfractionated heparin in
the combined end points of death/myocardial infarction/recurrent angina and myo-
cardial infarction/emergency revascularization respectively [22, 23]. Neither study
demonstrated a significant reduction in mortality.
In view of the equivalence, and probable superiority, of efficacy of LMW with
unfractionated heparin, combined with their ease of use and improved safety pro-
file, LMW heparin has largely replaced unfractionated heparin in non-ST elevation
acute coronary syndrome.
Direct Antithrombins. In contrast to heparins, direct antithrombins are independent

of antithrombin in their action on thrombin. The Organization to Assess Strategies
for Ischemic Syndromes (OASIS)-2 trial [24] compared hirudin with unfractionated
heparin in patients with non-ST elevation acute coronary syndrome. There was a
small but significant difference in the composite primary end point (cardiovascular
death/myocardial infraction/refractory ischemia) at 7 days: hirudin 5.6o/o vs unfrac-
tionated heparin 6.7o/o (RR 0.82, 95o/o CI 0.70-0.96, p=0.0125). There was an excess
of bleeding requiring transfusion in the hirudin group ( 1.2 vs 0.7o/o p = 0.01 ), but
no excess of life threatening bleeding episodes. Previous studies with hirudin in
acute coronary syndrome have shown small advantages over heparin of borderline
statistical significance [25]. In view of the small benefits and a perceived increased
bleeding risk, hirudin type agents have not achieved widespread acceptance. Use
has typically been restricted to cases of heparin-induced thrombocytopenia.
Initial reports of a synthetic derivative of hirudin, bivalirudin, show evidence of
improved efficacy compared to heparin, and further trials are awaited [26].
Warfarin. Use of warfarin in the recovery period after a myocardial infarction has been
shown to be associated with increased survival. Smith et al. [27] randomized 1214 pa-
tients at a mean period of 27 days post-myocardial infarction to warfarin or placebo
for an average of 37 months. There was a significant reduction in mortality with a
reduction in risk of 24% (95% CI 4-44%, p = 0.027). Studies comparing warfarin
and aspirin with aspirin alone in patients with non-ST elevation acute coronary syn-
drome revealed a significant reduction in ischemic events with the addition of warfar-
in [28]. This result has been confirmed in more recent studies [29], where warfarin at
a dose to maintain an international normalized ratio (INR) of 2.3 ± 0.6 was associated
with a significant reduction in a composite end-point of death/cerebrovascular acci-
dent (CVA)/myocardial infarction, although this was at the expense of a significant
excess of minor bleeding complications. Despite evidence of benefits, warfarin has
not come into widespread use - perhaps because of the bleeding risks and inconve-
nience and limitations that it imposes on the patient. With the advent of increasing
anti-platelet use - in particular clopidogrel and the GPIIb/IIIa inhibitors - the risk/
benefits of warfarin therapy would need to be re-evaluated.
Platelet Inhibitors
Aspirin. Aspirin acts as an anti-platelet agent by inhibition of thromboxane A2 pro-
duction through irreversible acetylation of platelet cyclooxygenase. The risks of as-
pirin are small: true allergy, though serious, is rare, and gastro-intestinal upset is
generally mild [30].
The benefits of aspirin in ST elevation myocardial infarction were seen in the Inter-
national Study of Infarct Survival (ISIS) 2, where treatment with 162.5 mg aspirin in
the acute stages gave rise to a significantly improved 30 day survival [9]. Furthermore,
the benefits of streptokinase and aspirin were found to be additive (Fig. 1).
Studies evaluating aspirin in unstable angina and non-Q wave myocardial infarc-
tion demonstrate a significant reduction in mortality and subsequent myocardial
infarction, with a risk reduction of up to 51% for the combined end point [31].
The dose of aspirin required to develop and maintain sufficient platelet inhibi-
tion remains controversial although there is an argument to administer the mini-
mum effective dose to minimize side effects [10].
Thienopyridine Derivatives. The thienopyridine derivatives reduce platelet aggrega-

tion by inhibition of ADP dependent pathways that activate the glycoprotein lib/
Ilia receptors.
Ticlopidine. There is evidence that ticlopidine has benefits additional to aspirin and
other conventional therapies for unstable angina. Balsano et al. demonstrated a re-
duction in combined mortality and myocardial infarction at 6 months in unstable
angina [32]. There is no evidence for ticlopidine in ST elevation myocardial infarc-
tion. Ticlopidine is associated with a significant risk of neutropenia, such that it is

no longer in widespread use in the UK.
Clopidogrel. The Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events

(CAPRIE) trial [30] compared aspirin with clopidogrel in a large (over 19000)
group of stable patients. The benefits were small: a combined end-point of death
from vascular disease, myocardial infarction and ischemic stroke over a mean of
1.9 years of 5.3% clopidogrel vs 5.8% aspirin (p = 0.04), but clopidogrel was found
to have a good safety profile with no evidence of an increased rate of neutropenia
above aspirin.
The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial
[33] studied 12562 patients presenting with non-ST elevation acute coronary syn-
dromes. The effects of clopidogrel (300 mg initial dose followed by 75 mg/day) in
addition to aspirin for 3-12 months in comparison to aspirin and placebo, were
studied with a median follow up of 9 months. A combined primary outcome of car-
diovascular death, nonfatal myocardial infarction or stroke, occurred in 9.3% of the
clopidogrel group vs 11.4% of the placebo group (RR 0.80; 95% CI 0.72-0.90;
p < 0.001). Interestingly, benefits could be detected in the clopidogrel group within
24 hours. Although bleeding episodes were more common in the clopidogrel group,
fatal bleeding, bleeding requiring surgical intervention and hemorrhagic stroke
were similar in both groups.
Since the CURE trial, clopidogrel is increasingly used as an adjunct to aspirin
for non-ST elevation acute coronary syndromes. Whether it should be advocated
for all acute coronary syndromes, and for what duration the treatment should be
continued, remains to be established. Clopidogrel is also in widespread use as an
adjunct to aspirin to reduce the risk of acute stent thrombosis after angioplasty.
Inhibitors of the platelet receptor glycoprotein lib/lila. The glycoprotein IIb/IIIa

(GPIIb/IIIa) receptor is a key component in platelet aggregation (Fig. 2). Activation
of platelets results in conformational changes of the receptor, exposing a fibrinogen
binding site. This allows the formation of fibrinogen bridges between platelets,
resulting in the formation of aggregates. Since this is a critical point in the develop-
ment of coronary thrombus at the site of plaque rupture, it represents a logical tar-
get in the treatment of unstable syndromes.
Intra-venous preparations of GPIIb/IIIa inhibitors include the chimeric human
and murine monoclonal antibody, abciximab, and the competitive inhibitors, eptifi-
batide, tirofiban and lamifiban. In contrast to the competitive inhibitors, abciximab
binds irreversibly to the GPIIb/IIIa receptor, resulting in platelet inhibition for a
long period (days) after the infusion is complete. The low fraction of unbound ab-
ciximab post infusion does, however, allow platelet infusions to be given with bene-
fit in situations of significant hemorrhage. The competitive antagonists have half
lives of some 2-4 hours.
There have been four large randomized trials evaluating GPIIb/IIIa inhibitors in
acute coronary syndromes in the absence of intervention. The Platelet glycoprotein
IIb/IIIa in Unstable angina Receptor Suppression Using Integrilin Therapy (PUR-
SUIT) trial [34] evaluated eptifibatide in non-ST elevation acute coronary syn-
drome. Patients with chest pain in the previous 24 hours and with either electro-
cardiograph (EKG) changes or raised enzymes were randomized to receive either
eptifibatide or placebo. After an initial bolus, an infusion was continued for at least
72 hours. In the early stages of the trial, two infusion doses of eptifibatide were
A>---<: •
Fibrinogen
Resting platelet with inactive
~ GPIIb/lllo 'K"''~
Thromboxane A 2
Serotonin Platelet activation results

in conformational change
of GPIIb/llla receptor
and fibrogen binding
Fig. 2. Platelet activation. Irrespective of the activating agent, the pathway to aggregation is through
conformational change of the GPIIb/llla receptor
used: either 1.3 or 2.0 J.Lg/kg/min. The low dose arm was dropped after it was ap-
parent that there was no excess of serious bleeding in the high dose group. Other
medications, including heparin, were continued at the discretion of the investiga-
tors. The combined primary end-point of death/myocardial infarction at 30 days
was significantly lower in the eptifibatide group, 14.2%, than the placebo, 15.7%,
(p=0.04).
The trials evaluating GPIIb/IIIa inhibitors in non-ST elevation acute coronary
syndromes are summarized in Table 1. There is a small but significant risk of
bleeding with these agents, an excess of serious bleeding noted in the high dose
lamifiban group [35], and there is a small but significant risk of thrombocytopenia.
There is evidence of some benefit with these agents in the combined end point of
death/myocardial infarction at 30 days, but this is small: approximately 16% (place-
bo) to 14.3%. However, in those patients who undergo percutaneous intervention,
the relative risk reduction is more pronounced, suggesting that these agents may
have a particular role in these patients. In some of the medical therapy trials sub-
groups of patients went on to undergo intervention (for example PURSUIT and
Platelet Receptor Inhibition in ischemic Syndrome Management [PRISM)), these
sub-groups being included in Table 2. Those patients who subsequently required
intervention showed a more marked reduction in events associated with the use of
GPIIb/IIIa inhibitors than those treated conservatively. It is likely that the patients
subsequently requiring intervention represented a high risk group, and it is likely
to be those patients who would have most to benefit from aggressive platelet inhibi-
tion.
Table 1. Trials of GPIIb/llla inhibitors for acute coronary syndromes
Name Agent No Endpoint Event Rate p

of patients (30 days)
Treatment Control
arm
PURSUIT eptifibatide 10948 Death/MI 14.2% 15.7% 0.04
Canadian Lamifiban lamifiban 365 Death/MI 2.5% 8.1% ns
PARAGON lamifiban 2282 Death/MI 10.6% 11.7% ns
PRISM tirofiban 3232 Death/Mil 15.9% 17.1% 0.34
refractory
ischemia
PRISM PLUS tirofiban 1915 Death/Mil 18.5% 22.3% 0.03
Refractory
ischemia
I Pooled results 18742 14.3% 16.0%
The Canadian Lamifiban trial was a pilot for the PARAGON trial. Angioplasty was encouraged in the
PRISM PLUS trial between 48+96 hours, and was performed on 30%
The TACTICS-TIMI 18 (Treat Angina with Aggrastat and Determine Cost of

Therapy with an Invasive or Conservative Strategy - Thrombolysis in Myocardial
Infarction) study has subsequently demonstrated a clear benefit in an invasive
strategy for these patients even when treated with a GPIIb/IIIa inhibitor. There is
consequently less impetus in evaluating these agents as a stand-alone therapy, such
that their primary role is now viewed as an adjunct to intervention, or as a holding
measure pending the ability to perform the intervention, as discussed below.
Pilot studies have suggested a potential role for GPIIb/IIIa as adjunctive therapy
for ST segment elevation myocardial infarction. There are theoretical arguments for
a combination treatment with fibrinolytics. The action of fibrinolysis in dissolving
fibrin can expose and increase the activity of thrombin. Thrombin as a potent
platelet activator can subsequently enhance platelet aggregation. Furthermore, the
activated platelet mass produces plasminogen activator inhibitor (PAI)-1, a potent
inhibitor of fibrinolytics.
Thrombolysis and Angioplasty in Myocardial Infarction (TAMI)-8 (70 patients)
demonstrated an improved coronary patency and a reduction in recurrent ischemia
in patients treated with delayed abciximab after tPA as compared to tPA alone. In a
large multi-center trial (Global Use of Strategies to Open occluded arteries [GUS-
TO] V) 16588 patients with ST elevation myocardial infarction were randomized to
front loaded tPA or half-dose tPA and full dose abciximab. Combination therapy
resulted in an improved 90 minute coronary patency rate (80 vs 55%) but no differ-
ence in 30 day mortality [36].
Intervention
Systemic treatments to lyse or inhibit coronary thrombus will always suffer from a
trade-off between efficacy and hemorrhagic risk. A logical development in treating
flow-limiting thrombosis is to consider physical restoration of flow, with percuta-
neous intervention, or bypass grafting where this is not appropriate. Such an
approach may have the added advantage of addressing the underlying unstable pla-
que responsible for the thrombosis.
Intervention in Acute Coronary Syndromes without ST Elevation/New LBBB: Patients

with unstable syndromes without trans-mural infarction have a high rate of pro-
gression to full thickness myocardial infarction or death when treated with conven-
tional medical therapy. It might be expected that early intervention, with the aim
of treating the unstable plaque and associated thrombus might improve outcome.
The TIMI IIIB study [12] aimed to compare an early invasive strategy with a con-
servative strategy. The invasive group were randomized to undergo cardiac cathe-
terization within 48 hours with subsequent appropriate revascularization, the con-
servative group only following this strategy if driven by clinical need. There were
no significant differences at 6 weeks between the groups (invasive:conservative) for
death (2.4 vs 2.5o/o) or myocardial infarction (5.1 vs 5.7o/o). However, there was ex-
tensive cross-over from the conservative group to the invasive strategy with 64o/o
undergoing cardiac catheterization (90o/o of these pre-discharge). Consequently, the
difference in rates of revascularization during the study period were small, 61 o/o of
the invasive group were revascularized compared to 49o/o of the conservative group.
The subsequent Veterans Affairs Non-Q Wave Infarction Strategies in Hospital
(VANQWISH) study undertook a similar design in patients with non-q wave myo-
cardial infarction [37]. Differences in the combined end points of death and myo-
cardial infarction were non-significant between the two groups; but were higher in
the invasive group: 29.9 vs 26.9o/o conservative. Again there was a high cross over,
with 44o/o of the conservative group undergoing catheterization, with a relatively
small difference in rates of revascularization: 44o/o invasive vs 33o/o conservative.
There was a significant rate of mortality in the invasive group who underwent cor-
onary artery bypass grafting (CABG): 11.6o/o at 30 days, with zero 30 day mortality
in the invasive group undergoing percutaneous intervention.
Thus, the TIMI IIIB and VANQWISH trials did not show any benefit from inter-
vention in acute coronary syndrome, but were limited by high cross-over and, in
the case of VANQWISH, an unexpectedly high mortality associated with CABG.
The Fragmin and fast Revascularization during InStability in Coronary artery
disease (FRISC) 2 study randomized 2457 patients, with non-ST elevation acute cor-
onary syndromes, to invasive or conservative arms on similar lines [38]. It was
planned to revascularize the invasive group as appropriate within 7 days of rando-
mization. In contrast to the previous studies there was a significant difference in
revascularization rates: invasive group 71 o/o within 10 days of admission, 77o/o with-
in 6 months; cf. the conservative group 9 and 37o/o respectively. The primary end
point of death/myocardial infarction at 6 months was significantly lower in the in-
vasive group at 9.4 vs 12.1 o/o (p = 0.03) (Fig. 3). There was a significantly higher
stent deployment rate than in the previous two studies: 65o/o of percutaneous inter-
ventions, although abciximab use was low (approximately 10o/o of procedures). Pa-
tients revascularized with bypass grafting suffered a 30 day mortality of some 2o/o.
The low cross-over rate from the conservative to invasive arms in FRISC 2 al-
lowed a more accurate assessment of the strategies, compared to the VANQWISH
and TIMI IIIB trials. Furthermore, the manner in which the intervention was per-
formed (significant stent usage) and the low reported surgical mortality, are more
in keeping with observed medical practice. As such, the FRISC 2 study is felt to -be
more representative of current clinical practice.
400 J. F. Coutts et aI.
12.1%
12
~
:E 8
...
.c
0
"'
Q/
Months
Fig. 3. Results of FRISC 2 Trial. Significant and sustained improvement in combined end point (death or
myocardial infarction). Note that in the first few weeks after randomization, there appears to be a higher
event rate in the invasive group. Adapted from [38)
Myocardial infarction Death

4
%
12 %
10.1 % 3 2.9 %
8
2
. _,_ ... --- ,_,-- .
, ---------- ...
1.9 %
,
4 p = 0.45
,, --- - p = O.l
0
2 3 4 5 6 0 2 3 4 5 6
Months Months
Fig. 4. Results of FRISC 2 Trial. Breakdown of combined end-point into constituents. Early rise in com-
bined end point of the invasive group is due to peri-procedural myocardial infarction rather than mortal-
ity. Adapted from [38)
The greatest benefit from an invasive strategy was observed in high-risk pa-
tients, i.e., those over 65, with chest pain at rest, with ST segment depression, or
with positive troponin. In common with the majority of interventional trials, fe-
males were poorly represented {30% of the study population). Indeed subsequent
data analysis failed to show a benefit for an invasive strategy for females in the
FRISC 2 study [39].
It was noted in the FRISC 2 study that there was a transient excess of myocardial
infarction in the group treated invasively, as defined by cardiac enzyme rise, with-
out an associated increased mortality (Fig. 4). In the percutaneous intervention
group this might be expected as a result of instrumentation of the thrombotic pla-
Fig. S. Results of CAPTURE Trial. Use of abciximab reduces the rate of peri-procedural MI. Adapted from
[40)
que: disruption of the thrombus with the angioplasty wire and balloon may result
in distal embolization and subsequent myocardial necrosis. This might, in theory,
be reduced by more potent platelet inhibition prior to intervention.
The c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE)
trial demonstrated that peri-procedural enzyme rise could be reduced by use of
GPllb/llla inhibitors [40]. The study evaluated 1265 patients with unstable angina
who had failed to respond to conventional therapy and subsequently underwent
cardiac catheterization. Those in whom angioplasty was deemed appropriate were
randomized to receive abciximab or placebo for 18-24 hours prior to performing
the intervention and for one hour afterwards. There was a significant difference in
the combined end-point of death/myocardial infarction/need for urgent revasculari-
zation or intra-aortic counter-pulsation assist device of 11.3% abciximab, vs 15.9%,
placebo (p =0.012) at 30 days {Fig. 5). There has been a series of studies reporting
significant benefits from the adjunctive use of GPIIb/IIIa inhibitors prior to percu-
taneous intervention for unstable syndromes {Table 2).
A recurring theme from these studies is that the benefit from the GPIIb/IIIa in-
hibitor is most pronounced in cases where the troponin is raised. Elevation of se-
rum troponin is a highly sensitive marker of myocardial damage. An appealing ex-
planation is that troponin positivity is a marker of thrombus friability - such pa-
tients would be expected to develop benefit from pre-treatment of platelet aggre-
gates before intervention.
There is thus evidence supporting an invasive strategy in non-ST elevation acute
coronary syndromes, with further evidence to support the adjunctive use of GPIIb/
Ilia inhibitors. Given that there is some evidence to support the use of GPIIb/IIIa
inhibitors in the absence of intervention (e.g., the PURSUIT study - see under
GPIIb/IIIa inhibitors), the question remains as to whether intervention offers any
further benefit when these agents are used. This was addressed in the TIMI 18/
TACTICS study [41]. Two thousand two hundred and twenty patients with evidence
of an acute coronary syndrome without major epicardial vessel occlusion were all
treated with tirofiban. Patients were randomized to an invasive strategy aiming to
-1>-
0
N
Table 2. Trials of GPIIb/llla inhibitors for acute coronary syndromes undergoing intervention I ~
:-n
,..,
0
Name Agent No Endpoint Event Rate p

of patients (30 days)
Treatment arm Control II ~
•
I EPIC abciximab 489 Death/MI/need for IABP/ 4.8% 12.8% 0.012
stent/revascularization
s EPILOG abciximab 2792 Death/MI/need for urgent 5.2% 11.7% <0.05
revascularization
I CAPTURE abciximab 1265 Death/MI/need for IABP/ 11.3% 15.9% 0.012
I IMPAG2 eptifibatide 4010 Death/MI/need for 9.2% 11.4% 0.063
I RESTORE tirofiban 2139 Death/MI/need for stent/ 10.3% 12.2% 0.16
Revascularization
I PURSUIT eptifibatide 2628 Death/MI 10.2% 12.4% 0.24
I PARAGON lamifiban 306 Death/MI 6.8% 15.5%
I• PRISM tirofiban 1099 Death/MI/refractory 21.6% 27.3%
ischemia
I PRISM PLUS tirofiban 475 Death/MI/refractory 8.8% 15.3% (PCI sub-group)
ischemia
undergo catheterization within 48 hours with revascularization as appropriate or to

a conservative strategy with ischemia-driven revascularization. There was a signifi-
cant crossover with 61 o/o of the conservative undergoing catheterization vs 98o/o of
the invasive group. Nonetheless, there was a significant difference in primary out-
come of death/myocardial infarction/re-admission with ischemia at 6 months:
15.9% in the invasive group vs 19.4% conservative (p=0.025). The observed bene-
fits in reduction of recurrent ischemia supports the view that angioplasty, particu-
larly with stent insertion may help in stabilizing coronary plaques, in a manner
that is not available with pharmacological approaches to restore flow.
Patients who benefit most from an invasive strategy are those at greatest risk.
Factors suggesting a patient is at high risk include raised enzymes and troponin
(probably the most important marker), EKG changes, rest pain, impaired left ven-
tricular function, advanced age, and co-existing conditions - particularly diabetes.
Major Epicardial Vessel Occlusion: Given the evidence supporting a role for interven-
tion in non-ST segment elevation acute coronary syndromes, it might be thought
that a greater benefit would be seen in trans-mural infarctions since intervention
would be expected to give high rates of recanalization with a lower risk of hemor-
rhage than fibrinolysis. Evidence is accumulating to support primary angioplasty
as an optimal strategy for ST elevation myocardial infarction.
In the pre-stent era, Grines et al. randomized 395 patients presenting with ST
elevation myocardial infarction within 12 hours of onset of symptoms to receive
either tPA or primary angioplasty [42]. There was a significant improvement in the
combined end point of in-hospital death or re-infarction for primary angioplasty
compared to tPA: 5.1 vs 12o/o respectively (p = 0.02). There was a non-significant re-
duction in in-hospital mortality (2.6 vs 6.5%, p = 0.06).
In an angiographic study, Zilstra et al. [43] randomized 142 patients to receive
either primary angioplasty or streptokinase. Patients were included if they pre-
sented with ST elevation within 6 hours of onset of symptoms (or up to 24 hours if
there was evidence of ongoing ischemia). Repeat angiography was performed in 63
of the 65 patients who actually underwent angioplasty in the percutaneous trans-
luminal coronary angioplasty (PTCA) group at 82 ± 67 days, whilst angiography
was performed in 68 of the 72 patients in the streptokinase group at 21 ± 31 days.
The infarct related vessel was patent in 91 o/o of the angioplasty group vs 68o/o of the
streptokinase group (p < 0.001). The authors noted a significant reduction in re-in-
farction in the angioplasty group.
A long-term follow up (mean of 5 years), by the same authors, with 395 patients
demonstrated a sustained reduction in mortality after primary angioplasty as com-
pared to streptokinase: 13 vs 24o/o (relative risk 0.54 with 95o/o confidence limits
0.36-0.87) [44]. Registry data [45] suggests a significant survival benefit from primary
angioplasty compared to fibrinolysis, although clearly these are non-randomized data.
Pooled data [46] suggest an overall benefit from primary angioplasty as com-
pared to in hospital fibrinolysis, with improved survival and a lower risk of compli-
cations: the risk of stroke being 0.7% for percutaneous intervention vs 2.0o/o for
fibrinolysis (OR 0.35, 95o/o CI 0.14-0.77, p =0.007).
Some studies have failed to show any benefit from primary angioplasty however,
for example GUSTO lib [47], although it has been argued this was due to technical
difficulties in performing the angioplasty. The importance of high volume centers
performing primary angioplasty has been demonstrated, where it is found that
those centers performing large numbers have significantly better results [48].
Initial results from angioplasty with intra-coronary stent placement for ST eleva-
tion acute coronary syndromes have been disappointing. Although stents dramati-
cally reduce the risk of abrupt vessel closure, in the acute setting there appears to
be an increased rate of distal embolization. Thus, despite good target vessel patency
there can be low, or no, flow. It remains to be seen whether this will be improved
with adjunctive therapy with GPIIb/IIIa antagonists.
In cases where fibrinolysis is felt to pose an unacceptable risk from hemorrhagic
complications, there is clear evidence that primary angioplasty is of benefit [49].
Routine angioplasty after fibrinolysis has not been shown to improve outcome
[50]. However, the role of 'rescue' angioplasty where fibrinolysis is deemed to have
failed on clinical and/or electrocardiographic grounds remains unclear. In a non-
randomized study of a sub-group of TIMI 4 patients, there was no evidence to sup-
port a benefit in undertaking rescue angioplasty [51]. It is possible that with
improvements in percutaneous interventions, in particular the use of GPIIb/IIIa
inhibitors, that rescue angioplasty will be more successful in the future, this ques-
tion being addressed in the ongoing Rapid Early Action for Coronary Treatment
(REACT) and MERLIN trials.
Evidence is accumulating favoring primary angioplasty as a strategy once the
patient has been admitted to hospital. It is likely that with improved stent technol-
ogy, and with improved adjunctive antithrombotic therapy that the advantages of
primary angioplasty will become greater in magnitude and significance. However,
the logistic difficulties in delivering patients to an experienced high volume labora-
tory are likely to persist. As would be expected, the benefits of primary angioplasty
fall significantly with time from the onset of symptoms [52]. As such, in the major-
ity of cases fibrinolysis remains the treatment of choice due to the delay in reach-
ing specialist services. Pre-hospital fibrinolysis represents an alternative approach
and studies comparing pre-hospital thrombolysis with primary angioplasty are in
progress [53].
Treatment of the Disease Process/Secondary Prevention

Restoration of flow in acute coronary syndromes represents crisis management.
Myocardium at risk may be salvaged with revascularization, but the disease process
persists. Even if the unstable plaque is deemed to be treated and rendered stable
with stent implantation, coronary disease is a diffuse entity and attention must be
turned to addressing the disease process itself.
Lifestyle and Risk Factor Modification: Medical interventions are significantly less
likely to have a successful outcome with an adverse risk factor profile. The main
aims are smoking cessation [54], control of blood glucose and blood pressure [55],
and diet modification with appropriate weight reduction.
Statins: The use of statins to reduce low density lipoprotein and total cholesterol in
the secondary prevention of ischemic heart disease is well established, e.g., [156].
In addition to direct effects on cholesterol, statins also appear to have beneficial ef-
fects on plaque stabilization [57], in improving endothelial function [58] and in the
reduction of platelet aggregability [59]. Although statins have been prescribed
widely in acute coronary syndromes, evidence supporting their acute use has been
lacking until recently. The large secondary prevention trials generally excluded pa-
tients within 3-6 months of acute presentation through, it would now appear un-
founded, concerns of acute plaque destabilization on commencement of therapy.
The recently published Myocardial Ischemia Reduction with Aggressive Choles-
terol Lowering (MIRACL) trial [60] randomly assigned 3086 patients with non-ST
elevation acute coronary syndromes to receive either 80 mg atorvastatin daily or
placebo within 24-96 hours of admission for 16 weeks. There was a reduction in
the combined primary end point of death/myocardial infarction/cardiac arrest/read-
mission with recurrent ischemia in the treatment group: 14.8% atorvastatin vs
17.4% placebo (RR 0.84, 95% CI 0.70-0.10, p=0.048). This result was primarily due
to a reduction in the frequency of re-admission with objective evidence of isch-
emia. There were no serious complications associated with early statin therapy. As
the authors point out, the lack of a demonstrable mortality benefit might be ex-
pected given the short duration of the study. The study does, however, support the
clinical impression that early use of statin therapy is safe. Given the benefits seen
in previous studies, and the observation that patients started on statin therapy on
hospital discharge are likely to continue the drug long term [61], a strong case can
be made for commencement of therapy during the admission with an acute coro-
nary syndrome.
Beta Blockade: There is an extensive literature evaluating beta-blockade in acute

coronary syndromes. Beta-blockers can reduce myocardial oxygen demand by re-
ducing heart rate and contractility, whilst the longer diastolic period may promote
coronary flow. The reduction in rate of left ventricular systolic pressure develop-
ment may further reduce the risk of rupture of vulnerable plaques, by reducing the
rate of stress development on the fibrous cap.
In a systematic review of trials, Freemantle et al. [62] studied 82 randomized
trials involving 54234 patients where beta-blockers were evaluated post myocardial
infarction. There was clear evidence of a reduction in the risk of death in long term
treatment trials (RR 23%, 95% CI 15-31 %). The evidence was not so clear for short
term trials: up to 6 weeks treatment, where there was a 4% reduction in the risk of
death (95% CI -8 to 15%). There was no clear evidence that a uniform policy of
early intra-venous beta-blocker conferred a significant advantage.
There has been a degree of controversy as to the benefits of beta blockade in ST
elevation myocardial infarction post fibrinolysis. The ISIS 1 trial demonstrated a
significant reduction in mortality with intra-venous atenolol in the pre-fibrinolytic
era [63]. The TIMI liB trial however, demonstrated no difference in mortality
between early (initial dose intra-venous) metoprolol and late (5 days) metoprolol in
thrombolyzed patients with acute myocardial infarction, although there was a
reduction in early ischemia, re-infarction and serious arrhythmias [50]. Although
direct evidence is lacking there is a consensus that beta-blockade should be given
irrespective of fibrinolysis [62].
There are less extensive data for beta blockers in non-ST elevation acute coro-
nary syndromes. A meta-analysis by Yusuf et al. [64] suggested a 13% reduction in
the risk of myocardial infarction in treated patients.
In the absence of significant contraindications, beta-blockers should be consider-
ed for all patients with acute coronary syndromes. As with all therapies, there is
continued evidence of their underuse [65].
ACE Inhibition: Angiotensin-converting-enzyme (ACE) inhibitors block the activation

of the renin-angiotensin system, effectively reducing peripheral vascular resistance.
They have been extensively studied in the context of ST elevation acute coronary
syndromes with subsequent impairment of left ventricular function. There is evi-
dence of benefit in reducing adverse remodelling, enhancing left ventricular func-
tion and in improving survival [66].
Data from the large ACE inhibitor trials suggested a potential benefit in reducing
the risk of cardiovascular events [67], but this has not been universally accepted.
The Heart Outcomes Prevention Evaluation (HOPE) trial [68] evaluated the effects
of ramipril in 9297 patients who were not known to have significant left ventricular
impairment but had known, or significant risk factors for, ischemic heart disease
over a mean period of 5 years. There were significant reductions in the indepen-
dent risks of cardiovascular death, myocardial infarction and stroke in the ramipril
group.
Taken together, the evidence suggests that in addition to their role in improving
hemodynamics, ACE inhibitors are beneficial in reducing adverse vascular events.
As such, they should be considered in all cases of acute coronary syndromes.
Calcium Channel Blockers: Calcium channel blockers are in widespread use for the
treatment of stable angina. Their value in acute syndromes is less clear however.
Early reports found no evidence of a survival benefit when given for acute presen-
tations [64]. More recent studies with verapamil (Danish Verapamil Infarction Trial
[DAVIT] II) [69] suggest a survival benefit in patients post myocardial infarction
without evidence of heart failure, with similar results for diltiazem [70]. Given the
extensive evidence supporting beta-blockade in acute coronary syndromes, the role
of calcium channel blockers is viewed very much as a second best option and their
use should be reserved for patients with significant contra-indications to beta
blockade. In these patients, negatively chronotropic agents, e.g., diltiazem or vera-
pamil are preferred.
I Design of a Management Strategy

In all patients, treatments are given to relieve pain and support the circulation as
required. Morphine and diamorphine remain the agents of choice for analgesia. Va-
sodilation associated with opiate use has beneficial hemodynamic effects, and the
anxiolysis in many ways mimics the effects of beta blockade. Intra-venous nitrates
are in widespread use to promote vasodilation, reducing left ventricular work, and
to alleviate ischemia, but there is no evidence of a survival benefit associated with
their use in non-ST elevation acute coronary syndromes [71]. There is some evi-
dence suggesting a survival benefit in ST elevation acute coronary syndromes [72],
but this is based on the meta-analysis of data from the 1980s, and it is not clear
whether the addition of nitrates to current strategies has an objective benefit.
An approach to specific management is given in Fig. 6. Management requires an
assessment of the immediate risk the patient is exposed to, with subsequent selec-
tion of strategy. Disease modification needs to be considered in each case.
•
Admission with clinical Aspirin & clopidogrel
evidence of ACS Heparin (LMW}
Beta-blocker Low
.
Stratify Risk
•
Supportive measures and Higher
clinical assessments If include: I Observation I
Rest pain
No EKG changes r----=;' •
Evidence ST elevation or new
LBBB Ml < 12 hours Raised enzymes or Failure to settle Failure to settle I Resolution I
I
troponin with objective without objective
Hemoclynamic evidence evidence of
Instability ischemia or ischemia
Aspirin
Consideration of thrombolysis
Advanced age development of '-===-----'
or Post infarct angina high •
risk features
primary angioplasty
Beta blocker High. Non· invasive
assessment
Primary angioplasty relatively pethaps out-patient
favoured If: Early invasive strategy
Gpllblllla inhibitor, espescially Consider Statin &
Rapid access available ACE inhibitor
High risk (anterior Mil evidence if troponin +ve
pre-discharge
•
shock/ previous Ml) Cardiac catheterization and
•
appropriate revascularization • Risk factors
Contra-indication to ....
I_Po_si_tive
_ _,
thrombolysis
•
Statin & ACE inhibitor
pre-discharge Negative
Risk factors Statin & ACE inhibitor pre-discharge
Rsik factors
Question diagnosis
Medical therapy
Consider Statin & ACE
Inhibitor
Risk factors
Fig. 6. Proposed management algorithm for acute coronary syndromes (ACS). LBBB: Left bundle branch
block; Ml: myocardial infarction; LMW: low molecular weight; ACE: angiotensin converting enzyme
I The Future
The complex, multi-factorial processes underlying coronary thrombosis suggest that
optimal strategies will require a multifaceted approach: probably involving inter-
vention with a variety of adjunctive measures. The observation that thrombosis
may arise from at least two mechanisms: plaque rupture and plaque erosion further
muddies the water.
Hybrid schemes combining fibrinolysis and platelet antagonists with acute an-
gioplasty have shown some initial promise, and are being further evaluated in the
Controlled Abciximab and Device Investigation to Lower Late Angioplasty Compli-
cations (CADILLAC)-2 and Facilitated Intervention with Enhanced Reperfusion
Speed to Stop Events (FINESSE) trials. The challenge will be to define the exact
combination of strategies that give optimal results, and to establish how best to tai-
lor these approaches to each individual patient.
References
1. Zaman AG, Helft G, Worthley SG, Badimon JJ (2000) The role of plaque rupture and
thrombosis in coronary artery disease. Atherosclerosis 149:251-266
2. Richardson PD, Davies MJ, Born GV (1989) Influence of plaque configuration and stress
distribution on fissuring of coronary atherosclerotic plaques. Lancet 2:941-944
3. Cheng GC, Loree HM, Kamm RD, Fishbein MC, Lee RT (1993) Distribution of circumferen-
tial stress in ruptured and stable atherosclerotic lesions. A structural analysis with histo-
pathological correlation. Circulation 87:1179-1187
4. Rauch U, Osende Jl, Fuster V, Badimon JJ, Fayad Z, Chesebro JH (2001) Thrombus forma-
tion on atherosclerotic plaques: pathogenesis and clinical consequences. Ann Intern Med
134:224-238
5. Farb A, Burke AP, Tang AL, et al (1996) Coronary plaque erosion without rupture into a
lipid core. A frequent cause of coronary thrombosis in sudden coronary death. Circulation
93:1354-1363
6. Davies MJ, Bland JM, Hangartner JR, Angelini A, Thomas AC (1989) Factors influencing
the presence or absence of acute coronary artery thrombi in sudden ischaemic death. Eur
Heart J 10:203-208
7. Giroud D, Li JM, Urban P, Meier B, Rutishauer W (1992) Relation of the site of acute myo-
cardial infarction to the most severe coronary arterial stenosis at prior angiography. Am J
Cardiol 69:729-732
8. Fibrinolytic Therapy Trialists' (FIT) Collaborative Group (1994) Indications for fibrinolytic
therapy in suspected acute myocardial infarction: collaborative overview of early mortality
and major morbidity results from all randomised trials of more than 1000 patients. Lancet
343:311-322
9. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group (1988) Rando-
mised trial of intravenous streptokinase, oral aspirin, both, or neither among 17187 cases
of suspected acute myocardial infarction: ISIS-2. Lancet 2:349-360
10. Collins R, Peto R, Baigent C, Sleight P (1997) Aspirin, heparin, and fibrinolytic therapy in
suspected acute myocardial infarction. N Engl J Med 336:847-860
11. Spinier SA, Mikhail PA (1997) Prehospital-initiated thrombolysis. Ann Pharmacother 31:
1339-1346
12. Anonymous (1994) Effects of tissue plasminogen activator and a comparison of early inva-
sive and conservative strategies in unstable angina and non-Q-wave myocardial infarction.
Results of the TIM! IIIB Trial. Thrombolysis in Myocardial Ischemia. Circulation 89:1545-
1556
13. Theroux P, Ouimet H, McCans J, et al (1988) Aspirin, heparin, or both to treat acute un-
stable angina. N Engl J Med 319:1105-1111
14. Theroux P, Waters D, Qiu S, McCans J, de Guise P, Juneau M (1993) Aspirin versus heparin
to prevent myocardial infarction during the acute phase of unstable angina. Circulation
88:2045-2048
15. Theroux P, Waters D, Lam J, Juneau M, McCans J (1992) Reactivation of unstable angina
after the discontinuation of heparin. N Engl J Med 327:141-145
16. Antman EM, Fox KM (2000) Guidelines for the diagnosis and management of unstable an-
gina and non-Q-wave myocardial infarction: proposed revisions. International Cardiology
Forum. Am Heart J 139:461-475
17. Klein LW, Wahid F, Van den Berg BJ, Parrillo JE, Calvin JE (1997) Comparison of heparin
therapy for < or= 48 hours to >48 hours in unstable angina pectoris. Am J Cardiol 79:
259-263
18. Hirsh J, Fuster V (1994) Guide to anticoagulant therapy. Part 1: Heparin. American Heart
Association. Circulation 89: 1449-1468
19. Hirsh J, Levine MN (1992) Low molecular weight heparin. Blood 79:1-17
20. Weitz Jl (1997) Low-molecular-weight heparins. N Engl J Med 337:688-698
21. Klein W, Buchwald A, Hillis SE, et al (1997) Comparison of low-molecular-weight heparin
with unfractionated heparin acutely and with placebo for 6 weeks in the management of
unstable coronary artery disease. Fragmin in unstable coronary artery disease study
(FRIC). Circulation 96:61-68
22. Cohen M, Demers C, Gurfinkel EP, et al (1997) A comparison of low-molecular-weight
heparin with unfractionated heparin for unstable coronary artery disease. Efficacy and
Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group. N Engl
J Med 337:447-452
23. Antman EM, McCabe CH, Gurfinkel EP, et al (1999} Enoxaparin prevents death and cardiac
ischemic events in unstable anginalnon-Q-wave myocardial infarction. Results of the
thrombolysis in myocardial infarction (TIMI) llB trial. Circulation 100:1593-1601
24. Organisation to Assess Strategies for Ischemic Syndromes (OASIS-2} Investigators (1999}
Effects of recombinant hirudin (lepirudin) compared with heparin on death, myocardial
infarction, refractory angina, and revascularisation procedures in patients with acute myo-
cardial ischaemia without ST elevation: a randomised trial. Lancet 353:429-438
25. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) lib investiga-
tors (1996) A comparison of recombinant hirudin with heparin for the treatment of acute
coronary syndromes. N Engl J Med 335: 775-782
26. Antman EM, Braunwald E (2001} A second look at bivalirudin. Am Heart J 142:929-931
27. Smith P, Arnesen H, Holme I (1990} The effect of warfarin on mortality and reinfarction
after myocardial infarction. N Engl J Med 323:147-152
28. Cohen M, Adams PC, Parry G, et al (1994} Combination antithrombotic therapy in un-
stable rest angina and non-Q-wave infarction in nonprior aspirin users. Primary end
points analysis from the ATACS trial. Antithrombotic Therapy in Acute Coronary Syn-
dromes Research Group. Circulation 89:81-88
29. Anand SS, Yusuf S, Pogue J, Weitz Jl, Flather M (1998} Long-term oral anticoagulant ther-
apy in patients with unstable angina or suspected non-Q-wave myocardial infarction: orga-
nization to assess strategies for ischemic syndromes (OASIS) pilot study results. Circula-
tion 98:1064-1070
30. CAPRIE Steering Committee (1996} A randomised, blinded, trial of clopidogrel versus
aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 348:1329-1339
31. Cairns JA, Gent M, Singer J, et al (1985} Aspirin, sulfinpyrazone, or both in unstable angi-
na. Results of a Canadian multicenter trial. N Engl J Med 313:1369-1375
32. Balsano F, Rizzon P, Violi F, et al (1990} Antiplatelet treatment with ticlopidine in unstable
angina. A controlled multicenter clinical trial. The Studio della Ticlopidina nell'Angina In-
stabile Group. Circulation 82:17-26
33. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK (2001) Effects of clopidogrel
in addition to aspirin in patients with acute coronary syndromes without ST-segment ele-
vation. N Engl J Med 345:494-502
34. The PURSUIT Trial Investigators (1998) Inhibition of platelet glycoprotein lib/Ilia with
eptifibatide in patients with acute coronary syndromes. Platelet Glycoprotein lib/Ilia in
Unstable Angina: Receptor Suppression Using Integrilin Therapy. N Engl J Med 339:436-
443
35. The PARAGON Investigators (1998} International, randomized, controlled trial of lamifiban
(a platelet glycoprotein lib/Ilia inhibitor}, heparin, or both in unstable angina. Platelet lib/
Ilia Antagonism for the Reduction of Acute coronary syndrome events in a Global Organi-
zation Network. Circulation 97:2386-2395
36. Topol EJ (2001} Reperfusion therapy for acute myocardial infarction with fibrinolytic ther-
apy or combination reduced fibrinolytic therapy and platelet glycoprotein lib/Ilia inhibi-
tion: the GUSTO V randomised trial. Lancet 357:1905-1914
37. Boden WE, O'Rourke RA, Crawford MH, et al (1998) Outcomes in patients with acute non-
Q-wave myocardial infarction randomly assigned to an invasive as compared with a con-
servative management strategy. Veterans Affairs Non-Q-Wave Infarction Strategies in Hos-
pital (VANQWISH) Trial Investigators. N Engl J Med 338:1785-1792
38. Fragmin and Fast Revascularisation during InStability in Coronary artery disease Investi-
gators (1999} Invasive compared with non-invasive treatment in unstable coronary-artery
disease: FRISC II prospective randomised multicentre study. Lancet 354:708-715
39. Lagerqvist B, Safstrom K, Stahle E, Wallentin L, Swahn E (2001} Is early invasive treatment
of unstable coronary artery disease equally effective for both women and men? FRISC II
Study Group Investigators. JAm Coli Cardiol 38:41-48
40. Anonymous (1997) Randomised placebo-controlled trial of abciximab before and during
coronary intervention in refractory unstable angina: the CAPTURE Study. Lancet 349:
1429-1435
41. Cannon CP, Weintraub WS, Demopoulos LA, et al {2001) Comparison of early invasive and
conservative strategies in patients with unstable coronary syndromes treated with the gly-
coprotein lib/Ilia inhibitor tirofiban. N Engl J Med 344:1879-1887
42. Grines CL, Browne KF, Marco J, et al {1993) A comparison of immediate angioplasty with
thrombolytic therapy for acute myocardial infarction. The Primary Angioplasty in Myocar-
dial Infarction Study Group. N Engl J Med 328:673-679
43. Zijlstra F, de Boer MJ, Hoorntje JC, Reiffers S, Reiber JH, Suryapranata H {1993) A com-
parison of immediate coronary angioplasty with intravenous streptokinase in acute myo-
cardial infarction. N Engl J Med 328:680-684
44. Zijlstra F, Hoorntje JC, de Boer MJ, et al {1999) Long-term benefit of primary angioplasty
as compared with thrombolytic therapy for acute myocardial infarction. N Engl J Med
341:1413-1419
45. Zahn R, Schiele R, SchneiderS, et al (2001) Primary angioplasty versus intravenous throm-
bolysis in acute myocardial infarction: can we define subgroups of patients benefiting most
from primary angioplasty? Results from the pooled data of the Maximal Individual Ther-
apy in Acute Myocardial Infarction Registry and the Myocardial Infarction Registry. J Am
Coll Cardiol 37:1827-1835
46. Yusuf S, Pogue J {1997) Primary angioplasty compared with thrombolytic therapy for acute
myocardial infarction. JAMA 278:2110-2111
47. The Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syn-
dromes (GUSTO lib) Angioplasty Substudy Investigators (1997) A clinical trial comparing
primary coronary angioplasty with tissue plasminogen activator for acute myocardial in-
farction. N Engl J Med 336:1621-1628
48. Magid DJ, Calonge BN, Rumsfeld JS, et al {2000) Relation between hospital primary angio-
plasty volume and mortality for patients with acute MI treated with primary angioplasty
vs thrombolytic therapy. JAMA 284:3131-3138
49. McCullough PA, O'Neill WW, Graham M, et al {1998) A prospective randomized trial of
triage angiography in acute coronary syndromes ineligible for thrombolytic therapy.
Results of the medicine versus angiography in thrombolytic exclusion (MATE) trial. J Am
Coll Cardiol 32:596-605
50. The TIMI Study Group {1989) Comparison of invasive and conservative strategies after
treatment with intravenous tissue plasminogen activator in acute myocardial infarction.
Results of the thrombolysis in myocardial infarction (TIMI) phase II trial. N Engl J Med
320:618-627
51. Gibson CM, Cannon CP, Greene RM, et al {1997) Rescue angioplasty in the thrombolysis
in myocardial infarction (TIMI) 4 trial. Am J Cardiol80:21-26
52. Cannon CP, Gibson CM, Lambrew CT, et al {2000) Relationship of symptom-onset-to-bal-
loon time and door-to-balloon time with mortality in patients undergoing angioplasty for
acute myocardial infarction. JAMA 283:2941-2947
53. Touboul P, Bonnefoy E {1998) [Comparison of primary angioplasty and prehospital throm-
bolysis in the acute phase of myocardial infarction. CAPTIM Study Group]. Arch Mal
Coeur Vaiss 91 Spec No 2:33-38
54. Jonas MA, Oates JA, Ockene JK, Hennekens CH {1992) Statement on smoking and cardio-
vascular disease for health care professionals. American Heart Association. Circulation
86:1664-1669
55. Hansson L, Zanchetti A, Carruthers SG, et al {1998) Effects of intensive blood-pressure
lowering and low-dose aspirin in patients with hypertension: principal results of the
Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet
351:1755-1762
56. Anonymous {1994) Randornised trial of cholesterol lowering in 4444 patients with coron-
ary heart disease: the Scandinavian Simvastatin Survival Study {4S). Lancet 344:1383-1389
57. Vaughan CJ, Murphy MB, Buckley BM {1996) Statins do more than just lower cholesterol.
Lancet 348:1079-1082
58. O'Driscoll G, Green D, Taylor RR (1997) Simvastatin, an HMG-coenzyme A reductase inhi-
bitor, improves endothelial function within 1 month. Circulation 95:1126-1131
59. Notarbartolo A, Davi G, Averna M, et a! (1995) Inhibition of thromboxane biosynthesis

and platelet function by simvastatin in type IIa hypercholesterolemia. Arterioscler Thromb
Vase Bioi 15:247-251
60. Schwartz GG, Olsson AG, Ezekowitz MD, eta! (2001) Effects of atorvastatin on early recur-
rent ischemic events in acute coronary syndromes: the MIRACL study: a randomized con-
trolled trial. JAMA 285:1711-1718
61. Fonarow GC, Gawlinski A, Moughrabi S, Tillisch JH (2001) Improved treatment of coronary
heart disease by implementation of a Cardiac Hospitalization Atherosclerosis Management
Program (CHAMP). Am J Cardiol 87:819-822
62. Freemantle N, Cleland J, Young P, Mason J, Harrison J (1999) beta Blockade after myocar-
dial infarction: systematic review and meta regression analysis. Br Med J 318: 1730-173 7
63. First International Study of Infarct Survival Collaborative Group (1986) Randomised trial
of intravenous atenolol among 16027 cases of suspected acute myocardial infarction:
ISIS-I. Lancet 2:57-66
64. Yusuf S, Wittes J, Friedman L (1988) Overview of results of randomized clinical trials in
heart disease. II. Unstable angina, heart failure, primary prevention with aspirin, and risk
factor modification. JAMA 260:2259-2263
65. Krumholz HM, Radford MJ, Wang Y, Chen J, Marciniak TA (1999) Early beta-blocker ther-
apy for acute myocardial infarction in elderly patients. Ann Intern Med 131:648-654
66. Latini R, Maggioni AP, Flather M, Sleight P, Tognoni G (1995) ACE inhibitor use in pa-
tients with myocardial infarction. Summary of evidence from clinical trials. Circulation
92:3132-3137
67. Lonn EM, Yusuf S, Jha P, et a! (1994) Emerging role of angiotensin-converting enzyme in-
hibitors in cardiac and vascular protection. Circulation 90:2056-2069
68. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G (2000) Effects of an angiotensin-
converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The
Heart Outcomes Prevention Evaluation Study Investigators. N Eng! J Med 342:145-153
69. Anonymous (1990) Effect of verapamil on mortality and major events after acute myocar-
dial infarction (the Danish Verapamil Infarction Trial II-DAVIT II). Am J Cardiol 66:779-
785
70. The Multicenter Diltiazem Postinfarction Trial Research Group (1988) The effect of diltia-
zem on mortality and reinfarction after myocardial infarction. N Engl J Med 319:385-392
71. Thadani U, Opie LH (1994) Nitrates for unstable angina. Cardiovasc Drugs Ther 8:719-726
72. Yusuf S, Collins R, MacMahon S, Peto R (1988) Effect of intravenous nitrates on mortality
in acute myocardial infarction: an overview of the randomised trials. Lancet 1:1088-1092
Pre-Hospital Reperfusion Strategies
to Optimize Outcomes in Acute Myocardial Infarction
P. Goldstein
I Introduction
The management of acute myocardial infarction (AMI) has improved dramatically
in recent years, with significant reductions in mortality. However, the 1-month
mortality rate following AMI remains 10-50%, with the majority of these deaths
occurring in the first hours after onset of pain [1, 2]. Data from a German registry
in the MONitor trends in CArdiovascular diseases {MONICA) project show that, of
the patients with AMI who die, 28% die within 1 hour of symptom onset, 38% die
within 4 hours, and 46% within the first 24 hours [3].
Thrombolytic therapy has consistently been shown to reduce both short- and
long-term mortality by approximately 20-25% compared with other conservative
treatments in patients with acute or evolving myocardial infarction, and has be-
come standard therapy for patients suffering an AMI [4]. Time is of the essence in
the early management of AMI, and although thrombolytic therapy improves out-
comes up to 12 hours after the onset of pain, its benefit is greatest in the first 1-2
hours [5, 6]. In this 'golden hour', the majority of damage to the myocardium is re-
versible but the percentage of salvageable myocardium decreases rapidly. Reperfu-
sion therapy should be initiated as early as possible to prevent necrosis, preserve
ventricular function and reduce morbidity and mortality. Guidelines from the Euro-
pean Society of Cardiology for the management of patients with AMI therefore re-
commend an interval of no more than 90 minutes between the onset of symptoms
and the initiation of thrombolytic therapy [2]. However, this target is proving hard
to attain, and much attention has been focused on reducing delays in treatment -
both through patient education and by optimizing the management of emergency
care services.
To date, the most successful strategies to reduce the time-to-treatment have been
those that improve pre-hospital management. Ambulance and emergency depart-
ment personnel have a key role to play in the diagnosis of AMI and the early initia-
tion of thrombolysis, in addition to the administration of other necessary treat-
ments, including pain relief and conjunctive reperfusion therapy such as aspirin
and heparin-based anticoagulants.
I The Importance of Early Reperfusion

A meta-analysis of 22 trials on thrombolytic therapy highlighted the relationship
between the delay before treatment and its subsequent benefit (Fig. 1) [5]. Early ad-
ministration of thrombolytic therapy, ideally at the pre-hospital stage, can signifi-
Pre-Hospital Reperfusion Strategies to Optimize Outcomes in Acute Myocardial Infarction 413
Time to Fibrinolytic Control/placebo

treatment (h) better better
0-1
~1-2
•
~2-3
~3-6
~6-12
--- ''
'
-------+--
'
''
~ 12-24
0.5 1.0 1.5

Odds ratio
Fig. 1. The effect of the time elapsed before thrombolytic treatment on mortality, based on a meta-anal-
ysis of 22 trials comparing thrombolytic therapy and placebo/controls. Odds ratios, plotted with 95% con-
fidence interval on a log scale, are significantly different over the six groups (Breslow-Day test, p = 0.001 ).
Areas of black squares proportional to amount of statistical information. Reproduced from (S] with per-
mission
cantly reduce mortality compared with in-hospital treatment [7). Programs such as
the National Heart, Lung, and Blood Institute's National Heart Attack Alert Pro-
gram recommend a decrease of 'door-to-drug' time [8]. However, despite increased
awareness of the importance of rapid reperfusion, the average delay between the
onset of symptoms and initiation of treatment has not changed significantly over
the past decade. In 1993, the Global Use of Strategies To Open occluded coronary
arteries (GUSTO) I trial highlighted an interval of 2.8 hours between the onset of
symptoms and start of therapy. The GUSTO III trial in 1995-1997, showed that this
interval had been reduced to 2.3 hours, mainly because of the reduced in-hospital
time. Although in-hospital time-to-treatment has decreased, the time to hospital
arrival has not changed, averaging 84 minutes [9, 10]. Patients who are elderly,
female, diabetic, or hypertensive are likely to experience the greatest pre-hospital
delays [9).
Reducing the time before initiation of treatment prevents damage to the myocar-
dium, improves left ventricular function, reduces the incidence of ventricular ar-
rhythmia and optimizes the management of patients suffering an AMI. Optimal
outcomes are achieved when the patency of the occluded vessel can be re-estab-
lished early, and then sustained. There appears to be a strong correlation between
increasing rates of Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow and
reduced mortality (Fig. 2; p<O.OOOOl) [11). In patients who achieve TIMI 3 flow
rates at 90 minutes, the 30-42-day mortality rate is reduced by one-third compared
with that of patients with more occluded arteries [11].
Pre-hospital initiation of thrombolytic therapy in patients with AMI by emer-
gency care teams or mobile intensive care unit(s) (ICUs) has been shown to be fea-
sible, safe and beneficial. Several large, controlled trials have evaluated the effects
of early, pre-hospital thrombolysis [12-15]. In the US Myocardial Infarction Triage
and Intervention Trial (MITI), the initiation of pre-hospital thrombolytic treatment
reduced the time-to-treatment by 33 minutes (from 110 minutes to 77 minutes)
414 P. Goldstein
12
.TIM!
10
0GUSTO
l 0TAMI
• German
.~ 8
-;;;
t::
0
E 6 Total number of
>. patients =4 281
"''
-o
4
"'
<t
I
...,
0
2 Number of
- patients
0
TIMI 0/1 TIMI2 TIMI3
Infarct-related artery flow grade at 90 min
Fig. 2. The relationship between 90-minute reperfusion (TIMI 3 flow) and mortality. There appears to be
a strong correlation between increasing rates of Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow
and reduced mortality (p<O.OOOOl). Reproduced from [11] with permission
[13]. In the European Myocardial Infarction Project (EMIP), patients assigned to

pre-hospital treatment received thrombolytic therapy an average of 55 minutes ear-
lier than those treated in hospital [12]. Importantly, the Grampian Region Early An-
istreplase Trial (GREAT), undertaken in a rural area of Scotland, indicates that time
savings of more than 2 hours can be made in non-metropolitan regions (an average
of 135 minutes were saved by pre-hospital treatment in GREAT) [14].
The combined data from these controlled clinical trials suggest that a strategy of
pre-hospital intervention can save, on average, 1 hour of time-to-treatment in the
vital first 3 hours following AMI, equating to 21 lives saved per 1000 patients
treated [5]. A separate meta-analysis has recently confirmed that pre-hospital
thrombolysis can save approximately an hour between the onset of pain and treat-
ment, and reduces the relative risk of all-cause hospital mortality by 17%, equating
to an absolute risk reduction of 2% [7].
I Pre-Hospital Management of Thrombolysis: Diagnosis
Rapid and accurate diagnosis is pivotal to the emergency care of a patient with sus-
pected AMI, and is a critical step in any pre-hospital management strategy. The
electrocardiogram (EKG) is a necessary prerequisite in screening patients with
chest pain. Moreover, the development of portable, battery-operated EKG machines
with computer-assisted interpretation facilities and the capability of transmitting
recordings back to the hospital base via telephone links has increased the utility of
the EKG as a diagnostic tool in emergency situations.
If an AMI is suspected, it is recommended that the emergency physician, para-
medic or general practitioner obtain a standard 12-lead EKG as soon as possible on
attending the patient [2]. Even at an early stage in an evolving myocardial infarc-
tion, the EKG reading is seldom normal, and a timely EKG can facilitate treatment
by identifying patients with true ischemic syndromes. A 17-lead EKG may be pre-
ferred however, as a standard 12-lead EKG does not include posterior leads and di-
agnosis of posterior myocardial infarction is often missed (16]. In addition, the 12-
lead EKG is not a particularly sensitive indicator of right ventricular damage, and
consequently right ventricular infarction is often overlooked. If a physician is on
hand, the diagnosis of AMI or myocardial ischemia can be confirmed rapidly. If no
physician is present, the emergency care team should record an EKG and transmit
it back to base for confirmation of diagnosis and treatment authorization. With a
confirmed diagnosis and no absolute contraindications, thrombolytic therapy can
be initiated without delay. Contraindications to thrombolytic treatment are shown
in Table 1 (2, 17].
The accuracy of pre-hospital diagnosis has been shown to be comparable with
that documented in trials of in-hospital thrombolysis. The results of MITI have
confirmed the feasibility of obtaining an accurate diagnostic EKG in the ambulance
or pre-hospital emergency setting (18]. In this trial, paramedics using a diagnostic
checklist screened all patients with chest pain. A computer-interpreted EKG was
then recorded and transmitted back to the hospital emergency department, where
an emergency physician made the treatment decision. In GREAT, where UK general
practitioners made the initial diagnosis, 98% of patients were found to have evi-
dence of AMI (14]. In Germany, Linderer et al. (15] reported a similar level of diag-
nostic accuracy, with no complications or deaths outside the hospital setting. In
EMIP, the largest trial of pre-hospital thrombolysis to date, 90% of diagnoses were
proved accurate (12].
Cardiac markers have potential for use as pre-hospital diagnostic tools in combi-
nation with the standard EKG. Serial sampling for early biological markers such as
MB subforms of creatinine kinase (CK-MB), myoglobin, troponin I, and troponin T
can provide reliable support for a diagnosis of AMI, and identify an additional
Table 1 . Contraindications to thrombolytic treatment [2, 17)
Absolute contraindications
Active internal bleeding
Suspected aortic dissection
Cancer
Stroke (or other cerebrovascular disorder) in the past year
Recent trauma or head injury (within 2-4 weeks)
Recent major surgery (< 3 weeks)
Known coagulation disorders or an international normalized ratio > 2-3
Relative contraindications
Severe hypertension (> 180/110) on presentation
Previous severe hypertension
History of stroke or other intracranial disease
Recent hemorrhage (within 2-4 weeks)
Pregnancy
Coumadin or warfarin therapy
Traumatic resuscitation
Allergy to, or previous administration of, streptokinase (in which case, the thrombolytic must be a
tissue-plasminogen activator)
Recent retinal laser treatment
Noncompressible punctures
416 P. Goldstein
small number of patients with acute coronary ischemia who are not identified by
the EKG [19-23]. Screening for a combination of biological markers provides the
most sensitive method for the early detection of AMI; myoglobin and either CK-
MB or troponin T, or a combination of CK-MB and troponin I appear to be effec-
tive measurements [19-21]. However, to provide qualitative 'bedside' diagnosis in
the ambulance or in the patient's home, these assays must be portable and widely
available, with rapid turnaround times (<20 minutes).
I Reducing Time-to-treatment: The French SAMU Experience

It is clear that in the early management of acute ischemic syndromes, saving time
saves lives, and several large studies have unequivocally shown that pre-hospital di-
agnosis and initiation of thrombolysis is feasible and safe. How practical is such a
strategy? The French Service d'Aide Medicale d'Urgence (SAMU), an emergency
dispatching center, offers a good example of pre-hospital management of AMI.
SAMU departments centralize and triage all emergency cases, and organize rapid
responses to ensure minimum treatment delays. If AMI is suspected, a mobile ICU
can be dispatched. The team on this unit is capable of confirming a diagnosis of
AMI or ischemic syndrome and initiating thrombolysis, in addition to any other
necessary treatment. Complications such as arrhythmias and cardiogenic shock can
also be treated in the mobile ICU.
Data on pre-hospital management of AMI from the Evaluation des Strategies
Therapeutiques dans l'Infarctus du Myocarde en phase aigiie (ESTIM) ile-de-France
registry have recently been reported [24, 25]. The registry covers a region compris-
ing 11 million inhabitants, 8 SAMU units and 75 SMUR (a French mobile ICU,
always with a physician in attendance). Information on all aspects of the time
sequence between the onset of symptoms, the time and type of patient call for
medical assistance, and the time-to-treatment in patients with a suspected AMI
have been collected. To date, the delay between the onset of pain and the call for
medical assistance was < 2 hours in over half of all cases, allowing the SAMU team
to take advantage of the therapeutic window for maximum thrombolytic benefit. In
the ESTIM registry, SAMU dispatched SMUR teams to confirm the patients' diag-
noses of AMI or ischemic syndromes, and patients were then either assigned to
pre-hospital thrombolysis or to primary angioplasty. The average time for the
SMUR to reach the patient was 19 minutes, and average time before the initiation
of thrombolytic therapy by the SMUR team was 37 minutes. Importantly, treatment
was started 1 hour and 25 minutes earlier in patients who received pre-hospital
thrombolysis than in those who underwent percutaneous coronary intervention
(PCI) [24].
I Optimizing Thrombolytic Therapy for Pre-hospital Administration

Until recently, the gold-standard thrombolytic regimen was the fibrin-specific agent,
alteplase (tPA), 100 mg, given as a front-loaded intravenous infusion over 90 min-
utes. This regimen offers proven efficacy, restoring patency in the infarcted artery
90 minutes after treatment in 60% of patients [26-28]. However, an accelerated in-
fusion of tPA is difficult to administer in a pre-hospital setting because intravenous
Table 2. Pharmacological and clinical characteristics of an ideal thrombolytic agent for pre-hospital use.
Adapted from [10) with permission
Pharmacological characteristics Clinical characteristics
Extended half-life (> 15 min) Single bolus administration

Increased fibrin specificity Easy to calculate dosing schedule
Increased lytic potency Good efficacy (rapid and complete reperfusion)
Resistance to inactivation by PAl-1 Low rate of reocclusion
Low prothrombotic potential Low risk of bleeding complications
Few or no procoagulation effects
PAI-1 : plasminogen activator inhibitor-1
lines must be set up and concomitant therapy with unfractionated (UF) heparin is
required. By contrast, the ideal thrombolytic agent for use in the MICU should be
simple to administer, preferably in a single bolus administration, have an easy-to-
calculate weight-adjusted dosing schedule, and offer improved safety (which is at-
tainable with weight-adjusted dosing), i.e., fewer bleeding complications, no antige-
nicity and resistance to inactivation by plasminogen activator inhibitor-! (PAI-l,
Table 2).
Genetic engineering has been used to overcome some of the limitations of tPA.
Reteplase, a bioengineered deletion mutant of tPA, has a longer half-life and can be
given as a double bolus [29]. However, the fibrin specificity of reteplase appears to
have been reduced by the modifications to the molecule. In the GUSTO III trial, re-
teplase failed to demonstrate equivalence or to demonstrate any advantages (other
than ease of administration) over alteplase in safety or efficacy [30]. Tenecteplase is
a triple-combination mutant of tPA, which offers a longer half-life, better fibrin
specificity and a higher resistance to inactivation by PAI-l than tPA [31]. Tenecte-
plase is administered as a weight-adjusted 5-10 second bolus injection. Importantly,
these features of tenecteplase have translated into proven clinical benefits: the re-
sults of the TIMI lOA and lOB trials and the Assessment of the Safety of a New
Thrombolytic-! (ASSENT-I) study have shown that bolus administration of tenec-
Table 3. Comparison of the pharmacological characteristics of selected thrombolytic agents. Adapted from
[10) with permission
tPA Tenecteplase Reteplase Streptokinase
Administration Accelerated infusion Single bolus Double bolus Infusion

(30 min spacing)
Half-life 4-6 min 20 min 18 min 23 min
Fibrin-specificity (tPA is the >t-PA <t-PA No
comparator)
Antigenicity No No No Yes
Resistance to PAI-1 No Yes Unknown No
inactivation
t-PA: tissue plasminogen activator; PAI-1: plasminogen activator inhibitor-1

418 P. Goldstein
teplase is likely to be of similar efficacy and safety as a front-loaded regimen of al-

teplase [32-34].
The ASSENT-2 trial confirmed the equivalence of bolus tenecteplase and acceler-
ated alteplase, and found that tenecteplase was associated with a reduction in the
incidence of major non-intracranial bleeding and blood transfusions [35, 36].
Furthermore, convenient single bolus administration saves valuable minutes by re-
ducing drug preparation time, and minimizes the likelihood of dosing errors [37].
Thus, tenecteplase, given as a convenient bolus dose, simplifies and reduces the
time taken to administer treatment and represents the new gold standard for pre-
hospital thrombolysis. The pharmacological characteristics of tenecteplase and the
other thrombolytic agents are summarized in Table 3.
Conjunctive Reperfusion Therapy
Paradoxically, lysis of an occluding clot has a prothrombotic effect. Rupture of the

plaque releases a pool of trapped thrombin and exposes tissue factor, surface-
bound von Willebrand factor and collagen (type I and III), which activate the in-
trinsic and extrinsic coagulation cascades. Optimal reperfusion treatment therefore
requires several components including antiplatelet and anticoagulant agents, in ad-
dition to a fibrinolytic drug, in order to prevent rethrombosis.
Oral aspirin is now widely accepted as standard antiplatelet treatment for pa-
tients suffering AMI. The second International Study of Infarct Survival (ISIS-2)
demonstrated that aspirin, 162.5 mg daily, reduced mortality after AMI by 21 o/o and
halved the 30-day risk of reinfarction and stroke [38]. These benefits were found to
persist for several years. Although the proven clinical benefits of aspirin have led to
its recommendation in current treatment guidelines, there is evidence that it is un-
derused as a first-line drug by family practitioners and emergency services [2, 38-
42].
Antithrombotic agents are also an important component of pharmacological re-
perfusion therapy. The addition of an anticoagulant such as UFH to the antiplatelet
and fibrinolytic regimen yields further improvements in outcomes, and is a com-
mon standard of care in many hospitals [43-45]. However, weight-adjusted UFH
has not been shown to improve outcomes in patients with AMI receiving streptoki-
nase as a thrombolytic agent, and is not currently recommended in this patient
group [26].
Low-molecular-weight (LMW) heparin(s), such as enoxaparin, have several
advantages over weight-adjusted UF heparin as adjuncts to thrombolysis (Table 4)
[46]. LMW heparin have a greater anti-Factor Xa:Ila ratio than UF heparin and of-
fer a more stable and predictable anticoagulant effect, obviating the need for moni-
toring [46]. Clinical studies comparing LMW heparin and UF heparin as adjuncts
to thrombolysis in AMI are few, but the data have shown reduced reocclusion and
reinfarction rates and improved patency of the infarcted vessel [45, 47, 48].
Despite the similarity of their molecular structure, LMW heparin differ in their
pharmacokinetics, pharmacodynamics and efficacy. To date, enoxaparin is the only
LMW heparin to have consistently demonstrated sustained benefits over UF hepa-
rin in clinical outcomes in the management of acute coronary syndromes (ACS), in-
cluding AMI, with no increase in the risk of bleeding [45, 46, 49-53]. Of particular
relevance to the pre-hospital environment, enoxaparin can be given as a convenient
Table 4. Advantages of low-molecular-weight heparins over unfractionated heparin in the management

of acute coronary syndromes [46]
Longer half-life, allowing once- or twice-daily subcutaneous dosing

Higher bioavailability
Greater anti-Factor Xa:lla activity
Predictable and stable anticoagulant effect (laboratory monitoring not required)
Resistance to inactivation by plasma proteins (e.g., von Willebrand factor)
Not inactivated by platelets (can bind platelet-bound Factor Xa)
less potential to cause heparin-induced thrombocytopenia
Fewer bleeding complications
subcutaneous injection, carries no requirement for monitoring in most patients,

and has a lower risk of adverse effects, such as major hemorrhage, than UF heparin
[53]. In addition, enoxaparin has been shown to provide protection by reducing
the release of von Willebrand factor, the early increase of which has been shown to
be associated with adverse clinical outcomes [54, 55].
The glycoprotein (GP) IIb/IIIa inhibitors are also under consideration as part of
the optimal reperfusion regimen in the emergency setting. It has been hypothesized
that the combination of early administration of GP IIb/IIIa inhibitors with primary
angioplasty may improve outcomes compared with angioplasty alone. The Abcixi-
mab before Direct angioplasty and stenting in Myocardial Infarction Regarding
Acute and Long-term follow-up (ADMIRAL) study has suggested that pre-hospital
administration of abciximab may be possible for patients with AMI who are re-
ferred for primary stenting [56].
Conjunctive pharmacological reperfusion therapy has recently been studied in a
large-scale trial comparing the efficacy and safety of several treatment regimens.
The ASSENT-3 trial evaluated tenecteplase and enoxaparin, half-dose tenecteplase,
abciximab and weight-adjusted UF heparin, and tenecteplase and weight-adjusted
UF heparin in patients with AMI [53]. The ASSENT-3 investigators found that the
combinations of tenecteplase plus enoxaparin, and reduced-dose tenecteplase plus
abciximab both reduced the incidence of ischemic complications compared with
UF heparin ( 11.4 and 11.1% for the enoxaparin and abciximab groups, compared
with 15.4% for UF heparin; p=0.0001), but there was an increase in bleeding com-
plications in the abciximab group. The incidences of the combined efficacy and
safety endpoint (a composite of 30-day mortality, in-hospital reinfarction or in-hos-
pital refractory ischemia, plus in-hospital intracranial hemorrhage or in-hospital
major bleeding) were 13.7% for enoxaparin, 14.2% for abciximab and 17.0% for UF
heparin (p=0.0081). In light of this, and given the ease of the subcutaneous admin-
istration of enoxaparin, the combination of tenecteplase and enoxaparin was con-
sidered to be the preferred treatment option. Drug administration by bolus greatly
facilitates pre-hospital medical reperfusion; the time involved in preparation and
administration of the drug is significantly reduced, and the potential for dosing er-
rors is minimized. Tenecteplase can be given as a single bolus and enoxaparin as a
single bolus followed by subcutaneous injections, thereby simplifying their use in
pre-hospital and emergency settings.
Pre-hospital treatment with tenecteplase and enoxaparin is currently being as-
sessed in the ASSENT-3+ trial, an open-label, randomized, international, multicen-
420 P. Goldstein
ter, parallel-group study. ASSENT-3+ will compare the safety and efficacy of pre-
hospital treatment using a regimen of single bolus tenecteplase plus single bolus
and subcutaneous injections of enoxaparin with that using single bolus tenecteplase
and intravenous UF heparin, in 1600 patients presenting with AMI within 6 hours
of symptom onset. The results of this trial are likely to have important implications
for the future of pre-hospital thrombolysis.
I Pre-Hospital Thrombolytic Therapy or Primary Angioplasty?

There is much debate over the choice of reperfusion strategy between thrombolysis
and primary angioplasty. In an ideal situation, when the interval from onset of pain
to catheterization at a high volume center is < 2 hours, primary angioplasty is con-
sidered to be the best option. However, studies have not demonstrated a clear dif-
ference in outcomes between pre-hospital thrombolysis and primary angioplasty
following AMI [57, 58]. Data from 3000 patients in the MITI registry found no sig-
nificant differences in hospital or long-term mortality between patients in the
thrombolysis group and those in the angioplasty group (in-hospital mortality 5.6
and 5.5% respectively, p = 0.93; adjusted hazard ratio for risk of death at 3 years
after primary angioplasty, 95% confidence interval, 0.8-1.2) [58]. These findings
were recently confirmed by the French Comparaison de la Angioplastie Primaire et
de la Thrombolyse Prehospitaliere la phase aigue de l'Infarctus du Myocarde (CAP-
TIM) study (n=840), which evaluated whether pre-hospital thrombolysis could
counterbalance the efficacy of primary angioplasty in AMI [57]. No significant dif-
ference between the treatment strategies was observed in the combined primary
endpoint of 30-day death, reinfarction or stroke (8.2% in the pre-hospital thrombo-
lysis group, 6.2% in the angioplasty group). There was a trend toward more favor-
able outcomes in the angioplasty group, as a result of a lower reinfarction rate. The
mortality rate, however, was lower in the pre-hospital thrombolysis group, with
33% of patients requiring rescue angioplasty. These data contrast with the recent
findings from the Danish Multicenter Randomized Trial on Thrombolytic Therapy
vs Acute Coronary Angioplasty in AMI (DANAMI-2) study (n= 1572), which
showed a clear advantage of an invasive strategy over fibrinolysis with front-loaded
alteplase (Anderson HR, presented at the 51st Annual Scientific Session of the
American College of Cardiology, Atlanta, USA, March 2002}. The incidence of the
combined endpoint (30-day death, reinfarction or stroke) was 8% for patients who
underwent angioplasty, compared with 13.7% for those who received fibrinolysis
(p = 0.003). Interestingly, the incidence of death at 30 days was only marginally
higher in the fibrinolysis group than in the angioplasty group (7.6 vs 6.6%,
p=0.35).
In many hospitals, it is not practical or feasible to undergo angioplasty within 2
hours, and the important treatment choices actually lie in the pre-hospital manage-
ment of patients, whether or not they are selected for angioplasty. Door-to-balloon
time is important: data from the Second National Registry of Myocardial Infarction
(NRMI-2} show no mortality benefit of primary intervention over thrombolysis in
patients in whom primary angioplasty was performed more than 2-3 hours after
arrival at hospital [59]. These data suggest that efforts should be made by physi-
cians and hospitals to reduce the door-to-balloon time, and support the current
American College of Cardiology/American Heart Association (ACC/AHA} guideline
recommending a door-to-balloon time of90±30 minutes [60].
The potential for combining thrombolytic and interventional strategies should

not be underestimated. The future may lie in a joint approach in which pre-hospital
thrombolysis is administered to improve early patency rates in patients awaiting
angioplasty, 90-minute angiography is performed routinely, and rescue angioplasty
is available for all incidences offailed thrombolysis [61, 62]. The Plasminogen-acti-
vator Angioplasty Compatibility (PACT) trial recently confirmed that tailored
thrombolytic regimens compatible with subsequent angiographic interventions lead
to a higher early patency rate on arrival in the catheterization laboratory {61 o/o pa-
tency in patients treated with rt-PA compared with 34o/o in the placebo group) [63].
Early recanalization facilitates the preservation of left ventricular function, and this
may therefore represent an important advantage for early thrombolysis.
I Cardiogenic Shock
Cardiogenic shock is the leading cause of death among patients hospitalized for
AMI [64]. Early revascularization has also been shown to improve outcomes in pa-
tients with AMI complicated by cardiogenic shock [65]. The Should We Emergently
Revascularise Occluded Coronaries for Cardiogenic Shock (SHOCK) trial showed
that, in patients with AMI complicated by cardiogenic shock, both the 30-day and
1-year survival rates were improved by a strategy of early surgical revascularization
(<6 hours) compared with initial medical stabilization using thrombolytic therapy
and rescue angioplasty [66]. In emergency medicine, and particularly in pre-hospi-
tal management, it is important to note that not all patients will be fit to be trans-
ported immediately or within easy reach of a hospital with catheterization facilities.
In such cases, an aggressive strategy of reperfusion with thrombolytic therapy
should be started if there is likely to be a delay of > 1 hour in transferring the pa-
tient for early angioplasty.
I Future Directions for Pre-hospital Management of AMI

For selected patient subgroups, a new treatment algorithm based on a reduced-dose
fibrinolytic agent, such as tenecteplase, enoxaparin and a GP IIb/IIIa inhibitor,
such as abciximab, may become possible in the pre-hospital setting. The results of
the ASSENT-3 trial with half-dose tenecteplase and abciximab, and the GUSTO V
trial involving half-dose reteplase and abciximab, suggest that there may be a place
for conjunctive therapy with GP IIb/IIIa inhibitors in younger patients who are
likely to undergo early coronary interventions [53, 67]. In diabetic patients, how-
ever, the results are inconsistent: in the ASSENT-3 trial, the tenecteplase and abcixi-
mab regimen was shown to be of no benefit, and perhaps even harmful, to this pa-
tient subgroup. By contrast, in the GUSTO V trial, there was a 0.6o/o reduction in
the mortality of diabetic patients treated with reteplase and abciximab. More pro-
spectively designed trials are needed to address these questions in such patient
subgroups.
422 P. Goldstein
Conclusion
The benefit of thrombolytic therapy is greatest when administered in the first 1-2
hours after the onset of chest pain. Very early initiation of thrombolysis has been
shown to increase survival rates and improve outcomes, and current guidelines for
the management of AMI recommend an interval of no longer than 90 minutes be-
tween the onset of pain and the administration of thrombolytic therapy. Pre-hospi-
tal administration of thrombolytic therapy has been proven to shorten the time to
reperfusion of the infarcted artery, and this strategy can greatly improve outcomes
for patients suffering AMI. Ease of administration, in particular treatment with a
single bolus, increases the likelihood of pre-hospital treatment by emergency care
teams. The administration of tenecteplase as a single bolus together with enoxapa-
rin as a single bolus and subcutaneously is an important advance, which reduces
the potential for dosing errors and simplifies preparation, thereby saving more
valuable minutes and, consequently, lives. Conjunctive reperfusion regimens, in-
cluding tenecteplase plus enoxaparin (in addition to oral aspirin), have demon-
strated the potential to further improve outcomes in patients with AMI. The on-
going ASSENT-3+ trial is evaluating pre-hospital reperfusion with single bolus
tenecteplase plus single bolus and subcutaneous injections of enoxaparin, and is
expected to offer important insights into the optimal regimen for pre-hospital man-
agement of acute coronary syndromes. An approach that combines early (ideally
pre-hospital) medical reperfusion with angiography and rescue angioplasty is also
being evaluated, and may represent the future for the management of AMI.
References
1. Tunstall-Pedoe H, Kuulasmaa K, Amouyel P, Arveiler D, Rajakangas AM, Pajak A (1994}
Myocardial infarction and coronary deaths in the World Health Organization MONICA
Project. Registration procedures, event rates, and case-fatality rates in 38 populations from
21 countries in four continents. Circulation 90:583-612
2. The Task Force on the Management of Acute Myocardial Infarction of the European Society
of Cardiology (1996} Acute myocardial infarction: pre-hospital and in-hospital manage-
ment. Eur Heart J 17:43-63
3. Liiwel H, Lewis M, Hormann A (1991} Prognostic significance of the pre-hospital phase in
acute myocardial infarction. Results of the Augsburg Infarct Registry 1985-1988]. Dtsch
Med Wochenschr 116:729-733
4. Newby LK, Rutsch WR, Califf RM, et al (1996} Time from symptom onset to treatment
and outcomes after thrombolytic therapy. GUST0-1 Investigators. J Am Coll Cardiol
27:1646-1655
5. Boersma E, Maas AC, Deckers JW, Simoons ML (1996} Early thrombolytic treatment in
acute myocardial infarction: reappraisal of the golden hour. Lancet 348:771-775
6. Stern R, Arntz HR ( 1998 ) Pre-hospital thrombolysis in acute myocardial infarction. Eur J
Emerg Med 5:471-479
7. Morrison LJ, Verbeek PR, McDonald AC, Sawadsky BV, Cook DJ (2000} Mortality and pre-
hospital thrombolysis for acute myocardial infarction. A meta-analysis. JAMA 283:2686-
2692
8. National Heart Attack Alert Program Coordinating Committee, 60 Minutes to Treatment
Working Group (1994} Emergency Department: rapid identification and treatment of pa-
tients with acute myocardial infarction. Ann Emerg Med 23:311-329
9. Gibler WB, Armstrong PW, Ohman EM, et al (2002} Persistence of delays in presentation
and treatment for patients with acute myocardial infarction: The GUSTO-I and GUSTO-III
experience. Ann Emerg Med 39:123-130
10. Wallentin L (2000) Reducing time to treatment in acute myocardial infarction. Eur J Emerg
Med 7:217-227
11. Cannon CP, Braunwald E (1994) GUSTO, TIMI and the case for early reperfusion. Acta
Cardiol49:1-8
12. The European Myocardial Infarction Project Group (1993) Pre-hospital thrombolytic ther-
apy in patients with suspected acute myocardial infarction. N Engl J Med 329:383-389
13. Brouwer MA, Martin JS, Maynard C, et al (1996) Influence of early pre-hospital thromboly-
sis on mortality and event-free survival (the Myocardial Infarction Triage and Intervention
[MITI] Randomized Trial). MIT! Project Investigators. Am J Cardiol 78:497-502
14. Rawles JM (1997) Quantification of the benefit of earlier thrombolytic therapy: five-year
results of the Grampian Region Early Anistreplase Trial (GREAT). Am J Coli Cardiol
30:1181-1186
15. Linderer T, SchrOder R, Arntz R, et al (1993) Pre-hospital thrombolysis: beneficial effects
of very early treatment on infarct size and left ventricular function. J Am Coli Cardiol
22:1304-1310
16. Morris F, Brady WJ (2002) ABC of clinical electrocardiography: Acute myocardial infarc-
tion- Part I. Br Med J 324:831-834
17. Braunwald E, Antman EM, Beasley JW, et al (2000) ACC/AHA guidelines for the manage-
ment of patients with unstable angina and non-ST-segment elevation myocardial infarction:
executive summary and recommendations. A report of the American College of Cardiol-
ogy/American Heart Association task force on practice guidelines (committee on the man-
agement of patients with unstable angina). Circulation 102:1193-1209
18. Kudenchuk PJ, Maynard C, Cobb LA, et al (1998) Utility of the pre-hospital electrocardio-
gram in diagnosing acute coronary syndromes: the Myocardial Infarction Triage and Inter-
vention (MITI) Project. Am J Coli Cardiol 32:17-27
19. Lindahl B, Venge P, Wallentin L (1995) Early diagnosis and exclusion of acute myocardial
infarction using biochemical monitoring. The BIOMACS Study Group. Biochemical Mar-
kers of Acute Coronary Syndromes. Coron Artery Dis 6:321-328
20. De Winter RJ, Koster RW, Sturk A, Sanders GT (1995) Value of myoglobin, troponin T, and
CK-MB mass in ruling out an acute myocardial infarction in the emergency room. Circula-
tion 92:3401-3407
21. Zimmerman J, Fromm R, Meyer D, et al (1999) Diagnostic marker cooperative study for
the diagnosis of myocardial infarction. Circulation 99:1671-1677
22. Jurlander B, Clemmensen P, Wagner GS, Grande P (2000) Very early diagnosis and risk
stratification of patients admitted with suspected acute myocardial infarction by the com-
bined evaluation of a single serum value of cardiac troponin-T, myoglobin, and creatine ki-
nase MB (mass). Eur Heart J 21:382-389
23. Newman J, Aulick N, Cheng T, et al (1999) Pre-hospital identification of acute coronary
ischemia using a troponin T rapid assay. Prehosp Emerg Care 3:97-101
24. De Vernejoul N, Lambert Y, Laperche T, Sauval P, Lapandry C (2001) Pre-hospital care of
acute myocardial infarction in France: ESTIM, a regional register. Eur Heart J (suppl) 22:25
(abst)
25. Lapandry C (2001) ESTIM ile-de-France. Resultats a un an. La Revue des SAMU XXII:201-
203
26. The GUSTO Angiographic Investigators (1993) The effects of tissue plasminogen activator,
streptokinase, or both, on coronary artery patency, ventricular function and survival after
acute myocardial infarction. N Engl J Med 329:1615-1622
27. Neuhaus KL, von Essen R, Tebbe U, et al (1992) Improved thrombolysis in acute myocar-
dial infarction with front-loaded administration of alteplase: results of the rt-PA-APSAC
patency study (TAPS). J Am Coli Cardiol 19:885-891
28. Cannon CP, McCabe CH, Diver DJ, et al (1994) Comparison of front-loaded recombinant
tissue-type plasminogen activator, anistreplase and combination thrombolytic therapy for
myocardial infarction: results of the Thrombolysis in Myocardial Infarction (TIMI) 4 trial.
JAm Coli Cardiol 24:1602-1610
29. Bode C, Peter K. Nordt T, et al (1997) New developments in thrombolytic therapy. Fibrino-
lysis Proteolysis 11:109-114
424 P. Goldstein
30. The Global Use of Strategies to Open Occluded Arteries (GUSTO III) Investigators (1997)
A comparison of reteplase with alteplase for acute myocardial infarction. N Engl J Med
337:1118-1123
31. De Marco E, Rebuzzi AG, Quaranta G, et al (1998) Lack of procoagulant effect after TNK-
plasminogen activator in patients with acute myocardial infarction. Eur Heart J 19:5 (abst)
32. Cannon CP, McCabe CH, Gibson CM, et al (1997) TNK-tissue plasminogen activator in
acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI)
lOA dose-ranging trial. Circulation 95:351-356
33. Cannon CP, Gibson CM, McCabe CH, et al (1998) TNK-tissue plasminogen activator com-
pared with front-loaded alteplase in acute myocardial infarction: results of the TIMI lOB
trial. Thrombolysis in Myocardial Infarction (TIMI) lOB Investigators. Circulation 98:2805-
2814
34. Van de Werf F, Cannon CP, Luyten A, et al (1999) Safety assessment of single-bolus admin-
istration of TNK tissue-plasminogen activator in acute myocardial infarction: the ASSENT-
I trial. The ASSENT-I Investigators. Am Heart J 137:786-791
35. Assessment of the Safety and Efficacy of a New Thrombolytic Investigators (1999) Single-
bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the
ASSENT-2 double-blind randomised trial. Lancet 354:716-722
36. Van de Werf F, Barron HV, Armstrong PW, et al (2001) Assessment of the safety and effi-
cacy of a new thrombolytic. Incidence and predictors of bleeding events after fibrinolytic
therapy with fibrin-specific agents: a comparison of TNK-tPA and rt-PA. Eur Heart J
22:2253-2261
37. Cannon CP (2000) Thrombolysis medication errors: benefits of bolus thrombolytic agents.
Am J Cardiol 85:17C-22C
38. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group (1988) Rando-
mised trial of intravenous streptokinase, oral aspirin, both, or neither among 17187 cases
of suspected acute myocardial infarction: ISIS-2. Lancet 2:349-360
39. Antiplatelet Trialists' Collaboration ( 1994) Collaborative overview of randomised trials of
antiplatelet therapy. I. Prevention of death, myocardial infarction and stroke by prolonged
antiplatelet therapy in various categories of patients. Br Med J 308:81-106
40. Epelde F, Garca-Castrillo Riesgo L, Loma-Osorio A, Verdier J, Recuerda Martnez E (2000)
[The use of acetylsalicyclic acid in patients with ischaemic cardiomyopathy cared for in
Spanish emergency services (results of the EVICURE study). Med Clin (Bare) 115:455-457
41. O'Shea EB (2001) A study of the use of aspirin by general practitioners in suspected myo-
cardial infarction. Ir Med J 94:48-50
42. Goldberg RJ, Steg PG, Sadiq I, et al (2002) Extent of, and factors associated with, delay to
hospital presentation in patients with acute coronary disease (the GRACE registry). Am J
Cardiol 89:791-796
43. Hsia J, Hamilton WP, Kleiman N, Roberts R, Chaitman BR, Ross AM (1990) A comparison
between heparin and low-dose aspirin as adjunctive therapy with tissue plasminogen acti-
vator for acute myocardial infarction. Heparin-Aspirin Reperfusion Trial (HART) Investiga-
tors. N Engl J Med 323:1433-1437
44. Bleich SD, Nichols TC, Schumacher RR, Cooke DH, Tate DA, Teichman SL (1990) Effect of
heparin on coronary arterial patency after thrombolysis with tissue plasminogen activator
in acute myocardial infarction. Am J Cardiol66:1412-1417
45. Ross AM, Molhoek P, Lundergan C, et al (2001) Randomized comparison of enoxaparin, a
low-molecular-weight heparin, with unfractionated heparin adjunctive to recombinant tis-
sue plasminogen activator thrombolysis and aspirin: second trial of Heparin and Aspirin
Reperfusion Therapy (HART II). Circulation 104:648-652
46. Turpie AGG, Antman EM (2001) Low-molecular-weight heparins in the treatment of acute
coronary syndromes. Arch Intern Med 161:1484-1490
47. Simoons M, Krzeminska-Pakula M, Alonso A, et al (2002) Improved reperfusion and clini-
cal outcome with enoxaparin as an adjunct to streptokinase thrombolysis in acute myocar-
dial infarction. The AMI-SK study. Eur Heart J 23:1282-1291
48. Baird SH, Me Bride SJ, Trouton TG, Wilson C (1998) Low molecular weight heparin versus
unfractionated heparin following thrombolysis in myocardial infarction. J Am Coll Cardiol
31:191A (abst)
49. Cohen M, Demers C, Gurfinkel EP, et al (1997) A comparison of low molecular weight he-
parin with unfractionated heparin for unstable coronary artery disease. Efficacy and Safety
of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events Study Group. N Engl J Med
337:447-452
SO. Antman EM, McCabe CH, Gurfinkel EP, et al (1999) Enoxaparin prevents death and cardiac
ischemic events in unstable angina/non-Q-wave myocardial infarction. Results of the
Thrombolysis in Myocardial Infarction (TIMI) liB trial. Circulation 100:1593-1601
51. Cohen M, Antman EM, Gurfinkel E, et al (2000) Impact of enoxaparin low molecular
weight heparin in patients with Q-wave myocardial infarction. Am J Cardiol 86:553-556,
A9
52. Goodman SG, Cohen M, Bigonzi F, et al (2000) Randomized trial of low molecular weight
heparin (enoxaparin) versus unfractionated heparin for unstable coronary artery disease:
one-year results of the ESSENCE Study. Efficacy and Safety of Subcutaneous Enoxaparin in
Non-Q Wave Coronary Events. J Am Coll Cardiol 36:693-698
53. The Assessment of the Safety and Efficacy of a New Thrombolytic Agent-3 (ASSENT-3) in-
vestigators (2001) Efficacy and safety of tenecteplase in combination with enoxaparin, ab-
ciximab or unfractionated heparin: the ASSENT-3 randomised trial in acute myocardial in-
farction. Lancet 358:605-613
54. Montalescot G, Philippe F, Ankri A, et al (1998) Early increase of von Willebrand factor
predicts adverse outcome in unstable coronary artery disease: beneficial effects of enoxa-
parin. French Investigators of the ESSENCE Trial. Circulation 98:294-299
55. Montalescot G, Collet JP, Lison L, et al (2000) Effects of various anticoagulant treatments
on von Willebrand factor release in unstable angina. JAm Coll Cardiol 36:110-114
56. Montalescot G, Barragan P, Wittenberg 0, et al (2001) Abciximab before Direct Angioplasty
and Stenting in Myocardial Infarction Regarding Acute and Long-Term Follow-up. Platelet
glycoprotein IIb/IIIa inhibition with coronary stenting for acute myocardial infarction. N
Engl J Med 344:1895-1903
57. Bonnefoy E, Lapostolle F, Leizorovicz A, Steg G, Me Fadden E (2002) Primary angioplasty
versus pre-hospital fibrinolysis in acute myocardial infarction: a randomised study. Lancet
360: 825-829
58. Every NR, Parsons LS, Hlatky M, Martin JS, Weaver WD (1996) A comparison of thrombo-
lytic therapy with primary coronary angioplasty for acute myocardial infarction. N Engl J
Med 335:1253-1260
59. Cannon CP, Gibson CM, Lambrew CT, et al (2000) Relationship of symptom-onset-to-bal-
loon time and door-to-balloon time with mortality in patients undergoing angioplasty for
acute myocardial infarction. JAMA 283:2941-2947
60. Ryan TJ, Antman EM, Brooks NH, et al (1999) Update: ACC/AHA Guidelines for the Man-
agement of Patients with Acute Myocardial Infarction: Executive Summary and Recommen-
dations. A Report of the American College of Cardiology/American Heart Association Task
Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction).
Circulation I 00:1016-1030
61. Juliard JM, Himbert D, Cristofini P, et al (1999) A matched comparison of the combination
of pre-hospital thrombolysis and standby rescue angioplasty with primary angioplasty. Am
J Cardiol 83:305-310
62. Loubeyre C, Lefevre T, Louvard Y, et al (2001) Outcome after combined reperfusion ther-
apy for acute myocardial infarction, combining pre-hospital thrombolysis with immediate
percutaneous coronary intervention and stent. Eur Heart J 22:1128-1135
63. Ross AM, Coyne KS, Reiner JS, et al (1999) A randomized trial comparing primary angio-
plasty with a strategy of short-acting thrombolysis and immediate planned rescue angio-
plasty in acute myocardial infarction: The PACT trial. JAm Coll Cardiol 34:1954-1962
64. Goldberg RJ, Samad NA, Yarzebski J, Gurwitz J, Bigelow C, Gore JM (1999) Temporal
trends in cardiogenic shock complicating acute myocardial infarction. N Engl J Med
340:1162-118
65. Barbash IM, Behar S, Battler A, et al (2001) Management and outcome of cardiogenic
shock complicating acute myocardial infarction in hospitals with and without on-site
catheterisation facilities. Heart 86:145-149
426 P. Goldstein: Pre-Hospital Reperfusion Strategies to Optimize Outcomes in Acute Myocardial Infarction
66. Hochman JS, Sleeper LA, White HD, et al (2001) SHOCK Investigators. Should we emer-
gently revascularize occluded coronaries for cardiogenic shock. One-year survival following
early revascularization for cardiogenic shock. JAMA 285:190-192
67. Topol EJ, The GUSTO V Investigators (2001) Reperfusion therapy for acute myocardial in-
farction with fibrinolytic therapy and platelet glycoprotein Ilbiiia inhibition: the GUSTO V
randomised trial. Lancet 357:1905-1914
Glucose, Free Fatty Acids, and Insulin
Following Acute Myocardial Ischemia
H. B. van Wezel and S. W.M de Jong
I Introduction
Adequate coronary revascularization may eventually lead to improved ventricular

function, increased quality of life, and prolonged life expectancy, especially in pa-
tients with viable dysfunctional (hibernating) myocardium. In light of the growing
cohort of elderly patients with chronic heart failure, future demand for surgical re-
vascularization will be significant. However, in spite of numerous cardioprotective
strategies, morbidity and mortality following coronary artery bypass grafting
(CABG) is still high in patients with chronic heart failure. Therefore, in these pa-
tients, the benefit of revascularization has to be balanced against the risk of mor-
bidity and mortality. Table 1 shows the high risks for octagenarians undergoing
cardiac operations [1].
Serious cardiovascular complications usually begin in the period following extra-
corporeal circulation. At this time, acute ventricular failure may develop, a condi-
tion probably caused by post-ischemic dysfunction or myocardial stunning. This
phenomenon may thus be superimposed on already, pre-operatively present, im-
paired ventricular function. The etiological mechanism involved in the occurrence
of both hibernating and stunned myocardium is not yet fully understood. There is,
however, evidence that the intramyocardial availability of glucose, free fatty acids
(FFA), and insulin is involved. Contractile function is sustained by the metabolism
of both glucose and fatty acids. Lopaschuk [2, 3] described a competitive mecha-
nism existing between both substrates used by the myocardium. Under normal
conditions fatty acids are the primary source of energy for the heart [2, 3]. During
periods of mild to moderate ischemia, glucose metabolism becomes more impor-
tant. At the same time, however, the level of circulating free fatty acids increases,
Table 1. High risk octogenarians undergoing cardiac operations. Adapted from [1)
CABG Valve procedure CABG+valve Total

N=36 N=20 N=17 N=73
l ln·hospital mortality 3 1 2 6 (8.2%)

I Paroxysmal AF 9 5 8 22 (30%)
I Renal failure 5 2 4 11 (15%)
I Respiratory failure 4 0 2 6 (8.2%)
Perioperative myocardial 4 0 2 6 (8.2%)
infarction
428 H. B van Wezel and S. W. M de Jong
which leads to inhibited glucose metabolism [2, 3]. In addition, chronic and acute
insulin resistance, even in non-diabetic patients, may also play a role.
I Glucose-Insulin-Potassium in Acute Myocardial Infarction
It has been known for decades that administration of insulin in patients with isch-
emic events may have positive effects on mortality. In 1962, Sodi-Pallares et al.
showed in patients with acute myocardial infarction (AMI) that infusion of glucose,
insulin and potassium (GIK) reduced electrocardiographic (EKG) signs of ischemia,
reduced ventricular ectopy, limited infarct size, and improved survival [4]. Follow-
ing this classical publication, the enthusiasm for the use of GIK was somewhat
dampened by a report from the The British Medical Research Council stating that
GIK therapy failed to show any positive effect on survival in patients with AMI.
However, papers describing the beneficial effect of GIK in patients with AMI con-
tinued to appear regularly. In 1995, Malmberg et al. demonstrated that insulin-glu-
cose infusion improved long-term prognosis in diabetic patients with AMI [5]. In
1997, Fath-Ordoubadi et al. described a meta-analysis of 9 randomized placebo-
controlled studies all using GIK in patients with AMI. These authors found that
GIK therapy led to a highly significant (28%) reduction in mortality [6]. In 1998,
the ECLA study group showed significant GIK-induced reduction in mortality in
patients with AMI who also underwent a reperfusion strategy [7].
In the early days of cardiac surgery, GIK was also used to induce cardioprotec-
tion and for weaning off bypass. However, the technique was abandoned with the
introduction of St. Thomas's cardioplegia and hypothermic cardiopulmonary by-
pass techniques in the mid seventies and the subsequent availability of inotropic
agents like dopamine and dobutamine and anesthetic agents with minimal cardio-
depressant and vasodilatory effects like the synthetic opioids.
In the late eighties, GIK therapy was "rediscovered" in the setting of cardiac sur-
gery for several reasons including: an increase in the number of patients with un-
stable coronary syndromes (i.e., severe myocardial ischemia preoperatively) requir-
ing emergency CABG; the introduction of warm cardioplegia and cardiopulmonary
bypass techniques (possibly allowing improved metabolic stimulation of normal
myocardial enzyme function); and more in general because it appeared that the
limits of adequate cardioprotection had been reached, especially in the growing co-
hort of elderly cardiac surgical patients with a history of severe, long existing coro-
nary artery disease (CAD), chronic heart failure and reduced contractile reserve
preoperatively. This type of patient in particular, frequently requires prolonged epi-
sodes of extracorporeal circulation for complicated coronary revascularization. In
these patients, hemodynamic abnormalities and acute heart failure frequently de-
velop following extracorporeal circulation. The standard therapy consists of large
doses of inotropic agents, nitroglycerin and/or peripheral vasopressors and intra-
aortic balloon pumping. The use of inotropic therapy at high infusion rates is asso-
ciated particularly with a number of undesirable side effects including tachycardia
and increased oxygen requirements of the (post-ischemic dysfunctional) myocar-
dium, and is often only effective for a limited period of time. The latter may be
due to acute beta receptor downregulation, an increase in plasma lipids in the pres-
ence of high endogenous and exogenous catecholamine levels, insulin resistance
and a reduction in myocardial glucose uptake and utilization.
Glucose, Free Fatty Acids, and Insulin Following Acute Myocardial Ischemia 429
Merhige et al. [8] performed a study to test the hypothesis that adrenergic stim-
ulation suppresses myocardial glucose uptake. They measured myocardial activity
of (2- 18F)-2-deoxyglucose (FDG) in glucose loaded dogs, randomly studied during
dopamine infusion, during insulin infusion, and during combined infusion. They
concluded that myocardial FDG uptake was significantly decreased when animals
were treated with dopamine, compared with treatment in the same animals with in-
sulin (p<0.03) or a combination of insulin and dopamine. The results demonstrate
that dopamine inhibits myocardial FDG uptake by raising the level of circulating
FFA and that this inhibition can be reversed by insulin on the basis of substrate
availability and competition [8]. These findings may have clinical importance in
patients requiring long term treatment with exogenous catecholamines.
I Glucose-Insulin-Potassium in Cardiac Surgery
In the past ten years, the above described considerations led to renewed interest in
the role of GIK therapy in patients undergoing CABG, especially following extracor-
poreal circulation and in the intensive care period [6, 7, 9, 10]. In 1995, Svedjeholm
et al. [9] used GIK successfully in an open uncontrolled study in cardiac surgical
patients with heart failure. They reported almost full recovery of hemodynamic
performance in the majority of patients at six hours following bypass [9]. In 1997,
Lazar et al. [10] described reduced inotropic requirement, improved cardiac index
and shorter duration of intensive care time and total hospital stay associated with
GIK therapy in a randomized placebo-controlled study in patients with unstable
angina during urgent CABG. Also in 1997, Taegtmeyer et al. [11] reported a retro-
spective analysis of cardiac surgical patients with impaired left ventricular (LV)
function randomly treated with GIK or placebo. They concluded that an "aggres-
sive" therapy of post-ischemic dysfunctional myocardium appeared to be beneficial,
when pharmacologic and mechanic measures fail to improve cardiac function [11].
In 2000, Lazaret al. [12] showed that GIK leads to reduced perioperative morbidity
in diabetics undergoing CABG. This is an important finding, since it has recently
been confirmed in a study involving more than 140000 patients undergoing CABG
that diabetes mellitus is a significant risk factor for short term morbidity and mor-
tality among those undergoing CABG [13].
In 2001, van den Berghe and co-workers [14] demonstrated that intensive insulin
therapy reduced morbidity and mortality in critically ill patients. They showed that
the subgroup of cardiac surgical patients receiving intensive insulin therapy (blood
glucose levels between 4.4 and 6.1 mMol/1) starting upon arrival in the ICU until
they were discharged to the ward, benefited significantly [14]. Figure 1 shows sig-
nificant differences in cumulative survival between groups, both in hospital stay
(p = 0.01) and in intensive care stay (p < 0.04).
This pivotal study for the first time showed that mortality can be significantly
improved in cardiac surgical patients using "metabolic modulation''. However, from
a theoretical point of view an even more pronounced effect of insulin therapy could
have been obtained if insulin and glucose infusion would have been initiated at the
start of reperfusion, i.e., when aortic cross clamping was discontinued. This theo-
retical improvement of the study protocol used by van den Berghe et al. is based
on the fact that it has been demonstrated in patients undergoing CABG that even
normal myocardium extracts predominantly glucose from coronary arterial blood
in the early reperfusion period following extracorporeal circulation [15]. At that
100 100
96 .... Intensive treatment
..,
'• 96
~
~ ..., '-- ---"--'- ----·------- ;;;
:::> 92 > 92
!::::! ·~
Conventional treatment
.E
:l
"' ......................... _----------
;;; 88 ]i 88 Conventional treatment
>
·~
·a.
:l "'0
Vl 84 ~
84
E'
80 80
0 20 40 60 80 100 120 140 160 0 so 100 150 200 250

a Days after admission b Days after admission
Fig. 1. Kaplan-Meier curves showing cumulative survival of 1548 critically ill patients who received either
conventional treatment or intensive insulin treatment in the ICU. Adapted from [14]
stage of surgical revascularization some degree of mild to moderate global myocar-

dial ischemia associated with post-ischemic dysfunction is usually present. Further-
more, extracorporeal circulation leads to reduction of insulin secretion, insulin re-
sistance and high levels of stress hormones [16]. These hormonal abnormalities are
associated with plasma hyperglycemia, low intracellular glucose availability, and
rapid breakdown of glycogen stores [17].
I Stress Hyperglycemia
In patients with AMI, a similar change in circulating levels of stress hormones
takes place. During the acute phase of myocardial infarction, a neurohumoral stress
response develops which is characterized by a dramatic rise of catecholamines in
blood and ischemic tissues. At the same time, cortisol and glucagon levels increase
which altogether results in decreased insulin sensitivity and impaired glucose
metabolism, while blood glucose levels are raised. This phenomenon is called stress
hyperglycemia [18]. In patients with AMI, stress hyperglycemia is a well known
characteristic. Several investigators demonstrated a relationship between admission
plasma glucose levels and in-hospital mortality [19- 21].
Norhammar et al. [19] performed a retrospective study investigating the rela-
tionship between admission plasma glucose levels and long term outcome in 197
non-diabetic patients after AMI. The investigators concluded that plasma glucose
levels in non-diabetic patients with AMI is a reflection of acute stress and may be
a marker of disturbed glucose metabolism, worsening prognosis. Therefore, high
plasma glucose levels are an independent predictor of long term outcome [19].
In 1995, Malmberg and colleagues published the DIGAMI study. Six hundred
twenty diabetic patients with AMI were included, 306 of which received a glucose-
insulin infusion for at least 24 hours followed by multidose subcutaneous insulin.
After a follow-up of 5 years, the investigators found that glucometabolic state, re-
fleeted by blood glucose levels, HbA1c and duration of diabetes mellitus, is a pre-
dictor of poor in-hospital outcome. Hyperglycemia was associated with extensive
myocardial damage, which causes heart failure and secondary stress [5]. The results
showed that the harmful effects of elevated blood glucose levels were attenuated by
insulin administration; in the control group there was an almost linear relationship
between blood glucose tertiles and long term mortality. The investigators concluded
that intensive insulin treatment reduces long-term mortality despite high admission
blood glucose and HbA1c [20].
In contrast to the well documented impact of stress hyperglycemia on outcome
in patients with AMI, this phenomenon has not been studied intensively in the set-
ting of CABG. To the best of our knowledge only Zindrou and co-workers [21] have
investigated the relationship between admission plasma glucose levels and 30-day
mortality. The study was performed among 878 non-diabetic patients undergoing
CABG. The subjects were stratified into quartiles based on their plasma glucose
levels. The authors found a positive correlation between admission plasma glucose
and 30-day mortality in women (p < 0.0001). The mortality rate appeared to be four
times higher among women in the third and fourth glucose quartiles compared
with men in the identical quartiles (p < 0.002) and with women in the lower quar-
tile& (p<0.03). The investigators concluded that there appeared to be a cutoff glu-
cose level of 6 mmoUl in women, above which mortality increased considerably
[21].
I The Effects of Insulin
In general, it can be stated that hyperglycemia occurs in diabetic and non-diabetic

patients with insulin deficiency or insulin resistance during cardiovascular stress. It
is associated with increased lipolytic activity and high circulating levels of FFA,
leading to unfavorable effects of excess fatty acids in the myocardium; they increase
ischemic damage and oxygen requirements, generate arrhythmias, and diminish
glucose metabolism. The ischemic myocardial tissue switches to anaerobic metabo-
lism and FFA and their unoxidized products accumulate, leading to arrhythmia,
pump failure, and myocardial cell death [22]. It has been suggested that post-isch-
emic dysfunction is caused by uncoupling of glycolysis from glucose oxidation [3,
23, 24]. This is probably caused by high rates of fatty acid fi-oxidation inhibiting
glucose oxidation [25].
Insulin may play a beneficial role in this context because it has a number of im-
portant effects, including: reduced peripheral lipolysis, associated with reduction in
circulating FFA concentration, and myocardial FFA uptake and increased intracellu-
lar glucose availability, leading to a decrease in the inhibition of glucose oxidation
through substrate competition at the level of the pyruvate dehydrogenase enzyme
complex [2, 3, 17, 25]. In addition, recent in-vitro data suggest that insulin may ex-
ert a direct cardioprotective effect [26] during reperfusion via an anti-apoptotic
mechanism [27, 29]. Since extracorporeal circulation is associated with apoptosis
in humans [30], the use of myocardial biopsies, to study the effect of insulin on the
incidence of apoptosis, seems promising. Finally, insulin may also be beneficial
through direct peripheral and coronary vasodilatation leading to reduction in LV
afterload and increases in coronary blood flow and myocardial substrate supply
[31].
432 H. B van Wezel and 5. W. M de Jong
I Negative Reports on GIK-Therapy in CABG
In spite of the above mentioned promising effects of insulin in combination with

glucose and potassium, not all studies describing the use of GIK or intensive insu-
lin therapy in cardiac surgery are showing a positive influence on clinical outcome.
Recently, a number of negative reports have appeared, all using a variety of
methods and patients: Smith et al. [32] compared GIK infusion against placebo in
patients with normal LV function undergoing CABG or off-pump coronary artery
bypass grafting (OP-CAB). They used a blood glucose target range of 5-10 mMol/1.
They demonstrated a significant reduction in FFA levels during GIK infusion. This
was interpreted as an adequate metabolic response to GIK infusion, which was con-
tinued until 6 h after aortic cross clamping (i.e., until ± 4 h after arrival in the
ICU). Using this relatively short GIK infusion time in their series of low risk cardi-
ac surgical patients, the researchers did not find any significant differences in fac-
tors reflecting major clinical benefit, including perioperative myocardial infarction,
use of inotropes or length of intensive care stay [32].
Groban et al. [33] described a post hoc analysis of a randomized masked clinical
trial of insulin therapy for prevention of neurobehavioural deficits following CABG
in low risk patients with a mean ejection fraction of 60% preoperatively. They used
an even shorter infusion period for insulin than Smith et al., because insulin infu-
sion was discontinued upon arrival in the ICU (i.e. ± 2 h after start of reperfusion).
They failed to demonstrate a reduction in the need for inotropic or antiarrhythmic
therapy [33].
Lell et al. [34] used the 'classical' metabolic cocktail originally described by
Lazar (glucose 25%, 50 IU insulin and 80 mMol/1 Kcl) but at a 50% higher infusion
rate than adviced by Lazar in OP-CAB patients with preoperative ejection fraction
> 80%. The authors concluded that GIK infusion was associated with insulin resis-
tant hyperglycemia. In addition, they found evidence for higher levels of cardio-
specific enzymes in individual patients and no demonstable clinical benefit [34].
Bruemmer-Smith et al. [35] investigated the impact of GIK solution on myocar-
dial cell death, using cardiac troponin I, as a sensitive and specific indicator of
myocytic injury. The subjects were patients with normal left ventricular function
undergoing CABG. They used the high dose GIK infusion (500 ml 50% dextrose so-
lution containing 100 IU insulin and 80 mmol potassium at an infusion rate of
0.75 ml!kg/hr) but it was only given during surgery. The results showed no differ-
ence in cardiac troponin concentrations between the GIK group and the control
group. Following this relatively short period of GIK infusion, in patients who did
not have impaired left ventricular function, this approach did not lead to a de-
crease in irreversible myocardial damage [35].
I Future Perspectives of GIK-Therapy in CABG
The above discussed reports by Smith, Groban, Lell, and Bruemmer-Smith, all have
in common that they described patients with normal LV function and low perio-
perative risk. In the hands of experienced clinicians these patients have low levels
of CK-MB and cardiac troponin 1 release from the myocardium and a very low re-
quirement for inotropic therapy, short duration of ICU stay, and total hospital stay.
In addition, post-ischemic dysfunction following extracorporeal circulation is
usually not pronounced because preoperative ventricular contractile reserve is high.

Therefore, it is not surprising that these authors failed to demonstrate beneficial ef-
fects of GIK therapy compared to placebo in relatively small groups of patients. In
addition, the methodology used in these studies varied significantly from the meth-
ods described in the classical studies by Svedjeholm, Taegtmeyer and Lazar or the
very convincing study by van den Berghe (using intensive insulin therapy). Smith
et al., Groban et al. and Bruemmer-Smith et al. used GIK or insulin treatment
respectively for a short period in the reperfusion phase only, whereas Lell et al. ob-
viously gave too much of a potentially 'good thing'. Furthermore, there were other
important differences in applied methodologies in those four recent negative stud-
ies, including: a diversity in reported content of glucose-insulin solutions, infusion
rates and duration of infusion of glucose and insulin, different types of cardiac sur-
gical patients, surgical cardioplegic techniques, and even types of operation (CABG
and OP-CAB).
To avoid the above described discrepancies in future studies, we need a high de-
gree of standardization of the concentrations used in the GIK solutions, infusion
rates and duration of infusions (probably as long as possible during ICU stay). As
an alternative, insulin can be infused separately from glucose and potassium to al-
low more flexibility in the adjustment of blood glucose and potassium levels by ad-
justing the insulin infusion rate (as described by van den Berghe). Insulin may also
be given as a hyperinsulinemic euglycemic clamp, using a fixed high infusion rate
of insulin with a separate glucose-potassium-phosphate infusion of which the infu-
sion rate is adjusted to maintain blood glucose levels at stable normal levels, as
suggested by Svedjeholm.
The type of cardiac surgical patients probably benefiting most from 'metabolic
modulation' are those with impaired LV function and/or those requiring urgent
coronary revascularization. Future research must be directed at such patients be-
cause their perioperative risk is still substantial and should be reduced.
I Conclusion
The dramatic effect of GIK-therapy on mortality in both AMI and CABG cannot be
ignored. However, there are also a number of negative studies. This may be ex-
plained by the wide variation in techniques used and the type of patients in these
studies. Therefore, standardization of infusion rates and composition of the "cock-
tails" is required. Since it appears that most studies in CABG are underpowered,
more large clinical trials are required to establish the preferred technique.
References
1. Gatti G, Cardu G, Lusa AM, Pugliese P {2002) Predictors of postoperative complications in
high risk octogenarians undergoing cardiac operations. Ann Thorac Surg 74:671-677
2. Lopaschuk GD {1998) Treating ischemic heart disease by farmacologically improving cardi-
ac energy metabolism. Am J Cardiol 82:14k-17k
3. Lopaschuk GD, Stanley WC (1997) Glucose metabolism in the ischemic heart. Circulation
95:313-315
4. Sodi-Pallares D, Testelli MR, Fishleder BL, et al {1962) Effects of an intravenous infusion of
a potassium-glucose-insulin solution on the electrocardiographic signs of myocardial in-
farction. Am J Cardiol 5:166-181
5. Malmberg K, Ryden L, Efendic S, et al (1995) Randomized trial of insulin-glucose infusion

followed by subcutaneous insulin treatment in diabetic patients with acute myocardial in-
farction (DIGAMI-study): effects on mortality at 1 year. JAm Coli Cardiol 26:57-65
6. Fath-Ordoubadi F, Beatt KJ (1997) Glucose-insulin-potassium therapy for treatment of
acute myocardial infarction. An overview of randomized, placebo-controlled trials. Circula-
tion 96:1152-1156
7. Diaz R, Paolasso EA, Piegas LS, et a! (1998) Metabolic modulation of acute myocardial in-
farction. The ECLA glucose-insulin-potassium pilot trial. Circulation 98:2227-2234
8. Merhige ME, Ekas R, Mossberg K, Taegtmeyer H, Gould KL (1987) Catecholamine stimula-
tion, substrate competition, and myocardial glucose uptake in conscious dogs assessed
with positron emission tomography. Circ Res 61 (suppl II):II124-II129
9. Svedjeholm R, Huljebrant I, Hakanson E, Vanhanen I (1995) Glutamate and high dose Glu-
cose-Insulin- Potassium (GIK) in the treatment of severe cardiac failure after cardiac opera-
tions. Ann Thorac Surg 59:S23-S30
10. Lazar HL, Phillipides G, Fitzgerald C, Lancaster D, Shemin RJ, Apstein C (1997) Glucose-
insulin-potassium solutions enhance recovery after urgent coronary artery bypass grafting.
J Thorac Cardiovasc Surg 113:354-362
11. Taegtmeyer H, Goodwin GW, Doenst T, Frasier OH ( 1997) Substrate metabolism as a de-
terminant for postischemic functional recovery of the heart. Am J Cardiol 80:3A-10A
12. Lazar H, Chipkin S, Philippides G, Bao Y, Apstein C (2000) Glucose-Insulin-Potassium so-
lutions improve outcomes in diabetics who have coronary artery operations. Ann Thorac
Surg 70:145-50
13. Carson JL, Scholz PM, Chen AY, Peterson ED, Gold J, Schneider SH (2002) Diabetes melli-
tus increases short-term mortality and morbidity in patients undergoing coronary bypass
graft surgery. JAm Coli Cardiol 40:418-423
14. Van den Berghe G, Wouters P, Weekers F, et al (2001) Intensive insulin therapy in critically
ill patients. N Eng! J Med 345:1359-1367
15. Pietersen HG, Langenberg CJM, Geskes G, et a! (1999) Myocardial substrate uptake and
oxidation during and after routine cardiac surgery. J Thorac Cardiovasc Surg 118:71-80
16. Chaney MA, Nikolov MP, Blakeman BP, Bakhas M (1999) Attempting to maintain normo-
glycemia during cardiopulmonary bypass with insulin may initiate postoperative hypogly-
cemia. Anesth Analg 89:1091-1095
17. Depre C, Vanoverschelde JLJ, Taegtmeyer H (1999) Glucose for heart. Circulation 99:578-
588
18. Capes SE, Hunt D, Malmberg K, Gerstein HC (2000) Stress hyperglycemia and increased
risk of death after myocardial infarction in patients with and without diabetes: a systematic
overview. Lancet 335:773-778
19. Norhammar A, Ryden L, Malmberg K (1999) Admission plasma glucose. Independent risk
factor for long-term prognosis after myocardial infarction even in non-diabetic patients.
Diabetes Care 22:1827-1831
20. Malmberg K, Norhammar A, Wedel H, Ryden L (1999) Glycometabolic state at admission:
important risk marker of mortality in conventionally treated patients with diabetes melli-
tus and acute myocardial infarction. Circulation 99:2626-2632
21. Zindrou D, Taylor KN, Bagger JP (2001) Independent risk factor in non-diabetic women
after coronary artery bypass grafting. Diabetes Care 24:1634-1639
22. Davies MJ, Lawrence IG (2002) DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in
Acute Myocardial Infusion): theory and practice. Diabetes, Obesity and Metabolism 4:289-
295
23. Opie LH (1992) Cardiac metabolism-emergence, decline, and resurgence. Part II. Cardio-
vasc Res 26:817-826
24. Liu B, el Alaoui-Talibi Z, Clanachan AS, Schulz R, Lopaschuk GD (1996) Uncoupling of
contractile function from mitochondrial TCA cycle activity and MV02 during reperfusion
of ischemic hearts. Am J Physiol 270 (1 Pt 2):H72-H80
25. Neely JR, Rovetto MJ, Whitmer JT, Morgan HE (1973) Effects of ischemia on function and
metabolism of the isolated working rat heart. Am J Physiol 225:651-658
26. Jonassen AK, Brar BK, Mjos OD, Sack, MN, Latchman DS, Yellon DM (2000) Insulin admi-
nistered at reox:ygenation exerts a cardioprotective effect in myocytes by a possible anti-
apoptotic mechanism. J Moll Cell Cardiol 32:757-764
27. Gottlieb RA, Engler RL {1999) Apoptosis in myocardial ischemia-reperfusion. Ann NY
Acad Sci 30:412-426
28. Ausma J, Thone F, Flameng W, et al {1998) Dedifferentiated cardiomyocytes from chronic
hibernating myocardium are ischemia-tolerant. Moll Cell Biochem 186:159-168
29. Van den Hoff MJB, Van den Eijnde SM, Viragh S, Moorman AFM (2000) Programmed cell
death in the developing heart. Cardiovasc Res 45:603-620
30. Aebert H, Cornelius T, Birnbaum DE, Siegel AV, Riegger GA, Schunkert H (1997) Induction
of early immediate genes and programmed cell death following cardioplegic arrest in hu-
man hearts. Eur J Cardiothorac Surg 12:261-267
31. Meyer C, Swaiger M (1997) Myocardial blood flow and glucose metabolism in diabetes
mellitus. Am J Cardiol 80:94A-101A
32. Smith A, Grattan A, Harper M, Royston D, Riedel BJCJ (2002) Coronary revascularization:
a procedure in transition from on-pump to off-pump? The role of glucose-insulin-potas-
sium revisited in a randomized, placebo-controlled study. J Cardiothorac Vase Anesth
16:413-420
33. Groban L, Butterworth J, Legault C, Rogers AT, Kon ND, Hammon JW (2002) Intraoperative
insulin therapy does not reduce the need for inotropic or antiarrhythmic therapy after car-
diopulmonary bypass. J Cardiothorac Vase Anesth 16:405-412
34. Lell W, Nielsen VG, McGiffm DC, Schmidt FE, Kirklin JK, Stanley AW (2002) Glucose-insu-
lin-potassium infusion for myocardial protection during off-pump coronary artery surgery.
Ann Thorac Surg 73:1246-1252
35. Bruemmer-Smith S, Avidan MS, Harris B, et al (2002) Glucose, insulin and potassium for
heart protection during cardiac surgery. Br J Anaesth 88:489-495
Quantifying Left Ventricular Ejection Effectiveness
M.R. Pinsky
I Introduction
Historically, left ventricular (LV) performance has been quantified by measuring in-
dices of global performance, such as stroke work, developed pressure and the LV
end-systolic pressure-volume relation (ESPVR) [1]. Suga and Sagawa [1] extended
their initial pioneering studies on contractility-defining end-systolic pressure-vol-
ume relationships (ESPVR) by incorporating the graphic area inside the LV pres-
sure-volume loop (stroke work or SW) plus the ESPVR-defined left-sided triangle
of potential work (Fig. 1), called the LV pressure-volume area (PVA) [2]. Measuring
myocardial oxygen consumption (MV0 2 ) as the product of arterio-coronary sinus
oxygen content difference and coronary sinus blood flow, they demonstrated that
changes in the LV PVA induced proportional changes in MV0 2 • Thus, increasing
either LV volume or ejection pressure increases MV0 2 in a predictable fashion.
Similarly, any process that reduces this PVA also reduces MV0 2 • This simple and
elegant construct allows physicians to predict with great accuracy the impact of
specific drugs and surgical interventions on LV ejection efficiency, defined as the
ratio of SW to MV0 2 • This construct assumes that myocardial contraction occurs
in a uniform fashion from initiation of systole to end-ejection, such that all compo-
nents of the contractile apparatus shorten to a minimal volume at the same instant.
Elastance·detined
potential
work
(PEl
LV volume LV volume
Fig. 1. The relationship between left ventricular (LV) pressure-volume loop generated during a single car-
diac cycle, end-systolic elastance-defined potential work and myocardial oxygen consumption (MV0 2)
Quantifying left Ventricular Ejection Effectiveness 437
However, when LV contraction is asynchronous, the close relation between SW and

ventricular volume degrades.
I Regional Contraction Asynchrony is the Most Common

Cardiac Contraction Abnormality
Contraction asynchrony is the most common contractile abnormality seen clini-
cally, accounting for much of the observed, clinically relevant increase in morbidity
from heart disease. Regional myocardial asynchrony, characterized by regional wall
motion abnormalities (RWMA), commonly occurs, however its impact on global LV
performance has not been quantified. RWMA are common in patients with normal
[3-5] and abnormal [6-8] cardiac physiology. RWMA are monitored intraoperative-
ly to detect regional myocardial ischemia [9-11]. If a quantitative measure of re-
gional myocardial dysfunction could be developed which was easy to use, it would
minimize subjective bias in the diagnosis of myocardial ischemia [12-14] and aid
in the evaluation of treatments and titration of therapies used to restore regional
myocardial function.
Global LV ejection reflects the summed contraction of a large series of cardiac
muscle cells whose function is altered by LV volume, arterial impedance, coronary
blood flow, and excitation-contraction coupling through the His-Purkinje system.
LV contraction is normally heterogeneous [6]. The apex and base differ in their on-
set of contraction and in their response to inotropes [15], the apex being slightly
phase lagged in relation to the base region and somewhat more dynamic. This de-
gree of asynchrony is necessary for proper mechanical functioning of the mitral
valve apparatus and causes minimal cardiac dilation. However, if LV contraction
becomes even more asynchronous among regions of the heart, then LV ejection ef-
fectiveness will decrease, as defined as external work (stroke work) to energy con-
sumed (MV02 ) ratio. Similarly, if asynchrony were to be reduced, then ejection effi-
ciency would improve.
Ventricular pacing and abnormally conducted beats increase contraction asyn-
chrony. Initially, ventricular pacing was thought to have minimal effects on con-
traction synchrony, because when viewed from the perspective of the whole ventri-
cle, little change could be ascertained when compared to normally conducted beats
[16]. However, Badke et al. [17] observed marked regional differences in myocardial
contraction when analyzed by multiple dimensions using ultrasonic crystals. What
effect does this pacing-induced asynchrony have on global LV function? Park et al.
[6] showed that increasing contraction asynchrony as exemplified by RV and LV
pacing in their model does not change the ESPVR slope (Ees) but does induce pro-
gressive LV dilation in proportion to the degree of asynchrony (Fig. 2).
Such parallel shifts of the LV ESVPR will have profound effects on LV contrac-
tion efficiency, because any process that results in an increased LV volume for a
constant LV ejection pressure and stroke volume (SV) will also increase MV0 2 • Sub-
jects with heart failure have a close correlation between conduction delays and con-
traction asynchrony [18]. Thus, the finding that many patients with prolonged QRS
heart failure treated with hi-ventricular pacing demonstrate a decrease in LV end-
diastolic volume (LVEDV) without a change in ejection pressure or SV, suggested
that this pacing improved ejection effectiveness by reducing this contractile asyn-
chrony [15]. Although redistribution of local work [19], blood flow, and metabo-
lism [20] have all been suggested as possible mechanisms by which hi-ventricular
438 M. R. Pinsky
Normal RV LV
Paced Paced
a
~ ~
::J
"'"'
~ "'
~
a. a.
::; ::;
LV volume LV volume
Fig. 2. Effect of increasing asynchrony of contraction by ventricular pacing on the LV end-systolic pres-
sure-volume relationship (ESPVR}. Adapted from the data from [6]
140
120
Ci 100
l:
E
.s
Cll
80
5VI
60
"'Cll
a.
::; 40
20
0
0 10 20 30 40 so 60
LV volume (ml)
Fig. 3. Effect of regional impairment in myocardial contractility by sub-segmental intracoronary infusion

of esmolol into a canine heart. Note the LV dilation but minimal change in the LV end-systolic pressure-
volume relationship (ESPVR}. (Reproduced from [21] with permission}
pacing improves LV performance in these subject, the mechanism has not been de-
fined. Importantly, the observation that some patients with wide QRS cardiomyo-
pathy received no benefit from hi-ventricular pacing, demonstrates that the mecha-
nism by which hi-ventricular pacing works to improve contractile effectiveness is
not understood.
We recently showed that regional dyskinesis, induced by sub-selective coronary
artery infusion of esmolol induced regional asynchrony, as defined by region-spe-
cific ultrasonic crystal measures, caused a similar rightward shift of the LV ESPVR
but did not alter Ees (Fig. 3) [21]. Importantly, these changes occurred without
Quantifying Left Ventricular Ejection Effectiveness 439
changes in QRS morphology. Thus, any form of contraction asynchrony (RWMA),

whether electrical or mechanical, causes cardiac dilation decreasing LV ejection ef-
fectiveness (SW/MV0 2 ).
Burkhoff et al. [22] demonstrated that although RV pacing altered both the LV
PVA and MV0 2 , their relationship to each other remained constant. However, they
used an isolated heart preparation for their analysis, whereas Ballard et al. [23],
using intact dogs, showed that RV pacing was associated with a higher MV0 2 and
thus lower LV ejection efficiency than seen with atrial pacing. Thus, in intact ani-
mals, increasing asynchrony decreased LV contraction efficiency, as defined by the
ratio of LV SW to MV0 2 •
This concept is clinically important because: 1) RWMA are the most common
cardiac abnormalities; 2) pacing normally increases contraction asynchrony; 3) pa-
tients requiring ventricular pacing usually have impaired ventricular pump func-
tion and coronary reserve; 4) clinical trials of pacing in heart failure patients are
now underway without clear titration end-points for therapy, other than measuring
developed pressure and QRS duration; and 5) inotropic agents used in patients with
RWMA may improve or impair LV ejection effectiveness, presumably based on their
effects on LV ejection synchrony. Potentially, changes in LV ejection synchrony re-
flect a primary determinant of both LV ejection effectiveness and the response of
the patient to therapeutic interventions, such as pacing and pharmacotherapies.
1 Hypothetical Relation between Asynchrony and MV02
If a region of the heart reaches its minimal volume late, relative to other regions of
the heart, then, not only is its contribution to global ejection diminished, the con-
tribution of the remaining contracting elements is also diminished because global
end-ejection will be delayed making these normally contracting segments reach
end-ejection early. Thus, asynchrony decreases LV ejection efficiency by a greater
amount than that predicted by the regional asynchrony itself (Fig. 4). Note in figure
4 that: 1) regional maximal shortening of affected elements may be unchanged or
increased despite a reduced contribution to global end-ejection; and 2) normal con-
tribution of normally contracting elements will also have a reduced contribution to
global end-ejection despite normal contraction synchrony. Collectively, this impair-
ment can be considered a phasic loss of ejection stroke volume. As LV ejection
asynchrony increases, MV0 2 should increase more than predicted from the LV PVA
relation described in figure 1 because the LV PVA will not describe all the mechani-
cal work done by the contracting myocardium. There are two primary theoretical
reasons for this assumption. First, asynchronously contracting myocardial elements,
though not completely contributing their contraction to global ejection, are still
contracting under load and require energy and contribute to MV0 2 • And second,
since global LV wall stress increases as LV volume increases, any process that in-
creases LV volume for a constant ejection pressure and SV must increase MV0 2 for
the entire heart.
Wiggers initially described the negative impact of ventricular pacing [24]. The
greater the distance the excitation wave front has to travel from the pacing site to
the His-Purkinje system, the greater will be the degree of asynchrony. This is mani-
fest electrically as a prolonged QRS duration, which has an inverse relation with
peak-developed pressure [22]. Usually asynchronous contraction occurs because of
440 M. R. Pinsky
c Normal Asynchrony
0
·c;,
~
tii
E
0
z
Ql
E ,
:;,
0 ,'
> ~......... "/ Phasic
~ ----------------------1---~ _jl ____ }~~~ -
Time nme
Fig. 4. Hypothetical effect of regional contraction asynchrony on global contraction. In this example, the
LV is modeled as a two-component system. In the example on the left, the two regions contract synchro-
nously and their effect on global stroke volume is equal to their sum. In the example on the right, the
affected region reached end-systole later even though the total shortening of each region is the same.
The net result is a reduction to summed stroke volume and a delay in the time to reach global end-sys-
tole
either conduction abnormalities or regional myocardial contractile pathology. With

regional myocardial contractile pathologically, such as during ischemia or stunning,
excitation usually proceeds normally but dysfunctional regions contract more
slowly. The impact of asynchrony on MV0 2 should be predictable from the LV PVA
analyses of Suga and Sagawa [1] (Fig. 5). With normal contraction, MV0 2 is pro-
portional to the SW (light gray area) plus the elastance-defined internal work (dark
gray area). With increasing asynchrony, LV ESPVR is shifted to the right, with vol-
ume on the x-axis. Thus, MV0 2 should increase in proportion to the increase in
'area' defined by the parallelogram of the LV ESPVR with and without asynchro-
nous contraction (lightest gray area). As will be described below, phase angle anal-
ysis will potentially allow us to define the position of the LV ESPVR if no asyn-
chronous contractions occur, thus defining this parallel shift induced by asyn-
chrony, and also to calculate the increased MV0 2 that asynchrony demands.
-
Asynchrony Normal
MV02
LV Volume
Increased
MV02
LV Volume
LV Volume
Fig. 5. Hypothesized effect of contraction asynchrony on MV02• Note that with increasing asynchrony of
contraction, the end-systolic pressure-volume relationship (ESPVR) shifts further to the right. Since myo-
cardial stress is a function on wall tension and thus absolute volume, MV0 2 should increase for the same
stroke work as asynchrony increases. Potentially, the increase in MV0 2, using the pressure-volume area
analysis will equal the parallelogram created by the shift of the original and the new ESPVR
I Clinical Applications of Asynchrony Reduction Therapy

Patients with dilated cardiomyopathy often develop abnormal conduction character-
ized by left bundle branch block (LBBB) [25]. LBBB contraction patterns induce
widespread LV wall motion abnormalities [26]. Blanc et al. showed that LV pacing
could improve LV ejection while decreasing LV filling pressure in 23 patients with
severe heart failure, although the mechanisms were not defined [27]. Potential
mechanisms include not only normalization of ventricular activation sequence, but
also increased filling time, decreased mitral regurgitation and optimizing mechani-
cal atrio-ventricular delay. Interestingly, Auricchio and Salo showed that optimiza-
tion of A-V sequential pacing to the left or right ventricular site was markedly dif-
ferent amongst patients [28]. Two major multicenter clinical trials of coronary sinus
pacing (to stimulate the LV free wall) were performed [29]. The preliminary data
from the CONTAK-CD (Guidant) study on 581 patients were presented at the
March 2001 American College of Cardiology (ACC) meeting. These data demon-
strated improved vo2, quality of life, exercise tolerance and increased time to death
(Abraham, presented at ACC, March 2001). However, improvement was variable,
442 M. R. Pinsky
with 40% of study patients also showing no improvement or worsening function as

compared to 60% in the control group. It is tantalizing to hypothesize that in these
clinical studies, the improvement in LV ejection parallels reductions in ejection
asynchrony. In support of this hypothesis, Kass et al. [15] demonstrated that pa-
tients with dilated cardiomyopathies and ventricular conduction delays had a re-
duction in LV end-systolic volume (ESV) for a constant EDV and ejection pressure
during LV pacing. No changes in LV diastolic compliance were seen. If pacing im-
proved LV contraction synchrony, then we would expect such a parallel shift in the
LV ESV at a constant ejection pressure. Potentially, LV epicardial pacing in those pa-
tients who had a favorable response reduced ejection asynchrony. Presently the US
Food and Drugs Administration (FDA) has approved these ventricular pacing de-
vices for the chronic management of wide complex QRS heart failure. It would be
very useful to know ahead of time if the high risk and high cost procedure would
benefit a specific patient.
I Regional Phase Angle Analysis Defines LV Ejection Effectiveness
We developed a canine model to validate a simplified method to quantify contrac-

tion asynchrony by measuring both the regional phase angle (a) and SV of each of
4 regional LV volumes defined by the electrode pair of the conductance catheter
aligned along the long axis of the LV lumen [30]. We also measured segmental
length changes using sonomicrometer crystals to serve as a gold standard for local
asynchrony. We induced regional dyskinesis by sub-selective left coronary artery
esmolol injection. This allowed us to measure ejection effectiveness (proportion of
regional stroke volume used in global ejection) and ejection efficiency (proportion
of total LV contraction that results in ejection) of involved (apical) and remote re-
gions of the heart during reversible LV dyskinesis. By dividing one cardiac cycle
into 360° and assigning global end-ejection at 0°, the amount of early or late con-
traction of a region can be measured as a phase angle a from 0° to± 180°. Assum-
ing that regional volume change during the cardiac cycle approximates a sine wave,
then the calculated effective regional stroke volume, that portion of the maximal re-
gional volume change that contributes to global ejection, will equal the product of
the maximal regional volume change and cos a. LV ejection efficiency can then be
defined as the ratio of 1: regional maximal stroke volumes to LV stroke volume, or
more simply the mean weighted average cos a of all LV regions. Data from one dog
for the involved apical regional volume are shown in figure 6. Note that during es-
molol infusion, the dyskinetic segment reaches minimal volume as a post-systolic
contraction. Only that portion of the apical contraction that coincided with global
end-ejection ejection contributes to LV ejection. The remainder of the delayed con-
traction occurs into a dilating LV. Apical and papillary regional phase angles in-
creased 10 to 16% relative to baseline (p < 0.05), whereas apical ultrasonic crystals
displayed a 27% increase in the phase angle (p < 0.05). Esmolol increased apical
and papillary mean regional systolic time intervals (p < 0.05), but reduced systolic
time intervals in the uninvolved basal regions (p = ns). Importantly, esmolol in-
duced no significant change in any regional maximal stroke volume, but induced
marked reductions in effective regional SV (Fig. 6). When regional stroke volumes
were measured as effective stroke volume, defined as the product of the maximal
Global End-Systole
4
lQj
E
::J
0
>
Qj
.><
2 g
"'
-;;;
u
·c.
~
90
0
One cardiac cycle (degrees)
Fig. 6. Effect of esmolol-induced apical dyskinesis on apical volume-time activity curves in an intact dog.
Four sequential regional volume-time curves are shown for baseline, esmolol-induced dyskinesis and then
recovery. Note that although esmolol induced a marked dilation of the apical region, absolute regional
stroke volume was unchanged, owing to the post-systolic contraction. Thus, measures of regional stroke
volume alone will not identify asynchronous contraction
15
l
Qj
Y = l.Ox + 0.2, r = 0.97
E
::J
0
>
Qj 10
.><
g
"'
Qj
>
·;:; 0
u o Baseline
~
Qj
5 • Esmolol
"0
Qj
~
Qj
"'
.a
0
0
0 5 10 15
Calculated effective stroke volume (ml)
Fig. 7. Relation between regional calculated and measured effective stroke volume under various condi-
tions in 7 dogs. Measured effective regional stroke volume is that proportion of the regional stroke vol-
ume contributing to LV ejection. Calculated effective stroke volume is the product of the absolute regional
stroke volume and the cosine of the phase angle of the region relative to global end-ejection
444 M. R. Pinsky
LV posterior wall Epicardium Endocardium

150 .--------------------,
Linear regression analysis
r =0.98
m =6.13 =Velocity gradient
.....
"'
E 100
5
~
·o
0
Qj
>
~ 50
~"'c:
$.
0
lOOmm/s
0 5 10 15
Distance (mm)
Fig. 8. Tissue Doppler imaging of the LV posterior wall during systole using an M-mode signal (left panel).
Note that as systole progresses, a color (tissue velocity) gradient develops across the posterior wall. This ve-
locity gradient for one time point during systole is illustrated as a transmyocardial velocity gradient (right
panel)
regional stroke volume and the cosine of its phase angle, apical stroke volume de"
creased and uninvolved chordal and basal stroke volumes increased (p < 0.05) [21].
However, referencing apical ejection volume to global end-ejection allowed us to
define the effective regional stroke volume. Importantly, we could also effectively
estimate estimating effective regional stroke volume by using the formula maximal
regional stroke volume cos (Fig. 7). Since maximal regional stroke volume is the
variable measured by regional echocardiographic studies, referencing it to phase
angle will allow for the accurate measure of effective regional stroke volume.
Echocardiographic tissue Doppler imaging (TDI) provides an objective quantita-
tive assessment of global and regional LV function. We applied this imaging pro-
cess in our above animal preparation of regional asynchrony induced by sub-selec-
tive intracoronary infusion of esmolol. TDI can measure not only tissue velocity
but also transmyocardial velocity gradient (Fig. 8) [31]. Since the ventricular wall
thickens during systole, a transmyocardial velocity gradient develops from the near
wall to the far wall. Although the velocity gradient is linear if transmural contrac-
tion is synchronous, it becomes non-uniform with asynchrony and regional isch-
emia. This TDI technique is important because it will allow for asynchrony analysis
to be made simultaneously over smaller regions of myocardium. Thus, it should
permit a more sensitive method for identification of asynchrony. Using this
approach we recently documented that color-coded TDI could be used to assess re-
gional myocardial asynchrony using a canine model of reversible anterior myocar-
dial ischemia [32]. Peak systolic endocardial velocity by TDI decreased from
4.4 ± 1.4 to 1.8 ± 1.5 cm/s during coronary occlusion and correlated with sonomicro-
metry measures (r = 0.75, p < 0.005). This depression was partially reversed by do-
butamine infusion.
Thus, one may use TDI to image myocardial performance on both a global and
regional level to an extent not previously realized. The potential for this and simi-
lar non-invasive echocardiographic techniques to qualify regional contractile dys-
function, their changes in response to pharmacological, pacing and surgical treat-
ments, and to incorporate them into a global patient management plan reflects
realities that require only implementation, not new technological discoveries or
new science.
I Conclusion
As our ability to image myocardial contraction improves, our understanding of the
determinants of global cardiac performance evolve. Presently, non-invasive or mini-
mally invasive imaging devices exist that allow for the accurate and detailed analy-
sis of myocardial contractile behavior throughout the cardiac cycle and in response
to specific therapies. With this knowledge has come the realization that simple
measures of global ventricular performance do not describe well either baseline
cardiac performance, cardiac disease processes, or their response to therapies. By
coupling regionai asynchrony and absolute velocity into a single parameter one can
assess more accurately global ventricular performance. Regional phase angle analy-
sis is one technique that has proven useful in asynchrony analysis. The stage is
now set for clinical trials of treatments with greater diagnostic accuracy and physi-
ological significance than imagined even 5 years ago.
Acknowledgement. This work was supported in part by NIH grant NHLBI K-24
HL67181-01Al.
References
1. Suga H, Sagawa K (1974) Instantaneous pressure-volume relationships and their ratio in
the excised supported canine left ventricle. Circ Res 35:117-134
2. Suga H, Hayashi T, Shirahata M (1981) Ventricular systolic pressure-volume area as predic-
tor of cardiac oxygen consumption. Am J Physiol240:H39-H44
3. LeWinter M, Kent R, Kroener J, Carew T, Covell J (1975) Regional differences in myocardial
performance in the left ventricle of the dog. Circ Res 37:191-199
4. Haendchen RV, Wyatt HL, Maurer G, et al (1983) Quantitation of regional cardiac function
by two-dimensional echocardiography I. Patterns of contraction on the normal left ventri-
cle. Circulation 67:1234-1245
5. Bonow RO (1990) Regional left ventricular nonuniformity: effects on left ventricular dia-
stolic function in ischemic heart disease, hypertrophic cardiomyopathy, and the normal
heart. Circulation 81:11154-III65
6. Park RC, Little WC, O'Rourke RA (1985) Effect of alteration of LV activation sequence on
the LV end-systolic pressure-volume relation in closed-chest dogs. Circ Res 57:706-717
7. Little W, Reeves R, Arciniegas J, Katholi R, Rogers E (1982) Mechanism of abnormal inter-
venticular septal motion during delayed left ventricular activation. Circulation 65:1486-
1491
8. Sunagawa K, Maughan WL, Burkhoff D, Sagawa K (1983) Left ventricular interaction with
arterial load studied in isolated canine ventricle. Am J Physiol 238:H773-H780
9. Gallagher KP, Matsuzaki M, Koziol JA, Kemper WS, Ross J (1984) Regional myocardial per-
fusion and wall thickening during ischemia in conscious dogs. Am J Physiol 247:H727-
H738
10. Buffington CW, Coyle RJ (1991) Altered load dependence of post-ischemic myocardium.
446 M. R. Pinsky: Quantifying Left Ventricular Ejection Effectiveness
11. Miura T, Bhargava V, Guth BD, et al (1993) Increased afterload intensifies asynchronous
wall motion and impairs ventricular relaxation. J Appl Physiol 75:389-396
12. Thys DM (1987) The intraoperative assessment of regional myocardial performance: Is the
cart before the horse? J Cardiothorac Anesth 1:273-275
13. Weiss JL, Buckley BH, Hutchins GM, Mason SJ (1981) 1\vo-dimensional echocardiographic
recognition of myocardial injury in man: comparison with post-mortem studies. Circula-
tion 63:401-408
14. Little WC, O'Roarke RA (1985) Effect of regional ischemia on the left ventricular end-sys-
tolic pressure-volume relation in chronically instrumented dogs. JAm Coli Cardiol 5:297-
302
15. Kass DA, Chen C-H, Curry C, et al (1999) Improved LV mechanics from acute VDD pacing
in patients with dilated cardiomyopathy and ventricular condition delay. Circulation
99:1567-1573
16. Grover M, Glanz SA (1983) Endocardial pacing affects left ventricular end-diastolic volume
and performance in the intact anesthetized dog. Circ Res 53:72-83
17. Badke FR, Boinay P, Covell JW (1980) Effect of ventricular pacing on regional ventricular
performance. Am J Physiol238: H858-H867
18. Toussaint J-F, Lavergne T, Kerrou K, et al (2002) Ventricular coupling of electrical and me-
chanical dyssynchronization in heart failure patients. Pacing Clin Electrophysiol 25:178-
182
19. Prinzen FW, Hunter WC, Wymann BT, et al (1999) Mapping of regional myocardial strain
and work during ventricular pacing: Experimental study using magnetic imaging tagging.
JAm Coli Cardiol 33:1735-1742
20. Delhass T, Arts T, Prinzen et al (1993) Regional fibre stress-fibre strain area as in the ca-
nine left ventricle. Pflugers Arch 423:78-87
21. Strum DP, Pinsky MR (2000) Esmolol-induced regional wall motion abnormalities do not
affect regional ventricular elastances Anesth Analg 90:252-261
22. Burkhoff D, Oikawa RY, Sagawa K (1986) Influence of pacing site on canine left ventricular
contraction. Am J Physiol 251:H428-H435
23. Baller D, Wolpers HG, Zipfel J, Bretschneider HJ, Hellige G (1988) Comparison of RA, RV
apex and AV sequential pacing on MV0 2 and cardiac efficiency: Pacing Clin Electrophysiol
11:394-403
24. Wiggers CJ (1925) The muscular reactions of mammalian ventricles to artificial surface
stimuli. Am J Physiol 73:346-378
25. Xiao HB, Roy C, Gibson DG (1994) Nature of ventricular activation in patients with dilated
cardiomyopathy: evidence for bilateral bundle branch block. Br Heart J 72:167-174
26. Freedman RA, Alderman EL, Sheffield LT, Saporito M, Fisher LD (1987) Bundle branch
block in patients with chronic coronary artery disease: angiographic correlates and prog-
nostic significance. JAm Coli Cardiol10:73-80
27. Blanc J-J, Etienne Y, Gilard M, et al (1997) Evaluation of different ventricular pacing sites
in patients with severe heart failure. Circulation 96:3273-3277
28. Auricchio A, Salo RW (1997) Acute hemodynamic improvement by pacing in patients with
severe congestive heart failure. Pacing Clin Electrophysiol 20:313-324
29. Auricchio A, Stellbrink C, Block M, et al (1998) Effect of pacing chamber and atrio-ventri-
cular delay on acute systolic function of paced heart failure patients in PATH-CHF Study.
Pacing Clin Electrophysiol 21 (Part 11):837 (abst)
30. Strum DP, Pinsky MR (2000) Modeling of asynchronous myocardial contraction by effec-
tive stroke volume analysis. Anesth Analg 90:243-251
31. Gorcsan JG, Strum DP, Mandarino WA, Gulati VK, Pinsky MR (1997) Quantitative assess-
ment of regional LV contractility by tissue Doppler imaging. Circulation 95:2423-2433
32. Gorcsan J III, Strum DP, Mandarino WA, Pinsky MR (2001) Color-coded tissue Doppler as-
sessment of the effects of acute ischemia on regional left ventricular function: comparison
with sonomicrometry. JAm Soc Echocardiogr 14:335-343
Cardiogenic Shock
S. M. Hollenberg
1 Introduction
Cardiogenic shock is one of the most challenging emergencies that intensivists

must face. Cardiogenic shock is a syndrome that ensues when the heart is unable
to deliver enough blood to maintain adequate tissue perfusion. A rigorous determi-
nation requires hemodynamic confirmation, with sustained systemic hypotension
(systolic arterial pressure < 90 mmHg or mean arterial pressure (MAP) 30 mmHg
or more below basal levels), adequate left ventricular (LV) filling pressures (pulmo-
nary artery wedge pressure> 15 mmHg), and a reduced cardiac output (cardiac in-
dex < 2.2 l!min/m 2 ) [ 1]. In clinical practice, the diagnosis of cardiogenic shock is
often made prior to such objective confirmation, by the presence of systemic arteri-
al hypotension with evidence of hypoperfusion in the setting of myocardial dys-
function.
Cardiogenic shock, resulting either from left ventricular pump failure or from
mechanical complications, represents the leading cause of in-hospital death after
myocardial infarction [2]. Despite advances in management of heart failure and
acute myocardial infarction, until very recently, clinical outcomes in patients with
cardiogenic shock have been frustratingly poor, with reported mortality rates rang-
ing from 50 to 80% [3]. Recently, however, there has been some cause for opti-
mism. There has been tremendous progress in averting shock in the course of myo-
cardial infarction and in treating cardiogenic shock once it develops. Progress has
resulted from the interplay of increased understanding of pathogenesis, more rapid
and aggressive institution of supportive measures, and, most importantly, applica-
tion of a strategy of early revascularization therapy.
Epidemiology of Cardiogenic Shock
The predominant cause of cardiogenic shock is left ventricular failure in the setting
of acute myocardial infarction [2]. Cardiogenic shock usually results from an exten-
sive acute infarction, although a smaller infarction in a patient with previously
compromised left ventricular function may also precipitate shock. Other important
causes include mechanical complications of infarction, right ventricular dysfunc-
tion, prolonged cardiopulmonary bypass, valvular disease, myocardial contusion,
sepsis with unusually profound myocardial depression, and cardiomyopathy [1, 2].
Concurrent conditions such as hemorrhage or infection may also contribute to
shock.
448 S.M. Hollenberg
Patients may have cardiogenic shock at initial presentation, but shock often
evolves over several hours [2, 4]. This is important because it suggests that early
treatment may potentially prevent shock. In the prospective SHOCK (Should We
Emergently Revascularize Occluded Coronaries for Cardiogenic Shock) trial regis-
try, however, the median time from hospital admission to shock onset was only 4.6
hours, which may indicate that the therapeutic window is relatively narrow for
many patients [2]. Comparison of the clinical characteristics of patients with early
and late shock in this registry revealed similar demographic, historical, clinical,
and hemodynamic characteristics, but shock tended to develop earlier in patients
with single-vessel disease than in patients with triple-vessel disease [5]. This dis-
tinction may have clinical implications. Since early shock in the setting of acute
myocardial infarction is more often due to occlusion of a single major coronary ar-
tery with ongoing infarction, it is tenable to hypothesize that early shock may be
more amenable to revascularization of the culprit vessel via thrombolysis or angio-
plasty, and that late shock may require more complete revascularization with multi-
vessel angioplasty or bypass surgery.
In myocardial infarction, shock is more likely to develop in patients who are el-
derly, diabetic, those who have histories of previous infarction, peripheral vascular
disease, and cerebrovascular disease, and those who have anterior infarction [6-9].
Angiographic evidence most often demonstrates multivessel coronary disease (in
the SHOCK trial, left main occlusion was found in 29%, 3-vessel disease in 58%, 2-
vessel disease in 20%, and !-vessel disease in 22% of patients) [10]. This factor is
important because development of compensatory hyperkinesis in myocardial seg-
ments not involved in an acute myocardial infarction is a normal response that
helps maintain cardiac output. Failure to develop such a response, either because of
previous infarction or because of high-grade coronary stenoses, is an important
risk factor for cardiogenic shock and death. [11]
I Pathophysiology
Cardiac dysfunction in patients with cardiogenic shock is usually initiated by myo-

cardial infarction or ischemia. The myocardial dysfunction resulting from ischemia
worsens that ischemia, creating a downward spiral (Fig. 1). Once a critical mass of
ischemic or necrotic left ventricular myocardium (usually about 40%) [12] fails to
pump, stroke volume and cardiac output begin to diminish significantly. Systolic
dysfunction leads to decreased systemic perfusion and hypotension, which reduces
coronary perfusion pressure, and induces compensatory peripheral vasoconstric-
tion and fluid retention. These compensatory mechanisms create a vicious cycle
that further worsens the systolic dysfunction. Likewise, myocardial ischemia in-
creases myocardial stiffness, increasing left ventricular end-diastolic pressure and,
thus, myocardial wall stress at a given end-diastolic volume [13]. The increased left
ventricular stiffness limits diastolic filling and may result in pulmonary congestion,
causing hypoxemia and worsening the imbalance of oxygen delivery and oxygen
demand in the myocardium, resulting in further ischemia and myocardial dysfunc-
tion [1]. The compensatory mechanisms that retain fluid in an attempt to maintain
cardiac output may add to the vicious cycle and further increase diastolic filling
pressures. The interruption of this cycle of myocardial dysfunction and ischemia
forms the basis for the therapeutic regimens for cardiogenic shock.
Cardiogenic Shock 449
Myocardial dysfunction
,·r·
Diastolic
I I
f ....
I Cardiac output
I Systemic
perfusion
I Coronary
perfusion
pressure
Compensatory
vasoconstriction;
Fluid retention
Death
Fig. 1. The 'downward spiral' in cardiogenic shock. Stroke volume and cardiac output fall with left ventri-
cle (LV) dysfunction, producing hypotension and tachycardia that reduce coronary blood flow. Increasing
ventricular diastolic pressure reduces coronary blood flow, and increased wall stress elevates myocardial
oxygen requirements. All of these factors combine to worsen ischemia. The falling cardiac output also
compromises systemic perfusion. Compensatory mechanisms include sympathetic stimulation and fluid re-
tention to increase preload. These mechanisms can actually worsen cardiogenic shock by increasing myo-
cardial oxygen demand and afterload. Thus, a vicious circle can be established. LVEDP: left ventricular
end-diastolic pressure. Adapted from [1) with permission
Another important concept regarding the pathophysiology of cardiogenic shock

is the notion that not all ischemic myocardium is irretrievably lost; areas of dys-
functional but viable myocardium can also cause or contribute to the development
of cardiogenic shock in patients after myocardial infarction. This reversible dys-
function can be described in two main categories: stunning and hibernation. Myo-
cardial stunning represents post-ischemic dysfunction that persists despite restora-
tion of normal blood flow; eventually, however, myocardial performance · recovers
completely [14]. The pathogenesis of stunning has not been conclusively established
but appears to involve a combination of oxidative stress, perturbation of calcium
homeostasis, and decreased myofilament responsiveness to calcium, all in the set-
ting of antecedent ischemia [14]. Hibernating myocardium is in a state of persis-
tently impaired function at rest due to severely reduced coronary blood flow; the
notion that function in such segments can be normalized by improving blood flow
is inherent in this definition [15]. Hibernation can be seen as an adaptive response
450 S.M. Hollenberg
to reduce contractile function of hypoperfused myocardium and restore equilib-

rium between flow and function, thereby minimizing the potential for ischemia or
necrosis. Repetitive episodes of myocardial stunning can coexist with, or mimic,
myocardial hibernation [15]. Consideration of myocardial stunning and hibernation
is vital in patients with cardiogenic shock because of their therapeutic implications.
Both stunned and hibernating myocardium retain inotropic reserve and can re-
spond to catecholamines [14]. Function of hibernating myocardium can improve
with revascularization, and function of stunned myocardium can improve with
time. The notion that some myocardial tissue may recover function has under-
scored the importance of expeditious initiation of supportive measures, including
both medications and intra-aortic balloon counterpulsation, to maintain blood
pressure and cardiac output in patients with cardiogenic shock.
I General Approach to the Patient with Cardiogenic Shock

After recognizing the presence of cardiogenic shock, the clinician must perform
the clinical assessment required to understand its cause while initiating supportive
therapy before shock causes irreversible damage to vital organs. The challenge is
that since speed is important to achieve a good outcome, evaluation and therapy
must begin simultaneously. While the evaluation must be thorough, neither over-
zealous pursuit of a diagnosis before stabilization has been achieved nor overzea-
lous empiric treatment without establishing the underlying pathophysiology is de-
sirable.
A practical approach is to make a rapid initial evaluation on the basis of a fo-
cused history, physical examination, and specific diagnostic procedures. The diag-
nosis of circulatory shock at the bedside is made by the presence of hypotension
along with a combination of clinical signs indicative of poor tissue perfusion, in-
cluding oliguria, a clouded sensorium, and cool, mottled extremities indicative of
reduced blood flow to the skin. Cardiogenic shock is diagnosed after documenta-
tion of myocardial dysfunction and exclusion of alternative causes of hypotension.
Echocardiography is an excellent initial tool for confirming the diagnosis of car-
diogenic shock and for sorting through the differential diagnosis, and should be
performed early as a routine. Echocardiography provides information on overall
and regional systolic function, and can rapidly diagnose mechanical causes of
shock such as papillary muscle rupture and acute mitral regurgitation, acute ven-
tricular septal defect, and free wall rupture and tamponade. In some cases, echo-
cardiography may reveal findings compatible with right ventricular infarction.
Invasive hemodynamic monitoring can be critical for confirming the diagnosis
and is extremely useful in allowing optimization of pharmacologic therapy in un-
stable patients, because clinical estimates of filling pressure can be unreliable [16],
and because changes in myocardial performance and compliance and therapeutic
interventions can change cardiac output and filling pressures precipitously.
Although cardiogenic shock is defined as a cardiac index less than 2.2 l!min/m2
and a pulmonary capillary wedge pressure greater than 15 mmHg, optimal filling
pressures may be higher than this in individual patients due to left ventricular dia-
stolic dysfunction.
________________ ,,~w----------w~-~~,--~~~~~--------
I Initial Management
Maintenance of adequate oxygenation and ventilation are critical. Many patients re-
quire intubation and mechanical ventilation, if only to reduce the work of breathing
and facilitate sedation and stabilization before cardiac catheterization. Some recent
studies have suggested that use of continuous positive airway pressure in patients
with cardiogenic pulmonary edema can decrease the need for intubation [17], but
the studies are small and need to be evaluated with some caution; failure of non-in-
vasive ventilation occurred at least half of the time.
Electrolyte abnormalities should be corrected, and morphine (or fentanyl if sys-
tolic pressure is compromised) used to relieve pain and anxiety, thus reducing ex-
cessive sympathetic activity and decreasing oxygen demand, preload, and afterload.
Arrhythmias and heart block may have major effects on cardiac output, and should
be corrected promptly with anti-arrhythmic drugs, cardioversion, or pacing. Mea-
sures that have been proven to improve outcome after myocardial infarction and
are routinely employed, such as nitrates, beta blockers, and angiotensin-converting
enzyme (ACE) inhibitors, have the potential to exacerbate hypotension in cardio-
genic shock, and should be withheld until the patient stabilizes.
Following initial stabilization and restoration of adequate blood pressure, tissue
perfusion should be assessed. If tissue perfusion remains inadequate, inotropic sup-
port or intra-aortic balloon pumping should be initiated. If tissue perfusion is ade-
quate but significant pulmonary congestion remains, diuretics may be employed.
Vasodilators can be considered as well, depending on the blood pressure.
The initial approach to the hypotensive patient should include fluid resuscitation
unless frank pulmonary edema is present. Patients are commonly diaphoretic and
relative hypovolemia may be present in as many as 20% of patients with cardio-
genic shock. Fluid infusion is best initiated with predetermined boluses titrated to
clinical endpoints of heart rate, urine output and blood pressure. Ischemia pro-
duces diastolic as well as systolic dysfunction, and thus elevated filling pressures
may be necessary to maintain stroke volume in patients with cardiogenic shock.
Patients who do not respond rapidly to initial fluid boluses or those with poor
physiologic reserve should be considered for invasive hemodynamic monitoring.
Optimal filling pressures vary from patient to patient; hemodynamic monitoring
can be used to construct a Starling curve at the bedside, identifying the filling
pressure at which cardiac output is maximized. Maintenance of adequate preload is
particularly important in patients with right ventricular infarction.
When arterial pressure remains inadequate, therapy with vasopressor agents may
be required to maintain coronary perfusion pressure. Maintenance of adequate blood
pressure is essential to break the vicious cycle of progressive hypotension with further
myocardial ischemia. Dopamine increases both blood pressure and cardiac output,
and is usually the initial choice in patients with systolic pressures less than 80 mmHg.
When hypotension remains refractory, norepinephrine may be necessary to maintain
organ perfusion pressure. Phenylephrine, a selective alpha-1 adrenergic agonist, may
be useful when tachyarrhythmias limit therapy with other vasopressors. Vasopressor
infusions need to be titrated carefully in patients with cardiogenic shock to maximize
coronary perfusion pressure with the least possible increase in myocardial oxygen de-
mand. Hemodynamic monitoring, with serial measurements of cardiac output, filling
pressures, (and other parameters, such as mixed venous oxygen saturation), allows for
titration of the dosage of vasoactive agents to the minimum dosage required to
achieve the chosen therapeutic goals [18].
452 S.M. Hollenberg
In patients with inadequate tissue perfusion and adequate intravascular volume,

cardiovascular support with inotropic agents should be initiated. Dobutamine, a se-
lective fJ 1-adrenergic receptor agonist, can improve myocardial contractility and in-
crease cardiac output, and is the initial agent of choice in patients with systolic
pressures greater than 80 mmHg. Dobutamine may exacerbate hypotension in some
patients, and can precipitate tachyarrhythmias. Use of dopamine may be preferable
if systolic pressure is less than 80 mmHg, although tachycardia and increased pe-
ripheral resistance may worsen myocardial ischemia. In some situations, a combi-
nation of dopamine and dobutamine can be more effective than either agent alone.
Phosphodiesterase inhibitors, such as milrinone, increase intracellular cyclic
AMP by mechanisms not involving adrenergic receptors, have both positive inotro-
pic and vasodilatory actions, and are less arrhythmogenic than catecholamines.
Milrinone, however, has the potential to cause hypotension and has a long half-life;
in patients with tenuous clinical status, its use is often reserved for situations in
which other agents have proven ineffective. Standard administration of milrinone
calls for a bolus loading dose followed by an infusion, but many clinicians eschew
the loading dose (or halve it) in patients with marginal blood pressure.
Intra-aortic balloon counterpulsation (IABP) reduces systolic afterload and aug-
ments diastolic perfusion pressure, increasing cardiac output and improving coro-
nary blood flow [19]. These beneficial effects, in contrast to those of inotropic or
vasopressor agents, occur without an increase in oxygen demand. IABP does not,
however, produce a significant improvement in blood flow distal to a critical coro-
nary stenosis, and has not been shown to improve mortality when used alone with-
out reperfusion therapy or revascularization. In patients with cardiogenic shock
and compromised tissue perfusion, IABP can be an essential support mechanism to
stabilize patients and allow time for definitive therapeutic measures to be underta-
ken [19, 20]. In appropriate settings, more intensive support with mechanical assist
devices may also be implemented.
I Myocardial Reperfusion
As previously noted, pathophysiologic considerations favor interventions to restore

flow to occluded arteries in patients with cardiogenic shock due to myocardial in-
farction. Fibrinolytic therapy has been shown to restore infarct artery patency, re-
duce infarct size, preserve left ventricular function, and decrease mortality in pa-
tients with acute infarction [21-23]. Although it has been clearly shown that fibri-
nolytic therapy can reduce the likelihood of subsequent development of shock after
initial presentation [4, 22, 24], its role in the management of patients who have al-
ready developed shock is less certain. The number of patients in randomized trials
is small since most fibrinolytic trials have excluded patients with cardiogenic shock
at presentation [25], but the available trials (Gruppo Italiano per lo Studio Della
Streptochinasi Nell'Infarto Miocardico [GISSI], International Study of Infarct sur-
vival [ISIS]-2, and Global Use of Strategies to Open Occluded Arteries [GUST0]-1)
[26] have not demonstrated that fibrinolytic therapy reduces mortality in patients
with established cardiogenic shock. On the other hand, in the SHOCK Registry
[27], patients treated with fibrinolytic therapy had a lower in-hospital mortality
rate than those who were not (54 vs 64%, p = 0.005), even after adjustment for age
and revascularization status (odds ratio 0.70, p=0.027).
________________ ,,~w----------w~-~~,--~~~~~--------
Fibrinolytic therapy is clearly less effective in patients with cardiogenic shock

than in those without. The explanation for this lack of efficacy appears to be the
low reperfusion rate achieved in this subset of patients. The reasons for decreased
thrombolytic efficacy in patients with cardiogenic shock probably include hemody-
namic, mechanical, and metabolic factors that prevent achievement and mainte-
nance of infarct-related artery patency [28]. Attempts to increase reperfusion rates
by increasing blood pressure with aggressive inotropic and pressor therapy and in-
tra-aortic balloon counterpulsation make theoretic sense, and two small studies
support the notion that vasopressor therapy to increase aortic pressure improves
thrombolytic efficacy [28, 29]. The use of intra-aortic balloon pumping to augment
aortic diastolic pressure may increase the effectiveness of thrombolytics as well.
To date, emergency percutaneous revascularization is the only intervention that
has been shown to consistently reduce mortality rates in patients with cardiogenic
shock. Use of angioplasty in patients with cardiogenic shock grew out of its use as
primary therapy in patients with myocardial infarction. An analysis of the first
1000 patients treated with primary angioplasty at the Mid America Heart Institute
showed a mortality of 44% in the subgroup of 79 patients presenting with cardio-
genic shock, substantially lower than the 80 to 90% mortality in historical controls
[30]. Most other reported case series also showed results with percutaneous inter-
vention superior to those with either fibrinolytic therapy or conservative medical
management, with mortality rates of approximately 40 to 50% [1]. Observational
studies from registries of randomized trials have also reported improved outcomes
in patients with cardiogenic shock selected for revascularization. Notable among
these are the GUSTO-I trial, in which patients treated with an 'aggressive' strategy
(coronary angiography performed within 24 hours of shock onset with revasculari-
zation by percutaneous transuminal coronary angioplasty [PTCA] or bypass sur-
gery) had significantly lower mortality {38% compared with 62%) [3I]. This benefit
was present even after adjustment for baseline characteristics [31] and persisted
out to one year [32].
The National Registry of Myocardial Infarction-2 (NRMI-2), which collected
26 280 shock patients with cardiogenic shock in the setting of myocardial infarction
between I994 and 1997, similarly supported the association between revasculariza-
tion and survival [33]. Improved short-term mortality was noted in those who then
underwent revascularization during the reference hospitalization, either via PTCA
{I2.8% mortality vs 43.9%) or coronary artery bypass grafting (CABG, 6.5 vs
23.9%) [33]. These data complement the GUSTO-I substudy data and are impor-
tant, not only because of the sheer number of patients from whom these values are
derived, but also because NRMI-2 was a national cross-sectional study which more
closely represents general clinical practice than carefully selected trial populations.
This extensive body of observational and registry studies showed consistent ben-
efits from revascularization, but could not be regarded as definitive due to their
retrospective design. Two randomized controlled trials have now evaluated revascu-
larization for patients with myocardial infarction.
The SHOCK study [10, 34] was a randomized, multicenter international trial
which assigned patients with cardiogenic shock to receive optimal medical manage-
ment - including IABP and thrombolytic therapy - or to cardiac catheterization
with revascularization using PTCA or CABG. The trial enrolled 302 patients and
was powered to detect a 20% absolute decrease in 30-day all-cause mortality rates.
Mortality at 30 days was 46.7% in patients treated with early intervention and 56%
in patients treated with initial medical stabilization, but this difference did not
454 S.M. Hollenberg
quite reach statistical significance (p = 0.11) [10 ]. It is important to note that the
control group (patients who received medical management) had a lower mortality
rate than that reported in previous studies; this may reflect the aggressive use of
thrombolytic therapy (64o/o) and balloon pumping (86o/o) in these controls. These
data provide indirect evidence that the combination of thrombolysis and IABP may
produce the best outcomes when cardiac catheterization is not immediately avail-
able. At 6 months, the absolute risk reduction with early invasive therapy in the
SHOCK trial was 13o/o (50.3o/o compared with 63.1 o/o, p = 0.027) [10], and this risk
reduction was maintained at 12 months (mortality 53.3 vs 66.4o/o, p < 0.03) [34].
Subgroup analysis showed a substantial improvement in mortality rates in patients
younger than 75 years of age at both 30 days (41.4 vs 56.8o/o, p=0.01) and 6
months (44.9 vs 65.0o/o, p=0.003). [10]
The SMASH (Swiss Multicenter trial of Angioplasty SHock) trial was indepen-
dently conceived and had a very similar design, although a more rigid definition of
cardiogenic shock resulted in enrollment of sicker patients and a higher mortality
[35]. The trial was terminated early due to difficulties in patient recruitment, for
two different reasons: early on, several European centers declined to participate be-
cause it was felt that it would not be ethical to undertake early invasive evaluation
in such extremely ill patients, and then, after publication of several encouraging
studies documenting the superiority of recutaneous intervention over thrombolysis
for acute myocardial infarction, many centers felt that it had become unethical not
to proceed to early evaluation and revascularization [36]. In the SMASH trial, a
similar trend in 30-day absolute mortality reduction similar to that in the SHOCK
trial of 9o/o was observed (69o/o mortality in the invasive group vs 78o/o in the medi-
cally managed group, RR=0.88, 95o/o CI=0.6-1.2, p=NS) [35]. This benefit was
also maintained at one year.
When the results of both the SHOCK and SMASH trials are put into perspective
with results from other randomized, controlled trials of patients with acute myocar-
dial infarction, an important point emerges: despite the moderate relative risk re-
duction (for the SHOCK trial 0.72, CI 0.54-0.95, for the SMASH trial, 0.88, CI,
0.60-1.20) the absolute benefit is important, with 9 lives saved for 100 patients
treated at 30 days in both trials, and 13.2 lives saved for 100 patients treated at one
year in the SHOCK trial. This latter figure corresponds to a number needed to treat
(NNT) of 7.6, one of the lowest figures ever observed in a randomized, controlled
trial in cardiovascular disease.
I Newer Developments
New approaches to revascularization for patients with acute myocardial infarction

and cardiogenic shock are evolving. Coronary artery stenting is becoming routine,
both in elective cases and as a component of primary angioplasty for acute myocar-
dial infarction. The Primary Angioplasty in Myocardial (PAMI) stent pilot [37] and
the Intracoronary Stenting and Antithrombotic Regimens (ISAR) [38] trials have
recently shown that primary stenting is feasible in patients with acute myocardial
infarction; normal coronary flow is restored in more than 90o/o of patients and
short-term outcome is good [39]. Data in patients with cardiogenic shock are more
sparse. A recent study of direct PTCA in patients with shock [40] reported a suc-
cess rate of 94o/o, with placement of stents in 47o/o of patients; the in-hospital mor-
________________ ,,~w----------w~-~~,--~~~~~--------
tality rate was 26%. Another study of stenting for failed angioplasty in patients
with cardiogenic shock reported a mortality rate of 27o/o [41].
Adjunctive glycoprotein lib/Ilia inhibition is also becoming more routine in
high-risk patients undergoing percutaneous coronary intervention. Recent data in-
dicate that abciximab added to stenting improves outcomes in patients with myo-
cardial infarction undergoing coronary stenting [42]. Although this approach has
not been tested formally in patients with cardiogenic shock, early results of conse-
cutive cases are very promising, and it seems likely that this strategy will improve
outcomes.
Techniques of surgical revascularization are improving as well, particular with
respect to strategies to minimize post-bypass myocardial dysfunction, and this will
likely translate into improved outcomes for patients with cardiogenic shock taken
emergently to the operating room. Finally, adjunctive therapies such as metabolic
interventions are being reexamined [43]. These therapies have the potential to
further improve outcomes after revascularization.
Other Settings
For patients who present in settings without the capability to perform cardiac cath-
eterization and revascularization, the available data suggest that stabilization with
intra-aortic balloon counterpulsation and thrombolysis followed by transfer to a
tertiary care facility may be the best management option. IABP may be a useful ad-
junct to thrombolysis in this setting by increasing drug delivery to the thrombus,
improving coronary flow to other regions, preventing hypotensive events, or by
supporting blood pressure and ventricular function until areas of stunned myocar-
dium can recover. In NRMI-2, of 21718 patients with myocardial infarction and
cardiogenic shock, 32o/o (6992} received IABP counterpulsation [44]. When patients
treated with fibrinolytic therapy were analyzed, those also treated with IABP coun-
terpulsation had a significantly lower mortality rate than those who were not
treated (49 vs 69%, p<0.001}. Similar results were obtained in the SHOCK Trial
Registry; patients treated with combined IABP and fibrinolytic therapy had a lower
mortality rate {47%} than those given fibrinolytic therapy alone (63%, p=0.007}
[27]. Although selection bias is clearly a confounding factor in these studies, two
retrospective studies [45, 46] have found that patients with cardiogenic shock
treated in the community hospital with IABP placement followed by thrombolysis
had improved in-hospital survival and improved outcomes after subsequent transfer
for revascularization.
Conclusion
Treatment of patients with cardiogenic shock has advanced in leaps and bounds.
What was once regarded as a uniformly fatal condition is now proving treatable.
Early revascularization for cardiogenic shock in the setting of acute myocardial in-
farction represents one of the most significant new advances in the treatment of
coronary artery disease. Application of these findings should serve to counteract
the tendency to be fatalistic when treating patients with severe shock, a tendency
which is often self-fulfilling. The potential for reversal of myocardial dysfunction
456 S.M. Hollenberg
with revascularization provides the rationale for supportive therapy to maintain

coronary and tissue perfusion until more definitive measures can be undertaken.
The intensity of research and the recent pace of advances in interventional cardiol-
ogy and in the treatment of myocardial infarction hold out the promise of further
insights that will translate into even more significant reductions in morbidity and
mortality from cardiogenic shock.
References
1. Hollenberg SM, Kavinsky CJ, Parrillo JE (1999) Cardiogenic shock. Ann Intern Med
131:47-59
2. Hochman JS, Boland J, Sleeper LA, et a! (1995) Current spectrum of cardiogenic shock and
effect of early revascularization on mortality. Results of an International Registry. Circula-
tion 91:873-881
3. Goldberg RJ, Yarzebske J, Lessard D, Gore JM (1999) A two-decades (1975 to 1995) long ex-
perience in the incidence, in-hospital and long-term case-fatality rates of acute myocardial
infarction: a community-wide perspective. JAm Coil Cardiol 33:1533-1539
4. Holmes DR Jr, Bates ER, Kleiman NS, et a! (1995) Contemporary reperfusion therapy for
cardiogenic shock: the GUSTO-I trial experience. The GUSTO-I Investigators. Global Utili-
zation of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries.
J Am Coil Cardiol 26:668-674
5. Webb JG, Sleeper LA, Buller CE, et a! (2000) Implications of the timing of onset of cardio-
genic shock after acute myocardial infarction: a report from the SHOCK Trial Registry.
SHould we emergently revascularize Occluded Coronaries for cardiogenic shocK? J Am Coil
Cardiol 36 (3 suppl A):1084-1090
6. Scheidt S, Ascheim R, Killip T (1970) Shock after acute myocardial infarction. A clinical
and hemodynamic profile. Am J Cardiol 26:556-564
7. Killip T, Kimball JT (1967) Treatment of myocardial infarction in a coronary care unit.
A two year experience with 250 patients. Am J Cardiol 20:457-464
8. Hands ME, Rutherford JD, Muller JE, et a! (1989) The in-hospital development of cardio-
genic shock after myocardial infarction: incidence, predictors of occurrence, outcome and
prognostic factors. The MILlS Study Group. J Am Coil Cardiol 14:40-46
9. Leor J, Goldbourt U, Reicher-Reiss H, Kaplinsky E, Behar S (1993) Cardiogenic shock com-
plicating acute myocardial infarction in patients without heart failure on admission: inci-
dence, risk factors, and outcome. SPRINT Study Group. Am J Med 94:265-273
10. Hochman JS, Sleeper LA, Webb JG, et a! (1999) Early revascularization in acute myocardial
infarction complicated by cardiogenic shock. N Eng! J Med 341:625-634
11. Grines CL, Topol EJ, Califf RM, et a! (1989) Prognostic implications and predictors of en-
hanced regional wall motion of the noninfarct zone after thrombolysis and angioplasty
therapy of acute myocardial infarction. The TAMI Study Groups. Circulation 80:245-253
12. Alonso DR, Scheidt S, Post M, Killip T (1973) Pathophysiology of cardiogenic shock.
Quantification of myocardial necrosis, clinical, pathologic and electrocardiographic corre-
lations. Circulation 48:588-596
13. Harizi RC, Bianco JA, Alpert JS (1988) Diastolic function of the heart in clinical cardiology.
14. Bolli R (1998) Basic and clinical aspects of myocardial stunning. Prog Cardiovasc Dis
40:477-516
15. Wijns W, Vatner SF, Camici PG (1998) Hibernating myocardium. N Eng! J Med 339:173-
181
16. Hansen RM, Viquerat CE, Matthay MA, et a! (1986) Poor correlation between pulmonary
arterial wedge pressure and left ventricular end-diastolic volume after coronary aftery by-
pass graft surgery. Anesthesiology 64:764-770
17. Pang D, Keenan SP, Cook DJ, Sibbald WJ (1998) The effect of positive pressure airway sup-
port on mortality and the need for intubation in cardiogenic pulmonary edema: a systema-
tic review. Chest 114:1185-1192
18. Hollenberg SM, Hoyt JW (1997) Pulmonary artery catheters in cardiovascular disease. New
Horiz 5:207-213
19. Willerson JT, Curry GC, Watson JT, et al (1975) Intraaortic balloon counterpulsation in pa-
tients in cardiogenic shock, medically refractory left ventricular· failure and/or recurrent
ventricular tachycardia. Am J Med 58:183-191
20. Bates ER, Stomel RJ, Hochman JS, Ohman EM (1998) The use of intraaortic balloon coun-
terpulsation as an adjunct to reperfusion therapy in cardiogenic shock. Int J Cardiol 65
(suppl 1):S37-S42
21. Fibrinolytic Therapy Trialists' (FTT) Collaborative Group (1994) Indications for fibrinolytic
therapy in suspected acute myocardial infarction: collaborative overview of early mortality
and major morbidity results from all randomised trials of more than 1000 patients. Lancet
343:311-322
22. GUSTO Investigators (1993) An international randomized trial comparing four thromboly-
tic strategies for acute myocardial infarction. N Engl J Med 329:673-682
23. Ryan TJ, Antman EM, Brooks NH, et al (1999) 1999 update: ACC/AHA guidelines for the
management of patients with acute myocardial infarction. A report of the American Col-
lege of Cardiology/American Heart Association Task Force on Practice Guidelines (Com-
mittee on Management of Acute Myocardial Infarction). JAm Coil Cardiol 34:890-911
24. AIMS Trial Study Group (1988) Effect of intravenous APSAC on mortality after acute myo-
cardial infarction: preliminary report of a placebo-controlled clinical trial. Lancet 1:545-
549
25. Col NF, Gurwitz JH, Alpert JS, Goldberg RJ (1994) Frequency of inclusion of patients with
cardiogenic shock in trials of thrombolytic therapy. Am J Cardiol 73:149-157
26. Gruppo Italiano per lo Studio Della Streptochinasi Nell'Infarto Miocardico (GISSI) (1986)
Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet
2:397-402
27. Sanborn TA, Sleeper LA, Bates ER, et al (2000) Impact of thrombolysis, intra-aortic balloon
pump counterpulsation, and their combination in cardiogenic shock complicating acute
myocardial infarction: a report from the SHOCK Trial Registry. SHould we emergently re-
vascularize Occluded Coronaries for cardiogenic shock? J Am Coil Cardiol 36 (3 suppl A):
1123-1129
28. Becker RC (1993) Hemodynamic, mechanical, and metabolic determinants of thrombolytic
efficacy: a theoretic framework for assessing the limitations of thrombolysis in patients
with cardiogenic shock. Am Heart J 125:919-929
29. Garber PJ, Mathieson AL, Ducas J, Patton JN, Geddes JS, Prewitt RM (1995) Thrombolytic
therapy in cardiogenic shock: effect of increased aortic pressure and rapid tPA administra-
tion. Can J Cardiol11:30-36
30. O'Keefe JH Jr, Bailey WL, Rutherford BD, Hartzler GO (1993) Primary angioplasty for
acute myocardial infarction in 1,000 .consecutive patients. Results in an unselected popula-
tion and high-risk subgroups. Am J Cardiol 72:107G-115G
31. Berger PB, Holmes DR Jr, Stebbins AL, Bates ER, Califf RM, Topol EJ (1997) Impact of an
aggressive invasive catheterization and revascularization strategy on mortality in patients
with cardiogenic shock in the Global Utilization of Streptokinase and Tissue Plasminogen
Activator for Occluded Coronary Arteries (GUSTO-I) trial. An observational study. Circula-
tion 96:122-127
32. Berger PB, Thttle RH, Holmes DR Jr, et al (1999) One-year survival among patients with
acute myocardial infarction complicated by cardiogenic shock, and its relation to early re-
vascularization: Results from the GUSTO-I trial. Circulation 99:873-878
33. Rogers WJ, Canto JG, Lambrew CT, et al (2000) Temporal trends in the treatment of over
1.5 million patients with myocardial infarction in the US from 1990 through 1999: the Na-
tional Registry of Myocardial Infarction 1, 2 and 3. J Am Coil Cardiol 36:2056-2063
34. Hochman JS, Sleeper LA, White HD, et al (2001) One-year survival following early revascu-
larization for cardiogenic shock. JAMA 285:190-192
35. Urban P, Stauffer JC, Bleed D, et al (1999) A randomized evaluation of early revasculariza-
tion to treat shock complicating acute myocardial infarction. The (Swiss) Multicenter Trial
of Angioplasty for Shock-(S)MASH. Eur Heart J 20:1030-1038
458 S.M. Hollenberg: Cardiogenic Shock
36. Urban P, Stauffer J-C (2002} Randomized trials of revascularization therapy for cardiogenic
shock. In: Hollenberg SM, Bates ER (eds) Cardiogenic Shock. Futura Publishing Company,
Armonk, pp 135-144
37. Stone GW, Brodie BR, Griffin JJ, et al (1998} Prospective, multicenter study of the safety
and feasibility of primary stenting in acute myocardial infarction: in-hospital and 30-day
results of the PAMI stent pilot trial. Primary Angioplasty in Myocardial Infarction Stent Pi-
lot Trial Investigators. JAm Coll Cardiol 31:23-30
38. Schomig A, Neumann FJ, Walter H, et al (1997} Coronary stent placement in patients with
acute myocardial infarction: comparison of clinical and angiographic outcome after rando-
mization to antiplatelet or anticoagulant therapy. J Am Coil Cardiol 29:28-34
39. Stone GW, Brodie BR, Griffin JJ, et al (1999} Clinical and angiographic follow-up after pri-
mary stenting in acute myocardial infarction: the Primary Angioplasty in Myocardial In-
farction (PAMI) stent pilot trial. Circulation 99:1548-1554
40. Antoniucci D, Valenti R, Santoro GM, et al (1998} Systematic direct angioplasty and stent-
supported direct angioplasty therapy for cardiogenic shock complicating acute myocardial
infarction: in-hospital and long-term survival. JAm Coil Cardiol31:294-300
41. Webb JG, Carere RG, Hilton JD, et al (1997} Usefulness of coronary stenting for cardia-
genic shock. Am J Cardiol 79:81-84
42. Montalescot G, Barragan P, Wittenberg 0, et al (2001} Platelet glycoprotein lib/Ilia inhibi-
tion with coronary stenting for acute myocardial infarction. N Engl J Med 344:1895-1903
43. Diaz R, Paolasso EA, Piegas LS, et al (1998} Metabolic modulation of acute myocardial in-
farction. Circulation 98:2227-2234
44. Barron HV, Every NR, Parsons LS, et al (2001} Use of intra-aortic balloon counterpulsation
in patients with cardiogenic shock complicating acute myocardial infarction: data from the
National Registry of Myocardial Infarction 2. Am Heart J 141:933-939
45. Kovack PJ, Rasak MA, Bates ER, Ohman EM, Stomel RJ (1997) Thrombolysis plus aortic
counterpulsation: improved survival in patients who present to community hospitals with
cardiogenic shock. JAm Coll Cardiol29:1454-1458
46. Stomel RJ, Rasak M, Bates ER (1994} Treatment strategies for acute myocardial infarction
complicated by cardiogenic shock in a community hospital. Chest 105:997-1002
Cardiopulmonary Resuscitation
Inhibition of the Sarcolemmal Sodium-Hydrogen
Exchanger: A Potential Treatment
for Resuscitation from Cardiac Arrest
R. J. Gazmuri, I. M. Ayoub, and J. Kolarova
I Introduction
Increased sarcolemmal sodium (Na+) influx with subsequent intracellular Na+ over-
load due to inability of the Na+-K+ pump to extrude Na+ has been recognized as
an important pathogenic mechanism of cell injury during ischemia and reperfusion
[1-5]. Na+ becomes a 'substrate' for reperfusion injury [6] and intensifies processes
detrimental to cell function (see below). The principal routes for Na+ entry are the
sarcolemmal sodium-hydrogen exchanger isoform-1 (NHE-1), the Na+-HC03 co-
transporter, and Na + channels. However, under conditions of ischemia and reperfu-
sion, NHE-1 seems to be the predominant route.
A large and growing body of knowledge already supports an important patho-
genic role of NHE-1 activation during ischemia and reperfusion. However, this
knowledge is almost exclusively limited to the quiescent (non-fibrillating) heart and
mostly addresses effects on regional myocardial ischemia. Our ongoing research
using· animal models of ventricular fibrillation (VF) provides evidence that NHE-1
activation may also play an important role during resuscitation from VF and that
NHE-1 inhibition may help ameliorate myocardial abnormalities known to limit re-
suscitability [7-9].
The recent development of highly selective NHE-1 inhibitors with excellent
safety profiles has prompted several clinical trials to examine the role of NHE-1 in-
hibition for myocardial protection during acute coronary syndromes [10, 11]. Clini-
cal studies in the cardiac arrest setting are eagerly awaited.
In this chapter, we first summarize the current understanding of the role that
NHE-1 activity plays during ischemia and reperfusion. We then discuss the poten-
tial effects of NHE-1 activity during cardiac arrest and closed-chest resuscitation.
Finally, we describe myocardial abnormalities that develop during VF and the ef-
fects of NHE-1 inhibition on these abnormalities and on cardiac resuscitability.
I NHE-1 During Myocardial Ischemia
NHE-1 belongs to a family of at least 7 mammalian membrane proteins identified

and cloned to date that transport H+ in exchange for Na+. Five of these exchangers
(NHE-1 to NHE-5) are expressed in plasma cell membrane, whereas NHE-6 and
NHE-7 are expressed in intracellular organelles. NHE-1 is the so-called 'housekeep-
ing' isoform and is ubiquitously found in the plasma membrane of virtually every
mammalian cell. It is the primary - if not the only - isoform expressed in sarco-
462 R. J. Gazmuri et al.
H+
t ~
... ~
H+
t
Anaerobic
f
Na+
Ca 2+
t
•...3Na+
Ca2+
metabolism
2K+ Ca2+
Fig. 1. Anaerobic metabolism prompts intracellular acidosis, which activates the sarcolemmal sodium-hy-
drogen exchanger isoform-1 (NHE-1) promoting sarcolemmal Na+ entry in exchange for H+. Na+ may also
enter the cell through the Na+-HC03 cotransporter (NBC) and voltage-gated Na+ channels (Ch). Because
the activity of the Na+-K+ pump (PUMP) is disabled during ischemia, Na+ accumulates, limiting Ca 2+ ex-
trusion and favoring Ca 2+ entry through the Na+-Ca 2+ exchanger (NCX) acting in reverse mode. Ca 2+ may
also enter the cell through voltage-gated channels. Adapted from [9] with permission
lemma of cardiac cells including the human heart [12]. NHE-1 has 815-aminoacids
forming 12 transmembrane-spanning segments and a 315-aminoacid cytoplasmic
hydrophilic carboxyl terminus domain. The transmembrane domain contains the
site of functional ion exchange and the site where inhibitors bind. The cytoplasmic
domain includes various sites for regulation via phosphorylation-dependent and
phosphorylation-independent reactions [13, 14].
Ischemia causes intense intracellular acidosis as a result of ATP hydrolysis, gen-
eration of lactic acid, and inadequate washout of metabolic end products. Acidosis,
in turn, activates the exchanger initiating an allosterically regulated electroneutral
Na+ -H+ exchange that attempts to normalize intracellular pH with consequent in-
creases in sarcolemmal Na+ influx. However, because the activity of the sarcolem-
mal Na+-K+ pump is reduced during ischemia [4], active extrusion of Na+ is cur-
tailed and Na+ accumulates in the cytosol (Fig. 1) [2, 4].
It is thought that as protons exit the cell and accumulate in the extracellular
space, the trans-sarcolemmal proton gradient declines, hence diminishing - but not
eliminating - the Na+-H+ exchange [2]. Upon reperfusion with normo-acidic fluid
(blood), a rapid wash out of the acidic extracellular space reestablishes the trans-
sarcolemmal proton gradient and intensifies - at least transiently - the Na+-H+ ex-
change. This causes additional intracellular Na+ overload.
The mechanism by which Na+ accumulation worsens ischemic and reperfusion
injury is not fully understood. Several observations suggest that cytosolic Na+ over-
load can have potentially detrimental effects on energy metabolism by intensifying
ATP use for Na+ extrusion by the Na+-K+ pump [15]. However, abundant evidence
points to Na+-induced sarcolemmal Ca2 + entry through the Na+-Ca2 + exchanger
Inhibition of the Sarcolemmal Sodium-Hydrogen Exchanger 463
(NCX) actin~ in its reverse mode as the major mechanism of cell injury [6, 16, 17].
Cytosolic Ca + overload is known to disrupt cell physiology in part by adversely af-
fecting structural and functional proteins. More recent studies have suggested that
Ca2 + overload in conjunction with ATP depletion and oxidative stress can also dis-
rupt mitochondrial function causing mitochondrial permeability transition [18].
This phenomenon is attributed to opening of a non-specific high-conductance pore
in the inner mitochondrial membrane and is characterized by mitochondrial swel-
ling, depolarization, and uncoupling.
Some investigators believe that most of the injury associated with NHE-1 occurs
during reperfusion as a result of rapid Na+ influx and the ensuing Na+-induced cy-
tosolic Ca2 + overload. Moreover, early reperfusion (before restoration of the Na+-
K+ pump activity) can rapidly reverse intracellular acidosis and exacerbate reperfu-
sion injury by precluding hydrogen ions to oppose adverse effects of Ca2+ overload
on structural and functional proteins. Earlier studies had in fact demonstrated that
a brief period of reperfusion with acid fluid protects from reperfusion injury [19].
This effect can now be elicited with NHE-1 inhibitors. Notwithstanding these ad-
verse effects of reperfusion, return of oxygen and energy substrates ends this mech-
anism of injury promptly as aerobic metabolism restores the Na+-K+ pump activity
and halts anaerobic acid production.
I NHE-1 Inhibitors
Evidence suggesting that sarcolemmal Na+-H+ exchange could play an important

pathogenic role during ischemia and reperfusion was first reported by Dr. Morris
Karmazyn more than 20 years ago using non-specific NHE inhibitors such as
amiloride and 5-amino substituted derivatives [1, 3]. Within the past decade, more
selective inhibitors - structurally less related to amiloride - have been developed
and confirmed these initial findings. These new compounds are more potent and
with no apparent effects on other ion transport or pH regulatory systems.
Extensive literature exists on the benzoylguanidine derivatives HOE-694 and
HOE-642 (cariporide), demonstrating consistent myocardial protection during isch-
emia and reperfusion [20]. Cariporide has been shown to be highly selective of the
isoform 1 without apparent effects on the NCX or fast Na+ currents. Cariporide has
only negligible biological actions on non-inactivating Na+ currents but these effects
are observed only at very high concentrations [20].
Within the past few years, new NHE-1 inhibitors such as TY-12533, KB-R9032,
SL 591227, SM-20550, eniporide, and zoniporide have been developed. These com-
pounds are structurally diverse but exert similar myocardial protective actions.
NHE-1 inhibitors have been investigated clinically in patients suffering acute
coronary syndromes requiring various emergent coronary interventions [10, 11]. In
the study by Rupprecht and coworkers, 40 mg of cariporide given before percuta-
neous coronary angioplasty in patients presenting with acute anterior myocardial
infarction improved global and regional left ventricular function [10]. In the well-
publicized Guard during ischemia against necrosis (GUARDIAN) trial, cariporide
had no significant effects on overall mortality, however, it improved outcome in a
smaller subset of patients who underwent coronary artery bypass graft and received
the highest studied dose of cariporide [11]. The positive effects on this subset of
patients prompted the ongoing EXPEDITION trial, specifically targeted to investi-
gate the effects of cariporide given perioperatively to patients undergoing coronary

artery bypass graft surgery.
I NHE-1 During Resuscitation from Cardiac Arrest
The conditions that develop during cardiac arrest are uniquely poised to trigger
maximal and sustained NHE-1 activity. The intense intracellular acidosis that devel-
ops rapidly after onset of cardiac arrest is the initial trigger for NHE-1 activation.
The subsequent resuscitation attempt, using closed-chest techniques, promotes re-
perfusion with coronary flows that rarely exceed 20% of normal. These low blood
flow levels are not sufficient to reverse ischemia [21] but sufficient to supply the
coronary circuit with normo-acidic blood, hence, washing out the excess of extra-
cellular protons but without reversing ischemia. These conditions favor NHE-1 to
remain active throughout the resuscitation effort and probably the initial minutes
after the return of spontaneous circulation.
In addition to these local mechanisms, the prominent stress response to cardiac
arrest triggers the release of neuroendocrine mediators that can further intensify
NHE-1 activity. For example, activation of a 1-adrenergic, endothelin-1, and angio-
tensin II receptors has been shown to increase the proton sensitivity of the exchan-
ger by activation of phospholipase C and subsequent phosphorylation of NHE-1,
hence increasing the Na +-H+ exchange activity for a given intracellular pH level. In
addition, metabolites produced during ischemia and reperfusion such as hydrogen
peroxide and lysophosphatidylcholine can also activate NHE-1.
I Effects of Ventricular Fibrillation on the Ischemic Myocardium

Because VF is the principal mechanism of sudden cardiac death, it is important to
discuss the effects of VF on the ischemic myocardium. VF determines myocardial
energy requirements that are at least comparable to - if not greater - than those of
the normally beating heart [22, 23]. For this reason, when VF precipitates cardiac
arrest and coronary blood flow ceases, a severe energy imbalance develops, leading
- within minutes - to intense myocardial ischemia and profound myocardial acido-
sis. In an isolated rat heart preparation, in which global myocardial ischemia was
established by reducing the coronary perfusion flow to 20% of normal, the concur-
rent presence of VF precipitated the development of ischemic contracture and
caused post-ischemic diastolic and systolic dysfunction [23]. In the same study, VF
increased coronary vascular resistance to approximately 200% of baseline, presum-
ably as a result of decreased luminal distending forces (reduced coronary flow) and
external compression of the coronary circuit by the fibrillatory activity [24]. Under
identical ischemic conditions, but in the absence of VF, ischemic contracture did
not occur, the coronary vascular resistance increased to only 150% of baseline, and
there was only minimal and transient post-resuscitation myocardial dysfunction
[23].
In addition to these metabolic and mechanical effects, VF can activate voltage-
gated channels promoting additional sarcolemmal Na + and Ca2 + influx. In an iso-
lated rat heart preparation, in which changes in intramyocardial Na+ were mea-
sured using atomic absorption spectrophotometry [7], increases in intramyocardial
•t
20
Oi
.:.<
.....
0
E
.5 16
E
:I
'C
0
VI
12
Control Ischemia - no VF lschemia - VF

(n = S) (n = S) (n = SJ
Fig. 2. Myocardial Na + content determined by flame atomic absorption spectrophotometry in isolated

Sprague-Dawley rat hearts during baseline perfusion (control) and after 25 minutes of ischemia (1 0 min-
utes of no-flow followed by 15 minutes of low-flow at 10% of baseline flow) with and without concur-
rent ventricular fibrillation (VF). Mean± SEM. * p < 0.05 vs control, t p < 0.05 vs ischemia-no VF. Adapted
from [7] with permission
Na+ prompted by ischemia were further accentuated when VF was present (Fig. 2).
In subsequent pilot studies conducted in collaboration with Dr. Rolf Brandes at
Lo~ola University (Gazmuri RJ 2000, unpublished), the effects of VF on cytosolic
Ca + were examined using surface spectrofluorometry in isolated rat hearts loaded
with indo-1. In these pilot studies, electrical induction of VF during myocardial
ischemia prompted immediate and sustained increases in cytosolic Ca2 + (Fig. 3).
These data indicate that during the global myocardial ischemia of cardiac arrest,
VF worsens ischemic injury by intensifying energy deficit and by accentuating in-
tracellular Na + and Ca2 + overload.
I Myocardial Abnormalities During Ventricular Fibrillation:

Effects of NHE-1 Inhibition
The global myocardial ischemia of cardiac arrest, the presence of VF, and 'ischemic
reperfusion' during closed-chest resuscitation bring forth the development of pro-
minent myocardial abnormalities that can limit resuscitability. A pathogenic model
depicting the interaction among VF, ischemia, and NHE-1 is depicted in Figure 4.
The specific myocardial abnormalities and the effects of NHE-1 inhibition are dis-
cussed below.
Ischemic Contracture and Closed-Chest Resuscitation

Ischemic contracture refers to progressive myocardial wall thickening with reduc-
tions in ventricular cavity size that occurs as a result of severe ischemia. Experi-
mentally, the onset of ischemic contracture is preceded by increases in cytosolic
Ca2 + and coincides with reductions in ATP levels to less than 10% of normal [25].
Coronary flow = 0 mVmln

1.0
::i
~
0
·;:; 0.9
e
b
"U
E 0.8
80
o;
J: 60
E
s 40
0..
~ 20 ll tl ll l
0
0 20 40 60 80 100 120
Seconds
Fig. 3. Effects of electrically-induced ventricular fibrillation (VF) on cytosolic ci+ (upper panel) during global
myocardial ischemia in an isolated Sprague-Dawley rat heart preparation. Spontaneous contractile activity
with declining left ventricular pressures (LVP) occurred between episodes of VF. a.u.= arbitrary units
Ischemic contracture can progress to an irreversible state described more than 30

years ago by Dr. Denton Cooley and colleagues as 'stone heart:
Ischemic contracture has been shown to occur during cardiac arrest in animal
models of VF [26] and in human victims during open-chest resuscitation after
failed closed-chest resuscitation [27]. Because ischemic contracture progressively
reduces the left ventricular cavity, it limits the amount of blood available for ejec-
tion during cardiac compression. This effect partly explains time-dependent reduc-
tions in coronary perfusion pressure, which can ultimately compromise resuscit-
ability.
Our studies in rodent and porcine models of VF indicate that during the rela-
tively short time interval of a typical episode of cardiac arrest and resuscitation,
ischemia alone is not sufficient to precipitate ischemic contracture. Under these
conditions, both VF and reperfusion are required [23]. This last requirement sug-
gests that reperfusion may have permissive effects on the genesis of ischemic con-
tracture.
Our research further indicates that NHE-1 inhibition using cariporide can mark-
edly attenuate ischemic contracture [7, 8]. In an isolated isovolumic rat heart model
of VF, cariporide attenuated increases in left ventricular pressure during VF and
ischemic low-flow myocardial reperfusion [8]. In an intact rat model of VF and
closed-chest resuscitation, less depth of chest compression was required in rats
treated with cariporide to attain the same coronary perfusion pressure as in control
rats [8]. In more recent studies in pigs instrumented with a transesophageal echo-
Worsening
myocardial injury
fig. 4. During ischemia, Na+ may enter the cell through the NHE-1 (activated by intracellular acidosis),
the Na+-HC03 cotransporter (NBC), and Na+ channels. Na+ extrusion by the Na+-K+ pump is progressively
curtailed as the ATP deficit intensifies during ischemia. VF favors additional Na + entry through voltage-
gated Na+ channels and accentuates the energy deficit (fibrillatory activity) further limiting Na+ extrusion.
The intracellular Na+ excess prompts Ca 2+ entry through the Na+-Ca 2+ exchanger (NCX) acting in reverse
mode. In addition, Ca 2+ may also enter the cell through voltage-gated channels. The combination of Na +
and Ca 2+ overload along with ATP depletion (and rapid normalization of intracellular acidosis during re-
perfusion) worsens myocardial ischemic injury contributing to the development of abnormalities that can
limit resuscitability
Doppler probe, cariporide prevented increases in left ventricular wall thickness

during VF and enabled chest compression to generate and maintain a coronary per-
fusion pressure above resuscitability thresholds throughout the resuscitation effort
(Ayoub IM 2002, unpublished).
Myocardial Readiness for Electrical Defibrillation

Delivery of electrical shocks immediately upon recognition of VF is regarded as an
essential component of the chain of survival. This approach is in fact supported by
several studies in which impressive resuscitation outcomes have been reported after
implementation of programs for early defibrillation by first responders and by
trained and even untrained laypersons using automated external defibrillators in
public venues [28, 29]. However, observations in a dog model of VF by Niemann
and coworkers [30] and studies in victims of out-of-hospital sudden cardiac death
by Cobb and coworkers [31] suggest that immediate delivery of electrical shocks
becomes less effective as the interval of untreated VF increases. Under these condi-
tions, a period of chest compression appears necessary to improve the responsive-
ness to electrical shocks.
In a rat model of VF and closed-chest resuscitation, in which VF was left un-
treated for 10 minutes, approximately 6 minutes of chest compression were required
to maximize the likelihood that electrical shocks could restore spontaneous circula-
tion [32]. In the same model, early and repetitive defibrillation attempts worsened
survival outcome. Analysis of amplitude and frequency characteristics of VF wave-
forms demonstrated that successful defibrillation was preceded by a gradual return
of VF waveform characteristics to those present immediately after induction of VF.
These observations suggest that metabolic abnormalities, which develop during
the interval of untreated VF, need to be reversed - or at least ameliorated - before
electrical shocks can successfully terminate VF and restore spontaneous circulation.
This effect is currently accomplished by promoting flow across the coronary circuit.
Whether additional benefit can be obtained from concurrently targeting pathways
of ischemic injury is unclear. Studies are awaited to determine whether NHE-1 in-
hibition during this 'obligatory' period of chest compression could facilitate suc-
cessful defibrillation.
Ventricular Arrhythmias after Return of Spontaneous Circulation

Electrical instability with recurrent episodes of VF commonly occurs after resusci-
tation from cardiac arrest. This may in part account for the nearly 30% incidence
of early post-resuscitation deaths [33]. The mechanisms involved are likely to be
akin to those associated with reperfusion arrhythmias after coronary occlusion. In
this setting, prominent repolarization abnormalities occur characterized by short-
ening of the action potential duration, change in action potential morphology to a
more triangular shape, decreased action potential amplitude, action potential dura-
tion alternans, and afterdepolarizations [34]. These abnormalities typically last for
approximately 5 to 10 minutes after reperfusion and are time coincident with the
period of maximal ventricular ectopic activity. Shortening of the action potential
duration is in part related to opening of sarcolemmal K;hp channels [35]. However,
recent evidence suggests that action potential shortening may be also associated
with NHE-1 activation [36].
In our rat and pig models of VF, prominent ventricular ectopic activity typically
occurs within the initial 5 minutes after return of spontaneous circulation and is
accompanied by episodes of recurrent VF that require additional defibrillation at-
tempts. Administration of cariporide markedly reduced post-resuscitation ventricu-
lar ectopic activity and fully prevented episodes of recurrent VF. In collaboration
with Dr. Michael R. Franz, we recorded endocardial monophasic action potentials
and documented marked shortening of the action potential duration during the ini-
tial post-resuscitation interval. Administration of cariporide almost completely pre-
vented the action potential shortening (Ayoub IM 2002, unpublished). Thus, NHE-1
inhibition appears to be a highly effective intervention for ameliorating repolariza-
tion abnormalities and preventing life-threatening ventricular arrhythmias during
the early post-resuscitation interval.
Post-Resuscitation Myocardial Dysfunction

Despite full restoration of myocardial blood flow, variable degrees of global myo-
cardial dysfunction can be documented after resuscitation from cardiac arrest in
animal models of VF and in human victims of sudden cardiac death [37-39]. Myo-
cardial dysfunction is a manifestation of global myocardial stunning and typically
reverses within hours or days. However, if sufficiently severe it may preclude the re-
turn of stable circulation and also contribute to early post-resuscitation deaths.
Myocardial dysfunction encompasses diastolic and systolic dysfunction. Diastolic
dysfunction is characterized by prominent left ventricular wall thickening with re-
ductions in cavity size that probably reflect resolving ischemic contracture. Systolic
dysfunction is characterized by decreases in contractility with reductions in ejec-
tion fraction, stroke volume, and cardiac output. The combination of diastolic al)_d
systolic dysfunction is particularly detrimental because increased myocardial stiff-
ness precludes ventricular dilatation as required to compensate for decreases in
contractility according to the Frank-Starling force-length relationship. Studies in
our rat and pig models of VF indicate that NHE-1 inhibition is remarkably effective
in preventing the development of diastolic dysfunction and in ameliorating systolic
dysfunction. As a result, NHE-1 inhibition favors earlier return of a stable circula-
tion.
I Conclusion
It is estimated that in the United States alone, approximately 350 000 individuals
suffer an episode of cardiac arrest every year. Yet, less than 5% survive and return
to productive lives. Interventions that can increase this dismal outcome - even by a
small fraction - could have a dramatic public health effect, saving thousands of
lives.
The growing experimental evidence already supports the rationale of NHE-1 in-
hibition for ameliorating myocardial ischemic and reperfusion injury. In the cardiac
arrest setting, the experimental evidence supports a potentially important role of
NHE-1 inhibition with capability for enhancing resuscitability by ameliorating isch-
emic contracture, reducing reperfusion arrhythmias, and improving post-resuscita-
tion myocardial function.
The benefits of NHE-1 inhibition seem not to be limited by species differences
[40]. Sarcolemmal NHE-1 is expressed in human myocardium [12] and clinical
trials have already demonstrated capability of NHE-1 inhibition to ameliorate myo-
cardial injury in patients undergoing emergent coronary interventions [10, 11].
Thus, effects similar to those herein reported in rat and pig models could also
apply to human victims of cardiac arrest and facilitate closed-chest resuscitation
from VF. Clinical studies on NHE-1 inhibition during cardiac resuscitation are
awaited.
Acknowledgement. This work was supported by two VA merit review grants entitled
'myocardial protection after cardiac arrest' and 'myocardial protection during ven-
tricular fibrillation: and by a bridge fund from the Finch University of Health
Sciences/the Chicago Medical School.
470 R.J. Gazmuri et al.
References
1. Karmazyn M (1988) Amiloride enhances postischemic ventricular recovery: Possible role
of Na+/H+ exchange. Am J Physiol 255:H608-H615
2. Lazdunski M, Frelin C, Vigne P (1985) The sodium/hydrogen exchange system in cardiac
cells: its biochemical and pharmacological properties and its role in regulating internal
concentrations of sodium and internal pH. J Mol Cell Cardiol17:1029-1042
3. Moffat MP, Karmazyn M (1993) Protective effects of the potent Na/H exchange inhibitor
methylisobutyl amiloride against post-ischemic contractile dysfunction in rat and guinea-
pig hearts. J Mol Cell Cardiol 25:959-971
4. Bersohn MM (1995) Sodium pump inhibition in sarcolemma from ischemic hearts. J Mol
Cell Cardiol 27:1483-1489
5. Avkiran M (1999) Rational basis for use of sodium-hydrogen exchange inhibitors in myo-
cardial ischemia. Am J Cardiol 83:10G-17G
6. Imahashi K, Kusuoka H, Hashimoto K, Yoshioka J, Yamaguchi H, Nishimura T (1999) In-
tracellular sodium accumulation during ischemia as the substrate for reperfusion injury.
Circ Res 84:1401-1406
7. Gazmuri RJ, Hoffner E, Kalcheim J, et a! (2001) Myocardial protection during ventricular
fibrillation by reduction of proton-driven sarcolemmal sodium influx. J Lab Clin Med 137:
43-55
8. Gazmuri RJ, Ayoub IM, Hoffner E, Kolarova JD (2001) Successful ventricular defibrillation
by the selective sodium-hydrogen exchanger isoform-1 inhibitor cariporide. Circulation
104:234-239
9. Gazmuri RJ, Ayoub IM, Kolarova JD, Karmazyn M (2002) Myocardial protection during
ventricular fibrillation by inhibition of the sodium-hydrogen exchanger isoform-1. Crit
Care Med 30:S166-S171
10. Rupprecht HJ, vom DJ, Terres W, et a! (2000) Cardioprotective effects of the Na(+)/H(+) ex-
change inhibitor cariporide in patients with acute anterior myocardial infarction under-
going direct PTCA. Circulation 101:2902-2908
11. Theroux P, Chaitman BR, Danchin N, et a! (2000) Inhibition of the sodium-hydrogen ex-
changer with cariporide to prevent myocardial infarction in high-risk ischemic situations.
Main results of the GUARDIAN trial. Guard during ischemia against necrosis (GUAR-
DIAN) Investigators. Circulation 102:3032-3038
12. Yokoyama H, Gunasegaram S, Harding SE, Avkiran M (2000) Sarcolemmal Na+/H+ exchan-
ger activity and expression in human ventricular myocardium. J Am Coli Cardiol 36:534-
540
13. Karmaz(.n M, Gan XT, Humphreys RA, Yoshida H, Kusumoto K (1999) The myocardial
Na(+)_H +) exchange: structure, regulation, and its role in heart disease. Circ Res 85:777-
786
14. Karmazyn M, Sostaric JV, Gan XT (2001) The myocardial Na+/H+ exchanger: a potential
therapeutic target for the prevention of myocardial ischaemic and reperfusion injury and
attenuation of postinfarction heart failure. Drugs 61:375-389
15. Mosca SM, Cingolani HE (2000) Comparison of the protective effects of ischemic precondi-
tioning and the Na+/H+ exchanger blockade. Naunyn Schmiedebergs Arch Pharmacol
362:7-13
16. An J, Varadarajan SG, Camara A, et a! (2001) Blocking Na<+)/H(+) exchange reduces
[Na<+)](i) and [ca< 2 +)](i) load after ischemia and improves function in intact hearts. Am J
Physiol 281:H2398-H2409
17. Mosca SM, Cingolani HE (2001) [The Na+/Ca2 + exchanger as responsible for myocardial
stunning]. Medicina (B Aires) 61:167-173
18. Halestrap AP, McStay GP, Clarke SJ (2002) The permeability transition pore complex: an-
other view. Biochimie 84:153-166
19. Kitakaze M, Weisfeldt ML, Marban E (1988) Acidosis during early reperfusion prevents
myocardial stunning in perfused ferret hearts. J Clin Invest 82:920-927
20. Scholz W, Albus U, Counillon L, et a! (1995) Protective effects of HOE642, a selective so-
dium-hydrogen exchange subtype 1 inhibitor, on cardiac ischaemia and reperfusion. Cardi-
ovasc Res 29:260-268
21. Ditchey RV, Horwitz LD (1985) Metabolic evidence of inadequate coronary blood flow dur-
ing closed-chest resuscitation in dogs. Cardiovasc Res 19:419-425
22. Ditchey RV, Goto Y, Lindenfeld J (1992) Myocardial oxygen requirements during experi-
mental cardiopulmonary resuscitation. Cardiovasc Res 26:791-797
23. Gazmuri RJ, Berkowitz M, Cajigas H (1999) Myocardial effects of ventricular fibrillation in
the isolated rat heart. Crit Care Med 27:1542-1550
24. Downey J (1976) Compression of the coronary arteries by the fibrillating heart. Circ Res
39:53-57
25. Koretsune Y, Marban E (1990) Mechanism of ischemic contracture in ferret hearts: Relative
roles of [Ca2 +]; elevation and ATP depletion. Am J Physiol 258:H9-H16
26. Klouche K, Weil MH, Sun S, et al (2002) Evolution of the stone heart after prolonged car-
diac arrest. Chest 122:1006-1011
27. Takino M, Okada Y (1996) Firm myocardium in cardiopulmonary resuscitation. Resuscita-
tion 33:101-106
28. Valenzuela TD, Roe DJ, Nichol G, Clark LL, Spaite DW, Hardman RG (2000) Outcomes of
rapid defibrillation by security officers after cardiac arrest in casinos. N Engl J Med
343:1206-1209
29. Caffrey SL, Willoughby PJ, Pepe PE, Becker LB (2002) Public use of automated external de-
fibrillators. N Engl J Med 347:1242-1247
30. Niemann JT, Cairns CB, Sharma J, Lewis RJ (1992) Treatment of prolonged ventricular fi-
brillation. Immediate countershock versus high-dose epinephrine and CPR preceding coun-
tershock. Circulation 85:281-287
31. Cobb LA, Fahrenbruch CE, Walsh TR, et al (1999) Influence of cardiopulmonary resuscita-
tion prior to defibrillation in patients with out-of-hospital ventricular fibrillation. JAMA
281:1182-1188
32. Kolarova JD, Ayoub IM, Yi Z, Gazmuri RJ. (2003) Optimal timing for electrical defibrilla-
tion after prolonged untreated ventricular fibrillation. Crit Care Med. (In press)
33. Kellermann AL, Hackman BB, Somes (1993) Predicting the outcome of unsuccessful pre-
hospital advanced cardiac life support. JAMA 270:1433-1436
34. Franz MR (2000) Monophasic action potentials recorded by contact electrode method.
Genesis, measurement, and interpretations. In: Franz MR (ed) Monophasic Action Poten-
tials. Bridging Cell and Bedside. Futura Publishing Company, Armonk, pp 19-45
35. Wirth KJ, Uhde J, Rosenstein B, et al (2000) KCATP) channel blocker HMR 1883 reduces
monophasic action potential shortening during coronary ischemia in anesthetised pigs.
Naunyn Schmiedebergs Arch Pharmacol 361:155-160
36. Wirth KJ, Maier T, Busch AE (2001) NHE1-inhibitor cariporide prevents the transient re-
perfusion-induced shortening of the monophasic action potential after coronary ischemia
in pigs. Basic Res Cardiol 96:192-197
37. Gazmuri RJ, Weil MH, Bisera J, Tang W, Fukui M, McKee D (1996) Myocardial dysfunction
after successful resuscitation from cardiac arrest. Crit Care Med 24:992-1000
38. Kern KB, Hilwig RW, Rhee KH, Berg RA (1996) Myocardial dysfunction after resuscitation
from cardiac arrest: An example of global myocardial stunning. J Am Coli Cardiol 28:232-
240
39. Mullner M, Domanovits H, Sterz F, et al (1998) Measurement of myocardial contractility
following successful resuscitation: quantitated left ventricular systolic function utilising
non-invasive wall stress analysis. Resuscitation 39:51-59
40. Karmazyn M (1999) Mechanisms of protection of the ischemic and reperfused myocar-
dium by sodium-hydrogen exchange inhibition. J Thromb Thrombolysis 8:33-38
Immediate Defibrillation
for Out-of-Hospital Ventricular Fibrillation
P. E. Pepe, J. G. Wigginton, and R. L. Fowler
Introduction
Despite well-developed emergency medical service (EMS) systems with rapid re-
sponse advanced cardiac life support (ACLS) capabilities, survival rates for sudden
out-of-hospital cardiac arrest have remained low in most venues, even for out-of-
hospital ventricular fibrillation (VF), the highly-reversible cause of most sudden
out-of-hospital cardiac arrest events [ 1-4]. These poor resuscitation rates have been
attributed most often to delays in the delivery of basic cardiopulmonary resuscita-
tion (CPR) by witnesses, or of rapid defibrillation by EMS personnel [3-4]. How-
ever, recent laboratory and clinical data have also begun to suggest that the current
standard of immediately providing countershock may be detrimental when VF has
been prolonged beyond several minutes [S-9].
Several studies now suggest that when myocardial energy supplies and oxygena-
tion begin to dwindle with prolonged VF, improvements in coronary artery perfu-
sion must first be achieved in order to prime the heart for successful return of
spontaneous circulation after defibrillation [5-7, 10-12]. Along with experimental
and supportive clinical evidence, histological and physiological studies have created
an evolving hypothesis that delivery of an electrical countershock to an ischemic
heart may be more damaging than when it is delivered immediately (within the
first two to three minutes) following the onset of VF [13-15]. In turn, according to
this paradigm, certain pharmacological and mechanical interventions should take
precedence to electrical countershock during resuscitative efforts if the counter-
shocks cannot be delivered immediately for VF.
Reason for Failed Trials of Resuscitation Interventions

This evolving concept of pre-shock interventions for VF may explain the lack of
success for previous clinical studies of so-called 'high dose epinephrine' (i.e.,
> 1 mg/kg doses) and other ACLS procedures [16-18]. In keeping with international
guidelines, these study protocols called for the use of the test intervention follow-
ing multiple countershocks in cases of VF [ 17 -19]. In contrast, the successful pre-
clinical studies had used the resuscitative drugs prior to countershock [20]. This
explanation has been substantiated by specific canine experiments that subse-
quently tested the resuscitation effects of high-dose epinephrine administered be-
fore and after countershocks [6]. In such studies, return of spontaneous circulation
was improved by first administering the high-dose epinephrine following 7.5 min-
utes of VF.
Immediate Defibrillation for Out-of-Hospital Ventricular Fibrillation 473
Several other animal models now .strongly corroborate this concept of 'drugs first'
in prolonged VF [7, 12]. Using a 'cocktail' (multiple-drug) regimen, including high-
dose epinephrine, anti-arrhythmics and anti-oxidants, Menegazzi and colleagues
demonstrated similar effects in terms of resuscitation and short-term survival in
swine that experienced eight minutes of VF prior to interventions [7]. Therefore,
these experiments may help to explain the relative lack of effectiveness of high-dose
epinephrine in clinical trials, particularly in the subset of patients presenting with VF.
In fact, in the clinical trials, the first drugs were usually given, on average, as
late as 17 minutes following notification of the sudden out-of-hospital cardiac ar-
rest event, even when only examining the cases of witnessed collapse alone [16].
Many of the cities in the study had excellent response intervals and higher than
average survival rates, thus indicating a relative 'best case' scenario. Thus, it could
be speculated further that the need for 'pre-shock' interventions would generally be
indicated in such prolonged periods of VF, particularly when compared with the
animal studies demonstrating the efficacy of 'drugs first' with much briefer periods
of arrest.
I When Should One Consider Interventions First?
Although these experimental studies seemed to demonstrate the need for 'high-dose
epinephrine' interventions prior to countershock, Yakaitis et al. had already shown
a marked improvement in outcomes using standard doses of epinephrine (coupled
with basic CPR procedures) prior to countershock in a canine model following only
five minutes of VF [5]. It is possible that higher doses of epinephrine may be
needed after more prolonged periods of VF [20]. Nevertheless, all of these studies
indicate the need for some supportive intervention prior to defibrillation attempts
when several minutes of untreated VF have elapsed.
More recently, some preliminary clinical studies have supported this evolving
concept in terms of providing basic CPR procedures (i.e., chest compressions) for a
short period prior to defibrillation in unmonitored out-of-hospital VF [8, 9]. In
such scenarios, there is, de facto, more than several minutes of VF while the emer-
gency response is being made, even in rapid-response EMS systems. In one of these
studies, conducted in the well-known rapid-response Seattle EMS system, there still
was a marked improvement in outcomes when first-responder firefighter crews pro-
vided 90 seconds of CPR prior to defibrillation attempts [8] (Fig. 1). Although this
study used an historical control (two years of no pre-shock CPR by the first re-
sponders versus a subsequent period using 90 seconds of CPR prior to defibrilla-
tion attempts), survival rates were clearly improved. This finding was particularly
compelling when analyzing the subset of patients receiving the 90 seconds of CPR
first when the EMS response intervals were greater than four minutes. In the cases
in which EMS responded in less than four minutes, there was little difference in
outcomes, but also clearly not worse with the 90 seconds of CPR first.
Before drawing final conclusions about this study, it should be noted that, even
in cases of witnessed collapses, there is also a finite amount of time before EMS is
called following the collapse and that there is another minute or two required to
reach the patient's side and deliver the shock after on-scene arrival of EMS. There-
fore, this 'four-minute response interval' may translate into a seven or eight-minute
period of VF and one should not immediately extrapolate a time frame for 'shock
474 P. E. Pepe et al.
40
%
• 1990-1993 0 1994-1996
30
20
10
0
Response Response
<4min >4min
Fig. 1. Comparison of years with defibrillation attempts first (1990-1993) versus years with provision of
90 seconds of basic cardiopulmonary resuscitation (CPR) prior to defibrillation attempts (1994-1996) in
out-of-hospital cases of ventricular fibrillation (VF) in Seattle, USA, stratified according to those patients
receiving an emergency response within 4 minutes versus those with response interval greater than 4
minutes
100
% • Shock 1st 0 3 min CPR 1st
80
p < 0.02
60
40
20
<Smin >5 min
Fig. 2. Comparison of out-of-hospital VF cases with defibrillation attempts first versus cases with provi-
sion of three minutes of basic cardiopulmonary resuscitation (CPR) prior to defibrillation attempts in Oslo,
Norway, stratified according to those patients receiving an emergency response within 5 minutes versus
those with response interval greater than 5 minutes
first' or 'CPR first'. In addition, one should note that basic CPR was provided by
bystanders in a large percentage of these cases (in all subgroups). Therefore, many
patients were already receiving some degree of basic CPR prior to the counter-
shock, even in the historical control period.
While the Seattle study may be subject to scrutiny because of the (historical
control) study design, Wik and colleagues in Oslo, Norway, later reported almost
identical results in their scientific presentation at the 2001 American Heart Associa-
tion meetings [9]. In their study, a controlled clinical trial, patients were random-
ized to either three minutes of chest compressions first versus shock first. Again,
those patients receiving basic CPR first did much better, particularly in the sub-
groups of patients with more than five-minute EMS response intervals (i.e., pre-
sumably at least eight to nine minutes of VF prior to professional intervention)
(Fig. 2). Although long-term survival rates were not reported, return of sponta-
neous circulation occurred in the group with three minutes of CPR first when re-
sponse intervals exceeded five minutes {62 versus 39%; p<0.02) and return of cir-
culation was similar in the groups for whom the response was less than five min-
utes. Recognizing that even these patients with less than five minutes response do
no worse with 'CPR first', the authors concluded that three minutes of CPR prior to
defibrillation attempts should always be indicated unless the patient collapsed in
front of the EMS.
Unfortunately, this proposed approach has not been totally delineated nor vali-
dated clinically, especially in terms of long-term survival; it also poses problems for
current resuscitation policies. In addition to conflicting with internationally ac-
cepted standards of patient management [19], this evolving concept may also pose
a glitch for current automated defibrillator initiatives such as certain public access
defibrillation initiatives [21, 22]. Especially with well-performed, immediately exe-
cuted basic CPR, successful defibrillation and return of spontaneous circulation can
be achieved after prolonged periods of arrest [3, 4]. In most cases of successful re-
suscitation from VF, resuscitative drugs are never needed, even after the counter-
shock [4, 16]. Therefore, one might interpret the evolving evidence in context. If
the heart remains well-perfused, then the shock may be delivered first.
In the early canine experiments by Yaikitis et al., it was demonstrated that, in
contrast to the aforementioned companion experiments examining five minutes of
VF, shocking first was clearly superior to providing other interventions first follow-
ing only one minute of VF [5]. Also, recent studies have indicated very high surviv-
al rates when patients are shocked within five minutes such as a recent study of
public access defibrillation at the Chicago (USA) airports [22]. In that study of
public use of automated defibrillators, three-quarters of the patients were resusci•
tated and achieved full neurological recovery when shocked within five minutes of
collapse. In fact, many of the patients were already awakening by the time of EMS
arrival at the scene. Nevertheless, the authors also noted that all survivors received
some period of chest compressions and other basic CPR techniques, even if briefly,
while awaiting defibrillation attempts.
One might, therefore, interpret that rapid defibrillation should be a priority in
the first few minutes after arrest, but that basic CPR may also be provided as long
as it does not delay the defibrillation attempts. However, after several minutes of
arrest (perhaps four or five minutes), basic CPR and perhaps other ACLS interven-
tions may need to .be provided prior to the shocks.
It is clear, however, that such judgments and time determinants are all guess-
work and that many factors, particularly the rapid provision of well-performed
early basic CPR, may be confounding variables. Therefore, somehow being able to
objectively delineate between a hypoxic and non-hypoxic heart might be a critical
adjunct to therapeutic decisions. It would also be important to define what thera-
pies are required at any given point (i.e., chest compressions alone, chest compres-
sions and epinephrine, high dose epinephrine and other drugs, or perhaps new al-
ternative CPR devices). Are chest compressions alone indicated after a few minutes
of VF? When do we need drug infusions first? When do we need multiple drugs or
higher doses? Should we try alternative CPR devices prior to countershock?
476 P. E. Pepe et al.
I Predicting the Need to Shock First

Fortunately, successful defibrillation and return of spontaneous circulation may be
more predictable with real-time scoring of the VF waveform signal, such as on-line
electrocardiographic median frequency or scaling exponent analysis [12, 23-27].
Conceptually, in a real-time setting, a defibrillator can perform an analysis of the
VF waveform and score it. If the score is high enough (or low enough depending
on the analysis), a shock would be advised. If missing the mark, other therapies
would be advised first and perhaps at progressively different levels depending on
the severity of the poor score. Studies have shown that basic CPR and certain phar-
macologic interventions can (but not always) improve the VF waveform score [12,
24-26]. Therefore, one might speculate that, in the future, there will be the develop-
ment of user-friendly technology with automated algorithms that will not only
guide the type and degree of initial therapeutic interventions, but also the duration
of resuscitative efforts.
I Conclusion
While the overall concept of providing certain therapeutic interventions prior to
countershock (in cases of prolonged VF) is very compelling, it must be appreciated
that there are multiple confounding variables. These variables include the dynamics
of the sensitivity and specificity of the proposed waveform analyses over time and
their specific relationships to successful return of spontaneous circulation. There
are also other factors such as the type of countershock delivered. Low-energy
biphasic shocks may behave differently than high-energy monophasic shocks or
other evolving energy delivery mechanisms [12, 28-30].
Nevertheless, the evolving evidence for pre-shock therapies following several
minutes of VF is compelling. While it will require aggressive, multi-faceted studies
to delineate the many confounding variables and the specific interventions that
should be delivered under specific circumstances, the preliminary data certainly are
promising. Interestingly, in many ways, these studies re-validate the importance of
the discovery of basic CPR as first described by Kouwenhoven, Knickerbocker and
Jude more than four decades ago [31]. In addition, today, with the introduction of
various promising resuscitative devices such as the active-compression-decompres-
sion (ACD) pump, "vest" CPR, the inspiratory threshhold valve and the minimally-
invasive direct cardiac massage (MIDCM), it is plausible that we may be able to re-
suscitate many more persons than ever before, particularly if these interventions
are applied prior to defibrillation attempts.
References
1. Zheng ZJ, Croft JB, Giles WH, et a! (2002) State-specific mortality from sudden cardiac
death- United States 1999. MMWR Morb Mortal Wkly Rep 51:123-126
2. American Heart Association (2002) Heart and Stroke Statistical Update. AHA Dallas, pp 1-13
3. Cummins RO, Ornato JP, Thies W, Pepe PE (1991) Improving survival from sudden cardiac
arrest: the "chain of survival" concept. Circulation 83:1832-1847
4. Becker LB, Pepe PE (1993) Ensuring the effectiveness of community-wide emergency cardi-
ac care. Ann Emerg Med 22:354-365
5. Yakaitis RW, Ewy GA, Otto CW, Taren DL, Moon TE (1980) Influence of time and therapy
on ventricular defibrillation in dogs. Crit Care Med 8:157-163
6. Niemann JT, Cairns CB, Sharnia J, Lewis RJ (1992) Treatment of prolonged ventricular fi-
brillation: immediate countershock versus high-dose epinephrine and CPR preceding coun-
tershock. Circulation 85:281-287
7. Menegazzi JJ, Seaberg DC, Yealy DM, Davis EA, MacLeod BA (2000) Combination pharma-
cotherapy with delayed countershock versus standard advanced cardiac life support after
prolonged ventricular fibrillation. Prehosp Emerg Care 4:31-37
8. Cobb LA, Fahrenbruch CE, Walsh TR, et al (1999) Influence of cardiopulmonary resuscita-
tion prior to defibrillation in patients with out -of-hospital ventricular fibrillation. JAMA
281:1182-1188
9. Wik L, Hansen TB, Fylling F, Vaagenes P, Steen P (2001) Three minutes of basic cardiopul-
monary resuscitation (CPR) of pre-hospital ventricular defibrillation (VF) patients in-
creases the number of patients who restore spontaneous circulation. Circulation (suppl)
104:17 (abst)
10. Kern KB, Garewal HS, Sanders AB, et al (1990) Depletion of myocardial adenosine tripho-
sphate during prolonged untreated ventricular fibrillation: effect on defibrillation success.
Resuscitation -20:221-229
11. Ditchey RV, Goto Y, Lindenfeld J (1992) Myocardial oxygen requirements during experi-
mental cardiopulmonary resuscitation. Cardiovasc Res 26:791-797
12. Angelos MG, Menegazzi JJ, Callaway CW (2001) Bench to bedside: Resuscitation from pro-
longed ventricular fibrillation. Acad Emerg Med 8:909-924
13. Gaba DM, Talner NS (1982) Myocardial damage following transthoracic direct current
countershock in newborn piglets. Fed Cardiol 2:281-288
14. Tacker WA, Van Fleet JF, Geddes LA (1979) Electrocardiographic and serum enzymatic al-
terations associated with cardiac alterations induced in dogs by single transthoracic
damped sinusoidal defibrillation shocks of various strengths. Am Heart J 98:85-193
15. Al-Khadra A, Nikolski V, Efimov IR (2000) The role of electroporation in defibrillation.
Circ Res 87:797-804
16. Pepe PE, Abramson NS, Brown CG (1994) ACLS - Does it really work? Ann Emerg Med
23:1037-1041
17. Brown CG, Martin DR, Pepe FE, et al (1992) Standard versus high-dose epinephrine in
out-of-hospital cardiac arrest- a controlled clinical trial. N Engl J Med 327:1051-1055
18. Callaham M, Madsen CD, Barton CW, et al (1992) A randomized clinical trial of high-dose
epinephrine and norepinephrine vs standard-dose epinephrine in prehospital cardiac ar-
rest. JAMA 268:2667-2672
19. 2000 Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiac Care (2000).
Circulation (suppl) 102:1-384
20. Brown CG, Werman HA, Davis EA, Hobson J, Hamlin RL (1987) The effects graded doses
of epinephrine on regional myocardial blood flow during cardiopulmonary resuscitation in
swine. Circulation 75:491-497
21. Weisfeldt ML, Kerber RE, McGoldrick RP, et al (1995) American Heart Association report
on the Public Access Defibrillation Conference December 8-10, 1994. Circulation 92:2740-
2747
22. Caffrey SL, Willoughby PJ, Pepe PE, Becker LB (2002) Public use of automated external de-
fibrillators. N Engl J Med 347:1242-1247
23. Brown CG, Dzwonczyk R (1996) Signal analysis of the human electrocardiogram during
ventricular fibrillation: frequency and amplitude parameters as predictors of successful
countershock. Ann Emerg Med 27:184-188
24. Strohmenger HU, Linder KH, Crown CG (1997) Analysis of the ventricular fibrillation ECG
signal amplitude and frequency parameters as predictors of countershock success in hu-
mans. Chest 111:584-589
25. Noc M, Weil MH, Gazmuri RJ, SunS, Biscara J, Tang W (1994) Ventricular fibrillation vol-
tage as a monitor of the effectiveness of cardiopulmonary resuscitation. J Lab Clin Med
124:421-426
26. Strohmenger HU, Linder KH, Keller A, Linder IM, Pfenninger E, Bothner U (1996) Effects
of graded doses of vasopressin on median fibrillation frequency in a porcine model of car-
diopulmonary resuscitation: Results of a prospective, randomized, controlled trial. Crit
Care Med 24:1360-1365
478 P. E. Pepe et al.: Immediate Defibrillation for Out-of-Hospital Ventricular Fibrillation
27. Weaver WD, Cobb LA, Dennis D, et al (1985) Amplitude of ventricular fibrillation wave-
form and outcome after cardiac arrest. Ann Intern Med 8:157-163
28. Cummins RO, Hazinski MF, Kerber RE, et al (1998) Low-energy biphasic waveform defi-
brillation evidence-based review applied to emergency cardiovascular care guidelines. Cir-
culation 97:1654-1667
29. Wang HE, Menegazzi JJ, Lightfoot CB, Callaway CW, Fertig KC, et al (2001) Effects of hi-
phasic versus monophasic defibrillation on the scaling exponent in a swine model of pro-
longed ventricular fibrillation. Acad Emerg Med 8:771-780.
30. Bardy GH, lvey TD, Allen MD, Johnson G, Mehra R, Greene HL (1989) A prospective ran-
domized evaluation of biphasic versus monophasic waveform pulses on defibrillation effi-
cacy in humans. JAm Coli Cardiol14:728-733
31. Kouwenhoven WB, Jude JR, Knickerbocker GG (1960) Closed-chest cardiac massage. JAMA
173:1064-1067
j Monitoring Systems
Cardiac Output Monitoring: Will New Technologies
Replace the Pulmonary Artery Catheter?
J. A. L. Pittman and K. J. Gupta
I Introduction
Since its introduction into clinical practice by Swan and colleagues in 1970, pulmo-
nary artery catheterization has remained the 'gold standard' of hemodynamic mon-
itoring for the critically ill medical or surgical patient. Although the original focus
of pulmonary artery catheter (PAC) monitoring was the measurement of pulmonary
artery and pulmonary artery wedge pressures [1], the catheter was soon modified
to allow intermittent measurement of cardiac output by the thermodilution method
[2]. Many would argue that the greatest value of PAC monitoring is not the accurate
estimation of left ventricular filling pressures, repeatedly shown to be an unreliable
estimate of preload [3-5], but rather the ability to measure cardiac output and so
titrate therapy to achieve hemodynamic goals. Several groups have reported the
benefits of optimizing cardiac index or systemic oxygen delivery (D0 2 ) in the man-
agement of the critically ill [6-9].
After several decades, the PAC continues to be widely used but there is an ex-
panding interest in alternative cardiac output monitors. There are several reasons
for this. First, various studies have reported on the complications of PACs [10] and
the possible increased morbidity and mortality associated with their clinical use
[ 11-13]. Alternatives to standard thermodilution cardiac output measurement have
focused on being less invasive and have tried to use techniques that avoid the risks
of inserting and using a PAC. Second, clinicians are better aware that abnormalities
of cardiac ouput cannot be reliably detected at the bedside by physical examina-
tion, even when the examination is performed by experienced clinicians (14, 15].
Clinicians are searching for a minimally invasive practical method of measuring
cardiac output to avoid the uncertainty of guessing the value. Third, advances in
technology over the past twenty years have provided a number of potentially more
practical techniques for cardiac output measurement. Some provide more continu-
ous cardiac output or stroke volume data, and offer additional cardiovascular and
respiratory measurements not available with the PAC. Although this discussion is
predominantly concerned with cardiac output measurement, clinicians may well
consider that the greatest value of a new cardiac output monitor is the additional
measured variables it provides. The significance of these variables will be better
understood as their clinical value is further defined. Fourth, and finally, experience
and expertise are required to correctly utilize and interpret the information the
PAC provides [16]. Clinicians may find some of the alternative technologies, even if
theoretically less robust, more applicable for use in their individual working envi-
ronments.
482 J. A.l. Pittman and K. J. Gupta
This chapter will briefly focus on several of these alternative methods of moni-
toring cardiac output, their operational principles, advantages, limitations and the
additional cardiovascular variables that they measure. The reader can then begin to
judge the PAC in this increasingly competitive field.
I What is the 'Gold Standard'?

Before clinicians adopt any new measurement devise they need to be convinced
that it compares favorably to the existing 'gold standard'. In the case of new cardiac
output monitors, 'accuracy' of measurement is determined invariably by compari-
son with the clinical standard, thermodilution cardiac output, using a PAC. While
many investigators have described a new cardiac output measurement technique by
reporting how well it correlates with thermodilution cardiac output (r2 value), the
preferred statistical techniques for describing agreement between two methods of
measurement is to report the bias between methods (mean difference) and the
standard deviation of the differences (or limits of agreement) [17]. Ideally cardiac
output measurements made with 'new' technology should have a small bias and
narrow limits of agreement when compared to cardiac output measurements from
the reference method. It is generally recognized that for the new technology to be
accepted the percentage limits of agreement should be within 30% of the reference
method [18]. Clinicians looking to adopt new measurement techniques into clinical
practice should be familiar with these methods of statistical analysis when deciding
whether a new cardiac output monitoring method is accurate enough to replace the
standard thermodilution method.
Ideally a new technology should not be judged against a technique that has po-
tentially significant inherent inaccuracy. The options are limited though. Electro-
magnetic flowmetry of the aortic root is close to an 'ideal' reference but is clearly
restricted by the invasive requirements of the technique. Thermodilution cardiac
output measurement was validated by comparison with both the Fick and the dye-
dilution methods of measuring cardiac output [19-21]. Both techniques can be very
accurate but, like electromagnetic flowmetry, require considerable time and techni-
cal expertise. This leaves the thermodilution technique as the usual comparator,
which although relatively easy to use, has a number of technical limitations that
make it a less than optimal as a 'gold' standard reference [11]. Sources of inaccu-
racy include:
I Right ventricular cardiac output measured by thermodilution is unequal to left
ventricular cardiac output in the presence of cardiac shunts
I Tricuspid regurgitation (and pulmonary regurgitation) usually causes cardiac
output to be underestimated [23, 24]
I Blood stream temperature variations confound accurate cardiac output measure-
ment (e.g., post bypass, IV fluid boluses, etc.) [25, 26]
I Marked beat-to-beat variations in right ventricular stroke volume (up to 50%)
may occur during the respiratory cycle. Depending on the timing of cold fluid
bolus injection, this may produce large variations in CO measurement [27, 28].
The latter two problems commonly complicate accurate thermodilution cardiac out-
put measurement. As a consequence of these limitations, clinicians should be aware
that technology of limited robustness could appear clinically acceptable when the
thermodilution technique is used as the reference comparison. As newer technolo-
Cardiac Output Monitoring: Will New Technologies Replace the Pulmonary Artery Catheter? 483
gies are validated it is possible that some of these will become more appropriate
reference methods than thermodilution.
I Thoracic Electrical Bioimpedance

A method based on the principles described by Kubicek in 1966, this technique de-
termines stroke volume based upon changes in electrical impedance of the thoracic
cavity occurring with the systolic ejection of blood from the heart [29, 30]. Perhaps
the least invasive technique available, this method requires placement of a series of
electrocardiograph (EKG)-type disposable skin electrodes on the neck, lower thor-
ax, and precordium. A small electrical current is passed through the outer electro-
des and the changes in thoracic electrical impedance are measured throughout the
cardiac cycle and mathematically processed to provide a measurement of stroke
volume and cardiac output. Thoracic fluid content is also calculated and may give
an indication of fluid balance. In general, this technique has had limited agreement
with thermodilution cardiac output, particularly in ventilated critically ill patients
[31]. Its current role seems more focused in the early (and noninvasive) identifica-
tion of patients at risk for perioperative complications [6, 30]. The technique is
limited to adult patients and is not accurate in severe aortic regurgitation or when
the thoracic cavity is open. The electrical current used may interfere with certain
pacemakers.
I Partial C02 He-breathing

This non-invasive measurement of cardiac output is based on a technique called
differential Fick partial carbon dioxide (C0 2 ) re-breathing. The Fick equation,
based on C02 as an indicator, states that cardiac output is equal to C0 2 elimination
divided by the venous-arterial difference in the C0 2 content. The partial re-breath-
ing method yields a differential form of the Fick equation by eliminating the need
to measure mixed venous C0 2 (assumed to be constant during the re-breathing
period and therefore cancelled out of the equation). This is then corrected for
shunt using functional hemoglobin saturation and a user-entered value for inspired
oxygen concentration (Fi02 ). The method can only be employed in tracheally intu-
bated patients who are receiving a stable pattern of mechanical ventilation and re-
quires the addition of a disposable extension to the patient breathing circuit that
contains a re-breathing valve, C0 2 sensor, and flow sensor [32]. Every three min-
utes, a 50-second partial C02 re-breathing maneuver is automatically triggered,
which causes a transient decrease in C02 elimination and increase in end-tidal
C0 2 • This provides the data required for the attached computer to calculate cardiac
output. These brief re-breathing episodes typically produce approximately a 10%
rise (3-5 mmHg/0.4-0.67 KPa) in PaC0 2 • This is usually well tolerated, but in cer-
tain patients (e.g., those with elevated intra-cranial pressure [ICP] or critical respi-
ratory disease) this may be a concern. Apart from the transient elevation in C0 2
this is an extremely safe technique that requires no additional catheters or invasive
procedures. Reports suggest reasonable agreement with thermodilution cardiac out-
put measurements, with the added convenience of frequent cardiac output measure-
ments updated every three minutes [33-35]. Finally, as a respiratory based monitor-
484 J. A. L. Pittman and K. J. Gupta
ing device, this system provides additional bedside measurements of a number of

potentially valuable respiratory parameters, including end-tidal C0 2 , C0 2 elimina-
tion rate, airway pressures, respiratory volumes (including dead space) and dy-
namic compliance.
I Esophageal Doppler
A number of ultrasound-based methods for measurement of cardiac output have

been described and applied clinically, including transtracheal Doppler using a
transducer mounted on an endotracheal tube [36], a PAC equipped with ultrasound
crystals [37], and Doppler ultrasonography utilizing a hand held probe placed in
the suprasternal notch [38]. However, none of these have had the sustained clinical
interest and experience of esophageal Doppler cardiac output measurement techni-
ques [39]. In brief, these devices use a specially designed esophageal probe, ap-
proximately the same size as a standard esophageal stethoscope. An ultrasound
transducer is fitted to the end of the probe and insonnates the descending aortic
blood flow to determine flow velocity. Stroke volume is thereby derived from the
spatially averaged flow velocity, ejection time, and aortic cross sectional area. The
latter may be determined by computer-based algorithm, or more recently, measured
directly by a second ultrasound M-mode transducer located in the esophageal
probe [40]. Esophageal Doppler cardiac output values are provided continuously,
since stroke volume, the fundamental measurement, is measured on a beat-to-beat
basis. Location of the optimal aortic ultrasound window can be identified by a vi-
sual and audible signal. It is important to note that blood flow velocity is measured
in the descending aorta, and, therefore, only represents a fraction of total cardiac
output, generally about 70%. This proportion remains reasonably constant and eso-
phageal Doppler cardiac output measurements can provide a reasonable indication
of changes in cardiac output. Several investigators have used this device to titrate
fluid therapy and have demonstrated reduced patient morbidity with this approach
to resuscitation [41, 42]. Despite several potential sources of error a good correla-
tion has been demonstrated between cardiac output measured by esophageal Dop-
pler and simultaneously by thermodilution and Pick methods [9, 43-46].
Thus far, the esophageal Doppler technique has been limited to tracheally intu-
bated patients, generally in the operating room setting. Smaller, more stable Dop-
pler probes may allow transnasal passage in non-mechanically ventilated patients.
In addition to cardiac output, the Doppler flow-velocity waveform provides infor-
mation on preload and contractility. The ventricular ejection time (or flow time)
corrected for heart rate provides an index of preload and the peak flow-velocity is
an indicator of contractility. These additional variables have proven useful as guides
to left ventricular performance and filling, and have shown better relationships to
left ventricular end-diastolic volume (LVEDV) than more traditional PAC-based
measurements [47]. The probe has been shown to be relatively easy to insert, and
it is not associated with major complications [48-50]. The technique, however, re-
quires practice and pattern recognition of the Doppler signal [51]. Small changes
in position can have significant impact on the signal generated and subsequently
the esophageal Doppler technique may be limited by the technical operator require-
ments that are necessary to achieve reliable and consistent hemodynamic measure-
ments.
I Lithium Indicator Dilution Cardiac Output Measurement
Development of miniaturized ion-selective electrodes has allowed the clinical reali-

zation of the lithium indicator dilution cardiac output (LiDCO) measurement tech-
nique. This method measures cardiac output by indicator dilution, the indicator
being a bolus injection of lithium chloride (0.3 mmol) via central or peripheral ve-
nous catheter, and the sensor being a lithium-selective electrode that measures a
lithium dilution curve sampled from a standard peripheral arterial catheter [52].
During each cardiac output measurement, arterial blood is drawn over the sensor
at a constant rate of 4 mls/min by an electric pump. Clinicians will recognize an in-
dicator dilution curve, similar to the thermal curve recorded with thermodilution
cardiac output measurement. However, since the indicator is sampled and mea-
sured on the arterial side of the circulation, the washout curve is longer and re-
flects a greater number of heartbeats and several respiratory cycles (20-40 s). As a
result, the method provides a better average of the respiratory cycle-induced
changes in stroke volume and so cardiac output can be measured with a single in-
jection rather than an average of several indicator curves. The LiDCO method
agrees well with standard thermodilution [53, 54] and electromagnetic flowmetery
[53] techniques and is possibly the most accurate measurement of cardiac output
readily available at the bedside. Peripheral or central venous injection of lithium
gives comparable cardiac output measurements [55]. The indicator dose of lithium
is l/300th of the therapeutic dose and should not have any physiological conse-
quences. It is recommended that measurements are limited to 10/day, although no
data exist for the repeated long-term use of lithium in this context. An accurate
plasma sodium and hemoglobin value is needed by the computer software to en-
sure correct calculation .of the cardiac output. The technology cannot be used in
patients on lithium therapy, and neuromuscular blocking drugs, such as vecuro-
nium, also adversely influence the sensor function. Lithium indicator dilution per-
mits reliable intermittent cardiac output measurements, requires only routinely
available arterial and venous access, and is comfortably tolerated even by the fully
conscious patient. It is therefore particularly applicable to intermediate risk ICU or
high dependency unit (HDU) patients.
I Pulse Contour Arterial Pressure Waveform Analysis
Pulse contour analysis has been investigated for many years as a less invasive meth-
od to measure cardiac output, either using an arterial catheter [56] or even non-in-
vasively with a finger cuff blood pressure device [57]. The pulse contour methods
generally analyze the systolic portion under the arterial pressure waveform (i.e., be-
tween the start of ventricular ejection and the dicrotic notch) to determine stroke
volume and thus can provide beat-to-beat measurement of cardiac output. All de-
vices require a direct measurement of cardiac output to calibrate their pulse con-
tour algorithms.
One of the newer versions of these devices uses trans-cardiopulmonary thermo-
dilution for calibration but requires central arterial catheterization (femoral, bra-
chial, or axillary) for adequate arterial waveform analysis [56, 58]. The trans-
cardiopulmonary thermodilution method seems to correlate well with the PAC cold
bolus thermodilution technique and Fick methods [59, 60] and avoids right heart
486 J. A. L. Pittman and K.J. Gupta
catheterization. Trans-cardiopulmonary thermodilution additionally allows several

specific volumes to be calculated using the cardiac output and transit times deter-
mined from the indicator dilution curve. The utility of these new volume measure-
ments has yet to be fully elucidated but global end-diastolic volume, the end-diasto-
lic volume of all four cardiac chambers, may prove to be a guide to cardiac preload
that is superior to central venous pressure (CVP) and pulmonary artery occlusion
pressure (PAOP) [61], and extravascular lung water measurement may be beneficial
in the prediction and treatment of pulmonary edema [62).
A newer alternative continuous method of cardiac output monitoring uses a
novel algorithm to determine beat-to-beat stroke volume from the mathematical
analysis of the peripheral arterial waveform [63]. This device uses the entire arteri-
al pressure waveform, which it initially changes into a volume wave via a look-up
table. The volume wave is then transformed into a nominal stroke volume via a
complex process called autocorrelation and then calibrated to the 'true' stroke vol-
ume by the lithium indicator dilution method. Continuous cardiac output, stoke
volume, heart rate (HR), and mean arterial pressure (MAP) are displayed by the
computer. Hemodynamic variation with respiration is also calculated in the form of
stroke volume variation (SVV), systolic pressure variation (SPV) and pulse pressure
variation (PPV). SPV, SVV, and PPV provide as meaningful an assessment of intra-
vascular volume as CVP, and have been shown to be good predictors of a change
of cardiac output in response to a fluid challenge [64-66]. Continuous calculated
D0 2 can also be displayed.
Pulse contour analysis has several potential problems that may influence accu-
racy and reliability. Cardiac output measurement may become inaccurate in the
presence of arrhythmias, aortic valve disease, a significantly dampened arterial
catheter signal, or following marked changes in arterial vascular compliance. The
substantial advantage of pulse contour analysis cardiac output measurement being
minimally invasive can be offset by the requirements of the calibration technique
(usually thermodilution cardiac output) but the newer device uses calibration tech-
niques that address this. The great advantage these technologies offer is safe, easy
to use, truly continuous cardiac output measurement in ventilated and sponta-
neously breathing patients.
Modifications of the PAC

Continuous Warm Thermodilution and the Volumetric PAC
A thermal coil incorporated into the right ventricular portion of a PAC provides a
method to semi-continuously monitor cardiac output. The coil heats the blood in a
pseudo-random sequence and analysis of the thermal signal detected at a thermis-
tor in the PAC tip generates a thermodilution curve [67, 68]. This is currently one
of the most widely used cardiac output measurement systems, but the signal to
noise ratio is poor with temperature changes measured in fractions of a degree,
and they have a 5 to 15 minute delay in responding to sudden flow changes. The
trade-off for a slower response time is a better 'averaged' cardiac output value than
that available from a bolus thermodilution measurement.
The volumetric PAC has a rapid response thermistor and an intra-cardiac EKG
electrode. This allows the recognition of a series of plateaus along the re-warming
phase of a thermodilution curve that are produced by the pulsatile ejection of
blood from the right ventricle (RV). The ratio of the temperature change of two
successive diastolic plateaus represent the fraction of blood remaining in the RV
(the residual fraction). This allows calculation of the RV ejection fraction (RVEF),
which when combined with the stroke volume allows calculation of the RVEDV.
Several groups have validated these measurements by comparing them with radio-
nuclide imaging, echocardiography and biplanar angiography [69-72]. It has been
suggested that the RVEDV index is a better indicator of preload in critically ill pa-
tients than the PAOP, and that it allows the prediction of a change of cardiac output
in response to a fluid challenge [73]. Whilst these modifications may have their
utility, neither avoids the problems associated with the use of PACs alluded to
above.
I Conclusion
The importance of measuring cardiac output in critically ill patients is accepted
but it is unclear how this can be best achieved. For several decades, the PAC has
been chosen for this function but as concerns have grown about the safety of right
heart catheterization the advantages and disadvantages of thermodilution cardiac
output measurement and of the PAC have had to be considered. A variety of new
technologies exploit this issue by being considerably less invasive with comparable
accuracy. Some show great promise, particularly pulse contour analysis, and slowly
the PAC is being discarded. Clinicians have found that the different technologies
allow cardiac output measurement in a broader range of patients and working en-
vironments than PAC monitoring. No one device claims pole position and just as
some clinicians will consider that the measurement of pulmonary artery pressure,
cardiac filling pressures and mixed venous oxygen saturations justify the continued
use of PACs, others will feel that it is the information additional to cardiac output
measurement that is the greatest value of a new cardiac output monitor. In this cur-
rently dynamic area of critical care medicine the responsibility lies with each clini-
cian to trial the available cardiac output monitors and determine which best suits
their patients' needs.
I References
1. Swan HJ, Ganz W, Forrester J, Marcus H, Diamond G, Chonette D (1970} Catheterization
of the heart in man with use of a flow-directed balloon-tipped catheter. N Engl J Med
283:447-451
2. Ganz W, Donoso R, Marcus H, Forrester J, Swan H (1971} A new technique for measure-
ment of cardiac output by thermodilution in man. Am J Cardiol 27:392-396
3. Baek SM, Makabali GG, Bryan-Brown CW, Kusek JM, Shoemaker WC (1975} Plasma expan-
sion in surgical patients with high central venous pressure (CVP): the relationship of blood
volume to hematocrit, CVP, pulmonary wedge pressure, and cardiorespiratory changes.
Surgery 78:304-315
4. Calvin J, Driedger A, Sibbald J (1981} Does the pulmonary capillary wedge pressure predict
left ventricular preload in critically ill patients. Crit Care Med 9:437-443
5. Lichtwark-Aschoff M, Zeravik J, Pfeiffer U (1992) Intrathoracic blood volume accurately
reflects circulatory volume status in critically ill patients with mechanical ventilation. In-
6. Boyd 0, Bennett ED (1999} Achieving the goal. Crit Care Med 27:2298-2299
488 J. A. L. Pittman and K. J. Gupta
7. Shoemaker W (1990) Use and abuse of the balloon tip pulmonary artery (Swan-Ganz)
catheter: Are patients getting their money's worth? Crit Care Med 18:1294-1296.
8. Singer M (1998) Cardiac output in 1998. Heart 79:425-428
9. Wilson J, Woods I, Fawcett J, et al (1999) Reducing the risk of major elective surgery: ran-
demised controlled trial of preoperative optimisation of oxygen delivery. Br Med J 318:
1099-1103
10. Sise M, Hollingsworth P, Brimm J (1981) Complications of the flow-directed pulmonary ar-
tery catheter: A prospective analysis in 219 patients. Crit Care Med 9:315-320
11. Connors A Jr, Speroff T, Dawson NV, et al (1996) The effectiveness of right heart catheteri-
sation in the initial care of critically ill patients. SUPPORT Investigators. }AMA 276:889-
897
12. Gnaegi A, Feihl F, Perret C (1997) Intensive care physician's insufficient knowledge of right
heart catheterization at the bedside: time to act? Crit Care Med 25:213-220
13. Iberti T, Fischer E, Leibowitz A (1990) A multicenter study of physicians knowledge of the
pulmonary artery catheter: Pulmonary Artery Study Group. JAMA 264:2928-2932
14. Eisenberg P, Jaffe A, Schuster D (1984) Clinical evaluation compared to pulmonary artery
catheterization in the hemodynamic assessment of critically ill patients. Crit Care Med
12:549-553
15. Tibby S, Hatherill M, Marsh M, Murdoch I (1997) Clinicians' abilities to estimate cardiac
index in ventilated children and infants. Arch Dis Child 77:516-518
16. Trottier S, Taylor R (1997) Physicians attitude toward and knowledge of the pulmonary ar-
tery catheter: Society of Critical Care Medicine membership survey. New Horiz 5:201-206
17. Bland J, Altman D (1986) Statistical methods for assessing agreement between two meth-
ods of clinical measurement. Lancet 1:307-310
18. Critchley L, Critchley J (1999) A meta-analysis of studies using bias and precision statistics
to compare cardiac output measurement techniques. J Clin Monit 15:85-88
19. Hodges M, Downs J, Mitchell L (1975) Thermodilution and Fick cardiac index determina-
tions following cardiac surgery. Crit Care Med 3:182-184
20. Olsson B, Pool J, Vandermoten P, Varnauskas E, Wassen R (1970) Validity and reproduci-
bility of determination of cardiac output by thermodilution in man. Cardiology 55:136-148
21. Stetz C, Miller RG, Kelly GE, Raffin TA (1982) Reliability of the thermodilution method in
the determination of cardiac out put in clinical practice. Am Rev Respir Dis 126:1001-1004
22. Schuster A, Nanda N (1984) Doppler echocardiographic measurement of cardiac output:
Comparison with a non-golden standard. Am J Cardiol 53:257-259
23. Boerboom L, Kinney T, Olinger G, Hoffmann R (1993) Validity of cardiac output measure-
ment by the thermodilution method in the presence of acute tricuspid regurgitation. J
Thorac Cardiovasc Surg 106:636-642
24. Cigarroa R, Lange R, Williams R, Bedotto J, Hillis L (1989) Underestimation of cardiac
output by thermodilution in patients with tricuspid regurgitation. Am J Med 86:417-420
25. Bazaral M, Petre J, Novoa R (1992) Errors in thermodilution cardiac output measurements
caused by rapid pulmonary artery temperature decreases after cardiopulmonary bypass.
26. Wetzel R, Latson T (1985) Major errors in thermodilution cardiac output measurement
during rapid volume infusion. Anesthesiology 62:684-687
27. Snyder J, Powner D (1982) Effects of mechanical ventilation on the measurement of cardiac
output by thermodilution. Crit Care Med 10:677-682
28. Stevens JH, Raffin TA, Mihm FG, Rosenthal MH, Stetz CW (1985) Thermodilution cardiac
output measurement. JAMA 253:2240-2242
29. Kubicek W, Karnegis J, Patterson R (1966) Development and evaluation of an impedance
cardiac output system. Aviat Space Environ Med 37:1208-1212
30. Shoemaker WC, Thangathurai D, Wo CC, et al (1999) Intraoperative evaluation of tissue
perfusion in high-risk patients by invasive and noninvasive hemodynamic monitoring. Crit
Care Med 27:2147-2152
31. Preiser J, Daper A, Parquier J, Contempre B, Vincent JL (1989) Transthoracic electrical
bioimpedance versus thermodilution technique for cardiac output measurement during
mechanical ventilation. Intensive Care Med 15:221-223
32. Capek J, Roy R (1988) Noninvasive measurement of cardiac output using partial C02 re-
breathing. IEEE Transactions Biomed Engin 35:653-661
33. Guzzi L, Jaffe M, Orr J (1998) Clinical evaluation of a new non-invasive method of cardiac
output measurement: Preliminary results in CABG patients. Anesthesiology 89:A543 (abst)
34. Odenstedt H, Stenqvist 0, Lundin S (2002) Clinical evaluation of a partial C02 rebreathing
technique for cardiac output monitoring in critically ill patients. Acta Anaesthesiol Scand
46:152-159
35. Watt RC, Loeb R, Orr J (1998) Comparison of a new non-invasive cardiac output technique
with invasive bolus and continuous thermodilution. Anesthesiology 89:A536 (abst)
36. Abrams J, Weber R, Holmen K (1989) Continuous cardiac output determination using
transtracheal Doppler: Initial results "in humans. Anesthesiology 71:11-15
37. Segal J, Nassi M, Ford A, Schuenemeyer T (1990) Instantaneous and continuous cardiac
output in humans obtained with a Doppler pulmonary artery catheter. J Am Coli Cardiol
16:1398-1407
38. Huntsman L, Stewart DK, Barnes SR, Franklin SB, Colocousis JS, Hessel EA (1983) Nonin-
vasive Doppler determination of cardiac output in man. Clinical validation. Circulation
67:593-602
39. Mark J, Steinbrook RA, Gugino LD, et al (1986) Continuous noninvasive monitoring of car-
diac output with esophageal Doppler ultrasound during cardiac surgery. Anesth Analg
65:1013-1020
40. Boulnois J-L, Pechoux T (2000) Non-invasive cardiac output monitoring by aortic blood
flow measurement with the Dynemo-3000. J Clin Monit Comput 16:127-140
41. Gan T, Arrowsmith J (1997) Oesophageal Doppler monitor. Br Med J 315:893-894
42. Sinclair S, James S, Singer M (1997) Intraoperative intravascular volume optimisation and
length of hospital stay after repair of proximal femoral fracture: randomised controlled
trial. Br Med J 315:909-912
43. Davies J, Allen D, Chant A (1991) Non-invasive Doppler-derived cardiac output: a valida-
tion study comparing this technique with thermodilution and Fick methods. Eur J Vase
Surg 5:497-500
44. Feinberg M, Hopkins WE, Davila-Roman VG, Barzilai B (1995) Multiplane transesophageal
echocardiographic Doppler imaging accurately determines cardiac output measurements in
critically ill patients. Chest 107:769-773
45. Freund P (1987) Transesophageal Doppler scanning versus thermodilution during general
anesthesia: an initial comparison of cardiac output techniques. Am J Surg 153:490-494
46. Singer M, Clarke J, Bennett E (1989) Continuous haemodynarnic monitoring by oesopha-
geal Doppler. Crit Care Med 17:447-452
47. DiCorte C, Latham P, Greilich PE, Cooley MV, Grayburn PA, Jessen ME (2000) Esophageal
Doppler monitor determinations of cardiac output and preload during cardiac operations.
Ann Thorac Surg 69:1782-1786
48. Singer M (1993) Esophageal Doppler monitoring of aortic blood flow: beat-by-beat cardiac
output monitoring. Int Anesthiol Clin 31:99-125
49. Singer M, BennettE (1991) Non-invasive optimization of left ventricular filling esophageal
Doppler. Crit Care Med 19:1132-1137
50. Valtier B, Cholley BP, Belot JP, de la Coussaye JE, Mateo J, Payen DM (1998) Noninvasive
monitoring of cardiac output in critically ill patients using transesophageal Doppler. Am J
51. Lefrant J, Bruelle P, Aya AG, et al (1998) Training is required to improve the reliability of
esophageal Doppler to measure cardiac output in critically ill patients. Intensive Care Med
24:347-352
52. Linton R, Band D, Haire K (1993) A new method of measuring cardiac output in man
using lithium dilution. Br J Anaesth 71:262-266
53. Kurita T, Morita K, Kato S, Kikura M, Ikeda K (1997) Comparison of the accuracy of the
lithium dilution technique with the thermodilution technique for measurement of cardiac
output. Br J Anaesth 79:770-775
54. Linton R, Band D, O'Brien T, Jonas M, Leach R (1997) Lithium dilution cardiac output
measurement: a comparison with thermodilution. Crit Care Med 25:1796-1800
490 J. A. L. Pittman and K. J. Gupta: Cardiac Output Monitoring
55. Garcia-Rodriguez C, Pittman J, Cassell C, Young C, Sum Ping J, Mark J (2002) Lithium Di-
lution Cardiac Output Measurement: A clinical assessment of central venous and peripheral
venous indicator injection. Crit Care Med 30:2199-2204
56. Riidig G, Prasser C, Key! C, Liebold A, Hobbhahn J (1999) Continuous cardiac output mea-
surement: pulse contour analysis vs thermodilution technique in cardiac surgical patients.
Br J Anaesth 82:525-530
57. Hirschi M, Binder M, Gwechenberger M, et a! (1997) Noninvasive assessment of cardiac
output in critically ill patients by analysis of the finger blood pressure waveform. Crit Care
Med 25:1909-1914
58. Zollner C, Haller M, Weiss M, et a! (2000) Beat-to beat measurement of cardiac output by
intravascular pulse contour analysis: A prospective criterion standard study in patients
after cardiac surgery. J Cardiothorac Vase Anesth 14:125-129
59. Tibby S, Hatherill M, Marsh MJ, Morrison G, Anderson D, Murdoch lA (1997) Clinical val-
idation of cardiac output measurements using femoral artery thermodilution with direct
ficks in ventilated children and infants. Intensive Care Med 23:987-991
60. Sakka S, Reinhart K, Meier-Hellmann A (1999) Comparison of pulmonary artery and arter-
ial thermodilution cardiac output in critically ill patients. Intensive Care Med 25:843-846
61. Reuter D, Felbinger TW, Moerstedt K, et a! (2002) Intrathoracic blood volume index mea-
sured by thermodilution for preload monitoring after cardiac surgery. J Cardiothorac Vase
Anesth 16:191-195
62. Bongard F (1984) Morphologic and physiologic correlates of increased extra-vascular lung
water. Surgery 96:395-403
63. Linton N, Linton R (2001) Estimation of changes in cardiac output from the arterial blood
pressure waveform in the upper limb. Br J Anaesth 86:486-496
64. Berkenstadt H, Margalit N, Hadani M, et a! (2001) Stoke volume variation as a predictor of
fluid responsiveness in patients undergoing brain surgery. Anesth Analg 92:984-989
65. Gunn S, Pinsky M (2001) Implications of arterial pressure variation in patients in the in-
tensive care unit. Curr Opin Crit Care 7:212-217
66. Michard F, Boussat S, Chemla D, et a! (2000) Relation between arterial changes in arterial
pulse pressure and fluid responsiveness in septic patients with acute circulatorty failure.
67. Mihm F, Gettinger A, Hanson CW 3rd, et a! (1998) A multicenter evaluation of a new con-
tinuous cardiac output pulmonary artery catheter system. Crit Care Med 26:1346-1350
68. Yelderman M, Ramsay MA, Quinn MD, et a! (1992) Continuous thermodilution cardiac
output measurements in intensive care patients. J Cardiothorac Vase Anaesth 6:270-274
69. Dhainaut J, Brunet F, Monsallier JF, et a! (1987) Bedside evaluation of right ventricular per-
formance using a rapid computerized thermodilution method. Crit Care Med 15:148-152
70. Jardin F, Brun-Ney D, Hardy A, Aegerter P, Beauchet A, Bourdarias JP (1991) Combined
thermodilution and two-dimensional echocardiographic evaluation of right ventricular
function during respiratory support with PEEP. Chest 99:162-168
71. Urban P, Scheidegger D, Gabathuler J, et a! (1987) Thermodilution determination of right
ventricular volume and ejection fraction: a comparison with biplane angiography. Crit
Care Med 15:652-655
72. Vincent JL, Thirion M, Brimioulle S, Lejeune P, Kahn RJ (1986) Thermodilution measure-
ment of right ventricular ejection fraction with a modified pulmonary artery catheter. In-
73. Diebel L, Wilson RF, Heins J, Larky H, Warsow K, Wilson S (1994) End-diastolic volume
versus pulmonary artery wedge pressure in evaluation cardiac of preload in trauma pa-
tients. J Trauma 37:950-955
Assessment of Cardiac Preload
and Volume Responsiveness using Echocardiography
M. Slama and J. L. Teboul
I Introduction
Assessment of cardiac preload and of preload reserve is an important issue in in-
tensive care unit (ICU) patients with cardiovascular compromise. For many de-
cades, central venous and pulmonary artery occlusion pressures (PAOP), which are
assumed to reflect right and left filling pressures respectively, have been used to as-
sess right and left cardiac preload. Although obtained from invasive catheterization,
they are still used by a lot of physicians in fluid infusion decision making process.
However, filling pressures, by nature, cannot fully reflect cardiac preload and more-
over, the existing literature does not support the use of such pressures to assess
fluid responsiveness [1]. Many approaches have been proposed to assess preload
using non-invasive techniques. Echocardiography and cardiac Doppler are exten-
sively used in the cardiologic field. However, echocardiography is now considered
by most European ICU physicians as the first line method to evaluate cardiac func-
tion in patients with hemodynamic instability, not only in terms of diagnosis but
also in terms of therapeutic decision making process [2, 3]. Regarding cardiac
preload and cardiac preload reserve, cardiac echo-Doppler can provide important
information through either measurements of static parameters, such as dimensions
of cardiac chambers, or of dynamic parameters such as respiratory variation of
Doppler velocities.
Static Echocardiographic and Doppler Indices
Left Ventricular Dimensions

The end-diastolic size of the left ventricle determines the strain of myocardial fiber
before systolic contraction, which represents the left ventricular (LV) preload. In
experimental and clinical studies, LV diameter, area, or volumes have been demon-
strated to be good indicators of preload since the LV size was observed to decrease
during provoked volume depletion and to increase after blood restitution [4-7].
Moreover, during provoked hypovolemia induced by stepwise blood withdrawal, the
LV size was found to correlate with the amount of blood withdrawal [7]. The best
way to quantify the LV size in ICU patients, is to measure the LV area using trans-
esophageal echocardiography (TEE). From a transgastric view, the LV end-diastolic
area can be measured at the papillary muscle level. Values of 5.2-18.8 cm 2 have
been found in a normal population [8]. A good correlation was found between LV
492 M. Slama and J. L. Teboul
area obtained from echocardiography and LV volume obtained from angiography

[9]. Cheung et al. [6] demonstrated that TEE was sensitive enough to assess
changes in cardiac preload, since in this study, 5% of blood volume change could
be detected using TEE measurement of LV end-diastolic area. In another study per-
formed in a pediatric department, TEE was able to detect 2.5% of blood volume
changes [5]. In contrast, others found a low sensitivity of TEE in tracking volume
status changes [10]. In a non-published study, we measured left ventricular size
using transthoracic echocardiography before and after hemodialysis. After 2 liters
ultrafiltration, which represents a blood volume loss of 250-300 ml, the LV size did
not change. Technical problems including low reproducibility of LV measurements
in ICU patients could explain these findings. In the same way, Axler et al. did not
observe any significant increase in LV dimensions after 500 ml fluid infusion in a
series of patients receiving mechanical ventilation [10]. Therefore, in our opinion,
LV end-diastolic area seems to have a low sensitivity to detect blood volume changes
in critically ill patients. Moreover, the LV size was never described as a predictive in-
dex of positive hemodynamic effect resulting from fluid expansion in patients with
shock. Because the LV size is a highly variable parameter, the individual 'optimal'
LV size to obtain the best preload to eject the highest stroke volume is unknown.
Patients with LV systolic dysfunction, dilated left ventricle, and a normal or high
LV diastolic pressure may experience a high preload while suffering from hypo-
volemic shock, because their preload may be insufficient to eject the best stroke
volume. After a small fluid challenge, such patients may increase LV size and stroke
volume without marked increase in LV end-diastolic pressure. Thus, the 'optimal' LV
size to obtain the optimal stroke volume in such patients cannot be comparable with
the optimal size of LV of patients without LV systolic dysfunction and dilated cardi-
omyopathy. It has to be noted that knowledge of the LV end-diastolic area was dem-
onstrated to be of little value to predict increases in cardiac output in response to fluid
infusion in patients with cardiovascular instability [1, 7, 11, 12]. Using ROC curve
analysis, Tavernier et al. [11] demonstrated, in patients with sepsis-induced hypoten-
sion, that responders and non-responders to fluid infusion could not be clearly dis-
criminated before fluid infusion by using baseline values of LV end-diastolic area mea-
sured using echocardiography. Moreover, considerable overlap of individual baseline
values of LV end-diastolic area was observed between responders and non-responders,
supporting the interpretation that a given LV end-diastolic area value cannot reliably
predict fluid responsiveness in an individual patient [1]. This finding was in agree-
ment with data reported by Feissel et al. [12] who did not observe any difference be-
tween the mean baseline value of LV end-diastolic area in responders and non-respon-
ders or any relationship between the baseline value of LV end-diastolic area and the
percent change in cardiac index in response to volume expansion.
Inferior Vena Cava Size
The inferior vena cava (IVC) is a highly compliant vessel that changes its size and
diameter with changes in blood volume and central venous pressure. Respiratory
changes in intrathoracic pressure and intraabdominal pressure (IAP) may also in-
fluence its diameter. The IVC can be visualized using echocardiography from a sub
costal view. Short axis or long axis views are used to measure the diameter or the
area of this vessel [13]. For decades, attempts were made to estimate central venous
pressure (CVP) from measurements of IVC dimensions. Because of the complex re-
Assessment of Cardiac Preload and Volume Responsiveness using Echocardiography 493
lationship between CVP, right heart function, blood volume and intrathoracic pres-
sures, however, divergent results have been reported depending on the disease cate-
gory of patients, the timing in measurement in the respiratory cycle, the presence
of significant tricuspid regurgitation, etc. While Mintz et al. [14] found a good pos-
itive correlation (r =0.72) between the end diastolic IVC diameter normalized for
body surface area and right atrial pressure, others found poor correlations between
absolute values of IVC dimensions and right atrial pressure [13, 15, 16]. More inter-
estingly, in spontaneously breathing patients, the collapsibility index, defined as the
inspiratory percent decrease in IVC diameter, was demonstrated to be well corre-
lated with the value of right atrial pressure [13, 15, 16]. In spontaneously breathing
patients, a collapsibility index >50% would indicate a right atrial pressure < 10
mmHg with good predictive accuracy, in terms of sensitivity and specificity [15].
Nevertheless, although respiratory variation in IVC diameter may indicate the level
of right atrial pressure, the knowledge of right atrial pressure is of little value for
managing patients with cardiovascular compromise, first, because filling pressures,
by nature, do not fully reflect preload, and second because a given value of filling
pressure does not provide relevant information on volume responsiveness in a giv-
en patient (see below). In patients receiving mechanical ventilation, while the col-
lapsibility index was reported to fail to reflect CVP [16], the respiratory changes in
the diameter of the IVC were shown to be highly correlated with the percent in-
crease in cardiac output induced by a 500 ml fluid infusion (Feissd M et al. unpub-
lished data).
Left Diastolic Pressures
Wedge, left atrial, or LV mean or end-diastolic pressures have been proposed to re-
flect LV preload. Such a proposal is incorrect, for the following reasons. First these
pressures are different one from each other, in particular in the case of mitral valve
disease or reduced LV compliance. Second, the relationship between LV diastolic
volume and pressure is not linear but curvilinear and depends on LV compliance,
such that for a given LV volume filling pressures are higher in patients with a re-
duced LV compliance than in those with normal LV compliance and that a change
in LV volume results in more marked changes in LV pressures in the former group
of patients. Despite these limitations, many studies have tried to assess LV filling
pressures, using cardiac Doppler. Different approaches have been described to eval-
uate the LV diastolic pressures.
Mitral flow: From a 4-apical view mitral flow may be recorded using pulsed Dopp-
ler. This flow is composed by an early (E wave) and a late wave (A wave). Several
indices have been found to correlate with diastolic pressures: ratio of E to A maxi-
mal velocity (E/A), deceleration time of E (DTE) wave, deceleration time of A wave
(DTA). A small E wave, E/A<1, DTE>150 ms [17], DTA»60 ms [18] are usually
associated with low LV diastolic pressures [19]. Unfortunately, mitral flow depends
on numerous factors, including LV relaxation and compliance, heart rate, etc. To
this extent, 'normal' mitral flow may be recorded in the presence of high LV pres-
sure in patients with LV diastolic dysfunction. Recently, it has been proposed to
'normalize' the velocity of the E wave (which is highly dependent on diastolic func-
tion) by a preload-independent Doppler parameter. Maximal early diastolic velocity
of the mitral annulus (Em) recorded using Doppler tissue imaging and early
494 M. Slama and J. L. Teboul
diastolic mitral flow propagation velocity (Vp) using M-mode color Doppler have
been proposed to assess the LV end-diastolic pressure. Values of E/Em<8 [20, 21]
and E/Vp<2.5 [22] were found to be associated usually with low LV end-diastolic
pressures. Finally, it must be stressed that in the presence of tachycardia (> 120
beats/min) or arrhythmias, little information can be drawn from transmitral flow
recordings in terms of assessment of filling pressures.
Venous pulmonary flow: Venous pulmonary flow can be used to assess LV end-dia-
stolic pressure. Kucherer et al. [23] were the first authors to report a relationship
between the left atrial pressure and the systolic fraction (SF) which is the ratio be-
tween velocity time integral (VTI) of systolic wave and the sum of VTI of diastolic
and systolic waves. A value of SF <55% was described as a sensitive parameter to
detect a high left atrial pressure (> 15 mmHg). This flow is also influenced by LV
diastolic function and hence should be used with caution in patients with LV dia-
stolic dysfunction.
Combination of mitral and venous pulmonary flows: During atrial contraction, the
blood is ejected into the LV (A wave on mitral flow) and into the pulmonary veins
(reverse a wave on venous pulmonary flow). In the presence of high LV diastolic
pressure, duration of the A wave shortened and the ratio between duration of the A
and a waves becomes less than 1. Therefore, normal or low LV diastolic pressures
are usually associated with a A/a ratio> 1 [24, 25].
Cardiac Output
The cardiac output can be easily measured using echocardiography and Doppler
[26]. Many methods using either transthoracic and/or transesophageal approaches
have been described and validated in ICU patients [27-29]. Measuring cardiac out-
put at the level of the aortic annulus represents the best procedure. Using the
transthoracic method, the aortic annulus diameter should be measured from a long
axis view of the LV at the level of insertion of the aortic valve while aortic blood
flow must be recorded using continuous wave Doppler from an apical S-chamber
view. Using the transesophageal approach, aortic area can be measured directly
and aortic flow can be obtained either from a transgastric S-chamber view or from
a transgastric proximal view with an angle of 110-130°. In terms of diagnosis of
volume depletion, the information provided by the sole measurement of cardiac
output is non specific, since hypovolemic conditions are associated with low cardi-
ac output values as are cardiac failure conditions. However, since echocardiography
also gives information on cardiac function, cardiac chamber dimensions, and mi-
tral and pulmonary vein flow patterns, combined measurements of several variables
may help to diagnose low volume status. For example, in a patient without history
of cardiac disease, the association of a low cardiac output with a normal ejection
fraction should most often lead to the diagnosis of hypovolemia, even if more
sophisticated indices are not recorded. Obviously, in the case of prior cardiac dys-
function, the diagnosis of volume depletion could be more difficult to make from
such static cardiac echo-Doppler measurements.
In summary, using echocardiographic static parameters, low volume status is
often characterized by a small LV size, E/A ratio<1, DTE>150ms, DTA»60 ms,
A/a> 1, SF>SS%, E/Em<8 and E!Vp«2.5, and low cardiac output.
I Dynamic Echocardiographic and Doppler Parameters

In patients receiving mechanical ventilation, the magnitude of stroke volume varia-
tion over a respiratory cycle has been proposed to provide relevant information on
volume status [30]. Indeed, by reducing the pressure gradient for venous return,
mechanical insufflation decreases the RV filling and consequently the RV stroke
volume if the right ventricle is sensitive to changes in preload. In this condition,
the following decrease in LV filling will also induce a significant decrease in LV
stroke volume if the left ventricle is sensitive to changes in preload. Therefore, the
magnitude of the respiratory changes in LV stroke volume, that reflects the sensi-
tivity of the heart to changes in preload induced by mechanical insufflation, has
been proposed as a predictor of fluid responsiveness [31]. Because the arterial pulse
pressure is directly proportional to LV stroke volume, the respiratory changes in LV
stroke volume have been shown to be reflected by changes in arterial pulse pressure
[32]. Accordingly, the respiratory changes in pulse pressure have been demon-
strated to accurately predict fluid responsiveness in mechanically ventilated patients
with septic shock [33].
The magnitude of the respiratory changes in systolic pressure has also been pro-
posed to assess fluid responsiveness in patients with acute circulatory failure related
to sepsis [34]. Using cardiac echo-doppler, LV stroke volume can be obtained by
calculating the product of aortic VTI and aortic area, measured at the level of the
aortic annulus. Because aortic area is assumed to be unchanged over the respirato-
ry cycle, respiratory variation in stroke volume can be estimated by respiratory
variation in VTI. Using this hypothesis, we have shown in a recent experimental
study, that the magnitude of the respiratory changes in VTI (recorded by transthor-
acic echocardiography at the level of aortic annulus) was a highly sensitive indica-
tor of blood withdrawal and blood restitution in rabbits receiving mechanical ven-
tilation [7]. Moreover, this dynamic parameter was able to predict fluid responsive-
ness more reliably than conventional static markers of cardiac preload measured by
echocardiography [4]. In a preliminary non published study in mechanically venti-
lated rabbits and using esophageal Doppler to record blood flow at the level of the
descending thoracic aorta, we found that the respiratory variation of aortic blood
velocity was correlated to the amount of blood withdrawal during a provoked hypo-
volemia. Magnitude of respiratory variation of descending aorta blood velocity
> 19% was highly predictive of more than 10% blood withdrawal (Fig. 1). The
superiority of such dynamic parameters over static ventricular preload parameters
to predict fluid responsiveness in critically ill patients has been recently empha-
sized [1]. In this way, Feissel et al. [12] using TEE, demonstrated that the magni-
tude of respiratory variation of the peak value of blood velocity recorded at the
level of the aortic annulus (AVpeak), was better than static measurement of LV
end-diastolic area for predicting the hemodynamic effects of volume expansion in
septic shock patients receiving mechanical ventilation. In this study, Feissel et al.
demonstrated that when patients with septic shock experienced a value of
AVpeak> 12%, 500 ml fluid infusion increased stroke volume and cardiac output
by more than 15% while decreasing proportionally AVpeak [12] (Fig. 2). In the
same way, Vieilard-Baron et al. [34] demonstrated that respiratory variations of
superior vena cava and RV outflow might be used in ventilated patients to assess
RV preload-dependence.
496 M. Slama and J.l. Teboul
0.7
0.6
0.5
E 0.4
0
M
0 0.3
v;
g 0.2
0.1
>
0
-0.1
-().2
Fig. 1. Respiratory variations of descending thoracic aortic flow velocities recorded using esophageal
Doppler in a rabbit after 30 ml of blood withdrawal
Fig. 2. Respiratory variations of aortic blood flow recorded using pulsed Doppler at the level of aortic
annulus in a patient with hypovolemia
It must be stressed that the use of dynamic parameters such as respiratory varia-
tion of surrogates of stroke volume to assess volemic status, must be applied only
in patients who receive mechanical ventilation with a perfect adaptation to their
ventilator and who do not experience any cardiac arrhythmias. In other cases,
other dynamic tests such as passive leg raising could be attempted to predict the
response to fluid infusion. In this way, an increase in stroke volume during passive
leg raising has been showed to predict the positive response (in terms of cardiac
output) to a subsequent fluid infusion in critically ill patients [35]. It remains to be
proved that non invasive measurement of cardiac output before and after passive
leg raising could be reliably used for this purpose.
Therefore, Doppler dynamic indices seem more reliable to assess cardiac pre-
load-dependence status than echocardiographic or Doppler static parameters.
References
1. Michard F, Teboul JL (2002) Predicting fluid responsiveness in ICU patients: a critical ana-
lysis of the evidence. Chest 121:2000-2008
2. Slama MA, Tribouilloy C, Lesbre JP (1993) Apport de l'echocardiographie transoesophagi-
enne en reanimation. In: Lesbre JP, Tribouilloy C (ed) Echocardiographie transoesophagi-
enne. Flammarion, Paris pp 153-158
3. Slama MA, Novara A, Van de Putte P, Dieblod B, Safavian A, Safar M (1996) Diagnostic and
therapeutic implications of transesophageal echocardiography in medical ICU patients with
unexplained shock, hypoxemia or suspected endocarditis. Intensive Care Med 22:916-922
4. Swenson JD, Harkin C, Pace NL, Astle K, Bailey P (1996) Transesophageal echocardiogra-
phy: an objective tool in defining maximum ventricular response to intravenous fluid ther-
apy. Anesth Analg 83:1149-1153
5. Reich DL, Konstadt SN, Nejat M, Abrams HP, Bucek J (1993) Intraoperative transesopha-
geal echocardiography for the detection of cardiac preload changes induced by transfusion
and phlebotomy in pediatric patients. Anesthesiology 79:10-15
6. Cheung AT, Savino JS, Weiss SJ, Aukburg SJ, Berlin JA (1994) Echocardiographic and
hemodynamic indexes of left ventricular preload in patients with normal and abnormal
ventricular function. Anesthesiology 81:376-387
7. Slama M, Masson H, Teboul JL, et al (2002) Respiratory variations of aortic VTI: a new in-
dex of hypovolemia and fluid responsiveness. Am J Physiol Heart Circ Physiol 283:H1729-
1733
8. Weyman AE (1994) Normal cross-sectional echocardiography measurements. In: Weyman
AE (ed) Principles and Practice of Echocardiography. Lea and Febiger, Philadelphia, pp
1289-1298
9. Clements PM, Harpole DH, Quill T, Jones RH, Me Cann RL (1990) Estimation of left ven-
tricular volume and ejection fraction by two-dimensional transesophageal echocardiogra-
phy: comparison with short axis imaging and simultaneous radionuclide angiography. Lan-
cet 64:331-336
10. Axler 0, Tousignant C, Thompson CR, et al (1997) Small hemodynamic effect of typical
rapid volume infusions in critically ill patients. Crit Care Med 25:965-970
11. Tavernier B, Makhotine 0, Lebuffe G, Dupont J, Scherpereel P (1998) Systolic pressure var-
iation as a guide to fluid therapy in patients with sepsis-induced hypotension. Anesthesiol-
ogy 89:1313-1321
12. Feissel M, Michard F, Mangin I, Ruyer 0, Faller JP, Teboul JL (2001) Respiratory changes
in aortic blood velocity as an indicator of fluid responsiveness in ventilated patients with
septic shock. Chest 119:867-873
13. Moreno FL, Hagan AD, Holmen JR, Pryor TA, Strickland RD, Castle CH (1984) Evaluation
of size and dynamics of the inferior vena cava as an index of right-sided cardiac function.
Am J Cardiol 53:579-585
14. Mintz GS, Kotler MN, Parry WR, Iskandrian AS, Kane SA (1981) Real-time inferior vena
caval ultrasonography: normal and abnormal findings and its use in assessing right-heart
function. Circulation 64: 1018-1025
15. Kircher BJ, Himelman RB, Schiller NB (1990) Noninvasive estimation of right atrial pres-
sure from the inspiratory collapse of the inferior vena cava. Am J Cardiol 66:493-496
16. Nagueh SF, Kopelen HA, Zoghbi WA (1996) Relation of mean right atrial pressure to echo-
cardiographic and Doppler parameters of right atrial and right ventricular function. Circu-
lation 93:1160-1169
17. Giannuzzi P, Imparato A, Temporelli PL, et al (1994) Doppler-derived mitral deceleration
time of early filling as a strong predictor of pulmonary capillary wedge pressure in postin-
farction patients with left ventricular systolic sysfunction. JAm Coll Cardiol 23:1630-1637
18. Tenenbaum A, Motro M, Hod H, Kaplinsky E, Vered Z (1996) Shortened Doppler-derived
mitral A wave deceleration time: an important predictor of elevated left ventricular filling
pressure. JAm Coll Cardiol27:700-705
498 M. Slama and J. L. Teboul: Assessment of Cardiac Preload
19. Slama M, Feissel M (2002) Oedeme aigu pulmonaire. In. Vignon P, Goarin JP (ed) Echo-
cardiographie Doppler en Reanimation, Anesthesie, et Medecine d'urgence. Elsevier, Paris,
pp 478-506
20. Nagueh SF, Middleton KJ, Kopelen HA, Zoghbi WA, Quinones MA (1997) Doppler tissue
imaging: a noninvasive technique for evaluation of left ventricular relaxation and estima-
tion of filling pressures. JAm Coli Cardiol 30:1527-1533
21. Sohn DW, Song JM, Zo JH et al. (1999) Mitral Annulus velocity in the evaluation of left
ventricular diastolic function in atrial fibrillation. JAm Soc Echocardiogr 12:927-931
22. Gonzalez-Vilchez F, Ares M, Ayuela J, Alonso L (1999) Combined use of pulsed and color
M-mode Doppler echocardiography for the estimation of pulmonary capillary wedge pres-
sure: an empirical approach based on an analytical relation. JAm Coli Cardiol 34:515-523
23. Kuecherer HF, Muhiudeen IA, Kusumoto FM et al. (1990) Estimation of mean left atrial
pressure from transesophageal pulsed Doppler echocardiography of pulmonary venous
flow. Circulation 82:1127-1139
24. Rossvoll 0, Hade LK (1993) Pulmonary venous flow velocities recorded by transthoracic
Doppler ultrasound: relation to left ventricular diastolic pressures. J Am Coli Cardiol 21:
1687-1696
25. Yamamoto K, Nishimura RA, Burnett JC, Redfield MM (1997) Assessment of left ventricu-
lar end-diastolic pressure by Doppler echocardiography: contribution of duration of pul-
monary venous versus mitral flow velocity curves at atrial contraction. J Am Soc Echocar-
diogr 10:52-59
26. Sahn DJ (1985) Determination of cardiac output by echocardiographic Doppler methods:
relative accuracy of various sites for measurement. J Am Coli Cardiol 6:663-664
27. Darmon PL, Hillel Z, Mogtader A, Mindich B, Thys D (1994) Cardiac output by transeso-
phageal echocardiography using continuous-wave Doppler across the aortic valve. Anesthe-
siology 80:796-805
28. Feinberg MS, Hopkins WE, Davila-Roman VG, Barzilai B (1995) Multiplane transesopha-
geal echocardiographic doppler imaging accurately determines cardiac output measure-
ments in critically ill patients. Chest 107:769-773
29. Katz WE, Gasior TA, Quinlan JJ, Gorcsan J 3rd (1993) Transgastric continuous-wave Dopp-
ler to determine cardiac output. Am J Cardiol 71: 853-857
30. Michard F, Teboul JL (2000) Using heart-lung interactions to assess fluid responsiveness
during mechanical ventilation. Crit Care 4:282-289
31. Perel A (1998) Assessing fluid responsiveness by the systolic pressure variation in me-
chanically ventilated patients. Systolic pressure variation as a guide to fluid therapy in pa-
tients with sepsis-induced hypotension. Anesthesiology 89:1309-1310
32. Jardin F, Farcot JC, Gueret P, Prost JF, Ozier Y, Bourdarias JP (1983) Cyclic changes in ar-
terial pulse during respiratory support. Circulation 68:266-274
33. Michard F, Boussat S, Chemla D, Anguel N, Mercat A, Lecarpentier Y, Richard C, Pinsky
MR, Teboul JL (2000) Relation between respiratory changes in arterial pulse pressure and
fluid responsiveness in septic patients with acute circulatory failure. Am J Respir Crit Care
Med 162:134-138
34. Vieillard-Baron A, Augarde R, Prin S, Page B, Beauchet A, Jardin F (2001) Influence of
superior vena caval zone condition on cyclic changes in right ventricular outflow during
respiratory support. Anesthesiology 95:1083-1088
35. Boulain T, Achard JM, Teboul JL, Richard C, Perrotin D, Ginies G (2002) Changes in BP in-
duced by passive leg raising predict response to fluid loading in critically ill patients.
Chest 121:1245-1252
Early Transesophageal Echo Doppler Approach
in Trauma: Emergence of a New Tool
0. Richard, J.M. Caussanel, andY. Lambert
I Introduction
Trauma-induced deaths represent the leading cause of mortality in people less than
45 years old and the 4th cause whatever the age, reaching up to 5.1 million deaths
in 1990, contributing to 10% of the overall world mortality [1].
In spite of numerous improvements in resuscitating severe trauma patients and
unremitting efforts on behalf of medical teams, the mortality rate remains high,
reaching 10% to 50% depending on the series. The majority of deaths occurs at an
early stage, the consequence of central nervous system (CNS) lesions, and severe
hemorrhage. The leading cause of trauma-induced deaths beyond 48 hours after
hospital admission is organ failure. This kind of failure occurs in 15 to 65% of the
patients, with a mortality rate of 35 to 60% among those with multiple organ fail-
ure (MOF) [2-4]. Currently, there is no reliable method to predict MOF [5, 6].
Early resuscitation of severe trauma is first based on physical examination like
heart rate and arterial blood pressure. These parameters are not accurate enough to
give a reliable circulatory status of the patient [7, 8]. Therapeutic adjustments
based on these clinical parameters are thus difficult to implement and control, even
after an initial aggressive therapy [9].
The transesophageal echo {TEE) Doppler system, which is a new non-invasive
hemodynamic monitor, could lead to an interesting approach in the rapid manage-
ment of severe trauma patients. Cardiovascular data immediately recorded by the
medical team offer new expectations: allowing detection of any hemodynamic vari-
ation at the scene and leading to a more appropriate treatment.
What are the Goals of Medical Treatment for Patients

with Severe Trauma?
Whatever the health care system involved, our intention is not to debate between
the 'scoop and run' approach or 'field stabilization', but to improve efficacy of the
first medical team who start initial management of a trauma patient.
In France, mobile medical intensive care units (ICUs), with an emergency physi-
cian on board, initiate treatment for multiple trauma patients. In other health care
organizations, physician approach starts as soon as the patient reaches the hospital
emergency room. The most frequent cause of polytrauma, in Europe, is the road
traffic accident [10, 11]. Furthermore, injuries are mainly blunt trauma, two thirds
are associated with severe brain damages. Penetrating traumas leading to major
bleeding are less frequent.
500 0. Richard et al.
Whatever the health care system, early therapeutic actions are difficult to deter-
mine: Should we stabilize the arterial blood pressure (BP) and how? Should we ad-
minister fluid or vasopressive drugs? There is still no answer to these questions of
paramount importance. Uncertainties related to the best immediate treatment arise
because we still lack reliable hemodynamic parameters to guide and orientate any
specific therapeutic choice. For instance, in severe head injuries, resuscitation is
based on specific goals related to blood pressure, Pa0 2 and PaC0 2 [12-15]. But the
technical way to achieve these goals remains to be defined. An access to 'point of
care testing' (arterial blood gas analysis) brings a first element of response. An-
other part of the puzzle could be solved in using the TEE Doppler approach. The
TEE Doppler is a non-invasive hemodynamic tool that displays a hemodynamic
profile based on new parameters like aortic blood flow, vascular resistance and aor-
tic stroke volume [16-18]. This continuous monitoring allows a more accurate fol-
low-up and helps in directing treatment. It is also helpful to anticipate and prevent
severe events, such as unexpected occurrence of a low aortic blood flow, undetect-
able with conventional techniques.
Lesions caused by the trauma and its related hemodynamic disturbances will
lead, at an early stage, to tissue hypoperfusion and a sudden drop in oxygen trans-
portation [19, 20]. Even before the release of inflammatory mediators leading to
the systemic inflammatory response syndrome (SIRS) [21, 22], the cardiocirculatory
malfunction will trigger the onset of MOF.
Maintaining good tissue perfusion by insuring sufficient aortic blood flow is an
essential therapeutic goal [23]. Physiological compensatory phenomena, like sym-
pathetic stimulation or release of endogenous catecholamines, maintain a relatively
normal arterial blood pressure, even when the cardiac output drops to a low level.
Nevertheless, in clinical practice, we are often disappointed because these precious
data are available too late after hospital admission. Furthermore, by the time these
cardiovascular indicators are noted and despite aggressive therapy, it is difficult to
reduce the occurrence of MOF [5, 6].
If we consider that determinants of the MOF syndrome appear very early after
the trauma and are the result of low regional blood flow, especially towards the or-
gans located below the diaphragm (kidneys, liver, bowels or mesentery), therefore
we should focus our attention on the best way to document a continuous hemody-
namic profile as soon as possible after a severe trauma.
The Transesophageal Echo Doppler Technique
Until now, monitoring and stabilizing severe trauma patients was based on heart
rate, arterial blood pressure, electrocardiogram (EKG), and pulse oximetry. Inser-
tion of a venous central line with its associated morbidity risk and cost was the
only acceptable technique to have more detailed hemodynamic parameters [24].
In the last 20 years, research on the clinical use of ultrasound Doppler methods
started to emerge. In 1978, a simple esophageal probe was developed by INSERM
(U281) in Lyon, France: an A-scan unit allowed measurement of the chest aortic di-
ameter and a continuous wave Doppler velocimeter to measure instantaneous blood
flow velocity [16, 25].
Early Transesophageal Echo Doppler Approach in Trauma: Emergence of a New Tool 501
Today, we use the ultimate generation of probe connected to the Hemosonic 100
(Arrow Inti., Reading, USA), which allows a continuous measurement of blood flow
in the descending aorta [26].
Ultrasonic Aortic Blood Flow Determination

The instantaneous flow, q(t), measured in a vessel by Doppler effect depends on the
speed 'v(t)' of the blood column at a particular point in 't' time, and on the cross
section of the vessel in relation to time A(t)
q(t) = A(t) X v(t)
The establishment of aortic blood flow (ABF) requires simultaneous measurement

of aortic cross section and blood velocity in the aorta, at the anatomical position
where both aorta and esophagus are parallel, approximately in between the 51h and
6th dorsal vertebra.
Measurement of Aortic Cross-Sectional Area (CSA) (Fig. 1)

The diameter measurement of the aortic lumen, d(t), is realized with a 10 MHz M-
mode echo transducer located on the distal tip of the probe. Thus, we can display
Transducer
b Echograph level indicator

/
Rotate the transducers to obtain best imag~ /~
Prox
"'7
/
__
Proximal wall
---...------- ......._
----:
-- "'7 ~
Dist
Distal wall
Valid
Fig. 1. a Central orientation of the M-mode transducer: probe correctly aligned in front of the aorta;
b Hemosonic 100 screen display of the corresponding M-mode image of the proximal and distal aortic
wall echoes
proximal and distal walls of the aorta and measure the distance; this provides the
CSA
A(t) = n/ 4 X d(t) 2 .
Measurement of Blood Velocity

Blood velocity is measured using the Doppler principle. Located close to the first
transducer, a second transducer generates a pulsed Doppler emission at a frequency
of 5 MHz. The pulsed Doppler transducer, used for both emission and reception, is
mounted at a 60° angle to the probe central axis. The velocity is measured through
the Doppler equation:
V(t) = fm / fo X c/ 2 X cos a
Probe Handle
Ultrasound Transducer
for diameter measurement
Pulsed Doppler Transducer ~1---ft.Jf--~ T6

for diameter measurement
Flexible insertion Tip
Descending aorta
Esophagus
Fig. 2. Transesophageal probe with 2 transducers facing the descending aorta

Where fm is the measured Doppler shift, f0 the frequency of emitted ultrasound

wave, c the acoustic velocity, and a the angle between the ultrasound wave and the
direction of the moving blood cells.
Procedure for Using the Probe

The 20F adult probe (6.8 mm outer diameter) is approximately 610 mm long. It is
embedded in a polyvinylchloride sheath. The two piezo-electric transducers (M-
Mode and Doppler) are situated at the distal end of the probe just prior to the flex-
ible silicone tip made into a soft, round and atraumatic shape to facilitate the inser-
tion and maintain a stable axial position of the probe parallel to the aorta with the
esophagus. The probe is inserted into a disposable elastomeric jacket, made of bio-
compatible material. The sheath is filled with sterile ultrasound gel that ensures
transmission of ultrasound wave without air interposition.
Once the trachea is intubated, the probe is inserted by either oral or nasal route.
The depth of the probe in the esophagus is obtained by positioning the echo-
graphic sensor at the level of the third intercostal tuxtasternal space. Then, the
probe handle is secured with an external fixed pole close to the patient's head
(Fig. 2).
To obtain the best of both Doppler images and a clear display of aortic walls,
the probe can rotate until the transducers are correctly aligned in front of the aorta.
When the distal aortic wall echo is considered satisfactory, data are computerized
by the monitor and the following hemodynamic parameters are displayed on the
screen:
I ABF: aortic blood flow (measured)
I HR: heart rate (computed from velocity curve)
I Sva: stroke volume in the aorta (computed)
TSVRa: total systemic vascular resistance for aortic circuit (computed)
LVET: left ventricular ejection time (computed)
Ace: maximum acceleration at the onset of systole (measured)
PV: peak velocity in systole (measured)
MAD: mean aortic diameter (measured).
Hemodynamic parameters are averaged over 15 cycles. The continuous display on

the screen of the aortic walls, the aortic diameter and the Doppler signal confirm
the reliability of the position and then the reliability of the measurement. In con-
junction, continuous monitoring can reveal the trends of the hemodynamic data
under evaluation. Finally, clinical or therapeutic events that may influence the
hemodynamic profile can be notified on the trend curves by pressing the 'event'
button on the monitor (Fig. 3).
Transesophageal Echo Doppler: Use and Perspective

Early detection of cardiocirculatory disorders and prompt adequate treatment in or-
der to prevent serious complication like organ failure are required during the very
first hours after the trauma [27-29]. Non-invasive TEE Doppler monitoring is easy
to use and reproducible [30]. On the trauma field or in the emergency room, the
rapid settlement of the TEE is a major asset that allows a hemodynamic profile to
be obtained in just a few minutes.
[ ABF ,.... 53
[ HR m 85 j[Lvrn
I:l=-
n 369) •
PPS
[ Trend ]
( Ace m 38.1 )( PV m 122 J / \,/.\:".'-·~,.r--~
(TSVRa m 1461 )(~;;Hg] MAP
(Dlamet~ 213 JTue Feb 26 • 23:49 Event
TueFeb26.2002 - -~·
,
-
;~·!·!~ ~
_ - Scr.Cpy
Other
Options
Fig. 3. Real time data screen with measured parameters (ABF, Ace, PV, MAD) and computed parameters
(SVa, HR, TSVRa, LVETi). See text for abbreviations
Logically, its use gives the chance, in clinical practice, to adjust the therapy
based on the displayed hemodynamic parameters: aortic blood flow, stroke volume
in the aorta and total systemic vascular resistance of the aortic circuit [18, 30, 31].
1 For severe head trauma patients with no active bleeding, in order to maintain a
mean arterial blood pressure (MAP) of 90 mmHg and avoid secondary cerebral
ischemia, we suggest a continuous measurement of MAP [12-14]. Interpreting
the arterial blood pressure data according to the ABF, Sva and TSVRa, the thera-
py can be orientated either towards fluid loading or towards the use of catecho-
lamines, i.e., when vascular resistances are low with a normal flow (neurogenic
hypotension) [32]. In all cases, continuous monitoring and trend analysis allow
for the assessment of real time hemodynamic status and help to adjust treatment
(Fig. 4).
I For polytrauma patients (penetrating or blunt trauma), with an unstable hemo-
dynamic condition, the arterial blood pressure and heart rate are useless in esti-
mating the amount of blood loss. Keeping in mind that treatment should not de-
lay surgery, monitoring Sva and ABF will help guide the vascular fluid loading
[33]. Increases in ABF or Sva will reflect efficacy of initial treatment more accu-
rately than any increase in arterial blood pressure.
Another asset provided by TEE Doppler is the possibility of determining factors

able to predict the occurrence of MOF. Continuous measurement of ABF and Sva as
early as possible after the trauma could help to quantify early low flow and poor
tissue perfusion states [29]. Correlation between these parameters and the occur-
rence of MOF has to be determined.
1/ml
i
3
0
0 10 20 30 40 50
Time (min)
MAP
I
1/ml
90
'-----..
80
70
60 ~
so
40 i
30
20
10
0
0 10 20 30 40 50
Time (min)
cyn·s·crr-5
TSVR
???
???
t
0+-~------~~,--.--~--,--.--,---r--;
0 10 20 30 40 50
Time (min)
Fig. 4. Very early hemodynamic status of a patient with severe brain injury. Continuous monitoring and
start of catecholamine treatment (arrow)
I Conclusion
Minimally invasive, hemodynamic monitoring using the TEE Doppler approach
opens exciting perspectives. Earlier diagnosis and continuous monitoring of circu-
latory deficiencies is very useful for the emergency physician to start adequate re-
suscitation and minimize tissue ischemia.
References
1. Meyer AA (1998) Death and disability from injury: a global challenge. J Trauma 44:1-12
2. Sauaia A, Moore FA, Moore EE, et al (1995) Epidemiology of trauma deaths: a reassess-
ment. J Trauma 38:185-193
3. Gennarelli TA, Champion HR, Sacco WJ, Copes WS, Alves WM (1989) Mortality of patients
with head injury and extracranial injury treated in trauma centers. J Trauma 29:1193-1202
4. Moore FA, Sauaia A, Moore EE, Haenel JB, Burch JM, Lezotte DC (1996) Postinjury multi-
ple organ failure: a bimodal phenomenon. J Trauma 40:501-512
5. Sauaia A, Moore FA, Moore EE, Norris JM, Lezotte DC, Hamman RF (1999) Multiple organ
failure can be predicted as early as 12 hours after injury. J Trauma 45:291-303
6. Cryer HG, Leong K, McArthur DL, et al (1999) Multiple organ failure: by the time you pre-
dict it, it's already there. J Trauma 46:597-606
7. Wo CCJ, Shoemaker WC, Appel PL, Bishop MH, Kram HB, Hardin E (1993) Unreliability
of blood pressure and heart rate to evaluate cardiac output in emergency resuscitation and
critical illness. Crit Care Med 21:218-223
8. McGee S, Abernethy WB, Simel DL (1999) Is this patient hypovolemic? JAMA 281:1022-
1029
9. Roberts I, Evans P, Bunn F, Kwan I, Crowhurst E (2001) Is the normalisation of blood pres-
sure in bleeding trauma patients harmful? Lancet 357:385-387
10. Tiret L, Hausherr E, Thicope M, et al (1990) the epidemiology of head trauma in Aquitaine
(France), 1986: a community-based study of hospital admissions and death. Int J Epidemiol
19:133-140
11. Jennett B (1996) Epidemiology of head injury. J Neurol Neurosurg Psychiatry 60:362-369
12. Chesnut RM, Marshall LF, Klauber MR, et al (1993) The role of secondary brain injury in
determining outcome from severe head injury. J Trauma 34:216-222
13. Chesnut RM (1995) Secondary brain insults after brain injury. Clinical perspectives. New
Horiz 3:366-375
14. Chesnut RM (1997) Avoidance of hypotension: conditio sine qua non of successful severe
head injury management. J Trauma 42 (suppl):S4-S9
15. Marion DW, Spiegel TP (2000) Changes in the management of severe traumatic brain in-
jury: 1991-1997. Crit Care Med 28:16-18
16. Lavandier B, Cathignol D, Muchada R, Xuan BB, Motin J (1985) Noninvasive aortic blood
flow measurement using an intraesophageal probe. Ultrasound Med Biol11:451-460
17. Singer M, Clarke J, Bennett ED (1989) Continuous hemodynamic monitoring by esopha-
geal Doppler. Crit Care Med 17:447-450
18. Cariou A, Monchi M, Joly LM, et al (1998) Non invasive cardiac output monitoring by
aortic blood flow determination: evaluation of the sometec dynemo-3000 system. Crit Care
Med 26:2066-2072
19. Lee CC, Marill KA, Carter WA, Crupi RS (2001) A current concept of trauma-induced mul-
tiorgan failure. Ann Emerg Med 38:170-176
20. Barton R, Cerra FB (1989) The hypermetabolism - Multiple organ failure syndrome. Chest
96:1153-1160
21. Beal AL, Cerra FB (1994) Multiple organ failure syndrome in the 1990s. Systemic inflam-
matory response and organ dysfunction. JAMA 271:226-233
22. Munford RS, Pugin J (2001) Normal responses to injury prevent systemic inflammation
and can be immunosuppressive. Am J Respir Crit Care Med 163:316-321
23. Kern JW, Shoemaker WC (2002) Meta-analysis of hemodynamic optimization in high-risk
patients. Crit Care Med 30:1686-1692
24. Connors AF, Speroff T, Dawson NV, et al (1996) The effectiveness of right heart catheteri-
zation in the initial care of critically ill patients. JAMA 276:889-897
25. Muchada R, Cathignol D, Lavandier B, Lamazou J, Haro D (1988) Aortic blood flow mea-
surement. Am J Noninvas Cardiol 2:24-31
26. Boulnois JLG, Pechoux T (2000) Non-invasive cardiac output monitoring by aortic blood
flow measurement with the dynemo 3000. J Clin Monit 16:127-140
27. Bishop MH, Shoemaker WC, Appel PL, et al (1993) Relationship between supranormal cir-
culatory values, time delays, and outcome in severely traumatized patients. Crit Care Med
21:56-63
28. Blow 0, Magliore L, Claridge JA, Butler K, Young JS (1999) The golden hour and the silver
day: detection and correction of occult hypoperfusion within 24 hours improves outcome
from major trauma. J Trauma 47:964-969
29. Shoemaker WC, Wo CCJ, Chan L, et al (2001) Outcome prediction of emergency patients
by non invasive hemodynamic monitoring. Chest 120:528-537
30. Bernardin G, Tiger F, Fouche R, Mattei M (1998) Continuous noninvasive measurement of
aortic blood flow in critically ill patients with a new esophageal echo-doppler system. J
Crit Care 13:177-183
31. Poeze M, Ramsay G, Greve JWM, Singer M (1999) Prediction of post operative cardiac sur-
gical morbidity and organ failure within 4 hours of intensive care unit admission using
esophageal Doppler ultrasonography. Crit Care Med 27:1288-1294
32. Singer M, Allen MJ, Webb AR, Bennett ED (1991) Effects of alterations in left ventricular
filling, contractility, and systemic vascular resistance on the ascending aortic blood velo-
city waveform of normal subject. Crit Care Med 19:1138-1145
33. Dark PM, Delooz HH, Hillier V, Hanson, Little RA (2000) Monitoring the circulatory re-
sponses of shocked patients during fluid resuscitation in the emergency department. Inten-
Management of Circulatory and Respiratory Failure
Using Less Invasive Hemodynamic Monitoring
F. Michard and A. Perel
1 Introduction/Technological Considerations
In patients instrumented with a central venous line and a thermodilution arterial
catheter, the transpulmonary thermodilution technique - currently available on the
"PiCCOplus" monitor (Pulsion Medical Systems, Munich, Germany) and on the
"CCO" cardiac output module of Philips Medical Systems - allows the simultaneous
assessment of valuable cardiovascular and dynamic heart-lung-interaction parame-
ters. After central venous injection of an ice-cold or room-tempered saline bolus, a
thermistor in the tip of the arterial catheter is used to measure the downstream
temperature changes. The cardiac output is then calculated by the analysis of the
thermodilution curve using a modified Stewart-Hamilton algorithm. The monitor
also calculates the mean transit time and the exponential downslope time of the
transpulmonary thermodilution curve. The product of cardiac output and mean
transit time is the volume of distribution of the thermal indicator [1]. This volume
of distribution, the so-called 'intrathoracic thermal volume', is made up of the in-
trathoracic blood volume (ITBV) and the extravascular lung water (EVLW) (Fig. 1).
The product of cardiac output and exponential downslope time is the 'pulmonary
thermal volume' [2], which is composed of the pulmonary blood volume and the
EVLW (Fig. 1). Therefore, the volume of blood contained in the four heart cham-
bers - called the global end-diastolic volume (GEDV) - is easily obtained as the
difference between the intrathoracic thermal volume and the pulmonary thermal
volume [3, 4] (Fig. 1). The ITBV has been shown to be quite consistently 25o/o
greater than the GEDV [4]. Therefore, the ITBV is estimated as 1.25XGEDV and
the EVLW as the difference between the intrathoracic thermal volume and the ITBV
[4] (Fig. 1).
I Transpulmonary Thermodilution in Shock States
Discrimination between High and Low Flow States

Acute circulatory failure is a clinical (cold extremities, low urine output, tachycar-
dia± systemic hypotension) and biological (renal or hepatic dysfunction, high lac-
tate level...) syndrome that is usually due to a low blood pressure and/or a low car-
diac output, since both pressure and flow are major determinants of organ function
(Fig. 2). A low cardiac output can be responsible for systemic hypotension, but a
low blood pressure can also result from systemic vasodilation (Fig. 2). Thus, in pa-
Management of Circulatory and Respiratory Failure Using Less Invasive Hemodynamic Monitoring 509
Ico X MTt = GEDV + PBV + EVLW I
[coxDSt=PBV+EVLW ~
~ 4 ~
IITBV = GEDV + PBV = 1.25 X GEDV I
I EVLW = (CO X MTt) -ITBV
G
Fig. 1. Assessment of global end-diastolic volume (GEDV) and extravascular lung water by transpulmonary
thermodilution.
CO= cardiac output, MTt =mean transit time, RA =right atrium, RV =right ventricle, PBV =pulmonary
blood volume, LA= left atrium, LV= left ventricle, DSt =downslope time, ITBV =intrathoracic blood volume
tients with acute circulatory failure, the measurement of cardiac output is useful to
discriminate between high and low flow states, and hence to identify patients who
may benefit from vasopressors (high cardiac output and low blood pressure) or
volume therapy and/or inotropic drugs (low cardiac output). The measurement of
cardiac output by transpulmonary thermodilution has been validated by many clin-
ical studies as compared to pulmonary artery thermodilution [5-8] and the Pick
method [9-11] both in children [8, 9, 11] and adult patients [S-7, 10]. The repro-
ducibility of cardiac output measured by this method is around So/o [5]. However,
the measurement of cardiac output alone is generally insufficient to determine the
correct therapeutic approach. In this regard, the major determinants of cardiac out-
put, namely preload, contractility and afterload, have to be measured to gain more
insight into the pathophysiology of the circulatory failure.
510 F. Michard and A. Perel
Fluid Inotropes
GEDVI GEFI
PPV,SWt
• •
Fig. 2. Usefulness of transpulmonary thermodilution derived parameters to understand the pathophysiolo-
gical mechanisms of acute circulatory failure and hence to choose the more appropriate therapeutic card.
AP =arterial pressure, CO= cardiac output, SVR =systemic vascular resistance, GEDV =global end-diastolic
volume, PPV =pulse pressure variation, SVV =stroke volume variation, GEF =global ejection fraction
Assessment of Cardiac Preload

In low flow states, assessment of cardiac preload may be useful to identify patients
who may benefit from volume loading. Cardiac filling pressures (central venous,
right atrial, and wedge pressures), though still being widely used, are not accurate
indicators of cardiac preload because of erroneous readings of pressure tracings
[12], discrepancies between measured and transmural pressures (particularly in pa-
tients ventilated with high levels of positive end-expiratory pressure (PEEP) or with
dynamic hyperinflation) [13], and simply because the physiological relationship be-
tween ventricular end-diastolic pressure and volume depends on ventricular com-
pliance [14]. Therefore, several volumetric (as opposed to pressure) parameters
have been proposed to assess cardiac preload at the bedside (Fig. 3). These include
the right ventricular end-diastolic volume (RVEDV) evaluated by fast response pul-
monary artery catheters [15-17], the left ventricular end-diastolic area (LVEDA)
measured by echocardiography [18-21], the ITBV evaluated by the double indicator
(thermo-dye) dilution technique [22-25], and more recently the GEDV that is
evaluated by the easy to apply single-indicator transpulmonary thermodilution
[3, 4, 26-28] (Fig. 3). The GEDV has been shown to behave as a true indicator of
cardiac preload. It increases with fluid loading but not with dobutamine, and its
increase following fluid loading is correlated with the increase in stroke volume
(consistent with the physiological relationship between preload and stroke volume)
[26-28]. Furthermore, although cardiac output and GEDV are derived from the
same thermodilution curve, a mathematical coupling between these two parameters
has been ruled out by several studies [28-30]. The assessment of GEDV does not
require a pulmonary artery catheter, is possible in neonates and infants [31]
(in contrast to the measurement of RVEDV), and can be repeated as often as
necessary (a single cold bolus, that can be done by a nurse, is sufficient) without
being operator-dependent (in contrast to the echocardiographic measurement of
LVEDA).
Management of Circulatory and Respiratory Failure Using less Invasive Hemodynamic Monitoring 511
RV end - diastolic volume (RVEDV) LV end - diastolic area (LVEDA)

(pulmonary artery thermodilution) (echocardiography)
Intrathoracic blood volume (ITBV) Global end - diastolic volume (GEDV)

(thermo-dye transpulmonary dilution) (transpulmonary thermodilution)
Fig. 3. Volumetric indicators of cardiac preload available at the bedside.

RV =right ventricular, LV= left ventricular
Prediction of Fluid Responsiveness

The real clinical endpoint of fluid loading in low flow states, is not to 'normalize'
but to adjust preload with regard to the underlying pathology in order to achieve
an increase in cardiac output using the volume pathway. Therefore, predictors of
fluid responsiveness (i.e., of a significant increase in cardiac output in response to
volume) are needed at the bedside. Because the slope of the relationship between
ventricular preload and stroke volume depends on ventricular contractility, asses-
sing ventricular preload alone is not sufficient to predict fluid responsiveness [32].
Even volumetric indicators of cardiac preload have been shown to be useful in pre-
dicting volume expansion efficacy only when they are low or high, but not for in-
termediate values [32]. In this regard, dynamic parameters, mainly the changes in
left ventricular stroke volume during mechanical ventilation, have been shown to
predict the hemodynamic effects of fluid loading [33, 34]. In deeply sedated me-
chanically ventilated patients, the respiratory changes in left ventricular stroke vol-
ume reflect the sensitivity of the heart to changes in preload induced by mechani-
cal insufflation, and hence the sensitivity of the heart to a potential volume loading
[34]. The response of the left ventricular stroke output to a mechanical breath can
be estimated by the systolic pressure variation and its dDown component [20, 35].
However, because the arterial pulse pressure (systolic minus diastolic pressure) is
directly proportional to left ventricular stroke volume, the respiratory changes in
pulse pressure have been shown to reflect even more closely those of left ventricu-
lar stroke volume, and hence to accurately predict fluid responsiveness [36]
(Fig. 4). The pulse pressure variation (PPV}, defined as the percentage of variation
of arterial pulse pressure over a floating period of 7.5 seconds, a parameter very
dose to the respiratory changes in pulse pressure, is now automatically calculated
and displayed on the PiCCOplus monitor.
45
•
40
•
.!: ~ 35
••
"' <II
<II ....
a~=> 30
c ~
"' <II.... 25 ....L.
va.
~
~~
o-
.. ::>
20 I
~
·a.
c.
iij
.,. .i::
15 •
-------- ~-------- -- -------- 1f --------~
t
<II <II
cr:t: 10
"' 5
0
Responders Non- responders
n = l6 n=24
Fig. 4. The respiratory changes in arterial pulse pressure accurately predict fluid responsiveness (adapted
from [36])
In addition, the PiCCOplus monitor also directly measures the left ventricular
stroke volume by pulse contour analysis of arterial pressure. The algorithm used
analyses the shape and the area under each stroke and uses mean stroke volume
derived from transpulmonary thermodilution cardiac output to calculate the actual
patient specific arterial compliance and impedance. Then compliance, impedance
and the incremental changes of arterial pressure wave form yield continuous pulse
contour stroke volume and cardiac output. Thus, the PiCCOplus monitor is able to
provide a beat-to-beat measurement of stroke volume in real time, including the
continuous calculation of the stroke volume variation (SVV). The SVV is defined
as the percentage change in stroke volume over a floating period of 7.5 seconds.
The continuously measured pulse contour cardiac output has been shown to be ac-
curate in many studies [7, 37-42]. Like changes in pulse pressure, the SVV has
been shown to be an accurate predictor of fluid responsiveness in patients under-
going brain [43] and cardiac surgery [44, 45].
Assessment of Cardiac Contractility/Function

In low flow states, assessment of cardiac contractility/function can be useful to
identify patients who may benefit from the administration of inotropic agents. Ac-
curate bedside assessment of cardiac contractility is very difficult since all hemody-
namic parameters are more or less dependent on afterload and preload conditions
[46]. Nevertheless, the ventricular ejection fraction, which is the ratio of stroke vol-
ume to ventricular end-diastolic volume, is commonly used to assess ventricular
function [46] (Fig. 5). Since the transpulmonary thermodilution provides the
GEDV, which is the volume of blood contained in the four heart chambers, the ra-
tio of stroke volume to a quarter of the GEDV represents the global ejection frac-
tion (GEF) of the heart. This parameter, automatically calculated and displayed by
the monitor, can be used to identify patients with right or/and left ventricular dys-
function (Fig. 5).
RVEF=~ ...2:!_= LVEF

RVEDV LVEDV
RV ejection fraction (RVEF) LV ejection fraction (LVEF)

(pulmonary artery thermodilution) (echocardiography)
}
~=GEF
GEDV/4
Global ejection fraction (GEF)

(transpulmonary thermodilution)
Fig. S. Available bedside indicators of cardiac function.

RV =right ventricular, RVEDV = RV end-diastolic volume, SV =stroke volume, LV= left ventricular, LVEDV =LV
end-diastolic volume, GEDV =global end-diastolic volume
1 Transpulmonary Thermodilution in Hypoxemic Patients
Detection of Patients with Pulmonary Edema
Chest X-ray, arterial blood gases and, hence, the current international definition of
acute lung injury/acute respiratory distress syndrome (ALI/ARDS) have been shown
to be of little value in identifying patients with pulmonary edema [47-51]. Several
techniques have been proposed to assess EVLW in humans [52-54]. Among these
techniques, double indicator (thermo-dye) dilution has been used most frequently
in ICU patients [55- 61], since other techniques (CT scan, nuclear magnetic reso-
nance [NMR] imaging, positron emission tomography [PET]) are not available at
the bedside. The double indicator dilution technique is, however, relatively time
consuming, cumbersome and expensive, and therefore has not been widely incor-
porated into clinical practice. The assessment of EVLW by a single (cold) indicator
has been recently validated against the double indicator (thermo-dye) dilution tech-
nique [3, 4] and the reference gravimetric method [62]. Therefore, the transpul-
monary thermodilution technique allows the reliable bedside assessment of EVLW
in critically ill patients using a simple cold saline bolus. Since the maintenance of
negative fluid balance has been shown to improve the outcome of patients with pul-
monary edema [57], the assessment of EVLW is useful to identify and follow pa-
tients who may benefit from such a therapeutic strategy. In other words, the rou-
tine measurement of EVLW may settle the ongoing controversy between the 'dry'
and 'wet' therapeutic approach to patients with ARDS [63]. Clinical studies are ur-
gently needed to confirm this significant potential value of EVLW measurements,
Finally, since the beneficial effects of fluid restriction/depletion in patients with
pulmonary edema may be associated with worsening hemodynamics, the simulta-
neous assessment of cardiac preload (GEDV) and of the sensitivity of the heart to
changes in preload (PPV and SVV) can be very helpful to deal with this issue.
Assessment of Pulmonary Vascular Permeability

By definition, EVLW is increased in both permeability and hydrostatic pulmonary
edema. In hydrostatic pulmonary edema, the increase in EVLW is due to an in-
crease in pulmonary blood volume and pressure. Therefore, the ratio of EVLW to
pulmonary blood volume is much higher in cases of permeability than in cases of
hydrostatic pulmonary edema (Fig. 6). The pulmonary blood volume is easily esti-
mated by the PiCCOplus monitor as 25% of the GEDV (4]. Therefore, the ratio of
EVLW to pulmonary blood volume - called the pulmonary vascular permeability
index (PVPI) [60) - is automatically calculated and displayed by the PiCCOplus
monitor. This parameter may be useful not only to discriminate between hydro-
static and permeability edema but also to assess the effects of various disease states
and therapeutic interventions on pulmonary vascular permeability [60].
Mechanisms of Arterial Hypoxemia

The main mechanisms of arterial hypoxemia are ventilation/perfusion mismatch
and intrapulmonary shunt. However, other mechanisms - mainly the 'Pv0 2 effect'
and a right-to-left intracardiac shunt - may also contribute to arterial hypoxemia
'Pv02 Effect~ In patients with increased intrapulmonary shunt, Pv0 2 is a major de-
terminant of Pa0 2 [64). By increasing peripheral oxygen extraction and hence de-
creasing Pv0 2 , a decrease in cardiac output is able to worsen arterial hypoxemia.
In this context, increasing cardiac output either by fluid loading or by inotropic
agents may result in increased Pv0 2 , which in turn may improve Pa0 2 [64]. There-
fore, the measurement of cardiac output is important to rule out a low cardiac out-
put and a possible 'Pv0 2 effect' in the presence of arterial hypoxemia. Moreover,
Permeability Hydrostatic
pulmonary edema pulmonary edema
EVLW
PBV
PVPI = EVLW/PBV >>>> PVPI = EVLW/PBV
Fig. 6. The pulmonary vascular permeability index (PVPI) is calculated as the ratio of extravascular lung
water (EVLW) to pulmonary blood volume (PBV). The PVPI is greater in permeability than in hydrostatic
pulmonary edema
the assessment of cardiac preload (GEDV) and of dynamic markers of fluid respon-
siveness (PPV and SVV) is useful to choose the most appropriate therapy to im-
prove cardiac output.
Right-to-Left lntracardiac Shunt. Intracardiac shunt from the right to the left atrium
through a patent foramen ovale may also cause hypoxemia. A patent foramen ovale
is present at autopsy in 20 to 34% of the general population [65]. The unique na-
ture of this membranous structure allows it to function as a unidirectional valve,
opening from right-to-left. The prevalence of right-to-left intracardiac shunt is
around 25% in patients with pulmonary hypertension [66] or during positive pres-
sure ventilation [67] and is potentiated by PEEP [68]. In patients with ALI/ARDS,
the real prevalence of right-to-left intracardiac shunt is unknown and may be clini-
cally significant because of the usually associated pulmonary hypertension, me-
chanical ventilation, and PEEP. Color Doppler examination of interatrial septum
and contrast echocardiography can diagnose right-to-left intracardiac shunt [67,
68] but are not routinely performed in ALIIARDS patients. A right-to-left intracar-
diac shunt is easily (a single cold saline bolus ... ) evidenced by the visual inspec-
tion of the transpulmonary indicator dilution curve [69] (Fig. 7). Indeed, in case of
right-to-left intracardiac shunting, one part of the indicator passes through the in-
teratrial septum and reaches rapidly the thermistor-tipped arterial catheter. As a re-
sult, the transpulmonary dilution curve appears prematurely and becomes biphasic
[69] (Fig. 7). Early recognition of such a shunt may have therapeutic implications
such as nitric oxide (NO) inhalation [70] or PEEP decrease/removal [68]. The effi-
cacy of these maneuvers can be immediately checked by the mere observation of
the shape of the transpulmonary indicator dilution curve.
t (s)
0 5 10 15 20 25
0
'\. ----·
\\ ....···············
.....:~....................... a
0.05
\\
\\
"
!:!)
u
0.10
0.15
0.20
a: •shunted• curve c =a + b:•effective• curve
b: •normal• curve d: curve without shunt
Fig. 7. Detection of right-to-left intracardiac shunt by transpulmonary thermodilution: the curve (c=effec-
tive curve) appears prematurely and is biphasic
Prediction of PEEP~Induced Hemodynamic Instability

In ventilated patients with ALI/ARDS, PEEP may improve pulmonary gas exchange.
However, it may also decrease cardiac output and thus offset the expected benefits
in terms of oxygen delivery. The PEEP-induced decrease in cardiac output is as-
sumed to be mainly due to a decrease in systemic venous return secondary to the
increased pleural pressure [71, 72]. The adverse hemodynamic effects of PEEP are
not predicted by conventional static hemodynamic parameters. In contrast, the res-
piratory changes in left ventricular stroke volume - assessed by arterial waveform
analysis - have been shown to be closely related to the decrease in cardiac output
in response to PEEP application [73, 74], such that the higher the respiratory
changes in arterial pressure on zero end-expiratory pressure (ZEEP), the more
marked the decrease in cardiac output after PEEP application [74]. Therefore, PPV
and SVV can also be used to predict and hence to prevent the deleterious hemody-
namic effects of PEEP.
1 Conclusion
Most of the hemodynamically unstable and/or severely hypoxemic patients are in-
strumented with a central venous line and an arterial line. Thus, advanced cardio-
respiratory monitoring by the transpulmonary thermodilution method simply re-
quires the use of a specific thermodilution arterial catheter, without any further in-
vasive and costly instrumentation. In patients with circulatory failure, the transpul-
monary thermodilution technique ;Ulows the simultaneous assessment of cardiac
output, cardiac preload (GEDV), cardiac contractility/function (GEF) and the pre-
diction of fluid responsiveness (PPV and SVV). Therefore, the transpulmonary ther-
modilution allows a better understanding of the pathophysiological mechanisms
(vasoplegia, hypovolemia, heart failure) of acute circulatory failure and hence the
choice of the most appropriate therapy (Fig. 2). In contrast to echocardiography,
transpulmonary thermodilution is a non-operator dependent technique that can be
used by all caregivers, in all ICUs, as often as is necessary, and that provides all he-
modynamic parameters within a few minutes. In hypoxemic patients, transpulmon-
ary thermodilution enables the identification of patients with pulmonary edema
(elevated EVLW) as well as the quantification of pulmonary edema and its response
to therapeutic maneuvers (e.g., fluid restriction/depletion). In addition, it enables
the assessment of pulmonary vascular permeability (PVPI), a better understanding
of the pathophysiological mechanisms of hypoxemia (pulmonary edema, low cardi-
ac output, right-to-left intracardiac shunt), and the prediction of the possible dele-
terious hemodynamic effects of PEEP. In conclusion, the transpulmonary thermodi-
lution technique provides the caregiver with a simple, reproducible and integrated
approach of the heart and the lungs (cardio-respiratory monitoring) that cannot be
considered separately in most critically ill patients.
References
1. Meier P, Zierler KL (1954) On the theory of indicator-dilution method for measurement of
blood flow and volume. J Appl Physiol 6:731-744
2. Newman EV, Merrel M, Genecin A, et al (1951) The dye dilution method for describing the
central circulation. An analysis of.factors shaping the time-concentration curves. Circula-
tion 4:735-746
Management of Circulatory and Respiratory Failure Usinq Less Invasive Hemodynamic Monitorinq 517
3. Neumann P (1999) Extravascular lung water and intrathoracic blood volume: double versus
single indicator dilution technique. Intensive Care Med 25:216-219
4. Sakka SG, Riihl CC, Pfeiffer UJ, Dewald 0, Reichart B (2000) Assessment of cardiac preload
and extravascular lung water by single transpulmonary thermodilution. Intensive Care
Med 26:180-187
5. Godje 0, Peyerl M, Seebauer T, Dewald 0, Reichart B (1998) Reproducibility of double-in-
dicator dilution measurements of intrathoracic blood volume compartments, extravascular
lung water, and liver function. Chest 113:1070-1077
6. Sakka SG, Reinhart K, Meier-hellmann A (1999) Comparison of pulmonary artery and ar-
terial thermodilution cardiac output in critically ill patients. Intensive Care Med 25:843-
846
7. Goedje 0, Hoeke K, Lichtwarck-Aschoff M, Faltchauser A, Lamm P, Reichart B (1999) Con-
tinuous cardiac output by femoral arterial thermodilution calibrated pulse contour analy-
sis: comparison with pulmonary arterial thermodilution. Crit Care Med 27:2407-2412
8. McLuckie A, Marsh M, Murdoch I, Anderson D (1996) A comparison of pulmonary and fe-
moral artery thermodilution cardiac indices in paediatric intensive care patients. Acta Pae-
diatr 85:336-338
9. Tibby SM, Hatherill M, Marsh MJ, Morrison G, Anderson D, Murdoch IA (1997) Clinical
validation of cardiac output measurements using femoral artery thermodilution with direct
Fick in ventilated children and infants. Intensive Care Med 23:987-991
10. Sakka SG, Reinhart K, Wegscheider K, Meier-Hellmann A (2000) Is the placement of a pul-
monary artery catheter still justified solely for the measurement of cardiac output. J Car-
diothorac Vase Anesth 14:119-124
11. Pauli C, Fakler U, Genz T, Hennig M, Lorenz HP, Hess J (2002) Cardiac output determina-
tion in children: equivalence of the transpulmonary thermodilution method to the direct
Fick principle. Intensive Care Med 28:947-952
12. Iberti TJ, Fischer EP, Leibowitz AB, Panacek EA, Silverstein JH, Albertson TE (1990) A
multicenter study of physician's knowledge of the pulmonary artery catheter. JAMA
264:2928-2932
13. Teboul JL, Pinsky MR, Mercat A, Kline RA (2000) Estimating cardiac filling pressure in
mechanically ventilated patients with hyperinflation. Crit Care Med 28:3631-3636
14. Calvin JE, Driedger AA, Sibbald WJ (1981) Does the pulmonary capillary wedge pressure
predict left ventricular preload in critically ill patients? Crit Care Med 9:437-443
15. Reuse C, Vincent JL, Pinsky MR (1990) Measurements of right ventricular volumes during
fluid challenge. Chest 98:1450-1454
16. Diebel LN, Wilson RF, Tagett MG, Kline RA (1992) End-diastolic volume. A better indicator
of preload in the critically ill. Arch Surg 127:817-822
17. Diebel L, Wilson RF, Heins J, Larky M, Warsow K, Wilson S (1994) End-diastolic volume
versus pulmonary artery wedge pressure in evaluating cardiac preload in trauma patients.
J Trauma 37:950-955
18. Thys DM, Hillel Z, Goldman ME, Mindich BP, Kaplan JA (1987) A comparison of hemody-
namic indices derived by invasive monitoring and two-dimensional echocardiography. An-
19. Cheung AT, Savino JS, Weiss SJ, Aukburg SJ, Berlin JA (1994) Echocardiographic and he-
modynamic indexes of left ventricular preload in patients with normal and abnormal ven-
tricular function. Anesthesiology 81:376-387
20. Tavernier B, Makhotine 0, Lebuffe G, Dupont J, Scherpereel P (1998) Systolic pressure var-
iation as a guide to fluid therapy in patients with sepsis-induced hypotension. Anesthesiol-
ogy 89:1313-1321
21. Tousignant CP, Walsh F, Mazer CD (2000) The use of transesophageal echocardiography
for preload assessment in critically ill patients. Anesth Analg 90:351-355
22. Lichtwarck-Aschoff M, Zeravik J, Pfeiffer UJ (1992) Intrathoracic blood volume accurately
reflects circulatory volume status in critically ill patients with mechanical ventilation. In-
23. Preisman S, Pfeiffer U, LiebermanN, Perel A (1997) New monitors of intravascular volume:
a comparison of arterial pressure waveform analysis and the intrathoracic blood volume.
24. Sakka SG, Bredle DL, Reinhart K, Meier-Hellmann A (1999) Comparison between in-
trathoracic blood volume and cardiac filling pressures in the early phase of hemodynamic
instability of patients with sepsis or septic shock. J Crit Care 14:78-83
25. Goedje 0, Seebauer T, Peyerl M, Pfeiffer UJ, Reichart B (2000) Hemodynamic monitoring
by double-indicator dilution technique in patients after orthotopic heart transplantation.
Chest 118:775-781
26. Wiesenack C, Prasser C, Key! C, Rodijg G (2001) Assessment of intrathoracic blood volume
as an indicator of cardiac preload: single transpulmonary thermodilution technique versus
assessment of pressure preload parameters derived from a pulmonary artery catheter. J
Cardiothorac Vase Anesth 15:584:588
27. Reuter DA, Felbinger TW, Moerstedt K, et al (2002) Intrathoracic blood volume index mea-
sured by thermodilution for preload monitoring after cardiac surgery. J Cardiothorac Vase
Anesth 16:191-195
28. Michard F, Alaya S, Zarka V, et al (2002) Effects of volume loading and dobutamine on
transpulmonary thermodilution global end-diastolic volume. Intensive Care Med 28:S53
(abst)
29. McLuckie A, Bihari D (2000) Investigating the relationship between intrathoracic blood
volume index and cardiac index. Intensive Care Med 26:1376-1378
30. Buhre W, Kazmaier S, Sonntag H, Weyland A (2001) Changes in cardiac output and intra-
thoracic blood volume: a mathematical coupling of data? Acta Anesthesiol Scand 45:863-
867
31. Schiffmann H, Erdlenbruch B, Singer D, et al (2002) Assessment of cardiac output, intra-
vascular volume status, and extravascular lung water by transpulmonary indicator dilution
in critically ill neonates and infants. J Cardiothorac Vase Anesth 16:592-597
32. Michard F, and Teboul JL (2002) Predicting fluid responsiveness in ICU patients. A critical
analysis of the evidence. Chest 121:2000-2008
33. Perel A (1998) Assessing fluid responsiveness by the systolic pressure variation in me-
chanically ventilated patients. Anesthesiology 89:1309-1310
34. Michard F, Teboul JL (2000) Using heart-lung interactions to assess fluid responsiveness
during mechanical ventilation. Crit Care 4:282-289
35. Perel A, Pizov R, Cotev S (1987) Systolic blood pressure variation is a sensitive indicator of
hypovolemia in ventilated dogs subjected to graded hemorrhage. Anesthesiology 67:498-
502
36. Michard F, Boussat S, Chemla D, et al (2000) Relation between respiratory changes in arter-
ial pulse pressure and fluid responsiveness in septic patients with acute circulatory failure.
37. Godje 0, Thiel C, Lamm P, et al (1999) Less invasive, continuous hemodynamic monitoring
during minimally invasive coronary surgery. Ann Thorac Surg 68:1532-1536
38. Buhre W, Weyland A, Kazmaier S, et al (1999) Comparison of cardiac output assessed by
pulse contour analysis and thermodilution in patients undergoing minimally invasive di-
rect coronary artery bypass grafting. J Cardiothorac Vase Anesth 13:437-440
39. Rodig G, Prasser C, Key! C, Hobbahn J (1999) Continuous cardiac output measurement:
pulse contour analysis versus thermodilution technique in cardiac surgical patients. Br J
Anaesth 82:525-530
40. Zollner C, Haller M, Weis M, et al (2000) Beat-to-beat measurement of cardiac output by
intravascular pulse contour analysis: a prospective criterion standard study in patients
after cardiac surgery. J Cardiothorac Vase Anesth 14:125-129
41. Goedje 0, Hoeke K, Goetz AE, et al (2002) Reliability of a new algorithm for continuous
cardiac output determination by pulse-contour analysis during hemodynamic instability.
42. Della Rocca G, Costa MG, Pompei L, Coccia C, Pietropaoli P (2002) Continuous and inter-
mittent cardiac output measurement: pulmonary artery catheter versus aortic transpul-
monary technique. Br J Anaesth 88:350-356
43. Berkenstadt H, Margalit N, Hadani M, et al (2001) Stroke volume variation as a predictor
of fluid responsiveness in patients undergoing brain surgery. Anesth Analg 92:984-989
44. Reuter DA, Kilger E, Felbinger TW, Schmidt C, Lamm P, Goetz AE (2002) Optimising fluid
therapy in mechanically ventilated patients after cardiac surgery by on-line monitoring of
Management of Circulatory and Respiratory Failure Using Less Invasive Hemodynamic Monitoring 519
left ventricular stroke volume variations: a comparison to aortic systolic pressure varia-
tions. Br J Anesth 88:124-126
45. Reuter DA, Felbinger TW, Schmidt C, et a! (2002) Stroke volume variations for assessment
of cardiac responsiveness to volume loading in mechanically ventilated patients after cardi-
ac surgery. Intensive Care Med 28:392-398
46. Robotham JL, Takata M, Berman M, Harasawa Y {1991) Ejection fraction revisited. An-
47. Baudendistel L, Shields JB, Kaminski DL {1982) Comparison of double indicator thermodi-
lution measurements of extravascular lung water (EVLW) with radiographic estimation of
lung water in trauma patients. J Trauma 22:983-988
48. Halperin BD, Feeley TW, Mihm FG, Giles C, Guthaner DF, Blank NE {1985) Evaluation of
the portable chest roentgenogram for quantitating extravascular lung water in critically ill
adults. Chest 88:649-652
49. Eisenberg PR, Hansbrough JR, Anderson D, Schuster DP {1987) A prospective study of
lung water measurements during patient management in an intensive care unit. Am Rev
50. Takeda A, Okumura S, Miyamoto T, Hagio M, Fujinaqo T {1995) Comparison of extravas-
cular lung water volume with radiographic findings in dogs with experimentally increased
permeability pulmonary edema. J Vet Med Sci 57:481-485
51. Michard F, Zarka V, Alaya S, et a! {2002) Extravascular lung water measurements in pa-
tients with ALI/ARDS. Intensive Care Med 28:S88 (abst)
52. Pfeiffer U, Backus G, Blume! G, eta! {1990) A fiberoptics based system for integrated mon-
itoring of cardiac output, intrathoracic blood volume, extravascular lung water, 0 2 satura-
tion, and a-v differences. In: Lewis F, Pfeiffer U {eds) Practical Applications of Fiberoptics
in Critical Care Monitoring. Springer, Berlin, pp 114-125
53. Lewis FR, Elings VB, Christensen JM {1992) Extravascular lung water measurements. In:
Artigas A, Lemaire F, Suter PM, Zapol WM (eds) Adult Respiratory Distress Syndrome.
Churchill, Livingstone, Edinburgh, pp 215-225
54. Schuster DP {1998) The evaluation of pulmonary edema by measuring lung water. In:
Tobin MJ (ed) Principles and Practice of Intensive Care Monitoring. McGraw-Hill, New
York, pp 693-705
55. Zeravik J, Pfeiffer UJ {1989) Efficacy of high frequency ventilation combined with volume
controlled ventilation in dependency of extravascular lung water. Acta Anaesthesiol Scand
33:568-574
56. Zevarik J, Borg U, Pfeiffer UJ {1990) Efficacy of pressure support ventilation dependent on
extravascular lung water. Chest 97:1412-1419
57. Mitchell JP, Schuller D, Calandrino FS, Schuster DP {1992) Improved outcome based on
fluid management in critically ill patients requiring pulmonary artery catheterization. Am
58. Bindels AJ, van der Hoeven JG, Meinders AE {1999) Pulmonary artery wedge pressure and
extravascular lung water in patients with acute cardiogenic pulmonary edema requiring
mechanical ventilation. Am J Cardiol 84:1158-1163
59. von Spiegel T, Giannaris S, Wietasch GJK, et a! {2002) Effects of dexamethasone on intra-
vascular and extravascular fluid balance in patients undergoing coronary bypass surgery
with cardiopulmonary bypass. Anesthesiology 96:827-834
60. Holm C, Tegeler J, Mayr M, et a! {2002) Effect of crystalloid resuscitation and inhalation
injury on extravascular lung water. Chest 121:1956-1962
61. Boussat S, Jacques T, Levy B, eta! {2002) Intravascular volume monitoring and extravascu-
lar lung water in septic patients with pulmonary edema. Intensive Care Med 28:712-718
62. Katzenelson R, Preisman S, Berkenstadt H, et a! {2001) Extravascular lung water measured
by a single indicator technique in dogs. Correlation with gravimetric measurements. Crit
63. Schuster DP {1995) Fluid management in ARDS: <<keep them dry» or does it matter? In-
64. Dantzker DR and Gutierrez G (1989) Effects of circulatory failure on pulmonary and tissue
gas exchange. In: Scharf SM, Cassidy SS (eds) Heart-lung Interactions in Health and Dis-
ease. Marcel Dekker, New York, pp 983-1019
520 F. Michard and A. Perel: Management of Circulatory and Respiratory Failure
65. Hagen PT, Scholz DG, Edwards WD (1984) Incidence and size of patent foFamen ovale dur-
ing the first ten decades of life: an autopsy study of 965 normal hearts. Mayo Clin Proc
59:17-20
66. Nootens MT, Berarducci LA, Kaufmann E, Devries S, Rich S (1993) The prevalence and sig-
nificance of a patent foramen ovale in pulmonary hypertension. Chest 104:1673-1675
67. Konstadt SN, Louie EK, Black S, Rao TL, Scanlon P (1991) Intraoperative detection of pa-
tent foramen ovale by transesophageal echocardiography. Anesthesiology 74:212-216
68. Cujec B, Polasek P, Mayers I, Johnson D (1993) Positive end-expiratory pressure increases
the right-to-left shunt in mechanically ventilated patients with patent foramen ovale. Ann
69. Swan HJC, Zapata-Diaz J, Wood EH (1953) Dye dilution curves in cyanotic congenital
heart disease. Circulation 8:70-81
70. Fellahi JL, Mourgeon E, Goarin JP, et al (1995) Inhaled nitric oxide-induced closure of a
patent foramen ovale in a patient with acute respiratory distress syndrome and life-threa-
tening hypoxemia. Anesthesiology 83:635-638
71. Viquerat CE, Righetti A, Suter PM (1983) Biventricular volumes and function in patients
with adult respiratory distress syndrome ventilated with PEEP. Chest 83:509-514
72. Potkin RT, Hudson LD, Weaver LJ, Trobaugh G (1987) Effect of positive end-expiratory
pressure on right and left ventricular function in patients with the adult respiratory dis-
tress syndrome. Am Rev Respir Dis 135:307-311
73. Pizov R, Cohen M, Weiss Y, Segal E, Cotev S, Perel A (1996) Positive end-expiratory pres-
sure-induced hemodynamic changes are reflected in the arterial pressure waveform. Crit
Care Med 24:1381-1387
74. Michard F, Chemla D, Richard C, et al (1999) Clinical use of respiratory changes in arterial
pulse pressure to monitor the hemodynamic effects of PEEP. Am J Respir Crit Care Med
159:935-939
Minimally Invasive Hemodynamic Monitoring
W. T. Peruzzi, R. Gould, and L. Brodsky
I Introduction
One of the most important goals of caring for critically ill patients is maintenance
of adequate organ perfusion; as such, hemodynamic monitoring has become a cor-
nerstone of critical care medicine. The ability to rapidly and accurately obtain and
interpret hemodynamic parameters, as well as to manipulate these parameters ac-
cording to clinical changes, remains a significant part of the intensivist's practice;
The primary parameters of interest to the intensivist are the physiologic markers of
preload, afterload, and contractility as well as well as the balance between oxygen
delivery (D02 ) and utilization. Today the intensivist has a multitude of monitors to
assist him in the hemodynamic monitoring of the patient. The pulmonary artery
catheter (PAC) remains a popular method for obtaining such important hemody-
namic information [1-3]. Some controversy regarding the risks and benefits of PAC
use [2, 4] has caused the intensivist to look to other techniques of hemodynamic
monitoring [1, 5].
While few would disagree that many clinical conditions exist for which PA cathe-
ritization is a very useful and important diagnostic tool, other somewhat less invasive
techniques have come to clinical availability and are finding a place in the care of pa-
tients with varying degrees and etiologies of hemodynamic instability. Among the al-
ternatives that have been gaining interest are transesophageal echocardiography
(TEE), new indicator dilution techniques (e.g., lithium chloride) [6, 7], pulse contour
analysis based on methods such as the PiCCO and PulseCO [5, 6], as well as bioim-
pedance [8, 9] and esophageal Doppler [5] and C02 rebreathing techniques [5, 10, 11].
Whatever the technique used, the intensivist must understand the principles and the
limitations of the method in order to maximize the utility of the monitor.
These techniques provide ongoing measurements, which permit us to follow
trends in disease progression and response to therapy. Some of the new technolo-
gies can provide continuous measurement and trending of heart rate (HR) and
stroke volume (SV) with calculation of cardiac output and derived parameters such
as stroke volume index (SVI), cardiac index (CI), systemic vascular resistance
(SVR), left cardiac work index (LCWI) and ejection fraction (EF) [9, 12-13]. As the
new and less invasive technologies become more available, they are increasingly
being tested in clinical settings [14, 15]. The question most asked is how well they
compare with invasive 'gold standard' methods in determining SV and cardiac out-
put, i.e., thermodilution cardiac output determinations [6, 16, 17]. However, it must
be kept in mind that more invasive monitors are not necessarily more accurate ..
The PAC, a somewhat complicated and invasive intensive care unit (ICU) procedure
commonly used to measure intracardiac pressures and derive the thermodilutjon car-
522 W. T. Peruzzi et al.
diac output curve, has been noted to be fraught with risks and spurious readings [18].
If the cardiac output measurement is done manually and intermittently, the informa-
tion is out of date immediately after any intervention, such as changes in mechanical
ventilation or drug therapy, which alters preload, afterload, chronotropy, or inotropy
[18]. Continuous thermodilution techniques now exist that average information over
several minutes and provide a constant output of information. This permits for better
trend monitoring, especially when the 'continuous cardiac output' technique is com-
bined with continuous mixed venous oxygen saturation (Sv0 2 ) monitoring.
Some new hemodynamic monitoring devices are less invasive and provide for
more continuous monitoring capabilities [6, 19-23]. Examples are the PiCO (ther-
modilution) [19], the LiDCO (lithium dilution) [6, 22] and the transonic (NaCl di-
lution) systems which do not require a PAC but do require a central venous cathe-
ter and an arterial catheter. Other examples of relatively non-invasive techniques
are the indirect Fick methods using C0 2 rebreathing or inhaled gases after tracheal
intubation to isolate the airway [10, 11, 24]. Advances have also been made in the
development of completely non-invasive techniques using thoracic bioimpedance
measurements [25, 26].
The ability to monitor and record trends is often more valuable than instanta-
neous measurements (8, 12-14, 27). Most of the advances being made in non-inva-
sive cardiac output monitoring include the ability to monitor parameters continu-
ously and to follow trends in therapy and interventions. Recent publications on the
use of continuous non-invasive monitoring during changes in patient hemodynamic
status have shown the benefit of trend monitoring in various clinical situations
[14-15, 27-30].
Pulmonary Artery Catheterization: The Controversy

PA catheterization remains the mainstay of ICU care when it is necessary to assess
the critically ill patient who is hemodynamically unstable without clear reason. The
PAC can provide information regarding important hemodynamic parameters and
assist the clinician in determining appropriate therapy. This can lead to a decrease
in secondary injuries in the critically ill patient population caused by either over-
or-under resuscitation. Recent data from the PAC consensus conference support the
use of this device in patients whose ICU course is complicated by acute respiratory
distress syndrome (ARDS), renal failure and/or sepsis [3, 6].
As all intensivists know, PA catheterization is achieved by inserting the PAC
through an existing central venous introducer sheath. The flow directed catheter is
then advanced, with the balloon at the tip inflated, to allow floatation into the pul-
monary artery. The position of the catheter is confirmed by recognition of the
characteristic waveforms [31]. This technique has proved clinically important for
the diagnosis of a number of serious conditions resulting in changes in cardiac
output, intravascular volume, and systemic vascular resistance (i.e., sepsis, the sys-
temic inflammatory response, spinal shock, cardiogenic shock, etc.) which are not
uncommon in the critically ill [32].
Controversy regarding such right heart catheterization techniques has been in
the forefront of the critical care literature recently [2, 3]. Various complications per-
taining to PA catherization have been reported and include technical difficulties
(i.e., with central venous catheterization or placement of the catheter across the
valves of the heart into the PA), life threatening arrhythmias, damage to valvular
Minimally Invasive Hemodynamic Monitoring 523
structures, air embolus, endocarditis and other infections, PA rupture, creation of

arterio-veinous fistulas, right atrial rupture, etc. [3, 31, 33]. This controversy was
led by a study from five teaching hospitals demonstrating that the group of patients
undergoing PA catheterization had an increased 30-day mortality and an increase
in hospital cost, in severity of illness-adjusted patient populations [2]. The study
was criticized by many because it presented statistical associations which were not
clearly demonstrated to be of a 'cause-and-effect' relationship. However, an impor-
tant inference from this study was that the benefits of PAC use are likely not to be
realized if the physician interpreting the information gleaned from the catheter is
not knowledgeable and skilled in hemodynamic assessment. The following year, the
Society of Critical Care Medicine (SCCM) released the recommendations of their
consensus conference [3]. These included that clinicians should carefully weigh the
risks and benefits of PA catheterization before insertion and that criteria for the
use of the PAC in specific clinical situations should be developed {Table 1).
Table 1. SCCM PAC Consensus Conference Recommendations, from [3) with permission
Disease/Disorder and question number Answer Grade Randomized,

controlled
trial
recommended
Myocardial infarction with

Hypotension or cardiogenic shock (I A) Yes E Yes
Mechanical complication (I B) Yes E Yes
Right ventricular infarction (I q Yes E Yes
Congestive heart failure (I D) Uncertain D Yes
Pulmonary hypertension Uncertain E Yes
Shock or hemodynamic instability (I F) Uncertain E Yes
Cardiac surgery (II A) Yes
Low risk No c
High risk Uncertain c
Peripheral vascular surgery (II B) Yes
Reduced complications Yes D
Reduced morbidity Uncertain D
Aortic Surgery (II q Yes
low Risk Uncertain B
High Risk Yes E
Geriatric patients undergoing surgery (II D) No E Yes
Neurosurgery (II E) Uncertain E Yes
Preeclampsia (II F) Not routinely E Yes
Trauma (Ill A) Yes E Yes
Sepsis/septic shock (IV) Uncertain D Yes
Supranormal oxygen delivery Yes
SIRS (VA) Uncertain B
High-risk surgery (V B) Uncertain c
I
Respiratory failure (VI B) Uncertain E Yes
Pediatric patients (VII B) Yes E Yes
Table 2. Minimally invasive cardiac output and hemodynamic monitoring systems. (Modified from [1]
with permission)
Technique/Product Advantages Disadvantages

Direct Fick Recognized gold standard Very invasive and very expensive in terms
of equipment and staff time. Requires
cardiac catheter, CVP. arterial line and
steady state metabolism.
Needs ICU admission.
PA catheterization with Accurate measurements of Very invasive and very expensive in terms
thermodilution cardiac output at the time of equipment and time.
taken if performed with Requires PA catheter, CVP and arterial lines
meticulous standards Isolated measurements. Needs ICU admission
PA Swan-Ganz CCO catheter Continuous beat to beat Very invasive and very expensive. Requires
with RVEF/OX right ventricular ejection PA catheter, CVP and arterial lines.
Mixed venous saturation fraction and mixed venous Needs ICU admission.
(Sv0 2) saturation with CO trend.
Derives RVEDV and RVESV
Scv0 2 System Continuous central venous Invasive, but less so than PA catheter.
Central mixed venous saturation gives CO trend Inaccurate in many situations but does show
saturation trend.
PICCO System Continuous trend of SV with Invasive, but less so than PA catheter.
Transpulmonary isolated Co measurement by Expensive in terms of equipment and time.
thermodilution thermodilution as required Requires CVP and arterial lines.
Arterial pulse contour
analysis
LiDCO System Continuous BP and arterial Invasive, but less so than PA catheter.
Lithium injection dilution waveform indicating cardiac Expensive in terms of equipment and time.
curve output changes with calibra- Requires CVP and arterial lines.
Arterial waveform analysis tion of the cardiac output
with the Pulse CO system by lithium dilution
Transonic System Gives cardiac output, Cl Partially invasive. Requires only a peripheral
Ultrasound Indicator NaCI and central blood volume IV and arterial lines.
dilution Local directed quantitative
flow
Indirect Rck No vascular assess required, Requires intubation and CMV for steady stat
C02 rebreathing for cardiac output deter- C02 metabolism.
mination only Requires C0 2 rebreathing.
NiCO System No vascular assess required Requires intubation and CMV for steady stat
Indirect Rck principle with Gives cardiac output every C0 2 metabolism.
partial C0 2 rebreathing 3 minutes Poor correlation in lung disease.
And respiratory parameters
TGE System No vascular invasion Expensive capital equipment.
Transgastric, Doppler echo Thin silicone probe (6 mm) Needs specialist expertise.
TEE System No vascular invasion Expensive capital equipment.
Transesophageal echo Needs specialist expertise.
Needs sedation.
Table 2 (continued)
Technique/Product Advantages Disadvantages
EIC Systems Completely noninvasive Needs baseline impedence (Zo).

Electrical lmpedence Safe and simple to use Affected by thoracic fluid and increased bod
Cardiography e.g. BioZ, Ideal for children weight.
TebCO, Steorra, CIC.
Cbll Chest Baseline Completely noninvasive None known.
lmpedence Independent of baseline New technology.
Independent EIC System impedence
e.g., Physioflow
CVP: central venous pressure, ICU: Intensive care unit, PA: Pulmonary artery, CCO: Continuous cardiac out-
put, RVEF: Right ventricular ejection fraction, RVEDV: right ventricular end-diastolic volume, RVESV: right
ventricular end systolic volume, SV: stroke volume, Cl: cardiac index, IV: Intravenous, CMV: controlled me-
chanical ventilation, Ox: oximetry
An added advantage to some PACs is the ability to measure the Sv02 • Depending
on the patient's pathophysiology, this may allow the intensivist to reasonably assess
the balance of oxygen supply and oxygen consumption at the tissue level. Normal
Sv0 2 is 70-75%, which means that under normal conditions oxygen extraction for
the whole body is 25 to 30. This measure is a valuable check against the potential
errors associated with the various other hemodynamic measurements.
There are several minimally invasive techniques to determine cardiac output and
related variables. The available technology is well outlined in Table 2. Some of
those with the greatest clinical utility will be discussed further in this article.
I Methods Using the Fick Principle

Pick postulated that oxygen uptake in the lungs is entirely transferred to the blood.
Therefore, cardiac output can be calculated as the ratio between oxygen consump-
tion and arteriovenous difference in oxygen. The technique requires central venous
and arterial catheters for mixed venous and arterial blood sampling. Oxygen con-
sumption assessments are not accurate in patients receiving an Pi0 2 greater than
60%, in patients with increased intrapulmonary shunting, or with hemodynami-
cally unstable patients; therefore, it is often not applicable in critically ill patients
[5).
The same principle is applicable not only to oxygen, but to any gas that diffuses
through the lungs, including C0 2 • The Pick principle applied to C0 2 is used in the
NICO monitor (Novametrix Medical Systems) [5, 10, 11]. This monitor consists of
a C0 2 sensor (infrared light absorption}, an airflow sensor and a pulse oximeter.
The technique is designed to non-invasively estimate cardiac output using intermit-
tent partial rebreathing through a disposable rebreathing loop. The rebreathing per-
mits the Pick equation to be rearranged such that the venous C0 2 content can be
eliminated from the equation; as such, the difference between the mixed venous
and arterial C0 2 contents can be approximated by changes in end tidal C0 2 multi-
plied by the slope of the C0 2 dissociation curve [5]. This technique will by con-
founded in patients with increased intrapulmonary shunt, in hemodynamically un-
stable patients, and can only be used in patients on mechanical ventilatory support.
To our knowledge, there are no conclusive data comparing this technique with in-
dicator dilution cardiac output measurements.
I Trans-Esophageal Echocardiography
TEE can be used for assessment of ventricular function, estimation of ejection frac-
tion (difference between end diastolic and end systolic volume) and assessment of
valvular function. It has gained significant popularity in the last decade and its
utility continues to be defined.
The technique of echocardiography can be used to assess cardiac output, and the
associated variables, primarily by utilizing a volumetric technique rather than a meth-
odology based on indicator geometric measurements of cardiac anatomy. The change
in the geometric dimensions of the ventricle during systole and diastole are deter-
mined and, from this change, the volume (stroke volume) change is extrapolated
[34]. This methodology is limited by the resolution of the ultrasound device, the as-
sumptions made about the 3-dimensional ventricular shape (circular vs. elliptical,
wall motion abnormalities) during extrapolation from areas to volumes, and user
variability. Devices with automated blood-endocardial border detection capability
can reduce the errors produced when assessing left ventricular cross-sectional area.
The issue of 'right and wrong' numbers or 'error' is problematic when dealing
with such measurements. In no circumstance are we dealing with an absolutely
known number; therefore, we are simply looking at different methods to assess the
same measurement. Frequently in such situations, it is necessary to rely on trends
to determine changes in a patient's condition over time, rather than a 'snap shot' at
a point in time [35-37].
An advantage of TEE is that it can be used in unstable patients and it tends to
give more information about filling volumes rather than pressures. Caution is re-
quired in patients with esophageal pathology, bleeding disorders and patients with
abnormalities of cervical spine and spinal cord. Unfortunately, it cannot be used
for continuous monitoring, the method requires expensive equipment, significant
operator expertise, and patients frequently require significant levels of sedation in
order to tolerate the procedure.
I Esophageal Doppler for Stroke Volume Measurement

This technique is based on the measurement of blood flow velocity in the descend-
ing aorta by means of a Doppler transducer at the tip of a flexible probe placed in
the esophagus. The probe is most easily placed orally if the patient is anesthetized
and mechanically ventilated. It is advanced to midthoracic level and positioned to
face the aorta in hopes of obtaining the characteristic aortic velocity signal [5].
The determination of SV, and subsequently cardiac output, via this method is based
on several assumptions: a) accurate measurement of blood flow velocity in the des-
cending aorta; b) a flat velocity profile in the descending aorta; c) an estimated
aortic cross sectional area close to the mean during systole; d) a constant division
of flow between the descending aorta (70%) and brachiocephalic and coronary ar-
teries (30%); and e) negligible blood flow in descending aorta in diastole [5, 38].
---~--~~~~,--~--~~"~,-~
Accurate measurements require good alignment between the Doppler beam and the
flow of blood, and knowledge of the angle at which the blood flow is insonated [5].
Small changes in the angle of insonation can result in significant differences in
measured values. All the red cells are assumed to be moving at the same speed and
the ratio of flows in cephalic and caudal territories (descending aorta) is assumed
to be constant, both of which may not be true under a variety of pathophysiologic
conditions [39-41].
Comparisons with thermodilution techniques suggest that esophageal Doppler can
be quite variable, but the bias in the measurements are consistent; thus, this technol-
ogy can provide a minimally invasive and clinically useful estimate of cardiac output
and detect hemodynamic changes in critically ill patients [5, 42]. The technique re-
quires no vascular invasion, can be placed via the oral or nasal route, and may be left
in place for some time; however, the equipment is expensive, it requires some special-
ist expertise for good placement, and patients often require sedation [ 1].
Pulse Contour Analysis

Pulse contour analysis is a technique based on a theory proposed by Wesseling et
al. [43], that the arterial pulse contour is proportional to stroke volume; as such,
pulse contour analysis can be used to determine and monitor cardiac output [44].
In pulse contour analysis, the pressure waveform is considered proportional to the
stroke volume and is estimated by the integral of the change in pressure from end
diastole to end systole over time. This technique was first described by measuring
the pulse contour in the aorta via femoral arterial access; however, there are com-
mercially available devices that permit such measurements via the axillary and pe-
ripheral arterial access points as well. Theoretically, the more peripheral the arterial
access point, the greater the potential for error in cardiac output determinations;
but, proper calibration, with indicator dilution techniques, and restriction of use to
good waveforms will serve to minimize the potential errors of the system.
Calibration of such systems requires an indicator dilution technique. The two
commercially available systems (PiCCO, Pulsion Medical, Munich, Germany and
PulseCo/LiDCO, LiDCO Ltd., London, UK) generally utilize different calibration
methods and different measurement sites. The PulseCo system is calibrated primar-
ily by using a lithium (Li) dilution technique (LiDCO), but can be, if so desired, ca-
librated with thermodilution as well. The advantage of the lithium dilution tech-
nique is that, at most, it requires a central venous catheter and can be calibrated a
peripheral intravenous catheter [45].
After calibration, the PulseCo gives the intensivist beat to beat information of
cardiac output, SV, SVR, systolic blood pressure variation. The PulseCo is not re-
commended for patients with aortic valve regurgitation, intra aortic balloon
pumps, peripheral arterial disease and highly dampened peripheral arterial lines.
The LidCO technique is based on the premise that the human body has no baseline
lithium; therefore, lithium chloride can be injected into the venous circulation and
then detected and measured quantitatively at an arterial site, thus, providing infor-
mation necessary for cardiac output determination from the lithium concentration-
time curve [5, 6]. This is accomplished by drawing blood over a lithium selective
electrode after venous injection of a known dose of lithium chloride (Fig. 1).
As with thermodilution techniques, the LiDCO can be used independently for in-
termittent determination and manipulation of hemodynamic parameters. This sys-
tern has been measured against and found to have overall agreement with other
methods of cardiac output measurement, particularly, thermodilution [6]. The use
of the LiDCO system requires either a central or peripheral venous catheter as well
as a well functioning arterial catheter. Garcia-Rodriguez et al. [45] have shown that
LiDCO assessments obtained with peripheral lithium injection agree well with cen-
trally obtained LiDCO assessments. Their comparison of 93 central lithium chloride
and 93 peripheral lithium chloride assessments showed good correlation. These
data are significant because they allow for rapid and accurate hemodynamic assess-
ment in patients in whom central venous access cannot be easily obtained. Thus,
some potential complications associated with the placement of a catheter into the
PA via the right heart, such as pulmonary infarction, PA rupture, arrhythmias, tri-
cuspid valve damage, etc., are avoided. The LiDCO device has the following limita-
tions: a) it can only be used three times within the stated period (this is based on
the excretion of the maximally suggested lithium dose in an anephric patient); b) it
is incompatible with simultaneous use of non-depolarizing neuromuscular blocking
agents because the ionic characteristics of this drug class interferes with the sensor
reading of lithium; and c) it only gives a static picture of the patient's hemody-
namic status.
The PiCCO system recommends arterial catheter placement in the femoral or ax-
illary sites. This is a limitation because many intensivists choose to avoid the femo-
ral region for intravascular access due to concerns about increased infection rates.
The concerns may or may not be valid, but they are present and must be acknowl-
edged, Thermodilution is the calibration method utilized with this system.
Arterial catheter
Fig. 1. Hamill n, Jessen ME (2002) PulseCO: Accurate monitoring of cardiac output from the arterial
waveform. Presented at gth Annual CTT meeting
I Bioimpedance Cardiography
This technique is a simple, readily reproducible, and completely non-invasive meth-
od for the determination of cardiac output [9, 13-14]. Specifically HR, SV, contrac-
tility, and SVR, and in some methods thoracic fluid content are determined. Bioim-
pedance can measure cardiac output with the same clinical accuracy as either the
Pick or thermodilution techniques and offers the potential for sequential measure-
ments of cardiac output in patients for whom invasive measurements are impracti-
cal or contraindicated [16, 46-48]. In addition, bioimpedance cardiography can de-
termine cardiac output on a beat-to-beat basis. The method is based on measure-
ment of chest wall impedance and the assumption that its changes over time are
determined by changes in water content, which in turn is due to flow of blood from
the left ventricle into the aorta [1]. The upslope of the waveform of change of im-
pedance over change in time is directly related to the velocity of blood in the as-
cending aorta, which is associated with contractility [1]. Bioimpedance can be used
in early stages of a disease which can potentially be complicated by hemodynamic
instability; it allows to follow on-line trends in cardiac output; it is safe, non-inva-
sive and easy to use [1]. Unfortunately, the rapid and frequent changes in intrathor-
acic fluid volume and tissue fluid content associated with critical illness, in con-
junction with the frequent atrial arrhythmias associated with critical illness, render
this technique of limited utility in the broad range of critically ill patients seen in
many ICUs [44].
I Conclusion
The intensivist today has an armamentarium of several relatively new techniques
that provide for minimally invasive hemodynamic assessments. None of these
methods, save bioimpedence technology, are completely non-invasive, however.
These new techniques do not exclude each other, as they have different advantages
and limitations and each has something to offer a given patient population, health
care institutional budget, and clinical user. It is clear however, that technology is
progressing toward a less invasive process and the patient population that will re-
quire a maximally invasive procedure in order to determine the hemodynamic pro-
file is shrinking.
References
1. Linton DM, Gilon DM (2002) Advances in noninvasive cardiac output monitoring. Ann
Cardiac Anesth 5:141-148
2. Connors Jr AF, Speroff T, Dawson NV, et al (1996) The effectiveness of right heart catheter-
ization in the initial care of critically ill patients. JAMA 276:889-897
3. Anonymous (1997) Pulmonary Artery Catheter Consensus Conference: consensus state-
ment. Crit Care Med 25:910-925
4. Cusack RJ, Rhodes A (1997) Pulmonary artery catheter - to use or not to use; that is the
question? Clin Intensive Care 11:117-119
5. Berton C, Cholley B (2002) Equipment r.eview: New techniques for cardiac output measure-
ment - oesophageal Doppler, Fick principle using carbon dioxide, and pulse contour analy-
sis. Crit Care 6:216-221
6. Linton R, Band D, O'Brien T, Jonas M, Leach R (1997) Lithium dilution cardiac output
measurement: a comparison with thermodilution. Crit Care Med 25:1796-1800
7. Linton RAP, Band DM, Haire KM (1993) A new method of measuring cardiac output in
man using lithium dilution. Br J Anaesth 71:262-266
8. Newman DG, Callister R (1999) The non-invasive assessment of stroke volume and cardiac
output by impedance cardiography: a review. Aviat Space Environ Med 70:780-789
9. Pianosi PT (1997) Impedance cardiography accurately measures cardiac output during ex-
ercise in patients with cystic fibrosis. Chest 111:333-337
10. Blanch L, Fernandez R, Benito S, et al (1988) Accuracy of an indirect carbon dioxide Pick
method in determination of the cardiac output in critically ill mechanically ventilated pa-
tients. Intensive Care Med 14:131-135
11. Arnold JH, Stenz RI, Thompson JE, Arnold LW (1996) Noninvasive determination of cardi-
ac output using single breath C0 2 analysis. Crit Care Med 24:1701-1705
12. Rosenberg P, Yancy CW (2000) Noninvasive assessment of hemodynamics: an emphasis on
bioimpedance cardiography. Curr Opin Cardiol15:151-155
13. Von Rueden KT, Turner M (1999) Advances in continuous, noninvasive hemodynamic sur-
veillance. Crit Care Nurs Clin North Am 11:63-75
14. Shoemaker WC Belzberg H, Wo CC, et al (1998) Multicenter study of noninvasive monitor-
ing systems as alternatives to invasive monitoring of acutely ill emergency patients. Chest
114:1643-1652
15. Summers RL, Kolb JC, Woodward LH, Galli RL (1999) Differentiating systolic from diasto-
lic heart failure using impedance cardiography. Acad Emerg Med 7:693-699
16. Castor G, Klocke RK, Stoll M, et al (1994) Simultaneous measurement of cardiac output by
thermodilution, thoracic elecrical bioimpedance and Doppler ultrasound. Br J Anaesth
72:133-138
17. Burchell SA, Yu M, Takiguchi SA, et al (1997) Evaluation of a continuous cardiac output
and mixed venous oxygen saturation catheter in critically ill surgical patients. Crit Care
Med 25:388-391
18. Tuman KJ, Gilbert CC, Ivankovich AD (1989) Pitfalls in interpretation of pulmonary artery
catheter data. J Cardiothorac Anesth 3:625-641
19. Kuntscher MV, Blome-Eberwein S, Pelzer M, Erdmann D, Germann G (2002) Transcardio-
pulmonary vs pulmonary arterial thermodilution methods for hemodynamic monitoring
of burned patients. J Burn Care Rehabil 23:21-26
20. Antonutto G, Girardis M, Tuniz D, di Prampero PE (1995) Noninvasive assessment of car-
diac output from arterial pressure profiles during exercise. Eur J Appl Physiol 72:18-24
21. Hirschi M, Kittler H, Woisetschlager C, et al (2000) Simultaneous comparison of thoracic
bioimpedance and arterial pulse waveform-derived cardiac output with thermodilution
measurement. Crit Care Med 28:1798-1802
22. Kurita T, Morita K, Kato S, et al (1997) Comparison of the accuracy of the lithium dilution
technique with the thermodilution technique for measurement of cardiac output. Br J
Anaesth 79:770-775
23. Eremenko A, Balykov I, Chaus N, Kislukhin V, Krivitski N (1998) Use of an extracorporeal
arteriovenous tubing loop to measure cardiac output in intensive care unit patients by ul-
trasound velocity dilution. ASAIO J 44:M462-M464
24. Davis CC, Jones NL, Sealey BJ (1978) Measurements of cardiac output in seriously ill pa-
tients using a C0 2 rebreathing method. Chest 73:167-172
25. Barney J (1996) Thoracic electrical bioimpedance device. Crit Care Med 24:1090-1091
26. Nakonezny PA, Kowalewski RB, Ernst JM, et al (2001) New ambulatory impedance cardio-
graph validated against the Minnesota Impedance Cardiograph. Psychophysiology 38:465-473
27. Barin E, Haryadi DG, Schookin SI, et al (2000) Evaluation of a thoracic bioimpedance car-
diac output monitor during cardiac catheterization. Crit Care Med 28:698-702
28. VanderMeer NJ, Vonk Noordegraaf A, Kamp 0, de Vries PM (1999) Noninvasive measure-
ment of cardiac output: two methods compared in patients with mitral regurgitation.
Angiology 50:95-101
29. Thangathurai D, Charbonnet C, Roessler P, et al (1997) Continuous intraoperative noninva-
sive cardiac output monitoring using a new thoracic bioimpedance device. J Cardiothorac
Vase Anesth 11 :440-444
30. Zacek P, Kunes P, Kobzova E, Dominik J (1999) Thoracic electrical bioimpedance versus ther-
modilution in patients post open-heart surgery. Acta Medica (Hradec Kralove) 42:19-23
31. Lee TL (1994) Pitfalls of Hemodynamic Monitoring. In: Faust RJ (ed) Anesthesiology
Review, 2nd ed, Churchill Livingstone, New York, pp 263-264
32. Murray MJ, Coursin DB, Pearl RG, Prough DS (2002) Critical Care Medicine Perioperative
Management 2nd Edition Lippincot, Williams & Wilkins, Philadelphia, pp 195-196
33. Tsagaropoulou AT, Vasiliadis K, Fessatidis I, Papavasi-Liou E, Spyrou P (2002) Beware
Swan-Ganz complications. Perioperative management. J Cardiovasc Surg 43:467-470
34. Brown J (2002) Use of echocardiography for hemodynamic monitoring. Crit Care Med 30:
1361-1364
35. Pinto FJ, Siegel LC, Chenzbraun A, et a! (1994) Online estimation of cardiac output with a
new automated border detection system using transesophageal echocardiography: A preli-
minary comparison with thermodilution. J Cardiothorac Vase Anes 8:625-630
36. Greim CA, Roewer N, Laux G, et al (1996) Online estimation of left ventricular stroke
volume using transoesophageal echocardiography and acoustic quantification. Br J Anaesth
77:365-369
37. Bland JM, Altman DG (1986) Statistical methods for assessing agreement between two
methods of clinical measurement. Lancet 1:307-310
38. Huntsman, Stewart DK, Barnes SR, Franklin SB, Colocousis JS, Hessel EA (1983) Noniva-
sive Doppler determination of cardiac output in man: clinical validation. Circulation 67:
593-602
39. Mark JB, Steinbrook RA, Gugino RD, et a! (1986) Continuous noninvasive monitoring of
cardiac output with esophageal Doppler ultrasound during cardiac surgery. Anesth Analg
65:1013-1020
40. Perrino AC, Flemming J, LaMantia KR (1991) Transesophageal Doppler cardiac output
monitoring: performance during aortic reconstrcuctive surgery. Anesth Analg 73:705-710
41. Cariou M, Monchi M, Joly LM, et al (1998) Nonivasive cardiac output monitoring by aortic
blood flow determination: evaluation of the Sometec Dynemo-3000 system. Crit Care Med
26:2066-2072
42. Laupland KB, Bands CJ (2002) Uility of esophageal Doppler as a minimally invasive hemo-
dynamic monitor: a review Canadian. J Anesth 49:393-401
43. Wesseling KH, deWitt B, Weber AP, et a! (1983) A simple device for the continuous mea-
surement of cardiac output. Adv Cardiovasc Phys 5:1-52
44. Chaney JC, Derdak (2002) Minimally invasive hemodynamic monitoring for the intensivist:
current and emerging technologies. Crit Care Med 30:2338-2345
45. Garcia-Rodriguez C, Pittman J, Cassel CH, et al (2002) Lithium dilution cardiac output
measurement: a clinical assessment of central venous and peripheral venous indicator in-
jection. Crit Care Med 30:2199-2204
46. Doering L, Lum E, Dracup K, Friedman A (1995) Predictors of between-method differences
in cardiac output measurement using thoracic electrical bioimpedance and thermodilution.
47. Marie P, Pendelton J, Smith R (1997) A comparison of hemodynamic parameters derived
from transthoracic electrical bioimpedance with those parameters obtained by thermodilu-
tion and ventricular angiography. Crit Care Med 25:1545-1550
48. Wong KL, Hou PC (1996) The accuracy of bioimpedance cardiography in the measurement
of cardiac output in comparison with thermodilution method. Acta Anaesthesiology Sin
34:55-59
I Oxygen Availability
Microvascular Alterations in Patients
with Circulatory Failure
D. De Backer, J. Creteur, and M. J. Dubois
1 Introduction
Many patients continue to die from acute circulatory failure despite improvement
in whole body hemodynamics. Early optimization of oxygen transport in patients
with septic shock can lead to a decrease in morbidity and mortality, but neverthe-
less a significant proportion of these patients will develop multiple organ failure
(MOF) and will ultimately die [1]. Several factors can be implicated in the develop-
ment of MOF including alterations in blood flow distribution between the various
organs but also alterations in metabolic pathways (cytopathic hypoxia). Multiple
studies have reported that an imbalance between oxygen demand and supply can
occur in the splanchnic area [2, 3], but the most commonly used therapeutic inter-
ventions (fluids, inotopic agents, red blood cell [RBC] transfusions) have usually
failed to improve regional blood flow alterations in septic patients [4, 5] so that
survival was not improved. On the other hand, several studies indicated that meta-
bolic pathways may be directly altered, so that giving more 'fuel' to the system
would not result in any improvement in tissue oxygenation. Several data support
the concept of cytopathic hypoxia. King et al. [6] reported that endotoxin impaired
oxygen consumption in mucosal samples in polarographic air-saturated chambers,
and related this effect to nitric oxide (NO). In humans, Brealey et al. [7] reported
that cytochrome complex I is significantly altered in muscle biopsies obtained in
patients with sepsis. Nevertheless, these alterations alone cannot explain all the fea-
tures observed in patients with septic shock. First, if cytopathic hypoxia were pro-
minent, therapeutic interventions such as early-goal oriented hemodynamic opti-
malization, as proposed by Rivers et al. [1], would probably not have been success-
ful. Second, cytopathic hypoxia is not compatible with the numerous data reporting
increased tissue C0 2 in septic shock [4, 5, 9], as C0 2 would be rapidly cleared if
blood flow was adequate. Hence, it is very likely that all these alterations coexist,
the respective part of each of them being undetermined.
In addition to regional blood flow alterations and to direct metabolic insult, mi-
crocirculatory alterations may play a crucial role in the development of MOF in
these patients.
I Specificity of the Microcirculation

The microcirculation is the place where most of the exchanges in oxygen and nutri-
ents between the blood and the tissues occur. Hence, its endothelial surface is the
largest in the body. This should be kept in mind in view of the major role of the
536 D. De Backer et al.
endothelium in the activation of inflammatory processes and in the coagulation

cascade.
The microcirculation differs from the systemic circulation in many aspects. First,
capillary P0 2 is much lower than arterial P0 2 , as oxygen may diffuse when an arte-
riole crosses a venule but also by consumption at the endothelial level. The high
metabolic rate of the microvasular wall suggests that it has several functions requir-
ing oxygen consumption. These functions include NO synthesis and generation of
reactive oxygen species (ROS). Second, the local hematocrit differs from the sys-
temic hematocrit as the consequence of the Farheus effect. In addition, capillary
hematocrit is heterogeneous as a consequence of an obligatory plasma layer in ves-
sels of varying diameter and non-linear hematocrit distribution at asymmetric cap-
illary branch points. Finally, the control of microvascular blood flow is complex
and depends both on local metabolic control and on systemic, humoral controls.
I Evidence for Microcirculatory Alterations in Experimental Studies
Numerous experimental studies have reported that microvascular blood flow is al-
tered in various conditions, and especially in sepsis [10-16]. Endotoxin administra-
tion induces severe microcirculatory alterations, including eliciting a severe arterio-
lar and venular vasoconstriction in rats [11], and a decreased capillary density in
dogs [17]. Severe microcirculatory alterations were also observed in normodynamic
models of sepsis obtained by cecal ligation and perforation. These alterations in-
cluded a decrease in the perfused capillary density and an increase in the number
of stopped-flow capillaries and in heterogeneity of spatial distribution of perfused
capillaries in striated muscles in rats [12]. Similar alterations were observed in the
small bowel mucosa [15].
Microvascular blood flow alterations may be responsible for alterations in tissue
metabolism, but one can also consider that flow is matching metabolism, with di-
rect metabolic alterations. It is difficult to separate these two opposite alternatives,
but various animal studies have reported that microvascular alterations have major
physiopathological implications. First, the coexistence of well perfused and non-
perfused capillaries will lead to a marked heterogeneity in blood flow which may
be responsible for the decrease in oxygen extraction capabilities that is observed in
sepsis [17-19]. Second, microvascular alterations are associated with zones of de-
creased intravascular P0 2 [20, 21], which is not compatible with primary metabolic
alterations. Finally, the transient flow observed in some capillaries may lead to focal
areas with ischemia/reperfusion injury.
Multiple causes can be evoked to explain these microvascular alterations. First,
various inflammatory and vasoactive mediators involved in sepsis such as tumor
necrosis factor (TNF) [22] and endothelin [23], can cause microvascular vasocon-
striction. On the contrary, NO seems to have a protective role since mice lacking
inducible NO presented less severe microvasular alterations after cecal ligation and
puncture than normal mice [24]. Second, microthrombi can transiently occlude mi-
crovessels, and microthrombi formation is facilitated in septic conditions [25, 26].
This mechanism is strongly highlighted by the results of a recent study demon-
strating that the administration of activated protein C (APC) significantly improved
survival in patients with severe sepsis [8]. Third, sepsis impairs the deformation of
leukocytes [27] and erythrocytes [28, 29] and promotes adhesion of leukocytes to
endothelial cells {29,·30]. Finally, interstitial edema may compress small vessels but
this was invalidated by the study by Piper et al. [14] reporting that the increase in
erythrocyte flow heterogeneity after cecal ligation and perforation in rats was not
related to tissue edema as measured by wet-to-dry ratio and albumin flux. Hence,
it is likely that many of these mechanisms contribute to the microvascular altera-
tions.
I Methods to Investigate the Microcirculation

in Critically Ill Patients
Most of the experimental studies were performed using intravital microscopy, the
gold standard technique for studying the microcirculation. Unfortunately, this tech-
nique cannot be used in humans, as large microscopes are generally applied on a
fixed tissue preparation while fluorescent dyes are infused. Alternative methods
have been used in humans, including phlethysmography, videomicroscopy of the
nailfold area, and laser Doppler technique. An extended review of the available
techniques can be found elsewhere [31]. Due to the intrinsic limitations of these
techniques, human data are more scarce. Using videomicroscopy of the nailfold
area, Freedlander and Lenhart [32] reported in 1922 that capillary stasis occurred.
However, these observations are quite old, and the definition of shock state,
although lethal, may be questioned in the absence of cardiovascular and respiratory
support. In addition, the nailfold area is probably not representative as it may be
subjected to vasoconstriction during changes in external temperature or during
chills, so that this area is of limited interest in critically ill patients. More recently,
various investigators [29, 33] used laser Doppler technique to investigate skin and
muscle microvascular blood flow and observed that basal blood flow may be de-
creased or increased compared to healthy volunteers. These studies are nevertheless
difficult to compare as skin microvascular blood flow differs according to the site
investigated [34]. More importantly, the increase in microvascular blood flow was
blunted after partial occlusion [35]. Nevertheless, the major limitation of the laser
Doppler technique is that it does not take into account the heterogeneity of micro-
vascular blood flow, the measured parameter representing the average of the veloci-
ties in all the vessels included in the investigated volume.
Orthogonal polarization spectral (OPS) imaging is a newly developed non-inva-
sive technique that allows the direct visualization of the microcirculation [36]. The
device, composed of a small camera and a few lenses, is small and can be used eas-
ily at the bedside. Briefly, polarized light is used to illuminate the area of interest.
The light is scattered by the tissue and collected by the objective lens. A polariza-
tion ftlter (analyzer), oriented orthogonal to the initial plane of the illumination
light, is placed in front of the imaging camera and eliminates the reflected light
scattered at or near the surface of the tissue that retains its original polarization
(glare). Depolarized light scattered deeper within the tissues passes through the
analyzer. High contrast images of the microcirculation are formed by absorbing
structures (e. g., blood vessels) close to the surface that are illuminated by the de-
polarized light coming from deeper structures. Due to its specific characteristics,
this device is particularly convenient for studying tissues protected by a thin
epithelial layer, such as mucosal surfaces. In critically ill patients, the sublingual
area is the most easily investigated mucosal surface. Other mucosal surfaces include
rectal and vaginal surfaces which are of limited accessibility, and ileal or colic mu-
cosa in patients with enterostomies. Images can also be generated in eyelids and in
the nailfold [37].
The use of OPS imaging techniques to visualize the microcirculation has been
validated against standard techniques. Vessel diameters and functional capillary
density were similar with OPS imaging and standard intravital fluorescence video-
microscopy applied in a hamster dorsal skinfold chamber [36] and on the surface
of solid organs in rats [38]. In addition, velocity in straight vessels was similar with
both techniques in mouse skin flaps and cremaster muscle preparations [39], as
well as in a model of pressure-induced ischemia in the dorsal skinfold chamber in
hamsters [40]. Recently, Mathura et al. [37] applied OPS imaging and capillaro-
scopy on the nailfold area in human healthy volunteers and observed an excellent
agreement in the measurement of capillary density and RBC velocity with both
techniques. Unfortunately, this quantitative approach cannot be used for observa-
tions of the sublingual microcirculation in humans due to the movement artifacts
generated by small movements of the tongue or respiratory movements. Hence, we
[41] developed a semi-quantitative method to determine capillary density and the
proportion of perfused capillaries.
1 Microvascular Blood Flow is Altered in Critically Ill Patients

Using the OPS technique in the sublingual area of patients in shock states, we [41]
recently observed that microcirculatory alterations are frequent in shock states. We
investigated 50 patients with severe sepsis (n = 8) or septic shock (n = 42) within 48
hours of the onset of sepsis. Compared to young healthy volunteers and age
matched controls (patients before cardiac surgery), septic patients presented a de-
crease in capillary density (4.5 [4.2-5.2] vs 5.4 [5.4-6.3] n/mm in controls, p<O.OS)
and a decrease in the proportion of the perfused capillaries (Fig. 1). Representative
video images can be seen at http://ajrccm.atsjournals.orglcgilcontent/full/166/1/98/
DCl. The decrease in capillary perfusion was due to an increase in the number of
capillaries with stagnant flow and in the number of capillaries with intermittent
100
"0
Q)
80
i•
"'
.Z-
a;~
a.., 60
.... Q)
0 "\:
c ...
o=:
·-
~
0
a. ...
u
40
a.
e
Q.
20
0
•
Volunteers Sepsis
Fig. 1. Proportion of perfused capillaries in patients with sepsis. Volunteers are represented by open rectan-
gles, patients with sepsis by gray rectangles.+++ represents p < 0.001 sepsis vs controls. Redrawn from [41)
100
0 Baseline
• Post-resuscitation
"'
Qj 80
l:l
Q)
>
""0
Q)
60
"'
~Q) 40
c.
0
~
20
0
All vessels Large vessels Small vessels
Fig. 2. Effects of resuscitation maneuvers on sublingual microcirculation (percentage of perfused vessels)

assessed by the Orthogonal Polarization Spectral imaging technique in 6 patients with septic shock.
Adapted from [53] with permission
flow (32 [27-39] and 32 [22-37]%, respectively, in septic patients vs 4 [3- 5] and 5
[4-6]%, respectively in controls). Interestingly, the alterations observed in patients
with septic shock were fully reversible after topical application of a high dose of
acetylcholine (proportion of perfused capillaries 94 [77-96] vs 44 [24-60]%,
p < 0.01 ), suggesting that the microcirculation can be manipulated. Current studies
are ongoing to determine the effects of various interventions on the microcircula-
tion in humans. In 6 patients with septic shock, we observed that dobutamine ad-
ministration partially reversed these alterations (Fig. 2). Vasodilators may be of val-
ue also (42]. Recently, Spronk et al. [43] reported that nitroglycerin improved the
sublingual microcirculation, but this was accompanied by marked hypotension. In
addition, the potential cytotoxic effects of NO donors should not be neglected and
further studies are needed before this intervention can be translated into clinical
practice.
Microcirculatory alterations can also be observed in other conditions than sep-
sis. We [44] observed that the proportion of perfused capillaries was also decreased
in patients with cardiogenic shock. In 28 patients submitted to cardiac surgery, we
observed that the proportion of perfused capillaries decreased after cardiopulmon-
ary bypass (from 88 [87-88] to 54 [Sl-56]%, p<O.OS), and remained altered during
the first hours of admission in the intensive care unit (ICU), and almost normal-
ized the day after surgery [45]. Interestingly, similar alterations were observed in
patients with heart operations performed without cardiopulmonary bypass. How-
ever, these alterations were less pronounced than in patients with septic or cardio-
genic shock.
I Link between Microcirculatory Alterations and Outcome
The alterations in microvascular blood flow can have important implications. In

rats submitted to 60 min of severe hemorrhage with subsequent restoration of
blood volume, Zhao et al. [46] observed that microvascular alterations were more
severe in rats who subsequently died compared to survivors, despite similar whole-
body hemodynamics. Similarly, Kerger et al. [47] reported that functional capillary
density and interstitial P0 2 in the hamster skinfold were lower in non-survivors
during hemorrhage and after resuscitation. Hence, in animal models microcircula-
tory alterations were related with outcome.
In our recent study in patients with severe sepsis [41], we observed that the se-
verity of microcirculatory alterations was more pronounced in non-survivors than
in survivors. We [48] daily investigated the sublingual microcirculation in a cohort
of 32 patients with septic shock up to shock resolution or death, and we observed
that microvascular blood flow rapidly resolved in survivors but remained altered in
non-survivors, whether these patients died in shock or from MOF after shock was
resolved. Hence, microvascular blood flow alterations are implicated in the patho-
physiological process involved in the development of MOF and death in septic pa-
tients.
I Sublingual PC02
Alterations observed in the sublingual area may not be representative of other
areas. The splanchnic circulation may be altered earlier, and recover later than
other parts of the body. Interestingly, the sublingual mucosa, which shares a similar
embryologic origin with the digestive mucosa, may also be of interest. Weil and co-
workers [49, 50] observed that sublingual PC0 2 was increased in various shock
states, reflecting the severity of shock states and was related to outcome. They also
reported that sublingual capnometry and gastric tonometry revealed parallel altera-
tions, suggesting that both areas can be similarly and simultaneously affected [51].
In addition, sublingual PC0 2 was inversely related with changes in tongue, splanch-
nic, and renal blood flows [52]. Hence, the sublingual region may be similarly
affected to other areas, including the splanchnic area. These observations led to the
conclusion that sublingual PC0 2 monitoring may serve as a technically simple,
non-invasive and rapid response monitor of the severity of circulatory shock states,
avoiding some of the methodological drawbacks of gastric tonometry.
Nevertheless, the interpretation of tissue C0 2 levels is difficult. In low flow
states, tissue hypercapnia is due to C0 2 stagnation (altered clearance) and, some-
times, tissue hypoxia (C02 is generated by the buffering of H+). When flow is
maintained, tissue C0 2 will be normal, even in the presence of cytopathic hypoxia,
as all the produced C0 2 will be immediately cleared. Hence, the presence of a
raised tissue C0 2 always suggests that blood flow is inadequate in comparison with
metabolism.
We have recently studied the evolution of sublingual PC0 2 (PslC0 2 ) during resus-
citation of patients with septic shock and compared it to the evolution of gastric mu-
cosal PC0 2 (PgC02 ) and sublingual microcirculation [53]. In 12 invasively monitored,
sedated and mechanically ventilated patients in the early phase of septic shock,
PslC02 was monitored continuously using a microelectrode C0 2 sensor (Capnoprobe
SL Model 2000 Sensor; Optical Sensor Inc, MN, USA), and PgC0 2 using gas tonome-
try (Tonocap; Datex, Helsinki, Finland). In 6 of these patients, sublingual microcircu-
lation was also assessed using the OPS imaging technique. PslC0 2 and PgC0 2 values
were well correlated (r = 0.53; p < 0.05) (Fig. 3). In each patient, resuscitation maneu-
vers (volume expansion, followed by the infusion of dopamine, with or without do-
butamine) increased mean arterial pressure (from 68 ± 5 to 79 ± 7 mmHg, p < 0.05)
and cardiac output (from 1.9±0.5 to 2.9±0.6 l/min·m2 , p<0.05). The sublingual-
100
r2 =0.53
c;
p < 0.05 •
J: 75
E
.5.
8 50
01
•
Q.
25+--------.---------.--------.--------,
25 50 75 100 125
Ps1C0 2 (mm Hg)
Fig. 3. Relation between sublingual PC0 2 (PsiC0 2) and gastric mucosal PC0 2 (PgC0 2) in 12 patients with
septic shock. Adapted from [53)
100 100
p < O.OS p=0.08
Oi 75 c; 75
J: J:
E E
.5. 53 ± 1 4
.5.
a. 50 * a. 50
~"'~
"'01 "'
01
0"' 28 ± 8 0"'
u
;r 25 *
u
C\
Q.
25 * 19 ± 7
*
0
Post- resuscitation Baseline Post - resuscitation
Fig. 4. Individual effects of resuscitation maneuvers on sublingual-arterial PC0 2 gradient (PsiC0 2gap) and
gastric mucosal-arterial PC0 2 gradient (PgC02gap) in 12 patients with septic shock. Adapted from [53)
arterial PC0 2 gradient (PslC0 2gap) progessively decreased from 53± 14 to 28 ± 8

mmHg (p < 0.05), and the gastric mucosal - arterial PC0 2 gradient (PgC0 2 gap) from
29±11 to 19±7 mmHg (p=0.08) (Fig.4). The relative decrease in PslC0 2 was more
significant and more rapid than the relative decrease in PgC0 2 ( -27 ± 11% and -
15 ± 9% , respectively; p < 0.05). The larger and more rapid response of PslC0 2 com-
pared to PgC0 2 during resuscitation can be explained by the shorter response time of
the sublingual capnometry device and/or by an incomplete improvement in gastric
mucosal blood flow. The decrease in PslC0 2 was accompanied by an improvement
in the the sublingual microcirculation with an increase in vessel density from
3.6 ± 0.2 to 5.3 ± 0.8 vessels/mm and an increase in the percentage of perfused capil-
laries from 42±5 to 59±5% (both p<O.OS) (Fig. 2). These observations related the
alterations in microcirculatory blood flow and tissue PC0 2 , indicating that a mis-
match between flow and metabolism occurred in these patients with septic shock.
One of the limitations of this study is that the patients were studied in an early phase
of septic shock, in a relatively hypodynamic status. In this condition, the parallel evo-
lution of PslC0 2 and PgC0 2 could only reflect the correction of systemic low blood
flow. In resuscitated patients with hyperdynamic septic shock, the sublingual PC0 2
and gastric tonometry monitorings may not be interchangeable. Nevertheless, PslC0 2
monitoring promises to serve as a technically simple and non-invasive method to as-
sess hemodynamic resuscitation in critically ill patients, and these observations en-
couraged us to conduct a larger clinical trial.
I Conclusion
The microcirculation is the key component in respiratory and nutrient exchange
between blood and the tissues, but is also markedly involved in the activation of
the inflammatory cascade and coagulation. Using OPS imaging techniques allows
the direct visualization of the microcirculation in critically ill patients. In addition,
the combination of OPS techniques with sublingual capnometry provides important
information about the adequacy of sublingual blood flow to metabolism. Microvas-
cular blood flow alterations are frequent in critically ill patients, and these altera-
tions can have important physiopathological implications. This opens a new area
for the investigation of the processes involved in the hemodynamic alterations of
shock states and these techniques offer the possibility to study new therapies
aimed at restoring the microcirculation.
References
1. Rivers E, Nguyen B, Havstadt S, et al (2001} Early goal-directed therapy in the treatment
of severe sepsis and septic shock. N Engl J Med 345:1368-1377
2. Dahn MS, Lange P, Lobdell K, Hans B, Jacobs LA, Mitchell RA (1987) Splanchnic and total
body oxygen consumption differences in septic and injured patients. Surgery 101:69-80
3. De Backer D, Creteur J, Noordally 0, Smail N, Culbis B, Vincent JL (1998} Does hepato-
splanchnic V0 2/D02 dependency exist in critically ill septic patients? Am J Respir Crit
Care Med 157:1219-1225
4. Gomersall CD, Joynt GM, Freebairn RC, Hung V, Buckley TA, OH TE (2000} Resuscitation
of critically ill patients based on the results of gastric tonometry: a prospective, ran-
domized, controlled trial. Crit Care Med 28:607-614
5. Lebuffe G, Levy B, Neviere R, et al (2002} Dobutamine and gastric-to-arterial carbon diox-
ide gap in severe sepsis without shock. Intensive Care Med 28:265-271
6. King CJ, Tytgat S, Delude RL, Fink MP (1999} Ileal mucosal oxygen consumption is de-
creased in endotoxemic rats but is restored toward normal by treatment with aminoguani-
dine. Crit Care Med 27:2518-2524
7. Brealey D, Brand M, Hargreaves I, et al (2002} Association between mitochondrial dysfunc-
tion and severity and outcome of septic shock. Lancet 360:219-223
8. Bernard GR, Vincent J-L, Laterre PF, et al (2001} Efficacy and safety of recombinant hu-
man activated protein C for severe sepsis. N Engl J Med 344:699-709
9. Friedman G, Berlot G, Kahn RJ, Vincent JL (1995} Combined measurements of blood lac-
tate concentrations and gastric intramucosal pH in patients with severe sepsis. Crit Care
Med 23:1184-1193
10. Cryer HM, Garrison RN, Kaebnick HW, Harris PD, Fink LM (1987} Skeletal microcircula-
tory responses to hyperdynamic Escherichia coli sepsis in unanesthetized rats. Arch Surg
122:86-92
11. Baker CH, Wilmoth FR (1984} Microvascular responses to E. coli endotoxin with altered
adrenergic activity. Circ Shock 12:165-176
12. Lam CJ, Tyml K, Martin CM, Sibbald W (1994) Microvascular perfusion is impaired in a
rat model of normotensive sepsis. J Clin Invest 94:2077-2083
13. Piper RD, Pitt-Hyde ML, Anderson LA, Sibbald WJ, Potter RF (1998) Leukocyte activation
and flow behavior in rat skeletal muscle in sepsis. Am J Respir Crit Care Med 157:129-134
14. Piper RD, Pitt-Hyde M, Li F, Sibbald WJ, Potter RF (1996) Microcirculatory changes in rat
skeletal muscle in sepsis. Am J Respir Crit Care Med 154:931-937
15. Farquhar I, Martin CM, Lam C, Potter R, Ellis CG, Sibbald WJ (1996) Decreased capillary
density in vivo in bowel mucosa of rats with normotensive sepsis. J Surg Res 61, 190-196
16. McCuskey RS, Urbaschek R, Urbaschek B (1996) The microcirculation during endotoxemia.
Cardiovasc Res 32:752-763
17. Drazenovic R, Samsel RW, Wylam ME, Doershuk CM, Schunacker PT (1992) Regulation of
perfused capillary density in canine intestinal mucosa during endotoxemia. J Appl Physiol
72:259-265
18. Walley KR (1996) Heterogeneity of oxygen delivery impairs oxygen extraction by periph-
eral tissues: theory. J Appl Physiol 81:885-894
19. Humer MF, Phang PT, Friesen BP, et al (1996) Heterogeneity of gut capillary transit times
and impaired gut oxygen extraction in endotoxemic pigs. J Appl Physiol 81:895-904
20. Ince C, Sinaasappel M (1999) Microcirculatory oxygenation and shunting in sepsis and
shock. Crit Care Med 27:1369-1377
21. Zuurbier CJ, van lterson M, lnce C (1999) Functional heterogeneity of oxygen supply-con-
sumption ratio in the heart. Cardiovasc Res 44:488-497
22. Vicaut E, Hou X, Payen D, Bousseau A, Tedgui A (1991) Acute effects of tumor necrosis
factor on the microcirculation in rat cremaster muscle. J Clin Invest 87:1537-1540
23. Groeneveld AB, Hartemink KJ, de Groot MC, Visser J, Thijs LG (1999) Circulating endothe-
lin and nitrate-nitrite relate to hemodynamic and metabolic variables in human septic
shock. Shock 11:160-166
24. Hollenberg SM, Broussard M, Osman J, Parrillo JE (2000) Increased microvascular reactiv-
ity and improved mortality in septic mice lacking inducible nitric oxide synthase. Circ Res
86:774-778
25. Diaz NL, Finol HJ, Torres SH, Zambrano Cl, Adjounian H (1998) Histochemical and ultra-
structural study of skeletal muscle in patients with sepsis and multiple organ failure syn-
drome (MOPS) Histol Histopathol 13:121-128
26. Schneider J (1993) Fibrin-specific lysis of microthrombosis in endotoxernic rats by saru-
plase. Thromb Res 72:71-82
27. Drost EM, Kassabian G, Meiselman HJ, Gelmont D, Fisher TC (1999) Increased rigidity
and priming of polymorphonuclear leukocytes in sepsis. Am J Respir Crit Care Med
159:1696-1702
28. Astiz ME, DeGent GE, Lin RY, Rackow EC (1995) Microvascular function and rheologic
changes in hyperdynamic sepsis. Crit Care Med 23:265-271
29. Kirschenbaum LA, Astiz ME, Rackow EC, Saha DC, Lin R (2000) Microvascular response
in patients with cardiogenic shock. Crit Care Med 28:1290-1294
30. Eichelbronner 0, Sielenkamper A, Cepinskas G, Sibbald WJ, Chin-Yee IM (2000) Endotoxin
promotes adhesion of human erythrocytes to human vascular endothelial cells under con-
ditions of flow. Crit Care Med 28:1865-1870
31. De Backer D, Dubois MJ (2001) Assessment of the microcirculatory flow in patients in the
intensive care unit. Curr Opin Crit Care 7:200-203
32. Freedlander SO, Lenhart CH (1922) Clinical observations on the capillary circulation. Arch
Intern Med 29:12-32
33. Young JD, Cameron EM (1995) Dynamics of skin blood flow in human sepsis. Intensive
Care Med 21:669-674
34. Stucker M, Steinberg J, Memmel U, et al (2001) Differences in the two-dimensionally mea-
sured laser Doppler flow at different skin localisations. Skin Pharmacol Appl Skin Physiol
14:44-51
35. Neviere R, Mathieu D, Chagnon JL, Lebleu N, Millien JP, Wattel F (1996) Skeletal muscle
microvascular blood flow and oxygen transport in patients with severe sepsis. Am J Respir
544 D. De Backer et al.: Microvascular Alterations in Patients with Circulatory Failure
36. Groner W, Winkelman JW, Harris AG, et al {1999) Orthogonal polarization spectral imag-
ing: a new method for study of the microcirculation. Nat Med 5:1209-1212
37. Mathura KR, Vollebregt KC, Boer K, De Graaf JC, Ubbink DT, Ince C {2001) Comparison
of OPS imaging and conventional capillary microscopy to study the human microcircula-
tion. J Appl Physiol 91:74-78
38. Langer S, von Dobschuetz E, Harris AG, et al (2000) Validation of the orthogonal polariza-
tion spectral imaging technique on solid organs. In: Messmer K (ed) Orthogonal polariza-
tion spectral imaging. Progress in Applied Microcirculation, vol 24. Karger, Basel, pp 32-
46
39. Laemmel E, Tadayoni R, Sinitsina I, et al (2000) Using orthogonal polarization spectral
imaging for the experimental study of microcirculation: comparison with intravital micro-
scopy. In: Messmer K (ed) Orthogonal polarization spectral imaging. Progress in Applied
Microcirculation, vol 24. Karger, Basel, pp 50-60
40. Harris AG, Sinitsina I, Messmer K {2000) The Cytoscan(TM) Model E-11, a new reflectance
microscope for intravital microscopy: Comparison with the standard fluorescence method.
J Vase Res 37:469-476
41. De Backer D, Creteur J, Preiser JC, Dubois MJ, Vincent JL (2002) Microvascular blood flow
is altered in patients with sepsis. Am J Respir Crit Care Med 166:98-104
42. Buwalda M, Ince C {2002) Opening the microcirculation: can vasodilators be useful in sep-
sis? Intensive Care Med 28:1208-1217
43. Spronk PE, lnce C, Gardien MJ, et al {2002) Nitroglycerin in septic shock after intravascu-
lar volume resuscitation. Lancet 360:1395-1396
44. De Backer D, Creteur J, Vincent J-L {2000) Microcirculatory alterations in cardiogenic and
septic shock. Intensive Care Med 26:S334 (abst)
45. Dubois MJ, De Backer D, Schmartz D, et al {2002) Microcirculatory alterations in cardiac
surgery with and without cardiopulmonary bypass. Intensive Care Med 28:S76 (abst)
46. Zhao KS, Junker D, Delano FA, Zweifach BW {1985) Microvascular adjustments during
irreversible hemorrhagic shock in rat skeletal muscle. Microvasc Res 30:143-153
47. Kerger H, Waschke KF, Ackern KV, Tsai AG, Intaglietta M (1999) Systemic and microcircu-
latory effects of autologous whole blood resuscitation in severe hemorrhagic shock. Am J
Physiol 276:H2035-H2043
48. Sakr Y, Dubois MJ, De Backer D, et al {2002) Time course alterations in patients with sep-
tic shock. Intensive Care Med 28:S15 (abst)
49. Nakagawa Y, Weil MH, Tang W, et al {1998) Sublingual capnometry for diagnosis and
quantitation of circulatory shock. Am J Respir Crit Care Med 157:1838-1843
50. Weil MH, Nakagawa Y, Tang W, et al {1999) Sublingual capnometry: a new noninvasive
measurement for diagnosis and quantitation of severity of circulatory shock. Crit Care
Med 27:1225-1229
51. Povoas HP, Weil MH, Tang W, Moran B, Kamohara T, Bisera J {2000) Comparisons be-
tween sublingual and gastric tonometry during hemorrhagic shock. Chest 118:1127-1132
52. JinX, Weil MH, Sun S, Tang W, Bisera J, Mason EJ {1998) Decreases in organ blood flows
associated with increases in sublingual PC02 during hemorrhagic shock. J Appl Physiol
85:2360-2364
53. Creteur J, De Backer D, Sakr Y, et al {2003) Sublingual PC0 2 monitoring in patients with
septic shock. Crit Care Med (abst) (in press)
Critical Tissue Oxygen Thresholds for the Induction
of Apoptosis in Critical Illness
B. Venkatesh, G. Gobe, and T. J. Morgan
I lntruduction
Cellular sensitivity and response to hypoxia play important roles in the pathogen-
esis of numerous disorders in critical care medicine. Defining the mechanisms by
which mammalian cells and organisms adapt to acute and chronic perturbations in
ambient oxygen tension is critical to the understanding of maintenance of homeo-
stasis and consequently the development of therapeutic strategies to counteract
hypoxia-induced cell damage.
The compensatory neurohumoral mechanisms triggered during the evolution of
shock lead to redistribution of blood flow away from the splanchnic and cutaneous
circulations in order to preserve oxygenated blood supplies to the heart and the
brain [1]. This has been demonstrated in well established models of hemorrhagic
and endotoxic shock, where gastrointestinal PC02 was found to be elevated during
hemorrhage and endotoxemia, was inversely correlated with tissue P02 and re-
turned to baseline with resuscitation [2-5]. Similar patterns have been demon-
strated also in patients with major burns [6]. Persistent mucosal hypoxia and hy-
percapnia, if severe, can lead to significant epithelial dysfunction. Potential adverse
consequences include altered epithelial permeability [7], bacterial translocation,
cytokine activation, multiple organ dysfunction syndrome (MODS) and death
[8, 9]. In addition, protein-losing enteropathy of critical illness has been demon-
strated in patients with burn shock [10].
Whilst these functional changes are defined, at least in part, the histological fea-
tures are so not well described. Tissue hypoxia can result in 2 types of cell death -
necrosis or apoptosis [11, 12]. Intuitively, hypoxic injury should cause 'accidental
cell death' or necrosis, where the cells swell, plasma and nuclear membranes dis-
rupt, cellular lysis occurs and there is an associated acute inflammatory response
that in itself may exacerbate the initial hypoxic injury response. However, the alter-
native mode of cell death, apoptosis, is also possible. During apoptosis, the cells
use their molecular machinery to shrink and bleb into membrane bound apoptotic
bodies, with or without nuclear fragments, that are easily phagocytosed by adjacent
tissue cells· or macrophages, thus keeping any acute inflammatory response to a
minimum. Because the process is under molecular control, there is potential for
active intervention and its description is, therefore, useful.
546 B. Venkatesh et al.
I Importance of Apoptosis in Critical Illness

It is now believed that apoptotic processes might underlie the pathogenesis of
MODS [11]. This is supported by data from laboratory and clinical studies. Apopto-
sis has been demonstrated in a number of experimental models of the systemic in-
flammatory response syndrome (SIRS), MODS, and sepsis. Endothelial cell apopto-
sis may play an important role in the genesis of sepsis-induced MODS [13]. Animal
models of shock, trauma and ischemia-reperfusion (common triggers for SIRS and
MODS) have demonstrated apoptotic cell death in the intestinal epithelium [14,
15]. Focal apoptosis of the intestinal epithelium occurs extremely rapidly (as little
as 2 hours) after trauma and shock in humans [16] . More recently, it has been sug-
gested that the alteration in cellular function and intestinal epithelial permeability
may well be related to the development of apoptosis [17]. Polymorphonuclear
(PMN) apoptosis is thought to be a significant contributor to the lung damage in
acute respiratory distress syndrome (ARDS) and inhibition of PMN apoptosis may
have survival benefit [18]. Coopersmith et al. have demonstrated that inhibition of
apoptosis had survival benefit in mice subjected to sepsis from cecal ligation and
puncture [19]. Thus, a common thread in suggested explanations of many aspects
of critical illness (including the pathogenesis of MODS) has been apoptosis of var-
ious tissues.
Although a number of pathophysiological processes can trigger apoptosis (Ta-
ble 1), one of the most common is tissue hypoxia [20, 21] and/or ischemia/reperfu-
sion injury [22]. The impetus for the development of monitoring of tissue oxygena-
tion came from recognition that perturbations in oxygen delivery (hypoxia and
hypotension) to, and in consumption by, tissues are common in critical illness
[23, 24]. Refinement in technology has made the measurement of oxygen tensions
further down in the oxygen cascade at the level of the tissue possible and applica-
ble by the bedside. With improved measurement and monitoring techniques, quan-
tification of oxygen thresholds for apoptosis becomes a possibility.
In this chapter, we will

I review the basic pathophysiology of hypoxia-induced apoptosis
I critically examine the evidence supporting the link between hypoxia and apoptosis
Table 1. Examples of the many factors that may induce apoptosis
Apoptogenk factors
Cytokine deprivation (e.g. EGF removal)
Receptor activation (e.g. Fas ligand)
Toxic growth factors (e.g. TNF-a)
Chemicals, drugs
Mild hypoxia
lschemia-reperfusion (e.g. oxygen or nitrogen derived free radicals, hydrogen peroxide)
y-, X- and UV irradiation
I Heat or cold shock
I Osmotic stress
I Ceramide
Critical Tissue Oxygen Thresholds for the Induction of Apoptosis in Critical Illness 547
I explore the data on critical tissue oxygen tensions and apoptosis

I discuss potential ways of modulating hypoxia-induced apoptosis in intensive
care practice and research.
I Pathophysiology of Hypoxia-Induced Apoptosis
The classic form of hypoxia-induced cellular demise is necrosis. However, sublethal

ischemic damage with or without reperfusion can lead to apoptosis. It is now be-
lieved that these forms of cell death are not mutually exclusive and that both pro-
cesses can co-exist in the same tissue. The final cellular response may be deter-
mined by the intensity and duration of the inciting event. To understand this pro-
cess in greater detail, the biology of apoptosis will be briefly reviewed.
The morphological changes of apoptosis, detailed earlier, have several biochem-
ical and molecular correlates. For example, endonuclease-induced double-strand
cleavage of nuclear DNA into fragments that are multiples of 180-200 base pairs
(bp) has formed the basis for many of the biochemical means of identifying apop-
tosis, including those used in situ in tissue sections. One of the earliest features of
apoptosis is a change in the plasma membrane in which phosphatidylserine is
translocated from the inner to the outer membrane. This may be one of the fea-
tures used by phagocytes to recognize apoptotic cells. Finally, apoptosis involves a
sequence of molecular events that includes the initiation, progression and comple-
tion of the process. The initiator phase depends on specific triggers. The Bcl-2 gene
family plays a major role in regulation of apoptosis initiation [25]. Within the
family of pro- and anti-apoptotic members, it is likely that their relative expression
levels and localization within mitochondrial membranes determine the fate of a cell
[26].
The mitochondrial protein, cytochrome c, is often released into the cytosol after
apoptosis initiation, and here it activates caspases, a family of pro-enzymes that
must be cleaved at their ·aspartate residues for their activation in the apoptotic pro-
cess. The Fas ligand is one of the members of the tumor necrosis factor (TNF) gene
family that is involved in immune surveillance and defence. Apoptosis is induced
when the Fas ligand binds to its cell surface receptor. Whilst many of these features
have been described in ischemic or hypoxic tissues, the role of apoptosis in the
pathogenesis of MODS of critical illness, particularly caused by hypoxia per se, has
not been fully defined.
In response to these triggers, the effector phase is activated which can proceed
through one of two pathways: an extrinsic pathway, which is caspase-8-mediated
and an intrinsic mitochondrial pathway, which is caspase-9-mediated [27]. Activa-
tion of either of these caspases finally results in activation of caspase-3, which in
turn leads to proteolysis and DNA fragmentation. Caspase-8 activation can be in-
itiated by Fas (death receptor) ligands such as TNF. Caspase-9 can be activated by
reactive oxygen species (ROS), radiation and chemotherapeutic agents. Hypoxia/re-
oxygenation may lead to apoptosis through both intrinsic and extrinsic pathways:
I Activation of Fas ligand [28]
I Mitochondrial damage [29]
I Oxygen free radicals.
I Evidence Supporting the Link Between Hypoxia and Acidosis

A number of animal studies have now established the link between hypoxia and
apoptosis (Table 2). In most, cell cultures from various animal models were incu-
bated under extreme hypoxia or total anoxia, in some cases for prolonged periods
of time. Varying degrees of apoptosis were demonstrable in these experiments.
Such studies have elucidated important pathophysiological aspects of hypoxia-in-
duced apoptosis. However, their results cannot be directly extrapolated to critical
illness since both the severity and duration of the hypoxia imposed were incompa-
tible with life.
I Critical Duration of Hypoxia

In the critically ill patient, tissue hypoxia may be, covert and transient [30].
Whether such episodes cause apoptosis has not been subjected to clinical trials, but
data from Hotchkiss et al seem to indicate that this is likely [16]. These authors ob-
Table 2. Summary of studies which link hypoxia and apoptosis
Author Experimental Tissue Methodology Rndings

model
Yaniv et al. Rodent Ventricular Hypoxia (1% oxygen for Increase in apoptosis in
[28] myocyte 22 h) or normoxia the hypoxic group by
culture 100%
Ding et al. Rodent Ileal mucosa - Normoxia (95% Oz, Apoptosis in all groups
[38] culture 5% C02), except a). Highest
- Normoxia +bacteria, apoptosis in group d
- Anoxia (95% Nl/5% C02
for 40 min) followed by
normoxia
- Anoxia+ bacteria
Guo et al. Rodent Ventricular Hypoxia (85% N2, 5% C02, Increase in apoptosis in
[20) myocyte 10% H2) or normoxia the hypoxic group
culture for 16 h
Holleyman Human Endothelial lschemia-reperfusion Marked increase in
et al. [39] cultures 2 hours of 100% N2 apoptosis in the IR
followed by 21% 02 group
Gillet al. Rodent Brain Total MCA occlusion, Apoptosis only in the
(40] Total CCA occlusion, hypoxia group, not in
Hypoxia (7.7% 02) the ischemic group
Pozzi et al. Rodent Langendorf Low-flow normoxia, Apoptosis similar in all
(21] heart low-flow hypoxia (LFH) for 3 groups.
preparation 6 hours, No flow ischemia
for 90 min followed by
reperfusion
Akhter et al. Pig Brain Graded hypoxia for 1 hour Severity of apoptosis
[31) 5 to 15% oxygen, proportional to severity
vs normoxia of hypoxia
served that patients who presented within 1.5-2 hrs of acute trauma and shock al-
ready had focal apoptosis in the gut. Examination of the subjects' notes revealed
that they had been hypotensive (systolic 60-90 mmHg) for brief periods of time
only (usually 5-20 min), suggesting that prolonged periods of ischemia are not es-
sential for the development of apoptosis.
I Do Critical Tissue P02 Thresholds Exist

at which the Apoptotic Process may be Triggered?
The biochemical, pathological, and clinical consequences of hypoxia have been

studied in experimental models and in patients surviving cardiac arrest. Data from
these studies support the notion that the extent of damage is proportional to the se-
verity and duration of oxygen deprivation. However, only one published study has
examined the relationship between graded hypoxia and apoptosis. Newborn piglets
were subjected to varying grades of arterial hypoxemia induced by Fi02 settings
ranging between 0.05 and 0.15 for 1 hour [31]. At the end of the experiment, cere-
bral cortical tissue was examined for the presence of apoptosis and measurement
of nucleotide concentrations. The extent of DNA fragmentation, used as an index of
apoptosis, was shown to be proportional to the severity of hypoxemia (as measured
by nucleotide concentrations). Whilst this was new information, no data were pre-
sented on arterial and tissue gas values. Hence critical P0 2 levels for apoptosis
could not be determined.
An investigation into the role of apoptosis in hypoxia- and hypoxia-reoxygena-
tion-induced injury has recently been initiated by us (unpublished data). We aimed
to determine critical P0 2 thresholds for the development of apoptosis in an an-
esthetized rodent model. By altering Fi02, subcutaneous P02 was reduced from
baseline to either 15-30 mmHg or 0-15 mmHg. In a second group of rats the ani-
mals were reoxygenated in incremental steps after the hypoxic episodes. Small in-
testine and skin were collected and fixed for histological examination at baseline
and at the selected hypoxia and reoxygenation time points. Preliminary data are re-
vealing. They show a direct correlation between levels of apoptosis and hypoxia or
hypoxia-reoxygenation. In the gut, apoptotic cells were found mainly in the highly-
vascularized connective tissue core of the villi (Fig. 1), in neutrophils as well as
connective tissue cells. In the skin, apoptosis was seen in the epidermis and also in
the epithelial cells of hair follicles. In the re-oxygenation experiments, some necro-
sis was found in the peaks of the villi, probably a result of prolonged hypoxia fol-
lowed by a burst of oxidative stress. The molecular pathways involved in such hyp-
oxia-induced apoptosis (and indeed necrosis) invite investigation. These may be
key pathways in the progression to MODS.
It appears that hypoxic stress may cause apoptosis or necrosis depending upon
the severity of the hypoxia. The results from our preliminary study support the
idea of critical P0 2 thresholds. It is likely that the architecture of the microcircula-
tion plays an important role. The Krogh model represented tissue oxygen supply as
arising solely from homogeneously distributed patterns of capillaries [32]. Based
on these principles, the existence of a microvascular lethal corner was proposed,
i.e. the tissue site most distant from any capillary and therefore most vulnerable to
impairment of capillary blood flow. However, the architecture of the capillary net-
work is far more complex than previously believed [33, 34]. For example, signifi-
Fig. 1. Villi from the small intestine of a rat at normoxic (a) and hypoxic (b) conditions are demon-
strated. In the hypoxia-affected villus, examples of the many apoptotic cells, located in the connective
tissue core, are arrowed
cant amounts of oxygen exit the arteriolar network prior to the capillary phase
[33]. Countercurrent circulations have been demonstrated in the gut, kidney and
other tissues, with diffusive shunting of gases between arterioles and adjacent
venules [35]. Features such as these may lead to a wide scatter of carbon dioxide
and oxygen tensions in different regions of the same tissue [36]
I Conclusion - Clinical Implications of Identifying Critical P02 Thresholds

Knowing critical tissue P0 2 thresholds will provide the clinician with practical re-
suscitation endpoints in hypoxia and shock, and may even modify the practice of
'permissive hypoxia' in severe respiratory failure [37] . In patients in whom it is dif-
ficult to achieve a Pa0 2 of > 60 mmHg, tissue P0 2 may require alternative means
of support, such as measures to facilitate oxygen unloading. Apoptosis, by its very
gene-driven nature, should be susceptible to modulation in at risk situations. Sim-
ply keeping tissue P0 2 above the critical thresholds as much as possible while ad-
ministering anti-apoptotic drugs may be sufficient to improve outcome in shock
and resuscitation. This should be a fruitful avenue of future investigation.
References
1. Neutze JM, Wyler F, Rudolph AM (1968) Changes in distribution of cardiac output after
hemorrhage in rabbits. Am J Physiol 215:857-864
2. Johnson BA, Weil MH (1991) Redefining ischemia due to circulatory failure as dual defects
of oxygen deficits and of carbon dioxide excesses. Crit Care Med 19:1432-1438
3. Venkatesh B, Morgan JT (2001) Monitoring tissue gas tensions in critical illness. In: Vin-
cent Jl (ed) Yearbook of Intensive Care and Emergency Medicine. Springer, Heidelberg,
pp 251-265
4. Venkatesh B, Morgan T, Lipman J (2000) Subcutaneous oxygen tensions provide similar in-
formation to ileal luminal C02 tensions in an animal model of haemorrhagic shock. Inten-
5. Venkatesh B, Morgan TJ {2000) Blood in the gastrointestinal tract delays and blunts the
PC02 response to transient mucosal ischaemia. Intensive Care Med 26:1108-1115
6. Venkatesh B, Meacher R, Muller MJ, Morgan TJ, Fraser J {2001) Monitoring tissue oxygena-
tion during resuscitation of major burns. J Trauma 50:485-494
7. Riddington DW, Venkatesh B, Boivin CM, et al {1996) Intestinal permeability, gastric intra-
mucosal pH, and systemic endotoxemia in patients undergoing cardiopulmonary bypass.
JAMA 275:1007-1012
8. Maynard N, Bihari D, Beale R, et al {1993) Assessment of splanchnic oxygenation by gas-
tric tonometry in patients with acute circulatory failure. JAMA 270:1203-1210
9. Mythen MG, Purdy G, Mackie LJ, McNally T, Webb AR, Machin SJ {1993) Postoperative
multiple organ dysfunction syndrome associated with gut mucosal hypoperfusion, in-
creased neutrophil degranulation and C1-esterase inhibitor depletion. Br J Anaesth 71:858-
863
10. Venkatesh B, Gough J, Ralston DR, et al {2001) Protein losing enteropathy in adult patients
with major burns. World Congress of Intensive and Critical Care Medicine, Sydney, Octo-
ber 2001 Abstract book p 56, F68
11. Papathanassoglou ED, Moynihan JA, Ackerman MH {2000) Does programmed cell death
(apoptosis) play a role in the development of multiple organ dysfunction in critically ill
patients? a review and a theoretical framework. Crit Care Med 28:537-549
12. Kerr JF, Gobe GC, Winterford CM, Harmon BV (1995) Anatomical methods in cell death.
Methods Cell Biol46:1-27
13. Hotchkiss RS, Tinsley KW, Swanson PE, Karl IE {2002) Endothelial cell apoptosis in sepsis.
Crit Care Med 30:S225-S228
14. Xu YX, Ayala A, Monfils B, Cioffi WG, Chaudry IH {1997) Mechanism of intestinal mucosal
immune dysfunction following trauma-hemorrhage: increased apoptosis associated with
elevated Fas expression in Peyer's patches. J Surg Res 70:55-60
15. Coopersmith CM, O'Donnell D, Gordon JI {1999) Bcl-2 inhibits ischemia-reperfusion-in-
duced apoptosis in the intestinal epithelium of transgenic mice. Am J Physiol 276:G677-
G686
16. Hotchkiss RS, Schmieg RE Jr, Swanson PE, et al {2000) Rapid onset of intestinal epithelial
and lymphocyte apoptotic cell death in patients with trauma and shock. Crit Care Med
28:3207-3217
17. Bertges DJ, Fink MP, Delude RL {2000) Hypoxic signal transduction in critical illness. Crit
Care Med 28:N78-N86
18. Lesur 0, Kokis A, Hermans C, Fulop T, Bernard A, Lane D {2000) Interleukin-2 involve-
ment in early acute respiratory distress syndrome: relationship with polymorphonuclear
neutrophil apoptosis and patient survival. Crit Care Med 28:3814-3822
19. Coopersmith CM, Chang KC, Swanson PE, et al {2002) Overexpression of Bcl-2 in the in-
testinal epithelium improves survival in septic mice. Crit Care Med 30:195-201
20. Guo K, Searfoss G, Krolikowski D, et al {2001) Hypoxia induces the expression of the pro-
apoptotic gene BNIP3. Cell Death Differ 8:367-376
21. Pozzi S, Malferrari G, Biunno I, Samaja M {2002) Low-flow ischemia and hypoxia stimulate
apoptosis in perfused hearts independently of reperfusion. Cell Physiol Biochem 12:39-46
22. Hung TH, Skepper JN, Charnock-Janes DS, Burton GJ {2002) Hypoxia-reoxygenation: a po-
tent inducer of apoptotic changes in the human placenta and possible etiological factor in
preeclampsia. Circ Res 90:1274-1281
23. Dantzker DR {1993) Adequacy of tissue oxygenation. Crit Care Med 21:S40-S43
24. Shoemaker WC, Appel PL, Kram HB {1991) Oxygen transport measurements to evaluate
tissue perfusion and titrate therapy: dobutamine and dopamine effects. Crit Care Med
19:672-688
25. Gobe G, Rubin M, Williams G, Sawczuk I, Buttyan R {2002) Apoptosis and expression of
Bcl-2, Bcl-XL, and Bax in renal cell carcinomas. Cancer Invest 20:324-332
26. Gobe G, Schoch E, Leighton J {1999) Molecular controls of radiation-induced apoptosis in
the neonatal rat kidney. Kidney Int 56:1305-1309
27. Kam PC, Ferch NI {2000) Apoptosis: mechanisms and clinical implications. Anaesthesia
55:1081-1093
552 B. Venkatesh et al.: Critical Tissue Oxygen Thresholds for the Induction of Apoptosis in Critical Illness
28. Yaniv G, Shilkrut M, Lotan R, Berke G, Larisch S, Binah 0 (2002} Hypoxia predisposes
neonatal rat ventricular myocytes to apoptosis induced by activation of the Fas (CD95/
Apo-1} receptor: Fas activation and apoptosis in hypoxic myocytes. Cardiovasc Res 54:
611-623
29. Santore MT, McClintock DS, Lee VY, Budinger GR, Chandel NS (2002} Anoxia-induced
apoptosis occurs through a mitochondria-dependent pathway in lung epithelial cells. Am J
Physiol282:L727-L734
30. Fiddian-Green RG, Haglund U, Gutierrez G, Shoemaker WC (1993} Goals for the resuscita-
tion of shock. Crit Care Med 21:S25-S31
31. Akhter W, Ashraf QM, Zanelli SA, Mishra OP, Delivoria-Papadopoulos M (2001} Effect of
graded hypoxia on cerebral cortical genomic DNA fragmentation in newborn piglets. Biol
Neonate 79:187-193
32. Krogh A (1919} The supply of oxygen to the tissues and the regulation of the capillary cir-
culation. J Physiol 52:457-474
33. Duling BR, Berne RM (1970} Longitudinal gradients in periarteriolar oxygen tension. A
possible mechanism for the participation of oxygen in local regulation of blood flow. Circ
Res 27:669-678
34. Duling BR, Kuschinsky W, Wahl M (1979} Measurements of the perivascular P0 2 in the
vicinity of the pial vessels of the cat. Pflugers Arch 383:29-34
35. Bohlen HG (1980} Intestinal tissue P02 and microvascular responses during glucose expo-
sure. Am J Physiol238:H164-H171
36. Lubbers DW, Baumgard H (1997} Heterogeneities and profiles of oxygen pressure in brain
and kidney as examples of the P02 distribution in the living tissue. Kidney Int 51:372-380
37. Bugge JF (1999} Pressure limited ventilation with permissive hypoxia and nitric oxide in
the treatment of adult respiratory distress syndrome. Eur J Anaesthesiol 16:799-802
38. Ding J, Magnotti LJ, Huang Q, Xu DZ, Condon MR, Deitch EA (2001} Hypoxia combined
with Escherichia coli produces irreversible gut mucosal injury characterized by increased
intestinal cytokine production and DNA degradation. Shock 16:189-195
39. Holleyman C, Larson D, Hunter K (2001) Simulation of ischemic reperfusion in endothelial
cell culture increases apoptosis. J Extra Corpor Techno! 33:175-180
40. Gill R, Soriano M, Blomgren K, et al (2002} Role of caspase-3 activation in cerebral ische-
mia-induced neurodegeneration in adult and neonatal brain. J Cereb Blood Flow Metab
22:420-430
Reflectance Spectrophotometry
and Tissue Oxygenation in Experimental
and Clinical Practice
M.P. Buise, J. van Bommel, and C. Ince
I Introduction
Maintenance of adequate oxygen delivery (D0 2 ) to the tissue cells can be consider-
ed a primary objective in intensive care and peri-operative patient management.
Generally, it is believed that tissue hypoxia plays a significant role in the develop-
ment of organ failure in critically ill patients and is a major factor in the pathogen-
esis of multi-organ dysfunction. The introduction of regional measurement techni-
ques has highlighted the inadequacy of the information being generated by global
measurements of hemodynamic and oxygen-related variables and has focused at-
tention on the processes underlying microcirculatory oxygenation. It should be ob-
vious that an adequate transport of oxygen by the cardiovascular system does not
guarantee its delivery to the critical tissues of the body [1]. For this reason, assess-
ment of tissue oxygenation is essential.
The ideal technique for the assessment of tissue oxygenation should provide
quantitative, accurate, and reproducible information. In addition, it should clearly
distinguish which compartment is being sensed, i.e., arterial, venous microcircula-
tory or tissue compartments [2, 3]. One of the techniques currently in use in both
clinical and experimental practice is reflection spectrophotometry. Reflection spec-
trophotometry, based on absorption and scattering of reflected visible light, can
provide information about hemoglobin oxygen saturation and hemoglobin concen-
tration in tissue. Reflection spectrophotometry has been used in animal and clinical
studies and is a non-invasive technique without the use of special indicator dyes.
Basically, reflection spectrophotometry records the difference in absorption (and
partly in scattering) between a standard reference and a sample (tissue) as a form
of relative absorbency. Diffuse reflection spectra from biological pigmented struc-
tures located in cells can provide us with information concerning basic mechanisms
of tissue function. The first measurements of such reflection spectra were per-
formed by Chance in the intact mitochondria [4]. In order to collect a spectrum
from oxygenated or partly deoxygenated hemoglobin out of the combined spectra
from divers cellular pigments, e.g., cytochromes, an algorithm is needed to extract
the relevant information from the raw data. In the past, various types of reflection
spectrophotometers have been developed for the assessment of tissue oxygenation,
each working with a somewhat different algorithm. The next section will describe
the theoretical background and technical details of two types of reflection spectro-
photometers. Essentially two classes of device exist: those working with an algo-
rithm based on the principle of isobestic points (these wavelengths where the
curves of oxygenated and deoxygenated hemoglobin intersect), using discreet exci-
tation wavelengths [5], and those reflection spectrophotometers based on the analy-
554 M.P. Buise et al.
sis of the full reflection spectra using the theory of Kubelka and Munk as developed
in Erlangen [6]. This chapter will review the use of reflection spectrophotometry
in the experimental and clinical assessment of tissue oxygenation. In our discussion
of the literature we will focus on investigations concerning the liver and gastroin-
testinal tract due to the role of splanchnic dysfunction in the pathogenesis of sep-
sis, leading to multi-organ failure (MOP) [7, 8].
I Technique and Theoretical Background
A decisive breakthrough in the application of reflection spectrophotometry was

achieved by the development of highly flexible micro-lightguides which solved the
problem of optimal adaptation of the optical instrument to the organs. Before that
time, application of tissue photometry was restricted to completely immobilized or-
gans due to the use of lenses which had to be adjusted. Another major improve-
ment was made by the development of microcomputers with the capacity to per-
form the required calculations in a short time frame. Nowadays, all the reflectance
spectrophotometers are build on the same principal: the visible light of a halogen
lamp is passed through a photodiode or bandpass-filter and guided by a micro-
lightguide fiber to the tissue of interest. Light waves irradiated into tissue are al-
tered along their course by absorption and scattering within the tissue. Both physi-
cal phenomena decrease the intensity of incident light penetrating the tissue. The
reflected light from the tissue is collected by detecting micro-lightguide fibers in
the same probe and led to a detection unit. With this information, it is possible to
calculate a reflection spectrum.
In the late 1970s, Sato and co-workers developed a tissue spectrophotometer
(Tissue spectrum analyzer TS-200, Sumitomo Electric Industries, Osaka, Japan)
[5, 9-11]. A reflectance spectrum is obtained in a region between 502 to 687 nm.
Ten spectra that have been taken sequentially with variable intervals are stored in a
memory system. The computer is programmed to subtract from these data a spec-
trum obtained from standard white material. In this way, the spectrophotometer
records the difference in absorption between a standard reference (absorption
almost zero) and a tissue sample according to:
(Er(tissue)J =log Ir(standard) fir( tissue)
Where [Er(tissue)J is the relative absorbency and Ir(standard) and Ir(tissue) are the in-
tensity of the diffusely reflected light from the white standard and the tissue, respec-
tively. In order to assess the hemoglobin concentration, the difference between the Er
at 569 nm and at 650 nm is determined: AEr(s 69 _65 o)· Because 569 nm is the isobestic
point of oxy- and deoxyhemoglobin (Fig. 1), at this wavelength absorption is depen-
dent on the concentration but not on the oxygen saturation status of hemoglobin. At
650 nm there is no hemoglobin absorption at all in this spectrum. Therefore, AEr(s 69 _
650 ) can be considered an estimate of the hemoglobin concentration.
Based on the spectral data of the reflected light, an index of the oxygen satura-
tion (IS0 2 ) of the hemoglobin is generated. The IS0 2 is estimated by a computer
using the different degrees of absorption at three wavelengths: 569, 577, and 586
nm. Wavelengths of 569 and 586 nm are isobestic points and 577 is the wavelength
of peak absorption of oxyhemoglobin. The following equation is used:
ISOz = {0.673 X [Er(577-586)- 9/17 X Er(569-586)J/Er(569-586)} X 100%
Reflectance Spectrophotometry and Tissue Oxygenation in Experimental and Clinical Practice 555
18
16
14
?:- 12
··:;:a 10
0 8
B
<( 6
4
2
472 492 512 522 552 572 592 612

Wavelength (nm)
Fig. 1. Absorption spectra of oxy- and deoxyhemoglobin. The spectra of these forms of hemoglobin have
their own characteristics with isobestic points at wavelengths of 569 and 586 nm
In this way, this spectrometer does not use the reflection spectra of all different
wavelengths but instead works with the spectra of only three discreet wavelengths.
In the other class of spectrophotometers, such as the Erlangen Micro-lightguide
spectroPHOtometer (EMPHO), monochromatic visible light with a wavelength be-
tween 502-630 om is used. By transmission of the remitted light through a rotating
interference bandpass-filter disk with a resolution of 2 om, a diffuse reflection
spectrum of 64 wavelengths is obtained. The bandpass-fllter allows a sampling ve-
locity of 100 spectra per second. Due to the high sampling rate and the small mea-
suring tissue volume, the device enables measurements of remission spectra in tis-
sue volumes containing only a few capillaries [12]. The algorithm used in the EM-
PHO is based on the two-flux theory of Kubelka and Munk, describing the optical
properties of an absorbing and scattering medium [13, 14]. According to this theo-
ry, the radiation flux directed inwards a sample is diminished along its path by
scattering and absorption. Therefore, the reflectance of light by a medium is depen-
dent on its absorption coefficient and on its scattering coefficient. The two-flux
theory was evaluated by Hoffman, who concluded that with some modification the
theory is a good approximation to describe tissue reflectance [15, 16]; in 1988
Diimmler developed an algorithm for the online evaluation of quantitative hemo-
globin oxygenation (HbS0 2 ) [17].
For the quantitative evaluation of HbS0 2 out of diffuse reflection spectra from
tissues, a mathematical procedure is required, involving the back scattering proper-
ties of the tissue and the absorption by hemoglobin and other tissue pigments. Fol-
lowing the derivation of the differential equations used in the Kubelka and Munk
two-flux theory, the relation between the wavelength-dependent absorption A(A.)
and wavelength-dependent scattering S(A.) of the tissue is formulated as:
A(A.)/S(A.) = (AO + C1el(A.) + C2e2(A.)/(SO+S1(A.))
Where AO is the basic absorption of the tissue, C1 is the concentration of oxyge-
nated hemoglobin, C2 is the concentration of deoxygenated hemoglobin, e1(A.) is
the wavelength-dependent extinction coefficient of oxygenated hemoglobin, e2(A.) is
the wavelength-dependent extinction coefficient of deoxygenated hemoglobin, SO is
the basic scattering of the tissue and Sl is the wavelength-dependent scattering of

the tissue. This relation depends on four parameters AO/SO, Cl/SO, C2/SO and Sl/
SO. Based on these four parameters and on the fact that oxygenated hemoglobin
has two absorption maxima while deoxygenated has only one single absorption
maximum (Fig 1.), the determination of spectra from fully oxygenated and fully
deoxygenated hemoglobin suffices to calculate the oxygenation state from mixed
spectra of unknown saturation:
Hb0 2 = Cl/Cl + C2
The hemoglobin concentrations are calculated as relative values because only the
ratios Cl/SO and C2/SO can be determined:
Hbcon=Cl+C2
Using these calculations, a raw curve is collected, influenced by a lot of noise from
the tissue surroundings. To obtain a corrected spectrum, the microcomputer has to
compare these raw data with a dark spectrum and a white standard spectrum. Be-
fore each measurement, a response spectrum from a standard white object is ob-
tained. The calculation for the determination of the collected spectrum is shown in
the following equation:
CS =DC-RS/DC-WSt
where CS is the corrected spectrum, DC is the dark curve, RS is the raw spectrum,
and WSt is the spectrum of the white standard. This Diimmler algorithm and its
usability in the EMPHO was validated and improved by Kessler and co-workers
(EMPHO II Bodenseewerk Geriitetechnik, Oberlingen, Germany) [18, 19].
In another spectrophotometer of the same class (0 2C, Lea Medizin Technik,
Giessen, Germany), the same algorithm is used as in the EMPHO but the interfer-
ence bandpass filter disk is replaced by a photodiode, allowing a higher sampling
rate of the spectra. Simultaneously, the perfusion of the same volume of tissue can
be determined by combining this spectrophotometer with laser Doppler flowmetry.
Theoretically, there is no interference between these techniques because of the dif-
ferent ranges of light used in these two optical techniques.
1 Experimental and Clinical Utility

Reflectance spectrophotometry has been applied in many studies focused on the
oxygenation of the microcirculation in the gastrointestinal tract and liver, due to
the importance of this region in, for instance, the development of disease processes
in critically ill patients. Sato and coworkers introduced reflection spectrophotome-
try for the assessment of tissue hemoglobin concentration. It was demonstrated
that in the intestine, the penetration depth (the catchment volume) of the spectro-
scopic reflectance was limited to mucosal and, to a lesser degree, submucosal ves-
sels [5]. They also showed that a change in gastric mucosal Hb concentration re-
flected a corresponding change in mucosal blood volume, and therefore, in gastric
mucosal blood flow [5, 20, 21]. In this way, reflection spectrophotometry was used
to assess the perfusion state of tissues. In patients with liver disease, it was ob-
served that the spectral intensity in a normal liver is higher than in cirrhotic livers,
indicating that in cirrhotic livers the regional hepatic blood volume was decreased.
Reflectance Spectrophotometry and Tissue Oxyqenation in Experimental and Clinical Practice 557
It also seems that the estimated saturation value in the hepatic tissue capillary
blood remained stable until the local blood hemoglobin concentration decreased to
0.55 absorbance. A further decrease in absorbance accompanies the lowering ofthe
estimated saturation values which suggests that, concomitant with the decrease in
blood supply, the amount of oxygen available for the liver decreases. The authors
concluded that reflection spectrophotometry measures both qualitatively and quan-
titatively the absorption of hemoglobin, thereby determining the hemoglobin con-
centration and the hemoglobin oxygen saturation. Compared to regional hepatic
blood flow measurements by radioisotope clearance technique, chemical liver func-
tion, and indocyanine green (ICG) tests, reflection spectrophotometry can be used
to assess local hepatic blood flow [10, 11].
Expanding on the possibilities to determine tissue blood flow using reflection
spectrophotometry, Leung and coworkers compared reflection spectrophotometry
to gastric mucosal blood flow measurements with hydrogen gas clearance, laser
Doppler flowmetry, and intravital microscopy flow measurements. The aim of their
studies was to validate reflection spectrophotometry against other mucosal blood
flow measurement techniques, and to define the limitations of reflection spectro-
photometry in assessment of gastroduodenal mucosal perfusion. Having studied
the patterns of mucosal hemoglobin concentration and saturation under conditions
of well defined hemodynamic changes in the mucosa, they concluded that different
local hemodynamic conditions generate characteristic changes in mucosal hemo-
globin concentration and saturation as measured with reflection spectrophotometry.
Hyperemia causes an increase in mucosal hemoglobin concentration and mucosal
saturation; mucosal ischemia due to congestion leads to an increase in mucosal he-
moglobin concentration and a decrease in mucosal saturation; and ischemia with-
out congestion causes a decrease in both mucosal hemoglobin concentration and
saturation. Other flow measurement techniques, such as laser Doppler flowmetry,
hydrogen gas clearance, and microspheres cannot distinguish between ischemia as-
sociated with congestion and ischemia without congestion. This can be considered
a major advantage of reflection spectrophotometry [22-24]. However, reflection
spectrophotometry does not correlate well with tissue blood flow in all conditions;
during changes of hemoglobin saturation due to hypoxia and hyperoxia laser Dop-
pler flowmetry but not reflection spectrophotometry provided a good reflection of
gastric mucosal blood flow. During acute normovolemic anemia neither laser Dop-
pler flowmetry nor reflection spectrophotometry corresponded with changes in
gastric mucoasal blood flow [25, 26].
Reflection spectrophotometry is used in many investigations concerning the lo-
cal autoregulatory mechanisms in the microcirculation under septic conditions, in-
dependent of systemic cardiopulmonary effects [27]. For instance, Radermacher
and coworkers observed an autonomous behavior of the hepatic and intestinal mi-
crovascular HbS02 during endotoxemia, irrespective of simultaneous changes in
the systemic circulation [28, 29]. Local hemodynamics are regulated by mecha-
nisms independent of the systemic circulation. In order to gain insight in these
mechanisms, for instance in the microcirculation of the intestinal serosa and muco-
sa, the effect of vasoactive medication on the mucosal and serosal microvascular
oxygenation has been studied [30-36]. A discrepancy between intestinal microvas-
cular blood flow and HbS0 2 during sepsis has also been found: the mucosal capil-
lary hemoglobin saturation was well preserved, despite a marked heterogeneity of
the microcirculatory blood flow as observed with orthogonal polarization spectral
(OPS) Imaging [37, 38]. These results demonstrate that the relation between micro-
vascular blood flow and tissue oxygenation is influenced by local regulatory pro-
cesses. Although these mechanisms are not yet fully understood, it is clear that
with data provided by reflection spectrophotometry more insight can be gained
into the regulation of tissue oxygenation during disease processes.
Reflection spectrophotometry has also been used to investigate the effects of
therapeutic interventions, such as mechanical ventilation, on tissue oxygenation.
Fournell and coworkers demonstrated that the use of positive end expiratory pres-
sure (PEEP) during mechanical ventilation can have a detrimental influence on the
oxygenation of the gastric mucosa [39]. In a clinical study, they expanded on this
research by the use of a combination of reflection spectrophotometry and laser
Doppler flowmetry, the so-called 0 2 C (Fournell et al., unpublished data). With this
device, oxygenation (reflection spectrophotometry) and blood flow (laser Doppler
flowmetry) in tissue can be measured simultaneously in the same place.
Our research group has recently started to use the 0 2 C during the intra-opera-
tive assessment of hepatic microvascular oxygenation during liver transplantation.
The rapid changes in microvascular blood flow and hemoglobin saturation during
the reperfusion-phase could be recorded in real-time and are shown in Fig. 2. The
portal vein and the hepatic artery were opened simultaneously after 24 seconds in
the recorded time frame. In the absence of blood flow and hemoglobin in the pre-
servation fluid, the saturation value of 35% is produced by the reflection spectra of
intracellular cytochromes. And although reflection spectrophotometry appears to
have more problems with very fast changes compared to laser Doppler flowmetry,
in ten seconds a stable signal was obtained during these measurements.
The 0 2 C was also applied by our group for the assessment of tissue oxygenation
and microvascular blood flow in the upper part (fundus) of the stomach during
gastric-tube reconstruction after esophagectomy, a treatment for esophageal cancer.
400
..R. ....9
100
..
.
.. . .
.... 'b . ..
350 o Blood flow
Q
• Saturation ~
80
300
250
5 60 ~
~
u. 200
0
0
VI
...J .0
150 40 J:
100
20
so
0 • o- .o ·o· .o. • o· .o • o- .o·
0 0
0 4 B 20 24 28 32 36 40 44 48 52 56 60
nme (s)
Fig. 2. Hepatic microvascular blood flow and HbS02 during reperfusion after liver transplantation in real
time. To create a rapid recirculation of the transplanted liver the hepatic artery and portal vein were
opened simultaneously. Both laser Doppler flowmetry (LDF) and reflectance spectrophotometry (RS) were
able to follow these changes
250 100
o Blood flow
200 • Saturation BO
'
'' . '
p
l
5 150
~
u..
'
''
''
.... 60
0
N
g '' VI
100 ' 40 ~
''
_..,' '
50 -- 20
0+------.-----.-----,------.-----+0
TO Tl T2 T3 T4
Fig. 3. Gastric fundus microvascular blood flow and Hb50 2 during gastric tube reconstruction. In the first
4 steps creation of the gastric tube showed a decrease in microvascular blood flow as measured with la-
ser Doppler flowmetry (LDF)-, but an increase in Hb50 2 as measured with reflectance spectrophotometry
(RS). Local application of nitroglycerin (T4) increases microvascular blood flow but has very little effect on
Hb0 2
This part of the esophagal tube in particular is notorious for its insufficient circula-
tion following the reconstruction, leading to anastomotic leakage and the develop-
ment of strictures [40, 41]. In Figure 3, we show the data of one patient during five
steps of the reconstruction. TO, the baseline measurement, is the phase before manip-
ulation of the vascularization of the stomach. T1 when the stomach, normally depen-
dent for its blood supply on four big arteries, has to survive on only one artery: the
right gastro-epiploi:c artery. Then, a gastric tube is created from the stomach with sta-
pling devices, impairing microvascularization (T2). During surgery, the stomach is
pulled up through the thorax, to the neck of the patient. At T3 the gastric tube is
pulled up to the cervical end of the esophagus, and the anastomosis is made. In an
attempt to improve gastric microcirculatory blood flow, nitroglycerin is applied top-
ically (T4). Although the microvascular blood flow decreased tremendously during
the procedure; HbS0 2 actually increases during the procedure. The local application
of an NO-donor increased microvascular blood flow but it showed no impressive
changes in HbS0 2 • These simultaneous measurements of flow and oxygenation on
the gastric tube have not been performed before, and more research into the nature
and the consequences of these findings is planned for the future.
Since its introduction in 1979, as a clinically applicable technique for the mea-
surement of hemoglobin oxygen saturation and hemoglobin concentration in the
microcirculation, reflection spectrophotometry has been used in many studies.
Meanwhile, validation of reflection spectrophotometry has proved very difficult due
to problems with both the definition of a golden standard, and the creation of an
in vitro model with similar absorption and scattering properties as living tissue
but without oxygen extraction. Only two authors have claimed in vitro validation
of this technique. Krug has validated the EMPHO using a solution of intralipid and
erythrocytes in a model existing of a micro-oxygenator and microflow chamber
[18]. In this study, the aim was to validate the algorithm and its accuracy with
different absorbency and scattering properties. After some modifications of the
~ 60
....
100
80
. .- .... .. .. .
I
I
:
I
,. ,
------------------J-------- · --- ~! - ~~ ----------
•
• I •
•
0
.
------------ ~lr~ --:- - ----------------------------
V'l
~40 e
1
I
·:
I
20 I
I
• • I
•
0+----.----.---~.----.----.----.----.
0 10 20 30 40 50 60 70
P02 (mmHg)
Fig. 4. Microvascular Hb502 vs Microvascular P0 2• An in vivo hemoglobin oxygen saturation curve can
be created between 20 and 80% saturation
Dummler algorithm, which had been adjusted by other researchers already, they
created hemoglobin spectra that correlate with the remission spectra from isolated
hemoglobin as known from the literature [42]. Validation of the algorithm of the
EMPHO for the splanchnic region was performed in 1994 by Hasibeder and co-
workers. They used a suspension of homogenized hemoglobin free intestinal muco-
sa in heparinized pig blood and simultaneously recorded tissue P0 2 and hemoglo-
bin saturation. They demonstrated a correlation between oxygen measurements
with Clark-type surface electrodes, reflection spectrophotometry and hemoglobin
oxygen saturation measurements with a hemoximeter for HbS0 2 values between
20- 80%. Our group has applied a similar approach by combining the oxygen-de-
pendent quenching of palladium (Pd)-porphyrin phosphorescence, a technique de-
scribed in previous papers [2], with HbS0 2 measurements in the pig intestine using
the 0 2 C. In Figure 4, it is shown that an in vivo hemoglobin oxygen saturation
curve can be created. Independent of the tissue P0 2 , the maximum saturation of
the tissue hemoglobin appears to be ±80%. By combining these data, more infor-
mation is provided on the relation between hemoglobin oxygen binding and tissue
oxygenation.
-The available reflection spectrophotometry devices, however, do have limitations.
For instance, not all investigations show corresponding results. The baseline satura-
tion measurements of Haisjackl et al. do not correspond with those from Leung et
al. [22], although the relative changes after comparable interventions were similar.
This might be due to three reasons. The penetration depth being dependent on the
intensity of the incident light and the distance between incident and detected light-
guides, the lights and lightguided fibers were not identical. In addition, the optical
properties of the tissue of each organ will result in different scattering and absorp-
tion properties of the incident and reflected light, making it difficult to extrapolate
parameters such as catchment volume between different tissues. Another reason
may be the difference between the two methods (algorithms) used in the two reflec-
tion spectrophotometers. To our knowledge there is no study comparing these two
forms of algorithm and technical device.
I Conclusion
Reflectance spectrophotometry is a powerful technique for the assessment of hemo-
globin oxygenation in tissue. Despite its limitations, it can be concluded that reflec-
tion spectrophotometry allows detection of changes in capillary hemoglobin satura-
tion and that this technique can be applied in patients suffering from sepsis. There-
fore, this may be a useful clinical resuscitation tool, especially in the light of the re-
cent microcirculatory measurements of sublingual microcirculation performed by
us and De Backer et al. [43] using OPS imaging. De Backer et al. have shown that
microcirculatory shut down is a characteristic of sepsis, with the severity of shut-
down correlating with patient outcome. We have confirmed this view in pressure
resuscitated septic shock patients, and showed that such microcirculatory shut
down can be reversed by recruitment of the microvessels by vasodilator therapy
[44, 45]. Whether such techniques will provide clinically useful resuscitation end
points still has to be determined.
References
1. Dantzker DR (1997) Monitoring tissue oxygenation, the search for the grail. Chest 111:12-
13
2. Siegemund M, van Bommel J, Ince C (1999) Assessment of regional tissue oxygenation.
4. Chance B (1952) Rapid and sensitive spectrophotometry I. Accelerated and stopped-flow
methods for the measurement of reaction kinetics and spectra of unstable compounds in
the visible region of the spectrum. Rev Sci Instrum 22:619-6272
5. Sato N, Takenobu K, Motoaki S, Kawano S, Abe H, Hagihara B (1979) Measurement ofhemo-
perfusion and oxygen sufficiency in gastric mucosa in vivo. Gastroeneterology 76:814-819
6. Frank KH, Kessler M, Appelbaum K, Dummler W (1989) The Erlangen micro-lightguide
spectrophotometer EMPHO 1. Phys Med Bioi 34:1883-1900
7. Dantzker DR (1993) The gastrointestinal tract. The canary of the body? JAMA 270:1247-
1248
8. Wilmore DW, Smith RJ, O'Dwyer ST, Jacobs DO, Ziegler TR, Wang XD (1988) The gut:
A central organ after surgical stress. Surgery 104:917-923
9. Sato N, Kamade T, Shichiri M, Kawano S, Abe H, Hagihara B (1979) Measurements of
haemoperfusion and oxygen sufficiency in gastric mucosa in vivo. Evidence of mucosal
hypoxia as the cause of hemorrhagic shock induced gastric mucosal lesion in rats. Gastro-
enterology 76:814-819
10. Sato N, Shichiri M, Hayaschi N (1978) Non-destructive measurements of concentrations of
respiratory enzymes and the rate of oxygen consumption in living liver tissue by reflec-
tance spectrophotometry. In: Dutton PL (ed) Frontiers in Bioenergetics. Academic Press,
New York, pp 507-1515
11. Sato N, Hayashi N, Kawano S, Kamade T, Abe H (1983) Hepatic hemodynamics in patients
with chronic hepatitis or cirrhosis as assessed by organ-reflectance spectrophotometry.
12. Brunner M, Ellerman R, Frank KH, Kessler M (1985) Measurements and processing of in-
tracapillary hemoglobin spectra by using as micro-lightguide spectrophotometer in con-
nection with a microcomputer. Adv Exp Med Biol191:909-916
13. Kubelka P, Munk F(1931) Ein Beitrag zur Optik der Farbanstriche. Z Technische Physik
11:76-77
14. Kessler M, Frank KH, Hoper J, Tauschek D, Ziindorf J (1992) Reflection Spectrometry. In:
Erdmann W, Bruley DF (ed) Oxygen Transport to Tissue XIV. Plenum Press, New York
pp 203-212
15. Hoffman J, Hannebauer F, Lubbers DW (1985) Simulation of the optical properties of an

absorbing and scattering medium using the monte-carlo technique compared with two-
and six-flux theories. In: Kreutzer F (ed) Oxygen Transport to Tissue VII, Plenum Press,
16. Hoffman J, Lubbers DW, Heise HM (1998} Applicability of the Kubelka-Munk theory for
the evaluation of reflectance spectra demonstrated for haemoglobin free perfused heart
tissue. Phys Med Bioi 43:3571-3587
17. Dummler W (1988} Bestimmung von Hamoglobin-Oxygenierung und relativer Hamoglobin-
Konzentration in biologische systemen durch auswertung von remissionspektren met hilfe
der Kubelka-Munk-Theorie. Thesis, Friedrich-Alexander-Universitat, Erlangen-Nurnberg
18. Krug A, Kessler M (1997} Validation and improvements of an algorithm for determination
of hemoglobin oxygenation, based on spectral data recorded by tissue spectrophotometer.
Proc SPIE 2979:344-354
19. Krug A (1998} Quantitative optische Gewebemessungen am Herzen und an der Leber.
Thesis, Friedrich-Alexander-Universitat Erlangen-Nurnberg
20. Kamade T, Sato N, Kawano S (1982} Gastric mucosal hemodynamics after thermal or head
injury. Gastroenterology 83:535-540
21. Kamade T, Kawano S, Sato N (1983} Gastric mucosal blood distribution and its changes in
the healing process of gastric ulcer. Gastroenterology 84:1541-1546
22. Leung FW, Morishita T, Livingston EH, Reedy T, Guth PH (1987} Reflectance spectrophoto-
metry for the assessment of gastroduodenal mucosal perfusion. Am J Physiol 252:G797-G804
23. Leung FW, Guth PH (1986} Interpretation of reflectance spectrophotometric measurements
of gastroduodenal mucosal hemodynamic changes. Clin Res 34:95A (abst)
24. Chung SCS, Leung JWC, Leung FW (1990} Effect of submucosal epinephrine injection on
lacal gastric blood flow. Dig Dis Sc 35:1008-1011
25. Casadevall M, Panes J, Pique, JM, Bosch J, Teres J, Rodes J (1992} Limitations of laser-
Doppler velocimetry and reflectance spectrophotometry in estimating gastic mucosal blood
flow. Am J Physiol 263:G810-G815
26. Panes J, Casadevall M, Pique JM, Bosch J, Whittle BJR, Teres J (1992} Effects of acute nor-
movolemic anemia on gastric mucosal blood flow in rats: Role of nitric oxide. Gastroenter-
ology 103:407-413
27. Hasibeder W, Germann R, Wolf HJ, et a! (1996} Effects of short-term endotoxemia and do-
pamine on mucosal oxygenation in porcine jejunum. Am J Physiol 270:G667-G675
28. Trager K, Matejovic M, Ziilke C, eta! (2000} Hepatic 0 2 exchange and liver energy metabo-
lism in hyperdynamic porcine endotoxemia: effects of iloprost. Intensive Care Med
26:1531-1539
29. Matejovic M, Radermacher P, Zulke C, et al (2000} Effects of the combined thromboxane
receptor antagonist and synthetase inhibitor DTTX-30 on intestinal 0 2 exchange and en-
ergy metabolism during hyperdynamic porcine endotoxemia. Shock 13:307-313
30. Germann R, Haisjackl M, Schwarz B, et al (1997} Inotropic treatment and intestinal muco-
sal tissue oxygnation in a model of porcine endotoxemia. Crit Care Med 25:1191-1197
31. Germann R, Haisjackl M, Hasibeder W, et a! (1994} Dopamine and mucosal oxygenation
in the porcine jejunum. J Appl Physiol 77:2845-2852
32. Germann R, Hasibeder W, Haisjackl M, et al (1995} Dopamine-1-receptor stimulation and
mucosal tissue oxygenation in the porcine jejunum. Crit Care Med 23:1560-1566
33. Schwarz B, Hofstotter H, Salak N, et a! (2001) Effects of norepinephrine and phenyl-ephr-
ine on intestinal oxygen supply and mucosal tissue oxygen tension. Intensive Care Med
27:593-601
34. Salak N, Pajk W, Knotzer H, et al (2001} Effect of epinephrine on intestinal oxygen supply
and mucosal tissue oxygen tension in pigs. Crit Care Med 29:367-373
35. Haisjackl M, Luz G, Sparr H, et a! (1997) The effect of progressive anemia on jejunal mu-
cosal and serosal tissue oxygenation in pigs. Anesth Analg 84:538-544
36. Germann R, Haisjackl M, Schwarz B, et al (1997} Dopamine and intestinal mucosal tissue
oxygenation in a porcine model of haemorrhage. Br J Anaesth 79:357-362
37. Tugtekin IF, Radermacher P, Theisen M, et a! (2001} Increased Ileal-mucosal-arterial PC0 2
gap is associated with impaired villus microcirculation in endotoxic pigs. Intensive Care
Med 27:757-766
38. Trager K, Radermacher P, Rieger KM, et al (2000) Norepinephrine and NG-monomethyl

-L-arginine in porcine septic shock : effects on intestinal oxygen exchange and energy
balance. Crit Care Med 28:2007-2014
39. Fournell A, Scheeren TWL, Schwarte LA (1998) Peep decreases oxygenation of the intest-
inal mucosa despite normalization of cardiac output. In: Hudetz and Bruley (ed) Oxygen
Transport to Tissue XX. Plenum press, New York, pp 435-440
40. Pierie I-PEN, De Graaf PW, Poen H, Van der Tweel I, Obertop H (1994) Impaired healing
of cervical oesophagastrostomies can be predicted by estimation of gastric serosal blood
perfusion by laser doppler flowmetry. Eur J Surg 160:599-603
41. Jacobi CA, Zieren HU, Zieren J, Muller JM (1998) Is tissue oxygen tension during esophag-
ectomy a predictor of esophagogastric anastomotic ealing? J Surg Res 74:161-164
42. Assendelft van W (1970) Spectrophotometry of haemoglobin derivates. Thesis Rijks Uni-
versiteit, Groningen
43. De Backer D, Creteur J, Preiser JC, Dubois MJ, Vincent JL (2002) Microcvascular blood
flow is altered in patients with sepsis. Am J Respir Crit Care Med 166:98-104
44. Buwalda M, lnce C (2002) Opening the microcirculation: Can vasodilators be useful in sep-
45. Spronk PE, Ince C, Gardien MJ, Mathura KR, Oudemans-van Straaten HM, Zandstra DF
(2002) Nitroglycerin in. septic shock after intravascular volume resucitation. Lancet 360:
1395-1396
The Case for Tissue Base Excess
T. J. Morgan and B. Venkatesh
I Introduction
Over many years a number of indices have enjoyed varying popularity as measures
of 'global' tissue well-being in critical illness. These have ranged from the plasma
lactate concentration to more invasive measurements such as oxygen delivery
(D0 2 ), oxygen consumption (V0 2 ) and their relationships, mixed venous oxygen
saturation (Sv0 2 ) and the veno-arterial PC0 2 gradient. However, all such global in-
dices have one major drawback. Since they are integrations derived from multiple
inputs, their sensitivity to isolated regional dysoxia is poor. For example, the mixed
venous oxygen tension (Pv0 2 ) is a flow-weighted average of post-capillary oxygen
tensions in all organs contributing to venous return. At a Pv0 2 of 40 mmHg, the
average intracellular P0 2 is 11 mmHg [1]. At a Pv0 2 of 26 mmHg, average intracel-
lular P0 2 has fallen below the 'Pasteur point' to 0.8 mmHg. Consequently a Pv02
< 26 mmHg is a highly specific marker of tissue dysoxia. However, a normal Pv0 2
does not in any way rule out small pockets of significant dysoxia. To take an ex-
treme example, a normal Pv0 2 can persist despite absolute ischemia in a major or-
gan, as in brain death. Furthermore, an elevated Pv0 2 is far from a reassurance,
since it can be a manifestation of tissue shunting [2], cytopathic hypoxia [3] or
some combination ofboth [4].
The importance of unrecognized regional dysoxia is also implicit in the concept
of covert compensated shock [5], in which a major hemodynamic threat is con-
cealed by maximally deployed homeostatic defences. Occult and persistent splanch-
nic vasoconstriction is characteristic of this condition [6, 7]. In covert shock, the
ileal microcirculatory architecture further increases the susceptibility of the
splanchnic mucosa to low flow dysoxia [8-10]. The possibility of a multi-pronged
attack on mucosal oxygenation has led to the famous description of the gut as 'the
canary of the body' [11], with splanchnic ischemia/reperfusion a recognized driver
of the multiple organ dysfunction syndrome [12, 13].
For the reasons just stated, the gut at first seemed the most promising early warn-
ing system, and the best organ to monitor in order to detect covert tissue dysoxia.
However, other tissue sites have since joined the gut as possible early warning surveil-
lance sites. They include the tongue [14], esophagus [15], liver and abdominal muscle
[16, 17], and subcutaneous tissue [18, 19]. There is now a growing interest in regional
indices such as tissue PC0 2 and P0 2 [20], tissue lactate [21], orthogonal polarization
spectroscopy [22], laser Doppler flowmetry [23], hepatosplanchnic blood flow [24],
and regional estimates of the mitochondrial redox state [25, 26].
However, most of these monitoring techniques are still research tools, very far
from clinical application. Only regional PC0 2 has come close to everyday clinical
The Case for Tissue Base Excess 565
application, primarily in the form of gastric tonometry [27]. Even this methodolo-
gy has major flaws limiting its wider utility and acceptance. The remainder of this
chapter provides a brief overview of gastric tonometry, the regional PC02 concept
in general and its pitfalls as applied to any tissue, and culminates in an exploration
of the idea of tissue base excess.
I Gastric Tonometry and Gastric lntramucosal pH [28, 29]
Here, gastric luminal PC0 2 is measured in a fluid equilibration medium placed in a

silicone balloon on the end of a modified nasogastric tube. In the original tech-
nique this medium was saline [30]. More recently other media, most notably air,
have been used [31]. During splanchnic hypoperfusion, intramucosal PC0 2 in-
creases, so that C02 diffuses into the gut lumen and the balloon contents. The in-
tramucosal pH (pHi) is then calculated from the measured PC0 2 in the fluid using
a modification of the Henderson-Hasselbalch equation, substituting arterial [HC03]
for mucosal [HC03]. Intramucosal acidosis is defined as pHi <7.3.
Intramucosal acidosis has been linked with such adverse outcomes as bleeding
from stress ulceration [32], weaning failure [33], acute respiratory distress syn-
drome (ARDS) after blunt trauma [34], morbidity after liver transplantation [35],
major complications post elective cardiac surgery [36], and multiple organ dysfunc-
tion syndrome and death [37-39]. However, despite these and other encouraging
reports [40-42], there is little evidence that titrating therapy to pHi improves out-
come [43, 44]. Thus, after more than 15 years of accumulated data, gastric tonome-
try is not an established regional monitoring tool [45].
A fundamental flaw has been the use of arterial [HC03] as a surrogate for muco-
sal [HC03] [46]. This has been overcome by changing the endpoint to the C0 2 gap
(see below), but there are other problems. For example the PC0 2 signal can be de-
graded by luminal blood and to a lesser extent by feeds [47, 48]. Large C0 2 gradi-
ents between mucosa and lumen can occur [49]. It is possible that in the end the
problems of interpreting PC0 2 measurements from inside the stomach will prove
close to insuperable. On the other hand, PC0 2 measurement in solid tissues has
distinct advantages, allowing the possibility of simultaneous pH measurement.
I The C02 Gap [50-52]
This is defined as the elevation of regional PC0 2 above arterial PC02 • As tissue
blood flow is lowered, regional PC0 2 and the C02 gap increase. If the flow reduc-
tion is gradual, the initial PC0 2 increase is wholly due to reduced clearance of
aerobically generated C0 2 , a process sometimes described as 'flow stagnation'. This
is the tissue equivalent of an acute respiratory acidosis. With the onset of anaerobic
metabolism, aerobic C0 2 production is progressively suppressed. However, C0 2 ac-
cumulation continues despite metabolic shutdown, due to tissue lactic acidosis with
proton titration of tissue and capillary HC03. Here the tissue acid-base status is
the equivalent of a mixed metabolic and respiratory acidosis.
The problem for the clinician confronted with an elevated C0 2 gap is that there is
no simple way to distinguish between these entirely different pathological processes
[53, 54]. Yet another flaw exists. The C0 2 gap is relatively insensitive to reductions
566 T. J. Morgan and B. Venkatesh
in D0 2 when flow is preserved. This has been well shown in hypoxic dysoxia [55, 56].
We have seen a similar insensitivity to mucosal hypoxia induced by severe anemia
during acute normovolemic hemodilution experiments (unpublished data).
Hence, the C0 2 gap is far from the ideal regional monitoring tool. What is
needed is a COrindependent measure of tissue acid-base status, a problem very
similar to that confronted many years ago by Siggaard-Andersen and colleagues in
the interpretation of intravascular acid-base status. Their solution was to use simul-
taneous measurements of PC0 2 , pH and [hemoglobin] to calculate a C0 2 -invariant
parameter of metabolic acid-base balance, which they termed whole blood 'base ex-
cess' [57]. As far back as 2001, Robert Schlichtig suggested that the same principles
could be used to derive tissue base excess (unpublished personal communication).
However there have been both theoretical and practical difficulties in progressing
this idea [58]. To better understand how these might be overcome, brief descrip-
tions of the physical chemical approach to acid-base and the base excess concept it-
self are required.
I The Physical Chemical Approach to Acid-Base

Peter Stewart's semi-quantitative analysis applies basic principles of physical chem-
istry to physiological fluids [59, 60]. In his approach, pH and [HC03] are depen-
dent variables determined by three independent variables, which in an open system
such as arterial blood are PC0 2 , strong ion difference ([SID]), and the total concen-
tration of non-volatile weak acid buffer ([AToTD·
Strong Ions and [SID]

Strong ions have unionized fractions so minute that they remain quantitatively un-
important under all physiologic acid-base conditions. Examples of strong ions in-
clude Na+, K+, Ca++, Mg++, Cl- and lactate. In physiology, strong cations exceed
strong anions, so that [SID] is [strong cations] - [strong anions]. Apart from Cl-,
strong ions are not subject to acid-base homeostatic loops, and are, thus, indepen-
dent variables as far as acid-base is concerned.
Since [SID] is a difference in charge concentration it is expressed in mEq/1.
[SID] in normal plasma is approximately 42 mEq/1. To preserve electrical neutrality,
the [SID] 'space' is filled passively by the buffer base anions. The only buffer base
components of quantitative importance are HC03 and the 'non-volatile buffer an-
ions' (A-). These are weak ions because at physiological pH they combine reversi-
bly with protons to form their conjugate parent molecules:
(Eq.l)
(Eq. 2)
In plasma, A- is predominantly the net negative charge on albumin, with ionised

inorganic phosphate normally making a much smaller contribution. The total buf-
fer base concentration ([A-] + [HC03]) is, thus, a dependent variable numerically
identical to the independent variable [SID]. In fact the easiest way to calculate plas-
ma [SID] is as [buffer base], a value often termed the 'effective' [SID].
HCO]
Anions plasma Cations Anions ISF
Fig. 1. Gamblegrams comparing proportional ionic concentrations in plasma and interstitial fluid (ISF).
Note the absence of A- in the weak ion (buffer base) component of interstitial fluid, leaving HC03 as the
sole occupant of the space defined by [SID)
How does [SID] exert its Influence on Acid-base?

If [SID] is reduced, [buffer base] must fall by an identical amount. The equilibria
of both buffer base reactions therefore shift to the right (Equations 1 and 2), reduc-
ing both [A-] and [HC03]. [SID] reduction thus forces [HC03] reduction, shifting
the PaC0 2 /pH relationship towards metabolic acidosis. Similarly an isolated in-
crease in [SID] causes a metabolic alkalosis. Thus, [SID] affects metabolic acid-base
status as an independent variable by influencing [buffer base] and its [HC03] com-
ponent.
How does lAror1 exert its Influence on Acid-base?

[ATOrl is ([A-]+ [HA]). In plasma, [Arorl is comprised largely of albumin and in-
organic phosphate. In erythrocytes, [Arorl is predominantly hemoglobin. Impor-
tantly, [Arorl in healthy interstitial fluid is negligible (Fig. 1). If [Arorl alters, [A-]
varies in parallel. When [SID] is held constant while [ATOrl changes, [buffer base]
(i.e. [A--]+ [HC03]) cannot change. Therefore, isolated [Arorl reductions increase
[HC03] by reducing [A-], causing a metabolic alkalosis. Conversely, isolated [Arorl
elevations cause a metabolic acidosis [61].
In the physical chemical approach, there are thus two determinants of the meta-
bolic acid-base status of body fluids, [SID] and [Arorl· Both are independent vari-
ables, and both affect metabolic acid-base status via the buffer base intermediary.
I The Concept of Base Excess

The usual definition of base excess is the concentration of strong acid or base re-
quired to return the pH of an in vitro specimen of whole blood to 7.4 while main-
taining PC0 2 at 40 mmHg by equilibration at 37 °C. However, there are two further
important pieces of information. First, the base excess concept can be applied to
any body fluid, not just whole blood. Second, the base excess of any fluid can also
be defined in physical chemical terms as the offset from normal of [buffer base]
(and thus of [SID]). In other words, base excess in any fluid compartment can be
calculated as (AA- + A[HCO:J]).
Plasma Base Excess

Plasma base excess is easy to derive. To calculate A- in plasma all that is required
is the pH and a value for the buffering capacity of bicarbonate-free plasma (nor-
mally 7.7 Slykes - mainly due to the variable net negative charge on albumin).
Thus A-=7.7X(pH -7.4) mmol/1. A[HC03] is calculated even more simply as
([HCO:J]-24.4) mmol/1. Plasma base excess is thus 7.7x(pH -7.4) + ([HC03] - 24.4)
mmol/1.
Whole Blood Base Excess

For whole blood, the base excess calculation becomes more complicated, since
whole blood consists of a plasma compartment and a red cell compartment. In
erythrocytes hemoglobin is the predominant source of A- rather than albumin, and
has approximately seven times its buffering capacity. Until 1977, all equations for
whole blood base excess were empirical descriptions of an alignment nomogram
which had been constructed from in vitro experiments on the blood of Danish
volunteers. In 1977 Siggaard-Andersen published the Van Slyke equation [62]. This
equation enables whole blood base excess to be calculated from pH, PaCOz, and
[hemoglobin] using linking equations for plasma and intra-erythrocytic buffering
and Gibbs-Donnan ionic distributions.
The equation for whole blood base excess can be written:
base excess= {[HC03]-24.4+(2.3 x [Hb]+ 7.7) x (pH -7.4)} x (1-0.023 x [Hb])
(Eq. 3)
where [HC03] and pH are plasma values and [Hb] is the blood hemoglobin con-
centration expressed in mmol/1. Siggaard-Andersen reported close agreement be-
tween this equation and its predecessor - the experimentally derived base excess
nomogram. Our group re-evaluated the in vitro accuracy of the Van Slyke equation
and confirmed that it quantifies metabolic acid-base change with acceptable de-
grees of precision and minimal bias at normal and low [Hb] across a wide range of
PC0 2 [63].
Extracellular Base Excess

In 1963, Schwarz and Relman pointed out that an isolated in vivo change in PaC0 2
shifts whole blood base excess in the opposite direction, although no overall extra-
cellular metabolic acid-base alteration has occurred [64]. This phenomenon is due
to ionic shifts between intravascular and interstitial compartments. For example,
when PaC0 2 rises, HC03 is generated maximally within erythrocytes, where buffer-
ing capacity is greatest due to hemoglobin. It diffuses down a concentration gradi-
ent to the plasma (as occurs in vitro) but then continues on into the interstitial
fluid. Cl- moves in the opposite direction, with final ionic distributions determined
according to Gibbs-Donnan equilibria and the laws of chemical equilibrium and
electroneutrality. Thus in vivo the rise in plasma [HC03] during hypercapnia will
not be as high as in vitro. Or put in physical chemical terms, when PC0 2 rises in
an in vitro specimen of whole blood, erythrocytic [SID] decreases, plasma [SID] in-
creases but whole blood [SID] and thus base excess do not change. When PaC0 2
rises in vivo, whole blood [SID] and thus whole blood base excess decrease, while
interstitial [SID] and base excess increase. Extracellular [SID] and base excess are
unaffected.
Thus in the in vivo situation, the only completely C0 2 -independent end-point
(and pure measure of metabolic acid-base status) is not plasma, whole blood or in-
terstitial base excess but extracellular base excess. How can this be derived? As it
turns out, if base excess is calculated from the measured plasma pH and PC0 2 but
at [hemoglobin] =50 g/1 (the approximate mean extracellular [hemoglobin]), total
extracellular buffering is emulated successfully [65]. Although base excess calcu-
lated in this way has been termed 'extracellular base excess', it is more commonly
known as 'standard base excess'.
Interstitial Base Excess

Healthy interstitial fluid belongs in a separate category, since it has negligible
[ATOrl (just small concentrations of inorganic phosphate and a very small amount
of albumin) [59]. The [A-] component of normal interstitial [buffer base] is thus
close to zero (Fig. 1). Therefore, interstitial [SID] is numerically identical to inter-
stitial [HC03] (or nearly so), and interstitial [HC03] represents almost the entire
interstitial buffer base concentration (Fig. 1). Interstitial base excess then becomes
the offset in interstitial [HC03]. Importantly, primary changes in PC0 2 have only a
small effect on interstitial [HC03]. For example, at a tissue PC0 2 of 160 mmHg, the
expected increase in interstitial [HC03] above normal amounts to only 1.26 mmol/1
(Fig. 2). By contrast, the change in plasma [HC03] in response to such a primary
PC0 2 elevation would exceed 6 mmol/1.
4
::::
0
E 2
5
<I>
g' 0 -t----=--==-;:;_-,.------.------,
~ -2
~ 80 120 160
8:z:
I
-4
-6
PC01 (mmHg)
Fig. 2. Relationship between interstitial PC0 2 and interstitial [HC03]. A normal tissue PC02 of 50 mmHg
is assumed
Knowing all this, How can we best Determine Tissue Base Excess?
Tissues consist of three main compartments - intracellular, interstitial, and intra-

vascular. A probe inserted atraumatically into any tissue will be exposed primarily
to its interstitial fluid. Attempting to measure tissue acid-base performance as a
homogeneous entity incorporating all three spaces introduces considerable com-
plexity [58]. A simpler approach is to define tissue base excess as the non-C0 2 off-
set in interstitial [HC03]. Normal interstitial [HC03] is reported as around 30-31
mmol/ [59, 66]. This value needs confirmation in tissues of interest.
With a perfectly inserted interstitial probe (zero insertion trauma), primary C0 2
effects on interstitial [HC03] are likely to be small enough to be ignored. However,
depending on the technique and the vascularity of the tissue there may be variable
contamination of the fluid around the probe by components of the other two
spaces, as a result of insertion trauma. Hence, the interstitial fluid being monitored
by a tissue probe may contain small amounts of albumin, hemoglobin and intracel-
lular contents, sources of AmT which introduce A- into the interstitial buffer base.
Under these circumstances, interstitial [HC03] may begin to alter more signifi-
cantly with primary alterations in PC0 2 • This is one of two main difficulties. The
other is that confounding interstitial AmT may also appear due to tissue damage
from surgical intervention or patient trauma, and in septic capillary leak .
Conclusion - Research Steps Required to Determine Tissue Base Excess
Tissue base excess determinations may already be possible in solid organs using
multi-parameter probes such as the Paratrend 7 (Diametrix Medical, UK). To pur-
sue this avenue further, we need to examine tissues of interest to determine the
normal [HC03] and whether this varies significantly with primary alterations in
PC0 2 • Our group has generated some preliminary data (unpublished) using the
Paratrend 7 sensor in rat subcutaneous tissue and muscle. So far, we have found
tissue [HC03] in rat subcutaneous tissue to be unexpectedly high at approximately
35 mmol/1, whereas in muscle it is close to the reported normal interstitial [HC03]
of around 31 mmol/1. Subcutaneous [HC03] appears to be quite stable over a wide
range of PC0 2 • Data from muscle show a small direct correlation between PC0 2
and [HC03], indicating the presence of A-, presumably due to insertion trauma.
With this kind of information, base excess algorithms can be constructed for in-
dividual tissues using the very simple formula:
Tissue base excess= Actual tissue [HCO~] -expected tissue [HCO~] . (Eq. 4)
Finally, all algorithms will need to be tested against a gold standard such as tissue
[lactate] [21].
References
1. Siggaard-Andersen 0, Fogh-Andersen N, G0thgen IH, Larsen VH (1995) Oxygen status of
arterial and mixed venous blood. Crit Care Med 23:1284-1293
3. Brealey D, Brand M, Hargreaves I, at al (2002) Association between mitochondrial dysfunc-
4. Tugtekin IF, Radermacher P, Theisen M, at al (2001) Increased ileal-mucosal PC02 gap is

associated with impaired villus microcirculation in endotoxic pigs. Intensive Care Med
27:757-766
5. Fiddian-Green RG (1992) Tonometry: theory and applications. Intensive Care World 9:60-
65
6. Adar R, Franklin A, Spark RF, Rosoff CB, Salzman EW (1976) Effect of dehydration and
cardiac tamponade on superior mesenteric artery flow: role of vasoactive substances. Sur-
gery 79:534-543
7. McNeill JR, Stark RD, Greenway CV (1970) Intestinal vasoconstriction after hemorrhage:
roles of vasopressin and angiotensin. Am J Physiol219:1342-1347
8. Ganong W (1997) Circulation through special regions. In: Ganong W, ed. Review of Medi-
cal Physiology. Appleton & Lange, Stamford, pp 567-585
9. Lundgren 0, Haglund U (1978) The pathophysiology of the intestinal countercurrent ex-
changer. Life Sci 23:1411-1422
10. Kiel JW, Riedel GL, Shepherd AP (1989) Effects of hemodilution on gastric and intestinal
oxygenation. Am J Physiol256:H171-H178
11. Dantzker DR (1993) The gastrointestinal tract. The canary of the body? JAMA 270:1247-
1248
12. Bif£1 and Moore EE (1996) Splanchnic ischemia/reperfusion and multiple organ failure. Br
J Anesth 77:59-70
13. Vallet B, Lebuffe G (1999) The role of the gut in multiple organ failure. In: Vincent J-L
(ed) Yearbook of Intensive Care and Emergency Medicine. Springer, Berlin Heidelberg,
pp 539-546
14. Well MH, Nakagawa Y, Tang W, et al (1999) Sublingual capnometry: A new noninvasive
measurement for diagnosis and quantitation of severity of circulatory shock. Crit Care
Med 27:1225-1229
15. Sato Y, Well MH, Tang W, et al (1997) Esophageal PC0 2 as a monitor of perfusion failure
during hemorrhagic shock. J Appl Physiol 82:558-562
16. Soller BR, Cingo N, Puyana JC, et al (2001) Simultaneous measurement of hepatic tissue
pH, venous oxygen saturation and hemoglobin by near infrared spectroscopy. Shock
15:106-111
17. Puyana JC, Soller BR, Parikh B, Heard SO (2000) Directly measured tissue pH is an earlier
indicator of splanchnic acidosis than tonometric parameters during hemorrhagic shock in
swine. Crit Care Med 28:2557-2562
18. Venkatesh B, Morgan TJ, Lipman J (2000) Subcutaneous oxygen tensions provide similar
information to ileal luminal 0 2 and C0 2 tensions in an animal model of hemorrhagic
shock. Intensive Care Med 26:592-600
i9. Venkatesh B, Meacher R, Muller M, Morgan TJ, Fraser J (2001) Monitoring tissue oxygena-
tion during resuscitation of major burns. J Trauma 50:485-494
20. Venkatesh B, Morgan TJ (2001) Monitoring tissue gas tensions in critical illness. In: Vin-
cent J-L, editor. Yearbook of Intensive Care and Emergency Medicine. Berlin Heidelberg:
Springer, pp 251-265
21. Venkatesh B, Morgan TJ (2002) Tissue lactate concentrations in critical illness. In: Vincent
J-L (ed) Yearbook of Intensive Care and Emergency Medicine. Springer, Heidelberg,
pp 587-599
22. Mathura KR, Alic L, Ince C (2001) Initial clinical experience with OPS imaging for obser-
vation of the human microcirculation. In: Vincent J-L (ed) Yearbook of Intensive Care and
Emergency Medicine. Springer, Heidelber, pp 233-244
23. Karzai W, Gunnicker M, Scharbert G, Vorgrimler-Karzai UM, Priebe HJ (1996) Effects of
dobutamine on oxygen consumption and gastric mucosal blood flow during cardiopulmo-
nary bypass in humans. Br J Anaesth 77:603-606
24. Uusaro A, Ruokonen E, Takala J (1995) Estimation of splanchnic blood flow by the Pick
principle in man and problems in the use of indocyanine green. Cardiovasc Res 30:106-
112
25. Simonson SG, Piantadosi CA (1996) Near-infrared spectroscopy. Crit Care Clin 12:1019-
1029
26. Beilman GJ, Cerra FB (1996) The future. Monitoring cellular energetics. Crit Care Clin
12:1031-1042
27. Uhlig T, Peste! G, Reinhart K (2002) Gastric mucosal tonometry in daily ICU practice. In:
Vincent J-L (ed) Yearbook of Intensive Care and Emergency Medicine. Springer, Heidel-
berg, pp 632-637
28. Kolkman JJ, Otte JA, Groeneveld ABJ (2000) Gastrointestinal luminal PC0 2 tonometry: an
update on physiology, methodology and clinical applications. Br J Anaesth 84:74-86
29. Lebuffe G, Robin E, Vallet B (2001) Gastric tonometry. Intensive Care Med 27:317-319
30. Fiddian-Green RG (1995) Gastric intramucosal pH, tissue oxygenation and acid-base bal-
ance. Br J Anaesth 74:591-606
31. Bennet-Guerrero E, Panah MH, Bodian CA, et al (2000) Automated detection of gastric lu-
minal partial pressure of carbon dioxide during cardiovascular surgery using the Tonocap.
32. Fiddian-Green RG, McGough E, Pittenger G, Rothman E (1983) Predictive value of intra-
mural pH and other risk factors for massive bleeding from stress ulceration. Gastroenterol-
ogy 85:613-620
33. Bouaachour G, Guiraud MP, Gouello JP, Roy PM, Alquier P (1996) Gastric intramucosal
pH: an indicator of weaning outcome from mechanical ventilation in COPD patients. Eur
Respir J 9:1868-1873
34. Roumen RM, Vreudge JPC, Goris JA (1994) Gastric tonometry in multiple trauma patients.
J Trauma 36:313-316
35. Downing A, Cottam S, Beard C (1993) Gastric mucosal pH predicts major morbidity fol-
lowing orthotopic liver transplantation. Transplantation Proc 25:1804
36. Mythen MG, Webb AR (1994) Intra-operative gut mucosal hypoperfusion is associated
with increased pot-operative complications and cost. Intensive Care Med 20:99-104
37. Marik P (1993) Gastric intramucosal pH: A better predictor of multiple organ dysfunction
syndrome and death than oxygen-derived variable in patients with sepsis. Chest 104:225-
229
38. Maynard N, Bihari D, Beale R, et al (1993) Assessment of splanchnic oxygenation by gas-
tric tonometry in patients with acute circulatory failure. JAMA 270:1203-1210
39. Friedman G, Berlot G, Kahn RJ, Vincent JL (1995) Combined measurements of blood lac-
tate concentrations and gastric intramucosal pH in patients with severe sepsis. Crit Care
Med 23:1184-1193
40. Gutierrez G, Palizas F, Doglio G, et al (1992) Gastric intramucosal pH as a therapeutic in-
dex of tissue oxygenation in critically ill patients. Lancet 339:195-199
41. Ivatury RR, Simon RJ, Havriliak D, Garcia G, Greenbarg J, Stahl WM (1995) Gastric muco-
sal pH and oxygen delivery and oxygen consumption indices in the assessment of the ade-
quacy of resuscitation after trauma: A prospective randomised study. J Trauma 39:128-136
42. Lebuffe G, Decoene C, Crepin F, Pol A, Vallet B (1999) Regional capnometry with air-auto-
mated tonometry detects circulatory failure earlier than conventional hemodynamics after
cardiac surgery. Anesth Analg 89:1084-1090
43. Pargger H, Hampl KF, Christen P, Staender S, Scheidegger D (1998) Gastric intramucosal
pH-guided therapy in patients after elective repair of infrarenal abdominal aneurysms: is it
beneficial? Intensive Care Med 24:769-776
44. Gomersall CD, Joynt GM, Freebairn RC, et al (2000) Resuscitation of critically ill patients
based on the results of gastric tonometry: a prospective, randomized, controlled trial. Crit
Care Med 28:607-614
45. Benjamin E, Oropello JM (1996) Does gastric tonometry work? No. Crit Care Clin 12:587-
601
46. Morgan TJ, Venkatesh B, Endre ZH (1999) Accuracy of intramucosal pH calculated from
arterial bicarbonate and the Henderson-Hasselbalch equation: assessment using simulated
ischemia. Crit Care Med 27:2495-2499
47. Morgan TJ, Venkatesh B, Bawa GPS, Purdie DM (2001) Transient mesenteric ischemic epi-
sodes tracked by continuous jejunal PC0 2 monitoring during liquid feeding. Intensive Care
Med 27:1408-1411
48. Venkatesh B, Morgan TJ (2000) Blood in the gastrointestinal tract delays and blunts the
PC02 response to transient mucosal ischemia. Intensive Care Med 26:1108-1115
49. Noc M, Well MH, SunS, Gazmuri RJ, Tang W, Pakula JL (1993) Comparison of gastric lu-
minal and gastric wall PC02 during hemorrhagic shock. Circ Shock 40:194-199
50. Vallet B, Tavernier B, Lund N (2000) Assessment of tissue oxygenation in the critically ill.
Eur J Anaesthesiol17:221-229
51. Schlichtig R, Mehta N, Gayoski TJP (1996) Tissue-arterial PC0 2 difference is a better mar-
ker of ischemia than intramural pH (pHi) or arterial pH-pHi difference. J Crit Care 11:51-
56
52. Heino A, Hartikainen J, Merasto ME, et al (1998) Systemic and regional PC0 2 gradients as
markers of intestinal ischemia. Intensive Care Med 24:599-604
53. Rozenfeld RA, Dishart MK, T0nnessen TI, Schlichtig R (1996) Methods for detecting local
intestinal ischemic anaerobic metabolic acidosis by PC0 2 • J Appl Physiol 81:1834-1842
54. Miller PR, Kincaid EH, Meredith JW, Chang MC (1998) Threshold values of intramucosal
pH and mucosal-arterial C02 gap during shock resuscitation. J Trauma 45:868-872
55. Vallet B, Teboul JL, Cain S, Curtis S (2000) Venoarterial C02 difference during regional
ischemic or hypoxic hypoxia. J Appl Physiol 89:1317-1321
56. Neviere R, Chagnon JL, Teboul JL, Vallet B, Wattel F (2002) Small intestine intramucosal
PC0 2 and microvascular blood flow during hypoxic and ischemic hypoxia. Crit Care Med
30:379-384
57. Astrup P, Jorgensen K, Siggaard-Andersen 0, et al (1960) Acid-base metabolism: New
approach. Lancet 1:1035-1039
58. Raza 0, Schlichtig R (2000) Metabolic component of intestinal PC0 2 during dysoxia. J Appl
Physiol 89:2422-2429
59. Stewart PA (1981) How to understand acid-base. In: Stewart PA (ed) A Quantitative Acid-
Base Primer for Biology and Medicine. Elsevier, New York, pp 1-286
60. Stewart PA (1983) Modern quantitative acid-base chemistry. Can J Physiol Pharmacal 61:
1444-1461
61. Rossing TH, Maffeo N, Fencl V (1986) Acid-base effects of altering plasma protein concen-
tration in human blood in vitro. J Appl Physiol 61:2260-2265
62. Siggaard-Andersen 0 (1977) The Van Slyke equation. Scand J Clin Lab Invest Suppl 37:15-
20
63. Morgan TJ, Clark C, Endre ZH (2000) The accuracy of base excess - an in vitro evaluation
of the Van Slyke equation. Crit Care Med 28:2932-2936
64. Schwartz WB, Reiman AS (1963) A critique of the parameters used in the evaluation of
acid-base disorders. N Engl J Med 268:1382-1388
65. Schlichtig R, Grogono AW, Severinghaus JW (1988) Human PaC02 and standard base ex-
cess compensation for acid-base imbalance. Crit Care Med 26:1173-1179
66. Worthley LIG (1994) Body fluid spaces. In: Worthley LIG (ed) Synopsis of Intensive Care
Medicine. Churchill Livingstone, Edinburgh, pp 421-427
Clinical Use of Venoarterial PC0 2 Difference
in Septic Shock
J. L. Teboul and X. Monnet
I Introduction
The venoarterial carbon dioxide (C0 2 ) pressure (PC0 2 ) gradient (APC0 2 ) is the
difference between PC0 2 in the mixed venous blood (PvC0 2 ) and the PC0 2 in the
arterial blood (PaC0 2 ). PaC0 2 and PvC0 2 represent the partial pressures of the dis-
solved C0 2 in arterial and mixed venous blood, respectively, which represent only a
fraction of arterial C02 content (CaC0 2 ) and mixed venous C0 2 content (CvC0 2 ),
respectively.
I C02 Carriage in the Blood

C0 2 is carried in the blood in 3 forms: dissolved; as bicarbonate; and in combina-
tion with proteins as carbamino compounds.
I Because C0 2 is 20 times more soluble than oxygen (0 2 ), its dissolved form plays
a more important role in the normal carriage in the blood.
I Bicarbonate is formed in the blood according to the following sequence:
C0 2 + H2 0 {'} H2 C03 {'} HC03 + H+
where H2 0 is water, H2 C03 is carbonic acid, HC03 is bicarbonate ion and H+ is
hydrogen ion. The first reaction is very slow in the plasma, but fast in the red
blood cell (RBC}, because of the presence of carbonic anhydrase in this cell. The
second reaction occurs rapidly within the red cell. When the concentrations of
HC03 and H+ in the cell rise, HC03 diffuses out of the RBCs into the plasma
but H+ cannot diffuse easily because the cell membrane is relatively imperme-
able to cations. Some of the protons liberated are bound to hemoglobin (Hb ):
H+ +Hb0 2 {'} H-Hb+0 2
This reaction occurs because reduced Hb is a better acceptor of H+ than the oxy-
genated Hb. In the peripheral blood, the loading of C0 2 is facilitated by the
presence of reduced Hb (Haldane effect). Thus, unloading 0 2 in peripheral capil-
laries facilitates the loading of C0 2 while oxygenation enhances the unloading of
C0 2 in the lung.
I Carbamino compounds are formed by the combination of C0 2 with terminal
amine groups of blood proteins, especially the globin of Hb. Reduced Hb can
load more C0 2 as carbamino compounds than Hb0 2 •
The greater part of the C0 2 content (CC0 2 ) is in the form of bicarbonate.
Clinical Use of Venoarterial PC0 2 Difference in Septic Shock 575
The shape of the relation between the PC0 2 and the total CC02 is curvilinear
although more linear than the 0 2 dissociation curve. Hematocrit, 0 2 saturation,
temperature and pH influence the PC02 /CC0 2 relationship.
I The Fick Equation
According to the Fick equation applied to cardiac output, the C02 excretion
(equivalent to C0 2 production [VC0 2 ] in a steady state) equals the product of car-
diac output by the difference between C02 content in mixed venous blood (CvC0 2 )
and arterial blood (CaC02 ):
VC02 =cardiac outputx (CvC0 2 - CaC0 2 )
The normal relationship between pressure and content of C02 is almost linear over
the usual physiological range of the C0 2 contents [1, 2]. Therefore, by rearranging
the Fick equation and substituting PC0 2 for CC0 2 , a modified Fick equation can
be obtained: VC0 2 =cardiac outputxkxAPC0 2 • Therefore, APC0 2 =kxVC0 2 /cardi-
ac output, where k is assumed to be constant. Accordingly, APC02 would be linear-
ly related to C0 2 production and negatively related to cardiac output.
1 Influence of C02 Production on APC02
C02 Production from Aerobic Pathway

The aerobic C0 2 generation is a normal terminal product of cellular oxidative me-
tabolism. Under normal aerobic conditions, CC02 in the efferent venous blood
must be higher than in the arterial blood. Under these conditions, the total C02
production (VC02 ) is directly proportional to total 0 2 consumption (V0 2 ):
VC02 = RxV0 2 where R is the respiratory quotient. R varies from 0.7 to 1 accord-
ing to the predominant energy source: when lipids are the major fuel sources, R is
close to 0.7 whereas under conditions of high carbohydrate intake R approaches 1.
Therefore, the aerobic C0 2 production should rise either with increased aerobic
metabolism or when a balanced feeding regimen is replaced by a high carbohydrate
intake regimen, even for a constant V02 •
Under these conditions of increased VC02, APC02 should increase except if car-
diac output can increase to the same extent.
C02 Production from Anaerobic Pathway

Under anaerobic conditions, H+ ions are generated by two mechanisms [3]:
1) excessive production of lactic acid related to accelerated anaerobic glycolysis,
since pyruvate can no longer be cleared by the Krebs cycle
2) hydrolysis of adenosine triphosphate (ATP) and of adenosine diphosphate
(ADP).
The protons generated will then be buffered by HC03 ions into the cell so that C02
will be generated.
576 J.l. Teboul and X. Monnet
Anaerobic decarboxylation of a ketoglutarate or oxaloacetate is a minor source

of anaerobic C0 2 production [3].
The production of C0 2 from anaerobic pathway is difficult to detect. Indeed, the
efferent venous blood flow can be high enough to wash out the C0 2 produced from
the tissues. Moreover, because of the marked fall in C0 2 production from the anae-
robic pathway that should occur under these circumstances, the total production of
C0 2 can markedly decrease [4]. Therefore, PC0 2 could be not augmented in the
draining vein and anaerobic C0 2 production not detected from the calculation of
APC0 2 • However, if afferent and efferent blood flows are artificially stopped, con-
tinued anaerobic C0 2 production would then be detected by measuring an in-
creased PC0 2 either in the organ itself or in the stagnant venous blood flow, de-
spite the fall in C0 2 production from the aerobic pathway [5].
I Influence of Cardiac Output on APC02
According to the modified Fick equation, APC0 2 is inversely correlated to cardiac

output. Indeed, under conditions of stable V0 2and VC0 2, APC02was observed to
increase along with the decrease in cardiac output [4, 6, 7]. Such an increase in
APC0 2 following cardiac output reduction is explained by the C0 2 stagnation phe-
nomenon. Because of slowing transit time, a greater than normal addition of C0 2
per unit of blood crossing the efferent microvessels tends to generate hypercapnia
in the venous blood. As long as pulmonary ventilation is adequate, a gradient will
develop between PvC0 2 and PaC0 2 • However, under spontaneous breathing condi-
tions, hyperventilation, stimulated by the reduced blood flow, may decrease PaC0 2
and thus may prevent the C0 2 stagnation-associated increase in PvC0 2 [8]. This
finding underlines the usefulness of calculating APC02 rather than simply measur-
ing PvC0 2, especially in the case of spontaneous breathing [9].
During hypoxic conditions in which V0 2 decreases along with D0 2 , relationships
between changes in cardiac output and APC0 2 are complex, as described below.
Tissue Hypoxia with Decreased Blood Flow

In the case of a decrease in systemic blood flow, aerobic metabolism decreases
while anaerobic metabolism increases. As long as the decrease in C02 production
related to the aerobic pathway is much greater than the increase in C0 2 production
related to the anaerobic pathway, the resulting C0 2 production will decrease. The
decrease in vco2 concomitant to the decrease in vo2 during the oxygen supply de-
pendent phase has been demonstrated in experimental studies in which blood flow
was progressively reduced [4, 7, 10]. As both V0 2 and venous efferent blood flow
decrease, APC0 2 should not be significantly altered unless very low values of blood
flow were achieved during the supply dependent period. Experimental studies [4, 6,
7] in which blood flow was reduced below the critical limit of supply dependency
showed that APC0 2 could increase significantly when very low values of cardiac
output were achieved. This fact can be explained by the two following reasons.
1) Because the relation between cardiac output and ACC0 2 is not linear but curvi-
linear (Fick equation), a dramatic increase in ACC0 2 must be observed for a de-
crease in cardiac output in its lowest range. In fact, even if this mathematical
phenomenon may be strong under conditions of maintained VC02 , it should be
Clinical Use of Venoarterial PC0 2 Difference in Septic Shock 577
Increase in VC02
8u
"'
vco2 isopleths
Cardiac output
Fig. 1. (CvOrCa0 2)/cardiac output relationships. According to the Fick equation, the (Cv0 2- Ca0Ncardiac
output relationship is curvilinear. Therefore, for a constant VC0 2 , changes in cardiac output result in large
changes in C0 2 gradient in the low values of cardiac output, whereas changes in cardiac output will not
result in significant changes in C0 2 gradient in the high values of cardiac output. These relationships are
more complex when changes in cardiac output are accompanied by changes in VC0 2 and thereby by a
transfer from one vco2 isopleth to another one (on the figure, vco2 increases from the left to the right)
attenuated in hypoxic conditions since the decrease in VC0 2 rightward shifts the
VC0 2 isopleth which describes the ~CC0 2 /cardiac output relationship (Fig. 1).
2) The striking ~PC0 2 at very low cardiac output widening may be explained
further by the curvilinearity of the relationship between CvC0 2 and PvC0 2 • In-
deed, this relationship is no longer linear in the highest range of CC0 2 so that
~PC0 2 changes are greater than ~PC0 2 changes in such extreme conditions [2] .
Furthermore, the disparities between CC0 2 and PC0 2 at high levels of CC0 2 are
exaggerated by a high 0 2 saturation and by the reduction in pH [2] which con-
stantly follows the increase in PvC0 2 and may be of further importance if meta-
bolic acidosis coexists. Consequently, in the case of low flow states, the increase
in PvC0 2 resulting from C0 2 stagnation is of a greater extent than the increase
in CvC0 2 •
Tissue Hypoxia with Maintained Blood Flow

We earlier pointed out that under conditions of tissue hypoxia, the increase in
anaerobic C0 2 production can be overridden by the decrease in aerobic C0 2 pro-
duction [4, 7, 10] such that ~PC0 2 would not increase under conditions of normal
or high blood flow, as assessed by several experimental studies. Indeed, the lower
quantities of C0 2 produced should be easily removed by a normal or elevated ve-
nous blood flow so that CvC0 2 and PvC0 2 should not increase. This point was
nicely demonstrated by Vallet et al. [11] using a model of isolated dog hind limb.
These authors showed that ~PC0 2 significantly increased when limb hypoxia was
created by ischemia (low blood flow) while it remained unchanged when hypoxia
was related to hypoxemia (maintained blood flow). Similar results were observed in
an in vivo study in pigs [12]. These studies underline that the absence of increased
578 J. L. Teboul and X. Monnet
APC0 2 does not preclude the presence of tissue dysoxia and that a decreased blood
flow is a major determinant in the increased APC0 2 •
Clinical Studies
Clinical studies in septic shock patients have also suggested that reduced blood
flow plays the key role in the widening of C0 2 gradient [13, 14]. Mecher et al. [13]
found that a subgroup of septic shock patients with APC0 2 > 6 mmHg
(9 ± 1 mmHg) had a mean cardiac output significantly lower than a subgroup of
those with APC0 2 ~ 6 mmHg. Interestingly, the two subgroups did not differ in
terms of blood lactate (6 ± 1 vs 5. 7 ± 1.1 mmol/1) and mean blood pressure (59± 3
and 63±4 mmHg). In others words, many patients in this study (18/37) had nor-
mal APC0 2 despite tissue hypoxia, probably because their high blood flow had eas-
ily removed the C0 2 produced at the periphery. In the subgroup of patients with
high APC0 2 , fluid loading had resulted in a decrease in APC0 2 along with an in-
crease in cardiac output [13]. The authors reasonably concluded that in patients
with septic shock, an increased APC0 2 is associated with a reduced systemic flow.
Clinical Use of APC0 2 in Sepsis
Interpretation of APC0 2 in Sepsis

Sepsis results in a complex form of circulatory shock. In most patients, in whom
early aggressive resuscitation has resulted in a hyperdynamic circulatory state, tis-
sue dysoxia results from the inability of tissues to extract enough 0 2 from the
blood [ 15]. Distributive abnormalities of macrocirculatory and microcirculatory
blood flow mainly explain sepsis-related 0 2 extraction impairment [16]. As a con-
sequence, the most frequent hemodynamic profile encountered in human septic
shock is characterized by high cardiac output and vasodilatation [17, 18]. However,
in some patients, relatively low values of cardiac output have been reported [13,
14], either because of insufficient fluid resuscitation [13] and/or because of the
presence of a patent sepsis-induced myocardial depression [15]. As we will discuss
below, APC0 2 might take a place in the cardiovascular monitoring of septic shock,
by identifying patients in whom cardiac output could be further raised.
APC0 2 can be calculated after simultaneous sampling of arterial blood (PaC0 2 )
and of mixed venous blood from the distal end of a pulmonary artery catheter
(PvC0 2 ). Under physiological conditions, APC0 2 ranges from 2 to 5 mmHg [1].
As developed above, although APC0 2 cannot serve as a reliable marker of tissue
hypoxia, it could be considered as a marker of adequacy of venous blood flow (i.e.,
cardiac output) to remove the total C0 2 produced by the peripheral tissues. The
clinical implications of this concept can be summarized as follows:
1) An increased APC0 2 may suggest that cardiac output is not high enough with
respect to the global metabolic conditions
2) under suspected hypoxic conditions (increased blood lactates), the existence of a
high APC0 2 could be one of the arguments that would incite the clinician to in-
crease cardiac output in the attempt to reduce tissue hypoxia
3) under aerobic conditions, observation of a high APC0 2 in a septic patient would
mean that blood flow is not high enough, even if the value of cardiac output is
measured in the normal range. This condition can be associated with a sepsis-
Clinical Use of Venoarterial PC02 Difference in Septic Shock 579
induced increased 0 2 demand and hence increased aerobic C0 2 production.

However, whether further increasing cardiac output can prevent short-term sub-
sequent risks of onset of tissue hypoxia actually remains to be proved.
In a patient with a high initial value of APC02 , following the course of APC0 2
can also be helpful to assess the effects on the global tissue metabolism of a
therapeutic intervention aimed at increasing cardiac output. Under conditions of
0 2 supply dependence, increase in cardiac output must be accompanied by in-
creases in V02 and hence in VC02 so that APC0 2 is expected to decrease by a
lesser extent than in case of 0 2 supply independence. Consequently, relatively
unchanged APC0 2 with therapy would not mean that the therapy has failed. In
this case, the therapeutic agent would be rather maintained and its dose even in-
creased until obtaining a frank decrease in APC0 2 that would indicate that the
critical level of D0 2 has been actually overpassed. Otherwise, APC02 can also be
helpful to choose the appropriate dose of a therapeutic agent known to have
thermogenic effects. For instance, catecholamines, by their p stimulation, may
exert calorigenic effects and are, therefore, able to increase both vo2 and vco2
[19]. Accordingly, APC0 2 - as an index of the VC0 2 /cardiac output ratio - was
shown to detect changes in 0 2 demand accompanying dobutamine-induced
changes in cardiac output [20]. In this regard, APC0 2 together with mixed ve-
nous 0 2 saturation (Sv0 2 ) [21] may help to titrate drug therapy.
4) A normal APC0 2 , suggests that cardiac output is high enough to wash out the
C0 2 produced from the peripheral tissues. However, it remains to be established
if cardiac output should be further increased in front of a normal APC0 2 under
hypoxic conditions. In this way, it must be remembered that increasing cardiac
output to supranormal values was not demonstrated to be beneficial in patients
with septic shock [22, 23].
Limitations in the Interpretation of APC02
When blood flow is high, a frequent condition in sepsis [15], large changes in car-
diac output will not result in significant changes in APC0 2 , because of the curvili-
nearity of the relationship between C0 2 gradients and cardiac output (Fig. 1). This
point was illustrated in a series of patients with high systemic blood flow but with-
out evidence of tissue hypoxia and in whom significant changes in cardiac output
were associated with unchanged APC0 2 values [24]. It must be kept in mind that
the APCO:Jcardiac output relationship will also depend on the level of VC0 2 , so
that a family of hyperbolic APC0 2 /cardiac output relationship curves for various
levels of VC0 2 (VC0 2 isopleths) can be drawn (Fig. 1) [25]. Accordingly, interpreta-
tion of APC0 2 changes (or of absence of changes) must be particularly cautious
under conditions of very high systemic blood flow.
It must be kept in mind that a normal APC0 2 does not preclude inadequacy of
blood flow with metabolic condition at a regional level, for instance in the splanch-
nic area, as demonstrated in an experimental study [26]. In septic shock patients
with high systemic blood flow (and presumably low APC0 2 ) inadequate splanchnic
blood flow [27] or increased difference between gastric mucosal and arterial PC0 2
[18] were reported. This point is of importance because gut mucosal ischemia
could play a pivotal role in the pathogenesis of multiple organ failure (MOF) [28].
There are numerous other potential causes of errors in PC02 measurements: in-
correct sample container, inadequate sample volume relative to anticoagulant vol-
580 J. L. Teboul and X. Monnet
ume, contaminated sample by air or venous blood or catheter fluid, improper

transport conditions, length of the delay between acquisition and analysis, etc.
Although all these potential errors may be prevented, there is still a proper instru-
ment imprecision of ± 1 mmHg, even in a laboratory with intense quality control
and using the more recent models of blood gas analyzers [29]. This range of error
is relatively low as compared to the normal range of APC0 2 • This point further em-
phasizes the fact that clinicians must be very careful in the interpretation of low
values of APC0 2 and of small changes in APC0 2 •
Combined Analysis of APC0 2 and OrDerived Parameters
Indirect evidence of anaerobic C0 2 production under conditions of tissue hypoxia

has been brought by studies reporting, along with a decrease in D0 2 , decreases in
V0 2 and VC0 2 (calculated from expired gas analysis) but with increased VC0 2 /V0 2
ratio [7, 10]. Under these conditions, an increased VC0 2 /V0 2 ratio means that
VC0 2 is less reduced than V0 2 when tissue hypoxia occurs. In others words, this
probably denotes the presence of anaerobic C0 2 generation in hypoxic tissues.
Therefore, the increase in the respiratory quotient was proposed to detect global
tissue hypoxia [10 ]. This could be the useful tool that one needs to detect global
tissue hypoxia. Since V0 2 is equal to the product of cardiac output and arteriove-
nous difference in 0 2 content (CA-V 0 2 ) and VC0 2 is proportional to the product of
cardiac output and APC0 2 , the APC0 2 /CA-v0 2 ratio could be used to detect global
anaerobic metabolism in patients with a pulmonary artery catheter in place. In a
series of 89 critically ill patients (148 measurements), we recently found a close
correlation between blood lactate level and APC0 2 /CA-v 0 2 ratio, while no correla-
tion was found between blood lactate level and APC0 2 alone and between blood
lactate level and CA_v0 2 alone [30]. The calculation of the APC0 2 /CA-v 0 2 ratio
can be helpful to assess the degree of anaerobic metabolism. The finding of this
study suggested that the APC0 2/CA-v 0 2 ratio - as a surrogate of the respiratory
quotient - could provide more relevant information on the occurrence of anaerobic
metabolism than the other 0 2 derived and C0 2 derived parameters obtained inva-
sively. Its simple calculation would be useful for clinicians while interpreting pul-
monary artery catheter data. Whether clinicians could more rapidly adapt therapy
on the basis of APC0 2 /CA-v 0 2 ratio than by monitoring blood lactate levels re-
quires further studies.
I Conclusion
APC0 2 can be considered as a marker of adequacy of cardiac output to global me-

tabolic condition. In patients with sepsis or septic shock monitored by a pulmo-
nary artery catheter, an increased APC0 2 could be an argument for raising cardiac
output with a view to preventing or reducing global hypoxia. However, it must be
kept in mind that systemic blood flow is commonly high in septic shock so that
APC0 2 is most often in the normal range. Furthermore, in such hyperdynamic
states, interpretation of APC0 2 changes (or of absence of changes) must be particu-
larly cautious.
Clinical Use of Venoarterial PC02 Difference in Septic Shock 581
References
1. Groeneveld ABJ (1998) Interpreting the venous-arterial PC02 difference. Crit Care Med
26:979-980
2. McHardy GJR (1967) The relationship between the differences in pressure and content of
carbon dioxide in arterial and venous blood. Clin Sci 32:299-309
3. Randall HM Jr, Cohen JJ (1966) Anaerobic C02 production by dog kidney in vitro. Am J
Physiol 211:493-505
4. Zhang H, Vincent JL (1993) Arteriovenous differences in PC02 and pH are good indicators
of critical hypoperfusion. Am Rev Respir Dis 148:867-871
5. Kette F, Well MH, Gazmuri RJ, Bisera J, Rackow EC (1993) Intramyocardial hypercarbic
acidosis during cardiac arrest and resuscitation. Crit Care Med 21:901-906
6. Vander Linden P, Rausin I, Deltell A, et al (1995) Detection of tissue hypoxia by arteriove-
nous gradient for PC02 and pH in anesthetized dogs during progressive hemorrhage. An-
esth Analg 80:269-275
7. Groeneveld AB, Vermeij CG, Thijs LG (1991) Arterial and mixed venous blood acid-base
balance during hypoperfusion with incremental positive end-expiratory pressure in the pig.
Anesth Analg 73:576-582
8. Rackow EC, Astiz ME, Mecher CE, Well MH (1994) Increased venous-arterial carbon diox-
ide tension difference during severe sepsis in rats. Crit Care Med 22:121-125
9. Benjamin E (1994) Venous hypercarbia: a nonspecific marker of hypoperfusion. Crit Care
Med 22:9-10
10. Cohen IL, Sheikh FM, Perkins RJ, Feustel PJ, Foster ED (1995) Effect of hemorrhagic shock
and reperfusion on the respiratory quotient in swine. Crit Care Med 23:545-552
11. Vallet B, Teboul JL, Cain S, Curtis S (2000) Veno-arterial C0 2 difference during regional
ischemic or hypoxic hypoxia. J Appl Physiol 89:1317-1321
12. Neviere R, Chagnon JL, Teboul JL, Vallet B, Wattel F (2002) Small intestine intramucosal
PC02 and microvascular blood flow during hypoxic and ischemic hypoxia. Crit Care Med
30:379-384
13. Mecher CE, Rackow EC, Astiz ME, Well MH (1990) Venous hypercarbia associated with
severe sepsis and systemic hypoperfusion. Crit Care Med 18:585-589
14. Bakker J, Vincent JL, Gris P, Leon M, Coffermils M, Kahn RJ (1992) Veno-arterial carbon
dioxide gradient in human septic shock. Chest 101:509-515
15. Parillo JE (1993) Pathogenetic mechanisms of septic shock. N Engl J Med 328:1471-1477
16. Astiz ME, Rackow EC (1986) Septic shock. Lancet 351:1501-1505
17. Groeneveld ABJ, Bronsveld W, Thijs LG (1986) Hemodynamic determinants of mortality in
human septic shock. Surgery 99:140-153
18. Levy B, Bollaert PE, Charpentier C, et al (1997) Comparison of norepinephrine and dobu-
tamine to epinephrine for hemodynamics, lactate metabolism and gastric tonometric vari-
ables in septic shock. A prospective, randomized study. Intensive Care Med 23:282-287
19. Chiolero R, Flatt JP, Revelly JP Jequier E (1991) Effects of catecholamines on oxygen con-
sumption and oxygen delivery in critically ill patients. Chest 100:1676-1684
20. Teboul Jl, Mercat A, Lenique F, Berton C, Richard C (1998) Value of venous-arterial PC0 2
gradient to reflect the 0 2 supply to demand in humans. Crit Care Med 26:1007-1010
21. Teboul JL, Boujdaria R, Graini L, Berton C, Richard C (1993) Cardiac index vs oxygen-de-
rived parameters for rational use of dobutamine in patients with congestive heart failure.
Chest 103:81-85
22. GattinoniL, Brazzi L, Pelosi P, et al (1995) A trial of goal-oriented hemodynamic therapy
in critically ill patients. Sv0 2 collaborative group. N Engl J Med 333:1025-1032
23. Alia I, Esteban A, Gordo F, et al (1999) A randomized and controlled trial of the effect of
treatment aimed at maximizing oxygen delivery in patients with severe sepsis or septic
shock. Chest 115:453-461
24. Bernardin G, Lucas P, Hyvernat H, Deloffre P, Mattei M (1999) Influence of alveolar ventila-
tion changes on calculated gastric intramucosal pH and gastric-arterial PC02 difference.
582 J. L. Teboul and X. Monnet: Clinical Use of Venoarterial PC02 Difference in Septic Shock
25. Teboul JL, Michard F, Richard C (1996) Critical analysis of venoarterial C0 2 gradient as a
marker of tissue hypoxia. In: Vincent JL (ed) Yearbook of Intensive Care and Emergency
Medicine. Springer, Heidelberg, pp 296-307
26. Heino A, Haetikainen J, Merasto ME, Alhava E, Takala J (1998) Systemic and regional
PC02 gradients as markers of intestinal ischemia. Intensive Care Med 24:599-604
27. Ruokonen E, Takala J, Kari A (1993) Regional blood flow and oxygen transport in septic
28. Fiddian-Green RG (1993) Associations between intramucosal acidosis in the gut and organ
failure. Crit Care Med 21:S103-S105
29. Crapo RO (1998) Arterial blood gases: quality assessment. In: Tobin M (ed) Principle and
Practice of Intensive Care Monitoring. Me Graw-Hill, New-York, pp 107-122
30. Mekontso-Dessap A, Castelain V, Anguel N, et al (2002) Combination of venoarterial PC0 2
difference with arteriovenous 0 2 content difference to detect anaerobic metabolism in pa-
tients. Intensive Care Med 28:272-277
I Fluid Therapy
Hypovolemia:
An Integration of Organ System Physiology
D.L. Traber
I Introduction
Hypovolemia is a significant problem for virtually all patients in critical care set-
tings. The human body requires several liters of fluid daily in order to accomplish
its function. Disease magnifies this fluid requirement. This need for augmented
water intake may be overlooked in the hospital setting, where patients are totally
dependent on the clinical team for all of their care. Thus, in many instances hypo-
volemia may be iatrogenic. There are many pathophysiological states in which the
individual loses fluid. Vomiting and diarrhea are classical examples of this, bleed-
ing into the intestinal tract, especially in the duodenal areas, and blood loss as a
result of accidents or operative procedures are also common sources of hypovole-
mia. A good understanding of the protective mechanisms, which are brought into
play with hypovolemia, is important to any medical functionary. Furthermore,
study of these protective reflexes offers a unique opportunity to review cardiovas-
cular function [1-4].
I 10% Removal of the Blood Volume
If individuals lose 10o/o of their blood volume and the cardiovascular status is eval-
uated 15 minutes later one would note that mean arterial pressure (MAP), cardiac
output, and total peripheral vascular resistance are all within normal limits. The
heart rate however would be somewhat elevated. The compensation in response to
this 'hypovolemic' insult mainly involves the baroreceptor reflexes and is illustrated
by the block diagram (Fig. 1). The initial removal of blood results in a diminution
in the pulmonary and venous blood volumes leading to a fall in ventricular dia-
stolic pressures and thus stroke volume and cardiac output. As the output falls the
arterial pressure diminishes. The reduction in ventricular after load will help to re-
store stroke volume but, more importantly, reduced arterial pressure removes ten-
sion from the wall of the baroreceptors in the carotid and aortic sinuses and conse-
quently the activity in their afferent enervation diminishes. The afferent activity of
the aortic and carotid depressor nerves is inhibitory to the vasomotor and cardio-
accelerator centers within the brain stem. The reduction in activity of barorecep-
tors, therefore, results in an increase in sympathetic outflow, the major efferent out-
put of the cardiovascular centers, and a reduction in the vagal efferent activity to
the heart. The reduction in vagal tone increases the heart rate. In humans the de-
nervated heart has a rate of near 100 beats/min. The resting heart rate of a normal
586 D. L. Traber
Blood loss
-+
Venous
capacitance a+
-+
Atrial
pressure
-+
Ventricular Sympathetic
diastolic volume outflow
-+
Stroke
volume r·
Fig. 1. Sequence of events that occurs with blood loss. The blood loss triggers a series of events that
minimizes the reduction in cardiac output and mean arterial pressure
enervated heart is 70 beats/min because at rest there is a vagal dominance. Thus

when the vagal tone is reduced, heart rate increases. This augmentation in heart
rate is potentiated by the elevated sympathetic activity; in addition to their chrono-
tropic action catecholamines also increase myocardial contractility. Both of these
adrenergic activities in the heart are mediated by stimulation of P-adrenergic re-
ceptors. Potentiated sympathetic activity to the peripheral vasculature results in
constriction of both the resistance and capacitance vessels. In this case, the re-
sponse is mediated by a stimulation of a adrenergic receptors. These changes in
autonomic activity rapidly return the arterial pressure to normal levels via their
inotropic and chronotropic influences on the heart. The myocardium thus produces
equivalent cardiac output at reduced filling pressures. A decreased filling reduces
atrial pressure, which reflects itself as a fall in volume in the pulmonary circuit and
large systemic vessels in the thorax [5, 6].
The inotropic and chronotropic influences on the myocardium remain elevated
even though the MAP has returned to normal levels. If the MAP were returned to
baseline levels one would predict that the activity of the baroreceptors would like-
wise be normalized. This is not the case. The inhibitory activities of the barorecep-
tor afferent fibers remain reduced. This is due to the more phasic responsiveness of
the baroreceptor. They respond more to the 'change' in pressure than to static pres-
sure. In the new steady state, cardiac output is normal and the heart rate is in-
creased. The stroke volume is thus reduced and, consequently, the pulse pressure
falls. As a result of the reduced pulse pressure there are fewer inhibitory impulses
fired by the baroreceptors with each pulse and, therefore, fewer impulses per given
time period. The reduction in baroreceptor activity is responsible for maintaining
Hypovolemia: An Integration of Organ System Physiology 587
the cardiac output and MAP at baseline or normal levels despite the presence of a
reduction in blood volume of 10%. Since this compensation is basically mediated
by autonomic activity, pharmacological agents that have autonomic actions can in-
terfere with the compensation [7, 8].
Since the cardiac output and MAP are at normal levels the systemic vascular resis-
tance must likewise be normal (R =QX P). The question is, if the sympathetic activity
is increased, why isn't the peripheral vasculature increased? Why is there no increase
in systemic vascular resistance? During this compensatory time period certain areas
of the systemic vasculature, such as the mucosa of the mouth and eye lid, tissues that
are not very active metabolically, are constricted. Other areas such as the coronary
circuit are actually dilated. In the latter case the myocardium utilizes considerably
more high-energy phosphate and thus oxygen when there is an increase in heart rate
and contractility. The resultant reduction in tissue oxygen, or the increase in adeno-
sine, dilates the coronary vessels. A similar process takes place in other tissues that are
metabolically active and through this mechanism the blood flow to metabolically ac-
tive organs is increased to match their metabolic demand. The local control of the vas-
cular tone of systemic arterioles is mainly through the release of vasoactive catabolites
such as hydrogen ion, C0 2 and adenosine, which override the catecholamine induced
vasoconstriction. In vascular beds of areas that are not metabolically active, such as
the skin and mucosa, there will not be an elevation of metabolites or a fall in oxygen
and consequently the vessels in these tissues remain constricted and blood flow in
these areas is reduced. Hypoperfusion of the mucosa gives it a white appearance
whereas the constriction of the skin gives it not only a white appearance (pallor)
but also a feeling of coldness. Increased sympathetic adrenergic activity to the apoc-
rine sweat glands to the skin causes the glands to produce a viscous secretion that
gives the skin a clammy feeling. In the areas such as the palm of the hands and the
underarms, the secretion of these glands is more profuse since apocrine glands are
more abundant in these areas. This finding may be used to identify individuals
who have sustained a loss of blood volume.
The changes in cardiovascular status, and the compensations that occur reflex-
ively, can also be illustrated using a Guytonion venous return diagram (Fig. 2).
Normal cardiac output
Set point or operation point
Hypovolemia
Normal venous retum
Atrial pressure
Fig. 2. Venous return (horizontally oriented curves) match cardiac output (vertical oriented curves) where
the two cross
588 D. L. Traber
Blood volume loss causes a shift of the venous return curve (horizontally orien-
ted curve) downward [9, 10]. The cardiac output curve (vertically oriented curve)
remains at its baseline position since myocardial contractility and heart rate do not
change until reflex compensation occurs. Consequently, before reflex compensation,
the set point, where the venous return and cardiac output curves cross, shifts
downward, i.e., cardiac output falls. As reflex compensation occurs, the increased
sympathetic output (alpha adrenergic) increases the tone of the capacitance vessels
shifting the venous return curse upward. The increased heart rate and myocardial
contractility shifts the cardiac output curve to the left, returning the set point, and
thus cardiac output, back to normal levels.
Though the cardiovascular status of a supine individual can be returned to nor-
mal limits through the adjustments discussed above, the individual would be highly
susceptible to stresses placed upon their cardiovascular system. The reader might
compare the situation of a 10% blood loss to that which exists in an individual
who has given a unit of blood. This is 500 ml and would be almost equivalent to
10% of the blood volume of a 70-kg man. Upon standing many of these individuals
do not have enough cardiac output to sustain their cerebral circulation and thus
faint. Others may not be able to withstand exercise to the extent of a normal indi-
vidual. Therefore, the situation of depletion of 10% of the blood volume is not nor-
mal and the organism must return itself to normality in order to sustain life for a
prolonged time period. The mechanisms necessary to accomplish this are not
nearly as well understood as those responsible for the early cardiovascular compen-
sations [11, 12]. We do know that the level of renin and vasopressin are elevated.
Early work by Henry and Gauer indicated that these changes were associated with
a lowering of the left atrial pressure. The atria have been identified by some as the
volume receptor of the body. Thus when vascular volume is reduced, a net reduc-
tion in left atrial pressure occurs which results in the release of atrial natriuretic
factor, aldosterone and antidiuretic hormone to restore the volume to normal [13,
14]. The mechanisms responsible for this restoration involve changes in thirst and
renal function. Renin and angiotensin are thought to stimulate the thirst mecha-
nism, which would encourage the individual to drink additional fluids and thus
restore vascular volume to normal levels [15]. The hormones also interact with the
kidney such that it will produce less urine as a result of increased reabsorption of
both ions and water. The renin angiotensin mechanism produces this response
through stimulation of the glomerulosa layer of the adrenal cortex and elaboration
of aldosterone. This steroid hormone stimulates sodium and water reabsorption
from the collecting ducts and distal segments of the nephron. In addition, natriure-
tic factors are released that cause an increase in sodium and water reabsorption.
The end result of these two actions is to restore vascular volume towards normal,
but with the dilution of the cellular components. Consequently, an individual who
has sustained hemorrhage is often found to be anemic. Before compensation, the
concentration of cells remains as it was before fluid loss since we removed the
same percentages of cells and plasma as are present in the blood. The anemia oc-
curs as a result of the compensatory mechanism, i.e., drinking fluid, reduced uri-
nary output etc., brought into play to restore vascular volume [16].
The anemia that is present at this point is important in stimulating an elevated
production of erythrocytes. This anemia signals the elevated output of the hor-
mone, erythropoietic releasing factor, from the kidney [17]. This interacts with the
plasma protein leading to the production of erythropoietin, which stimulates the
stem cells of the bone marrow to produce new red blood cells. This can be seen in
blood smears as the peripheral circulation of an individual in this situation con-

tains more nucleated erythrocytes (reticulocytes). The loss of erythrocytes also re-
sults in a loss of iron present in the hemoglobin of these cells. Erythropoietin also
increases iron absorption from the gastrointestinal tract. However, if dietary iron is
not supplemented, the individual can develop an iron deficiency anemia. This oc-
curs in individuals who sustain chronic blood losses over several days. A smear of
their blood will show not only a reduction in erythrocytes but the cells will also be
hypochromic and small in size (microcytic).
I Removal of 20% of the Blood Volume
An individual who has sustained a 20o/o reduction in blood volume demonstrates

an arterial pressure that is within normal limits and a cardiac output that is re-
duced. The total peripheral vascular resistance is elevated. The mechanisms respon-
sible for these changes are much the same as were discussed above except that, in
this instance, in order to restore the blood pressure to normal levels the sympa-
thetic outflow to the arterioles becomes more apparent. This is a most interesting
compensatory mechanism since it tends to restrict blood flow to non-vital areas.
The microvasculature of vital areas tends to be refractory to this outflow of sympa-
thetic activity. The microcirculation of the cerebral areas is a prime example of this
since the catecholamines have very little effect on the resistance of the cerebral vas-
cular beds. The microcirculation to the heart, as we noted above, shows a vasodila-
tion. The coronary microcirculation responds more to tissue hypoxia than to the
direct sympathetic stimulation of its vasculature. In other tissues 'metabolic vasodi-
lation' is overcome by the action of vasoconstrictors catecholamines, vasopressin
and angiotensin. When sepsis is combined with hypovolemia, a frequent occurrence
since vascular permeability is often increased with sepsis, compensatory vasocon-
striction is frequently prevented by release of the potent dilator, nitric oxide (NO)
[18, 19].
The increase in resistance in other tissues results in a peculiar type of vascular
compensation related to the mechanism responsible for fluid flux from the extra-
vascular to vascular compartment. This is determined by the components of the
Starling equation [20, 21]:
Qf = Kf[(Pmv- Pi) -Qnpl- ni)]
1) hydrostatic pressure, which tends to have a net effect of forcing fluid from the
vascular system, that is defined in the equation as the difference between the mi-
crovascular (Pmv) and the interstitial pressures (Pi), and
2) protein oncotic pressure exerted by the plasma proteins, that is defined by the
differential between the plasma oncotic (npi) and interstitial oncotic (ni) pres-
sures. This differential in oncotic pressure is likewise influenced by the degree
with which proteins can move across the microvasculature membranes repre-
sented by the reflection coefficient (a). With the constriction of the arterioles,
the hydrostatic pressure of the microvasculature is reduced below the level of
the oncotic pressure and thus fluid would be drawn into the vasculature from
the extravascular spaces. This mechanism, however, is limited by a self-imposed
negative feedback loop since, as the fluid is reabsorbed, the protein in the plas-
590 D. L. Traber
rna is diluted while that in the interstitium is concentrated and, consequently,

the oncotic pressure gradient is increased, thus tending to reduce further fluid
leakage. This self-transfusion that occurs in the hemorrhaged individual with an
elevated peripheral resistance, will also contribute to the anemia that is seen
with blood loss.
The remainder of the compensation that occurs with a 20% blood loss is essentially
the same as with 10%, i.e., thirst mechanisms restoring the reduced volume and
the anemia stimulating the production of the lost erythrocytes.
30% Loss of Blood Volume
With a 30% blood loss, the arterial pressure falls in addition to the cardiac output,
and the peripheral resistance rises. The blood flow to essential organs is main-
tained through dilatory mechanisms. This is true to a large extent with the brain
and the heart and to a lesser extent to such organs as the kidney. The mechanisms
responsible for the vasodilation are those which have been purported to normally
regulate blood flow to the tissues: in the case of the brain, the tissue pH; in the
case of the heart, the mechanisms are related to oxygen demand (i.e., AMP,
adenosine, etc.); and in the case of the kidney, perhaps to baroreceptor mechanisms
that exist on the afferent arteriole. The remainder of the vascular beds are con-
stricted through their sympathetic mechanisms. Elevated levels of the vasoconstric-
tors, such as antidiuretic hormone (vasopressin), constrictions as well as angioten-
sin II, may amplify these sympathetic mechanisms. The elevation of angiotensin
occurs secondary to sympathetic stimulation and/or renal renin secretion. The
vasopressin release from the neurohypothesis is mediated through baroreceptor
modulation.
The body's triage mechanisms, which maintain blood flow to vital organs at the
expense of those that are non-vital, are at best a temporary 'stop-gap' measure. The
situation of volume depletion to this extent can rapidly develop into a terminal
event for the organism if volume is not restored. There are a number of areas
where positive feedback loops can develop, for example, the areas which are con-
stricted must continue to have energy production in order to remain viable. The
production of high-energy phosphates in these tissues in the absence of oxygen
will, therefore, be produced by anaerobic glycolysis. This leads to the formation of
fixed acids such as pyruvic and lactic acid. These are said to be fixed acids since
they are not eliminated by respiratory mechanisms. They are, however, buffered by
bicarbonate thus leading to the formation of additional carbonic acid that is elimi-
nated through the lungs as a result of stimulation of respiratory mechanisms. These
net elevations in hydrogen ions stimulate central respiratory mechanisms, which re-
sult in a reduction of the PaC0 2 • This will produce a cerebral vasoconstriction. Pre-
viously the blood flow to the brain had been maintained through vasodilatory
mechanisms responding to a hypotension/pH mechanism. The underlying mecha-
nism for this control relates to the pH of the cerebral interstitium. This is in equi-
librium with the PaC0 2 • If the arterial pressure falls there is a reduction in blood
flow to the brain. As this occurs, the pH in the interstitial fluids falls. This reduc-
tion in pH induces a vasodilation, which then restores the cerebral blood flow
(CBF) to normal levels. If on the other hand the PaC0 2 falls the interstitial pH will
rise and there will be a vasoconstriction of the cerebral vessels and a reduction in
CBF. Thus the vasodilation which takes place as a result of the reduced pressure is
overridden when the PaC0 2 are diminished as a result respiratory compensation to
a metabolic acidosis.
The cerebral hypoxia that occurs as a result of the reduced CBF, will have a pro-
found effect upon the individual as the cerebrum becomes deprived of oxygen.
Through this mechanism, brain damage can occur which may lead to destruction
of the regulatory mechanisms responsible for maintenance of circulation and other
vital functions, ultimately leading to death. The greater the failure of these vital
functions the more severe the metabolic acidosis and, thus, the less the circulation
to the head.
Coronary insufficiency can of course occur as a result of the decreased pressure
gradient for myocardial perfusion, i.e., the falling arterial pressure. In addition, the
coincident tachycardia associated with volume depletion, decreases the myocardial
efficiency. This impairment of myocardial function can reverse some of the benefi-
cial effects seen by the positive inotropic influences that occur. The positive ino-
tropic effects reduce the ftlling pressure required for a given stroke volume thus re-
ducing the left atrial pressure. The fall in left atrial pressure reduces pressure in the
pulmonary vasculature thus diminishing the volume in this very compliant vascular
system. If the oxygen consumption of the heart is impaired there will be a resultant
reduction in myocardial contractility. With a fall in contractility the filling pressure
would be more profound, pooling blood in the pulmonary area. In normal individ-
uals, the arterial pressure must fall to a very low level (-50-60 mmHg) before these
changes are noted. However, coronary atherosclerosis and the increased 0 2 de-
mands imposed by the inotropism and increased heart rate will raise this figure. If
the pressure falls below 50 mmHg there is also a great danger that ventricular
fibrillation may occur. This is an almost universal vector of death in the acutely
hypovolemic individual.
The effects of the myocardial insufficiency in affecting venous return are also re-
lated to the presence of circulating myocardial depressant factors. One of these, dis-
covered by Dr. Allen Lefer and his group, is referred to as the myocardial depres-
sant factor and is formed in the pancreas consequent to an inadequate tissue perfu-
sion [22, 23]. The hypoxia leads to a breakdown of the lysosomal membranes and
release of proteolytic enzymes. These interact with protein in the pancreas to yield
the factor that enters the circulation via the lymphatics. The factor, a polypeptide,
depresses the myocardium and may also have some vasoconstrictor abilities both
of which will lead to a further depression of the circulation, greater pancreatic hyp-
oxia, greater production of the depressant factor, and hence a positive feedback
loop. Recent evidence would also indicate that, during shock-like states, as a result
of an elevation of the glucocorticords, gluconeogenesis is accelerated. Part of the
process of gluconeogenesis involves the breakdown of protein to amino acids. As a
result, blood levels of the amino acids are elevated and certain of these have been
shown to depress the myocardium.
These lesions coincident with hypovolemia are reversible if the volume is re-
stored soon after the initial blood loss. If, however, the organism is left in a vol-
ume-depleted state for a prolonged time many of the processes may become irre-
versible. A recent meta-analysis has reported that hypovolemia and inadequate re-
suscitation are a major determinant of patient outcome [24]. Consequently, timely
restoration of blood volume is an important component of critical care and emer-
gency medicine [25].
592 D. L. Traber
Conclusion
Following blood loss, cardiovascular reflexes are brought into play to return MAP
and cardiac output at baseline levels. As loss continues, arterial pressure falls and
mechanisms are put into play to maintain flood flow to the heart and brain.
Although these mechanisms are essential to survival, they may be overridden by
other reflexes.
References
1. Stoner HB, Little RA (1985) Problems of homeostasis in the injured patient. Acta Chir
Scand Suppl 522:107-118
2. Njoku MJ, Hoffman WD (1996) Hypovolemic shock. In: Murry MJ, Coursin DB, Pearl RG,
Prough DS (eds) Critical Care Medicine, Perioperative Management. Lippincott .. Raven, New
York, pp 285-294
3. Cox CS, Traber DL, Zwischenberger JB, et a! (1993) Cardivascular function in acute burns.
In: Schlag G, Red! H (eds) Pathophysiology of Shock, Sepsis and Organ failure, Springer,
Berlin, pp 242-256
4. Maier RV (2002) Shock, Chapter 38, Part 2: Cardinal manifestations and presentations of
diseases. In: Braunwald E, Fauci AS, Isselbacher KJ, et a! (eds) Harrison's Online. The
McGraw-Hill Companies, New York, pp 1-27
5. Plante GE (2002) Vascular response to stress in health and disease. Metabolism 51 (suppl
1):25-30
6. Rothe CF (1983) Reflex control of veins and vascular capacitance. Physiol Rev 63:1281-
1342
7. Brown DL (1987) Anesthetic agents in trauma surgery: are there differences? Int Anesthe-
sia! Clin 25:75-90
8. Wagner DL (1984) Shock in the operating room. Am J Emerg Med 2:92-99
9. Guyton AC (1991) Cardiac output venous return and their regulation, Chapter 20. In: Guy-
ton AC (ed) Textbook of Medical Physiology, 8th edn. WB Saunders, Philadelphia, pp 221-
233
10. Guyton AC, Colman CE, Jones TG (1973) Cardiac Output and its Regulation. WB Saunders,
Philadelphia, pp 85-110
11. Sawka MN (1992) Physiological consequences of hypohydration: exercise performance and
thermoregulation. Med Sci Sports Exerc 24:657-670
12. Gonzalez RR (1987) Biophysical and physiological integration of proper clothing for exer-
cise. Exerc Sport Sci Rev 15:261-295
13. Sander Jensen K (1991) Heart and endocrine changes during central hypovolemia in man.
Dan Med Bull 38:443-457
14. Rossi NF, Schrier RW (1986) Role of arginine vasopressin in regulation of systemic arterial
pressure. Annu Rev Med 37:13-20
15. Fitzsimons JT (1998) Angiotensin, thirst, and sodium appetite. Physiol 78:583-686
16. Singer GG, Brenner BM (2002) Chapter 49: Fluid and electrolyte disturbances, Part 2: Car-
dinal manifestations and presentations of diseases. In: Braunwald E, Fauci AS, Isselbacher
KJ, et a! (eds) Harrison's Online. The McGraw-Hill Companies, New York, pp 1-33
17. Herndon DN, Hayward PG, Rutan RL, eta! (1992) Growth hormones and factors in surgi-
cal patients Adv Surg 25:65-97
18. Collins JL, Vodovotz Y, Billiar TR (2001) Biology of nitric oxide: measurement, modulation
and models, Chapter 68. In: Souba, WW, Wilmore, DW (eds) Surgical Research. Academic
Press, San Diego, pp 949-970
19. Sherwood, E, Traber DL (2001) Chapter 19. The systemic inflammatory response syn-
drome. In: Herndon, DN (ed) Total Burn Care, 2nd ed. WB Saunders Co Ltd., London, pp
257-270
20. Starling EH (1896) On the absorption of fluids from the connective tissue spaces. J Physiol
(Lond) 19:312-326
21. Courtice FC (1984) Chapter 1 The development of concepts of fluid balance. In: Staub NC,
Taylor AE (eds) Edema. Raven Press, New York, pp 1-38
22. Kistler EB, Lefer AM, Hugli TE, et al (2000) Plasma activation during splanchnic arterial
occlusion shock. Shock 14:30-34
23. Lefer AM (1989) Induction of tissue injury and altered cardiovascular performance by
platelet-activating factor: relevance to multiple systems organ failure. Crit Care Clin 5:331-
352
24. Wolf SE, Rose JK, Desai MH, et al (1997) Mortality determinants in massive pediatric
burns. An analysis of 103 children with >or=80% TBSA burns (>or=70% full-thickness).
Ann Surg 225:554-565
25. Kreimeier U, Messmer K (2002) Small-volume resuscitation: from experimental evidence to
clinical routine. Advantages and disadvantages of hypertonic solutions. Acta Anaesthesiol
Scand 46:625-638
New Light on Volume Therapy in the Critically Ill?
J. Boldt
Introduction
Hypovolemia is extremely common among intensive care unit (ICU) patients. Fluid
deficits in the ICU patient can occur in the absence of obvious fluid loss secondary
to vasodilation or generalized alterations of the endothelial barrier resulting in dif-
fuse capillary leak. Patients with sepsis/septic shock, in particular, often show large
fluid deficits. Sepsis is characterized by a pan-endothelial injury with subsequent
development of increased endothelial permeability, loss of proteins, and interstitial
edema [1, 2]leading to fluid shift from the intravascular to the interstitial compart-
ment.
In a prospective review of 111 consecutive patients who died in hospital after
admission for treatment of injuries, the most common defects in patient manage-
ment were related to inadequate fluid resuscitation [3]. Adequate volume replace-
ment therapy may help to improve organ function and reduce patient morbidity or
even mortality. It has been reported that, in approximately 50% of septic patients,
adequate volume replacement alone may reverse hypotension and restore hemody-
namics [4].
Although the importance of adequate volume replacement is widely accepted,
the 'ideal' strategy for volume therapy has been the focus of debate for several years
and there are no universally accepted guidelines [5]. This chapter focuses on new
aspects of volume therapy in the critically ill. Studies and meta-analyses dealing
with this problem that have been published during the last three years in the Eng-
lish language are analyzed. Letters, brief reports and experimental or animal stud-
ies were not included because animal models of hypovolemia cannot mimic the al-
terations found in humans.
I New Aspects on:
Coagulation
Coagulopathy is a frequent complication in ICU patients or during surgery. The
choice of volume replacement strategy may also have an important impact on the
coagulation process. When compared with colloids, crystalloids are frequently pre-
ferred because they are inexpensive and appear to be almost free of significant neg-
ative side effects [6]. Interest has recently focused on the influence of crystalloids
on hemostasis. There is convincing evidence that the use of crystalloids has a sub-
New Light on Volume Therapy in the Critically Ill? 595
stantial influence on coagulation. Ruttmann et al. [7, 8] and Ng et al. [9] showed
that in vivo dilution with crystalloids resulted in significant enhancement of coagu-
lation. The reason for the hypercoagulable state appears to be an imbalance be-
tween naturally occurring anticoagulants and activated procoagulants with a reduc-
tion in antithrombin III probably being the most important [7]. Others have also
documented hypercoagulability with the use of crystalloids [10]. This increase in
coagulation seems to be independent of the type of crystalloid used [10]. An early
study reported that the increase in coagulation in patients in whom crystalloids
were given during surgery was associated with an increased incidence of deep vein
thrombosis [11]. Thus taking new data into account, crystalloids can no longer be
considered as 'good' with regard to the coagulation process.
No new studies on coagulation are available with the use of colloids such as
albumin, dextrans or gelatins.
The lack of acceptance of hydroxyethylstarch (HES) for volume replacement is
most likely due to reports on abnormal coagulation. When looking at reports on
HES showing compromised blood coagulation and increased bleeding tendency, it
becomes obvious that mostly the first-generation, high-molecular weight (HMW)
HES preparations (mean molecular weight [Mw] 450 kDa, degree of substitution
[DS] 0.7 [Hetastarch]) or HES preparations with a high DS (0.62} were used. High-
substituted HES preparations are especially associated with negative effects on
blood clotting and consequently increased postoperative bleeding tendency [12,
13]. This was confirmed by a study in patients scheduled for minor elective surgery
in whom either 15 ml/kg body weight saline solution (n= IS) or 15 ml/kg body
weight of a HES preparation with a medium Mw (200 kDa) but a high DS (0.62)
was given [14]. A reduced GPIIb-IIIa expression and a reduced maximal amplitude
(MA; measured by thrombelastography) were seen only in the HES group.
The weight average Mw of the HES preparation used seems to play a certain role
in the influence on coagulation. In a study in healthy volunteers either 500 ml of
HES with a Mw of 70 kDa or HES with a Mw of 200 kDa was given over 30 min
[15]. von Willebrand factor (vWF), prothrombin time (PT}, and maximal amplitude
(MA; measured by thrombelastography [TEG]) were slightly, but significantly, more
altered by HES 200 than by HES 70.
Recent papers using new HES specifications have shed new light on this prob-
lem. A modified HMW-HES (Hextend®) and a third-generation, new low-molecular
weight/low-substituted HES (Mw 130; DS 0.4) have been developed for clinical use
to avoid negative effects on coagulation. Hextend® is a modified, physiologically
'balanced' first generation HMW-HES preparation (molar substitution: 0.7; weight
average molecular weight: approximately 670 kDa, mean molecular weight [Mw]
550 kDa) containing balanced electrolytes (Na+: 143 mmol/1, cl-: 124 mmoUl,
lactate: 28 mmol/1, ca++: 2.5 mmoUl, K+: 3 mmoUl, Mg++: 0.45 mmol/1, glucose:
5 mmol/1) [16, 17]. This specific HES preparation is reported to deteriorate coagula-
tion significantly less than standard HMW-HES (Hetastarch) [18, 19]. Others, how-
ever, could not verify that modification of a high-molecular weight (Mw 550 kDa),
high-substituted (DS: 0.7} HES preparation (Hextend®) eliminated the negative
effects on coagulation [20].
The third-generation HES (HES 130/0.4) shows favorable physico-chemical prop-
erties compared with other HES solutions [21]. The impact on coagulation also ap-
pears to be favorable [22]. In 50 healthy patients undergoing minor elective surgery
10 ml/kg of saline or 10 ml/kg of 4 different HES preparations including the new
HES 130/0.4 were given [23]. After infusion of HES 130/0.4, platelet function (mea-
596 J. Boldt
sured by PFA-100TM closure times) remained unaffected, whereas the other HES
preparations (HES 70/0.5; HES 200/0.5; HES 450/0.7) resulted in a significant in-
crease in PFA-100™ closure times indicating considerable alterations in platelet
function. Using activated TEG, it was shown that infusion of approximately 2500 ml
of HES 130/0.4 in patients undergoing major abdominal surgery was associated
with almost no negative impact on hemostasis [20, 24]. This HES specification also
showed no negative influence in cardiac surgery patients on coagulation time (CT),
clot formation time (CFT), and maximum clot firmness (MCF) measured by a
modified, activated TEG technique [25]. HES 130/0.4 also seems to possess benefi-
cial effects on bleeding tendency. In in vivo studies using HES 130/0.4 in orthope-
dic [26] and cardiac surgery patients [27], less bleeding and less use of blood/
blood products with HES 130/0.4 than with a conventional HES 200/0.5 preparation
was reported.
Renal Function
Dextran-induced acute renal failure has been recognized for a long time. The
pathogenesis of acute renal failure after dextran infusion appears to be multifactor-
ial including 'hyperoncotic' acute renal failure, tubular obstruction, and direct tox-
icity.
Conflicting results on the effects of HES on renal function may be due to the
use of different HES preparations, varying clinical protocols, selection of patients,
and different criteria for volume administration. Recently some negative effects of
HES on kidney function have been published in two case reports [27, 28]. More-
over, in a multicenter study in 129 ICU patients with sepsis or septic shock the ef-
fects of HES were assessed [29]. The patients received either gelatin (3% fluid-mod-
ified gelatin; n = 64) or a highly-substituted HES preparation (Mw 200 kDa, DS
0.62, n=65) for volume therapy. The median cumulative volume replacement was
31 ml/kg with HES and 43 ml/kg with gelatin. Acute renal failure (defined as a two-
fold increase in serum creatinine concentration or need for renal replacement ther-
apy) developed in 27 of the HES-treated patients (42%) and in 15 of the gelatin-in-
fused patients (23%, p < 0.028). Differences in creatinine concentrations became sig-
nificantly different 6 days after first use of HES. Unfortunately, the two volume
groups showed different creatinine levels already prior to the start of volume thera-
py: median serum creatinine concentration was 143 Jlmol/1 in the HES- and 114
Jlmol/1 in the gelatin-treated patients. Compared with the gelatin-group, use of the
slow degradable HES preparation (HES 200/0.62) was an independent risk factor
for the occurrence of acute renal failure. Despite a higher incidence of acute renal
failure in the HES-treated patients, mortality was not significantly different between
the two groups.
In a study in cardiac surgery patients who are at particular risk of developing
postoperative renal dysfunction, a new ('third generation') HES with a medium Mw
(130 kDa) and a low DS (0.4) was infused [30]. Renal function remained un-
changed by HES administration and similar to that in gelatin-treated control group.
In patients without altered renal function undergoing middle ear surgery [31], low
doses (15 ml/kg) of different HES preparations (6% HES 450/0.7; 6% HES 200/0.62;
6% HES 200/0.5) did not result in impaired kidney function assessed by sensitive
markers of altered renal integrity (e.g. a 1-microglobulin, D-acetyl-/1-glucosamidase
[NAG], Tamm-Horsfall-protein, inulin clearance).
Organ Perfusion/Microcirculation
During hypovolemia, the microcirculation is impaired, initiating a vicious cycle of
progressive tissue damage that may finally lead to development of multiple organ
failure (MOF). By adequately restoring intravascular fluid volume, organ perfusion
may be guaranteed, nutritive microcirculatory flow be improved, and activation of
a complex series of damaging cascades be avoided. Whether the kind of fluid ther-
apy can influence the vicious cycle induced by hypovolemia has not been definitely
decided yet. In some (older) experimental studies, it has been demonstrated that
compared to colloids even a massive crystalloid resuscitation alone is less likely to
achieve adequate restoration of (microcirculatory) blood flow [32, 33].
Only very few new data are available on organ perfusion, microcirculation and
tissue oxygenation in humans in whom different types of plasma substitutes have
been used. In critically ill hypovolemic patients who suffer~d from sepsis syn-
drome, volume expansion with a lOo/o mean-molecular weight (MMW) HES prepa-
ration (Mw 250 kDa; Pentastarch) did not change abnormal intramucosal C0 2
tension, gastric-arterial PC0 2 gradient, and gastric intramucoasal pH (pHi) despite
increasing cardiac index, oxygen delivery, and filling pressures [34]. In another
study in septic hypovolemic patients, 500 ml of gelatin or HES 200/0.62 was used
to assess the effects on splanchnic perfusion by volume therapy [35]. Only gelatin
infusion increased pHi significantly (+0.5o/o [from 7.27±0.08 to 7.31±0.07]),
whereas pHi slightly decreased in the HES-treated patients (-0.5o/o [from 7.26±0.11
to 7.22±0.08]).
Tissue oxygenation appears to be as important as tissue perfusion. The influence
of different volume replacement on tissue oxygenation has been studied mostly in
the experimental setting [32]. In patients undergoing major abdominal surgery, the
influence of a new, third-generation HES (HES 130/0.4, n=21), on tissue P02 was
compared to patients who received only saline solution (n=21) for volume replace-
ment [36]. Using flexible minimal-invasive microsensoric POrcatheters, tissue P0 2
(Pti0 2 ) was monitored for 24 hrs after surgery. Although systemic hemodynamics
and oxygenation data were kept unchanged from baseline and were similar in both
groups within the entire study period, Pti0 2 increased significantly in the HES-
treated patients (maximum +59o/o), whereas it decreased in the control group (max-
imum -23o/o). Thus, intravascular volume replacement with HES 130/0.4 improved
tissue oxygenation during and after major surgical procedures compared to a crys-
talloid-based volume replacement strategy.
Metabolic Situation
Significant alterations in acid-base balance develop in patients who are infused with
large amounts of 0.9o/o saline solution. A hyperchloremic acidosis [37] only occurs
when considerable amounts of normal saline solution are infused. The use of Ring-
er's lactate is not associated with this phenomenon [38].
Use of considerable amounts of colloids may also be associated with metabolic
acidosis. Acute normovolemic hemodilution (ANH) (aim: hematocrit 22o/o) in pa-
tients undergoing gynecologic surgery using either 5o/o albumin or 6o/o HES 200/0.5
resulted in metabolic acidosis in both groups [39]. A dilution of extracellular bicar-
bonate or changes in strong iron differences and albumin concentration may be ex-
planations for this type of acidosis. Others found decreases in base-excess only
after use of standard HMW-HES and not with albumin [40].
598 J. Boldt
Little information exists as to the clinical value of this type of acidosis. Negative
consequences of hyperchloremic acidosis on organ function have been elucidated
in some studies; in patients undergoing abdominal aortic aneurysm repair, either
lacated Ringer's solution (total dose: 6800 ml) or normal saline (total dose:
7000 ml) was used for volume replacement in a double-blinded fashion [41]. Only
the normal saline-treated patients developed hyperchloremic acidosis; they needed
significantly more blood products than the Ringer's lactate patients. There is also
some evidence that hyperchloremic acidosis may impair end organ perfusion. In el-
derly patients undergoing elective open surgical procedures, either conventional
HMW-HES (Hetastarch) or a hetastarch in a balanced electrolyte and glucose for-
mulation (Hextend®) was used [42). Only patients treated with the conventional he-
tastarch developed hyperchloremic acidosis (postoperative base excess: -·0.2 versus
-3.8 mmol/1). Gastric tonometry indicated improved gastric mucosal perfusion in
the balanced hetastarch solution (Hextend) when compared to a saline-based hetas-
tarch solution.
Outcome
Large prospective studies that show the superiority of a specific volume replace-
ment strategy with regard to outcome are still lacking. Although several studies
have assessed the different volume replacement strategies, there are no convincing
guidelines regarding the choice of fluid for volume replacement in the criti<;ally ill.
In the published meta-analysis comparing colloids with crystalloids, the conclu-
sions are sometimes even divergent. Some of these studies have buoyed readers
with false hopes about the importance of a certain volume replacement regimen
("Resuscitation with colloids was associated with ... four extra deaths for every 100
patients resuscitated:' [43 )).
I Volume Therapy in the Light of New Reviews and Meta-Analyses
In a systematic review concerning crystalloids versus colloids in fluid resuscitation,

Choi et al. [44) identified 17 relevant primary studies out of 105 articles from 1966
to 1996. Pulmonary edema, mortality and length of stay were evaluated. In the sub-
group 'Critical Care' only 3 studies were analyzed - two of them were more than
15 years old and one more recently published study from 1994 included (non-ICU)
patients undergoing interleukin-2-based therapy for metastatic cancer and volume
therapy.
In a Cochrane Review, a systematic review was made of colloids versus crystal-
loids for fluid resuscitation in critically ill patients [45]. This meta-analysis, which
focused on mortality, included 26 trials comparing crystalloids with different col-
loids, nine trials comparing colloids prepared in hypertonic crystalloids with iso-
tonic crystalloids, and three trials comparing hypertonic crystalloids with colloids
were included. There was no evidence that resuscitation with colloids reduces the
risk of death in patients with trauma, burns and following surgery.
In another systematic review from the Cochrane Group, hypertonic-based vol-
ume replacement regimens were compared with crystalloid-based volume replace-
ment in critically ill patients [46). Although a mass of studies has been published
on this topic, only 12 studies were included in the analysis. The authors concluded
that there is no evidence that one strategy of volume therapy is superior to the
other in patients with trauma (5 studies included), burns {3 studies), or those un-
dergoing surgery (4 studies). The results concerning trauma patients are in contrast
to an older meta-analysis on hypertonic volume replacement including 12 studies
comparing hypertonic saline-based volume therapy with dextran-based volume re-
placement [47]. This meta-analysis suggested a favorable survival benefit for hyper-
tonic saline treatment of traumatic hypotension.
The influence of an expensive albumin-based volume therapy on mortality com-
pared to other less expensive volume replacement strategies was compared in a
meta-analysis of randomized controlled trials [48]. Trials involving surgery and
trauma {27 studies), burns (4 studies), hypoalbuminemia (5 studies), high-risk
neonates (6 studies), ascites (5 studies), and other indications (8 studies) were in-
cluded. None of the analyzed factors (outcome, mortality) were significantly influ-
enced by either of the volume replacement regimens. There was overall no benefi-
cial effect of albumin on mortality in these 55 studies including 3504 patients.
It has been questioned whether such meta-analyses are appropriate instruments
to examine the value of different fluid strategies in the critically ill [49], because
mortality was not the end point of most of the studies assessing the value of differ-
ent volume replacement strategies.
Some more recently published analyses have focused on the effects of plasma
substitutes on blood coagulation [12, 50]. In their review, de Jonge and Levi [12],
selected articles that provided data on the effects of all colloids on hemostasis and
postoperative blood loss in humans. They concluded that all artificial colloids are
potentially associated with an increased bleeding tendency after infusion of very
large volumes. Rapidly degradable HES preparations (e.g., HES 200/0.5) and gela-
tin-based plasma expanders appear not to impair the coagulation process.
Wilkes et al. [50] carried out a meta-analysis on postoperative bleeding in cardi-
ac surgery patients in whom either albumin or HES has been given. Both solutions
were used either before or after cardiopulmonary bypass (CPB) or as an addition
to the priming solution. Postoperative bleeding was significantly higher in the
HMW HES (hetastarch) patients than in the albumin-treated group (9 studies with
354 patients included, 95% CI: -0.49 to -0.05). When HES with a lower Mw
(200 kDa) was compared with albumin (8 studies with 299 patients included), there
was no longer any statistical difference in the postoperative bleeding tendency
(95% CI: -0.44 to +0.01). The differences in mean bleeding volume in the included
studies comparing albumin with HES 200 ranged from 40 ml higher bleeding vol-
ume in the albumin patients up to 209 ml higher bleeding volume in the HES pa-
tients. Aside from lacking statistical significance, this difference in bleeding volume
in cardiac surgery is without relevance. The use of blood and blood products was
not systematically analyzed in this meta-analysis.
I Conclusion
Adequate management of the underlying insult is a prerequisite of treating the cri-

tically ill ICU patient - however, supportive therapies including sufficient volume
therapy can also be of considerable importance. What have we learnt from the in-
formation that has been published on volume replacement strategies during the last
3 years?
600 J. Boldt
I Crystalloids are far from just 'inert' plasma substitutes. They may have a signifi-
cant impact on coagulation (hypercoagulability) and on the metabolic situation
(acidosis). They are the substances with the most negative influence on the mi-
crocirculation and organ perfusion.
I There are few data on albumin, gelatins and dextrans.
I The use of HES in the critically ill still remains a potent topic of debate. Consid-
erable effort has been devoted to developing new HES preparations with excel-
lent effects on the microcirculation and without negative side effects (coagula-
tion, kidney function). Two modifications have reached the market in the last
years: First, Hextend, a modified, physiologically 'balanced' first-generation,
high-molecular weight HES and second a new third-generation HES preparation
with a lower mean molecular weight and lower degree of substitution than con-
ventional HES specifications.
A second 'message' from the last few years is not to become addicted to the myths
of meta-analyses. What we need are not more meta-analyses continuously pooling
'old' data, mixing them and using more sophisticated statistical methods, but well-
controlled studies in different types of patients (trauma, burns, sepsis, general sur-
gery, cardiac surgery) comparing different types of volume replacement strategies
(cystalloids, albumin, gelatins, dextrans, different HES preparations) with well-de-
fined end-points apart from outcome (Fig. 1). Original research on this problem
may be more useful for improving patient management than will additional meta-
analyses [51].
Reduced
D02 und V02
Fig. 1. Influence of hypovolemia on organ systems. MODS: multiple organ dysfunction syndrome
References
1. Morisaki H, Sibbald WJ (1993) Issues in colloid and transfusion therapy of sepsis. In: Vin-
cent JL (ed) Yearbook of Intensive Care and Emergency Medicine. Springer, Heidelberg,
pp 357-372
2. Fleck A, Raines G, Hawker F, Trotter J, Wallace PI, Ledingham IM (1985) Increased vascu-
lar permeability: a major cause of hypalbuminaemia in disease and injury. Lancet i:781-
784
3. Deane SA, Gaudry PL, Woods P, et al (1988) The management of injuries - a review of
death in hospital. Aust NZ J Surg 58:463-469
4. Task Force of the American College of Critical Care Medicine, Society of Critical Care
Medicine (1999) Practice parameters for hemodynamic support of sepsis in adult patients
in sepsis. Crit Care Med 27:639-660
5. Miletin MS, Steweart TE, Norton PG (2002) Influences on physicians' choices for intrave-
nous colloids. Intensive Care Med 28:917-924
6. Hillman K, Bishop G, Bristow P (1997) The crystalloid versus colloid controvery: present
status. Balliere's Clin Anaesth 11:1-13
7. Ruttmann TG, James MFM, Finlayson J (2002) Effects on coagulation of intravenous crys-
talloid or colloid in patients untergoing peripheral vascular surgery. Br J Anaesth 89:226-
230
8. Ruttmann TG, James MFM, Lombard EM (2001) Haemdilution-induced enhancement of
coagulation is attenuated in vitro by restoring antithrombin III to predilution concentra-
tions. Anaesth Intensive Care 29:489-493
9. Ng KFJ, Lam CCK, Chan LC (2002) In vivo effect of haemodilution with saline on coagula-
tion: a randomized controlled trial. Br J Anaesth 88:475-480
10. Boldt J, Raisch G, Suttner S, Kumle B, Schellhaas A (2002). Are lactated Ringer's solution
and normal saline solution equal with regard to coagulation? Anesth Analg 94:378-384
11. Janvrin SB, Davies G, Greenhalgh RM (1980) Postoperative deep vein thrombosis caused
by intravenous fluids during surgery. Br J Surg 67:690-693
12. deJonge E, Levi M (2001) Effects of different plasma substitutes on blood coagulation: a
comparative review. Crit Care Med 29:1261-1267
13. Treib J, Haass A, Pindur G, et al (1996) All medium starches are not the same: influence of
hydroxyethyl substitution of hydroxyethyl starch on plasma volume, hemorrheologic condi-
tions, and coagulation. Transfusion 36:450-455
14. Stogermiiller B, Stark J, Willschke H, Felfernig M, Hoerauf K, Kozek-Langenecker SA
(2000) The effect of hydroxyethylstarch 200 kDa on platelet function. Anesth Analg
91:823-827
15. Jamnicki M, Bombelli T, Seifert B, et al (2000) Low- and medium-molecular-weight hydro-
xyethylstarches - comparison of their effects on blood coagulation. Anesthesiology
93:1231-1237
16. Wilkes NJ, Woolf RL, Powanda MC, et al (2002) Hydroxyethyl starch in balanced electrolyt
solution (Hextend®) - pharmacokinetic and pharmacodynamic proffies in healthy volun-
teers. Anesth Analg 94:538-544
17. Gan TJ, Bennett-Guerrero E, Phillips-Bute B, et al (1999) Hextend®, a physiologically ba-
lanced plasma expander for large volume use in major surgery: a randomized phase III
clinical trial. Anesth Analg 88:992-998
18. Mahla E, Lag T, Vicenzi M, et al (2001) Thrombelastography for monitoring prolonged hy-
percoagulability after major abdominal surgery. Anesth Analg 92:572-577
19. Martin G, Bennett-Guerrero E, Wakeling H et al (2002) A prospective, randomized compar-
ison of thrombelastographic coagulation proffie in patients receiving lactated Rnger's solu-
tion, 6% hetastarch in a balanced-saline vehicle, or 6% hydroxyethyl starch in saline during
major surgery. J Cardiothorac Vase Anesth 16:441-446
20. Boldt J, Raisch G, Suttner S, Kumle B, Schellhaass F (2002) Effects of a new modified,
balanced hydroxyethyl starch preparation (Hextend®) on measures of coagulation. Br J
Anaesth 89:722-728
602 J. Boldt
21. Waitzinger J, Bepperling F, Pabst G, Opitz J, MUller M, Baron JF (1988) Pharmacokinetics

and tolerability of a new hydroxyethylstarch (HES) specification (HES 130/0.4) after single-
dose infusion of 6 or 1Oo/o solution in healthy volunteers. Clin Drug Invest 16:151-160
22. Franz A, Braunlich P, Gamsjager T, Felfernig M, Gustorff B, Kozek-Langenecker SA (2001)
The effects of hydroxyethyl starches of varying molecular weights on platelet function.
23. Entholzner EK, Mielke LL, Calatzis AN, Feyh J, Hipp R, Hargasser SR (2000) Coagulation
effects of a recently developed hydroxyethyl starch (HES 130/0.4) compared to hydroxethyl
starches with higher molecular weight. Acta Anaesthesiol Scand 44:1116-1121
24. Haisch G, Boldt J, Krebs C, Kumle B, Suttner S, Schulz A (2201) The influence of intravas-
cular volume therapy with a new hydroxyethyl starch preparation (6% HES 130/0.4) on
coagulation in patients undergoing major abdominal surgery. Anesth Analg 92:565-571
24. Haisch G, Boldt J, Krebs C, et al (2001) The influence of a new hydroxyethyl starch pre-
paration (6% HES 130/0.4) on coagulation in cardiac surgical patients. J Cardiothorac Vase
Anesth 15:316-321
25. Langeron 0, Doelberg M, Ang ET, Bonnet F, Capdevila X, Coriat P (2001) Voluven®, a low-
er substituted novel hydroxyethyl starch (HES 130/0.4), causes fewer effects on coagulation
in major orthopedic surgery than HES 200/0.5. Anesth Analg 92:855-862
26. Huet RCGG, Siemons AW, Baus D, et al (2000) A novel hydroxyethyl starch (Voluven®) for
effective perioperative plasma volume substitution in cardiac surgery. Can J Anaesth 47:
1207-1215
27. De Labarthe A, Jacobs F, Blot F, et al (2001) Acute renal failure secondary to hydroxyethyl-
starch administration in a surgical patient. Am J Med 111:417-418
28. Peron S, Mouthon L, Guettier C, et al (2001) Hydroxyethyl starch-induced renal insuffi-
ciency after plasma exchange in a patient with polymyositis and liver cirrhosis. Clin Ne-
phrol 55:408-411
29. Schortgen F, Lacherade JC, Bruneel F, et al (2001) Effects of hydroxyethylstarch and gelatin
on renal function in severe sepsis: a multicenter randomised study. Lancet 357:911-916
30. Boldt J, Lehmann A, Riimpert R, et al (2000) Volume therapy with a new hydroxyethyl
starch solution in cardiac surgical patients before cardiopulmonary. J Cardiothorac Vase
Anesth 14:264-268
31. Dehne MG, Muhling J, Sablotzki A, et al (2001) Hydroxyethylstarch (HES) does not directly
affect renal function in patients with no prior renal impairment. J Clin Anesth 13:103-111
32. Funk W, Baldinger V (1995) Microcirculatory perfusion during volume therapy. Anesthe-
siology 82:975-982
33. Wang P, Hauptman JG, Chaudry IH (1990) Hemorrhage produces depression in microvas-
cular blood flow which persists despite fluid resuscitation. Circ Shock 32:307-318
34. Forrest DM, Baigorri F, Chittock DR, Spinelli JJ, Ruse! JA (2000) Volume expansion using
pentastarch does not change gastric-artial PC0 2 gradient or gastric intramucosal pHi in
patients who have sepsis syndrome. Crit Care Med 28:2254-2258
35. Asfar P, Kerkeni N, Labadie F, Gouello JP, Brenet 0, Alquier P (2000) Assessment of hemo-
dynamic and gastric mucosal acidosis with modified fluid gelatin versus hydroxyethyl
starch: a prospective, randomized study. Intensive Care Med 26:1282-1287
36. Lang K, Boldt J, Suttner S, Haisch G (2001) Colloids versus crystalloids and tissue oxygen
tension in patients undergoing major abdominal surgery. Anesth Analg 93:405-409
37. Prough DS, Bidani A (1999) Hyperchloremic metabolic acidosis is a predictable conse-
quences of intraoperative infusion of 0.9% saline. Anesthesiology 90:1247-1249
38. Takil A, Eti Z, Irmak P, Giigus Y (2002) Early postoperative respiratory acidosis after large
intravascular volume infusion of lactated Ringer's solution during major surgery. Anesth
Analg 95:294-298
39. Rehm M, Orth V, Scheingraber S, Kreimeier U, Brechelsbauer H, Finsterer U (2000) Acid-
base changes cause by 5% albumin versus 6% hydroxyethyl starch solution in patients un-
dergoing acute normovolemic hemodilution. Anesthesiology 93:1174-1183
40. Waters JH, Bernstein CA (2000) Dilutional acidosis following hetastarch or albumin in
healthy volunteers. Anesthesiology 93:1184-1187
41. Waters JH, Gottlieb A, Schoenwald P, Popovich MJ, Sprung J, Nelson DR (2001) Normal
saline versus Ringer's lactate solutions for intraoperative fluid management in patients un-
dergoing abdominal aortic aneurysm repair: an outcome study. Anesth Analg 93:817-822
42. Wilkes NJ, Woolf R, Mutch M, et al (2001) The effects of balanced versus saline-based he-
tastarch and crystalloid solutions on acid-base and electrolyte status and gastric mucosal
perfusion in elderly surgical patients. Anesth Analg 93:811-816
43. Schierhout G, Roberts I (1998) Fluid resuscitation with colloids or crystalloids in critically
ill patients: a systematic review of randomised trials. Br Med J 316:961-964
44. Choi P, Yip G, Quinonez L, Cook D (1999) Crystalloids versus colloids in fluid resuscita-
tion: A systematic review. Crit Care Med 27:200-210
45. Alderson P, Schierhout G, Roberts I, Bunn F (2002) Colloids versus crystalloids for fluid re-
suscitation in critically ill patients. Cochrane Database Syst Rev CD001208
46. Bunn F, Roberts I, Tasker R, Akpa E (2002) Hypertonic versus crystalloid fluid resuscita-
tion in critically ill patients. Cochrane Database Syst Rev CD002045
47. Wade CE, Kramer GC, Grady JJ, Fabian TC, Younes RN (1997) Efficacy of hypertonic 7.5o/o
saline and 6o/o dextran-70 in treating trauma: a meta-analysis of controlled clinical studies.
Surgery 122:609-616
48. Wilkes MM, Navickis RJ (2001) Patient survival after human albumin administration - a
meta-analysis of randomized controlled trials. Ann Intern Med 135:149-164
49. Astiz ME, Rackow EC (1999) Crystalloid-colloid controversy revisited. Crit Care Med
27:34-35
50. Wilkes MM, Navickis RJ, Sibbald WJ (2001) Albumin versus hydroxyethyl starch in cardio-
pulmonary bypass surgery: a meta-analysis of postoperative bleeding. Ann Thorac Surg
72:527-533
51. Cook D, Guyatt G (2001) Editorial: Colloid use for fluid resuscitation: evidence and spin.
Ethyl Pyruvate: A Novel Anti-inflammatory Agent
M.P. Fink
Introduction: Pyruvate is a Scavenger of Reactive Oxygen Species (ROS)

Pyruvate, CH 3 COCoo-, plays a central role in intermediary metabolism, being the
final product of glycolysis and the starting substrate for the tricarboxylic acid
(TCA) cycle. Pyruvate probably also functions in cells as an endogenous antioxi-
dant [1-3]. The capacity of pyruvate to function as an antioxidant was first de-
scribed in 1904 by Holleman, who showed that simple aliphatic a-keto carbox:ylates
reduce hydrogen peroxide (H 2 0 2 ) nonenzymatically in a reaction that yields carbon
dioxide and water [4]. In the case of pyruvate, this reaction is both rapid and stoi-
chiometric [S-7].
Recognition that pyruvate is an effective ROS scavenger prompted investigators
to use this compound as a therapeutic agent for the treatment of various pathologi-
cal conditions that are thought to be mediated, at least in part, by redox-dependent
phenomena. One of the earliest efforts in this regard was carried out by Salahudeen
et al., who showed that infusing a solution of sodium pyruvate preserves kidney
function in rat models of ROS-mediated acute renal failure [8]. Other investigators
reported that treatment with pyruvate ameliorates organ injury or dysfunction in a
variety of other animal models of redox stress, such as myocardial [9], intestinal
[10], or hepatic [11] ischemia/reperfusion (I!R)-induced injury. Sodium pyruvate-
containing solutions also have been shown to have salutary effects in animal mod-
els of galactose- [12] or diabetes-induced cataract formation [13], stroke [14] and
hemorrhagic shock [IS] and in vitro models of damage to the lens of the eye
caused by exposure to galactose [16], fructose [17] or oxidants [18].
Despite these promising findings, the usefulness of pyruvate as a therapeutic
agent is limited by its poor stability in solution. Aqueous solutions of pyruvate rap-
idly undergo an aldol-like condensation reaction to form parapyruvate (2-hydrox:y-
2-methyl-4-ketoglutarate) [19-22], a potentially toxic inhibitor of a critical step in
the mitochondrial TCA cycle [19, 20]. Aqueous solutions of pyruvate also sponta-
neously undergo hydration to form pyruvate hydrate (2,2-dihydroxyproprionate)
[22]. Neither parapyruvate nor pyruvate hydrate are capable of scavenging ROS.
Treatment with Ethyl Pyruvate is Protective in a Rat Model

of Mesenteric Ischemia and Reperfusion
In order to take advantage of the beneficial effects of pyruvate while circumventing
the problem of its poor stability in solution, our laboratory formulated a derivative
of pyruvic acid, namely ethyl pyruvate (EP), in a Ringer's-type Ca2 +- and K+ -con-
Ethyl Pyruvate: A Novel Anti-inflammatory Agent 605
taining balanced salt solution [23]. The therapeutic efficacy of this formulation,
called Ringer's ethyl pyruvate solution (REPS), initially was evaluated in a well-
characterized rat model of mesenteric I/R. Male rats were subjected to 60 min of
mesenteric ischemia followed by 60 min of reperfusion. Controls (n = 6) received
intravenous Ringer's lactate solution (RLS) according to this dosing schedule:
1.5 ml!kg bolus prior to ischemia, 3.0 ml!kg bolus prior to resuscitation, and
1.5 ml!kg· h by continuous infusion. Two experimental groups received similar vol-
umes of either sodium pyruvate solution (n = 6) or REPS (n = 9). To assess mucosal
permeability and histology, five 10 em long segments of small intestine were ob-
tained at the following time points: baseline; after 30 and 60 min of ischemia {I30
and I60, respectively); and after 30 and 60 min of reperfusion (R30 and R60, re-
spectively). Mucosal permeability to a macromolecular hydrophilic tracer, fluores-
cein isothiocyanate-labelled dextran (mw 4000 Da; FD4), was assessed ex vivo using
an everted gut sac method, as previously described by our laboratory [24, 25]. In
controls infused with RLS, mucosal permeability to FD4 increased at I30 by "' 6-
fold and remained significantly greater than the baseline value at all subsequent
time points [23]. Infusion of sodium pyruvate solution or REPS solution signifi-
cantly ameliorated mucosal hyperpermeability at the R30 and R60 time points.
Treatment with EP provided better preservation of normal ileal mucosal histology
than did treatment with sodium pyruvate solution.
1 Resuscitation from Hemorrhagic Shock with an EP-containing

Solution Improves Survival and Ameliorates Intestinal Mucosal
Hyperpermeability in Rats and Mice
We sought to extend our studies with EP, formulated as REPS, to rodent models of
hemorrhagic shock. In the first study in this effort, rats were bled to a mean arteri-
al pressure (MAP) of 40 mmHg until 40% of the shed blood was returned [26].
The animals then were resuscitated over 60 min with the remaining shed blood
plus twice the shed blood volume as either RLS or REPS. Four of 8 (50%) of RLS-
treated rats survived 4 h after resuscitation whereas 7/7 {100%) of REPS-treated
rats survived (p < 0.05). Two similar groups of rats were subjected to the same hem-
orrhagic shock protocol and resuscitated with either RLS (n =4) or REPS (n =5).
The rats were killed 60 min after resuscitation for determination of ileal mucosal
permeability to FD4 and hepatic content of malondialdehyde (MDA), a biochemical
marker of lipid peroxidation. Hepatic MDA content was also determined in samples
from three normal rats. Ileal mucosal permeability determined one hour after re-
suscitation from hemorrhagic shock was significantly greater in rats infused with
RLS as compared with REPS. Subjecting rats to hemorrhagic shock followed by re-
suscitation with RLS significantly increased hepatic MDA content as compared to
the values measured in samples from normal rats. Treatment with REPS, however,
significantly decreased MDA levels, supporting the view that EP is an ROS scaven-
ger.
Our first clue that EP might have anti-inflammatory effects came from a study of
hemorrhagic shock using male C57Bl/6 mice [27]. Blood was withdrawn over
10 min until MAP decreased to 30 mmHg. MAP was maintained at 30 mmHg for
two hours, at which time the animals were resuscitated by administration of all re-
maining shed blood plus twice the shed blood volume of either RLS or REPS. Sham
606 M.P. Fink
0.3 45
40
35
a~E
u u 0.2
0
c ~ 0
0
30
~~ X 25
~c
~ ·e
....
0>
::::>
20
o-- 0.1 u. 15
u.£ v
10
5 t
0 0
a Sham RLS REPS b Sham RLS REPS
Fig. 1. Effect of resuscitation with Ringer's lactate solution (RLS) or Ringer's ethyl pyruvate solution (REPS)
on ileal mucosal permeability (Panel a) and bacterial translocation to mesenteric lymph nodes (Panel b)
assessed 4 h after the end of shock. Three groups of mice were studied. Sham (n = 7) were subjected to
anesthesia and vascular cannulation but not subjected to hemorrhagic shock. RLS (n = 12) were subjected
to hemorrhagic shock for 2 h and resuscitated with RLS. REPS (n = 8) were subjected to hemorrhagic
shock for 2 h and resuscitated with REPS. Results are means± SE. * indicates p <0 .05 versus Sham group.
t indicates p < 0.05 versus RLS group. CFU: colony forming units. From [27] with permission
600 •
500
400
..._
~
2 300
~
<(
200 Fig. 2. Effect of resuscitation with Ringer's lac-
tate solution (RLS) or Ringer's ethyl pyruvate so-
100
lution (REPS) on circulating alanine aminotrans-
0 ferase (ALT) concentration assessed 4 h after
the end of shock. Groups and symbols are the
same as in Figure 1. From [27] with permission
controls were subjected to the same anesthetic and cannulation procedures, but
were not subjected to hemorrhagic shock. In a preliminary experiment designed to
assess the affect of REPS on mortality in this model, five (50%) of 10 mice sub-
jected to hemorrhagic shock and resuscitated with RLS survived for 24 hours,
whereas 11 (92%) of 12 hemorrhaged mice resuscitated with REPS survived
(p = 0.029). In a subsequent study, the mice were sacrificed four hours after resusci-
tation (or sham resuscitation). Treatment with REPS instead of RLS prevented the
development of ileal mucosal hyperpermeability to FD4 following resuscitation
from hemorrhagic shock (Fig. 1A). In addition, bacterial translocation to mesenter-
ic lymph nodes, which was extensive in the RLS group, was virtually abrogated
when the shocked mice were resuscitated with REPS (Fig. 18). The mean plasma
alanine aminotransferase (ALT) concentration was significantly greater in the RLS
group than in the sham-operated control group (Fig. 2). However, plasma levels of
Liver Ileum Colon Liver

r-------A-------~ r------~----~ r------A------~~
E VI VI 0
E VI
"' 0 E VI
"' 0 <Xl
"'+ "' "'+
_J 10 _J 10 _J 10
¥ J..
"'
.r;
VI
a: CL
+
CL
"'
.r;
VI
a: CL
+
CL
+ "'
.r;
VI
a: CL
+
CL
u.
z :X:
a "'a:
_J
VI
_J
a:
VI
_J
a:
VI
_J
a:
VI
_J
a:
VI
_J
a:
"0
0
"0
0
u u
Liver Ileum Colon

~~ ~
V"' V"' V"' V"' VI

CL _J _J
b UJ a: CL
UJ a:
CL
w
a: a: a:
Fig. 3. Effects of hemorrhagic shock and resuscitation on DNA binding of NF-KB in liver, ileal mucosa,
and colonic mucosa. Electrophoretic mobility shift assay (EMSA) was performed using nuclear extracts pre-
pared from tissues obtained 4 h after starting resuscitation or 4 h after the end of the sham procedure.
Panel a compares samples obtained from animals in the Sham and Ringer's lactate solution (RLS) groups,
and also depicts the results of supershift assays using antibodies against the p65 and pSO subunits of
NF-KB. Shown as well are the results of cold competition experiments using a 100-fold molar excess of
either unlabeled (specific) NF-KB duplex oligonucleotide or unlabeled (nonspecific) hypoxia-inducible fac-
tor (HIF)-1 duplex oligonucleotide. Panel b compares samples obtained from animals in the RLS and Rin-
ger's ethyl pyruvate solution (REPS) groups. Reprinted from [27] with permission
this marker of hepatocellular injury were significantly lower in the REPS group
than in the RLS group. Hemorrhagic shock and resuscitation is associated with
activation of the pro-inflammatory transcription factor, nuclear factor kappa B
(NF-KB) [28, 29]. Resuscitation with REPS instead of RLS decreased NF-KB activa-
tion in liver and colonic mucosa (Fig. 3). Resuscitation with REPS instead of RLS
also decreased tumor necrosis factor (TNF), cyclooxygenase (COX)-2, inducible ni-
tric oxide synthase (iNOS), and interleukin (IL)-6 mRNA expression in liver, ileal
mucosa or colonic mucosa, as determined by semiquantitative reverse transcription
and polymerase chain reaction (RT-PCR). Hepatic, ileal mucosal, and colonic mu-
cosal IL-6 mRNA levels increased in hemorrhaged mice resuscitated with RLS but
not those resuscitated with REPS (Fig. 4).
608 M.P. Fink
2.5
~ 2.0
·v;
c IL-6
<11
"tl 1.5
..
<11
> 1.0
Liver
18S
"iii
cc
"' 0.5
0
a RLS REPS
0.30
-~ 0.25
"'c<11 0.20 IL-6
"tl
<11 0.15
...> 0.10
Ileum
"'
"iii
cc 0.05 18S
0
b Sham RLS REPS
0.18
~ 0.16
·v; 0.14
c 0.12 IL-6
<11
"tl 0.10
<11 Colon
.2: 0.08
:;; 0.06
"iii 0.04
cc 0.02 18S
0
c
"'cc_,
Sham RLS REPS E "'w
Cl.
"'
..c cc
"'
Fig. 4. Expression of ll-6 mRNA in samples of hepatic (Panel a), ileal mucosal (Panel b) and colonic mu-
cosal (Panel c) tissue from mice subjected to HS/R or the sham procedure. Results were obtained using
semi-quantitative RT-PCR. Bands visualized after agarose gel electrophoresis of PCR reaction products were
scanned using a NucleoVision imaging workstation and quantified using GeiExpert™ release 3.5. Data in
bar graphs are means± SE (n = 4 per condition). Representative gels are depicted. Reprinted from [27]
with permission
I Resuscitation with REPS Prolongs Survival and Modulates Plasma

Cytokine and Nitrite/Nitrate Concentrations in a Rat Model
of Lipopolysaccharide-induced Shock
Further evidence that EP has anti-inflammatory activity came from a study of pro-
found shock induced by injecting male Sprague-Dawley rats with a large intrave-
nous bolus (20 mg/kg) of lipopolysaccharide (LPS) [30]. When MAP decreased to
60 mmHg, 3-5 ml boluses of either REPS (n=lO) or RLS (n=lO) were infused as
needed to prevent MAP from decreasing further. By design, the maximal volume of
fluid infused was 7 ml!kg and was the same in both groups. Resuscitation with
REPS as compared to .RLS prolonged survival (498 ± 48 versus 362 ± 30 min;
p=O.OOl), and was associated with significantly lower plasma levels of nitrite/ni-
---~--~~~~,--~--~~"~,-~
trate (marker of NO production) and IL-6 and higher levels of the anti-inflamma-
tory cytokine, IL-10.
Delayed Treatment with EP Improves Survival in Mice

with Established Lethal Sepsis
The notion that EP has anti-inflammatory effects was further substantiated by in
vitro studies showing that EP inhibits activation of two important pro-inflamma-
tory signaling molecules, namely NF-KB and p38 mitogen-activated protein kinase
(MAPK), in LPS-stimulated RAW 264.7 murine macrophage-like cells [31]. In order
to extend these observations to an in vivo system, Balb/c mice received graded
doses of EP followed 30 min later by an injection of E. coli LPS (5 mg/kg, i.p.) [31].
Pretreatment with a single dose of EP (40 mg/kg) conferred significant protection
from lethal endotoxemia (p<O.OOS). A lower dose of EP (4 mg/kg) provided partial
protection. Pretreatment of endotoxemic mice with EP (40 mg/kg, i.p.) significantly
decreased serum levels of both TNF and high mobility group protein (HMG)Bl.
The latter protein was recently identified as a late-acting cytokine-like mediator of
LPS-induced lethality [32]. When treatment was delayed until four hours after the
onset of endotoxemia (i.e., after the monophasic spike in TNF release induced by
LPS injection), EP still afforded significant protection against mortality. This obser-
vation suggested that delayed therapy with EP might block the release of HMGBl.
This idea was subsequently confirmed by showing that treatment with EP begin-
ning four hours after LPS injection significantly attenuated the systemic release of
HMGB1 measured at 20 h after the onset of endotoxemia.
Endotoxemia in rodents is a useful paradigm for studying inflammation in vivo,
but probably is not an ideal animal model of serious infection in humans [33]. Ac-
cordingly, we also evaluated the effects of EP in mice with peritonitis induced by
cecal ligation and perforation (CLP), a widely accepted model of human polymicro-
bial sepsis. Anesthetized mice underwent CLP. All animals received a single injec-
tion of the antibiotic, imipenem (0.5 mg/kg) 12 hours later. All animals were resus-
citated with normal saline (20 ml!kg) 24 hours after surgery. Injections of vehicle
or graded doses of EP (0.4-40 mg/kg per dose) were given at 24, 30, 48 and 54 h
after CLP. Delayed treatment with the highest dose of EP (40 mg/kg per dose) sig-
nificantly improved survival. Studies using separate groups of mice subjected to
CLP showed that treatment with EP (40 mg/kg) starting 24 h after the onset of sep-
sis significantly decreased circulating levels of HMGB1 measured at 30 h. At pres-
ent, EP is the only known compound that is capable of inhibiting the release of
HMGB1 in vitro and in vivo.
Delayed Treatment with EP Ameliorates LPS-induced Gut Mucosal

Hyperpermeability in Mice
We [34, 35] and others [36, 37] have shown that administration of LPS to rodents
increases intestinal mucosal permeability to various hydrophilic macromolecules,
such as FD4. Accordingly, we sought to determine whether treatment with EP could
ameliorate this deleterious effect of LPS administration [38]. Four groups of mice
(n = 5 each) were studied. All of the agents were injected intraperitoneally. Each an-
610 M.P. Fink
imal in the control group was injected with 1.0 ml of phosphate-buffered saline
(PBS) and then with 0.31 ml of RLS 1, 6, and at 12 h later. Each mouse in the
LPS + RLS group was injected with 1.0 ml of a well-sonicated suspension of LPS
(0.1 mg!ml; 4 mg!kg) in PBS. One, 6, and 12 h later, these mice were injected with
0.31 ml of RLS. Mice in the early EP (LPS+EARLY EP) group were injected with
the same dose of LPS suspension and then were injected with 0.31 ml of a solution
of EP (3.23 mgfml; 40 mg!kg) 1, 6, and 12 h later. The EP was dissolved in a bal-
anced salt solution containing 130 mM NaCl, 4 mM KCl, and 2.7 mM CaCh. Mice
in the late EP (LPS +LATE EP) group were injected with the same dose of LPS and
then 6 and 12 h later with 0.31 ml per dose of EP solution. Eighteen hours after
the injection of LPS (or the PBS vehicle in the control group}, the mice were
anesthetized with intramuscular injections of sodium pentobarbital (90 mg/kg},
and segments of ileum were excised for determination of mucosal permeability
using an everted gut sac method and the mesenteric lymph node complex was har-
vested to measure bacterial translocation. Delayed treatment with EP beginning
either 1 or even 6 h after the onset of endotoxemia significantly ameliorated LPS-
induced gut mucosal hyperpermeability and bacterial translocation.
I Pyruvate and Pyruvate Esters have Distinct Pharmacological Effects
Following stimulation with "cytomix" (a cocktail of cytokines containing interferon

[IFN]-y, IL-1P and TNF}, monolayers of Caco-2 human enterocyte-like cells mani-
fest increased permeability to hydrophilic probes, such as FD4 [39]. Co-incubation
of the cells with EP - but not added sodium pyruvate - prevents the development
of hyperpermeability in this reductionist model of altered intestinal epithelial bar-
rier function induced by pro-inflammatory mediators [38]. In another system, mes-
enteric 1/R-induced ileal epithelial injury in rats, EP is clearly more effective on a
millimole-for-millimole basis than is sodium pyruvate [23]. Similar findings indi-
cating that EP is more effective than sodium pyruvate were reported by Varma et
al., who compared the two compounds in an in vitro study of redox-mediated cellu-
lar injury [18]. In other words, our laboratory's data as well as some published
findings by others suggest that the pharmacological effects of EP are distinct from
those of pyruvate.
Given their close chemical similarity, it is remarkable that differential pharmaco-
logical effects have been observed when EP and pyruvate have been compared
head-to-head in models of inflammation and/or redox stress. Nevertheless, there
are data from studies in a totally unrelated field - the regulation of insulin secretion
by pancreatic islet cells - that support the idea that the pharmacological actions of
pyruvate esters are quite distinct from those of pyruvate anion. In 1996, Mertz et
al. reported that insulin secretion by cultured mouse pancreatic islet cells is stimulat-
ed by adding methyl pyruvate but not sodium pyruvate to the culture medium [40].
These investigators further showed that methyl pyruvate, but not sodium pyruvate,
causes closure of ATP-sensitive potassium channels, triggers a sustained rise in intra-
cellular calcium ion concentration, and increases insulin secretion more effectively
than glucose. Zawalich and Zawalich subsequently showed that methyl pyruvate,
but not sodium pyruvate, is a potent insulin secretagogue in freshly isolated rat pan-
creatic islet cells [41]. The authors of this study speculated that methylation renders
pyruvate more "membrane-permeable" and thereby allows higher levels of the com-
pound to accumulate in mitochondria. Recently, however, Lembert et al. showed that

there is no difference in the rate of ATP production by isolated pancreatic P-cell mi-
tochondria following incubation with pyruvate as compared to methyl pyruvate, sug-
gesting that both compounds readily enter mitochondria and support oxidative phos-
phorylation to an equal extent [42]. Thus, the differential permeability hypothesis
seems unlikely to be right, and it is more probable that esters of pyruvate are phar-
macologically distinct from pyruvate anion because they interact in a different way
with one or more intracellular molecular targets.
I How does EP Inhibit Activation of NF-KB?
As noted above, EP inhibits activation of the key pro-inflammatory transcription

factor, NF-KB, in a variety of in vitro and in vivo systems. EP, like pyruvate, is an
anti-oxidant [18, 26]. Thus, it is possible that EP inhibits activation of NF-KB (and
perhaps other signaling pathways as well) by scavenging ROS. Several observations,
however, suggest that EP-mediated inhibition of NF-KB activation may entail more
than an anti-oxidant effect. First, oxidant stress (1-10 mM H2 0 2 } fails to activate
NF-KB in Caco-2 [43] or DLD-1 (44] enterocyte-like cells, yet EP blocks activation
of NF-KB in cytomix-stimulated Caco-2 cells [38]. Second, other well known ROS
scavengers, such as pyrollidine dithiocarbamate and dimethyl sulfoxide, fail to
block IL-1/J-induced NF-KB activation in Caco-2 cells [43], yet EP effectively inhib-
its cytomix-induced NF-KB activation in this same cell line [38]. Third, N-acetyl-
cysteine (NAC), an effective ROS scavenger, fails to inhibit activation of NF-KB in-
duced by TNF or IL-1/J in ECV304 endothelial cells [45]. NAC also fails to block
LPS-induced NF-KB activation in J 774.1 murine macrophage-like cells [46]. In con-
trast, EP inhibits activation of NF-KB induced by cytomix (TNF, IL-1/J, and IFN-y)
in Caco-2 cells [38] or by LPS in RAW 264.7 murine macrophage-like cells [31].
Since EP is such a simple molecule, what possible mechanism other than ROS
scavenging could explain its ability to inhibit NF-KB activation? One hypothesis is
suggested by recent observations, regarding the mechanism of action of partheno-
lide and other sesquiterpene lactones that inhibit NF-KB activation. These agents
alkylate a critical cysteine residue (Cys 38 } in the p65 subunit, and thereby interfere
with DNA binding by activated NF-KB heterodimers [47-49]. The key functionality
in this class of NF-KB inhibitors is an exocyclic methylene group conjugated to a
carbonyl group. This highly reactive pharmacophore reacts with nucleophiles, espe-
cially cysteine sulfhydryl groups, in a Michael-type addition [50-52].
EP, but not pyruvate, bears some chemical similarity to parthenolide and related
compounds. Like most ketones, pyruvate can exist in two tautomeric forms: ketone
or enol. In an aqueous solvent at physiologic pH, the keto H enol equilibrium for
pyruvate lies very far to the left (i.e., in favor of the keto tautomer) [53, 54]. Enoli-
zation of pyruvate is thermodynamically unfavorable, in part, because the conju-
gated carboxyl groups in the keto form help to delocalize the negative charge of
the carboxylate anion. EP, however, cannot form a carboxylate anion; hence, enoli-
zation is thermodynamically more favorable. Furthermore, the enolate anion, which
results from dissociation of the 2-hydroxy proton of the enol form of EP, is stabi-
lized by the presence of divalent metal cations, such as Mg2 + or Ca2 + [55, 56]. In
its enol configuration, EP bears structural resemblance to the active site of parthe-
nolide. Accordingly, it is conceivable that some of the biological effects of EP are
612 M.P. Fink
mediated by alkylation of p65. By the same token, several other NF-KB inhibitors,
such as the alkylating agents, 2-chloro-1,3-dinitrobenzene and N-ethylmaleimide
[57], inhibit NF-KB DNA binding by modifying a key thiol group (Cys 62 ) in the
pSO subunit. Thus, it also is conceivable that EP inhibits activation of NF-KB via
this mechanism.
Acknowledgements. This work was supported by grants from the NIH (GM53789,
GM37631 and GM58484) and DARPA (N65236-00-1-5434). Drs. Runkuan Yang, Pen-
ny L. Sappington, Luis Ulloa, Kevin J. Tracey, Russell L. Delude, Alfred Ajami, Car-
rie Sims and Xiaonan Han all played invaluable roles in generating the data and/or
the ideas that form the basis for this manuscript.
References
1. O'Donnell-Tormey J, Nathan CF, Lanks K, DeBois CJ, de la Harpe J (1987) Secretion of
pyruvate. An antioxidant defense of mammalian cells. J Exp Med 165:500-514
2. Brand KA (1997) Aerobic glycolysis by proliferating cells: protection against oxidative
stress at the expense of energy yield. J Bioenerg Biomembr 29:355-364
3. Brand KA, Hermfisse U (1997) Aerobic glycolysis by proliferating cells: a protective strat-
egy against reactive oxygen species. FASEB J 11:388-395
4. Holleman MAF (1904) Notice sur !'action de l'eau oxygenee sur les acetoniques et sur le
dicetones 1.2. Reel Trav Chim Pays-bas Belg 23:169-171
5. Adickes F, Andresen G (1943) Zur kenntnis der reihe der normalen aliphatischen fl-oxysau-
ren und der a-ketosauren. Ann Chern 50:41-57
6. Bunton CA (1949) Oxidation of a-diketones and a-keto-acids by hydrogen peroxide. Nature
163:144
7. Melzer E, Schmidt H (1988) Carbon isotope effects on the decarboxylation of carboxylic
acids. Biochem J 252:913-915
8. Salahudeen AK, Clark EC, Nath KA (1991) Hydrogen peroxide-induced renal injury. A pro-
tective role for pyruvate in vitro and in vivo. J Clin Invest 88:1886-1893
9. Bunger R, Mallet RT, Hartman DA (1989) Pyruvate-enhanced phosphorylation potential
and inotropism in normoxic and postischemic isolated working heart. Near-complete pre-
vention of reperfusion contractile failure. Eur J Biochem 180:221-233
10. Cicalese L, Lee K, Schraut W, Watkins S, Borle A, Stanko R (1999) Pyruvate prevents ische-
mia-reperfusion mucosal injury of rat small intestine. Am J Surg 171:97-100
11. Sileri P, Schena S, Morini S, et al (2001) Pyruvate inhibits hepatic ischemia-reperfusion
injury in rats. Transplantation 72:27-30
12. Gupta SK, Mohanty I, Trivedi D, Tandon R, Srivastava S, Joshi S (2002) Pyruvate inhibits
galactosemic changes in cultured cat lens epithelial cells. Ophthalmic Res 34:23-28
13. Zhao W, Devamanoharan PS, Henein M, Ali AH, Varma SD (2000) Diabetes-induced bio-
chemical changes in rat lens: attenuation of cataractogenesis by pyruvate. Diabetes Obes
Metab 2:165-174
14. Lee JY, Kim YH, Koh JY (2001) Protection by pyruvate against transient forebrain ischemia
in rats. J Neurosci 21:1-6
15. Slovin PN, Huang CJ, Cade JR, et al (2001) Sodium pyruvate is better than sodium chlor-
ide as a resuscitation solution in a rodent model of profound hemorrhagic shock. Resusci-
tation 50:109-115
16. Varma SD, Devamanoharan PS, Rutzen AR, Ali AH, Henein M (1999) Attenuation of galac-
tose-induced cataract by pyruvate. Free Rad Res 30:253-263
17. Zhao W, Devamanoharan PS, Varma SD (2000) Fructose induced deactivation of antioxi-
dant enzymes: preventive effect of pyruvate. Free Rad Res 33:23-30
18. Varma SD, Devamanoharan PS, Ali AH {1998) Prevention of intracellular oxidative stress
to lens by pyruvate and its ester. Free'Rad Res 28:131-135
19. Montgomery CM, Webb JL (1956) Metabolic studies on heart mitochondria. II. The inhibi-
tory action of parapyruvate on the tricarboxylic acid cycle. J Biol Chern 221:359-368
20. Montgomery CM, Fairhurst AS, Webb JL (1956) Metabolic studies on heart mitochondria.
III. The action of parapyruvate on a-ketoglutaric oxidase. J Biol Chern 221:369-376
21. Willems JL, de Kort AFM, Vree TB, Trijbels JMF, Veerkamp JH, Monnens LAH (1978) Non-
enzymatic conversion of pyruvate in aqueous solution to 2,4-dihydroxy-2-methylglutaric
acid. FEBS Lett 86:42-44
22. Margolis SA, Coxon B (1986) Identification and quantitation of the impurities in sodium
pyruvate. Anal Biochem 58:2504-2510
23. Sims CA, Wattanasirichaigoon S, Menconi MJ, Ajami AM, Fink MP (2001) Ringer's ethyl
pyruvate solution ameliorates ischemia/reperfusion-induced intestinal mucosal injury in
rats. Crit Care Med 29:1513-1518
24. Wattanasirichaigoon S, Menconi MJ, Delude RL, Fink MP (1999) Effect of mesenteric ische-
mia and reperfusion or hemorrhagic shock on intestinal mucosal permeability and ATP
content in rats. Shock 12:127-133
25. Wattanasirichaigoon S, Menconi MJ, Delude RL, Fink MP (1999) Lisofylline ameliorates in-
testinal mucosal barrier dysfunction caused by ischemia and ischemia/reperfusion. Shock
11:269-275
26. Tawadrous ZS, Delude RL, Fink MP (2002) Resuscitation from hemorrhagic shock with
Ringer's ethyl pyruvate solution improves survival and ameliorates intestinal mucosal hy-
perpermeability in rats. Shock 17:473-477
27. Yang R, Gallo DJ, Baust JJ, et al (2002) Ethyl pyruvate modulates inflammatory gene ex-
pression in mice subjected to hemorrhagic shock. Am J Physiol 283:G212-G222
28. Meldrum DR, Shenkar R, Sheridan BC, Cain BS, Abraham E, Harken AH (1997) Hemor-
rhage activates myocardial NF-kappaB and increases TNF-alpha in the heart. J Mol Cell
Cardiol 29:2849-2854
29. Hierholzer C, Harbrecht B, Menezes JM, et al (1998) Essential role of induced nitric oxide
in the initiation of the inflammatory response after hemorrhagic shock. J Exp Med 187:
917-928
30. Venkataraman R, Kellum JA, Song M, Fink MP (2002) Resuscitation with Ringer's ethyl
pyruvate solution prolongs survival and modulates plasma cytokine and nitrite/nitrate con-
centrations in a rat model of lipopolysaccharide-induced shock. Shock 18:507-512
31. Ulloa L, Ochani M, Yang H, et al (2002) Ethyl pyruvate prevents lethality in mice with es-
tablished lethal sepsis and systemic inflammation. Proc Natl Acad Sci USA 99:12351-12356
32. Wang H, Bloom 0, Zhang M, et al (1999) HMG-1 as a late mediator of endotoxin lethality
in mice. Science 285:248-251
33. Fink MP, Heard SO (1990) Research review: laboratory models of sepsis and septic shock.
J Surg Res 49:186-196
34. Unno N, Wang H, Menconi MJ, et al (1997) Inhibition of inducible nitric oxide synthase
ameliorates lipopolysaccharide-induced gut mucosal barrier dysfunction in rats. Gastroen-
terology 113:1246-1257
35. Sappington PL, Yang R, Yang H, Tracey KJ, Delude RL, Fink MP (2002) HMGB1 B box in-
creases the permeability of Caco-2 enterocytic monolayers and impairs intestinal barrier
function in mice. Gastroenterology 123:790-802
36. Casellas F, Aguade S, Soriano B, Accarino A, Molero J, Guarner L (1986) Intestinal perme-
ability to 99"'Tc-diethylenetriaminopentaacetic acid in inflammatory bowel disease. Am J
Gastroenterol 81:767-770
37. Deitch EA, Specian RD, Berg RD (1991) Endotoxin-induced bacterial translocation and mu-
cosal permeability: role of xanthine oxidase, complement activation, and macrophage pro-
ducts. Crit Care Med 19:785-791
38. Sappington PL, Han X, Yang R, Delude RL, Fink MP (2003) Ethyl pyruvate ameliorates in-
testinal epithelial barrier dysfunction in endotoxemic mice and immunostimulated Caco-2
enterocytic monolayers. J Pharmacal Exp Ther 304:464-476
39. Chavez A, Menconi MJ, Hodin RA, Fink MP (1999) Cytokine-induced epithelial hyperper-
meability: role of nitric oxide. Crit Care Med 27:2246-2251
40. Mertz RJ, Worley JFI, Spencer B, Johnson JH, Dukes ID (1996) Activation of stimulus-
secretion coupling in pancreatic P-cells by specific products of glucose metabolism. J Biol
Chern 271:4838-4845
614 M.P. Fink: Ethyl Pyruvate: A Novel Anti-inflammatory Agent
41. Zawalich WS, Zawalich KC (1997) Influence of pyruvic acid methyl ester on rat pancreatic
islets. Effects on insulin secretion, phosphoinositide hydrolysis, and sensitization of the
beta cell. J Bioi Chern 272:3527-3531
42. Lembert N, Joos HC, !dahl L-A, Ammon HPT, Wahl MA {2001) Methyl pyruvate initiates
membrane depolarization and insulin release by metabolic factors other than ATP. Bio-
chem J 354:345-350
43. Parikh AA, Moon MR, Pritts TA, et al {2000) IL-1beta induction of NF-kappaB activation
in human intestinal epithelial cells is independent of oxyradical signaling. Shock 13:8-13
44. Salzman AL, Denenberg AG, Ueta I, O'Connor M, Linn SC, Szabo C {1996) Induction and
activity of nitric oxide synthase in cultured human intestinal epithelial monolayers. Am J
Physiol 270:G565-G573
45. Bowie AG, Moynagh PN, O'Neill LAJ (1997) Lipid peroxidation is involved in the activation
of NF-KB by tumor necrosis factor but not interleukin-1 in the human endothelial cell line
ECV304. J Bioi Chern 272:25941-25950
46. Chandel NS, Trzyna WC, McClintock DS, Schumacker PT (2000) Role of oxidants in NF-
kappa B activation and TNF-alpha gene transcription induced by hypoxia and endotoxin. J
Immunol165:1013-1021
47. Lyss G, Knorre A, Schmidt TJ, Pahl HL, Merfort I {1998) The anti-inflammatory sesquiter-
pene lactone helenalin inhibits the transcription factor NF-kappaB by directly targeting
p65. J Bioi Chern 273:33508-33516
48. Schmidt TJ, Lyss G, Pahl HL, Merfort I {1999) Helenanolide type sesquiterpene lactones.
Part 5: the role of glutathione addition under physiological conditions. Bioorg Med Chern
7:2849-2855
49. Garcia-Pineres AJ, Castro V, Mora G, et al {2001) Cysteine 38 in p65/NF-kappaB plays a
crucial role in DNA binding inhibition by sesquiterpene lactones. J Bioi Chern 276:39713-
39720
50. Dupuis G, Mitchell JC, Towers GH {1974) Reaction of alantolactone, an allergenic sesquiter-
pene lactone, with some amino acids. Resultant loss of immunologic reactivity. Can J Bio-
chem 52:575-581
51. Hay AJB, Hamburger M, Hostettmann K, Hoult JRS (1994) Toxic inhibition of smooth
muscle contractility by plant-derived sesquiterpenes caused by their chemically reactive
alpha-methylenebutyrolactone functions. Br J Pharmacol112:9-12
52. Schmidt TJ {1999) Toxic activities of sesquiterpene lactones: structural and biochemical
aspects. Curr Org Chern 3:577-608
53. Chiang Y, Kresge AJ, Pruszynski P {1992) Keto-enol equilibria in the pyruvic acid system:
determination of the keto-enol equilibrium constants of pyruvic acid and pyruvate anion
and the acidity constant of pyruvate enol in aqueous solution. JAm Chern Soc 114:3103-
3107
54. Keeffe JR, Kresge AJ, Schepp NP {1990) Keto-enol equilibrium constants of simple mono-
functional aldehydes and ketones in aqueous solution. J Am Chern Soc 112:4862-4868
55. Hynes MJ, O'Regan BD {1979) Kinetics and mechanisms of the reactions of nickel(II) and
pentane-2,4-dione. J Chern Soc, Dalton Trans 162-166
56. Hynes MJ, O'Shea MT (1983) Kinetics and mechanisms of the reactions of nickel(II), co-
balt(II), copper(II), and iron(III) with 1,1,1-trifluoropentane-2,4-dione. J Chern Soc, Dalton
Trans 331-336
57. Brennan P, O'Neill LA (1998) Inhibition of nuclear factor kappaB by direct modification in
whole cells - mechanism of action of nordihydroguaiaritic acid, curcurnin and thiol modi-
fiers. Biochem Pharmacol 55:965-973
Clinical Use of Artificial Oxygen Carriers
N. Dettori, R. Kocian, and D. R. Spahn
I Introduction
Artificial oxygen carriers aim at improving oxygen delivery (D0 2 ). Artificial oxygen
carriers, therefore, may be used as an alternative to allogeneic blood transfusions
or to improve tissue oxygenation and function of organs with marginal oxygen
supply [1, 2]. Modified hemoglobin solutions and perfluorocarbon (PFC) emulsions
are currently undergoing clinical testing. This chapter is based on a recent review
article [3] where more detailed references may be found. Current knowledge of ar-
tifical oxygen carriers is based on published data from approximately 500-1000 pa-
tients treated with these compounds and a similar number of control patients. Un-
fortunately, there is still a significant amount of non-published data that renders
the overall assessment of these solutions difficult.
The concept of augmented acute normovolemic hemodilution (augmented
ANH™) will also be discussed. In augmented ANH, patients are hemodiluted prior
to surgery. During the course of the intervention, a further reduction is expected
in the hemoglobin concentration. In order to maintain tissue oxygenation, an artifi-
cial oxygen carrier is administered. The autologous blood harvested during pre-
1.0
c0 0.8
·;::
u
~ 0.6
~
c:
0
·;:: 0.4
~
a 0 - raffinose polymerized Hb
"'
<1\
0.2
0
0 5 10 15 20
P02 (kPa)
Fig. 1. Oxygen dissociation curve of native human blood (Human RBCs) and different modified Hb solu-
tions (PEG-Hb, a-a cross-linked Hb and 0-raffinose polymerized Hb) (modified from [4] with permission)
616 N. Dettori et al.
20 Blood
5 Vol %, 0 2 - Ex. '" 25 %
=c
--
].
15
ccu
c
0
10
u
N
0
50
0
0 20 40 60 80
P0 2 (kPa)
Fig. 2. Oxygen dissociation curve of native human blood (Blood) [21] and perflubron emulsion (PFC) [17].
5 Vol% of oxygen can be offloaded by blood and by perflubron emulsion. With perflubron emulsion,
however, higher arterial oxygen partial pressure (P0 2) values are required. Perflubron emulsion-transported
oxygen is more completely off-loaded than blood-transported oxygen resulting in approximate oxygen ex-
traction (OrEx.) ratios of 90% and 25%
operative hemodilution is finally re-transfused at the end of surgery. Thereby, the

need for allogeneic blood transfusion is reduced.
Artificial oxygen carriers can be divided into two principal groups: solutions of
modified hemoglobin and emulsions of PFC. Hemoglobin may originate from out-
dated human blood, be of bovine origin or genetically engineered [1, 2, 4]. The
molecule of native human hemoglobin must be modified in order to decrease oxy-
gen affinity and to prevent rapid dissociation of the native az-fJ2 tetramer into a-fJ
dimers. This topic has been reviewed in detail previously [1, 2, 4].
The characteristics of oxygen transport by modified hemoglobin solutions and
PFC emulsions are fundamentally different. The majority of hemoglobin solutions
exhibit a sigmoidal oxygen dissociation curve, similar to blood (Fig. 1). PFC emul-
sions are, on the other hand, characterized by a linear relationship between oxygen
partial pressure (P0 2 ) and oxygen content. Thus, the majority of the hemoglobin
solutions have oxygen transport and unloading capacities similar to those of blood
(Fig. 2). This indicates that even for a relatively low P0 2, a substantial quantity of
oxygen is transported, contrary to PFC emulsions, which require a relatively high
P0 2 to optimize the transport of oxygen.
I Hemoglobin Solutions
The efficacy of hemoglobin solutions to transport and release oxygen in the tissues
has been shown in a variety of studies on animal models, including extreme hemo-
dilution, hemorrhage, surgical trauma and sepsis (referenced in [3]). It has been
deonstrated that treatment with a-a-Diaspirin cross linked hemoglobin (DCLHb)
improves wound healing, stimulates proliferation of hepatic cells, and decreases
splanchnic bacterial translocation, in comparison with transfusion of fresh auto-
logous blood. In septic oxygen supply dependent rats, the administration of DCLHb
increased oxygen uptake similar to transfusion of fresh ( < 6 days old) red blood
cells (RBCs) whereas animals treated with stored RBCs presented a high mortality.
Furthermore, DCLHb enabled extreme, virtually RBC free, hemodilution in pigs
with no subendocardial ischemia at a hematocrit of 1o/o. In a similar model, but
with critical coronary stenosis, pigs resuscitated with DCLHb survived experimen-
tal hemorrhagic shock more frequently than animals resuscitated with albumin.
Therefore, modified hemoglobin solutions improved oxygen transport and tissue
oxygenation. Moreover, as they do not require cross-matching, these, solutions hold
promise as an interesting alternative to allogeneic blood transfusions and as oxygen
therapeutics, which migh be of great importantce also in the pre-hospital resuscita-
tion of trauma victims or for specific conditions in intensive care medicine.
Due to genetic or chemical modifications of the native hemoglobin molecules,
which largely prevents degradation of the arP2 tetramer into a-P dimers, nephro-
toxicity is no longer a complication of these solutions [5]. On the other hand, all
these solutions induce, by vasoconstriction, an increase in the systemic and pulmo-
nary artery pressure (PAP). The mechanisms involved include nitric oxide {NO)
scavenging, endothelin release and a sensitization of peripheral a-adrenergic recep-
tors [1, 2, 4]. NO produced by the endothelial cells is intended to react with the
Fe2 + in the guanylate cyclase located in the smooth muscle cells of the vessel wall
to modulate the vascular tone towards vasodilation. It has been speculated that, in
particular unpolymerized, hemoglobin molecules may penetrate into the suben-
dothelial layers of vessel walls to scavenge NO and thus to induce vasoconstriction.
Although the pressure response of hemoglobin solutions may be minimized by gen-
eral anesthesia, vasoconstriction remains a limitation in the development of hemo-
globin based oxygen carriers [6] since any increase in blood pressure may aggra-
vate blood loss in trauma victims and compromise survival. Indeed, a study in
trauma victims was terminated prematurely due to an increased mortality in pa-
tients treated with DCLHb [7], and the development of this hemoglobin solution
has now been stopped [8].
Nevertheless, allogeneic blood transfusion may be reduced with the use of
DCLHb in patients undergoing cardiac surgery [8]. In a prospective, randomized
multicenter study, 209 patients were allocated to receive either packed allogeneic
RBCs or up to 750 ml of a 10o/o DCLHb solution when reaching a defined transfu-
sion trigger following cardiopulmonary bypass. In the DCLHb group, 59o/o of pa-
tients avoided allogeneic blood transfusions until the first postoperative day, while,
by study protocol, 100o/o of patients randomized to the control group had been
transfused. At hospital discharge, 19o/o of patients in the DCLHb group had still
avoided any allogeneic transfusion as compared to none in the control group. In
emergency surgery, also, the number of allogeneic blood transfusions was reduced
by the use of a hemoglobin solution [9].
Three recent phase III trials in cardiac and orthopedic surgery deserve mention
[10-12]. 0-raffinose cross-linked human hemoglobin in conjunction with intra-
operative hemodilution reduced the need for allogeneic blood transfusions in 299
patients undergoing coronary artery bypass surgery [10] {Table 1). Reported side
effects included a 1Oo/o elevation of arterial blood pressure, a higher incidence of
episodes of hypertension, and a transient elevation of bilirubin linked to hemoglo-
bin metabolism [13]. In the second study regarding cardiac surgery [12], 98 pa-
tients were randomized at the first postoperative transfusion decision, to a treated
group receiving HBOC-201, a bovine derived hemoglobin based oxygen carrier,
Table 1. Efficacy data of published phase Ill trials of currently developed artificial oxygen carriers
Product Type of Number of Autologous Reference Manufacturer

surgery subjects blood
harvesting
0-raffinose cross-linked CABG 299 lAD [10, 13) Hemosol Inc.

human hemoglobin httpJ/www.hemosol.com
HemolinkTM
I Bovine derived hemo- Major 693 None [11) Biopure Corp.
globin based oxygen orthopedic http://www.biopure.com
carrier, HBOC-201, surgery
Hemopur~
Cardiac 98 None [12)
surgery
Perflubron emulsion Major 492 ANH [20) Alliance Pharmaceutica
Oxygenr™ tumor Corp.
I surgery http://www.allp.com
CABG =Coronary artery bypass graft surgery, lAD= Intraoperative blood donation, ANH =Acute normovole-
mic hemodilution.
All companies which were involved in the development of artificial oxygen carriers were contacted at
least 3 times by the first author (DRS) but only the above 3 companies responded
and a control group receiving allogenic RBC transfusions. Twenty-four percent of

the patients in the treated group avoided any transfusion vs. 0% in the control
group (p < 0.05). In 693 patients undergoing major orthopedic surgery, HBC0-201
increased the percentage of patients avoiding any allogenic blood transfusion from
0% (patients were randomized at the first perioperative transfusion decision) to
59% for the entire study period of 6 weeks [11]. There were no clinically significant
differences between the HBOC-201 and the RBC groups for laboratory results, ex-
cept for amylase which was elevated on day 1 and lipase which was elevated
through day 5 in the HBOC-201 group, but returned to baseline by the 6 week fol-
low up visit [14]. Adverse events occurring more frequently in the HBOC-201
group included anemia, gastrointestinal (abdominal pain, dysphagia, nausea, vomit-
ing, jaundice), cardiovascular (hypertension, tachycardia), and cutaneous events,
whcih were mild and self-limited. Mortality and serious adverse events were seen
in comparable rates [14]. This corresponds with the side effect profile of HBOC-
201, which was published recently [15]. In this study, escalating doses of 0.6-2.5 gl
kg of HBOC-201 (corresponding to infusion volumes of 380 ± 87 to 1384 ± 309 ml)
were given to 42 patients and data were compared to 26 control patients receiving
lactated Ringer's solution. Blood pressure was slightly but significantly higher in
HBOC-201 dosed patients, a trend (p =0.06-0.08) towards elevated postoperative
lipase levels and late methemoglobinemia (peak at the third postoperative day)
were observed, and in 23 of 42 patients (58%) IgG-antiHBOC-201 antibodies were
detected at follow-up. In contrast, renal function, platelet count, blood coagulation
parameters and general clinical laboratory values were similar in both groups [15].
Since hemoglobin solutions are colored, they may interfere with certain colori-
metric laboratory methods currently used in clinical chemistry. In contrast, ABO
and Rh typing and cross-match testing do not seem to be affected (referenced in [3]).
---~--~~~~,--~--~~"~,-~
I PFC Emulsions
PFCs are carbon-fluorine compounds characterized by a high gas dissolving capaci-
ty (oxygen, carbon dioxide [C0 2 ] and other gases), low viscosity, and chemcial and
biologic inertness [16]. PFCs are virtually immiscible with water and thus, need to
be emulsified. A stable 60% perflubron emulsion (58% perfluorooctyl bromide and
2% perfluorodecyl bromide) has been developed, which is, in general, clinically
well tolerated [16].
After intravenous administration, the perflubron emulsion is taken up by the reti-
culoendothelial system (RES). This uptake determines intravascular half life (t 112 ),
which also depends on the total dose given. Thus, after a 1.8 g/kg perflubron emul-
sion dose, t 112 is approximately 10 hours. After the initial uptake of the PFC emul-
sion into the RES, the droplets of the emulsion are slowly broken down, the PFC
molecules are taken up in the blood again (bound to blood lipids) and transported
to the lungs, where the unaltered PFC molecules are finally excreted via exhalation.
At the present time, metabolism of PFC molecules is unknown in humans [1, 16].
Perflubron emulsions have been assessed in a variety of hemodilution studies in
animal models. At a hematocrit of 10%, a massive rise in mixed venous P0 2 and
mixed venous oxygen saturation (Sv0 2 ) was observed in dogs. When perflubron is
administered, the percentage of metabolized oxygen originating from endogenous
Hb decreases, indicating that the oxygen transported by perflubron emulsions is
preferentially metabolized, most likely due to their excellent oxygen unloading
characteristics [17]. Perflubron emulsion also improves survival of severely hemodi-
luted dogs undergoing cardiopulmonary bypass. In addition, after hemodilution to
a hemoglobin concentration of 7 g/dl, mixed-venous P0 2 was higher in perflubron
emulsion treated animals than in control animals. Cardiac function was also im-
proved after perflubron emulsion administration at a Hb level of 3 g!dl. This may
be explained by an increased in D0 2 at the level of very narrow capillaries, where
the size of the perflubron emulsion particles ("' 0.16Jlm in diameter) allows their
passage much more easily than for the relatively large erythrocytes {7-8 Jlm in di-
ameter). Thus, the local oxygenation of tissues, and in particular of the myocar-
dium, is increased (referenced in [3]).
Perflubron emulsions have also been used in humans (referenced in [3]). In a
prospective randomized multicenter study, patients undergoing orthopedic surgery
were hemodiluted preoperatively to a hemoglobin level of 9 g/dl [8]. After the pa-
tients had reached a predefined transfusion trigger, they were randomized into 4
groups: A, standard of care (retransfusion of 450 ml of autologous blood at an un-
changed Fi0 2 of 0.4); B and C, perflubron emulsion (0.9 or 1.8 glkg) with colloid to
a total 450 ml and ventilation with an Fi0 2 of 1.0; and D, infusion of 450 ml of col-
loid with ventilation with an Fi0 2 of 1.0. Perflubron emulsion at 1.8 g/kg was most
successful in reversing transfusion triggers in 97% of patients as compared to 60%
in the control group. In addition, transfusion trigger reversal lasted longer in the
perflubron emulsion 1.8 g/kg group {80 min) than in the control (55 min) and col-
loid groups (30 min) [18]. Thus, physiologic transfusion triggers may be treated at
least as successfully with perflubron emulsion than with autologous blood. This
illustrates the remarkable capacity of perflubron emulsions to deliver available oxy-
gen easily to the areas of the body with the greatest needs.
PFC emulsions also have side effects. Volunteers experienced mild 'flu-like'
symptoms with myalgia and light fever and an approximately 15% decrease in
platelet count 3 days post-dosing returning to normal by day 7 [16]. However, tra-
ditional coagulation tests, bleeding time and platelet aggregation, were unaffected
by perflubron emulsion. Finally, enrollment in a phase III study in cardiac surgery
was voluntarily suspended in 2001 due to an apparent imbalance in adverse neuro-
logic outcome [4]. Experts, however, agree that these events were not directly re-
lated to the PFC emulsion used but to the rapid blood harvesting procedure early
on cardiopulmonary bypass. In fact, in the same study it was observed, in a subset
of patients monitored with gastric tonometry, that in PFC treated patients, the gas-
tric mucosal pH were higher, indicating improved splanchnic oxygenation, resulting
in earlier postoperative bowel movement [19].
Augmented ANH with perflubron emulsion has recently been shown to reduce
the need for allogeneic blood transfusion in 492 patients undergoing major non-
cardiac surgery. PFC-treated patients first underwent ANH to a hemoglobin of
8.0±0.5 g!dl, followed by administration of perflubron emulsion (Table 1). The PFC
group had significantly fewer transfusions of allogeneic and pre-donated autologous
blood at 24 hours (1.5±4.8 vs. 2.1±3.9 units; median 0 vs. 1 unit; p=0.013). de-
spite a higher estimated intraoperative blood loss. The percentage of subjects com-
pletely avoiding transfusions was also significantly higher (52 vs. 43o/o; p = 0.048).
However after postoperative day 3, although differences were still present, they were
no longer statistically significant [20]. The efficacy was particularly high in the pro-
tocol-defined target population, representing patients with major blood loss
(~20 ml/kg) (3.4±2.9 vs. 4.9±2.4 units; median 2 vs. 4 unit; p<0.001) but a signif-
icant reduction on allogeneic blood transfusion was observed already in patients
with moderate blood loss (~ 10 ml/kg), which was sustained until hospital dis-
charge. In the protocol-defined target population, the percentage of patients avoid-
ing any blood and blood components remained significantly greater until day of
discharge (24 vs. 13o/o, p =0.011). Although more serious adverse events were ob-
served in the group of patients undergoing augmented ANH with perflubron emul-
sion, no organ system was specifically involved and overall tolerance was good
[20]. Again, lower platelet counts were found postoperatively in patients given per-
flubron emulsion but this was of limited clinical relevance since neither platelet
transfusions, postoperative bleeding events nor postoperative allogeneic blood
transfusions were more frequent in these patients. In fact, overall allogeneic blood
products (RBCs, fresh frozen plasma, platelets) were transfused less in the group of
patients treated by augmented ANH and perflubron emulsion [20]. Augmented
ANH with perflubron emulsion thus appears promising as a treatment option for
patients undergoing non-cardiac, moderate to high blood loss surgery.
I Future Uses of Artificial Oxygen Carriers
The future use of hemoglobin solutions and PFC emulsions may include a combi-
nation of ANH with an artificial oxygen carrier during the operation, a procedure
termed augmented ANH (Fig. 3). Augmented ANH is a concept in which patients
will undergo ANH to relatively low hematocrit levels prior to surgical blood loss.
ANH, thus, may be performed preoperatively or early during the operation, but
prior to the phase of major blood loss. In the phase of major surgical blood loss,
colloids and crystalloids will be administered to avoid hypovolemia and artificial
oxygen carriers. will be co-administered to maintain tissue oxygenation. As a conse-
quence, lower hematocrit levels can be safely tolerated. Towards the end of the op-
A 8 c
15 ANH Surgery I period of Retransfusion
:0 high blood loss
.....
.!:')
c::: Total 0 2
.g 10 off-loading
~ capacity
cQl
u
c:::
0
u 5
Ql
·e
>
~
w
0
0 2 4 6 8 80
Time(h)
Fig. 3. Augmented-ANH (A-ANH) (modified from [22] with permission). The concept of Augmented-ANH
is split into three periods. (A) ANH with conventional volume replacement without the use of artificial
oxygen carrierts prior to major blood loss targeting relatively low hematocrit levels. (B) During surgery,
when the hematocrit is expected to fall further, an artificial oxygen carrier is given to enhance tissue oxy-
genation. Note, that total oxygen off-loading capacity from combined red blood cell based- and artificial
oxygen carrier based-oxygen transport is maintained above the individual transfusion trigger. (C) Once
surgical hemostasis has been achieved the ANH blood is re-transfused to increase the endogenous hemo·
globin level above the individual transfusion trigger. Therefore, the decreasing contribution of artificial
oxygen carrier based-oxygen transport will not adversely affect oxygenation of the organism
eration, the autologous blood harvested during ANH will be retransfused. This will
increase postoperative hematocrit levels and D0 2 will again be provided by endoge-
nous RBCs. Therefore, greatly elevated arterial P0 2 values are not necessary in the
postoperative period and the relatively short half life of all artificial oxygen carriers
(< 24 h) will not compromise their success in reducing perioperative allogeneic
blood transfusion requirements (Fig. 2).
I Conclusion
Great progress has been achieved in the development of artificial oxygen carriers in
recent years but no artificial oxygen carrier has achieved market approval yet in
the US, Canada or Europe. Achieving market approval obviously is the next major
goal. A Biologic License Application was submitted in July 2002 to the U.S. Food
and Drug Administration (FDA) for HBOC-201 to achieve regulatory approval, and
this has been accepted for future evaluation in October 1, 2002. However, we should
be thinking already of the necessary education of healthcare professionals to under-
stand these new concepts, the physiology and the specifics of each of these com-
pounds. Only in the hands of the experienced can artificial oxygen carriers be used
to the benefit of patients.
622 N. Dettori et al.: Clinical Use of Artificial Oxygen Carriers
References
1. Spahn DR, Pasch T (2001) Physiological properties of blood substitutes. News Physiol Sci
16:38-41
2. Winslow RM (2000) Blood substitutes. Advanced Drug Delivery Reviews 40:131-142
3. Spahn DR, Kocian R (2003) Place of artifical oxygen carriers in reducing allogeneic blood
transfusions and augmenting tissue oxygenation. Can J Anaesth (in press)
4. Stowell CP, Levin J, Spiess BD, Winslow RM (2001) Progress in the development of RBC
substitutes. Transfusion 41:287-299
5. Viele MK, WeiskopfRB, Fisher D (1997) Recombinant human hemoglobin does not affect re-
nal function in humans: analysis of safety and pharmacokinetics. Anesthesiology 86:848-858
6. Winslow RM (2000) Alpha-alpha-crosslinked hemoglobin: was failure predicted by preclini-
cal testing? Vox Sang 79:1-20
7. Sloan EP, Koenigsberg M, Gens D, et al (19999) Diaspirin cross-linked hemoglobin
(DCLHb) in the treatment of severe traumatic hemorrhagic shock: a randomized con-
trolled efficacy trial. JAMA 282:1857-1864
8. Lamy ML, Daily EK, Brichant J-F, et al (2000) Randomized trial of Diaspirin cross-linked
hemoglobin solution as an alternative to blood transfusion after cardiac surgery. Anesthe-
siology 92:646-656
9. Gould SA, Moore EE, Hoyt DB, et al (1998) The frrst randomized trial of human polymer-
ized hemoglobin as a blood substitute in acute trauma and emergent surgery. J Am Coli
Surg 187:113-120
10. Carmichael FJ, Biro GP, Cheng DC (2001) Phase III clinical trial of hemolink in conjunc-
tion with intraoperative autologous donation (lAD) in cardiac surgical patients. Artif Cells
Blood Substit Immobil Biotechnol 29:102 (abst)
11. Jahr JS (2001) A novel blood substitute: Use of HBOC-201 (Hemopure) to decrease need
for RBC: Results of pivotal trail in orthopedic surgery patients. Crit Care Med 29 (suppl):
A160 (abst)
12. Levy JH, Goodnough LT, Greilich P, et al (2002) Polymerized bovine hemoglobin solution
as a replacement for allogeneic red blood cell transfusion after cardiac surgery: results of a
randomized, double-blind trial. J Thorac Cardiovasc Surg 124:35-42
13. Cheng DC, Martineau R, MacAdams C, et al (2001) Safety of Hemolink as an oxygen thera-
peutic in patients undergoing coronary artery bypass graft surgery. Anesth Analg 92
(suppl):SCA3 (abst)
14. Jahr JS, Stewart LM, MacKenzie C, Bourke D, williams JP (2002) Pivotal phase III study:
safety of polymerized bovine hemoglobin (HBOC-201, Hemopure) as compared to RBC in
patients undergoing orthopedic surgery. Anesthesiology 96:A243 (abst)
15. Sprung J, Kindscher JD, Wahr JA, et al (2002) The use of bovine hemoglobin glutamer-250
(Hemopure) in surgical patients: Results of a multicenter, randomized single-blind study.
16. Riess JG (2001) Oxygen carriers ("Blood substitutes") - raison d'etre, chemistry, and some
physiology. Chern Rev 101:2797-2920
17. Keipert PE, Faithfull NS, Bradley JD, et al (1994) Oxygen delivery augmentation by low-
dose perfluorochemical emulsion during profound normovolemic hemodilution. Adv Exp
Med Biol 345:197-204
18. Spahn DR, van Bremt R, Theilmeier G, et al (1999) Perflubron emulsion delays blood
transfusion in orthopedic surgery. Anesthesiology 91:1195-1208
19. Frumento RJ, Mongero LM, Naka Y, Bennett Guerrero E (2002) Preserved gastric tono-
metric variables in cardiac surgical patients administered intravenous perflubron emulsion.
20. Spahn DR, Waschke K, Standi T, et al (2002) Use of perflubron emulsion to decrease allo-
geneic blood transfusion in high-blood loss non-cardiac surgery: results of a European
phase 3 study. Anesthesiology 96:1338-1349
21. Looker D, Abbott-Brown D, Cozart P, et al (1992) A human recombinant haemoglobin de-
signed for use as a blood substitute. Natue 356:258-260
22. Spahn DR (1999) Blood substitutes: artifical oxygen carriers: perfluorocarbon emulsions.
Crit Care 3:R93-R97
Is There a Role for Red Blood Cell Transfusion
in the Critically Ill Patient?
H. L. Corwin, M.D. Hampers, and S.D. Surgenor
I Introduction
The value of red blood cell (RBC) transfusion in clinical practice was unchallenged
through most of this century [ 1]. However, in the early 1980s transfusion practice
began to come under systematic scrutiny [2-4]. Initially, the primary concerns re-
lated to the risks of transfusion-related infections, particularly human immunodefi-
ciency virus (HIV) and hepatitis. However, the issues are now much more complex.
The examination and debate over RBC transfusion risks over the last two decades
has led to a more critical examination of transfusion benefits. Further complicating
these issues has been the growing shortage of RBCs available for transfusion. This
chapter will focus on the evidence regarding the role of RBC transfusion in the
treatment of the critically ill patient today.
I Transfusion Practice
The issues surrounding RBC transfusion are particularly important in the critically
ill. Anemia is very common in the critically ill; almost 95% of patients admitted to
the intensive care unit (ICU) having a hemoglobin level below normal by ICU day
3 [5]. As a consequence of this anemia, critically ill patients receive a large number
of RBC transfusions. Over 50% of patients admitted t<;> the ICU receive RBC transfu-
sions during their ICU stay [6, 7]. In those patients with an ICU length of stay greater
than one week, the proportion of patients transfused rises to 85% [7]. These transfu-
sions are not restricted to early in the ICU stay, rather these patients tend to be trans-
fused at a constant rate of 2 to 3 units per week. In a survey of ICUs across the United
States conducted a decade ago, 14% of all ICU patients and 27% of patients in surgical
ICUs received at least one unit of transfused RBC on a given day [8].
Recent data from both Western Europe and the United States confirm that de-
spite ongoing scrutiny, RBC transfusion practice has changed little over the last de-
cade [9, 10].
Between 37 and 45% of ICU patients receive on average almost 5 RBC units dur-
ing their ICU stay. Following ICU discharge, 13% of critically ill patients still re-
ceive additional RBC transfusions, and for these patients the mean number of RBCs
given is almost 3 units. The transfusion 'trigger' in both studies (hemoglobin level
of 8.4 gldl and 8.6 gldl) was consistent across countries and institutions as well as
consistent with RBC transfusion practice of almost a decade ago [6-8].
What determines whether a patient receives a blood transfusion? There are
widespread deficiencies in knowledge of transfusion risks and indications among
624 H. L. Corwin et al.
physicians [11]. Therefore, it is not surprising that the variability in transfusion

practice between individual physicians and institutions is striking. Variation has
been documented in the coronary artery bypass graft surgery (CABG) population,
which consumes 10 to 20% of national RBC transfusions [12]. Among elective, pri-
mary CABG operations at 24 academic centers, institutional RBC transfusion rates
varied widely from 27 to 92% of patients [13]. Goodnough et al. also observed
variation in institutional RBC transfusion rates, from 17 to 100% of patients at 18
centers performing CABG surgery [14]. Mean RBC transfusions ranged from 0.4 to
6.3 units per patient in this study. The observed variation was not explained by pa-
tient or process characteristics. Furthermore, it was determined that 15% of the
RBCs transfusions in this study were inappropriate [15].
In critically ill patients, almost half of all transfusions, and almost two thirds of
those for non-acute blood loss, were performed for either no identifiable indication
or a low hematocrit alone [7]. Among non-ICU medical patients, 35% of RBC
transfusions were judged either non-justified or equivocal [2, 16]. Similarly, other
investigators have found the number of inappropriate transfusions ranging from 4
to as high as 57% [14, 15].
I Transfusion Risks
It is clear that the view of blood transfusion as 'risk free' is no longer tenable.
Transfusion associated infection and medical errors associated with RBC transfu-
sion remain a constant, albeit uncommon, concern [17-20]. For the critically ill pa-
tient, what is of more consequence is the accumulating evidence that blood transfu-
sion has profound negative effects on the immune system [21-23]. A variety of im-
munomodulatory effects associated with blood transfusion have been described in-
cluding decreased CD4 and interleukin (IL)-2-receptor-positive helper cells, in-
creased CDS suppresser cells, decreased natural killer cells, increased numbers of B
cells, decreased IL-2 production, and increased PGE2 production. These effects may
persist for months or longer. It is not clear what component of blood is responsible
for the immune suppression, although leukocytes and.Jor some agent in plasma
have been suggested as the causative agent. There are now considerable clinical
data bearing on the clinical significance of these changes.
A significant association between the number of blood transfusions and risk of
subsequent infection has been reported in patients following trauma, burns, and a
variety of surgical procedures both elective and emergency [21-23]. The threshold
number of transfusions that is associated with an increased risk of infection is not
clear. Patients who receive allogenic blood transfusions experience increased mor-
bidity, hospital stays, and costs [24]. These effects may result from white blood cell
(WBC) components contained in RBC transfusions. Leukoreduction of transfused
RBCs, has been associated with a significant reduction of infection rates following
colorectal surgery [25]. Universal leukocyte reduction of transfused RBCs has been
suggested as a means of reducing the toxicity of RBC transfusion [26, 27]. However,
others have questioned whether the available data at this point support the consid-
erable expense associated with the universal adoption of this change in transfusion
practice [18].
Clearly in an environment like the ICU, where much of the morbidity and mor-
tality is directly related to infection, if blood transfusion does in fact increase the
risk for infection it is of major concern. Recently, Moore et al. [28] reported there-
Is There a Role for Red Blood Cell Transfusion in the Critically Ill Patient? 625
suits of a prospective cohort study of trauma patients. They found that there was a
dose response relationship between early blood transfusion and later development
of multiple organ failure (MOF). This was independent of other measures of shock.
Similarly, Taylor and associates have demonstrated an association between RBC
transfusion and nosocomial infection and mortality in the critically ill [29]. This
effect was apparent even after adjustment for severity of illness. For each RBC unit
transfused the risk of nosocomial infection increased by a factor of 1.5.
I Transfusion Efficacy
Historically, a hemoglobin of 10 g/dl and a hematocrit of 30o/o have been the gener-
ally accepted minimum levels, particularly in the surgical setting. First proposed in
1942 [30], over the years, the acceptance of the '10130' rule as the appropriate
'transfusion trigger' has become more a matter of faith than of data. There is now
considerable evidence that lower levels of hemoglobin can be tolerated. Hematocrits
of 10 to 20o/o have been achieved in both dogs and baboons using normovolemic
hemodilution without untoward effects to the animals [31]. Weiskopf et al. induced
normovolemic hemodilutional anemia to hemoglobin levels of 5 g/dl in healthy hu-
man patients prior to surgery as well as normal volunteers. They found no evi-
dence for reduced oxygen delivery associated with acute anemia [32].
A wealth of data regarding the impact of anemia on surgical outcome comes
from studies of Jehovah's Witness patients. Carson et al. observed 125 Jehovah's
Witness patients undergoing surgery; no patient with a hemoglobin level > 8 g!dl
and blood loss < 500 ml died [33]. In a study of elective surgery in 107 Jehovah's
Witness patients, Spence et al. noted that mortality was related more to blood loss
than preoperative hemoglobin [34]. They observed that surgery was safely per-
formed in patients with hemoglobin levels as low as 6 g/dl, providing blood loss
was less than 500 mi. In a summary of the experience in Jehovah's Witness patients
undergoing major surgery a 1.4o/o mortality rate attributable to anemia was ob-
served among 1404 patients [35]. Ninety percent of deaths were in patients under-.
going cardiovascular operations. Carson et al. [36] reported the experience of 300
patients who had a post-operative hemoglobin level ~8 g/dl. The odds of death in
these patients increased 2.5 times for each gram decrease in hemoglobin level be-
low 8 gldl. Morbidity and mortality was particularly high at hemoglobin levels be-
low 5 to 6 gldl.
While it seems clear that hemoglobin levels falling significantly below the '10/30'
threshold can be tolerated in many patients, it is not clear that this is applicable to
the entire critically ill patient population. Experimental studies have shown that an-
imals with experimental coronary stenosis tolerate anemia less well than normal
animals [37]. Similarly, patients with cardiovascular disease also experience in-
creased risk of morbidity and mortality when exposed to anemia. In a study of
1,958 non-cardiac surgical Jehovah's Witness patients both a low preoperative he-
matocrit and blood loss increased the risk of serious morbidity or death particular-
ly among patients with cardiovascular disease [38]. In high risk patients under-
going arterial bypass procedures, a postoperative hematocrit of < 28o/o was asso-
ciated with increased myocardial ischemia and morbid cardiac events [39]. Similar-
ly, patients with cardiac disease undergoing radical prostatectomy had a higher in-
cidence of perioperative ischemic events if anemic [40 ]. This was particularly ap-
parent if patients were also tachycardic.
The expected benefit from RBC transfusion is to improve oxygen delivery, and thus
prevent cellular injury. However, it has been difficult to demonstrate this benefit in
clinical practice. In a study of patients with gastrointestinal bleeding, patients who
received only colloid solutions had lower mortality and morbidity than patients
who were transfused with RBCs [41]. Similarly, perioperative transfusions in patients
undergoing orthopedic procedures with hemoglobin levels 8 g/dl or higher did not
impact on mortality [42]. Other studies also document a lack of improvement in tis-
sue oxygenation after RBC transfusion, despite an increase in oxygen delivery. Die-
trich et al. observed no improvement in oxygen utilization among patients with shock
who had hemoglobin levels increased from 8.3 to 10.5 g!dl by transfusion of 3 units of
RBCs [43]. Similarly, in another study of septic patients, blood transfusion (hemoglo-
bin 9.6 increased to 11.6 g!dl) did not improve tissue oxygen uptake, despite a signif-
icant increase in calculated oxygen delivery [44]. These patients were known to have
abnormal oxygen uptake by demonstrating an increase in oxygen uptake in response
to dobutamine. In contrast, some critically ill patients will increase oxygen uptake in
response to blood transfusion, but no predictor could be found to identify those pa-
tients who responded to transfusion [45, 46].
Transfused RBCs, especially during the time period immediately following trans-
fusion, are not 'normal'. Storage of RBCs temporarily decreases 2,3 diphosphogly-
cerate (DPG) levels, interfering with the ability of RBCs to unload oxygen, and im-
pairing RBC deformability. The duration of storage may also be an important de-
terminant of the efficacy of RBCs. In a study of septic patients, patients receiving
RBC units stored for greater than 15 days developed more evidence of splanchnic
ischemia compared with those receiving blood stored for less than 15 days [47]. A
follow-up study employing a rat sepsis model demonstrated that transfusion of
'fresh' RBCs acutely increased systemic oxygen uptake, whereas transfusion of RBCs
stored for 28 days failed to improve tissue oxygenation [48]. In a study of trauma
patients who receive between 6 and 20 RBC units in the first 12 hours following in-
jury, the mean age of transfused RBCs, number of units older than 14 days, and
number of units older than 21 days were all independent predictors of organ failure
[49]. A recent study has shown that the average age of RBCs transfused in the US
is 21 days [10].
The best evidence available regarding the efficacy of blood transfusion among
critically ill patients is the randomized controlled trial by Hebert et al. [50]. They
compared a liberal transfusion strategy (hemoglobin 10 to 12 g/dl) to a restrictive
transfusion strategy (hemoglobin 7.0 to 9.0 g!dl). Overall in-hospital mortality was
significantly lower in the restrictive strategy group, although the 30-day mortality
rate was not significantly different. However, in those patients who were less ill
(APACHE < 20) or younger (<55 years of age) the 30-day mortality rates were sig-
nificantly lower for the patients in the restrictive transfusion group. Therefore, a re-
strictive strategy is at least equivalent and possibly superior, in some patients, to a
more liberal transfusion strategy. Stated differently, transfusing critically ill patients
to hemoglobin levels greater than 10 g/dl, the historic 'standard', is of no clinical
benefit and in fact may result in worse clinical outcomes for some patients. A sepa-
rate analysis of patients who required mechanical ventilation did not demonstrate
any advantage in weaning from mechanical ventilation associated with a more lib-
eral transfusion strategy [51].
Other studies have also demonstrated that RBC transfusion may in fact result in
worse clinical outcomes. In the recent study of transfusion practice in Western
Europe, RBC transfusion was associated with organ failure and, for similar degree
of organ failure, RBC transfusion was associated with an increased risk of death
[5]. As noted above, RBC transfusion within the initial 12 hours following injury
was an independent predictor of subsequent MOP [28] and RBC transfusion was an
independent predictor of nosocomial infection [29].
Are there any critically ill patients who might benefit from RBC transfusion? He-
bert et al. reported results from a sub-group of critically ill patients from his origi-
nal study who had cardiovascular disease [52]. No significant difference in mortal-
ity between the two transfusion strategies was observed in this sub-group. However,
in the patients with severe ischemic heart disease, a trend of decreased survival
was observed in the group managed with the restrictive strategy. This was the only
sub-group in the study that favored the liberal transfusion strategy. Consistent with
an RBC benefit in patients with ischemic cardiac disease are the results of a large
retrospective review of elderly patients (> 65 years of age) with acute myocardial
infarction [53]. In this study, patients with baseline hematocrits less than 33% had
improved mortality with RBC transfusion.
Recently the results of a study of early goal directed in patients with severe sep-
sis were reported [54]. In this study, a strategy of early goal directed therapy re-
sulted in a significant improvement in clinical outcome (mortality, 30.5% goal di-
rected therapy versus 46.5% standard therapy). The goal directed therapy algorithm
included RBC transfusion to achieve a central venous oxygen saturation ;::: 70%.
Although a significantly greater number of patients were transfused in the goal di-
rected group (64% goal directed versus 18%) it is not clear what, if any, indepen-
dent contribution RBC transfusion made to the improvement in clinical outcome.
I Conclusion
In conclusion, there is little to support the view that 'routine' transfusion of allo-
geneic RBCs is beneficial to critically ill patients. While there is clear evidence of
risks associated with RBC transfusion, there is little evidence supporting efficacy of
RBC transfusion for critically ill patients. The Hebert study [50], suggests that for
most critically ill patients a transfusion strategy which maintains a hemoglobin lev-
el between 7 g/dl and 9 g!dl is at least equivalent, and for some patients preferable,
to a more aggressive transfusion strategy of maintaining a hemoglobin level be-
tween 10 and 12 g/dl. The exception to this may be the patient with active ischemic
cardiac disease, in whom a higher transfusion trigger would be appropriate. What
the optimal hemoglobin level is for the critically ill is still unclear.
References
1. Spence RK, AC Cernaiau, J Carson, AJ Del Rossi (1993) Transfusion and surgery. Curr
Prob Surg 30:1101-1192
2. Welch HG, KR Meehan, LT Goodnough (1992) Prudent stategies for elective red blood cell
transfusion. Ann Intern Med 116:393-402
3. Consensus Conference (1988) Perioperative red blood cell transfusion. JAMA 260:2700-
2703
4. American College of Physicians (1992) Practice strategies for elective blood cell transfu-
sion. Ann Intern Med 116:403-406
5. Rodriguez RM, Corwin HL, Pearl RG, Corwin MJ, Enny C, Gettinger A (2001) Anemia in
the critically ill: Role of nutritional deficiency and erythropoietin response. J Crit Care
16:36-41
6. Littenberg B, Corwin HC, Gettinger A, Leichter J, AuBuchon J (1995) A practice guideline

and decision aide for blood transfusion. Immunohematology 11:88-94
7. Corwin HC, Parsonnet KC, Gettinger A (1995) RBC transfusion in the ICU: Is there a rea-
son? Chest 108:767-771
8. Groeger JS, Guntupalli KK, Strosberg M, et a! (1993) Descriptive analysis of critical care
units in the United States: Patient characteristics and intensive care unit utilization. Crit
Care Med 21:279-291
9. Vincent JL, Baron JF, Gattinoni L, et a! (2002) Anemia and blood transfusion in critical ill
patients. JAMA 288:1499-1507
10. Corwin HL, Abraham E, Fink MP, et a! (2001) Anemia and blood transfusion in the criti-
cally ill: Current clinical practice in the US - The CRIT Study. Crit Care Med 29 (suppl):A3
(abst)
11. Salem-Schatz S, Avorn J, Soumerai SB(1990) Influence of clinical knowledge, organizational
context, and practice style on transfusion decision making. JAMA 264:476-483
12. Lawrence L (1986) Detailed Diagnoses and Procedures for Patients Discharged from Short
Stay Hospitals, United States. 1984. Hyattsville, MD. National Center for Health Statistics.
Vital and health statistics. Series 13: Data from the National Health Survey; No. 86 DHHS
publication No. PHS 86-1747
13. Stover EP, Seigel LC, Parks R, et a! (1998) Variability in transfusion practice for coronary
artery bypass surgery despite national consensus guidelines. Anesthesiology 88:327-333
14. Goodnough LT, Johnston MFM, Toy PTCY (1991) The variability of transfusion practice in
coronary artery bypass surgery. JAMA 265:86-90
15. Goodnough LT, Soegiarso RW, Birkmeyer JD, Welch HG (1993) Economic impact of inap-
propriate blood transfusions in coronary artery bypass graft surgery. Am J Med 94:509-
514
16. Saxena S, Weiner JM, Rabinowitz A, Fridey J, Shulman lA, Carmel R (1993) Transfusion
practice in medical patients. Arch Intern Med 153:2575-2580
17. Walker RH (1987) Transfusion risks. Am J Clin Pathol 88:374-378
18. Goodnough LT, Brecher ME, Kanter MH, AuBuchon JP (1999) Transfusion Medicine. N
Eng! J Med 340:438-447
19. Linden JV, Wagner K, Voytovich AE, Sheehan J (2000) Transfusion errors in New York
State: an analysis of 10 years' experience. Transfusion 40:1207-1213
20. Williamson LM, Lowe S, Love EM, et a! (1999) Serious hazards of transfusion (SHOT) in-
itiative: analysis of the first two annual reports. Br Med J 319:16-19
21. Blumberg N, Heal JM (1994) Effects of transfusion on immune function. Arch Pathol Lab
Med 118:371-379
22. Landers DF, Hill GE, Wong KC, Fox IJ (1996) Blood transfusion-induced immunomoduala-
tion. Anesth Analg 82:187-204
23. Mickler TA, Longnecker DE (1992) The immunosuppressive aspects of blood transfusion. J
24. Vamvakas EC, Craven JH (1998) Allogenic blood transfusion, hospital charges, and length
of hospitalization: A study of 487 consecutive patients undergoing colorectal cancer resec-
tion. Arch Pathol Lab Med 122:145-151
25. Jensen LS, Kissmeyer-Nielsen P, Wolff B, Qvist N (1996) Randomised comparison of leuko-
cyte depleted versus huffy coat poor blood transfusion and complications after colorectal
surgery. Lancet 348:841-845
26. Blumberg N, Heal JM (1998) Blood transfusion: The silent epidemic. Arch Pathol Lab Med
122:117-118
27. American Association of Blood Banks (1998) BPAC recommends universalleukoreduction.
AABB News Briefs 20:16
28. Moore FA, Moore EE, Sauaia A (1997) Blood transfusion: An independent risk factor for
postinjury multiple organ failure. Arch Surg 132:620-625
29. Taylor RW, Manganaro L, O'Brien J, Trottier SJ, Parkar N, Veremakis C (2002) Impact of al-
logeneic packed red blood celltransfusion on nosocomial infection rates in the critically ill
patient. Crit Care Med 30:2249-2254
30. Adam RC, Lundy JS (1942) Anesthesia in cases of poor risk. Some suggestions for decreas-
ing the risk. Surg Gynecol Obstet 74: 1011-1101
31. Levine E, Rosen A, Sehgal L, GouldS, Sehgal H, Moss G (1990) Physiologic effects of acute
anemia: Implications for a reduced transfusion trigger. Transfusion 30:11-14
32. Weiskopf RB, Viele MK, Feiner J, et al (1998) Human cardiovascular and metabolic re-
sponse to acute, severe isovolemic anemia. JAMA 279:217-221
33. Carson JL, Spence RK, Poses RM (1988) Severity of anaemia and operative mortality and
morbidity. Lancet 1:727-729
34. Spence RK, Carson JL, Poses R, et al (1990) Elective surgery without transfusion: Influence
of preoperative hemoglobin level and blood loss on mortality. Am J Surg 159:320-324
35. Kitchens CS (1993) Are transfusions overrated? Surgical outcome of Jehovah's Witnesses.
Am J Med 94:117-119
36. Carson JL, Noveck H, Berlin JA, Gould SA (2002) Mortality and morbidity in patients with
very low postoperative Hb levels who decline blood transfusion. Transfusion 42:812-818
37. Geha AS (1976) Coronary and cardiovascular dynamics and oxygen availability during
acute normovolemic anemia. Surgery 80:47-53
38. Carson JL, Duff A, Poses RM (1996) Effect of anaemia and cardiovascular disease on surgi-
cal mortality and morbidity. Lancet 348:1055-1060
39. Nelson AH, Fleisher LA, Rosenbaum SH (1993) Relationship between postoperative anemia
and cardiac morbidity in high-risk vascular patients in the intensive care unit. Crit Care
Med 21:860-866
40. Monk TG, Goodnough LT, Brecher M; Colberg JW, Andriole JL, Catalona W (1999) A pro-
spective randomized comparison of three blood conservation strategies for radical prosta-
tectomy. Anesthesiology 91:24-33
41. Alexiu 0, Mircea N, Balaban M, Furtunescu B(1975) Gastrointestinal hemorrhage from
peptic Ulcer. An evaluation of bloodless transfusion and early surgery. Anaesthesia 30:609-
615
42. Carson JL, Duff A, Berlin JA, et al (1998) Perioperative blood transfusion and postoperative
mortality JAMA 279:199-205
43. Dietrich KA, Conrad SA, Hebert CA, Levy GL, Romero MD (1990) Cardiovascular and me-
tabolic response to red blood transfusion in critically ill volume resusitated patients. Crit
Care Med 18:940-944
44. Lorente JA, Landin L, De Pablo R, Renes E, Rodriguez-Diaz R, Liste D (1993) Effects of
blood transfusion on oxygen transport variables in sepsis. Crit Care Med 21:1312-1318
45. Robbins JM, Keating K, Orlando R, Yeston NS (1993) Effects of blood transfusion on oxy-
gen delivery and consumption in critically ill surgical patients. Contemp Surg 43:281-285
46. Steffes CP, Bender JS, Levison MA (1991) Blood transfusion and oxygen consumption in
surgical sepsis. Crit Care Med 19:512-517
47. Marik PE, Sibbaid WJ (1993) Effect of stored-blood transfusion on oxygen delivery in pa-
tients with sepsis. JAMA 269:3024-3029
48. Fitzgerald RD, Martin CM, Dietz GE, Doig GS, Potter RF, Sibbald WJ (1997) Transfusing
red blood cells stored in citrate phosphate dextrose adenine-1 for 28 days fails to improve
tissue oxygenation in rats. Crit Care Med 25:726-732
49. Zallen G, Offner PJ, Moore EE, et al (1999) Age of transfused blood is an independent risk
factor for postinjury multiple organ failure. Am J Surg 178:570-572
50. Hebert P, Wells G, Blajchman MA, et al (1999) A multicenter, randomized, controlled clini-
cal trial of transfusion requirements in critical care. N Engl J Med 340:409-417
51. Hebert PC, Blajchman MA, Cook DJ, et al (2001) Do blood transfusions improve outcomes
related to mechanical ventilation. Chest 119:1850-1857
52. Hebert PC, Yetsir E, Martin C, et al (2001) Is a low transfusion threshold safe in critically
ill patients with cardiovascular diseases? Crit Care Med 29:227-234
53. Wu WC, Rathore SS, Wang Y, Radford MJ, Krumolz HM (2001) Blood transfusion in el-
derly patients with acute myocardial infarction. N Engl J Med 345:1230-1236
54. Rivers E, Nguyen B, Havstad S, et al (2001) Early goal directed therapy in the treatment of
severe sepsis and septic shock. N Engl J Med 345:1368-1377
Transfusion Triggers
L. T. Goodnough
I Introduction: The Benefit of Transfusion
The therapeutic goal of a blood transfusion is to improve oxygen delivery (D0 2 )

and consumption (V0 2 ) according to the physiologic need of the recipient. The
usual response to an acute reduction in hemoglobin concentration in the normo-
volemic state is to increase cardiac output to maintain adequate D0 2 [ 1] (Fig. 1).
The heart is, therefore, the principal organ at risk in acute anemia. Myocardial
anaerobic metabolism, indicating inadequate D0 2 , occurs when lactate metabolism
in the heart converts from lactate uptake to lactate production. The normal whole-
body oxygen-extraction ratio (0 2 ER, the ratio of V0 2 to D0 2 ) is 20 to 25%. The
0 2 ER approaches 50% when myocardial lactate production occurs, indicating anae-
robic metabolism. In a normal heart, this lactate production and an 0 2 ER of 50%
occur at a hemoglobin concentration of approximately 3.5-4 gldl [2]. In a model of
coronary stenosis, the anaerobic state occured at a hemoglobin concentration of ap-
proximately 6-7 g/dl [3]. No single number, either extraction ratio or hemoglobin
concentration, can serve as an absolute indicator of transfusion need. However, the
use of such a physiologic value in conjunction with clinical assessment of the pa-
10 25
~ 8
.....
c :0
20 :X:
~ 6
~
~
X s
".S"' 4
1.!)
Cl.
u
15 ~
~"' <"'i
J 2
0+--------.--------r-------~----L 0
0 5 10 15
Hb (g%)
Fig. 1. Effect of anemia on cardiac index (CI) and diphosphoglycerate (DPG). From [1) with permission
----~-~--
tient's status permits a rational decision regarding the appropriateness of transfu-

sion prior to the onset of hypoxia or ischemia [4].
Mortality
If a transfusion is appropriate, then a benefit should occur. In a literature assess-
ment of the benefit of transfusion, data on mortality are the clearest. In a review of
16 reports of the surgical outcome in Jehovah's Witnesses who underwent major
surgery without blood transfusion, mortality associated with anemia occurred in
1.4% of the 1404 operations [5]. In one large study, the risk of death was found to
be higher in patients with cardiovascular disease than in those without [6]. A fol-
low-up analysis [7] of a subset of these patients reported that the odds of death in
patients with a postoperative hemoglobin level of $;8 g/dl increased 2.5 times for
each gram decrease in hemoglobin level; while no deaths occurred in 98 patients
with postoperative levels of 7.1 to 8.0 g/dl, 34.4% of 32 patients with postoperative
levels of 4.1 to 5.0 g/dl died. These data suggest that in surgery-induced anemia,
survival in patients at risk is improved if blood transfusion is administered to
maintain hemoglobin ;: : 7 g/dl. In a large, retrospective study of elderly patients
who underwent surgical repair of hip fracture, the use of perioperative transfusion
in patients with hemoglobin levels as low as 8.0 g/dl did not appear to influence
30-day or 90-day mortality [8].
In a multi-institutional study [9], 418 critical care patients received red blood
cell (RBC) transfusions when the hemoglobin concentration dropped below 7.0 g/
dl, with the maintenance of hemoglobin concentration in the range of 7.0 to 9.0 g/
dl, and 420 patients received transfusions when the hemoglobin concentration
dropped below 10.0 g/dl, with hemoglobin concentration levels maintained in the
range of 10.0 to 12.0 g/dl. The 30-day mortality rates were not different in the two
groups (18.7 vs. 23.3%, p=O.ll), indicating that a transfusion threshold as low as
7.0 g/dl is as safe as a higher transfusion threshold of 10.0 g/dl in critical care pa-
tients. A follow-up analysis found that the more restrictive strategy of RBC transfu-
sion appeared to be safe in most patients with cardiovascular disease; but among a
subgroup of 257 patients with ischemic heart disease, there was an insignificant (p
>0.30) decrease in overall survival among the patients treated according to the re-
strictive transfusion strategy [10]. Clearly, more data are needed to determine when
transfusion in this setting is beneficial, particularly in patients known to have risk
factors for ischemic heart or cerebral disease.
A study by Wu et al. [11] analyzed the relationships among anemia, blood trans-
fusion, and mortality in a retrospective analysis of nearly 80 000 elderly (> 65 y)
patients hospitalized for acute mycardial infarction. In this study, lower hematocrit
values on admission were associated with higher 30-day mortality rates. Anemia
(defined as hematocrit < 39%) was present on hospital admission in nearly half
(43.7%) of patients and was clinically significant (i.e., 33% or lower) in 10.4% of
patients. Finally, transfusion in patients with hematocrit levels < 33% at admission
was associated with significantly lower 30-day mortality.
Morbidity
Data on the relationship between transfusion and morbidity are less clear. A reduc-
tion in morbidity may be possible with transfusion in critically ill patients, espe-
cially those with hypoxia or sepsis, by optimizing D0 2 and minimizing the fre-
632 L. T. Goodnough
quency of potential complications. In one study [12], hemodynamic and oxygen

transport measurements were examined in five severely burned male patients who
did not receive blood transfusions for 36-48 hours after the operative incision. The
hemoglobin concentration level was then raised 3 gldl with multiple transfusions.
While transfusion raised the red cell mass significantly and increased D02, the
physiologic benefit seemed marginal. The 0 2 ER, in particular, was not markedly
deranged before the transfusion, which indicates that the compensation for the ane-
mia was quite adequate. In addition, there was no change in V0 2, which suggests
that blood transfusion may not benefit critically ill patients without known risk
factors.
In a report by Babineau et al. [13], the benefit of transfusion was examined in
30 surgical intensive care unit (ICU) patients who were normovolemic and hemo-
dynamically stable. Once again, transfusion increased the hemoglobin concentra-
tion level and total D0 2 but had a negligible effect on V0 2 • There were no impor-
tant hemodynamic benefits in this group of patients. One can conclude from these
data that the assumed benefit of an increase in the red cell mass does not always
translate into a true benefit in terms of oxygen transport in critically ill patients.
Silent perioperative myocardial ischemia has been observed in patients under-
going noncardiac [14] as well as cardiac [15] surgery. A study of elderly patients
who were undergoing elective, noncardiac surgery found that intraoperative or
postoperative myocardial ischemia was more likely to occur in patients with hema-
tocrits below 28 percent, particularly in the presence of tachycardia [16]. Hemoglo-
bin levels ranging from 6.0 to 10.0 gldl - a range in which indicators other than
hemoglobin concentration may identify patients who may benefit from blood -
therefore need to be the most closely scrutinized [4, 17]. In the absence of a physi-
ologic need or known risk factors in a stable, nonbleeding patient, a decline in he-
moglobin concentration level alone is not a good reason to give a transfusion [18].
Whether blood transfusion is associated with a clinically significant immunomodu-
latory effect (e.g., perioperative infections) has been the subject of debate [19, 20].
A recent study [21] found no effect on mortality, length of hospital stay, or health
care costs when leukoreduced blood transfusions were compared to non-leukore-
duced.
I Guidelines For Transfusion

Guidelines for blood transfusion have been issued by several organizations includ-
ing a National Institutes of Health (NIH) consensus conference on perioperative
transfusion of red cells [22], the American College of Physicians (ACCP) [23], the
American Society of Anesthesiologists (ASA) [15], and the Canadian Medical Asso-
ciation (CMA) [24]. These guidelines recommend that blood not be transfused pro-
phylactically and suggest that in patients without risk factors, the threshold for
transfusion should be a hemoglobin level of 6.0 to 8.0 g!dl. A hemoglobin concen-
tration of 8.0 gldl seems an appropriate threshold for transfusion in surgical pa-
tients with no risk factors for ischemia, whereas a threshold of 10 to 11 g!dl can be
justified for patients who are considered at risk. A recent mathematical analysis
suggested that surgical blood losses that exceed 70 to 120% (e.g., 3500 to 6000 ml
in a 70 kg patient with a 5 1 blood volume) of patients' baseline estimated blood
volumes are necessary before any blood transfusion [25], but this model assumes a
perisurgical RBC transfusion trigger of between 18 to 21 o/o hematocrit. The study
by Hebert et al. [9] concluded that critically ill patients could tolerate hemoglobin
concentrations as low as 7 g/dl, but that no conclusions could be made for patients
with risk factors for cardiac or cerebral ischemia. Evidence is accumulating that pa-
tients with known risk factors may benefit from higher hemoglobin transfusion
thresholds [10, 11]. With substantial improvements in blood safety [26, 27], concern
has been expressed that patients are now at risk of undertransfusion [28, 29]. The
study by Wu et al. [11] provides evidence for the first time that patients with a specific
clinical presentation are affected adversely by the underuse of transfusion. On the ba-
sis of this study, hematocrit levels have been recommended to be maintained above
33% in patients who present with acute myocardial infarction [30].
,References
1. Finch CA, Lenfant C (1972) Oxygen transport in man. N Engl J Med 286:407-415
2. Levy PS, Chavez RP, Crystal GJ, et al (1992) Oxygen extraction ratio: a valid indicator of
transfusion need in limited coronary reserve? J Trauma 32:769-774
3. Levy PS, Kim SJ, Eckel PK, et al (1993) Limit to cardiac compensation during acute iso-
volemic hemodilution: influence of coronary stenosis. Am J Physiol 265:H340-349
4. Goodnough LT, Despotis GJ, Hogue CW (1995) On the need for improved transfusion indi-
cators in cardiac surgery. Ann Thorac Surg 60:473-480
5. Kitchens CS (1993) Are transfusions overrated? Surgical outcome of Jehovah's Witnesses.
Am J Med 94:117-119
6. Carson JL, Duf A, Poses RM, et al (1996) Effect of anaemia and cardiovascular disease on
surgical mortality and morbidity. Lancet 348:1055
7. Carson JL, Novock H, Berlin JA, Gould SA (2002) Mortality and morbidity in patients with
very low postoperative hgb levels who decline blood transfusion. Transfusion 42:812-818
8. Carson JL, Duff A, Berlin JA, et al (1998) Perioperative blood transfusion and postoperative
mortality. JAMA 279:199-120
9. Hebert PC, Wells G, Blajchman MA, et al (1999) A multicenter, randomized, controlled
clinical trial of transfusion requirements in critical care. N Engl J Med 340:409-417
10. Hebert PC, Yetisir E, Martin C, et al (2001) Is a low transfusion threshold safe in critically
ill patients with cardiovascular disease? Crit Care Med 29:227-234
11. Wu WC, Rathore SS, Wang Y, Radford MJ, Krumholtz KM (2001) Blood transfusion in el-
derly patients with acute myocardial infarction. N Engl J Med 345:1230-1236
12. Gore DC, DeMaria EJ, Reines HD (1992) Elevations in red blood cell mass reduce cardiac
index without altering the oxygen consumption in severely burned patients. Surg Forum
43:721-723
13. Babineau TJ, Dzik WH, Borlase BC, Baxter JK, Bistrian BR, Benotti PN (1992) Reevaluation
of current transfusion practices in patients in surgical intensive care units. Am J Surg
164:22-25
14. Mangano DT, Browner WS, Hollenberg M, et al (1990) Association of perioperative myo-
cardial ischemia with cardiac morbidity and mortality in men undergoing noncardiac sur-
gery. N Engl J Med 323:1781-1788
15. Rao TLK, Montoya A (1985) Cardiovascular, electrocardiographic and respiratory changes
following acute anemia with volume replacement in patients with coronary artery disease.
Anesth Dev 12:49-54
16. Hogue CW Jr, Goodnough LT, Monk TG (1998) Perioperative myocardial ischemic episodes
are related to hematocrit level in patients undergoing radical prostatectomy. Transfusion
38:924-931
17. Practice guidelines for blood component therapy: a report by the American Society of An-
esthesiologists Task Force on Blood Component Therapy (1996) Anesthesiology 84:732-747
18. Welch HG, Mehan KR, Goodnough LT (1992) Prudent strategies for elective red blood cell
transfusion. Ann Intern Med 116:393-340
19. Blajchman MA (1999) Transfusion-associated immunomoducation and universal white cell
reduction. Are we putting the cart before the horse? Transfusion 39:667-670
634 L. T. Goodnough: Transfusion Triggers
20. Goodnough LT (2000) The case against universalleukoreduction (and for the practice of
evidence-based medicine). Transfusion 40:1522-1152
21. Dzik S, Anderson JK, Oneill M, Assmann SF, Kalish LA, Stowel C (2000) A prospective ran-
domized clinical trial of universalleukoreduction. Transfusion 41:15
22. Consensus Conference: Perioperative red cell transfusion (1988) JAMA 260:2700-2703
23. American College of Physicians. Practice strategies for elective red blood cell transfusion
(1992) Ann Intern Med 116:403-406
24. Expert Working Group (1997) Guidelines for red blood cell and plasma transfusions for
adults and children. Can Med Assoc J 156:Suppl11:S1-S24
25. Weiskopf RB (2001) Efficacy of acute normovolemic hemodilution assessed as a function
of fraction of blood volume lost. Anesthesiology 94:439-446
26. Goodnough LT, Brecher ME, Kanter MH, Aubuchon JP (1999) Medial Progress: Transfusion
Medicine, Part I. Blood Transfusion. N Engl J Med 340:439-447
27. Dodd RY, Notari EP, Stramer SL (2002) Current prevalence and incidence of infectious dis-
ease markers and estimated window-period risk in the American Red Cross donor popula-
tion. Transfusion 42:475-479
28. Valeri CR, Crowley JP, Loscalzo J (1998) The red cell transfusion trigger: has a sin of com-
mission now become a sin of omission? Transfusion 38:602-610
29. Lenfant C (1992) Transfusion practices should be audited for both undertransfusion and
overtransfusion. Transfusion 32:873-874
30. Goodnough LT, Bach RG (2001) Anemia, transfusion, and mortality. N Engl J Med
345:1272-1274
I Renal Failure
Use of Dopaminergic Agonists
for Renal Protection in the ICU
P. T. Murray
I Introduction
The mortality of acute renal failure is commonly 50-80% in the intensive care unit
(ICU), and has not declined significantly since the initial marked benefit of acute
dialysis therapy, despite numerous advances in renal replacement technologies and
critical care over several decades. Most acute renal failure in ICU patients is caused
by either prerenal azotemia (reversible renal insufficiency due to renal hypoperfu-
sion) or acute tubular necrosis (ATN). ATN results from a variety of ischemic and
nephrotoxic insults, often in additive or synergistic combination. Because renal hy-
poperfusion plays a role in the pathogenesis of prerenal azotemia and ATN, 'low-
dose' dopamine is commonly used as a renal vasodilator aiming to prevent or treat
acute renal failure in the ICU. This chapter reviews the use of dopamine and a nov-
el dopaminergic agonist called fenoldopam for renal protection in the ICU.
Renal Perfusion in the ICU
Adequacy of renal perfusion is determined by the balance of renal blood flow

(RBF), intrarenal blood flow distribution, and parenchymal oxygen consumption.
There are three main determinants of RBF:
1) cardiac output,
2) renal perfusion pressure (RPP, proportional to mean arterial pressure [MAP],
within the autoregulatory range), and
3) glomerular hemodynamic factors (primarily afferent and efferent arteriolar tone)
[1-2].
In addition, renal tissue oxygenation is also determined at two other, less recog-
nized levels:
4) corticomedullary blood flow distribution (adequacy of medullary blood flow),
and
5) renal tubular oxygen consumption (driven largely by reabsorption of filtered so-
dium chloride). ·
Cardiac Output
The kidneys normally receive 20-25% of cardiac output, although their combined
weight is less than 1% of total body weight, resulting in the highest tissue perfu-
638 P. T. Murray
sion in the body. Cardiac dysfunction diminishes renal perfusion both directly and
indirectly. Decreased cardiac output not only directly lowers RBF, but also activates
a number of renal vasoconstrictor systems. Decreased effective arterial blood vol-
ume resulting from decreased cardiac output activates neurohumoral responses
(sympathetic nervous system, renin-angiotensin system, and vasopressin secretion)
which have opposing effects on renal perfusion, tending to augment RPP but also
causing renal vasoconstriction. Any intervention restoring cardiac output and sys-
temic perfusion, therefore, augments renal perfusion by reversing the aforemen-
tioned influences. For example, the net effect of inotropic therapy on renal perfu-
sion in critically ill patients was illustrated in a study by Duke and colleagues, who
showed that the P-adrenergic agonist dobutamine at < 3 !lg/kglmin increased creati-
nine clearance, whereas dopamine at < 3 !lg/kg/min increased urine output without
affecting glomerular filtration rate (GFR) [3].
Renal Perfusion Pressure

Autoregulation maintains RBF and GFR within a narrow range at MAPs between
85-180 mmHg. This regulatory process is achieved by modulation of afferent arte-
riolar tone by two influences: a local myogenic reflex in the afferent arteriolar wall,
and a process called tubuloglomerular feedback [2]. The tubuloglomerular feedback
mechanism functions as follows: the macula densa is a chloride-sensing nephron
segment distal to the thick ascending limb of the loop of Henle (TALH); increased
chloride delivery past the TALH results in afferent arteriolar vasoconstriction due
to tubuloglomerular feedback, which normally serves to defend intravascular vol-
ume, by limiting GFR when salt excretion is excessive. Conversely, when renal per-
fusion, GFR, and tubular chloride concentration decrease, tubuloglomerular feed-
back and afferent tone are down-regulated. Although not generally regarded as a
controversial critical care issue to the same degree as oxygen delivery strategies,
the appropriate MAP and RPP target for titration of vasopressor therapy is another
area of clinical uncertainty. Standard recommendations suggest that fluids and va-
soactive drugs should be titrated to maintain a MAP ;::::60 mmHg [1]. Although gen-
erally accepted as the target MAP in septic shock resuscitation, 60-70 mmHg is on
the steep portion of the renal autoregulation curve, and is associated with a preci-
pitous decrement in RBF and GFR from normal, even in dogs and healthy human
subjects [4]. It is not commonly appreciated that autoregulation extends predomi-
nantly over a high range of MAP (85-180 mmHg), preventing hypertensive renal
injury, rather than truly protecting against decrements in RPP, RBF, and GFR. In
patients with chronic hypertension, in whom the curve is right-shifted, this prob-
lem is likely exacerbated, but current recommendations for shock resuscitation do
not account for this potential problem. Furthermore, if renal injury does result in
ATN, abundant experimental data suggest that autoregulation is lost, and that RBF
becomes linearly pressure-dependent, resulting in fresh ATN lesions with subse-
quent hypotension and hypoperfusion insults [5]. Therefore, these issues have rele-
vance not only for prevention of renal injury/ATN, but also its supportive manage-
ment, in which maintenance of adequate RPP may become even more critical than
in the presence of uncomplicated prerenal azotemia.
Renovascular Resistance
Beyond provision of adequate cardiac output and systemic oxygen delivery (D0 2 ),
and maintenance of optimal RPP, reversal of local renal vasoconstrictor influences
is the third therapeutic component ensuring renal perfusion in shock [2]. As dis-
cussed above, renal vasoconstriction occurs in shock, through multiple mecha-
nisms. Even in septic shock and cirrhosis, two states marked by diminished sys-
temic vascular resistance (SVR) and hypotension, renal vasoconstriction occurs and
is well-documented to be the cause of hepatorenal syndrome. Specifically, in hepa-
torenal syndrome, acute renal failure occurs in cirrhotic patients with normal kid-
neys but profound renal vasoconstriction that critically impairs renal perfusion and
glomerular filtration. Renal vasoconstriction is also thought to play a role in the
pathogenesis of septic acute renal failure [2], along with hypovolemia (septic veno-
dilation, capillary leak), and impaired systemic D0 2 leading to development of pre-
renal azotemia [1]. In addition, additive or synergistic nephrotoxic insults (inflam-
matory mediators, pigments, drugs, etc) may precipitate ATN when prerenal azote-
mia is not effectively prevented or reversed [6]. Acute renal failure due to sepsis is
the major cause of the continued high mortality rate of acute renal failure in the
ICU. For example, a recent prospective multicenter ICU study of acute renal failure
found that subjects with septic acute renal failure had a far higher mortality rate
(74 vs 45%, p<0.001) than those without sepsis [7].
The importance of renal vasoconstriction and regional hypoperfusion in causing
acute renal failure has not been precisely defmed in sepsis or the majority of other
cases of acute renal failure in the ICU. Nevertheless, theoretically any agent which off-
sets renal vasoconstriction might decrease the incidence of prerenal azotemia and
ATN in the ICU. It seems preferable to adopt a prophylactic strategy for prevention
or reversal of vasoconstriction-induced prerenal azotemia, reversing an often clini-
cally-unapparent contributor to the pathogenesis of ATN, rather than attempting to
intervene after frank renal injury has occurred. This concept, though theoretically at-
tractive, remains unproven at this time. Increased renovascular resistance may be re-
versed by use of generalized renal vasodilators, or by specific pharmacologic antago-
nists of known renal vasoconstrictor substances. The latter approach has been shown
to increase renal perfusion and GFR in experimental sepsis, with positive results using
pharmacologic antagonists of endothelin, leukotrienes, thromboxane, and platelet-ac-
tivating factor (PAF); clinical studies have not been done with any of these agents in
critically ill humans. The former approach is best represented by the use of dopamin-
ergic agonists for renal vasodilation in critically ill patients.
I Therapeutic Uses of Dopamine in the ICU

Dopamine is an endogenous catecholamine, which plays physiologic roles in neuro-
transmission, vascular, and renal function. Dr. Leon Goldberg and colleagues devel-
oped dopamine as a pharmacologic agent for treatment of congestive heart failure
and shock. Goldberg and colleagues established that relative selectivity of dopa-
mine for catecholamine receptors varies with dose/plasma concentration: broadly
speaking dopamine is a vasopressor (a-adrenergic agonist) at high doses, an ino-
trope (P-adrenergic agonist) at moderate doses, and a dopaminergic agonist/renal
vasodilator at low doses (up to 2-3 f!g/kg/min) [1], although there is significant
overlap in dose-response curves for each receptor subtype [8].
640 P. T. Murray
Why might dopamine help improve renal function in patients at risk of, or in
evolution to, acute renal failure (prerenal or ATN)? Dopamine can act in a dose-de-
pendent manner to augment RBF at all 3 levels discussed above, possessing ino-
tropic, vasopressor, and renal vasodilatory effects [1]. In addition, dopamine may
augment urine output by direct inhibition of tubular sodium absorption and indi-
rectly by inhibiting aldosterone production. Dopamine at doses in the range of 2-
10 ~-tg/kg/minute has positive inotropic ({1-adrenergic) effects, and has been shown
to induce a greater increment in cardiac output than norepinephrine in canine and
human studies. In addition, dopamine at > 5 ~-tg/kg/min has an under-appreciated
venoconstrictor effect, resulting in higher ventricular filling pressures/volumes for
any volume of infused fluids than an equivalent dose of the mixed /11- and /12 -adre-
nergic agonist dobutamine. Dopamine at > 5-10 ~-tg/kg/min increasingly activates a-
adrenoceptors and causes systemic vasoconstriction, in addition to a positive ino-
tropic effect, becoming predominantly a vasopressor at > 20 ~-tg/kg/min. Dopamine
is an inferior vasopressor to the agents more widely used to achieve systemic vaso-
constriction, all of which have greater a-adrenergic activity (norepinephrine,
phenylephrine, high-dose epinephrine). In fact, dopamine becomes an ineffective
vasopressor during prolonged shock, because it acts indirectly by prevention of
neuronal norepinephrine reuptake, and stores are exhausted in extremis, so that di-
rect-acting a-agonists are more reliable pressors.
Dopamine is widely administered at low/'renal' doses in patients with shock and
oliguria, particularly when renal insufficiency develops. Dopamine at doses of 0.5-
2.0 ~-tg/kg/min has been shown in healthy humans to increase renal perfusion, along
with a lesser increase in GFR, and increased urine output, which results in large
part from antagonism of tubular sodium reabsorption [1]. These effects are less
well documented in ICU patients; two recent ICU studies found no increase in GFR
(or gastric pH, in one study) at approximately 3 ~-tg/kg/min in this population, de-
spite increased urine output [3, 9]. By contrast, other recent data suggest that low-
dose dopamine does acutely improve GFR in septic subjects, but that this effect di-
minishes over 48 hours of infusion; this study and another by Juste and colleagues
found that dopamine failed to alter GFR in vasopressor-supported patients with
frank septic shock [10, 11]. Other literature suggests that dopamine may be useful
to offset renal vasoconstriction induced by a-agonists (norepinephrine, phenyl-
ephrine, high-dose epinephrine) [12-15]. Although renal function clearly benefits
from attainment of adequate RPP, these a-adrenergic agents can also cause renal ar-
terial vasoconstriction, raising concerns regarding potential opposing effects on re-
nal perfusion. Data from dogs [12], healthy human subjects [13, 14], and hyperten-
sive pressor-supported neurosurgical patients [15] suggests that norepinephrine-in-
duced renal vasoconstriction may be blunted by concomitant low-dose dopamine
therapy. Since norepinephrine induces hypertension in healthy subjects, however,
these data are not necessarily applicable to hypotensive septic patients. The net re-
sult of potential beneficial and harmful renal effects of norepinephrine therapy on
renal perfusion, function, and viability in septic shock, and any protective effect of
concomitant low-dose dopamine therapy in this setting, remain unclear. Recent re-
views of the literature have found no definite indications for the use of dopamine
to prevent or treat acute renal failure in any setting [16-18], but the rationale of
minimizing development of renal vasoconstriction-induced prerenal azotemia and
synergistic ATN by use of selective renal vasodilators remains attractive. Finally, an
emerging literature documents the cytoprotective effects of catecholamines, inde-
pendent of effects on ventricular function or vascular tone, suggesting a potential
---~--~~~~,--~--~~'"~,-~
perfusion-independent mechanism by which dopamine therapy might be renal pro-

tective [19].
Contrary to the theoretical benefits outlined above, no study has demonstrated
efficacy (improved GFR) or effectiveness (avoidance of renal replacement therapy
or death) of low-dose dopamine therapy for renal protection in ICU patients.
Although there have been many negative studies of low-dose dopamine for the pro-
phylaxis or therapy of acute renal failure in the ICU and a variety of other high-
risk settings, these have generally been small, under-powered, and prone to false-
negative results. Extensive scholarly reviews [16] and adequately-powered meta-
analyses [17, 18] have similarly failed to find evidence that dopamine prevents or
alters the course of acute renal failure. In the ICU setting, however, the definitive
study to answer this question has been done: the ANZICS group has shown that
low-dose dopamine as it is frequently used does not alter the course of acute renal
failure in the ICU [20].
I will review the findings of the pivotal ANZICS low-dose dopamine study in de-
tail. This 328 patient trial was conducted in 23 ICUs in Australia and New Zealand
[20]. ICU patients with systemic inflammatory response syndrome (SIRS) and early
acute renal dysfunction were double-blind randomized to receive either dopamine
2 f!g/kg/min or placebo infusion, until they died, required renal replacement thera-
py, had a serious adverse event possibly attributable to study drug (generally ar-
rhythmia), had resolution of SIRS and renal dysfunction for 24 hours, or were
transferred from the ICU. Early renal dysfunction was defined by oliguria (urine
output <0.5 ml/kg/hour for ~4 hours) or increased serum creatinine (>1.7 mg/dl
with normal baseline or increment of > 0.9 mg/dl in < 24 hours without rhabdo-
myolysis). Notable exclusions were baseline advanced chronic renal insufficiency
(serum creatinine > 3.4 mg/dl), renal transplantation, and recent acute renal failure
episode (< 3 months). Randomization of 328 patients produced groups with similar
baseline characteristics, including serum creatinine of 2.1 mg/dl, blood urea nitro-
gen (BUN) 40 mg/dl, 68-69% oliguric, MAP of 80 mmHg (supported by catechola-
mine vasoactive drugs in approx. 60%), and central venous pressure (CVP) of
14 cmH 2 0, predominantly on mechanical ventilation (86%). Of note, although most
of these clinical parameters are typical of those who receive low-dose dopamine to
treat early renal dysfunction in United States ICUs, it seems that hemodynamic
support is titrated to higher MAP levels in the Southern Hemisphere, and this may
have affected the results by optimizing renal perfusion.
The primary endpoint of this study was peak serum creatinine reached during trial
infusion, and this did not differ between groups; on average, both groups increased
from 2.1 mg/dl to 2.8 mg/dl (Fig. 1). Similarly, there was no difference between the
groups in a variety of other parameters including serum urea, or the proportion of
patients reaching serum creatinine values above 3.4 mg!dl (34-35%) (Fig. 2), or even
urine output during any period (Fig. 3). Clinical endpoints including frequency of re-
nal replacement therapy (22-24%) (Fig. 2), duration of mechanical ventilation, length
of ICU or hospital stays, and mortality were similarly unaffected by study drug as-
signment. This study was conclusively negative, with 90% power to detect a 25% dif-
ference in the primary endpoint of peak serum creatinine. Clearly, low-dose dopamine
is not indicated to treat early renal dysfunction in the ICU.
Some clinicians continue to use low-dose dopamine for putative renal protection,
despite the increasing weight of evidence to the contrary, in many cases insisting that
this approach is at worst ineffective but harmless. There is a common misconception
that low dose dopamine therapy, while not necessarily efficacious, is at least without
642 P. T. Murray
5
• Dopamine
'i5 0 Placebo
...... 4
.s
01
"'c:
·c
3
·;::;
~ 2
v
E
:1
(,j
Vl
0
Peak SCr SCr increase
Fig. 1. Primary endpoint of the ANZICS low-dose dopamine trial. There was no difference between the
dopamine and placebo groups in peak serum creatinine (SCr) concentration or increase in serum creati-
nine from baseline during treatment. Data from [20)
40
• Dopamine
0 Placebo
30
~
i:
"'> 20
"'
'iii
c:
Ill
a:
10
0
SCr > 3.4 mg/dl Renal replacement
Fig. 2. Secondary endpoints of the ANZICS low-dose dopamine trial. There was no significant difference
between the dopamine and placebo groups in the number of patients whose serum creatinine (SCr) con-
centration exceeded 3.4 mg/dl or who needed renal replacement therapy. Data from [20)
significant adverse effects; in fact, side effects include mesenteric ischemia, arrhyth-
mias, gastrointestinal dysmotility, and other disorders [21-25]. Most concerning in
this regard are data suggesting that a-adrenergic effects (splanchnic vasoconstriction)
may develop in some individuals at doses as low as 5 llg/kg/min [21, 22]. Arrhythmias
are a common side effect of dopamine therapy in critically ill patients; for example, in
a cardiac surgery study, use of low-dose dopamine was the only independent predic-
tor of the development of perioperative arrhythmias in a multivariate analysis [23).
Activation by dopamine of myocardial fJ receptors, in part due to the overlapping
dose-response curves for dopaminergic or fJ receptor activation [8], is the likely cause
of such arrhythmias. In addition, dopamine metabolism is subject to marked interin-
dividual variation in critically-ill subjects [26], and dosing is further complicated by
250
• Dopamine
200 0 Placebo
:2
.....
l
~ 150
s-
:l
:l
0
Ql
100
.!:
:5 50
0
Baseline >1 h >24h >48h
Fig. 3. Urine output in the ANZICS low-dose dopamine trial. Urine output increased similarly in both
groups during trial infusion (dopamine [DP] and placebo [PL]), without a significant difference in loop
diuretic doses received by the groups. Data from [20]
the difficulties of weight-based regimens. In fact, dopamine disposition is variable en-

ough that one could argue that precise prescription limited to one receptor subtype is
impossible. Other side effects include nausea/vomiting, hypothyroidism [24], lym-
phocyte dysfunction [25], ileus, and hypoventilation.
Two studies suggest that dopamine may even worsen the outcome of acute renal
failure [27, 28]. In fact, the renal effects of dopamine may not necessarily be bene-
ficial to patients in shock, since it appears that dopamine preferentially increases
cortical blood flow [29], without augmenting perfusion to the medulla. Although
the kidneys are the most perfused organs in the body, as discussed above, this
statement applies only to the cortex, not the medulla. The medulla receives only
6% of total RBF (0.3 versus 5 ml/min/gram to the cortex), and exists in a baseline
hypoxic state (P0 2 10 versus 50 mmHg in cortex), despite containing two sites per-
forming a large proportion of tubular work and oxygen consumption (the S3 distal
segment of proximal tubule, and the TALH). Increased cortical blood flow favors
glomerular filtration, but inadequate medullary blood flow may continue to deprive
the S3 and TALH segments (which must absorb this filtrate) of the necessary oxy-
gen and nutrient supply to simultaneously perform reabsorptive work and remain
viable. This phenomenon may explain the failure of low-dose dopamine prophylaxis
to achieve benefit in studies to date, despite the documented capacity to increase
RBF. Therefore, even the prophylactic use in shock of renal vasodilators, to preserve
RBF and prevent development of acute renal failure, may be harmful if regional
RBF is adversely affected. Another reason for the poor results of renal vasodilators
for prevention and management of ATN may be the fact that increased RBF may
not be desirable in all forms or stages of acute renal failure. Prevention of gross hy-
poperfusion and injury, or synergistic injury contributed to by hypoperfusion, may
be possible with dopaminergic agonists. By contrast, if renal tubular injury (ATN)
has already developed, increased RBF theoretically stresses subcritically injured
nephron segments, by requiring oxygen consumption for reabsorption of filtered
sodium. Therefore, although tubuloglomerular feedback-induced afferent arteriolar
vasoconstriction contributes to diminished RBF and GFR in ATN, this phenomenon
also protects injured tubular segements from further hypoxic stress and injury. Re-
644 P. T. Murray
storation of renal perfusion at this stage (ATN) in the evolution of acute renal fail-
ure may thus be counter-productive, unless accompanied by blockade or renal tu-
bular sodium absorption, or other cytoprotective or regenerative therapies. These
considerations strengthen the case for use of renal vasodilators in early acute renal
failure rather than established ATN.
Therapeutic Uses of Fenoldopam in the ICU
Fenoldopam is the other dopaminergic agonist currently used in the ICU. Fenoldo-
pam was also developed by Dr. Goldberg, by modifying dopamine to achieve great-
er dopaminergic selectivity. Fenoldopam is a pure and potent dopaminergic ago-
nist, acting only at DA-1 (not DA-2) receptors, without eliciting a- or /1-adrenergic
effects at any dose [30-33]. It is a potent parenteral antihypertensive agent; in se-
verely hypertensive subjects, fenoldopam was equally effective in lowering blood
pressure (BP) in comparison to nitroprusside [30-32]. In a subset of hypertensive
emergency patients in whom detailed renal function studies were performed, it was
shown that GFR increased during BP lowering by fenoldopam therapy, and slightly
decreased in nitroprusside-treated patients [34, 35]. Fenoldopam was similarly
shown to be superior to nitroprusside in the preservation of RBF in anesthetized
dogs during induced hypotension [36-38]. Fenoldopam also causes renal vasodila-
tion at low doses ( <0.1 ).lg/kg/min) which have no effect on systemic BP in healthy
[39, 40] and mechanically-ventilated [41, 42] human subjects. Fenoldopam was
additionally shown to reverse cyclosporin-induced renal vasoconstriction in renal
transplant recipients [43], and radiocontrast-induced vasoconstriction in dogs [44].
In contrast to dopamine, experimental data suggest that renal vasodilation with fe-
noldopam preferentially augments medullary blood flow [38]. This potentially criti-
cal difference between the agents may be explained by the absence of DA-2 receptor
activation by fenoldopam, although the distribution and function of renal DA-2 re-
ceptors is not well understood [45, 46], and there may be an alternative explanation
for this phenomenon. In addition to systemic and renal vasodilation, fenoldopam
has other regional circulatory effects. Limited data from animals and human sub-
jects suggest that fenoldopam is a mesenteric and coronary vasodilator [32, 33, 47-
49]; of note, since splanchnic vasodilation in cirrhotics has been demonstrated [47,
48], caution should probably be exercised in using this drug in patients with
known esophageal varices. Several studies have demonstrated that fenoldopam can
effectively reduce afterload and increase cardiac output in congestive heart failure
patients [31, 50]. The pulmonary vascular effects of fenoldopam have not been ex-
plicitly studied. New data in an isolated lung preparation show that DA-1 stimula-
tion augments alveolar edema clearance in injured lungs, with obvious implications
for the management of acute lung injury [51]. In addition to antihypertensive and
afterload-reducing effects, this agent clearly has the potential to act as a useful re-
nal vasodilator in ICU patients. I will review the emerging data that may ultimately
support the indication of fenoldopam therapy for the prophylaxis or therapy of
acute renal failure in high-risk populations.
Pilot studies suggest that fenoldopam may be effective in the prevention of
radiocontrast nephropathy, and is potentially useful for perioperative renoprotec-
tion during high-risk cardiovascular surgical procedures. Radiocontrast nephropa-
thy is a well-studied form of human acute renal failure, and its pathogenesis is
thought to involve both ischemia (renal vasoconstriction) and dye-nephrotoxicity
---~--~~~~,--~--~~'"~,-~
[52]. However, when global RBF was measured during radiocontrast administration
in humans it was not diminished [53]. In animal models, while cortical blood flow
increases flowing radiocontrast administration, medullary blood flow is diminished
[52, 54]. Thus, intra-renal blood flow distribution may be altered in humans receiv-
ing radiocontrast, but this has not been studied to date. Since fenoldopam pre-
vented radiocontrast-induced renal vasoconstriction in dogs [44], a pilot study was
performed to see if fenoldopam was similarly effective in humans. In a randomized,
placebo-controlled study of 51 patients with chronic renal insufficiency undergoing
coronary angiography, Tumlin and colleagues showed that fenoldopam preserved
renal plasma flow 1 hour post-contrast, but not at later time points [55]. Among
the secondary endpoints, there was a non-significant trend towards a lower inci-
dence of radiocontrast nephropathy (defined as a 0.5 mg/dl or 25o/o increment in
creatinine at 48 hours post-dye) in fenoldopam-treated subjects (21 vs 41 o/o with sa-
line alone, p=O.l5), and a significantly lower serum creatinine by 72 hours post-
dye in the fenoldopam group {3.5 vs 2.8 mg/dl with saline alone, p < 0.05). Based
upon these data, a 300 patient, placebo-controlled trial of fenoldopam for this indi-
cation was conducted, and data analysis of this trial is imminent [56]. Animal ex-
periments [57] and small human studies in patients undergoing coronary artery by-
pass grafting (CABG) [58] and aortic crossclamp surgery [59] suggest that fenoldo-
pam may prevent or ameliorate the course of acute renal failure in patients under-
going cardiovascular surgery. Experimental evidence suggests that fenoldopam may
even favorably alter the course of evolving acute renal failure caused by hypovole-
mia [60]. It is important to emphasize that because fenoldopam caused dose-depen-
dent systemic vasodilation (beginning at a dose of approximately O.l!lg/kg/min),
renal vasodilation may be accompanied by hypotension, and extreme caution must
be exercised in the experimental or therapeutic use of this drug in critically ill pa-
tients. A three center randomized, double-blind, placebo-controlled trial of fenoldo-
pam therapy for early acute renal failure in the ICU is currently in progress in the
United States. In this trial, a blinded infusion of 0.05-2 !lg/kg/min fenoldopam or
placebo is given for 72 hours to ICU patients with early acute renal failure, titrated
to maintain a MAP of ?:70 mmHg. The sites are Emory University, Atlanta (James
Tumlin, M.D.), the University of Texas, Houston (Andrew Shaw, M. B.; Kevin Finkel,
M.D.), and the University of Chicago (P. Murray, M.D.). This 300 subject trial aims
to definitively determine whether pure dopaminergic stimulation and renal vasodi-
lation can favorably alter the course and outcome of acute renal failure in the ICU.
I Conclusion
Dopamine is commonly used in critically ill patients, for inotropic and vasopressor
support, and at lower doses in attempts to prevent or ameliorate acute renal failure.
A significant body of evidence, including a rigorous randomized, placebo-con-
trolled trial, has proven that low-dose dopamine does not ameliorate acute renal
failure in the ICU, and is not indicated for this purpose. Fenoldopam is a pure
DAl-receptor dopaminergic agonist, currently indicated for titratable control of hy-
pertension in hospitalized patients. Fenoldopam is a renal vasodilator, and may be
useful for the prevention and therapy of acute renal failure in a variety of high-risk
settings (radiocontrast, perioperative, ICU). Current trials will determine whether
or not fenoldopam is effective in the prophylaxis of radiocontrast nephropathy or
treatment of early acute renal failure in the ICU.
646 P. T. Murray
References
1. Murray PT (1999) Pathogenesis and management of septic shock. Seminars in Anesthesia,
Perioperative Medicine, and Pain: 18:192-203
2. Murray PT, Wylam ME, Umans JG (2000) Nitric oxide and septic vascular dysfunction. An-
esth Analg 90:89-101
3. Duke GJ, Briedis JH, Weaver RA (1994) Renal support in critically ill patients: low-dose
dopamine or low-dose dobutamine. Crit Care Med 22:1919-1925
4. Bersten AD, Holt AW (1995) Vasoactive drugs and the importance of renal perfusion pres-
sure. New Horiz 3:650-661
5. Kelleher SP, Robinette JB, Conger JD (1984) Sympathetic nervous system in the loss of
autoregulation in acute renal failure. Am J Physiol 246:F379-F386
6. Zager RA (1992) Endotoxemia, renal hypoperfusion, and fever: interactive risk factors for
aminoglycoside and sepsis-induced acute renal failure. Am J Kidney Dis 20:223-230
7. Neveu H, Kleinknecht D, Brivet F, Loirat P, Landais P (1996) Prognostic factors in acute re-
nal failure due to sepsis. Results of a prospective multicentre study. Nephrol Dial Trans-
plant 11:293-299
8. D'Orio V, El Allaf D, Juchmes J, Marcelle R (1984) The use of low doses of dopamine in in-
tensive care medicine. Arch Int Physiol Biochem 92:S11-S20
9. Olson D, Pohlman A, Hall JB (1996) Administration of low-dose dopamine to nonoliguric
patients with sepsis syndrome does not raise intramural gastric pH nor improve creatinine
clearance. Am J Respir Crit Care Med 154:1664-1670
10. Lherm T, Troche G, Rossignol M, Bordes P, Zazzo JF (1996) Renal effects of low-dose do-
pamine in patients with sepsis syndrome or septic shock treated with catecholamines. In-
11. Juste RN, Panikkar K, Soni N (1998) The effects of low-dose dopamine infusions on hemo-
dynamic and renal parameters in patients with septic shock requiring treatment with nor-
adrenaline. Intensive Care Med 24:564-568
12. Schaer GL, Fink MP, Parrillo JE (1985) Norepinephrine alone versus norepinephrine plus
low-dose dopamine: enhanced renal blood flow with combination pressor therapy. Crit
Care Med 13:492-496
13. Richer M, Robert S, Lebel M (1996) Renal hemodynamics during norepinephrine and low-
dose dopamine infusions in man. Crit Care Med 24:1150-1156
14. Hoogenberg K, Smit AJ, Girbes ARJ (1998) Effects of low-dose dopamine on renal and sys-
temic hemodynamics during incremental norepinephrine infusion in healthy volunteers.
15. Benmalek E, Behforouz N, Benoist J-F, et al (1999) Renal effects of low-dose dopamine
during vasopressor therapy for posttraumatic intracranial hypertension. Intensive Care
Med 25:399-405
16. Denton MD, Chertow GM, Brady HR (1996) Renal-dose dopamine for the treatment of
acute renal failure: Scientific rationale, experimental studies and clinical trials. Kidney lnt
49:4-14
17. Kellum JA, Decker JM (2001) Use of dopamine in acute renal failure: A meta-analysis. Crit
Care Med 29:1526-1531
18. Marik PE (2002) Low-dose dopamine: a systematic review. Intensive Care Med 28:877-883
19. Schnuelle P, Lorenz D, Mueller A, et al (1999) Donor catecholamine use reduces the allo-
graft rejection and improves survival after cadaveric renal transplantation. Kidney lnt
56:738-746
20. ANZICS Clinical Trials Group (2000) Low-dose dopamine in patients with early renal dys-
function: a placebo-controlled randomised trial. Lancet 356:2139-243
21. Neviere R, Mathieu D, Chagnon J-L, et al (1996) The contrasting effects of dobutamine
and dopamine on gastric mucosal perfusion in septic patients. Am J Respir Crit Care Med
154:1684-1688
22. Segal JM, Phang PT, Walley KR (1992) Low-dose dopamine hastens onset of gut ischemia
in a porcine model of hemorrhagic shock. J Appl Physiol 73:1159-1164
23. Chiolero R, Borgeat A, Fisher A (1991) Postoperative arrhythmias and risk factors after
open heart surgery. Thorac Cardiovasc Surg 39:81-84
24. Van den Berghe G, de Zegher F (1996) Anterior pituitary function during critical illness
and dopamine treatment. Crit Care Med 24:1580-1590
25. Devins SS, Miller A, Herndon BL, eta! (1992) Effects of dopamine on T-lymphocyte prolif-
erative responses and serum prolactin concentrations in critically ill patients Crit Care
Med 20:1644-1649
26. Juste RN, Moran L, Hooper J, Soni N (1998) Dopamine clearance in critically ill patients.
27. Chertow GM, Sayegh MH, Allgren RL, Lazarus, JM (1996) Is the administration of dopa-
mine associated with adverse or favorable outcomes in acute renal failure? Auriculin Anari-
tide Acute Renal Failure Study Group. Am J Med 101:49-53
28. Abizaid AS, Clark CE, Mintz GS, et al (1999) Effects of dopamine and aminophylline on
contrast-induced acute renal failure after coronary angioplasty in patients with preexisting
renal insufficiency. Am J Cardiol 83:260-263
29. Neiberger RE, Passmore JC (1979) Effects of dopamine on canine intrarenal blood flow dis-
tribution during hemorrhage. Kidney Int 15:219-226
30. Murphy MB, Murray C, Shorten GD (2001) Fenoldopam- a selective peripheral dopamine-
receptor agonist for the treatment of severe hypertension. N Eng! J Med 345:1548-1556
31. Bodner A, Murray P (2000) Fenoldopam: A Dopaminergic Vasodilator. Current Concepts
in Hypertension 4:5-6
32. Brogden RN, Markham A (1997) Fenoldopam. A review of its pharmacodynamic and phar-
macokinetic properties and intravenous clinical potential in the management of hyperten-
sive urgencies and emergencies. Drugs 54:634-650
33. Singer I, Epstein M (1998) Potential of dopamine A-1 agonists in the management of acute
renal failure. Am J Kidney Dis 31:743-755
34. Elliott WJ, Weber RR, Nelson KS, et al (1990) Renal and hemodynamic effects of intrave-
nous fenoldopam versus nitroprusside in severe hypertension. Circulation 81:970-977
35. Shusterman NH, Elliott WJ, White WB (1993) Fenoldopam, but not nitroprusside, im-
proves renal function in severely hypertensive patients with impaired renal function. Am J
Med 95:161-168
36. Aronson S, Goldberg LI, RothS, et al (1990) Preservation of renal blood flow during hypo-
tension induced with fenoldopam in dogs. Can J Anesth 37:380-384
37. Aronson S, Goldberg LI, Roth S, et al (1991) Effects of fenoldopam on renal blood flow
and systemic hemodynamics during isoflurane anesthesia. J Cardiothorac Vase Anesth
5:29-32
38. Kien ND, Moore PG, Jaffe RS (1992) Cardiovascular function during induced hypotension
by fenoldopam or sodium nitroprusside in anesthetized dogs. Anesth Analg 74:74-82
39. Mathur VS, Swan SK, Lambrecht LJ, et al (1999) The effects of fenoldopam, a selective do-
pamine receptor agonist, on systemic and renal hemodynamics in normotensive subjects.
40. Allison NL, Dubb JW, Ziemniak JA, et al (1987) The effect of fenoldopam, a dopaminergic
agonist, on renal hemodynamics. Clin Pharmacol Therap 41:282-288
41. Poinsot 0, Romand JA, Favre H, Suter PM (1993) Fenoldopam improves renal hemody-
namics impaired by positive pressure. Anesthesiology 79:680-684
42. Schuster HP, Suter PM, Hemmer M, et al (1991) Fenoldopam improves renal dysfunction
secondary to ventilation with PEEP. Intensivmedizin 28:348-355
43. Jorkasky DK, Audet P, Shusterman N, et al (1992) Fenoldopam reverses cyclosporine-in-
duced renal vasoconstriction in kidney transplant recipients. Am J Kidney Dis 19:567-572
44. Bakris GL, Lass NA, Glock D (1999) Renal hemodynamics in radiocontrast medium-in-
duced renal dysfunction: a role for dopamine- I receptors. Kidney Int 56:206-210
45. Siragy HM, Felder RA, Howell NL, et al (1990) Evidence that dopamine-2 mechanisms con-
trol renal function. Am J Physiol 259:F793-F800
46. Carey RM, Siragy HM, Ragsdale NV, et al (1990) Dopamine-! and Dopamine-2 mechan-
isms in the· control of renal function. Am J Hypertens 3:59S-63S
47. Germann R, Hasibeder W, Haisjackl M, et al (1995) Dopamine-1-receptor stimulation and
mucosal tissue oxygenation in the porcine jejunum. Crit Care Med 23:1560-1566
48. Vlavianos P, Polson RJ, Settin A, et al (1990) Haemodynamic and pharmacokinetic study of
intravenous fenoldopam in patients with hepatic cirrhosis. Br J Clin Pharmacol29:19-25
648 P. T. Murray: Use of Dopaminergic Agonists for Renal Protection in the ICU
49. Hadengue A, Moreau R, Bacq Y, et al (1991) Selective dopamine DA1 stimulation with fe-
noldopam in cirrhotic patients with ascites: a systemic, splanchnic, and renal hemody-
namic study. Hepatology 13:111-116
50. Patel JJ, Mitha AS, Sareli P, de Vaal JB (1993) Intravenous fenoldopam infusion in severe
heart failure. Cardiovasc Drugs Ther 7:97-101
51. Barnard ML, Ridge KM, Saldias F, et al (1999) Stimulation of the dopamine l receptor in-
creases lung edema clearance. Am J Respir Crit Care Med 160:982-986
52. Heyman SN, Brezis M, Epstein FH, et al (1991) Early renal medullary hypoxic injury from
radiocontrast and indomethacin. Kidney Int 40:632-642
53. Weisberg LS, Kurnik PB Kurnik BR (1992) Radiocontrast-induced nephropathy in humans:
role of renal vasoconstriction. Kidney Int 41:1408-1415
54. Liss P, Nygren A, Erikson, U, Ulfendahl HR (1998) Injection of low and iso-osmolar con-
trast medium decreases oxygen tension in the renal medulla. Kidney Int 53:698-702
55. Tumlin JA, Wang A, Murray PT, Mathur VS (2002) Fenoldopam mesylate blocks reductions
in renal plasma flow after radiocontrast dye infusion: A pilot trial in the prevention of con-
trast nephropathy. Am Heart J 143:894-903
56. Stone GW, Tumlin JA, Madyoon H, et a! (2001) Design and rationale of CONTRAST - a
prospective, randomized placebo-controlled trial of fenoldopam mesylate for the preven-
tion of radiocontrast nephropathy. Rev Cardiovasc Med 2 (Suppl 1): S31-S35
57. Halpenny M, Markos F, Snow HM, et al (2000) The effects of fenoldopam on renal blood
flow and tubular function during aortic cross-clamping in anaesthetized dogs. Eur J Anaes-
thesiol17:491-498
58. Halpenny M, Lakshmi S, O'Donnell A, et al (2001) Fenoldopam: renal and splanchnic ef-
fects in patients undergoing coronary artery bypass grafting. Anaesthesia 56:953-960
59. Halpenny M, Rushe C, Breen P, et al (2002) The effects of fenoldopam on renal function in
patients undergoing elective aortic surgery. Eur J Anaesthesia! 19:32-39
60. Halpenny M, Markos F, Snow HM, et a! (2001) Effects of prophylactic fenoldopam infusion
on renal blood flow and renal tubular function during acute hypovolemia in anesthetized
dogs. Crit Care Med 29:855-860
Interpreting the Mechanisms of CRRT in Sepsis:
The Peak Concentration Hypothesis
C. Tetta, R. Bellomo, and C. Ronco
I Introduction
Acute renal failure is increasingly seen as part of the multiple organ dysfunction
syndrome (MODS) in critically ill patients [1, 2]. MODS is the most frequent cause
of death in patients admitted to intensive care units (ICUs) [3]. Severe sepsis and
septic shock are the primary causes of MODS [4, 5] and develop as a result of the
host response to infection by Gram-negative and Gram-positive bacteria [6]. Sepsis
encompasses a complex mosaic of interconnected events. Molecules such as bacteri-
allipopolysaccharides (LPS), microbiallipopeptides, microbial DNA, peptidoglycan
and lipoteichoic acid interact with the Toll-like receptors (TLR) and related mole-
cules (MD-2, MyD88), the principal sensors of the innate immune response [7-9].
Stimulus-receptor coupling activates different signal transduction pathways leading
to exacerbated generation of cytokines, and phospholipase ATdependent, arachi-
donic acid-derived platelet-activating factor (PAF), leukotrienes, and thromboxanes.
At the plasma level, activation of the complement (C3a, CSa, and their desarginated
products) and coagulation pathways interacts with the process as products gener-
ated in the fluid phase may in turn trigger and sustain cell activation. Other agents
play a role in the pathophysiology of sepsis such as surface-expressed and soluble
adhesion molecules, kinins, thrombin, myocardial depressant substance(s), endor-
phin, and heat shock proteins.
Continuous renal replacement therapies (CRRT) allow extracorporeal treatment
in critically ill patients and those with hypercatabolism and fluid overload [3, 10-
12]. CRRT have commonly used three types of depurative mechanisms: convection,
diffusion, and adsorption by the filtering membrane. In addition to removing ex-
cess fluid and waste products in septic patients, the possibility that CRRT may re-
move bacterial LPS and other mediators introduced the concept of blood purifica-
tion [13-21].
In the present chapter, we will review some recent advances in the pathogenesis
of sepsis in view of the possible effects of CRRT and related innovative techniques
in restoring the normal hemodynamic and immunologic homeostasis. Understand-
ing how the mechanisms of sepsis may be affected by CRRT may open the concept
of them being not only supportive, but also preventive therapies, i.e., preventing
tissue and organ damage.
650 C. Tetta et al.
I The Pathogenesis of Sepsis

In physiological conditions, the biological activity of sepsis-associated mediators is
under the control of specific inhibitors that may act at different levels. In sepsis,
the homeostatic balance is altered and a profound disturbance of relative produc-
tion of different mediators may be observed (as reviewed in ref. [22]). On one side,
the spill over into the circulation of mediators intended to have autocrine or para-
crine effects generates systemic effects including endothelial damage [23], proco-
agulant, fibrinolytic, complement activities, hemodynamic shock and vaso-paralysis
[24-30]. On the other side, monocytes present a profound inability to produce cyto-
kines when they are challenged with different stimuli ex vivo [31, 32].
The pathogenesis of sepsis was initially described as an overproduction of pro-
inflammatory factors in the host. The concept was established on the basis of sev-
eral studies. The injection of LPS into the experimental animal and healthy human
subjects reproduces the initial phase of bacterial infection [33]. In human subjects,
LPS alters capillary integrity and affects the cardiovascular system [33], causes pro-
duction of cytokines [25, 26, 34, 35], and activates the coagulation-fibrinolytic
pathways [36]. Peak concentrations of interleukin (IL)-1, tumor necrosis factor
(TNF), IL-6, and IL-8 occur within 2-3 hours of LPS infusion [25, 26]. Recent stud-
ies on knockout mice have shown that intercellular adhesion molecule (ICAM)-1-
mutant mice are resistant to the lethal outcome of endotoxin-induced pneumonitis
[37].
What is the relevance of circulating cytokines? The presence or absence of de-
tectable levels of cytokines within biological fluids reflects a rather complex balance
between enhancing and inhibitory signals acting on producer cells, between pro-
duction and catabolism, and between their binding to the target cells and the mod-
ulation of their receptors on the cell surface [22]. Furthermore, their presence does
not necessarily parallel their activity and a possible interplay between a given cyto-
kine and its relative inhibitor (if known) should be considered [22]. Cavaillon et al.
[22] coined the expression of circulating cytokines as being "the top of the iceberg"
implying that neither their presence nor their absence can reflect the complex in-
terplay at the tissue level. Despite the fact that their peak concentrations may reflect
an exacerbated production, these levels do not necessarily stand for enhanced
bioactivity.
The concept of sepsis as a simply pro-inflammatory event has been subsequently
challenged [31, 32, 38, 39].
In sepsis, cell-associated cytokines in peripheral blood mononuclear cells
(PBMC) are decreased, as is the capacity of these cells to produce several cytokines
such as TNF-a, IL-la, IL-1/J, IL-6, IL-10, and IL-12 [40-42], but not IL-l receptor
antagonist (IL-lra) [43]. Hyporesponsiveness is not only present in monocytes but
occurs in whole blood [44] and is associated with increased plasma levels of IL-l 0
and prostaglandin E2 which are potent inhibitors of the production of pro-inflam-
matory cytokines [41, 42, 45]. To describe the occurrence of an excessive anti-in-
flammatory response, expressions such as compensated anti-inflammatory response
syndrome (CARS) [46], monocyte deactivation, immunoparalysis or more simply
cell hyporesponsiveness indicate the inability of cells to respond ex vivo to LPS
stimuli due to overproduction of anti-inflammatory cytokines. Adib-Conquy et al.
[47] demonstrated that, on LPS activation, PBMC of patients with sepsis show pat-
terns of nuclear factor-kappa B (NF-KB) expression that resemble those reported
during LPS tolerance; global down-regulation of NF-KB in survivors of sepsis and
Interpreting the Mechanisms of CRRT in Sepsis: The Peak Concentration Hypothesis 651
trauma patients and the presence of large amounts of the inactive homodimer in
the non-survivors of sepsis. In the clinical setting of severe sepsis, Bone et al. [46]
proposed that at a given time, pro-inflammatory response predominates in patients
with shock or immune depression. However, a large amount of evidence now sug-
gests that in patients with sepsis, pro- and anti-inflammatory responses may co-ex-
ist but in different compartments. Based on these concepts, Cavaillon et al. [39] re-
cently proposed that a pro-inflammatory response predominates within the in-
flamed tissues while circulating leukocytes show hyporeactivity. A restrained in-
flammatory response within the blood stream should avoid the endothelial activa-
tion leading to overexpression of adhesion molecules, adherence, and degranulation
of leukocytes. It would avoid fatal clotting and organ failure. Nevertheless, peak
concentrations of either LPS or different cytokines have been variably reported and
in some reports their levels, alone or in combination, have been even considered as
useful markers in severity scores [48]. Following the intravenous injection of LPS,
a lag phase occurs and is followed after 1 hr by a steep increase in TNF levels
reaching a maximum at 1.5 h. TNF plasma concentrations are sharply reduced at
3 hr when both IL-6 and IL-8 increase. Cytokine production is blunted by cycloox-
ygenase inhibition. Studies on human subjects infused with LPS characterized the
initial inflammatory (TNF, IL-6, IL-8) and hemostatic (thrombin-antithrombin
[TAT] complexes, plasmin-antiplasmin [PAP] complexes, tissue plasminogen activa-
tor [tPA]) responses [26, 33, 49]. Taylor et al. [29] studied the receptor and oxida-
tive enzymatic responses of phagocytes in the human model of endotoxemia and
correlated them with the response of molecular markers of hemostatic and inflam-
matory system activation and endothelial injury. These authors established that the
compensated response to LPS consists of two stages: an immediate symptomatic in-
flammatory stage followed by an asymptomatic stage that is characterized by a re-
currence of hemostatic activity, appearance of complement activation products
complexed to C-reactive proteins and evidence of endothelial injury [29]. In partic-
ular, these authors showed the occurrence of a two-step response: an early response
characterized by the degranulation of neutrophils (as detected by elevation of elas-
tase-a1anti-trypsin complexes) coinciding with peak concentrations of TNF, IL-6
and regulatory responses such as IL-10 and activated protein C; and a late response
characterized by hemostatic activity as reflected by the appearance of a large peak
of soluble fibrin and a second and greater decrease in circulating factor VIla con-
centration coupled with the appearance of increased concentrations of plasma tis-
sue factor antigen. This second phase was also characterized by sustained, mark-
edly elevated levels of C-reactive protein (CRP), and CRP-bound activated comple-
ment components [29]. A crucial aspect of these studies is that peak concentrations
of LPS and of several cytokines appear at different time intervals. The intravenous
injection of pro-inflammatory cytokines (TNF, IL-l) reproduces very closely the
pattern of hemodynamic and intravascular changes induced by the injection of LPS
[29].
In the human setting of sepsis, the finding of elevated levels of different pro-
and anti-inflammatory cytokines has been variable, suggesting the possibility that
their production may occur at a different time from sampling, that their production
in a given patient is compartmentalized, or both these possibilities. We suggest that
the pro-/anti-inflammatory responses associated with sepsis may occur in sequence
or alternately (the sequential or serial sepsis theory). On the other hand, the events
associated with sepsis may occur simultaneously (the parallel sepsis theory) in that
the pro-/anti-inflammatory responses may coexist in different districts or systems
652 C. Tetta et al.
Inflammation
Pnl-lnfllmln-.y
responM
Sepsis ------ ---- · ---- ·- · · · · ·- ----,
Serial Theory _ ___Jt...__ _,~ __ -~~~~~~ ~~~~:. ~~ immunohomeostasis : - -
Time
Fig. 1. The serial or sequential theory of sepsis and the parallel theory. According to the serial theory,
the sequence of events starts temporally with the stimulus such as endotoxin dissemination and a sys-
temic inflammatory response follows with a spill over into the circulation of several pro-inflammatory
mediators. Subsequently, a potent inhibition of the inflammatory process and a consequent cell hypore-
sponsiveness occurs. In the parallel theory, both processes occur simultaneously and a parallel synthesis
of pro- and anti-inflammatory mediators coexists in different districts of the body
(Fig. 1). In the sequential sepsis theory, temporary prevalence of the pro-inflamma-
tory response should be probably treated with high dose steroids assuming that a
timely intervention is possible thanks to an early and accurate biological monitor-
ing. Otherwise, the therapy may overlap with the next coming period of the anti-
inflammatory response and may even favor bacterial colonization and infection dis-
semination. Indeed, in this period, protective anti-microbial therapy should be ad-
ministered. The time of intervention becomes crucial in order to prescribe the right
therapy for the right disorder. Alternatively, if the parallel sepsis theory is consider-
ed, none of the two therapies may be adequate and a question mark remains on
the most sound therapeutic approach (Fig. 2).
In intensive care medicine, blocking one mediator has not led to measurable out-
come improvement in patients with sepsis [SO]. Possibly more rigidly defined sub-
groups would benefit from TNF-antagonizing treatments [51]. On the other hand,
it has been shown that antagonizing a cytokine may lead to deleterious consequences
leading to substantially higher mortality [52]. A low-level TNF response seems to be
necessary for the host defense to infection [53, 54], and high levels seemingly need to
be modulated by an anti-inflammatory feedback. In sepsis, however, impaired regula-
tion may cause an excessive anti-inflammatory response that generates monocyte 'im-
munoparalysis' and exposes the host to further infections. Both processes (inflamma-
tion and anti-inflammation) are designed to act in response to specific stimuli in a
well-balanced fashion defined as immune homeostasis.
Furthermore, the time point of therapeutic intervention in the septic process
seems to be crucial. As the network acts like a cascade, early intervention would
High Dose Antimicrobial

Steroids agents
Pro-inflammatory
mediators
Anti -inflammatory
mediators Onhibitors) J]. lmmunohomeostasis
Anti-inflammatory nme
response
Pro-/anti-inflammatory mediators
Which pharmacological therapy?
lmmunohomeostasis
nme
Fig. 2. In the sequential theory, peaks of pro-inflammatory mediators are followed by peaks of anti-in-
flammatory mediators. In the parallel theory, a mixture of pro- and anti-inflammatory mediators coexists.
The sequential theory leads to the conclusion that, if pro- and anti-inflammatory activities could be moni-
tored, specific therapies could be targeted for selected actions in different moment of the time course of
the syndrome. In the parallel theory, one therapy or another may be effective at one time but deleterious
at another. CRRT: continuous renal replacement therapy
seem most beneficial. On the other hand, sepsis does not fit a one-hit model.
Neither single-mediator-directed nor one-time interventions, therefore, seem appro-
priate. One of the major criticisms attributed to continuous blood purification
treatments in sepsis - its lack of specificity - could turn out to be a major strength.
Non-specific removal of soluble mediators - be they pro- or anti-inflammatory -
without completely eliminating their effect may be the most logical and adequate
approach to a complex and long-running process like sepsis (Fig. 2). The concept
of cutting peaks of soluble mediators, e.g., through continuous hemofiltration is a
paradigm called by us "the peak concentration hypothesis" [55].
I CRRT
For several years, the issue of the ability of hemofiltration to remove inflammatory
mediators has remained controversial. Numerous ex vivo as well as animal and hu-
man studies have shown that synthetic filters in common use in hemofiltration can
extract nearly every substance involved in sepsis to a certain degree (as reviewed
in ref. [56]). Prominent examples are complement factors [57, 58], TNF, IL-l, IL-6
[15, 59-61], IL-8 [62], and PAF [21, 63]. Regarding plasma cytokine levels, their de-
crease nevertheless appeared to be of minor degree. Other studies could not show
any influence of CRRT on cytokine plasma levels [64-66]. On the other hand, sig-
654 C. Tetta et al.
nificant clinical benefits in terms of hemodynamic improvement have been

achieved even without measurable decreases in cytokine plasma levels [67]. Ob-
viously the removal of substances different to the measured cytokines was respon-
sible for the achieved effect. In contrast, bioactive substances, including some of
the measured cytokines, were removed causing the observed beneficial effect. In a
recent study, Mariano et al. [62] evaluated the priming activity of sera from septic
patients on polymorphonuclear neutrophils. This activity was related to ultrafil-
trable mediators among which IL-8 seemed to be among the most relevant. The re-
sults of this study [62] further suggest that several mediators may act in concert in
altering the functional responses of the circulating leukocytes. When the response
to sepsis is viewed in a network perspective, absolute values would be less relevant
than relative ones within an array of interdependent mediators, as even small de-
creases could induce major balance changes. This outlook makes measurement of
cytokine plasma levels debatable while more local or tissue levels should be mea-
sured whenever possible. These issues are still extremely controversial and no
definitive solution exists either in favor or against the use of CRRT as a therapy of
blood purification in sepsis. In this context a further step has been taken to clarify
the immunologic impact of CRRT by measuring a more downstream event integrat-
ing the influence of several cytokines: monocyte responsiveness [38-42, 68].
In spite of some encouraging results as mentioned, the extent of achievable clini-
cal benefit with conventional CRRT (using conventional filters and flow rates) in
sepsis has generally been disappointing [69]. Consequently, attempts were made to
improve the efficiency of the methodology regarding removal of soluble sepsis
mediators by increasing the amount of plasma water exchange, i.e., increasing ul-
trafiltration rates.
Animal studies provided great support to this concept. Starting in the early nine-
ties, several studies using different septic animal models examined the effects of
high ultrafiltration rates (up to 300 ml!kg/h) on physiological parameters and out-
come. In a landmark study, a porcine model of septic shock induced by endotoxin
infusion was investigated [70]. The animals developed profound arterial hypoten-
sion and a decrease in cardiac output, stroke volume, and right ventricular stroke
work index. By high volume hemofiltration (HVHF, at 6 1/h), right ventricular func-
tion, blood pressure, and cardiac output showed a remarkable improvement com-
pared to control and sham-filtered animals [70, 71]. The same group extended their
findings in the same model by intravenous administration of ultrafiltrate from
LPS-infused animals into healthy animals. These healthy animals developed hemo-
dynamic features similar to septic shock, while animals infused with ultrafiltrate
from healthy animals showed a moderate blood pressure rise (71]. In a further
study by the same group, a bowel ischemia-reperfusion model in pigs was investi-
gated. HVHF started before clamping of the superior mesenteric artery significantly
diminished bowel damage and prevented hemodynamic deterioration (72]. These
studies established that a convection-based treatment can remove substances with
hemodynamic effects resembling septic shock, when sufficiently high ultrafiltration
rates are applied.
Several studies have confirmed and refined these results. In three [73-75], the
correlation of survival with ultrafiltration rate was demonstrated. Significant im-
provements in cardiac function, systemic and pulmonary vascular resistance, and
hepatic perfusion were found [74]. Another study in lambs showed significant im-
provements in lung function [76]. Only a minority of studies identified reduced
mediator plasma levels [75, 77].
A very recent study in pigs made septic by induced pancreatitis compared low-vol-
ume continuous veno-venous hemoflltration (CVVH) with HVHF of 100 ml/kg/h. In
the same study, the influence of frequent fllter changes on survival, and changes in
TNF levels as well as monocyte and polymorphonuclear neutrophil function were
analyzed [75]. Early filter change allowed the effect of cytokine removal by adsorption
on the filter to be delineated since membrane capacity was saturated after a few hours.
By changing fllters, adsorption continued to a certain extent. In this model, a hyper-
dynamic septic state is induced through an intervention which approximates under-
lying conditions encountered in human sepsis. Additionally, the intervention started
late to simulate real clinical conditions. Hemofiltration was commenced when the
animals developed the clinical picture of hyperdynamic septic shock. HVHF was
superior in all mentioned endpoints. Of relevance, increasing ultrafiltration rate
had more effect than frequency of fllter change [75].
Closer to human sepsis has been the finding that the ultraflltration dose is cor-
related to outcome in critically ill patients with acute renal failure. In a large ran-
domized, controlled study including 425 patients, an ultraflltration dose of 35 ml/
kg/h increased survival rate from 41 to 57% compared to a dose of 20 ml/kg/h
[78]. Eleven to 14% (per randomization group) of the patients had sepsis. In these
subgroups there was a trend of a direct correlation between treatment dose and
survival even above 35 ml/kglh in contrast to the whole group where a survival pla-
teau was reached.
This finding lends support to the concept of a 'sepsis dose' of hemoflltration in
septic patients contrasting to a 'renal dose' in critically ill patients without systemic
inflammation, the former being probably distinctly higher (without a proven upper
limit). Of note, there was no increase in adverse effects even with the highest ultra-
filtration dose.
Over recent years, several human studies have examined the clinical effects of
HVHF. In 20 children undergoing cardiac surgery, zero-balanced HVHF was admin-
istered with ultrafiltration rates equivalent to 7-91/h for a 70 kg adult [79]. Endpoints
correlating to the cardiopulmonary bypass-associated delayed inflammatory response
were examined. There was a significant reduction in postoperative blood loss and
time to extubation, and improvement in the arterial-alveolar oxygen gradient.
In a prospective cohort-analysis in 306 critically ill patients with various under-
lying diseases, a mean ultraftltration rate of 3.8 1/h was applied [80]. Observed sur-
vival rates were significantly higher in the treated population compared to pre-
dicted survival by three well validated scores.
In another trial in 11 septic patients with shock and MODS, a randomized
cross-over design of 6 1/h vs. 1 1/h ultraflltration was applied [81]. The HVHF-
group displayed significantly greater reduction in vasopressor requirements. Both
treatment groups showed a decrease in C3a and CSa plasma levels that was signifi-
cantly greater in the HVHF-group [81].
Impressive clinical results were obtained in an evaluation of short-term HVHF
in 20 patients in catecholamine-refractory septic shock [82] comprising a patient
cohort with very poor expected survival. A control group was not defined. Only
one four-hour session of HVHF removing 35 1 of ultraflltrate replaced by bicarbo-
nate-containing fluid was applied as soon as mean blood pressure could not be sta-
bilized above 70 mmHg with dopamine, norepinephrine and epinephrine after ap-
propriate volume resuscitation. HVHF was followed by conventional CVVH. End-
points were increase in cardiac index, mixed venous oxygen saturation and arterial
pH, and decrease in norepinephrine requirements. Eleven patients reached all pre-
656 C. Tetta et al.
defined endpoints and showed impressively good survival (9 out of 11) at 28 days.
Nine patients did not reach all endpoints and had a 100% mortality rate. Apart
from responding to HVHF, only time from admission to start of HVHF and body
weight were survival-associated factors in the analysis. Patients with higher body
weight did worse possibly because they received a smaller ultrafiltration dose per
body weight, as speculated by the authors [82].
These trials still need cautious interpretation with respect to their limited design
but they certainly deliver sound evidence of feasibility and efficacy to set the stage
for a large-scale trial on HVHF in sepsis.
Other approaches to achieve higher mediator clearance in sepsis have been
sought. Apart from increasing ultrafiltration rates, higher removal rates of middle
molecular weight molecules could be achieved by enlarging membrane pore size.
Animal data [83, 84], as well as preliminary clinical data [85], demonstrate feasibil-
ity and probable superior removal rates of selected cytokines using more open
membranes. A study in 30 patients with severe sepsis using continuous plasmafil-
tration for 34 hrs [86] found attenuation of the acute phase response and a trend
towards clinical benefit although not significant (fewer failing organs).
A further step to increase mediator removal has been achieved with plasma fil-
tration coupled with adsorption and followed by dialysis or filtration (CPFA) [87].
Using an experimental model of acute endotoxemia in the rabbit, Tetta et al.
[88] showed that non-selective adsorption of cytokines and other pro-inflammatory
mediators known to be produced in excess during sepsis could improve survival.
The simultaneous removal of peak concentrations of TNF and PAF could also possi-
bly prevent the formation of other biologically active substances, such as prosta-
glandins/leukotrienes, other cytokines, molecules up- or down-regulating mem-
brane receptors, selectins, and adhesion molecules, thus amplifying and perpetuat-
ing the immunologic disorders. The results that stem from these studies strongly
support the concept that a relationship would link the simultaneous removal of dif-
ferent mediators to the improved survival. As stated above, the non-selective, simul-
taneous removal of different mediators may not necessarily imply that the goal of
blood purification be achieved only on the basis of a significant reduction of the
circulating cytokines. Much more effective would be the impact on the functional
responses of cells implicated in the pathogenesis of sepsis (Fig. 3). In a very recent
study [68], we tested the hypothesis that non-selective removal of mediators could
improve hemodynamics and restore leukocyte responsiveness in patients with sep-
tic shock. The aim of this study was in response to the open question as to how
CRRT may have a beneficial effect on the hemodynamic and immune response as-
sociated with severe sepsis. Immunomodulating substances (with molecular weight
in the range of 5-50 kDa) may be eliminated by diffusion, adsorption or convection
depending on the rather variable cut-off of highly permeable membranes (range
from 30 to 40 kDa) [67]. Adsorption is only a transient phenomenon. Thus, the ef-
fect of CRRT could be limited because of the low convective clearance of many sol-
uble mediators. The use of a plasmafiltration membrane coupled with an adsorp-
tion device in CPFA could enhance unselective removal and improve hemodynamic
stability compared to CRRT. CPFA was associated with the restoration of stable he-
modynamics, particularly due to an increase in mean arterial pressure (MAP). This
change in blood pressure led to a significant reduction in norepinephrine require-
ment. CPFA also restored in vitro leukocyte responsiveness to LPS. The magnitude
of this effect was significantly greater with CPFA than with continuous veno-venous
hemodiafiltration (CVVHDF). Plasma levels of TNF-a and IL-10, however, were not
Inflammation ·c:~::>
-e
.e
---,
'' "'
Qj
---------- >
~
B
..
"'
'0
:!!
Time
Inflammation "E
·c:
::>
.0
~
"'
Qj
>
~
5
:;;
'0
ell
Anti -Inflammation
:!!
Time
Fig. 3. In both theories (sequential and parallel} the concept introduced by the peak concentration hypo-
thesis suggests that a non-selective control of the peaks of inflammation and immunoparalysis may con-
tribute to bring the patient to a lesser degree of derangement and closer to the self defense induced by
a nearly normal immune homeostasis
significantly changed during CPFA or CVVHDF but they did not display concentra-
tion peaks [68].
Patients' leukocyte responsiveness was evaluated by measuring spontaneous and
LPS-stimulated production of TNF-a. We used the whole blood cytokine assay as it
measures cytokine production in the presence of a wide range of modulating fac-
tors (e.g., soluble receptors, natural inhibitors, proteases, etc.). The spontaneous ex
vivo production of TNF-a by patients' whole blood was normal in all patients at
the start but it was increased at the end of treatment with CPFA [68]. The sponta-
neous ex vivo production of TNF-a was also further increased by passage through
the hemodiafilter. These changes in ex vivo cell responsiveness could be due to a
less biocompatible circuit, exposure to cytokine-inducing substances, removal of a
dialyzable suppressive 'uremic toxin', or removal of other inhibitors of cell respon-
siveness. Diffusion of suppressive 'uremic toxins' may be important in acutely
uremic patients. In agreement with this contention, a study in l2 critically ill p~
tients with acute renal failure comparing low-volume CVVH (1500 ml!h) with a dif-
fusive technique was performed in a non-randomized, comparative fashion [89].
High-flux bicarbonate dialysis amounting to 4200 rnl/h was used and the effect on
monocyte responsiveness (ex vivo endotoxin-stimulated TNF-production) was stud-
ied [89]. Both techniques resulted in early improvement but only the diffusive tech-
nique showed persistent effects. Ultrafiltrate contained monocyte-suppressive activ-
ity only with high-flux dialysis [89].
Ronco et al. [68] evaluated LPS-stimulated TNF-a production in vitro; it was
markedly inhibited at the start of treatment in all patients. An eight- to ten-fold in-
658 C. Tetta et al.
crease in LPS-stimulated TNF-a production was observed after 10 hrs of CPFA at

both sites 2 and 3, suggesting that this effect was not affected by diffusion/convec-
tion. Only a 5-fold increase could be seen in LPS-stimulated TNF-a production
after CVVHDF. Finally, the in vitro assessment of the effect of septic plasma on
TNF-a production by normal inflammatory cells showed that, at the start of treat-
ment, LPS-stimulated TNF-a production was suppressed by plasma obtained before
and after the resin. Although such suppression was decreased by passage through
the resin, it was not fully eliminated by it. We speculated that the resin was not able
to completely adsorb suppressive soluble factors in a biologically significant
amount in a single pass. However, after 10 hours of CPFA, the inhibitory effect of
septic plasma was markedly attenuated. The ability of CPFA to restore immune cell
responsiveness may be clinically beneficial.
I Conclusion
A vast array of mostly water-soluble mediators play a strategic role in the septic
syndrome. In contrast to targeting single mediators, therapeutic interventions fo-
cused at the non-selective removal of pro- and anti-inflammatory mediators seems
a rational concept. A further advantage may be achieved by a continuously acting
therapy, such as CRRT. Therefore, sequentially appearing peaks of systemic media-
tor overflow could be curbed and persistently high plasma levels could be reduced.
This process is proposed as the underlying biological rationale for a series of inno-
vative therapies in sepsis. The whole story of antagonizing pro- and anti-inflamma-
tory processes by reducing the relative excess of active substances is termed the
"peak concentration hypothesis".
Recent animal and human trials have delivered much support to this concept. It
has been conclusively shown that treatment dose in CRRT is a major factor con-
cerning survival in acute renal failure in the critically ill patient. There is accumu-
lating evidence of increased efficacy of high volume hemofiltration compared to
conventional CVVH in terms of laboratory and clinical improvement including sur-
vival. Machines to perform HVHF safely are available on the market. Yet the evi-
dence still is not strong enough to recommend HVHF outside clinical studies, tak-
ing into account the possible adverse effects of the technique. A large-scale clinical
trial is urgently needed to resolve the issue.
Other blood purification techniques using large pore membranes or plasma fil-
tration with adsorbent perfusion are in the early stages of clinical testing. They are
conceptually promising and possibly constitute an important refinement.
References
1. Cosentino F, Chaff C, Piedmonte M (1994) Risk factors influencing survival in ICU acute
renal failure. Nephrol Dial Transplant 9 (suppl 4):179-182
2. Liano G, Pascual J (1996) Acute renal failure. Madrid Acute Renal Failure Study Group.
Lancet 347:479
3. Bellomo R, Ronco C (1998) Indications and criteria for initiating renal replacement ther-
apy in the intensive care unit. Kidney Int Suppl 66:S106-S109
4. The ACCP/SCCM Consensus conference committee (1992) Defmitions for sepsis and organ
failure and guidelines for the use of innovative therapies in sepsis. Chest 101:1644-1655
5. Camussi G, Montrucchio G, Diminioni L, Dionigi R (1995) Septic shock: the unravelling of
molecular mechanism. Nephrol Dial Transplant 10:1808-1813
6. Glauser MP, Zanetti G, Baumgartner JD, Cohen J (1991) Septic shock: pathogenesis. Lancet
338:732-736
7. Medzhitov R, Preston-Hurlburt P, Janeway CA Jr (1997) A human homologue of the Droso-
phila Toll protein signals activation of adaptive immunity. Nature 388:394-397
8. Shimazu R, Akashi S, Ogata H, et al (1999) MD-2 a molecule that confers lipopolysaccha-
ride responsiveness on Toll-like receptor 4. J Exp Med 189:1777-1782
9. Medzhitov R, Preston-Hurlburt P, Kopp E, et al (1998) My88 is an adaptor protein in the
hToll/IL-1 receptor family signaling pathways. Mol Cell 2:253-258
10. Van Bommel EFH, Bouvy ND, So KL, et al (1995) Acute dialytic support for the critically
ill: Intermittent hemodialysis versus continuous arteriovenous hemodiaffitration. Am J
Nephrol 15:192-200
11. Bellomo R, Mehta R (1995) Acute renal replacement in the intensive care medicine: Now
and tomorrow. New Horiz 3:760-767
12. Canaud B, Mion C (1995) Extracorporeal treatment of acute renal failure: methods, indica-
tions, quantified and personalized therapeutic approach. Adv Nephrol 24:271-281
13. Silvester W, Bellomo R, Ronco C (1998) Continuous versus intermittent renal replacement
therapy in the critically ill. In: Ronco C, Bellomo R (eds) Critical Care Nephrology. Kluwer
Academic Publishers, Dordrecht, pp 1225-1238
14. Bellomo R, Tipping P, Boyce N (1993) Continuous veno-venous hemoffitration with dialysis
cytokines from the circulation of septic patients. Crit Care Med 21:522-526
15. Schetz M, Ferdinande P, Van der Berghe G, et al (1995) Removal of pro-inflammatory cyto-
kines with renal replacement therapy: sense or nonsense? Intensive Care Med 21:169-176
16. Van Bommel EFH, Hesse CJ, Jutte NHPM, et al (1995) Cytokine kinetics during continuous
hemoffitration: a laboratory and clinical study. Contrib Nephrol116:62-75
17. Bellomo R, Tipping P, Boyce N (1995) Interleukin-6 and interleukin-8 extraction during
continuous venovenous-hemodiaffitration in septic acute renal failure. Renal Fail 17:457-
466
18. Millar AB, Armstrong L, van der Linden J, et al (1993) Cytokine production and hemofil-
tration in children undergoing cardiopulmonary bypass. Ann Thorac Surg 56:1499-1502
19. Journois D, Pouard P, Greely WJ, et al (1994) Hemofiltration during cardiopulmonary by-
pass in pediatric cardiac surgery. Anesthesiology 81:1181-1189
20. Goldfarb S, Golper TA (1994) Proinflammatory cytokines and hemofiltration membranes. J
Am Soc Nephrol 5:228-232
21. Ronco C, Tetta C, Lupi A, et al (1995) Removal of platelet-activating factor in experimental
continuous arteriovenous hemoffitration. Crit Care Med 23:99-107
22. Cavaillon JM, Munoz C, Fitting C, et al (1992) Circulating cytokines: The top of the ice-
berg? Circ Shock 38:145-152
23. Reidy MA, Bowyer DE (1997) Scanning electron microscopy: morphology of aortic en-
dothelium following injury by endotoxin and during subsequent repair. Atherosclerosis
26:319-328
24. Gil LY, Rosello AM, Torres AC, et al (2002) Modulation of soluble phases of endothelial/
leukocyte adhesion molecule 1, intercellular adhesion molecule 1, and vascular cell adhe-
sion molecule 1 with interleukin 1p after experimental endotoxic challenge. Crit Care Med
(in press)
25. Dinarello CA, Cannon JC, Wolff SM, et al (1986) Tumor necrosis factor (cachectin) is an
endogenous pyrogen and induces production of interleukin 1. J Exp Med 163:1433-1440
26. van Deventer SJH, Bueller HR, ten Cate JW, et al (1990) Experimental endotoxemia in hu-
mans: analysis of cytokine release and coagulation, fibrinolytic and complement pathways.
Blood 76:2520-2526
27. Rosenberg RD, Aird WC (1999) Vascular-bed specific hemostasis and hypercoagulable
states. N Engl J Med 340:1555-1564
28. Esmon CT (2000) The protein C pathway. Crit Care Med 28:S44-S48
29. Taylor FB, Haddad PA, HackE, et al (2001). Two-stage response to endotoxin infusion into
normal human subjects:Correlation of blood phagocyte luminescence with clinical and la-
boratory markers of the inflammatory, hemostatic response. Crit Care Med 29:326-334
30. Faust SN, Levin M, Harrison OB, et al (2001) Dysfunction of endothelial protein C activa-
tion in severe meningococcal sepsis. N Engl J Med 345:408-416
660 C. Tetta et al.
31. Pinsky MR (2001) Sepsis: a pro- and anti-inflammatory disequilibrium syndrome. Contrib
Nephrol 132:354-366
32. Cavaillon JM, Adib-Conquy M, Cloez-Tayarani I, Fitting C (2001) Immunodepression in
sepsis and SIRS assessed by ex vivo cytokine production is not a generalized phenomenon:
a review. J Endotoxin Res 7:85-93
33. Suffredini AF, Fromm RE, Parker MM, et al (1989) The cardiovascular response of normal
humans to the administration of endotoxin. N Engl J Med 321:280-287
34. Matrich GD, Danner RL, Ceska M, et al (1991) Detection of interleukin 8 and tumor necro-
sis factor in normal humans after intravenous endotoxin: The effect of antiinflammatory
agents. J Exp Med 173:1021-1024
35. Michie HR, Manogue KR, Spriggs DR, et al (1988) Detection of circulating tumor necrosis
factor after endotoxin administration. N Engl J Med 318:1481-1486
36. Suffredini AF, Harpel PC, Parrillo JE (1989) Promotion and subsequent inhibition of plas-
minogen activator after administration of intravenous endotoxin to normal subjects. N
Engl J Med 320:1165-1172
37. Kumasaka T, Quinlan W, Doyle N, et al (1996) Role of the intercellular adhesion molecule
(ICAM-1) in endotoxin-induced pneumonitis using ICAM-1 anti-sense oligonucleotides,
anti-ICAM-1 monoclonal antibodies and ICAM-1 mutant mice. J Clin Invest 97:2362-2369
38. Volk HD, Reinke P, Krausch D, et al (1996) Monocyte deactivation: rationale for a new
therapeutic strategy in sepsis. Intensive Care Med (suppl 4):S474-S481
39. Cavaillon JM, Adib-Conquy M, Cloez-Tayarani I, Fitting C (2001) Immunosuppression in
sepsis and SIRS assessed by ex-vivo cytokine production is not a generalized phenomenon:
a review. J Endotoxin Res 7:85-93
40. Munoz C, Cadet J, Fitting C, et al (1991) Dysregulation of in vitro cytokine production by
monocytes during sepsis. J Clin Invest 88:1747-1754
41. Randow F, Syrbe V, Meisel C, et al (1995) Mechanism of endotoxin desensitization: involve-
ment ofinterleukin-10 and transforming growth factor. J Exp Med 181:1887-1892
42. Brandtzaeg P, Osnes L, Ostebo R, et al (1996) Net inflammatory capacity of human septic
shock plasma evaluated by a monocyte-based target cell assay: identification of interleu-
kin-10 as a major functional deactivator of human monocytes. J Exp Med 184:51-60
43. Marie C, Muret J, Fitting C, et al (2000) Interleukin-1 receptor antagonist production dur-
ing infectious and noninfectious systemic inflammatory response syndrome. Crit Care Med
28:2277-2282
44. Granowitz EV, Porat R, Mier JW, et al (1993) Intravenous endotoxin suppresses the cyto-
kine response of peripheral blood mononuclear cells in healthy humans. J Immunol
151:1637-1645
45. Knudsen PJ, Dinarello CA, Strom TB (1986) Prostaglandins posttranscriptionally inhibit
monocyte expression of interleukin 1 activity by increasing intracellular cyclic adenosine
monophosphate. J Immunol137:3189-3194
46. Bone RC, Grodzin CJ, Balk RA (1997) Sepsis: A new hypothesis for pathogenesis of the dis-
ease process. Chest 112:235-243
47. Adib-Conquy M, Adrie C, Moine P, et al (2000) NF-kappaB expression in mononuclear
cells of patients with sepsis resembles that observed in lipopolysaccharide tolerance. Am J
48. Gogos CA, Drosou E, Bassaris HP, Skoutelis A (2000) Pro- versus anti-inflammatory cyto-
kine profile in patients with severe sepsis: a marker for prognosis and future therapeutic
options. J Infect Dis 181:176-180
49. Parrillo JE, Burch C, Stelhamer JH, et al ( 1985) A circulating myocardial depressant sub-
stance in humans with septic shock: septic shock patients with a reduced ejection fraction
have a circulating factor that depresses in vitro myocardial cell performance. J Clin Invest
76:1539-1553
50. Zeni F, Freeman B, Natanson C (1997) Anti-inflammatory therapies to treat sepsis and sep-
tic shock: a reassessment. Crit Care Med 25:1095-1100
51. Abraham E, Glauser MP, Butler T, et al (1997) p55 tumor necrosis factor receptor fusion
protein in the treatment of patients with severe sepsis and septic shock. A randomized
controlled multicenter trial. Ro 45-2081 study group. JAMA 277:1531-1538
52. Fisher CJ, Agosti JM, Opal SM (1996) Treatment of septic shock with the tumor necrosis
factor receptor: Fe fusion protein. N Eng! J Med 334:1697-1702
53. Echtenacher B, Falk W, Manne! D, Krammer PH (1990) Requirement of endogenous tu-
mour necrosis factor/cachectin for recovery from experimental peritonitis. J Immunol 145:
3762-3766
54. van der Meer JWM (1988) The effects of recombinant interleukin-1 and recombinant tu-
mor necrosis factor on non-specific resistance to infection. Biotherapy 1:19-25
55. Ronco C, Ricci Z, Bellomo R (2001) Importance of increased ultrafiltration volume and im-
pact on mortality: sepsis and cytokine story and the role of continuous veno-venous he-
moflltration. Curr Opin Nephrol Hypertens 10:755-761
56. Silvester W (1997) Mediator removal with CRRT: complement and cytokines. Am J Kidney
Dis 30 (suppl 4):S38-S43
57. Hoffmann JN, Hartl WH, Deppisch R, et a! (1995) Hemofiltration in human sepsis: evi-
dence for elimination of immunomodulatory substances. Kidney Int 48:1563-1570
58. Gasche Y, Pascual M, Suter PM, et a! (1996) Complement depletion during haemoflltration
with polyacilonitrile membranes. Nephrol Dial Transplant 11:117-119
59. Goldfarb S, Golper TA (1994) Proinflammatory cytokines and hemoflltration membranes.
J Am Soc Nephrol 5:228-232
60. Kellum JA, Johnson JP, Kramer D, et a! (1998) Diffusive vs. convective therapy: effects on
mediators of inflammation in patients with severe systemic inflammatory response syn-
drome. Crit Care Med 26:1995-2000
61. Braun N, Giolai M, Rosenfeld S, et a! (1993) Clearance of interleukin-6 during continuous
veno-venous hemoflltration in patients with septic shock. A prospective, controlled clinical
study. J Am Soc Nephrol 4:336 (abst)
62. Mariano F, Tetta C, Guida GE, Triolo G, Camussi G (2001) Hemofiltration reduces the priming
activity on neutrophil chemiluminescence in septic patients. Kidney Int 60:1598-1605
63. Mariano F, Guida G, Donati D, et a! (1999) Production of platelet-activating factor in pa-
tients with sepsis-associated acute renal failure. Nephrol Dial Transplant 14:1150-1157
64. Sander A, Armbruster W, Sander B, et a! (1997) Haemofiltration increases IL-6 clearance
in early systemic inflammatory response syndrome but does not alter IL-6 and TNF alpha
plasma concentrations. Intensive Care Med 23:878-884
65. De Vriese AS, Colardyn FA, Philippe JJ, et a! (1999) Cytokine removal during continuous
hemoflltration in septic patients. J Am Soc Nephrol 10:846-853
66. Cole L, Bellomo R, Journois D, et a! (2002) A phase II randomized, controlled trial of con-
tinuous hemofiltration in sepsis. Crit Care Med 30:100-106
67. Heering P, Morgera S, Schmitz FJ, eta! (1997) Cytokine removal and cardiovascular hemo-
dynamics in septic patients with continuous venovenous hemoflltration. Intensive Care
Med 23:288-296
68. Ronco C, Brendolan A, Lonnemann G, et a! (2002) A pilot study of coupled plasma filtra-
tion with adsorption in septic shock. Crit Care Med 30:1250-1255
69. De Vriese AS, Vanholder RC, Pascual M, et a! (1999) Can inflammatory cytokines be re-
moved efficiently by continuous renal replacement therapies? Intensive Care Med 25:903-
910
70. Grootendorst AF, van Bommel EFH, van der Hoven B, eta! (1992) High volume hemofiltra-
tion improves hemodynamics of endotoxin-induced shock in the pig. J Crit Care 7:67-75
71. Grootendorst AF, van Bommel EFH, van Leengoed LA, et a! (1993) Infusion of ultrafiltrate
from endotoxemic pigs depresses myocardial performance in normal pigs. J Crit Care
8:161-169
72. Grootendorst AF, van Bommel EFH, van Leengoed LA, eta! (1994) High volume hemofll-
tration improves hemodynamics and survival of pigs exposed to gut ischemia and reperfu-
sion. Shock 2:72-78
73. Lee PA, Matson JR, Pryor RW, Hinshaw LB (1993) Continuous arteriovenous hemoflltration
therapy for Staphylococcus aureus-induced septicemia in immature swine. Crit Care Med
21:914-924
74. Rogiers P, Zhang H, Smail N, et a! (1999) Continuous venovenous hemofiltration improves
cardiac performance by mechanisms other than tumor necrosis factor-alpha attenuation
during endotoxic shock. Crit Care Med 27:1848-1855
662 C. Tetta et al.: Interpreting the Mechanisms of CRRT in Sepsis: The Peak Concentration Hypothesis
75. Yekebas EF, Eisenberger CF, Ohnesorge H, et al (2001) Attenuation of sepsis-related immu-
noparalysis by continuous veno-venous hemofiltration in experimental porcine pancreati-
tis. Crit Care Med 29:1423-1430
76. Nagashima M, Shin'oka T, Nollert G, et al (1998) High-volume continuous hemofiltration
during cardiopulmonary bypass attenuates pulmonary dysfunction in neonatal lambs after
deep hypothermic circulatory arrest. Circulation 98 (suppl19):11378-384
77. Bellomo R, Kellum JA, Gandhi CR, Pinsky MR (2000) The effect of intensive plasma water
exchange by hemofiltration on hemodynamics and soluble mediators in canine endotoxe-
mia. Am J Respir Crit Care Med 161:1429-1436
78. Ronco C, Bellomo R, Homel P, et al (2000) Effects of different doses in continuous vena-
venous haemofiltration on outcomes of acute renal failure: a prospective randomised trial.
Lancet 356:26-30
79. Journois D, Israel Biet D, Pouard P, et al (1996) High-volume, zero-balanced hemoflltration
to reduce delayed inflammatory response to cardiopulmonary bypass in children. Anesthe-
siology 85:965-976
80. Oudemans-van Straaten HM, Bosman RJ, et al (1999) Outcome of critically ill patients
treated with intermittent high-volume haemoflltration: a prospective cohort analysis. Inten-
81. Cole L, Bellomo R, Journois D, et al (2001) High-volume hemoflltration in human septic
shock. Intensive Care Med 27:978-986
82. Honore PM, Jamez J, Wauthier M, et al (2000) Prospective evaluation of short-term, high-
volume isovolemic hemoflltration on the hemodynamic course and outcome in patients
with intractable circulatory failure resulting from septic shock. Crit Care Med 28:3581-
3587
83. Lee PA, Weger G, Pryor RW, Matson JR (1998) Effects of filter pore size on efficacy of con-
tinuous arteriovenous hemoflltration therapy for staphylococcus aureus-induced septicemia
in immature swine. Crit Care Med 26:730-737
84. Kline JA, Gordon BE, Williams C, et al (1999) Large-pore hemodialysis in acute endotoxin
85. Morgera S, Buder W, Lehmann C, et al (2000) High cut off membrane haemoflltration in
septic patients with multiorgan failure. A preliminary report. Blood Purif 18:61 (abst)
86. Reeves JH, Butt WW, Shann F, et al and the Plasmafiltration in Sepsis Study Group (1999).
Continuous plasmaflltration in sepsis syndrome. Crit Care Med 27:2096-2104
87. Tetta C, Cavaillon JM, Schulze M, et al (1998) Removal of cytokines and activated comple-
ment components in an experimental model of continuous plasma filtration coupled with
sorbent adsorption. Nephrol Dial Transplant 13:1458-1464
88. Tetta C, Gianotti L, Cavaillon JM, et al (2000) Coupled plasma filtration-adsorption in a
rabbit model of endotoxic shock. Crit Care Med 28:1526-1533
89. Lonnemann G, Bechstein M, Linnenweber S, et al (1999) Tumor necrosis factor-alpha dur-
ing continuous high-flux hemodialysis in sepsis with acute renal failure. Kidney Int Suppl
72:S84-S87
SLEDD and Hybrid Renal Replacement Therapies
for Acute Renal Failure in the ICU
W. Van Biesen and N. Lameire
Introduction: Terminology and Definitions of Hybrid Therapies

Acute renal failure with need for renal replacement therapy in the intensive care
unit (ICU) is a complex and devastating condition, with a reported mortality rate
as high as 50-80% [1, 2]. Although gross mortality rates have only declined slightly
over the past decades, it is accepted that survival has enhanced by improvement in
overall care, since the comorbidity of patients and the severity of the diseases
treated has also increased dramatically [3]. Although acute renal failure by itself
contributes to the overall mortality of critically ill patients, it is important to un-
derstand that acute renal failure mostly develops as a consequence of other under-
lying comorbidities, and that patients often do not die of their acute renal failure
but from these underlying conditions. Thus, the idea that by inventing 'the perfect
renal replacement therapy-machine', no more patients with ICU-related acute renal
failure will die, will remain an illusion. Furthermore, acute renal failure mostly re-
covers if the patient survives. Renal replacement therapy in acute renal failure
should thus be seen as a bridging therapy that allows the patient to survive while
the native kidneys recover. The main objective of renal replacement therapy should,
thus, be to avoid additional harm to the patient as much as possible while clearing
the uremic waste products and maintaining the 'milieu interieur' as closely possible
to normal.
Despite much debate, some very important and relevant questions regarding the
treatment of acute renal failure still remain unanswered. This is mainly because it
is hard, if not impossible, to conduct prospective randomized studies with a fair
and equal distribution of all risk factors in different treatment arms because of the
rather high mortality, and the wide scatter in underlying comorbidities. The con-
troversy between continuous renal replacement therapy (CRRT) and intermittent
hemodialysis is an excellent example, where, in addition, the situation is still
further encumbered by the lack of clear definitions of the treatments used, and the
polarization and conflict of interest between intensivists and nephrologists [5, 6].
Only a limited number of centers have a documented balanced distribution of treat-
ment modalities [5, 7, 8] (Fig. 1). A recent survey showed that resource availibility,
convenience and practical limitations are more decisive in the choice of a given re-
nal replacement therapy modality than the conviction that one therapy is superior
over another [6]. It is clear that when focusing on teaching and development of
treatment guidelines, real-world conditions should be taken into account. There-
fore, a renal replacement therapy modality for ICU-related acute renal failure
should be easy to use, convenient, and should nevertheless be able to deliver a
broad range of different therapy modalities while trying as much as possible to re-
664 W. Van Biesen and N. lameire
70
.... • p <0.05
- p<O.Ol
.... p<0.001
60
~
-~ so
a
<!'! 40
t-"
0:
0: 30
u
c 20
0
~
10
0
All <20 20-25 25-33 >33
Apache score
Fig. 1. Distribution of CRRT and IHD/SLEDD in the ICU of the University Hospital Ghent. Figure shows the
percentage of ICU-related acute renal failure patients on CRRT (light gray boxes), stratified per category of
APACHE score. The dark gray boxes indicate survival in the IHD/SLEDD group, and the white boxes in the
CRRT group. It appears that in all categories of severity of disease as assessed by the APACHE score, mor-
tality is higher in the CRRT group
'Classic IHD'
I 'Classic IHD' 4 hours 3 times/week
'
'Classic IHD' 4 hours, daily
'
'Slow (adaptable and daily) hemodiafiltration'
t
CWHD high volume
CWHD
CWH
CAVHD
CAVH
Fig. 2. Evolution of IHD and CRRT to a hybrid regimen. CWH: continuous venovenous hemofiltration;
CAVH: continuous arteriovenous hemofiltration; CWHD: continuous venovenous hemodialysis; CAVHD: con-
tinuous arteriovenous hemodialysis
duce the workload to the end user (the ICU nurse). Both IHD and CRRT have their
own limitations, and by trying to improve both techniques, both become more and
more similar (Fig. 2). This has resulted in the development of 'hybrid techniques'
like SLEDD (slow low efficient daily dialysis or slow extended daily dialysis).
Although the dose of dialysis for an acute renal failure patient in the ICU is still
SLEDD and Hybrid Renal Replacement Therapies for Acute Renal Failure in the ICU 665
-·..
..... , .. .. . . ..
Pressure gradient
Fig. 3. Schematic representation of diffusive (upper panen and convective (lower panen transport over a
semi-permeable membrane
not definitely established, it is quite accepted that daily treatment is usually needed
in critically ill patients [9-11]. Nephrologists with ICU experience also realized that
some potential modifications of the IHD technique, like hemodiafiltration have
been underused in the ICU. On the other hand, CRRT has become progressively
more complex, and the original concept of an 'easy-going technique' without need
for high-tech equipment has long since been replaced by high volume, double
pump CRRT machines. Despite much effort, no study has ever been able to prove
that one modality is superior over another [12, 13].
Although the difference in treatment duration, being so-called 'continuous' for
CRRT and 'intermittent' for intermittent hemodialysis, is the most obvious differ-
ence between the two modalities, other additional differences might be more im-
portant to distinguish both modalities. From a physiological point of view, the ma-
jor difference is that intermittent therapies rely mostly on diffusion, whereas the
continuous techniques rely mostly on convection. Figure 3 depicts the principles of
diffusion and of convection. In the recipients with a semi-permeable membrane,
the molecules move at random in the solvent, and the probability that they will hit
and pass a pore is linearly related to their concentration. Therefore, more molecules
will be transported from compartment A (with the higher concentration) to com-
partment B than vice versa. The net result is called 'diffusive transport'. This diffu-
sive transport is thus driven by a concentration gradient. In addition, the amount
of solute transfer is also dependent on the geometrical size of the molecule. In dia-
lysis, a high concentration gradient between the blood and the dialysate compart-
ment is maintained by increasing the dialysate flow; in this way, the concentrations
of the different solutes in the dialysate at the level of the membrane are kept low. If
there is also water flux over the membrane, this water flux will drag other mole-
666 W. Van Biesen and N. Lameire
cules with it through the pores. This solute drag is called 'convective transport'.
This convective transport depends on the water flux over the membrane, and thus
on the porosity of the membrane for water. In contrast with diffusive transport, the
amount of solute transported is independent on the size of the solute, as long as
the smallest diameter of the molecule is lower than the pore size (the so-called cut-
off level of the membrane). For convective treatments, the membrane must have a
high hydraulic conductivity, to allow large water fluxes over the membrane.
From a practical point of view, intermittent hemodialysis is almost always per-
formed with a 'dialysis machine' with need for a water treatment system that deli-
vers on-line high-quality dialysate fluid [14]. This system allows high dialysate
flows, and highly efficient removal of small solutes. In contrast, CRRT is mostly
performed with a special device, without a separate water treatment system, and
the substitution and dialysate fluids are delivered in industrially prepared, sterile
bags. Today, bicarbonate-buffered substitution fluid is recommended, which has to
be mixed from a two-compartment bag just before use [15]. These fluids are expen-
sive, and their handling and stockage is cumbersome. In addition, bags have to be
replaced every 2 hours, which can potentially lead to touch contamination and in-
creases the work-load of the ICU nurse. Therefore, the flows of blood and of dialy-
sate and/or substitution fluid are mostly limited in CRRT, necessitating the continu-
ity of the treatment to obtain adequate efficiency [16].
In this chapter, we will consider all those techniques that have no separate water
treatment system as 'CRRT', whereas all techniques that have some form of local
water treatment, will be considered as 'intermittent hemodialysis', independent of
the treatment duration. Note that this definition does not specify whether the so-
lute removal is convective or diffusive, although CRRT in general will have a major
component of (convective) hemofiltration. 'Hybrid therapies' such as SLEDD are
those techniques where a conventional dialysis monitor with on-line fluid prepara-
tion is used for treatments that extend the usual duration of a 'conventional inter-
mittent dialysis' session of 3-4 hours/treatment. SLEDD treatments offer the best
balance between advantages and disadvantages of both CRRT and intermittent he-
modialysis, as they allow a nearly unlimited capacity to tailor the treatment to the
needs of the patient while using one single machine.
Rationale for SLEDD
Hemodynamic Stability
As already stated, avoiding additional complications should be the first aim of renal
replacement therapy in the ICU. Hemodynamic instability is often a major problem
in ICU patients. This instability can further be enhanced by starting renal replace-
ment therapy, due to changes in circulating volume and in osmolarity. In a typical
ICU-patient with acute renal failure, there is a conflicting situation between third-
space fluid overload, in the form of edema, ascites, pleural effusion, and intravascu-
lar underfilling, leading to hypotension. During the extracorporeal treatment, ex-
cess fluid is removed from the blood compartment. The rate-limiting step for re-
moval of fluid from the body is the transport rate between the extravascular and
the intravascular compartments. In many ICU patients, the fluid transport between
the intra and extravascular fluid compartments is hampered by alterations in the
permeability of the capillaries by inflammation, and the alteration in plasma colloid
or crystalloid osmolarity by hypo-albuminemia and/or electrolyte disturbances.

Therefore, the fluid removal rate is often limited.
Changes in osmolarity, also, can cause hemodynamic instability. During hemo-
dialysis, there is diffusive transport from osmotically active substances down a con-
centration gradient from the blood to the dialysate. As this transport exceeds the
transport of water during regular hemodialysis, this results in a decrease in plasma
osmolarity. During hemofiltration, transport of solutes is driven by solute drag,
and the ultrafiltered fluid is isotonic. Therefore, there is no change in the blood os-
molarity, at least if the substitution fluid has a comparable osmolarity as the blood.
Fox and Henderson [17] found a more pronounced increase in heart rate response,
and a greater decline in peripheral resistance during hemodialysis as compared to
hemofiltration in patients with end stage renal disease.
During hemofiltration, there is often a decrease in body core temperature, as the
temperature of the substitution fluid is not completely warmed to body temperature
[18]. This cooling will result in vasoconstriction, and thus better preservation of
blood pressure. However, this vasoconstriction may also further deteriorate tissue
perfusion, and cardiac output.
There are only limited data actually showing that CRRT is really superior over in-
termittent hemodialysis with regard to hemodynamic stability, while other, prospec-
tive and randomized studies, found no difference. Davenport et al. [19] found, in
patients with hepatic failure, a stable blood pressure during CRRT, whereas a small
blood pressure drop was noted in patients on intermittent hemodialysis. This differ-
ence was only present during the start of the renal replacement therapy. Misset et al.
[20] did not find a difference in hemodynamic stability between patients on CRRT or
on intermittent hemodialysis, either for mean arterial blood pressure (MAP) or for
need of vasopressor agents. By applying sodium modeling during intermittent hemo-
dialysis, Paganini et al. [21] could enhance hemodynamic stability, while increasing
the ultrafiltered volume. This once again demonstrates that intermittent hemodialysis
can be greatly improved for ICU-related acute renal failure when some available mod-
ifications are used [22]. Kumar et al. [23] found a comparable hemodynamic stability
in patients on SLEDD as compared to patients on CRRT.
The implementation of SLEDD allows the tailoring of the treatment to the needs
of the patient and the ICU staff. With one single technique and machine, the treat-
ment can be slow and gentle (if needed), and the intensity of the treatment can be
increased (while reducing treatment time) if the patient's condition further im-
proves during the course of his disease.
Adequacy
Some recent studies have pointed to a relationship between delivered dialysis dose
in acute renal failure and patient survival, for both intermittent hemodialysis and
CRRT [24, 25]. However, only few centers measure some form of adequacy parame-
ters besides the follow-up of the serum urea or creatinine plasma levels [3]. For
water as well as for solutes, there is a compartmentalization over the body. As out-
lined above, the rate-limiting step is the equilibration of the solutes between the ex-
travascular compartment(s) and the blood. If the extracorporeal extraction exceeds
this equilibration, the blood concentration will go down, and the efficiency of the
removal of the toxic solute decreases. If the dialysis is stopped, further equilibration
will occur, resulting in an increase of blood levels of the solute in the minutes after
cessation of the therapy, a phenomenon called 'rebound'. The magnitude of this re-
bound increases with the efficiency of the dialysis treatment, and with the resis-
tance for equilibration between the blood and the extravascular compartments.
During CRRT, the efficiency is low, and the treatment is continuous, leading to vir-
tually little or no rebound. However, due to the low efficiency of the technique, the
treatment has to be performed on a continuous basis to achieve adequacy goals.
During short-term, high efficient intermittent hemodialysis, the reduction in blood
concentration of small solutes like urea is up to 80o/o and there is usually an impor-
tant rebound [26]. Spiegel et al. [27] demonstrated that not the duration of the
therapy, but the efficiency, was the main determinant of the amount of urea re-
bound. The overestimation of delivered dose with treatments of the same efficiency,
but different duration will, therefore, be the same. However, since treatments with
longer duration are mostly less efficient, the difference between estimated and mea-
sured adequacy will decrease with longer treatment duration. In CRRT, it takes
some time before blood levels of certain markers like creatinine or urea come be-
low certain thresholds. Clark et al. [28] have shown that it takes 48-72 hours to ob-
tain stable blood levels of urea during CRRT, because removal rate is low due to
the low efficiency of the technique. In intermittent hemodialysis, a saw-tooth pat-
tern in blood urea levels is observed, with levels part of the time being under, and
part of time above the desired blood levels of toxin markers. During SLEDD, the
extraction rate nearly equals the equilibration rate, at least for some small solutes
like urea. Marshall et al. [29] analyzed urea kinetics during a SLEDD session of 12
hours, with a blood flow of 200 ml/min, and a dialysate flow of 100 ml/min and ob-
served virtually no rebound under these conditions. A single pool urea kinetic
model performed as adequately as a two pool model, again pointing to the fact that
during SLEDD performed under these conditions, there is no urea disequilibrium.
Clark et al. [28] calculated that with a daily intermittent hemodialysis session of
4 hours, it is not possible to maintain a blood urea nitrogen (BUN) below 60 mg!dl
in a 90 kg patient. This goal can, however, easily be achieved if the duration of the
dialysis session is extended. Schlaeper et al. [30] compared the efficiency of SLEDD,
with a blood flow of 200 ml/min, and a dialysate flow of 100 ml/min to that of
CRRT with a dialysate or substitution fluid flow of 15-35 mVmin and a blood flow
of 150-200 mVmin. They found a daily Kt/V of 2.4 for SLEDD, whereas for inter-
mittent hemodialysis, this was only 0.9-1.4. In the setting of chronic dialysis, long-
term nocturnal dialysis has been associated with excellent phosphorus removal, in-
dicating that during extended, slow dialysis sessions, an excellent equilibration of
phosphorus between the extravascular and the intravascular compartments is
achieved. Also in the setting of ICU-related acute renal failure, Tan et al. [31] dem-
onstrated a good phosphate control during CRRT, in contrast with intermittent he-
modialysis. However, the patients in the intermittent hemodialysis group received
dialysis only 3 times/week during 4 hours.
I Practical Aspects of SLEDD
Technical Requirements
The hardware to perform SLEDD consists of a dialysis monitor on one hand, and a
water treatment system on the other. As the efficiency in SLEDD can vary from low
to high, there is need for some form of on-line prepared dialysis or substitution
~
Technical Room
ICU Room A
G* D. D* D. D*
D~ D' D' D. D~
a ICU Room B
8 Technical Room
ICU Room A
B* D. D* D. D*
D; D. D. D. o~
L
b ICU Room B
Technical Room
ICU Room A
Fig. 4. Different set -ups for a water treatment

system in the ICU. a Central water treatment
with pipe-line distribution to the dialysis moni-
tor. b Compact water treatment system
c L-------~IC~U~R~o~o~m~B~________J
mounted on the dialysis machine. c Batch sys-
tem: example Genius®
fluid, to avoid the need for expensive, industrially prepared fluids delivered in bags.
There are different ways to obtain this goal (Fig. 4). One can opt for a central water
supply, with a pipe-line distribution system to deliver the treated water on the spot
where it is needed to feed the dialysis monitor (Fig. 4 a: a= water softener; b =char-
coal filter; c =particle filter; d =reverse osmosis unit; e = ICU post. Note that at
every dialysis post, there should also be a drain to collect spent dialysate). A sec-
ond option is a compact water treatment system that is incorporated in the dialysis
monitor (Fig. 4 b: Here, there is only need for a water supply (softened tap water)
and a drain at the bedside of the patient to feed the system). A third option is to
prepare the water in a central place, and to bring it to the location of the dialysis
monitor in a big jar, the so-called 'batch-method' (Fig. 4 c: the water is prepared at
a central place, and transported in a big jar to the place where the dialysis is per-
formed. There is no need for a tap or a drain at the bedside. f =Preparator® for fill-
ing and emptying the Genius® tank). Each of these systems has its pro's and con's,
and it depends on the size of the ICU, and the number of acute renal failure pa-
tients to be treated, which system would be preferred. A central water delivery sys-
tem is expensive, and needs regular maintenance to assure perfect water quality.
The pressure on the tap water distribution system should also .be sufficient to feed
the system. A central delivery system is, thus, only a useful option in an ICU-unit
where a great number of acute renal failure patients are treated. In addition, all po-
tential cases of acute renal failure in the hospital should then be centralized in that
unit, because the system is not mobile. This is a major drawback, as most contem-
porary large hospitals have separated medical, coronary and surgical ICUs and
burn units. A compact water treatment system for each dialysis monitor separately
is in our opinion a better option. If the hospital or the ICU has a water distribution
system that delivers centrally softened water (less than 0.1 dH and! or less than
1.8 ppm CaC03 ), this system will consist of a charcoal cartridge and a reverse
osmosis membrane. These systems can be made very compact, and are mostly
mounted in the dialysis monitor itself to limit the square meters needed to place
the equipment. They allow the preparation of sterile, contaminant free, water at the
bedside starting from tap water, and these systems can thus be used for dialysis at
any location in the hospital where there is a tap and a drain. The system can, thus,
also be used in the chronic program, i.e., to dialyze the hospitalized chronic renal
failure patients at the bedside. The combination of a dialysis monitor and a com-
pact water treatment system is probably for most hospitals the most ideal hard-
ware, as it ensures the lowest cost/utility index. In the 'batch system', the water is
prepared in a central place, and then transported in a big jar to the place where
the actual dialysis is performed. In the original format, a small badge of 20-30 li-
ters of dialysate was prepared, and transported in an open aluminum container. As
the microbiological sterility of this fluid could not be guaranteed, the water could
only be used for dialysis. Because of the low available volume, the dialysate was of-
ten recirculated, which, of course, considerably diminished the efficiency of the
treatment. This technique has therefore been abandoned in most ICUs, and should
only be accepted in emergency situations, where no other options are available,
e.g., for dialysis in disaster areas. This old procedure has, however, regained new
interest, as a new, actualized format has been proposed in the last few years. In the
Genius® system [32] the dialysate is prepared in a special device, called the pre-
parator, which delivers ultrapure dialysate. The dialysate is then pumped into a 75
or 90 liter container made of glass, with an incorporated ultraviolet (UV) radiation
system that ensures further microbiological purity [33]. The system contains a dia-
lysis monitor, which circulates the dialysate in a single pass, closed loop circuit.
The fresh dialysate is pumped from the top of the container, whereas the spent dia-
lysate is pumped back into the tank at the bottom. Due to physico-chemical differ-
ences between fresh and spent dialysate, there is no mixing, and there is no recir-
culation of dialysate [35].
Whatever water treatment system is used, it is essential that the delivered water
is of the highest purity, as even limited levels of contamination lead to induction of
the inflammatory cascade [34], which can worsen the systemic inflammatory re-
sponse already present in ICU patients. It has been argued that the quality of the
industrially prepared substitution fluids is superior to that of on-line prepared
fluids. However, the combination of a good water treatment system and a modern
dialysis monitor also allows the production of ultra pure water [36], and in indus-
trially prepared dialysis fluids, contamination can also occur [37].
Although in principle, all modern dialysis monitors can be used for SLEDD,
some special considerations should be taken into account. The monitor should be
compact, to fit around the bedside in an, in general, already very crowded ICU-en-
vironment. The monitor should also be user-friendly, and basic alarms should be
easy to understand so that they can be handled by the ICU-nurse, to avoid 'sudden
death' situations of the machine. The monitor should be able to deliver the different
treatment modalities (hemodialysis, hemodiafiltration, hemofiltration), and dialy-
sate flow rate and treatment time should be adjustable over a wide range. Despite
this flexibility of the monitor, all treatment modalities should, after they have been
set up and initiated by the renal nurse, look similar to the ICU-nurse in charge
[29, 30]. An important advantage of the use of 'regular' dialysis monitors over
CRRT machines is the accuracy of the ultrafiltration control. CRRT machines
mostly use weighing scales, or balancing chambers to control the volume of the in-
stilled and ultrafiltered volumes. These weighing scales are prone to decalibration,
and their accuracy is limited. In view of the currently advocated high exchange vol-
umes, even errors of 1% can already lead to imbalances in fluid status of up to 1 1/
24 hours, which is difficult to accept in hemodynamically unstable ICU patients.
Dialysis monitors offer more precise ultrafiltration control because they have inter-
nal balancing chambers that match incoming and outgoing fluid flows very accu-
rately. In the Genius® system, ultrafiltration is based on the principle that the dialy-
sate tank is a closed container, and that fluids are not compressible at the low pres-
sures present in the circuit. Therefore, all excess fluid (=ultrafiltration) is allowed
to escape through an ultrafiltration line, and collected in a separate recipient for
volumetric control.
Depending upon the desired dialysis modality (hemodialysis, hemodiafiltration,
or hemofiltration), all different types of membranes can be used for SLEDD. This
is in contrast with most CRRT machines, where the membranes are mostly deliv-
ered as a package with the tubing system, which of course increases the cost.
Although the debate of complement-activating vs low-complement activating and of
high-flux vs low flux membranes is still pending [38], most authors advocate the
use of low complement-activating high flux membranes for SLEDD. High flux mem-
branes have, at least theoretically, the advantage that there is internal back-filtra-
tion, which enhances the convective clearance, and thus the removal of larger so-
lutes, like, e.g., phophorus. Also, the larger pore size, and the three-dimensional
structure provide an increased surface area for adsorption of toxins to the mem-
brane. In addition, most high flux membranes have a so-called asymmetrical com-
position, meaning that the permeability is high from the blood-side to the dialysate
side, but low from the dialysate side to the blood side. Because of this property, it
is less likely that eventual contaminants present in the dialysate will pass across the
membrane to the blood compartment. Low flux membranes have a much smaller
thickness, and, therefore, a more limited reflection capacity from dialysate to blood
side. Therefore, in contrast with what one intuitively would imagine, induction of
systemic inflammation by contaminants in the dialysate is less pronounced in high
flux than in low flux dialysis. It is of note that the Genius® system can only work
with a high flux membrane, as there is only a limited transmembranous pressure
gradient, so that if a low flux filter were be used, no ultrafiltration would be ob-
tained.
Organizational and Nursing Aspects

One of the principles of good clinical practice in an open ICU is a smooth coopera-
tion between the different medical disciplines, in this case the nephrology team
and the ICU-team. This is extremely important in the dialysis treatment of an acute
renal failure patient, most particularly with SLEDD, as this treatment will always
require a strict cooperation between the two teams.
From the medical part, the dialysis treatment prescription should be adapted on
a daily basis in consensus between the attending nephrologist and intensivist. Most
ideally, the nephrologist will offer his knowledge on epuration therapy and fluid
handling, to achieve the treatment goals that are forwarded by the intensivist, who
should remain responsible for the overall management of the patient.
For the nursing part, treatment protocols should be prepared, documenting and
defining the responsibilities of the different nursing teams. The renal nurse should
be in charge of the installation of the equipment, the programming of the desired
treatment, and the start and termination of the actual dialysis treatment, including
connecting and disconnecting the patient. Once the treatment has started, the ICU
nurse should perform hourly monitoring and documentation, and should be able
to manage the basic alarms according to simple algorithms. In any case, a renal
nurse should be available within an acceptable period of time for advice or assis-
tance. It is essential that, before the SLEDD program is implemented, the renal de-
partment provides theoretical and hands-on training of the ICU personnel. In addi-
tion, regular update sessions, and short, bed-side refreshing of important points
should be given. The renal department should also be responsible for the mainte-
nance of the machines and the water treatment system. Although, as far as we
know, no formal studies have been done on this subject so far, it is our personal
experience that satisfaction with the SLEDD concept is high both with the renal as
well as with the ICU nursing team. The procedure is time-saving for both teams,
and increases the efficiency. The ICU nurse is liberated from the hourly fluid bal-
ances and bag exchanges, and faces a lower workload. In addition, in view of the
reduced treatment time, there is more time left for the actual nursing of the pa-
tient, or for medical-technical interventions, which are often a cumbersome task to
do while the patient is connected to a CRRT machine.
Anticoagulation in SLEDD
Anticoagulation and the associated bleeding risk are still the greatest peril of extra-
corporeal treatments. Fiaccadori et al. [39] found a gastro-intestinal bleeding rate
of 13.4% in a patient population with acute renal failure, with an odds ratio of 2 for
patients on CRRT. Ward et al. [40] demonstrated that 25o/o of new episodes of
bleeding were attributable to anticoagulation. Martin et al. [41] found that 3.5 to
lOo/o of deaths in the ICU were associated with the use of anticoagulation. It is clear
that anticoagulation is one of the Achilles' heels of CRRT, where a continuous
struggle is fought between patient bleeding and filter clotting. The major problems
are the protracted treatment time, with need for long periods of continuous anti-
coagulation, and the price of the filter sets, which prohibits frequent change of
clotted filters. Reported filter lives vary from a few hours to a few days, depending
on the anticoagulation level obtained [42]. Filter clotting not only increases treat-
ment cost and workload (and frustration) of the ICU staff, but also limits the effi-
cacy of the treatment. SLEDD has some important advantages over CRRT with re-
gard to anticoagulation and bleeding risk. In a study of Kumar et al. [23], 31.9% of
patients on SLEDD, vs only 2.7% on CRRT, could be dialyzed without any anticoa-
gulation, and the doses of heparin needed in the remaining patients were far lower
in the SLEDD patients.
I Actual Clinical Experience with SLEDD
Although it appears that, based on personal contacts with nephrologists in charge

of ICU-related acute renal failure patients, SLEDD-like approaches are being used
in many centers around the world, the literature on this subject is rather limited.
Lonnemann et al. [33] used the Genius system, with a blood and dialysate flow rate
of 70 mUmin, during 18 hours a day. This resulted in a urea clearance of 65 Uday,
and a mean ultrafiltration volume of 120 mUhour without any reported hemody-
namic instability. Kumar et al. [23] compared the clearance, hemodynamic stability
and anticoagulation needs of patients on SLEDD with those of patients treated by
continuous venovenous hemofiltration (CVVH) with a mean blood flow of 170 ml/
min, and an exchange volume of 2 Uhour. There was no difference in hemody-
namic stability, nor in the need for vasopressive agents. An excellent metabolic
control was obtained with both modalities.
I Conclusion
The use of SLEDD has some important advantages that certainly will increase its
popularity in the future. SLEDD offers the advantages of intermittent hemodialysis
(high efficiency, practicality, economy, good ultrafiltration control, no peed for in-
dustry prepared substitution fluids) in combination with the advantages of CRRT
(extended treatment, smooth metabolic control) in a modular fashion, using one
single type of dialysis machine. Usually, the treatment is started as a 'slow dialysis'
with a low blood flow (typically 150 ml/min in double needle) and a low dialysate
flow (typically 100-300 ml!min). The ultrafiltration rate is usually also low (max.
350 ml/hour). The use of hemodialysis monitors with adapted software allows the
implementation of on-line hemofiltration or hemodiafiltration). Daily evaluation of
the patient by nephrologist and intensivist is needed and this collaboration will im-
prove the treatment of the patient. Daily adaptation of dialysis duration, which can
range from nearly continuous to regular intermittent hemodialysis is feasible. The
blood and dialysate flows, as well as the type of artificial kidney can be adapted to
the needs of the patient. There is an important cost-containment, as the need for
expensive 'all-in' sets can be avoided arid as the 'conventional' artificial kidneys
and tubings of the chronic dialysis program can be used (better price-setting nego-
tiation, no stock problems). Expensive substitution fluid bags are also not needed,
as dialysate is prepared on-line. Compared with CRRT, the reduced treatment dura-
tion not only reduces the labor costs, but also allows more possibilities for diagnos-
tic or therapeutic interventions. Finally, a substantial reduction in need for anticoa-
gulation is realized, and heparin free dialysis is possible.
For all these reasons, we believe SLEDD has an important potential for the treat-
ment of acute renal failure in the ICU.
References
1. Chertow GM, Christiansen CL, Cleary PD, Munro C, Lazarus JM (1995) Prognostic stratifi-
cation in critically ill patients with acute renal failure requiring dialysis. Arch Intern Med
155:1505-1511
2. Brivet FG, Kleinknecht DJ, Loirat P, Landais PJ ( 1996) Acute renal failure in intensive care
units-causes, outcome, and prognostic factors of hospital mortality; a prospective, multi-
center study. French Study Group on Acute Renal Failure. Crit Care Med 24:192-198
3. Hyman A, Mendelssohn DC (2002) Current Canadian approaches to dialysis for acute renal
failure in the ICU. Am J Nephrol 22:29-34
4. McCarthy JT (1996) Prognosis of patients with acute renal failure in the intensive-care unit:
a tale of two eras. Mayo Clin Proc 71:117-126
5. Lameire N, Van Biesen W, Vanholder R, Colardijn F (1998) The place of intermittent he-
modialysis in the treatment of acute renal failure in the ICU patient. Kidney Int Suppl
66:S110-S119
6. Ronco C, Zanella M, Brendolan A, Milan M, Zamperetti N, Bellomo R (2001) Answers
from the first international course on critical care nephrology questionnaire. Contrib Ne-
phrol 132:196-209
7. Mehta RL, Letteri JM (1999) Current status of renal replacement therapy for acute renal
failure. A survey of US nephrologists. The National Kidney Foundation Council on Dialysis.
Am J Nephrol 19:377-382
8. Hyman A, Mendelssohn DC (2002) Current Canadian approaches to dialysis for acute renal
failure in the ICU. Am J Nephrol 22:29-34
9. Paganini EP, Kanagasundaram NS, Larive B, Greene T (2001) Prescription of adequate re-
nal replacement in critically ill patients. Blood Purif 19:238-244
10. Schiffl H, Lang SM, Fischer R (2002) Daily hemodialysis and the outcome of acute renal
failure. N Engl J Med 346:305-310
11. Bonventre JV (2002) Daily hemodialysis-will treatment each day improve the outcome in
patients with acute renal failure? N Engl J Med 346:362-364
12. Mehta RL, McDonald B, Gabbai FB, et al (2001) A randomized clinical trial of continuous
versus intermittent dialysis for acute renal failure. Kidney Int 60:1154-1163
13. Lameire N, Van Biesen W, Vanholder R (1999) Dialysing the patient with acute renal failure
in the ICU: the emperor's clothes? Nephrol Dial Transplant 14:2570-2573
14. Dhondt A, Van Biesen W, Vanholder R, Lameire N (2001) Selected practical aspects of in-
termittent hemodialysis in acute renal failure patients. Contrib Nephrol 132:222-235
15. Leblanc M, Moreno L, Robinson OP, Tapolyai M, Paganini EP (1995). Bicarbonate dialysate
for continuous renal replacement therapy in intensive care unit patients with acute renal
failure. Am J Kidney Dis 26:910-917
16. Leblanc M, Tapolyai M, Paganini EP (1995) What dialysis dose should be provided in acute
renal failure? A review. Adv Ren Replace Ther 2:255-264
17. Fox SD, Henderson LW (1993) Cardiovascular response during hemodialysis and hemofil-
tration: thermal, membrane, and catecholamine influences. Blood Purif 11:224-236
18. van der Sande FM, Kooman JP, Konings CJ, Leunissen KM (2001) Thermal effects and
blood pressure response during postdilution hemodiafiltration and hemodialysis: the effect
of amount of replacement fluid and dialysate temperature. JAm Soc Nephroll2:1916-1920
19. Davenport A, Will EJ, Davison AM (1993) Effect of renal replacement therapy on patients
with combined acute renal and fulminant hepatic failure. Kidney Int Suppl 41:S245-S251
20. Misset B, Timsit JF, Chevret S, et al (1996) A randomized cross-over comparison of the he-
modynamic response to intermittent hemodialysis and continuous hemoftltration in ICU
patients with acute renal failure. Intensive Care Med 22:742-746
21. Paganini EP, Sandy D, Moreno L, Kozlowski L, Sakai K (1996) The effect of sodium and ul-
trafiltration modelling on plasma volume changes and haemodynamic stability in intensive
care patients receiving haemodialysis for acute renal failure: a prospective, stratified, ran-
domized, cross-over study. Nephrol Dial Transplant 11 (suppl 8):32-37
22. Schortgen F, Soubrier N, Delclaux C, et al (2000) Hemodynamic tolerance of intermittent
hemodialysis in critically ill patients: usefulness of practice guidelines. Am J Respir Crit
Care Med 162:197-202
23. Kumar VA, Craig M, Depner TA, Yeun JY (2000) Extended daily dialysis: A new approach
to renal replacement for acute renal failure in the intensive care unit. Am J Kidney Dis
36:294-300
24. Ronco C, Bellomo R, Homel P, et al (2000) Effects of different doses in continuous veno-ve-
nous haemoflltration on outcomes of acute renal failure: a prospective randomised trial.
Lancet 356:26-30
25. Tapolyai M, Fedak S, Chaff C, Paganini EP (1994) Delivered dialysis dose may influence
acute renal failure outcome in ICU patients. JAm Soc Nephrol 5:530A (abst)
26. Schneditz D, Daugirdas JT (2001) Compartment effects in hemodialysis. Semin Dial
14:271-277
27. Spiegel DM, Baker PL, Babcock S, Contiguglia R, Klein M (1995) Hemodialysis urea
rebound: the effect of increasing dialysis efficiency. Am J Kidney Dis 25:26-29
28. Clark WR, Mueller BA, Kraus MA, Macias WL (1997) Extracorporeal therapy requirements
for patients with acute renal failure. J Am Soc Nephrol 8:804-812
29. Marshall MR, Golper TA, Shaver MJ, Alam MG, Chatoth DK (2002) Urea kinetics during
sustained low-efficiency dialysis in critically ill patients requiring renal replacement ther-
apy. Am J Kidney Dis 39:556-570
30. Schlaeper C, Amerling R, Manns M, Levin NW (1999) High clearance continuous renal
replacement therapy with a modified dialysis machine. Kidney Int Suppl 72:S20-S23
31. · Tan HK, Bellomo R, M'Pis DA, Ronco C (2001) Phosphatemic control during acute renal
failure: intermittent hemodialysis versus continuous hemodiafiltration. Int J Artif Organs
24:186-191
32. Fassbinder W (1998) Renaissance of the batch method? Nephrol Dial Transplant 13:3010-
3012
33. Lonnemann G, Floege J, Kliem V, Brunkhorst R, Koch KM (2000) Extended daily vena-
venous high-flux haemodialysis in patients with acute renal failure and multiple organ dys-
function syndrome using a single path batch dialysis system. Nephrol Dial Transplant
15:1189-1193
34. Schindler R, Lonnemann G, Schaffer J, et al (1994) The effect of ultrafiltered dialysate on
the cellular content of interleukin-1 receptor antagonist in patients on chronic hemodialy-
sis. Nephron 68:229-233
35. Dhondt A, Vanholder R, DeSmet R, Glorieux G, Waterloos M, Lameire N (2003) Studies on
dialysate mixing in the Genius(R)single pass batch system for hemodialysis therapy.
Kidney Int (in press)
36. Vaslaki L, Karatson A, Voros P, et al (2000) Can sterile and pyrogen-free on-line substitu-
tion fluid be routinely delivered? A multicentric study on the microbiological safety of on-
line haemodiaflltration. Nephrol Dial Transplant 15 (suppl 1):74-78
37. Williams PF, Foggensteiner L (2002) Sterile/allergic peritonitis with icodextrin in CAPD
patients. Perit Dial Int 22:89-90
38. Jaber BL, Cendoroglo M, Balakrishnan V, et al (2000) Impact of dialyzer membrane selec-
tion on cellular responses in acute renal failure: a crossover study. Kidney Int 57:2107-
2116
39. Fiaccadori E, Maggiore U, Clima B, et al (2001) Incidence, risk factors, and prognosis of
gastrointestinal hemorrhage complicating acute renal failure. Kidney Int 59:1510-1519
40. Ward DM, Mehta RL (1993) Extracorporeal management of acute renal failure patients at
high risk of bleeding. Kidney Int Suppl 41:S237-S244
41. Martin PY, Chevrolet JC, Suter P, Favre H (1994) Anticoagulation in patients treated by
continuous venovenous hemoflltration: a retrospective study. Am J Kidney Dis 24:806-812
42. Schetz M (2001) Anticoagulation in continuous renal replacement therapy. Contrib Nephrol
132:283-303
I Brain-lung Interactions
Advanced Airway Management
in the Neurologically Injured Patient
A. Gabrielli, L. J. Caruso, and A. J. Layon
1 Introduction
A systematic approach to airway management has been shown to reduce the likeli-
hood of an adverse outcome in the operating room [1-4]. Accordingly, in this chap-
ter we discuss the unique challenges involved in the airway management of the
neurologically injured patient and offer a strategy that may improve neurologic
outcome after central nervous system (CNS) injury.
I General Consequences of Hypoxia and Hypercapnia
D0 2 (oxygen delivery, in ml/min) is the bulk movement of blood oxygen, and is

proportional to cardiac output and arterial oxygen content (Ca0 2 ). It is described
by the equation:
D0 2 = [(cardiac output x Ca0 2 ) + 0.003 (Pa0 2 ) ].
While the Pa0 2 is a component of D0 2 , it is the least important. However, the pres-
ence of bulk D0 2 to the tissue does not guarantee tissue oxygenation, as passive
movement of oxygen down a concentration gradient to the mitochondria is respon-
sible for cellular oxygenation. Nevertheless, with ventilation failure, both hypoxia
and hypoxemia result, with consequent progressive global hypoxia. The CNS is the
most sensitive organ to hypoxia, with irreversible damage starting about three min-
utes after the Pa0 2 falls below 30 mmHg [5]. If not promptly corrected, all cases of
hypoxia trigger cardiac dysrhythmias leading to low cardiac output state, severe
bradycardia, peripheral dilatation, systemic hypotension, severe metabolic acidosis,
and death.
Adequate ventilation is necessary to remove carbon dioxide (C0 2 ) from the tis-
sues. Hypoventilation results in hypercapnia with acute respiratory acidosis and
acidemia (pH < 7.35) with, in the apneic, non-hypermetabolic patient, a predictable
increase in PaC0 2 of about 3 mmHg/min. Respiratory acidosis in the absence of
hypoxia may provoke sympathetic nervous system activity with consequent hyper-
tension, tachycardia, cerebral vasodilatation, and increased intracranial pressure
(ICP). In healthy individuals, altered mental status, severe acidemia, and cardiac ar-
rest occur with a PaC0 2 > 80 to 100 mmHg; small increases in C0 2 beyond normal
can none-the-less cause significant worsening of ICP and hemodynamic instability
in patients with CNS injuries. With combined hypoventilation and hypoxia, severe
bradycardia and rapid deterioration of neurologic condition will be noted.
680 A. Gabrielli et al.
Hypoxia and Secondary CNS Injury

While the CNS may be immediately damaged by the primary trauma or pathology,
secondary injury from hypoxia (Pa0 2 < 60 mmHg) can be responsible for rapid
clinical deterioration. A well-known example of neurologic deterioration associated
with hypoxia is found in the pre-hospital care of closed head injury, where both
hypoxia (oxygen saturation < 90% or Pa0 2 < 60 mmHg) and hypotension (systolic
BP <90 mmHg) are directly related to a poor long-term outcome [6]
When hypoxia is associated with neurological injury, secondary damage will re-
sult, causing a complex cascade of inflammatory and biochemical processes involv-
ing both neurons and supportive cells. In general, CNS damage from decreased
D0 2 has a multifactorial pathogenesis, described below, with failure of the Na +IK+
pump, and the intracellular shift of Na+, H2 0, and ionized calcium being the pri-
mary events [6]. The subsequent inflammatory reaction, triggered by intracellular
release of oxygen free radicals, free fatty acid, and proteolytic enzymes, results in
intracellular and then intravascular acidosis. Upon reperfusion of previously isch-
emic CNS cells, ionic membrane pump inefficiency results in osmotic edema, blood
brain barrier disruption, and further CNS hypoperfusion. Oxygen free radical
burst, and activation of lipase, nucleases, and proteases may cause DNA injury and
apoptosis.
The Importance of an Organized Approach to the Airway
The technique chosen for securing an airway depends on the anatomic characteris-
tics of the airway itself and specific injury-associated clinical factors. An organized
treatment algorithm can provide for immediate correction of oxygenation and ven-
tilation, and minimize iatrogenic events. Both the American (ASA) and the Cana-
dian (CSA) Societies of Anesthesiologists have set standards for managing the air-
way in the operating room, which may be used as guidelines for use in the neuro-
logically injured patient [2, 3, 7] (Figs. 1 and 2).
Predicting a Difficult Airway

Overall failure to intubate the trachea after direct laryngoscopy is noted in 1 to 3
cases per 1000 attempts, and failure to bag-valve-mask ventilate is noted in 1 to 3
cases per 10000 attempts [2]. A systematic examination of the airway is the key to
recognizing anatomy that may result in a difficult intubation and planning for its
safe management [8-10] (Table 1). Such a systematic approach takes into considera-
tion several important risk factors such as patient weight, head, neck, and jaw
movement, the presence of a receding mandible, and upper incisor angulation [9].
This approach is prospectively useful as a positive predictor of difficult intubation
in 92% of cases [10].
Anatomical observation of the upper airway should be integrated with knowl-
edge of other possible airway compromising congenital, or acquired, clinical condi-
tions (Table 2). A modification of the Mallampati classification [11] (Fig. 3a) is
now in widespread use [12] (Fig. 3b). The Mallampati class two airway is divided
into classes two and three for progressive increase of the tongue/oropharynx view
ratio; class four describes a condition in which the oropharynx is completely ob-
Advanced Airway Management in the Neurologically Injured Patient 681
~AMERICAN SOCIETY
~ OF A.NESTHESIOLOGISTS
DIFFICULT AIRWAY ALGORITHM

1. As~ss the likelihood and clinical impact of basic man~gement problems
A) Difficult i ntubatlon
8) Difficult ventilation
q Difficulty with patitmt cooperation or consent
2. Consider the relative merits and feasibility of basic management choices:
A) Non· surgical techntque for initial vs. Surgical technique for initial
approach to Intubation approach to Intubation
Intubation attempts aftt!'r indlKtion of

Bl Awake intubation }
vs. gener.~l anesthesia
q
~~~~~
Preservation of spontaneous }
~======~
vs. J Ablation of spontaneous ve-ntilation
ventilation . 1
~------------------
3. Develop primary and alternative strategies:
A) B)
Awake intubation Intubation attempts after
'
induction of general anesthesia
~
Airway approached by Airway secured by Initial intubation initial intubation
non-surgical intubation surgical access• attempts successful' attempts unsuccessful
Succeed' Fail
From this point onwards
repeatedly consider
the advisability of:
cancel case Consider feasibility Surgical 1. Retuming to sponta!WOUS wntilation
of other optionstol airway 2. Awakening the patient
3. CAtting lot holp
Non - Emergency pathway Emergency pathway

Patient anesthetized. intubation unsuccessful. Patient anesthetized, intubation unsuccessful,
Mask ventilation adequate Mask ventilation Inadequate
l
Alternative approaches Call for help
to intubatlon!bl
'
, __ ____..1_ _----,1 ¢
Succeed'
'
Fall after ~-~~ One more
mukiple attempts intubation attempt
Emergency non -sur~ical
airway ventilation d!
' ' '

r--.,.-----11 I I
Surgical
airway- ~
Surgery under
mask anesthesia
Awaken
patien ~
Succeed
~
Fail Fail
~
Succedd
Emergency
surgical Definitive
airwaY' airway(d
• Confirm intubation with exahaled C0 2

(a) Other options lndude (but are not limited to): surgery (c) See awake intubation
under mask anesthesia. Surgery under local anesthesia (d) Options for emergency non-wrgical airway ventilation
infiltration or regional nerve blockade, or intubation include (but are not limited to): transtracheal jet
attempts after Induction of general anesthesia.+ vennlation, laryngeal mask ventilation, or esophageal
(b) Alternative approaches to difficult intubation indude (bu1 tracheal combitube ventilation.
an! not limited to): use of different laryngoscope blades, (e) Options for establishing a definitive airway include (but
awake intubation, blind oral or nasal intubation, fiberoptk are not limited to): returning to awake state with
Intubation, Intubation stylet or tube changer, light wand. spontaneous ventilation, tracheotomy, or endotracheal
retrograde Intubation, and surgical airway access. intubation
Fig. 1. The Difficult Airway Algorithm presented by the American Society of Anesthesiology in 1993. The
algorithm includes awake intubation. (From [3) with permission)
IInduction of general anesthesia I

I
LVentilation possible?_]
I Ventilation possible I Ventilation not possible
I I
I Direct laryngoscopy
Glonis visualized?
Consider immediate direct laryngoscopy
or
utilize alternative to mask bag ventilation
I (laryngeal mask comb~ube)
Glonis not visualized
Optimize laryngoscopy
or
utilize alternative to direct laryngoscope
Can ventilate
Consider waking patient
or
l Cannot
ventilate
l
I II I
proceed to tracheal intubation
I
l
Optimize laryngoscopy ' Consider waking
(OELM or BURP, patient
second blade or adjunct) Establish transtracheal airway
(Retrograde, cricothyrotomy, tracheostomy)
I I Utilize alternative to direct laryngoscope

[ (Light stylet, fibreoptic scope, transtracheal airway')1
1
•rronsrrocheol airway indicored in con·venrilore I connor •inrubore scenario in rare drcumsronces only
Fig. 2. The Difficult Airway Algorithm presented by the Canadian Society of Anesthesiology in 1999, post
induction of general anesthesia. (From [2] with permission)
scured by the tongue when the mouth is wide open. A clear clinical correlation ex-
ists between the Mallampati classification and the difficulty of direct laryngoscopy
in both prospective and retrospective studies. However, in about 7% of cases an air-
way judged 'intermediate' or class two will result in a difficult or impossible visua-
lization of the vocal cords by direct laryngoscopy [11].
Visualization of the larynx by direct laryngoscopy can also be divided into four
classes as designated by Cormack et al. [13] (Fig. 4). When the patient is comatose
or uncooperative, the chin-laryngeal cartilage prominence distance can be used to
rapidly evaluate the airway. A distance of three fingerbreadths or more suggests
adequate room for a successful direct layngoscopy. If a medical record of previous
intubation (e.g., anesthesia record) is available it should be quickly reviewed as it
could give the physician invaluable information in emergent airway evaluation.
Aspiration of Gastric Contents and the Difficult Airway

Tracheo-bronchial aspiration of saliva or gastric contents is described in 16 to 27%
of all patients requiring intubation [14]. The aspirated material usually represents
saliva or blood, with minimal clinical consequences. Aspiration of gastric contents
may be secondary to regurgitation or vomiting in the patient with incompetent
laryngeal reflexes due to altered mental status, or simply from use of a hypnotic
agent to facilitate intubation. In the operating room, the incidence of pulmonary as-
piration of gastric contents ranged from 1.1% in a series of 10 000 elective anes-
Table 1. Preoperative airway examinations, acceptable endpoints and significance of endpoints. Modified
from [9) with permission
Preop examination Acceptable endpoints Significance of endpoints
Dental
- length of upper incisors with Qualitative/short incisors long incisors. Blade enters mouth
mouth fully open in cephalad direction
- Involuntary: Maxillary teeth No overriding of maxillary teeth Overriding maxillary teeth. Blade
anterior to mandibular teeth anterior to the mandibular teeth enters mouth in a more cephalad
(buck teeth) direction
- Voluntary: Protrusion of man- Anterior protrusion of the man- Test of TMJ function: means good
dibular teeth anterior to the dibular teeth relative to the max- mouth opening and jaw, will dis-
maxillary teeth illary teeth place anteriorly with laryngoscopy
- Inter-incisor distance >3 em laryngoscope blade can be easily
inserted between teeth
I Pharynx
- Oropharyngeal class ~Class II Tongue is small in relation to size
Samsoon & Young of oropharyngeal cavity
- Narrowness of palate Should not appear very narrow A narrow palate decreases the oro
and/or highly arched pharyngeal volume and room for
both blade and endotracheal tube
- Mandibular space length :?:S em or :?:3 ordinary-sized fin- larynx is relatively posterior to
(thyromental distance) ger breadths other upper airway structures
- Mandibular space compliance Qualitative palpation of normal laryngoscopy retracts tongue into
(MS) resistance/softness the MS. Compliance of the MS de~
terrnines if tongue fits into MS
Neck
- length of neck Qualitative. A quantitative index A short neck decreases the ability
is not yet available to align the upper airway axes
- Thickness of neck Qualitative. A quantitative index A thick neck decreases the ability
is not yet available to align the upper airway axes
- Range of motion of head Neck flexed and chest 35°+ The sniff position aligns the oral,
and neck head extended on neck 80°= pharyngeal and laryngeal axes to
sniff position create a favorable line of sight
thetics of ASA Physical Status Class I, to 29% in 10000 emergency anesthetics in

ASA Physical Status Classes IV and V [15, 16]. Although no specific data have been
described in CNS injured patients, in emergency cases the incidence of gastric as-
piration may be up to 30-fold more likely, with hypoxemia from severe ventilation-
perfusion (V /Q) mismatch the most severe consequence. As a result of aspiration-
induced alveolar-capillary membrane damage, loss of circulating fluid volume into
the lung causing increased extra vascular lung water, systemic hemoconcentration,
hypotension, tachycardia, and, possibly, hypovolemic shock aggravating
the hypoxemia may be seen. Pulmonary hypertension may occur secondary to
bronchospasm, loss of functioning alveoli, and left ventricular dysfunction [ 17]. In
neurologically injured patients, pulmonary aspiration can contribute to secondary
CNS injury through hypoxia, hypotension, and pulmonary hypertension, with de-
creased cerebral venous return causing acute increase in ICP.
Table 2. Airway compromising conditions. Reproduced from [47] with permission
Pathologic condition Prindpal pathologic/dinical features

I Supralaryngeal
1. Pierre Robin syndrome Micrognathia, macroglossia, cleft soft palate
2. Treacher Collins syndrome Auricular and ocular defects; malar and mandibular
hypoplasia
3. Goldenhar's syndrome Auricular and ocular defects; malar and mandibular
hypoplasia; occipitalization of atlas
4. Down's syndrome Poorly developed or absent bridge of the nose;
macroglossia
5. Klippei-Feil syndrome Congenital fusion of a variable number of cervical
vertebrae; restriction of neck movement
I Sublaryngeal
1. Goiter Compression of trachea, deviation of larynx-trachea
I Infections
1. Supraglottic Laryngeal edema
2. Croup Laryngeal edema
3. Abscess (intraoral, retropharyngeal) Distortion of the airway and trismus
4. Ludwig's angina Distortion of the airway and trismus
Arthritis
1. Rheumatoid arthritis Temporomandibular joint ankylosis, cricoarytenoid
arthritis, deviation of larynx, restricted mobility of
cervical spine
2. Ankylosing spondylitis Ankylosis of cervical spine; less commonly, ankylosis
of temporomandibular joints; lack of mobility of
cervical spine
I Benign tumors
Ex: cystic hygroma, lipoma, adenoma, goiter Stenosis or distortion of the airway
Malignant tumors
Ex: carcinoma of tongue, larynx or thyroid Stenosis or distortion of the airway; fixation of
larynx or adjacent tissues secondary to infiltration
or fibrosis from irradiation
I Trauma
Example: facial injury, cervical spine injury and Edema of the airway, hematoma, ongoing nose/
laryngeal-tracheal trauma sinus/laryngeal bleeding, unstable fracture(s) of the
maxillae, mandible and cervical vertebrae
Obesity Short, thick neck; redundant tissue in the
oropharynx; sleep apnea
Aaomegaly Macroglossia; prognathism
Acute bums Edema of airway
\
}
I
b Class I Class II Class Ill Class IV
Fig. 3. a Mallampati Airway Classification. Relative size of the tongue to the oropharyngeal opening A:
Class I. B: Class II. C: Class Ill. (From [11] with permission); b Samsoon and Young Airway Classification
(From [12] with permission)
I Strategy For Airway Management

A management strategy organized in algorithm form facilitates a systematic
approach to the airway in the critically ill neurologically injured patient, decreases
time of reaction, and decreases the risk of an adverse outcome. This is particularly
essential for patients who have an unrecognized difficult airway upon first attempt
to intubate, when a difficult airway is recognized but the patient is uncooperative
or rapidly deteriorating due to CNS pathology or hypoxia, or for unplanned extu-
bation in the ICU [18]. In the latter group, consideration should be given to early
elective tracheostomy especially if the Glasgow Coma Scale score is less than eight
[19].
Patient Preparation before Attempting Intubation

Regardless of the intubation technique or urgency of intubation, pre-oxygenation
should be attempted before induction, to minimize the chance of desaturation. The
apnea time necessary to reach critical Sp0 2 ( < 90%) after induction cannot always
Grade I
Grade II
Grade Ill
~ GradeiV
Fig. 4. Cormack and Lehane direct laryngoscopy
classification. (From [49] with permission)
100 --=,F=F===t=:::::r::-T-11~
F=t:;;:::;_:::::F~
\
-1---\---r--....._
--I-- '\
----,
90 ~-++-+--"d----+--+---*---1
\ \ \ IModeratolyllll
\-+---1
I , ~~ , l70kgaduk I
::P • Normal 1
~ 80 -t-- + - - + - - + - -'t-JlOkg _\ C
~ \ vchl~ ' \ ~~~~

~=-' \ \ lo 1\\
70 +--+-+-t~Obese'\ \
I \ I Mean time to fKO!If':l"'
of twitd1 htlght from
1
60 ' -+--- +"11\f--'. 1 mglkg Succinykhollne l.v.
-!::--+--+--+----'--!-+-
0 I • \ 10 ~ so ~ \ 90~
0 2 3 4 5 6 u7 8 9 1cfA
Time of Ve = 0 (min}
Fig. 5. Graphic extrapolation of arterial oxygen saturation post induction and paralysis with succinylcho-
line in obese (A), pediatric (8), moderately critically ill (C), and normal patients (D) without ventilation.
Critical desaturation precedes full recovery from succinylcholine in all the patients. (From [20] with per-
mission)
---~--~~~~,--~--~~~~,-~
be predicted; it is expected to be decreased in critically ill patients due to decreased

functional residual capacity (FRC), pulmonary dysfunction, or increased metabolic
rate [20]. Other factors may influence rapid desaturation when intubation is at-
tempted in the neurologically impaired. The obese, and those with underlying pul-
monary disease, have a decreased FRC, and V/Q mismatch. Decreased FRC may be
further aggravated by the supine position and paralysis. Metabolic rate and oxygen
consumption are increased in the pediatric population. The critically ill are at in-
creased risk of rapid desaturation because of the combination of increased oxygen
consumption, V/Q mismatch, and decreased oxygen delivery.
An Fi0 2 of 1.0 is used to attempt rapid and full tissue denitrogenation, requiring
several minutes to achieve, and possible only with a tight mask fit on the patient,
using either a rubber mask-strap or providing firm pressure to a mask connected
to an Ambu bag or a Mapleson D system. Pre-oxygenation is particularly important
if the use of succinylcholine is contemplated as the average time to critical desa-
turation is usually shorter than the mean recovery time from an intubation dose
(Fig. 5), even in healthy individuals [20]. A dose of 0.25 mg/kg (ED 95 for succinyl-
choline) is sufficient to briefly relax the vocal cord in the majority of the patients.
Aspiration prophylaxis should be considered in all 'full stomach' patients. How-
ever, neutralization of gastric secretions with sodium citrate (15 to 30 ml by
mouth) shortly before intubation is often impossible if an adequate level of con-
sciousness, or the gag reflex, is absent. The use of H2 blockers, proton pump inhi-
bitors, or metoclopramide does not provide adequate protection in these patients
because of slow onset of action. Thus, acid aspiration protection relies upon effec-
tive cricoid pressure (the Sellick maneuver).
Achieving Effective Mask Ventilation

A fundamental step in managing the airway, ventilation by bag-valve-mask, requires
a high-flow, fresh gas source to compensate for facemask leaks and allow genera-
tion of positive pressure to overcome respiratory system resistance. Jaw thrust and
neck extension, usually necessary to open the airway, is not an option if neck in-
jury is present or suspected. The mask should be sized to cover the nose at the lev-
el of the nose bridge and the mouth just above the chin. Circumferential mask-
straps should not be used if increased ICP is a concern because of the risk of re-
ducing the cerebral venous return. Lack of seal secondary to facial hair may be
overcome using gauze soaked in petroleum jelly to fill facial contours under the
mask cushion. Plastic film over facial hair, or even a defibrillator contact pad with
a small hole cut in the middle at the level of the mouth opening have been used
[21]. While ventilating, the chest must not rise excessively, as this implies lung
over-inflation, increasing risk of gastric insufflation, decreased venous return, and
hypotension. Ensuring that the airway pressure is < 20 cmH 2 0 by connecting a
pressure manometer to a Mapleson D system may minimize the incidence of gas-
tric insufflation; an inspiratory time of ~ 1.5 seconds and a gentle squeeze of the
Mapleson D or Ambu bag minimizes peak airway pressure and risk of aspiration
[22] and reduces the risk of extreme hyperventilation with cerebral vessel vasocon-
striction. Cricoid pressure is the maneuver to limit gastric insufflation during ven-
tilation of the unprotected airway and should always be used.
Overcoming Airway Obstruction Due to Soft Tissue Collapse

The upper airway of the patient with altered mental status often totally obstructs.
Particularly in more obese patients, the combination of stupor, redundant oropha-
ryngeal soft tissue, a bulky tongue, and a thick chin and neck pad may interfere
with the ability to ventilate. Various clinical signs may be noted during airway ob-
struction (Table 3).
Various methods may be used to overcome upper airway obstruction, but are
limited to patients without significant neck/cervical spine pathology. Lifting the
chin pad while applying jaw thrust straightens the hypopharyngeal soft tissue, fa-
cilitating ventilation. Insertion of an oral airway or tilting the head laterally while
ventilating reduces the risk of lingual airway occlusion. Finally, two-person mask
ventilation may be attempted.
Achieving the Best Laryngoscopic View

The patient should be placed in optimal position before an intubation attempt. The
'sniffing' position (slight flexion of the neck and extension of the head and the
neck) is usually the best way to align the oropharyngeal and laryngeal axes. In the
obese patient, the sniffing position can be modified by placing a pad under both
the shoulders and the head. Elevation of the shoulder and scapulae, in particular,
allows better extension of the neck in obese patients. In the ICU or emergency de-
Table 3. Clinical signs of airway obstruction during positive and negative pressure ventilation. From [48]
with permission
Auditory Gurgling in epiglottic area (esophageal ventilation)

Crowing or stridor (laryngeal)
Stridor (laryngeal)
Snoring (pharyngeal)
Wheezing (small airway)
Absent breath sounds
Tactile Deueased reservoir compliance
Decreased expiratory return
Airway vibration
Large facemask leak
I Visual Decreased chest wall/inward abdominal excursion
Accessory muscle recruitment
Puffed cheeks/neck
Abdominal rocking
Abdominal distention
Cyanosis
Nasal flaring
Suprasternal notch retraction
I Objective Increased airway pressure
Absence of C0 2 waves on capnograph
Low measured expired volume
Hypoxemia (pulse oximeter)
---~--~~~~,--~--~~"~,-~
partment, temporary removal of bed rail or bed frames should be considered to fa-
cilitate operator access to the airway.
If the patient is in the Emergency Department unconscious or a cervical spine
injury is present or suspected, manipulation of the airway should be performed
particularly carefully, minimizing movement to a gentle chin lift or forward man-
dibular thrust to maintain an open airway. The use of a plastic oral airway is not
recommended if the patient is not intubated because it can contribute, via a strong
gag reflex, to emesis with sudden neck movement and potential aspiration of gas-
tric contents. Immediate control of the airway with an endotracheal tube should be
performed. Although a blind nasal intubation is a practical way to get the job done,
it should never be performed where there is suspicion of intracranial injury with
basal skull fracture or when there is obvious facial bone deformation. In such cone
ditions, oral endotracheal intubation with in line manual cervical immobilization
and cricoid pressure should be performed. This airway maneuver, when correctly
executed, requires three rescuers [23].
Visualization of the larynx can be optimized through external manipulations,
usually applied by the right hand or by an assistant while applying cricoid pres-
sure. The optimal external laryngeal manipulation (OELM) [24] and the backward,
upward, rightward laryngeal displacement (BURP) [25] describe, respectively, the
American and Canadian approaches to external manipulation of the larynx to im-
prove vocal cord visualization during laryngoscopy.
Choosing the Laryngoscope Blade

Mcintosh blades are recommended when a relatively small mouth opening, large
tongue and/or redundant subcutaneous tissue are present. A Mcintosh # 4 is our
blade of choice because it can be adapted to either small or large adults. Alterna-
tively, the Miller blade may be optimal for visualization of the vocal cords in pa-
tients with a small mandibular space, large incisors, and/or a large, floppy epiglot-
tis. This is the blade of choice for the pediatric population, due to the relatively
larger size of the pediatric epiglottis.
A commonly used adjunct device for direct laryngoscopy in severely injured pa-
tients is the gum elastic stylet [26]. Under direct laryngoscopy, the flexible stylet
tip is blindly passed under the epiglottis into the trachea. The endotracheal tube is
then passed over the stylet, thereby allowing tracheal intubation. During insertion,
counter-clockwise rotation of the endotracheal tube by 90° to 180° is recommended
to prevent its tip from impinging on the right vocal cord. The gum elastic stylet
can be used to limit the extension of the neck in patients with a cervical collar or
neck injury. A number of laryngoscopic blades have recently been introduced to
improve access to the larynx when it is anterior; these are all anecdotally advanta-
geous in cases of difficult airway or limited mouth opening. A detailed review is
available in the literature [27].
When to Consider Alternatives to Direct Laryngoscopy after

Unsuccessful Attempts
Numerous attempts at direct laryngoscopy, or edema from previous intubation or
trauma may degrade the quality of the airway due to laryngeal edema and bleeding.
This may also make mask ventilation progressively more difficult or impossible.
Airway degradation after numerous attempts at direct layngoscopy is the most

common reason for the 'cannot ventilate' scenario and adverse respiratory events
[1]. It is generally accepted that 3 to 4 attempts at direct laryngoscopy are the max-
imum number before switching to an alternative plan or resuming mask ventila-
tion. It is our impression that the number of direct laryngoscopy attempts is often
proportional to the experience of the physician/physician-in-training. To limit the
possibility of adverse respiratory events, we recommend that the inexperienced op-
erator not be allowed to perform laryngoscopy in patients with obvious anatomy
compatible with difficult intubation, or when positioning is limited by in-line axial
stabilization of the head, until he/she has a track record of successfully intubating
less challenging airways. The presence of an expert laryngoscopist standing by has
proven effective to assure safety of critically ill patients requiring endotracheal in-
tubation [28].
I Developing a Difficult Airway Algorithm

in the Neurologically Injured Patient
A systematic approach to the difficult airway in the Emergency Department and
neuro ICU is the key to prevent disastrous secondary injuries caused by hypoxia. A
difficult airway algorithm can generally be organized into three different parts:
1 Part One: Predictable difficult intubation due to recognized difficult airway.
I Part Two: Unpredictable difficult airway with ability to ventilate by mask.
I Part Three: Unpredictable difficult airway, with inability to ventilate or oxygenate
the patient, immediately after the use of hypnotic agents and/or muscle relaxant,
or after a short period of successful ventilation (Fig. 6).
Part One: The Predictable Difficult Airway

The more satisfactory management of these patients is endotracheal intubation
using a flexible fiberoptic bronchoscope and maintaining spontaneous ventilation.
This technique is usually feasible only in awake and cooperative patients, but can
occasionally be extended to the obtunded patient with careful planning. Although
time is usually insufficient to administer H2 blockers or proton pump inhibitors,
the awake patient may be given 15 to 30 ml of sodium citrate to neutralize gastric
acid prior to initiating the procedure. Intravenous glycopyrolate (0.2 mg) given 10
to 15 minutes before intubation, minimizes secretions and may improve fiberoptic
airway visualization. The tip of the fiberoptic bronchoscope is wetted with an anti-
fogging agent, and the endotracheal tube is pre-heated in warm saline.
Four percent lidocaine (4 to 6 ml, up to 4 mg/kg) is nebulized into an aero-
solized facemask ten minutes before beginning the procedure. Bilateral superior
laryngeal and glossopharyngeal nerve blocks, using 2 to 3 ml of 1% lidocaine may
be performed, but, like the transtracheal block, they are rarely necessary if ade-
quate local anesthetic is nebulized in the pharynx and trachea. The total amount of
local anesthetic should not exceed the calculated toxic dose. Gentle external pres-
sure on the larynx without neck extension may facilitate the exposure of the vocal
chords. Specialized airways, such as the Berman, Ovassapian, and Williams may fa-
cilitate the placement of the endotracheal tube in front of the vocal cords, deep into
the hypopharynx. As conscious sedation may be contraindicated in the critically ill,
Sectio n 1 Sectio n 2 Section 3
• Always consider calling for help (e.g.. technical, medical

surgical etc.) when difficulty with mask ventillation
and/or tracheal intubation is encountered
.. Consider the need to preserve spontaneous ventilation
Succeed
Cancel case
Regroup (e.g..
different peiSOilnel
equipment)
! "---..
Fail
Awaken / Surgical when Extubate
Anesthesia with ailway appropnate ' over jet
stylet
mask ventilation
Fig. 6. Navigating the difficult airway algorithm. Part One: The predictable difficult intubation approached
awake. Part Two: The unpredictable difficult intubation with ability to ventilate by mask. Part Three: The
unpredictable difficult intubation with inability to ventilate by mask. (From [48] with permission)
adequate topical anesthetic applied to the pharynx must be performed before an

elective intubation.
Nasotracheal intubation is an alternative to the oral route for patients with a
large tongue or oropharyngeal edema, and an alternative for the spontaneously
breathing, uncooperative patient, or when secretions are excessive. Facial or poste-
rior fossa trauma, or coagulopathy are absolute contraindications to this approach.
In the absence of these conditions, we pre-treat the mucosa of both nostrils with a
solution of 0.1% phenylephrine, followed by progressive dilation, using nasal trum-
pets lubricated with 2% lidocaine jelly. Labetalol and esmolol are used to blunt the
hypertensive response to airway manipulation; supplemental oxygen is provided.
When awake intubation is not feasible and with imminent respiratory failure, part
two and three of the difficult airway algorithm should be immediately executed.
Part Two: Strategy for the 'Cannot Intubate' Patient,

when Bag-Valve-Mask (BVM) Ventilation is Still Possible
If laryngoscopy does not result in visualization of the glottis after 3 to 4 attempts,
despite use of OELM or BURP, the patient should be ventilated and a pre-planned
alternative route of intubation carried out. The laryngeal mask airway (LMA) - Fas-
trach® - is our first choice to facilitate placement of the endotracheal tube
(Fig. 7 a). The device is available in sizes 3, 4, and 5 for, respectively, small, normal,
Fig. 7. a Fastrach® intubating LMA. A silicone wire reinforced cuffed endotracheal tube is placed in the
laryngeal mask airway with the help of a silicone extension. (From [48) with permission); b Fiberoptic in-
tubation of a laryngeal mask airway with a Rae endotracheal tube. The swivel adapter in place allows
ventilation during the procedure. (From [16) with permission)
and large adults, is latex-free, and permits single-handed insertion from a neutral
position without placing fingers in the patient's mouth. The wire-reinforced endo-
tracheal tube is available in sizes 7 and 8 mm. An alternative is fiberoptic intuba-
tion, following LMA placement. If a regular LMA is placed, fiberoptic intubation
should be performed with a longer endotracheal tube (Rae tube) to facilitate the
exchange. This maneuver can be quickly performed while the patient is still breath-
ing spontaneously under the hypnotic effect of the induction agent. Positive pres-
---~--~~~~,--~--~~'"~,-~
sure ventilation may be provided during the procedure through a Portex® right an-
gle adapter (Fig. 7b) [16]. To minimize air trapping and barotrauma, ventilation is
provided manually rather than mechanically.
Part Three: Strategy for 'Cannot Ventilate, Cannot Intubate' Scenario
The 'cannot ventilate, cannot intubate' scenario is, perhaps, the intensivist's worst
nightmare. Depending upon the length of pre-oxygenation time, the patient's oxy-
gen consumption, intra-pulmonary shunting, and FRC, oxygen desaturation may be
rapid. Pediatric, obese, pregnant, and critically ill patients are particularly prone to
early and deep desaturation. The first step in this scenario is to immediately re-
quest help, including surgical backup. In many cases, this help may be lifesaving.
Two-person mask ventilation should be attempted before moving to another por-
tion of the algorithm. Other personnel may be delegated to perform cricoid pres-
sure or in-line manual axial stabilization, obtain supplies, and/or to control hemo-
dynamics pharmacologically.
The presence of large masses or severe swelling above the vocal cords (including
tumor masses or facial trauma) may preclude the successful use of non-invasive al-
ternative airway devices. This problem will be reviewed in the paragraph dedicated
to the transtracheal approach to the airway.
In general, the 'cannot ventilate, cannot intubate' scenario situation can be re-
solved only with either the placement of an LMA [29-34] or a Combitube® [35-42]
A limitation of these techniques is that none will be effective when the difficult
airway is secondary to pathology above the vocal cords, as with hematoma, pha-
ryngeal abscess, neoplasia, airway edema, or massive facial trauma. In these cases,
the only approach likely to be successful is emergency surgical airway and/or trans-
tracheal catheter placement. Both are reviewed below.
1. Emergency tracheostomy is usually performed via a vertical incision from the cri-
coid cartilage down, for approximately 1 em, in the direction of the sternal notch.
A #11 surgical blade is preferably utilized. While a skilled operator can rapidly
approach the trachea through this route, serious bleeding may occur via laceration
of the anterior jugular and superior thyroid veins, the cricothyroid artery, and
other vessels of the thyroid isthmus. If the procedure is successful and tracheal in-
tubation is confirmed, as soon as the patient is stabilized the next step is to imme-
diately surgically revise the tracheostomy.
2. Emergency cricothyrotomy is a valid alternative to the emergency tracheostomy for

the intensivist not skilled or trained in the surgical approach to the airway. This
technique requires identification of the cricothyroid membrane (ligament), which
lies directly under the skin and is composed primarily of elastic tissue [43]. It cov-
ers the cricothyroid space, averaging 9 mm in height and 3 em in width. The mem-
brane is located in the anterior neck between the thyroid cartilage superiorly and
the cricoid cartilage inferiorly.
Because the vocal cords are usually located a centimeter or more above the cri-
cothyroid space, they are usually not injured, even during emergency cricothyrot-
omy. The anterior jugular veins run vertically in the lateral aspect of the neck and
are usually spared injury during the procedure. There is, however, considerable
variation in both the arterial and venous vessel patterns. While the arteries are al-
ways located deep to the pretracheal fascia and are easily avoided during a skin in-
cision, veins may be found in both the pretracheal fascia and between the pretra-
cheal and superficial cervical fascias. To minimize the possibility of bleeding, the
cricothyroid membrane should be incised at its inferior third.
This technique has the advantage of achieving access to the airway through a re-
latively avascular part of the neck, especially in lean individuals. However, the cri-
cothyroid membrane is not always easy to appreciate in obese patients or those
with a short neck. In any event, the successful placement of cricothyroidotomy
should be followed by an elective tracheostomy, or fiberoptic intubation, as soon as
possible, because long-term cricothyroidotomy may be associated with cricoid ma-
lacia, stenosis and/or lesions of the vocal cords. Our technique of choice is the per-
cutaneous cricothyroidotomy as described by Melker using the Seldinger technique
(Fig. 8). The main advantage of this technique is the blunt dissection of the subcu-
taneous tissues all the way to the cricothyroid membrane [43]. An airway catheter
is then introduced over a dilator threaded over the guidewire. This technique al-
lows the insertion of an airway larger than the initial needle or catheter, and often
of sufficient internal diameter to allow ventilation with conventional ventilation de-
vices, suctioning, and spontaneous ventilation (Fig. 9).
While this technique is relatively atraumatic, it does require some knowledge of
the anatomy of the neck, and previously established proficiency in using the kit.
Thus, this technique is not recommended for the physician unfamiliar with this de-
vice. A cuffed version of the device has recently been released.
)-JIO~IOI)IIIIII•IIIIII
~~---e
a:;:,
Introducer needle TFE catheter introducer needle

Syringe 18 gauge appropriate length 18 gauge appropriate length
Amplatz extra stiff wire guide

0.38 inch (0.97 mm) diameter <talnless steel appropriate length with flexible tip
~~
~Scalpel
Fig. 8. Melker emergency cricothyrotomy catheter kit. (Courtesy of Cook Critical Care, Inc., Bloomington, IN)
Thyroid cartilage
.. Access site
Cricoid cartilage
Airway catheter
I
D F
Fig. 9. Percutaneous approach to the cricothyroid membrane with the Melker cricothyrotomy kit. (Cour-
tesy of Cook Critical Care, Inc., Bloomington, IN)
3. Needle cricothyroidotomy is an alternative to the use of the more complex crico-

thyroidotomy or tracheostomy. This can be achieved with a large caliber Angio-
cath®, usually #12 or #14 gauge, or a specialized armored catheter. Needle crico-
thyroidotomy always requires the use of a jet device to provide ventilation (Fig. 10).
Transtracheal catheter ventilation can be used to temporarily oxygenate patients
who cannot be mask ventilated or intubated when no other back-up material is
available. The cricothyroid membrane is punctured percutaneously with an over-
the-needle catheter. The needle is removed and the catheter is attached to a high
frequency jet ventilator. Although oxygenation may be adequate with transtracheal
catheter ventilation, passive exhalation is usually insufficient to sustain ventilation,
and hypercarbia as well as significant air trapping may result, with disastrous con-
sequences for the patient with increased ICP or low intracranial compliance. Other
Fig. 10. Manual jet ventilator with pressure regulator, to be connected to a wall oxygen source or to an
oxygen tank regulator. (From [48) with permission)
complications directly related to needle jet ventilation with the required high pres-
sure oxygen source include needle displacement in the subcutaneous tissue with
massive subcutaneous emphysema, barotrauma with pneumothorax or tension
pneumothorax, air trapping with severe hemodynamic instability due to impeded
venous return to the right atrium, and right-to-left ventricular septal shift. The nee-
dle or catheter may break or bend if the patient coughs or moves, resulting in res-
piratory obstruction. Of these complications, subcutaneous air injection with loss
of anatomical landmarks and pneumothorax, and catheter kinking appear to be the
most serious and widely encountered. The use of this technique for more than
short intervals to 'bridge' to another technique is inappropriate, because the com-
plications may be lethal.
I Confirming Endotracheal Intubation

Several methods to confirm tracheal intubation have been recommended.
Visual Inspection of the Airway after Passage of the Tube

Despite one's best efforts, direct observation of the endotracheal tube tip and cuff
passing through the vocal cords is not always possible, especially in the patient
with an anterior larynx or redundant epiglottis. Several maneuvers can be used to
assess proper placement of the endotracheal tube. When the use of these maneu-
vers is rapid and systematic, they do not substantially increase the time to confirm
endotracheal intubation.
1 Moisture condensation into the endotracheal tube on exhalation: Implies humi-
dified gas is being exhaled.
I Pulmonary inflation: Chest rise on inflation and bilateral breath sounds with a
slight decrease in perceived compliance toward the end of expansion and the
lack of gurgling sounds in the epigastric area are quite useful for confirmation.
This may be somewhat unreliable in the obese patient.
1 Suction bulb: Recently, a suction bulb connected with the proximal end of the
endotracheal tube has been used to confirm tracheal intubation during CPR
(Fig. 11 a). If the endotracheal tube is properly placed, negative pressure will re-
sult in the bulb filling with air. If the endotracheal tube is placed in the esopha-
gus, the negative bulb pressure will result in esophageal collapse and the bulb
will not inflate. The device is disposable, small and lightweight. The compressed
75-ml self-inflating bulb is attached to the endotracheal tube through a standard
Fig. 11. Suction bulb (A) and syringe (B) to detect esophageal intubation during cardiopulmonary resusci-
tation
15-mm plastic fitting. The biggest advantage of this method is that it does not
rely upon end tidal C0 2 to confirm intubation of the trachea - an advantage in
situations of extreme low cardiac output, cardiac arrest, or sudden increase of
dead space ventilation (e.g., pulmonary embolism) [44, 45].
Syringe air aspiration: This is a 60-ml disposable lightweight syringe. The barrel
is connected to a standard 15-mm plastic fitting (Fig. llb). When the endotra-
cheal tube is in the esophagus, withdrawal of the plunger will cause the wall of
the esophagus to collapse, preventing free aspiration of air. This device shares
the advantage with the self-inflating bulb of being reliable even in conditions of
low cardiac output [46].
Detection of exhaled C0 2 : The most reliable method of ensuring tracheal intuba-
tion is the presence and persistence of C0 2 in gas exhaled from the endotracheal
tube. This may be appreciated using a color indicator (more often) or a capno-
graph. On occasion, in an esophageal intubation, C0 2 may be briefly present in
exhaled gas. In these cases the C0 2 does not persist for more than a few breaths.
More difficult is the interpretation of correct endotracheal tube placement in pa-
tients with severe reduction of cardiac output or total cardio-circulatory arrest.
As the amount of the C0 2 exhaled is directly proportional to the cardiac output,
it may not be displayed at all in case of total cardio-circulatory arrest or with in-
efficient CPR.
Conclusion
In summary, a systematic approach to airway management in neurologically in-

jured patients is necessary and provides a stepwise analysis of the best alternative
options to avoid hypoxia and hypoventilation. Furthermore, any algorithm will
work best when the physician applies, within the general guidelines of difficult air-
way management, the technique they are most familiar with, thus using the tech-
nique with the best chance of success.
References
1. Caplan RA, Posner KL, Ward RJ, et al (1990) Adverse respiratory events in anesthesia- A closed
claims analysis. Anesthesiology 72:828-833
2. Crosby ET, Cooper RM, Douglas MJ, et al (1998) The unanticipated difficult airway with
recommendations for management. Can J Anaesth 45:757-776
3. American Society of Anesthesiologists Task Force on Management of the Difficult Airway
(1993) Practice guidelines for management of the difficult airway. Anesthesiology 78:597-
602
4. Benumof JL (1991) Management of the difficult adult airway - With special emphasis on
awake tracheal intubation. Anesthesiology 75:1087-1110
5. Leach RM, Treacher DS (1998) ABC of oxygen. Oxygen transport - 2. Tissue hypoxia. Br
Med J 317:1370-1373
6. The Brain Trauma Foundation (2000) Resuscitation of blood pressure and oxygenation. J
Neurotrauma 17:471-478
7. Safar P (2000) On the future of reanimatology. Acad Emerg Med 7:75-89
8. Benumof JL (1999) The unanticipated difficult airway. Can J Anaesth 46:510-515
9. Benumof JL (1999) The ASA difficult airway algorithm - New thoughts/considerations.
Lecture 134, ASA Refresher Course Lectures. American Society of Anesthesiologists, Park
Ridge
---~--~~~~,--~--~~"~,-~
10. Wilson ME, Spiegelhalter D, Robertson JA, et al (1988) Predicting difficult intubation. Br J
Anaesth 61:211-216
11. Mallampati SR, Gatt SP, Gugino LG, et al (1985) A clinical sign to predict difficult tracheal
intubation: A prospective study. Can Anaesth Soc J 32:429-434
12. Samsoon GLT, Young JRB (1987) Difficult tracheal intubation: A retrospective study. Anaes-
thesia 42:487-490
13. Cormack RS, Lehane JR, Adams AP, Carli F (2000) Laryngoscopy grades and percentage
glottic opening. Anaesthesia 55:184
14. LoCicero J (1989) Bronchopulmonary aspiration. Surg Clin North Am 69:71-76
15. Warner MA, Warner ME, Weber JG (1993) Clinical significance of pulmonary aspiration
during the perioperative period. Anesthesiology 78:56-62
16. Benumof JL (1996) Laryngeal mask airway and the ASA difficult airway algorithm. An-
17. Kinni ME, Stout MM (1986) Aspiration pneumonitis: Predisposing conditions and preven-
tion. J Oral Maxillofacial Surg 44:378-384
18. Chevron V, Menard JF, Richard JC, et al (1998) Unplanned extubation: risk factors and pre-
dictive criteria for reintubation. Crit Care Med 26: 1049-1053
19. Koh WY, Lew TWK, Chin NM, Wong MFM (1997) Tracheostomy in a neuro-intensive care
setting: Indication and timing. Anaesth Intensive Care 25:365-368
20. Benumof JL, Dagg R, Benumof R (1997) Critical hemoglobin desaturation will occur before
return to an unparalyzed state following 1 mg/kg intravenous succinylcholine. Anesthesiol-
ogy 87:979-982
21. Thomas DI (1999) Overcoming the beard. Anaesthesia 54:100
22. Ruben H, Knudsen EJ, Carugati G (1961) Gastric inflation in relation to airway pressure.
Acta Anaesth Scand 5:107-116
23. Cohen M (1993) Initial resuscitation of the patient with spinal cord injury. Trauma Quar-
terly 9:38-43
24. Benumof JL, Cooper SD (1996) Quantitative improvement in laryngoscopic view by opti-
mal external laryngeal manipulation. J Clin Anesth, 8:136-140
25. Takahata 0, Kubota M, Mamiya K, et al (1997) The efficacy of the "BURP" maneuver dur-
ing a difficult laryngoscopy. Anesth Analg 84:419-421
26. Dogra S, Falconer R, Latta IP (1990) Successful difficult intubation: Tracheal tube place-
ment over a gum-elastic bougie. Anaesthesia 45:774-776
27. Cooper SD (1996) The evolution of upper airway retraction: New and old laryngoscopy
blades. In: Benumof JL (ed) Airway Management: Principles and Practice. Mosby-Year-
book, St. Louis, pp:374-411
28. Schwartz DE, Matthay MA, Cohen NH (1995) Death and other complications of emergency
airway management in critically ill adults. A prospective investigation of 297 tracheal intu-
bations. Anesthesiology 83:431-432
29. Verghese C, Brimacombe JR (1996) Survey of laryngeal mask airway usage in 11910 pa-
tients: Safety and efficacy for conventional and non-conventional usage. Anesth Analg
82:129-133
30. Pennant JH, Walker MB (1992) Comparison of the endotracheal tube and the laryngeal
mask in airway management by paramedical personnel. Anesth Analg 74:531-534
31. Mahiou P, Narchi P, Beyrac P, et al (1992) Is laryngeal mask easy to use in case of difficult
intubation? Anesthesiology 77:1228A (abst)
32. Akbar AN, Muzi M, Lopatka CW, et al (1996) Neurocirculatory responses to intubation
with either an endotracheal tube or a laryngeal mask airway in humans. J Clin Anesth
8:194-197
33. Rabey PG, Murphy PJ, Langton JA, et al (1992) Effect of laryngeal mask airway on lower
oesophageal sphincter pressure in patients during general anaesthesia. Br J Anaesth
69:346-348
34. Brimacombe JR, Berry AM (1997) Cricoid pressure. Can J Anaesth 44:414-425
35. Klein H, Williamson M, Sue-Ling HM, et a! (1997) Esophageal rupture associated with the
Combitube. Anesth Analg 85:937-939
36. Vezina D, Lessard MR, Bussieres J, et al (1998) Complications associated with the use of
the esophageal-tracheal Combitube®. Can J Anaesth 45:76-80
700 A. Gabrielli et al.: Advanced Airway Management in the Neurologically Injured Patient
37. Atherton GL, Johnson JC (1993) Ability of paramedics to use the Combitube® in prehospi-
tal cardiac arrest. Ann Emerg Med 22:1263-1268
38. Frass M, Frenzer R, Zdrahal F, et al (1987) The esophageal tracheal Combitube® - Preli-
minary results with a new airway for CPR. Ann Emerg Med 16:768-772
39. Staudinger T, Brugger S, Watschinger B, et al (1993) Emergency intubation with the Com-
bitube® - Comparison with the endotracheal airway. Ann Emerg Med 22:1573-1575
40. Wagner A, Roeggla M, Roeggla G, et al (1995) Emergency intubation with the Combitube
in a case of severe facial burn (correspondence). Am J Emerg Med 13:681-683
41. Klauser R, Roeggla G, Pidlich J, et a! (1992) Massive upper airway bleeding after thrombo-
lytic therapy - Successful airway management with the Combitube®. Ann Emerg Med
21:431-433
42. Mercer M (2000) Respiratory failure after tracheal extubation in a patient with halo frame
cervical spine immobilization. Rescue therapy using the Combitube airway. Br J Anaesth
86:886-891
43. Caparosa RJ, Zavatsky AR (1957) Practical aspects of the cricothyroid space. Laryngoscope
67:577-591
44. Zaleski L, Abello D, Gould MI (1993) The esophageal detector device: Does it work? An-
45. Kasper CL, Deem S (1998) The self-inflating bulb to detect esophageal intubation during
emergency airway management. Anesthesiology 88:898-902
46. Cardoso MMSC, Banner MJ, Melker RJ, et al (1998) Portable devices used to detect endo-
tracheal intubation during emergency situations: A review. Crit Care Med 26:957-964
47. Benumof JL (1996) Airway Management - Principles and Practice. Mosby Yearbook, St.
Louis, p 129
48. Gabrielli A, Layon AJ (2002) Management of the difficult airway. In: Kirby RR, Gravenstein
N, Lobato EB, Gravenstein JS (eds) Clinical Anesthesia Practice, edn 2. WB Saunders, Phi-
ladelphia, pp 1010-1022
49. Cormack RS, Lehane J (1984) Difficult tracheal intubation in obstetrics. Anesthesia
39:1105-1111
Treatment Conflicts between the Injured Brain
and the Lung
T. Lescot, L. Abdennour, and L. Puybasset
I Introduction
Management of acute brain injury is focused on preventing, detecting, and correct-

ing systemic secondary insults such as hypoxemia, hypocapnia, and hypercapnia,
which are known to worsen patient prognosis. According to the international
guidelines, tracheal intubation and mechanical ventilation are required after brain
injury in every comatose patient having a Glasgow coma scale equal to or less than
8. Artificial ventilation is used to prevent the risks of airway obstruction and as-
piration. It also permits the easy control of PaC0 2 and Pa0 2 and allows the admin-
istration of potent sedative drugs.
Head injury patients frequently have secondary organ failure. These dysfunctions
can be either primary like lung contusion or secondary to the brain trauma itself
like pneumonia, acute lung injury (ALI) or acute distress respiratory syndrome
(ARDS), and neurogenic pulmonary edema.
The therapeutic interactions between the brain and the lung are complex: severe
head trauma can be the cause of different pulmonary injuries, which by themselves
limit the therapeutic options in the treatment of the brain injury. From the opposite
side, some treatments against intracranial hypertension (ICH) are directly responsi-
ble for a worsening of the lung status.
I Impact of Mechanical Ventilation on Cerebral Blood Flow
The simplest way to decrease intracranial pressure (ICP) is to reduce PaC0 2

(Fig. 1). Reduction in ICP is secondary to a decrease in cerebral blood volume. The
impact of a sudden change in blood volume on ICP depends on the brain compli-
ance and on the position of the patient on the Langfitt's curve. Accordingly, a given
change in PaC0 2 and cerebral blood volume will markedly decrease ICP in a non-
compliant brain and induce nearly no change in pressure in a compliant brain.
Such a decrease in cerebral blood volume also occurs when the mean arterial pres-
sure (MAP) is increased. However, both therapies have opposite effects on cerebral
blood flow (CBF).
Cerebral arteries respond to highly localized perivascular alteration of PaC0 2
and pH. During chronic hypocapnia, the CBF remains constant, suggesting that the
C0 2 itself does not control the cerebral vascular cerebral tone. It is likely that the
local pH rather than local C0 2 is the mediator of the regulation of tone. The cas-
cade of mediators that links the extracellular pH to the cerebral vascular tone is
702 T. Lescot et al.
0 12 24 36 48
0 12 24 36 48
0 12 24 36 48
nme (min)
Fig. 1. From the top to the bottom, the figure shows the changes in intracranial pressure (ICP), end-tidal
C02 (ETC0 2), mean velocity of the left middle cerebral artery, pulsatility index and jugular vein oxygen
sautration (Sjv0 2) induced by a progressive increase in minute ventilation. Cerebral blood flow (CBF) as-
sessed by the Doppler velocity or by the value of Sjv0 2 is directly correlated to the ETC0 2 value
complex and interrelated, the final mediator being the intracellular calcium. Most
studies report a change in global CBF of 1 to 2 ml/100 glmin for each mmHg
change in PaC0 2 . Reducing PaC0 2 acutely to 25-30 mmHg decreases the global ce-
rebral blood flow by 40 to 50o/o.
J.F. Payen et al. [1] studied, by contrast-enhanced magnetic resonance imaging
(MRI) technique, the relationship between the change in ventilation and in CBF in
rats. The authors demonstrated that hypercapnia results in a significant increase in
CBF in the brain-studied regions, although there was no direct correlation between
the change in cerebral blood volume and flow. Carmona Suazo et al. [2] investi-
Treatment Conflicts between the Injured Brain and the Lung 703
gated the effect of hyperventilation on cerebral oxygenation by the use of continu-

ous monitoring of brain tissue oxygen pressure (Pbr0 2 }. Acute hypocapnia signifi-
cantly decreased Pbr0 2 indicating a risk of secondary ischemic damage during hy-
perventilation in severe head injury patients. These conclusion were also those of
Imberti et al. [3] who observed similar results, clearly suggesting that hyperventila-
tion can compromise cerebral oxygenation. The guidelines of the Joint Committee
on Trauma and Critical Care of American Association of Neurologic Surgeon indi-
cate that the use of aggressive or prophylactic hyperventilation must be avoided in
patients with severe head trauma [4]. However, Diringer et al. [5] showed that both
moderate (PaC0 2 =30 ± 2 mmHg) and severe (PaC0 2 =25 ± 2 mmHg) hypocapnia
decreased CBF. This reduction in CBF however, was not associated with any change
in cerebral oxygen consumption (CMR0 2 ), suggesting that CBF reduction asso-
ciated with hypocapnia need not necessarily result in energy failure. These results
imply that hyperventilation requiring high tidal volume and respiratory rate may
be justified in at least some patients who require it for ICP control.
However, hypercapnia cannot be tolerated in these patients. In patients with de-
creased compliance or increased alveolar dead space, PaC0 2 can be effectively re-
duced to normal values by increasing the frequency rate and decreasing the instru-
mental dead space [6]. Decreasing the instrumental dead space can be achieved by
replacing the heat and moisture exchanger (HME) by a humidifier and by suppres-
sing the connecting tube between the Y piece and the intubation tube.
Severe head trauma patients who develop ALI may require high positive end-ex-
piratory pressure (PEEP) levels. The use of PEEP for treatment of pulmonary dysfunc-
tion may potentially affect cerebral perfusion pressure (CPP), both through a rise in
ICP and a reduction in the MAP. Luce et al. [7] showed experimentally that increasing
PEEP raises ICP through a decrease in cerebral venous outflow. However, subsequent
clinical studies demonstrated that this effect is clinically insignificant. Cooper et al.
[8] observed that the application of a PEEP level of 10 cmH 2 0 in 33 patients with se-
vere head trauma increased ICP by 1.3 cmH 2 0 only. McGuire et al. [9] also failed to
demonstrate any negative impact of PEEP on ICP in patients with brain edema due to
head injuries or subarachnoid hemorrhage (SAH). Recently, Huynh et al. [10] ob-
served a trend toward a decrease in ICP with increased PEEP levels. However, because
of the retrospective nature of the study, the authors could not exclude time as an in-
dependent variable contributing to the changes in ICP levels.
It can be concluded from all these clinical data that the strategy of increasing
PEEP to maintain oxygenation appears to be feasible without compromising CPP in
patients with traumatic brain injury and concomitant ALI. However, it is safer to
measure ICP, CPP and blood flow velocity by transcranial Doppler to optimize to
the cerebral perfusion when implementing high PEEP levels in these patients.
Pulmonary Complications of Severe Brain Injury
Pulmonary complications such as atelectasis, thoracic trauma, and aspiration lead-

ing to pneumonia, ALI and ARDS are frequent in patients with severe head injury
(Fig. 2). They all contribute significantly to the morbidity and mortality rates of
these patients.
The Traumatic Coma Data Bank, evaluating the major determinants of recovery
after traumatic brain injury, showed that pneumonia is the second most frequent
Pulmonary complications Treatment complications

• Pneumonia • Barbiturates
• Atelectasis • Hypothermia
• Aspiration • Hypertension/ hypervolemia
• Neurogenic edema • Neuromuscular blockers
• Associated thoracic trauma
Acute lung Injury
Fig. 2. Scheme summarizing the consequences of brain injury on lung function
complication occurring after severe head injury and has a significant influence on
the overall outcome in patients [11]. The incidence of ventilator-associated pneu-
monia (VAP) is estimated as high as 50% in these patients [12]. Risk factors such
as initial aspiration of oropharyngeal content during the resuscitation phase, and
colonization of the lower airway following intubation render acute brain-injured
patients at high risk of developing pulmonary infection. The pattern of colonization
and pneumonia of brain-injured patients suggest that these patients suffer from an
alteration of airway immune defenses very early during the course of their illness
[13]. The most frequent etiologic agents found initially include Staphylococcus au-
reus, Streptococcus pneumoniae and Haemophilus influenzae. Previous (short-term)
antibiotic treatment is protective against initial tracheobronchial colonization with
these agents, but represents a risk factor for subsequent lower airway colonization
by other Gram-negative enteric bacilli and Pseudomonas spp. According to Piek's
statistical model [11], if pneumonia could be eliminated as a single complication,
2.9% of all patients would shift from an unfavorable to a favorable outcome.
Furthermore, because pulmonary infections are frequently associated with other
complications (such as ARDS, hypoxia, septic shock, and subsequent multisystem
organ failure [MOF]), the actual number of patients who might benefit from pre-
vention and treatment of pulmonary infections is potentially much higher.
Thoracic-associated traumas are also frequent. In a large series of 3406 cases of
severe trauma, 45% of the trauma patients had a combined head and pulmonary
contusion [14].
Head injury is a major risk factor for the development of pulmonary complica-
tions after trauma. In a large series of 3280 cases of patients with multiple trauma,
the incidence of ALI was 11.2% [15]. In this study, head injury and surgery were
risk factors for pneumonia, atelectasis, and respiratory failure. Bratton et al. [16]
evaluated the incidence of ALI associated with traumatic brain injury from the
trauma data bank. They observed that 20% of the patients developed ALI in the
first 5 days following severe exclusive head injuries. These patients had no history
of proven aspiration, or concurrent thoracic, diaphragmatic, cervical spine, or tho-
racic spine injuries. Lower Glasgow coma scales scores, more frequent periods of
increased ICP, and worse global computed tomography (CT) finding on the initial
scan were more frequently found among the patients who developed ALI. However,
no specific anatomic brain lesion identified by cranial CT during the acute phase
of the injury was associated with an increased risk of ALI.
ALI labeled as 'neurogenic pulmonary edema' represents the most severe form of
lung disease associated with central nervous system (CNS) injury, and has typically
been reported in cases of fatal or nearly fatal head injury. Its physiopathology re-
mains unclear. An autopsy study performed on exclusive severe head trauma pa-
tients who died immediately at the scene of the accident or within 96 hours after
the trauma showed a significant increase in lung weight compared to patients who
died from non-CNS injuries [17].
Neurogenic pulmonary edema was also found in 23% of the 457 patients studied
by Solenski et al. [18] after aneurysmal SAH. Neurogenic pulmonary edema charac-
terized by an irregular respiratory pattern and associated with pink frothy airway
fluid containing high protein concentration {>4.5 g/dl) is observed in 2% of pa-
tients after aneurysmal SAH [19]. Neurogenic pulmonary edema may result from a
disruption of pulmonary capillary endothelium due to aneurysmal SAH-induced
pulmonary vasoconstriction [20]. Although the pathogenesis of neurogenic pulmo-
nary edema is not well known, specific destructive lesions in the CNS have been
observed to cause pulmonary edema in experimental animals. For example, lesions
in the nucleus tractus solitarus region increase pulmonary arterial pressure inde-
pendently of systolic arterial blood pressure resulting in increased pulmonary vas-
cular permeability [21]. Pulmonary edema may also result from aneurysmal SAH-
induced cardiac failure or from fluid therapy to prevent or treat vasospasm.
I Influence of the Treatment of Severe Head Injury on Lung Function
The occurrence of refractory brain hypertension during the first days following the
onset of head trauma often requires a therapeutic escalation through the use of
therapeutics such as neuromuscular blockers, hypothermia, and thiopental that
have a high potential to deteriorate the lung status further through mechanical ef-
fects or through direct immunosuppressive effects (Fig. 2).
Barbiturates, particularly pentobarbital and thiopental sodium, have been used
effectively in brain-injured patients with increased ICP that is refractory to sodium
management, cerebrospinal fluid (CSF) drainage and moderate hyperventilation.
The first published series of head injury patients receiving this therapy in 1979
[22] found that high dose barbiturate reduced elevated ICP in most patients who
were declared refractory to a rigorous regime of ICP management. Other studies
showed that high-dose barbiturates, when added to routine conventional manage-
ment, is useful for aborting elevation of ICP. Barbiturates seem to provide some
protection to the brain against anoxia, ischemia, and cerebral edema by. decreasing
the oxygen consumption of the brain, reducing the CBF, and stabilizing the mem-
branes. However, barbiturates have a number of serious adverse effects. Cordato et
al. [23] reported that prolonged barbiturate infusion induce respiratory complica-
tions in 76%, lung infection in 55%, arterial hypotension in 58%, hypokalemia in
82%, hepatic dysfunction in 87% and renal dysfunction in 47% of the treated pa-
tients.
Continuous barbiturate infusion is also known to produce immunosuppression
by inhibiting lymphocyte function [24], affecting neutrophil function, and depres-
sing the humoral immune response through a decrease in immunoglobulin produc-
tion [25]. The use of barbiturates is by itself a statistical predictor of an increased
risk of pneumonia [26].
Experimentally, treatment with moderate systemic hypothermia reduces the rate
of cerebral edema and death after brain injury in laboratory animals by protecting
the brain from cerebral ischemia. The beneficial effects of hypothermia have been
attributed mainly to a decrease in brain energy demand. Some studies demon-
strated that mild hypothermia reduces the release of neurotransmitters and free
fatty acid and possibly of glutamate and dopamine during the ischemic insult. In
1996, Metz et al. [27] showed that hypothermia at 33 °C reduces cerebral oxygen
consumption by approximately 45% and, thereby, improves the cerebral oxygen
supply-demand balance. They observed a decrease in ICP without significant re-
bound effect after rewarming as also demonstrated by two further studies [28, 29].
However, it was later demonstrated in a large randomized multicenter trial that
early hypothermia maintained during 24 h has no benefit on outcome after severe
head trauma [30]. In the Metz study, the authors pointed out the adverse effects of
mild hypothermia. They observed conduction disturbances, sinus bradycardia, ven-
tricular irritability, platelet dysfunction, renal failure, pancreatitis, and hypokale-
mia. They also observed impairment of pulmonary gas exchange principally caused
by atelectasis in basal alveolar units inducing a marked drop in the Pa0 2 /Fi0 2 ratio
not reversible by rewarming.
In patients with severe head injury, the occurrence of hypotension has been as-
sociated in several studies with a poor neurological outcome. Induced hypertension
has been advocated to raise CPP to at least 75 mmHg. Increased pulmonary hydro-
static pressure, however, can increase the amount of water accumulating within the
lung [31]. The implementation of hypertension could increase the incidence and se-
verity of symptomatic ARDS. The effects of induced hypertension on the incidence
and the severity of ARDS in the head-injury population has been studied by Con-
tant et al. [32] comparing two acute-care management strategies for severe head in-
jury: a CBF-targeted protocol and an ICP-targeted protocol. The CBF-targeted pa-
tients received a higher fluid intake and a larger dose of pressor agents than the
control group. As a consequence, the incidence of ARDS was five times higher in
the CBF-targeted group than in the ICP-targeted protocol (15 vs 3.3%).
After SAH, the combination of hypervolemia, hemodilution, and hypertension
('triple H') is the cornerstone of the prevention and treatment of vasospasm. Treat-
ment of vasospasm with either prophylactic or therapeutic triple H therapy has
been associated with a higher frequency of pulmonary edema, most likely because
of the induced hypervolemic state [18]. The pulmonary adverse effect of the triple-
H therapy can be further aggravated by the disruption of pulmonary capillary en-
dothelium due to aneurysmal SAH-induced pulmonary vasoconstriction.
Finally, the use of neuromuscular blockers to reduce ICP or to induce hypother-
mia has also severe pulmonary adverse effects.
I All and ARDS Influence the Outcomes of Brain Injury

The development of ALI or ARDS dramatically complicates the treatment of head-
injured patients (Fig. 3). Many therapies that are protective for the injured lung de-
crease CPP and raise ICP. Keeping pulmonary hydrostatic pressure low to minimize
edema formation through fluid restriction and diuretics decreases CBF. Reducing
tidal volumes to minimize barotrauma and allowing hypercapnia severely increases
cerebral blood volume and ICP. Proning the patient may dramatically increase ICP
by reducing jugular venous return.
In the context of head trauma, patients with ALI demonstrated lower Glasgow
coma scale scores, a worse neurological outcome, and an increased risk of death,
compared to patients who did not develop ALI [16). The percentage of patients in
a vegetative state or dead at 6 months post-injury is more than doubled in patients
who develop ARDS (68.8% compared with 29.7%) [32]. No significant differences
in the type of injury and the admission CT scans is noted between the patients with
and without ARDS. The average ICP is higher, and the amount of treatment re-
quired to manage ICH greater in the patients with ARDS. In addition, the incidence
of refractory ICH is significantly higher in the group of patients developing ARDS
(55.6 VS 22.2%).
I Conclusion
The interactions between the brain and the lung are complex. They can be divided
into physiopathological and therapeutic interactions. First, CBF depends directly on
the mechanical ventilator settings. Second, brain injury by itself puts a high strain
on the lung. Third, most of the therapies used to reduce ICP deteriorate lung func-
tion. Fourth, the occurrence of lung complications increases the morbidity and the
mortality of brain injury. The challenge for the clinician in charge of these patients
is to balance the risks and the benefits of the therapies implemented in order to
protect the brain without harming the lung.
Treatment of head injury Treatment of acute lung injury

Optimize CPP: Optimize oxygenation:
• adequate intravascular volume • keep pulmonary hydrostatic pressure low
pressors to keep blood pressure high to minimize edema formation
IICP
• restrict fluids, give diuretics to minimize
IBP edema formation
• give pulmonary vasodilators, e.g. NO increase
PEEP, use inverse I:E ratio
Control intracranial pressure Minimize lung barotrauma

• Controlled mechanical ventilation
avoid hypocapnia, avoid hypoxia .. • low tidal volumes
• Accept hypercapnia to minimize peak
• Use hyperventilation pulmonary pressures
Fig. 3. Potential therapeutic conflicts between the treatment of head injury and of All
References
1. Payen JF, Vath A, Koenigsberg B, Bourlier V, Decorps M (1998) Regional cerebral plasma
volume response to carbon dioxide using magnetic resonance imaging. Anesthesiology
88:984-992
2. Carmona Suazo JA, Maas AI, van den Brink WA, van Santbrink H, Steyerberg EW, Avezaat
CJ (2000) C0 2 reactivity and brain oxygen pressure monitoring in severe head injury. Crit
Care Med 28:3268-3274
3. Imberti R, Bellinzona G, Langer M (2002) Cerebral tissue P0 2 and Sjv0 2 changes during
moderate hyperventilation in patients with severe traumatic brain injury. J Neurosurg
96:97-102
4. Muizelaar JP, Marmarou A, Ward JD, et al (1991) Adverse effects of prolonged hyperventi-
lation in patients with severe head injury: a randomized clinical trial. J Neurosurg 75:731-
739
5. Diringer MN, Videen TO, Yundt K, et a! (2002) Regional cerebrovascular and metabolic ef-
fects of hyperventilation after severe traumatic brain injury. J Neurosurg 96:103-108
6. Richecoeur J, Lu Q, Vieira S, et al (1999) Expiratory washout vs optimization of mechani-
cal ventilation during permissive hypercapnia in patients with severe acute respiratory dis-
tress syndrome. Am J Respir Crit Care Med 160:77-85
7. Luce JM, Huseby JS, Kirk W, Butler J (1982) Mechanism by which positive end-expiratory
pressure increases cerebrospinal fluid pressure in dogs. J Appl Physiol 52:231-235
8. Cooper KR, Boswell PA, Choi SC (1985) Safe use of PEEP in patients with severe head in-
jury. J Neurosurg 63:552-555
9. McGuire G, Crossley D, Richards J, Wong D (1997) Effects of varying levels of positive
end-expiratory pressure on intracranial pressure and cerebral perfusion pressure. Crit Care
Med 25:1059-1062
10. Huynh T, Messer M, Sing RF, Miles W, Jacobs DG, Thomason MH (2002) Positive end-ex-
piratory pressure alters intracranial and cerebral perfusion pressure in severe traumatic
brain injury. J Trauma 53:488~492
11. Piek J, Chesnut RM, Marshall LF, et al (1992) Extracranial complications of severe head in-
jury. J Neurosurg 77:901-907
12. Hsieh AH, Bishop MJ, Kubilis PS, Newell DW, Pierson DJ (1992) Pneumonia following
closed head injury. Am Rev Respir Dis 146:290-294
13. Ewig S, Torres A, El-Ebiary M, et al (1999) Bacterial colonization patterns in mechanically
ventilated patients with traumatic and medical head injury. Incidence, risk factors, and as-
sociation with ventilator-associated pneumonia. Am J Respir Crit Care Med 159:188-198
14. Regel G, Lobenhoffer P, Grotz M, Pape HC, Lehmann U, Tscherne H (1995) Treatment re-
sults of patients with multiple trauma: an analysis of 3406 cases treated between 1972 and
1991 at a German Level I Trauma Center. J Trauma 38:70-78
15. Hoyt DB, Simons RK, Winchell RJ, et al (1993) A risk analysis of pulmonary complications
following major trauma. J Trauma 35:524-531
16. Bratton SL, Davis RL (1997) Acute lung injury in isolated traumatic brain injury. Neurosur-
gery 40:707-712
17. Rogers FB, Shackford SR, Trevisani GT, Davis JW, Mackersie RC, Hoyt DB (1995) Neuro-
genic pulmonary edema in fatal and nonfatal head injuries. J Trauma 39:860-866
18. Solenski NJ, Haley EC Jr, Kassell NF, eta! (1995) Medical complications of aneurysmal sub-
arachnoid hemorrhage: a report of the multicenter, cooperative aneurysm study. Partici-
pants of the Multicenter Cooperative Aneurysm Study. Crit Care Med 23:1007-1017
19. Theodore J, Robin ED (1976) Speculations on neurogenic pulmonary edema (NPE). Am
20. Lagerkranser M, Pehrsson K, Sylven C (1982) Neurogenic pulmonary oedema. A review of
the pathophysiology with clinical and therapeutic implications. Acta Med Scand 212:267-
271
21. Darragh TM, Simon RP (1985) Nucleus tractus solitarius lesions elevate pulmonary arterial
pressure and lymph flow. Ann Neurol 17:565-569
---~--~~~~,--~--~~"~,-~
22. Marshall LF, Smith RW, Shapiro HM (1979) The outcome with aggressive treatment in
severe head injuries. Part II: acute and chronic barbiturate administration in the manage-
ment of head injury. J Neurosurg 50:26-30
23. Cordata DJ, Herkes GK, Mather LE, Gross AS, Finfer S, Morgan MK (2001) Prolonged thio-
pentone infusion for neurosurgical emergencies: usefulness of therapeutic drug monitor-
ing. Anaesth Intensive Care 29:339-348
24. Neuwelt EA, Kikuchi K, Hill SA, Lipsky P, Frenkel E (1982) Barbiturate inhibition of lym-
phocyte function. Differing effects of various barbiturates used to induce coma. J Neuro-
surg 56:254-259
25. Salo M (1989) Effects of thiopentone on immunoglobulin production in vitro. Br J Anaesth
63:716-720
26. Craven DE, Kunches LM, Kilinsky V, Lichtenberg DA, Make BJ, McCabe WR (1986) Risk
factors for pneumonia and fatality in patients receiving continuous mechanical ventilation.
27. Metz C, Holzschuh M, Bein T, et al (1996) Moderate hypothermia in patients with severe
head injury: cerebral and extracerebral effects. J Neurosurg 85:533-541
28. Marion DW, Penrod LE, Kelsey SF, et al (1997) Treatment of traumatic brain injury with
moderate hypothermia. N Engl J Med 336:540-546
29. Shiozaki T, Sugimoto H, Taneda M, et al (1998) Selection of severely head injured patients
for mild hypothermia therapy. J Neurosurg 89:206-211
30. Clifton GL, Miller ER, Choi SC, et al (2001) Lack of effect of induction of hypothermia
after acute brain injury. N Engl J Med 344:556-563
31. Smith WS, Matthay MA (1997) Evidence for a hydrostatic mechanism in human neuro-
genic pulmonary edema. Chest 111:1326-1333
32. Coutant CF, Valadka AB, Gopinath SP, Hannay HJ, Robertson CS (2001) Adult respiratory
distress syndrome: a complication of induced hypertension after severe head injury. J Neu-
rosurg 95:560-568
Ventilatory Management in Head Injured Patients
P. Pelosi, G. Apostolou, and D. Chiumello
I Introduction
It is common knowledge that in head injured patients the principal morbidity and
mortality is frequently caused by the primary disease, i.e., cerebral nervous system
(CNS) injury and its neurological consequences [1, 2]. However, it has been recog-
nized that neurological outcome may also depend on the prevention of 'secondary'
brain injury due to the negative effects on cerebral parenchyma of increased intra-
cranial pressure (ICP) and/or altered cerebral volemia [3].
Moreover, extracerebral organ dysfunction is also frequent in head injured pa-
tients, influencing morbidity and mortality [4, 5]. Ventilatory management can
markedly affect the regulation of cerebral volemia, ICP control, and lung function.
However, few studies have investigated the role of mechanical ventilation in the
clinical management of head injured patients. The aim of this chapter is to discuss
ventilatory management and its pathophysiological rationale:
1) in the early phase after head injury;
2) in the stable phase (1 week after head injury); and
3) in the weaning phase.
I Ventilation in the Early Phase after Head Injury
Cerebral Ischemia versus Hyperperfusion

Normal neurological aerobic metabolism, combined oxygen and glucose consump-
tion, lead to normal carbon dioxide (C0 2 ) production which in turn mediates the
normal microcirculatory diameter. Since cerebral blood flow (CBF) and oxygen
consumption are normally coupled, cerebral extraction of oxygen remains in the
normal range. After severe head injury the cerebral consumption of oxygen is de-
creased due to the trauma by itself, and to sedative medication. Accordingly, de-
creased neuronal aerobic metabolism and C0 2 production lead to a physiologic
and proportional decrease in CBF ('intact metabolic autoregulation'), and, therefore,
the cerebral extraction of oxygen remains normal, indicating a good balance be-
tween blood flow and oxygen consumption. If CBF is low relative to a decreased
oxygen consumption, cerebral extraction of oxygen increases to compensate for the
excessive decrease in CBF ('oligemic cerebral hypoxia'). Conversely, if CBF is high
relative to decreased oxygen consumption ('defective metabolic autoregulation'), ce-
rebral oxygen extraction decreases ('relative cerebral hyperperfusion' or 'luxury
perfusion') [6].
Ventilatory Management in Head Injured Patients 711
Clinical conditions leading to severe ischemia of the brain are certainly asso-
ciated with a worse clinical outcome [7]. However, the main question is whether a
moderate ischemia (relative hypoperfusion) or a hyperemia (relative hyperperfu-
sion) is better to prevent 'secondary' brain injury.
Studies evaluating CBF alone have overemphasized the occurrence of regional or
global brain ischemia [8, 9]. This is because true ischemic metabolites cannot be
evaluated by any standard technique for measuring CBF alone (e.g., stable xenon
computerized tomography [CT] CBF measurements, or single photon emission CT).
Bouma et al. reported that 33o/o of severe head injured patients presented an early
ischemia [10]. However, reduced flow levels were not associated with increased oxy-
gen extraction, indicating an adequate coupling between reduced blood flow and
pathologically decreased oxygen consumption. On the contrary, Jaggi et al. have
shown that cerebral oxygen consumption is approximately 50o/o below normal in
brains with a high probability of favorable clinical recovery [11]. Thus, ischemic
thresholds for CBF in humans in recoverable coma would be expectedly 50o/o less
than the levels normally reported in animal studies [12].
Cormio et al. speculated on possible regional cerebral ischemia, despite having
only performed global measurements regarding CBF, reporting a favorable outcome
in hyperemic patients [ 13]. However, the mortality of this category of patients was
markedly higher (50o/o) than commonly reported, associated with a poor neurologi-
cal outcome. In contrast, Cruz has shown in a large series of patients that initially
moderately increased cerebral extraction of oxygen up to approximately 52o/o was
associated with a good neurological outcome, in contrast with initially low oxygen
extraction found in at least 20o/o of the patients [14].
Cerebral extraction of oxygen may be initially low, normal, or moderately in-
creased, but phasic changes towards relative cerebral hyperperfusion represent a
general rule in patients with traumatic brain swelling, especially after the first 12
hours [15].
These data suggest that 'moderate' ischemia is likely better tolerated by the brain
than hyperemia, and moderate to profound hyperventilation can be proposed to re-
duce relative hyperperfusion in the early phases after head injury.
Clinical Studies on Hyperventilation

The theoretical advantages of hyperventilation as cerebral vasoconstriction for in-
tracranial pressure (ICP) control and reversal of brain and cerebrospinal fluid
(CSF) acidosis, can be balanced by cerebral vasoconstriction to such an extent that
cerebral ischemia ensues with a minimum effect on acid-base homeostasis in the
CSF. In 1991, Muizelaar et al. published the only randomized study investigating
the effects of profound preventive hyperventilation (PaC0 2 24-28 mmHg) com-
pared to moderate hyperventilation (PaC0 2 30-35 mmHg) on mortality and dis-
ability outcome in patients with severe head injury [16]. They found that prophy-
lactic profound hyperventilation induced a 'slowness' in neurological recovery with
increased severe disability or vegetative state at 6 months, in patients with less se-
vere motor scores (4-5) at the time of injury without significant outcome differ-
ences in relation to moderately hyperventilated patients at one year post injury.
In fact, the design of this study and interpretation of the results was not
straightforward. First, the authors investigated a small population of patients, un-
derpowered to reach any statistical significance on mortality and neurological out-
come. Second, although the average Glasgow Coma Score (GCS) of the patients in-
712 P. Pelosi et al.
eluded in the study was around 6, only 14o/o of patients had an ICP>20 mmHg in-
dicating an overall very moderate severity of head trauma. Accordingly, profound
hyperventilation was initially contraindicated in as many as 86o/o of the hyperventi-
lated patients. Third, even though the physiological measurements involving CBF
and arteriojugular oxygen content differences did not reveal any evidence of hypo-
capnic-induced cerebral ischemia, adverse effects of profound hyperventilation were
emphatically addressed. In this respect, because of the small number of patients,
only 5-6 subjects with more severe lesion types (such as diffuse axonal injury) ran-
domly assigned to the profound hyperventilated group could have adequately ex-
plained a 'slowness' in neurological recovery, rather than an adverse effect of hyper-
ventilation itself. Fourth, the authors did not point out sufficiently that in more se-
vere patients (with a motor score of 1-3, and likely with higher ICP), the mortality
rate was 18o/o higher in moderately hyperventilated patients, claimed not to be sta-
tistically significant. Because mortality rates have ranged from approximately 30 to
40o/o in several other series of head injured patients, an 18o/o increase in mortality
represented approximately half of avoidable deaths.
Unexpectedly, the clinical application of this study was that profound hyperven-
tilation was no longer suggested as a first-line intervention in ICP management, in-
dependent of the severity of head injury.
Other non-randomized studies investigated the role of hyperventilation in head
injured patients. Gordon and Rossanda have long reported a substantial mortality
reduction in a retrospective analysis of severely brain injured patients subjected to
'semi-empirical' (not optimized) hyperventilation [17]. Finally, a recent European-
American survey on a large population of head injury patients reported that,
among other therapeutic maneuvers, profound hyperventilation could be associated
with a better outcome [18].
Based upon these findings and different from common clinical applications, even
non-optimized profound hyperventilation in the early phases after severe head in-
jury seems to be effective at reducing mortality, without affecting neurological out-
come, at least in more severe patients.
How to Optimize Profound Hyperventilation in Head Injury

The protocol we use in clinical practice is focused on a cumulative treatment
scheme aimed to maintain: 1) ICP < 20 mmHg; 2) normal cerebral extraction of
oxygen between 24 to 42o/o; 3) when increased ICP (::::20 mmHg) is associated with
normal to decreased cerebral extraction of oxygen, 'optimized' hyperventilation is
gradually maximized, aimed at the simultaneous normalization of both parameters
(ICP and cerebral extraction of oxygen). Conversely, in the presence of elevated ICP
associated with normal to increased cerebral extraction of oxygen, mannitol boluses
(25o/o mannitol fast intravenous boluses up to a serum osmolality of 315 to 320
mosm/1) are administered, also aimed at the simultaneous normalization of both
parameters. Once 'optimized' hyperventilation has been maximized, in patients re-
quiring barbiturate and/or hypothermic therapies, mannitol administration is re-
sumed if necessary, once the serum osmolality has returned to normal values :::;315
mosm/1. Only under extreme life saving circumstances, despite maximum ongoing
non-surgical treatment, is mannitol administrated rapidly despite high osmolality.
Under these circumstances, decompressive craniotomy is adopted immediately after
extreme mannitol administration. Once a normal and stable ICP :::;20 mmHg has
been achieved for at least 24 h, the above described cumulative protocol is reversed
gradually from the final to the first step. However, no randomized prospective trials
have proved the possible beneficial effect on outcome of this 'integrated' approach.
Cruz has performed a prospective, non-randomized, matched-control study in pa-
tients with small lateral ventricles, with a resulting rate of compromised basilar cis-
terns of over 60% in both groups [6]. Intracranial hypertension (ICH) was initially
documented in all patients from both groups and those who underwent moderate
and profound 'optimized' hyperventilation presented a statistically significant better
long-term clinical outcome than patients who were just mildly hyperventilated.
In conclusion, severe head injured patients frequently have ICH, with different
patterns of cerebral extraction (high, normal, low}, which need different manage-
ment approaches, not properly guided by ICP monitoring alone. Monitoring of ce-
rebral oxygen extraction, by using unilateral jugular bulb saturations, allows a
practical and reliable tool for the bedside assessment of cerebral oxygenation and
optimization of ventilation.
I Ventilatory Management in the Stable Phase

(1 Week after Head Injury)
Recently, it has been emphasized that the outcome in head injured patients is more
frequently the result of a progressive dysfunction of organ systems remote from the
site of the primary disease process, i.e., multiple organ dysfunction process [19].
Table 1 summarizes the average prevalence of extracerebral complications (parti-
tioned into overall and severe) in head injured patients, as reported by the most re-
cent literature. Several reports indicate that medical complications after head injury
may significantly contribute to the overall mortality rate [4, 20, 21]. These studies
found that pulmonary alterations accounted for up to SOo/o of the deaths after head
injury. The mortality was significantly higher in patients with head injury asso-
ciated with at least one organ failure compared to patients with head injury alone
(65 vs 17%, respectively). The occurrence of pulmonary failure was also associated
with an increase in intensive care unit (ICU) and hospital stay [22].
Table 1. Prevalence of extracerebral organ dysfunction in head injured patients

Total Severe
I Pulmonary pneumonia 40% 25%
embolism <1% 100%
I Gut 40% 5%
I Cardiac arrhythmia 30% 5%
cardiac failure 5% 1%
I Metabolic electrolyte disorders 30% 2%
diabetes insipidus 7% 7%
I Hepatic 25% 4%
I Hematologic 20% 6%
Renal 10% 15%
We can identify three major causes of pulmonary complications in head injured

patients:
1) neurogenic pulmonary edema;
2) abnormalities in ventilation perfusion mismatch;
3) structural parenchymal abnormalities, which likely play the most relevant role.
Structural Parenchymal Abnormalities

We can identify several main causes of structural parenchymal alterations in head
injured patients, among them:
1) abnormal breathing pattern;
2) release of inflammatory mediators;
3) release of catecholamines ('sympathetic storm');
4) pulmonary infectious processes.
Abnormal breathing pattern. Abnormal breathing patterns are commonly seen after
head injury. In particular, both hyperventilation and hypoventilation have been de-
scribed. Hyperventilation is usually associated with periods of hypoventilation
which can induce, together with a reduction in cough reflexes and impaired airway
patency from inspissated secretions, alveolar atelectasis and consolidation [23].
Release of inflammatory mediators. Head injury causes a marked release in the brain
and in the systemic circulation of pro- and anti-inflammatory agents which can
lead to peripheral organ dysfunction, predominantly of the lung and to a moder-
ate-severe immunodepression [24].
Thus, the release of these inflammatory mediators can lead to multiple organ
failure (MOF) where the lung parenchyma appears to be a preferential and more
susceptible target. However, possible further mechanisms for head injury-related
symptoms of systemic inflammation include the high incidence of aspiration pneu-
monia in poor-grade patients, which can provide a nidus for systemic inflamma-
tion. Impaired pulmonary gas-exchange could further contribute to systemic in-
flammation, as invasive strategies of mechanical ventilation can cause volutrauma
and barotrauma which in turn can trigger pulmonary cytokine release [25].
Release of catecholamines. Head injury is followed by prolonged sympathetic hyper-

activity, which may lead to hypertension and/or tachycardia. This circulatory hy-
peractivity induces an increase in cerebral blood volume, and/or CBF and hence
ICP increase [26]. Moreover, the outcome after head injury appears to be related to
the intensity of the plasma catecholamines [27]. Catecholamines, and mainly nor-
epinephrine, have been shown to produce two prevalent effects on the lung: 1) in-
crease in alveolar capillary barrier permeability; 2) increase in pulmonary lymph
flow. In fact, several studies have shown that increased permeability may be
mediated by sympathetic activity [28].
Pulmonary infectious processes. Head injured patients are characterized by an in-

creased risk of developing ventilator associated pneumonia (VAP) [29]. The inci-
dence of VAP is estimated to range between 30-50% of head injured patients, being
extremely severe in only 20-25% of the cases. Table 2 shows the independent risk
factors for VAP in head injured patients. It is evident that altered consciousness has
been found to be an important independent risk factor for VAP in the majority of
Table 2. Independent risk factors for ventilator associated pneumonia (VAP) in head injured patients
Risk
Risk factors related to brain injury
I• Altered conscience 6.6
Risk factors associated to the treatment of brain injury
I Aspiration 7.o
I Emergency intubation 6.4
I Mechanical ventilation >3 day 2.3
Risk factors associated to the treatment
of a general population of aitically ill patients
I• Reintubation 5.4
I Age > 60 years 5.3
I Supine position 4.8
Previous disease 3.6
I Prior antibiotics 2.9
the studies which included these patients in their research. VAP can be arbitrarily
divided into 'early' pneumonia, if it occurs within the first 4 days after admission
in ICU, and 'late' pneumonia, if it occurs later. 'Early' pneumonia accounts for
about 50% of the overall VAP during the ICU stay [30] .
We recently investigated in a group of mechanically ventilated head injured pa-
tients:
1) the prevalence of VAP;
2) the prevalence of systemic immune response syndrome (SIRS), sepsis and septic
shock;
3) the optimization of pneumonia diagnosis.
We studied 48 patients, (34 male), with an average age of 45.8± 19.2 years and GCS
9.8 ± 3 9. . The etiology of head injuries was traumatic in 34.8% of the patients. VAP
was defined as the presence of a positive bronchoalveolar lavage (BAL) (cfu > 104 ).
The prevalence of VAP was 52%, and the majority (56%) were defined as 'late'
pneumonia. We found that at least 52% of the patients without VAP presented SIRS
criteria, and 26% SIRS criteria associated with the use of vasoactive drugs ('sepsis
like syndrome'). On the other hand, all the patients with VAP had sepsis criteria
and 52% septic shock criteria, indicating the marked severity of VAP in these pa-
tients. Moreover, we found that chest X ray alterations, increased temperature
(T > 38 oq and Pa0 2/Fi0 2 < 200 mmHg were the main signs associated with VAP.
In patients with VAP, the chest X ray was positive (at least one quadrant, partially
opaque) in 96% of the patients. However, chest X ray was altered in 88% in one
quadrant only, in 24% in two quadrants, and 4% in three quadrants independent of
the severity of respiratory failure.
When CT scans were performed, a typical dependent distribution of densities was
found, with the non-dependent lung substantially better aerated. However, when these
patients were turned prone we found a more or less complete reopening of the den-
sities. This suggests that during VAP in head injured patients the main alteration is the
formation of atelectasis and not consolidation in the dependent lung [31].
We found also that the simultaneous presence of T > 38 °C and Pa0 2 /Fi0 2 < 200
mmHg, could be useful to suspect pneumonia and to decide the timing of chest X
ray, reducing the need for unnecessary exposures and workload.
Thus, it is important to know that in head injured patients:
1) it is not always easy to discriminate if 'sepsis-like' symptoms are really due to
infection or not; and
2) a well defined protocol to diagnose infection, and in particular VAP, early, is
mandatory
Prevention of Pulmonary Infectious Processes

Since YAP plays a relevant role in the outcome of head injured patients, it is ex-
tremely important to prevent it. Unfortunately, very few studies have investigated
the efficacy of specific protocols to prevent VAP.
We believe that the main goals should be:
1) to prevent lung infection;
2) to prevent lung collapse and/or consolidation.
Prevention of lung infection
1 Antibiotic prophylaxis with a cephalosporin of second generation (cefuroxime or
cefoxitin) or ampicillin-sulbactam can be useful to prevent 'early' pneumonia.
However, some studies reported an increased rate in 'late' pneumonia if antibiot-
ic prophylaxis is used for more than 24 hours [32].
I Selective digestive decontamination (SDD) has been proposed to reduce the mi-
crobiological load in the oropharynx and in the stomach. Recently, a large me-
taanalysis, reported that SDD can be effective to reduce ICU stay and mortality
when associated with i.v. prophylaxis [33].
I Upright position has been suggested to reduce VAP and ICU stay in a general
population of critically ill patients. The upright position is, anyway, usually
adopted in head injured patients to reduce ICP, when necessary [34].
I Continuous oropharyngeal aspiration has been found to reduce oropharyngeal
contamination and the occurrence of VAP [35].
I Correct use of antacid drugs: the routine use of antacid drugs seems to be reason-
able, because head injured patients are at increased risk of gastric hemorrhage. A
recent randomized trial suggests that the use of H2 antagonists reduces the inci-
dence of clinically important gastric bleeding, with no increase in VAP [36].
I Nutrition is important to positively affect outcome in head injured patients, but
the respective role of enteral and parenteral nutrition is not clear {37].
I Protocols to regulate physician and nurse hygiene are warranted. In particular, a
careful handwashing policy seems to reduce the incidence of infections and im-
prove patient outcome [38].
I ICU and hospital antibiotic policies to regulate ICU and hospital antibiotic use
are warranted to reduce the risk of developing resistant microorganisms and to
reduce costs [39].
Prevention of lung collapse and/or consolidation
I The use of fibroscopy to clear secretions could be very important to reduce the
formation of micro-macro atelectasis, consolidation and lobar infections. How-
ever, the excessive use of this technique can have negative effects on cerebral
homeostasis [40]. ·
I Fluid balance: it is not clear if head injured patients should be maintained more
hypervolemic or hypovolemic. It is possible that excessive overfluid treatment
can increase interstitial lung edema and favor lung collapse. On the other hand
hypervolemia has been advocated for the treatment of these patients [41].
I Specific drugs
- low dose of corticosteroids could be useful to reduce the local and systemic
inflammatory response. However, up to now the routine use of corticosteroids
is discouraged in head injured patients [42].
- anti-sympathetic drugs (clonidine) and selective P1 antagonists could be useful
to reduce the negative systemic effects of the sympathetic storm [43].
I Mechanical ventilation is also likely important to avoid progressive collapse and
consolidation of the lung. However, many aspects in the ventilatory management
are not clear:
- the superiority of controlled or assisted ventilation;
- the use of preventive recruitment maneuvres and positive end-expiratory pres-
sure (PEEP, applied before lobar consolidation occurs);
- the routine use of prone position or kinetic therapy.
Among all these different maneuvers to prevent and treat respiratory failure due to
VAP in head injured patients, prone position is gaining more and more attention.
Beuret et al. investigated, in a small prospective randomized trial, whether a daily
prone position compared with staying in the supine position reduced the incidence
of worsening lung function and VAP in comatose patients requiring mechanical
ventilation [44]. The patients were proned for at least 4 hours a day, in the horizon-
tal position, head out of bed, with respect of the axis head-neck-trunk, to avoid
any obstacle to cerebral venous return. They found that preventive prone position-
ing effectively reduced lung worsening from 55 to 10% at 28 days, and the inci-
dence of VAP approximately halved from 44.2/1000 days of intubation to 22/1000
days of intubation. Moreover, a favorable neurological outcome and survival were
increased in the prone group (from 46 to 60% and from 54 to 72%, respectively).
Two other non randomized studies investigated the beneficial effects of prone
position in severe head injured patients with posttraumatic acute respiratory dis-
tress syndrome (ARDS) [45, 46]. Prone position was maintained for 20 hours a day,
and repeated when necessary. These studies found a marked improvement in oxy-
genation, partially maintained when patients were repositioned supine, and improv-
ing with time. No major adverse effects have been reported during positioning.
Thus, we believe that prone positioning can be useful to prevent and treat respi-
ratory failure due to traumatic or non-traumatic respiratory failure in head injured
patients, but under strict clinical, ICP and cerebral oxygen extraction monitoring.
I Weaning in Head Injured Patients
Prospective studies of weaning protocols have been performed in mechanically ven-

tilated critically ill patients [47, 48]. These studies concluded that: 1) to start a wean-
ing trial the patients had to have an improvement or resolution of the underlying
cause of acute respiratory failure, adequate gas exchange (Pa0 2/Fi0 2 > 200 mmHg)
with a PEEP:5:5 cmH 2 0, a core temperature <38°C, a hemoglobin level above 10 g/
dl, no further need for vasoactive and sedative agents; 2) a daily T-tube or pressure
support (5-7 cmH 2 0) trial for 30-120 minutes is mandatory to accelerate weaning.
Several other indexes have been proposed as possible predictors of successful

weaning such as: vital capacity, minute ventilation, maximum inspiratory pressure,
rapid shallow breathing index.
However, these measures do not examine patient's consciousness, ability to clear
respiratory secretions or to protect lower airways from aspiration, and, therefore,
do not provide clinicians with information about the patient's need for an artificial
airway. Moreover, patients with acute head injury and impaired consciousness have
not been included in previous weaning trials as well as tracheostomized patients.
'IWo recent trials investigated whether classical weaning criteria and procedures
can be applied in head injured patients [49, 50]. In the first study, the authors, in a
prospective cohort of consecutive intubated head injured patients, evaluated daily:
intubation status, spontaneous ventilatory parameters, gas exchange, neurological
status and specific outcomes [49]. The majority of the patients {73o/o) were extu-
bated within 48h of meeting defined readiness criteria. Patients with delayed extu-
bation developed more pneumonias {38 vs 21o/o), had longer ICU and hospital stays
and higher hospital charges. Practice variation existed after stratifying for differ-
ences in GCS scores ( 10 vs 7) at time of meeting readiness criteria, particularly for
comatose patients. There was a similar reintubation rate independent of GCS higher
or lower than 8. This study suggested that it is not useful to delay extubation in
head injured patients when impaired neurological status is the only concern
prolonging intubation. In the second study, the authors investigated in a random-
ized study if a respiratory therapist-driven weaning protocol incorporating daily
spontaneous breathing trials, improved clinical management in head injured pa-
tients [50]. They found that implementation of such a protocol, based on tradi-
tional physiologic parameters had practical limitations and no significant effect in
this category of patients. Moreover, GCS2':8 was found to be associated with a bet-
ter prediction of successful weaning, independent of Pa02 /Fi02 ratio and rapid
shallow breathing.
I Conclusion
Ventilatory management plays a relevant role in the management of head injured
patients in the different phases of the disease. In the early phases (within the first
week after head injury), profound hyperventilation physiologically targeted on cere-
bral oxygen extraction is likely to reduce mortality and improve neurological out-
come. However, a randomized prospective controlled trial is warranted to better de-
fine the relative importance of hyperventilation by itself and cerebral oxygen ex-
traction monitoring. During the stable phase (1 week after head injury) prone posi-
tioning seems to be useful to prevent and treat VAP and associated respiratory fail-
ure. Finally, the usual criteria to predict successful weaning do not apply in head
injured patients. Whether different protocols combining respiratory parameters
with neurological measures lead to superior outcomes in this population requires
further investigation.
Acknowledgements. The authors are particularly indebted to the medical and nurs-
ing staff of the intensive care unit of Ospedale di Circolo di Varese for their helpful
support. In particular they thank Dr. G Minoja, Dr. P Severgnini, Dr. D Gasberti,
Dr. D Maraggia, Dr. M Raso, Dr. R Di Stella and E Lucchini for their valuable sug-
gestions.
References
1. Kassell NF, Tomer JC, Haley EC, Jane JA, Adams HA, Kongable GL (1990) The interna-
tional cooperative study on the timing of aneurysm surgery. Part 1: overall management
results. J Neurosurg 73:18-36
2. Kassell NF, Tomer JC, Jane JA, Haley EC Jr, Adams HA (1990) The international coopera-
tive study on the timing of aneurysm surgery. Part 2: Surgical results. J Neurosurg 73:37-
47
3. Robertson CS, Valad.ka AB, Hannay HJ, et al (1999) Prevention of secondary ischemic in-
sults after severe head injury. Crit Care Med 27:2086-2095
4. Solenski N, Haley C, Kassell NF, et al (1995) Medical complications of aneurysmal sub-
arachnoid hemorrhage: a report of the multicenter, cooperative aneurysm study. Crit Care
Med 23:1007-1017
5. Clifton GC, Miller ER, Choi SC, et al (2001) Lack of effect of induction of hypothermia
after acute brain injury. N Engl J Med 344:556-563
6. Cruz J (1998) The first decade of continuous monitoring of jugular bulb oxyhemoglobin
saturation: management strategies and clinical outcome. Crit Care Med 26:344-351
7. Obrist WD, Langfitt TW, Jaggi JL (1984) Cerebral blood flow and metabolism in comatose
patients with acute head injury. Relationship to intracranial hypertension. J Neurosurg
61:241-253
8. Marion DW, Darby J, Yonas H (1991) Acute regional cerebral blood flow changes caused
by severe head injuries. J Neurosurg 74:407-414
9. Ritter AH, Muizelaar JP, Barnes T, et al (1999) Brain stem blood flow, papillary response
and outcome in patients with severe head injuries. Neurosurgery 44:941-948
10. Bouma GJ, Muizelaar JP, Choi SC, et al (1991) Cerebral circulation and metabolism after
severe traumatic brain injury. The elusive role of ischemia. J Neurosurg 75:685-693
11. Jaggi JL, Obrist WD, Gennarelli JA, Langfitt TW (1990) Relationship of early cerebral blood
flow and metabolism to outcome in acute head injury. J Neurosurg 72:176-182
12. Jones TH, Morazetz RB, Crowell RM, et al (1981) Threshold of focal cerebral ischemia in
awake monkeys. J Neurosurg 54:773-782
13. Cormio M, Valadva AB, Robertson CS (1999) Elevated jugular venous oxygen saturation
after severe head injury. J Neurosurg 90:9-15
14. Cruz J (1996) Relationship between early patterns of cerebral extraction of oxygen and
outcome from severe acute traumatic brain swelling: cerebral ischemia or cerebral viability?
15. Cruz J (1993) Combined continuous monitoring of systemic and cerebral oxygenation in
acute brain injury: preliminary observations. Crit Care Med 21:1225-1232
16. Muizelaar JP, Marmarou A, Ward JD, et al (1991) Adverse effects of prolonged hyperventi-
lation in patients with severe head injury: a randomized clinical trial. J Neurosurg 75:731-
739
17. Gordon E, Rossanda M (1970) Further studies on cerebrospinal fluid acid base status in
patients with brain lesions. Acta Anaesthesiol Scan 14:97-109
18. Hukkelhoven CW, Steyerberg EW, Forace E, Habbema JD, Marshall LF, Maas AI (2002) Re-
gional differences in patients characteristics case management and outcomes in traumatic
brain injury: experience from the tirilazad trials. J Neurosurg 97:549-557
19. Knaus WA, Draper EA, Wagner DP, et al (1985) Prognosis in acute organ-system failure.
Ann Surg 202:685-693
20. Le Roux PD, Elliott JP, Downey L, et al (1996) Improved outcome after rupture of anterior
circulation aneurysms: a retrospective 10-year review of 224 good grade patients. J Neuro-
surg 85:39-49
21. Hernesnierni J, Vapalathi M, Niskanen M, et al (1993) One-year outcome in early aneurysm
surgery: a 14 year experience. Acta Neurochirurgica 122:1-10
22. Gruber A, Reinprecht A, Illievich UM, et al (1999) Extracerebral organ dysfunction and
neurologic outcome after aneurysmal subarachnoid hemorrhage. Crit Care Med 27:505-514
23. North J, Jennett S (1974) Abnormal breathing patterns associated with acute brain damage.
Arch Neurol 31:338-344
24. Nieto-Sampedro M, Berman MA (1987) Interleukin-1 like activity in rat brain: sources, tar-
gets, and effect of injury. J Neurosci Res 17:214-219
25. Tremblay L, Valenza F, Ribeiro SP, Slutsky AS (1997) Injurious ventilatory strategies in-
crease cytokines and c-FOS mRNA expression in an isolated rat lung model. J Clin Invest
99:944-952
26. Rosner MJ, Nesome HH, Becker DP, et a! (1984) Mechanical brain injury: the sympatho-
adrenal response. J Neurosurg 61:76-86
27. Woolf PD, Hamill RW, Lee LA, et a! (1987) The predictive value of catecholamines in as-
sessing outcome in traumatic brain injury. J Neurosurg 66:875-882
28. Moss G, Staunton C, Stein A (1973) The centrineurogenic etiology of the acute respiratory
distress syndrome. Am J Surg 126:37-41
29. Hsieh AH, Bishop MJ, Kubilis PS, et a! (1992) Pneumonia following closed head injury.
30. Langer M, Mosconi P, Cigada M, et a! (1989) Long-term respiratory support and risk of
pneumonia in critically ill patients. Am Rev Respir Dis 140:302-305
31. Pelosi P, Colombo G, Gamberoni C, et a! (2001) Acute respiratory failure in brain injured
patients. Recent Res Devel Respir Crit Care Med 1:19-37
32. Sirvent JM, Torres A, El-Ebiabry M, et a! (1997) Protective effect of intravenously adminis-
tered cefuroxime again nosocomial pneumonia in patients with structural coma. Am J Re-
spir Crit Care Med 155:1729-1734
33. D'Amico R, Pifferi S, Leonetti C, et a! (1998) Effectiveness of antibiotic prophylaxis in criti-
cally ill adult patients: systematic review of randomized controlled trials. Br Med J
316:1275-1285
34. Drakulovic MB, Torres A, Bauer TT, et a! (1999) Supine body position as a risk factor for
nosocomial pneumonia in mechanically ventilated patients: a randomized trial. Lancet
354:1851-1858
35. Shorr AF, O'Malley PG (2001) Continuous subglottic suctioning for the prevention of venti-
lator associated pneumonia: potential economic implications. Chest 119:228-235
36. Cook D, Guyatt G, Marshall J (1998) A comparison of Sucralfate and Ranitidine for the
prevention of upper gastrointestinal bleeding in patients requiring mechanical ventilation
N Eng! J Med 338:791-797
37. Taylor SJ, Fettes SB, Jewkes C, et a! (1999) Prospective, randomized, controlled trial to de-
termine the effect of early enhanced enteral nutrition clinical outcome in mechanically ven-
tilated patients suffering head injury. Crit Care Med 27:2525-2531
38. Bischoff WE, Reynolds TM, Sessler CN, et a! (2000) Handwashing compliance by health
care workers: the impact of introducing an accessible, alcohol-based hand antiseptic. Arch
Intern Med 160:1017-1021
39. Scott G (2000) Prevention and control of infections in intensive care. Intensive Care Med
26:522-525
40. Froman C (1988) Alterations of respiratory function in patients with severe head injuries.
Br J Anaesth 40:354-360
41. York J, Arrillaga A, Graham R, et a! (2000) Fluid resuscitation of patients with multiple in-
juries and severe closed head injury: experience with an aggressive fluid resuscitation
strategy. J Trauma 48:376-380
42. Anderson P, Roberts I (1997) Corticosteroids in acute traumatic brain injury: systematic
review in randomized controlled trials. Br Med J 314:1855-1862
43. Kariya N, Shindoh M, Nishi S, et a! (1999) Oral clonidine to control hypertension after
head injury. Eur J Emerg Med 6:77-79
44. Beuret P, Carton MJ, Nourdine K, Kaaki M, Tramoni G, Ducreux JC (2002) Prone position
as prevention of lung injury in comatose patients: a prospective randomized controlled
study. Intensive Care Med 28:564-569
45. Voggenreiter G, Neudeck F, Aufmkolk M, et a! (1999) Intermittent prone position in the
treatment of severe and moderate post traumatic lung injury. Crit Care Med 27:2375-2382
46. Fridrich P, Krafft P, Hochlerthner H, Mauritz W (1996) The effects of long term prone po-
sitioning in patients with trauma induced adult respiratory distress syndrome. Anesth An-
alg 83:1206-1211
47. Esteban A, Frutos F, Tobin MJ, et a! (1995) A comparison of four methods of weaning pa-
tients from mechanical ventilation. Spanish Failure Collaborative Group. N Eng! J Med
332:345-350
48. Brochard L, Rauss A, Benito S, et al (1994) Comparison of three methods of gradual with-
drawal from ventilatory support during mechanical ventilation. Am J Respir Crit Care Med
150:896-903
49. Coplin WM, Pierson DJ, Cooley KD, Newell DW, Rubenfield GD (2000) Implications of ex-
tubation delay in brain injured patients meeting standard weaning criteria. Am J Respir
50. Namen AM, Ely EW, Tatter SD, et al (2001) Predictors of successful extubation in neurosur-
gical patients. Am J Respir Crit Care Med 163:658-664
I Neurological Crises
Induction of Ischemic Tolerance in the Brain:
A Novel Neuroprotective Strategy?
A.M. Brambrink and I. P. Korner
I Introduction
Neurons are strongly dependent on continuous substrate delivery; accordingly

physiologic resistance of neuronal tissues against ischemia is very low. Even short
periods of cerebral ischemia can, therefore, cause severe neuronal damage. Certain
surgical procedures (for example, during cardiovascular- or neuro-surgery) may in-
volve periods of decreased or diminished cerebral perfusion, putting the patient at
risk for neuronal damage and subsequent neurological deficit. Physicians caring for
these patients will try to prevent or reduce damage using different neuroprotective
strategies (aimed mainly at the reduction of cerebral metabolism). In addition to
this, a modulation of neuronal ischemic tolerance ('preconditioning') prior to re-
spective operative interventions may add substantially to the further improvement
in patient outcome.
I Ischemic Tolerance in the Brain
Cellular ischemic tolerance can be improved in tissues of various origins. Induction

of 'ischemic tolerance' was first observed in the heart [1], and was also found in
the brain about four years later. Rats which had been exposed to short, non-lethal
episodes of cerebral ischemia (1-2 minutes, ischemic preconditioning) prior to a
prolonged and otherwise lethal period of cerebral ischemia, presented with a signif-
icantly reduced neuronal deficit and less neurohistopathologic damage compared to
animals that had not been pretreated [2].
Induced ischemic tolerance in the brain can be observed during two periods
after classical ischemic preconditioning, similar to the pattern seen in the heart.
Tolerance against subsequent cerebral ischemia results as early as 30 minutes after
the preconditioning ischemic episode and lasts for about two hours ('rapid' isch-
emic preconditioning) [3, 4]. Twenty-four hours later, a second window of ischemic
tolerance can be observed, which is maintained for 2 to 7 days ('delayed' ischemic
preconditioning) [2, 5-7]. In contrast to findings in the myocardium, however, only
delayed ischemic preconditioning results in long-lasting protection of neurons
against ischemia, whereas rapid ischemic preconditioning seems to only postpone
the development of postischemic cell death and resulting brain damage [3].
726 A.M. Brambrink and I. P. Korner
Non - lethal
ischemic episode
Signal Rapid
• adenosine ~ p reconditioning
• bradykinin • KATP-channels
..
• norepinephrine
t
- i_g_n -al_a_m..!.p-1-ifi-•c-a-ti-o n- -,
. -S II ···~~~ - Delayed
and transduction precond itioning
• e.g. G- proteins altered expression of, e.g.
4 • iNOS
• protein kinases
• transcription facto rs • immediate early genes
• heat shock proteins
Fig. 1. This graph summarizes possible elements and time course of the proposed signal cascade that
may lead to ischemic tolerance in neuronal tissues after ischemic preconditioning, according to the recent
literature
I Mechanisms of Tolerance Induction
Some cellular mechanisms involved in the induction of ischemic tolerance in neurons

are similar to those previously identified in the heart (Fig. 1): During a short ischemic
episode, adenosine (extracellular signal), among others, is released from neuronal
cells. Subsequently, adenosine A1 -receptor stimulation (signal transduction) results
in opening of ATP-dependent potassium channels causing hyperpolarization of cell
membranes (effector [8]). This hyperpolarization of preconditioned cell membranes
reduces the overall need for ATP and economizes the cellular energy balance during
post-ischemic reperfusion. Thus, rapid development of ischemic tolerance in the
brain may primarily depend on a reduction of cellular metabolic needs, as has been
described for the heart [9]. In addition to this, rapid preconditioning of neuronal tis-
sues seems to involve a glutamate-dependent signal transduction [10].
As mentioned before, sustained neuronal ischemic tolerance that results in long-
lasting neuroprotection, requires at least one day to develop after induction by
short ischemic episodes [3]. Delayed ischemic preconditioning might therefore rely
on a specific alteration of gene and protein expression, initiated after extracellular
signaling has caused an activation of transcription and translation factors via dif-
ferent intracellular signal transduction cascades. In accordance with this, several
potential effectors, whose expression is upregulated by ischemic preconditioning
have already been identified in the brain, e.g., inducible nitric oxide synthase
(iNOS), various immediate early genes (IEG), as well as different heat shock-asso-
ciated proteins (HSP, Fig. 1) [11-14].
Since programmed cell death (apoptosis) seems to be an important mechanism
of post-ischemic neuronal cell death [15], a modulated expression of apoptosis-reg-
Induction of Ischemic Tolerance in the Brain: ANovel Neuroprotective Strategv? 727
ulating genes may also be involved in the induction of neuronal ischemic tolerance.
Increased levels of bcl-2, an anti-apoptotic member of the bcl-2 family of cell
death-regulating genes, have been observed in ischemia-vulnerable brain regions
after ischemic preconditioning [16] .
I Chemical Preconditioning of Neuronal Tissue

It was reported recently that neuronal ischemic tolerance can also be induced by
the application of certain chemicals. Using various experimental paradigms, pre-
treatment with a single dose of the mitochondrial toxin 3-nitropropionic acid (3-
NPA, a permanent inhibitor of the respiratory chain complex II) was consistently
associated with significant neuroprotection ('chemical' preconditioning) [10].
An early increase in neuronal tolerance against hypoxia (hippocampal slices
[10]) and against global cerebral ischemia (whole animal preparations [17]} was
observed a few hours after application of 3-NPA in rats ('rapid' chemical precondi-
tioning). Others reported that chemical preconditioning using 3-NPA - similar to
ischemic preconditioning - induced profound tolerance against global and focal ce-
rebral ischemia beginning 24 hr after the application of 3-NPA and lasting for
about 3 days ('delayed' chemical preconditioning) [6, 7, 18]. Treatment of rats witi:l
a single dose of 3-NPA (20 mg/kg b. w.) i. p. improved neuronal survival after subse-
quent global ischemia in two ischemia vulnerable brain regions, the neocortex and
hippocampus, by approximately 20 and 30%, respectively [18].
c0 #
z< '~
a:~
cu 2
E~
~cu
":'cu
u.~ 1
.0';0
~
0
Fig. 2. Quantitative real-time RT-PCR analysis of relative expression of bcl-2 mRNA in whole rat brain
(modified from [46]). Experimental groups were pretreated only (vehicle [sodium chloride 0.9%], V; or
with 3-nitropropionic acid [3-NPA], NPA; n = 5, respectively), were pretreated and 24 hours later subjected
to 15 minutes of global cerebral ischemia and 3 hours of reperfusion (vehicle+ ischemia, V+I; 3-
NPA +ischemia, NPA +I; n= 5, respectively), or were sham operated (SHAM; n = 5). Results are presented
as means± standard deviation. Quantitative differences represent relative changes in mRNA expression
from pretreatment only/vehicle (relative expression= 1, One Way Analysis of Variance). Relative expression
of bcl-2 mRNA was significantly higher (# p < 0.05) 24 hours after 3-NPA, compared to pretreatment only/
vehicle. In addition, post-ischemic bcl-2 mRNA levels were higher in 3-NPA pretreated animals compared
to pretreatment only/vehicle, sham, and ischemia/vehicle (# p < 0.05)
While rapid chemical preconditioning of neuronal cells was shown to be asso-

ciated with adenosine receptor activation [10], the mechanism of delayed chemical
preconditioning remained unclear.
It seemed likely that a differential regulation of gene and protein expression
might be responsible for the effects of delayed chemical preconditioning in the
brain, similar to the mechanisms postulated for classic ischemic preconditioning.
We, therefore, performed a series of designated experiments to answer the question
whether chemical preconditioning, too, might alter the expression of regulators of
programmed cell death. Our work was focused on the expression patterns of anti-
apoptotic bcl-2 and pro-apoptotic bax mRNA and their respective proteins in rat
brain after chemical preconditioning using 3-NPA, with and without subsequent ce-
rebral ischemia. Bcl-2 and Bax proteins function as antagonists, Bcl-2 being able to
heterodimerize with and inhibit the function of Bax [19]. The ratio of Bcl-2 and
Bax present in a cell at a given time seems to influence the decision whether apop-
tosis is initiated or not [20].
I Effects of 3-NPA on bcl-2/bax Transcription

Animals developed no behavioral or neurological abnormalities after application of
3-NPA, nor was there any evidence of necrotic or apoptotic cell damage in the his-
tomorphologic analysis after 3-NPA pretreatment caused an increased transcription
of anti-apoptotic bcl-2 that was sustained after subsequent transient cerebral isch-
emia. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) re-
vealed a 1.5-fold increased relative expression of brain bcl-2-mRNA in animals pre-
treated with 3-NPA, compared to those receiving normal saline (vehicle) (Fig. 2).
Relative bax-mRNA expression was not changed by 3-NPA pretreatment (non-
ischemic animals), although a change was observed after the ischemic brain insult:
Three hours after global ischemia, bax mRNA expression was almost two-fold in-
3 #
Fig. 3. Bax mRNA expression, in contrast to bcl-2 mRNA, was not changed 24 hours after 3-NPA treat-
ment in non-ischemic animals. However, 3 hours after global cerebral ischemia bax mRNA increased sig-
nificantly without 3-NPA preconditioning (p < 0.05 compared to all other groups). In contrast, bax mRNA
expression remained similar to baseline when animals were pretreated with 3-NPA 24 hours prior to isch-
emia (see legend for Figure 2 for abbreviations and further details). Modified from [46] with permission
Induction of Ischemic Tolerance in the Brain: A Novel Neuroprotective Strategy? 729
creased in animals receiving saline 24 hours before the insult, compared to sham
control. In contrast, when animals were pretreated with 3-NPA, post-ischemic bax-
mRNA expression was significantly reduced (Fig. 3).
The ratio of bcl-2/bax mRNA remained altered after chemical preconditioning
followed by global cerebral ischemia, bcl-2-mRNA being increased and bax-mRNA
decreased in brains pretreated with 3-NPA, compared to saline pretreated controls.
Similar to findings reported for other neuroprotective strategies [21-25], these data
show that differential gene expression in favor of bcl-2 after 3-NPA is maintained
in the rodent brain during post-ischemic recovery.
I Effects of 3-NPA on bcl-2/bax Translation

Bax and Bcl-2 protein expression was analyzed to verify that the observed changes
in gene transcription actually result in an alteration of the translational pattern.
Immunohistochemical protein staining was done on brain slices to be able to iden-
tify brain regions and cell populations showing altered protein expression.
The modulation of the bcl-2/bax ratio in favor of bcl-2, that was observed at the
transcriptional level after 3-NPA treatment, was present at the protein level, too .
1
• p < O.OS vs. naive
# p<0.0SV>.96h
CAl
Brain regions
0 Naive ~ 3h3-NPA 0 12h3 - NPA ~ 24h3 -NPA • 96h3-NPA
Fig. 4. Changes of neuronal Bcl-2-protein expression in selected brain regions at different times after 3-
nitropropionic acid (3-NPA) injection (semiquantitative evaluation of immunoreactivity. Immunoreactivity
was graded according to a score ranging from zero for no staining at all, to four for strong immunoreac-
tivity (zero [0], faint {1}, mild I2}, moderate [3], and strong [4]). The results for each brain region are ex-
pressed as means± standard deviation of the immunoreactivity score for all animals of the respective
group (n = 5). Immunoreactivity for Bcl-2-protein in neurons increased over the first hours following 3-
NPA-injection, and was statistically different (p < 0.05) 24 hours after administration in CA 1, CA2 and CA4
subregions of hippocampus and neocortex, compared to untreated controls (naive). Modified from [46)
with permission
Neuronal immunoreactivity for Bcl-2-protein increased over the first hours follow-
ing 3-NPA-injection, reaching statistical significance at 24 hours after 3-NPA ad-
ministration in CAl, CA2 and CA4 of the hippocampus, as well as in the neocortex,
compared to naive control animals (Fig. 4). It should be noted that baseline immu-
noreactivity for Bcl-2 in CA3 of the hippocampus was already in the moderate
range. Animals with 3-NPA-pretreatment observed for 96 hours, showed no further
increase in Bcl-2-immunoreactivity, and exhibited near baseline levels in some
areas of the hippocampus, e.g., CAl, CA2, CA3. However, Bcl-2-immunoreactivity
remained at higher levels in CA4, dentate gyrus and neocortex (Fig. 4).
Immunoreactivity for Bax-protein, in contrast, was significantly decreased from
baseline (p<O.OS) at 96 hours after 3-NPA-administration in CA2, CA3, and CA4 of
the hippocampus, as well as in the dentate gyrus and neocortex (Fig. 5). No differ-
ences were observed at earlier time points.
After global cerebral ischemia, Bcl-2-immunoreactivity in viable cells (no isch-
emic morphology) was not different from baseline values during early postischemic
recovery (3, 12 and 24 hours). However, after four days of reperfusion Bcl-2-protein
expression in surviving neurons of all brain areas evaluated was significantly more
pronounced compared to naive controls (96 hours, p <0.05, Fig. 6). In contrast, im-
munoreactivity for Bax protein in viable neurons after global cerebral ischemia was
not statistically different from baseline at all time points evaluated (Fig. 7).
• p< O.OS vs. naive
Ir
4
-;;:' & p< 0.05 "'· 3 h
0'
l
$ p< O.OS vs. 12 h
# p< O.OS vs. 2• h J
1
Q)
0v 3
L .L
1I l
~ ~. •
~
·;;;
.S
c:
Q)
2
rV I~ •
•
~
I•
~s
~
~
~ .
§
~
~
~
~
~
§
01
c: ~
·c: ~
~
~
~
'!§ ~ ~ ~ ~
~ ~ ~
I
"'
.!::! 1 ~ ~ ~ ~ ~ ~
~
0 ~ ~
~
~ ~
~
~
~
u
~ ~ ~ ~
~
~ ~ ~ ~ ~
0
CAl CA2 CA3 CA4 Dentate Cortex Thalamus
Brain regions
0 Naive ~ 3 h 3- NPA 0 12 h 3 -NPA IS:J 24 h 3 -NPA • 96 h 3-NPA
Fig. S. Neuronal Bax protein expression 96 hours after 3-nitropropionic acid (3-NPA) administration, in
contrast to Bcl-2, was significantly lower than at baseline (p < 0.05) in all brain areas except hippocampal
CA 1 and thalamus. No differences were observed at earlier time points (semiquantitative evaluation of im-
munoreactivity); see legend of Figure 4 for further details; modified from [46) with permission
Induction of Ischemic Tolerance in the Brain: ANovel Neuroprotective Strategy? 731
*
.
4 *
'i' * • p < 0.05 vs. baseline
0'
J
~
0
J~
~ 3
~
l;- *
..
·v;
<:
.£
i%
~
~ ~
~
~ 12 ~
1~
2 ~ ~
~ l:i: !>:: ~
J
~
~
§
01
<:
·c: ~ ~ ~
11 ~
~ ~ ~
·~
J"] ~ ~
~
~I
-~ 1 ~
0VI !>:: l:i:
~
~~
~
~
0
~
~ ~
~
0
CA1 CA2 CA3 CA4 Dentate Cortex Thalamus
Brain regions
0 Naive ~ 3h3-NPA 0 12h3-NPA ~ 24h3-NPA • 96h3- NPA
Fig. 6. Bcl-2-protein expression in viable neurons (non-ischemic morphology) at 3, 12 and 24 hours after
global cerebral ischemia was not different from baseline. However, after four days (96 hours) of recovery,
Bcl-2-protein expression was significantly increased in all brain areas evaluated (p < 0.05; semiquantitative
evaluation of immunoreactivity); see legend for Figure 4 for further details; modified from [46] with per-
mission
I Implications for Ischemic Tolerance

Our results suggest changes in the balance of pro- and anti-apoptotic proteins as
one potential explanation for the observed protection provided by chemical precon-
ditioning using 3-NPA in rats. After a single dose of 3-NPA in rats we observed an
elevated bcl-2/bax-ratio at the transcriptional (RT-PCR, whole brain) and transla-
tional level (immunohistochemistry, brain slices). The increase in Bcl-2-protein ex-
pression occurred in neurons known to be especially vulnerable for ischemic cell
death, e.g., in hippocampal CAl, CA2, CA4, and neocortex. These findings are in
accordance with reports on differential gene expression following 'classical' isch-
emic preconditioning [16, 26-29], showing increases particularly in gene products
involved in neuronal survival.
The observed changes in Bcl-2- and Sax-protein expression occurred after a sig-
nificant time delay (24 and 96 hours, respectively). This corresponds to earlier ob-
servations showing that sustained ischemia tolerance in the brain requires at least
24 hours to develop after 3-NPA [18] and classical ischemic preconditioning [2,
30]. Increases in the bcl-2/bax ratio have been proposed to prevent apoptotic cell
death in the brain [19]. Our data suggest that 3-NPA promotes an early increase in
this ratio resulting from elevated Bcl-2 protein expression (around 24 hours), while
reductions in Bax protein levels are responsible for an elevated bcl-2/bax ratio at
later time points (around 96 hours). This may in part explain the range of protec-
tion (1-3 days) reported for 3-NPA-induced ischemic tolerance.
""0
J l~
~
m
0
~ 3 .r~
i=' ~ ~~
~
l J
·;;; ~ ~
0::: ~ ;:;::
~ ~
.s ~ ~ ~ ~
Cll
2 ~ ~ ~
%: ~
0'1
~ ~ ~ ~ ~
·c:0::: ~ ~ ~
~
~ ~ ~ ~
-~ ~ ~
I
~ ~ ~
I
"'
.!:/
0VI
1
§ ~
;:;::
~
~
0 ~ ~
;:;::
5- ~ ~
~
~
0
CAl CA2 CA3 CA4 Dentate Cortex Thalamus
Brain regions
0 Na ive ~ 3h 3- NPA 0 12h 3-NPA ~ 24h 3-NPA • 96h 3- NPA
Fig. 7. Postischemic Bax protein expression in viable neurons (non-ischemic morphology), in contrast to
Bcl-2 expression, was not statistically different from baseline at all time points. However, during early re-
covery from ischemia (12 hours), there was a trend towards lower Sax-protein expression in viable neu-
rons of all brain regions, except the hippocampal CA2 and thalamus (semiquantitative evaluation of im-
munoreactivity); see legend for Figure 4 for further details; modified from [46) with permission
I Proposed Model for Chemical Preconditioning using 3-NPA
Our presented observations, combined with data previously reported by others,

suggest a signal transduction pathway leading to an increased ischemia tolerance in
neurons, which includes temporarily elevated levels of reactive oxygen species
(ROS) and de novo protein synthesis (Fig. 8). The ROS burst, which peaks 3 hours
after 3-NPA [6] is generated upstream of the succinate dehydrogenase, and might
be a direct result of partial respiratory chain inhibition (e.g., [31]). As Bcl-2 oper-
ates as a free radical scavenger [32], increased levels of ROS may initiate bcl-2 tran-
scription and translation. During subsequent periods of cerebral ischemia/reperfu-
sion the Bcl-2 protein surplus may (i) neutralize post-ischemic free radicals, pro-
tecting neurons against their deleterious effects (pre-mitochondrial activity of Bcl-2
[33]). Additionally, (ii) Bcl-2 heterodimerizes with Bax (mitochondrial activity),
thereby blocking its pro-apoptotic functions (induction of mitochondrial transition
pores [34]), cytochrome c release and subsequent activation of caspases [35], and
modulation of calcium flux between different cell compartments [36]. Bcl-2 also ap-
pears (iii) to activate signal transduction cascades leading to phosphorylation,
thereby inactivating pro-apoptotic homologues, e.g., Bax and Bad [37]. Antioxidant
as well as anti-apoptotic activities of Bcl-2 result in increased resistance against
subsequent ischemia and delayed neuronal damage. The reduced abundance of neu-
ronal Bax-protein 4 days after 3-NPA may in part be responsible for the prolonged
state of ischemic tolerance reported in the literature.
Protection after cerebral ischemia

Preconditioning
=> 0 2- radical scavenging activity
3-NPA => ROS => Bcl - 2 => anti -apoptotic activity
~
8
I
f ROS (SOD) Bcl-2 f more
neuronal cells
~
survive
Fig. 8. The diagram illustrates the proposed mechanism resulting in delayed ischemic tolerance after
chemical preconditioning using a single dose of the mitochondrial toxin 3-nitropropionic acid (3-NPA).
Our data, in accordance with results from other groups, suggest that application of 3-NPA may increase
the intracellular generation of reactive oxygen species (ROS). Increased ROS levels may subsequently in-
duce expression of Bcl-2, which is both, a radical scavenger and an inhibitor of apoptosis. The radical
scavenging activity as well as a direct inhibition of apoptosis may help to reduce post-ischemic neuronal
damage and cell death and improve neuronal survival, therefore, inducing neuronal ischemic tolerance
This suggested pathway unquestionably represents only parts of one possible

signal transduction cascade. Other members of the bcl-2 family with anti-apoptotic
activity, e.g., Bel-xi [38] may also be induced by 3-NPA, and add to the resulting
ischemia tolerance. Additionally, chemical preconditioning might depend on mech-
anisms independent of those described above. Potential pathways include down-
regulation of Ca2 +-permeability mediating subunits of glutamate receptors [29, 39],
blockade of Ca 2 +-entry into mitochondria [40], or differential expression of, e.g.,
neurotrophic or vascular growth factors [27], or cytokine and receptor proteins
which modulate the post-ischemic immune response [5, 42, 43] . Additional expres-
sion studies on a genome-wide basis are needed to recognize the whole spectrum
of changes in gene regulation after chemical preconditioning.
I Conclusion
Chemical preconditioning using 3-NPA in rats is associated with a differential ex-
pression of the bcl-2 and bax genes during ischemia tolerance with and without
ischemia/reperfusion. These results suggest alterations in the balance between pro-
and anti-apoptotic proteins as a potential explanation for the reported protection
provided by chemical preconditioning using 3-NPA in rats (Fig. 8). The differential
transcription/translation of bcl-2 and bax observed indicates that both genes can
be induced by chemical preconditioning. In the near future, treatment strategies
aimed at a modulation of cerebral bcl-2/bax expression may prove to be beneficial
for patients at risk for intraoperative brain ischemia.
Accordingly, our current work is dedicated to the investigation of several phar-
macological substances (e.g., different antibiotics), already in clinical use for other
indications [44, 45]. These substances, similar to 3-NPA, specifically influence me-
tabolism and/or homeostasis of mitochondria and might therefore, via the mecha-
nisms described above, induce neuronal ischemia tolerance, making them potential
candidates for use as preconditioning agents in humans.
References
1. Murry CE, Jennings RB, Reimer KA (1986) Preconditioning with ischemia: a delay of lethal
cell injury in ischemic myocardium. Circulation 74:1124-1136
2. Kitagawa K, Matsumoto M, Tagaya M (1990) "Ischemic tolerance" phenomenon found in
the brain. Brain Res 528:21-24
3. Perez-Pinzon MA, Xu GP, Dietrich WD, Rosenthal M, Sick TJ (1997) Rapid preconditioning
protects rats against ischemic neuronal damage after 3 but not 7 days of reperfusion fol-
lowing global cerebral ischemia. J Cereb Blood Flow Metab 17:175-182
4. Stagliano NE, Perez-Pinzon MA, Moskowitz MA, Huang PL (1999) Focal ischemic precon-
ditioning induces rapid tolerance to middle cerebral artery occlusion in mice. J Cereb
Blood Flow Metab 19:757-761
5. Barone PC, Whigte RF, Spera PA, Ellison J, Currie WX, Feuerstein GZ (1998) Ischemic pre-
conditioning and brain tolerance. Temporal histological and functional outcomes, protein
synthesis requirement, and interleukin-1 receptor antagonist and early gene expression.
Stroke 29:1937-1951
6. Wiegand F, Liao W, Busch C (1999) Respiratory chain inhibition induces tolerance to focal
cerebral ischemia. J Cereb Blood Flow Metab 19:1229-1237
7. Sugino T, Nozaki K, Takagi Y, Hashimoto N (1999) 3-Nitropropionic acid induces ischemic
tolerance in gerbil hippocampus in vivo. Neurosci Lett 259:9-12
8. Neurteaux C, Lauritzen I, Widmann C, Lazdunski M (1995) Essential role of adenosine,
adenosine AI receptors, and ATP-sensitive K+ chanels in cerebral ischemic precondition-
ing. Proc Natl Acad Sci USA 92:4666-4670
9. Gross GJ, Fryer RM (1999) Sarcolemmal versus mitochondrial ATP-sensitive K+-channels
and myocardial preconditioning. Circ Res 84:973-979
10. Riepe MW, Esclaire F, Kasischke K, et al (1997) Increased hypoxic and ischemic tolerance
by chemical inhibition of oxidative phosphorylation: "chemical preconditioning". J Cereb
Blood Flow Metab 17:257-264
11. Nandagopal K, Dawson TM, Dawson VL (2001) Critical role for nitric oxide signaling in
cardiac and neuronal ischemic preconditioning and tolerance. J Pharmacol Exp Ther
297:474-478
12. Schaller B, Graf R (2002) Cerebral ischemic preconditioning: An experimental phenome-
non or a clinical important entity of stroke prevention? J Neurol 249:1503-1511
13. Andoh T, Chock PB, Chieueh CC (2002) Preconditioning-mediated neuroprotection: role of
nitric oxide, cGMP, and new protein expression. Ann NY Acad Sci 962:1-7
14. Truettner J, Busto R, Zhao W, Ginsberg MD, Perez-Pinzon MA (2002) Effect of ischemic
preconditioning on the expression of putative neuroprotective genes in the rat brain. Brain
Res Mol Brain Res 103:106-115
15. Honkaniemi J, Massa SM, Breckinridge M, Sharp FR (1996) Global ischemia induces apop-
tosis-associated genes in hippocampus. Brain Res Mol Brain Res 42:79-88
16. Shimazaki K, Ishida A, Kawai N (1994) Increase in Bcl-2 oncoprotein and the tolerance to
ischemia-induced neuronal death in the gerbil hippocampus. Neurosci Res 20:95-99
17. Nakase H, Heimann A, Uranishi R, Riepe MW, Kempski 0 (2000) Early-onset tolerance in rat
global cerebral ischemia induced by a mitochondrial inhibitor. Neurosci Lett 290:105-108
18. Brambrink AM, Noppens R, Dick WF, Heimann A, Kempski 0 (1998) 3-nitropropionic acid
(3-NPA) induces tolerance against global brain ischemia in rats. Abstr Soc Neurosci 24:253
(abst)
19. Oltvai ZN, Milliman CL, Korsmeyer SJ (1993) Bcl-2 heterodimerizes in vivo with a con-
served homolog, bax, that accelerates programmed cell death. Cell 74:609-619
20. Krajewski S, Mai J, Krajewska M, Sikorska M, Mossakowski M, Reed J (1995) Upregulation
of Bax protein levels in neurons following cerebral ischemia. J Neurosci 15:6364-6376
21. Martinou J, Dubois-Dauphin M, Staple JK, et al (1994) Overexpression of bcl-2 in trans-

genic mice protects from naturally occurring cell death and experimental ischemia. Neuron
13:1017-1030
22. Niwa M, Hara A, Iwai T (1997) Expression of Bax and Bcl-2 protein in the gerbil hippo-
campus following transient forebrain ischemia and its modification by phencyclidine. Neu-
rology Res 19:629-633
23. Zhu Y, Prehn JHM, Culmsee C, Krieglstein J (1999) The beta2-adrenoceptor agonist clenbu-
terol modulates Bcl-2, Bcl-xl and Bax protein expression following transient forebrain
ischemia. Neuroscience 90:1255-1263
24. Dubal DB, Shughrue PJ, Wilson ME (1999) Estradiol modulates bcl-2 in cerebral ischemia:
a potential role for estrogen receptors. J Neurosci 19:6385-6393
25. Antonawich FJ, Federoff HJ, Davis JN (1999) Bcl-2 transfection, using a herpes simplex
virus amplicon, protects hippocampal neurons from transient global ischemia. Exp Neurol
156:130-137
26. Abe H, Nowak TS Jr (1996) Gene expression and induced ischemic tolerance following
brief insults. Acta Neurobiol Exp (Warsz) 56:3-8
27. Kawahara N, Croll SD, Wiegand SJ, Klatzo I (1997) Cortical spreading depression induces
long-term alteration of BDNF levels in cortex and hippocampus distinct form lesion ef-
fects: implications for ischemic tolerance. Neurosci Res 29:37-47
28. Ide T, Takada K, Qiu JH, et al (1999) Ubiquitin stress response in postischemic hippocam-
pal neurons under nontolerant and tolerant conditions. J Cereb Blood Flow Metab 19:750-
756
29. Yamaguchi K, Yamaguchi F, Miyamoto 0, Hatase 0, Tokuda M (1999) The reversible
change of GluR2-RNA editing in gerbil hippocampus in course of ischemic tolerance. J
Cereb Blood Flow Metab 19:370-375
30. Kato H, Liu Y, Araki T (1991) Temporal profile of the effects of pretreatment with brief
cerebral ischemia on the neuronal damage following secondary ischemic insult in the ger-
bil: cumulative damage and protective effects. Brain Res 553:238-242
31. Garcia-Ruiz C, Colell A, Morales A, Kaplowitz N, Fernandez-Checa JC (1995) Role of oxi-
dative stress generated from the mitochondrian electron transport chain and mitochondrial
glutathion status in loss of mitochondrial function and activation of transcription factor-
kappa B: studies with isolated mitochondria and rat hepatocytes. Mol Pharmacol 48:825-
834
32. Hockenberry DM, Oltvai ZN, Yin XM, Milliman CL, Korsmeyer SJ (1993) Bcl-2 functions
in an antioxidant pathway to prevent apoptosis. Cell 75:241-251
33. Ellerby HM, Martin SJ, Ellerby LM, et al (1997) Establishment of a cell-free system of neu-
ronal apoptosis: comparison of premitochondrial, mitochondrial, and postmitochondrial
phases. J Neurosci 17:6165-6178
34. Zamzami N, Brenner C, Marzo I, Susin SA, Kroemer G (1998) Subcellular and submito-
chondrial mode of action of bcl-2 like oncoproteins. Oncogene 16:2265-2282
35. Jiirgensmeier JM, Xie Z, Deferaux Q, Ellerby L, Bredesen D, Reed JC (1998) Bax directly in-
duces release of cytochrome c from isolated mitochondria. Proc Natl Acad Sci USA
95:4997-5002
36. Paschen W, Doutheil J (1999) Disturbances of the functioning of endoplasmatic reticulum:
a key mechanism underlying neuronal cell injury? J Cereb Blood Flow Metab 19:1-18
37. Zha J, Harada H, Yang E, Jockel J, Korsmeyer SJ (1996) Serine phosphorylation of death
agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L). Cell
87:619-628
38. Chen J, Graham SH, Nakayama M, et al (1997) Apoptosis repressor genes bcl-2 and bcl-x-
long are expressed in the rat brain following global ischemia. J Cereb Blood Flow Metab
17:2-10
39. Sharnloo M, Wieloch T (1999) Changes in protein tyrosine phosphorylation in the rat brain
after cerebral ischemia in a model of ischemic tolerance. J Cereb Blood Flow Metab
19:173-183
40. Perez-Pinzon MA, Mumford PL, Carranza V (1998) Calcium influx from the extracellular
space promotes NADH hyperoxidation and electrical dysfunction after anoxia in hippo-
campal slices. J Cereb Blood Flow Metab 18:215-221
736 A.M. Brambrink and I. P. Korner: Induction of Ischemic Tolerance in the Brain
41. Carriedo SG, Sensi SL, Yin HZ, Weiss JH (2000} AMPA exposures induce mitochondrial
Ca2+ overload and ROS generation in spinal motor neurons in vitro. J Neurosci 20:240-250
42. Ohtsuki T, Matsumoto M, Kuwahara K, et al (1992} Influence of oxidative stress on induced
tolerance to ischemia in gerbil hippocampal neurons. Brain Res 599:246-252
43. Wang X, Li X, Erhardt JA, Barone FC, Feuerstein GZ (2000} Detection of tumor necrosis
factor-a mRNA induction in ischemic brain tolerance by means of real time polymerase
chain reaction. J Cereb Blood Flow Metabol 20:15-20
44. Brambrink AM, Diehl K, Heimann A, Riepe MW, Kempski 0 (2000} Erythromycin induces
tolerance against cerebral ischemia in rats. Abstr Soc Neurosci 26:266 (abst)
45. Korner IP, Kempski 0, Brambrink AM (2002} Pharmacological preconditioning: effects of
erythromycin pretreatment on expression of bcl-2 mRNA in rat brain. Anesthesiology
97:A803 (abst)
46. Brambrink AM, Schneider A, Noga H, et al (2000} Tolerance-inducing dose of 3-nitropro-
pionic acid modulates bcl-2 and bax balance in the rat brain: a potential mechanism of
chemical preconditioning. J Cereb Blood Flow Metab 20:1425-1436
Positron Emission Tomography:
Anticipated Usefulness in Critical Care Settings
F. Lamontagne, F. Benard, and 0. Lesur
I Introduction
Intensive care has progressed continuously over the past decades with the emer-
gence of technologies and knowledge aimed at better supporting critically ill pa-
tients. Insults which, in the past, were considered nearly always fatal are nowadays
frequently warded off. However, this reality has also complicated the practice of
critical care in two different respects: First, in yielding new pathological entities,
the most important being multiple organ dysfunction syndrome (MODS). MODS is
now the leading cause of death in the intensive care unit (ICU) with a mortality
rate approaching lOOo/o when dysfunction is severe and a large number of organs
have been affected [1]. Second, patients often present very complicated clinical pic-
tures, each element potential of being at the same time the consequence and the
cause of the next. For example, coagulopathy can either be the cause or the effect
of postoperative bleeding, and pulmonary insufficiency either the cause or the ef-
fect of cardiac failure. Added to the fact that critically ill patients are seldom able
to contribute adequately to physical examination, the intensivist is faced with pro-
blematic clinical challenges and a relative paucity of effective paraclinical tools.
Moreover, in spite of the epidemiological importance of this syndrome and of
the resources that have been put forward, the precise physiopathological mechani-
sms behind MODS are still unknown. The ongoing debate as to the final pathway
toward organ dysfunction, whether it be microcirculatory failure, apoptosis, or cy-
topathic hypoxia [2-4], is being fostered by the lack of adequate research instru-
ments, especially for in vivo studies.
Positron emission tomography (PET) imaging on the other hand is a functional
imaging system specifically designed to measure chemical reactions at the cellular
level under physiological and/or pathological conditions. The technology is used
for in vivo studies and is also available for whole body imaging. Already exten-
sively used in the fields of oncology, dementia, cardiology, and many others, we be-
lieve that this technique has immense potential in ICUs both as a research and clin-
ical tool.
In the present chapter, we will briefly review the technical aspects of PET imag-
ing, followed by a short description of currently used PET tracers in our view rele-
vant to the ICU, and finally conclude with perspectives for the future.
738 F. Lamontagne et al.
1 Positron Emission Tomography

Nuclear imaging relies on the decay of unstable elements and on the consequent
emission of ionizing energy. Single photon emission is the type of energy on which
conventional nuclear imaging is dependent. A challenge in conventional nuclear
imaging resides in the selection of unstable elements encompassing the correct
physical properties for clinical use, namely the proper type and the quantity of en-
ergy released from the decay of selected radioisotopes, i.e., too much energy being
deleterious to the patient, too little being inadequate for imaging purposes. Techne-
tium, gallium, indium, and thallium radioisotopes are the most frequently used ele-
ments in single photon emission imaging. Downfalls include the limited physiologi-
cal extent of these elements, which command their union with other elements (of-
ten cellular elements, e.g., red cells, white cells .... ) as well as the size of the result-
ing units, which often excludes the study of smaller scale cellular physiology. The
advent of positron emission imaging has opened the path to new possibilities. The
procedure still depends on the decay of unstable elements but, in this instance, the
elements degrade in a different manner than that for conventional nuclear imaging.
The selected radioisotopes consist of elements rendered unstable in a cyclotron by
the bombardment of accelerated protons, thereby, creating new elements with un-
stable neutron :proton ratios. It is the nature of the radioactive decay which differ-
entiates PET from conventional nuclear imaging. The radioisotopes utilized in PET
emit positrons, that is, positively charged electrons; particles with negligible mass
but possessing an electric charge. Positrons travel a small distance until they en-
counter an electron (negatively charged particle). The result is the annihilation of
both particles and the emission of photons traveling in opposite directions, 180 o
from each other. The tomograph is a photon sensitive camera which surrounds the
source containing the radioisotopes, and composed of crystals which absorb the
photons' energy. Some of the electrons which constitute the crystals are thus ener-
gized by the radiation (photons) and redistribute this energy in the form of light
in order to recover a state of stability. It is this light, or scintillation of the crystals,
which is then amplified via photomultipliers, converted into electrical current and
finally computer-digitized to reveal images (Fig. 1).
Since each of the emitted photons travels at the speed of light, both reach the
crystals at roughly the same time, notwithstanding their relative proximity to the
camera. The computer is programmed to interpret two simultaneous light signals
as coming from the same annihilation process. It then draws a straight Hne uniting
the two excited crystals. Since the tomograph surrounds the emitting source, the
result is an amalgam of lines oriented in a multitude of directions in which the
confluence of these lines can be treated as an image of the source containing the
radioisotopes.
The most important advantages of PET over traditional nuclear medicine imag-
ing is greater image resolution resulting from the bi-directional release of photons
and the much greater versatility of the tracers. Radioisotopes have been obtained
from atoms nearly as ubiquitous as nitrogen, carbon, and oxygen. These smaller
elements are insertable in a multitude of molecules which enter biological pathways
thus enabling images of what was once hidden to the eye to be viewed, including
chemical reactions occurring at the cellular level [5]. The following constitutes an
overview of some of these tracers. As stated earlier, the list is not exhaustive but
rather represents a list of techniques which in our view have the greatest potential
of being pertinent to the field of critical care medicine.
Positron Emission Tomography: Anticipated Usefulness in Critical Care Settings 739
Photo-multiplier,
Subsequent detection analysis
and tmage treatment
Fig. 1. Schematic representation of positron annihilation and consequent photon emission
1 Tracers
The tracers outlined herewith are designed to illustrate four main cellular functions
or dysfunctions: cellular perfusion, oxygen consumption, glucose uptake, and hyp-
oxia (Table 1). Again, emphasis must be placed on the clinical and experimental
importance of these targets in critical care settings, where the mere elucidation of
the effective volume in a given patient can eliminate the need for invasive diagnost-
ic techniques of uncertain yield and reduce the risks linked to over- or undertreat-
ment with respect to volume repletion, for example.
As can be seen, there is some overlap between the uses of the various tracers de-
picted. For example, we mention three tracers capable of reflecting tissue perfusion
and two destined for imaging of oxygen consumption. The reasons for this overlap
are simple: first, the ideal marker has yet to be identified, and second, it was dis-
covered that the same marker may illustrate different cellular functions depending
on the timing of tracer distribution one chooses to focus on. This introduces the
notion of kinetic studies, namely the behavior of each tracer as a function of time
and its significance. For instance, in the time-lapse distribution of acetate, the ini-
Table 1. Markers and their functions
Tissue perfusion Oxygen consumption Glucose uptake Hypoxia

H2tso FOG Cu-ATSM
n NH3
11C Acetate
K1
Vascular
Tissue cells
Compartment
K2
Fig. 2. Simplified bi-compartmental model of radioisotope distribution. K1: radioisotope movement into
tissue; K2: radioisotope movement out of tissue
tial rise in tissue radioactivity represents tissue perfusion or acetate entering the
cells and thereafter, the fraction of labeled C0 2 exiting the cells and reentering the
vascular compartment, correlates with oxygen consumption (Fig. 2).
Labeled Water
Labeled water (i.e., a water molecule labeled with an oxygen radioisotope: H2 150)
has already been used extensively as a perfusion agent. Since water easily diffuses
through cell membranes, and because water is an inert molecule (not normally me-
tabolized), it represents a direct reflection of the amount of nutritious fluid deliv-
ered to tissues. The labeled water molecule diffuses back and forth from the vascu-
lar space to the interstitium to the intra-cellular compartment until equilibrium is
reached. Regions which are hypoperfused are delineated as areas with the least iso-
tope capture. The use of this tracer has been extensively validated through compar-
ison with studies using radioactive microspheres and intracoronary Doppler, pri-
marily for use in the myocardium and central nervous system in both healthy and
diseased subjects [6-10]. Limitations reside in the short half life of the radioiso-
topes (+/-120 s), a weak signal emission, and the necessity of imaging the vascular
compartment in parallel since water diffuses without discrimination between vascu-
lar and tissular compartments.
13 NH3
A second marker of tissue perfusion is 13 N marked ammonia ( 13 NH 3 ). This small
molecule moves from the vascular space to tissue both by active transport (so-
dium-potassium pump) and passive diffusion. Therefore, initial extraction ofam-
monia in tissues is essentially independent of blood flow. On the down side, ammo-
nia is rapidly metabolized to urea and glutamine which contaminates both blood
and tissue activity measurements. However, kinetic modeling has enabled the
tracer's initial passage into the extravascular space to be separated from its tissue
retention through metabolic conversion. This requires measurement of the radio-
activity curve in the arterial vascular compartment either by direct assessment
through arterial sampling or by identifying anatomic regions of interest related to
the intravascular compartment (e.g., left ventricle). Once the mathematical handling
has been accounted for, 13 NH 3 is a more efficient approach to perfusion measures,
resulting in less technical acrobatics and better quality imaging. The use of this
marker has also been well validated through comparison with labeled micropsheres
and H2 15 0 for its use in the myocardium, but has not proven to be useful in perfu-
sion studies of the brain, mostly because the first pass extraction is too small [11-
15].
11 C Acetate
11 C acetate has been shown to be useful in at least two respects: as a perfusion
agent and as an estimate of oxygen consumption. Our description will focus on the
heart since most studies using this tracer have been performed in this organ. When
injected in the circulation, labeled acetate is extracted into the myocardium where
it is converted to acetyl-CoA by acetyl-CoA synthetase in the mitochondrial matrix.
The complex is then oxidized via the tricarboxylic acid (TCA) cycle thereby releas-
ing 11 C0 2 or 11 C-bicarbonate (which exits the cells rapidly), and a fixed number of
reducing equivalents, NADH and FADH 2 • The reducing equivalents subsequently
transfer their electrons to oxygen molecules, a process called oxidative phosphory-
lation, responsible for the production of ATP or cell fuel. It is assumed that cell
clearance of 11 C parallels cell oxygen consumption. Simply put, if oxygen input is
cut from a cell, the reducing equivalents can no longer transfer the electrons they
carry; henceforth accumulation of these products hinders the TCA cycle, resulting
in an accumulation of acetyl CoA and ultimately in a diminished clearance of 11 C
(Fig. 2). This approach has been verified in healthy and pathological conditions in
both animal and human models [16-20]. A more detailed study of the kinetics of
labeled acetate later lead to the observation that the initial extraction of 11 C acetate
from the blood corresponded to blood flow in the myocardium [20-25]. Labeled
acetate is, therefore, able to reveal both tissue perfusion and oxygen consumption
in the same examination.
The most straightforward method of measuring oxygen consumption is by direct

tracing of 15 0. Radioisotopes are administered by direct inhalation of 15 0 2 or by
bolus administration of H2 15 0, which enter the circulation and ultimately the cellu-
lar compartment. The oxygen particle then undergoes a reduction process (i.e., oxi-
dative phosphorylation) and the radioisotope 15 0 accumulates in the form of water
in cellular and extracellular spaces by way of passive diffusion. Again the kinetics
of the tracer are amenable to mathematical modeling and, therefore, the metabolic
rate of oxygen consumption (rMMR0 2 ) as well as the oxygen extraction fraction
(rOEF) are calculable [11, 26-31]. As with 11 C acetate, organ systems thoroughly
studied with 15 0 2 are few, with the main focus on the myocardium and brain.
18Fiuor
18 Fluor is different from the other radioisotopes in that it is not normally part of a
large number of physiologically active molecules. However, it is successfully substi-

tuted to hydroxyl radicals (OH-) and, therefore, mimics their presence. Most note-
worthy of the compounds involving 18F is fluorodeoxyglucose (FDG), a glucose ana-
log, extracted from the circulation much in the same way as glucose. It is phos-
phorylated inside the cell but not further metabolized. It reflects cellular uptake of
glucose and consequently mirrors the metabolic activity of cells, acquiring energy
Fig. 3. Pet cardiac imaging. Top images: perfusion deficit in the inferolateral region of the myocardium
with 13 NH 3; bottom images: viable myocardium in the inferolateral region with enhanced capture of FDG
mainly from glucose such as the case of neurons. It is no surprise that FDG has
served in monitoring the metabolism of the central nervous system (CNS) in nor-
mal and pathological states such as dementia, epilepsy and neuropsychiatric disor-
ders [32]. One of the other many applications of FDG resides in its ability to delin-
eate myocardial viability prior to revascularization. Dyskinetic or akinetic areas of
myocardium in which FDG uptake is superior to a defined threshold are more
likely to recover contractile function after coronary revascularization. FDG uptake
can also be relatively enhanced when compared with blood perfusion, a situation
referred to as mismatch, indicating cell suffering and viability at the same time
(Fig. 3).
With head trauma patients, increased FDG uptake in the brain was shown to be
a negative prognostic factor, correlating with poor survival. The latter observation
has led to the suggestion that increased glycolysis follows loss of aerobic metabo-
lism in damaged neurons [30, 33-37].
Cu-ATSM
Finally, Cu-ATSM is a compound designed to reflect hypoxia. Initially destined to
trace hypoxia in tumors (which are then more likely to be treatment resistant), it
was later shown to be useful for other areas such as the myocardium. Two charac-
teristics explain the potential of this tracer. First, it has high membrane permeabil-
ity and diffuses readily into the mitochondria. Second, it has a low redox potential,
hence conferring relative stability in normal tissue, but nonetheless retaining a re-
dox potential similar to that of NADH. In states of hypoxia, the electrons accumu-
lated in the mitochondria (which normally would be transferred to oxygen) are
transferred to Cu-ATSM. The redox state of the molecule traps it inside the mito-
chondria until reoxygenation occurs and the electrons are taken back from the
ATSM molecule. The molecule subsequently rediffuses away rapidly. Fixation of
ATSM was demonstrated in ischemic myocardium resulting in negative images of
those obtained with MIBI (methoxyisobutyl sonitrile) or acetate [38, 39].
I Future Perspectives in Critical Care Applications
The present chapter has but outlined some of the clinical applications of a few PET
scan markers. One should specially bear in mind the wide array of uses for each
individual marker as it relates to critically ill patients, such as, for instance, the im-
portance of glucose uptake as a marker of myocardial viability and as a prognostic
index of cerebral integrity after trauma. Another example is the usefulness of 11 C
acetate in evaluating both tissue perfusion and oxygen consumption. It is our opin-
ion that the same physiopathological events that can be studied with PET might
contribute to organ dysfunction in critically ill patients.
One can easily appreciate how the precise evaluation of tissue perfusion and
oxygen consumption would invaluably assist the clinician. Titration of volume re-
pletion, evaluation of the efficacy of vasoactive drugs and of blood replacement
could be achieved with PET scanning. It might also be possible to compare cellular
perfusion with oxygen consumption during the same PET investigation. Another
void potentially filled in the short term by PET imaging is the evaluation of non-
specific encephalopathy of the critically ill patient by use of FDG or a perfusion
agent or both. The benefits of PET scanning could be felt both in the prognostic
and diagnostic assessment of the confused to comatose patient.
From an experimental perspective and with MODS standing out as the prototype of
pathologies encountered in the ICU, it is tempting to conclude that PET could contrib-
ute to the elucidation of MODS pathophysiology. When reviewing the various hypoth-
eses regarding organ dysfunction in MODS [2-4], most cited theories have been ad-
dressed, albeit in various contexts, by PET technology. Could the dysfunctional mi-
crovascular unit be imaged by perfusion studies? The resolution of PET images being
less than perfect, it is improbable that one could image the heterogeneity of the per-
fusion in this way. However, a quantitative estimation of the amount of nutritious
fluid actually reaching the cells of an entire organ or of a section of an organ, all
of which can be achieved in vivo, is certainly worthy of interest. Likewise, in consider-
ing other pathogenetic hypotheses, verifying in vivo at which point organ dysfunction
parallels diminished oxygen consumption and/or delivery and if the two are neces-
sarily related is surely warranted, bearing in mind the proposed relative implication
of cytopathic hypoxia and dysfunctional microcirculatory units. On a final note, the
use of most of the aforementioned tracers has been validated in the heart and the
brain. Although tracer metabolism may vary from one organ to the next, if one con-
siders that MODS is by essence a polymorphic disease, validating the use of the PET
scan in other more numerous organ systems should prove interesting. Furthermore,
whole body PET imaging is indeed feasible given that the half life of the tracer is long
enough to allow distribution in the entire body before imaging. In fact, human PET
cameras are designed for whole body imaging due to the large proportion of oncolo-
gical applications of the apparatus.
It is certainly possible to foresee how validated tools could find applications in
ICU in the short term. Other tools will become readily available as the search for
new tracers flourishes. As our understanding of tracer kinetics progresses, new
uses of known markers will also become a reality. For example, vascular permeabil-
ity studies, most of which are presently limited to ex vivo studies, may soon be ad-
dressed in vivo by PET. Work in that direction with 13N-NH 3 at the blood brain
barrier has already been initiated [40]. In the same manner, an albumin molecule
labeled with a positron emitting atom is in the making with the potential of be-
coming an important asset to permeability imaging. Finally, and perhaps most ex-
citing of all, is the potential imaging of apoptosis, with respect to MODS. Annexin
has now become available as a probe for apoptotic cells. Whether or not it will be
possible to label annexin is yet to be proven but ongoing work in that direction is
already progressing, closing the loop on the different pathways leading to MODS
and amenable to functional imaging by PET [41-44].
I Conclusion
PET offers a multitude of advantages over other imaging technologies. It permits
quantitative appreciation of key events in the biological processes mandatory to cel-
lular function. By imaging cell physiology rather than cell anatomy, PET brings
medical imaging to a new level and will undeniably permit a greater understanding
of puzzling medical entities.
PET plays already an important clinical role in the field of oncology. In addition,
many of the existing validated PET markers address questions relevant to organ
dysfunction. For this reason, it seems likely that this technology could also contrib-
ute to a better understanding of unresolved questions pertaining to the field of crit-
ical care medicine. Whether or not PET will prove to be also a practical tool from a
clinical standpoint remains to be demonstrated. However, considering the impor-
tance of organ dysfunction syndromes in the critically ill, the potential benefits ob-
tained from PET imaging warrant further attention.
References
1. Marshall JC, Cook DJ, Christou NV, Bernard GR, Sprung CL, Sibbald W (1995} Multiple
organ dysfunction score: a reliable descriptor of a complex outcome. Crit Care Med 23:
1638-1652
2. Papathanassoglou ED, Moynihan JA, Ackerman MH (2000} Does programmed cell death
play a role in the development of multiple organ dysfunction in critically ill patients? A re-
view and a theoretical framework. Crit Care Med 28:537-549
3. Fink MP, Evans TW (2002} Mechanisms of organ dysfunction in critical illness: report
from a round table conference held in Brussels. Intensive Care Med 28:369-375
4. Marshall JC (2001} Inflammation, coagulopathy, and the pathogenesis of multiple organ
dysfunction syndrome. Crit Care Med 29 (7 suppl):S99-Sl06
5. Thrall JH, Ziessman HA (2001} Single-photon emission computed tomography and posi-
tron emission tomography. In: Nuclear medicine: The Requisites, 2nd ed. Mosby, St-Louis,
pp 33-47
6. Bergmann SR, Fox KA, Rand AL (1984} Quantification of regional myocardial blood flow
in vivo with H/ 5 0. Circulation 70:724-733
Positron Emission Tomography: Anticipated Usefulness in Critical Care Settinqs 745
7. Walsh MN, Geltman EM, Steele RL, et a! (1990) Augmented myocardial perfusion reserve
after coronary angioplasty quantified by positron emission tomography with H2 15 0. J Am
Coli CardioliS:119-I27
8. Bergmann SR, Herrero P, Markham J, Weinhemer CJ, Walsh MN (I989) Noninvasive quan-
tification of myocardial blood flow in human subjects with oxygen-IS-labeled water and
positron emission tomography. J Am Coli Cardiol I4:639-6S2
9. Ter-Pogossian MM, Herscovitch P (198S) Radioactive oxygen-IS in the study of cerebral
blood flow, blood volume, and metabolism. Semin Nucl Med IS:377-394
IO. Bergmann SR (I997) Clinical applications of myocardial perfusion assessments made with
oxygen-IS water and positron emission tomography. Cardiology 88:7I-79
Il. Hutchins GD, Schaiger M, Rosenspire KC, Krivokapich J, Schelbert H, Kuhl DE (I990) Non
invasive quantification of regional blood flow in the human heart using 13 N ammonia and
dynamic positron emission tomographic imaging. JAm Coli Cardiol IS:l032-I042
12. Muzik 0, Beanlands RSB, Hutchins GD, Mangner TJ, Nguyen N, Schwaiger M (I993) Vali-
dation of Nitrogen-13-ammonia tracer kinetic model for quantification of myocardial
blood flow using PET. J Nucl Med 34:83-9I
I3. Bellina CR, Parodi 0, Camici P, et a! {1990) Simultaneaous in vitro and in vivo validation
of nitrogen-13-ammonia for the assessment of regional myocardial blood flow. J Nucl Med
31:133S-1343
I4. Bol A, Melin JA, Vanoverschelde JL, et a! (1993) Direct comparison of 13 N ammonia and
15 0 water estimates of perfusion with quantification of regional myocardial
blood flow by
microspheres. Circulation 87:S12-S2S
1S. Nitzsche EU, Choi Y, Czernin J, Hoh CK, Huang S-C, Schelbert HR (1996) Noninvasive
quantification of myocardial blood flow in humans. Circulation 93:2000-2006
16. Armbrecht JJ, Buxton DB, Schelbert HR (I989) Validation of nc acetate as a tracer for
noninvasive assessment of oxidative metabolism with positron emission tomography in
normal, ischemic, postischemic, and hyperemic canine myocardium. Circulation 81:1S94-
I60S
17. Brown MA, Myears DW, Bergmann SR (I989) Validity of estimates of myocardial oxidative
metabolism with nc acetate and positron emission tomography despite altered patterns of
substrate utilization. J Nucl Med 30:I87-193
I8. Buxton DB, Nienaber CA, Luxen A, et a! (I989) quantification of regional myocardial oxy-
gen consumption in vivo with nc acetate and dynamic positron emission tomography. Cir-
culation 79:134-142
19. Ukkonen H, Knuuti J, Katoh C, et a! (200I) Use of nc and 15 0 2 PET for the assessment of
myocardial oxygen utilization in patients with chronic myocardial infarction. Eur J Nucl
Med 28:334-339
20. Klein LJ, Visser FC, Knaapen P, et a! (2001) Carbon-11 acetate as a tracer of myocardial
oxygen consumption. Eur J Nucl Med 28:6SI-668
21. Porenta G, Cherry S, Czernin J, et al (I999) Noninvasive determination of myocardial
blood flow, oxygen consumption and efficiency in normal humans by carbon-11 acetate
positron emission tomography imaging. Eur J Nucl Med 26:146S-1S74
22. Sciacca RR, Akinboboye 0, Chou RL, Epstein S, Bergmann SR (2000) Measurement of
myocardial blood flow with PET using 11 C acetate. J Nucl Med 42:63-70
23. Sun KT, Yeatman LA, Buxton DB, et a! (1998) Simultaneaous measurement of myocardial
oxygen consumption and blood flow using carbon-11 acetate. J Nucl Med 39:272-280
24. Chan SY, Brunken RC, Phelps ME, Schelbert HR (I99I) Use of the metabolic tracer car-
bon-11-acetate for evaluation of regional myocardial perfusion. J Nucl Med 32:66S-672
2S. Gropler RJ, Siegel BA, Geltman EM (I99I) Myocardial uptake of carbon-11-acetate as an
indirect estimate of regional myocardial blood flow. J Nucl Med 32:24S-2SI
26. Raichle ME, Grubb RL, Eichling JO, et a! (I976) Measurement of brain oxygen utilization
with radiotracer oxygen-IS. Experimental verification. J Appl Physiol 40:638-640
27. Frakowiak RSJ, Lenzi GL, Jones T, et al (1980) Quantitative measurement of regional cere-
bral blood flow and oxygen metabolism in man using 0-1S and positron emission tomo-
graphy: theory, procedure, and normal values. J Comput Assist Tomogr 4:727-736
28. Yamamoto Y, de Silva R, Rhodes C, et a! ( I996) Ventricular hypertrophy, congestive heart
failure, metabolism: noninvasive quantification of regional myocardial metabolic rate for
746 F. Lamontaqne et al.: Positron Emission Tomography: Anticipated Usefulness in Critical Care Settings
oxygen by use of 150 2 inhalation and positron emission tomography: experimental valida-
tion. Circulation 94:808-816
29. Okazawa H, Yamauchi H, Sugimoto K, et a! (2001) Quantitative comparison of the bolus
and steady-state methods for measurement of cerebral perfusion and oxygen metabolism:
positron emission tomography study using 150-gas and water. J Cereb Blood Flow Metab
21:793-803
30. Yamaki T, Imahori Y, Ohmori Y, eta! (1996) Cerebral hemodynamics and metabolism of
severe diffuse brain injury measured by PET. J Nucl Med 37:1166-1170
31. Ishii K, Sasaki M, Kitagaki H, Sakamoto S, Yamaji S, Maeda K (1996) Regional difference
in cerebral blood flow and oxidative metabolism in human cortex. J Nucl Med 37:1086-
1088
32. Silveramn DH, Small GW, Chang CY, et a! (2001) Positron emission tomography in evalua-
tion of dementia: regional brain metabolism and long-term outcome. JAMA 286:2120-2127
33. Tillisch J, Brunken R, Marshall R, eta! (1986) Reversibility of cardiac wall-motion abnorm-
alities predicted by positron tomography. N Eng! J Med 314:884-888
34. Tamaki N, Yonekura Y, Yamashita K, et al (1989) Positron emission tomography using
fluorine-18 deoxyglucose in evaluation of coronary artery bypass grafting. Am J Cardiol
64:860-865
35. Gerber B, Vanoverschelde J-L, Bol A, et a! (1996) Coronary heart disease, myocardial in-
farction, thrombolytic agents: myocardial blood flow, glucose uptake, and recruitment of
inotropic reserve in chronic left ventriculat ischemic dysfunction: implications for the
pathophysiology of chronic myocardial hibernation. Circulation 94:651-659
36. Lucignani G, Paolini G, Landoni C, et a! (1992) Presurgical identification of hibernating
myocardium by combined use of technetium-99m hexakis 2-methoxyisobutylisonitrile sin-
gle photon emission tomography and fluorine-18 fluoro-2-deoxy-D-glucose positron emis-
sion tomography in patients with coronary artery disease. Eur J Nucl Med 19:874-881
37. Knuuti MJ, Saraste M, Nuutila P, et al (1994) Myocardial viability : fluorine-18-deoxyglu-
cose positron emission tomography in prediction of wall motion recovery after revasculari-
zation. Am Heart J 127:785-796
38. Fujibayashi Y, Cutler CS, Anderson CJ, et a! (1999) Comparative studies of Cu-64-ATSM
and C-11-acetate in an acute myocardial infarction model: ex vivo imaging of hypoxia in
rats. Nuc Med Bioi 26:117-121
39. Fujibayashi Y, Taniuchi H, Yonekura Y, Ohtani H, Konishi J, Yokoyama A (1997) Copper-
62-ATSM: a new hypoxia imaging agent with high membrane permeability and low redox
potential. J Nucl Med 38:1155-1160
40. Lockwood AH, Yap EWH, Wong W-H (1991) Cerebral ammonia metabolism in patients
with severe liver disease and minimal hepatic encephalopathy. J Cereb Blood Flow Metab
11:337-341
41. Narula J, Acio ER, Narula N, et al (2001) Annexin-V imaging for noninvasive detection of
cardiac allograft rejection. Nature Med 7:1347-1352
42. Dumont EA, Reutelingsperger CPM, Smits JFM, et al (2001) Real-time imaging of apoptotic
cell-membrane changes at the single-cell level in the beating murine heart. Nature Med
7:1352-1355
43. Reutelingsperger CPM, Dumont E, Thimister PW, et al (2002) Visualization of cell death in
vivo with the annexin AS imaging protocol. J Immunol Meth 265:123-132
44. Balnkenberg FG, Tait J, Ohtsuki K, Strauss HW (200) Apoptosis: the importance of nuclear
medicine, Nucl Med Commun 21:241-250
Measurement of Regional Cerebral Blood Flow
by Near Infrared Spectroscopy
and lndocyanine Green Dye Dilution
E. Keller, A. Nadler, and H. Alkadhi
I Introduction
After subarachnoid hemorrhage (SAH), the complex changes of cerebral hemody-
namics and oxygenation pattern with the development of cerebral vasospasm are
underestimated if transcranial Doppler (TCD) monitoring and angiography are
considered singularly. The role of TCD in predicting symptomatic cerebral vaso-
spasm is limited to the cases in which very high blood flow velocities are detected
[1]. Discrepancies between radiographic findings and delayed ischemic deficits may
depend on the relationship between local cerebral oxygen-requirement and -deliv-
ery, which only can be determined if cerebral blood flow (CBF) and cerebral oxy-
gen extraction can be estimated. Low CBF has been identified as an independent
predictor of poor outcome after SAH [2]. Nevertheless the established methods for
bedside measurement of CBF with inert tracers such as the nitrous oxide dilution
method or the 133Xenon dilution technique are technically difficult and time con-
suming [3, 4]. Stable xenon-enhanced computed tomography (CT), positron emis-
sion tomography (PET) and magnetic resonance spectroscopy are powerful re-
search tools [S-8], but require that the patient is transported to the imaging unit,
which carries a potential high risk. Recently a new double indicator dilution tech-
nique for bedside monitoring of CBF in combination with jugular bulb oximetry
became available [9, 10]. Nevertheless first examinations in patients with SAH show
that the sensitivity of the new method to detect cerebral vasospasm may be limited
by the technique measuring only global CBF values [11]. TCD and jugular bulb oxi-
metry using optical fibers [12] give indices that can be related to changes in CBF
but do not measure true flows. Furthermore, techniques based on jugular bulb cat-
heters, represent only global cerebral oxygenation and perfusion. A decrease in the
jugular bulb oxygen saturation (Sjv02 ) may be useful only in detecting severe prox-
imal cerebral vasospasm, leading to significant reduction of hemispheric blood
flow. The sensitivity of Sjv02 to detect smaller ischemic areas secondary to cerebral
vasospasm of single vessels is limited [11]. In cases of distal arterial narrowing,
techniques measuring regional values of local cortical perfusion, representing se-
lected vascular territories, may be more sensitive. Monitoring of partial pressure of
brain tissue oxygen (Pbt0 2 ) is suitable for detecting focal changes in cerebral oxy-
genation pattern [13]. PbtOrmonitoring, nevertheless, using intraparenchymatous
brain catheters is an invasive method, giving accurate results only in sedated pa-
tients. Moreover, cerebral vasospasm may occur in different vascular territories not
observed with the PbtOrmonitoring. The limitations of the available techniques
encourage the development of a practical method for measuring regional cerebral
perfusion non invasively in different vascular territories.
748 E. Keller et al.
1 Near Infrared Spectroscopy (NIRS)

NIRS measurements are based upon the finding that light in the near infrared re-
gion penetrates biological tissue and is absorbed differently by the chromophores
oxygenated and deoxygenated hemoglobin [14]. Edwards and Elwell, based on the
Pick principle, proposed to measure CBF by monitoring changes in oxygenated he-
moglobin in response to changes in inspired oxygen as a tracer [15, 16]. The pe-
ripheral concentration of the tracer is measured using pulse oximetry and the accu-
mulation of tracer in the brain is measured by NIRS. This technique showed a
good correlation with the 133Xenon dilution method in neonates [17]. In animal ex-
periments and in adults, coefficients of variation of repeated measurements were
high and the oxygen-dilution method showed poor correlation with established
methods [16, 18]. Furthermore, under clinical conditions patients with brain dam-
age may be especially vulnerable to oxygen desaturations already as small as 3-4%,
which correspond to the resolution of the oxygen-dilution method [19].
I The NIRS lndocyanine Green (ICG) Dye Dilution Method

ICG, which has been approved by the United States Food and Drug Administration,
has been widely used in medical diagnosis since 1956 [20] with very few side ef-
fects [21]. ICG, for dilute solutions in blood, absorbs a maximum of infrared light
between 790 and 805 nm, which lies at an isobestic point for reduced hemoglobin
and oxyhemoglobin. Colacino et al. first injected ICG into the carotid artery of
ducks and analyzed the clearance curve of the dye by NIRS [22]. Kuebler et al. ap-
plied the mathematical model used in fluorescein flowmetry on the first circulatory
passage of an ICG bolus through the porcine cerebral vasculature as monitored by
NIRS [23]. Data obtained were compared with cerebral and galea! blood flow values
assessed by a radioactive microsphere reference sampling technique. Blood flow in-
dex (BPI), as a relative measure of regional CBF (rCBF), was defined as the coeffi-
cient between maximum ICG signal obtained by NIRS and the rise time. The
authors found that BPI correlated significantly with rCBF in brain cortex as mea-
sured by the radioactive microsphere technique. Nevertheless, the data were re-
stricted to studies of the porcine head and the consistency between the newly de·
veloped method and the standard reference method calculated according to Bland
and Altman was rather wide. These discrepancies between the two methods did not
allow clinical routine use [23]. The combination of NIRS and ICG dye dilution to
estimate rCBF has been described in adults [24, 25] and newborn infants under-
going cardiopulmonary bypass [26-28]. Using ICG, the signal-to-noise ratio im-
proved substantially compared to the method employing oxygen as a tracer [26].
However, in all studies the input signal of the head, the arterial concentration of
the tracer, was quantified invasively by an arterial fiberoptic-catheter placed in the
aorta, or in the arterial line of the cardiopulmonary bypass circuit [24-27, 29, 30].
Therefore, the methods are unsuitable for non-invasive CBF measurement. Hopton
described measurements of cerebral blood volume (CBV) employing NIRS and ICG
as the intravascular marker [29], but, still, the ICG concentration in the peripheral
blood was measured by high-performance liquid chromatography, which makes the
method inconvenient for rapid serial measurements in clinical practice.
Measurement of Regional Cerebral Blood Flow 749
I NIRS with Optodes on the Scalp
The objective of the present project with NIRS optodes on the scalp was to develop
a non-invasive method. Therefore, a completely new approach to analyze the ICG
dilution curves has been developed.
Instrumentation
Four near NIRS optodes were placed bilaterally on the forehead, two emitters and
two detectors, 5 em apart (Fig. 1). Changes in optical density changes were re-
corded by the NIRS-system (Oxymon-Systems, Nijmegen, Netherlands, 10 Hz sam-
pling frequency, 769, 850, 905 nm). Central venous injections of 25 mg ICG (12.5
Fig. 1. Four NIRS diodes, emitter and detector 5 em apart, are placed bilaterally on the forehead using a
flexible headband
mg/1 ml aqua dest.) were performed. The appearance of ICG in the optical field
and the dye dilution curves were recorded.
Signal Processing
New algorithms to analyze our ICG dilution curves have been developed [31]. Data
analysis is performed separating the signals in the arterial and venous compart-
ments in the optical segment detected by NIRS [32]. The different compartments
can be identified by their special changes in blood volume. The arterial blood vol-
ume pulsates with systole and diastole. As in pulse oximetry, these pulsations are
used to identify the arterial compartment of the optical segment. Using digital
bandpass filters the arterial contribution to the ICG indicator dilution curve is qua-
litatively identified. The cumulative NIRS signal obtained over the cortex can be
quantified as:
cr~~ue(t) = Ji(t')- o(t')dt'

tO
where i(t') represents the inlet and o(t') the outlet of the system. The convolution
integral:
o(t') = i(t'- u) x g(u)
describes the relationship between input and output function, where g(u) is also
termed 'transport function' in the context of indicator dilution theory [33]. By
iterative approximation, the arterial contribution (input function) and the venous
contribution (output function) to the ICG indicator dilution curve and the trans-
port function is quantified. If the parameters of the characteristic transport func-
tion are known, the mean transit time (mtt1cG) can be calculated. The regional ce-
rebral blood volume (rCBV) is defined as the volume fraction of blood in cerebral
tissue. As ICG remains strictly intravascular CBV can be calculated from:
rCBV -_ cTissue(t)/CBlood(t)
ICG ICG
where cf~'Gue is the accumulation of ICG in the examined brain tissue and C~~'God
the concentration of ICG in the blood. rCBF is calculated from rCBV divided by
the corresponding regional mean transit time of ICG (rmtt1cG).
Examinations in Healthy Volunteers

In 11 healthy volunteers, 22 pairs of comparative measurements using the NIRS
ICG dye dilution technique and perfusion-weighted magnetic resonance imaging
(MRI) were performed [34]. For clinical practice, not absolute values, but detection
of reliable changes in cerebral hemodynamics during the illness course is essential.
Kolbitsch et al., using perfusion-weighted MRI, showed in human volunteers, that
increasing mean airway pressure by continuous positive airway pressure (CPAP)
breathing significantly increases rmtt and reduces rCBF [35]. Therefore, for valida-
450
400
....
:sE
"0.
0
350
300 .
......
... 0
6
.
~ 250
...... 6
• -6 0
l 200 0
~ 150
... 0 ~
~·
1.1..
e3
a:
100
50
0
0 5 10 15 20 25 30 35
a RCBFNIRS (ml/100 g/min)
200
lQ 150
z
1.1..
e3-c 100
~
0
~ .E 5o 0
~
oc...._
~01
g 0
,P 0 00 f'\0~ D.
~
0 0 0
~~ 0 h
cu ~ -so 0 0
~.s
~ -100
~
0 -150
-200
0 100 200 300 400 500
b Mean rCBFMRI< rCBFNIRS (ml/100 g/min)
Fig. 2. a Bivariate scatter diagram between regional cerebral blood flow (rCBF) estimated by near infrared
spectroscopy (NIRS) and by perfusion-weighted magnetic resonance imaging (MRI). e Values from left
hemisphere with PEEP 0 mbar; .6. values from right hemisphere with PEEP 0 mbar; 0 values from left
hemisphere with PEEP 10 mbar; 6, values from right hemisphere with PEEP 10 mbar. rCBV: regional cere-
bral blood volume. b Analysis of agreement according to Bland and Altman between rCBF and regional
cerebral blood volume (rCBV) values estimated by NIRS and by perfusion-weighted MRI. Plot of the differ-
ence between rCBFMRI and rCBFNIRS against their mean. For comparisons between the two methods NIRS
data are normalized to the mean value of the corresponding MRI data
tion of the NIRS ICG dye dilution methodology in healthy volunteers the effects of
increased mean airway pressure on cerebral perfusion were examined. With CPAP
breathing, rmttrcG significantly increased (from 8.4±2.6 to 10.1±3.3 s, p=0.012)
and rCBFNrRs significantly decreased (from 18.5±6.9 to 16.1 ±6.2 ml/100 glmin,
p = 0.034). Seventy-five percent of the rCBFNrRs values and 83% of the rCBV NIRs val-
ues decreased or increased simultaneously with the corresponding values obtained
by perfusion-weighted MRI. Agreement between the two measurement methods is
assessed in bivariate scattergrams (Fig. 2 a) and Bland and Altman plots (Fig. 2 b).
The mean value for rCBFNrRs in healthy volunteers was 18.5 ml/100 g/min. The re-
sults for rCBFNrRs are in agreement with previous NIRS measurements, which re-
ported values of 6 to 30 ml/100 g/min, but are low in comparison with reported
PET and single photon emission computed tomography (SPECT) measurements.
The low results for NIRS measurements provide evidence for the extracerebral con-
tribution to the optical path length when scalp recordings with NIRS signals are
made in adults. Owen-Reece and coworkers performed paired measurements from
the scalp and the open dura in neurosurgical patients and suggest that the differ-
ences in CBF and CBV between scalp and dura measurements are likely to be
caused by the optical effect of extracerebral tissue, powerfully scattering light [36].
The authors concluded that in NIRS measurements on the scalp, CBF is approxi-
mately underestimated by a factor 3 which coincides with the ratio of the optical
path length in the brain compared with the total path length [36]. Although the ex-
tracerebral path length is long, the validity of NIRS measurements has been justi-
fied by the argument that, as the extracerebral path has a much lower specific
blood volume than cerebral tissue, it merely acts as a dead space and is hemodyna-
mically inert [29, 36].
Examinations in Patients after SAH

In 10 patients with aneurysmal SAH, 63 NIRS ICG dye dilution measurements were
obtained routinely every 24 hours [37]. No complications associated with the mea-
surement method occurred. Filtering the data showed that the amplitude of pulsa-
tile absorption changes was high enough for further signal processing in 52 mea-
surements. The mean value for rmttrcG was 8.7 s (range 3.8 to 12.2 s) for the right
hemisphere. For the left hemisphere, the mean value for rmttrcG was 8.2 s (5 to
13.8 s). Thirty-two pairs of repeated measurements were performed within 15 mins.
under stable clinical conditions (unchanged intracranial pressure [ICP], mean arte-
rial blood pressure [MAP] and PaC0 2 ). The correlation of repeated measurements
for rmttrcG was 0.82.
One patient with cerebral vasospasm and delayed ischemic deficit worsened de-
spite triple-H therapy, and was treated after diagnostic angiography with super-
selective papaverine infusion into the vasospastic vessels [38]. Comparative ICG
dye dilution measurements of both hemispheres were performed with NIRS on the
scalp immediately before and after superselective papaverine infusion into the right
sided vasospastic vessels. After intraarterial papaverine infusion, the ICG dilution
curve amplitude of the initially hypoperfused right hemisphere increased, whereas
the ICG dilution curve of the contralateral unaffected hemisphere remained un-
changed. These observations indicate that data obtained by NIRS on the scalp are
significantly affected by the intracerebral vessels, which in this setting were selec-
tively influenced by papaverine infusion.
I NIRS with Optodes Placed in the Subdural Space
The effects of bone and surface tissue blood flow on transcutaneous reflectance-
mode NIRS has been extensively discussed in clinical investigations [19, 39, 40].
Studying the effect of the cerebrospinal fluid (CSF) layer in a more complex model,
Cui et al. found that at an emitter-detector separation of 5.0 em, 55% of the NIR
light path length was in the scalp and skull, 20% in the CSF, and only 15% of the
NIR path length was in the cerebral cortex [41]. Because CSF has low scattering
and absorption coefficients, the authors postulated that the CSF is acting as a chan-
nel for the light. Most attempts to subtract extracerebral contamination involve spa-
tial resolved spectroscopy (SRS) [42]. Nevertheless interindividual variability of an-
atomical structures (bone thickness, extracerebral vasculature, liquor space, etc.)
may restrict the reliability of SRS. In the present project, the prototype of a subdu-
ral NIRS probe could be developed and inserted in a first patient [43]. The new
subdural NIRS probe gives the opportunity to measure directly the concentration
of the chromophores in the cortex without the influence of extracerebral tissue.
Instrumentation
A conventional subdural probe for ICP monitoring (NMT Neurosciences, Frankfurt,
Germany) was supplied with a 250 mm long NIRS probe consisting of two fiber
bundles (Fig. 3). Each fiber bundle terminated in a 90-degree prism, one to couple
the infrared light into the tissue and one to couple it back into the fibers. The dis-
tance between the two prisms is 35 mm [43]. In a patient with intracerebral hemor-
rhage, after evacuation of the hematoma and before complete closing of the dura,
the combined subdural ICP-NIRS probe was inserted between dura and cortex plac-
ing the tip of the probe over the left frontal lobe (Fig. 4). In addition to the subdu-
ral NIRS probe, two NIRS optodes were placed on the forehead, emitter and detec-
tor 5 em apart (conventional NIRS). ICG (ICG-Pulsion; Pulsion Medical Systems,
Munich, Germany) in a dose of 25 mg (soluted in 2 ml aqua dest) was injected into
a tube leading into an antecubital vein, followed by the injection of 10 ml glucose
5% flush. The appearance of ICG in the optical fields and the dye dilution curves
Fig. 3. Subdural ICP NIRS probe: A conventional subdural probe for ICP monitoring was supplied with a
2 mm thick and 10 em long NIRS probe consisting of two fiber bundles
Fig. 4. Subdural ICP NIRS probe. Inserted through a burr hole in the skull, the probe is in direct contact
with the brain and elimination of extracranial contamination is gained
obtained by the subdural NIRS probe and the conventional NIRS probe on the
scalp were recorded simultaneously.
Examinations in a Patient after Intracerebral Hemorrhage

In this single patient, no complications associated with the insertion of the subdu-
ral NIRS probe or with the measurement procedure occurred. Eight simultaneous
measurements with conventional NIRS (optodes placed on the scalp) and the sub-
dural NIRS probe were performed. rmtt1cG values obtained by the subdural probe
were lower with a mean value of 9.2 s compared to those obtained by conventional
NIRS with a mean value of 10.2 s. rCBF and rCBV estimated by conventional NIRS
were lower (rCBFmean 16.2 ml/100 g/min and rCBV mean 2.4 ml/100 g) than the corre-
sponding values obtained by the subdural NIRS probe (rCBFmean 18.5 ml/100 g/min
and rCBV mean 3.0 ml/100 g). This corresponds to cerebral angiography showing that
the transit time of radiopaque material is longer in the extracerebral vasculature
than in the brain vessels. However, there are limitations of the subdural NIRS tech-
nique to be considered. The probe must be inserted, as far as possible, in direct
contact to the brain surface. CSF, known to cause light tracking, or postsurgical
blood collections in the subarachnoid, subdural, or intraparenchymal tissue may
interfere with measurements from the subdural space. Illuminated brain tissue thus
may represent an optically heterogeneous compartment of different absorbing com-
ponents. Furthermore, unpredictable patterns of flow may occur through damaged
tissues.
I Conclusion
The NIRS ICG dye dilution technique is a promising method for serial bedside CBF
measurements in the ICU environment. The NIRS method with optodes on the
scalp has the advantage of being non-invasive, does not require the patient to be
transported and provides data within minutes at the bedside. The technique could
be a powerful tool in detection and treatment of cerebral vasospasm after aneurys-
mal SAH. Further investigations in a larger set of patients are needed to evaluate
its diagnostic accuracy in the detection and treatment of cerebral vasospasm. The
preliminary data in a limited number of volunteers indicate that measurements are
in agreement with corresponding values obtained by perfusion-weighted MRI.
The new subdural NIRS probe will provide the opportunity to measure directly
the concentration of the chromophores in the brain, without the influence of extra-
cerebral tissue. Combined monitoring of ICP and NIRS will be of special clinical
value in patients with severe stroke, SAH, and head trauma, already provided with
subdural ICP probes for treatment of intracranial hypertension and being especially
at risk for secondary ischemic brain damage. Eliminating extracerebral contamina-
tion, subdural NIRS methodology may become of major importance as a monitor-
ing technique in the environment of intensive care and stroke units. To further
evaluate whether the new techniques are precise and accurate methods of estimat-
ing CBF, more repeated measurements and comparisons with a standard method
for CBF measurement have to be made.
Acknowledgements. The university of Zurich, the Gebert Riif and the EMDO-stiftung
Zurich, Switzerland financially supported the study. The authors thank Mr. Peter
Roth, Department of Neurosurgery, University of Zurich for the artificial drawings.
References
1. Vora YY, Suarez-Almazor M, Steinke DE, Martin ML, Findlay JM (1999) Role of transcra-
nial Doppler monitoring in the diagnosis of cerebral vasospasm after subarachnoid hemor-
rhage. Neurosurgery 44:1237-1248
2. Lennihan L, Mayer S, Fink ME, et al (2000) Effect of hypervolernic therapy on cerebral
blood flow after subarachnoid hemorrhage. Stroke 31:383-391
3. Kety SS, Schmidt CF (1945) The determination of cerebral blood flow in man by the use
of nitrous oxide in low concentrations. Am J Physiol 143:53-60
4. Obrist WD, Thompson HK, Wang HS, Wilkinson WE (1975) Regional cerebral blood flow
estimated by 133Xe inhalation. Stroke 6:245-256
5. Frackowiak RS, Lenzi GL, Jones T, Heather JD (1980) Quantitative measurement of regional
cerebral blood flow and oxygen metabolism in man using 150 and positron emission tomo-
graphy: theory, procedure, and normal values. J Comput Assist Tomogr 4:727-736
6. Heiss WD (1990) Pathophysiology of stroke as determined by PET. Stroke 21:2-3
7. Ostergaard L, Smith DF, Vestergaard-Poulsen P, et al (1998) Absolute cerebral blood flow
and blood volume measured by magnetic resonance imaging bolus tracking: comparison
with positron emission tomography values. J Cereb Blood Flow Metab 18:425-432
8. Saunders DE, Howe FA, van den Boogart A, et al (1995) Continuing ischemic damage after
acute middle cerebral artery infarction in humans demonstrated by Short-Echo Proton
Spectroscopy. Stroke 26:1007-1013
9. Keller E, Wietasch G, Ringleb P, et al (2000) Bedside monitoring of cerebral blood flow
(CBF) in patients with acute hemispheric stroke. Crit Care Med 28:511-516
10. Wietasch GJK, Mielck F, Scholz M, et al (2000) Bedside assessment of cerebral blood flow
by double-indicator dilution technique. Anesthesiology 92:367-375
11. Hegner T, Krayenbiihl N, Hefti M, Yonekawa Y, Keller E (2001) Bedside monitoring of cere-
bral blood flow in subarachnoid hemorrhage. Acta Neurochirurgica Suppl 77:131-134
12. Robertson CS, Narayan RK, Ziya LG, et al (1989) Cerebral arteriovenous oxygen difference
as an estimate of cerebral blood flow in comatose patients. J Neurosurg 70:222-230
13. Fandino J, Stocker R, Prokop S, Imhof HG (1999) Correlation between jugular bulb oxygen
saturation and partial pressure of brain tissue oxygen during C0 2 and 0 2 reactivity tests
in severely head-injured patients. Acta Neurochir (Wien) 141:825-834
14. Jobsis FF (1977) Noninvasive infrared monitoring of cerebral and myocardial oxygen suffi-
ciency and circulatory parameters. Science 198:1264-1267
15. Edwards AD, Wyatt JS, Richardson C, et a! (1988) Cotside measurement of cerebral blood
flow in ill newborn infants by near infrared spectroscopy. Lancet 2:770-771
16. Elwell CE, Cope M, Edwards AD, et al (1994) Measurement of changes in cerebral hemody-
namics during inspiration and expiration using near infrared spectroscopy. Adv Exp Med
Bioi 345:619-624
17. Bucher HU, Edwards AD, Ipp AE, Due G (1993) Comparison between Near Infrared Spec-
troscopy and 133Xenon Clearance for estimation of cerebral blood flow in critically ill pre-
term infants. Pediatr Res 33:56-60
18. Newton CR, Wilson DA, Gunnoe E, et al (1997) Measurement of cerebral blood flow in
dogs with near infrared spectroscopy in the reflectance mode is invalid. J Cereb Blood
Flow Metab 17:695-703
19. Elwell CE, Cope M, Edwards AD, et al (1994) Quantification of adult cerebral hemody-
namics by near-infrared spectroscopy. J Appl Physiol 77:2753-2760
20. Fox IJ, Brooker LGS, Heseltine DW, Wood EH (1956) A new dye for continuous recording
of dilution curves in whole blood independent of variations in blood oxygen saturation.
Circulation 14:937-938
21. Keller E, Ishihara H, Nadler A, et a! (2002) Evaluation of brain toxicity following near in-
frared light exposure after indocyanine green dye injection. J Neurosci Methods 117:23-31
22. Colacino JM, Grubb B, Jobsis FF (1981) Infra-red technique for cerebral blood flow: com-
parison with xenon 133 clearance. Neurol Res 3:17-31
23. Kuebler WM, Sckell A, Habler 0, et al (1998) Noninvasive measurement of regional cere-
bral blood flow by near-infrared spectroscopy and indocyanine green. J Cereb Blood Flow
and Metab 18:445-456
24. Hongo K, Kobayashi S, Okudera H, Hokama M, Nakagawa F (1995) Noninvasive cerebral
optical spectroscopy: Depth-resolved measurements of cerebral hemodynamics using indo-
cyanine green. Neurol Res 17:89-93
25. McCormick PW, Stewart M, Goetting MG, Dujovny M (1991) Noninvasive cerebral optical
spectroscopy for monitoring cerebral oxygen delivery and hemodynamics. Crit Care Med
19:89-97
26. Chow G, Roberts IG, Fallon P, et a! (1997) The relation between arterial oxygen tension
and cerebral blood flow during cardiopulmonary bypass. Eur J Cardiothorac Surg 11:633-
639
27. Roberts I, Fallon P, Kirkham FJ, et a! (1993) Estimation of cerebral blood flow with near
infrared spectroscopy and indocyanine green. Lancet 342:1425
28. Roberts IG, Fallon P, Kirkham FJ, et a! (1998) Measurement of cerebral blood flow during
cardiopulmonary bypass with near-infrared spectroscopy. J Thorac Cardiovasc Surg
115:94-102
29. Hopton P, Walch TS, Lee A (1999) Measurement of cerebral blood volume using near-infra-
red spectroscopy and indocyanine green elimination. J Appl Physiol 87:1981-1987
30. Patel J, Marks K, Roberts I, Azzopardi D, Edwards AD (1998) Measurement of cerebral
blood flow in newborn infants using near infrared spectroscopy with indocyanine green.
Pediatr Res 43:34-39
31. Keller E, Nadler A, Imhof HG, eta! (2002) New methods for monitoring cerebral oxygena-
tion and hemodynamics in patients with subarachnoid hemorrhage. In: Yonekawa Y, Sa-
kurai Y, Keller E, Tsukahara T (eds) New Trends in Cerebral Aneurysm Management, Vol
suppl 82, Springer, New York, pp 87-92
32. Wolf M, Due G, Keel M, et a! (1997) Continuous noninvasive measurement of cerebral ar-
terial and venous oxygen saturation at the bedside in mechanically ventilated neonates.
33. Bassingthwaighte JB (1967) Circulatory transport and the convolution integral. Mayo Clin
Proc 42:137-154
34. Keller E, Nadler A, Alkadhi H, et al (2002) Non invasive measurement of regional cerebral
blood flow and regional cerebral blood volume by near infrared spectroscopy and indocya-
nine green dye dilution. J Neurosurg Anesthesia! 14:261
35. Kolbitsch C, Lorenz IH, Hormann C, et al (2000) The impact of increased mean airway
pressure on contrast-enhanced MRI measurement of regional cerebral blood flow (rCBF),
regional cerebral blood volume (rCBV), regional mean transit time (rMTT), and regional
cerebrovascular resistance (rCVR) in human volunteers. Hum Brain Mapp 11:214-222
36. Owen-Reece OH, Elwell CE, Harkness W, et al (1996) Use of near infrared spectroscopy to
estimate cerebral blood flow in conscious and anaesthetized adult subjects. Br J Anaesth
76:43-48
37. Keller E, Nadler A, Niederer P, Yonekawa Y (2001) A non invasive method to estimate cere-
bral hemodynamics and oxygenation in patients after aneurysmal subarachnoid hemor-
rhage with near infrared spectroscopy and indocyanine green dye dilution. J Cereb Blood
Flow Metab 21:S505
38. Keller E, Wolf M, Martin M, et al (2001) Estimation of cerebral oxygenation and hemody-
namics in cerebral vasospasm using indocyaningreen (ICG) dye dilution and near infrared
spectroscopy (NIRS). J Neurosurg Anesthesiol13:43-48
39. McCormick PW, Stewart M, Lewis G, Dujovny M, Ausman JI (1992) Intracerebral penetra-
tion of infrared light. J Neurosurg 76:315-318
40. Owen-Reece H, Elwell CE, Wyatt JS, Delpy DT (1996) The effect of scalp ischemia on mea-
surement of cerebral blood volume by near-infrared spectroscopy. Physiol Meas 17:279-286
41. Cui W, Kumar C, Chance B (1991) Experimental study of migration depth for the photons
measured at sample surface. Proc Soc Photooptical Instrumentation Eng 1431:180-191
42. Matcher SJ, Kirkpatrick P, Nahid K, Cope M, Delpy DT (1995) Absolute quantification
methods in tissue near infrared spectroscopy. Proc SPIE 2389:486-495
43. Keller E, Nadler A, Niederer P, Yonekawa Y (2001) Near infrared spectroscopy (NIRS) in
the adult head: Elimination of extracerebral contamination by a new subdural NIRS probe.
J Cereb Blood Flow Metab: 21:s506 (abst)
Invasive Multimodal Online Monitoring
in Severe Stroke Patients
T. Steiner and F. Meisel
I Introduction
'Malignant' stroke is one of the most severe and disabling diseases in neurology. It is
defined as an acute stroke greater than two thirds of the territory of the middle cere-
bral artery (MCA) and progressive neurologic symptoms. About lOo/o of these patients
develop sudden and massive hemispheric edema within 2 to 5 days after the onset of
symptoms [1, 2]. Edema formation, followed by increased intracranial pressure (ICP)
and mass shifts/herniation is a continuous, dynamic process. Therefore, close surveil-
lance of the patient and continuous monitoring is of utmost importance.
If conservative treatment is administered, mortality is very high (72-78%). New
therapeutic approaches like hemicraniectomy and hypothermia may decrease mor-
tality substantially {20 or 44o/o) [3-5]. However, survival is highly dependent on the
right timing of therapeutic interventions. Because of poor respiration, most pa-
tients require analgosedation, intubation and respiratory support. Thus, clinical
and neurological assessment in these patients is difficult. Extended monitoring is
desired. In space-occupying MCA infarction, sooner or later primarily healthy brain
tissue of the contralateral hemisphere becomes involved in the process of expand-
ing edema. Therefore, protection of the contralateral hemisphere is the major thera-
peutic and, hence, monitoring target in these patients.
I Monitoring in Patients with Malignant Stroke

The optimal monitoring device would allow online continuous surveillance of dif-
ferent parameters of cerebral compliance. Dynamic processes should be detectable
well in advance. Based on the information gathered, physicians would be able to
base their therapeutic decisions on a more scientific base.
However, the questions of optimal time and choice of interventional procedure
have not yet been answered. One reason for this dilemma is that not a single reli-
able monitoring parameter of brain function in analgosedated and mechanically
ventilated patients with elevated ICP is known. Different common diagnostic tests
are used. Neuroradiologic assessment (computed tomography [CT] scan, magnetic
resonance imaging [MRI]) fails to deliver continuous information. They only deli-
ver serial, momentary pictures. Also, patient transport remains a considerable
stress factor.
Only ICP measurement has routinely been used to monitor patients in intensive
care units (ICUs). A remarkable number of studies have been published on thera-
peutic strategies for elevated ICP, ranging from physical measures (head and trunk
Invasive Multimodal Online Monitoring in Severe Stroke Patients 759
Fig. 1. Bilateral multimodal monitoring with Pbr0 2, ICP, temperature and microdialysis in a patient with
right-sided malignant MCA infarction and hemicraniectomy. Probes on the left side of the patient are in-
serted through one 3-lumen (PbrOb ICP, temperature) and a 1-lumen screw (Microdialysis). On the right
side of the patient's skull Pbr0 2-, temperature-, and microdialysis-probes are inserted through a 3-lumen
screw. The ICP-probe is applied through the craniotomy
elevation, mechanical ventilation) and pharmacological treatment to invasive inter-

ventions (craniotomy, hypothermia). However, continuous ICP monitoring to evalu-
ate cerebral perfusion pressure (CPP) may not reflect the needs of the individual
patient [6-8]. Also, continuous ICP measurement is known to have technical limita-
tions; value distortion is a big problem. Using Sj0 2 (jugular venous oxygen satura-
tion) as an additional instrument is also problematic, at least in stroke patients,
since the variability in measurements as a result of shunting is great [9, 10].
Furthermore, this technique is prone to technical problems.
Especially during the first days following cerebral infarction, a better and more
specific understanding of pathophysiologic processes and changes is desired.
During recent years, a promising new device has raised new hopes of reaching
the goal of a more individual and valid measurement and observation of different
cerebrovascular brain diseases. Continuous measurement of the partial oxygen
pressure of brain tissue (Pbr0 2 ) by microprobes within the frontal white matter of
the brain may represent an important additional parameter to monitor comatose
patients on our ICUs (Fig. 1). The purpose is to gain information on the underlying
metabolic and circulatory processes. Several experimental studies have shown great
reliability in detecting changes in P0 2 due to changes in blood oxygenation and
changes in ICP and CPP [11, 12].
So far, clinical experience in Pbr0 2 monitoring has been gained mainly from pa-
tients suffering from severe head injury or subarachnoid hemorrhage (SAH) [8,
13]. However, the pathophysiological mechanisms after diffuse brain damage and
SAH cannot be compared with the space-occupying edema after large focal isch-
emia, which might affect the value of the monitoring in these patients. So far, only
760 T. Steiner and F. Meisel
Fig. 2. CT-scan performed 3 days after installation of multimodal monitoring probes
a few studies of multimodal monitoring in patients with malignant stroke have

been conducted.
Multimodal monitoring generally includes measurement of Pbr0 2, ICP, mean ar-
terial pressure (MAP) and CPP. For technical reasons, brain temperature is also
continuously registered. Pbr0 2 is registered using a polarographic Clarke-type mi-
croprobe (Clark-type flexible catheter, GMS, Kiel, Germany). Acquisition of tem-
perature data is required by the oxygen pressure probe for auto-calibration pur-
poses in order to receive valid results. ICP is measured either with pieccoelectronic
(e.g., Codman MicroSensor ICP transducer) or pneumatic (e.g., Spiegelberg III) sig-
nal transmitting probes. All probes are inserted and fixed through transcranial
screws. MAP is measured using a regular arterial line. After installation is com-
pleted, the positioning of the probe catheters should be checked and documented
by cerebral CT scan. Data can be obtained either from one or, as performed re-
cently, from both hemispheres (Fig. 2).
Parameters are displayed and stored continuously by multimodal interface de-
vices (e.g., LICOX-MMM System for multimodal monitoring, GMS, Kiel, Germany)
coupled with a regular personal computer. Events, which could influence one or
more parameters, can be logged into the monitoring software application. Trend
calculations and simple statistical analysis are provided by the software, or are ex-
changed easily for further research and analysis.
---~--~~~~,--~--~~"~,-~
The monitoring probes should be installed at an early stage of the disease. Ede-
ma formation starts within the infarcted area of the MCA territory. Therefore, we
positioned the probes within the white matter of the frontal lobe, assuming that the
anterior cerebral artery territory is normally perfused. Normal Pbr0 2 values were
measured with 33 to 36 mmHg in patients with brain tumors or SAH [11]. In nor-
mothermic stroke patients, Pbr0 2 values of between 25 and 35 mmHg were mea-
sured after hemicraniectomy and of 18 to 36 mmHg after rewarming in the contra-
lateral hemisphere and under normoxic conditions [12, 14, 15].
Multimodal monitoring can be used to monitor and control drug effects on cere-
bral compliance. In a first study, we observed the therapeutic effect of anti-edema
substances. Regarding osmotic agents (hyper-HAES, mannitol), 50 to 60% of these
episodes were associated with a positive effect on Pbr0 2 and CPP. This effect was
registered less often after glycerol. One reason for this observation might be that in
some patients, glycerol was routinely applied during the initial course of disease,
independent of whether these patients had significantly elevated ICP [14]. Thus, in
some episodes, there was only little effect on CPP and/or Pbr0 2 because the de-
crease in ICP was too little. This suggestion is supported by Unterberg and co-
workers, who observed significant increases in Pbr02 when the CPP was in the
range between 50 and 70 mmHg [8]. However, further increases in CPP did not
lead to further significant increases in Pbr0 2 • Interestingly, pharmacologically in-
duced decreases in ICP did not always lead to an improvement in Pbr0 2 (and/or
CPP). In contrast, bilateral decreases in Pbr0 2 could be observed in a significant
number of cases [14]. This effect was mainly registered after the administration of
drugs such as thiopental and tromethamine, which led to a decrease in the ICP
through a reduction in cerebral blood flow (CBF). Thiopental reduces cerebral me-
tabolism, CBF, and, to a certain extent, systemic pressure. The effect of trometha-
mine is probably mediated by pH-coupled vasoconstriction and reduction in CBF.
Our results led us to suspect that the use of certain antiedema drugs might have fa-
cilitated ischemic events: From the treatment of traumatic brain injury (TBI), it is
well known that ischemic events occur despite 'successful' ICP treatment [16].
Adding Pbr0 2 to ICP/CPP monitoring might help to detect drug-associated isch-
emic events. On the other hand, it is known that the Pbr0 2 is the product of oxy-
gen supply and demand. Thus, we should also take into consideration that a de-
crease in Pbr0 2 might be the result of an autoregulatory response to a drug-asso-
ciated depression of cerebral metabolism. To answer this question conclusively,
more measurements must be performed and, the monitoring perhaps be extended,
for example, to microdialysis or CBF measurements, to better assess the branches
of supply and demand of cerebral oxygen metabolism. We found a pattern change
in the Pbr0 2 curve between 6 to 18 hours before transtentorial herniation [14]. Ob-
viously, it is too soon and the number of such observations is too small at this mo-
ment to draw any conclusions. It would be necessary to know whether this phe-
nomenon can be reproduced by other groups, because this would have a major im-
pact on prognosis and therapy planning. Obviously, changes like those that have
just been described can only be observed with bilateral multimodal monitoring [17,
18]. These observations are examples of how monitoring might be used to predict
pathophysiological changes at an early stage of the course of the disease.
Also, this monitoring technique can be used to control the effect of invasive
therapeutic procedures (Fig. 3). The reduction in ICP, as expected by hemicraniec-
tomy and hypothermia, can be assessed. Even more important, the direct effect on
cerebral metabolism can be monitored.
762 T. Steiner and F. Meisel
140 mmHg mm Hg, Temp. 44
130 40
120 36
32
28
100
24
90
20
80
16
12
8
50 4
40 0
00:23 00:56 01:30 02:03 02:36 03:10 03:43 04:16 04:50 05:23 05:56 06:30 07:33 07:36
- - ICPii p0 0 2 re ------ Tempre - - CPPTrend

- - ICPre - ·- ··Pu02 1i - - - Templi - - - - MAPTrend
Fig. 3. Course of multimodal monitoring curves over 8 h in a patient with left-sided malignant stroke.
The patient received moderate hypothermia treatment, but died later because of transtentorial herniation
Technically, the use of multimodal monitoring is highly dependent on the ex-

perience of the operator and the users of the system. Although it is an invasive pro-
cedure, reported complications are little. White matter tissue destruction as regu-
larly seen in patients with extraventricular drainage does not occur, because the
probes used are much smaller in diameter. The most common side effect was post-
operative bleeding from the installation site.
I Conclusion
The advantage of this type of multimodal monitoring over other methods such as
near infrared spectroscopy (NIRS), Doppler ultrasound to observe midline shift, or
microdialysis lies in the continuity of data acquisition and in its availability. Dy-
namic changes in ICP, CPP, and cerebral oxygenation such as occur in patients with
large strokes who develop progressing hemispheric edema, call for continuous
monitoring. Only in this way can conclusions be drawn from trends, which is
hardly possible with serial observations. Furthermore, using this protocol of multi-
modal monitoring, the gain of information seems to be associated with fewer com-
plications than with conventional methods of ICP monitoring [19]. This is because
probes and burr holes are smaller, and fewer burr holes are needed, because up to
3 probes can be inserted through one screw. The smaller diameter of the probes
and how the probes can be fixed within the insertion screw reduces bleeding, infec-
tion, and disconnections. It should be borne in mind that we deal with a subgroup
of seriously ill and, mostly, relatively young stroke patients. We have repeatedly
seen and reported that these patients can profit from invasive treatment if the tim-
ing of treatment is optimized. It would be very dangerous to transport these pa-

tients during the period of critically elevated ICP, and thus it is not possible to per-
form CT or MRI. On the other hand, several studies have shown that the type of
monitoring that was used in our investigation is not linked with an increased risk
of complications if used by experienced personnel. Furthermore, it has not been
shown yet that other noninvasive methods can provide similar information [20].
Thus, we believe that multimodal monitoring is ethically acceptable in this sub-
group of patients. Although the number of patients is relatively small, the number
of measured episodes is comparatively large. Our results, however, indicate that
multimodal monitoring might have a major impact on therapy guided by monitor-
ing. Multimodal monitoring might help not only to control therapy but also to op-
timize the timing of invasive therapies in two ways: by avoiding a potentially dan-
gerous therapy and by identifying those patients who will profit most from this
therapy at an early stage in the course of the disease. Furthermore, multimodal
monitoring might help to increase our understanding of the pathophysiological
mechanisms underlying postischemic edema formation. The number of patients
does not allow any conclusions to be drawn about risk and cost-effectiveness at this
stage; these questions can only be answered in larger, carefully performed studies.
Various researchers have already concluded that multimodal monitoring is more
dependable and precise than arterial oxygen saturation (e.g. jugular bulb oxygena-
tion) or ICP alone [6-8, 9, 10]. In particular, ICP is always an indirect parameter of
the metabolic situation and is influenced by other processes. The application of
multimodal monitoring allows a direct, online determination of brain compliance
and metabolic changes in brain tissue. The placement of probes in the white matter
has several advantages to other measurement procedures:
I Oxygenation is measured directly in the region of interest
I Data are obtained continuously in real-time
I Therapeutic interventions can be monitored through more than just one param-
eter
I Only a small rate of complications is noted.
However, we showed that monitoring of drug therapy and interventions is possible

and might deliver very important online information on the brain compliance in
otherwise not assessable patients. The Pbr0 2 is the result of oxygen supply and de-
mand. Our study supports the assumption that hypothermia leads to a decrease in
the oxygen turnover [14].
The goal of multimodal monitoring is to improve therapy and individual care
for patients with stroke. Still, difficulties and problems remain unapproached:
Which clinical situations are correlated to significant changes in cerebral oxygen
pressure? Is it possible to use the evaluated parameters to assess outcome and prog-
nosis at an early stage of the disease? May we identify situations that lead to altera-
tions of the autonomous regulation? Another important question is whether we will
be able to apply our experiences to improve our therapy of stroke.
Multimodal parenchymal monitoring in acute stroke, although limited to criti-
cally ill patients, is a promising new method in neurological care. We are still
learning about its benefits, limitations and application in clinical routine. But by
gaining a better knowledge through more research, we may overcome current prob-
lems. By creating a more individual treatment with better outcome, patients may
benefit from this novel strategy.
764 T. Steiner and F. Meisel: Invasive Multimodal Online Monitoring in Severe Stroke Patients
References
1. Hacke W, Schwab S, Horn M, Spranger M, De Georgia M, von Kummer R (1996) "Malig-
nant" middle cerebral artery territory infarction. Arch Neurol 53:309-315
2. Berrouschot J, Sterker M, Bettin S, Koster J, Schneider D (1998) Mortality of space-occupy-
ing ("malignant") middle cerebral artery infarction under conservative intensive care. In-
3. Rieke K, Schwab S, Krieger D, et al (1995) Decompressive surgery in space occupying
hemispheric infarction: Results of an open, prospective trial. Crit Care Med 23:1576-1587
4. Schwab S, Steiner T, Aschoff A, et al (1998) Early hemicraniectomy in patients with com-
plete middle cerebral artery infarction. Stroke 29:1888-1893
5. Schwab S, Schwarz S, Spranger M, Keller E, Bertram M, Hacke W (1998) Moderate hy-
pothermia in the treatment of patients with severe middle cerebral artery infarction. Stroke
29:2461-2466
6. Bullock R, Chesnut RM, Clifton G, et al (1995) Guidelines for the Management of Severe
Head Injury. The Brain Trauma Foundation, New York
7. Rosner MJ, Rosner SD, Johnson AH (1995) Cerebral perfusion pressure: management pro-
tocol and clinical results. J Neurosurg 83:949-962
8. Unterberg AW, Kiening KL, Hartl R, Bardt T, Sarrafzadeh AS, Lanksch WR (1997) Multi-
modal monitoring in patients with severe head injury: evaluation of the effect of treatment
on cerebral oxygenation. J Trauma 42:S32-S37
9. Sheinberg M, Kanter MJ, Robertson CS, Contant CF, Narayan RK, Grossman RG (1992)
Continuous monitoring of jugular venous oxygen saturation in head injured patients. J
Neurosurg 76:212-217
10. Robertson CS, Narayan RK, Gokoslan ZL, et al (1989) Cerebral arteriovenous oxygen dif-
ference as an estimate of cerebral blood flow in comatose patients. J Neurosurg 70:222-230
11. Maas AIR, Fleckenstein W, de Jong DA, Wolf M 1993) Effect of increased ICP and de-
creased cerebral perfusion pressure on brain tissue and cerebrospinal fluid oxygen tension.
In: Avezaat CIJ, van Eijndhoven JHM, Maas AIR, Tans JTJ (eds) Intracranial Pressure VIII.
Springer, Berlin, pp 233-237
12. Maas AIR, Fleckenstein W, de Jong DA, Santbrink H (1993) Monitoring cerebral oxygena-
tion: experimental studies and preliminary clinical results of continuous monitoring of cer-
ebrospinal fluid and brain tissue tension. Acta Neurochir 59 (suppl):S0-57
13. Dings J, Jager A, Meixensberger J, Roosen K (1998) Brain tissue P0 2 and outcome after se-
vere head injury. Neurol Res 20:S71-S75
14. Steiner T, Pilz J, Schellinger P, et al (2001) Multimodal online monitoring in middle cere-
bral artery territory stroke. Stroke 32:2500-2506
15. Meixensberger J, Dings J, Kuhnigk H, Roosen K (1993) Studies of tissue p02 in normal
and pathological human brain tissue. Acta Neurochir 59 (suppl):58-63
16. van Santbrink H, Maas AI, Avezaat CJ (1996) Continuous monitoring of partial pressure of
brain tissue oxygen in patients with severe head injury. Neurosurgery 38:21-31
17. Sahuquillo J, Poca MA, Arribas M, Garnacho A, Rubio E (1999) Interhemispheric supraten-
torial intracranial pressure gradients in head-injured patients: are they clinically important?
J Neurosurg 90:16-26
18. Chambers IR, Kane PJ, Signorini DF, Jenkins A, Mendelow AD (1998) Bilateral ICP moni-
toring: its importance in detecting the severity of secondary insults. Acta Neurochir 71
(suppl):42-43
19. Aschoff A, Steiner T (1999) Messung von Hirndruck und Perfusionsdruck. In: Schwab S,
Erbguth F, Haman G, Hacke W (eds) Neurologische Intensivmedizin. Springer, Heidelberg,
pp 271-303
20. Stolz E, Gerriets T, Fiss I, Babacan SS, Seidel G, Kaps M (1999) Comparison of transcranial
color-coded duplex sonography and cranial CT measurements for determining third ventri-
cle midline shift in spaceoccupying stroke. Am J Neuroradiol 20:1567-1571
Critical Care of Myasthenic Crisis
N. Janjua and S. A. Mayer
I Introduction
Myasthenia gravis is an autoimmune disorder caused by antibodies directed against

the postsynaptic acetylcholine receptor (AchR) of skeletal muscle [1, 2]. The disease
carries a 2:1 female to male predominance and follows a bimodal age distribution,
peaking before age 50 among women and again in late midlife among men [3, 4].
Older cases of newly diagnosed myasthenia are more commonly associated with
thymoma. Myasthenic crisis, defined as respiratory failure requiring mechanical
ventilation, is a potentially life-threatening complication that occurs in approxi-
mately 15 to 20% of patients [2, 5]. An even greater percentage of all patients
affected with the disease experience some degree of respiratory muscle weakness
[2, 5, 6].
Approximately a third of patients who survive their first crisis will later experi-
ence a second crisis [2]. Although crisis can occur in any patient with myasthenia,
thymoma appears to be an important risk factor, since it is generally associated
with a more aggressive disease course [7, 8, 9], and is identified twice as often
among patients in crisis (,...., 30%) [2] as among myasthenics in general (,...., 15%)
[1, 10, 11].
I Precipitating Factors
Myasthenic crisis is most often precipitated by infection (40%); the most common
causes are bacterial pneumonia, viral upper respiratory tract infections, aspiration
pneumonitis, and bronchitis [12-14]. Accordingly, a thorough search for infection
should be performed in every patient admitted for crisis. However, it is probably
wisest to avoid full-course empiric antibiotics in patients with viral infections or
simple aspiration pneumonia, in order to minimize the risk of Clostridium difficile
colitis, which can have a devastating effect on the course of the illness [2].
Other important precipitants of crisis include changes in medications such as
withdrawal (or initiation) of steroids or withdrawal of anticholinesterase medica-
tion [2]. Aside from drugs used in the treatment of myasthenia gravis, there is a
wide range of medications known to worsen myasthenia, of which the intensivist
should be well aware (Table 1). When any myasthenic is admitted to the hospital, it
is important to identify and avoid such provoking factors. In addition, alpha-inter-
feron and d-penicillamine, used in the treatment of rheumatoid arthritis, may in-
766 N. Janjua and S. A. Mayer
Table 1. Drugs that can exacerbate weakness in myasthenia gravis. Adapted from [6) with permission
Antibiotics
- Aminoglycosides (gentamycin, streptomycin, others)
- Peptide antibiotics (polymyxin B, Colistin)
- Tetracyclines (tetracycline, doxycycline, others)
- Erythromycin
- Clindamycin
- Ciprofloxacin
- Ampicillin
Antiarrhythmics
- Quinidine
- Procainamide
- lidocaine
Neuromuscular junction blockers (vecuronium, pancuronium, others)
Quinine
Steroids
I Thyroid hormones (thyroxine, levothyroxine, etc.)
Beta-blockers (propranolol, timolol, others)
Phenytoin
D-penidllamine •
I Alpha-interferon a
• May induce autoimmune myasthenia gravis, see text
duce de novo immune mediated disease in a patient without a previously estab-

lished diagnosis [3].
Other medical comorbidities such as anemia, or concomitant exacerbations of
other autoimmune diseases such as systemic lupus erythematosis (SLE), and even
normal physiologic functions such as menstruation, pregnancy and parturition
[15] can trigger crises. Hyperthyroidism, usually in the form of Graves' disease, has
an increased association with myasthenia gravis [16]. Thyrotoxicosis may lead to a
hypermetabolic state causing increased total body C0 2 and producing excessive
work of breathing [17]. Furthermore, treatment of a hyperthyroid state with beta
adrenergic blocking agents may precipitate crisis in a patient with myasthenia [16].
In a full 30% of patients, no precipitating factor is identified, and the exacerba-
tion of myasthenic weakness appears to be spontaneous [2, 12].
I Differential Diagnosis
Occasionally, a patient presenting with new onset generalized weakness and respi-
ratory failure presents a diagnostic challenge. Other causes of ocular or oropharyn-
geal weakness and respiratory failure to be considered in the differential diagnosis
of myasthenia gravis include organophosphorus poisoning, Lambert-Eaton syn-
drome, Guillain-Barre syndrome, botulism, tick paralysis, polymyositis, critical ill-
ness myopathy, mitochondrial myopathy, motor neuron disease, diphtheria, Grave's
disease, and brainstem vascular lesions (e.g., aneurysm, arteriovenous malforma-
tion) [1, 3, 5, 6]. Even classic central nervous system (CNS) disease such as multi-
Critical Care of Myasthenic Crisis 767
---~--~~~~,--~--~~'"~,-~
pie sclerosis may mimic myasthenia gravis in its propensity for oculobulbar in-
volvement, symptom variability, and late-day fatigability.
Cholinergic Crisis
'Cholinergic crisis' is a controversial entity. In prior decades, depolarizing blockade
from standard acetylcholinesterase inhibitors such as pyridostigmine had been
thought to play a major role in precipitating crisis in a large subset of patients [6,
13, 18-20]. The diagnosis is supported by skeletal muscle weakness associated with
excessive secretions, diarrhea, sweating, bradycardia, fasciculations, and improve-
ment after discontinuation of anticholinesterase medication. Key in the differentia-
tion of between myasthenic crisis and crisis due to excessive cholinergic depolari-
zation is examination of the pupil size, which should be small or pinpoint in the
latter condition.
Clinical Presentation and Pathophysiology

Life-threatening respiratory compromise develops in myasthenic patients through
two mechanisms of equal importance:
1) respiratory muscle weakness (diaphragm and intercostals), which leads to im-
paired lung expansion, hypoventilation, and a weak cough, and
2) oropharyngeal weakness, which leads to aspiration of secretions and inability to
clear the upper airway.
Although crisis is usually associated with generalized weakness, 20% of patients do

not have limb weakness at the time of intubation [2]. With progressive respiratory
muscle weakness, the ability to maintain normal lung expansion is lost, and the
force of coughing is diminished, which prevents adequate clearing of the airway.
Patients are often asymptomatic in the early stages, but as weakness progresses (vi-
tal capacity < 30 ml!kg), atelectasis, reduced lung compliance, ventilation-perfusion
mismatch, and hypoxia develop. This leads to a further increase in the work of
breathing, and as vital capacity approaches 15 ml!kg, rapid shallow breathing and
hypercapnia develop. At this stage, the situation can rapidly and unexpectedly dete-
riorate once muscle fatigue develops and the patient can no longer compensate with
increased respiratory effort [6].
Diagnostic Testing
Attempt to establish a diagnosis is done by one of the following means: direct assay
of circulating antibodies, edrophonium (Tensilon®) administration, and electrical
testing. Each method has its limitations.
A variety of antibodies modulating AchR have been identified. The most com-
monly tested include binding antibodies, blocking antibodies, and modulating anti-
bodies. While AchR binding antibodies may be as high as 80% in patients with
general myasthenia, they are found in only 50% of ocular myasthenics [3]. There-
fore if the diagnosis of myasthenic crisis is highly suspected in a seronegative pa-

tient, treatment should not be withheld.
The interpretation of response to edrophonium, a rapid onset, short acting cho-
linesterase inhibitor, is highly subjective unless clear ptosis or other unequivocal
changes in extraocular movement are present. In a patient presenting in myasthe-
nic crisis, a more relevant measure may be to follow changes in the forced vital ca-
pacity before edrophonium or neostigmine and at several intervals afterwards, be-
ginning at two minutes post administration. Occasionally patients may acutely suf-
fer bradyarrhythmias following administration of cholinesterase inhibitors [3] and,
thus, should always be under direct supervision, including cardiac monitoring till
the duration of action of the drug is complete (in the case of edrophonium ap-
proximately ten minutes). A 1-2 mg dose is administered first, and if tolerated the
remaining 8 mg is pushed over 60 s.
The utility of electrical testing in diagnosing myasthenia gravis is dependent on
examiner and center expertise. Single fiber electromyogram (EMG) and repetitive
nerve stimulation, usually offered in academic centers, enhance the sensitivity of
neurophysiologic testing in myasthenia. For patients without limb involvement,
proximal nerves should be used, and where available, small facial nerves/muscles.
I Management
The initial management of the myasthenic patient with shortness of breath is direc-
ted toward assessing the adequacy of ventilation and possible need for immediate
intubation. The patient's overall comfort level and the rapidity with which the dys-
pnea has developed are both important to assess. Rapid, shallow breathing, with in-
ability to generate adequate tidal volumes, is an important danger sign of signifi-
cant respiratory muscle fatigue. Diaphragmatic strength can be estimated by pal-
pating for normal outward movement of the abdomen with inspiration; with severe
weakness, inspiration is associated with spontaneous inward movement of the dia-
phragm (paradoxical respirations). The patient's ability to count from 1 to 25 in a
single breath crudely and quickly assesses ventilatory reserve. The strength of the
patient's cough should be observed. A wet, gurgled voice and pooled oropharyngeal
secretions are the best clinical signs of significant dysphagia. When severe, weak-
ness of the glottic and oropharyngeal muscles can lead to stridor, which is indica-
tive of potentially life-threatening upper airway obstruction. The presence or ab-
sence of a gag reflex is a poor indicator of the patient's ability to swallow. Dyspha-
gia is best screened for by asking the patient to sip three ounces of water; coughing
is diagnostic of aspiration, and if present, the patient should be made 'nil by
mouth' until swallowing can be formally assessed by videoflouroscopy or other
means [6, 21]. In the interim, patients should be fed with small-bore nasoduodenal
tubes.
The simplest and most direct way to evaluate respiratory function in patients
with myasthenia is frequent bedside measurement of vital capacity. Arterial blood
gases are also important to monitor, but abnormalities (hypoxia and hypercarbia)
usually develop late in the cycle of respiratory decompensation, and thus are not
sensitive for detecting early ventilatory failure. As a general rule, intubation in
myasthenic patients with impending respiratory failure should be performed before
significant blood gas abnormalities develop. However, this is often difficult to ac-
complish in clinical practice.
Table 2. Pulmonary function tests in patients with myasthenic crisis. Adapted from (6] and (2] with
permission
Normal Criteria for Criteria for Criteria for

Intubation Weaning Extubation
Vital Capacity >60 ml/kg ::>:15 ml/kg ~10 ml!kg ~25 ml!kg
Negative Inspiratory Force > 70 cmH 20 <20 cmH20 ~20 cmH 20 ~40 cmH20
I Positive Expiratory Force > 100 cmH 20 <40 cmH 20 ~40 cmH 20 ~so cmH20
Vital capacity, the volume of exhaled air after maximal inspiration, is normally
60-70 ml!kg. Reduction of vital capacity to 30 rnl/kg is associated with a weak
cough, accumulation of oropharyngeal secretions, atelectasis, and hypoxemia. A vi-
tal capacity of 15 ml/kg ( ~ 11) is generally considered the level at which intubation
is required (Table 2). However, a number of other factors must also be considered,
including the rate of respiratory deterioration, arterial blood gas values, and the pa-
tient's overall comfort level and baseline vital capacity. In general, conservative
early intubation is recommended, since the early institution of positive pressure
ventilation may prevent increasing degrees of atelectasis, and lead to earlier extuba-
tion. Noninvasive positive pressure ventilation (NPPV) may be considered by some
clinicians as a temporizing measure to stabilize the patient and avoid intubation
[22]. However, this mode of ventilation does not protect against the risk of aspira-
tion from upper airway and pharyngeal weakness and in practice discomfort from
the mask precludes adequate rest for the patient.
We advocate admission to an intensive care unit (ICU) and serial measurements
of vital capacity (two to four times daily) for all myasthenic patients with dyspnea
and reduced vital capacity who do not require immediate intubation. Peak
respiratory muscle pressures also provide valuable information and should be
followed closely in myasthenia gravis patients. Negative inspiratory force, normally
< -70 cmH 20 (i.e., more negative than -70 cmH2 0), measures the strength of the dia-
phragm and other muscles of inspiration, and generally reflects the ability to main-
tain normal lung expansion and avoid atelectasis. Positive expiratory force, normally
> 100 cmH20, measures the strength of the muscles of expiration, and correlates with
strength of cough and the ability to clear secretions from the airway.
Criteria for intubation included vital capacity < 15 rnl/kg, peak inspiratory force
> -20 cmH2 0, and peak expiratory force < 40 cmH 2 0. These values, in the absence
of hypoxia, fever, pneumonia, or other adverse medical conditions, may also be
used to indicate readiness for weaning from mechanical ventilation [5, 6].
Nasotracheal intubation may be preferable to orotracheal intubation in myasthe-
nic patients because it is more comfortable and poses less risk of tube displace-
ment. All cholinergic medications should be discontinued upon intubation, because
they are unnecessary in an intubated patient and promote excessive secretions,
mucous plugging, and atelectasis. The initial goals of mechanical ventilation are to
promote lung expansion and provide rest. Early intubation and the use synchro-
nized intermittent mandatory ventilation (SIMV) with a high-pressure, high-volume
ventilator strategy may reverse and limit progressive alveolar collapse and atelec-
tasis. Larger tidal volumes ( ~ 15 rnl/kg) are combined with lower rates (6-8/min)
in order to maintain normal minute ventilation (6-10 l!min) and PC0 2 levels
( ~ 40 mmHg). Positive end-expiratory pressure (PEEP) is applied generously at
770 N. Janjua and S. A.Mayer
levels of 5-15 cmH 2 0, as long as peak airway pressures are maintained within
acceptable limits ( < 40 cmH 20). Because most patients in crisis do not have signifi-
cant lung disease (e.g., acute respiratory distress syndrome [ARDSJ) and have nor-
mal lung compliance, aggravation of pulmonary injury from barotrauma is not a
major concern. In addition to these measures, aggressive pulmonary toilet, with
fiberoptic bronchoscopy in some cases, is maintained to further prevent atelectasis
and lung consolidation.
Because one of the immediate goals of ventilation in myasthenia gravis patients
is to provide rest, intravenous sedation with short acting agents such as fentanyl,
propofol, lorezepam, or dexmetetomidate should be administered liberally the first
few days to avoid ventilator associated discomfort and anxiety. However, patients
who are on intravenous sedatives should have such medications interrupted regu-
larly to assess neurologic status [23]. This practice has been shown to reduce the
duration of mechanical ventilation. While in a dedicated neurocritical care unit this
practice is standard of care, this may not be the case for a neurologist called for
consultation in other critical care units.
Patients with longstanding myasthenic weakness and chronic C0 2 retention
should be intentionally hypoventilated (PC0 2 ~45 mmHg). Overventilating to nor-
mal or reduced PC0 2 levels will result in alkalosis and renal serum bicarbonate
wasting. This in turn will make it more difficult to successfully wean the patient,
due to loss of the capacity to buffer and respiratory acidosis that will ensue when
the patient is permitted to breath independently [6].
In our practice, anticholinesterase therapy is discontinued for as long as
myasthenia gravis patients remain on mechanical ventilation to avoid excess secre-
tions that may worsen atelectasis and lung consolidation. Though some have used
intravenous pyridostigmine in crisis patients, bradyarrhythmias may result from
this form of treatment [24, 25]. When switching from oral to intravenous forms of
medication, the physician should keep in mind dosing differences (Table 3). Failure
Table 3. Anticholinergic drugs used to treat myasthenia gravis. From [32] with permission
Route Equivalent Onset Maximal Dosage Range

Dosage Response
Pyridostigmine Bromide po• 60 mg 30 to 60 min 1 to 2 h 30-120 g

(Mestinon ~) q 3-8 h
IM, IVb 2 mg 5 to 10 min 20 to 30 min -
Pyridostigmine long-acting PO 1 to 2 h 3to 5 h 180 mg per
(Mestinon Timespan~~>) day at night
Neostigmine bromide PO 15 mg 30 min 1 hr 15-30 mg
(Prostigmon ~">) every
2 to 3 h
Neostigmine methylsulfate IVb 0.5 mg 1 to 2 min 20 min 0.5-1 mg
(Prostigmon~~> injectable) every 2 h
IM 1.5 mg 30 min 1 hour 1.5- 3 mg
every
2 to 3 h
• Can be given as a tablet or as a liquid

b Equivalent IV dose of pyridostigmine or neostigmine is one thirtieth of the oral dose
to adequately reduce corresponding intravenous to oral dose could result in a 30-

fold medication overdose. Additionally, mechanical difficulties arise in attempting
to administer the timed release form of pyridostigmine (Mestinon Timespan®) to
patients receiving nasogastric/duodenal tube feeds as this form of pyridostigmine
cannot be crushed.
I Weaning
Weaning of the myasthenic patient from mechanical ventilation should be initiated
when;
1) strength is improving;
2) vital capacity exceeds 10 ml/kg;
3) negative inspiratory force negatively exceeds -20 cmH2 0;
4) oxygenation is normal (Fi0 2 40o/o); and
5) the patient is free of infection or other medical complications.
We advocate weaning with daily trials (2-12 h) of continuous positive airway pres-
sure (CPAP) and pressure support to levels of 5-15 cmH2 0. Additionally, patients
should be hemodynamically stable and not have elevated airway resistance
(> 20 cmH2 0/Us) [17]. Pressure support is a preset level of pressure delivered with
each inspiratory effort, which reduces the overall work of breathing; the level
should be adjusted to attain spontaneous tidal volumes of 300-500 ml and a com-
fortable breathing pattern at a rate of 10-25 breaths per minute. Agitation or dis-
tress associated with an increased respiratory rate and decreasing tidal volume in-
dicates tiring, at which point the weaning trial should be stopped and the patient
returned to SIMV for rest overnight. The number of hours that the patient tolerates
CPAP, a reflection of endurance, should be considered the main outcome of the
weaning trial. Arterial blood gases are most useful at the end of a weaning trial,
when the patient becomes tired or uncomfortable, in order to determine whether
hypoxia or hypercarbia is present. Once the patient is able to tolerate CPAP for
prolonged periods (greater than four hours), the level of pressure support can be
gradually reduced by 1-3 cmH 20 each day, which allows the patient to gradually
assume more of the work of breathing. In many instances, the weaning process is
facilitated by giving low-doses of intravenous sedation (fentanyl or lorazepam) to
patients who are anxious, agitated, uncomfortable, or 'fighting' the ventilator [6].
In individual patients, the ability of the patient to tolerate CPAP with minimal
pressure support (5 cmH2 0} for extended periods of time (12-24 h) is probably the
single best predictor of successful extubation. We restart anticholinesterase therapy
at half the baseline dosage on the day of, or one day prior to, extubation. Fluctuat-
ing pulmonary function tests, excessive secretions, or concurrent medical problems
(i.e., infection, cardiovascular instability) are relative contraindication& to extuba-
tion. Extubation should always be performed early in the day, as some patients
may require reintubation within the next four to eight hours.
Previous analysis has identified risk factors present at baseline which are associated
with prolonged intubation:
1) preintubation serum bicarbonate 30 mg/dl
2) peak vital capacity postintubation < 25 ml/kg, and
3) age >50 years [2].
1.00
- Cum. survival
o Event times
"0 c Censor limes
~
"'
..c 0.75
;:!
.!:
0>
c
·c:
·;;; 0.50 ...~~-~~-~~~-~-~-~~-~-a~---··-···························-······
E
(!!
c
0
't: 0.25
0
Q.
2
Q.
0 14 28 42 56 70 84 98 112
Time (days)
Fig. 1. Kaplan-Meier survival curve depicting the proportion of patients remaining intubated (until death
or extubation) over time in 73 episodes of myasthenic crisis. Censored times are for three patients for
whom data were not available. Reproduced from [2] with permission
With reference to vital capacity, this is normally depressed the first two days after
intubation and should only be used for prognostication thereafter. Elevated serum
bicarbonate levels are probably a more reliable marker of chronic respiratory acido-
sis than preintubation PC0 2 levels, which may transiently normalize in some pa-
tients with increased respiratory effort. Although these three predictors of pro-
longed intubation need prospective validation, they may serve as clinically useful
criteria for estimating the need for mechanical ventilation beyond two weeks, the
interval at which tracheostomy is usually performed. The likelihood of successful
extubation can also be judged using pulmonary function tests. The same series
showed mean vital capacity at extubation of approximately 25 ml!kg (1.751), mean
peak inspiratory force of -40 cmH 2 0, and mean peak expiratory force of+ 50 cmH 2 0
[2].
The median duration of crisis in most published clinical series is two weeks
(Fig. 1), and this is the point at which most clinicians perform tracheostomy in pa-
tients who require continued mechanical ventilation. Tracheostomy has several ad-
vantages over long-term intubation, including:
1) increased comfort;
2) reduced risk of permanent tracheolaryngeal injury;
3) increased ease of weaning from the ventilator (reduced dead space and less re-
sistance to flow from the endotracheal tube); and
4) improved ability to manage and suction secretions.
---~--~~~~,--~--~~'"~,-~
I Immunotherapy
The mainstay of immunotherapy for short-term improvement of myasthenic symp-

toms is plasmapheresis. The mechanism by which this achieves effect in myasthe-
nia is by removal of AchR antibodies as well as other circulating complement com-
ponents [3, 26] and cytokines, which may give this treatment modality some theo-
retical advantage over intravenous immunoglobulin. Although widely used and con-
sidered effective, plasmapheresis for crisis has not been compared with placebo in
a controlled clinical trial [27, 28]. We institute plasmapheresis in almost all patients
in crisis unless contraindicated by medical comorbidity. Our standard regimen is
five exchanges of 2 to 3 1 every 1-2 days. After about four or five sessions, the de-
cline in AchR antibodies is not further reduced significantly [3]. A large bore cen-
tral catheter is often necessary to facilitate the exchange of large volumes of plas-
ma. Intravenous immunoglobulin, if administered, is dosed at 400 mg/kglday for
five days.
The use of steroids in acute crisis is controversial, as acutely they may worsen
the degree of muscle weakness in the already decompensated patient. Furthermore,
use of steroids may increase the rate of infection, precipitate hyperglycemia, and
lead to secondary muscle wasting and steroid-induced myopathy. We initiate ste-
roids (prednisone, 1 mg/kg) in patients who are in the midst of a prolonged crisis
(over two weeks) on the rationale that more aggressive immunosuppression will be
necessary to control their disease and wean them from mechanical ventilation.
Steroid sparing immunosuppressants such as azathioprine or cytoxan may be
begun at the discretion of the physician, but their effects are not complete for up
to six months, so it cannot be expected that these agents will reduce the duration
of crisis.
Complications
Medical complications are undoubtedly the largest modifiable risk factor for pro-
longed intubation in myasthenic crisis. In our experience, all medical complications
were associated with an excess number of days on mechanical ventilation [2]. Fever
was the most common complication (70%), followed by pneumonia (50%), atelecta-
sis (40% ), anemia treated with transfusion, C. difficile diarrhea, and congestive
heart failure. Complications of crisis were significantly more common in older pa-
tients [9]. Anemia treated with transfusion was associated with reduced hematocrit
at the start of crisis, and in the majority of cases resulted from the combined ef-
fects of bedrest, hydration, and phlebotomy, rather than gastrointestinal bleeding.
Based on these findings, we have developed management guidelines aimed at mini-
mizing complications and decreasing the duration of crisis. Given the high preva-
lence of atelectasis among patients in crisis, the importance of regular chest physi-
cal therapy and aggressive fiberoptic bronchoscopy for the treatment of severe at-
electasis or lobar collapse deserves special emphasis.
Complications of plasmapheresis include pneumothorax and infection related to
line placement, hypotension and congestive heart failure related to fluid shifts, and
mild coagulopathy related to depletion of coagulation proteins. Hemolysis second-
ary to kinking in the tubing and rarely, air embolization may also occur [4]. Also,
instances of phrenic nerve injury due to internal jugular cannulation attempts have
774 N. Janjua and S.A. Mayer
Table 4. Ten strategies to minimize the duration of myasthenic crisis. Adapted from [26) with permission
1. Perform conservative early intubation to prevent atelectasis, infiltrates, or worsening muscle

weakness that might occur if intubation is delayed
2. Discontinue anticholinesterase medications (i.e. pyridostigmine), which can aggravate
secretions and mucous plugging, immediately upon intubation
3. Initiate plasmapheresis as soon as possible. Insert a large bore central venous catheter
to avoid delayed or incomplete treatments early in the course of crisis due to inadequate
venous access
4. Avoid or discontinue medications which can exacerbate myasthenic weakness (Table 1)
5. Employ a ventilator strategy using large tidal volumes (- 15 ml/kg) and generous levels
of positive end expiratory pressure (5-15 cmH 20), to expand collapsed alveoli and prevent
further atelectasis
6. Perform fiberoptic bronchoscopy aggressively in patients with significant mucous plugging
or lung collapse, to clear trapped secretions and promote lung reexpansion
7. Reserve full-course antibiotics for culture-documented infections, to avoid Clostridium
difficile infection
8. Discontinue intravenous sedation daily and perform spontaneous breathing trials as soon
as possible
9. Diagnose and treat hypokalemia and hypophosphatemia, which can exacerbate muscle weakness
10. After two weeks, perform tracheostomy, which facilitates weaning by reducing dead space
and the extra work of breathing associated with an endotracheal tube
been reported in the literature [29-31]; which if caused would be particularly de-
vastating in a neuromuscular patient. We do not exchange patients with active fever
or infection, or severe anemia.
I Prognosis
Although it can be life-threatening, with proper respiratory support, myasthenic
crisis alone should never be fatal. The mortality of crisis has declined from over
40% in the early 1960s to approximately 5% since the late 1970s [2, 12], due pri-
marily to improvements in respiratory care and ICU management. Future efforts
should focus on reducing the duration of intubation and disability at hospital dis-
charge (Table 4) [6].
References
1. Drachman D (1994) Myasthenia gravis. N Eng! J Med 330:1797-1810
2. Thomas CE, Mayer SA, Gungor Y, eta! (1997) Myasthenic crisis: clinical features, mortality,
complications, and risk factors for prolonged intubation. Neurology 48:1253-1260
3. Pascuzzi R (2001) Pearls and pitfalls in the diagnosis and management of neuromuscular
junction disorders. Semin Neurology 21 :425- 440
4. Yavagal DR, Mayer SA (2002) Respiratory complications of rapidly progressive neuromus-
cular syndromes: Guillain-barre syndrome and myasthenia gravis. Semin Respir Crit Care
Med 23:221-228
5. Fink ME (1993) Treatment of the critically ill patient with myasthenia gravis. In: Ropper
AH (ed) Neurological and Neurosurgical Intensive Care, 3rd ed. Raven Press, New York, pp
351-362
---~--~~~~,--~--~~"~,-~
6. Mayer SA (1997) Intensive care of the myasthenic patient. Neurology 48 (suppl 5):S70-S75
7. Saltis LM, Martin BR, Traeger SM, Bonfiglio MF (1993) Continuous infusion of pyridog-
stigmine in the management of myasthenic crisis. Crit Care Med 21:938-940
8. Stricker RB, Kwiatkowska BJ, Habis JA, Kiprov DD (1993) Myasthenic crisis: response to
plasmapheresis following failure of intravenous gamma-globulin. Arch Neurol 50:837-840
9. Thomas CE, Mayer SA, Gungor Y, et al (1996) Effect of age on the course and outcome of
myasthenic crisis. Crit Care Med 24 (suppl):A70 (abst)
10. Donaldson DH, Ansher M, Horan S, Rutherford RB, Ringel SP (1990) The relationship of
age to outcome in myasthenia gravis. Neurology 40:786-790
11. Lewis, JE, Wick MR, Scheithauer BW, Bernatz PE, Taylor WF (1987) Thymoma. Cancer
60:2727-2743
12. Cohen MS, Younger D (1981) Aspects of the natural history of myasthenia gravis: crisis
and death. Ann NY Acad Sci 377:670-677
13. Ferguson IT, Murphy RP, Lascelles RG (1982) Ventilatory failure in myasthenia gravis. J
Neurol Neurosurg Psychiatry 45:217-222
14. Sellman MS, Mayer RF (1985) Treatment of myasthenic crisis in late life. South Med J
78:1208-1210
15. Burke ME (1993) Myasthenia gravis and pregnancy. J Perinat Neonatal Nurs 7:11-21
16. Tanwani LK, Lohano V, Ewart R, Broadstone VL, Mokshagundam SP (2001) Myasthenia
gravis in conjunction with Graves' disease: a diagnostic challenge. Endocr Pract 7:275-278
17. Manthous, Hall JB (1998) Liberation from mechanical ventilation, a decade in progress.
Chest 114:886-901
18. Jenkins R, Witorsch P, Smyth NP (1970) Aspects of treatment in myasthenia gravis. South
Med J 63:1127-1130
19. Osserman KE, Genkins G (1963) Studies in myasthenia gravis: reduction in mortality rate
after crisis. JAMA 183:97-101
20. Tether JE (1955) Management of myasthenic and cholinergic crises. Am J Med 19:740-742
21. DePippo KL, Holas MA, Reding MJ (1992) Validation of the 3 oz water swallow test for as-
piration after stroke. Arch Neurol49:1259-1261
22. Gracey DR, Divertie MB, Howard FM (1983) Mechanical ventilation for respiratory failure
in myasthenia gravis: two-year experience with 22 patients. Mayo Clin Proc 58:597-602
23. Kress JP, Pohlman AS, O'Connor MF, Hall JB (2000) Daily interruption of sedative infu-
sions in critically ill patients undertiong mecha nical ventilation. N Eng! J Med 342:1471-
1477
24. Berrouschot J, Baumann I, Kalichewski P (1997) Therapy of myasthenic crisis. Crit Care
Med 25:1228-1235
25. Saltis LM, Martin BR, Traeger SM, Bonfiglio MF (1993) Continuous infusion of pyridog-
stigmine in the management of myasthenic crisis. Crit Care Med 21:938-940
26. Thorlacius S, Mollnes TE, Garred P, et a! (1988) Plasma exchange in myasthenia gravis:
changes in serum complement and immunoglobulins. Acta Neurol Scand 78:221-227
27. Grob D, Arsura EL, Brunner NG, Namba T (1987) The course of myasthenia gravis and
therapies affecting outcome. Ann NY Acad Sci 505:472-499
28. Stricker RB, Kwiatkowska BJ, Habis JA, Kiprov DD (1993) Myasthenic crisis: response to
plasmapheresis following failure of intravenous gamma-globulin. Arch Neurol 50:837-840
29. Depierraz B, Essinger A, Morin D, Goy JJ, Buchser E (1989) Isolated phrenic nerve injury
after apparently atraumatic puncture o( the internal jugular vein. Intensive Care Med
15:132-134
30. Hadeed HA, Braun TW (1988) Paralysis of the hemidiaphragm as a complication of inter-
nal jugular vein cannulation: a report of a case. J Oral Maxillofac Surg 46:409-411
31. Topaz 0, Sharon M, Rechavia E, Mager A, Chetbuon I (1987) Traumatic internal jugular
vein cannulation. Ann Emerg Med 16:1394-1395
32. Marshall RS, Mayer SA (1997) On Call Neurology. WB Saunders, Philadelphia
Neuromuscular Abnormalities in Critical Illness
T. Sharshar, M.D. Outin, and B. de Jonghe
Introduction
It is now well established that critical illness can be complicated by neuromuscular
disorders, conventionally termed critical-illness neuromuscular abnormalities (CIN-
MA) that can affect nerve, neuromuscular junction or muscle. Failure to wean from
ventilatory support is a major cause of prolonged intensive care unit (ICU) stay
with associated morbidity, mortality and cost. CINMA may play a significant role
in this. In addition, it can have an impact on long-term functional outcome. De-
spite numerous studies on the incidence and risk factors for CINMA as well as its
clinical, electrophysiological and histopathological features, several key areas re-
main unclear. Specifically, the pathophysiological substrate of CINMA, the electro-
physiological and histological changes, and the relationship between these abnor-
malities and actual functional impairment have not been fully elucidated. In addi-
tion, advances in understanding of this condition have had only limited impact in
terms of developing effective preventative and therapeutic interventions. An excep-
tion to this is the recently established benefit of maintaining normoglycemia in cri-
tically ill patients. Systematic recognition of this condition requires intensivists to
be aware of its clinical findings, the indications for neurophysiological testing and
biopsy, and the tools for the assessment of respiratory muscle strength. Manage-
ment requires a multidisciplinary approach and does not stop at the ICU door.
History and Classification

Clarence Olsen reported in 1956 that peripheral nerve lesions could complicate a
variety of critical illnesses [1]. In 1984, Couturier et al. [2] and Bolton et al. [3]
both described cases of motor weakness developing after prolonged sepsis and
characterized electrophysiologically by an axonal sensory-motor polyneuropathy.
Previously, MacFarlane and Rosenthal [4] had observed an acute quadriplegic myo-
pathy in a patient treated with steroids and neuromuscular blocking agents for
acute severe asthma. Since then, neuromuscular disorders in critically ill patients
have been extensively reported but often heterogeneously categorized, according to
their clinical, electrophysiological, or histological features [5].
In addition to collections of case reports or small series [5], two different but
not exclusive approaches have been adopted. The first is to consider CINMA as a
distinct component of multiple organ failure (MOF) that may be detected earlier by
neurophysiological or neuropathological means [6]; the second is to focus on its
Neuromuscular Abnormalities in Critical Illness 777
clinical impact in areas of particular relevance to the intensivist such as paralysis

or weaning failure [7]. Accordingly, each approach addressed distinct populations
of critically ill patients: those with and without electrophysiological or histopatho-
logical neuromuscular abnormalities and those with and without clinical symptoms.
Moreover, these populations have been studied at different stages of their ICU stay;
i.e., for the first approach at an early stage (usually between the 5th and 7th day)
and, for the second approach, at a later stage when the patient can be clinically ex-
amined. Despite these discrepancies, which hamper the pooling of data from sepa-
rate studies, a clearer picture of CINMA has now developed.
Various classifications of CINMA have been proposed. It is usual to refer to the
classification, originally developed by Bolton (8] and recently updated by Hund [9]
in which four main entities are distinguished:
1) Critical illness polyneuropathy (CIP);
2) Critical illness myopathy (CIM);
3) Thick filament myopathy {TFM);
4) Necrotizing myopathy (NM).
There are a number of problems with this approach, however.
First, it is based on anatomical distinction (nerves versus muscles) and histolog-
ical findings but does not take into account clinical features or pathophysiological
mechanisms. It is clinically difficult to distinguish a myopathic from a neuropathic
weakness, all the more since CIP and CIM are often associated, leading to the use
of the term of critical illness polyneuromyopathy (CIPNM) [10, 11]. Electrophysio-
logical testing and, eventually, a biopsy are still necessary to confirm the diagnosis.
However, electrophysiological testing can be technically limited in critically ill pa-
tients and may fail to distinguish between neuropathy and myopathy. A biopsy is
an invasive procedure whose clinical and therapeutic benefits are questionable.
Second, the pathophysiological mechanisms of each category have not been com-
prehensively elucidated and overlap exists between them. For example, both CIP
and CIM are thought to result from an inflammatory process. Likewise, neuromus-
cular blocking agents have been implicated in the pathogenesis of both TFM and
NM. The fact that these entities share pathophysiological mechanisms and can oc-
cur simultaneously suggests that they are different expressions of the same patho-
physiological process. In addition, the different proposed mechanisms do· not nec-
essarily explain the weakness [12]. In other words, although abnormalities of
nerves or muscles are commonly present in critically ill patients and their patho-
genesis is beginning to be elucidated, it remains unclear how these abnormalities
relate to the presence or absence of clinically apparent weakness [12].
Third, this classification excludes weakness related to prolonged neuromuscular
blockade, which must be considered in patients having been treated by neuromus-
cular blocking agents (NMBAs) [13].
Fourth, this classification is only possible post-hoc, once diagnostic procedures
have been carried out. Finally, although these categories may have a physiological
interest this, hitherto, has not led to any therapeutic benefit, as no specific treat-
ment is available.
778 T. Sharshar et al.
I Incidence, Risk Factors and Pathophysiological Mechanisms
The incidence of CINMA varies considerably according to the inclusion and diag-
nostic criteria used. In many studies, a selected (e.g., patients with sepsis, cardio-
vascular surgery or organ transplantation) or relatively small population of criti-
cally ill patients has been included [5, 14]. Moreover, the diagnosis has sometimes
been based on electrophysiological and sometimes on histopathological findings.
Thus, the incidence of CINMA diagnosed by electrophysiological testing ranges
from 47 to lOOo/o [5, 15-17] and that based on histopathological findings from 71
to 96o/o [18]. Electrophysiological abnormalities have been found from the second
day in ICU [19]. In contrast, few studies have been focused on the incidence of
weakness related to CINMA. A recent multi-center French prospective study in a
general non-selected ICU population found that 25o/o of patients mechanically venti-
lated for more than 7 days had a muscle weakness at the time of recovery of awake-
ness [7].
The identification of risk factors for specific CINMA ought to be an important
step in understanding their pathogenesis and for the development of preventive or
curative therapy. Several indicators have been proposed, including inflammatory
mediators, metabolic derangement and therapy administered. Few prospective co-
hort studies including multivariate analyses of risk factors are available (Table 1).
The existence of MOF or severe sepsis, particularly if prolonged, is strongly as-
sociated with the occurrence of CINMA [5, 7-9, 20] . Studies have shown an inci-
Table 1. Risk factors of critical illness-neuromuscular abnormalities (CINMA) identified by multivariate

analyses
Study Population Incidence of CINMA Risk factors for CINMA

and diagnosis criteria (Multivariate analyses)
Witt et al. n=43, 30 cases (69.8%) Duration of mechanical ventilation

[15] Mechanical ventilation Electrophysiological before the diagnosis
>5 days, Hyperglycemia
Sepsis and 2 organ Hypoalbuminemia
failures
Campellone n=87, 7 cases (8.0%) Corticosteroids
et al. [28) Liver transplantation Clinical I APACHE-II
Garnacho- n=73, SO cases (68.5%) Plasma hyperosmolality
Montero Mechanical ventilation Electrophysiological Parenteral nutrition
et al. [25) > 10 days, NMBAs
Sepsis and organ failure I Central nervous system disorders
Renal replacement therapy
(protective effect)
De Jonghe n=95, 24 cases (25.3%) Duration of mechanical ventilation
et al. [7] Mechanical ventilation Clinical Female sex
"?.7 days Time with "?.2 organ failure
Corticosteroids
De Letter n=98 32 cases (33%) SIRS
et al. [20) Mechanical ventilation Clinical and electro- APACHE Ill
~7 days physiological
dence ranging from 70 to 94o/o of patients with severe sepsis or MOF developing a
CIP or CIPNM [7, 15, 17, 21]. In addition, severity of critical illness, organ dys-
function score and number of organs involved were higher in patients with CIP
[16, 20, 22]. We have recently shown that the number of days with more than two
organ dysfunctions is an independent risk factor for critical illness paralysis [7].
The presence of sepsis and MOF as risk factors has raised speculation about the
pathophysiological processes involved, notably the possibility that peripheral nerve
ischemia related to microcirculatory disturbances that would induce release of in-
flammatory cytokines (especially tumor necrosis factor [TNF]-a}, activation of
complement or formation of local free radicals [8, 9]. However, a characteristic his-
tological picture of nerve damage related to microcirculatory disturbances has not
been found in muscle specimens from affected patients [23] and TNF-a levels were
not higher in patients with CIP than in controls [24]. In contrast, local immune ac-
tivation was evidenced by a recent immuno-histological study [11] showing the
presence of macrophages, Th-cells, pro-inflammatory and anti-inflammatory cyto-
kines, adhesion molecules (intercellular adhesion molecule [ICAM], vascular cell
adhesion molecule [VCAM]) and an up-regulation of human leukocyte antigen
(HLA)-1 and HLA-DR in the muscle of patients with CIPNM. Moreover, in critically
ill patients, expression of HLA-DR , TNF-aR75 and interleukin (IL)-10 were higher
in those with CIPNM. Cytokines also have an effect on skeletal muscle protein me-
tabolism, by modulating enzymatic degradation and synthesis, and inhibiting the
actions of anabolic hormones on protein turnover. TNF-a is an important mediator
of sepsis-induced muscle catabolism through up-regulation of ubiquitin-proteasome
proteolytic pathways [9]. In addition to a loss of contractile proteins, muscle weak-
ness can result from an alteration of muscle membrane excitability that can be in-
duced by steroids or TNF-a [9]. Moreover, a circulating neurotoxic factor has been
found in some patients with CIP [22], but there was no significant correlation be-
tween electrophysiological diagnosis of CIP and serum neurotoxicity.
The duration of mechanical ventilation prior to the diagnosis of CINMA is also a
risk factor, irrespective of the duration of MOF [7, 15]. This finding suggests that dis-
use has a pathogenic role in mechanically ventilated patients who are often sedated.
Central neurologic failure has been identified as an independent risk factor of
CINMA [25]. This may be an association rather than a causal link as many causes
of encephalopathy can also induce CINMA.
Various therapeutic agents have been implicated in the pathogenesis of CINMA
[5, 9]. Corticosteroid myopathy is a well-established condition in non-ICU patients
characteristically causing type II fibre atrophy and myelinolysis. These lesions are
the consequence of muscle steroid-receptor stimulation by exogenous corticoste-
roids [26], which are upregulated by muscle denervation [27]. CIP or CIM has been
preferentially reported in patients treated for acute severe asthma or organ trans-
plantation [28]. It has been found recently that the administration of steroids is an
independent risk factor for critical illness paralysis. Although the two main indica-
tions for corticosteroids in this study were chronic obstructive pulmonary disease
(COPD) exacerbation and septic shock, their deleterious effects did not depend on
cumulative dose or treatment duration [7]. The former is of particular interest as
these patients often find weaning from mechanical ventilation problematic. Second,
although NMBAs (except succinylcholine) are considered to be involved in the
pathogenesis of TFM and NM [23, 29], neurogenic electrophysiological and histo-
pathological changes have been reported after prolonged use of NMBAs [10]. The
combination of NMBAs with steroids can be especially deleterious as denervation
induced by pharmacological blockade of the neuromuscular junction increases the

number of local steroids receptors [9]. However, use of NMBAs has been identified
as a risk factor in only one study [25]. Third, it has been reported that affected pa-
tients were more frequently treated with catecholamines, furosemide, or aminogly-
cosides [5, 6, 14, 16, 30]. However, these drugs have never been retained as risk
factors in a multivariate analysis.
Various metabolic derangements may induce a neuropathy but their role in the
pathogenesis of CINMA is unclear. First, several studies have shown that renal fail-
ure was more frequent in affected patients [7, 16, 22] and urea levels correlated
with electrophysiological severity [14, 16]. Renal insufficiency has not, however,
been retained as an independent risk factor. In addition, the possible role of renal
replacement therapy remains controversial. Renal replacement therapy was not a
risk factor in a study in open-heart surgery patients [30], had a protective effect in
the study conducted by Garmacho-Montero [25], and was an independent predictor
of CINMA in another recent study [31]. Second, blood glucose levels have been
shown to be higher in affected patients than in controls [7, 15, 32] and hyperglyc-
emia was an independent risk factor [15]. In addition, it has been shown that in
post-surgical patients the incidence of CINMA was lower when blood glucose levels
were strictly controlled by insulin [31]. Other metabolic factors, including dyskale-
mia, hypermagnesemia, dysphosphatemia, have been suspected but their patho-
genic role remains to be proven. The relationship between hypoalbuminemia and
CIP reported in some studies [32] has not been confirmed recently [14]. Nutritional
factors have also been implicated and parenteral nutrition has been recently identi-
fied as an independent risk factor for CIP [25].
We have recently identified female gender as an independent risk factor for criti-
cal illness paralysis. In this study, most women were older than 50 years old. This
finding raises the issue of endocrine factors in the pathogenesis of CINMA, notably
sex hormone deficiency.
From a pathophysiological point of view, the following conclusions can be
drawn. CIP and CIM are considered to result from inflammatory mediators, espe-
cially cytokines, released during sepsis or MOF. Hyperglycemia and nutritional fac-
tors seems to be involved in the pathogenesis of CIP. TFM and NM are considered
to be induced by corticosteroids and NMBAs but also potentialized by coexisting
CIP. It is obvious that all these pathogenic factors (sepsis, metabolic or nutritional
disturbances, treatment by steroids and NMBA) can coexist in a critically ill pa-
tient, resulting in a mixture of these four entities.
I Clinical Presentation
CINMA becomes clinically apparent either with the occurrence of motor weakness
or by a failure to wean from ventilatory support. Paralysis can be suspected in
semi-conscious patients when a painful stimulus induces a facial response but no
limb movement. Muscle weakness can be described using the Medical Research
Council (MRC) sum-score (Table 2) [33]. There is typically a symmetrical, flaccid
tetra-paresis sparing the face with decreased or absent tendon reflexes and muscle
wasting [5, 7, 9]. Normal, or even exaggerated, tendon reflexes do not preclude the
diagnosis of CINMA, however [34, 35]. Muscle atrophy may be masked by tissue
edema. In some cases, a mild motor weakness is observed at the time of wakeful-
Table 2. Medical Research Council sum-score [33]

Movement tested on each side Score for each movement
I Arm abduction 0=no movement

Flexion at the elbow 1 =flicker of movement
I Wrist extension 2 =movement with gravity eliminated
I Hip flexion 3 =movement against gravity
Extension at the knee 4 =movement against resistance
Foot dorsiflexion 5 =normal power
Each limb is scored from 0 to 15. The total score ranges from 0 (tetraplegia) to 60
ness, which recovers clinically in less than a week. Subjective or objective sensory
impairment favors the diagnosis of polyneuropathy but its absence does not pre-
clude the diagnosis.
Weaning failure in the presence of adequate gas exchange and cardiovascular sta-
bility may be due to respiratory muscle weakness. It has been claimed that neuro-
muscular impairment is the cause of 50 to 70% of weaning failure [36]. This diag-
nosis is more likely if neurological examination reveals a generalized muscle weak-
ness. Impaired cough and paradoxical abdominal movement during breathing must
be sought systematically. Respiratory muscle weakness can be missed at the time of
weaning and may be a cause of late acute respiratory failure after the discharge
from ICU [37]. Vital capacity (VC), maximal inspiratory and expiratory pressure
(Pimax and Pemax) measurement are straightforward means to evaluate muscle
respiratory strength and can be performed at the bedside and in intubated or tra-
cheostomized patients. If normal, they exclude respiratory muscle weakness. Re-
duced values however must be interpreted in the light of the patient's cooperation,
coordination, and motivation to achieve a correct measure of strength. Direct phre-
nic nerve injury must be considered where there is weaning failure following cardi-
ac surgery.
In patients where CINMA is considered possible, differential diagnoses must be ex-
cluded [9]. Spinal cord injuries must be ruled out by adequate neuroimaging in
any post-traumatic patient with weakness. Various neurological diseases can be de-
compensated or revealed by critical illness or intensive care treatment, such as
myasthenia gravis, motor neurone disease or acid maltase myopathy. Acute inter-
mittent porphyria is exacerbated by many of the drugs commonly administered to
critically ill patients. The diagnosis of Guillain-Barre syndrome or botulism can
also be missed at admission and organophosphate poisoning can also cause a dif-
fuse weakness. These diagnoses can often be ruled out by accurate history taking,
neurological examination and, if need be, electrophysiological testing or biopsy.
The existence of cerebral lesions must also not prevent an appropriate diagnosis of
co-existing CIP.
I Laboratory Parameters
Serum creatine kinase (CK) levels vary considerably in patients with CINMA. They
are usually normal or slightly increased in most types of CINMA [34] but can be
dramatically increased in NM [38]. Therefore, normal CK levels do not rule out the
diagnosis of CIMNA [22, 32]. Moreover, high levels can be observed in other condi-
tions (e.g., seizure, ischemic damage of the leg).
Cerebrospinal fluid (CSF) analysis has rarely been performed in patients with
CINMA and usually showed a normal or moderately elevated protein level [34].
There is no indication for a routine CSF analysis unless a differential diagnosis
such as Guillain-Barre syndrome is considered.
I Electrophysiological Findings
Standard electrophysiological testing consists of studies of motor nerves and sen-
sory nerves and needle electromyography of lower and upper limbs. This can be
completed by repetitive stimulation when a neuromuscular blockade related either
to NMBAs or neuromuscular diseases (myasthenia gravis, botulism) is suspected.
Electrophysiological testing can disclose combined or separately: 1) an axonal mo-
tor, sensory, or sensorimotor polyneuropathy; 2) a myopathy. Axonal polyneuropa-
thy is characterized by normal motor nerve conduction velocities but a decrease in
the compound muscle action potentials (CMAP). On needle electromyography stud-
ies there are fibrillation potential or positive sharp waves in a widespread distribu-
tion. Sensory nerve conduction studies show a decrease in the sensory nerve action
potentials (SNAPs). The typical electrophysiological signs of myopathy are, during
a voluntary effort, a decrease in motor unit potential amplitude and exaggerated re-
cruitment of these potentials in comparison to that generated by voluntary contrac-
tion. Myopathy is also characterized by normal SNAPs. Features of demyelination
should make one reconsider the diagnosis of CINMA.
Axonal polyneuropathy is the most common electrophysiological abnormality re-
ported. The respective incidence of pure sensory, pure motor and sensorimotor ax-
onal polyneuropathy has varied across studies, depending on the population se-
lected and technique used [35, 39, 40]. We found that sensorimotor axonal poly-
neuropathy was present in all paralyzed patients [7]. The degree of weakness and
reflex abnormality seems to be more severe in patients with sensorimotor poly-
neuropathy with or without denervation [40]. The co-existence of myopathic elec-
trophysiological features is seen in at least 40% of patients with axonal polyneuro-
pathy [35]. Isolated myopathic changes have only rarely been reported.
The utility and validity of these electrophysiological categories is questionable as
electrophysiological testing is often not sensitive enough to differentiate neuro-
pathic from myopathic changes. Electrophysiological testing can be hampered by
the electrical environment in the ICU, which produces artefacts~ It can also be lim-
ited by tissue edema or failure to achieve a sustained contraction, which may blunt
SNAP and lead to misinterpretation of electromyographic trace, respectively. Thus,
the lack or presence of SNAP does not rule out a neuropathy or myopathy. Muscle
spontaneous activity (fibrillation) and spontaneous positive sharp waves can also
exist in myopathy. Direct muscle fibre stimulation, quantitative electromyography
and motor unit number estimation, improve the electromyographic detection of
myopathy [39]. By using this means, it has been shown that myopathy is much
more common that polyneuropathy in critical illness [39].
Clinically, cranial nerves are spared, though facial muscle denervation has been
documented on- electromyography. Electrophysiological assessment of cranial nerves
is not indicated in routine clinical settings.
Electrophysiological testing of the phrenic nerves and diaphragm can complete
the electrophysiological investigation, notably in patients with weaning failure.
Phrenic nerve latencies or diaphragmatic CMAP were abnormal in 46 to 77% of pa-
tients with CIP [35, 41]. But, in patients with weaning failure, Sander et al. [42]
showed that:
I respiratory impairment in ICU patients may often be unrelated to either CIP or
diaphragmatic denervation;
1 only about half of ventilator dependent CIP patients have diaphragmatic dener-
vation;
1 diaphragmatic denervation in ICU patients frequently may be attributable to
causes other than CIP, such as mediastinal pathology. This study raises issue on
the relationships between CINMA and weaning failure.
We think that the two main indications for standard electrophysiological testing are
weakness and respiratory failure. This testing should be done in patients in whom
another neurological diagnosis is suspected or if weakness or weaning failure per-
sists. In our study, we electrophysiologically investigated our patients if weakness
persisted seven days after the return of wakefulness [7]. There is no indication to
perform electrophysiological testing routinely at an early stage in critical illness as
it as yet is unlikely to influence management.
I Histopathological Findings
Nerve biopsies have shown primary acute axonal degeneration in 36 to 100% of pa-
tients with CINMA [32, 34, 43]. Demyelination is not found. Nerve biopsies can
also be normal in up to 64% of patients [32], highlighting discrepancies between
electrophysiological results and histological findings. This discrepancy can be ex-
plained by the time of nerve biopsy, as histopathological changes are more pro-
nounced with course of the disease. Moreover, lack of histological abnormalities
does not preclude existence of axonal dysfunction [44] or the existence of damage
at the horn cell level.
Muscle biopsy [9] can show neurogenic atrophy usually observed in CIP or pri-
mary myopathic changes that include:
I fiber abnormalities (abnormal size, atrophy, fatty degeneration, nuclei interna-
lised nuclei, rimmed vacuoles) usually observed in CIM;
I loss of type-II fibers and myosin (thick) filament that led to the term of TFM;
I muscle fibers necrosis that was reported in necrotizing myopathy but also in CIP
and CIM.
In patients with well-documented CIPNM, neuropathic changes were present in

37% of cases, myopathic changes in 40%, both neuropathic and myopathic changes
in 23% and muscle necrosis fibers in 30% [11]. Respective incidence of these ab-
normalities depends on the population studied, their exposure to drug or sepsis
and the time of muscle biopsy in the disease course. In patients with CINMA iden-
tified by weakness, muscle biopsy shows a fiber-11 atrophy with myosinolysis and
myonecrosis in 100% and 50% of cases respectively [7]. In patients with CINMA
electrophysiologically identified, fiber atrophy was the most frequent abnormality,
the next being muscle fiber necrosis and neurogenic atrophy and type II fiber atro-
phy [40]. In a single patient, all these abnormalities can be present. Serum CK
levels do not correlate with histological findings. There is also no clear relation
between histolopathological and neurophysiological changes, although patients with
normal electrophsyiological testing had no histological abnormalities [40 ].
Biopsy is an invasive procedure whose clinical and therapeutic benefit is limited.
There is no indication for biopsy in routine clinical practice unless a differential
diagnosis is suspected.
I Assessment of Diaphragmatic Dysfunction

An accurate assessment of diaphragmatic strength requires invasive tests that mea-
sure variation in esophageal (Pes), gastric, transdiaphragmatic pressure generated
by a voluntary maximal contraction and by magnetic stimulation of the phrenic
nerves. In intubated or tracheostomized patients, intratracheal pressure can be
measured instead of Pes. These techniques have been recently reviewed [45].
I Prognosis
CINMA is associated with increased mortality, weaning failure and functional abil-
ity. ICU mortality rate was significantly higher in patients with neurophysiologi-
cally documented CIP than in those without {48 versus 14%) [6]. This mortality is
likely related to sepsis and MOE Garnacho-Montero et al. [25] reported that in-
hospital mortality but not ICU-mortality was significantly increased in electrophys-
iologically documented CIP {84 versus 55%). However, CIP has never been reported
as an independent predictor of ICU or hospital mortality. In a two-year follow-up
study, the mortality rate in 19 patients with CIP was 10% [44]. We have found that
28% of ICU-paralyzed patients died over 9 months of follow-up [7].
The duration of mechanical ventilation has been repeatedly found to be longer
in patients with CIP [25, 46] or ICU-acquired paralysis [7], except in two studies
[16, 42]. Demonstration that CINMA itself, as distinct from the various risk factors
for CINMA, is an independent cause of weaning failure awaits confirmation by ade-
quately powered prospective studies using multivariate analysis. Other concomitant
risk factors for weaning failure such as cardiac failure, COPD or cachexia must be
considered.
CINMA is characterized by spontaneous recovery but the time course of this
varies considerably and unpredictably. The long-term functional prognosis of CIN-
MA depends on the population selected, duration of follow-up, and criteria of dis-
ability used [47]. Functional sequellae in patients with CIP ranged from 22 to 53%
after at least one year of follow-up [16, 41, 44]. Outcome appears difficult to predict
with clinical or electrophysiological data. Three parameters have been reported to
be correlated with poor recovery: duration of stay in the critical care unit, duration
of sepsis, and weight loss [44]. We found that the median duration of paralysis was
21 days and that one patient of 15 survivors remained paralyzed after nine months
[7]. A recent review of rehabilitation outcomes in the literature pointed out that the
validity of the studies was moderate to poor, most outcome measures used were
considered to be less relevant for rehabilitation medicine, and that it remains un-
clear whether long-term outcome is determined by CINMA itself or by other fac-
tors, such as initial illness and co-morbidity [47]. This emphasizes the necessity of
studies on long-term outcome of CINMA.
Therapy
It is likely that effective therapy to resolve sepsis or MOP and shorten the duration
of mechanical ventilation and immobilization would have a positive effect on CIN-
MA. It seems also reasonable to weight the patient's need of sedation, NMBA and
steroids. Strict control of glycemia by insulin is the only strategy that has been
shown, in a randomized trial, to reduce the incidence (by 44%) of CIP in surgical
patients [31]. The impact of renal replacement therapy could be similarly assessed.
Physiotherapeutic maneuvers such as passive mobilization or electrical stimulation
of limbs deserves to be tested.
Intravenous immunoglobulin (Ivlg) has been proposed as a curative therapy. A
retrospective study showed that Ivlg administered in 33 patients who survived
MOP or Gram-negative sepsis may prevent or mitigate CIP [48]. However, Ivig was
not found to improve neurological outcome of CIP in three patients [49]. Once
CINMA has been diagnosed, intensive physiotherapy, decubitus and thrombosis
prophylaxis should be provided as well as psychological support and accurate infor-
mation on the functional prognosis. After discharge from the ICU, patients with
CINMA should enter an intensive rehabilitation program.
An assessment of respiratory muscle strength by measurement of VC, Pimax and
Pemax should be done systematically in patients with CINMA or even in patients
with prolonged mechanical ventilation before their discharge from ICU, in order to
avoid subsequent neuromuscular respiratory failure [37].
I Conclusion
CINMA are undoubtedly a frequent complication of critical illness whose identified
risk factors are sepsis, organ failure, mechanical ventilation, and use of steroids.
The role of renal replacement, NMBAs and parenteral nutrition deserves to be con-
firmed. Inflammatory mediators and, recently, female gender are implicated. CIN-
MA are usually revealed by generalized weakness or weaning failure. The measure-
ment of MRC score, VC, Pimax and Pemax is often sufficient for detection of skele-
tal muscle and respiratory muscle weakness. Electrophysiological testing is often
required to confirm a CINMA but also to rule out a differential diagnosis. Indica-
tion for muscle biopsy should be discussed case by case. In order to prevent or di-
minish the risk of CINMA, control of glycemia but also careful use of steroids and
NMBAs are important. Curative therapy for CINMA is not available. Rehabilitation
and psychological support are both important. Demonstration that CINMA itself is
an independent risk factor for weaning failure and long-term disability awaits con-
firmation by adequately powered prospective studies using multivariate analysis.
Management of patients with CINMA requires the full multidisciplinary team to

engage in the short-term but also long-term functional outcome.
Acknowledgement. The authors thank Nicholas S. Hopkinson for his helpful com-
ments and assistance.
References
1. Olsen C (1956) Lesions of peripheral nerves developing during coma. JAMA 160:39-41
2. Couturier J, Robert D, Monier P (1984) Polynevrites complicant des sejours prolonges en
reanimation. Lyon Med 252:247-249
3. Bolton C, Gilbert J, Fhahn A, Sibbald W (1984) Polyneuropathy in critically ill patients. J
Neurol Neurosurg Psychiatr 47:1223-1231
4. MacFarlane I, Rosenthal F (1977) Severe myopathy after status asthmaticus. Lancet ii:615
5. De Jonghe B, Cook D, Sharshar T, et al (1998) Acquired neuromuscular disorders in criti-
cally ill patients: a systematic review. Intensive Care Med 24:1242-1250
6. Leijten F, Harinck-de-Weerd J, Poortvliet D, de-Weerd A (1995) The role of polyneuropathy
in motor convalescence after prolonged mechanical ventilation. JAMA 275:442-443
7. De Jonghe B, Sharshar T, Lefaucheur J, et al (2002) Paresis acquired in the intensive care
unit: A Prospective Multicenter Cohort Study. JAMA 288:2859-2867
8. Bolton C (1996) Sepsis and the systemic inflammatory response syndrome: neuromuscular
manifestations. Crit Care Med 24:1408-1416
9. Hund E (2001) Neurological complications of sepsis: critical illness polyneuropathy and
myopathy. J Neurol 248:929-934
10. Op-de-Coul A, Verheul G, Leyten A, Schellens R, Teepen J (1991) Critical illness polyneu-
romyopathy after artificial respiration. Clin Neurol Neurosurg 93:27-33
11. De Letter MACJ, van Doorn PA, Savelkoul H, et al (2000) Critical illness polyneuropathy
and myopathy (CIPNM): evidence for local immune activation by cytokine-expression in
the muscle tissue. J Neuroimmunol106:206-213
12. Breuer A (1999) An outdated concept. Muscle Nerve 424-424
13. Segredo V, Caldwell J, Matthay M, et al (1992) Persistant paralysis in critically ill patients
after long-term administration of vecuronium. N Engl J Med 327:524-528
14. Thiele Rl, Jakob H, Hund E, et al (2000) Sepsis and catecholamine support are the major
risk factors for critical illness polyneuropathy after open heart surgery. J Thorac Cardio-
vasc Surg 48:145-150
15. Witt N, Zochodne D, Bolton C, et al (1991) Peripheral nerve function in sepsis and multi-
ple organ failure. Chest 99:176-184
16. Leijten F, de-Weerd A, Poortvliet D, et al (1996) Critical illness polyneuropathy in multiple
organ dysfunction syndrome and weaning from the ventilator. Intensive Care Med 22:856-
861
17. Berek K, Margreiter J, Willeit J, et al (1996) Polyneuropathies in critically ill patients: a
prospective evaluation. Intensive Care Med 22:849-855
18. Coakley J (1993) Preliminary observations on the neuromuscular abnormalities in patients
with organ failure and sepsis. Intensive Care Med 19:323
19. Tennila A, Salmi T, Pettila V, et al (2000) Early signs of critical illness polyneuropathy in
ICU patients with systemic inflammatory response syndrome or sepsis. Intensive Care Med
26:1360-1363
20. De Letter MACJ, Schmitz PIM, Visser LH, et al (2001) Risk factors for the development of
polyneuropathy and myopathy in critically ill patients. Crit Care Med 29:2281-2286
21. Hund E, Genzwurker H, Bohrer H, et al (1997) Predominant involvement of motor fibres
in patients with critical illness polyneuropathy. Br J Anaesth 78:274-278
22. Druschky A, Herkert M, Radespiel-Troger M, et al (2001) Critical illness polyneuropathy:
clinical findings and cell culture assay of neurotoxicity assessed by a prospective study. In-
23. Zochodne D, Ramsay D, Saly V, Shelley S, Moffatt S (1994) Acute necrotizing myopathy of
intensive care: electrophysiological studies. Muscle Nerve 17:285-292
24. Verheul GA, de Jongh-Leuvenink J, Op de Coul AA, van Landeghem AA, van Puyenbroek
MJ (1994) Tumor necrosis factor and interleukin-6 in critical illness polyneuromyopathy.
Clin Neurol Neurosurg 96:300-304
25. Garnacho-Montero J, Madrazo-Osuna J, Garcia-Garmendia JL, et al (2001) Critical illness
polyneuropathy: risk factors and clinical consequences. A cohort study in septic patients.
26. Konagaya M, Bernard PA, Max SR (1986) Blockade of glucocorticoid receptor binding and
inhibition of dexamethasone-induced muscle atrophy in the rat by RU38486, a potent glu-
cocorticoid antagonist. Endocrinology 119:375-380
27. Du Bois DC, Almon RR (1981) A possible role for glucocorticoids in denervation atrophy.
Muscle Nerve 4:370-373
28. Campellone J, Lacomis D, Kramer D, Cott AV, Giuliani M (1998) Acute myopathy after liver
transplantation. Neurology 50:46-53
29. Ramsay D, Zochodne D, Robertson D, Nag S, Ludwin S (1993) A syndrome of acute severe
muscle necrosis in intensive care unit patients. J Neuropathol Exp Neurol 52:387-398
30. Thiele Rl, Jakob H, Hund E, et al (1997) Critical illness polyneuropathy: a new iatrogeni-
cally induced syndrome after cardiac surgery? Eur J Cardiothorac Surg 12:826-835
31. Berghe Gvd, Wouters P, Weekers F, et al (2001) Intensive insulin therapy in the critically ill
patients. N Engl J Med 345:1359-1367
32. Latronico N, Fenzi F, Recupero D, et al (1996) Critical illness myopathy and neuropathy.
Lancet 347:1579-1582
33. Kleyweg R, VanDerMeche F, Schmitz P (1991) Interobserver agreement in the assessment
of muscle strength and functional abilities in Guillain-Barre syndrome. Muscle Nerve
14:1103-1109
34. Hund E, Fogel W, Krieger D, De-Georgia M, Hacke W (1996) Critical illness polyneuropa-
thy: clinical findings and outcomes of a frequent cause of neuromuscular weaning failure.
35. Zifko UA, Zipko HT, Bolton CF (1998) Clinical and electrophysiological findings in critical
illness polyneuropathy. J Neurol Sci 159:186-193
36. Lemaire F (1993) Difficult weaning. Intensive Care Med 19:S69-73
37. Latronico N, Guarneri B, Alongi S, Bussi G, Candiani A (1999) Acute neuromuscular respira-
tory failure after ICU discharge. Report of five patients. Intensive Care Med 25:1302-1306
38. Barrett S, Mourani S, Villareal C, Gonzales J, Zimmerman J (1993) Rhabdomyolysis asso-
ciated with status asthmaticus. Crit Care Med 21:151-153
39. Trojaborg W, Weimer L, Hays A (2001) Electrophysiological studies in critical! illness asso-
ciated weakness: myopathy or neuropathy- a reappraisal. Clin Neurophysiol 112:1586-1593
40. Coakley J, Nagendran K, Yarwood G, Honavar M, Hinds C (1998) Patterns of neurophysio-
logical abnormality in prolonged critical illness. Intensive Care Med 24:801-807
41. Zifko UA (2000) Long-term outcome of critical illness polyneuropathy. Muscle Nerve
999:S49-S52
42. Sander HW, Saadeh PB, Chandswang N, Greenbaum D, Chokroverty S (1999) Diaphrag-
matic denervation in intensive care unit patients. Electromyogr Clin Neurophysiol 39:3-5
43. Leijten F, de-Weerd A (1994) Critical illness polyneuropathy. A review of the literature, de-
finition and pathophysiology. Clin Neurol Neurosurg 1996:10-19
44. de Seze M, Petit H, Wiart L, et al (2000) Critical illness polyneuropathy. A 2-year follow-
up study in 19 severe cases. Eur Neurol 43:61-69
45. Polkey M, Moxham J (2001) Clinical aspects of respiratory muscles dysfunction in the cri-
tically ill. Chest 119:926-939
46. Coronel B, Mercatello A, Couturier J, et al (1990) Polyneuropathy: potential cause of diffi-
cult weaning. Crit Care Med 18:486-489
47. Van der Schaaf M, Beelen A, Groot Id (2000) Critical illness polyneuropathy: a summary
of the litterature on rehabiliatation outcome. Dishability and Rehabiliation 22:808-810
48. Mohr M, Englisch L, Roth A, Burchardi H, Zielmann S ( 1997) Effects of early treatment
with immunoglobulin on critical illness polyneuropathy following multiple organ failure
and gram-negative sepsis. Intensive Care Med 23:1144-1149
49. Wijdicks E, Fulham J (1994) Failure of high-dose intravenous immunoglobulins to alter
the clinical course of critical illness polyneuropathy. Muscle Nerve 17:1494-1495
I Emergency Medicine ... I
lnterhospital Pediatric Intensive Care Transport
G.D. Vos and G. Ramsay
I Introduction
Recent developments in providing intensive care for children have lead to centrali-
zation in tertiary centers. The reason is the evidence that critically ill children show
a better clinical outcome when treated in tertiary pediatric intensive care units
(ICUs) than when treated in non-tertiary pediatric centers [1-4]. Major problems
hindering the transfer of all children, requiring tertiary pediatric intensive care, to
specialized centers are:
the lack of sufficient pediatric intensive care beds in tertiary centers
I the reluctance of physicians in general hospitals to refer these critically ill chil-
dren, and
I the organization of safe transportation of these children on a regular basis.
From the literature it is known that interhospital transport of critically ill children
by non-trained personnel tends to be associated with a higher incidence of major
complications than transport by specialized pediatric retrieval teams [5-8). Specia-
lized transport teams are able to produce a higher degree of stabilization of the pa-
tient prior to and during transport [6, 7]. Specialized pediatric retrieval teams must
provide all equipment and materials necessary for advanced life support and emer-
gency treatment of children of all ages and body weights. It is generally accepted
that instability of the patient and complications during transport are minimized by
optimal resuscitation and stabilization prior to transport [9-12] and by avoiding
interruptions in ventilation and monitoring en route [13].
Centralization of Pediatric Intensive Care
In a study in the US [2], it was shown that the mortality of infants and children
needing intensive care treated in non-tertiary centers was 10% higher than in ter-
tiary centers (odds ratio 1.1) when their calculated risk of mortality (PRISM) was
less than 5%. In the more severe illness group (PRISM 5-30%) the increase in mor-
tality was 230% for the group of patients treated in a non-tertiary center versus ter-
tiary center, while in the highest mortality group (PRISM more than 30%) the in-
crease was 8 times (Table 1 a).
In a comparison study [1] of Trent, a province in the UK with fragmentated in-
tensive care for children, versus Victoria, a province in Australia with highly orga-
nized tertiary pediatric intensive care, the odds ratio for the risk of death was 2.09
792 G. D. Vos and G. Ramsay
Table 1a. Odds ratios of the observed mortality of pediatric intensive care patients in non-tertiary inten-
sive care units in comparison to tertiary centers [2]
PRISM <S% 5-30% >30%

Odds ratio 1.1 2.3 8.0
Table 1 b. Comparison of Trent (fragmentated ICU care for pediatric patients) versus Victoria (centraliza-
tion of pediatric intensive care) [1]
Trent Victoria
Admission rate 1.22/1000 1.18/1000

Length of stay (days) 3.93 2.14
Mortality rate 7.3 5.0
Odds ratio risk of death Trent vs Victoria 2.09 (adjusted for severity of illness)
Table 2. Indications for referral to a tertiary center
IPrimary indication for referral Percentage
Respiratory failure 50.7

Circulatory 35.3
Neurologic 11.5
Metabolic 2.4
I Other 0.1
100.0
adjusted for severity of illness (Table 1 b). The calculated excess death of pediatric
patients in the ICU was 42.8% for Trent in comparison to Victoria. The excess
death of all deaths in children in Trent was 11.1 %. The authors made the interpre-
tation that for the whole UK there was an excess death of 453 pediatric patients an-
nually. The same results of improvement of care of pediatric intensive care patients
in tertiary centers was shown in a Dutch study [3].
With these and other studies [1-4] showing that critically ill children have a bet-
ter outcome if treated in tertiary pediatric ICUs rather than in non-tertiary pedia-
tric centers the provision of intensive care for children has become centralized in
tertiary centers in most countries. This trend towards centralization brings the
need for a professional interhospital pediatric intensive care transport system.
The general criteria for the transfer of critically ill infants and children to ter-
tiary centers are given by Pollack et al. [2] and the American Academy of Pediatrics
[14]. In general these criteria can be compressed to the need for artificial ventila-
tion for a period longer than 24 hours or more than one organ dysfunction. The
reasons for transfer are in practice very wide as shown in a recent study in the
Netherlands (Table 2), the results being similar to those reported in the literature
[5, 6]. Respiratory insufficiency was the primary indication for transfer in one half
of the cases. Most of these patients were suffering from a respiratory syncytial
lnterhospital Pediatric Intensive Care Transport 793
---~--~~~~,--~--~~"~,-~
virus (RSV) infection, while upper airway obstruction and pneumonia were also
frequently given diagnoses of respiratory insufficiency. Circulatory insufficiency
also turned out to be an important primary indication for transfer. Septic shock,
especially meningococcal septic shock was the most frequently mentioned diagno-
sis in this group. Within the group of patients with neurological disturbances the
most frequently reported diagnosis was status epilepticus.
Accompanying Personnel for Pediatric Intensive Care Transport

Most studies comparing professional transport teams and transports accompanied
by non-experienced specialists are case studies without comparison of the two
groups in one study or without retrospective comparison [5, 6]. Prospective studies
have not been published. Recently one case-control study of the interhospital trans-
port of adult intensive care patients has been published [7]. In this study it was
shown that the use of a specialist transfer team may significantly improve the acute
physiology of critically ill patients and may reduce early mortality in the ICU. In a
study of 331 pediatric interhospital transports of children with meningococcal dis-
ease a significant improvement in outcome was shown for children admitted to a
pediatric ICU in association with improvements in initial management at the refer-
ring hospitals, the use of a mobile intensive care service, and the centralization of
care in a specialist unit [8].
Complications of intensive care transport in general and especially pediatric in-
tensive care transport have been described in the literature with a variation of com-
plications from 5 to 75% [5, 7, 13, 15-19]. There is a difference in the definition of
complications during transport of critically ill patient between these articles and
there is no uniformity according to the time of these complications (before, during,
or directly after transport). The majority of complications given in the literature
are a decrease in the Pa0 2/Fi0 2 ratio, variation of end-tidal C0 2 , and fall in blood
pressure. Mortality during transport is rare and the cause of death, whether techni-
cal failure, incorrect decision for transfer, or insufficient training and expertise is
not given. One case control study in adult intensive care transport reveals a signifi-
cantly higher mortality rate in transported patients compared to not transported
patients in a matched population for severity of illness (APACHE-II}, 51 versus
23% (p<O.Ol) [17].
In a recent Dutch study there was a high incidence of complications reported
during transports accompanied by non-trained specialists over the last three years
(Table 3). Complications during an average transport were reported by 42.4% of
the respondents. Circulatory complications were reported in 44.2% (hypotension,
bradycardia, tachycardia, circulatory arrest}, respiratory complications in 18.3%
(ventilatory, accidental detubation, endotracheal tube obstruction), complications
with the maintenance of body temperature in 6.7% and neurological deterioriation
in 11.6%. These reported complications during transports accompanied by non-
trained specialists are similar to those in the study of Barry et al. [5], who also re-
ported a high incidence of serious and critical events during pediatric intensive
care transports accompanied by non-experienced specialists.
These studies show that a professional team should accompany interhospital pe-
diatric intensive care transport. The members of this team may differ in various
countries but should include a medical specialist and/or a nurse, both trained in
pediatric intensive care and in the transport of critically ill patients.
Table 3. Complications during interhospital pediatric intensive care transport accompanied by non-experi-
enced specialists
Complication Percentage •
None 57.6
Hypotension/shock 25.9
Neurological detoriation 11 .6
Bradycardia 10.3
Ventilation problems 8.0
Loss of IV line 8.0
Tachycardia 6.7
Endotracheal tube obstruction 5.8
Hypothermia 4.9
Accidental detubation 4.5
I Hyperthermia 1.8
Asystole 0.9
Pulseless electrical activity 0.4
Other 3.1
a Percentages do not add up to lOOo/o, because the respondent could report multiple complications
I Equipment for Pediatric Intensive Care Transport

A Dutch study shows that the equipment and the materials available during trans-
ports accompanied by non-trained specialists appear to be non-standardized and
do not match the criteria for the monitoring and treatment during transfer of criti-
cally ill patients (Table 4). Equipment for the monitoring of some vital signs like
electrocardiograph (EKG), respiration, pulse oximetry, and non-invasive blood
pressure was reported to be available during the majority of transports. More ad-
vanced monitoring in the critically ill patient like capnography, invasive blood
pressure, and temperature was unavailable during most transports. Therefore, in
our opinion the level of monitoring during the majority of these transports is com-
parable with the level of medium care, and far from the level of intensive care, as it
should be in such situations.
During these transports accompanied by non-trained specialists of infants and
small children {less than 15 kg), artificial ventilation was mostly done by handbag-
ging, because there was generally no ventilator available during transport suitable
for these patients. In older children, artificial ventilation was also done by hand-
bagging in most transports, because of a lack of knowledge of the ventilator present
during transport. During most transports, ventilation appeared to be without any
control since parameters like inspiratory and expiratory volume, cycle time, or
pressure were not monitored. Manual ventilation during transport results in greater
fluctuation of ventilatory parameters from an established baseline than does the
use of a transport ventilator [13] . In most cases no positive end-expiratory pressure
(PEEP) valve appeared to be used, so most of the patients were ventilated with zero
PEEP and thus not according to the state-of-the-art open lung concept.
There are guidelines on intensive care transport for adults, children and neo-
nates giving a list of equipment, materials and medication.
Table 4. Equipment and materials available (percentages} during transport by non-experienced specialists
Available Not available Unknown
EKG/respiration monitor 99.5 0.5

Pulse oximetry 96.0 1.5 2.5
Temperature 37.7 46.2 16.1
Non-invasive blood pressure 86.5 9.0 4.5
Invasive blood pressure 3.5 89.0 7.5
Capnography 6.0 82.4 11 .6
Defibrillator 78.4 5.5 16.1
Oxygen 97.5 0.5 2.0
Oxygen mask 98.5 1.5 1.5
Resuscitation bag 94.0 5.0 5.0
Intubation materials 94.0 1.0 5.0
Suction unit 91.5 1.5 7.0
Suction catheters 75.4 3.0 21.6
Thoracocentesis tube 29.1 34.2 36.7
Heimlich valve 18.6 38.2 43.2
Ventilator 48.2 32.2 19.6
Venous access 95.0 0.5
lntraosseous needle 39.2 27.6
4.5 .
33.2
Perfusors 76.9 5.0 18.1
CPR chart 52.8 25.1 22.1
Medication for CPR 93.5 2.5
4.0
Medication for intubation 52.8 23.6
23.6
Medication for sedation 75.9 8.0 16.1
Medication for shock 66.3 15.1 18.6
Medication for convulsion 84.4 2.5 13.1
Checklist for equipment and materials 28.1 39.7 32.2
The General Requirements for Transport

The stand-alone time for the equipment during transport should be sufficient for
the worse case scenario. In case of a failure of electricity or gas supplies of the am-
bulance, the stand-alone time is determined as the maximum time from departure
from the referring hospital (loading) until arrival in our unit (unloading). The
stand-alone time is dependent on the distances in the region and the complexity of
the traffic. In order to save electrical power and gases the unit must be compatible
with the ambulance supplies (electrical power, air and oxygen) and the referring
hospital supplies. The maximum electrical power necessary should not exceed 1200
VA, which is the maximum available by the 220 volt a.c. equipment of the ambu-
lance. All equipment should be technically reliable, transportable and batteries
must be reliable for the time of the demanded power supply. The personnel of the
transport team should be able to reach the ventilator, monitor, perfusors and dis-
posables without having to disconnect their safety belt. All functions of the equip-
ment including alarms should approach the level of the pediatric ICU.
Argument for the Choice of Equipment and Materials

The requirements for transport are listed in Table 5. Monitoring during transport
should be comparable to that on the pediatric ICU with similar vital function mon-
itoring and with similar alarm functions. During transport, a minimum of EKG,
respiratory rate, pulse oximetry and non-invasive blood pressure should be moni-
tored. If indicated invasive blood pressure, temperature and capnography measure-
ment should be possible.
Point-of-care blood testing might be of importance during transport especially
for potassium, calcium, glucose, blood gas, and hematocrit.
Although the indication for electric shock therapy in children is rare, a defibril-
lator should be available.
Ventilatory management during transport should be comparable to the ventila-
tion and alarm functions on the pediatric ICU. The same ventilator as is in use on
the pediatric ICU is preferable, not only because of the functions, but also to allow
a rapid exchange in case of a technical failure. A striking deficiency of specially de-
veloped transport ventilators is a reliable alarm function for inspiratory and expira-
tory volumes. Most ventilators designed for use on the ICU can be used during
transport if the external backup battery is sufficient for at least the defined stand-
alone time.
With the availability of both oxygen and air during transport it is possible to
ventilate the patients with inspiratory oxygen fractions ranging from 0.21 to 1.0.
All gas cylinders have to be connected to a pressure regulator and filling pressures
be read on barometers fitted on the pressure regulator. Working pressure (post reg-
ulator pressure) can be read both for oxygen and air.
Since a gas driven (Venturi) suction unit would use too much gas, a suction unit
with a 12 volt driven unit with an internal battery with a capacity of at least the
stand alone time is preferable.
All medication for advanced life support, management of all kinds of potential
derangements, sedation and further specific needs of the patient should be stored
in a way easy to access. Medication has to be easily removable for storage in a re-
frigerator between transports.
A halogen flashlight is advisable for use in the dark and for the introduction of
central venous lines. The flashlight has to be water-resistant and luminescent for
safety reasons.
Our experience has taught that during most transports four perfusion pumps
are sufficient in combination with two infusible pressure infusors. The pumps must
be equipped with internal batteries with a capacity of at least the stand-alone time.
The connection points of the syringes are best mounted pointed downwards to
avoid gas embolism.
The Transport Trolley

A transport trolley containing all equipment and materials required for transport,
including the ventilator and gas supplies is useful with the precondition that these
should be readily accessible with optimal view of the patient and the equipment.
Table 5. Required equipment and materials for pediatric intensive care transport
Monitoring EKG, respiratory rate, pulse oximetry, temperature,

Blood pressure non-invasive (cuffs neonatal, infant, child, adult),
Blood pressure invasive,
Capnography,
Point-of-care blood testing
Defibrillator 5-400 J capacity with pediatric and adult paddles
airway management Laryngoscope with blades Miller 0,1 and Macintosh 1-4 Endotracheal
tubes (uncuffed 2.0-6.0 and cuffed 5.0-9.0),
Magill forceps (pediatric and adult),
Endotracheal tube stylettes,
Oral airways 0-5,
Suction unit and suction catheters,
Stethoscope,
Chest tubes and Heimlich valve,
Nebulizer,
Oxygen delivery devices (nasal cannulas, oxygen masks),
Artificial humidifier
Ventilatory management Resuscitation bags (child and adult),
PEEP valve,
Face masks (infant, child, adult)
Mechanical ventilator (neonatal, pediatric, adult)
Gas supplies Oxygen and air, with pre and post pressure regulator manometer,
flowmeter -15 1/min
Plug-ins for oxygen and air in ambulance and referring hospital
Fluid management Intravenous cannulas,
Intra-osseous needles,
Central venous lines,
Infusion pumps,
Fluids (normal saline, 5% dextrose),
Tubing, needles, syringes
Medication Pulmonary
bronchodilators aerosol, salbutamol for iv, corticosteroids
Circulatory
adenosine, atropine, calcium chloride, diuretics, dobutamine,
dopamine, epinephrine, norepinephrine, lidocaine, sodium bicarbonate,
vasodilators
Neurologic
anticonvulsants, mannitol, muscle relaxants, naloxone, opiate, sedative
Other
antibiotics, clemastine, colloids, SO% dextrose, potassium
Electrical power Plug-in connection in ambulance and referring hospital
other materials Adhesive tape, arterial line maintenance system, nasogastric tubes
(6, 8, 10, 12 Fr), urinary bladder catheters (infant, child, adult), scissors,
resuscitation chard, alcohol wipes, flashlight
Heavy equipment and materials have to be in a central position of the trolley for
the stability of the unit.
I Conclusion
The benefit of the centralization of the care of critically ill infants and children in
tertiary pediatric ICUs can only be achieved if the risks of the transfer are mini-
mized. During interhospital pediatric intensive care transport the level of treatment
and monitoring should be as close as possible to the level on the pediatric ICU.
The necessity for fully-fledged professional interhospital pediatric transport fa-
cilities is evident from the insufficient level of care during transports accompanied
by non-trained specialists, which lead to a high incidence of serious and critical
complications during these transports. Professional, fully equipped retrieval teams
should be organized on a continuous basis, staffed by specialists trained in pedia-
tric intensive care and pediatric intensive care transport. Only then can the level of
care during transport meet the criteria of the latest state of the art in transport
medicine and be at equal standing with the level of care on the pediatric ICU itself.
References
1. Pearson G, Shann F, Barry P, et al (1997) Should paediatric intensive care be centralised?
Trent versus Victoria. Lancet 349:1213-1217
2. Pollack MM, Alexander SR, Clarke N, Ruttimann UE, Tesselaar HM, Bachulis AC (1991)
Improved outcomes from tertiary center pediatric intensive care: a statewide comparison
of tertiary and nontertiary care facilities. Crit Care Med 19:150-159
3. Gemke RJ, Bonsel GJ (1995) Comparative assessment of pediatric intensive care: a national
multicenter study. Pediatric Intensive Care Assessment of Outcome (PICASSO) Study
Group. Crit Care Med 23:238-245
4. Gemke RJ (1997) Centralisation of paediatric intensive care to improve outcome. Lancet
349:1187-1188
5. Barry PW, Ralston C (1994) Adverse events occurring during interhospital transfer of the
critically ill. Arch Dis Child 71:8-11
6. Britto J, Nadel S, Maconochie I, Levin M, Habibi P (1995) Morbidity and severity of illness
during interhospital transfer: impact of a specialised paediatric retrieval team. Br Med J
311:836-839
7. Bellingan G, Olivier T, Batson S, Webb A (2000) Comparison of a specialist retrieval team
with current United Kingdom practice for the transport of critically ill patients. Intensive
Care Med 26:740-744
8. Booy R, Habibi P, Nadel S, et al (2001) Reduction in case fatality rate from meningococcal
disease associated with improved healthcare delivery. Arch Dis Child 85:386-390
9. Ridley SA, Wright IH, Rogers PN (1990) Secondary transport of critically ill patients. Hos-
pital Update, April:289-300.
10. Ridley S, Carter R (1989) The effects of secondary transport on critically ill patients.
Anaesthesia 44:822-827
11. Runde CJ, Reeve WR, Wallace PG (1992) Preparation of the critically ill for interhospital
transfer. Anaesthesia 47:327-331
12. American College of Emergency Physicians (2001) Managed health care organizations and
emergency care. Ann Emerg Med 38:487-488
13. Dockery WK, Futterman C, Keller SR, Sheridan MJ, Aki BF (1999) A comparison of man-
ual and mechanical ventilation during pediatric transport. Crit Care Med 27:802-806
14. Anonymous (1999) Guidelines for developing admission and discharge policies for the
pediatric intensive care unit. Pediatric Section Task Force on Admission and Discharge
Criteria, Society of Critical Care Medicine in conjunction with the American College of
---~--~~~~,--~--~~"~,-~
Critical Care Medicine and the Committee on Hospital Care of the American Academy of
Pediatrics. Crit Care Med 27:843-845
15. Bleeker JK, Rutten FL, van Leeuwen FL, Jansen YG (1993) [The quality of ambulance trans-
portation between regional hospitals and a central hospital]. Ned Tijdschr Geneeskd
137:1091-1095
16. Braman SS, Dunn SM, Amico CA, Millman RP (1987) Complications of intrahospital trans-
port in critically ill patients. Ann Intern Med 107:469-473
17. Szem JW, Hydo LJ, Fischer E, Kapur S, Klemperer J, Barie PS (1995) High-risk intrahospi-
tal transport of critically ill patients: safety and outcome of the necessary "road trip". Crit
Care Med 23:1660-1666
18. Marx G, Vangerow B, Hecker H, et a! (1998) Predictors of respiratory function deteriora-
tion after transfer of critically ill patients. Intensive Care Med 24:1157-1162
19. Wallen E, Venkataram ST, Grosso MJ, Kiene K, Orr RA (1995) Intrahospital transport of
critically ill pediatric patients. Crit Care Med 23:1588-1595
Carbon Monoxide Poisoning:
A Critical Care and Emergency Medicine Approach
J. Varon and P. E. Marik
I Introduction
Carbon monoxide is the leading cause of injury and death due to poisoning world-
wide [1, 2]. This colorless, odorless and toxic gas is a product of incomplete com-
bustion of any carbon-containing fuel. The sources of carbon monoxide are plenti-
ful, and with the exception of carbon dioxide, carbon monoxide is the most abun-
dant pollutant present in the lower atmosphere [3]. Motor vehicles and other inter-
nal-combustion engines, heaters, appliances that use carbon-based fuels, and
household fires are the main sources of this poison. Carbon monoxide poisoning is
also the most common cause of death in combustion-related inhalation injury [1,
2]. The true incidence of non-lethal carbon monoxide exposure and poisoning is
not known and subacute unrecognized cases occur.
I Epidemiology
Carbon monoxide is a health hazard that poses difficult diagnostic challenges, how-
ever, carbon monoxide poisoning undoubtedly has been recognized for many mil-
lennia. Soon after our ancestors a,ttempted to build fires in non-ventilated shelters,
carbon monoxide exposure and poisoning occurred. The first accurate description
of carbon monoxide poisoning was recorded by Claude Bernard in the later part of
the nineteenth century; he first proposed that the toxic effects of carbon monoxide
resulted from the formation of carboxyhemoglobin. Over the past century many
advances have been made in our understanding of the pathophysiology of carbon
monoxide poisoning.
The true incidence of carbon monoxide poisoning worldwide is unknown, as
many non-lethal exposures go undetected [2]. It has been estimated that more than
one-third of all cases of carbon monoxide poisoning are undiagnosed. Every year
between 10 000 and 40 000 persons will seek medical attention in an emergency de-
partment or will miss at least one day of normal activity due to carbon monoxide
poisoning [4]. Mortality rates have varied significantly between 1 and 31o/o in large
series [2]. However, it appears from epidemiological data that from 1979 through
1988, unintentional deaths from carbon monoxide poisoning in the United States
have declined consistently [5].
As previously mentioned, the most common sources for carbon monoxide in-
clude motor vehicle exhaust fumes, smoke from fires, furnaces, gas-powered en-
gines, wood stoves, paint and paint-removers containing methylene chloride. In the
Carbon Monoxide Poisoning: A Critical Care and Emergency Medicine Approach 801
United States, carbon monoxide from motor vehicle exhausts (either intentional or
unintentional) is the single most common cause of carbon monoxide poisoning
deaths [6]. It is interesting to note that from 1979 to 1988, of the 11547 uninten-
tional carbon monoxide deaths, 57% were caused by motor vehicle exhaust; and of
these 83% were associated with stationary vehicles [6]. Most motor vehicle-related
carbon monoxide deaths occurred in garages, even when the garage doors or win-
dows were open, suggesting that passive ventilation may not be adequate enough
to reduce risk in semi-closed spaces. Worldwide, smoke inhalation from all types
of fires is the second leading cause of carbon monoxide poisoning. Indeed, most
immediate deaths from building fires are due to carbon monoxide poisoning and,
therefore, fire fighters are at a high risk.
Epidemics of carbon monoxide poisoning commonly occur during winter
months and sources include misuse of non-electric heating or cooking devices (in-
cluding indoor charcoal) as well as snow-obstructed motor vehicle exhaust systems.
These epidemics are particularly common during winter storms due to power cuts
and the use of alternative methods of heating and cooking. We have previously re-
ported clusters of cases with carbon monoxide poisoning related to indoor cooking
even during summer months [1, 7].
It is well known that urban environments contain higher ambient carbon mon-
oxide concentrations, primarily due to automotive emissions, and that non-smok-
ing city dwellers commonly have carboxyhemoglobin levels in the 1-2% range. To-
bacco smoke is another significant source of carbon monoxide, containing approxi-
mately 4% carbon monoxide. Smokers have carboxyhemoglobin levels typically in
the 4-5% range and some as high as 9%. Hence, their carboxyhemoglobin levels
must be interpreted accordingly in cases of suspected carbon monoxide poisoning.
Another agent that deserves special mention is methylene chloride, because it is
contained in many paints and paint removers and its vapors are readily absorbed
through the lungs. Once it reaches the circulation, methylene chloride is converted
into carbon monoxide by the liver.
I Pathophysiology
The brains of patients who die following carbon monoxide poisoning are usually
edematous with multiple petechial lesions and hemorrhages (8]. In patients that
survive the initial insult but die at a later time, histological findings typical of brain
anoxia are prominent [9, 10]. It is interesting to note that the severity of these lesions
has been correlated with the degree of hypotension rather than with hypoxia [11].
Mechanisms of Tissue Hypoxia and Cellular Asphyxia

Inhaled carbon monoxide rapidly diffuses across the alveoli and binds with hemo-
globin to produce carboxyhemoglobin, displacing oxygen and reducing systemic ar-
terial oxygen content (Ca0 2 ). The relative affinity of carbon monoxide for hemoglo-
bin averages 250-fold greater than that of oxygen, with some variation among indi-
viduals. Therefore, even relatively small concentrations of the gas in the environ-
ment can result in toxic concentrations in human blood.
Various mechanisms of carbon monoxide toxicity have been proposed and in-
clude:
802 J. Varon and P. E. Marik
I a decrease in the oxygen-carrying capacity of blood

I alterations in the dissociation characteristics of oxyhemoglobin, further decreas-
ing oxygen delivery to the tissues
I a decrease in cellular respiration by binding with cytochrome a3
I binding to myoglobin, potentially causing myocardial and skeletal muscle dys-
function.
The most well understood mechanism by which carbon monoxide toxicity occurs
is competitive binding to the hemoglobin heme groups [12, 13]. This effect is aug-
mented by the characteristic allosteric properties of the hemoglobin molecule. He-
moglobin's tetrameric structure undergoes a conformational change when carbon
monoxide is bound at one of the four heme sites, with a resulting increase in the
affinity of the remaining heme groups for oxygen. This not only shifts the oxygen-
hemoglobin dissociation curve to the left, but distorts its sigmoidal shape towards
a hyperbola. The result is an 'impaired' hemoglobin that is poorly equipped to re-
lease oxygen at the tissue level. This diminished oxygen delivery will be then
sensed by the central nervous system (CNS), stimulating ventilatory efforts and in-
creasing minute ventilation. The latter will increase uptake of carbon monoxide
and raise carboxyhemoglobin levels, and will result in a respiratory alkalosis,
further shifting the oxygen-hemoglobin dissociation curve to the left. As carbon
monoxide exposure continues, central respiratory depression arises, possibly result-
ing from cerebral hypoxia.
The mean half-life of carboxyhemoglobin is 320 minutes in healthy volunteers
on room air [9, 14]. The administration of 100% oxygen at one atmosphere reduces
the half life to 80.3 minutes, while 100% oxygen at three atmospheres will reduce
the half life to 23.3 minutes [14]. Coburn has estimated that at any time, approxi-
mately 10 to 15% of the total body burden of carbon monoxide is bound to extra-
vascular hemoproteins [15]. Carbon monoxide binds to cardiac and skeletal myo-
globin. The affinity for carbon monoxide among these proteins varies widely. For
example, cardiac myoglobin binds three times more carbon monoxide than skeletal
myoglobin [9]. Carboxymyoglobin dissociation is slower than carboxyhemoglobin
due to the increased affinity of carbon monoxide for myoglobin. Indeed, the so-
called 'rebound effect' with delayed return of symptoms has occasionally been re-
ported, and correlates with a recurrence of carboxyhemoglobin elevation. Presum-
ably, this is due to late release of carbon monoxide from myoglobin with subse-
quent binding to hemoglobin.
Mechanisms of Ischemia
Carbon monoxide can cause tissue hypoxia as well as tissue injury by impairing
perfusion. Animal models of carbon monoxide intoxication, as well as human ex-
perience, indicate that myocardial depression, peripheral vasodilation, and ventric-
ular arrhythmia causing hypotension may be important in the genesis of neurologic
injury. Animals that do not die acutely, but instead show neurological deterioration
over the days subsequent to the poisoning, appear to have suffered a combined
hypoxic and ischemic insult during the acute exposure [16]. In other animal mod-
els, carbon monoxide poisoning has been found to result in progressive hypoten-
sion, primarily as a result of peripheral vasodilation [17].
Carbon Monoxide-induced Reperfusion Injury

Carbon monoxide poisoning may pathophysiologically manifest as reperfusion in-
jury. Thorn has reported that carbon monoxide causes brain lipid peroxidation
after, but not during carbon monoxide exposure [18]. In addition, this investigator
has demonstrated that pretreating rats with allopurinol prevents lipid peroxidation
following carbon monoxide exposure [19]. It has been postulated that this oxidative
injury is mediated largely by leukocytes. Leukocyte sequestration as the result of
vascular events increases significantly in brain microvasculature following exposure
to carbon monoxide. In rats made leukopenic or treated with monoclonal anti-CD-
18 F(ab) fragments formation of xanthine oxidase and lipid peroxidation is inhib-
ited following carbon monoxide poisoning.
It is possible that excitatory amino acids mediate some of the neurological inju-
ries after cerebral hypoperfusion, and delayed neuronal death following carbon
monoxide poisoning may involve excitatory amino acids [20].
I Symptomatology
Many victims of acute carbon monoxide poisoning die or suffer permanent, severe
neurological injury despite treatment. Unfavorable cognitive sequelae can occur im-
mediately after exposure and persist or be delayed, but generally occur within 20
days of carbon monoxide exposure [21]. It has been estimated that as many as SOo/o
of those who recover consciousness and survive may experience varying degrees of
more subtle but still disabling neuropsychiatric sequelae. As might be expected
with the various signs and symptoms, there are no uniform neuropathological
changes associated with carbon monoxide poisoning.
The clinical features of acute carbon monoxide exposure and poisoning are more
dramatic than those resulting from chronic exposure. At low carboxyhemoglobin
levels in patients with chronic cardiopulmonary problems, such as angina and
chronic obstructive pulmonary disease (COPD), the symptoms may be exacerbated,
since cardiac myoglobin binds with great affinity and rapidly reduces myocardial
oxygen reserve. Chest pain due to myocardial ischemia may occur, as can cardiac
dysrhythmias. Subacute or chronic carbon monoxide poisoning presents with less
severe symptoms (e.g., nausea, vomiting, headache) and patients may initially be
misdiagnosed as having other illnesses such as gastroenteritis [22].
The clinical presentation of acute carbon monoxide poisoning is variable, but in
general, the severity of observed symptoms correlates roughly with the observed
level of carboxyhemoglobin. However, clinicians must be careful when using these
values in terms of diagnosis, as the non-specificity of the presenting symptoms
makes definitive diagnosis difficult. In addition, there have been several reports of
levels near zero with patients showing neurologic deficits ranging from partial pa-
ralysis to coma [23-25]. Therefore, carboxyhemoglobin levels should not be used
alone to determine the risk of morbidity or mortality.
Most of the data comparing symptomatology with carboxyhemoglobin levels
come from experiments in healthy males, without the confounder of time lapse in
specimen collection [14]. With levels less than lOo/o, the patient is usually asympto-
matic. On occasion, subtle symptoms such as diminished visual brightness discrim-
ination or auditory dysfunction are present at these low levels of carboxyhemo-
globin [26]. As carboxyhemoglobin increases above 20o/o, the patient may develop
Table 1 . Delayed neurological sequelae of carbon monoxide poisoning

I Auditory disturbances Gait disturbances
I Blindness (cortical) Hemiplegia
Choreoathetosis Parkinson's-like syndrome
Dementia Peripheral neuropathy
I Depression I Seizures
Disorientation I Speech disturbances
headache, dizziness, confusion and nausea. In addition to alterations in the neuro-

logical status, tachycardia and tachypnea may also be noted. Overall, symptoms
and physical findings are related to impaired cardiopulmonary function or to neu-
rological disturbances. The cherry-red coloration of the skin is often absent and it
is an extraordinarily rare occurrence except among those who have died [27].
Coma and seizures due to cerebral edema are common with levels greater than
40%, and death is likely above 60%. As mentioned before, carboxyhemoglobin
levels per se have not been identified as a risk factor for carbon monoxide-
mediated morbidity or mortality.
In cases of acute, subacute, and chronic carbon monoxide exposure, the occur-
rence of illness in household pets concurrent with, or just preceding, the onset of a
patient's own illness should alert to the possibility of carbon monoxide poisoning
[28]. Due to their smaller size and in general higher metabolic rates, pets may be
more obviously and more severely affected by carbon monoxide intoxication than
their owners.
A wide variety of neuropsychiatric problems has been reported to arise insidiously
in some patients after their recovery from the acute effects of carbon monoxide poi-
soning [29]. These delayed neurological sequelae have been described following re-
covery from acute carbon monoxide poisoning. Up to 10% of survivors show gross
neurologic or psychiatric impairment that is obvious to the physician (such as par-
kinsonism, persistent vegetative state, akinetic mutism, agnosia, apraxia, visual im-
pairment, amnestic/confabulatory state or psychosis) [2, 29, 30] (Table 1). Dementia,
cortical blindness, hemiplegia, disorientation, personality changes can also be ob-
served [30 ].
I Diagnosis
A history of potential carbon monoxide exposure is the most reliable indicator of
poisoning. However, if the history of exposure is not evident, then a high index of
suspicion is needed to make the diagnosis. Any patient at a fire scene should be
immediately evaluated for carbon monoxide poisoning. Confirming the diagnosis
may be difficult in some patients, as carboxyhemoglobin may be low or undetect-
able because of the time between exposure and emergency department presentation
[29]. The normal carboxyhemoglobin level is 1 to 3%, as result of endogenous pro-
duction of carbon monoxide by the heme catabolism and low-level environmental
carbon monoxide exposure. Cigarette smokers increase their carboxyhemoglobin
level by an average of 5% per pack smoked per day, and otherwise healthy smokers
tolerate carboxyhemoglobin levels of 10% without symptoms. Although a consensus
on absolute levels of carboxyhemoglobin requiring hyperbaric oxygen (HBO) thera-

py does not exist, the level of carboxyhemoglobin is utilized by the majority of hy-
perbaric facilities in recommending HBO therapy [31].
When evaluating a patient for potential carbon monoxide poisoning, the clini-
cian needs to consider several factors. The patient needs to be examined for evi-
dence of thermal injury and the presence of other gas inhalation. In many patients
from residential fires, elevated blood cyanide levels have been reported [32]. A sig-
nificant correlation has been found between the carboxyhemoglobin and the blood
cyanide [32]. Similarly, if the patient presents with carbon monoxide poisoning as
the result of a suicidal attempt, a multiple drug screen (including acetaminophen,
salicylate and ethanol) should be obtained.
An electrocardiogram (EKG) must be obtained in all patients with significant car-
bon monoxide exposure, and if abnormal, serial creatine kinase (CK), troponin-1, and
lactate dehydrogenase (LDH) determinations or other serum markers of myocardial
injury should be performed, and the patient kept under close observation.
As a delayed neurological syndrome can occur in many patients, it has been re-
commended that all carbon monoxide poisoning patients undergo psychometric
testing [2]. However, some studies of short psychometric tests do not appear to
correlate with the development of neuropsychiatric sequelae [2]. In patients with
neuropsychiatric sequelae, a head computed tomography (CT) or magnetic reso-
nance imaging (MRI) scan may reveal characteristic abnormalities which include:
bilateral necrosis of the globus pallidus as well as the cerebral cortex, hippocampus,
and substantia nigra [2, 29].
Carbon monoxide poisoning in the absence of a reliable history of exposure may
be difficult to ascertain. Some of the various differential diagnoses include: viral ill-
nesses, food poisoning, depression, transient ischemic attack, coronary artery dis-
ease, arrhythmias, and functional illnesses among others. The most common mis-
diagnosis is a 'flu-like' syndrome [33]. We reported a 12 member family that pre-
sented to the emergency department in groups of 4 persons with symptoms consis-
tent with food ·poisoning after drinking unrefrigerated milk [1]. However, several
other affected members of the same household had not consumed the same milk.
Further investigation revealed severe carbon monoxide poisoning which was found
to be related to indoor barbecue grill usage that day.
I Management
Primary classification of patients based mainly on carboxyhemoglobin levels is in-
appropriate and potentially misleading, as the level alone is a poor predictor of the
degree of injury. However, any patient with a carbon monoxide Hb level > 25%
should be admitted, even if asymptomatic. In cases of less severe poisoning, close
observation and hospital admission with administration of 100% oxygen should be
undertaken until the patient is asymptomatic [29].
In addition to supportive care to date, the mainstay of therapy for carbon mon-
oxide poisoning is the administration of supplemental oxygen, ventilatory support
and monitoring for cardiac dysrhythmias. Most clinicians agree that 100% oxygen
should be administered prior to laboratory confirmation when carbon monoxide
poisoning is suspected. The goal of this therapy is to improve the oxygen content
of the blood by maximizing the fraction dissolved in plasma (Pa02 ). Once oxygen
treatment begins, observation must continue long enough to prevent delayed seque-
lae as carboxymyoglobin unloads.
Other modes of therapy of severe carbon monoxide poisoning have been under
investigation for several decades [2]. Hypothermia was used in the 1950s and 1960s
in the management of these patients. However, at the beginning of the 1970s
controlled studies showed no benefit in improving survival after severe carbon
monoxide poisoning [34].
Whether or not to use HBO clinically, and, if so, when to use it, are matters that
have been debated since it emerged in 1960. Treatment utilizing this modality was
first successful in Glasgow [35]. Since then, the clinical use of HBO for carbon
monoxide poisoning has occurred with increasing frequency. Indeed, over 2500 car-
bon monoxide-intoxicated patients were treated in North American chambers in
1992 [31]. Practice guidelines have been developed on the basis of clinical experi-
ence and inferences of efficacy in uncontrolled studies. Results of past controlled
trials comparing HBO therapy and normobaric oxygen therapy have been inconclu-
sive due to methodological difficulties.
The use of HBO treatment for victims of carbon monoxide poisoning is based
on the following clinical and laboratory information:
I HBO produces a more rapid reduction in carboxyhemoglobin levels. The half-life
of carboxyhemoglobin is 4-5 hours in normal volunteers. The administration of
100% oxygen at sea level decreases the half life of carboxyhemoglobin to 80 min-
utes by administration of 100% and to 22-23 minutes by treatment with HBO at
3 atmospheres absolute (ATA) [14, 36]. At 3 ATA, the oxygen dissolved in blood
approaches 6 vol%; this is adequate to supply basal oxygen requirements to the
body with normal cardiac output in the absence of functional hemoglobin
I HBO therapy induces cerebral vasoconstriction, and may reduce intracranial
pressure and the development of cerebral edema
I HBO therapy results in a more rapid dissociation of carbon monoxide from the
respiratory cytochrome system
I HBO may antagonize the oxidative injury that occurs after carbon monoxide
poisoning.
Goulon and coworkers demonstrated that HBO (2 ATA), when administered within
six hours of poisoning, dramatically reduced mortality and morbidity [37]. Thorn
has demonstrated that oxygen at 3 ATA, but not at 1 ATA prevents brain lipid per-
oxidation when administered to rats beginning 45 minutes subsequent to carbon
monoxide poisoning [38]. It is known that HBO therapy prevents the conversion of
xanthine dehydrogenase to xanthine oxidase, a leukocyte-mediated reaction [39].
This effect has been postulated to occur due to diminished B2-integrin-mediated
leukocyte adherence [39].
HBO therapy is often recommended for patients with acute carbon monoxide
poisoning, especially if they have lost consciousness or have severe poisoning [40].
Case reports, a few small case series, and retrospective studies have suggested that
the mortality and morbidity among patients treated with HBO appears improved
beyond that expected with ambient pressure supplemental oxygen therapy. In a
study by Thorn and associates, 60 patients with mild to moderate carbon monoxide
poisoning who presented within 6 hours were studied in a prospective randomized

fashion. None of these patients had a history of loss of consciousness. Delayed neu-
rological sequelae developed in 7 of 30 patients (23%) in the control group and none
in the HBO group [41]. In a similar study, Ducasse and colleagues evaluated and
treated 26 non-comatose patients with acute carbon monoxide poisoning [42]. At
12 hours no patient (0/13) in the HBO group had abnormal clinical findings compared
to 5 of 13 in the normobaric oxygen group. In both studies, the authors failed to blind
the patients and examiners to the treatment given [43]. These studies highlighted the
fact that the optimal benefit from HBO may be obtained when this therapy is offered
within 6 hours of intoxication and with at least 2.5 ATM of HBO.
A recent study by Weaver and associates using HBO within 24 hour of exposure
to carbon monoxide appeared to reduce the risk of cognitive sequelae at 6 weeks
and 12 months after acute carbon monoxide poisoning [44]. On the basis of these
studies, some authors recommend the use of HBO therapy, particularly because the
neurological manifestations may persist for variable intervals after the carbon mon-
oxide exposure [45].
Most advocates of HBO therapy are to be found in specialized treatment centers
with ready access to hyperbaric chambers. The implications of recommending HBO
for patients in rural areas or cities without chambers cannot be underestimated.
The cost of HBO therapy may have important implications, since this therapy is 4
to 5 time as expensive as treating a patient with normobaric oxygen, not including
transport costs which may run over $3000 for aeromedical evacuation. Disadvan-
tages of HBO therapy include the risks associated with transport of the patient to a
treatment center, hyperoxic seizures, and barotrauma [46].
Currently, the official recommendations of the Undersea and Hyperbaric Medical
Society for HBO therapy include those patients with signs of serious intoxication
regardless of their carboxyhemoglobin levels [47]. This includes patients with a his-
tory of unconsciousness, presence of neurological signs, cardiovascular dysfunction
or severe acidosis. Pregnant women should be evaluated with liberal criteria for
HBO due to the increased toxicity risk to the fetus.
In the absence of access to HBO therapy, severe poisoning should be treated
with 100% oxygen, with endotracheal intubation in patients who cannot protect
their airway. Some authors have suggested that in these patients, consideration
should be given to transfusion of packed red blood cells [48].
I Prognosis
The data regarding the overall prognosis in patients with carbon monoxide poison-
ing are inconclusive and contradictory. Whereas definitive studies are lacking, it
appears that roughly 30% of patients with severe poisoning have a fatal outcome
[49]. As mentioned before, some studies have estimated that 11% of survivors have
long-term neuropsychiatric deficits, including 3% whose neurologic manifestations
are delayed [50]. One third of carbon monoxide poisoning victims may have subtle
but lasting memory deficits or personality changes [30].
Clinical indicators of a poor prognosis in patients with carbon monoxide poi-
soning include altered consciousness at presentation, advanced age, patients with
underlying cardiovascular disease, metabolic acidosis, and structural abnormalities
on CT or MRI scanning [49].
I Conclusion
Carbon monoxide poisoning continues to be a significant health problem world-
wide. Carbon monoxide poisoning is associated with significant morbidity and
mortality. The history of exposure and carboxyhemoglobin levels should alert the
physician to this diagnosis acutely. In the absence of exposure history, carbon mon-
oxide poisoning must be considered when 2 or more patients from the same house-
hold are similarly or simultaneously sick. A directed history and physical exam
may elicit the diagnosis. If suspicion remains, carboxyhemoglobin testing should
be done and oxygen therapy should be started empirically while results are pend-
ing. If carbon monoxide poisoning is confirmed, the source must be identified and
recommendations for correction or avoidance made. Early and up to 24 hours
post-exposure, HBO treatment may have a role in preventing neurological sequelae
in severely poisoned patients.
References
1. Gasman J, Varon J, Gardner J (1990) Revenge of the barbecue grill-carbon monoxide poi-
soning. West J Med 153:656-657
2. ThornS, Keirn L (1989) Carbon monoxide poisoning: A review. Epidemiology, pathophys-
iology, clinical fmdings, and treatment options including hyperbaric therapy. Clin Toxicol
27:141-156
3. Jaffe LS (1970) Sources, characteristics and fate of atmospheric carbon monoxide. Ann NY
Acad Sci 174:76-88
4. Hampson N, Norkool D (1992) Carbon monoxide poisoning in children riding in the back
of Pickup trucks. JAMA 267:538-540
5. Cobb N, Etzel R (1991) Unintentional carbon monoxide-related deaths in the United States,
1979 through 1988. JAMA 266:659-663
6. Centers for Disease Control and Prevention (1996) Deaths from motor-vehicle-related un-
intentional carbon monoxide poisoning - Colorado, 1996, New Mexico, 1980-1995, and
United States, 1979-1992. JAMA 276:1942-1943
7. Varon J, Marik PE, Fromm RE, Gueler A (1999) Carbon monoxide poisoning: a review for
clinicians. J Emerg Med 17:87-93
8. Sadovnikoff J, Varon J, Sternbach J (1992) Carbon monoxide poisoning: An occult epi-
demic. Postgrad Med 92:86-96
9. Coburn R (1970) Carbon monoxide body stores. Ann NY Acad Sci 174:11-22
10. Myers R, Linberg S, Cowley R (1979) Carbon monoxide poisoning: The injury and its
treatment. JACEP 8:479-484
11. Ginsberg MD, Myers RE, McDonaugh BF (1974) Experimental carbon monoxide encepha-
lopathy in the primate: II. Clinical aspects, neuropathy, and physiologic correlation. Arch
Neural 30:209-216
12. Guy C, Salhany J, Eliot R (1971) Disorders of hemoglobin-oxygen release in ischemic heart
disease. Am Heart J 82:824-832
13. Rodkey F, O'Neal J, Collison H (1974) Relative affinity of hemoglobin S and hemoglobin A
for carbon monoxide and oxygen. Clin Chern 20:83-84
14. Petersen J, Stewart R (1970) Absorption and elimination of carbon monoxide by active
young men. Arch Environ Health 21:165-171
15. Coburn RF (1970) The carbon monoxide body stores. Ann NY Acad Sci 174:11-22
16. Song SY, Okeda R, Funata N, Higashino F (1983) An experimental study of the pathogen-
esis of selective lesion of the globus pallidus in acute carbon monoxide poisoning in cats.
Acta Neuropathol 61:232-238
17. Penney DG (1990) Acute carbon monoxide poisoning: animal models: A review. Toxicology
62:103-116
18. Thorn SR (1990) Carbon monoxide-mediated brain lipid peroxidation in the rat. J Appl
Physiol 68:997-1003
19. Thorn SR (1992) Dehydrogenase conversion to oxidase and lipid peroxidation in brain after
carbon monoxide poisoning. J Appl Physiol 73:1584-1589
20. Ishimaru H, Katoh A, Suzuki H (1992) Effects of N-methyl-D-aspartate receptor antago-
nists on carbon monoxide-induced brain damage in mice. J Pharmacol Exp Ther 261:349-
352
21. Ernst A, Zibrak JD (1998) Carbon monoxide poisoning. N Engl J Med 339:1603-1608
22. Heckerling P, Leikin J, Maturen A, Terzian C, Segarra D (1990) Screening hospital admis-
sions from the emergency department for occult carbon monoxide poisoning. Am J Emerg
Med 8:301-304
23. Norkool DM, Kirkpatrick JN (1985) Treatment of acute carbon monoxide poisoning with
hyperbaric oxygen: a review of 115 cases. Ann Emerg Med 14:1168-1171
24. Myers RAM, Thorn S (1995) Carbon monoxide and cyanide poisoning. In: Kindwall EP
(ed) Hyperbaric Medicine Practice. Best Publishing, Flagstaff, pp 343-372
25. Myers RAM (1989) Do arterial blood gases have value in prognosis and treatment deci-
sions in carbon-monoxide poisoning. Crit Care Med 17:139-142
26. McFarland RA, Roughton FJW, Halperin MH (1944) The effect of carbon monoxide and
altitude on visual thresholds. J Aviat Med 15:381-384
27. Matthew H (1971) Acute poisoning: Some myths and misconceptions. Br Med J 1:519-522
28. llano AL, Raffin TA (1990) Management of carbon monoxide poisoning. Chest 97:165-169
29. Meredith T, Vale A (1988) Carbon monoxide poisoning. Br Med J 296:77-78
30. Smith JS, Brandon S (1973) Morbidity from acute carbon monoxide poisoning at three-
year follow-up. Br Med J 1:318-321
31. Hampson N, Dunford RG, Kramer CC, Norco! DM (1995) Selection criteria utilized for hy-
perbaric oxygen treatment of carbon monoxide poisoning. J Emerg Med 13:227-231
32. Baud FJ, Barriot P, Toffis V, et a! (1991) Elevated blood cyanide concentrations in victims
of smoke inhalation. N Eng! J Med 325:1761-1766
33. Dolan M (1985) Carbon monoxide poisoning. Can Med Assoc J 133:393-399
34. Pearce E, Zacharias A, Alday J, Hoffman B, Jacobson J (1972) Carbon monoxide poisoning:
experimental hypothermic and hyperbaric studies. Surgery 72:229-239
35. Smith G, Ledingham IM, Sharp GR (1962) Treatment of coal-gas poisoning with oxygen at
2 atmospheres pressure. Lancet 1:816-818
36. Pace N, Strajnan E, Walker E (1950) Acceleration of carbon monoxide elimination in man
by high pressure oxygen. Science 111:652-654
37. Goulon M, Bariois A, Rapin M, Nouailhat F, Grosbuis S, Labrousse J (1969) Intoxication
oxycarbonee et anoxie aigue par inhalation de gaz de charbon et d'hydrocarbures. Ann
Med Interne (Paris) 120:335-345
38. Thorn SR (1990) Antagonism of carbon monoxide-mediated brain lipid peroxidation by hy-
perbaric oxygen. Toxicol Appl Pharmacol105:340-344
39. Thorn SR (1993) Functional inhibition of leukocyte B2 integrins by hyperbaric oxygen in
carbon monoxide-mediated brain injury in rats. Toxicol Appl Pharmacol 123:248-256
40. Tibbles PM, Edelsberg JS (1996) Hyperbaric-oxygen therapy. N Eng! J Med 334:1642-1648
41. Thorn SR, Taber RL, Mendiguren II, Clark JM, Hardy KR, Fisher AB (1995) Delayed neuro-
psychologic sequelae after carbon monoxide poisoning: Prevention by treatment with
hyperbaric oxygen. Ann Emerg Med 25:474-480
42. Ducasse JL, Celis P, Marc-Vergnes JP (1995) Non-comatose patients with acute carbon
monoxide poisoning: hyperbaric or normobaric oxygenation? Undersea Hyperbaric Med
22:9-15
43. Olson KR, Seger D (1995) Hyperbaric oxygen for carbon monoxide poisoning: Does it
really work? Ann Emerg Med 25:535-537
44. Weaver LK, Hopkins RO, Chan KJ (2002) Hyperbaric oxygen for acute carbon monoxide
poisoning. N Eng! J Med 347:1057-1067
45. Thorn SR (2002) Hyperbaric oxygen therapy for acute carbon monoxide poisoning. N Eng!
J Med 347:1105-1106
46. Hampson NB, Simonsons SG, Kramer CC, Piantodosi CA (1996) Central nervous system
oxygen toxicity during hyperbaric treatment of patients with carbon monoxide poisoning.
Undersea Hyperbaric Med 23:215-219
810 J. Varon and P. E. Marik: Carbon Monoxide Poisoninq: A Critical Care and Emergency Medicine Approach
~
47. Camporesi EM (1996) Hyperbaric Oxygen Therapy: A Committee Report 7-10. Undersea
and Hyperbaric Medical Society, Kensington
48. Marzella L, Myers R (1986) Carbon monoxide poisoning. Am Fam Physician 34:186-194
49. Piantadosi C (1991) The role of hyperbaric oxygen in carbon monoxide, cyanide and sul-
fide intoxications. Prob Resp Care 4:215-231
50. Choi I (1983) Delayed neurologic sequelae in carbon monoxide intoxication. Arch Neural
40:433-435
Club Drugs: A New Challenge in Clinical Toxicology
P. Lheureux, A. Penaloza, and M. Gris
1 Introduction
The recreational abuse of toxic substances is an increasing problem and is now a
frequent source of emergency department visits in most developed countries, espe-
cially at night and during weekends [1, 2]. Among the wide variety of compounds
that are observed, special attention must be paid to the 'club drugs'.
'Club drugs' is a vague term that refers to a wide variety of drugs mainly used
by teenagers and young adults who are part of the nightclub or bar scene, or attend
raves or trances which are night-long (and sometimes week-end-long) dancing
events, often held in big warehouses. The sought-after effects of this practice con-
sist of intoxicating 'highs' that are said to deepen the rave emotional and sensory
experience, to increase the feelings of openness and emotional closeness to others
(empathogen drugs), to reduce inhibitions, thereby removing the communication
barriers and increasing the sociability (entactogen drugs). Their use is favored by
their relatively low cost as compared with other common street drugs.
The toxicity that might be expected from this form of drug abuse is difficult to
determine in a particular community because many uncertainties exist about the
drug sources, about the pharmacological agents actually involved, about the chemi-
cals used to manufacture them, and about the possible contaminant or adulterant
substances that are included in the final product. However, recent science is show-
ing that serious damage may occur from the use of these drugs.
I The Various Classes of Club Drugs

The most common substances in this group are included in two families: the stimu-
lants - hallucinogenic compounds like methamphetamine, lysergic acid diethylmide
(LSD), 3,4-methylenedioxymethamphetamine (MDMA or 'Ecstasy') or related com-
pounds, and the anesthetic-like compounds such as Rohypnol, ketamine, or gam-
ma-hydroxybutyrate (GHB). Many users tend however to experiment with a variety
of 'club drugs' in combination. Another problem is that these drugs are often com-
bined with alcohol or 'energy beverages' and that such combinations can lead to
unexpected adverse reactions and even death.
812 P. Lheureux et al.
Rohypnol
Rohypnol® is the trade name for flunitrazepam. It is or has been used in more than 60
countries as a treatment for insomnia, as a sedative, and as a presurgery anesthetic.
Its illicit use began in Europe in the 1970s and appeared in the early 1990s in the US
where this substance is not approved for clinical use and its importation is banned [3].
Street names of Rohypnol include 'rophies', 'roofies', 'roche', 'roach', 'forget-me
pill', and 'rope'. Clonazepam is a very similar drug also sold as 'roofies' (US: Klo-
nopin® -Mexico and Europe: Rivotril®).
Rohypnol may induce profound sedative-hypnotic effects, muscle relaxation and
profound amnesia. Therefore, it is used in date rape, often mixed with alcohol; it
can incapacitate the victims and prevent them from resisting sexual assault. More-
over, individuals will usually not remember the events that they experienced while
under the effects of the drug. 'Roofies' are also sometimes abused to enhance the
effects of heroin and other opiates. Rohypnol is usually taken orally, although there
are reports that it can be snorted or injected. Physical and psychological depen-
dence may develop; withdrawal is commonly associated with seizures. Common
side effects of Rohypnol include drowsiness, visual disturbances, dizziness, confu-
sion, anterograde amnesia, gastrointestinal disturbances, urinary retention and de-
creased blood pressure. Overdose may be lethal when mixed with alcohol and/or
other central nervous system (CNS) depressants.
Flumazenil may be useful in management but it should be used very carefully;
indeed acute withdrawal may be associated with seizures, as can occur with benzo-
diazepine sudden reversal in subjects who have simultaneously ingested proconvul-
sant drugs such as GHB or amphetamine derivatives.
Gamma-hydroxybutyrate
GHB is an. endogenous short chain fatty acid that can be found in the CNS, the
kidney, the heart, the skeletal muscle and the fat tissue. Central GHB receptors have
been observed in the CNS. GHB is mainly a inhibitory neurotransmitter, closely re-
lated to gamma-aminobutyric acid (GABA), the main inhibitory neuromediator in
the CNS. It has been suggested that GHB can also produce direct GABA-B receptor
stimulation at high doses.
GHB was developed as an anesthetic agent in the 1960s, but rapidly abandoned
because of its serious adverse effects. It is increasingly involved in poisonings, over-
doses, and 'date rapes', and has resulted in several fatalities [4, 5]. GHB affects the
release of dopamine in the brain, causing effects ranging from relaxation or sleep
at low doses to profound CNS depression at high doses.
Some medical uses have been developed; use in insomnia and in general an-
esthesia has been abandoned, but more recently, GHB has been proposed as an ad-
junct to the treatment of alcohol dependence and narcolepsy.
The sought-after effects of GHB in abusers are various:
1 Abuse occurs in body builders because of the alleged properties of GHB to en-
hance effects of steroids and to stimulate growth hormone release, and thereby
to burn fat and improve muscle building. GHB is a component of many dietary
supplements available in health food stores and gymnasiums.
I Nightclubs and the rave scene are another context of abuse of GHB because of
its relaxing, euphoriant and hallucinogenic properties that induce a pleasant, al-
cohol-like 'high' and an entactogen effect.
Club Drugs: A New Challenge in Clinical Toxicology 813
1 Although unproven, GHB has also been suggested to have aphrodisiac properties
that induce enhancement of sexual performance.
1 Finally, this drug is used in chemical submission as a 'date-rape' drug, because
of its sedative and memory impairing properties that are stronger than those of
benzodiazepines. It is almost tasteless and can easily be added to drinks, with-
out changing the taste or aspect.
GHB is known under several names: G, gamma-OH, Blue Nitro, Midnight Blue, Re-
newTrient, Reviarent, SomatoPro, Serenity, Enliven, 'Fountain of Youth', female via-
gra, Grievous Bodily Harm or GBH, Liquid Ecstasy, Liquid X, Georgia Home Boy,
Goop, Scoop, Somatomax, growth hormone booster, Cherry Meth, Soap ...
There are also two related compounds that are ingredients in the production of
GHB, or are converted into GHB by the body: gamma-butyrolactone (GBL) and
1,4-butanediol (BDO) [6-8]. BDO, 1,4-butanediol, {1,4-butylene glycol, 1,4-tetra-
methylene glycol) is an industrial chemical used as a synthetic intermediate. It is
rapidly absorbed and metabolized to GHB; it is thus like a pro-drug for GHB. Its
toxicological profile reflects that of GHB. Many food supplements available on the
Internet contain BDO.
GHB is often manufactured in homes with recipes and ingredients found and pur-
chased on the Internet. The synthesis appears to be very simple (gamma-butyrolacto-
ne +strong base). It is usually sold as a premixed liquid form contained in small glass
jars or as a white powdered material sometimes prepared in capsules. Blue coloring of
premixed solutions is often recommended on the Internet to avoid confusion with
water and to avoid addition to a drink without knowledge by the user.
The main danger associated with GHB abuse is its sharp dose-response curve
(Table 1); effects are reported to be extremely dose-sensitive and each person })as a
different response to each dose level. The problem is that there are various non-
standard preparations. The powder material is usually pure GHB but for the liquid
form, there is a wide variety of concentrations with a single dose ranging from a
few drops to a full glass. Finally, uninformed users often mix GHB with alcohol,
which drastically increases the chance of vomiting and unconsciousness. Some
guidelines for proper use can be found on the found on the Internet:
"On an empty stomach (a full stomach delays the effects}, take 1/8-1/4 of a sin-
gle dose to test for personal allergic reactions to the chemical. Get a sense of
whether GHB feels OK for you. Wait several hours (if not days) before deciding.
One hour is NOT enough to l,<now, and if you take more you will be compounding
doses. Write down your observations, marking time, dosage, and all effects. In-
crease in small increments {1/4 dose per event) from this original dose until you
find your desired level. This will take several tries, as GHB trials should be sepa-
rated by at least one week" [9].
The potential of GHB to induce dependence is controversial. According to Chin
et al. [10], GHB is not addictive and no investigator has reported any long-term ad-
verse effects, addictive or dependent qualities associated with this compound. Re-
cent data have however suggested that prolonged use of high doses GHB may lead
to tolerance and dependence and a withdrawal syndrome that consists of insomnia,
anxiety, agitation, tremor or delirium may be observed [11]; it resolves without se-
quelae in 3 to 12 days.
GHB is a rapidly acting {10-20 min-peak 20-60 min) and short-acting (2-4
hours) substance. Onset and duration of effects depend on the dose. For low dose
(0.5-1.5 g), effects are similar to those df 1-3 units of alcohol; it relieves anxiety
and produces mild relaxation, euphoria and increased sociability. However, as for
alcohol, ataxia, decreased motor skills and mild dizziness are observed, and it is in-
appropriate for users to drive or operate heavy machinery even at these low doses.
Medium doses (1-2.5 g) increase the relaxing effects and appreciation for music,
dancing, or talking. Positive mood changes are reported, but adverse effects are in-
creased including slurring of speech, silliness, and slight incoherency, as well as
feelings of nausea. A positive sexual effect is reported by users and consists of an
increase in tactile sensitivity, relaxation, increased male erectile capacity, and
heightened experience of orgasm in woman. With high doses (2-3.5 g), some peo-
ple will experience extremely positive feelings; they commonly report euphoria,
feeling music deeply, joyous dancing, and other such very positive effects. However,
many people accidentally overdose with such heavy doses and an extra quarter
gram can be the difference between euphoria and vomiting. GHB overdose usually
results from ingestion of 4 to 8 g, but has been reported with as little as 2 g. Such
doses result in strong drowsiness, but the patient may develop violent agitation
during noxious stimuli; in the more severe stage of overdose, the patient is com-
pletely non-responsive for 1 to 4 hours and profound sedation may last for 8 to 12
hours. Mild hypothermia, miosis, asymptomatic bradycardia, hypotension and res-
piratory depression are often associated so that this condition may be confused
with opiate overdose. Mild to extreme nausea and vomiting is frequent so that
there is a high risk of aspiration. Convulsions (seizure-like activity) or rhythmic
muscular twitching are frequently observed. The risk of true seizures is markedly
increased when GHB is combined with stimulants like methamphetamine for exam-
ple. G or GHB is sometimes written on the right hand of the user as commonly re-
commended on the Internet.
The dilemma of GHB overdose management is to know whether it is better to
further sedate the patient or to allow him/her to wake up spontaneously. Of course,
in severely overdosed victims, the ABC (airway, breathing, circulation) sequence is
the rule and rapid sequence intubation is the preferred means to protect the air-
ways. However, as recovery occurs, spontaneous extubation is frequent and is asso-
ciated with a high risk of aspiration. Therefore, we prefer to control the duration of
sedation with continuous administration of short acting agents such as midazolam
or propofol to control extubation after gastric emptying.
Antidotes have no value in the management of GHB overdose. A reversal effect
has been reported with physostigmine in some case [12], but this substance is dan-
gerous, especially in a condition already associated with bradycardia and seizures.
Flumazenil has no consistent effect and high dose naloxone have only been re-
ported to have some efficacy when GHB is associated with alcohol [ 13].
Table 1 . Usual dose-effect relationship of GHB
Treatment for alcohol withdrawal 0.15 g (3 times daily)

Low dose abuse 0.5-1.5 g
Medium dose abuse 1-2.5 g
High dose abuse 2-3.5 g
Mild overdose (can induce heavy sleep) 3-5 g
Severe overdose (unarousable sleep, coma, convulsions, vomiting) >5g
Lethal dose: hypotension, bradycardia, respiratory depression probably ~ 2 g/kg
Ketamine
Ketamine is a sedative-hypnotic with analgesic properties, marketed in many coun-
tries as an injectable general anesthetic, approved for both human and veterinary
practice since 1970. About 90o/o of the ketamine legally sold is intended for veterin-
ary use, but it is often stolen from supply sources. This substance gained popular-
ity for abuse in the 1980s [14].
Large doses cause reactions similar to those associated with use of phencyclidine
(PCP), such as dream-like states and hallucinations, although ketamine has a more
rapid onset and is less potent. It is sometimes used as an alternative to cocaine or
as a 'date rape' drug. Ketamine is produced in liquid form or as a white powder. Its
street names are Special K, K, Vitamin K, Cat Valiums. Ketamine is often snorted
or smoked with marijuana or tobacco products, sometimes injected intramuscularly.
Sought-after effects of ketamine are different depending on the dose; ketamine
can induce everything from feelings of pleasant weightlessness to near-death ex-
periences. Side effects of low-doses only consist of impaired attention, learning
ability, and memory disturbances. However, higher doses may result in delirium,
amnesia, impaired motor function, high blood pressure, CNS depression, and po-
tentially fatal respiratory problems. Treatment is supportive.
Substituted Amphetamines
Substituted amphetamines are obtained from the structural modifications of the
mescaline molecule. These products are related to amphetamines in their chemical
structure, but have both stimulant and hallucinogenic properties. Their production
is quite simple and is especially active in The Netherlands and Belgium (clandes-
tine 'meth labs'). A lot of contaminants may be contained in these substances that
are widely diffused through megadancings and 'rave' parties. Little information is
available about the toxicity of these drugs, except for MDMA ('Ecstasy').
Sought-after effects of these substances include stimulation, facilitation of heavy
and prolonged exertion and mood-enhancement with increased self-awareness and
heightened emotional and sensory experiences, without producing marked visual
or sensory distortions (these effects are observed at a typical MDMA dose 75-100
mg). Loss of inhibition is associated with feelings of openness and emotional close-
ness to others (empathy), removal of communication barriers and increased socia-
bility (entactogens).
Ecstasy or MDMA is not a true designer drug, since it was developed by
E. Merck in 1914 as an appetite suppressant. However, it has never been used clini-
cally for that purpose. In the 1970s, it was proposed as an adjunct in psychother-
apy, but was then banned in 1985 because of its toxicity and potential for abuse;
there was indeed a marked increase in the recreational abuse by the early 1980s
and mainly in the last decade. For example, it is estimated that as many as half a
million to a million people abuse MDMA every week in the UK. This wide abuse
has been associated with a marked reduction in the price of the drug. Ecstasy and
derivatives are sometimes sold as white to off-white powders, but most frequently
as tablets and capsules of varying colors. Ecstasy is orally ingested, sometimes
snorted and rarely injected. The typical dose of MDMA ranges from 30 to 180 mg.
Onset of effects is observed after 30-60 min and the peak at 90 min. The plateau
effect lasts approximately 3-6 hours and is followed by an unpleasant 'come down':
confusion, paranoid ideas, depression (that may last for hours or days) that
promote repeated use or abuse of other drugs (especially cannabis, but also opiates or
benzodiazepines like temazepam). The development of true dependence is uncom-
mon at usual doses, but chronic and compulsive patterns of use are frequent.
Ecstasy produces indirect (and direct) sympathomimetic stimulation in the CNS
as other amphetamines. It increases the release of neurotransmitters (norepineph-
rine, dopamine) and produces peripheral a- and /3-adrenergic actions. MDMA,
methylenedioxyamphetamine (MDA), and methylenedioxyethylamphetamine
(MDEA), two analogs of MDMA, have potent serotoninergic properties. They pro-
mote the release of serotonin, block the reuptake of serotonin and inhibit mono-
amine oxidase (MAO). This explains the overlap of signs and symptoms of MDMA
toxicity with those of the serotonin syndrome.
Short-term effects are frequent and include restlessness, sleep disorders, appetite
suppression, talkativeness, hyperactivity, euphoria, dry mouth, dilated pupils,
blurred vision, sudation, increased muscle tone, hyperreflexia, muscle pain, trismus
(jaw-clenching). Anxiety and panic attacks, pronounced visual and auditory halluci-
nations may be observed at larger doses, as well as nausea, vomiting, abdominal
pain and diarrhea.
Ecstasy has often been presented as the 'killer drug' in the tabloid newspapers.
However, sudden death appears relatively uncommon; 200-500 cases have been re-
ported in the US in the last 10-15 years. In the UK, 42 cases were reported for the
period 1987-1996; that means about 1 death/3.4 million exposures. The main cause
of sudden death is over-heating and exhaustion, due to the combination of hot and
crowed ambient settings, heat production by muscles during dancing and dysregu-
lation of temperature control due to amphetamines. Death may also result from car-
diovascular complications: arrhythmias, ischemia or hypertension crises and result-
ing cerebrovascular accidents. Acute hyponatremic encephalopathy with cerebral
edema is less frequently observed. Other secondary severe complications include
seizures, rhabdomyolysis, renal failure, and disseminated intravascular coagulation
(DIC). Toxic hepatitis and bone marrow depression have also been reported in
some cases.
Treatment is mainly symptomatic and supportive if only mild psychomotor stim-
ulation is observed. The health care personnel must adopt a calm, reassuring and
non-threatening behavior and the patient must be placed in a quiet environment.
To prevent the patient from harming themselves or others, gentle sedation with oral
benzodiazepines may be used. Antipsychotic medications should be avoided be-
cause they reduce the seizure threshold.
Complications must be anticipated and treated speedily, and close monitoring of
all symptomatic cases is important. Special attention must be paid to temperature
control Tachycardia and hypertension usually resolve with sedation. Beta-blockers
must be used with caution because unopposed alpha action may result in an
increase in the severity of hypertension. Rapidly acting titratable agents such as
nitroprusside or calcium channel blockers (nicardipine, nifedipine) may be used.
Arrhythmias may be treated as usual.
Street names of MDMA include Ecstasy, Essence, Clarity, Lover's Speed, X,
XTC ... Some analogs of MDMA are:
1 Tenamfetamine or methylenedioxyamphetamine (MDA - Adam, love pill) is of-
ten sold as MDMA and is probably more dangerous.
N-ethyl-3,4-tenamfetamine or methylenedioxyethylamphetamine (MDEA - Eve,
MDE) is shorter in action than MDMA and is believed to have sedative rather
than stimulant effects. Therefore, it less frequently encountered.
I N-methyl-1-(3,4-methylendioxyphenyl)-2-butanamine (MBDB) has appeared

more recently is Europe; its street name is Fido, Superman, Pastis, TNT ...
For all these substances, 'ecstasy' is now a kind of generic name.
Other substituted amphetamines have been developed as designer drugs:
I STP (serenity, tranquility, peace, 'serenity') is a potent substance (DOM or 4-
methyl-2,5-dimethoxyamphetamine). The typical dose of 1 to 3 mg induces
mood alterations and minor perceptual alterations similar to mescaline. Larger
doses are responsible for pronounced and long lasting hallucinations (8 to 10
hours). Side effects are frequent.
I DOB is 4-bromo-2,5-dimethoxyamphetamine and is also called bromo-STP or
'Golden Eagle'. It is sometimes falsely presented as LSD, impregnated on paper.
A typical dose of 1-5 mg induces both potent hallucinogenic and sympathomi-
metic properties with a long duration of action; onset of effects occurs 3 to 4 h
after ingestion and it takes up to 24 hours to resolve. Peripheral ischemia has
been reported as a result of diffuse vascular spasm ('ergotism').
I 2C-B or Nexus is 4-bromo-2,5-dimethoxyphenethylamine and is also called bro-
mo, toonies, bromo-mescaline, Venus, Erox, Zenith. It is sometimes falsely pre-
sented as LSD, MDMA, or 'synthetic khat'. The effects are very similar to
MDMA, but with stronger hallucinogenic effects and fewer sympathomimetic
side effects.
These substances are usually ingested, sometimes snorted, but impregnation in su-
gar cubes or blotter tabs has also been observed.
Two dangerous substances have recently emerged:
I 4 MTA (4-methylthioamphetamine) was synthesized as a new approach in the
treatment of depression. It works by a combination of two effects: a MAO-A in-
hibitor action and a very potent serotonin-releasing action. Actually, it has little
effect on dopamine and norepinephrine release. This substance is emerging as a
'club drug'. The probable source is The Netherlands. The usual dose is similar to
MDMA (100-140 mg). Some deaths have been reported in the UK, The Nether-
lands, and in Belgium. The sought-after effects of this drug are not clear, since
effects last rather long (approximately 12 hours), the stimulant effect is much
less important than with MDMA, and this substance does not produce hallucina-
tions or visual distortions. Conversely, side effects are frequent (thirst, increased
ocular pressure) and toxicity is similar to the 'serotonin syndrome'.
I PMA (4-MA; para or 4-methoxyamphetamine) and PMMA (4-MMA; para or 4-
methoxymethylamphetamine) have strong stimulant and hallucinogenic proper-
ties. They are strong MAO-A inhibitors. Tablets are sold as ecstasy on the dance
scene and can sometimes be recognized by the Mitsubishi logo. These sub-
stances have a low safety index (usual dose 50 mg; serious side effects can result
from 60-80 mg); effects are slower than those of MDMA, encouraging users to
overdose. Deaths have recently been reported in several countries, including
Belgium, especially from convulsions and severe hyperthermia. A case of intra-
cranial hemorrhage has also been reported.
A very particular aspect of MDMA is 'aggregation toxicity'. In animal models, be-

havioral and toxic effects are massively enhanced if mice given the drug are
grouped together as opposed to being alone. Acute toxicity in solitary mice is also
increased by loud noise, high ambient temperature, and dehydration. All these con-
ditions are usually encountered in nightclubs, and these observations are the base
for recommendations about access to adequately ventilated 'cooling-off' areas.
Another particular aspect of MDMA toxicity is hyponatremia [15-17]. First re-
ported after MDMA abuse in 1993 [18], hyponatremia may be associated with ence-
phalopathy and convulsions [19, 20] and even death [21]. The mechanisms involve
extracellular fluid volume depletion (sudation, vomiting), impending renal failure,
consumption of excessive amounts of water (harm reduction advice to prevent de-
hydration), MDMA-induced thirst, amphetamine and derivative-induced repetitive
behavior (observed in animals and humans), stimulation of vasopressin (ADH) re-
lease. Management of this complication depends on the main pathophysiologic
components involved: saline infusion, water restriction, increase of solute-free water
excretion (furosemide, urea). Administration of hypertonic saline (or mannitol)
may be considered if intracranial pressure (ICP) or cerebral edema is suspected, to
prevent cerebral damage. Every patient needs close monitoring of natremia.
MDMA has also been associated with the development of severe hepatitis, first re-
ported in 1992 [22] and increasing in incidence. Severe hepatitis may occur after
incidental or regular ingestion, after a variable latency of days to weeks. Two pat-
terns have been reported:
1 hepatitis may develop shortly after ingestion in association with acute profound
systemic effects (hyperthermia, etc.); a toxlab screen will usually detect MDMA
1 hepatitis may also be delayed (days to weeks) and MDMA will no longer be de-
tected in the toxlab screen.
MDMA induced hepatitis should be suspected in young adults presenting with a
hepatitis-like illness and negative viral studies. The pathophysiology is unclear. It
seems not to be dose related. Various hypotheses have been proposed: toxic
(MDMA, metabolites, adulterants), idiosyncratic, genetic predisposition, P450 in-
duction, or conversely CYP2D6 deficiency, hyperthermia, hemodynamic changes in
hepatic circulation, ... [23]. Spontaneous recovery is often observed, but fulminant
hepatic failure has occurred and (auxiliary) liver transplantation has been per-
formed in some cases [24].
One of the most worrying aspects of the widespread consumption of Ecstasy
and related compounds is the potential to induce chronic neurotoxicity [25]. In
terms of public health, this issue is probably much more critical than the limited
number of acute reactions or deaths that have been reported. This problem is still
not completely resolved and very active research is currently underway on this top-
ic [26, 27]. Lesions of serotonin and, to a lesser extent, of dopamine terminals have
been shown in the CNS after a few doses of MDMA in every animal species stud-
ied. Higher primates may be particularly susceptible to this kind of damage.
Although no definitive proof exists, recent data in humans highly suggest that neu-
rotoxicity also occurs and could result in psychosis, depression, behavioral disor-
ders or memory disturbances, for example. Recovery of such lesions is very slow
and probably incomplete and some data have suggested similarities between Ec-
stasy-induced damage and Alzheimer's disease [28].
I Club Cocktails
Mixing drugs is always a bad idea since many have a synergistic effect on each
other so that the effect is unpredictable and often more pronounced than expected
(2+2=5 or more). However, it is an increasing practice. A 'flip' is a combination of
Ecstasy and another drug. Ecstasy is alleged to insure a positive trip and to make
the other drug friendlier and very intense. Some common examples of such combi-
nations are the Candy Flipping (LSD & MDMA), the Hippy Flipping ('funny mush-
rooms' & MDMA), the Love Flipping (mescaline & MDMA), the Kitty Flipping (ke-
tamine & MDMA), the Elephant Flipping (PCP & MDMA), the Robo Flipping (dex-
trometorphan & MDMA), the Nexus Flipping (2-CB & MDMA). 'Adam and Eve in
the garden of Eden' is a mixture of MDMA, MDEA, and MBDB!
I Conclusion
Because 'Club drugs' have increasing popularity, critical care professionals should
be familiar with these agents. Indeed, several life threatening conditions such as de-
lirium, coma, respiratory depression, cardiac arrhythmias, hyperthermia, rhabdo-
myolysis, DIC, hyponatremic encephalopathy or acute renal and liver failure may
result from the abuse of these substances and may bring the consumer to the emer-
gency department or the intensive care unit. Data about the toxicological risks and
the available therapeutic options are therefore important.
References
1. Graeme KA (2000} New drugs of abuse. Emerg Med Clin North Am 18:625-636
2. Williams H, Dratcu L, Taylor R, Roberts M, Oyefeso A (1998) "Saturday night fever":
ecstasy related problems in a London accident and emergency department. J Accid Emerg
Med 15:322-326
3. Simmons MM, Cupp MJ (1998) Use and abuse of flunitrazepam. Ann Pharmacother
32:117-119
4. Li J, Stokes SA, Woeckener A (1998} A tale of novel intoxication: seven cases of gamma-
hydroxybutyric acid overdose. Ann Emerg Med 31:723-728
5. Nicholson KL, Balster RL (2001} GHB: a new and novel drug of abuse. Drug Alcohol
Depend 63:1-22
6. Ingels M, Rangan C, Bellezzo J, Clark RF (2000} Coma and respiratory depression follow-
ing the ingestion of GHB and its precursors: three cases. J Emerg Med 19:47-50
7. Dupont P, Thornton J (2001} Near-fatal gamma-butyrolactone intoxication - first report in
the UK. Hum Exp Toxicol20:19-22
8. Zvosec DL, Smith SW, McCutcheon JR, Spillane J, Hall BJ, Peacock EA (2001} Adverse
events, including death, associated with the use of 1,4-butanediol. N Engl J Med 344:87-94
9. The Vaults of Erowid at http://www.erowid.org/chemicals/ghb/ghb_dose.shtrnl
10. Chin MY, Kreutzer RA, Dyer JE (1992) Acute poisoning from gamma-hydroxybutyrate in
California. West J Med 156:380-384
11. Miotto K, Darakjian J, Basch J, Murray S, Zogg J, Rawson R (2001) Gamma-hydroxybutyric
acid: patterns of use, effects and withdrawal. Am J Addict 10:232-241
12. Viera AJ, Yates SW (1999) Toxic ingestion of gamma-hydroxybutyric acid. South Med J
92:404-405
13. Hunderup MC, Jorgensen AJ (1999} Poisoning with gamma-hydroxybutyrate. Cases re-
ported in connection with "cultural festivals" in August 1999 in Kolding. Ugeskr Laeger
161:6939-6940
14. Weiner AL, Vieira L, McKay CA, Bayer MJ (2000} Ketamine abusers presenting to the
emergency department: a case series. J Emerg Med 18:447-451
820 P. Lheureux et al.: Club Drugs: A New Challenge in Clinical Toxicology
15. Henry JA, Fallon JK, Kiernan AT, Hutt AJ, Cowan DA, Forsling M (1998) Low-dose MDMA
("ecstasy") induces vasopressin secretion. Lancet 351:1784
16. Ajaelo I, Koenig K, Snoey E {1998) Severe hyponatremia and inappropriate antidiuretic
hormone secretion following ecstasy use. Acad Emerg Med 5:839-840
17. Hall AP {1997) Hyponatraemia, water intoxication and 'ecstasy'. Intensive Care Med
23:1289
18. Maxwell DL, Polkey MI, Henry JA (1993) Hyponatremia and catatonic stupor after taking
"ecstasy''. Br Med J 307:1399
19. Holmes SB, Banerjee AK, Alexander WD {1999) Hyponatremia and seizures after ecstasy
use. Postgrad Med J 75:32-33
20. Magee C, Staunton H, Tormey W, Walshe JJ {1998) Hyponatraemia, seizures and stupor
associated with ecstasy ingestion in a female. Ir Med J 91:178
21. O'Connor A, Cluroe A, Couch R, Galler L, Lawrence J, Synek B {1999) Death from hypo-
natraemia-induced cerebral oedema associated with MDMA ("Ecstasy") use. N Z Med J
112:255-256
22. de Man RA, Wilson JH, Tjen HS {1993) [Acute liver failure caused by methylenedioxy-
methamphetamine ('ecstasy')]. Ned Tijdschr Geneeskd 137:727-729
23. Jones AL, Simpson KJ {1999) Review article: mechanisms and management of hepatotoxi-
city in ecstasy (MDMA) and amphetamine intoxications. Aliment Pharmacal Ther 13:129-
133
24. Garbino J, Henry JA, Mentha G, Romand JA (2001) Ecstasy ingestion and fulminant hepa-
tic failure: liver transplantation to be considered as a last therapeutic option. Vet Hum Tox-
icol 43:99-102
25. Morgan MJ {2000) Ecstasy (MDMA): a review of its possible persistent psychological
effects. Psychopharmacology (Berl) 152:230-248
26. Croft RJ, Klugman A, Baldeweg T, Gruzelier JH {2001) Electrophysiological evidence of
serotonergic impairment in long-term MDMA ("ecstasy") users. Am J Psychiatry 158:1687-
1692
27. McCann UD, Ricaurte GA, Molliver ME {2001) "Ecstasy" and serotonin neurotoxicity: new
findings raise more questions. Arch Gen Psychiatry 58:907-908
28. Jones GR {2001) Causes of Alzheimer's disease: paracetamol (acetaminophen) today? Am-
phetamines tomorrow? Med Hypotheses 56:121-123
I Gl Crises
New Insights into the Pathophysiology
and Severity Assessment of Acute Pancreatitis
D. J. van Westerloo, M. J. Bruno, and T. van der Poll
I Introduction
Acute pancreatitis is an acute sterile inflammation of the pancreas. The diagnosis

is made on the basis of a distinct clinical syndrome consisting of acute onset ab-
dominal pain radiating to the back and frequently accompanied by nausea and/or
vomiting, combined with a more than threefold increase of serum amylase or lipase
above the upper limit of normal. In the western world the most common causes of
acute pancreatitis are alcohol abuse and gallstones [1]. The disease is characterized
by the premature activation of digestive enzymes in the pancreas, followed by a
massive immunological response resulting in autodigestion of the gland, local, and
subsequent systemic inflammation. The incidence of the disease varies between
5-20 per 100000 persons per year, with 10-20% of patients developing severe pan-
creatitis of whom up to 30% may die as a result of the development of secondary
complications such as pancreatitis-associated lung injury, infectious complications
or multiple organ failure (MOF) [1]. This chapter will focus on recent develop-
ments in the understanding of the pathophysiology and immunopathology of acute
pancreatitis and its complications and discuss the importance of early severity pre-
diction including the merits of various prognostic markers.
I Pathophysiology
The pathophysiology of acute pancreatitis can be divided into several phases. An in-
tra-acinar phase, a local inflammatory phase, a systemic inflammatory phase and, in a
subset of patients, a fourth phase with the development of extra pancreatic or infec-
tious complications. In the majority of cases the inflammatory process is contained
within the pancreas itself and resolves in a matter of days. However, in up to 20%
of cases, the disease takes a more serious turn and complications develop. These com-
plications can be local (e.g., infection of pancreatic necrosis, pseudocyst-formation)
or systemic (e.g., sepsis, acute respiratory distress syndrome [ARDS]) [1]. The devel-
opment of extra pancreatic involvement is associated with a poorer prognosis.
Experimental Models of Acute Pancreatitis

This chapter will focus on the pathophysiology and immunopathology of acute
pancreatitis and on the lessons learned from experimental studies and their impli-
cations for staging and clinical management of the disease. Human studies of acute
824 D.J. van Westerloo et al.
pancreatitis face several problems. First, patients usually present for medical care
between 12 and 24 hours after onset of symptoms. At this point of the disease, the
intra-acinar phase has already fully developed and the essential primary events can
no longer be assessed. Second, the pancreas is not readily accessible for sampling,
which significantly limits the possibilities of studying pathophysiological events on
a (sub)cellular level. Therefore, most of the developments in the understanding of
acute pancreatitis are derived from animal models. Many animal models of pan-
creatitis have been developed in rodents, rabbits, dogs, pigs and opossums. The
most widely used animal model for edematous pancreatitis is the cerulein model
(hyperstimulation), in which pancreatitis is induced in rodents by 6-12 hourly in-
traperitoneal injections of the cholecystokinin (CCK) analog, cerulein. This model
is characterized by the development of edema, neutrophil sequestration in the pan-
creas, mild necrosis and systemic inflammation as well as mild pancreatitis-asso-
ciated lung injury. Severe necrotizing pancreatitis can be induced by the retrograde
injection of taurocholate in the pancreatic duct in rats, or by the administration of
a choline deficient ethionine (CDE)-supplemented diet to young female mice. Final-
ly, a so far underused human model is post-endoscopic retrograde cholangiopan-
creatography (ERCP) pancreatitis. The risk of pancreatitis after ERCP can be as
high as 15o/o in selected patients. Post-ERCP pancreatitis in humans is a feasible
model to study pathophysiological events and potential inhibitors in !this setting
especially because the initial noxious event is well-defined in time and patients can
be followed during the essential first hours of disease progression.
Intra-Pancreatic Digestive Enzyme Activation

The first and key event in the pathophysiology of acute pancreatitis is the premature
activation of digestive enzymes in the pancreas [2] (Fig. 1). Although the understand-
ing of this phenomenon is expanding rapidly, the mechanisms leading to it are still
largely unknown. In the normal pancreas, several mechanisms protect the organ from
autodigestion. First, all proteolytic and lipolytic pancreatic enzymes are stored as zy-
mogens, pro-enzymes, and will become active only after activation by enzymes in the
duodenum. However, within the acinary cell, lysosomal hydrolases have the capacity
to activate trypsinogen and other zymogens as well. Therefore, one of the most im-
portant lines of defense is the physical separation into granules of these zymogens
and activating hydrolases. At present, two theories have been postulated as to the site
and mechanisms of early enzyme activation in acute pancreatitis the co-localization
and the trypsinogen auto-activation, theory.
Co-Localization Theory: The leading theory is that, in acute pancreatitis, this separa-
tion is lost and that zymogens and hydrolases co-localize leading to intra-acinar
enzyme activation [3] (Fig. 1). Direct proof for this so called co-localization theory
is still lacking. However, studies have indicated that co-localization of lysosomal hy-
drolases with digestive enzyme zymogens occurs before zymogen activation in ex-
perimental pancreatitis and that the co-localization of these two types of enzymes
occurs within the compartment in which zymogen activation occurs. In vitro data
indicate that the lysosomal hydrolase, cathepsin B, may play a pivotal role in the
early activation of trypsinogen. When pancreatic acini are exposed to a supramaxi-
mally stimulating dose of cerulein, the activation of trypsinogen is prevented by in-
hibitors of the lysosomal hydrolase cathepsin B (CTSB) [4]. Recent in vivo evidence
indicates that a redistribution of lysosomal cathepsin B into a zymogen-containing
New Insights into the Pathophysiology and Severity Assessment of Acute Pancreatitis 825
Co localization
Early activation
Autodigestion
Fig. 1. Co-localization of zymogens and lysosomal hydrolases leads to premature enzyme activation and
autodigestion of the pancreas
subcellular compartment triggers trypsinogen activation [5]. In this study [5],

CTSB knockout mice were protected from cerulein-induced acute pancreatitis. In
another study, inhibitors of cathepsin B prevented the activation of trypsinogen
and dramatically reduced the severity of experimental pancreatitis in two different
animal models [6]. Therefore, there is growing evidence that cathepsin B might
play a pivotal role in the intrapancreatic activation of trypsinogen in vivo and
pharmacological inhibition of cathepsin B might be a valuable option to prevent
pancreatitis or reduce its severity. However, more evidence from human studies is
needed to confirm that co-localization actually occurs in humans and that it is not
applicable to rodent pancreatitis alone.
Trypsinogen Auto Activation Theory: One of the most interesting aspects of trypsino-
gen is that it is capable of auto activating, as well as inhibiting, itself. Under nor-
mal circumstances only a fraction of human trypsinogen activates to trypsin. How-
ever, in the presence of secretory blockade combined with an enhanced sensitivity
to trypsinogen activation, this process may become uncontrolled and lead to auto-
digestion of the gland. Two lines of defense regulate the auto-activation properties
of trypsinogen. The first failsafe mechanism to eliminate prematurely activated
trypsinogen is dependent on the action of a small peptide called pancreatic secre-
tory trypsin inhibitor (PSTI) also referred to as serine protease inhibitor Kazal type
1 (SPINK1) [7]. SPINK1 inhibits trypsin by blocking its active site. Due to its lim-
ited availability (ratio to trypsin 1: 5), SPINK1 is only capable of inhibiting 20% of
all potential trypsin activity. However, SPINK1 is an important defense mechanism
against prematurely activated trypsinogen. In recent years, it has become clear that
the frequency of SPINK1 mutations {N34S, P55S) in patients with idiopathic
chronic pancreatitis is increased up to 25% [9]. However, since SPINK1 mutations
are common in the general population {2%) there is no clear-cut direct causal rela-
tion between the presence of a SPINK1 mutation and chronic pancreatitis; in fact
there are far more 'healthy' carriers than chronic pancreatitis patients with a
SPINK1 mutation. SPINK1 mutations are, therefore, considered disease-modifying

genes. A second line of defense is formed by trypsin itself. To keep its own activity
in check, trypsin hydrolyzes the chain connecting the two globular domains of the
trypsin molecule at position R122H. Mutations of the gene encoding for this
R122H domain result in an inactivation-resistant trypsin. Basically, both mutations
in the SPINK gene and in the gene encoding for the R122H probably lower the
threshold for the development of acute and chronic pancreatitis. So this theory pos-
tulates that, whereas in the normal pancreas low levels of trypsinogen are activated
constantly to trypsin, under the influence of environmental and genetic factors the
normal protective mechanisms are bypassed and pancreatitis may develop.
Pancreatic Inflammation
As a result of intrapancreatic enzyme activation, an autodigestive process is ini-
tiated which is followed by a massive inflammatory response (Figs. 2 and 3). This
second inflammatory phase in the pathophysiology of acute pancreatitis is charac-
terized by the involvement of several soluble inflammatory mediators, cytokines
and chemokines [8]. All of these mediators are involved in the inflammatory cas-
cade subsequent to acinar cell damage but do not play a causal role in the disease.
To illustrate this, treatment of isolated acinar cells directly with pro-inflammatory
cytokines, such as interleukin-1 beta (IL-1p) or tumor necrosis factor alpha (TNF-
a), does not result in co-localization of zymogen granules and lysosomes or the ac-
tivation or release of enzymes. Moreover, perfusion of the isolated human pancreas
with IL-1P and TNF-a does not induce acute pancreatitis [8].
Cytokines, including TNF-a, are primarily produced by immune-competent cells
but by pancreatic acinar cells as well [9]. Many experimental anti-cytokine thera-
pies have been administered following induction of experimental pancreatitis, and
some have proved to be effective. Usually, the cytokine network is discussed as
consisting of pro-inflammatory cytokines, anti-inflammatory cytokines and soluble
inhibitors of pro-inflammatory cytokines. At the end of this section, we will review
the mechanisms by which the cytokine network is activated during the first phase
of the inflammatory response and the role of these mediators in acute pancreatitis
as well as the involvement of neutrophils in pancreatitis.
Transcription Factors: Experimental evidence indicates that the inflammatory process

is initiated by the early activation of the transcription factor nuclear factor K-B
(NF-KB). NF-KB is a transcription factor that, upon degradation and activation,
translocates to the nucleus where it activates a plethora of stress-related genes such
as genes encoding cytokines, chemokines, growth hormones, adhesion molecules
and acute phase proteins. To illustrate the importance of NF-KB, neutralization of
NF-KB, either by the antioxidant N-acetyl cysteine (NAC) or NF-KB antibody ame-
liorates experimental CCK-induced pancreatitis [10, 11]. Furthermore, NF-KB levels
are highest in areas most damaged by pancreatitis, and the activation of NF-KB
alone induces an inflammatory response in the pancreas [12]. In a recent study,
NF-KB was directly activated within the pancreas using adenoviral-mediated trans-
fer of an active subunit, RelA/p65 (Adp65), delivered by intraductal injection [12].
This led to the activation of NF-KB, the expression of NF-KB target genes, and an
inflammatory response causing widespread damage to pancreatic acinar cells.
The activation and degradation of NF-KB is in turn mediated by several intracel-
lular messenger pathways such as the mitogen-activated protein kinase (MAPK)
New lnsiahts into the Pathoohvsiology and Severity Assessment of Acute Pancreatitis 827
Trigger Acinary phase Local inflammation
Primary event Reaction to tissue Mediator release

damage
Alcohol Activation of Cytokines

Gallstones immunecompetent --+
ll-1 --+
--+ --+
Post ERCP cells TNF
Trauma Co-localization of ll-6
Neutrophils IL-10
Medication zymogens and
lysosomal hyd rolases Monocytes
Hypercalcemia
Macrophages
Hyperlipidemia
l.•
Platelets lipid mediators
Hereditary PAF
Endothelial activation
Chemokines
Cytokine production IL-8
by adnar cells
Oxygen radikals
NO
Neutrophil mediated
trypsinogen activation
Local complications Distant or systemic

complications
Shock
Respiratory failure
Necrosis
of pancreatic tissue Infections
of peripancreatic fat Abscesses Reduction of
Pneumonia antibacterial host
Infection Peritonitis defense
Pseudocyst forma~on Sepsis
Local obstruction
Systemic i:lammation /
------------ systemic inflammation

ARDS
SIRS
MOFS
lmmunoparalysis
Fig. 2. Pathophysiology scheme of acute pancreatitis
pathway. Inhibition of this specific pathway, for example by administration of the

small molecule CNI-1493, a synthetic guanylhydrazone which inhibits the phos-
phorylation of p38 MAP kinase, attenuated the production of IL-1/3 and TNF-a
mRNA in pancreatic as well as pulmonary tissue associated with decreased severity
of pancreatitis and pancreatitis-associated lung injury [13, 14].
Pro-Inflammatory Cytokines and Platelet Activating Factor (PAF): From animal models,
as well as clinical studies, we know that IL-1/3, IL-6, TNF-a and the lipid mediator
PAP all play an important pro-inflammatory role in the disease [15-18].
I TNF-a: TNF-a is released in response to a variety of stimuli by monocytes and
macrophages. Injection of high doses of TNF-a into experimental animals causes
a syndrome that is indistinguishable from septic shock. TNF-a is one of the
828 D. J. van Westerloo et al.
Unknown primary event
Co - localization
Intra-acinar enzyme activation
Local inflammatory response - Recovery
!
Systemic inflammation
SIRS / MOF Pulmonary injury Infectious complication
!
Local I extra pancreatic
Fig. 3. Schematic overview of disease progression in acute pancreatitis
most important cytokines in the pathogenesis of sepsis and is associated with a

plethora of inflammatory diseases, such as rheumatoid arthritis and Crohn's dis-
ease [19]. TNF-a is a pivotal and major component of the inflammatory cascade
and induces the upregulation of various other cytokines such as IL-lP and IL-6.
TNF-a has been detected in high concentrations in serum of patients with acute
pancreatitis, however, its release is very phasic and TNF-a is rapidly degraded
by the liver. A better alternative to obtain insight into the TNF-a load is to mea-
sure soluble TNF receptors (sTNFR), which persist in the circulation and can be
detected in the plasma of patients with acute pancreatitis [20]. Increased levels
of circulating sTNFR predicted organ failure in patients with pancreatitis even
when TNF levels were not detectable [17]. In animal models, anti-TNF-a anti-
body, as well as inhibiting of TNF-a release, ameliorate acute pancreatitis [21].
Timing of anti-TNF therapy seems to be essential. In a study that used the CDE
model, blockade of TNF by the administration of a soluble TNF receptor attenu-
ated the severity of pancreatitis, decreased levels of inflammatory cytokines, and
improved survival. Delaying antagonism until pancreatitis was manifest and cir-
culating cytokines were elevated but not yet maximal was more protective than
prophylactic TNF antagonism (survival benefit was 20% in the prophylactic and
40% in the delayed therapy group) [15].
I IL-IP: IL-lP is another potent pro-inflammatory cytokine that is derived predom-
inantly from macrophages. IL-lP activates neutrophils, up regulates adhesion mol-
ecules and induces a shock-like state in animals when injected at high doses. The
antagonist for IL-lp, IL-l receptor antagonist (IL-lra) is also produced within the
pancreas during acute pancreatitis and levels of IL-lP and IL-lra correlate with the
severity of acute pancreatitis [22]. Administration of recombinant IL-l ra, as well as
targeted disruption of the IL-l receptor gene (IL-l receptor knockout mice) de-
creased the severity of cerulein-induced pancreatitis [23]. If, in the same model,
IL-l converting enzyme (ICE) (which cleaves pro-IL-lP to IL-lP) was inhibited,
the extent of acinar necrosis and parenchymal destruction was significantly re-
duced [24].
I IL-6: IL-6 is an important cytokine that is upregulated in a large variety of in-
flammatory conditions, such as sepsis, burns, infections, surgery and pancreati-
tis [25]. IL-6 is produced by a wide range of cells in response to stimulation by

endotoxin, IL-lp, and TNF-a [26]. A major role of IL-6 is the stimulation of the
synthesis of acute phase proteins, such as C-reactive protein (CRP). IL-6 levels
are raised in patients with acute pancreatitis and correlate with disease severity
[27].
PAF: PAF has multiple actions of which platelet activation is the least important
in the context of acute pancreatitis. More important is the ability of PAF to acti-
vate neutrophils, first locally in the pancreas and, after leakage from the pan-
creas to the circulation, systemically. Furthermore, PAF enhances the permeabil-
ity of the capillary endothelium, thus promoting tissue edema and endothelial
leakage. Therefore, antagonism of PAF has long been regarded as a potential
treatment option in acute pancreatitis. Indeed, in animal models of pancreatitis,
PAF ameliorated local pancreatic damage as well as pancreatitis associated sys-
temic inflammation, as judged by lower serum cytolcine levels (TNF, IL-l, IL-6),
and less lung injury [28]. Unfortunately, after initially promising data, a recent,
large, multi-center trial evaluating the effect of lexipafant, a potent PAF antago-
nist, was stopped due to lack of clinical efficacy [29, 30].
Anti-inflammatory Cytokines:
IL-10: IL-10 is a prominent anti-inflammatory cytokine. Plasma levels are ele-
vated in animal models of endotoxemia and IL-10 inhibits the release of pro-in-
flammatory cytokines (i.e., IL-lP, IL-6, and TNF-a) from monocytes/macro-
phages [31]. In acute pancreatitis, levels are markedly raised within the first
24 h of an attack followed by a steady decline over the following days. Experi-
mental evidence shows that IL-10 plays a very important anti-inflammatory role
in pancreatitis. In IL-10 knockout mice, pancreatitis is more severe and after the
administration of recombinant IL-l 0 or in IL-l 0 transgenic mice, local and sys-
temic inflammation is largely ameliorated [32]. With regard to human pancreati-
tis, there are data that suggest that prophylactic administration of IL-10 reduces
the incidence of post ERCP pancreatitis [33].
Chemokines and Neutrophils: Finally, the overwhelming production of chemokines

and cytolcines leads to activation and influx of neutrophils. Acute pancreatitis is
characterized by a strong influx of neutrophils. This is of pathogenetic significance
since neutrophil depletion ameliorates the severity of experimental acute pancreati-
tis [34]. Leukocyte migration is a multi-step process involving neutrophil rolling,
firm adhesion and transmigration through the endothelial layer (reviewed in [35]).
The attraction of leukocytes, their adhesion to the endothelial wall, and extra-
vasation into tissues is essential for inflammation and the host response to in-
flammation. One of the most important adhesion molecules involved in rolling and
firm adhesion is intercellular adhesion molecule-1 (ICAM-1). Pancreatitis severity
and associated lung injury is reduced by approximately 50% in mice-deficient in
ICAM-1, an extent comparable to that seen in mice depleted of neutrophils. Com-
bining ICAM-1 deficiency and neutrophil depletion does not provide additional
protection [36]. Chemokines, a group of small chemotactic proteins, provide the
signals that convert the low-affinity, selectin-mediated interaction of leukocyte ad-
hesion into the higher-affinity, integrin-mediated interaction that leads to extrava-
sation of leukocytes. Chemokines can be produced by virtually all cells given the
appropriate stimulus and, therefore, the dramatic increase in the secretion of che-
mokines during inflammation results in the selective recruitment of leukocytes into

inflamed tissue. CXC chemokines are a subset of chemokines that can be further
divided into two different groups on the basis of the presence or absence of a 3
amino acid motif termed 'ELR'. ELR-positive CXC chemokines are chemotactic for
neutrophils and include, among others, IL-8, epithelial neutrophil-activating protein
78 (ENA-78) and growth-related oncogene-alpha (GRO-a) in humans and KC and
macrophage inflammatory protein (MIP)-2 in mice. IL-8, ENA-78 and GRO-a are
detected in high concentrations in the blood of patients during an attack of acute
pancreatitis and are prognostic for clinical outcome [37]. Anti-IL-8 treatment de-
creases the severity of acute pancreatitis in animal models [38]. Recently, Gukovs-
kaya et al. [39] have shown that neutrophils do not only play a role in the immuno-
logical response to tissue damage but are themselves capable of activating digestive
enzymes in the pancreas. This finding is very interesting since it indicates that
neutrophil migration to the pancreas might lead to a positive feedback loop which
sustains the continuous activation of pancreatic enzymes, pancreatic damage and
subsequent inflammation. Whereas neutrophils may be needed to clear cellular
debris and provide a first line of protection against infection or pancreatic necrosis
they may in fact do more harm than good. Therefore, inhibition of neutrophil in-
flux, either by interfering with the transmigration process or by inhibition of CXC
chemokines, might be a valuable therapeutic approach in the treatment of acute
pancreatitis. This possibility is confirmed by data obtained in various animal mod-
els, e.g., hyperstimulation pancreatitis in ICAM knockout mice and rabbits treated
with anti IL-8, in which inhibition of neutrophil migration is associated with a bet-
ter outcome [40, 41].
Systemic Inflammation
In most patients, the inflammatory process is self-controlled; the inflammation sub-
sides with pancreatic rest and supportive measures. However, in a subset of pa-
tients the inflammatory process is not controlled. As a result of the release of acti-
vated pancreatic enzymes, cytokines, chemokines and other mediators, and migra-
tion of activated neutrophils and monocytes from the pancreas, a systemic inflam-
matory syndrome (SIRS) may develop. All of these mediators and activated cells
trigger a generalized capillary endothelial leakage leading to hypovolemia, hypo-
tension and fluid sequestration in the lungs. The most frequently affected extra-
pancreatic organ is the lung, in which pancreatitis may lead to pancreatitis-asso-
ciated lung injury, a syndrome quite indistinguishable from ARDS [42]. Moreover,
hypovolemia and hypoxemia lead to reduced oxygen delivery to vital organs such
as the kidney (renal failure) and the gut (intestinal ischemia). Intestinal ischemia is
especially important since it reduces the mucosal barrier function of the gut
against translocation of bacteria making the host very susceptible to subsequent
infectious complications. Ultimately pancreatitis-associated SIRS may lead to MOF
and death.
Infectious Complications
The most prevalent and serious complications of pancreatitis are, however, infec-
tious in nature [43]. Infectious complications, primarily bacterial contamination of
pancreatic necrosis, peripancreatic fat tissue, or abscess formation, in the pancreas,
but also extrapancreatic such as nosocomial pneumonia, are important contributors
to pancreatitis-related morbidity [43, 44]. Pancreatic infections develop in 40-70%

of patients with necrotizing pancreatitis with a mortality rate up to 50% [43]. The
vast majority of these infections are caused by Gram-negative organisms derived
from the gut [43]. Pancreatic infection is caused by bacterial translocation from the
gut lumen to the blood stream and secondarily to the pancreas. Three principle
causes have been implicated in this process: reduced motility with disruption of in-
testinal flora, mucosal barrier damage caused by hypoperfusion, and immune sys-
tem failure [45]. Many studies have been undertaken to evaluate the effect of proph-
ylactic broad spectrum antibiotics or selective gut decontamination in pancreatitis
patients at high risk for infection [46]. The outcome of most of these studies indi-
cates that this may in fact be beneficial, although there is some concern and evi-
dence of secondary complications such as fungal superinfection&. However, the
problem is to identify which patients are at high risk for infectious complications
and might benefit the most from prophylactic antibiotics. The diagnostic dilemma
is to distinguish between sterile and infected pancreatic necrosis. Diagnosis of pan-
creatic infection can be made by the clinical picture, rising CRP levels and high
Ranson scores (>4), but more reliably by computed tomography (CT) scan and
CT-guided fine needle aspiration (FNA) and culture [47]. If pancreatic infection is
proven, surgery is indicated because further conservative treatment will lead to al-
most 100% mortality in patients with signs of sepsis. Therefore, the treatment is
primarily surgical. Surgical methods for the treatment of necrosis and infection
vary and the best method has yet to be identified; even in the most experienced
hands the mortality is still between 15 and 80% [47, 48].
It has already been mentioned that decreased immune function enhances the
risk of bacterial translocation and pancreatic infection. Recent studies have further
suggested that in severely ill patients antibacterial host defense is significantly im-
paired [49]. This state is called immunoparalysis and patients with this syndrome
are far more susceptible to infections. Preliminary data from our group show that
concurrent pancreatitis renders mice more susceptible to pneumonia caused by
Pseudomonas aeruginosa, a frequently encountered bacterial pathogen in nosoco-
mial pneumonia, which in turn aggravates the severity of pancreatitis [50]. The
same phenomenon can be seen in mice with concurrent pancreatitis and abdom-
inal sepsis [51]. Therefore, in the case of pancreatitis and secondary infectious
complications there might be evidence for a pathological vicious circle in which
bacterial host defense is impaired and further inflammation due to infection leads
to enhancement of the severity of local damage in the pancreas.
I Identification of High Risk Patients

One of the most important clinical issues in acute pancreatitis is to find prognostic
markers that identify patients who will develop mild self-limiting disease and pa-
tients who will progress to a more complicated outcome [52]. Finding a reliable
marker would have major implications for the medical management of pancreatitis
patients. Patients evaluated as being at high risk should then receive intensive ob-
servation and care, and possibly in the future experimental immune-modifying
drugs as well as prophylactic antibiotics.
Clinical Scoring Systems

Initial clinical assessment can be used to grade pancreatitis severity. Upon presen-
tation in the emergency room the history should include a duration of symptoms,
considering that an onset of symptoms shorter than 12 hours before seeking medi-
cal care is a prognostic indicator for an adverse outcome. Another rapid prognostic
indicator is calculation of the body mass index (BMI). Patients with a BMI over 30
kg!m 2 have a mortality of 35%, as compared to 5% in patients with a lower BMI
[53]. However, the overall prognostic power of clinical assessment is very limited.
Several studies have shown that only in very specialized centers does clinical assess-
ment have a sensitivity to predict severe disease of more than 60% and a specificity
of 80%, whereas the initial clinical assessment of inexperienced physicians only has
a sensitivity of 40% and a specificity of 60% [54, 55] . To overcome these issues,
several specific clinical scoring systems have been developed. All of these scoring
systems have their merits but also their drawbacks. The best known and the most
widely used prognostic scoring system is the Ranson score. Ranson's original paper,
published in 1974, described an 11 point scoring system that predicts severe pan-
creatitis if 3 points are present [56]. However, a major drawback of this system is
that it cannot appropriately be used in patients with biliary pancreatitis. To over-
come this, a modified Ranson score has been developed (Table 1). However, the
problem with the Ranson score remains which system should be used in an indi-
Table 1. Modified Ranson's criteria for the assessment of severity of acute pancreatitis. A severe attack is
predicted by the presence of three or more positive factors in patients with gallstone pancreatitis [59]
On admission After 48 hours

Age > 70 years Hematocrit fall >10%
WBC > 18x109/l Serum calcium < 2 mmoVI
Blood glucose >12 mmol/1 Base deficit >5 meq/1
lDH >400 lUll BUN increase >0.5 mmol/1
AST > 210 lUll Fluid sequestration > 6 litres
Arterial P0 2 < 60 mmHg
Table 2. Modified Glasgow criteria for the assessment of severity of acute pancreatitis. Asevere attack is
predicted by the presence of three or more positive factors [59]
During the first 48 hours

Serum albumin <32 g/1
Serum calcium <2.0 mmol/1
WBC >15x109/l
AST > 200 lUll
LDH >600 lUll
Arterial P02 <8.0 kPa
Blood glucose (non DM) >10 mmoVI
Plasma urea > 16 mmol/1
Table 3. Modified Balthazar score for the assessment of acute pancreatitis severity by CT scan. The score
ranges from 0-10 [59]
Score Necrosis Score

Normal 0 0 0
I Focal, diffuse enlargement. Contour irregularity. <30% 2
Inhomogeneous attenuation
I Previous, plus peripancreatic haziness/steady densities 2 30-50% 4
I Previous, plus ill-defined peripancreatic fluid collection 3 >50% 6
Previous, plus 2 ill-defined peripancreatic fluid collections 4
vidual patient, making the results of the score difficult to interpret in large trials.
The Ranson-derived 8 point Glasgow score is more appropriate for use in individual
patients since it is not cause dependent, is easy to perform and is as good as the Ran-
son score (Table 2). The major drawback of the Ranson and Glasgow scoring systems
is that a delay of 48 hours is necessary to make a good assessment. Overall, the Ran-
son and Glasgow scores have a sensitivity of 70 and 55o/o, and a specificity of 67 and
91 o/o, respectively, for severity assessment.
Contrast-Enhanced CT Scan
Contrast CT has been utilized to assess severity in acute pancreatitis. Most studies
have used the score originally described by Balthazar, modified for contrast-en-
hanced CT scanning (Table 3). Unfortunately, it takes three to five days before ne-
crosis can be appreciated on a CT scan and before that time CT scans have a very
low sensitivity and specificity in predicting severe pancreatitis [57}. Actually, the
value of contrast-enhanced CT scan is quite comparable to that of the clinical scor-
ing systems. We believe that the value of CT scans as a prognostic indicator is lim-
ited, although CT scans do help in patients who have progressed to severe disease
and especially in those suspected of pancreatic infection.
Serum Markers
New serum markers of disease severity have recently emerged and their potential
for providing additional information on the severity of the disease is currently
being evaluated.
I CRP: The most readily available serum marker is CRP, widely available, cheap
and currently underused in the clinical setting. CRP levels over 120 mg/1 de-
tected 95o/o of necrotizing pancreatitis cases confirmed by laparotomy in a clini-
cal study. Unfortunately, the delay of this test is at least 24-48 hours, and there-
fore it is more comprehensive to use it to monitor disease progression than for
providing early prognostic indication.
I IL-6: As mentioned before, IL-6 is one of the most potent inducers of the acute
phase response. Since CRP is a quite reliable indicator of severity and CRP is in-
duced by IL-6 it is conceivable that IL-6 might be a reliable and earlier indicator
of severity. Indeed, IL-6 is an excellent indicator of severity, as good as CRP, but
with a delay that is approximately 24 hours shorter. However, the test is expen-
sive and the lack of an automated assay has kept its use from the clinic so far.
I TAP: Recently a new test has been introduced, urinary trypsinogen activation
peptide (TAP) [58]. The hypothesis behind the test is that necrotizing pancreati-
tis is associated with a massive activation of pancreatic zymogens, such as tryp-
sinogen, whereas edematous pancreatitis is associated with a much less. severe
zymogen activation. To quantify zymogen activation, and thereby early pancrea-
titis severity, TAP is measured. TAP is a small peptide which is released in equi-
molar concentrations during the activation of trypsinogen to trypsin. TAP is in-
ert and is excreted in the urine within two hours. TAP levels in the urine over
2 nmoVl on admission predict a severe attack with a sensitivity of 85% and a
specificity of 90% [58]. The measurement of urinary TAP concentrations repre-
sents the best means of early and rapid (the test takes 4 hours) prediction of
pancreatitis severity. However, the test is only used in highly specialized centers
as of now, because it is relatively unknown and highly expensive although cur-
rently commercially available (Biotrin, Ireland).
I Conclusion
The key event in the pathophysiology of acute pancreatitis is the co-localization of
digestive zymogens with activating hydrolases within the acinar cell. The mecha-
nism leading to this co-localization is, as yet, unidentified. The result is acinar cell
damage which is followed by a primary local activation of acinar and immune
competent cells, leading to activation of intracellular stress pathways, cytokine and
chemokine production and the migration of neutrophils to the inflamed pancreas.
Experimental studies have indicated that inhibition of several of these processes
leads to diminished inflammation and a better outcome. However, whether these
promising results can be duplicated in human disease remains to be evaluated.
An important subset of patients will develop extrapancreatic complications. In this
group of patients morbidity and mortality is high due to serious systemic inflamma-
tion and the development of infectious complications. In such cases, administration of
prophylactic antibiotics or selective gut decontamination seems beneficial.
Risk assessment for stratified patient management by means of prognostic test-
ing should be performed in every patient. Current clinical guidelines advise using a
clinical (Ranson, Glasgow), a radiological (contrast CT, in selected patients), and a
serum (CRP, urinary TAP) indicator of severity in all patients with acute pancreati-
tis. Patients identified as high risk should receive intensive clinical observation and
care, maximal supportive treatment, experimental drugs if feasible, or prophylactic
antibiotics.
At present, various immunomodulatory interventions are being evaluated and it
is conceivable that such treatment will become standard in the care of patients sus-
pected of developing severe pancreatitis.
References
1. Mergener K, Baillie J (1998) Acute pancreatitis. Br Med J 316:44-48
2. Steer ML, Saluja AK (1993) Experimental pancreatitis: studies of the early events that lead
to cell injury. In: Lian V, Go W, Dimagno EP, et al (eds) The Pancreas: Biology, Pathobiol-
ogy and Disease. Raven Press, New York, pp 11-36
3. Steer ML (1999) Early events in acute pancreatitis. Baillieres Best Pract Res Clin Gastroen-
terol13:213-225
4. Saluja AK, Donovan EA, Yamanaka K, Yamaguchi Y, Hofbauer B, Steer ML (1997) Cerulein-
induced in vitro activation of trypsinogen in rat pancreatic acini is mediated by cathepsin B.
5. Halangk W, Lerch MM, Brandt-Nedelev B, et al (2000) Role of cathepsin B in intracellular
trypsinogen activation and the onset of acute pancreatitis. J Clin Invest 106:773-781
6. Van Acker GJ, Saluja AK, Bhagat L, Singh VP, Song AM, Steer ML (2002) Cathepsin B inhi-
bition prevents trypsinogen activation and reduces pancreatitis severity. Am J Physiol
283:G794-G800
7. Witt H, Luck W, Hennies HC, et al (2000) Mutations in the gene encoding the serine pro-
tease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Nat Genet 25:213-216
8. Norman J (1998) The role of cytokines in the pathogenesis of acute pancreatitis. Am J Surg
175:76-83
9. Gukovskaya AS, Gukovsky I, Zaninovic V, et a! (1997) Pancreatic acinar cells produce, re-
lease, and respond to tumor necrosis factor-alpha. Role in regulating cell death and pan-
creatitis. J Clin Invest 100:1853-1862
10. Gukovsky I, Gukovskaya AS, Blinman TA, Zaninovic V, Pando! SJ (1998) Early NF-kappaB
activation is associated with hormone-induced pancreatitis. Am J Physiol 275:G1402-
G1414
11. Grisham MB (1999) NF-kappa B activation in acute pancreatitis: protective, detrimental, or
inconsequential? Gastroenterology 116:489-492
12. Chen X, Ji B, Han B, Ernst SA, Simeone D, Logsdon CD (2002) NF-kappa B activation in
pancreas induces pancreatic and systemic inflammatory response. Gastroenterology
122:448-457
13. Denham W, Yang J, Wang H, Botchkina G, Tracey KJ, Norman J (2000) Inhibition of p38
mitogen activate kinase attenuates the severity of pancreatitis-induced adult respiratory
distress syndrome. Crit Care Med 28:2567-2572
14. Denham W, Fink G, Yang J, Ulrich P, Tracey KJ, Norman J (1997) Small molecule inhibi-
tion of tumor necrosis factor gene processing during acute pancreatitis prevents cytokine
cascade progression and attenuates pancreatitis severity. Am Surg 63:1045-1049
15. Norman JG, Fink GW, Messina J, Carter G, Franz MG (1996) Timing of tumor necrosis fac-
tor antagonism is critical in determining outcome in murine lethal acute pancreatitis. Sur-
gery 120:515-521
16. Norman JG, Fink GW, Sexton C, Carter G (1996) Transgenic animals demonstrate a role
for the IL-l receptor in regulating IL-lbeta gene expression at steady-state and during the
systemic stress induced by acute pancreatitis. J Surg Res 63:231-236
17. de Beaux AC, Goldie AS, Ross JA, Carter DC, Fearon KC (1996) Serum concentrations of
inflammatory mediators related to organ failure in patients with acute pancreatitis. Br J
Surg 83:349-353
18. Osman MO, Jacobsen NO, Kristensen JU, et al (1998) IT 9302, a synthetic interleukin-10
agonist, diminishes acute lung injury in rabbits with acute necrotizing pancreatitis. Sur-
gery 124:584-592
19. Van Deventer SJ (1997) Tumour necrosis factor and Crohn's disease. Gut 40:443-448
20. Kaufmann P, Tilz GP, Lueger A, Demel U (1997) Elevated plasma levels of soluble tumor
necrosis factor receptor (sTNFRp60) reflect severity of acute pancreatitis. Intensive Care
Med 23:841-848
21. Hughes CB, Grewal HP, Gaber LW, et a! (1996) Anti-TNF alpha therapy improves survival
and ameliorates the pathophysiologic sequelae in acute pancreatitis in the rat. Am J Surg
171:274-280
22. Fink GW, Norman JG (1997) Specific changes in the pancreatic expression of the interleu-
kin 1 family of genes during experimental acute pancreatitis. Cytokine 9:1023-1027
23. Norman JG, Fink G, Franz M, et al (1996) Active interleukin-1 receptor required for maxi-
mal progression of acute pancreatitis. Ann Surg 223:163-169
24. Rau B, Paszkowski A, Lillich S, Baumgart K, Moller P, Beger HG (2001) Differential effects
of caspase-l!interleukin-1beta-converting enzyme on acinar cell necrosis and apoptosis in
severe acute experimental pancreatitis. Lab Invest 81:1001-1013
25. Papanicolaou DA, Wilder RL, Manolagas SC, Chrousos GP (1998) The pathophysiologic
roles of interleukin-6 in human disease. Ann Intern Med 128:127-137
26. Van der Poll T, van Deventer SJ (1998) The role of interleukin 6 in endotoxin-induced in-
flammatory responses. Prog Clin Biol Res 397:365-377
27. Berney T, Gasche Y, Robert J, et al (1999) Serum profiles of interleukin-6, interleukin-8,
and interleukin-10 in patients with severe and mild acute pancreatitis. Pancreas 18:371-377
28. Lane JS, Todd KE, Gloor B, et al (2001) Platelet activating factor antagonism reduces the
systemic inflammatory response in a murine model of acute pancreatitis. J Surg Res
99:365-370
29. Kingsnorth AN, Galloway SW, Formela LJ (1995) Randomized, double-blind phase II trial
of Lexipafant, a platelet-activating factor antagonist, in human acute pancreatitis. Br J Surg
82:1414-1420
30. Johnson CD, Kingsnorth AN, Imrie CW, et al (2001) Double blind, randomised, placebo
controlled study of a platelet activating factor antagonist, lexipafant, in the treatment and
prevention of organ failure in predicted severe acute pancreatitis. Gut 48:62-69
31. Van der Poll T, Jansen PM, Montegut WJ, et al (1997) Effects of IL-10 on systemic inflam-
matory responses during sublethal primate endotoxemia. J Immunol158:1971-1975
32. Van Laethem JL, Eskinazi R, Louis H, Rickaert F, Robberecht P, Deviere J (1998) Multisys-
temic production of interleukin 10 limits the severity of acute pancreatitis in mice. Gut
43:408-413
33. Deviere J, Le Moine 0, Van Laethem JL, et al (2001) Interleukin 10 reduces the incidence
of pancreatitis after therapeutic endoscopic retrograde cholangiopancreatography. Gastro-
enterology 120:498-505
34. Bhatia M, Saluja AK, Hofbauer B, Lee HS, Frossard JL, Steer ML (1998) The effects of neu-
trophil depletion on a completely noninvasive model of acute pancreatitis-associated lung
injury. Int J Pancreatol24:77-83
35. Satoh A, Shimosegawa T, Fujita M, et al (1999) Inhibition of nuclear factor-kappa B activa-
tion improves the survival of rats with taurocholate pancreatitis. Gut 44:253-258
36. Frossard JL, Saluja A, Bhagat L, et al (1999) The role of intercellular adhesion molecule 1
and neutrophils in acute pancreatitis and pancreatitis-associated lung injury. Gastroenter-
ology 116:694-701
37. Shokuhi S, Bhatia M, Christmas S, Sutton R, Neoptolemos JP, Slavin J (2002). Levels of the
chemokines growth-related oncogene alpha and epithelial neutrophil-activating protein 78
are raised in patients with severe acute pancreatitis. Br J Surg 89:566-572
38. Denham W, Yang J, Fink G, Zervos EE, Carter G, Norman J (1997) Pancreatic ascites as a
powerful inducer of inflammatory cytokines. The role of known vs unknown factors. Arch
Surg 132:1231-1236
39. Gukovskaya AS, Vaquero E, Zaninovic V, et al (2002) Neutrophils and NADPH oxidase
mediate intrapancreatic trypsin activation in murine experimental acute pancreatitis. Gas-
troenterology 122:974-984
40. Rau B, Paszkowski A, Esber S, et al (2001) Anti-ICAM-1 antibody modulates late onset of
acinar cell apoptosis and early necrosis in taurocholate-induced experimental acute pan-
creatitis. Pancreas 23:80-88
41. Bhatia M, Brady M, Zagorski J, et al (2000) Treatment with neutralising antibody against
cytokine induced neutrophil chemoattractant (CINC) protects rats against acute pancreati-
tis associated lung injury. Gut 47:838-844
42. Guice KS, Oldham KT, Johnson KJ, Kunkel RG, Morganroth ML, Ward PA (1988) Pancreati-
tis-induced acute lung injury. An ARDS model. Ann Surg 208:71-77
43. Schmid SW, Uhl W, Friess H, Malfertheiner P, Buchler MW (1999) The role of infection in
acute pancreatitis. Gut 45:311-316
44. Chastre J, Fagon JY (2002) Ventilator-associated pneumonia. Am J Respir Crit Care Med
165:867-903
45. Runkel N, Eibl G (1999) Pathogenesis of pancreatic infection. In: Buchler M (ed) Acute Pan-
creatitis: Novel Concepts in Biology and Therapy. Blackwell Science, Boston, pp 255-261
46. Luiten EJ, Hop WC, Lange JF, Bruining HA (1995) Controlled clinical trial of selective de-
contamination for the treatment of severe acute pancreatitis. Ann Surg 222:57-65
47. Bassi C, Falconi M, Valerio A, Marcucci S, Graziani R, Pederzoli P (1999) Identification of
pancreatic infection. In: Buchler M (ed) Acute Pancreatitis: Novel Concepts in Biology and
Therapy. Blackwell Science, Boston, pp 277-282
48. D'Egidio A, Schein M (2002) Surgical strategies in the treatment of pancreatic necrosis and
infection. Br J Surg 78:133-137
49. Nakos G, Malamou-Mitsi VD, Lachana A, et al (2002) Immunoparalysis in patients with se-
vere trauma and the effect of inhaled interferon-gamma. Crit Care Med 30:1488-1494
50. Van Westerloo DJ, Schultz MJ, Bruno MJ, van Deventer S, van der Poll T (2002) Acute pan-
creatitis renders mice more susceptible to Pseudomonas pneumonia, which in turn aggra-
vates the severity of pancreatitis. Evidence for a pathological vicious circle. ICAAC 2002
abstract book, ASM Press, Herndon, B808
51. Van Westerloo DJ, Weijer S, Bruno MJ, et al (2002) Acute pancreatitis impairs antibacterial
host defense in abdominal sepsis in mice. ICAAC 2002 abstract book, ASM Press, Hern-
don, B1421
52. Windsor JA (2000) Search for prognostic markers for acute pancreatitis. Lancet 355:1924-
1925
53. Funbell I, Bornman P, Weakley S, Terblanche J, Marks I (1993) Obesity: an important prog-
nostic factor in acute pancreatitis. Br J Surg 80:484-486
54. Larvin M, McMahon MJ (1989) APACHE II score for assessment and monitoring of acute
pancreatitis. Lancet 2:201-205
55. Heat D, Imrie CW (1994) The Hong Kong criteria and severity prediction in acute pan-
creatitis. Int J Pancreatol15:1-7
56. Ranson H, Rifkind K, Roses D, Fink S, Eng K, Spencer F (1974) Prognostic signs and the
role of operative management in acute pancreatitis. Surg Gynaecol Obstet 139:69-81
57. Munoz-Bongrand N, Panis Y, Soyer P, et al (2001) Serial computed tomography is rarely
necessary in patients with acute pancreatitis: a prospective study in 102 patients. JAm Coil
Surg 193:146-152
58. Neoptolemos JP, Kemppainen EA, Mayer JM, et al (2000) Early prediction of severity in
acute pancreatitis by urinary trypsinogen activation peptide: a multicentre study. Lancet
355:1955-1960
59. Imrie CW (1999) Ransom, Glasgow, APACHE II systems: is the score a bore? In: Buchler M
(ed) Acute Pancreatitis: Novel Concepts in Biology and Therapy. Blackwell Science, Boston,
pp 199-209
Necrosectomy for Severe Acute Pancreatitis
A. Leppaniemi
Introduction
Acute pancreatitis is encountered in about 3% of hospital admissions for acute ab-

dominal pain [1]. There is great variation in the incidence of acute pancreatitis
ranging from 10 and 15 per 100000 inhabitants/year in the United Kingdom and
Germany, respectively [2-4], up to 80 per 100000 in the United States [5]. In Fin-
land, an increase in the incidence from 47 to 73 per 100000 inhabitants/year was
noted from 1970 to 1989 [6].
The etiology of acute pancreatitis can be attributed to either gallstones or alco-
hol in about 80% of cases [7] but the relative proportion of the two varies widely
from country to country. Gallstones are associated with the majority of cases in the
United Kingdom [8], whereas alcohol is the most common etiological factor in the
United States [9] and Finland [6].
Fitz made the first classification of acute pancreatitis in 1889, classifying the dis-
ease into hemorrhagic, suppurative, and gangrenous forms [10]. Attempts to classi-
fy acute pancreatitis on morphological criteria resulted in the Marseilles [11] and
Marseilles-Rome [12] classifications. A clinically based classification system of acute
pancreatitis and its complications was made in Atlanta in 1992, and published in
detail by Bradley in 1993 [13]. A total of 8 clinical and morphological entities were
identified: mild and severe acute pancreatitis, interstitial edematous pancreatitis,
sterile and infected necrotizing pancreatitis, fluid collections, pseudocyst, and pan-
creatic abscess. For clinical use, the Atlanta classification is not optimal, because its
definition of severe acute pancreatitis includes also patients with low risk of death,
such as patients with uncomplicated peripancreatic necrosis, pseudocyst, or ab-
scess. In addition, some manifestations, such as pseudocysts may take several
weeks before becoming apparent.
Based on their experience from several prospective studies, the Ulm group pre-
sented a new classification of acute pancreatitis in 1991 using pathomorphological
criteria to differentiate the disease into four entities (with respective frequencies in
their series of 1396 patients): acute interstitial edematous pancreatitis (71%), acute
necrotizing pancreatitis with sterile (14%) or infected (6%) necrosis, pancreatic ab-
scess (3%}, and postacute pseudocyst (6%) [14]. Necrotizing pancreatitis is macro-
scopically characterized by focal or diffuse areas of devitalized pancreatic paren-
chyma and peripancreatic fatty tissue necrosis involving different retroperitoneal
areas. Hemorrhage is variably present. Microscopic findings include extensive inter-
stitial fatty tissue necrosis with vessel damage and necrosis affecting both acinar
and ductal cells as well as the islet cell compartment [14].
In the majority of patients with acute pancreatitis, the disease takes a mild
course, and clinical improvement can be achieved with fluid resuscitation and man-
agement of pain in a few days with subsequent benign course and few complica-
tions. In about 20-30% of patients, a more severe form can be seen, characterized
by a two-phase systemic disease. During the initial phase, a systemic inflammatory
response caused by the complex effects of several pro-inflammatory mediators acti-
vated by pancreatic and peripancreatic necrosis dominates the clinical picture and
may lead to early multiple organ failure (MOF) within the first 72 hours [15]. If the
process cannot be limited by natural defense systems or treatment, the second
phase ensues, with progression to septic, local pancreatic or other complications
[16]. Infection of the peripancreatic necrosis can be seen in 30-71% of patients
with necrotizing pancreatitis [14]. The late phase of severe pancreatitis (at > 4
weeks) may be associated with pancreatic abscesses or pseudocysts.
In this chapter, the main emphasis is on the surgical management of infected or
sterile necrosis in patients with severe acute pancreatitis. Other surgical or endo-
scopic interventions associated with the management of acute pancreatitis, such as
diagnostic laparotomy for acute abdomen revealing unsuspected cases of acute pan-
creatitis, endoscopic sphincterotomy to treat biliary obstruction in biliary pancre-
atitis or endoscopic placement of a nasojejunal feeding tube, percutaneous drainage
of pancreatic abscesses, management of intestinal or pancreatic fistulas, pseudo-
cysts, hemorrhagic complications or abdominal compartment syndrome, and chole-
cystectomy following biliary pancreatitis will not be commented on in detail.
I Mortality in Acute Pancreatitis

According to a recent study, the overall results of the treatment of acute pancreati-
tis have improved over the last 20 years for multifactorial reasons, such as recogni-
tion of signs of severity, early implementation of organ-specific therapy, and newer
endoscopic, surgical and angiographic therapy for infection, cysts, and bleeding
[17]. In a series of 1442 patients with acute pancreatitis from Ulm, the overall hos-
pital mortality rate was 4% [18].
The variations in the defmition of severe acute pancreatitis and subsequent in-
clusion criteria of various studies hamper the evaluation of the outcome of the se-
vere forms of the disease. In the above mentioned study from Ulm, the hospital
mortality rate for 300 patients with necrotizing pancreatitis was 17%, 21% for sur-
gically treated patients (17% in patients with sterile necrosis and 26% in patients
with infected necrosis), and 6% in patients managed non-surgically [18].
In a recent study from the Meilahti Hospital at the University of Helsinki, Fin-
land, comprising 1374 patients with acute pancreatitis (79% alcohol-related), 270
patients (20%) had severe acute pancreatitis based on either computed tomography
(CT) and C-reactive protein (CRP) levels, histologically confirmed operative or au-
topsy findings, or early signs of organ failure combined with elevated CRP levels
[19]. The overall mortality rate was 24%; 14% for primary admissions and 31% for
patients transferred from other hospitals. Patient-related factors, such as advanced
age and need of chronic medication, and the development of circulatory, respirato-
ry, or renal failure were identified as independent prognostic factors in a multivari-
ate logistic regression analysis.
840 A. Leppaniemi
Of the 172 patients with severe acute pancreatitis accompanied by single or mul-
tiple organ failure (comprising the fraction with the most severe form of the dis-
ease) treated from 1995 through October 2002 at the Intensive Care Unit (ICU) of
the Meilahti Hospital at the University of Helsinki, 47 (27%) died during the hospi-
tal stay (Leppaniemi, unpublished observations).
1 Surgical Techniques in Managing Necrotizing Pancreatitis
The majority of patients with acute necrotizing pancreatitis can be managed non-
surgically, but some of its manifestations and especially complications require sur-
gical intervention. In the past, various surgical procedures have been used to
remove the pancreatic and peripancreatic necrotic tissue, ranging from peritoneal
lavage to pancreatic resection as shown in Table 1, describing the evolution of
management of severe pancreatitis at the Meilahti Hospital, University of Helsinki.
Although the improved outcome is mostly associated with other factors, such as ag-
gressive early fluid therapy, infection prophylaxis, and especially improved intensive
care, the current method of careful removal of the necrotic peripancreatic tissue
mainly by digital necrosectomy has been almost universally accepted and is prac-
ticed in most centers.
Peripancreatic necrosectomy is usually performed with blunt finger dissection
avoiding damage to the pancreas itself and the adjacent vascular and visceral struc-
tures. Occasionally, the disease process has more or less eroded through the body
of the pancreas, in which case the tail can be removed by careful blunt dissection
avoiding splenectomy. Attempts should be made to close the main pancreatic duct
at the proximal pancreatic stump although in many cases identification of the duct
is impossible. It should be noted, however, that resection of an intact pancreas as a
treatment option is considered as overtreatment and is not recommended.
Recently, endoscopic variations for the management of peripancreatic necrotic
collections have been introduced and include endoscopic retroperitoneal drainage
or lumboscopic necrosectomy, and percutaneous necrosectomy and sinus tract en-
doscopy. The value of these techniques is still under assessment [23, 24].
Table 1. Surgical management and hospital mortality in patients treated for severe acute pancreatitis at
the Meilahti hospital, University of Helsinki, Finland 1967-97
Years [ref] No. of patients Management Mortality (%)

1%7-73 [20) 26 Conservative 96
42 Open lavage 69
1974-78 [20) 30 Pancreatic resection 37
1979-82 [21) 17 Open lavage 47
18 Pancreatic resection 22
1984-88 [22) 10 Percutaneous lavage 10
11 Pancreatic resection 27
1989-97 [19] 270 Necrosectomy 24
Most of the current controversy in the operative management of severe acute pan-
creatitis centers around the indications and timing of necrosectomy, the roles of ad-
junctive procedures, and the need for re-operation during the postoperative period.
I Indications and Optimal Timing for Necrosectomy
In the 1980s, surgical management of necrotizing pancreatitis was considered to be

the treatment of choice to prevent irreversible organ damage and reduce mortality.
In a series of 130 patients with necrotizing pancreatitis, 110 (85%) underwent sur-
gical treatment; among the 95 patients included in a prospective clinical trial and
undergoing necrosectomy and postoperative continuous lavage, the indications for
surgery consisted of increasing systemic complications (sepsis, organ dysfunction,
metabolic insufficiency) in 78 patients {82%), persisting or increasing local compli-
cations in 14 patients {15%), and acute abdomen in 3 patients {3%). The overall
hospital mortality rate was 8.4%; 5 of the 8 deaths were caused by sepsis, 2 by mas-
sive diffuse local hemorrhage, and one by cardiogenic shock [25].
In 1991, a concept of non-surgical management of sterile necrosis with early
antibiotic treatment was used by Bradley and Allen [26] in 11 consecutive patients
with no deaths. In the same study, 27 patients with infected necrosis were treated
surgically by open drainage with a mortality rate of 15%. A study by Karimgani et
al. [27], comprising 26 patients with sterile necrosis showed, however, that patients
with severe sterile necrosis have a high mortality rate whether treated medically or
surgically, whereas patients with favorable prognostic factors survive whether
treated medically or surgically.
To evaluate the role of infection of the necrosis as the main parameter of surgi-
cal decision making, Buchler et al. [28] performed a retrospective analysis of a pro-
spective database of 86 patients with necrotizing pancreatitis; 57 patients had ster-
ile and 29 infected necrosis confirmed with CT-guided fine-needle aspiration (FNA)
specimen. Of the 57 patients with sterile necrosis, all but one patient {2%) were
managed non-surgically with an overall death rate of 2/57 {3.5%). Surgical treat-
ment was used in 27/29 patients {93%) with infected necrosis with a death rate of
7/29 (24%).
Using infection of the necrosis as the main determinant for identifying patients
who will benefit from necrosectomy is an attractive concept but not without con-
troversy. The sensitivity of FNA can be as high as 96% [28] but it usually requires
multiple serial aspirates because there are no guarantees that a sterile necrosis
based on a single aspiration specimen remains sterile. Rau et al. [29] used ultraso-
nographically guided FNA cytology in 94 patients with necrotizing pancreatitis
demonstrating sensitivity and specificity rates of 88% and 90%, respectively. How-
ever, a total of 1-9 aspirations (mean 2.0) were needed. The timing of the FNA with
respect to the onset of symptoms had an impact on the diagnostic accuracy. Three
of four false-negative aspirates and all six false-positive results were observed with-
in the first week after the onset of symptoms. Only one false-negative and no false-
positive aspirates were observed if the examination was performed during the sec-
ond week of the disease or later.
Although the volume of the pancreatic necrosis could play a role in the intensity
of the inflammatory reaction, risk of infection, and the development of organ fail-
ures, there is too much overlapping for the volume criteria to be a reliable indicator
842 A. Leppaniemi
for the need of surgical management as noted by Warshaw [30]. Nevertheless, the
volume and extension of the necrotic areas could have importance as surgical tar-
gets, because, intuitively, surgical removal of a very limited amount of necrosis
would have little effect on the overall condition of the patient.
Poor response to non-surgical management is another concept proposed to iden-
tify patients requiring surgical treatment. In a series of 172 patients with sterile
pancreatic necrosis, all patients were initially treated with supportive measures
alone (extensive fluid replacement, nasogastric suction, and monitoring of vital
functions in the ICU) [31]. In 107 patients (62%), persisting or advancing organ
complications, abdominal complications, or both, despite maximum conservative
management for 3-5 days resulted in necrosectomy and continuous closed lavage,
whereas 65 responders were treated non-surgically. The mortality rates following
surgical and non-surgical management were 13.1 o/o and 6.2%, respectively. The
authors concluded that although most patients with limited and sterile necrosis re-
spond to intensive care, persisting or advancing organ complications reflected in
APACHE II scores and CRP-levels would require operative intervention early in the
course of the disease. A recent analysis from Glasgow comprising 121 patients with
predicted severe pancreatitis, however, showed that organ dysfunction that resolved
during the first week had a benign course and did not contribute to mortality [32].
Using infection of the necrosis as the main determinant for necrosectomy im-
plies that the timing of surgery is directly dependent on the time infection develops
in the necrosis, which in most cases occurs at 2-3 weeks from the onset of the dis-
ease [28, 33]. At the other end of the time spectrum, centers advocating debride-
ment and drainage in patients with non-resolving or significant new signs of sys-
temic inflammatory response, even with negative FNA, show best outcomes, if the
operation is not delayed beyond 4 weeks [34].
A prospective randomized study compared early necrosectomy within 48-72
hours of onset (n = 25) to late necrosectomy performed at least 12 days after onset
(n= 11) [35]. Although the difference in mortality in favor of late necrosectomy (56
vs. 27%) did not reach statistical significance, the odds ratio for mortality was 3.4
times in the early necrosectomy group prompting termination of the study. In a
subset analysis of patients with or without infected necrosis, the timing of surgery
had no effect on mortality in patients with sterile necrosis (early 30% vs. late
25%), whereas early necrosectomy in patients with infected necrosis was associated
with significantly higher mortality rates than late necrosectomy (73 vs. 29%). Of
the 14 deaths in patients undergoing early necrosectomy, 3 of the deaths in patients
with sterile necrosis were caused by pulmonary thromboembolism, bronchial ob-
struction due to a foreign body, and postoperative bleeding, whereas all 11 deaths
in patients with early necrosectomy for infected necrosis were caused by single or
multiple organ system failures (10 patients) or sepsis (one patient). Although the
number of patients in this study is small, the results suggest that withholding sur-
gery at an early stage of the disease is beneficial, even in the presence of infection
of the necrosis, and that early surgery does not prevent subsequent fatal organ fail-
ures in patients with demonstrated early infection.
A recent retrospective study of 26 patients with necrotizing pancreatitis showed
a trend towards higher mortality in patients debrided within 2 weeks of diagnosis,
when compared with late (> 2 weeks) necrosectomy (29 vs. 18%), and a statistically
significant risk of an increased number of severe complications [36].
Current knowledge favors surgical debridement of the infected peripancreatic and
retroperitoneal necrosis especially if associated with clinical deterioration or persis-
Necrosectomy for Severe Acute Pancreatitis 84 3
Table 2. Indications and timing of surgical interventions in patients with necrotizing pancreatitis
Time from onset Indication Type of surgical intervention

Any Erosion of adjacent organs with gastroin- laparotomy, surgical repair
testinal perforation or major hemorrhage
Any Abdominal compartment syndrome Decompressive laparotomy
3-4 weeks Infected necrosis and persistent or Necrosectomy and closed lavage
recurrent organ failures or drainage
3-4 weeks Extensive sterile necrosis and progressive Necrosectomy and drainage
organ failures
After 3-4 weeks Incomplete necrosectomy with recurrent Re-necrosectomy, repeated or left
inflammation open, as needed
tent organ failures following the initial phase of 1-2 weeks. Using poor response to
conservative management as an indication for early (within first 2 weeks) surgery
seems not to be justified with the exception of the development of early complications
requiring prompt surgical management, such as major hemorrhage not controllable
with angioembolization, perforation of the gastrointestinal or biliary tract (not amen-
able to endoscopic stenting), or abdominal compartment syndrome. The optimal tim-
ing of the necrosectomy is within 3-4 weeks from the onset of the disease. The indi-
cations and timing of surgical intervention are summarized in Table 2.
I Postoperative Care: Adjunctive Procedures and Re-Operation

Surgical debridement of peripancreatic and retroperitoneal necrosis is most com-
monly performed through open surgery with careful blunt dissection and removal
of all amorphous necrotic material. Alternative techniques, such as interventional
radiological drainage procedures (except for ripe and accessible abscesses) or peri-
toneal lavage techniques are not effective enough in removing infected peripancrea-
tic necrosis and clearing up the retroperitoneal space. However, endoscopic varia-
tions for the management of peripancreatic necrotic collections have been intro-
duced and include endoscopic retroperitoneal drainage or lumboscopic necrosect-
omy, and percutaneous necrosectomy and sinus tract endoscopy [23, 24]. The value
of these techniques is still under assessment.
Most of the current controversy in the techniques for operative management of
necrotizing pancreatitis center around what type of drainage or lavage should ac-
company necrosectomy, should there be planned re-operations at regular intervals
or re-operations only on-demand, or should the abdomen be left open with regular
revisions or dressing changes at 2-3 day intervals [18, 33, 37-42]. Each treatment
modality has been associated with good results in experienced hands but a large,
multi-center clinical trial would be needed to identify the best option overall.
Although individualized treatment tailoring the surgical therapy to the intra- and
post-operative situations is justified, it can be assumed that in cases of massive or
ongoing necrosis, the goal of surgical therapy will not always be achieveq by a sin-
gle intervention but has occasionally to be complemented with further surgical
treatment [43].
844 A. Leppaniemi
If the abdomen is closed at the initial necrosectomy, followed by extensive drain-

age and/or closed lesser sac lavage, close monitoring of the balance of the lavage
solutions and possible signs of hemorrhage, maintaining the drains functional with
regular flushing, and regular measurements of the intra-abdominal pressure (lAP)
through a Foley catheter are carried out at the ICU. Any signs of surgical complica-
tions associated with the drains and lavage should be evaluated by a surgeon to de-
cide whether urgent reoperation is required. If the abdomen is left open, special at-
tention should be given to avoiding intestinal lesions during the change of dres-
sings, which for the first few times should be performed in the operation room un-
der light inhalation anesthesia.
I Conclusion
Surgical intervention in patients with necrotizing pancreatitis seems not to be justi-

fied during the first 2 weeks from the onset of symptoms irrespective of the infec-
tion status of the necrosis or the presence of organ failures, with the exception of
complications requiring prompt surgical intervention, such as major hemorrhage
not controllable with angioembolization, perforation of the gastrointestinal or bili-
ary tract (not amenable to endoscopic stenting), or abdominal compartment syn-
drome. Surgical debridement of the necrosis is postponed until 3-4 weeks of the
onset if there is an established infection of the necrosis associated with poor re-
sponse to non-surgical management with persistent or recurrent signs of organ fail-
ures. Positive FNA results alone in a patient with an improving clinical condition
are not an indication for surgery. In the presence of sterile necrosis and failure to
attribute worsening clinical condition and progressive organ failure to other causes
(catheter sepsis, pneumonia, or other non-surgically treated infections) after the
initial 2-week phase is a strong indication for surgical debridement, especially in
patients with extensive retroperitoneal necrosis.
The aim of the initial surgical intervention, ideally performed 3-4 weeks after
the onset of the disease, is to remove all necrotic tissue in one setting without
causing iatrogenic organ injury or excessive bleeding, aided with postoperative
drainage and/or lavage. Re-necrosectomy, either preplanned every few days or on-
demand, are indicated if the initial necrosectomy is incomplete or with recurrent
signs of severe inflammation, and the option of leaving the abdomen open for
further interventions should be considered.
References
1. Banerjee A, Kaul A, Bache E, Parberry A, Doran J, Nicholson M (1994) Multicentre audit
of death from acute pancreatitis. Br J Surg 81:1541
2. Corfield A, Cooper M, Williamson R (1985) Acute pancreatitis: a lethal disease of increas-
ing incidence. Gut 26:724-729
3. Giggs J, Bourke J, Katschinski B (1988) The epidemiology of primary acute pancreatitis in
Greater Nottingham: 1969-1983. Soc Sci Med 26:79-89
4. Assmus C, Petersen M, Gottesleben F, Druke M, Lankisch P (1996) Epidemiology of acute
pancreatitis in a defined German population. Digestion 57:A217 (abst)
5. Lankisch P (1999) Epidemiology in acute pancreatitis. In: Buchler M, Uhl W, Friess H,
Malfertheimer P ·(eds) Acute Pancreatitis, Novel Concepts in Biology and Treatment. Black-
well Wissenschafts-Verlag, Berlin, pp 145-153
---~--~~~~,--~--~~'"~,-~
6. Jaakkola M, Nordback I (1993) Pancreatitis in Finland between 1970 and 1989. Gut
34:1255-1260
7. Karne S, Gorelick F (1999) Etiopathogenesis of acute pancreatitis. Surg Clin North Am
79:699-710
8. Leese T, Shaw D, Holliday M (1988) Prognostic markers in acute pancreatitis: can pancrea-
tic necrosis be predicted? Ann R Coli Surg Engl 70:227-232
9. Steinberg W, Tenner S (1994) Acute pancreatitis. N Engl J Med 330:1198-1210
10. Moynihan B (1925) Acute pancreatitis. Ann Surg 81:132-142
11. Singer MV, Gyr K, Sarles H ( 1985) Revised classification of pancreatitis. Gastroenterology
89:683-685
12. Sarles H, Adler G, Dani R, et al (1989) The pancreatitis classification of Marseilles-Rome
1988. Scand J Gastroenterol 24:641-642
13. Bradley III EL (1993) A clinically based classification system for acute pancreatitis. Sum-
mary of the International Symposium on Acute Pancreatitis, Atlanta, GA, September 11
through 13, 1992. Arch Surg 128:586-590
14. Beger HG, Rau B, Mayer J, Pralle U (1997) Natural course of acute pancreatitis. World J
Surg 21:130-135
15. Wilson P, Manji M,, Neoptolemos J (1998) Acute pancreatitis as a model of sepsis. J Anti-
mikrob Chemother 41:51-63
16. Neoptolemos J, Raraty M, Finch M, Sutton R (1998) Acute pancreatitis: the substantial hu-
man and financial costs. Gut 42:886-891
17. Bank S, Singh P, Pooran N, Stark B (2002) Evaluation of factors that have reduced mortal-
ity from acute pancreatitis over the past 20 years. J Clin Gastroenterol 35:50-60
18. Beger HG, Rau B, Isenmann R, Mayer J (1998) Surgical treatment of acute pancreatitis.
Ann Chir Gynaecol 87:183-189
19. Halonen KI, Leppaniemi AK, Puolakkainen PA, et al (2000) Severe acute pancreatitis: prog-
nostic factors in 270 consecutive patients. Pancreas 21:266-271
20. Kivilaakso E, Friiki 0, Nikki P, Lempinen M (1981) Resection of the pancreas for acute ful-
minant pancreatitis. Surg Gynecol Obstet 152:493-498
21. Kivilaakso E, Lempinen M, Miikelainen A, Nikki P, Schroder T (1984) Pancreatic resection
versus peritoneal lavation for acute fulminant pancreatitis. A randomized prospective
study. Ann Surg 199:426-432
22. Schroder T, Sainio V, Kivisaari L, Puolakkainen P, Kivilaakso E, Lempinen M (1991) Pan-
creatic resection versus peritoneal lavage in acute necrotizing pancreatitis. A prospective
randomized trial. Ann Surg 214:663-666
23. Gambiez LP, Denimal FA, Porte HL, Saudemont A, Chambon J-P, Quandalle PA (1998) Ret-
roperitoneal approach and endoscopic management of peripancreatic necrosis collections.
Arch Surg 133:66-72
24. Carter CR, McKay CJ, Imrie CW (2000) Percutaneous necrosectomy and sinus tract endo-
scopy in the management of infected pancreatic necrosis: an initial experience. Ann Surg
232:175-180
25. Beger HG, Buchler M, Bittner R, Block S, Nevalainen T, Roscher R (1988) Necrosectomy
and post-operative local lavage in necrotizing pancreatitis. Br J Surg 75:207-212
26. Bradley III EL, Allen K (1991) A prospective longitudinal study of observation versus sur-
gical intervention in the management of necrotizing pancreatitis. Am J Surg 161:19-25
27. Karimgani I, Porter KA, Langevin RE, Banks PA (1992) Prognostic factors in sterile pan-
creatic necrosis. Gastroenterology 103:1636-1640
28. Buchler MW, Bloor B, Muller CA, Friess H, Seiler CA, Uhl W (2000) Acute necrotizing pan-
creatitis: treatment strategy according to the status of infection. Ann Surg 232:619-626
29. Rau B, Pralle J, Mayer M, Beger HG (1998) Role of ultrasonographically guided fine-needle
aspiration cytology in the diagnosis of infected pancreatic necrosis. Br J Surg 85:179-184
30. Warshaw AL (2000) Pancreatic necrosis. To debride or not to debride - that is the ques-
tion. Ann Surg 232:627-629
31. Rau B, Pralle U, Uhl W, Schoenberg MH, Beger HG (1995) Management of sterile necrosis
in instances of severe acute pancreatitis. J Am Coli Surg 181:279-288
32. Buter A, Imrie CW, Carter CR, Evans S, McKay CJ (2002) Dynamic nature of early organ
dysfunction determines outcome in acute pancreatitis. Br J Surg 89:298-302
846 A. leppaniemi: Necrosectomy for Severe Acute Pancreatitis
33. Farkas G, Marton J, Mandi Y, Szederkenyi E (1996) Surgical strategy and management of
infected pancreatic necrosis. Br J Surg 83:930-933
34. Fernandez-dei Castillo C, Rattner DW, Makary MA, Mostafavi A, McGrath D, Warshaw AL
(1998) Debridement and closed packing for the treatment of necrotizing pancreatitis. Ann
Surg 228:676-684
35. Mier J, Luque-de Leon E, Castillo A, Robledo F, Blanco R (1997) Early versus late necro-
sectomy in severe necrotizing pancreatitis. Am J Surg 173:71-75
36. Hungness ES, Robb BW, Seeskin C, Hasselgren P-0, Luchette FA (2002) Early debridement
for necrotizing pancreatitis: is it worthwhile? JAm Coli Surg 194:740-745
37. Tsiotos GG, Luque-de Leon E, Soreide JA, et al (1998) Management of necrotizing pancre-
atitis by repeated operative necrosectomy using a zipper technique. Am J Surg 175:91-98
38. van Goor H, Sluite WJ, Bleichrodt RP (1997) Early and long term results of necrosectomy
and planned re-exploration for infected pancreatic necrosis. Eur J Surg 163:611-618
39. Bosscha K, Hulstaert PF, Hennipman A, et al (1998) Fulminant acute pancreatitis and in-
fected necrosis: results of open management of the abdomen and "planned" re-operations.
JAm Coli Surg 187:255-262
40. Fugger R, Gotzinger P, Sautner T, et al (1995) Necrosectomy and laparostomy - a com-
bined therapeutic concept in acute necrotizing pancreatitis. Eur J Surg 161:103-107
41. Bradley III EL (1987) Management of infected pancreatic necrosis by open drainage. Ann
Surg 206:542-550
42. Paye F, Frileux P, Lehman P, Ollivier J-M, Vaillant JC, PareR (1999) Re-operation for severe
pancreatitis. A 10-year experience in a tertiary care center. Arch Surg 134:316-320
43. Kasperk R, Riesener K-P, Schumpelick V (1999) Surgical therapy of severe acute pancreati-
tis: a flexible approach gives excellent results. Hepatogastroenterology 46:467-471
Acute Liver Failure in the ICU
E. Sizer, J. Wendon, and W. Bernal
I Introduction - Definition
Acute liver failure is a rare clinical syndrome resulting from severe hepatocyte in-
jury, usually in the absence of pre-existing chronic liver disease. It is characterized
by the onset of encephalopathy following the liver injury; jaundice is present in
most patients but, in cases of hyperacute liver failure, encephalopathy may precede
clinical jaundice. The prognosis in acute liver failure is variable, with mortality
ranging from 10-90% without transplantation. The important factors determining
outcome are principally: underlying etiology, age of the patient and time course
over which the syndrome develops [1].
The most recent classification of the syndrome has tried to combine these fea-
tures to link clinical features with prognosis (hyperacute, acute and subacute) [2]
(Table 1).
Acute Liver Failure in the Intensive Care Unit (ICU)

The management of acute liver failure in the ICU remains a challenge; it is a rare
clinical syndrome associated with high morbidity and mortality. Currently, emer-
gency liver transplantation remains the only treatment associated with survival
benefit in those patients who display poor prognostic characteristics. Early identifi-
cation of this cohort is, therefore, important as improved intensive care support
and intervention may allow a greater proportion to remain 'transplantable'; however
the availability of donor organs limits this treatment modality in some cases. Cur-
rent research interest remains focused on 'artificial liver support' a strategy which
may provide a bridge to transplantation or indeed regeneration.
I Etiologies
The etiology of acute liver failure displays marked geographical variation. Viral
causes, drugs, and toxins represent the vast majority of etiologies, although there is
a proportion of cases where no cause is found - the so called 'seronegative hepati-
tis'. Worldwide, acute hepatitis B is the commonest cause of acute liver failure. In
westernized countries, drug related hepatotoxicity (especially secondary to acetami-
nophen) is an important cause of acute liver failure [1].
848 E. Sizer et aI.
Table 1. Suggested classification of acute liver failure [2] with associated prognosis
Jaundice to Risk of cerebral edema Survival

encephalopathy
Hyperacute Less than 7 days Ver; high 36%

Acute 8-28 days High 7%
Subacute 5-26 weeks Low 14%
Table 2. Kings criteria [3]
Acetaminophen Induced Non Acetaminophen Induced

pH< 7.3 (irrespective of grade of encephalopathy) PT > 100 sees {INR > 6.5) irrespective of grade of
following volume resuscitation and > 24 hrs post encephalopathy PH< 7.3 following volume resusci-
~~~ ~~
OR
PT > 100 sees (INR > 6.5) AND creatinine Any 3 of the following variables (in association
>300 mol/1 in patients with grade III-IV with encephalopathy)
encephalopathy within a 24 hr time frame Age <10 yrs or > 40 yrs
Etiology: NANB or drug induced
Jaundice to encephalopathy > 7 days
PT >50 sees (INR> 3.5)
Bilirubin> 300 j.UTlOI/1
PT: prothrombin time; NANB: non-A, non-B; INR: international normalized ratio
Prognostic Determinants
There are no universally accepted criteria for transplantation in acute liver failure,
however, the King's College Hospital (KCH) criteria are the most widely used [3]
(Table 2). They have been validated and have consistently shown that patients meet-
ing the criteria have >85% mortality without emergency transplantation [4-7]. The
Clichy criteria use grade of encephalopathy and Factor V levels to distinguish those
in poor prognosis groups.
Lactate has been used as a clinical marker to allow the rapid and accurate iden-
tification of those patients with acetaminophen induced liver failure that have a
poor prognosis [8]. Blood lactate values alone enabled identification of those pa-
tients likely to die both faster and with the same accuracy as the KCH Criteria (cut
off values 3.5 mmol/1 early after admission and 3.0 mmol/1 after volume resuscita-
tion). This study has led to proposed modification of the KCH criteria in acetami-
nophen induced liver failure (Table 3). As yet, these modifications have not been
validated by other transplant centers.
Acute Liver Failure in the ICU 849
Table 3. Proposed modification of the KCH criteria for transplantation in acetaminophen-induced acute
liver failure [8)
Strongly consider listing for transplantation if:

Arterial lactate concentration > 3.5 mmol/l after early fluid resuscitation
List for transplantation if:
Arterial pH< 7.3 OR arterial lactate concentration> 3.0 mmol/1 after adequate fluid resuscitation
OR concurrently:
Serum creatinine> 300 J.lmol/1, INR > 6.5 and grade Ill encephalopathy or above
I Management
Transplantation
Transplantation has revolutionized the outcome of acute liver failure. Mortality of
>80% has been improved to the extent that five year survival after transplantation
may now approach 90% [9]. The improved survival rates since the first use of this
technique are largely due to improved medical management of the complications of
acute liver failure, prevention and aggressive treatment of sepsis, and the refine-
ment of the criteria indicating poor prognosis within acute liver failure. Auxiliary
liver transplantation, a technique that involves sub-total recipient hepatectomy and
implantation of a reduced size graft has evolved in recognition of the regenerative
ability of hepatocytes. Potential future regeneration of the native liver would obvi-
ate the need for graft function and thus allow immunosuppressive therapy to be
withdrawn and the graft to atrophy. The procedure is technically difficult, as both
portal and arterial supplies are constructed de novo; in addition, a duplicate biliary
drainage system has to be created. In the short-term post operatively, recovery may
be delayed both due to 'small size' donor graft function and the continued presence
of injured liver [10].
Intracranial Hypertension (ICH)

Encephalopathy associated with acute liver failure is characterized by a rapid reduc-
tion in conscious level, cerebral edema and ICH. This triad remains responsible for
a large proportion of the mortality associated with acute liver failure. Up to 40% of
those superurgently listed for transplantation with acute liver failure die as a result
of cerebral edema and herniation [5]. The pathogenesis associated with this se-
quence of events remains unclear; however, the astrocyte plays a central role in the
metabolism of ammonia and production of glutamine within the central nervous
system (CNS) [11]. Interest has also focused on the altered regulation of cerebral
blood flow (CBF) in this scenario, with cerebral vasodilatation and increased CBF
in patients with cerebral edema and ICH [11]. A unified theory of cerebral edema
in acute liver failure proposes that cerebral circulatory changes are secondary to
the generation of glutamine within the CNS. Hypothermia has been shown to delay
onset and improve survival of cerebral edema within the setting of acute liver fail-
ure, traumatic brain injury (TBI) and ischemic brain injury [12-14]. Mild (35 oq
hypothermia has been shown to reduce passage of ammonia across the blood brain
barrier [ 15]. It is tempting to assume this leads to a reduction in the activity of
850 E. Sizer et al.
glutamine synthase and thus reduced osmolality within the astrocyte, leading to
less edema formation. However, a reduction in extracellular glutamine has not been
shown. Interestingly there is a reduction in extracellular glutamate associated with
hypothermia; this may be the explanation for the observed delayed onset encepha-
lopathy seen in conjunction with N-methyl-D-aspartate (NMDA) antagonists in ani-
mal models of acute liver failure [16].
Monitoring of ICP
The risk of death secondary to cerebral edema in this group has already been men-
tioned. Patients at risk of developing cerebral edema and ICH are electively sedated,
intubated, and ventilated. The speed of progression from grade 1 to grade 4 ence-
phalopathy in acute liver failure should not be underestimated and may occur with-
in only a few hours. Sedation allows safe clinical management of the patient and re-
duces cerebral irritability but it does remove some of the early clinical signs of a
raised ICP leaving the end stage pupillary and vasomotor abnormalities as the first
indications in some cases. In order to detect these changes at an earlier stage and
perhaps allow modulation of the development of ICH, several methods of monitor-
ing ICP have been used.
1 ICP monitors
Measuring ICP has no effect on survival overall but increases the survival time
and, thus, time available for transplantation; this may be due to increased possi-
bility for targeted therapeutic intervention, to manipulate ICP/CPP [17].
ICP monitoring may be valuable in providing information to allow the manipu-
lation of both ICP and CPP. However, insertion is not without risk. Several dif-
ferent systems have been used in the setting of acute liver failure. Complication
rates vary with the type of device. In one study, overall complication rates were
3.8% for extradural systems, 20% for subdural systems, and 22% for parenchy-
mal monitors. The incidence of fatal intracerebral hemorrhage was 1% for extra-
dural systems, 5% for subdural, and 4% for parenchymal monitoring systems
[18]. The incidence of nonfatal intracerebral hemorrhage is not known.
Jugular venous bulb saturation
Blood sampling or continuous oximetry via an indwelling catheter can provide
information about global cerebral oxygen utilization notwithstanding the limita-
tions of the system. Low jugular venous saturation in comparison to mixed ve-
nous oxygen saturation may indicate decreased delivery (optimize cardiac out-
put, flow and CPP) as well as increased oxygen utilization (e.g., nonconvulsive
status epilepticus). Jugular venous saturations higher than mixed venous satura-
tions may reflect hyperemia, ischemia and failure of oxygen utilization. In con-
junction with clinical indications of cerebral irritability, reverse jugular satura-
tion monitoring appears useful in guiding management maneuvers and may re-
present a less invasive modality than ICP monitoring. Persistent or repeated ab-
normal results may indicate the need for ICP monitoring.
Cerebral artery Dopplers.
The use of the Doppler method to measure blood flow velocities in cerebral ar-
teries is relatively new [19]. The pulsatility and resistance indexes appear more
reproducible than CBF velocities. The technique may be of some use in assessing
cerebral artery C0 2 responsiveness should hyperventilation be considered as a
strategy to control high ICP [20].
I Optic nerve ultrasound

Optic nerve sheath diameter has been shown to correlate with a raised ICP in
the pediatric population [21]. Its widespread use as a non-invasive method of
screening for raised ICP has not been investigated, primarily due to the large in-
ter-individual variability inherent in the technique.
Treatment of Raised ICP
There are no robust, evidence based, absolute values for either minimum CPP or
maximum ICP that influence outcome in the setting of acute liver failure. However,
a raised ICP and a prolonged CPP <50 mmHg or an ICP consistently > 40 mmHg
[22] are associated with poor neurological recovery in this group of patients. In the
past, refractory ICH > 40 mmHg has been regarded as a contraindication to trans-
plantation [23]; this has become a relative contraindication especially since the re-
ported complete neurological recovery of four patients with both ICP > 35 mmHg
and CPP <50 mmHg for prolonged periods pre transplantation [24].
Treatment of raised ICP can be divided into strategies to minimize baseline ICP
and those to prevent and treat surges in ICP.
As for the TBI population attention should be paid to patient position; it has
been suggested that 20 degrees reverse Trendelenberg position provides optimal
ICP without compromising CPP [25]. Care should be taken with neutral neck and
tracheal tube tape positioning to avoid venous engorgement.
The basic tenets of care for patients with cerebral edema of any cause hold true
for patients with acute liver failure, i.e., normovolemia, avoidance of hypotension,
avoidance of hypoxia (Pa0 2 >10 kPa), normocapnea (PaC0 2 4.5-5.5 kPa), and eu-
glycemia.
Bolus sedation may be required prior to stimulating interventions and a minimal
intervention regime instituted.
Acute surges in ICP should be controlled as soon as possible. Depending on the
severity of the surge and the ease of manipulation several strategies may be re-
quired.
1 Mannitol. Mannitol, an osmotic diuretic, is the first line treatment of high ICP
in acute liver failure. Its use is associated with survival benefit in this group
[26]. Repeated boluses may be used providing serum osmolality is controlled
(< 320 mOsm/1) although caution should be used in order to avoid hypovolemia
secondary to its diuretic effect in those with preserved renal function [27] and
hypervolemia in those who are anuric. In the latter, mannitol can be safely used
providing adequate renal replacement therapy is in progress [28].
Propofol. Studies in TBI have shown that propofol is associated with prolonged
reduction in ICP after bolus injection and is also efficacious in reducing ICP
surges associated with agitation [29]. Its use in acute liver failure is theoretically
promising as it is associated both with reduction in cerebral metabolic rate for
oxygen (CMR0 2 ) and cerebral vasoconstriction and reduction in CBF [30]. One
of the advantages it has over thiopentone is that its pharmacokinetics are unal-
tered by liver failure. It is used both as the primary agent for sedation and also
in the 'rescue' management of raised ICP. More traditionally, thiopentone has
been used in the treatment of refractory ICH. It also acts as a cerebral vasocon-
strictor and reduces CMR0 2 , however, due to its prolonged clearance in the con-
text of hepatic failure; neurological assessment may be difficult.
852 E. Sizer et al.
1 Hypertonic saline. Hypertonic saline reduces ICP in the setting of TBI [31]; it
also improves CPP without altering mean arterial pressure (MAP). The mecha-
nism would appear to be related to dehydration of brain tissue. Currently there
is no reported experience using hypertonic saline in patients with acute liver
failure and raised ICP.
I Hyperventilation. Hyperventilation remains a controversial strategy in the man-
agement of cerebral edema and raised ICP. Hyperventilation has been shown tore-
store CBF autoregulation in acute liver failure [32] probably because cerebral ar-
teries are maximally dilated at 'normal' PaC0 2 • In the short term, and as 'rescue'
therapy, hyperventilation may allow maintenance of cerebral vessel tone, autoregu-
latory ability and thus reduce ICP. However, it has been previously shown in acute
liver failure that hyperventilation reduces both CMR0 2 and CBF [33] with a rise in
jugular venous lactate. It may be inferred from this that there may be a degree of
ischemia and dysoxia; which paradoxically may exacerbate any existing edema.
Hyperventilation should be reserved for the emergency treatment of refractory
ICH and should be guided by jugular bulb saturation (34].
1 As mentioned above mild hypothermia has been shown to delay the onset of ce-
rebral edema in animal models of acute liver failure. There have been several
case reports and a series showing survival benefit in this group as a conse-
quence of its implementation. Hypothermia reduced ICP, increased CPP, reduced
CBF and reduced vasopressor requirements in this cohort [35], however without
transplantation mortality was 100%.
I Indomethacin. Indomethacin is a known cerebral vasoconstrictor [36]; in animal
models of acute liver failure it has been shown to prevent the development of ce-
rebral hyperemia, cerebral edema, and ICH. The mechanism of action is unclear
as other inhibitors of cyclooxygenase (aspirin, ibuprofen) do not exhibit these
properties [37]. Indomethacin has been administered to patients with TBI and
edema with good results [38]; there is a case report of its successful use in re-
fractory ICH in acute liver failure [39] but no controlled trials. Obviously the
theoretical concerns over renal vasoconstriction and gastrointestinal hemorrhage
may dissuade its use in these high risk patients.
I As an extreme measure in the management of intractable ICH and acute liver
failure, hepatectomy and portocaval shunt formation has been advocated in the
absence of a suitable donor organ [40]. Case reports have delivered conflicting
views on the benefit of this procedure. Recently, a reduction in circulating pro-
inflammatory cytokines was demonstrated associated with both a reduced vaso-
pressor requirement and decreased CBF. ICP was significantly reduced although
remained elevated until transplantation [41].
I Systemic Inflammatory Response Syndrome (SIRS)/Sepsis

Patients with acute liver failure are highly susceptible to infection, both bacterial
and fungal. This is primarily due to impaired host response with impaired phago-
cyte function and decreased opsonization secondary to reduced complement levels.
In addition these patients frequently have multiple invasive monitoring lines. In-
deed proven infection rates of 80% (bacterial) and 32% (fungal) have been docu-
mented [42].
During the time course of the syndrome, the pattern of organisms responsible
changes: Gram positive infection predominates in the first four days; Gram negative
infection becomes increasingly prevalent in the next week, and fungal infection in-
creasingly important in the second week. The clinical manifestations of these infec-
tions are most commonly pneumonia, bacteremia, and urinary tract infection
(UTI).
Prophylactic treatment with intravenous antibiotics significantly reduces the in-
cidence of sepsis and improves encephalopathy but has no effect on mortality [43].
Both animal models of acute liver failure and sepsis [44] and retrospective stud-
ies of large numbers of human acute liver failure patients have emphasized the im-
portance of an inflammatory process driving both the degree of hepatic injury and
the severity of encephalopathy. In both these studies the presence of inflammation
± infection also increased mortality. In humans, both the severity of the inflamma-
tory response and the presence of proven infection was associated with decreased
survival.
Renal Failure
Renal failure is a common complication of acute liver failure with the incidence re-
ported as approximately SSo/o [45]. The cause of acute renal failure in this setting
may be multifactorial. Renal failure may be secondary to liver failure itself (hepa-
torenal syndrome), due to a directly toxic effect (e.g., acetaminophen}, or due to
pre renal causes such as hypovolemia and ischemia. The pathophysiology of acute
liver failure-associated renal failure is complex, with a reduction in MAP secondary
to the characteristic circulatory effects of acute liver failure. Sympathetic activation
results in renal vasoconstriction and production of vasoactive mediators [46].
Management of acute renal failure entails optimization of volume status and pre-
renal parameters. Renal replacement therapy should be instituted following conven-
tional indications (acidosis, fluid overload, and hyperkalemia). Continuous hemofil-
tration, as opposed to intermittent hemodialysis, is preferred as the profound elec-
trolyte and volume shifts associated with the latter may cause hemodynamic insta-
bility, and exacerbation of cerebral edema [47], associated with excess mortality.
There is interest in the use of high volume exchange (90 ml/kg/hr) in the setting of
acute liver failure. High volume hemofiltration (HVHF) has been shown to decrease
vasopressor requirements in septic shock; these changes have been attributed to re-
moval of soluble inflammatory mediators [48]. There is some evidence that the
same applies in acute liver failure although currently no proven survival benefit has
been demonstrated.
The prognosis of acute renal failure in the setting of acute liver failure is good,
with recovery as liver function improves whether spontaneously or as a result of
transplantation.
Plasmapharesis
High volume plasmapharesis has been used in the treatment of acute liver failure
with improvement of conscious level, improvement of the hemodynamic changes
and a reduction in arterial ammonia concentration [49]. The mechanism for there-
duction in ammonia levels is not simply a function of clearance via the extracorpo-
real circuit. Postulated mechanisms include increased hepatic urea synthesis and
glutamine synthesis in muscle. A multicenter randomized controlled trial is cur-
rently in progress in acute liver failure examining survival benefit and 'bridging to
transplantation'. A disadvantage of plasmapharesis is that not only are hepatotoxic
854 E. Sizer et al.
mediators removed but possible hepatic growth factors promoting regeneration as

well. One proposed method to prevent loss of important plasma protein bound re-
generative factors is the incorporation of selective plasma filters into the plasma-
pharesis circuit. In an animal model of acute liver failure, the use of this system in-
creased survival, liver function as assessed by indocyanine green (ICG) clearance
and promoted regeneration [50].
Optimizing Medical Management

Due to the rarity of the syndrome, early liaison with transplant centers is recom-
mended. Specialist intensive care, with particular emphasis on the management of
cerebral edema, and circulatory failure associated with acute liver failure can im-
prove survival, allowing early recognition of those in poor prognosis groups and
listing for emergency transplantation. As discussed above in the case of refractory
ICH, two stage emergency hepatectomy and transplantation may be appropriate.
Resuscitation, elective sedation, intubation and ventilation may be necessary prior
to transfer, especially in the case of mid range encephalopathy where the risk of
progression and cerebral herniation during transfer is significant.
Hemodynamic instability is a common feature of acute liver failure. Characteris-
tically, vascular tone fails resulting in profound vasodilatation, hypotension, and a
hyperdynamic cardiac output. At the microcirculatory level, oxygen utilization is
impaired with abnormal shunting demonstrable. Hyperlactatemia is common,
although this may not be solely due to tissue hypoxia; both the gut and the liver
have been shown to be net producers of lactate in acute liver failure [51]. The
pathogenesis of these circulatory changes is multifactorial, however nitric oxide
(NO) is in part implicated [52]. High vasopressor requirements are common. As
such, acute liver failure shares many of the features of septic shock and, as has
already been mentioned, SIRS/sepsis exacerbate the severity of liver injury and the
level of encephalopathy. Recent work has shown that impaired adrenal function
(as assessed by a short synachthen test) in the setting of acute liver failure impairs
the response to pressors as it does in sepsis [53].
In terms of the general care of patients with acute liver failure, attention to me-
tabolic homeostasis is important, specifically blood glucose control. Whilst hypo-
glycemia is an ominous sign and concentrated glucose infusions may be necessary
to support blood glucose levels, it has been increasingly recognized that hypergly-
cemia within the ICU population is detrimental to outcome, both in terms of mor-
bidity (sepsis, acute renal failure, transfusion requirement, critical illness neuro-
pathy) and mortality (ICU and hospital) [54]. Tight blood glucose control (blood
glucose 4.5-6.0 mmol/1) using individualized insulin sliding scale regimes would
seem to be a standard of care to aim towards.
I Future Strategies
Artificial Support
Artificial liver support devices attempt to bridge patients with acute liver failure
either to transplantation or regeneration of the native liver. Broadly speaking, there
are two types of systems undergoing clinical evaluation: those based on extracorpo-
real blood purification techniques derived from technology used in renal replace-
ment therapy, and those which provide both detoxifying and synthetic hepatic
functions. Purification techniques have incorporated a variety of methods such as
hemodialysis, charcoal hemoperfusion, cation-exchange resins or all of the above
in the case of the MARS system (molecular adsorbent recycling system). Unfortu-
nately, none of these systems has shown any improvement in long-term survival in
controlled studies as of yet. It appears that removal of toxins alone seems insuffi-
cient to allow patients with acute liver failure to regenerate native liver function
and survive; some form of exogenous synthetic function also seems important.
Current strategies employ a hybrid system combining biological and mechanical
support. Integral in each of these systems is a mechanical component providing
purification and a physical barrier between patient and the biologically active com-
ponent of the system. The hepatocyte component can be human or xenogenic.
References
1. O'Grady J (2000) Acute liver failure. In: O'Grady J, Lake J, Howdle P (eds) Comprehensive
Clinical Hepatology, 1st edn. Mosby, London, pp 30.1-30.2
2. O'Grady JG, Schalm SW, Williams R (1993) Acute liver failure: redefining the syndromes.
Lancet 342:273-275
3. O'Grady JG, Alexander GJ, Hayllar KM, Williams R (1989) Early indicators of prognosis in
fulminant hepatic failure. Gastroenterology 97:439-445
4. Shakil A, Kramer D, Mazariegos G, Fung J, Rakella J (2000) Acute liver failure: clinical fea-
tures, outcome analysis, and applicability of prognostic criteria. Liver Transplant 6:163-169
5. Makin A, Wendon J, Williams R (1995) A 7 year experience of severe acetaminophen-in-
duced hepatotoxicity (1987-1993). Gastroenterology 109:1907-1916
6. Mitchell I, Bihari D, Chang R, Wendon J, Williams R (1997) Earlier identification of pa-
tients at risk from acetaminophen induced acute liver failure. Crit Care Med 26:279-284
7. Bernal W, Wendon J, Rela M, Heaton N, Williams R (1998) Use and outcome of liver trans-
plantation in acetaminophen induced acute liver failure. Hepatology 27:1050-1055
8. Bernal W, Donaldson N, Wyncoll D, Wendon J (2002) Blood lactate as an early predictor
of outcome in paracetamol-induced acute liver failure: a cohort study. Lancet 358:558-563
9. Lerut J, Ciccarelli 0, Roggen F, et al (2000) Progress in adult liver transplantation for acute
liver failure. Transplantation Proc 32:2704-2706
10. Chenard-Neu MP, Boudjema K, Bernau J, et al (1996) Auxiliary liver transplantation: regen-
eration of the native liver and outcome in 30 patients with fulminant hepatic failure. A
multicentre European study. Hepatology 23:1119-1127
11. Blei A, Larsen F (1999) Pathophysiology of cerebral edema in fulminant hepatic failure.
J Hepatol31:771-776
12. Traber P, DalCanto M, Ganger D, Blei AT (1989) Effect of body temperature on brain edema
and encephalopathy in the rat after hepatic devascularisation. Gastroenterology 96:885-891
13. Marion DW, Penrod LE, Kelsey SF, et al (1997) Treatment of traumatic brain injury with
moderate hypothermia. N Engl J Med. 336:540-546
14. Busto R, Dietrich WD, Globus MYT, Valdes I, Scheinberg P, Ginsberg MD (1987) Small dif-
ferences in intra-ischaemic brain temperature critically determine the extent of ischaemic
neuronal injury. J Cereb Blood Flow Metab 7:729-738
15. Rose C, Michalak A, Pannuzio M, Chatauret N, Rambaldi A, Butterworth R (2000) Mild
hypothermia delays the onset of coma and prevents brain edema and extracellular brain
glutamate accumulation in rats with acute liver failure. Hepatology 31:872-877
16. Vogels BAPM, Mass MAW, Daalhuisen J, Quack G, Chamuleau RAFM (1997) Memantine, a
non-competitive NMDA-receptor antagonist improves hyperammonia-induced encephalo-
pathy and acute hepatic encephalopathy in rats. Hepatology 25:820-827
17. Keays RT, Alexander GJM, Williams R (1993) The safety and value of extradural intracra-
nial pressure monitors in fulminant hepatic failure. J Hepatol 18:205-209
18. Blei AT, Olafsson S, Webster S, Levy R (1993) Complications of intracranial pressure moni-
toring in fulminant hepatic failure. Lancet 34:690-691
856 E. Sizer et al.
19. Kudo M (2001) Cerebral vascular resistance in hepatic insufficiency. J Gastroenterol Hepa-
tol 16:845-847
20. Srauss GI, Moller K, Holm S, Sperling B, Knudsen GM, Larsen FS (2001) Transcranial
Doppler sonography and internal jugular bulb saturation during hyperventilation in
patients with fulminant hepatic failure. Liver Transpl 7:352-358
21. Helme K, Burdelski M, Hansen HC (2000) Detection and monitoring of intracranial pres-
sure dysregulation in liver failure by ultrasound. Transplantation 70:392-395
22. Donovan JP, Shaw BW Jr, Langnas AN, Sorrell MF (1992) Brain water and acute liver fail-
ure: the emerging role of intracranial pressure monitoring. Hepatology 16:267-268
23 Lucey MR, Brown KA, Everson GT, et al (1997) Minimal criteria for placement of adults on
the liver transplant waiting list: a report of a national conference organized by the Ameri-
can Society of Transplant Physicians and the American Association for the Study of Liver
Diseases. Liver Transpl Surg 3:628-637
24. Davies MH, Mutimer D, Lowes J, Elias E, Neuberger J (1994) Recovery despite impaired
cerebral perfusion in fulminant hepatic failure. Lancet 343:1329-1330
25. Davenport A, Will EJ, Davison AM (1990) Effect of posture on intracranial pressure and
cerebral perfusion pressure in patients with fulminant hepatic failure and renal failure after
acetaminophen self-poisoning. Crit Care Med 18:286-289
26. Hanid MA, Davies M, Mellon PJ, et a! (1980) Clinical monitoring of intracranial pressure
in fulminant hepatic failure. Gut 21:866-869
27. Inoue S, Ninaga H, Kawaguchi M, Furuya H (1998) A case of shock subsequent to treat-
ment of intracranial hypertension by mannitol injection combined with hyperventilation.
J Neurosurg Anesthesiol10:113-115
28. Nau R (2000) Osmotherapy for elevated intracranial pressure: a critical reappraisal. Clin
Pharmacokinet 38:23-40
29. Kelly DF, Goodale DB, Williams J, et al (1999) Propofol in the treatment of moderate and
severe head injury: a randomised, prospective double-blinded pilot trial. J Neurosurg 90:
1042-1052
30. Sakai K, Cho S, Fukusaki M, Shibata M, Sumikawa K (2000) The effects of Propofol with
and without Ketamine on human cerebral blood flow velocity and C02 response. Anesth
Analg 90:377-382
31. Horn P, Munch E, Vajkoczy P, et a! (1999) Hypertonic saline solution for control of ele-
vated pressure in patients with exhausted response to mannitol and barbiturates. Neurol
Res 21:758-764
32. Strauss G, Hansen BA, Knudsen GM, Larsen FS (1998) Hyperventilation restores cerebral
blood flow autoregulation in patients with acute liver failure. J Hepatol 28:199-203
33. Wendon JA, Harrison PM, Keays R, Williams R (1994) Cerebral blood flow and metabolism
in fulminant liver failure. Hepatology 19: 1407-1013
34. Larsen FS, Knudsen GM, Hansen BA (1997) Pathophysiological changes in cerebral circula-
tion, oxidative metabolism and blood-brain barrier in patients with cute liver failure. J He-
patol 27:231-238
35. Jalan R, Damink S, Deutz N, Lee A, Hayes P (1999) Moderate hypothermia for uncon-
trolled intracranial hypertension in acute liver failure. Lancet 354:1164-1168
36. Harrigan MR, Tuteja S, Neudeck BL (1997) Indomethacin in the management of elevated
intracranial pressure: a review. J Neurotrauma 14:637-650
37. Markus HS, Vallance P, Brown MM (1994) Differential effect of three cyclooxygenase inhi-
bitors on human cerebral blood flow velocity and carbon dioxide reactivity. Stroke
25:1760-1764
38. Jensen K, Ohrstrm J, Cold GE, Astrup J (1991) The effects of indomethacin on intracranial
pressure, cerebral blood flow and cerebral metabolism in patients with severe head injury
and intracranial hypertension. Acta Neurochir 108:116-121
39. Clemmesen JO, Hansen BA, Larsen FS (1997) Indomethacin normalizes intracranial pres-
sure in acute liver failure: a twenty-three-year-old woman treated with indomethacin. He-
patology 26:1423-1425
40. Rozga J, Podesta L, LePage E, et a! (1993) Control of cerebral edema by total hepatectomy
and extracorporeal liver support in fulminant hepatic failure. Lancet 342:898-899
41. Jalan R, Pollok A, Shah S, Madhaven K, Simpson K (2002) Liver derived pro-inflammatory
cytokines may be important in producing intracranial hypertension in acute liver failure.
J Hepatol 73:536-538
42. Rolando N, Philpott-Howard J, Williams R (1996) Bacterial and fungal infection in acute
liver failure. Semin Liver Dis 16:389-402
43. Rolando N, Wade J, Davalos M, Wendon J, Philpott-Howard J, Williams R (2000) The sys-
temic inflammatory response syndrome in acute liver failure. Hepatology 32:734-739
44. Takada Y, Ishiguro S, Fukunaga K, et al (2001) Increased intracranial pressure in a porcine
model of fulminant hepatic failure using amatoxin and endotoxin. J Hepatol 6:825-831
45 Moore K (1999) Renal failure in acute liver failure. Eur J Gastroenterol Hepatol 11:967-975
46. Moore K, Wendon J, Frazer M, Karani J, Williams R, Badr K (1992) Plasma endothelin im-
munoreactivity in liver disease and the hepatorenal syndrome. N Engl J Med 327:1774-
1778
47. Davenport A, Will EJ, Davison AM (1991) Continuous vs intermittent forms of haemofiltra-
tion and/or dialysis in the management of acute renal failure in patients with defective cer-
ebral autoregulation at risk of cerebral oedema. Contrib Nephrol 93:225-233
48. Cole l, Bellomo R, Journois D, Davenport P, Baldwin I, Tipping P (2001) High-volume
haemoflltration in human septic shock. Intensive Care Med 27:978-986
49. Clemmesen JE, Kondrop J, Nielsen LB, Larsen FS, Ott P (2001) Effects of high-volume plas-
mapharesis on ammonia, urea, and amino acids in patients with acute liver failure. Am J
Gastroenterol 96:1217-1223
50. Ho DWY, Fan ST, To J, et al (2002) Selective plasma filtration for treatment of fulminant
hepatic failure induced by D-galactosamine in a pig model. Gut 50:869-876
51. Murphy ND, Kodakat SK, Wendon J, et al (2001) Liver and Intestinal lactate metabolism in
patients with acute hepatic failure undergoing liver transplantation. Crit Care Med 29:
2111-2118
52. Leifeld L, Fielenbach M, Dumoulin FL, Speidel N, Saauerbruch T, Spengler U (2002) In-
ducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) expres-
sion in fulminant hepatic failure. J Hepatol 37:613-619
53. Harry R, Auzinger G, Wendon J (2002) The clinical importance of adrenal insufficiency in
acute hepatic dysfunction. Hepatology 36:395-402
54. Van den Berghe G, Wouters P, Weekers F, et al (2001) Intensive insulin therapy in the criti-
cally ill patient. N Engl J Med 345:1359-1367
I Metabolic Support
Critical Role of Hormones in Traumatic Injury
and Outcome
T. S. A. Samy, L. W. Rue III, and I. H. Chaudry
I Introduction
Besides the undesirable effects on cardiovascular function due to blood loss and hyp-
oxia, a major consequence of traumatic injury is immunosuppression. Experimental
studies demonstrate that depression of immune functions after trauma-hemorrhage is
severe in young males, and ovariectomized (OVX) and aged females, as opposed to
proestrus females in whom immune function is maintained. Moreover, the survival
rate of proestrus females subjected to sepsis after trauma-hemorrhage is significantly
higher than age-matched males or OVX females. In addition, administration of 17/3-
estradiol, dehydroepiandrosterone (DHEA), or prolactin to males, and 17/]-estradiol
to OVX females after trauma-hemorrhage restores immune functions similar to in-
jured animals. Sex steroids, thus, play a critical role in trauma outcome and recent
studies implicate increased synthesis and lowered catabolism of Sa-dihydrotestoster-
one for immunodepression in males, and continued synthesis of 17/]-estradiol for the
maintenance of immune functions in proestrus females following trauma-hemor-
rhage. Hormones are chemical messengers that coordinate the activities of different
cells. Hormones are chemically diverse, synthesized by specific glands, and secreted
directly into the blood that carries them to their sites of action where they specifically
regulate the functions of tissues that respond. Nonetheless, many hormones or mol-
ecules possessing hormone-like activity are also synthesized in the peripheral tissues
and they regulate tissue functions locally. Furthermore, T lymphocytes and macro-
phages express receptors for androgen and estrogen and T lymphocytes locally meta-
bolize sex steroids. Since these cells are also the sites of cytokine production, local
synthesis of active steroids in these cells is significant.
Recent studies have revealed several mechanisms of hormone action. Many hor-
mones bind to the cell surface or intracellular receptors and trigger a cascade of
enzymatic reactions, the majority of which are enzyme protein phosphorylations.
Since the immune response following trauma-hemorrhage is gender-dimorphic and
involves neuro-endocrine and immune systems, interaction among the hypothala-
mus, pituitary, adrenal and the gonads is plausible and a coordination of events be-
tween these systems and the immune system is anticipated. Trauma is not a disease
in the conventional sense, but the consequence of the pathophysiologic response is
an immediate result of tissue or organ injury. Since the association between hor-
mones and the immune system is evident following trauma, the hormonal status of
the individual at the time of injury is critical and the sex steroid hormonal milieu
prevailing at the time of injury, to a large extent influences either the depression or
the maintenance of immune functions after trauma. The presence of sex steroid
hormone receptors in the immune cells and the ability of immune cells to metabo-
862 T. S. A. Sa my et al.
lize active steroids locally enables them to become targets for immune modulation
following trauma. Knowledge of the functions of immune cells early after trauma
will potentially lead to therapeutic modulation of immune functions by administer-
ing hormonal agonist/antagonists immediately after the injury, thereby helping to
prevent sepsis and decreasing mortality in both genders.
I Trauma-hemorrhage
Injury resulting from trauma and hemorrhage is one of the most common occur-
rences in industrialized countries [1]. A number of factors can potentially increase
the injured patient's risk of developing sepsis and multiple organ failure (MOP),
which have mortality rates of up to 80%. The most important consequence of trau-
ma is the development of immune suppression. Studies indicate that cytokines are
the principal mediators of the inflammatory response to injury and high levels of
circulating pro-inflammatory cytokines have been associated with a poor outcome
following trauma [2, 3]. Mouse and rat models have demonstrated an incidence of
profound suppression following trauma-hemorrhage in addition to undesired out-
comes in cardiovascular and hepatocellular functions [4-6] (Fig. 1). The suppres-
sion of immune functions following trauma-hemorrhage is evidenced by the altera-
Trauma -hemorrhage
Midline laparotomy, mean arterial pressure 30+ 5 mm Hg, 90 min
followed by Ringers-lactate resuscitation (4X the shed blood volume}
Males and ovariectomized females J Proestrus females J
!
No immune suppression observed. The change in T
cell steroidogenic enzyme activity observed
consistent with continued synthesis of 17~-estradiol
in T cells
Immune suppression:
• Change in cytokine release
• Change in T lymphocyte functions
• Change in macrophage functions
• Decrease in antigen precenting capacity
• Change in T cell steroidogenic enzymes activity
observed in low catabolism of
Sa· dihydrotestosterone and decrease In T cell
17P-estradiol synthesis in males
-
Restoration of immune functions:
• Prior castration
• Administration of flutamide, 4-
hydroxyandrostendione, 17p-estradiol,
metoclopramide, prolactin or
dehydroepiandrosterone
Fig. 1. The effects of trauma-hemorrhage on immune function of male and female mice
Critical Role of Hormones in Traumatic Injury and Outcome 863
tion in macrophage and T lymphocyte functions, in the increased release of tumor

necrosis factor (TNF}-a, interleukin (IL)-1 and IL-6, attenuated release ofT H1 cyto-
kines IL-2 and interferon (IFN}-y, and augmented release of TH2 cytokines, IL-4
and IL-10. The primary aim of the immune system is to maintain homeostasis,
where defense against infection by immune reactions is balanced with the second-
ary goal of minimizing immune-mediated damage to the individual. Thus, the equi-
librium in the immune system disappears following trauma-hemorrhage by blood
loss and accompanying hypoxia, which is evident by the increased release of pro-
inflammatory cytokines [4-6]. Since splenic macrophages, Kupffer cells, and T lym-
phocytes are the sites of synthesis for the majority of cytokines, a change in the re-
lease of cytokines following trauma-hemorrhage, suggests phenotypic alterations in
these cytokine secreting cells. Studies have also demonstrated divergence in the im-
mune responses in males and females following trauma-hemorrhage [7-9]. Males
develop immunosuppression, whereas proestrus females are not immunosuppressed
and ovariectomy provokes immunosuppression in females similar to that seen in
males following trauma-hemorrhage (Fig. 1). Moreover, studies implicate the in-
volvement of sex steroids, especially Sa-dihydrotestosterone and 17P-estradiol, in
the divergent immune responses of males and females, since parenteral administra-
tion of flutamide (an androgen receptor antagonist) in males [10, 11] and 17/J-es-
tradiol in males and OVX females after trauma-hemorrhage [12, 13] restores im-
mune functions similar to those observed in normal animals. Steroid hormones,
i.e., androgen, estrogen, progestin, and corticosteroid, have intracellular receptors
that bind to DNA, function as transcription factors, and regulate cytokine genes
[14, 15]. It is, thus, not surprising that sex steroids play a significant role in the
outcome of trauma-hemorrhage.
I Role of Hormones in Trauma-hemorrhage
Hormones are chemical messengers that coordinate the activities of different

tissues and regulate cellular functions. They are chemically diverse and consist of
derived amino acids and lipids, steroids, polypeptides, and simple and complex
proteins (Table 1). These chemical messengers are integrally involved in the patho-
logical consequences of trauma-hemorrhage. Several recurring motifs in hormone
reaction have been revealed, which are associated with the regulation of mediators
for cell proliferation, cell differentiation and tissue functions. Since gender di-
morphism is recognized in the outcome of trauma-hemorrhage and prolactin [16],
Table 1. Hormones and mediators with hormone-like activity

I Amino add derivatives: Thyroxine
I Peptides: Oxytocin, vasopressin
I Proteins: Insulin, growth hormone, prolactin, luteinizing hormone (lH),
follicle stimulating hormone (FSH), thyroid stimulating hormone
(TSH), growth factors (IGF, EGF, etc.)
I Steroids: Androgens, estrogens, progestins, corticosteroids
I Arachidonic acid metabolites Prostaglandins, leukotrienes
DHEA [17] and 17fJ-estradiol [12, 13] exhibit salutary effects in the care of trauma-
hemorrhage, understanding of the role of the hormones in the pathophysiology of
trauma is essential. Knowledge about the effects of gonadal steroids is particularly
important because the local metabolism of active steroids in the peripheral tissues
is associated with immune functions and their involvement in the regulation of cy-
tokine genes.
I Sex Steroids
Gonads and adrenal glands are the primary sites of synthesis of sex steroids, i.e.,
testosterone, Sa-dihydrotestosterone and 17P-estradiol. Nonetheless, several studies
have demonstrated the presence of steroidogenic enzymes, Sa-reductase, aromatase,
3fJ-hydroxysteroid dehydrogenase (3fJ-HSD), and 17fJ-hydroxysteroid dehydrogenase
(17P- HSD) in peripheral tissues indicating the metabolism of sex steroids locally in
tissues, including spleen and T lymphocytes (Fig. 2) [18-20]. Because of their high
potency, rapid turnover, and involvement in cellular regulatory functions, the ex-
tra-gonadal metabolism of active steroids is particularly significant since their local
synthesis is for carrying out specific tissue functions and inactivating them rapidly
afterwards. Since T lymphocytes and macrophages express receptors for androgen
and estrogen [20] and since the T lymphocytes have the ability to synthesize active
steroids locally [21], alterations in the activity of these enzymes in the cells follow-
ing trauma-hemorrhage is critical for the availability of active steroids for receptor
binding and activation of cytokine genes.
Studies demonstrate that the expression and activity of Sa-reductase, aromatase,
and 17fJ-HSD changes in the T lymphocytes alter following trauma-hemorrhage, in
a gender dimorphic manner (Fig. 3). In males, the Sa-reductase activity increases
greater than two-fold in T lymphocytes following trauma-hemorrhage demonstrat-
ing the increased synthesis of Sa-dihydrotestosterone by these cells [21]. Among
the androgens, Sa-dihydrotestosterone is the most potent since its binding affinity
to the androgen receptor is six-fold greater and transcriptional activity more pro-
longed than that of testosterone [22, 23]. Sa-dihydrotestosterone can be metabolized
Cholesterol
P4SOK< 1
3~·HSD
170H- Pregnenolone 170H-Progesterone
P4SOK< l 1P450K<
3~ - HSD aromatase
Dehydroepiandrosterone - Androstenedione -Estrone
17P-HSD +H ll H- 17~-HSD +H ll H-
Sa- Dihydrotestosterone Testosterone - 17~-Estradiol

Sa-reductase aromatase
3a-HSD1
17~- HSD H-
Sa-Androstane - 3~. 17~-diol - - - Androsterone
Fig. 2. Pathway for the synthesis of gonadal steroids. For 17fi-HSD redox reactions, +H: reduction, W: oxi-
dation
Consequence of trauma-hemorrhage:
• Increased synthesis and low catabolism of Sa-dihydrotestosterone in males.
• Persistent synthesis of 17~-estradiol in proestrus females but not in OVX females.
T lymphocytes, after T-H

Male Female
Proestrus ovx
Sa-reductase t ~ +
aromatase ~ t NC
3~-HSO NC NC NC
3a-HSD t
17~-HSD reduction NC 1 t NC
17~ - HSD oxidation ~2 ~ f
NC: no change;': Androstenedione- testosterone;>: Adiol androsterone;>: 17~·estradiol- estrOne
Fig. 3. The effect of trauma-hemorrhage on steroidogenic enzyme activities. ovx: ovariectomized
by 3a-hydroxysteroid dehydrogenase, and 17/J-HSD (oxidative) into androsterone, a

metabolite that is inactive because of its inability to bind to the androgen receptor.
However, studies show no alteration in the activity of 3a-hydroxysteroid dehydro-
genase and a decrease in the expression of 17/J-HSD type IV, (which by oxidative
function converts Sa-androstane-3/1,17/J-diol into androsterone) in male T lympho-
cytes following trauma-hemorrhage. This suggests a lack of Sa-dihydrotestosterone
catabolism in T lymphocytes of trauma-hemorrhaged males, and consequently re-
sults in elevated levels of Sa-dihydrotestosterone within the cells [24]. Additional
evidence for the immunosuppressive effects of Sa-dihydrotestosterone comes from
studies which show:
I that pre-castrated males do not show immunosuppression following trauma-
hemorrhage because of lowered Sa-reductase activity, and concomitant decreased
Sa-dihydrotestosterone synthesis [24]
I the salutary effects of flutamide, a competitive binder of the androge.n receptor
in normal males following trauma-hemorrhage due to inactivation of the andro-
gen receptor [10, 11]
I impaired catabolism of Sa-dihydrotestosterone associated with decreased release
of IL-6 in T lymphocytes of males following trauma-hemorrhage [24].
Furthermore, studies have also shown salutary effects of 4-hydroxy androstenedione

in males following trauma-hemorrhage because of its potential inhibitory effects on
Sa-reductase activity [2S]. Aromatase activity, however, is low in T lymphocytes of
males and its activity is not altered following trauma-hemorrhage.
In proestrus females, Sa-dihydrotestosterone levels are low in the T lymphocytes
because of reduced Sa-reductase activity. In contrast, aromatase as well as 17/J-HSD
(reductive) activities significantly increase in proestrus females following trauma-
hemorrhage suggesting increased synthesis of 17/J-estradiol (Fig. 3). The synthesis
of 17fJ-estradiol from androstenedione in these cells is through testosterone and not
estrone [21]. The lack of change in 17/J-HSD oxidative activities or in the expres-
sion of oxidant type IV isomer leads to less conversion of 17/1-estradiol to estrone,
which does not bind to estrogen receptor, in the trauma-hemorrhaged animals. In
contrast, in ovariectomized animals, activities of aromatase and 17fJ- HSD (reduc-
tive) are low in T lymphocytes compared to proestrus females following trauma

hemorrhage. This results in lower 17P-estradiol production and consequent immu-
nosuppression. Since aromatase catalysis is a complex reaction involving two sepa-
rate enzymes, aromatase P450 and a flavoprotein NADPH-cytochrome P450 reduc-
tase [26], and three distinct steps, other factors such as the availability of cofactors
linked to the reaction should also be taken into consideration while assessing the
aromatase activity.
Among the other steroidogenic enzymes, the activity of 3-HSD is not altered either
in males or proestrus females following trauma-hemorrhage or after gonadectomy.
However, based on analysis of the expression of different isomers, the oxidative
and reductive activities of 17P- HSD appear to change in T lymphocytes of males
and females following trauma-hemorrhage. The change in these enzyme activities
emphasizes the importance of this enzyme in immune responses following injury.
Normally, the reductive catalysis by 17P-HSD leads to biosynthesis of an active andro-
gen or an active estrogen. The oxidative catalysis of 17P- HSD, alternatively, leads to
the synthesis of inactive steroids, androsterone from Sa-dihydrotestosterone and es-
trone from 17P-estradiol (Fig. 2). Studies have shown the presence of several 17P-
HSD isotypes, each exhibiting a favored substrate, reaction direction, and unique tis-
sue distribution in human and mouse tissues [27, 28]. Thus, the expression of differ-
ent 17P- HSD isotypes in tissues or cells is important for correlation of active steroid
production to cytokine release and for the establishment of mechanisms for gender
dimorphic immune responses in trauma-hemorrhagic shock.
Nuclear receptors function in development, metabolism, and reproduction and
play an important role in diseases and pathological states. They are· key ligand-de-
pendent and -independent transcription factors, which are responsible for modulat-
ing tissue and cellular responses to a host of hormones and metabolites [29]. They
include steroid receptors such as androgen receptor (AR), estrogen receptor (ER),
and glucocorticoid receptor (GR). It was previously believed that hormone binding
to a receptor results in activation of the receptor and subsequent cellular response.
However, more recent understanding of the mechanisms has revealed a far more
complex reaction. Several cytoplasmic and nuclear accessory proteins and many
enzyme tyrosine phosphokinases have been identified, which regulate the appear-
ance of the active ligand-bound receptor in the cytoplasm and/or nucleus, and
modulate nuclear localization, DNA binding, and eventually activation or repression
of gene expression. The identification of nuclear factors as coactivators and core-
pressors has opened a pathway to greater understanding of hormone action at the
gene level. Immune cells, i.e., T lymphocytes and macrophages, which are the sites
of cytokine synthesis, express receptors for both androgen and estrogen [20, 25]
and the need now is to define how these receptor interactions are integrated to es-
tablish tissue and cellular specificity with respect to immune functions, especially
in relation to gender dimorphism following trauma-hemorrhage.
I Significance of Hypothalamus-pituitary-adrenal-gonadal (HPAG)

Immune Communication following Trauma-hemorrhage
The regulatory role of sex steroids in immune functions and its contribution to dif-
ferences in the outcome of males and females to trauma-hemorrhage focuses on
the importance of HPAG interactions following injury [30-32]. Neuroendocrine-im-
Hypothalamus
Paraventricular lA\ Peptidergic

Epinephrine, __ nucleus o;::_; neurons
Norepinephrine ®® Supraoptic
nucleus
Adrenal
glands
~Ovary
a
17~- Estradiol/
~ Testis cytokine
Glucocorticoids, Gonads feedback
dehydroepiandrosterone
\
LEndothelial
Thymocytes
0 Monoeytes
~r:::JO
Testosterone
~
g _..- 17{3-Estradio/
cells
Immune qj' <§) Cytokines
cells Macrophages, Dendritic - - - - - {TNF-CL, IL-l,
cells, T lymphocytes IL-6)
Fig. 4. Interaction of hypothalamus-pituitary-adrenal-gonad and immune systems
mune interaction is vital for survival from pathological states occurring from tissue
injury and sepsis. A reciprocal regulation between the central nervous system
(CNS) and the immune system exists through which the CNS signals the immune
system via hormonal and neural pathways and the immune system signals through
cytokines (Fig. 4). The primary hormonal pathway by which the CNS regulates the
immune system is the HPAG axis. The association of the axis coordinates bidirec-
tionally between neuroendocrine and immune functions following trauma-hemor-
rhage by activating compensatory mechanisms for the release of mediators needed
for homeostasis. A good example of a compensatory mechanism is the activity of
DHEA, an adrenal steroid present in the tissues and present in the circulation in re-
latively high concentrations as sulfate ester. In post-menopausal women, where the
ovaries are deficient in producing estrogen, DHEA is the source for 17P-estradiol
production. In trauma-hemorrhage, dehydroepiandrosterone exhibits salutary ef-
fects in the immune response by its activation of the estrogen receptor after conver-
sion to 5~-androstene 3P,17P-diol [18, 33]. The epinephrine released during stress
from trauma stimulates the CNS immediately after the injury [34]. The immune
modulators that are released subsequently, such as TNF-a, IL-l and IL-2 and IL-6,
then activate the HPAG axis whose response is seen in the increased secretion of:
868 T.S.A. Samy et al.
i) hormone releasing factors corticotropin releasing factor (CRH) and gonadotropin

releasing hormone (GnRH), and ii) the hormones adrenocorticotropin (ACTH),
leuteinizing hormone (LH), follicle stimulating hormone (FSH), growth hormone
and prolactin. ACTH in sequence stimulates adrenal gland and LH and FSH the go-
nads to secrete steroids (Fig. 4). Among the hormones, prolactin, testosterone, 5a-
dihydrotestosteone and 17/1-estradiol exercise profound salutary effects on the im-
mune system following trauma-hemorrhage. Since many neuroendocrine pathways
are involved in the regulation of immune functions, each with its own molecular
endpoints, the potential for disruption in these interactions is great following trau-
ma-hemorrhage. A thorough understanding of the communication at all levels be-
tween the HPAG axis and immune systems is, thus, essential to identify the disrup-
tion in the communication following trauma-hemorrhage and provide an opportu-
nity for therapeutic protection with anti-inflammatory compounds such as the pi-
tuitary adenyl cyclase activating peptide or the vasoactive intestinal peptide (VIP).
I Regulation of Immune Cells Early following Trauma-hemorrhage
There are two kinds of immune reaction: innate immunity that is non-specific, and
acquired immunity that is specific. In trauma injury, understanding the mechanism
of the innate immune response is important, since modulation of the functions of
the bone marrow derived macrophages and dendritic cells early after the injury
may lead to prevention of harmful effects of trauma, that is immunodepression,
and provide defense against the invading pathogens to prevent sepsis [35-37].
Many cells participate in these responses; among them are cells of myeloid origin,
the dendritic cells, and the macrophages all of which contribute significantly to the
development of inflammatory responses via their expression of several costimula-
tory molecules and production of cytokines. Moreover, functions of these cells are
amenable to modulation by cytokines, steroids, infection and drug therapy. These
cells originate from CD34+ bone marrow stem cells and are a heterogeneous popu-
lation that display differences in anatomic location, cell surface phenomenon, and
function. The development of macrophages and dendritic cells from stem cells and
their relationship to other bone marrow derived cells is illustrated in Figure 5. The
phenotypic diversity, receptor expression, and the mediators they release reflect the
functional differences in macrophages and myeloid dendritic cells. Thus, identifica-
tion of phenotypic markers and of receptors such as TREM (triggering receptor ex-
pressed on myeloid cells) [38, 39] and Toll [40-42] expressed specifically on macro-
phages, myeloid dendritic cells, T lymphocytes and their precursors in the course
of differentiation and maturation is important not only for elucidation of their in
vivo trafficking, but also for understanding the functional distinction between these
two cells. Macrophages and T lymphocytes are the primary sites for the production
of cytokines, chemokines and other mediators. Thl or the Th2-inducing capacity
of myeloid dendritic cells is not an intrinsic feature and both induction abilities
are acquired by uncommitted immature dendritic cells in response to signals deliv-
ered by the local environment [43, 44]. Inflammation in response to trauma-hemor-
rhage elicits changes in the microenvironment, which affects macrophage and dendri-
tic cell activation and maturation. Macrophages in the circulation or infiltrated in tis-
sues, such as Kupffer cells, affect a wide range of immune responses such as cyto-
kine and chemokine releases, antigen recognition, capture, clearance and transport.
Pluripotent .
stem cells - Natural k1ller cells
Mast c~lls, eosinophils . _

! ~
Myeloid cells
Lymphocytes - - B lymphocytes
1
+
basophlls and neutrophlls
! T lymphocytes
- IL-4,
+IL- 1 211~
Thl
Monocytes l . . ._____ Na'i ve - - Th2

Serum, M-CSF, 1 COB+ cells CD4 + TH cells + IL-4.
GM- CSF / IL- 4 t -IL-12
no differentiation, Veiled cells GM- CSF/ MCP-1,

M-CSF, Estradi;jj'/ IL-4 Estradiol?
/ - GM-CSF/IL-4
Macrophages Dendritic cells
+GM- CSF/IL-4
Fig. 5. Development of marcophages and Th 1 and Th2 lymphocyte clones
T lymphocytes, on the other hand, are provoked to producing Thl- or Th2-biased

cytokines. Recent studies demonstrate that, in response to stimulation by endoge-
nously produced cytokines such as IL-4, IL-10, IL-12 and IFN-y, monocyte-derived
dendritic cells of bone marrow influence the differentiation of naive Th cells into
Thl and Th2 cells that mediate cellular immunity (Fig. 5). Since changes in the re-
lease of these cytokines occur following trauma-hemorrhage, phenotypic and func-
tional changes in both the macrophage and dendritic cell phenotypes would be ex-
pected. Thus, differentiation of macrophage and dendritic cells, from immature to
mature cells, is of considerable importance for the polarization of immune re-
sponses following trauma-hemorrhage. Since sex steroids regulate cytokine genes
at the gene level and since estrogen has the ability to bring about phenotypic
changes in myeloid precursor cells [45], it is also important to determine whether
in the absence of estrogen, cell phenotypes that are tailored to the release of media-
tors that would produce immune suppression preponderate in bone marrow, in pe-
ripheral blood mononuclear cells (PBMC) and in the infiltrated tissues. In other
words, the presence of estrogen or treatment with an estrogen may generate
changes in the cell phenotype, which would initiate cells to release specific media-
tors that will prevent immunosuppression following trauma-hemorrhage. Thus,
study of the immuno pathogenesis of trauma-hemorrhage at the cellular level and
its complications from the sex steroid perspective will provide a better understand-
ing of the mechanisms leading to severity of injury and immunologic perturbation
in the male and the female.
Endothelial cells that line the vasculature are also monocyte-influenced cells in-
volved in vascular functions relative to blood flow, blood coagulation and cytokine
release [46, 47]. They are functionally unique to the tissue of origin and function
differently depending on the milieu. Interaction of endothelial cell, dendritic cell
and T lymphocytes are important in immunological processes. Since perturbations
of the immune system largely contribute to the pathogenesis of vessel injury and
since immune suppression concomitant with the release of pro-inflammatory cyto-
kines, TNF-a, IL-l and IL-6, following trauma-hemorrhage is significant, it is con-
ceivable that the release of cytokines contributes to suppression of vascular func-

tions by engaging endothelial cells in the process. Since gender dimorphism in im-
mune function is observed following trauma-hemorrhage, it is essential to deter-
mine whether endothelial cell functions are differentially influenced in tissues of
males and females due to differences in the circulatory sex steroid profile. The role
of endothelial cells is, thus, important in the outcome from trauma-hemorrhage
and, once the molecular mechanisms of endothelial cell activation are better de-
fined, therapies that allow for selective vascular endothelial modulation can be de-
veloped.
Future Prospects
The major consequence of trauma-hemorrhage is severe immunosuppression.
Immunomodulatory intervention early after trauma aimed at modification of the
hyper-inflammatory phase, i.e., systemic inflammatory response syndrome, could
potentially avoid subsequent pathogenic infection and sepsis progress. Animal stud-
ies have indicated that immune function following trauma is gender dimorphic and
sex steroids play a decisive role in the depression or maintenance of immune func-
tions following injury. The benefits of 17/J-estradiol, and the unfavorable effects of
Sa-dihydrotestosterone, in immune function are demonstrated with the use of
gonadectomized animals as well as in in vivo studies by parenteral administration
of hormonal agonists and antagonists to animals following trauma-hemorrhage.
Steroid hormones are capable of regulating immune functions by: i) involvement in
differentiation and proliferation of the immune cell; ii) metabolic conversion into
an active steroid locally in the immune cell; and iii) modulation of cytokine genes
as a transcription factor after interaction with intracellular cognate receptors. Trau-
ma is not a typical disease but an instantaneous pathological outcome of severe
blood loss and accompanying hypoxemia. The observation that young females re-
spond better to trauma than males clinically [48] and that proestrus females re-
spond better than ovariectomized females and males brings to attention the impor-
tance of 17/J-estradiol in trauma outcome. Since steroids are involved in the devel-
opment of immune cells from precursor bone marrow stem cells, modulation of
such cells with selective estrogen agonists early after trauma injury along with fluid
resuscitation, may help in the maintenance of immune functions and in the preven-
tion of pathological alterations and, thus, mortality from sepsis. Such an adjunct
therapeutic strategy is realistic with the use of agents that enhance aromatase activ-
ity, decrease Sa-reductase activity and those that react with sex steroid receptors to
regulate cytokine genes.
Acknowledgement. These investigations were supported by NIH grant ROl-GM-

37127.
References
1. Bonnie RJ (2002) Reducing the Burden of Injury: Advancing Prevention and Treatment.
National Academy Press, Washington, D.C.
2. Yao YM, Redl H, Bahrami S, Schlag G (1998) The inflammatory basis of trauma/shock-as-
sociated multiple organ failure. Inflamm Res 47:201-210
3. Napolitano LM, Faist E, Wichmann MW, Coimbra R (1999) Immune dysfunction in trau-
ma. Surg Clin North Am 79:1385-1416
---~--~~~~,--~--~~'"~,-~
4. Chaudry IH, Ayala A, Ertel W, Stephan RN (1990) Hemorrhage and resuscitation: immuno-
logical aspects. Am J Physiol 259:R663-R678
5. Zellweger R, Ayala A, DeMaso CM, Chaudry IH (1995) Trauma-hemorrhage causes pro-
longed depression in cellular immunity. Shock 4:149-153
6. Xu YX, Ayala A, Chaudry IH (1998) Prolonged immunodepression after trauma and he-
morrhagic shock. J Trauma 44:335-341
7. Wichmann MW, Angele MK, Ayala A, Cioffi WG, Chaudry IH (1997) Flutamide: A novel
agent for restoring the depressed cell-mediated immunity following soft-tissue trauma and
hemorrhagic shock. Shock 8:242-248
8. Wichmann MW, Zellweger R, DeMaso CM, Ayala A, Chaudry IH (1996) Enhanced immune
responses in females, as opposed to decreased responses in males following haemorrhagic
shock and resuscitation. Cytokine 8:853-863
9. Zellweger R, Wichmann MW, Ayala A, SteinS, DeMaso CM, Chaudry IH (1997) Females in
proestrus state maintain splenic immune functions and tolerate sepsis better than males.
10. Angele MK, Ayala A, Cioffi WG, Bland Kl, Chaudry IH (1998) Testosterone: the culprit for
producing splenocyte immune depression after trauma hemorrhage. Am J Physiol
274:C1530-C1536
11. Angele MK, Wichmann MW, Ayala A, Cioffi WG, Chaudry IH (1997) Testosterone receptor
blockade after hemorrhage in males. Restoration of the depressed immune functions and
improved survival following subsequent sepsis. Arch Surg 132:1207-1214
12. Knoferl MW, JarrarD, Angele MK, eta! (2001) 17/1-estradiol normalizes immune responses
in ovariectomized females after trauma-hemorrhage. Am J Physiol 281:C1131-C1138
13. Knoferl MW, Angele MK, Schwacha MG, Bland Kl, Chaudry IH (2002) Preservation of
splenic immune functions by female sex hormones after trauma-hemorrhage. Crit Care
Med 30:888-893
14. Tsai MJ, O'Malley BW (1994) Molecular mechanisms of action of steroid/thyroid receptor
superfamily members. Annu Rev Biochem 63:451-486
15. McDonnell DP (1998) Definition of the molecular mechanism of action of tissue-selective
oestrogen-receptor modulators. Biochem Soc Trans 26:54-60
16. Zellweger R, Zhu XH, Wichmann MW, Ayala A, DeMaso CM, Chaudry IH (1996) Prolactin
administration following hemorrhagic shock improves macrophage cytokine release capa-
city and decreases mortality from subsequent sepsis. J Immunol 157:5748-5754
17. Catania RA, Angele MK, Ayala A, Cioffi WG, Bland Kl, Chaudry IH (1999) Dehydroepian-
drosterone restores immune functions following trauma-hemorrhage by a direct effect on
T lymphocytes. Cytokine 11 :443-450
18. Labrie F, Belanger A, Luu-The V, eta! (1998) DHEA and the intracrine formation of andro-
gens and estrogens in peripheral target tissues: its role during aging. Steroids 63:322-328
19. Simpson ER, Clyne C, Speed C, Rubin G, Bulun S (2001) Tissue-specific estrogen biosynth-
esis and metabolism. Ann NY Acad Sci 949:58-67
20. Samy TSA, Knoferl MW, Zheng R, Schwacha MG, Bland Kl, Chaudry IH (2001) Divergent
immune responses in male and female mice after trauma-hemorrhage: dimorphic altera-
tions in T lymphocyte steroidogenic enzyme activities. Endocrinology 142:3519-3529
21. Samy TSA, Schwacha MG, Cioffi WG, Bland Kl, Chaudry IH (2000) Androgen and estrogen
receptors in splenic T lymphocytes: effects of flutamide and trauma-hemorrhage. Shock
14:465-470
22. Singh SM, Gauthier S, Labrie F (2000) Androgen receptor antagonists (antiandrogens):
structure-activity relationships. Curr Med Chern 7:211-247
23. Roy AK, Chatterjee B (1995) Androgen action. Crit Rev Eukaryo Gene Express 5:157-176
24. Zheng R, Samy TSA, Schneider CP, Rue LW III, Bland Kl, Chaudry IH (2002) Decreased
5a-dihydrotestosterone catabolism suppresses T lymphocyte functions in males after trau-
ma-hemorrhage. Am J Physiol 282:C1332-C1338
25. Schneider CP, Nickel EA, Samy TSA, Schwacha MG, Bland Kl, Chaudry IH (2000) The aro-
matase inhibitor 4-hydroxyandrostenedione restores immune responses following trauma-
hemorrhage in males and decreases mortality from subsequent sepsis. Shock 14:347-353
26. Simpson ER, Mahendroo MS, Means GD, et a! (1994) Aromatase cytochrome 450, the en-
zyme responsible for estrogen biosynthesis. Endocr Rev 15:342-355
872 T. S. A. Sa my et al.: Critical Role of Hormones in Traumatic Injury and Outcome
27. Moustenen MVJ, Poutanen MH, lsomaa VV, Vihko PT, Vihko RK (1997) Cloning of mouse
17fi-hydroxysteroid dehydrogenase type 2 and analyzing expressions of the mRNAs for
types 1, 2, 3, 4 and 5 in mouse embryos and adult tissues. Biochem J 325:199-205
28. Labrie F, Luu-The V, Lin SX, et al (2000) Intracrinology: role of the family of 17fi-hydro-
xysteroid dehydrogenases in human physiology and disease. J Mol Endocrinol25:1-16
29. Olefsky JM (2001) Nuclear receptor mini review series. J Biol Chern 276:36863-36864
30. Gaillard RC, Spinedi E, Chautard T, Pralong FP (2000) Cytokines, leptin, and the hypotha-
lamic-pituitary-adrenal axis. Ann NY Acad Sci 917:647-657
31. Webster Jl, Tonelli L, Sternberg EM (2002) Neuroendocrine regulation of immunity. Annu
Rev Immunol20:125-163
32. Dunn AJ (2000) Cytokine activation of the HPA axis. Ann NY Acad Sci 917:608-617
33. Schmidt M, Kreutz M, Loffier G, Scholmerich J, Straub RH (2000) Conversion of dehydro-
epiandrosterone to downstream steroid hormones in macrophages. J Endocrinol 164:161-
169
34. Molina PE (2001) Noradrenergic inhibition of TNF upregulation in hemorrhagic shock.
Neuroimmunomodul 9:125-133
35. Akagawa K (1994) Differentiation and function of human monocytes. Hum Cell 7:116-120
36. Lipscomb MF, Masten BJ (2002) Dendritic cells: immune regulators in health and disease.
Physiol Rev 82:97-130
37. Palucka KA, Taquet N, Sanchez-Chapuis F, Gluckman JC (1998) Dendritic cells as the term-
inal stage of monocyte differentiation. J Immunol160:4587-4595
38. Bouchon A, Dietrich J, Colonna M (2000) Cutting edge: inflammatory responses can be
triggered by TREM-l, a novel receptor expressed on neutrophils and monocytes. J Immu-
nol164:4991-4995
39. Bouchon A, Facchetti F, Weigand MA, Colonna M (2001) TREM-l amplifies inflammation
and is a crucial mediator of septic shock. Nature 410:1103-1107
40. Muzio M, Mantovani A (2001) Toll-like receptors (TLRs) signaling and expression pattern.
J Endotoxin Res 7:297-300
41. Kaisho T, Akira S (2002) Toll-like receptors as adjuvant receptors. Biochim Biophys Acta
1589:1-13
42. Carl VS, Brown-Steinke K, Nicklin MJ, Smith MF Jr (2002) Toll-like receptor 2 and 4
(TLR2 and TLR4) agonists differentially regulate secretory interleukin-1 receptor antago-
nist gene expression in macrophages. J Biol Chern 277:17448-17456
43. Peters JH, Xu H, Ruppert J, Ostermeier D, Friedrichs D, Gieseler RK (1993) Signals re-
quired for differentiating cells from human monocytes in vitro. Adv Exp Med Biol
329:275-280
44. Vieira PL, de Jong EC, Wierenga EA, Kapsenberg ML, Kalinski P (2000) Development of
Thl-inducing capacity in myeloid dendritic cells requires environmental instruction. J Im-
munol164:4507-4512
45. Scott Thurmond T, Murante FG, Staples EJ, Silverstone AE, Korach KS, Gasiewicz TA
(2000) Estrogen receptor in hematopoietic stem cell development and B lymphopoietic ma-
turation in the male mouse. Endocrinology 141:2309-2318
46. Biedermann BC (2001) Vascular endothelium: checkpoint for inflammation and immunity.
News Physiol Sci 16:84-88
47. Vapaatalo H, Mervaala E (2001) Clinically important factors influencing endothelial func-
tion. Med Sci Monit 7:1075-1085
48. George RL, McGwin G, Windham ST, et al (2003) Age-related gender differential in out-
come following blunt trauma or penetrating trauma. Shock (in press)
Hyperglycemia and the Lung
R. J. Cusack, J. Ball, and B. J. Philips
1 Introduction
An estimated 150 million people worldwide have diabetes [1]. A further 200 million
have glucose intolerance and 40% of these will become diabetic over 5-10 years. By
2010 it is expected there will be 220 million diabetics, the majority of who will
have type II diabetes, an increase compounded by an increasing prevalence of obe-
sity and sedentary habit. The potential morbidity and mortality has serious world-
wide economic implications [2].
Diabetes mellitus and glucose intolerance, as defined by the World Health Orga-
nization (WHO) and the American Diabetes Association (ADA), depend on either a
fasting plasma glucose ~ 7 mmol/1, or the symptoms of diabetes plus a casual plas-
ma glucose ~ 11.1 mmol/1, on two or more occasions. In addition, the WHO defini-
tion of diabetes includes a plasma glucose ~ 11.1 mmol/1 two hours after a standard
75g oral glucose load. Impaired fasting glucose is defined as a fasting plasma glu-
cose ~6.1 mmol/1, and impaired glucose tolerance as a plasma glucose of 7.8-
11 mmol/1 two hours after 75 g glucose. The fasting plasma glucose limits for the
diagnosis of diabetes mellitus have been lowered in recognition of the development
of complications of diabetes at lower plasma glucose concentrations. The plasma
glucose threshold for developing diabetic retinopathy is estimated to be as low as
7 mmol/1 [3]. In the Paris prospective study of middle aged men, made over
20 years, coronary heart disease was more common in individuals with a fasting
plasma glucose >5.8 mmol/1 [4].
Diabetics are at increased risk of developing acute metabolic disturbances, and a
variety of chronic complications specific to diabetes. Cardiovascular, renal, ophthal-
mic, neurological, and cutaneous disorders are all well recognized. In addition, dia-
betics may also be at increased risk from other acute medical conditions, not
usually associated with diabetes, such as peritonitis, respiratory failure and liver
diseases [5].
Acute Illness
Stress hyperglycemia and insulin resistance are common in acutely ill patients [6, 7].
In a recent study, 2030 consecutive admissions to a general hospital in the USA were
for hyperglycemia using the WH 0 criteria. Thirty eight percent of all admissions were
hyperglycemic; one third of these were not previously known to be diabetic. Patients
with newly diagnosed hyperglycemia were more likely to die (mortality rate 16%)
874 R. J. Cusack et al.
than patients with either known diabetes (3o/o) or normoglycemia {1.7o/o) [7]. Stress
hyperglycemia is associated with poor outcome from acute myocardial infarction,
stroke, traumatic brain injury, burns, and, in animal models, endotoxic shock [8].
In critically ill patients, strict control of glucose (and/or insulin therapy) decreased
mortality by as much as 32o/o. This staggering result, was predominantly due to a de-
crease in the incidence of severe infective complications [6]. A similar decrease was
observed for the requirement for renal support and duration of ventilatory support.
Hyperglycemia is associated with infection. Diabetes is an independent risk fac-
tor for death from pulmonary tuberculosis [9] and is associated with an increased
risk of pulmonary infection by Staphylococcus aureus and Gram-negative organ-
isms. Pulmonary infections by other organisms, e.g., influenza virus and strepto-
coccus, are associated with increased morbidity and mortality in diabetic patients
[10] and diabetes has been found to be an independent disease modifier for pneu-
monia in young patients. In older patients it is associated with an increase in se-
verity of chronic obstructive pulmonary disease (COPD) [11].
I Pathogenesis of Hyperglycemic Complications

The pathogenesis of hyperglycemic complications is thought to involve a micro-an-
giopathy in association with glycosylation of tissue proteins [12]. Four differing hy-
potheses as to how hyperglycemic induced damage occurs have received consider-
able attention. These include: a) increased polyol pathway flux; b) increased ad-
vanced glycation end product (AGE) formation; c) activation of protein kinase C
(PKC) and d) increased hexosamine pathway flux [13]. In brief:
a) Aldose reductase catalyses the dihydronicotinamide adenine dinucleotide phos-
phate (NADPH) dependant reduction of glucose. Normally this enzyme has a
low affinity for glucose, however, when intracellular levels of glucose are high, there
is increased conversion of glucose to sorbitol. The net effects are a depletion of
NADPH and intracellular glutathione, and increased intracellular oxidative stress.
b) AGEs are cross-linked modified proteins, formed in response to increased intra-
cellular glucose. Both structural and circulating proteins may be affected withal-
teration in their function [12]. Vascular structures and macrophages appear to
be particularly affected and in bovine lung vasculature, an AGE binding protein
has been isolated and termed 'receptor for advanced glycated end products'
(RAGE) [14]. Co-localization of AGEs and RAGE occurs at sites of diabetic mi-
cro-vascular injury and may indicate a role for this receptor-ligand interaction
in the development of diabetic complications [15].
c) Hyperglycemia increases the activity of protein kinase C (PKC) causing an in-
crease in endogenous nitric oxide, and increases in vascular endothelial growth
factor {VEGF), plasminogen activator inhibitor-! (PAI-l), and nuclear factor-
kappa B (NF-KB). The result is vasoconstriction, increased vascular permeability
and a pro-inflammatory response [13].
d) Increased intracellular glucose results in an increased diversion of glucose into
the hexosamine pathway. The result is pro-inflammatory with an increased intra-
cellular production of PAI-l and transforming growth factor-fJ (TGF-/3) [13].
A unifying theory has been suggested which brings these four mechanisms to-
gether. Hyperglycemia is thought to directly induce mitochondrial superoxide over-
production by the inhibition of electron transport at complex III within the mito-
Hyperglycemia and the Lung 875
chondria. This inhibits the enzyme glyceraldehyde-3-phosphate dehydrogenase

(GAPDH) thus slowing glycolysis, and increasing the substrates required to en-
hance the mechanisms described [13].
I Diabetes and the Lung
The consequences of micro-vascular disease in diabetic patients affect all major

organ systems of the body resulting in renal impairment, diffuse autonomic and
peripheral neuropathy, strokes, ischemic heart disease, and blindness. One largely
ignored area, however, has been the impact of hyperglycemia on lung function.
The lung, with its large microvascular circulation and extensive delicate network
of connective tissue, would appear to be highly vulnerable to the pathological pro-
cesses of diabetes. Despite this, impaired respiratory function is not recognized as
a common complication in diabetes. However, in 1989, Lange and colleagues [16]
measured lung function in 11 763 people of whom 2.5o/o had diabetes and a further
7.1 o/o were glucose intolerant. Increased plasma glucose was negatively associated
with vital capacity and forced expiratory volume in 1 second (FEV 1).
The literature examining lung function in diabetes is contradictory. However,
many studies are small and only include young, type I, patients. In these patients,
respiratory compromise may be masked by a large physiological reserve in lung
function. In addition, few studies control for confounding factors such as asthma
and smoking [17]. Nevertheless, clinically relevant deterioration in respiratory
function tests has been reported and may be most significant when additional risk
factors for respiratory dysfunction also exist. Diabetics have been shown to have
decreases in lung volumes including forced vital capacity (FVC) and FEV 1 [18],
pulmonary elastic recoil [19], inspiratory muscle capacity [18], and diffusion ca-
pacity (expressed per alveolar volume) [19].
Ramirez and colleagues [20] observed respiratory function changes in two groups
of diabetics over 6 years. Patients receiving intensive insulin therapy (8 patients) ver-
sus standard twice daily insulin (10 patients) had significantly better FVC and lung
diffusing capacity for carbon monoxide (DLCO) than the standard group. They sug-
gested that good glycemic control might slow down deterioration in lung volumes. In
a study of 150 patients with cystic fibrosis, deterioration in lung function was ob-
served to coincide with the onset of glucose intolerance and the rate of decline was
strongly associated with the severity of glucose intolerance over a 4 year period [21].
Abnormalities in the pulmonary vasculature may result in impaired gas ex-
change and studies have looked for decreases in DLCO in patients with diabetes.
Results are conflicting [22-24], ranging from no abnormalities to extensive changes
in all measured parameters. In an attempt to get an improved overview of lung
function changes seen in diabetic patients, Sandler and colleagues [19] examined
life long non-smoking, insulin dependent diabetics. The aim was to assess the na-
ture and prevalence of pulmonary dysfunction in these patients and the association
with age and disease duration. Forty patients and 40 aged matched controls were
assessed with detailed lung function tests. Abnormal lung function was found in
60o/o of patients. No difference was detected in lung volumes or airflow between the
groups, but there was a reduced DLCO corrected to alveolar volume. This was at-
tributed to lower pulmonary capillary blood volumes in the diabetic patients and
these abnormalities correlated with the duration of diabetes.
876 R.J. Cusack et al.
DLCO increases in normal subjects when changing from sitting to the supine
position and is attributed to the recruitment of upper pulmonary lobe capillaries.
This increase in DLCO normally decreases with age but the decline is exaggerated
in diabetic patients [22], perhaps reflecting abnormalities in the pulmonary vascu-
lature.
Histopathological evidence of lung involvement in diabetes has been described
in both animals and humans. Rats with streptozocin-induced diabetes, have ultra-
structure changes in type 2 pneumocytes, non-ciliated bronchiolar epithelium, and
tissue connective proteins [25], and pulmonary venous resistance is observed to in-
crease within two weeks of the onset of diabetes [26]. In diabetic hamsters, plasma-
lemma! vesicle bodies develop in the capillary endothelium, alveoli collapse, and
the lung interstitium enlarges in response to 6 weeks of hyperglycemia [27]. Bio-
chemical changes identified within the lung include: elevated lysyl oxidase (an en-
zyme related to cross-linking of elastin and collagen), suppression of aniline p-hy-
droxylase activity, diminished insulin-like-growth-factor-1 (IGF-1}, elevated activity
of angiotensin-converting enzyme (ACE), and increased susceptibility to glycation
of lung proteins [28-30]. Human post-mortem findings in diabetic patients have
detailed alveolar epithelial and pulmonary capillary basement laminae thickening
[31] throughout the lung and a specific type of nodular fibrosis of the lung [32].
Control of Breathing
Mortality is increased in diabetic patients with autonomic neuropathy compared to
those without [33]. Often these deaths occur because of a sudden cardio-respiratory
arrest and an obvious cause (e.g. myocardial infarction, cardiac arrhythmia) may
be absent. Consequently, the control of respiration in diabetics has attracted some
attention.
Respiratory Drive to C02 and Oxygen 2

Diabetics may have a reduced ventilatory response to hypoxia, occurring in asso-
ciation with autonomic neuropathy [34]. More recent studies have shown that dia-
betic patients have an increased perception of dyspnea when hypoxic and make an
increased respiratory effort, but changes in tidal volume are decreased compared to
controls [35]. Abnormal peripheral airway function is thought to be responsible for
this altered response to hypoxia.
Contradictory results have been reported of the respiratory response to a hyper-
capnic challenge in diabetic patients, varying from a reduced ventilatory response,
an unchanged response, or an increased ventilatory response [34, 36, 37]. A recent
explanation for these contradictory results was put foreword by Tantucci and col-
leagues [38] who sub-divided the patients with diabetes into those without an auto-
nomic neuropathy, those with signs of parasympathetic neuropathy, and those with
combined sympathetic and parasympathetic neuropathy. Diabetic patients with a
combined autonomic neuropathy had an increased response to hypercapnia com-
pared to controls (non-diabetics) and diabetics without detectable neuropathy or
isolated parasympathetic neuropathy had a reduced response compared to controls.
Sleep Apnea
Sleep produces changes in the respiratory system involving the central drive activ-
ity and neural control of both upper airway and thoracic muscles. The most com-
mon form of sleep disordered breathing is obstructive sleep apnea (OSA) with a
prevalence in the middle aged population of 2% for women and 4% for men. Many
conditions are associated with OAS including obesity, anatomically small pharyn-
geal airway, primary hypertension, and a family history.
Although obesity is also associated with type II diabetes, there appears to be an
independent association between diabetes and sleep disturbances. Ficker and col-
leagues [39] found that 26% of diabetic patients with an autonomic neuropathy
had clinically significant OSA compared to none without autonomic neuropathy. No
differences were found between the 2 groups in terms of body mass index (BMI),
diabetes type, or duration of diabetes. More recently, diabetics were found to have
a significantly greater apnea-hypopnea index than non-diabetics, again matched for
BMI, smoking history, and age [40 ].
Immune Function and the Lung (Table 1)

White cell dysfunction: The alveolar macrophage plays an important early role in the
control and clearance of infections in the lung. Abnormalities of chemotaxis and
phagocytosis [41] by monocytes in diabetics has been described and reduced pha-
gocytosis and bactericidal action is reported for alveolar macrophages in diabetic
rats [42]. The microbe killing action of macrophages is achieved by a respiratory
burst generating superoxide anions, hydrogen peroxide, hydroxyl radicals and lyso-
somal factors, and is reduced in in vitro studies of alveolar macrophages from dia-
betic rats (43].
Polymorphonuclear cells (PMN) are an essential component in the host defense
against bacterial invasion. Abnormalities of PMN chemotaxis, bactericidal activity,
and adherence, have been described in patients with diabetes mellitus (44] and the
Table 1. Summary: Hyperglycemia and immune function

Component of immune system Effect of hyperglycemia
Polymorphonuclear cells Impaired phagocytosis

Impaired chemotaxis
Decreased bactericidal activity
Decreased adherence
Increased apoptosis
Lymphocytes Decreased response (all subsets)
Monocytes Impaired chemotaxis
Impaired phagocytosis
Decreased respiratory burst
Immunoglobulins Non-enzymatic glycosylation
Decreased concentrations (lgA, lgG, lgM)
Collectins (SP-A, SP-D) Non-enzymatic glycosylation
Impaired opsonization
878 R.J. Cusack et al.
normal delay in neutrophil apoptosis in response to lipopolysaccharide is reduced

in diabetes, suggesting an impaired neutrophil response [45]. This is a possible ex-
planation for the decreased risk diabetics have for developing acute respiratory dis-
tress syndrome (ARDS) [46].
The question arises, are these abnormalities a consequence of diabetes or hyper-
glycemia? Hyperglycemia per se, is believed to adversely effect leukocytes [47] and
good glucose control has been shown to improve their function. [48].
Immune Proteins: Pulmonary surfactant is a complex mixture of lipids and proteins

secreted into the alveoli by Clara cells. There are 4 surfactant proteins: SP-A, SP-B,
SP-C and SP-D, of which SP-A and SP-D belong to a family of collagenous host defense
lectins (collectins). They are characterized by a collagen-like domain and a carbohy-
drate recognition domain (CRD}, the latter binds with carbohydrate moieties on in-
coming pathogens and enhances their uptake by neutrophils and macrophages. SP-A
and SP-D are active against various bacteria and viruses including E. coli, S. pneumo-
niae, S. aureus, Pseudomonas and influenza virus [49]. In vitro studies have shown
that these carbohydrate domains become 'pre-glycosylated' in the presence of glucose,
rendering the collectin inactive [SO]. Similar glycosylation of immunoglobulins has
been described, an effect reversed by good glucose control [51].
Conclusion
Hyperglycemia, whether acute or chronic, impacts significantly on the lungs.
Chronic hyperglycemia decreases lung volumes and DLCO, interferes with the con-
trol of respiration and impairs immune responses. Stress hyperglycemia increases
susceptibility to infection, in particular pneumonia, and may have effects on the
lung as yet unrecognized. The evidence from van den Berghe and colleagues sug-
gests that intensive intervention can prevent the adverse effects of hyperglycemia,
though some of the benefit may be due to the administration of insulin rather than
controlling glucose per se. Nevertheless, as the prevalence of diabetes and glucose
intolerance rises, the management of hyperglycemia will become increasingly im-
portant. Maintaining strict glycemic control within physiological limits should be
considered a valuable and readily achievable goal.
References
1. Zimmet P, Alberti KG, Shaw J (200 1) Global and societal implications of the diabetes epi-
demic. Nature 414:782-787
2. American Diabetes Association (1998) Economic consequences of diabetes mellitus in the
US in 1997. Diabetes Care 21:296-309
3. DECODE Study Group on behalf of the European Diabetes Epidemiology Study Group
(1998) Will new diagnostic criteria for diabetes mellitus change phenotype of patients with
diabetes? Reanalysis of European epidemiological data. Br Med J 317:371-375
4. Balkau B, Bertrais S, Ducimetiere P, Eschwege E (1999) Is there a glycemic threshold for
mortality risk? Diabetes Care 22:696-699
5. Ray NF, Thamer M, Taylor T, Fehrenbach SN, Ratner R (1996) Hospitalization and expen-
ditures for the treatment of general medical conditions among the US diabetic population
in 1991. J Clin Endocrinol Metab 81:3671-3679
6. van den Berghe G, Wouters P, Weekers F, eta! (2001) Intensive insulin therapy in the criti-
cally ill patient. N Eng! J Med 345:1359-1367
7. Umpierrez GE, Isaacs SO, Bazargan N, You X, Thaler LM, Kitabchi AE (2002) Hyperglyce-
mia: an independent marker of in-hospital mortality in patients with undiagnosed dia-
betes. J Clin Endocrinol Metab 87:978-982
8. Johan Groeneveld AB, Beishuizen A, Visser FC (2002) Insulin: a wonder drug in the criti-
cally ill? Crit Care 6:102-105
9. Oursler KK, Moore RD, Bishai WR, Harrington SM, Pope OS, Chaisson RE (2002) Survival
of patients with pulmonary tuberculosis: clinical and molecular epidemiologic factors. Clin
Infect Dis 34:752-759
10. Lovering AM, MacGowan AP, Anderson P, Irwin D (2001) Epidemiology and resource utili-
zation for patients hospitalized for lower respiratory tract infection. Clin Microbial Infect
7:666-670
11. Zanobetti A, Schwartz J (2001) Are diabetics more susceptible to the health effects of air-
borne particles? Am J Respir Crit Care Med 164:831-833
12. Ulrich P, Cerami A (2001) Protein glycation, diabetes, and aging. Recent Prog Harm Res
56:1-21
13. Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nat-
ure 414:813-820
14. Schmidt AM, Mora R, Cao R, et a! (1994) The endothelial cell binding site for advanced
glycation end products consists of a complex: an integral membrane protein and a lactofer-
rin-like polypeptide. J Bioi Chern 269:9882-9888
15. Soulis T, Thallas V, Youssef S, et a! (1997) Advanced glycation end products and their re-
ceptors co-localise in rat organs susceptible to diabetic microvascular injury. Diabetologia
40:619-628
16. Lange P, Groth S, Kastrup J, et a! (1989) Diabetes mellitus, plasma glucose and lung func-
tion in a cross- sectional population study. Eur Respir J 2: 14-19
17. Sandler M (1990) Is the lung a 'target organ' in diabetes mellitus? Arch Intern Med
150:1385-1388
18. Wanke T, Formanek D, Auinger M, Popp W, Zwick H, Irsigler K (1991) Inspiratory muscle
performance and pulmonary function changes in insulin-dependent diabetes mellitus. Am
19. Sandler M, Bunn AE, Stewart RI (1987) Cross-section study of pulmonary function in pa-
tients with insulin-dependent diabetes mellitus. Am Rev Respir Dis 135:223-229
20. Ramirez LC, Dal Nogare A, Hsia C, et a! (1991) Relationship between diabetes control and
pulmonary function in insulin-dependent diabetes mellitus. Am J Med 91:371-376
21. Milia CE, Warwick WJ, Moran A (2000) Trends in pulmonary function in patients with
cystic fibrosis correlate with the degree of glucose intolerance at baseline. Am J Respir Crit
Care Med 162:891-895
22. Fuso L, Cotroneo P, Basso S, et a! (1996) Postural variations of pulmonary diffusing capa-
city in insulin-dependent diabetes mellitus. Chest 110:1009-1013
23. Maccioni FJ, Colebatch HJ (1991) Lung volume and distensibility in insulin-dependent dia-
betes mellitus. Am Rev Respir Dis 143:1253-1256
24. Strojek K, Ziora D, Sroczynski JW, Oklek K (1992) Pulmonary complications of type 1 (in-
sulin-dependent) diabetic patients. Diabetologia 35:1173-1176
25. Kida K, Utsuyama M, Takizawa T, Thurlbeck WM (1983) Changes in lung morphologic
features and elasticity caused by streptozotocin-induced diabetes mellitus in growing rats.
26. Russ RD, Tobin BW (1996) Alteration of segmental vascular resistance in the pulmonary
circulation of diabetic rats. Can J Physiol Pharmacal 74:1010-1015
27. Popov D, Simionescu M (1997) Alterations of lung structure in experimental diabetes, and
diabetes associated with hyperlipidaemia in hamsters. Eur Respir J 10:1850-1858
28. Irizar A, Ioannides C (1995) Extrahepatic expression of P450 proteins in insulin-dependent
diabetes mellitus. Xenobiotica 25:941-949
29. Myint H, Chacko J, Mould S, Ross F, Oscier DG (1995) Karyotypic evolution in a granulo-
cytic sarcoma developing in a myeloproliferative disorder with a novel (3;4) translocation.
Br J Haematol 90:462-464
880 R. J. Cusack et al.: Hyperglycemia and the Lung
30. Ofulue AF, Khadempour MH, Thurlbeck WM (1994) Diminished levels of insulin-like
growth factor-! in lungs in streptozotocin-induced diabetes: relation to nutritional status
and growth. Exp Lung Res 20:27-40
31. Weynand B, Jonckheere A, Frans A, Rahier J (1999) Diabetes mellitus induces a thickening
of the pulmonary basal lamina. Respiration 66:14-19
32. Farina J, Furio V, Fernandez-Acenero MJ, Muzas MA (1995) Nodular fibrosis of the lung in
diabetes mellitus. Virchows Arch 42 7:61-63
33. Ziegler D (1994) Diabetic cardiovascular autonomic neuropathy: prognosis, diagnosis and
treatment. Diabetes Metab Rev 10:339-383
34. Sobotka PA, Liss HP, Vinik AI (1986) Impaired hypoxic ventilatory drive in diabetic pa-
tients with autonomic neuropathy. J Clin Endocrinol Metab 62:658-663
35. Scano G, Filippelli M, Romagnoli I, et al (2000) Hypoxic and hypercapnic breathlessness in
patients with type I diabetes mellitus. Chest 117:960-967
36. Wanke T, Abrahamian H, Lahrmann H, et al (1993) No effect of naloxone on ventilatory re-
sponse to progressive hypercapnia in IDDM patients. Diabetes 42:282-287
37. Nishimura M, Miyamoto K, Suzuki A, et al (1989) Ventilatory and heart rate responses to
hypoxia and hypercapnia in patients with diabetes mellitus. Thorax 44:251-257
38. Tantucci C, Scionti L, Bottini P, et al (1997) Influence of autonomic neuropathy of different
severities on the hypercapnic drive to breathing in diabetic patients. Chest 112:145-153
39. Ficker JH, Dertinger SH, Siegfried W, et al (1998) Obstructive sleep apnoea and diabetes
mellitus: the role of cardiovascular autonomic neuropathy. Eur Respir J 11:14-19
40. Elmasry A, Lindberg E, Berne C, et al (2001) Sleep-disordered breathing and glucose meta-
bolism in hypertensive men: a population-based study. J Intern Med 249:153-161
41. Waltenberger J, Lange J, Kranz A (2000) Vascular endothelial growth factor-A-induced che-
motaxis of monocytes is attenuated in patients with diabetes mellitus: A potential predictor
for the individual capacity to develop collaterals. Circulation 102:185-190
42. Sima AA, O'Neill SJ, Naimark D, Yagihashi S, Klass D (1988) Bacterial phagocytosis and in-
tracellular killing by alveolar macrophages in BB rats. Diabetes 37:544-549
43. Mohsenin V, Latifpour J (1990) Respiratory burst in alveolar macrophages of diabetic rats.
44. Andersen B, Goldsmith GH, Spagnuolo PJ (1988) Neutrophil adhesive dysfunction in dia-
betes mellitus; the role of cellular and plasma factors. J Lab Clin Med 111:2 75-285
45. Tennenberg SD, Finkenauer R, Dwivedi A (1999) Absence of lipopolysaccharide-induced
inhibition of neutrophil apoptosis in patients with diabetes. Arch Surg 134:1229-1233; dis-
cussion 1233-1224
46. Moss M, Guidot DM, Steinberg KP, et al (2000) Diabetic patients have a decreased inci-
dence of acute respiratory distress syndrome. Crit Care Med 28:2187-2192
47. von Kane! R, Mills PJ, Dimsdale JE (2001) Short-term hyperglycemia induces lymphopenia
and lymphocyte subset redistribution. Life Sci 69:255-262
48. Rassias AJ, Givan AL, Marrin CA, Whalen K, Pahl J, Yeager MP (2002) Insulin increases
neutrophil count and phagocytic capacity after cardiac surgery. Anesth Analg 94:1113-
1119
49. Hartshorn KL, Crouch E, White MR, et al (1998) Pulmonary surfactant proteins A and D
enhance neutrophil uptake of bacteria. Am J Physiol 274:L958-969
50. Reading PC, Allison J, Crouch EC, Anders EM (1998) Increased susceptibility of diabetic
mice to influenza virus infection: compromise of collectin-mediated host defense of the
lung by glucose? J Virol 72:6884-6887
51. Hennessey PJ, Black CT, Andrassy RJ (1991) Nonenzymatic glycosylation of immunoglobu-
lin G impairs complement fixation. JPEN J Parenter Enteral Nutr 15:60-64
Glycolysis in Sepsis and other Stress Conditions
S. Karyampudi and M. Singer
I Introduction
Glycolysis is derived from the Greek words glycos, sugar (sweet), and lysis, dissolu-
tion. The glycolytic (Embden-Meyerhof) pathway is the only extra-mitochondrial
process that allows the cell to directly produce usable energy in the form of ATP.
Glucose (a six carbon chain molecule) is metabolized to two pyruvate (three carbon
chain) molecules with a net gain of two ATP molecules. Glycolysis is, however, rela-
tively inefficient; the yield of two molecules of ATP per molecule of glucose is ap-
proximately 5% of the potential 36-38 ATP molecules generated in total by anaero-
bic (glycolytic+tricarboxylic acid cycle) and aerobic (oxidative phophorylation)
metabolism.
Glycolysis involves ten distinct enzymatically catalyzed steps (Fig. 1). Most are
free-floating within the cytosol though some are incorporated into the cell and out-
er mitochondrial membranes. The fraction of enzymes becoming bound increases
with a rising H+ concentration or ischemia [1]. Two ATP molecules are used in the
'investment' stage to produce fructose-1,6-biphosphate. This is then cleaved to two
three-carbon triose phosphates that, in turn, are converted to pyruvate in the 'yield'
stage, producing four molecules of ATP, thus generating a net gain of two mole-
cules of ATP.
The metabolism of glucose is highly complex and involves many steps. It inter-
sects with the metabolism of fats and proteins and its intermediates provide a
branch point to other metabolic pathways. The rate-limiting and/or controlling en-
zymes of glycolysis are considered to be hexokinase, phosphofructokinase (PFK),
and pyruvate kinase. PFK is frequently touted as the key regulatory glycolytic en-
zyme [2] though pyruvate kinase has also been championed [3]. The Pasteur effect
(the phenomenon whereby anaerobic conditions stimulate glycolysis) increases gly-
colytic activity in all cells, though other more potent stimuli exist, such as protein
phosphorylation [4].
I Side Reactions
An important side-reaction of the glycolytic pathway is the pentose phosphate

pathway. All cells depend upon this pathway to combat oxidant damage. NADPH
and pentose sugars so produced are necessary for reduction of glutathione (an im-
portant antioxidant), nucleotide synthesis, redox reactions required for synthesis of
fatty acids, cholesterol, steroid hormones, bile salts, and for hydroxylation reactions
882 S. Karyampudi and M. Singer
0~
The
Hexokinase
~-.:6~P
~~
•
0 ~~~H]
investment
stage of
Glycolysis.
~
PFK
}-+1 Oihydroxyacetone-P I
GAPDH
The yield part

of glycolysis
I 2- Phosphoglycerate I
• H20
~
Pyruvate Kinase • 'co2
I Pyruvate ] ~ I Lacme
(1:7
eJ GD
Fig. 1. The breakdown of glucose occurs through glycolysis (the Embden-Meyerhof pathway). There is a
net gain of 2 ATP molecules as dihydroxyacetone-P is converted to glyceraldehyde 3-P during the second
half of the pathway by triose phosphate isomerase enzyme. G-6-P: glucose-6-phosphate; F-1,6-BP: fruc-
tose-1 ,6-biphosphate; PEP: phosphoenol pyruvate; PFK: phosphofructokinase; GAPDH: glyceraldehyde 3-
phosphate dehydrogenase
involved in hepatic detoxification and excretion of drugs. These side-reactions will

reduce the yield of energy produced per molecule of glucose. During normal cell
respiration about So/o of glucose-6-phosphate molecules are diverted to the pentose
phosphate pathway [5]. Furthermore, in erythrocytes, an added 19% of glycolytic
intermediates are diverted to 2,3 diphosphoglycerate (DPG) [6], an allosteric regu-
lator of the oxygen affinity of hemoglobin abetting oxygen release. The concentra-
tion of this molecule increases during hypoxic states.
Glycolysis in Sepsis and other Stress Conditions 883
I Sepsis
Sepsis culminating in organ failure is the leading cause of death in intensive care
[7]. However, pathophysiological mechanisms whereby systemic inflammation leads
to organ dysfunction remain poorly understood. Among many pathways stimulat-
ed, a marked endocrine response occurs, resulting in increased levels of catechola-
mines, glucagon, growth hormone, and glucocorticoids. Altered glucose metabolism
is a commonly observed sequel of sepsis as all of the above hormones exert their
influence on the blood glucose level. This effect is initially achieved by mobilizing
liver stores, but this short-lived effect is followed by hypoglycemia which may be
severe enough to endanger the function of glucose-dependent cells.
It has been suggested that the glycolytic contribution to energy production in-
creases to 10% in sepsis [8]. This may be due to increased pathway activity and/or
decreased mitochondrial function. We have recently demonstrated inhibition of mi-
tochondrial enzyme activity in muscle biopsies taken from patients in septic shock
[9]. This increase in glycolysis may thus be a compensatory mechanism to sustain
an adequate level of energy provision needed to sustain cell integrity, though not
necessarily any of its specialized functions. Indeed, Louis Pasteur showed that ex-
cluding air from growing yeast cells did not kill them, but merely slowed their
growth and multiplication, while at the same time consuming much more glucose.
During hypoxia, the mitochondrial cristae disintegrate, cytochrome enzyme synthe-
sis is greatly depressed, and the mitochondria become swollen or destroyed. These
changes do not necessarily indicate irreversible cell damage, but may be a form of
adaptation to their new environment. Although extreme, this example of yeast cell
adaptation in anoxia may reflect mammalian cell adaptations during a septic crisis.
Hyperlactatemia, increased muscle glucose uptake, but decreased muscle glucose
content, are well recognized in sepsis [10], however, energy metabolism distur-
bances remain poorly understood. The two bioenergetic pathways (glycolysis and
mitochondrial respiration) have never been studied concomitantly, potentially lead-
ing to a misinterpretation of individual changes in substrates, intermediates, or
products within a sole metabolic pathway [11].
Despite the increase in glucose uptake seen in sepsis, there is also insulin resis-
tance, even with the use of a hyperinsulinemic-euglycemic clamp (a technique
whereby supplementary insulin is infused with adequate amounts of glucose to
maintain euglycemia) [12].
The literature reveals considerable contradictions with both increased [3, 11, 13]
and decreased [14, 15] glycolytic activity being reported during sepsis. On closer
inspection those studies showing increased activity are taken from short-term
models (4-6 hours), whereas decreased activity is found in longer term models
(48-72 hours). This discrepancy is explained by a temporal change in activity of
the glycolytic enzymes, which we have demonstrated in a long-term rat model of
faecal peritonitis. Interestingly, the more severely affected animals manifested a
lower initial increase in activity, but a greater subsequent fall [16].
Glycolysis occurs independent of the oxygen level; indeed, many tissues appear
to generate lactate under aerobic conditions (so-called aerobic glycolysis) [17].
High rates of oxidative phosphorylation and glycolysis are also not mutually exclu-
sive [18]. Cellular glucose uptake and glycolytic flux may well be stimulated by
mediators produced during the systemic inflammatory response. Increased intracel-
lular Na+ may actually increase glycolytic activity during mild sepsis [19], possibly
through activation of the Na+/glucose symport which drives large amounts of glu-
cose into the cell. Glycolysis can provide up to one-third of the ATP supply re-
quired by muscles during exercise (tail muscles of the rattle snake}; fatigue is
avoided in these muscles by increased blood flow, which rapidly carries away the
products of glycolysis [18].
Glycolysis is a more rapid energetic pathway than the tricarboxylic acid (Krebs')
cycle into which it feeds. Therefore, pyruvate, the end-product of glycolysis, cannot
be totally integrated into the Krebs' cycle and its overproduction and accumulation
will contribute to hyperlactatemia. However, the fact that the respiratory chain con-
tinues to function, albeit at a lower level, suggests that oxygen is sufficient in sup-
ply but underutilized [20]. The decrease in oxidative phosphorylation thus results
in a decrease in adenosine triphosphate (ATP) production. This may explain activa-
tion of glycolysis via PFK stimulation. Glycolysis may thus compensate, at least in
part, for aerobic energy production failure, concomitant to which there is lactate
overproduction [11].
I Nitric Oxide {NO} and Glycolysis

The well-documented reduction in cellular energy state occurring during septic
shock has prompted investigation of the actions of NO and its congeners on the
enzyme complexes involved in production of ATP. Considerable evidence points to
the inhibitory action of NO on mitochondrial complexes [9]. Data regarding its ef-
fects on glycolysis are incomplete; only glyceraldehyde-3-phosphate dehydrogenase
(GAPDH) has been shown to be inhibited by NO [8]. There is a reversible inhibi-
tion acting through S-nitrosation of its active site Cys 149 , and an irreversible action
through a subsequent covalent attachment of NADPH to the enzyme [21]. The sup-
pressive effects of NO on GAPDH led to the proposal that NO would reduce glyco-
lytic flux in NO-producing cells [22]. Paradoxically, however, while NO indeed de-
creases cellular GAPDH activity, there is evidence it simultaneously increases glyco-
lytic flux [23]. This paradox may be explained by NO enhancing acyl phosphatase
activity of GAPDH while inhibiting its dehydrogenase activity, thereby uncoupling
glycolytic flux from the synthesis of ATP [8].
Lactic Acidosis
Hyperlactatemia is a reliable predictor of poor outcome in critically ill patients
[24]. High lactate levels have been traditionally assumed to be a sign of tissue hyp-
oxia [24], a condition thought to contribute to the development of multi-organ fail-
ure (MOF). Variation in lactate levels over time has been highlighted as a useful
tool to assess patient response to treatment [25]. However, it is now acknowledged
that an increased lactate may reflect conditions other than hypoperfusion, includ-
ing enhanced aerobic glycolysis, and/or decreased lactate clearance, and/or a down-
stream problem such as altered pyruvate flux via a decrease in pyruvate dehydro-
genase (PDH) activity [26].
There is considerable evidence to support the notion that sepsis promotes in-
creased glycolysis [3, 11, 13], as well as inhibiting PDH via a reversible phosphory-
lation process to the inactive isozyme [27]. By adding dichloroacetate, Shangraw et
al. stimulated PDH activity, resulting in a 50% decrease in plasma lactate levels.
However, they failed to reverse sepsis-induced insulin resistance during insulin-

stimulated glucose uptake at either whole-body or tissue levels [12]. Evidence from
other medical conditions, such as cardiogenic shock, also suggests that an increase
in non-oxidative glucose disposal is the major contributor towards lactic acidemia.
Furthermore, air-breathing vertebrates that have adapted to low concentrations of
0 2 depend on increased glycolysis for survival [28]; they have developed means of
coping with the profound lactic acidemia that invariably develops.
In humans, investigators have found the reverse true under hyperoxic conditions
(compared to normoxia). Muscle samples were taken from healthy human volun-
teers before and after exercise; maximal performance improved by 38%, glycogen
was depleted twice as much, whereas lactate accumulation was lower [29]. These
data suggest a higher oxidation rate for pyruvate and NADH in mitochondria,
thereby lowering the degree of metabolic acidosis.
During sepsis, poor tissue perfusion due to decreased delivery of oxygen would
in itself lead to lactic acidemia, however only some improvement is seen in the
acidosis upon fluid and oxygen resuscitation. This implies that the lactic acidemia
may indeed be a by-product of normal cellular coping mechanisms, e.g., up-regula-
tion of glycolysis to help the cells (and organs) survive the septic insult.
The stress response elicited by sepsis involves simultaneous mobilization of both
glucose and free fatty acids (FFA). The rate of FFA oxidation is determined by their
rate of transfer into the mitochondria via the carnitine palmitoyltransferase (CPT)
enzyme system; this, in turn, is regulated by the metabolism of glucose. The high
FFA concentrations and increased tissue triglyceride stores can limit glucose clear-
ance from the blood, thereby contributing to the development of hyperglycemia.
Excessive metabolism of glucose to facilitate the metabolism of FFAs can also result
in lactic acidemia [30 ].
Ischemia
Ischemic preconditioning has been used by cardiac surgeons to reduce damage to

the myocardium during surgery, though the mechanism is not fully understood.
The glycolytic pathway may be integral to this preconditioning process though
there is contradictory evidence. A brief (five minute) episode of ischemia can pro-
tect the isolated rat heart from a prolonged (40 minute) period of ischemia. This
protection is associated with decreased tissue acidosis while ATP utilization and
anaerobic glycolysis occur at much slower rates [31]. Furthermore, glycogenolysis
is reduced without affecting anaerobic glycolysis, suggesting increased glucose up-
take [32]. Either preservation of ATP or reduction of the cellular load of catabolites
may be responsible for delaying ischemic cell death.
Preconditioning inhibits rat heart mitochondrial ATPase, leading to sparing of
high-energy phosphates and improving the time-averaged energy state during isch-
emia [33]. Preservation of mitochondrial oxidative phosphorylation and inhibition
of glycolysis during ischemia can contribute to preconditioning-induced cardiopro-
tection. This may possibly be due to reduced production of glycolytic metabolites
and a decrease in proton production from glucose during sustained ischemia lead-
ing to a concomitant attenuation of intracellular acidosis [34]. The decrease in in-
tracellular acidosis observed in ischemic preconditioning must either come from
decreased H+ production or increased efflux via the Na +/H+ exchange pump, with
glycolytic ATP powering this process [35]. There is evidence both for [36] and
against [37] an increase in efflux. Interestingly, a low pH will inhibit glycolysis [38]
whereas a high pH stimulates glycolysis by activating PFK-1, the main rate control-
ling enzyme [39].
Conversely, the ischemic heart is dependent on glycolysis for ATP generation,
and therapies that increase glucose utilization during ischemia improve survival.
About 80% of the supply of ATP utilized by severely ischemic tissues in the face of
impaired oxidative phosphorylation comes from anaerobic glycolysis using glyco-
gen as the principal substrate [40]. More recently, clinical trials have suggested that
therapeutic measures that augment glucose metabolism in the ischemic heart, such
as a glucose-insulin-potassium (GIK) infusion, may have significant effects on sur-
vival [41]. Delivery of glucose to the glycolytic pathway appears to be a major con-
trolling site of glycolysis in low-flow ischemia. Downstream regulation is then dis-
tributed along the pathway with no one site exerting greater inhibition than re-
duced glucose delivery [42].
The mechanisms that govern this beneficial effect remain to be completely eluci-
dated but may include enhanced glucose uptake and glycolysis by the ischemic
myocardium [43]. GLUT4-mediated transport represents a major mechanism by
which the heart increases glucose uptake during ischemia. Glucose availability and
uptake plays a key role in regulating glycolysis and enhanced glycolysis is critical
to myocardial recovery [44]. A possible mechanism for the increase in glycolytic
activity is the presence of mRNA abundance for glycolytic enzymes and glucose
transporter proteins during ischemic conditions, thus increasing enzyme activity
and content [45].
The story is muddied by the fact that fasting also protects the heart from isch-
emic injury and is associated with a lower lactate/pyruvate (L:P) ratio and in-
creased glycogen utilization during ischemia [46]. In contrast, increasing glycogen
content in hearts from fed animals using insulin will limit glycogen utilization, in-
crease ischemic injury, and impair both functional and metabolic recovery. Com-
pared to the insulin-treated hearts, hearts from fasted animals had both less acido-
sis and less rapid depletion of ATP during ischemia, as well as lower accumulation
of glycolytic intermediates. This hints at a increased rate of glycolysis in the fasting
group associated with a greater ability to clear the products of glycolysis; if the L:P
ratio increase causes an acidosis, glycolysis would be inhibited, leading to faster
ATP depletion, further acidosis, further inhibition of glycolysis, and thus a rapid
downward spiral leading to increased ischemic injury [47].
In no-flow ischemic conditions, the overall glycolytic flux may be limited by
GAPDH, through inhibition by the accumulation of lactate and protons, however
no allosteric control of GAPDH by lactate has been found in a purified enzyme
preparation [48]. GAPDH has recently started to assume a more important role due
to its inhibition by NO [22, 49]. Inhibition of GAPDH activity may represent an
important point at which glycolysis is limited, as incubation of the inhibited en-
zyme under both mild and strong reducing conditions failed to reactivate the en-
zyme [50]. All of these control mechanisms are, however, somewhat academic if de-
livery of glucose to the glycolytic pathway is impaired.
---~--~~~~,--~--~~'"~,-~
I The Effects of Insulin
The pivotal in vivo role of insulin is to control fuel homeostasis. It exerts its effect
on three main target tissues: liver, fat and skeletal muscle [51]. In vivo studies re-
veal that skeletal muscle is the principal tissue responsible for about 75% of insulin
stimulated glucose disposal following glucose loading [52]. Hyperglycemia in itself
has a negative effect on the regulation of glucose transport into the cells and could
be one factor leading to the development of peripheral insulin resistance in skeletal
muscle. In rodents, substantial evidence has accumulated to suggest that chronic
hyperglycemia can directly contribute to the development of peripheral insulin re-
sistance [53]. Insulin-stimulated glucose transport is fully restored to normal in
isolated skeletal muscle from Type II diabetic patients after a 2-hour exposure in
vitro to media containing low (4 mmol/1), but not high (8 mmol/1} glucose [54].
The hyperglycemia measured during sepsis could thus be either cause or effect of
the insulin resistance seen.
During acidosis there is both disrupted secretion of insulin and a reduced action
of insulin on target tissues [39]. This may be a protective mechanism to limit the
extent of acidosis caused by glycolysis but, ironically, this may be the one process
that assists the cells to maintain their normal function. There is growing evidence
that during stress from whatever cause, glucose which enters the cell is getting
channelled into glycolysis [55, 56] thereby accelerating the pathway.
Although the primary energy source for normal myocardium is FFA, glucose ap-
pears to be a more favorable energy substrate for the myocardium during ischemia
and reperfusion. GIK solutions have been shown to limit ischemic damage in ex-
perimental models of ischemia. Animals receiving GIK during the periods of coro-
nary occlusion and reperfusion had significantly less tissue acidosis, better recov-
ery, and smaller infarct size. GIK enhances myocardial performance during isch-
emia and results in faster recovery after coronary artery bypass graft (CABG) sur-
gery for unstable angina [57].
Conclusion
Glycolysis is clearly affected during sepsis, though activity varies both temporally
and with severity. The extent to which changes are pathologically influenced, or are
an adaptive attempt to compensate for other processes such as mitochondrial inhi-
bition requires further study. Likewise, the potential therapeutic importance of en-
hancing glycolytic flux merits investigation.
References
1. Gray SM, Adams V, Yamashita Y, Le SP, Goddard-Finegold J, McCabe ER (1994) Hexoki-
nase binding in ischemic and reperfused piglet brain. Biochem Med Metab Biol 53:145-148
2. Depre C, Rider MH, Hue L (1998) Mechanisms of control of heart glycolysis. Eur J Bio-
chem 258:277-290
3. Liu MS, Zhang JN (1985) Glycolytic and tricarboxylic acid cycle intermediates in dog livers
during endotoxic shock. Biochem Med 34:335-343
4. Marsin AS, Bertrand L, Rider MH, et al (2000) Phosphorylation and activation of heart
PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia. Curr Biol
10:1247-1255
5. Ben Yoseph 0, Camp DM, Robinson TE, Ross BD (1995) Dynamic measurements of cere-
bral pentose phosphate pathway activity in vivo using [1,6-13C2,6,6-2H2]glucose and mi-
crodialysis. J Neurochem 64:1336-1342
6. Mulquiney PJ, Bubb WA, Kuchel PW (1999) Model of 2,3-bisphosphoglycerate metabolism
in the human erythrocyte based on detailed enzyme kinetic equations: in vivo kinetic
characterization of 2,3-bisphosphoglycerate synthase/phosphatase using 13C and 31P
NMR. Biochem J 342:567-580
7. Parrillo JE (1993) Pathogenetic mechanisms of septic shock. N Engl J Med 328:1471-1477
8. Albina JE, Mastrofrancesco B, Reichner JS (1999) Acyl phosphatase activity of NO-inhib-
ited glyceraldehyde-3-phosphate dehydrogenase (GAPDH): a potential mechanism for un-
coupling glycolysis from ATP generation in NO-producing cells. Biochem J 341:5-9
9. Brealey D, Brand M, Hargreaves I, et al (2002) Association between mitochondrial dysfunc-
10. Mizock BA (2000) Metabolic derangements in sepsis and septic shock. Grit Care Clin
16:319-336
11. L'Her E, Sebert P (2001) A global approach to energy metabolism in an experimental mod-
el of sepsis. Am J Respir Grit Care Med 164:1444-1447
12. Shangraw RE, Jahoor F, Wolfe RR, Lang CH (1996) Pyruvate dehydrogenase inactivity is
not responsible for sepsis-induced insulin resistance. Grit Care Med 24:566-574
13. Lang CH, Bagby GJ, Spitzer JJ (1984) Carbohydrate dynamics in the hypermetabolic septic
rat. Metabolism 33:959-963
14. Ardawi MS, Jamal YS, Ashy AA, Nasr H, Newsholme EA (1990) Glucose and glutamine me-
tabolism in the small intestine of septic rats. J Lab Clin Med 115:660-668
15. Gellerich FN, Trumbeckaite S, Hertel K, et al (1999) Impaired energy metabolism in hearts
of septic baboons: diminished activities of Complex I and Complex II of the mitochondrial
respiratory chain. Shock 11:336-341
16. Karyampudi S, Brealey D, Stidwill R, Taylor V, Singer M (2002) The effect of sepsis on the
key glycolytic enzymes in a rodent model of organ failure. Intensive Care Med 28:S96
(abst)
17. Levraut J, Ciebiera JP, Chave S, et al (1998) Mild hyperlactatemia in stable septic patients
is due to impaired lactate clearance rather than overproduction. Am J Respir Grit Care
Med 157:1021-1026
18. Kemper WF, Lindstedt SL, Hartzler LK, Hicks JW, Conley KE (2001) Shaking up glycolysis:
Sustained, high lactate flux during aerobic rattling. Proc Natl Acad Sci USA 98:723-728
19. Chai J, Diao L, Sheng Z (1999) [Impact of intracellular Na+ concentration alteration on in-
tracellular aerobic glycolysis in skeletal muscles in sepsis]. Zhonghua Yi Xue Za Zhi
79:546-548
20. Gnaiger E, Lassnig B, Kuznetsov A, Rieger G, Margreiter R (1998) Mitochondrial oxygen
affinity, respiratory flux control and excess capacity of cytochrome c oxidase. J Exp Bioi
201:1129-1139
21. Mohr S, Stamler JS, Brune B (1996) Posttranslational modification of glyceraldehyde-3-
phosphate dehydrogenase by S-nitrosylation and subsequent NADH attachment. J Bioi
Chern 271:4209-4214
22. Vedia L, McDonald B, Reep B, et al (1992) Nitric oxide-induced S-nitrosylation of glyceral-
dehyde-3-phosphate dehydrogenase inhibits enzymatic activity and increases endogenous
ADP-ribosylation. J Bioi Chern 267:24929-24932
23. Albina JE, Mastrofrancesco B (1993) Modulation of glucose metabolism in macrophages by
products of nitric oxide synthase. Am J Physiol 264:C1594-C1599
24. Mizock BA, Falk JL (1992) Lactic acidosis in critical illness. Grit Care Med 20:80-93
25. Bakker J, Gris P, Coffernils M, Kahn RJ, Vincent JL (1996) Serial blood lactate levels can
predict the development of multiple organ failure following septic shock. Am J Surg
171:221-226
26. Astiz ME, Rackow EC (1998) Septic shock. Lancet 351:1501-1505
27. Vary TC (1996) Sepsis-induced alterations in pyruvate dehydrogenase complex activity in
rat skeletal muscle: effects on plasma lactate. Shock 6:89-94
28. Jackson DC (2000) Living without oxygen: lessons from the freshwater turtle. Comp Bio-
chem Physiol A Mol Integr Physiol 125:299-315
29. Linossier MT, Dormois D, Arsac L, et al (2000) Effect of hyperoxia on aerobic and anaero-
bic performances and muscle metabolism during maximal cycling exercise. Acta Physiol
Scand 168:403-411
30. Wolfe RR, Martini WZ (2000) Changes in intermediary metabolism in severe surgical ill-
ness. World J Surg 24:639-647
3L Murry CE, Richard VJ, Reimer KA, Jennings RB (1990) Ischemic preconditioning slows en-
ergy metabolism and delays ultrastructural damage during a sustained ischemic episode.
Circ Res 66:913-931
32. de Jonge R, Bradamante S, Speleman L, Willem DJ (1998) Carbohydrates and purines in
underperfused hearts, protected by ischemic preconditioning. J Mol Cell Cardiol 30:699-
708
33. Vuorinen K, Ylitalo K, Peuhkurinen K, Raatikainen P, Ala-Rami A, Hassinen IE (1995) Me-
chanisms of ischemic preconditioning in rat myocardium. Roles of adenosine, cellular en-
ergy state, and mitochondrial F1FO-ATPase. Circulation 91:2810-2818
34. Finegan BA, Lopaschuk GD, Gandhi M, Clanachan AS (1995) Ischemic preconditioning in-
hibits glycolysis and proton production in isolated working rat hearts. Am J Physiol
269:H1767-H1775
35. Satoh H, Sugiyama S, Nomura N, Terada H, Hayashi H (2001) Importance of glycolytically
derived ATP for Na+ loading via Na+/H+ exchange during metabolic inhibition in guinea
pig ventricular myocytes. Clin Sci (Lond) 101:243-251
36. Salvi S (2001) Protecting the myocardium from ischemic injury: a critical role for al-
pha(1)-adrenoreceptors? Chest 119:1242-1249
37. Gabel SA, Cross HR, London RE, Steenbergen C, Murphy E (1997) Decreased intracellular
pH is not due to increased H+ extrusion in preconditioned rat hearts. Am J Physiol
273:H2257-H2262
38. Morand C, Remesy C, Demigne C (1994) Control of lactate utilization by extracellular pH
in isolated rat liver cells. Metabolism 43:157-162
39. Inoue Y, Kaneko T (1992) [Effects of pH on the endocrine system and metabolism]. Nip-
pon Rinsho 50:2124-2128
40. Depre C, Vanoverschelde JL, Taegtmeyer H (1999) Glucose for the heart. Circulation
99:578-588
41. Diaz R, Paolasso EA, Piegas LS, et al (1998) Metabolic modulation of acute myocardial in-
farction. The ECLA (Estudios Cardiologicos Latinoamerica) Collaborative Group. Circula-
tion 98:2227-2234
42. King LM, Opie LH (1998) Glucose delivery is a major determinant of glucose utilisation
in the ischemic myocardium with a residual coronary flow. Cardiovasc Res 39:381-392
43. Apstein CS (1998) Glucose-insulin-potassium for acute myocardial infarction: remarkable
results from a new prospective, randomized trial. Circulation 98:2223-2226
44. Tian R, Abel ED (2001) Responses of GLUT4-deficient hearts to ischemia underscore the
importance of glycolysis. Circulation 103:2961-2966
45. Feldhaus LM, Liedtke AJ (1998) mRNA expression of glycolytic enzymes and glucose trans-
porter proteins in ischemic myocardium with and without reperfusion. J Mol Cell Cardiol
30:2475-2485
46. SchaeferS, Ramasamy R (1997) Glycogen utilization and ischemic injury in the isolated rat
heart. Cardiovasc Res 35:90-98
47. Swanson RA, Farrell K, Stein BA (1997) Astrocyte energetics, function, and death under
conditions of incomplete ischemia: a mechanism of glial death in the penumbra. Glia
21:142-153
48. Mochizuki S, Neely JR (1979) Control of glyceraldehyde-3-phosphate dehydrogenase in car-
diac muscle. J Mol Cell Cardiol11:221-236
49. Zhang J, Snyder SH (1992) Nitric oxide stimulates auto-ADP-ribosylation of glyceralde-
hyde-3-phosphate dehydrogenase. Proc Natl Acad Sci USA 89:9382-9385
50. Knight RJ, Kofoed KF, Schelbert HR, Buxton DB (1996) Inhibition of glyceraldehyde-3-
phosphate dehydrogenase in post-ischaemic myocardium. Cardiovasc Res 32:1016-1023
51. Zierath JR, Krook A, Wallberg-Henriksson H (2000) Insulin action and insulin resistance
in human skeletal muscle. Diabetologia 43:821-835
890 S. Karyampudi and M. Singer: Glycolysis in Sepsis and other Stress Conditions
52. DeFronzo RA, Jacot E, Jequier E, Maeder E, Wahren J, Felber JP (1981) The effect of insu-
lin on the disposal of intravenous glucose. Results from indirect calorimetry and hepatic
and femoral venous catheterization. Diabetes 30:1000-1007
53. Song XM, Kawano Y, Krook A, et al (1999) Muscle fiber type-specific defects in insulin sig-
nal transduction to glucose transport in diabetic GK rats. Diabetes 48:664-670
54. Zierath JR, Galuska D, Nolte LA, Thorne A, Kristensen JS, Wallberg-Henriksson H (1994)
Effects of glycaemia on glucose transport in isolated skeletal muscle from patients with
NIDDM: in vitro reversal of muscular insulin resistance. Diabetologia 37:270-277
55. Cave AC, Ingwall JS, Friedrich J, et al (2000) ATP synthesis during low-flow ischemia: in-
fluence of increased glycolytic substrate. Circulation 101:2090-2096
56. Van den Berghe G, Wouters P, Weekers F, et al (2001) Intensive insulin therapy in the criti-
cally ill patient. N Engl J Med 345:1359-1367
57. Lazar HL (1997) Enhanced preservation of acutely ischemic myocardium and improved
clinical outcomes using glucose-insulin-potassium (GIK) solutions. Am J Cardiol 80:90A-
93A
Dehydroepiandrosterone (DHEA}
and its Sulfate (DHEAS) in Critical Illness
A. Beishuizen and A. B. J. Groeneveld
1 Introduction
Dehydroepiandrosterone (DHEA) is the most abundant circulating hormone in the
human body and can be converted to either androgens or estrogens. It is readily
conjugated to its sulfate ester, DHEAS, and they are designated as DHEA(S) here
when used together [1]. DHEA has received considerable attention in the lay and
scientific press for its anti-aging effects and as mediator of several diseases. A num-
ber of reports have suggested that DHEAS levels are inversely related to cardiovas-
cular disease and mortality, but findings have not been consistent [2]. In the USA,
DHEA is currently available as an over-the counter drug; as a precursor of testos-
terone, entitled as a "fountain of youth" [3] or "the last elixir".
The physiological role and biological actions of DHEA(S) are not well known. At
present, the only proven indication for administration of DHEA is adrenal insuffi-
ciency with favorable effects on well-being, mood, and sexuality [4].
However, recent studies have shown that adrenal androgens are capable of mod-
ulating the host response following major illnesses such as trauma [3], and DHEA
is thought to play an important role in the complex interaction between the neu-
roendocrine and the immune system during critical illness [5-9]. Several investiga-
tors have indicated that DHEA could potentially be used as adjunctive therapy for
sepsis, infections, trauma, shock, and major blood loss in order to reduce morbid-
ity and mortality [5, 10, 11].
In this chapter, we will address the metabolism and physiology of DHEA and
discuss the potential use of DHEA in the treatment of critically ill patients, target-
ing immune depression organ dysfunction.
I Physiology of DHEA(S)
Metabolism
Adrenal steroids are derived from pregnelone, which in turn is synthesized largely
from cholesterol. DHEA is an important intermediate in the sex steroid pathway
(Fig. 1). The conjugation of DHEA to DHEAS is mediated by sulfotransferase, and
the reverse reaction is mediated by sulfatase [3, 12]. DHEA(S) can be converted in
the adrenal gland and peripheral tissues to the more potent androgens such as tes-
tosterone, dihydrotestosterone, androstenedione and estrogens. DHEA(S) is synthe-
sized by the enzyme cytochrome P450C17 that catalyzes both the hydroxylation of
892 A. Beishuizen and A. B. J. Groeneveld
DHEAS - STS
DHEA -ST
DHEA
13{3-HSD
aromatase
Androstenedione Estrone
17{3-HSD ll aromatase
117{3-HSD
Testosterone 17(3-estradiol
Sa-reductase 1
Sa- dihydrotestosterone
Fig. 1. DHEA(S) metabolism: conversion of DHEA(S) to androgens and estrogens. Abbreviations: DHEA-ST,
DHEA-sulfotransferase; STS, sulfotransferase; 3 and 17P-HSD, 3 and 17P-hydroxysteroid dehydrogenase
the C17 pregnenolone (17a-hydroxylase activity) and cleavage of the residual two
carbon side-chain at C17 (17,20-lyase activity) in the adrenal zona reticularis. The
dual function of this enzyme allows direction of the steroid precursors along sev-
eral different pathways. The steroidogenic enzyme P450C17 converts virtually no
17a-hydroxyprogesterone to androstenedione; therefore, the biosynthesis of all sex
steroids in humans proceeds through DHEA. Only DHEA can be converted to an-
drostenedione by the activity of 3P-hydroxysteroid dehydrogenase {3,8HSD), and
then further converted to testosterone and estradiol (Fig. 1). Whereas DHEAS is the
hydrophilic storage form that circulates in the blood, only lipophilic DHEA can be
converted intracellularly to androgens and estrogens. Thus, tissue specific synthesis
of DHEA sulfotransferase and steroid sulfatase determines the ratio of DHEA acti-
vation (by conversion to sex steroids) to transient DHEA inactivation (by secretion
of the sulfate ester back into the bloodstream). DHEA and DHEAS undergo contin-
uous interconversion.
Secretion
Humans and other primates are the only species with the capacity to synthesize and
secrete DHEA(S) in quantities surpassing all other known steroids [13]. There is a
unique age-related adrenal secretory pattern for DHEA(S) during the human life span.
Fetal adrenals produce massive amounts of DHEA(S). At birth, the fetal zone of the
adrenals regresses, and the zona reticularis only starts to synthesize DHEA(S) again
at 5 to 7 years of age, defining the adrenarche. Thereafter, there is an accelerated in-
crease through the period of puberty, and the maximum blood concentration is
reached during the third decade of life, with serum levels for men being higher than
for woman. Then blood levels decline (2%/year) leaving a residual value of 10-20% at
age eighty [3,14]. The age-related decline in DHEA(S) secretion shows a high inter-
individual variability and is accompanied by a reduction in the size of the zona reti-
cularis. By contrast, serum cortisol concentrations can even increase with aging,
therefore contributing to an increase in the cortisol:DHEA(S) ratio.
Dehydroepiandrosterone (DHEA) and its Sulfate (DHEAS) in Critical Illness 893
Regulation
The main regulator of adrenal androgen production is pituitary ACTH; indeed, in
the absence of ACTH, adrenal androgen levels are low. However, there is no feed-
back control at the hypothalamo-pituitary level [3]. On the other hand, immune
(T cell)-endocrine (adrenal gland) interactions are involved in the stimulation of
adrenal androgen secretion [15]. DHEA oscillates with cortisol, but serum DHEAS
shows almost no diurnal variation, consistent with its low metabolic clearance rate
(13 I!day), the lowest of any steroid [3]. In the blood, DHEA and DHEAS are pri-
marily bound to albumin; only small amounts circulate in non-protein bound form.
DHEAS is relatively strongly bound to albumin and forms a circulating reservoir.
DHEA is probably more active at the tissue level [1]. The serum level of DHEAS
(j.tg/ml) is 300-500 times higher than that of DHEA (nglml) and 20 times higher
than of any other steroid hormone [1].
Mechanisms of Action
Although its exact physiological role remains to be established, DHEA serves as a
precursor for sex steroid metabolism. DHEA administration leads to a sexually di-
morphic pattern of conversion: significant increases of circulating androgens in
women and of circulating estrogens in men. It causes androgenic and estrogenic ef-
fects in men and women, respectively. In general, it is difficult to assess whether
the actions of DHEA are attributable to DHEA itself, to its metabolites, or to a
combination of both [16]. All immunomodulating effects might be mediated by ste-
roids derived from downstream conversion of DHEA, which effectively occurs in
human macrophages. Downstream DHEA receptors were recently identified on hu-
man T lymphocytes and monocytes [17]. It has also been postulated that DHEA is
an "anti-hormone" that cannot serve to excite in the true classical sense of hor-
mone action, but de-excites metabolic processes, which overproduce when DHEA is
in short supply [16, 18]. This is supported by data indicating that DHEA can modi-
fy stress-mediated injury by buffering or antagonizing the effects of glucocorticoids
[16, 18].
Effects of DHEA(S)
The effects of DHEA(S) are summarized in Table 1. The immunological effects of
DHEA(S) have not been studied adequately in humans. Epidemiological data show
that the decline of immunocompetence during aging correlates with decreasing
DHEAS levels. The administration of DHEAS results in the augmentation of anti-
body responses to foreign antigens and a reversal of dysregulated cytokine produc-
tion by T cells, including stimulation of interleukin (IL)-2 and reduction in IL-6
production [19]. DHEA is both an enhancer and a regulator of IL-2 production by
Th1 cells [18]. The lipopolysaccharide (LPS)-induced production of tumor necrosis
factor (TNF)-a was significantly blocked by DHEA, both in vivo and in vitro [20].
Another report showed that DHEA at physiological concentrations synergizes with
LPS to increase the production of proinflammatory cytokines, which suggests that
the effects of DHEA on TNF-a production are dose-dependent [17].
DHEA can be administered orally or parentally, including the transdermal route.
There is no rationale behind the oral administration of DHEAS because it will
largely be hydrolyzed to DHEA in the acidic milieu of the stomach [3]. After oral
Table 1. Effects of DHEA(S) on different organ systems
Organ system Effects Reference
CNS Neurosteroid with neurotrophic effects [16]

Neuroprotective in ischemic stroke [16]
Inverse association DHEAS and cognitive decline [1]
cvs inverse relation DHEA(S) and mortality [2]
'j? no protective effect on cardiovascular mortality [1]
I Coagulation 0 decrease PAl-l and tPA [16]
Metabolic system Inconsistent effects on lipid profiles and insulin sensitivity [16]
Skeleton Anabolic and antiosteolytic effects on bone [1]
I Immune system Stimulation of IL-2 production by Thl cells [18]
Reduction of IL-6 production [19, 36]
Reduction of TNF-a release [20]
Improved activity T cell immunity [5, 7]
Antiglucorticoid action [16, 39]
Enhancement of NK cell and monocyte cytotoxicity [17]
In mice: protection against a variety of infections [5, 7, 8, 20)
CNS: central nervous system; CVS: cardiovascular system; PAl-l: plasminogen activator inibitor type 1; tPA:
tissue plasminogen activator antigen; NK: natural killer
administration, DHEA is largely absorbed and converted to DHEAS in the hepatos-

planchic system, and the blood concentration of DHEAS increase rapidly.
I DHEA(S) in Critical Illness

DHEA(S) as a Diagnostic Marker
Clinical data have been obtained in a very large number of observational studies,
in which plasma concentrations of DHEA were measured in various situations. The
only established fact is that circulating concentrations show wide interindividual
variability and a tendency to fall with age. Low DHEA levels have not so far been
linked to any specific health disorders. Data on the role of DHEA(S) levels in criti-
cally ill patients are limited (Table 2). Parker et al. demonstrated a d ivergence in
adrenal steroid secretion; wherein serum cortisol was increased in thermally in-
jured adult men, whereas the serum DHEAS concentration was reduced [21] . Addi-
tional studies confirmed the decrease in DHEAS levels in critically ill men, but re-
ported increased levels of androstenedione [22, 23] or decreased levels of androste-
nedione [24] . Luppa et al. studied serum androgens in a large group of critically ill
patients and also found markedly decreased DHEAS levels in both males and fe-
males, mainly in the patients with a prolonged clinical course [25) . In postmeno-
pausal woman with acute critical illness, decreased levels of DHEAS and testoster-
one were found, whilst cortisol, androstenedione, and estrogen levels were in-
creased [26]. These data suggest that inhibition of adrenal androgen secretion pre-
Table 2. lnterventional studies in animals and humans with critical illness with DHEA
Refef'l!nce Subjects DHEA Model Effects

[20] CD-1 mice 100 mg/kg lethal dose of LPS mortality reduction, l TNF-a release
[S) 0 mice 30 mg/kg polymicrobial sepsis survival, l TNF-a release, j Tcell
immunity
[5) 0 mice 20 mg/kg hemorrhagic shock improved cellular immune function
[38) ~ mice 25 mg/kg burn injury reversal of susceptibility to infections
[9) pigs 4-20 mg/kg post-traumatic LPS no effect on SIRS or pulmonary
failure
[40) o rats 30 mg/kg trauma-hemorrhage restoration of hepatocellular function
and cardiac depression
[4) ~ humans 50 mg/day adrenal insufficiency improvement in well-being
and sexuality
[41) humans 50 mg·day adrenal insufficiency improved well-being, self-esteem,
fatigue
LPS: lipopolysaccharide
ferentially affects DHEA with a simultaneous effect on the peripheral production

and/or conversion of testosterone.
In contrast, experimental endotoxemia in healthy volunteers leads to an acute
rise in plasma DHEA levels, which was blunted by ibuprofen .[27]. The change in
DHEA(S) levels appears to be dose-dependant and in fact displays a complex tem-
poral pattern [28]. It was suggested that the elevation of DHEA was caused by stim-
ulation of the zona reticularis by ACTH and endotoxin-induced cytokines.
In a large study, Folan et al. found a remarkable association between DHEA(S)
levels and APACHE II scores in female ICU patients [29], which contrasted findings
by others [22, 25]. These discrepant findings of DHEA(S) levels may be explained
by duration of illness/stress and gender.
DHEAS as a Sign of Exhausted Adrenal Reserve

Recently, we looked at the time course of DHEAS (immunostimulator) compared to
cortisol (immunosuppressor), ACTH (inducer of DHEAS), and cytokines (stimula-
tors of the hypothalamo-pituitary-adrenal [HPA] axis) in patients with critical ill-
ness and matched controls. We found extremely low DHEAS levels in patients with
septic shock and to a lesser degree in multitrauma patients, confirming the already
mentioned dissociation between cortisol (increased) and DHEAS (decreased) [21].
Interestingly, we found the lowest DHEAS and the highest cortisol levels in non-
survivors and the most severely ill patients, indicating that the DHEAS/cortisol ra-
tio might be a prognostic indicator for the outcome of critical illness, in particular
septic shock. The sustained hypercortisolism during severe critical illness in the
presence of low DHEAS levels could theoretically evoke an imbalance between im-
munosuppressive and immunostimulatory pathways and may, therefore, have a role
in the increased susceptibility to infectious complications [1]. However, the inter-
pretation of cortisol values measured in critically ill patients is troublesome. Serum
cortisol levels that are regarded as high in healthy individuals may be inappropri-
ately low in some critically ill patients, indicating the presence of relative or func-
tional adrenal insufficiency [30, 31]. In the patients with a subnormal response to
extra stimulation by ACTH, considering that their HPA axis is already maximally
stimulated [31], significantly lower serum concentrations of DHEAS were observed,
indicating that the DHEAS depletion might be a sign of limited adrenocortical re-
serve arising during the course of critical illness. Therefore, we suggest that a low
DHEAS level might be a sign for an exhausted adrenal adaptation during critical
illness.
The dissociation between blood levels of cortisol and DHEAS seems to be a con-
tradiction, because both hormones are synthesized and secreted mainly by the
adrenal cortex. However, DHEAS is produced mainly in the zona reticularis of the
adrenal cortex, possibly indicating that a differential alteration in the cortical zone
is responsible for DHEAS deficiency during severe critical illness [32]. A dimin-
ished activity of 17,20-desmolase within the zona reticularis has been postulated,
but not proven [24, 25]. Although ACTH, the main regulator of adrenal glucocorti-
coid production, also stimulates adrenal androgen production, ACTH alone is un-
able to maintain a normal cortisol/androgen ratio. Furthermore, during prolonged
critical illness, dissociation between cortisol (high) and ACTH (low) develops, sug-
gesting non-ACTH pathways responsible for maintaining the sustained hypercorti-
solism [33]. These low ACTH concentrations may, at least in part, play a role in the
observed DHEAS depletion in the prolonged disease phase [34]. Dopamine infusion
strongly suppresses DHEAS concentrations in critically ill patients, without affect-
ing serum cortisol [35]. The suppressive effect of dopamine on DHEAS levels could
be linked to the concomitant suppression of circulating prolactin. We found a rela-
tion between dopamine use and DHEAS levels, but only during the acute phase of
illness. Furthermore, we found a strong negative correlation between IL-6 and
DHEAS in the acute phase. IL-6 levels decreased significantly in time, while DHEAS
concentrations remained low. In healthy subjects, serum IL-6 inversely correlated
with DHEAS and DHEA administration led to inhibition of IL-6 secretion from
monocytes, indicating a functional link between DHEAS and IL-6 [36]. In addition,
IL-6 can act synergistically with ACTH on the adrenal glands to release cortisol
[37]. IL-6 may, therefore, be a pivotal regulator of DHEAS and cortisol in critical
illness.
Animal Studies
The synthesis and production of DHEA(S) are unique features of humans and some
primates. Plasma DHEA levels are so low in most animal species that they are diffi-
cult to measure, hindering studies of the impact of DHEA. Nevertheless, most data
on DHEA(S) levels during sepsis or the immunological effects of DHEA-treatment
in experimental sepsis or inflammation are derived from animal models [17, 27,
38]. At pharmacological dosage, DHEA protects mice from a variety of lethal infec-
tions. The enhanced resistance to infection, as reported in most studies, may be re-
lated to the counteracting effects of DHEA on the immunosuppressive effects of
glucocorticoids [18, 38]. DHEA has been shown to reduce lethality after burn in-
jury or LPS administration in mice [8, 39]. Danenberg et al. found that the mortal-
ity of mice exposed to lethal doses of endotoxin was reduced from 95 to 24% by a
single dose of 100 mg/kg DHEA given 5 minutes before LPS [20].
The administration of DHEA at the end of fluid resuscitation in a large animal
trauma-hemorrhage model restored cardiac and hepatocellular functions [40]. In
---~--~~~~,--~--~~"~,-~
this study, plasma DHEA increased 20-fold, while 17/i-estradiol and testosterone
were unaltered, indicating that DHEA was directly responsible for the observed
beneficial effects. However, the effects on organ function were abolished using es-
trogen receptor antagonists, suggesting that DHEA directly uses the estrogen recep-
tor. Under similar conditions of trauma-hemorrhage the use of DHEA after fluid
resuscitation restored the cellular immunity [6]. After subsequent induction of
polymicrobial sepsis, mortality was decreased by continuing DHEA treatment. In
contrast, in another large-animal model of trauma and delayed sepsis, DHEA failed
to reduce pulmonary dysfunction and systemic inflammatory response syndrome
(SIRS) [9]. Oberbeck et al. demonstrated an increased survival, a reduction of
TNF-a release and improved activity of T cell immunity in a model of polymicro-
bial sepsis [5]. In addition, DHEA improved the depressed immune functions fol-
lowing trauma-hemorrhage and decreased the mortality of animals subjected to
subsequent sepsis [6]. It seems that DHEA can improve immune function and sur-
vival from subsequent sepsis, but not following the administration of endotoxin
[11]. Furthermore, DHEA can prevent some of the features of multiple organ dys-
function in animal models of hemorrhagic shock.
Human Studies
The potential therapeutic application of DHEA is broad, and it has been used in a
number of clinical settings such as neuropsychiatric disorders, multiple sclerosis,
systemic lupus erythematosus (SLE), aging, human immunodeficiency virus (HIV)
disease, coronary heart disease, ischemic stroke, colon carcinoma, and influenza
[16]. Variable effects have been reported in these diseases. At present, the only evi-
dence-based indication is the use of DHEA in patients with adrenal insufficiency
(Table 2) [41, 42]. However, the optimal dose of DHEA is unknown. Oral adminis-
tration of 25-50 mg DHEA in subjects with pathologically low serum DHEAS levels
restores the serum DHEA(S) to concentrations within the normal range of young
adults, whereas 100-200 mg per day leads to supraphysiological hormone concen-
trations. DHEA is an inexpensive and readily available drug. Even long-term ad-
ministration seems safe, well tolerated and with only mild and transient side effects
such as mild facial acne and increased serum production, reflecting increased an-
drogen production. However, some questions are unanswered: should one monitor
and normalize DHEA(S) levels or are beneficial effects related to an increase in lev-
els of androgens or other metabolites?
In spite of the observed beneficial effects of DHEA treatment in animal models
of sepsis or trauma-hemorrhage no human interventional studies in the critically
ill have been performed. It has been proposed to use short-term administration of
DHEA in male trauma patients as an adjunct to fluid therapy in order to improve
the depressed immunological and cardiovascular responses [11].
I Conclusion
The past few years have seen exciting progress in the field of DHEA research. Re-
placement of DHEA in patients with adrenal insufficiency has demonstrated the
important role of endogenous DHEA for well-being, mood and sexuality in hu-
mans, suggesting that the central nervous system is a major target for DHEA ac-
898 A. Beishuizen and A. B.J. Groeneveld
tion. In other clinical settings, such as advanced age, cardiovascular disease or SLE,
inconsistent beneficial effects have been reported. In the setting of critical illness, a
clear DHEA-deficiency state is present: the adrenal androgen production declines,
whereas adrenal cortisol production is maintained at a high level [21, 25]. DHEAS
levels are extremely low in septic shock and to a lesser degree in multitrauma,
when compared to age-gender matched controls. Non-survivors of sepsis and criti-
cally ill patients with abnormal responses to ACTH-testing had the lowest DHEAS
values, suggesting that DHEAS might be a prognostic marker and a sign for ex-
hausted adrenal reserve in critical illness.
DHEA is a proimmune and proinflammatory steroid hormone, which provides
an immunostimulatory influence opposing the effects of glucocorticoids. Hypercor-
tisolism in the prolonged phase of critical illness continues to exert its beneficial
hemodynamic effects, but the benefit for the host defense of a sustained hypercor-
tisolism in the presence of low DHEAS levels is questionable, as prolonged imbal-
ance between immunosuppressive and immunostimulatory hormones of adrenocor-
tical origin may participate in the increased susceptibility for infections [43].
Whether or not to substitute DHEA in DHEA(S)-deficient states such as sepsis or
trauma remains to be elucidated. In the light of the beneficial biological effects of
DHEA administration and the experimental indications that DHEA has salutary ef-
fects on depressed immune and organ functions, studies should be undertaken to
determine the clinical value of DHEA in the treatment of critically ill patients.
References
1. Ebeling P, Koivisto VA (1994) Physiological importance of dehydroepiandrosterone. Lancet
343:1479-1481
2. Trivedi DP, Khaw KT (2001) Dehydroepiandrosterone sulfate and mortality in elderly men
and women. J Clin Endocrinol Metab 86:4171-4177
3. Baulieu EE (1996) Dehydroepiandrosterone (DHEA): a fountain of youth? J Clin Endocrinol
Metab 81:3147-3151
4. Arlt W, Callies F, van Vlijmen JC, et al (1999) Dehydroepiandrosterone replacement in wo-
men with adrenal insufficiency. N Engl J Med 341:1013-1020
5. Oberbeck R, Dahlweid M, Koch R, et al (2001) Dehydroepiandrosterone decreases mortal-
ity rate and improves cellular immune function during polymicrobial sepsis. Grit Care
Med 29:380-384
6. Angele MK, Catania RA, Ayala A, Cioffi WG, Bland KI, Chaudry IH (1998) Dehydroepian-
drosterone: an inexpensive steroid hormone that decreases the mortality due to sepsis fol-
lowing trauma-induced hemorrhage. Arch Surg 133:1281-1288
7. Araneo BA, Shelby J, Li GZ, Ku W, Daynes RA (1993) Administration of dehydroepiandros-
terone to burned mice preserves normal immunologic competence. Arch Surg 128:318-325
8. Ben Nathan D, Padgett DA, Loria RM (1999) Androstenediol and dehydroepiandrosterone
protect mice against lethal bacterial infections and lipopolysaccharide toxicity. J Med Mi-
crobial 48:425-431
9. Schurr MJ, Fabian TC, Croce MA, Varnavas LE, Proctor KG (1997) Dehydroepiandroster-
one, an endogenous immune modulator, after traumatic shock. Shock 7:55-59
10. Loria RM, Inge TH, Cook SS, Szakal AK, Regelson W (1988) Protection against acute lethal
viral infections with the native steroid dehydroepiandrosterone (DHEA). J Med Virol
26:301-314
11. JarrarD, Kuebler JF, Wang P, Bland Kl, Chaudry IH (2001) DHEA: a novel adjunct for the
treatment of male trauma patients. Trends Mol Med 7:81-85
12. Parker LN (1991) Control of adrenal androgen secretion. Endocrinol Metab Clin North Am
20:401-421
---~--~~~~,--~--~~"~,-~
13. van Weerden WM, Bierings HG, van Steenbrugge GJ, de Jong FH, Schroder FH (1992)
Adrenal glands of mouse and rat do not synthesize androgens. Life Sci 50:857-861
14. Orentreich N, Brind JL, Vogelman JH, Andres R, Baldwin H (1992) Long-term longitudinal
measurements of plasma dehydroepiandrosterone sulfate in normal men. J Clin Endocrinol
Metab 75:1002-1004
15. Wolkersdorfer GW, Lohmann T, Marx C, et a! (1999) Lymphocytes stimulate dehydroepian-
drosterone production through direct cellular contact with adrenal zona reticularis cells: a
novel mechanism of immune-endocrine interaction. J Clin Endocrinol Metab 84:4220-4227
16. Regelson W, Kalimi M (1994) Dehydroepiandrosterone (DHEA) - the multifunctional ste-
roid. II. Effects on the CNS, cell proliferation, metabolic and vascular, clinical and other ef-
fects. Mechanism of action? Ann NY Acad Sci 719:564-575
17. McLachlan JA, Serkin CD, Bakouche 0 (1996) Dehydroepiandrosterone modulation of lipo-
polysaccharide-stimulated monocyte cytotoxicity. J Immunol 156:328-335
18. Regelson W, Loria R, Kalimi M (1994) Dehydroepiandrosterone (DHEA) - the "mother
steroid". I. Immunologic action. Ann NY Acad Sci 719:553-563
19. Daynes RA, Araneo BA, Ershler WB, Maloney C, Li GZ, Ryu SY (1993) Altered regulation
of IL-6 production with normal aging. Possible linkage to the age-associated decline in de-
hydroepiandrosterone and its sulfated derivative. J Immunol 150:5219-5230
20. Danenberg HD, Alpert G, Lustig S, Ben Nathan D (1992) Dehydroepiandrosterone protects
mice from endotoxin toxicity and reduces tumor necrosis factor production. Antimicrob
Agents Chemother 36:2275-2279
21. Parker LN, Levin ER, Lifrak ET ( 1985) Evidence for adrenocortical adaptation to severe ill-
ness. J Clin Endocrinol Metab 60:947-952
22. Wade CE, Lindberg JS, Cockrell JL, et a! (1988) Upon-admission adrenal steroidogenesis is
adapted to the degree of illness in intensive care unit patients. J Clin Endocrinol Metab
67:223-227
23. Semple CG, Gray CE, Beastall GH (1987) Adrenal androgens and illness. Acta Endocrinol
(Copenh) 116:155-160
24. Lephart ED, Baxter CR, Parker CR, Jr (1987) Effect of burn trauma on adrenal and testicu-
lar steroid hormone production. J Clin Endocrinol Metab 64:842-848
25. Luppa P, Munker R, Nagel D, Weber M, Engelhardt D (1991) Serum androgens in inten-
sive-care patients: correlations with clinical findings. Clin Endocrinol (Oxf) 34:305-310
26. Spratt DI, Longcope C, Cox PM, Bigos ST, Wilbur-Welling C (1993) Differential changes in
serum concentrations of androgens and estrogens (in relation with cortisol) in postmeno-
pausal women with acute illness. J Clin Endocrinol Metab 76:1542-1547
27. Bornstein SR, Wolkersdorfer GW, Tauchnitz R, Preas· HL, Chrousos GP, Suffredini AF
(2000) Plasma dehydroepiandrosterone levels during experimental endotoxemia and anti-
inflammatory therapy in humans. Crit Care Med 28:2103-2106
28. Schuld A, Mullington J, Friess E, et a! (2000) Changes in dehydroepiandrosterone (DHEA)
and DHEA-sulfate plasma levels during experimental endotoxinemia in healthy volunteers.
J Clin Endocrinol Metab 85:4624-4629
29. Folan MM, Stone RA, Pittenger AL, Stoffel JA, Hess MM, Kroboth PD (2001) Dehydro-
epiandrosterone, dehydroepiandrosterone-sulfate, and cortisol concentrations in intensive
care unit patients. Crit Care Med 29:965-970
30. Beishuizen A, Thijs LG (2001) Relative adrenal failure in intensive care: an identifiable
problem requiring treatment? Best Pract Res Clin Endocrinol Metab 15:513-531
31. Beishuizen A, Vermes I, Hylkema BS, Haanen C (1999) Relative eosinophilia and functional
adrenal insufficiency in critically ill patients. Lancet 353:1675-1676
32. Parker CR Jr, Slayden SM, Azziz R, et a! (2000) Effects of aging on adrenal function in the
human: responsiveness and sensitivity of adrenal androgens and cortisol to adrenocortico-
tropin in premenopausal and postmenopausal women. J Clin Endocrinol Metab 85:48-54
33. Vermes I, Beishuizen A, Hampsink RM, Haanen C (1995) Dissociation of plasma adreno-
corticotropin and cortisol levels in critically ill patients: possible role of endothelin and at-
rial natriuretic hormone. J Clin Endocrinol Metab 80:1238-1242
34. Beishuizen A, Thijs LG, Vermes I (2002) Decreased levels of dehydroepiandrosterone sul-
phate in severe critical illness: a sign of exhausted adrenal reserve? Crit Care 6:434-438
900 A. Beishuizen and A. B. J. Groeneveld: Dehydroepiandrosterone (DHEA) and its Sulfate (DHEAS)
35. van den Berghe G, de Zegher F, Wouters P, et al (1995) Dehydroepiandrosterone sulphate

in critical illness: effect of dopamine. Clin Endocrinol (Oxf) 43:457-463
36. Straub RH, Konecna L, Hrach S, et a! (1998) Serum dehydroepiandrosterone (DHEA) and
DHEA sulfate are negatively correlated with serum interleukin-6 (IL-6), and DHEA inhibits
IL-6 secretion from mononuclear cells in man in vitro: possible link between endocrinose-
nescence and immunosenescence. J Clin Endocrinol Metab 83:2012-2017
37. Mastorakos G, Chrousos GP, Weber JS (1993) Recombinant interleukin-6 activates the hy-
pothalamic-pituitary-adrenal axis in humans. J Clin Endocrinol Metab 77:1690-1694
38. Gennari R, Alexander JW (1997) Arginine, glutamine, and dehydroepiandrosterone reverse
the immunosuppressive effect of prednisone during gut-derived sepsis. Crit Care Med
25:1207-1214
39. Araneo B, Daynes R (1995) Dehydroepiandrosterone functions as more than an antigluco-
corticoid in preserving immunocompetence after thermal injury. Endocrinology 136:393-
401
40. Jarrar D, Wang P, Cioffi WG, Bland KI, Chaudry IH (2000) Mechanisms of the salutary ef-
fects of dehydroepiandrosterone after trauma-hemorrhage: direct or indirect effects on car-
diac and hepatocellular functions? Arch Surg 135:416-422
41. Hunt PJ, Gurnell EM, Huppert FA, et al (2000) Improvement in mood and fatigue after de-
hydroepiandrosterone replacement in Addison's disease in a randomized, double blind
trial. J Clin Endocrinol Metab 85:4650-4656
42. Callies F, Fassnacht M, van Vlijmen JC, et al (2001) Dehydroepiandrosterone replacement
in women with adrenal insufficiency: effects on body composition, serum leptin, bone
turnover, and exercise capacity. J Clin Endocrinol Metab 86:1968-1972
43. Van den Berghe G, de Zegher F, Bouillon R (1998) Clinical review 95: acute and prolonged
critical illness as different neuroendocrine paradigms. J Clin Endocrinol Metab 83:1827-
1834
Vasopressin and Hypothalamic-Pituitary-Adrenal
Axis Relationships
F. Lauzier, N. Gallo-Payet, and 0. Lesur
I Introduction
The relationship between vasopressin and the hypothalamo-pituitary-adrenal (HPA)
axis has been established for many years, one that occurs at almost every level of
the HPA axis, as described in a recent review [1]. Unfortunately, few clinical impli-
cations have been drawn from this finding, until now. Many fundamental studies
have demonstrated the complexities of these physiological interactions. In an era of
renewed interest for vasopressin and corticosteroid supportive therapies in sepsis
[2, 3], the time has come for critical care specialists to gain better insight into how
these two important hormonal systems interact together in physiological condi-
tions. The present chapter is aimed at extrapolating this knowledge to septic set-
tings and targeting specific queries and areas of future research.
I Vasopressin: an Overview
Vasopressin is a nonapeptide produced mainly by the supraoptic and paraventricu-
lar nuclei of the hypothalamus (Fig. 1). More specifically, the synthesis of vasopres-
sin occurs in two types of neurons: magnocellular (in both hypothalamic nuclei)
and parvocellular (in the paraventricular nucleus only). The magnocellular system
communicates directly with the neurohypophysis (also called posterior pituitary)
while the parvocellular system communicates with the adenohypophysis through
the median eminence and the long portal vessels [1]. The neurohypophysis, which
serves as a reservoir for vasopressin, can also communicate with the anterior pitu-
itary via short portal vessels [4].
Vasopressin exerts its physiological effect by binding to three different receptors,
all coupled to the G protein superfamily of receptors [5]. The V1a receptor (V1aR),
located primarily in the vascular smooth muscle, induces vasoconstriction (Table 1).
This receptor is also found in several other tissues such as liver, kidney, brain, spleen,
myometrium, bladder and adrenals glands [6]. The V1b receptor (V1bR), also called
the V3 receptor, is located in the anterior pituitary corticotropes and is responsible for
the effects of vasopressin on ACTH secretion. Stimulation of these receptors induces
phosphoinositide breakdown via Gq111 coupling to phospholipase C and generation of
the two second messengers inositol triphosphate and diacylglycerol, which respec-
tively increase intracellular calcium and activate protein kinase C. Finally, the V2 re-
ceptor (V2R) is responsible for water retention by the renal collecting tubule system
through activation of a Gs protein and adenylyl cyclase, leading to production of cy-
clic adenosine monophosphate (cAMP).
902 F. Lauzier et al.
Parvocellular neurons
Optic chiasma
Adrenal zona ----1------::~

glomerulosa
Adrenal zona --lc+-F=--

fasciculata
Fig. 1. Vasopressin (AVP) and hypothalamic-pituitary-adrenal axis relationships. CRH: corticotropin releas-
ing hormone; ACTM: adrenocorticotropic hormone
The secretion of vasopressin by the magnocellular system is under control of

several stimili, all of which can be classified into three main categories of regula-
tion (for review see [3]): osmotic, hemodynamic and hormonal regulation. While
osmotic stimuli are dependent on osmoreceptors located centrally and peripherally
(hepatic portal vein communicating with the brain via the vagus nerve), hemody-
namic regulation is governed by volume (baroreceptors of the atrium and ventri-
Vasopressin and Hypothalamic-Pituitary-Adrenal Axis Relationships 903
Table 1. Vasopressin receptors
Vl a receptor Vl b receptor V2 receptor
Coupling Gq/Phospholipase C Gs/adenylyl cyclase

Messenger Inositol tri-phosphate and diacylglycerol Cyclic AMP
Localization
- Principal Smooth muscle cells Adenohypophysis Renal collecting duct
- Secondary Adrenal cortex and medulla, Adrenal medulla Platelets
Liver, kidney, brain, spleen, bladder, Endothelium
Myometrium
Effects
- Principal Vasoconstriction ACTH secretion Water reabsorption
- Secondary CRF secretion (adrenal medulla) Catecholamines secretion Platelet aggregation
Cortisol secretion
Aldosterone secretion
des, inhibitory effect) and blood pressure stimuli (baroreceptors of the the aortic
arch and carotid sinuses, stimulatory effect). Hormonal regulation involves many
other stimuli such as corticotropin releasing hormone (CRH) [7-9], adrenocortico-
tropic hormone (ACTH) [10], cortisol, PaC0 2, Pa02 , histamine, prostaglandins, do-
pamine, norepinephrine, phenylephrine, acetylcholine and angiotensin II (ATII)
(for review see [3, 11]). Interaction between these various regulatory categories is
well documented. In fact, osmotically-induced vasopressin release into the periph-
eral circulation is dependent on stimulation of angiotensin receptor type 1 (AT 1),
found in the cerebral periventricular aera and in supraocptic/paraventricular nuclei
[12]. The effects of CRH, ACTH and cortisol on vasopressin are discussed in the
following sections.
I Effect of CRH on Vasopressin Secretion

Many studies have demonstrated that CRH stimulates vasopressin neurons [7-9]. In
fact, in conscious dogs submitted to hyperosmolality, administration of CRH pro-
voked a greater increase in vasopressin response than hypertonic saline alone [7].
Indirect data indicate that CRH may act directly on vasopressin secretion. Indeed,
dogs exposed to CRH and hypertonic saline secreted more vasopressin at equal
ACTH levels than dogs solely exposed to CRH. In humans, differing CRH proper-
ties have been observed. CRH administration (2 11g/kg IV) in human volunteers did
not increase vasopressin levels [13]. However, a vasopressin response to hypertonic
saline infusion was clearly increased by concomitant CRH administration [9]. These
effects may be mediated through CRH type 1 and type 2 receptors located in the
supraoptic and paraventricular nuclei of the hypothalamus [14].
I Effect of ACTH on Vasopressin Secretion

Few studies have addressed the effect of ACTH on vasopressin secretion. However,
short-loop feedback effects of ACTH on CRH and vasopressin secretion have been
clearly demonstrated [10 ]. When exposed to a high chronic dose of ACTH, the
number of detectable CRH and vasopressin-immunoreactive cells in the parvocellu-
lar paraventricular nucleus of adrenalectomized/hypophysectomized rats is notice-
ably decreased [10]. Strangely, no effect of ACTH on CRH and vasopressin mRNA
expression has been observed. It is unclear however if ACTH exerts its negative
feedback directly on vasopressin synthesis or through CRH inhibition.
I Effect of Corticosteroids on Vasopressin Secretion

Many studies have explored the negative feedback of glucocorticoids on vasopressin
secretion. It has recently been established that glucocorticoid inhibition of vaso-
pressin secretion under osmotic stimuli occurs via a glucocorticoid receptor located
either in the hypothalamus or the neurohypophysis [15]. When exposed to a hyper-
tonic solution, rat hypothalamo-pituitary explants are unable to secrete vasopressin
if pre-treated with glucocorticoid [15]. This inhibition is totally reversible if gluco-
corticoid is co-administrated with the glucocorticoid antagonist RU-486. Interest-
ingly, under chronic stress conditions, glucocorticoids increase V1b receptor mRNA
levels on parvocellular neurons, enhance V1bR binding capacities, and facilitate
coupling to phospholipase C [16]. This receptor up-regulation is also associated
with greater vasopressin-stimulated ACTH production in vivo than in controls. It
can be extrapolated that even though cortisol exerts negative feedback on plasma
vasopressin levels, it preserves adenohypophysis corticotrophic response capabil-
ities during chronic stress by up-regulating V1b receptors.
Concurrently, in vivo experiments have clearly demonstrated that glucocorticoids
inhibit vasopressin secretion under various conditions. Basal vasopressin levels are
blunted in Crhr r 1- mice when exposed to corticosterone replacement therapy [17].
Moreover, chronic administration of glucocorticoids to conscious dogs decreases
basal vasopressin independent of osmotic or hemodynamic status [18] and also
blocks the normal expected increase in vasopressin in dogs exposed to hypertonic
saline [19]. On the other hand, acute administration of glucocorticoid acts differ-
ently; it inhibits hypotension/hypoxemia-induced vasopressin secretion, but is un-
able to do so during hypertonic stress [20].
Similar observations have been reported in humans as well. Inappropriate secre-
tion of vasopressin occurs in both untreated hypopituitarism [21] and Addison's
disease [22], even in the absence of hypovolemia. Glucocorticoid supplement thera-
py almost completely corrects vasopressin levels and hyponatremia in these pa-
tients. The negative feedback of the adrenal gland on vasopressin appears to be re-
lated to cortisol, since withdrawal of fludrocortisone (mineralocorticoid) does not
alter vasopressin levels or natremia in Addison's disease [23]. In summary, physio-
logical repletion of glucocorticoid inhibits the basal increase in vasopressin ob-
served in human adrenal insufficiency (either primary, secondary, or tertiary),
while acute administration of glucocorticoid inhibits the vasopressin response to
hemodynamic stress in animals (see also Fig. 1).
I Effect of Vasopressin on the Anterior Pituitary

Having explored the effect of the HPA axis on vasopressin secretion, we will now
focus on vasopressin actions on the HPA complex. Vasopressin has been established
for many years as a secretagogue of ACTH in normal conditions [24]. As stated
above, this action is mediated by V1b receptors, abundantly present in the adeno-
hypophysis. Although V1a and V1b receptors basically share the same cascade of
second messengers, V1b receptors exhibit a lower affinity for some vasopressin
agonists, indicating distinct properties [25]. The V1b receptor has also been re-
cently cloned [26]. In CRH receptor 1-deprived mice, basal ACTH levels are normal,
but blocking V1b receptors in these mice significantly decreased basal levels of
ACTH [17]. Moreover, paraventrical nuclei of Crhr1- mice exhibited an increase in
vasopressin messenger RNA expression as well as an increment in vasopressin-like
immunoreactivity in the median eminence [17].
In humans, IM administration of 10 U vasopressin in volunteer subjects induced
a mean peak increment in ACTH of 6.3 pg/ml at 40 minutes [27], followed by are-
turn to basal levels after approximately 60 minutes. This increase in ACTH was im-
mediately followed by a drastic rise in cortisol levels (peak of 36.3 pg/ml at 40 min-
utes). When co-administered with vasopressin, CRH (1 f.Lg/kg, IV) induced a further
5-fold increase in ACTH compared to CRH alone {75.0 pglml vs 14.6 pg/ml). This
particular experiment demonstrates that IM vasopressin injection is a potent stimu-
lus of ACTH secretion both alone and by acting synergistically with CRH in nor-
mal conditions. In contrast, another study in humans demonstrated that achieve-
ment of vasopressin plasma levels similar to those observed in water-deprived sub-
jects {6.5 to 7.3 pmol/1) with vasopressin IV infusion had no effect on either ACTH
or cortisol secretion [28]. Nevertheless, by infusing doses of 100 and 300 nglmin to
these volunteers, plasma levels increased to 60 and 239 pmol/1 respectively. This
was accompanied by a moderate increase in both ACTH (maximum levels: 4.4 and
8.7 pmol/1) and cortisol (maximum levels: 209 and 348 nmol/1. In contrast to corti-
sol, which increased progressively during the 1-hour vasopressin infusion, ACTH
increase was blunted 30 minutes after the onset of the experiment. It must be
noted, however, that severe hemorrhage can also incur similar vasopressin levels to
those elicited with high-dose vasopressin infusion.
While the CRH response is important in maintaining adequate ACTH levels in
stressful conditions, the vasopressin response also appears to be primordial. Rivier
and Vale demonstrated that blockage of vasopressin receptors of ether-stressed rats
decreases plasma ACTH levels [29]. Moreover, it has been shown that neurohypo-
physectomized dogs rendered hypotensive with nitroprusside exhibit clearly
blunted responses in vasopressin, ACTH and cortisol augmentation [30]. Bolus ad-
ministration of vasopressin completely restored the response of ACTH and cortisol
to stress, while physiological basal repletion of vasopressin did not. Interestingly,
the parvocellular neurons were shown to be functional (as proven by a normal in-
crease in ACTH when animals were submitted to CRH) in this model. A cephalic
action on magnocellular neurons was necessary to maintain the interaction be-
tween vasopressin and ACTH during hypotension. In fact, peripheral IV injection
of vasopressin was not as effective as intracarotid infusion in restoring the normal
stress response of the HPA axis [31]. Together, these data indicate that vasopressin
may be primordial in preserving HPA axis integrity during stressful conditions.
While parvocellular vasopressin and CRH play a major role in the ACTH response
to stress, the acute rise in magnocellular vasopressin secretion appears essential in

preserving physiological conditions (Fig. I).
I Effect of Vasopressin on the Adrenal Gland
In addition to its role on the hypothalamo-pituitary complex, several data indicate

that vasopressin may act directly on the adrenal gland, both on the cortex and on
the medulla (Fig. 1).
Action of Vasopressin on the Adrenal Cortex

In the adrenal zona glomerulosa, vasopressin stimulates both mitotic activity and
aldosterone secretion. After initial in vivo studies indicated that vasopressin may
be a growth-promoting factor for the external zona glomerulosa [33] or stimulate
aldosterone secretion in dogs [34, 35], further in vitro studies confirmed the direct
action of vasopressin in these processes, which are mediated through the VIa re-
ceptor subtype. These actions have been described in many species, including man
(for review see [36]).
From a morphological perspective, one of the major properties of the adrenal
gland, and particularly of glomerulosa cells, is the high degree of plasticity, where
cell proliferation, migration and steroidogenesis interplay to control homeostasis
and adaptive responses to metabolic disorders, such as stress [37] or sodium-defi-
cient situations [38]. Interestingly, vasopressin induces a high rate of mitotic activ-
ity in the zona glomerulosa, resulting in a large increase in growth of this zone
after six days of treatment, as observed for sodium-deficient dietary conditions [33,
36].
Several in vivo reports suggest a role of vasopressin in the regulation of adrenal
steroid secretion. Indeed, by treating dexamethasone-exposed rats (ACTH-depleted)
with vasopressin, adrenal cortex atrophy can be prevented [39]. In addition, Brattle-
boro rats (vasopressin-deprived) exhibit a decrease in aldosterone levels, in spite of
normal ACTH secretion [40]. In vitro evidences further confirmed that vasopressin
stimulates steroid secretion by approximately two fold, which is much lower than
that observed with ACTH (ten to twenty fold increase), but similar to that observed
with angiotensin II [4I]. However, although VIa receptors are found in the zona
fasciculata of all species, vasopressin stimulates cortisol [4I, 42] but not corticoster-
one secretion [43]. Thus, the presence of VIa receptors in rodents (rat) is not yet
correlated with any particular functional activity. These observations suggest that
vasopressin may act directly on the activity of the P450aldo (also called
P450C11B2) to stimulate aldosterone, and on the P450 CI7 hydroxylase activity
(only found in cortisol-secreting species) to convert pregnenolone (PS) into 17a-
OH-P5, necessary for further processing into cortisol.
In chronically water-deprived dogs (with high basal levels of vasopressin, angio-
tensin II and plasma renin activity), ACTH is more efficient in increasing plasma
glucocorticoid concentrations than in water-repleted dogs [44]. This greater ability
appears to be mediated through the VI receptor since co-administration of a Vl re-
ceptor antagonist (but not of angiotensin II antagonist) restored normal cortisol se-
cretion. At similar ACTH concentrations, neurohypophysectomized dogs exposed to
CRH demonstrated a clearly blunted glucocorticoid response compared to normal
---~--~~~~,--~--~~'"~,-~
dogs [45]. These animals, when treated with ACTH, showed a lesser increase in
glucocorticoid than control dogs, which suggests an independent vasopressin action
on the regulation of adrenal secretion regulation [30]. This action appears to re-
quire the presence of ACTH, however. In fact, dexamethasone-treated dogs (with
abolished ACTH levels) did not secrete cortisol in response to vasopressin injection
[46]. Upon restoring normal ACTH levels, vasopressin infusion resulted in stimula-
tion of glucocorticoids. In contrast, humans with surgically treated Cushing's dis-
ease exhibited slightly higher cortisol levels when exposed to CRH (100 J-Lg IV tid)
and vasopressin (10 VI IM tid) for three days, along with constantly low ACTH lev-
els [47]. These results suggest that CRH and/or vasopressin act independently of
the pituitary source of ACTH and can act directly on the adrenal gland in a human
in vivo model of ACTH deficiency. Meanwhile, a contradicting study conducted in
healthy humans suggests that vasopressin-induced cortisol secretion is fully
mediated by ACTH [48]. In fact, the linear correlation between cortisol secretion
and ACTH levels appears to be the same in both vasopressin-treated and ACTH-
treated volunteers. Unfortunately, in spite of the fact that in vitro experiments
clearly demonstrate a direct action of vasopressin on the adrenal gland and that in
vivo manipulation in various animal models support this physiological effect, simi-
lar implications in humans under acute stress conditions have yet to be clearly
demonstrated.
Vasopressin and the Adrenal Medulla

The presence of vasopressin in chromaffin cells has been reported in several mam-
malian species, including rat, hamster, cow, guinea pig, and humans. Vasopressin-
positive chromaffin cells were identified not only in the medulla, but also through-
out the cortex, mainly in medullary rays and in the zona glomerulosa (for review
see [36, 49, 50]). Moreover, recent data indicate the presence of both Vla and Vlb
receptors [49, 50] whereby Vlb receptors present in chromaffin cells mediate cate-
cholamine secretion, while Vla receptors are expressed in non-parenchymal cells
(blood vessel wall).
The presence of high concentrations of vasopressin, in both rat and human
adrenal medulla [49, 51] strongly suggests that adrenocortical function is under
paracrine medullar control. Indeed, corticotropin releasing factor (CRF) is found in
the medulla and its administration, alone or in combination with vasopressin, can
stimulate ACTH secretion from chromaffin cells, which in turn has been described
to also act on the cortex
Potential Relationship between Vasopressin

and Corticosteroids in Sepsis
At present, extrapolating this substantial basin of knowledge to septic conditions
remains difficult. Both relative adrenal insufficiency [52] and vasopressin [53] de-
pletion have been described in septic shock. Pathophysiological explanations for
these phenomenons are still controversial [54]. For instance, tumor necrosis factor
(TNF)-a, an inflammatory mediator implicated in sepsis pathophysiology, impairs
adrenal synthesis, while corticostatin, a peptide released by immune cells during
infection, inhibits corticotropin activity. Peripheral resistance to glucocorticoids
may also be involved [54]. Hemorrhaging, necrosis, platelet aggregation, and mi-
crothrombi are a common occurrence throughout the adrenal cortex during sepsis
and could certainly be partially responsible for adrenal failure. Only a few studies
have explored the potential implication of secondary adrenal insufficiency. Why is
it septic patients have similar ACTH levels compared to healthy subjects throughout
their evolution [55]? By administering 200 1-1g of CRH to these patients, ACTH
achieved similar increments to those observed in normal subjects. If it is assumed
that the CRH response is preserved during sepsis, then failure of ACTH to increase
under this stressful condition could be explained by the relative absence of other
corticotrophic-releasing peptides, such as vasopressin. Fortunately, adrenal insuffi-
ciency is reversible upon resolution of acute illness and is, of course, treatable.
During septic shock, administration of low doses of hydrocortisone with fludrocor-
tisone for at least seven days decreases mortality [2]. On the other hand, the conse-
quences of this therapy on actual vasopressin levels are unknown.
In contrast, low-dose vasopressin replacement appears to be in vogue in many
intensive care units (ICUs) since vasopressin deficiency has been described in
many reported cases [53]. While not clearly understood, vasopressin deficiency
seems to be explained by autonomic dysfunction observed in sepsis [3]. Restoration
of physiological levels of this hormone leads to strong vasoconstriction, to partial
and sometimes total reversal of catecholamine resistance, and finally better urine
output and creatinine clearance [56]. Unfortunately, there are no studies at this
time exploring the potential action of vasopressin on the HPA axis in sepsis. It is
unknown whether the positive feedback exerted by vasopressin on the HPA axis is
preserved in sepsis or not. Is vasopressin involved in relative adrenal insufficiency
by providing inadequate ACTH levels or by not acting directly on the adrenal
gland? Is vasopressin repletion able to restore HPA axis integrity? These questions
still remain unanswered.
I Conclusion
Interaction between vasopressin and the HPA axis appears to be extremely complex,
although recent observations in cases of sepsis suggest that this relationship could
be important for septic patients. Vasopressin acts on the adenohypophysis to in-
duce ACTH secretion. While many in vivo experimental results clearly demonstrate
the direct effect of vasopressin on the adrenal cortex and medulla, its clinical sig-
nificance is contested, even in normal conditions. Treatment of septic shock with
low doses of hydrocortisone may further decrease vasopressin levels already known
to be low in septic patients. Whether physiological vasopressin replacement. during
this often fatal syndrome can partially reverse adrenal insufficiency or increase ca-
techolamine secretion by direct adrenal medullar stimulation remains to be con-
firmed.
References
1. Viau V (2002) Functional cross-talk between the hypothalamic-pituitary-gonadal and adre-
nal axes. J Neuroendocrinol 14:506-513
2. Annane D, Sebille V, Charpentier C, et a! (2002) Effect of treatment with low doses of hy-
drocortisone and fludrocortisone on mortality in patients with septic shock. JAMA
288:862-871
---~--~~~~,--~--~~"~,-~
3. Holmes CL, Patel BM, Russell JA, Walley KR (2001) Physiology of vasopressin relevant to
management of septic shock. Chest 120:989-1002
4. Baertschi AJ (1980) Portal vascular route from hypophysial stalk/neural lobe to adenohy-
pophysis. Am J Physiol 239:R463-469
5. Barberis C, Mouillac B, Durroux T (1998) Structural bases of vasopressin/oxytocin receptor
function. J Endocrinol 156:223-299
6. Grazzini E, Boccara G, Joubert D, et a! (1998) Vasopressin regulates adrenal functions by
acting through different vasopressin receptor subtypes. Adv Exp Med Bioi 449:325-334
7. Raff H, Skelton MM, Merrill DC, Cowley AW Jr (1986) Vasopressin responses to corticotro-
pin releasing factor and hyperosmolality in conscious dogs. Am J Physiol 251:R1235-1239
8. Klingbeil CK, Keil LC, Chang D, Reid lA (1988) Effects of CRF and ANG II on ACTH and
vasopressin release in conscious dogs. Am J Physiol 255:E46-E53
9. Yamada K, Tamura Y, Yoshida S (1989) Effect of administration of corticotropin-releasing
hormone and glucocorticoid on arginine vasopressin response to osmotic stimulus in nor-
mal subjects and patients with hypocorticotropinism without overt diabetes insipidus. J
Clin Endocrinol Metab 69:396-401
10. Sawchenko PE, Arias C (1995) Evidence for short-loop feedback effects of ACTH on CRF
and vasopressin expression in parvocellular neurosecretory neurons. J Neuroendocrinol
7:721-731
11. Sklar AH, Schrier RW (1983) Central nervous system mediators of vasopressin release.
Physiol Rev 63:1243-1280
12. Qadri F, Waldmann T, Wolf A, Hohle S, Rascher W, Unger T (1998) Differential contribu-
tion of angiotensinergic and cholinergic receptors in the hypothalamic paraventricular nu-
cleus to osmotically induced AVP release. J Pharmacol Exp Therap 285:1012-1018
13. Conaglen JV, Donald RA, Espiner EA, Livesey JH, Nicholls MG (1984) The effect of ovine
corticotropin-releasing factor on catecholamine, vasopressin, and aldosterone secretion in
normal man. J Clin Endocrinol Metab 58:463-466
14. Arima H, Aguilera G (2000) Vasopressin and oxytocin neurones of hypothalamic supraop-
tic and paraventricular nuclei co-express mRNA for Type-1 and Type-2 corticotropin-re-
leasing hormone receptors. J Neuroendocrinol 12:833-842
15. Papanek PE, Sladek CD, Raff H (1997) Corticosterone inhibition of osmotically stimulated
vasopressin from hypothalamic-neurohypophysial explants. Am J Physiol 272:R158-R162
16. Aguilera G, Rabadan-Diehl C (2000) Vasopressinergic regulation of the hypothalamic-pitu-
itary-adrenal axis: implications for stress adaptation. Regul Pept 96:23-29
17. Muller MB, Landgraf R, Preil J, eta! (2000) Selective activation of the hypothalamic vaso-
pressinergic system in mice deficient for the corticotropin-releasing hormone receptor 1 is
dependent on glucocorticoids. Endocrinology 141:4262-4269
18. Papanek PE, Raff H (1994) Physiological increases in cortisol inhibit basal vasopressin re-
lease in conscious dogs. Am J Physiol 266:R1744-R1751
19. Papanek PE, Raff H (1994) Chronic physiological increases in cortisol inhibit the vasopres-
sin response to hypertonicity in conscious dogs. Am J Physiol 267:R1342-R1349
20. Raff H, Skelton MM, Cowley AW Jr (1990) Cortisol inhibition of vasopressin and ACTH re-
sponses to arterial hypotension in conscious dogs. Am J Physiol 258:R64-R69
21. Oelkers W (1989) Hyponatremia and inappropriate secretion of vasopressin (antidiuretic
hormone) in patients with hypopituitarism. N Eng! J Med 321:492-496
22. Dingman JF, Despointes RH (1960) Adrenal steroid inhibition of vasopresin release from
the neurohypophysis of normal subjects and patients with Addison's disease. J Clin Invest
39:1851-1863
23. Oelkers W, Bahr V (1987) Effects of fludrocortisone withdrawal on plasma angiotensin II,
ACTH, vasopressin, and potassium in patients with Addison's disease. Acta Endocrinol
(Copenh) 115:325-330
24. McCann SM (1957) The ACTH-releasing activity of extracts of the posterior lobe of the pi-
tuitary in vivo. Endocrinology 60:664
25. Jard S, Gaillard RC, Guillon G, eta! (1986) Vasopressin antagonists allow demonstration of
a novel type of vasopressin receptor in the rat adenohypophysis. Mol Pharmacol 30:171-
177
26. Sugimoto T, Saito M, Mochizuki S, et al (1994) Molecular cloning and functional expres-
sion of a eDNA encoding the human V1b vasopressin receptor. J Biol Chern 269:27088-
27092
27. Liu JH, Muse K, Contreras P, et al (1983) Augmentation of ACTH-releasing activity of syn-
thetic corticotropin releasing factor (CRF) by vasopressin in women. J Clini Endocrinol
Metab 57:1087-1089
28. Hensen J, Hader 0, Bahr V, Oelkers W (1988) Effects of incremental infusions of arginine
vasopressin on adrenocorticotropin and cortisol secretion in man. J Clin Endocrinol Metab
66:668-671
29. Rivier C, Vale W (1983) Modulation of stress-induced ACTH release by corticotropin-re-
leasing factor, catecholamines and vasopressin. Nature 305:325-327
30. Raff H, Merrill DC, Skelton MM, Brownfield MS, Cowley AW Jr (1988) Control of adreno-
corticotropin secretion and adrenocortical sensitivity in neurohypophysectomized con-
scious dogs: effects of acute and chronic vasopressin replacement. Endocrinology
122:1410-1418
31. Raff H, Papanek PE, Liard JF, Cowley AW Jr (1994) The effect of intracarotid vasopressin
infusion on ACTH release in neurohypophysectomized, conscious dogs. Am J Physiol
267:R653-R658
32. Kornberger E, Prengel AW, Krismer A, et al (2000) Vasopressin-mediated adrenocorticotro-
pin release increases plasma cortisol concentrations during cardiopulmonary resuscitation.
33. Payet N, Isler H (1976) Adrenal glomerulosa mitotic stimulation by posterior pituitary hor-
mones. Cell Tissue Res 172:93-101
34. Hilton JG, Scian LF, Westermann CD, Kruesi OR (1959) Effect of synthetic lysine vasopres-
sin on adrenocortical secretion. Science 129:971
35. Payet N, Lehoux J (1979) A comparative study of the role of vasopressin and ACTH in the
regulation of growth and function of rat adrenal glands. J Steroid Biochem 12:461-467
36. Gallo-Payet N, Guillon G (1998) Regulation of adrenocortical function by vasopressin.
Horm Metab Res 30:360-367
37. Pignatelli D, Magalhaes M, Magalhaes M (1998) Direct effects of stress on adrenocortical
function. Horm Metab Res 30:464-474
38. Aguilera G, Catt K (1983) Regulation of aldosterone secretion during altered sodium in-
take. J Steroid Biochem 19:525-530
39. Payet N, Lehoux JG (1980) A comparative study of the role of vasopressin and ACTH in
the regulation of growth and function of rat adrenal glands. J Steroid Biochem 12:461-467
40. Mazzochi G, Malendowicz LK, Meneghelli V, Gottardo G, Nussdorfer GG (1995) In-vitro
and in-vivo studies of the effects of arginine-vasopressin on the secretion and growth of
rat adrenal cortex. Histol Histopathol10:359-370
41. Guillon G, Trueba M, Joubert D, et al (1995) Vasopressin stimulates steroid secretion in hu-
man adrenal glands: comparison with angiotensin-11 effect. Endocrinology 136:1285-1295
42. Perraudin V, Delarue C, Lefebvre H, Contesse V, Kuhn JM, Vaudry H (1993} Vasopressin
stimulates cortisol secretion from human adrenocortical tissue through activation of V1 re-
ceptors. J Clin Endocrinol Metab 76:1522-1528
43. Gallo-Payet N, Guillon G, Balestre MN, Jard S (1986} Vasopressin induces breakdown of
membrane phosphoinositides in adrenal glomerulosa and fasciculata cells. Endocrinology
119:1042-1047
44. Brooks VL, Keil LC (1992) Vasopressin and angiotensin II in reflex regulation of ACTH,
glucocorticoids, and renin: effect of water deprivation. Am J Physiol 263:R762-R769
45. Raff H, Merrill D, Skelton M, Cowley AW Jr (1985} Control of ACTH and vasopressin in
neurohypophysectomized conscious dogs. Am J Physiol 249:R281-284
46. Brooks VL, Blakemore LJ (1989) Vasopressin: a regulator of adrenal glucocorticoid produc-
tion? Am J Physiol 256:E566-E752
47. Fukata J, Usui T, Tsukada T, et al (1990) Effects of repetitive administration of corticotro-
pin-releasing hormone combined with lysine vasopressin on plasma adrenocorticotropin
and cortisol levels in secondary adrenocortical insufficiency. J Clin Endocrinol Metab
71:1624-1631
---~--~~~~,--~--~~"~,-~
48. Bahr V, Hensen J, Hader 0, Boike T, Oelkers W (1991) Stimulation of steroid secretion by
adrenocorticotropin injections and by arginine vasopressin infusions: no evidence for a di-
rect stimulation of the human adrenal by arginine vasopressin. Acta Endocrinol (Copenh)
125:348-353
49. Grazzini E, Lodboerer AM, Perez-Martin A, Joubert D, Guillon G (1996) Molecular and
functional characterization of V1b vasopressin receptor in rat adrenal medulla. Endocri-
nology 137:3906-3914
50. Grazzini E, Breton C, Derick S, et al (1999) Vasopressin receptors in human adrenal medul-
la and pheochromocytoma. J Clin Endocrinol Metab 84:2195-2203
51. Nussdorfer GG (1996) Paracrine control of adrenal cortical function by medullary chro-
maffin cells. Pharmacal Rev 48:495-530
52. Annane D, Sebille V, Troche G, Raphael JC, Gajdos P, Bellissant E (2000) A 3-level prognos-
tic classification in septic shock based on cortisol levels and cortisol response to cortico-
tropin. JAMA 283:1038-1045
53. Landry DW, Levin HR, Gallant EM, et al (1997) Vasopressin deficiency contributes to the
vasodilation of septic shock. Circulation 95:122-1125
54. Annane D (2001) Corticosteroids for septic shock. Crit Care Med 29 (7 suppl):Sll7-S120
55. Schroeder S, Wichers M, Klingmuller D, et al (2001) The hypothalamic-pituitary-adrenal
axis of patients with severe sepsis: altered response to corticotropin-releasing hormone.
56. Patel BM, Chittock DR, Russell JA, Walley KR (2002) Beneficial effects of short-term vaso-
pressin infusion during severe septic shock. Anesthesiology 96:576-582
Clinical Applications of Indirect Calorimetry
in the Intensive Care Setting
P. Singer and J.D. Cohen
I Introduction
Metabolic stress, a result of the rapidly changing and complex nature of severe ill-
ness, is common in critically ill patients. Although the importance of nutritional
support has received increasing interest over recent years, this is usually provided
in an empiric manner without necessarily taking into account the specific nutri-
tional and, especially, energy requirements of a particular patient. These factors
may be of considerable importance to patients in the intensive care unit (ICU). Un-
der-nutrition, as indicated by a severely negative energy balance (> 10000 kCal dur-
ing the ICU stay) has been associated with a higher mortality in critically ill pa-
tients at risk for developing multiple organ failure (MOF) [1], while over-nutrition
in artificially-fed patients especially with carbohydrates may increase postoperative
length of stay, increase rates of infection and mortality [2]. It would, therefore,
seem that an accurate daily and individualized evaluation of energy expenditure
would be the best way to administer appropriate energy support in these metaboli-
cally brittle patients.
I Assessment of Energy Requirements
Energy expenditure may be assessed using predictive equations, for example using
the Harris-Benedict equation [3]. However, while these formulas may provide use-
ful information in stable patients, they have been shown to be less accurate in criti-
cally ill patients. This is also true when the formulas are corrected by 'stress fac-
tors' which may result in both over and underestimation of true energy require-
ments [4-6]. This is because many factors (see Table 1), often occurring simulta-
neously, may affect the basal metabolic rate [7] and under these circumstances,
even the most elaborate equations cannot reliably be expected to predict energy ex-
penditure. Based on the mean of hundreds of measurements, we have previously
shown [8] that there was an average error of 16% in percentage prediction both
above and below the calculated as compared to predicted energy expenditure (Table
2). Therefore, we concluded, as have others [9, 10], that measuring energy expendi-
ture is much more satisfactory than estimating it. In fact, if energy expenditure is
not measured, using an average value for energy intake for all patients is just as
good as, and very much simpler than, predicting each individual energy expendi-
ture by the Harris-Benedict or other formulas.
Clinical Applications of Indirect Calorimetry in the Intensive Care Setting 913
Table 1. Factors modifying resting energy expenditure (REE)
Increased REE Decreased REE
Size (height-weight) Increasing age

Fever, shivering Hypothermia
Increased work of breathing Appropriately adapted mechanical ventilation
Pain, stress, visit by relatives, nursing care, Sedation, analgesia
activity, chest physiotherapy
Sepsis Multi-organ failure
Nutrition Starvation
Catecholamines, pressor agents Beta-blockers
Table 2. Mean error of predicted REE (calculated by Harris-Benedict equation) compared to measured REE
after adjusting for various stress factors
Procedure Average error compared to

measured values (%)
Adding an individual estimate for stress to each individual prediction 18

Adding 3.4 kcal/kg/day to each individual prediction 19
Adding 4.8 kcal/kg/day to each individual prediction 16
Adding a value of 1839 kcal/day for all patients 18
Assuming a value of 25.5 kcal/kg/day for all patients 19
I So How should we Measure Energy Expenditure?
Indirect calorimetry is a non-invasive method of measuring energy expenditure,

which may be used in ventilated and non-ventilated patients. The principle of indi-
rect calorimetry derives from the fact that the human body burns its available fuels
(carbohydrates, fat, and protein) utilizing oxygen and producing carbon dioxide,
water and nitrogen [ 11]. In this model, all the oxygen is completely utilized and
the expired C0 2 is derived only from complete oxidation of fuels. Indirect calori-
metry measures the respiratory gas exchange, V0 2 (oxygen consumption) and
vco2 (carbon dioxide production), and these values are then used to calculate rest-
ing energy expenditure (REE) and substrate utilization if an adequate urinary ni-
trogen measurement is available [12]. The measurement of urinary nitrogen secre-
tion (NM) is not mandatory for the calculation of REE. Even if this measurement
is not performed, there is an error of only about 1-2% between the REE derived
from indirect calorimetry and the true energy expenditure calculation [13]. The
most important equations to note are:
REE = 3.91 V02 + 1.1 VC02-3.34 NM (1)
Respiratory quotient (RQ) = VC0 2/V0 2 (2)
Carbohydrate Utilization=4.45 VCOr3.21 VOr2.87 NM (3)
Fat Utilization = 1.67 VOr 1.67 VC0 2-1.92 NM (4)
914 P. Singer and J.D. Cohen
In addition, the REE can be derived from V0 2 alone according to the following
equation:
REE = V0 2 X 4.838 X 1.44 (5)
if the patient does not have respiratory failure and is in a stable condition. In con-
ditions of acute lung injury (ALI), this equation does not take into account the V0 2
of the lung, which may reach 15-20% of the total V0 2 [12].
It is important to remember that total daily energy expenditure (TDEE) is made
up of 3 components: REE, which comprises 75-90% of TDEE; thermogenesis (from
nutrient intake inducing the thermic effect of food; and environmental shivering/
non-shivering) and physical activity [14]. Thus, what is measured depends on
whether the patient is fed or fasting, active or sedated, and pyrexial or not. Activity
particularly increases energy expenditure in ICU patients and this so-called activity
energy expenditure (AEE) can make up to 25% of the REE [15]. In general, the
more critically ill the patient, the more frequent are the requirements for interven-
tions and procedures, so that the difference between the TDEE and REE becomes
small [16].
I Accuracy and Limits of Indirect Calorimetry

Energy expenditure in the intensive care patient is variable and requires frequent
measurements. There is no consensus regarding the optimal duration of measure-
ment or time of the day to perform indirect calorimetry. Smyrnios et al. measured
REE over a 30-minute period and compared it to 24-hour measurements [17]. The
average REE measured over 24 hours was 1490±486 kCal/d and the average REE
derived from the 30-minute measurement was 1501 ± 503 kCal/d. They concluded
that a 30-minute study may predict REE adequately for most clinical purposes. The
authors added that the accuracy might be maximized if the 30-minute study was
performed between 11 pm and 3 pm, and when minute volume, heart rate and sys-
tolic blood pressure were near the day's average. Petros et al. [18] decreased the
period measured even further to a 5-minute steady state test, finding very good
correlation with the 30-minute steady state test (r =0.972), particularly in sponta-
neously breathing and in sedated patients.
The correct application of the technique should take into account some impor-
tant practical aspects. Without heeding these, errors of measurement may lead to
misinterpretation of the results:
1) After an adequate warm up of the calorimeter, a gas and volume calibration
must be performed.
2) Collection of expiratory gases must be performed carefully since any significant
gas leak could lead to large errors [19]. Patients with chest tubes or air fistulae
should not be assessed with this technique.
3) As the V0 2 is calculated according to the Haldane transformation, the measure-
ment should be limited to patients receiving an inspired oxygen fraction (Fi0 2 )
equal to or less than 0.6 and when there are no wide fluctuations in Fi0 2 [20-
22]. Indirect calorimetry measurements are invalid in patients receiving nitric
oxide (NO).
4) Gas exchange measurement should ideally reflect tissue exchange, and this is
best achieved when the patient is in a steady state. No acute changes in ventila-
tion should be performed for at least 60 to 120 min prior to the measurement
[22, 23]. In addition, hemodynamic stability as well as stable body temperature

is preferred. The best way to assess stability prior to measurement is the finding
of a stable value of end tidal C02 (ETC02 ) for 20-30 minutes before the mea-
surement.
The commercially available instruments are accurate and precise and V02 can be
measured with an accuracy of 1.5 to 5.0%. Two metabolic monitors, the Deltatrac II
and M-COVX, were recently compared in twenty mechanically ventilated, critically
ill patients [24] with measurements performed at Fi02 of 0.3, 0.5 and 0.7 respec-
tively. Within-machine and between-machine precision (reproducibility) and accu-
racy were assessed for V0 2 , VC02 , RQ and REE. Within-machine reproducibility
was < 1 ml!min for VC0 2 , < 2.5 ml/min for V0 2, < 5 kCal/d for REE, and < 0.01 for
RQ. Between-machine precision study reproducibility was < 0.2% for RQ, and < 2%
for V02> VC0 2 , and REE. Finally, accuracy was within 3% for V02 , VC02 and RQ,
and within 0.2% for RQ, demonstrating a very high level of precision. The limits of
agreement were large. At lower Fi02, the Deltatrac performed better for VC02>
while at a higher Fi0 2, the M-COVX was superior for measuring V0 2 •
I Why Should we Measure Energy Expenditure?
To Assess Energy Balance

The measurement of energy balance by indirect calorimetry appears to have its
greatest application in monitoring the needs of severely ill patients, and in mal-
nourished hospitalized subjects requiring enteral or parenteral nutritional support.
As already mentioned [1], it has been demonstrated that there is a relation between
an energy deficit greater than 10000 kCal for the ICU stay and the survival of criti-
cally ill patients.
Energy intake is equal to the sum of fat, protein and carbohydrate intake, and
should include the intake of dextrose, starch and lactate (Table 3). In daily practice,
energy intake may be underestimated when patients receive large amounts of dex-
trose, for example in the correction of hypernatremia or for replacement of ultrafil-
trate during continuous forms of renal replacement therapy, and these calories are
not taken into account when estimating energy balance. On the other hand, energy
intake may be overestimated when the prescribed amount of calories are not admi-
nistered for practical and technical reasons (e.g., problems related to infusion sys-
tems, uncertainty about adequate gastric drainage).
In our ICU department, we have recently measured daily REE to assess the pre-
valence of negative energy balance (unpublished data, Singer P, 2002). More than
Table 3. Caloric equivalent for protein, fat and carbohydrate administered intravenously
Dextrose Starch Lactate Fat Amino acids

(HAES) Kcal/mM
Energy (Kcal/g) 3.4 4.1 0.310 9.3 4.3
Oxygen (1/g} 0.746 0.829 2.019 0.965
Carbon dioxide (1/g} 0.746 0.829 1.427 0.781
70o/o of the patients tested had a negative cumulative energy balance at the end of
their ICU stay despite an aggressive early enteral feeding approach, the use of pro-
tocols and the daily use of indirect calorimetry measurements. In addition, many
patients did not reach an intake of more than 800 kCal/day until the 15th ICU day.
Additional calorie intake administered through dextrose So/o in water (DSW) fluid
infusions was also evaluated and varied from 10 glday to 100 glday (340 kCal). To-
tal energy balance over the ICU stay varied from -8271 kCal to +4747 kCal. These
findings lend further support to the importance of an efficient monitoring tool
such as indirect calorimetry to prevent over, as well as under, nutrition.
To Assess the Metabolic Effect of Drugs

(Sedatives, Analgesics, Catecholamines)
REE may be modified by the use of commonly used drugs in the ICU. Thus, the
use of sedation and neuromuscular blockade, by decreasing motor activity, has
been shown to decrease REE especially in children. In severely head-injured pa-
tients [25], however, the decrease the REE seen in patients receiving sedation was
found to be related to a decrease in temperature rather than the sedative effect. The
metabolic and respiratory stresses associated with the administration of the respi-
ratory stimulant naloxone [26] have been shown to be a result of the return of nor-
mal thermoregulation. Anesthesia too has been shown to affect energy expenditure.
Thus, induction of anesthesia in cirrhotic patients with end stage liver disease
(who typically have an elevated REE and low RQ) for orthotopic liver transplanta-
tion has been associated with reduced energy production of up to SOo/o compared
to the preoperative values, with vo2 affected more than vco2 [27].
Beta-blockade with propranolol, by blunting the sympathetic response not only
decreases tachycardia but also significantly decreases REE in burn patients
(p<O.OS) [28]. On the other hand, the use of dobutamine has been shown to result
in significant dose-related increases in V0 2 and REE both in normal men (dobuta-
mine at 10 ~g/kg/min increased REE by 33o/o when compared to control [29]) and
in patients with septic shock [30].
Non-Metabolic Applications of Indirect Calorimetry

Ventilatory Assessment: When the data from indirect calorimetry are augmented by
an arterial blood gas analysis of carbon dioxide (PaC0 2 ), the dead space to tidal
volume ratio (V d!Vt) can be determined for an individual patient using the follow-
ing formula:
Vd/Vt= l-(0.863xVC0 2/paC0 2 xVm) (6)
This information may be useful in the process of weaning from mechanical ventila-
tion. Pelaez Fernandez et al. [31], for example, studied 20 ventilated patients while
increasing or decreasing their minute volume by 74 and 42o/o respectively. They
showed that changes in minute ventilation resulted in corresponding changes in
Vd!Vt. This might allow the attending healthcare team to detect worsening lung
function early during the weaning process and to intervene appropriately to im-
prove the situation.
Increased production of carbon dioxide especially during the weaning process
may result in an increased minute ventilation load and failure to wean from me-
chanical ventilation. This may be the result of overfeeding with carbohydrates and
---~--~~~~,--~--~~'"~,-~
this effect may be assessed by measuring the RQ, which should be maintained be-
tween 0.8 and 0.9. However, excessive administration of total calories may be a
more important cause of an increase in VC0 2 [32]. We have also shown that de-
creasing the total caloric intake may result in a significant decrease in vco2 within
20 hours (Singer P and Elwyn DH, unpublished data, 2002).
Grading Sepsis and Multiorgan Failure: It has been shown that REE differs in varying
grades of the systemic inflammatory response syndrome (SIRS). Thus, critically ill
patients with SIRS have been shown to have a higher REE than patients with non-
SIRS or non-septic SIRS [33] so that classifying patients into three grades may be a
valid predictor of the degree of metabolic stress. Kreymann et al. [34] demon-
strated that V0 2 and resting metabolic rate were enhanced by about 30% in pa-
tients with sepsis; however, patients developing sepsis syndrome and septic shock
had much lower values when compared to patients with uncomplicated sepsis. In
addition, these authors showed that the resting metabolic rate increased signifi-
cantly during recovery from septic shock. They suggested that measuring metabolic
parameters could be used for monitoring the development of more severe sepsis
and shock. A lower than expected or declining REE may also have prognostic im-
plications. Forsberg et al. [35] showed that non-survivors of intensive care follow-
ing MOF due to intraabdominal sepsis had a comparatively reduced hypermetabo-
lism when compared to survivors. This is further supported by a study from Hart
et al. [36] who showed that declining energy expenditure appeared to be a harbin-
ger of mortality in severely burned patients.
Hemodynamic Assessment: Increasing D0 2 to supranormal levels, spontaneously or

therapeutically, correlates with better survival in the critically ill patient, although
not all patients who attain an elevated oxygen delivery (D0 2 ), generally agreed to
be greater than 600 ml/min/m 2 , will survive [37]. Schaffartzik et al. [38] showed a
moderate correlation between V0 2 and D0 2 in septic patients being treated with
dobutamine in various doses. Thus, using a metabolic monitor, it may be possible
to guide inotropic support without resorting to more invasive methods.
Conclusion
Critically ill patients are severely metabolically stressed. Certain disease processes,
such as sepsis and burns, may markedly increase energy requirements whereas
other interventions (e.g., anesthesia, hypothermia) and medications (beta-blockers,
sedation) may decrease the metabolic response. Providing adequate, but not exces-
sive, sources of energy is an important goal of ICU caregivers as both under and
overnutrition have been associated with adverse outcomes. Energy requirements
are most accurately assessed using indirect calorimetry, which should ideally be
measured on a daily basis to capture the complex and changing metabolic status of
the critically ill patient. Indirect calorimetry can also be used to provide respiratory
and hemodynamic data, which further aid the physician in managing these pa-
tients.
References
1. Barlett RH, Dechert RE, Mault JR, Ferguson SK, Kaiser AM, Erlandson EE (1982) Measure-
ment of metabolism in multiple organ failure. Surgery 10:771-779
2. Vo NM, Waycaster M, Acuff RV, Lefemine AA (1987) Effects of postoperative carbohydrate
overfeeding. Am Surg 53:632-635
3. van Lanschot JJB, Feenstra BWA, Vermeij CG, Bruining HA (1986) Calculation versus mea-
surement of total energy expenditure. Crit Care Med 14:981-985
4. Flancbaurn L, Chohan PS, Sambucco S, Verducci J, Burge JC (1999) Comparison of indirect
calorimetry, the Pick method, and predictive equations in estimating the energy require-
ments of critically ill patients. Am J Clin Nutr 69:461-466
5. Coss-Bu JA, Jefferson LS, Walding D, David Y, Smith EO, Klish WJ (1998) Resting energy
expenditure in children in a pediatric intensive care unit: comparison of Harris-Benedict
andTalbot predictions with indirect calorimetry values. Am J Clin Nutr 67:74-80
6. Casati A, Colombo S, Leggieri C, Muttini S, Capocasa T, Gallioli G (1996) Measured versus
calculated energy expenditure in pressure support ventilated ICU patients. Minerva An-
esthesiol 62:165-170
7. McClave SA, Snider HL, Greene L, et al (1992) Effective utilization of indirect calorimetry
during critical care. Nut Pract 9:61-68
8. Singer P (1989) Measurement or estimation of energy Expenditure. In: Bursztein S, Elwyn
DH, Askanazy J, Kinney JM (eds) Energy Metabolism, Indirect Calorimetry and Nutrition,
1st ed. Williams & Wilkins, Baltimore, pp 241-249
9. Verhoeven JJ, Hazelzet JA, van der Voort, Joosten KF (1998) Comparison of measured and
predicted energy expenditure in mechanically ventilated children. Intensive Care Med 24:
464-468
10. Weissman C, Kemper M (1996) Metabolic measurements in the critically ill. Crit Care Clin
11:169-197
11. Bursztein S (1989 ) The theoretical framework. In: Bursztein S, Elwyn DH, Askanazi J, Kin-
ney JM (eds) Energy Metabolism, Indirect Calorimetry and Nutrition. Williams & Wilkins,
Baltimore, pp 27-83
12. Bursztein S, Saphar P, Singer P, Elwyn DH (1989) A mathematical analysis of indirect
calorimetry measurements in acutely ill patients. Am J Clin Nutr 50:227- 230
13. Brandi LS, Grana M, Mazzanti T, Giunta F, Natali A, Ferrannini E (1992) Energy expendi-
ture and gas exchange measurement in postoperative patients: thermodilution vs indirect
caloriemtry. Crit Care Med 20:1273-1283
14. McClave SA, Snider HL (1992) Use of indirect calorimetry in clinical nutrition. Nutr Clin
Pract 7:207-221
15. Frankenfield DC, Wiles CE, Bagley S, Siegel JH (1994) Relationship between resting and
total energy expenditure in injured and septic patients. Crit Care Med 22:1796-1801
16. Weissman C, Kemper M, Elwyn DH, Askanazi J, Hyman AI, Kinney JM (1986) The energy
expenditure of the mechanically ventilated critically ill patient: an analysis. Chest 89:254-
259
17. Smyrnios NA, Curley FJ, Shaker KG (1997) Accuracy of 30-minute indirect calorimetry
studies in predicting 24-hour energy expenditure in mechanically ventilated critically ill
patients. JPEN J Parenter Enteral Nutr 21:168-174
18. Petros S, Engelmann L (2001) Validity of an abbreviated indirect calorimetry protocol for
measurement of resting energy expenditure in mechanically ventilated and spontaneously
breathing critically ill patients. Intensive Care Med 27:1107-1109
19. Bracco D, Chiolero R, Pasche 0, Revelly P (1995) Failure in measuring gas exchange in the
ICU. Chest 104:1406-1410
20. Ultman J, Bursztein S (1981) Analysis of error in the determination of respiratory gas ex-
change at varying FI02 • J Appl Physiol 50:210-216
21. Tissot S, Delafosse B, Bernard 0, Bouffard Y, Viale JP, Annat G (1995) Clinical validation
of the Deltatrac monitoring system in mechanically ventilated patients. Crit Care Med
21:149-153
22. Browning JA, Linberg SE, Turney SF, Chodoff P (1982) The effects of fluctuating FI0 2 on
metabolic measurements in mechanically ventilated patients. Crit Care Med 10:82-85
---~--~~~~,--~--~~"~,-~
23. Henneberg S, Soderberg D, Groth T, Stjernsrom H, Wiklund L (1987) Carbon dioxide pro-
duction during mechanical ventrilation. Crit Care Med 15:8-13
24. Me Lellan S, Walsh T, Burdess A, Lee A (2002) Comparison between the Datex-Ohmeda M-
COVX metabolic monitor and the Deltatrac II in mechanically ventilated patients. Intensive
Care Med 28:870-876
25. Bruder N, Raynal M, Pellisier D, Courtinat C, Francois G (1998) Influence of body tem-
perature, with or without sedation, on energy expenditure in severe head-injured patients.
26. Just B, Delva E, Camus Y, Lienhard A (1992) Oxygen uptake during recovery following na-
loxone. Relationship with intraoperative heat loss. Anesthesiology 76:60-64
27. Benoventura J, Pittoni G, Michielan F, et a! (1995) Energy expenditure (EE) and substrate
utilization (SU) in the peri operative period in orthotopic live transplantation. Rocz Akad
Med Bialymst 40:195-208
28. Hart DW, Wolf SE, Chinkes DL, La! SO, Ramzy PI, Herndon DN (2002) Beta-blockade and
growth hormone after Burn. Ann Surg 236:450-457
29. Green CJ, Frazer RS, Underhill S, Maycock P, Fairhurst JA, Campbell IT (1992) Metabolic
effects of dobutamine in normal man. Clin Sci 82:77-83
30. Schaffartzik W, Sanft C, Scharfer JH, Spies C (2000) Different dosages of dobutamine in
septic shock patients: determining oxygen consumption with a metabolic monitor inte-
grated in a ventilator. Intensive Care Med 26:1719-1722
31. Pelaez Fernandez J, Asensio Martin MJ, Sanchez Sanchez M, Garcia de Lorenzo Mateos A,
Jimenez Lendinez M (1999) Non-metabolic application of indirect calorimetry. Nutr Hosp
14:23-30
32. Talpers SS, Romberger DJ, Gunce SB, Pingleton SK (1992) Nutritional associated increased
carbon dioxide production: excess total calories vs high proportion of carbohydrate cal-
ories. Chest 102:551-555
33. Moriyama S, Okamoto K, Tabira Y, et a! (1999) Evaluation of oxygen consumption and
resting energy expenditure in critically ill patients with systemic inflammatory response
syndrome. Crit Care Med 27:2133-2136
34. Kreymann G, Grosser S, Buggisch P, Gottschall C, Matthaei S, Grten H (1993) Oxygen con-
sumption and resting metabolic rate in sepsis, sepsis syndrome and septic shock. Crit Care
Med 21:1012-1019
35. Forsberg E, Soop M, Thorne A (1991) Energy expenditure and outcome in patients with
multiple organ failure following abdominal injury. Intensive Care Med 17:403-409
36. Hart DW, Wolf SE, Herndon DN, et a! (2002) Energy expenditure and caloric balance after
burn: increased feeding leads to fat rather than lean mass accretion. Ann Surg 235:152-161
37. Kelly KM (1996) Does increasing oxygen delivery improve outcome? Yes. Crit Care Clin
12:635-644
38. Schaffartzik W, Sanft C, Schaefer JH, Spies C (2000) Different dosages of dobutamine in
septic shock patients: determining oxygen consumption with a metabolic monitor inte-
grated in a ventilator. Intensive Care Med 26:17 40-17 46
Management, Education, and Ethics
Can Nosocomial Infections and Iatrogenic Events
Serve as Quality-of-Care Indicators in the ICU?
M. Garrouste Orgeas, L. Soufir, and J. F. Timsit,
on behalf of the OUTCOMEREA group
I Introduction
The measurement of quality of care is receiving increasing attention from intensi-

vists. Quality of care can be measured in many different domains. In a hospital,
quality of care depends both on the quality of the economic and organizational op-
eration of the institution (evaluated by managers, decision-makers, and politicians)
and on the quality of clinical activities. This last component is familiar ground to
caregivers and patients, since it is centered on the patients and their interactions
with the institution. A recent report from the Institute of Medicine identified six
quality goals: care should be safe, effective, patient-centered, timely, efficient, and
equitable [1].
Quality Indicators? Definition and Applicability to ICUs
The quality of patient care can be evaluated from several different viewpoints.
According to Donabedian's model [2], quality depends on structural factors (equip-
ment, quality and level of human resources), care procedures (the intervention(s)
used in the patient), and outcomes (recovery, clinical remission, functional gain).
An indicator is a marker for performance that reflects only part of the effects of
an activity. Indicators must be relevant (significant impact on health), operational
(events amenable to modification), and valid (measurable, diagnostically accurate,
and reproducible). Finally, if they are to be used on a routine basis, indicators
should be widely accepted by the medical community, easy to collect, and per-
ceived positively by the caregivers [3]. Quality indicators are not yet well accepted
by caregivers as tools for comparing intensive care units (ICUs) because their prop-
erties have not been fully characterized and because caregivers remain somewhat
wary of performance measurement. These are major obstacles to the use of out-
comes indicators for comparing ICUs.
I Selection of Quality Indicators
Recently, Berenholtz et al. [4] systematically reviewed the literature from 1965 to
2000 and selected 66 studies published from 1991 to list quality indicators that
could be broadly applied to improve ICU outcomes. They identified six outcome
measures: ICU mortality, ICU length of stay greater than seven days, average ICU
924 M. Garrouste Orgeas et al.
length of stay, average days on mechanical ventilation, sub-optimal management of

pain, and patient/family satisfaction. There were six process measures: effective as-
sessment of pain, appropriate use of blood products, prevention of ventilator-asso-
ciated pneumonia (VAP), appropriate sedation, peptic ulcer disease prophylaxis,
and deep venous thrombosis prophylaxis. Access measures were delayed admission,
delayed discharge, cancelled surgery cases, and hours on emergency department
by-pass. Finally, complication measures were unplanned ICU readmissiions, cathe-
ter-related bloodstream infection, and rate of resistant infections. However, the se-
lection of these complication measures is open to criticism because, when assessing
quality of care in ICU patients, the outcome of the admission illness is difficult to
separate from the consequences of intensive care. Intuition suggests that nosoco-
mial infections and iatrogenic events may be good indicators for poor quality of
care in ICUs. Nevertheless, their occurrence is often more heavily dependent on pa-
tient-related factors than on the care process.
Ideally, preventable events should be separated from non-preventable events. Un-
fortunately, few adverse events are related to egregious mistakes that are easy to
identify and to prevent. Thus, when comparing adverse event rates, careful atten-
tion should be given to the characteristics of the patient population. One method
for comparing ICUs is benchmarking, in which adverse event rates are compared
across ICUs with similar theoretical risks of infection. Although benchmarking is
gaining ground, both the level of theoretical risk and the acceptable range are diffi-
cult to define. Furthermore, it is difficult to compare diagnostic and therapeutic in-
terventions across ICUs.
Nosocomial Infection and Multi-Resistant Bacteria Colonization

as Quality Indicators?
Nosocomial infections affect more than 2 million people annually in the United States
and 5 to 35% of patients admitted to ICUs [5]. They are the price to pay for modern
technology and invasive medical procedures. Pathophysiological factors in nosoco-
mial infections include host colonization by endogenous or exogenous multiresistant
microorganisms such as methicillin-resistant Staphylococcus aureus, vancomycin-re-
sistant enteroccocci, extended-spectrum, beta-lactamase-producing Gram-negative
bacilli and yeasts. VAP, surgical site infections, catheter-related infections, and urinary
tract infections contribute to over 80% of nosocomial infections.
For many years, nosocomial infection has been felt to be of potential usefulness
as a quality-of-care indicator related to structures, procedures, and outcomes. No-
socomial infection has several characteristics usually seen in good indicators: it is
common, and it is related to diagnostic and therapeutic procedures. However, the
considerable controversy surrounding the influence of nosocomial infection on
morbidity and mortality, the preventability of nosocomial infection, and the best
methods for expressing results constitute a major stumbling block to comparisons
of ICUs.
Nosocomial infection is sufficiently common to serve as an indicator. A preva-
lence of 20.6% was reported by Vincent et al. in the European Prevalence of Infec-
tion in Intensive Care (EPIC) study, which included 10038 patients from 1417 Euro-
pean ICUs in 1992 [6]. Studies of rates of reported nosocomial infection show that
different ICUs measure different things and, therefore, that variability is markedly
Can Nosocomial Infections and Iatrogenic Events Serve as Quality-of-Care Indicators in the ICU? 925
dissimilar across ICUs. This is evident from the first results of the European HE-
LICS project [7], whose objective is to standardize nosocomial infection monitoring
in European ICUs. To date, it includes six national surveillance networks (REA-SE
in France, NSIH-ICU in Belgium, PREZIES-ICU in The Netherlands, ENVIN-UCI in
Spain, KISS-ICU in Germany, and NNIS (CDC) in the US) and over 500000 ICU
admissions. As shown in Table 1, differences in the definitions of nosocomial infec-
tion preclude comparisons across these networks.
The nosocomial infection selected for monitoring must be a robust indicator
that is easy to define. The NOSOREF survey conducted by the OutcomeRea group
[8] found considerable differences in practices regarding the diagnosis of noso-
comial infection. The 244 completed questionnaires showed, for instance, that rou-
tine culturing of central venous lines was performed in only 55% of ICUs. Similarly,
urine cultures were done at admission in only 30% of ICUs and at predefined inter-
vals during the stay in one-third of ICUs. The differences were particularly conspic-
uous regarding the methods used to diagnose nosocomial pneumonia. Plugged tele-
scopic catheter, protected specimen brush (PSB) and broncho-alveolar lavage (BAL)
were performed often or always in 42%, 30%, and 42% of ICUs, respectively. This
heterogeneity in practices is an obstacle to comparisons of ICUs.
Which Nosocomial Infections could Serve as Quality Indicators?

Surgical site infection is probably not a good quality indicator for ICUs because
the diagnosis is usually made after ICU discharge. Thus, 80 to 85% of surgical site
infections are diagnosed within the first 3 weeks after surgery [9], and 12 to 84%
are diagnosed after discharge from the hospital, leading to underestimation of the
prevalence if patients are not routinely reevaluated after discharge [10, 11].
Nosocomial VAP raises several problems as a quality-of-care indicator. The rate
of nosocomial VAP varies with a host of factors, including the patient case-mix
(age, immunodepression, severity at admission, severe chronic comorbidities),
events that occur during the ICU stay (aspiration, organ failure, reintubation), and
treatments (H 2 -receptor antagonists, antacids, sedatives) [12]. Therefore, the pre-
ventability of nosocomial VAP remains in doubt. Finally, the relation between noso-
comial infection and attributable mortality is unclear [13]. In most studies, excess
mortality was found among the patients with nosocomial pneumonia [13-15].
However, others found no difference in mortality between patients with and with-
out nosocomial pneumonia [16-18]. Attributable mortality of nosocomial pneumo-
nia was studied in 742 patients admitted for longer than 4 days to four pilot ICUs
in the Outcome Rea database. The four ICUs used the same standardized diagnostic
criteria. Excess mortality was evaluated using a Cox model with time-dependent
covariates and adjustment on severity and severity changes within the first 3 ICU
days [19]. Nosocomial pneumonia was associated with excess mortality (relative
risk [RR] = 1.6; 95% confidence interval [95% CI], 1.10-234}. The amount of excess
mortality varied widely across ICUs. Moreover, late-onset pneumonia was asso-
ciated with excess mortality only in the subgroup of patients for whom initial anti-
biotic therapy was inadequate (i.e., who had pneumonia due to strains resistant to
the first-line antimicrobials). Although case-mix and occurrence of nosocomial
pneumonia are intimately linked, the evaluation of preventive measures and of their
impact on the incidence of pneumonia may be a good quality marker, as nosoco-
\J:)
N
0'\
Table 1. Discrepancies in definitions of nosocomial infection across six European networks [6) ~
~
- !:!:
Network name NSIH-ICU REA-SE PREZIES-ICU ENVIN-UCI KISS-ICU NNIS (CDC) 0c:
Country Belgium France The Netherlands Spain Gennany United States ~
0
lndusion criteria stay >48 h stay >48 h stay >48 h stay > 24 h all patients all patients ca,
catheter 1 catheter day counted 1 catheter day counted 1 catheter day counted 1 catheter day counted 1 catheter day 1 catheter day "'"'
~
at catheter insertion at catheter insertion starting at the 24th at catheter insertion counted at catheter counted at catheter
~
3 catheters on 1 day 3 catheters on 1 day hour of use 3 catheters on 1 day insertion insertion
=1 catheter day =1 catheter day 3 catheters on 1 day = 3catheter days 3 catheters on 1 day 3 catheters on 1
=3 catheter days =1 catheter day day = 1catheter day
Definition of ICU- > 2 days after > 2 days after Not present at Not incubating at Not incubating Not incubating at
acquired infection ICU admission ICU admission admission admission at admission admission
Which infections? First infection only First infection only All infections All infections All infections All infections
mial pneumonia is both common and associated with excess mortality (at least
when inappropriately treated). However, definitions and patient case-mix vary
widely and should be reported in detail to allow valid comparisons.
Central catheter-related infection may meet several of the criteria required of
quality-of-care indicators. Patient-related risk factors play only a limited role in the
occurrence of catheter-related infection (remote foci of infection, acute severity,
chronic comorbidities), which is related primarily to the quality of care. Several
factors involved in catheter-related infection are amenable to modification, includ-
ing selection of the insertion site [20-22], experience of the operator, aseptic tech-
nique during insertion, maintenance of a closed system, frequency of line changes,
quality of monitoring, and number of manipulations. Furthermore, a consensus has
been developed regarding the definition and diagnosis of catheter-related infection
[23]. However, catheter-related sepsis without positive blood cultures remains diffi-
cult to define. Catheter colonization (determined using semi-quantitative or quanti-
tative culture) and catheter-related bacteremia are probably easy to define. A recent
literature review suggests that catheter tip colonization may be a good surrogate
for catheter-related bloodstream infection [24]. Catheter-related bloodstream infec-
tion is less severe when caused by coagulase-negative staphylococci than by other
microorganisms such as Staphylococcus aureus or Candida spp. Thus, quantitative
tip culture positive for microorganisms other than coagulase-negative staphylococci
may be a useful indicator. Finally, catheter-related bloodstream infections are acces-
sible to prevention strategies [25] and related to the nurse workload. For example,
Fridkin et al. [26] reported an outbreak of catheter-related bloodstream infections
apparently associated with total parenteral nutrition in surgical patients. After ad-
justment on confounding parameters (type of nutrition, duration of mechanical
ventilation, hospital length of stay), the only factor associated with infection was
the patient-to-nurse ratio. As compared with a ratio of 1, the relative risks were
3.95 (95o/o Cl, 1.07-14.5), 16.6 (95o/o CI, 1.15-211), and 61.5 (95o/o CI 1.23-3.074) for
ratios of 1.2, 1.5, and 2, respectively.
Colonization is a prerequisite for the development of nosocomial infection. Car-
riage of methicillin-resistant Staphylococcus aureus (MRSA), is related to the quality
of measures taken to prevent transmission, which occurs only through the contami-
nated hands of caregivers. The organism is usually in the anterior nasal cavities. Risk
factors for MRSA carriage include diabetes, dialysis, intravenous drug abuse, major
skin lesions, and acquired immunodeficicency syndrome (AIDS). The likelihood of
skin carriage is dependent on the organism count in the nasal cavities: 44o/o of pa-
tients with more than 100 000 S. aureus colonies by nasal specimen culture have the
organism on their skin, as compared to only 4o/o of patients with lower colony counts
[27]. Skin carriage is secondary to nasal carriage [28]. Although not associated with
an increased mortality, MRSA colonization has major consequences [29]. A 3.3-fold
increase in glycopeptide use has been reported in MRSA-colonized patients without
documented infection, as compared to non-colonized patients [29].
I Can Iatrogenic Events Serve as Quality-of-Care Indicators?

According to Institute of Medicine estimates released in November 1999 [30], 7o/o
of hospitalized patients in the US suffer significant medical errors, 44 000 to 98 000
die each year from errors in care, and 50 billion dollars are spent annually as a re-
sult of these errors.
ICUs are particularly vulnerable to medical errors and adverse events. Corner-
stones of patient safety include the development of a culture of safety that is based
on a nonpunitive approach, and improved systems for measuring errors and ad-
verse events.
An iatrogenic event is defined as any adverse event that occurs during the ICU
stay and is independent of the patient's underlying disease. The causal nature of
the relation between a medical intervention and the event can be established by the
presence of three criteria, which have been described in the literature and adapted
to ICUs:
a reasonable time interval between the procedure and the occurrence of the
complication. For drug overdoses, assays showing abnormally high levels should
be obtained if at all possible. Mechanical and technical events should meet
widely accepted criteria described in the literature.
the iatrogenic event is a known complication of the procedure and has been re-
ported in the literature.
the event cannot be explained by the characteristics and/or natural history of
the underlying disease; a therapeutic error is defined as abatement of the symp-
toms after correction of the error (if the patient dies, the iatrogenic event is con-
sidered to have contributed to or caused the death only when no other cause of
death can be identified).
The definition of iatrogenic events is not agreed on. In particular, for most of these
events, there are no investigations capable of establishing iatrogenicity. Definitions
can rely on the clinical characteristics (cardiac arrest), underlying mechanisms
(hypoxic cardiac arrest complicating pneumothorax), or causal procedure (compli-
cations of venous catheterization). Finally, many questions remain unanswered re-
garding the selection of the best iatrogenic indicator. For instance, should side ef-
fects of drugs occurring in the absence of errors in prescription or administration
be classified among iatrogenic events? Is pain or emotional distress associated with
medical procedures an iatrogenic event?
Adverse events are health problems that are unrelated to the underlying medical
condition [31]. However, most ICU patients have several conditions that interact
with one another, so that causal relations with adverse events are difficult to evalu-
ate.
Iatrogenic events can be divided into three severity groups [32]: minor complica-
tions that do not require specific treatment, moderate complications that require
treatments used routinely, and major complications that require life-support treat-
ment (e.g., artificial ventilation or renal replacement therapy).
The iatrogenic event rate in ICUs has been estimated at 3 [33] to 31% [34]. The
incidence of severe complications has varied across studies from 20 [35] to 50%
[32], with part of this variability being related to differences in definitions. Respira-
tory and cardiovascular events are the most common iatrogenic events in the litera-
ture. In a multicenter European study [35] of 2894 patients, respiratory and cardio-
vascular events contributed 41% and 24% of reported iatrogenic events, respec-
tively. Cardiovascular iatrogenic events include hypotension, unpredictable cardiac
arrest, and rhythm disturbances; among them, 41% are major events (i.e., either re-
quire intensive care or cause death). Among respiratory events, 51% are major
events. Unplanned extubation, acute respiratory distress, and laryngeal dyspnea are
the most common major respiratory events. Pneumothorax is rarely responsible for
serious complications. Finally, 77% of iatrogenic events are related to human error.
Iatrogenic events have major clinical consequences. There is evidence that they
may be associated with excess mortality in ICUs [36, 37]. In published surveys, the
physicians felt that 10 to 20% of iatrogenic events in patients who died contributed
significantly to the fatal outcome [32, 35, 38]. However, a recent statistical analysis
that adjusted for the variability of reviewers' ratings found that the impact of iatro-
genic events on mortality may be considerably overestimated [39].
The preventability of iatrogenic events is debatable. No studies on the prevent-
ability of iatrogenic events in ICUs are available. High rates of preventable iatrogen-
ic events have been reported (28% for drug-related events [40], 56% for all iatro-
genic events [41]). Again, even outside the ICU, definitions for preventability can
be expected to show considerable variation [39], and the proportion of preventable
events is probably markedly overestimated.
However, most iatrogenic events are related to human error and can be pre-
vented by better education of healthcare professionals. Both monitoring and educa-
tion should probably focus on events involving drugs, particularly errors in the ad-
ministration of vasopressors, sedatives, and analgesics [42], which carry a high risk
of patient harm. Development of prescription assistance tools and closer collabora-
tion with pharmacists [40] have been found effective in reducing drug-related iatro-
genic effects.
Finally, iatrogenic event monitoring should be widely accepted by the medical
community and perceived positively by all caregivers. However, errors are often dif-
ficult to accept. The first step in developing a reporting procedure is achievement
of a consensus among the healthcare staff. The system must be blame-free, to avoid
finger-pointing or guilt. The reporting process must be accepted by the staff as a
tool that contributes to quality improvement.
Which Iatrogenic Events Could Serve as Quality Indicators?

Few iatrogenic events exhibit the characteristics of a good quality-of-care indicator
(Table 2). Unplanned extubation and pneumothorax are easy to define and repro-
ducible, but their preventability in patients on artificial ventilation is unclear [43,
44]. All-cause barotrauma was associated with a 1.99 (95% CI, 1.33-2.97) indepen-
dent risk of mortality in a recent prospective multicentre cohort study in 5183 me-
chanically ventilated patients [43]. Other catheter-related complications such as
thrombosis, inadvertent puncture of incompressible vessels should also be dis-
cussed. However, the consequences of catheter-related thrombosis are not precisely
known and the definition of mechanical complications are not clear enough [45,
46]. Unexpected cardiac arrest is a serious event but can be related to a broad vari-
ety of mechanisms. Human errors are difficult to define, and their reporting may
be perceived negatively by the caregivers. Side effects of drugs commonly used in
ICU patients (sedatives, inotropic agents, antibiotics) could be used but do not
seem to be reliably collected.
Extubation-related events may be the most easily reportable iatrogenic event in
ICUs. They include self-extubation by the patient, inadvertent extubation during
care, and failed planned extubation. These three situations require reintubation,
which carries a risk of nosocomial pneumonia [47] and constitutes a dysfunction
of care. Extubation-related events are fairly common (self-extubation and inadver-
tent extubation, 3-16% [48-50], failed planned extubation, 2-19% [51], with an
overall occurrence rate of 15% among patients on mechanical ventilation, yielding
an incidence density of about 16/1000 ventilation days. Extubation-related events
\0
......
C>
Table 2. Potential quality indicators among adverse events in intensive care units ~
G'\
Potential quality indicator [3) Frequent Easy to define, Important morbidity/ Preventable Easy to survey a"'c::
reproducible mortality ;;
0
~ 1 Hypotension [35) +++ + +I? + + .a
~ Unplanned extubation: Self-extubation ++ +++ - ? ++ "'e:
[53, 54) ~
:-
"'
I Unplanned extubation: Accidental + +++ ++ ? ++
extubation [53)
= Pneumothorax [43, 44) ++ + + + +
i Arrhythmia [35) ++ + ? ? 0
1 Cardiac arrest [35) + +++ +++ - +++
I Errors of medication: drug prescription +++ ++ + +++ 0
[35, 42)
I Errors of medication: drug administration +++ ++ + +++ 0
[35, 40, 42, 55, 56)
I Human errors [35, 40, 56, 57) +++ + + +++ +
are easy to identify and are associated with longer mechanical ventilation, ICU stay,
and hospital stay durations [52]. In addition, inadvertent extubation carries a risk
of nosocomial pneumonia (RR, 5.3; 95%CI, 2.8-9.9) [52]. Preventive steps can be
taken to decrease extubation-related events (weaning protocols and extubation cri-
teria, daily evaluation of readiness for extubation, nursing care protocols ... ). Thus,
iatrogenic extubation may be a good indicator for monitoring quality of care in the
ICU.
Each of these events stems from a specific dysfunction: inadvertent extubation re-
flects a workload-independent dysfunction in nursing care [49], whereas self-extuba-
tion and failed planned extubation reflect a dysfunction in medical decisions charac-
terized by failure to recognize that the patient was ready for extubation. Failed
planned extubation indicates that extubation was performed too early, whereas self-
extubation often indicates that extubation was left too late. Consequently, these two
events should be evaluated jointly, and the optimal self-extubation over failed planned
extubation ratio may be a good indicator of quality of care.
I Conclusion
Quality improvement in ICUs is a priority and involves the entire hospital.
Although multiple quality-of-care indicators have been described, many are not
suitable for use on an .everyday basis. Reporting of nosocomial infections is the
rule in many countries, and both catheter-related bloodstream infections and colo-
nization by MRSA seem to exhibit the characteristics of useful indicators. Iatrogen-
ic events have a broad field of application and are difficult to define. Furthermore,
reproducible reporting of iatrogenic events is extremely difficult to achieve. Self-ex-
tubation is easy to define and provides information on the overall quality of care
by physicians and nurses.
I References
1. Committee on Quality of Health Care in America (2001) Crossing the Quality Chasm: A
New Health System for the 21st Century. National Academy Press, Washington
2. Donabedian A (1988) The quality of care: How can it be assessed. JAMA 260:1743-1748
3. The Quality Indicator Study Group (1995) An approach to the evaluation of quality indica-
tors of the outcome of care in hospitalized patients, with a focus on nosocomial infection
indicators. Infect Control Hosp Epidemiol16:308-316
4. Berenholtz SM, Dorman T, Ngo K, et al (2002) Qualitative review of intensive care unit
quality indicators. J Crit Care 17:1-12
5. Eggimann P, Pittet D (2001) Infection control of ICU. Chest 120:2059-2093
6. Vincent JL, Bihari DJ, Suter PM, et al (1995) The prevalence of nosocomial infection in in-
Care (EPIC) Study. EPIC International Advisory Committee. JAMA 274:639-644
7. Suetens C, Savey A, Labreuw J, et al (2001) Towards a European surveillance of nosocomial
infections in intensive care unit: The HELICS project. Intensive Care Med 27:5204 (abst)
8. L'Heriteau F, Alberti C, Troche G, et al (2002) NOSOREF: a French survey of nosocomial
infections surveillance in intensive care units. Intensive Care Med 28:S83 (abst)
9. Mertens R, Jansen B. and Kurx X {1994) A computerized nation wide network for nosoco-
mial infection surveillance in Belgium. Infect Control Hosp Epidemiol15:171-179
10. Ferraz EM, Ferraz AA, Coelho HS, et al {1995) Postdischarge surveillance for nosocomial
wound infection: does judicious monitoring find cases? Am J Infect Control 23:290-294
11. Holtz TH, Wenzel RP (1992) Postdischarge surveillance for nosocomial wound infection: a
brief review and commentary. Am J Infect Control 20:206-213
12. Chastre J, Fagon JY (2002) Ventilator-associated pneumonia. Am J Respir Crit Care Med
165:867-903
13. Timsit JF, Chevret S, Valcke J, et a! (1996) Mortality of nosocomial pneumonia in ventilated
patients: influence of diagnostic tools. Am J Respir Crit Care Med 154:116-123
14. Fagon JY, Chastre J, Hance AJ, et a! (1993) Nosocomial pneumonia in ventilated patients: a
cohort study evaluating attributable mortality and hospital stay. Am J Med 94:281-288
15. Bercault N, Boulain T (2001) Mortality rate attributable to ventilator-associated nosocomial
pneumonia in an adult intensive care unit: a prospective case-control study. Crit Care Med
29:2303-2309
16. Kollef MH, Silver P, Murphy DM, et a! (1995) The effect of late-onset ventilator-associated
pneumonia in determining patient mortality. Chest .108:1655-1662
17. Papazian L, Bregeon F, Thirion X, eta! (1996) Effect of ventilator-associated pneumonia on
mortality and morbidity. Am J Respir Crit Care Med 154:91-97
18. Heyland DK, Cook DJ, Griffith L, et a! (1999) The attributable morbidity and mortality of
ventilator-associated pneumonia in the critically ill patient. The Canadian Critical Trials
Group. Am J Respir Crit Care Med 159:1249-1256
19. Moine P, Timsit JF, De Lassence A, et a! (2002) Mortality associated with late-onset pneu-
monia in the intensive care unit: results of a multi-center cohort study. Intensive Care Med
28:154-163
20. Merrer J, De Jonghe B, Golliot F, et a! (2001) Complications of femoral and subclavian ve-
nous catheterization in critically ill patients: a randomized controlled trial. JAMA 286:700-
707
21. Timsit JF, Sebille V, Farkas JC, et a! (1996) Effect of subcutaneous tunneling on internal ju-
gular catheter-related sepsis in critically ill patients: a prospective randomized multicenter
study. JAMA 276:1416-1420
22. Timsit JF, Bruneel F, Cheval C, eta! (1999) Use of tunneled femoral catheters to prevent ca-
theter-related infection. A randomized, controlled trial. Ann Intern Med 130:729-735
23. O'Grady NP, Alexander M, Dellinger EP, et a! (2002) Guidelines for the prevention of intra-
vascular catheter-related infections. Centers for Disease Control and Prevention. MMWR
Recomm Rep 51:1-29
24. Rijnders BJ, Van Wijngaerden E, Peetermans WE (2002) Catheter-tip colonization as a sur-
rogate end point in clinical studies on catheter-related bloodstream infection: how strong
is the evidence? Clin Infect Dis 35:1053-1058
25. Eggimann P, Harbarth S, Constantin MN, et a! (2000) Impact of a prevention strategy tar-
geted at vascular-access care on incidence of infections acquired in intensive care. Lancet
355:1864-1868
26. Fridkin SK, Pear SM, Williamson TH, et a! (1996) The role of understaffing in central ve-
nous catheter-associated bloodstream infections. Infect Control Hosp Epidemiol 17:150-
158
27. White A (1961) Relation between nasal and dissemination of staphylococci. J Lab Clin Med
58:273-277
28. Reagan DR, Doebbeling BN, Pfaller MA, et a! (1991) Elimination of coincident Staphylo-
coccus aureus nasal and hand carriage with intranasal application of mupirocin calcium
ointment. Ann Intern Med 114:101-106
29. Garrouste-Orgeas M, Timsit JF, Kallel H, et a! (2001) Colonization with methicillin-resistant
Staphylococcus aureus in ICU patients: morbidity, mortality, and glycopeptide use. Infect
30. Kohn LT, Corrigan JM, Donaldson MS (1999) To Err is Human: Building a Safe Health Sys-
tem. National Academy Press, Washington
31. Steel K, Gertman PM, Crescenzi C, et a! (1981) Iatrogenic illness on a general medical ser-
vice at a university hospital. N Eng! J Med 304:638-642
32. Trunet P, Le Gall JR, Lhoste F, et a! (1980) The role of iatrogenic disease in admissions to
intensive care. JAMA 244:2617-2620
33. Abramson NS, Wald KS, Grenvik AN, et a! (1980) Adverse occurrences in intensive care
units. JAMA 244:1582-1584
34. Giraud T, Dhainaut JF, Vaxelaire JF, et al (1993) Iatrogenic complications in adult intensive
care units: a prospective two-center study. Crit Care Med 21:40-51
35. Soufir L, Alberti C, Romand JA, et al {2000) Incidence of iatrogenic events in intensive care
units: a prospective observational multicenter study. Intensive Care Med 26:S271 (abst)
36. Brun-Buisson C, Doyon F, Cadet J {1996) Bacteremia and severe sepsis in adults: a multi-
center prospective survey in ICUs and wards of 24 hospitals. French Bacteremia-Sepsis
Study Group. Am J Respir Crit Care Med 154:617-624
37. Arnow PM, Quimosing EM, Beach M {1993) Consequences of intravascular catheter sepsis.
Clin Infect Dis 16:778-784
38. Rubins HB, Moskowitz MA (1990) Complications of care in a medical intensive care unit. J
Gen Intern Med 5:104-109
39. Hayward RA, Hofer TP {2001) Estimating hospital deaths due to medical errors: prevent-
ability is in the eye of the reviewer. JAMA 286:415-420
40. Bates DW, Cullen DJ, Laird N, et al (1995) Incidence of adverse drug events and potential
adverse drug events. Implications for prevention. ADE Prevention Study Group. JAMA
274:29-34
41. Thomas EJ, Brennan TA (2000) Incidence and types of preventable adverse events in el-
derly patients: population based review of medical records. Br Med J 320:741-744
42. Calabrese AD, Erstad BL, Brandl K, et al {2001) Medication administration errors in adult
patients in the ICU. Intensive Care Med 27:1592-1598
43. Esteban A, Anzueto A, Frutos F, et al {2002) Characteristics and outcomes in adult patients
receiving mechanical ventilation: a 28-day international study. JAMA 287:345-355
44. Chen KY, Jerng JS, Liao WY, et al (2002) Pneumothorax in the ICU: patient outcomes and
prognostic factors. Chest 122:678-683
45. Kooij JDB, van der Znadt FM, van Beek EJR, et al {1997) Pulmonary embolism in deep vei-
nous thrombosis of the upper extremity: more often in catheter-related thrombosis. Neth J
Med 50:238-242
46. Timsit JF (2002) Central venous access in intensive care unit patients: is the subclavian
vein the royal route? Intensive Care Med 28:1006-1008
47. Torres A, Gatell JM, Aznar E, et al {1995) Re-intubation increases the risk of nosocomial pneu-
monia in patients needing mechanical ventilation. Am J Respir Crit Care Med 152:137-141
48. Boulain T {1998) Unplanned extubations in the adult intensive care unit: a prospective
multicenter study. Association des Reanimateurs du Centre-Ouest. Am J Respir Crit Care
Med 157:1131-1137
49. Chevron V, Menard JF, Richard JC, et al {1998) Unplanned extubation: risk factors of devel-
opment and predictive criteria for reintubation. Crit Care Med 26:1049-1053
50. Christie JM, Dethlefsen M, Cane RD {1996) Unplanned endotracheal extubation in the in-
tensive care unit. J Clin Anesth 8:289-293
51. Epstein SK {2002) Decision to extubate. Intensive Care Med 28:535-546
52. Epstein SK, Nevins ML, Chung J {2000) Effect of unplanned extubation on outcome of me-
chanical ventilation. Am J Respir Crit Care Med 161:1912-1916
53. de Lassence A, Alberti C, Azoulay E, et al (2002) Impact of unplanned extubation and rein-
tubation after weaning on nosocomial pneumonia risk in the intensive care unit: a pro-
spective multicenter study. Anesthesiology 97:148-156
54. Atkins PM, Mion LC, Mendelson W, et al (1997) Characteristics and outcomes of patients
who self-extubate from ventilatory support: a case-control study. Chest 112:1317-1323
55. Cullen DJ, Bates DW, Leape LL {2000) Prevention of adverse drug events: a decade of pro-
gress in patient safety. J Clin Anesth 12:600-614
56. Cullen DJ, Sweitzer BJ, Bates DW, et al {1997) Preventable adverse drug events in hospita-
lized patients: a comparative study of intensive care and general care units. Crit Care Med
25:1289-1297
57. Risser DT., Rice MM, Salisbury ML, et al {1999) The potential for improved teamwork to
reduce medical errors in the emergency department. The MedTeams Research Consortium.
Ann Emerg Med 34:373-383
Hospital and ICU Organizational Structure and Quality
of Care for Surgical Patients
J. B. Dimick, P. J. Pronovost, and P. A. Lipsett
Introduction
The quality of care for surgical patients varies depending on where they choose to
receive their operation [1-3]. In the United States, two recent reports from the In-
stitute of Medicine (IOM) have focused on the frequency of medical errors and the
poor quality of health care services received by some patients. In the first report is-
sued in 1998 "To Err is Human: Building a Safer Health System'' [2], the IOM com-
mittee concluded that between 44 000 and 98 000 Americans die each year as a re-
sult of medical errors. These estimates were based largely on two population-based
investigations [2]. One of these studies, conducted in the large states of Utah and
Colorado, demonstrated that 2.9% of hospitalized patients experience adverse
events. Of these adverse events, 6.6% lead to death and more than half of these ad-
verse events were related to medical errors that could have been prevented.
In the second report issued by the IOM in 2001, "Crossing the Quality Chasm:
A New Health System for the 21st Century" [3], The Committee on the Quality of
Health Care in America concluded that "Quality problems are everywhere, affecting
many patients. Between the health care we have and the care we could have lies not
just a gap, but a chasm'' [3]. Health care systems suffer from inefficiency in trans-
lating evidence into practice and effectively dispersing new ideas and technology.
Patients, health care payers, and providers are seeking to define, identify, and ob-
tain the highest quality of care. The issues of adverse events and quality of care are
particularly relevant for critically ill patients. Intensive care units (ICUs) assume
the responsibility of managing the most complex patients who, by nature of their
primary diseases, have the highest risk of adverse outcomes such as complications
and mortality. Indeed, the evidence suggests that nearly every patient admitted to
an ICU suffers a potentially significant mistake. The minority of these lead to harm
but they have the potential to cause significant morbidity or mortality.
In recent years, a growing body of evidence has demonstrated the importance of
several hospital and ICU organizational structural factors that are important for op-
timizing outcomes for critically ill patients. Several studies have shown a relation-
ship between physician, nurse, and pharmacist staffing and outcomes. The purpose
of the current review is to describe the evidence suggesting the importance of these
hospital and ICU structural variables to outcomes for high-risk surgical patients.
Hospital and ICU Organizational Structure and Quality of Care for Surqical Patients 935
Variation in The Quality of Health Care

Over the last two decades, enormous strides have been made in the care of the sur-
gical patient. In part, the development of ICUs with specially trained nurses, physi-
cians, and other health care professionals has allowed a reduction in operative mor-
tality for most high-risk surgical procedures. Surgical patients may require inten-
sive care under two circumstances. Patients may be admitted to the unit for post-
operative monitoring if the risk of postoperative complications is high due to either
the complexity of the operation or the patient's comorbid diseases. Such preventa-
tive or proactive intensive care can identify and treat small changes in physiologic
parameters with appropriate prompt intervention in an effort to prevent or mini-
mize the extent of postoperative complications. The second reason patients require
intensive care is if they had an uncomplicated procedure but developed life-threa-
tening complications and require mechanical ventilation, invasive cardiac monitor-
ing, or other intensive care services.
Mortality and postoperative complication rates vary markedly between hospitals
and across geographic regions [4-9]. For example, in a study of patients under-
going abdominal aortic surgery in Maryland, Pronovost and colleagues demon-
strated tremendous variation in rates of postoperative complications [4]. Several of
the complications placed patients at an increased risk of mortality, length of stay,
and increased health care costs. The study concluded that reducing the complica-
tion rate at hospitals at the 75th percentile to the 25th percentile could result in vari-
able cost savings depending on the complications. Cost saving varied between
$ 20 000 for an episode of reoperation for bleeding to $ 300 000 for an episode of
aspiration [4]. In addition to vascular surgery, general surgical procedures have
variable outcomes depending on where they are performed. For esophageal resec-
tion and hepatic resection, both mortality and complication rates vary several-fold
across the 38 hospitals in Maryland [5, 6]. Given the variation in both mortality
and complications for these vascular and general surgical procedures, reducing the
variation should be made a priority and will improve outcomes for patients in need
of high-risk surgical procedures.
When investigating the quality of care it is important to maintain a distinction
between structure, process, and outcomes of a provider-patient encounter. Structure
relates to the material resources, human resources, and organizational structure of
a health care organization; process relates to what is done to and for the patient;
and outcome is how the process and structure allow patients to achieve desired
changes in health status [10]. Structural attributes associated with outcomes after
high-risk surgery include provider experience (hospital or surgeon volume), ICU
physician and nurse staffing, and participation of pharmacists in ICU rounds [11-
27]. Since it is rarely possible to randomize patients to different health care set-
tings, the relationship of structural attributes and outcomes is largely based on ob-
servational data [28, 29].
Underlying the differences in organizational structure are processes of care that
translate into differences in outcomes or quality. When considering the process of
care it is important to consider three distinct phases of care of the surgical patient,
which include preoperative, intraoperative, and postoperative phases of care. Several
health care processes can be linked to improved outcomes during each stage. Exam-
ples include the appropriate cardiac and pulmonary evaluation and optimization
before the operation (preoperative phase), use of perioperative antibiotics, resusci-
tation, and surgical technique (intraoperative phase), and invasive monitoring, on-
936 J. B. Dimick et al.
Table 1. Matrix of quality assessment for surgical patients
Structure Process Outcome
Preoperative Volume-based referral Pulmonary testing Optimization

Cardiac evaluation Preparation
Intraoperative Available technology Antibiotics Mortality
Anesthesia specialists Surgical technique Complications
Anesthesia skill
Postoperative ICU physician staffing Early extubation Mortality
Nurse-to-patient ratios Resuscitation Complications
Monitoring Quality of Life
Nutrition Satisfaction
going resuscitation, and the prompt diagnosis and management of complications

(postoperative phase) (Table 1).
The comparison of outcomes has become an extremely common method of de-
termining the relative quality of care for medical centers. However, outcomes reflect
the quality of care only as much as the differences in structure and processes con-
tribute to changes in the health status of a patient. Changes in health status occur
as a result of many factors other than the processes of care including demographic
characteristics, severity of the primary illness, and comorbid diseases. Comparing
outcomes therefore requires rigorous control of competing factors - otherwise
known as risk adjustment [28, 29]. Therefore, given the observational nature of the
studies linking structural variables to outcomes it is important to consider the ade-
quacy of risk adjustment and the possible effect of residual confounding on the ob-
served associations.
I Provider Volume and Outcomes
One aspect of structure that has been the focus of intense debate is provider (sur-
geon or hospital) experience with a certain surgical procedure or medical condi-
tion. Some skepticism about the relationship of volume to outcome in health care
is based on the lack of adjustment for clinical differences between high and low
volume centers [30]. The population-based studies on the volume-outcome effect
are largely derived from state and national administrative datasets, but do include a
number of reports with rigorous clinical case-mix adjustment. The majority of re-
ports, including those with robust risk adjustment, demonstrate a variable but per-
sistent relationship of higher procedural volume with improved outcomes [31, 32].
Several surgical procedures have superior outcomes when performed at high vol-
ume centers, with more technically complex procedures showing a stronger rela-
tionship with volume [25-27]. Examples of procedures with a strong volume-out-
come effect include cardiac surgery, complex vascular surgery, and major cancer
surgery. The evidence of a volume-outcome effect has been sufficient enough for
the IOM to recommend regionalization of esophageal and pancreatic surgery for
malignant indications [33].
In response to the IOM reports on medical errors and quality of care problems,
several private and public organizations, including several Fortune 500 companies,
Hospital and ICU Organizational Structure and Quality of Care for Surgical Patients 937
have formed a coalition, the Leapfrog Group, in an effort to improve the quality of
care provided to their employees. This group represents approximately 10% of the
United States population. The three suggested policies include 24-hour staffing of
ICUs with board-certified intensivists, computerized physician order entry (CPOE),
and selective referral to high volume hospitals based on minimal volume standards
[34].
Hospital volume is not the only important provider-level variable affecting out-
come. Other provider characteristics, such as surgical specialty and individual sur-
geon volume, may also have a major influence on quality of care and should be
considered in a discussion of the relationship of organizational structure to out-
comes. The most comprehensive analysis of provider volume and surgeon specialty
has been reported in the Dartmouth Atlas of Vascular Health Care [35]. In addition
to differences for individual surgeon volume, there was also variation in mortality
depending on the specialty of the surgeon. Vascular surgeons' mortality rates
(4.4%) and cardiac surgeons' mortality rates (5.4%) were lower than those of gener-
al surgeons {7.3%). Other studies have documented the importance of individual
surgeon volume and surgeon specialty in contributing to several complex surgical
procedures [36-38]. Given the evidence that hospital volume is not the only impor-
tant provider-level variable, health policy efforts suggesting regionalizion should
consider these other provider level variables.
I ICU Physician Staffing
Some of the variation in outcomes across medical centers after complex surgery
can be explained by surgeon and hospital volume. However, the organizational fac-
tors and care processes that explain the relationship between volume and outcome
remain unclear. The organization of ICUs may contribute to this relationship. Pre-
vious studies have shown that the presence of a physician with specialty training in
ICU care has a positive impact on important clinical and economic outcomes for
both medical and surgical patients [ 11-19]. Alternatively, some investigations focus
on whether the ICU is open or closed though these titles may better reflect the
management of the ICU than who is providing care. In an open type ICU the main
caregiver is not an intensivist but remains either an internal medicine physician or,
in the case of surgery patients, the surgeon who performed the procedure. In gener-
al, we can consider whether or not an ICU has high intensity or low intensity phy-
sician staffing. The high intensity physician staffing includes both closed ICUs and
the presence of an intensivist as the primary physician responsible for the patient
in the ICUs.
The most comprehensive analysis of data regarding ICU physician staffing and
outcomes has recently been performed in the form of a systematic review [39]. Pro-
novost and colleagues reviewed 27 observational studies. Seventeen studies reported
hospital mortality. All but one of the studies reported a reduction in hospital mor-
tality with high intensity staffing. The random effects pooled estimate of the unad-
justed relative risk for high intensity versus low intensity staffing was 0.71 {95% CI
0.62-0.82). Fifteen studies evaluated the impact of ICU physician staffing on ICU
mortality. Overall, 14 out of these 15 studies {93%) showed a decrease in ICU mor-
tality rate for ICU patients with high intensity physician staffing. The random ef-
fects pooled estimate of the unadjusted relative risk for high intensity versus low
intensity staffing was 0.61 (95o/o CI 0.50-0.75). Nine studies evaluated the impact of
ICU physician staffing on hospital length of stay (LOS). After adjusting for baseline
severity, most studies (5 of 9) reported a reduction of total hospital LOS with high
intensity staffing. No studies reported a statistically significant increase in hospital
LOS with high intensity ICU physician staffing. Similarly, thirteen studies evaluated
the impact of ICU physician staffing on ICU LOS. Ten of 13 studies (77o/o) reported
a reduction in ICU LOS with high intensity staffing. No studies reported a statisti-
cally significant increase in hospital LOS with high intensity ICU physician staffing
[39].
One recent study from Maryland investigated the relationship of daily rounds by
an ICU physician to outcomes after abdominal aortic surgery across the hospitals
in Maryland. A prospective survey was sent to all non-federal hospitals in Mary-
land and was linked to the state hospital discharge database. The main findings of
the study were a 3-fold reduction in risk-adjusted mortality at hospitals that had
daily rounds by an ICU physician [13]. Patients without daily rounds by an ICU
physician were also at an increased risk of several complications including cardiac
arrest (2.9-fold increase), acute renal failure (2.2-fold increase), septicemia (1.8-fold
increase), platelet transfusion (6.4-fold increase), and reintubation (2-fold increase)
[13].
In a similar observational study of patients having esophageal resection, we
found that daily rounds by an ICU physician following esophageal resection were
associated with a decrease in LOS and hospital cost, but no reduction in in-hospital
mortality [11]. These observations could be at least partially explained by a reduc-
tion in postoperative complications. Patients without daily rounds by an ICU physi-
cian were more likely to experience complications that were predominantly pulmo-
nary in origin (reintubation, pneumonia, and pulmonary insufficiency) but also in-
cluded acute renal failure [11].
Having daily rounds by an ICU physician was also a predictor of complications
and mortality after hepatic resection in Maryland [12]. Specifically, not having dai-
ly rounds by an ICU physician was associated with an increase in reintubation (16-
fold increase), pulmonary insufficiency (8-fold increase), pneumonia (3.7-fold in-
crease), and acute renal failure (9-fold increase) [12]. These additional findings for
two high-risk general surgical procedures lend external validity to our previous
study on aortic surgery by showing improved outcomes for an additional high-risk
surgical procedure associated with daily rounds by an ICU physician. However, the
generalizability of these findings is limited because all of these studies used the
same survey instrument and were conducted in the same geographic area (Mary-
land). In addition to the improved clinical outcomes demonstrated in these studies,
daily rounds by an ICU physician are associated with reduced costs making ICU
physician staffing a dominant effect (improves quality and reduces costs).
In addition to these statewide studies, there have been two recent single-center
observational studies performed evaluating risk-adjusted outcomes for patients
with higher intensity ICU staffing compared to either concurrent or historical con-
trol groups [18, 19]. Hanson and colleagues examined a prospective cohort of pa-
tients who were cared for by an organized critical care service directed by a board-
certified intensivist (high intensity) compared to a concurrent control group cared
for by the regular ward team and supervised by the attending surgeon (low inten-
sity). There were 100 patients in each group and they were similar with respect to
baseline demographics and surgery type. Despite having higher levels of severity of
illness, patients managed by the organized critical care service had decreased com-
plications, ICU length of stay, and charges with no differences in mortality between
the two groups [18].
Ghorra and colleagues reported outcomes for patients before and after imple-
menting a closed ICU structure at a tertiary care center [19]. They examined 125
patients in the open-unit period and 149 in the closed-unit period. During the
closed unit-period the mortality rate was lower than during the open-unit period
(14.4 vs 6.04%, p = 0.012). Similarly, the overall complication rate was also higher
during the open-unit period (55.84 vs 44.14%, p = 0.002). Patients during the
closed-unit period also had a decreased length of stay and received fewer consulta-
tions [19].
Each of these studies demonstrates the importance of an organized critical care
team and the presence of a board-certified critical care specialist. Currently, very
few surgical ICUs have a physician staffing structure that would be considered high
intensity. If all ICUs were to convert to a higher intensity staffing the demand for
intensive care specialists would quickly outstrip the available supply. One solution
to having on-site ICU staffing would be to have access to a remote ICU specialist
using telemedicine technology. Rosenfeld and colleagues conducted an observa-
tional study during a 16 week period of remote ICU physician oversight in a 10
bed surgical ICU at a tertiary care center [40]. Intensivists provided management
with remote monitoring methodologies such as video conferencing and computer-
based data transmission. Using these technologies, the intensivists communicated
with on-site personnel to effect changes in patient care. To assess the benefit of the
remote management program, outcomes were compared with two 16-wk periods
within the year before the intervention. Risk-adjusted ICU mortality decreased dur-
ing the intervention period by 68 and 46%, compared with baseline in the two peri-
ods from prior to using the remote monitoring system. Risk-adjusted hospital mor-
tality decreased by 33 and 30%, and the incidence of ICU complications was de-
creased by 44 and 50%. ICU length of stay decreased by 34 and 30%, and ICU costs
decreased by 33 and 36%, respectively. The role of telemedicine in providing re-
mote ICU physician staffing is not defined. In remote areas with small ICUs, a tele-
communication link between several small hospitals and a central monitoring ICU
physician may improve outcomes in this setting.
I ICU Nurse Staffing
Surgical patients suffer enormous morbidity and mortality as a result of postopera-

tive complications. The subtle physiologic disturbances that prompt early interven-
tion and prevent or minimize the impact of complications are usually detected at
the nursing level. Recent studies have shown the importance of ICU nurse staffing
on determining postoperative outcomes. Given the widespread efforts to contain
costs, there has been reduced numbers of nurses caring for hospitalized patients.
With fewer nurses for more patients, the nursing staff has less time to spend ad~
dressing the needs of individual patients. The importance of individualized care is
especially important in the ICU setting and decreasing nursing staff in this setting
is likely to decrease quality and increase costs with more frequent adverse postop-
erative events.
Using the survey of ICU characteristics in Maryland we studied the relationship
of nurse staffing to outcomes after aortic, esophageal, and hepatic surgery. These
observational studies demonstrated a significant increase in morbidity and resource

utilization for patients receiving post-operative care in ICUs with fewer nurses. Pa-
tients undergoing abdominal aortic surgery who had fewer nurses in the ICU (three
or more patients per nurse) had an increased risk of medical or surgical complica-
tions (47 vs 34). Specifically, patients with fewer nurses had an increased risk of
pulmonary failure (4.5-fold increase) and reintubation (1.6-fold increase) [22].
For esophageal resection the findings were similar. For this procedure, having
fewer nurses during the night was associated with a 39% increase in length of stay
(4 days) and a 32% increase in direct hospital cost ($ 4810). Several post-operative
complications including reintubation, pneumonia, and septicemia were associated
with having fewer nurses and may explain the increased resource utilization [23].
For hepatic resection, another high-risk surgical procedure, there was also a signifi-
cant increase in post-operative pulmonary complications and resource utilization
for patients receiving post-operative care in intensive care units with a single nurse
caring for more than three ICU patients at night. At night, a unit with nurses car-
ing for three or more patients was associated with an increase in direct hospital
cost of$ 1248 (14% increase) [21].
Many other investigators have shown an association between nurse staffing and
patient outcomes across a variety of other settings. Fridkin and colleagues found
that a reduction in the nurse-to-patient ratio from 1:1 to 1:2 independently in-
creased the risk for catheter-related bloodstream infection [41]. An observational
study from Blegen and colleagues found that total hours of care from all nursing
personnel for all inpatient units within a hospital were associated directly with the
rates of pressure sores, patient satisfaction, and death [42]. Similarly, Archibald
and colleagues demonstrated that the nosocomial infection rate in a pediatric car-
diac ICU was inversely associated with the nursing hours per patient day ratio
[43].
Nurse staffing ratios have an impact not only on patient care but also the level
of job satisfaction and burnout for nurses. In a recent article by Aiken and col-
leagues, a survey of more than 10000 nurses was linked to outcomes for 230000 pa-
tients having general, orthopedic, and vascular surgical procedures during 1998 to
1999 in the state of Pennsylvania [44]. The authors demonstrated a 7% increase in
the risk of adjusted 30 day mortality with each additional patient added per nurse.
Further, for each additional patient per nurse, there was a 23% increased risk of
burnout and a 15% increased risk of job dissatisfaction [44]. Though these results
were not specific to the ICU, the implications can clearly be extrapolated to criti-
cally ill patients. In fact, given the higher rate of adverse events in the ICU it is
likely that outcomes are more affected by inadequate nurse staffing in this setting.
The results of these studies have striking face validity and prove that decreasing
nurses will decrease quality, increase complications, and increase cost. As the num-
ber of patients each nurse cares for increases, the time that can be devoted to each
patient decreases. By reducing the time available to devote to direct patient care,
the decreased level of care from low nurse to patient ratios may lead to pulmonary
and infectious complications that may account for increased length of stay, and cost
for post-operative patients for a variety of postoperative patients. Efforts of hospital
policy makers to reduce costs by reducing nurse staffing may therefore be counter-
productive resulting in increased patient morbidity and increased health care cost.
I ICU Pharmacists
Medical errors should be considered a threat to public health, especially in hospita-

lized patients. Large, population-based studies have shown that medical errors oc-
cur in 3% of all hospitalizations [2]. The most common type of medical errors oc-
cur with the ordering or delivery of medications [3]. Critically ill patients receive
several medications and are clearly at a high risk of harm from a medication error.
In addition to specialty trained nurses and physicians there is evidence emerg-
ing that inclusion of other health care professionals in daily rounds can improve
outcomes or prevent harm for critically ill patients. Leape and colleagues [45] con-
ducted a study of patients in a medical ICU at a large urban hospital where a phar-
macist participated in the morning rounds of the ICU team and was available
throughout the day for consultation. Compared to a historical group of control pa-
tients without daily rounds by a pharmacist, the rate of preventable adverse drug
events decreased by 66% from 10.4 to 3.5 per 1000 patient days during the period
of observation. The decrease in adverse drug events was achieved by the pharma-
cist making suggestions directly to the physician, which the physician complied
with in 99% of the cases.
Other similar studies have demonstrated a similar effect of increased pharmacist
participation and the decreased occurrence of adverse drug events as well as
decreased resource utilization [46, 47]. Involving a pharmacist in the daily ICU
rounds has the potential to improve the quality of care as well as decrease cost by
eliminating unnecessary medications or providing less costly, but equally effective,
alternatives.
Summary and Implications
Several hospital and ICU organizational characteristics have a clear association

with outcomes and provide an opportunity to improve quality of care. The relation-
ship of increased provider volume to improved outcomes is consistent across proce-
dures but varies with complexity. More complex procedures demonstrate a stronger
relationship. Health policy efforts are currently suggesting regionalization of several
complex surgical procedures. The structure and process variables that contribute to
the effect of volume on outcome are, for the most part, not known. Better out-
comes cannot be simply explained by better surgeons at higher volume settings.
The overall system of care for a given procedure is better at higher volume centers.
Differences in ICU structure likely contribute to the superior outcomes and account
for some of the empirically observed volume-outcome effect. Higher intensity ICU
physician staffing and adequate nurse to patient ratios are important to prevent
complications and death after high-risk surgical procedures.
As previously mentioned, the Leapfrog group, a coalition of private and public
payers in the United States, has set forth several health policy changes to improve
the safety of patients. These suggestions include both selective referral to higher
volume centers as well as mandatory ICU physician staffing as initial patient safety
goals. Yound and Birkmeyer have calculated the magnitude of universal adoption
of these policies and estimated that selective referral would save approximately
2600 lives and that implementing mandatory ICU physician staffing would, using
the most conservative estimate of effectiveness (15% reduction), save approximately
53 850 lives each year in the United States. However, this estimate was based on a
conservative estimate of a 15% relative risk reduction of mortality with higher in-
tensity ICU physician staffing [48]. The recent meta-analysis by Pronovost and col-
leagues [39] suggests intensivists are associated with a 30% relative risk reduction,
increasing the lives saved to 162000 annually rather than 53850. Unfortunately,
these organizational characteristics are often invisible to patients when making de-
cisions about where to receive health care. Given the importance of these hospital
referral patterns and ICU organizational changes, priorities should be directed to-
wards health policy implementing these changes.
Conclusion
ICU organizational structure, hospital and provider volume all influence patient
outcome. A recent meta-analysis of the effect of ICU physician staffing suggests
that more than 160000 lives could be saved if a high intensity model of ICU staff-
ing were uniformly adopted. In addition, ICU physician staffing is associated with
a reduced hospital and ICU LOS.
References
1. Chassin M, Galvin RW (1998) The urgent need to improve health care quality. Institute of
Medicine national roundtable on health care quality. JAMA 280:1000-1005
2. Institute of Medicine (1998) To Err is Human: Building a Safer Health System. National
Academy Press, Washington
3. Institute of Medicine (2001) Crossing the Quality Chasm: A New Health System for the
Twenty-first Century. National Academy Press, Washington
4. Pronovost PJ, Garrett E, Dorman T, et a! (2001) Variations in complication rates and op-
portunities for improvement in quality of care for patients having abdominal aortic sur-
gery. Langenbecks Arch Surg 386:249-256
5. Dimick JB, Stanley JC, Axelrod DA, et a! (2002) Variation in death rate after abdominal
aortic aneurysmectomy in the United States: Impact of hospital volume, gender, and age.
Ann Surg 235:579-585
6. Dimick JB, Pronovost PJ, Cowan JA, Lipsett PA (2003) Postoperative complication rates
after hepatic resection in Maryland hospitals. Arch Surg 138:41-46
7. Dimick JB, Pronovost PJ, Cowan JA, Lipsett PA (2003) Surgical volume and quality of care
for esophageal resection: Do high-volume hospitals have fewer complications? Ann Thorac
Surg (in press)
8. Weingart SN, Iezzoni LI, Davis RB, et a! (2002) Use of administrative data to find substan-
dard care: validation of the complications screening program. Med Care 38:796-806
9. Lawthers AG, McCarthy EP, Davis RB, Peterson LE, Palmer RH, Iezzoni LI (2000) Identifi-
cation of in-hospital complications from claims data. Is it valid? Med Care 38:785-795
10. Donabedian A (1980) Explorations in Quality Assessment and Monitoring. Vol. 1. The De-
finition of Quality and Approaches to its Assessment. Health Administration Press, Ann
Arbor
11. Dimick JB, Pronovost PJ, Heitmiller RF, Lipsett PA (2001) Intensive care unit physician
staffing is associated with decreased length of stay, hospital cost, and complications after
esophageal resection. Crit Care Med 29:753-758
12. Dimick JB, Pronovost PJ, Lipsett PA (2002) The effect of ICU physician staffing and hospi-
tal volume on outcomes after hepatic resection. J Intensive Care Med 17:41-47
13. Pronovost PJ, Jenckes MW, Dorman T, et a! (1999) Organizational characteristics of inten-
sive care units related to outcomes of abdominal aortic surgery. JAMA 281:1310-1317
14. Reynolds NH, Haupt MT, Thill-Baharozian M, Carlson RW (1998) Impact of critical care
physician staffing on patients with septic shock in a university hospital medical intensive
care unit. JAMA 260:3446-3450
15. Li TCM, Phillips MC, ShawL, Cook FE, Natanson C, Goldman L (1984) On-site Physician
Staffmg in a Community Hospital Intensive Care Unit. JAMA 252:2023-2027
16. Pollack MM, Katz RW, Ruttiman UE (1988) Improving the outcome and efficiency of inten-
sive care: The impact of an intensivist. Crit Care Med 16:11-17
17. Carson SS, Stocking C, Podsadecki T, et al (1996) Effects of organizational change in the
medical intensive care unit of a teaching hospital. JAMA 276:322-328
18. Hanson III CW, Deutschman CS, Anderson III HL (1999) Effects of an organized critical
care service on outcomes and resource utilization: a cohort study. Crit Care Med 27:270-
274
19. Ghorra S, Reinert SE, Cioffi W, Buczko G, Simms HH (1999) Analysis of the effect of con-
version from open to closed surgical intensive care unit. Ann Surg 229:163-171
20. Aiken LH, Clarke SP, Sloane DM, Sochalski J, Silber JH (2002) Hospital nurse staffing and
patient mortality, nurse burnout, and job dissatisfaction. JAMA 288:1987-1993
21. Dimick JB, Swoboda SM, Pronovost PJ, Lipsett PA (2001) Effect of nurse-to-patient ratio in
the intensive care unit on pulmonary complications and resource use after hepatectomy.
Am J Crit Care 10:376-382
22. Pronovost PJ, Dang D, Dorman T, et al (2001) Intensive care unit nurse staffmg and the
risk for complications after abdominal aortic surgery. Eff Clin Pract 4:199-206
23. Amaravadi RK, Dimick JB, Pronovost PJ, Lipsett PA (2000) ICU nurse-to-patient ratio is
associated with complications and resource use after esophagectomy. Intensive Care Med
26:1857-1862
24. Leape LL, Cullen DJ, Clapp MD, et al (1999) Pharmacist participation on physician rounds
and adverse drug events in the intensive care unit. JAMA 282:267-270
25. Gordon TA, Bowman HM, Tielsch JM, Bass EB, Burleyson GP, Cameron JL (1998) State-
wide regionalization of pancreaticoduodenectomy and its effect on in-hospital mortality.
Ann Surg 228:71-78
26. Birkmeyer JD, Siewers AE, Finlayson EV, et al (2002) Hospital volume and surgical mortal-
ity in the United States. N Engl J Med 346:1128-1137
27. Begg, CB, Cramer LD, Hoskins WJ, Brennan MF (1998) Impact of hospital volume on op-
erative mortality for major cancer surgery. JAMA 280:1747-1751
28. Randolph AG, Pronovost P (2002) Reorganizing the delivery of intensive care could im-
prove efficiency and save lives. J Eval Clin Pract 8:1-8
29. Pronovost P, Angus DC (1999) Using large-scale databases to measure outcomes in critical
care. Crit Care Clin 15:615-631
30. Daley J, Henderson WG, Khuri SF (2001) Risk-adjusted surgical outcomes. Annu Rev Med
52:275-287
31. Birkmeyer JD (2000) Should we regionalize major surgery? Potential benefits and policy
considerations. JAm Coll Surg 190:341-349 .
32. Halm EA, Lee C, Chassin MR (2002) Is volume related to outcome in health care? A sys-
tematic review and methodologic critique of the literature. Ann Intern Med 137:511-520
33. Institute of Medicine (2001) Interpreting the Volume-Outcome Relationship in the Context
of Cancer Care. National Academy Press, Washington
34. Birkmeyer JD, Finlayson EV, Birkmeyer CM (2001) Volume standards for high-risk surgical
procedures: potential benefits of the Leapfrog initiative. Surgery 130:415-422
35. Cronenwett J, Birkmeyer J (2000) The Dartmouth Atlas of Vascular Health Care. AHA
Press, Chicago
36. Hillner BE, Smith TJ, Desch CE (2000) Hospital and physician volume or specialization
and outcomes in cancer treatment: importance in quality of cancer care. J Clin Oncol
18:2327-2340
37. Tu JV, Austin PC, Johnston KW (2001) The influence of surgical specialty training on the
outcomes of elective abdominal aortic aneurysm surgery. J Vase Surg 33:447-452
38. Hannan EL, Popp AJ, Feustel P, et al (2001) Association of surgical specialty and processes
of care with patient outcomes for carotid endarterectomy. Stroke 32:2890-2897
944 J. B. Dimick et al.: Hospital and ICU Organizational Structure and Quality of Care for Surgical Patients
39. Pronovost PJ, Angus DC, Dorman T, Robinson K, Dremsizov TT, Young TL (2002) Physi-
cian staffing patterns and clinical outcomes in critically ill patients: A systematic review.
JAMA 288:2151-2162
40. Rosenfeld BA, Dorman T, Breslow MJ, et al (2000) Intensive care unit telemedicine: alter-
nate paradigm for providing continuous intensivist care. Crit Care Med 28:3925-3931
41. Fridkin SK, Pear SM, Williamson TH, Galgiani JN, Jarvis WR (1996) The role of under-
staffing in central venous catheter-associated bloodstream infections. Infect Control Hosp
Epidemiol17:150-158
42. Blegen MA, Goode CJ, Reed L (1998) Nurse staffing and patient outcomes. Nurse Res
47:43-50
43. Archibald, LK, Manning ML, Bell LM, Banerjee S, Jarvis WR (1997) Patient density, nurse-
to-patient ratio and nosocomial infection risk in a pediatric cardiac intensive care unit. Pe-
diatr Infect Dis J 16:1045-1048
44. Aiken LH, Clarke SP, Sloane DM, Sochalski, J, Silber JH (2002) Hospital nurse staffing and
45. Leape LL, Cullen DJ, Clapp MD, et a! (199) Pharmacist participation on physician rouds
and adverse drug events in the intensice care unit. JAMA 282:267-270
46. Gandhi PJ, Smith BS, Tataronis GR, Maas B (2001) Impact of a pharmacist on drug costs
in a coronary care unit. Am J Health Syst Pharm 58:497-503
47. Krupicka Ml, Bratton SL, Sonnenthal K, Goldstein B (2002) Impact of a pediatric clinical
pharmacist in the pediatric intensive care unit. Crit Care Med 30:919-921
48. Young MP, Birkmeyer JD (2000) Potential reduction in mortality rates using an intensivist
model to manage intensive care units. Eff Clin Pract 3:284-289
Volume and Outcome in Pediatric Critical Care:
How Much is Enough?
R. S. Watson and M. E. Hartman
I Introduction
Decades of observational studies have documented an inverse relationship between

patient volume and mortality in adult medicine, particularly related to surgical
procedures [1-3]. The weight of evidence is so great as to have led Arnold Epstein
to call for an end to the debate in a recent New England Journal of Medicine edito-
rial, titled "Volume and outcome - It is time to move ahead" [4]. However, what
that means for pediatric critical care is less clear, for the evidence of a volume-out-
come relationship in pediatric critical care is much less extensive. And while pedia-
tric critical care may be more regionalized in some countries than adult critical
care, many critically ill children in the United States are still treated and die at
non-tertiary centers [S-7]. Whether that is appropriate in light of the current state
of the literature is unsettled.
The nature of pediatric critical care makes it likely that a volume-outcome rela-
tionship exists. Critical illness in childhood is, at the population level, a relatively
rare event. It makes intuitive sense that physicians who commonly see uncommon
diseases and disease processes will become more adept at managing them than
physicians who see them infrequently. On the other hand, perhaps the heterogene-
ity of patients in pediatric critical care makes it difficult or impossible to accumu-
late enough experience in any given disorder to make a demonstrable difference.
Or, alternatively, perhaps pediatric critical care is already there. If critically ill chil-
dren are no longer treated at low volume centers, then the volume-outcome debate
is irrelevant. Perhaps the current level of regionalization of pediatric critical care
has already maximized outcome.
I Pediatric Critical Care has yet to Move Ahead
In the UK, the landmark study by Pearson et al. comparing Trent to Victoria
showed both lack of regionalization and worse outcome in Trent [8]. In the US,
Pollack et al. found in 1993 that 40% of US pediatric ICUs had 4 to 6 beds and that
only 6% had more than 18 [9]. Angus and colleagues found that 40% of neonates
who died in 1994 in New York and California did so at hospitals without extra cor-
poral life support, pediatric cardiac surgical, or pediatric neurosurgical services
[10]. More recently, Kanter reported that 27% of non-neonatal, pediatric hospital
deaths in New York State in 1997 occurred in hospitals without a board-certified
pediatric intensivist on staff. Even more striking was the finding that 35% of deaths
946 R. S. Watson and M. E. Hartman
in New York City occurred in non-intensivist hospitals [5]. Preliminary work from
6 large US states has found that non-teaching, non-children's hospitals provided
care for nearly one fourth of ventilated children older than 1 year in the US in
1999 [11] and 24% of children who died after hospital admission [7].
I The Volume-outcome Relationship in Critically Ill Children

Pediatric Cardiac Surgery
After evidence had accumulated in adult cardiac surgery that higher volume centers
and surgeons tended to have better outcomes than their smaller and less busy counter-
parts, several studies were performed in the US and UK to determine whether similar
relationships exist in the operative repair of congenital heart disease (Table 1). The
studies relied on large datasets to generate enough numbers of these uncommon pro-
cedures, either administrative discharge data or more clinically-rich cardiac surgery
registry data. Because of the wide range of baseline mortality risk associated with dif-
ferent cardiac defects and reparative procedures, most studies controlled for case-mix
at different centers by categorizing procedures by complexity.
Jenkins et al. studied 283.3 children from 37 centers in two US states undergoing
repair of congenital heart disease in the late 1980s [12]. Using hospital discharge
data, they found a significant association between increasing patient volume and
lower mortality rates, accounting for clustering of patients within each institution.
Prior to performing analyses, they categorized centers by annual case volume (< 10,
10-100, 101-300, and >300 cases/year) and procedures by complexity. The risk of
dying in-hospital was much lower if the center performed at least 300 cases an-
nually. Below this threshold, no consistent trends in mortality by annual case vol-
ume were seen. The relationship between volume and mortality was greater with
increasing complexity of procedure, with little difference between high and low vol-
ume hospitals for the simplest procedures. The authors did not examine effects of
individual surgeon volume.
Subsequently, Hannan et al. studied 7169 patients at 16 New York state hospitals
between 1992 and 1995 using a pediatric cardiac surgery registry that included in-
dividual surgeon volume [13]. A clear volume relationship was found, both at the
institutional and individual levels. Hospitals with an annual pediatric cardiac sur-
gery volume of at least 100 patients per year had a mortality rate of 5.95%, while
those treating less than 100 patients per year had a mortality rate of 8.26%. Sur-
geons operating less frequently, less than 75 cases per year, had a significantly
higher mortality rate (8.77%) than their colleagues performing more cases (5.90%).
Although the maximum differential in mortality rates was found at the above-noted
cutoff volumes, the authors found that the inverse relationship between volume and
mortality was present across all procedure volumes. Although the authors did not
take clustering (the fact that in multi-institutional studies, patients treated in the
same institution are not completely independent) into account in their analysis, the
strength of their findings suggests that they would remain significant even if using
more robust statistical techniques.
Sollano et al. also examined cardiovascular operations in New York state in the
early 1990s [14]. In contrast to Hannan et al. [13], they used hospital discharge
data, included patients of all ages, and analyzed an additional 2 years of data (1990
to 1995). Their analysis included 7199 repairs of congenital cardiac defects per-
Table 1. Volume-outcome studies related to pediatric cardiac surgery volume
Study Centers (n) Cases (n) Years Procedure volume Mortality OR OR Units
(center/year) [95% Cl)
Jenkins et al. [12] 37 us 2833 1988-89 1-602 0.33 Hospital caseload of > 300 cases/yr
Hospitals [0.20-0.56) vs 101-300 cases/yr
0.34 Hospital caseload of > 300 cases/yr
[0.19-0.63) vs 10-100 cases/yr
0.13 Hospital caseload of > 300 cases/yr
[0.027-0.63) vs < 10 cases/yr
Sollano et al. [14] 16 NYS 7199 1990-95 1-449 0.944 Per 100 cases/hospitaVyr Cf
Hospitals [0.92-0.97) 2"
3
Spiegelhalter [15] 12 UK NP 1991-95 NP 0.994 Per additional open case/hospital/yr
Hospitals [0.991 -0.997) (in children <1 yr old)
"'"':::>0..
0
0.993 Per additional open case/hospital/yr <=
[0.988-0.998) (in children 2: 1yr old) §
3
Hannan et al. (13] 16 NYS 7169 1992-95 19-379 0.73 Hospital caseload of > 100 cases/yr "'s·
Hospitals p<O.o5" vs < 100 cases/yr ~
0..
0.65 Surgeons performing > 75 cases/yr ~-
p<O.o5• vs < 75 cases/yr ::>.
,...
("'\
Stark et al. [16) 5 UK 1378 1997-98 NP Not :a·
Hospitals significant b j [
("'\
• Confidence interval not available "'fi?

b Few deaths after adjusting for procedure type and age group :I:
OR odds ratio; Cl confidence interval; NYS New York state (US); NP not provided ~
s:
<=
,...
:::r
v;·
:::>
"'
0
<=
10
~
':g
'-I
formed at 16 hospitals. Hospitals were categorized into 6 volume groups, with simi-
lar numbers of patients per group. The two highest volume groups contained only
one hospital each. They did not have data related to individual surgeon volume,
and they also did not account for clustering. The authors found a significant in-
verse relationship between volume and mortality (OR=0.94/100 cases/year [95%
CI: 0.92 to 0.97]). The most marked volume-related differences were found among
the sickest patients (neonates and those undergoing procedures of the greatest
complexity). There was no relationship for cases involving children over 12 years of
age, nor in neonates undergoing the simplest procedures.
In the UK, Spiegelhalter looked at mortality rates in children undergoing cardiac
surgery between 1991 and 1995 at 12 English hospitals using two different adminis-
trative data sources (a hospital discharge data set and a cardiac surgery registry)
[15] . ·He stratified patients by type of procedure and analyzed volume as a continu-
ous variable (i.e., he did not select a volume threshold). In children < 1 year of age
undergoing open procedures, he found that the odds of death decreased by 0.56%
(95o/o CI: 0.92 to 0.20%) to 0.61% (95o/o CI: 0.90 to 0.31%] per patient per year per
center, depending on the data source. In children one year of age and older under-
going open procedures, the odds of death was reduced by 0.22% (0.6% to increased
odds by 0.14%] to 0.7% (1.17% to 0.23%) per patient per center per year. There
was no significant volume-outcome association for closed procedures, although a
similar trend (lower mortality at busier centers) was noted.
Most recently, Stark et al. examined 1378 operations performed by 11 surgeons
at 5 hospitals in the UK in 1997 and 1998 [16]. Four out of five centers performed
between 108 and 161 open operations annually, and the fifth center performed 481.
There was no correlation between center size and outcome. However, the number
of cases performed by particular centers and the number of deaths were too small
for adequate power to discern differences in performance.
Pediatric Intensive Care Units

Only three large studies have examined the volume-outcome relationship as it re-
lates to pediatric ICU volume (Table 2). In these studies, rich, prospectively col-
lected clinical data were used to assess unit characteristics associated with outcome,
and sophisticated severity of illness adjustment was performed using the Pediatric
Risk of Mortality (PRISM) score [17].
Table 2. Volume-outcome studies related to pediatric ICU volume
Study Cente~ Patients Yea~ Patient Beds/PICU Mortality OR OR Units

(n) (n) volume [95% Cl)
{year)
Pollack 16 us 5415 1989 156-756 4-14 Not significant

et al. [18) PICUs
Tilford 16 us 11106 1993 147-1378 4-20 0.95 Per 100
et al. [19] PIC Us [0.91-0.99] admissions/yr
Ruttiman 32 us 11 165 1993-94 168-1812 4-40 0.96 Per 120
et al. [20] PIC Us [0.93-0.99] patients/yr
PICU Pediatric Intensive Care Unit; OR odds ratio; Cl confidence interval

Volume and Outcome in Pediatric Critical Care: How Much is Enough? 949
---~--~~~~,--~--~~"~,-~
In their landmark study on the effect of pediatric ICU organizational factors on

mortality, Pollack et al. examined 5400 admissions to 16 US pediatric ICUs in 1989
[18]. They found that the presence of a pediatric intensivist reduced severity-ad-
justed mortality, but teaching hospital affiliation increased mortality (explained,
perhaps, by residents caring for pediatric ICU patients). They found no significant
effect of volume of patients or pediatric ICU size on mortality. Although the study
had a power of 90% to detect a 2% change in mortality, the range of volume (156
to 756 patients per year) and number of patients studied was smaller than that of
two subsequent studies that did find a volume-outcome relationship, one of which
was performed by several of the authors of this study.
The first study to demonstrate lower mortality at higher volume pediatric ICUs
was published in the year 2000 and performed by Tilford et al. [19]. These investi-
gators studied over 11106 admissions in 1993 to 16 US pediatric ICUs, with a range
of 147 to 1378 admissions per year. Their thorough analysis accounted for cluster-
ing using multilevel models, and they found a severity-adjusted mortality OR=0.95
for each 100 patients admitted per year (95% CI: 0.91 to 0.99). They also found a
small but statistically significant effect on length of stay (LOS), with higher volume
units having a shorter severity-adjusted LOS (incident rate ratio= 0.98 per 100 pa-
tients per year [95% CI: 0.975 to 0.985]).
Also using data from the early 1990s, Ruttimann, Patel, and Pollack studied
11165 patients at 32 US pediatric ICUs [20]. The size range of these units (4 to 40
beds, 168 to 1812 annual admissions) was more diverse than the prior two studies.
They found that severity-adjusted hospital mortality was lower in larger units
(OR=0.96 per 120 patients/year [95% CI: 0.93 to 0.99]). In addition, they examined
the issue of diversity of diagnoses admitted to a particular unit, reasoning that va-
riations in patient heterogeneity may render the overall volume of admissions to a
multidisciplinary pediatric ICU a crude and incomplete measure of a unit's experi-
ence (e.g., a unit admitting 300 patients per year with multiple different diagnoses
is quite different than one admitting 300 oncology patients). In sophisticated ana-
lyses, they found that increased diversity of patient diagnoses was associated with
longer LOS in low volume units, but in units admitting at least 840 patients per
year, there was no relationship. Surprisingly, units admitting a narrower diagnostic
spectrum of patients did not have lower severity-adjusted mortality rates.
I How can Pediatric Critical Care Move Ahead?
The volume-outcome relationship in pediatric critical care leads to complex ques-

tions for health services researchers, policy makers, and clinicians. What else do
we need to know to optimize outcome for the greatest number of children? Have
we learned enough to change health policy, at least at a regional level? Finally, what
do we do now, if anything, with this information as we make treatment (or triage)
decisions for our patients?
Research
The basis for the volume-outcome relationship is complex and may be informed by
more detailed (though onerous) examination of the myriad of components of care.
Observational studies have yet to establish the direction of causality in the volume-
outcome relationship. However, it may be impossible to determine whether higher

volume centers perform better because of their more extensive experience ('practice
makes perfect') or whether high volume centers became so because of the better
quality of their care (the selective referral hypothesis). The answer is no doubt a
combination of the two, and the importance of each likely varies by region and
center.
Policy changes must be accompanied by evaluation. The assessment of centers
that are undergoing shifts in volume is crucial, not necessarily to settle the direc-
tion of causality, but to begin to identify more specific organizational factors that
are associated with performance. And we do not need to wait for changing patterns
of care. We can learn now from the examination of outliers (large units that per-
form poorly and small units that perform well).
Potential Pitfalls of Increasing Regionalization: Is it possible that some patients will

be harmed by increased regionalization? The economic, social, and emotional costs
of regionalization for children have yet to be studied. Because the benefit of in-
creased volume appears to be unequal across diagnoses and illness severity, pa-
tients who are at low risk for adverse outcome might receive little or no benefit
from obtaining care at high volume centers. In these patients, in particular, the
risks or costs of receiving care at a remote, high volume center may outweigh po-
tential benefits. In the long term, if regionalization is applied inappropriately, it
may discourage parents from seeking care. On the other hand, for most parents,
the choice between the inconvenience of being sent to a remote (high volume) cen-
ter and an increased chance of death at a local facility would be no choice at all.
Not Just How Much is Enough, But How Much is Too Much? If there is a threshold ef-
fect, there may also be a point where improved efficiency cannot be sustained. For
example, Ruttimann et al. [20] concluded that diagnostic diversity is associated
with efficiency only in low-volume units, and as the number of patients seen in a
unit increases, the narrowness of the diagnostic spectrum becomes less and less
important [20]. In addition, there might be a point at which increasing center vol-
ume may have deleterious effects, particularly if the increase in volume is not ac-
companied by an increase in capacity at the center. The Neonatal Staffing Study
Group found that mortality was higher in units with increased workload, and pa-
tients admitted to neonatal ICUs at full capacity were more likely to die than pa-
tients admitted to units at half capacity [21].
Health Policy
As Dr. Epstein points out [4], few health care professionals would send their own
family members to undergo a high-risk, elective operation at a hospital where such
operations were rarely performed if good alternatives were nearby. The same is no
doubt true for critically ill children. Efforts to educate parents and physicians are
appropriate to increase demand for high volume centers. Similarly, programs by
professional societies or governmental regulatory bodies that use more intrusive
methods to decrease the proportion of critically ill children managed in low-vol-
ume hospitals may be needed. Finally, with evidence that high volume centers may
be more efficient, payors may ultimately provide incentives to use them. However,
as noted above, provisions need to be made for increased capacity at high volume
centers.
Volume and Outcome in Pediatric Critical Care: How Much is Enough? 951
---~--~~~~,--~--~~"~,-~
Initial efforts could be focused on metropolitan areas and on children for whom
the differences in mortality between high and low hospitals are greatest (e.g., chil-
dren undergoing complicated repair of congenital heart disease). For pediatric ICU
services, the highest risk population is less clear, because no severity of illness
threshold has been found for which high volume care is more important. And in
neither pediatric cardiac surgery nor pediatric critical care has the volume thresh-
old above which outcome is clearly better (and below which, clearly worse) been
definitively established. Jenkins et al. [12] found that two hospitals with surgical
caseloads above 300/year outperformed smaller centers, whereas Hannan et al. [13]
noted that a cutoff of 100/year provided the greatest discrimination. With increas-
ing volume above 100, though, outcomes continued to improve. Other studies of
surgical caseload did not look for a specific threshold. Nor was a specific threshold
sought in any of the three studies of pediatric ICUs. Only two of these studies
found a volume-outcome relationship [19, 20]. However, in the study that did not
[18], the largest unit included in the study had 756 admissions per year. This is an
important difference from the other two studies which included units with 1400
[19] to 1800 [20] patients per year. Perhaps somewhere between 800 and 1400 pa-
tients per year is a point at which a performance threshold is reached.
Conclusion
Not surprisingly, the relationship between volume and outcome appears to exist
also for services for critically ill children. As in studies of adults, the exact etiology
of this relationship is not clear, nor is the threshold at which a center can be ex-
pected to perform well. As the bedside practice of critical care is increasingly en-
riched by positive randomized trials, where and how this evidence is applied will
become more important. Although some physicians and institutions will resist re-
gionalization, increasing the proportion of care that is provided in high-volume
centers seems prudent. However, it is only one step toward improving the quality
of care for critically ill children. Further exploration of the specific components of
care that are responsible for the volume-outcome relationship will enhance the per-
formance of all hospitals.
References
1. Luft HS, Bunker JP, Enthoven AC (1979) Should operations be regionalized? The empirical
relation between surgical volume and mortality. N Eng! J Med 301:1364-1369
2. Birkmeyer JD, Siewers AE, Finlayson EVA, et a! (2002) Hospital volume and surgical mor-
tality in the United States. N Eng! J Med 346:1128-1137
3. Dudley RA, Johansen KL, Brand R, Rennie DJ, Milstein A (2000) Selective referral to high-
volume hospitals: Estimating potentially avoidable deaths. JAMA 283:1159-1166
4. Epstein AM (2002) Volume and outcome - it is time to move ahead. N Eng! J Med
346:1161-1164
5. Kanter RK (2002) Regional variation in child mortality at hospitals lacking a pediatric in-
tensive care unit. Crit Care Med 30:94-99
6. Hartman ME, Watson RS, Linde-Zwirble WT, Kochanek PM, Angus DC (2002) Is the man-
agement of severe pediatric TBI in the US appropriately regionalized? Crit Care Med
30(suppl12):A14 (abst)
7. Watson RS, Linde-Zwirble WT, Hartman ME, et a! (2003) ICU use at the end-of-life in US
children. Crit Care Med 30(suppl 12):A147 (abst)
952 R. S. Watson and M. E. Hartman: Volume and Outcome in Pediatric Critical Care: How Much is Enough?
8. Pearson G, Shann F, Barry P, et al (1997) Should paediatric intensive care be centralised?

Trent versus Victoria. Lancet 349:1213-1217
9. Pollack MM, Cuerdon TC, Getson PR (1993) Pediatric intensive care units: Results of ana-
tional survey. Crit Care Med 21:607-614
10. Angus DC, Linde-Zwirble WT, Griffin M, Clermont G, Clark RH (2001) Epidemiology of
neonatal respiratory failure in the US: Projections from California and New York. Am J Re-
spir Crit Care Med 164:1154-1160
11. Watson RS, Linde-Zwirble WT, Hartman ME, Clermont G, Angus DC (2002) Epidemiology
of mechanical ventilation in non-infant US children. Crit Care Med 30(suppl 12):A131
(abst)
12. Jenkins KJ, Newburger JW, Lock JE, Davis RB, Coffman GA, Iezzoni LI (1995) In-Hospital
Mortality for Surgical Repair of Congenital Heart-Defects - Preliminary-Observations of
Variation by Hospital Caseload. Pediatrics 95:323-330
13. Hannan EL, Racz M, Kavey RE, Quaegebeur JM, Williams R (1998) Pediatric cardiac sur-
gery: the effect of hospital and surgeon volume on in-hospital mortality. Pediatrics
101:963-969
14. Sollano JA, Gelijns AC, Moskowitz AJ, et al (1999) Volume-outcome relationships in cardio-
vascular operations: New York State, 1990-1995. J Thorac Cardiovasc Surg 117:419-428
15. Spiegelhalter DJ (2002) Mortality and volume of cases in paediatric cardiac surgery: retro-
spective study based on routinely collected data. Br Med J 324:261
16. Stark J, Gallivan S, Lovegrove J, et al (2000) Mortality rates after surgery for congenital
heart defects in children and surgeons' performance. Lancet 355:1004-1007
17. Pollack MM, Ruttimann UE, Getson PR (1988) Pediatric risk of mortality (PRISM) score.
18. Pollack MM, Cuerdon TT, Patel KM, Ruttimann UE, Getson PR, Levetown M (1994) Impact
of quality-of-care factors on pediatric intensive care unit mortality. JAMA 272:941-946
19. Tilford JM, Simpson PM, Green JW, Lensing S, Fiser DH (2000) Volume-outcome relation-
ships in pediatric intensive care units. Pediatrics 106:289-294
20. Ruttimann UE, Patel KM, Pollack MM (2002) Relevance of diagnostic diversity and patient
volumes for quality and length of stay in pediatric intensive care units. Pediatr Crit Care
Med 1:133-139
21. Tucker J, The UK Neonatal Staffing Study Group (2002) Patient volume, staffing, and work-
load in relation to risk-adjusted outcomes in a random stratified sample of UK neonatal
intensive care units: a prospective evaluation. Lancet 359:99-107
Human Factors and ICU Outcomes
D. T. Huang, J. B. Sexton, and D. C. Angus
I Introduction
In the last few years, the issue of patient safety has become a health care priority
in many industrialized countries. For example, in the United States, the 1999 Insti-
tute of Medicine's (IOM) report "To Err is Human" estimated that 44 000 to 98 000
patients die each year from medical errors [1], prompting a large business consor-
tium, the Leapfrog Group, to issue three recommendations to improve patient safety
[2]. One of their recommendations, encouraging properly credentialed intensive
care unit (ICU) physician staffing, was welcomed by the ICU community as a key
organizational variable that could independently improve patient outcomes and has
received considerable attention. In addition, the accrediting body for all US hospi-
tals, the Joint Commission on Accreditation of Healthcare Organizations (JCAHO),
is creating a set of ICU Core Measures as a means of measuring the quality of
health care delivered in ICUs. As of October 2002, JCAHO is soliciting comments
on its 11 proposed measures, which range from APACHE III adjusted mortality to
optimal pain management and rate of resistant infections (http://www.jcaho.org/
accredited+organizations!hospitals!oryx!core+measures!icu.htm).
Somewhat lost in the discussion however, has been the potential impact of the
human factors of ICU organization, that of teamwork, job satisfaction and other
psychosocial variables. Nevertheless, a 2002 European Society of Intensive Care
Medicine (ESICM) statement defines intensive care medicine as "combin[ing] physi-
cians, nurses and allied health professionals in the coordinated and collaborative
management of patients" [3], while a 2001 Society of Critical Care Medicine
(SCCM) best practice model recommendation endorses "a model wherein dedicated
ICU personnel ... all work as a team" [4]. This chapter will discuss the conceptual
interaction between human factors and outcomes, review its application in the avia-
tion industry and the potential relevance to intensive care medicine, and provide
suggestions for future research.
I How Do Human Factors Affect Outcomes?
For the purposes of this discussion, human factors will be defined as those perso-
nal and interpersonal psychological characteristics that affect the learning and ex-
ecution of essential tasks. These include factors such as teamwork, working condi-
tions, job satisfaction and morale. Industry has long accepted the notion that hu-
man factors can strongly impact job performance. Even in medicine, it is fairly
954 D. T. Huang et al.
Input Process Outcome
Patient and team

performance
1 ! outcomes
Patient safety
Patient satisfaction
Team input Team process Team efficie ncy
factors factors
Human factors Team formation & management Human facto rs

Individual skill Technical procedures Skill development
personality I Motivation Communication skills Turnover
1ieam composition Decision processes Absenteeism
n1me pressure Situational awareness
National culture Conflict resolution Individual and
physical condition
organizational
outcomes
Fig. 1. Team performance model of inputs, processes and outcomes. Adapted from [5) with permission
common to find warm sounding mission statements and written ICU policies ap-
pealing to the concept that better teamwork equals better care. However, the reci-
procal notion, that poor human factors lead to worse patient outcomes, is not as
universally embraced. The underlying mechanisms by which human factors can im-
pact outcomes are multiple.
First, human factors do not in and of themselves cause outcomes; rather, they
serve as contexts in which outcomes unfold. Human factors predict behaviors and
cognitions [5], which in turn are linked to outcomes [6]. Moreover, the relationship
between human factors and outcomes is likely a mutual one; factors impact out-
comes and those outcomes subsequently influence factors. Helmreich and collea-
gues [5] have created a model wherein input factors from individuals, groups, orga-
nizations and environments create a framework that guides team processes, the
quality of which lead to subsequent outcomes, with feedback loops from the out-
comes back to the input and process factors (Fig. 1).
On a less conceptual level, it is not difficult to conceive of numerous ways in
which human factors might influence patient care and hence patient outcome. As
Dr. Greenfield, past president of the American Surgical Association (ASA), has
noted, low morale among nurses and hostility towards hospital administration have
resulted at least partly from having their training wasted on excessive clerical and
janitorial work, as well as verbal abuse from physicians [7]. In addition, physicians
sometimes disregard nursing input, especially when the nurses are unfamiliar to
them [8]. Under these working conditions, it would not be surprising for many
nurses to lapse into a passive role and not provide their patients with their full in-
tellectual and emotional commitment. Even those personnel not directly involved
in hands-on patient care might significantly impact ICU function. For instance,
ward clerks act as conduits between physicians, nurses and patient family members,
as well as playing an integral role in obtaining necessary items for patients. A per-
sonable, motivated senior clerk can ease the tension of a grieving family by politely
Human Factors and ICU Outcomes 955
explaining visitation rules, and speed diagnoses by promptly ordering a physician's

radiology requests, while a disgruntled clerk can significantly increase nursing
workloads though inefficiency, forcing nurses to perform extra clerical duties.
Lastly, conflict often arises within ICUs between physicians over the management
of a patient, leading to confusion amongst nurses and other ICU personnel over
whose orders to follow. That patients might suffer as a result of these examples is
not difficult to imagine.
I Evidence From Industry of the Impart of Human Factors

on Performance
The impact of human factors has been most thoroughly investigated in the aviation
industry. Almost 30 years ago, the aviation industry set out to systematically deter-
mine how to reduce errors and prevent accidents. One of the most significant find-
ings was that breakdowns in communication, rather than technology, were respon-
sible for the majority of accidents. Safety experts estimate that up to 70% of all
aviation accidents are wholly or at least partly due to human error, frequently due
to poor crew coordination or contingency planning, as opposed to frank knowledge
deficits [9, 10]. To address this, in 1979 the National Aeronautics and Space Admin-
istration (NASA) organized a workshop that created the concept of Crew Resource
Management (CRM), a management philosophy that emphasizes the role of human
factors and team training in high stress environments [11].
Since then, CRM has become a required component of training in the aviation
industry worldwide and has become widely accepted both by management and
flight crew members [12]. While it is impossible to definitively prove that the wide-
spread adoption of CRM has been directly responsible for the improved aviation
safety record over the past 20 years, most safety experts believe that CRM has
played a major role in this success. Its role in medicine continues to be an area of
both great interest and debate. In 2001, the US Agency for Healthcare Research and
Quality (AHRQ) issued a report stating "it cannot yet be concluded that CRM is a
practice that can reduce medical errors", but allowed that "additional research ... is
warranted" [13]. Ironically, a somewhat circular argument was made that, "for the
analogous reasons that aviation has adopted CRM based on face validity, health
care decision makers may wish to consider face validity in lieu of massive research
investments:'
Perhaps the most important byproduct of CRM was the creation of the Cockpit
Management Attitudes Questionnaire (CMAQ). It resulted from the difficulty in
measuring and quantifying teamwork and communication. Direct observation of
working cockpit crews yielded highly accurate data but was very time consuming.
The CMAQ was designed to serve as a proxy measurement tool to evaluate the atti-
tudes of crew members toward stress, status hierarchies, leadership, and interperso-
nal interaction issues [14]. Over the last two decades, the CMAQ has been exten-
sively refined through multiple validation samples and has been shown to be able
to detect change and, most importantly, to predict performance [15-17].
---~--~~~~,--~--~~'"~·-~
Evidence from Healthcare on The Impact of Human Factors

on Outcomes
In 1986, Dr. William Knaus and colleagues explored the relationship between hu-
man factors and outcomes, using an ICU cohort of 5030 ICU patients in 13 hospi-
tals [18]. After adjusting for diagnosis, operative status, Therapeutic Intervention
Scoring System (TISS) score, APACHE II, and indication for ICU admission, a
three-fold variation in standardized in-hospital mortality rates was found. ICU phy-
sician staffing patterns, hospital teaching status, and the amount of specialized
treatment had no association with mortality rates. In contrast, hospitals with better
ICU personnel interaction and coordination had lower mortality rates. Specifically,
better performing hospitals were noted to have excellent communication and re-
spect between physicians and nurses, comprehensive nursing education programs,
high degrees of coordination of care and greater nursing autonomy, while poorer
performing hospitals were notable for frequent disagreements, mistrust, and per-
sonality conflicts amongst ICU personnel.
Two follow-up studies by Knaus and colleagues were unable to demonstrate a
human factors association with mortality, but did find an association with other
ICU outcomes. Human factors were measured via site visits, interviews and a
unique measurement tool, the ICU Nurse-Physician Questionnaire (INPQ). This
survey instrument measured "caregiver interaction" as defined by unit culture, lea-
dership, communication, coordination, problem-solving/conflict management, and
unit cohesiveness and effectiveness [19]. The first follow-up study looked at nine
ICUs and found that ICUs with lower risk-adjusted mortality rates could not be
distinguished by level of caregiver interaction.
The second follow-up study used a larger sample size of 42 ICUs and looked at
additional ICU outcomes besides mortality [20]. Caregiver interaction was found to
be significantly associated with lower risk-adjusted length of stay, lower nurse turn-
over and greater perceived ability to meet family member needs, but had no asso-
ciation with risk-adjusted mortality. Conversely, technology was found to be signifi-
cantly associated with decreased risk-adjusted mortality, but had no association
with length of stay or nurse turnover and actually had a negative association with
perceived ability to meet family members needs. The authors hypothesized that
mortality may be more impacted by technology, while efficiency, as estimated by
length of stay, may be more affected by caregiver interaction. Of particular note is
that neither technological availability nor nurse staffing ratios were related to nurse
turnover rates; only caregiver interaction was negatively associated with nurse turn-
over.
A 1996 study comparing 25 ICUs to a theoretically ideal organizational structure
found similar results [21]. Units closer to this ideal had higher nurse retention and
morale, but severity-adjusted mortality, length of stay and patient satisfaction were
unchanged. This linkage between human factors and nurse retention rates has been
confirmed in several studies [22, 23].
Recent data point to the importance of a stable nursing workforce. A study by
Aiken and colleagues examined the associations between nursing workload, job sa-
tisfaction and patient outcomes [24]. Analyses of linked data from 10184 nurse sur-
veys and 232342 surgical patients from 168 Pennsylvania hospitals found that in
hospitals with high patient-to-nurse ratios, surgical patients had higher risk-ad-
justed mortality and nurses had higher rates of burnout and job dissatisfaction.
Similar results between workload and mortality were seen in a United Kingdom
reu [25], and between patient-to-nurse ratios and mortality in 799 hospitals in 11
US states [26]. Improvements in human factors that lead to higher nurse retention
rates, might thus indirectly affect patient outcomes. With the current US nursing
shortage crisis, these observations have profound health care delivery implications
as hospitals compete to recruit and retain nurses [27, 28].
Additional evidence of the importance of human factors in the IeU comes from
the work of Dr. Judith Baggs. Baggs and colleagues first developed a seven-item
scale that asked reu providers at the time of a patient's transfer out of an reu,
their perception of the degree of collaboration associated with making the transfer
decision [29]. They theorized that the decision to transfer a patient could be im-
proved by collaboration and that poor decisions would result in negative outcomes,
as defined by a combined endpoint of death or reu readmission. This scale was
utilized in a single reu and found a negative correlation between the level of
nurse-reported collaboration and patient outcomes [30]. The scale was then applied
to nurses and physicians in three organizationally different reus to measure pa-
tient-level collaboration [31]. Site visits and interviews of unit leadership comprised
the unit-level assessments of collaboration. Only the medical reus' nurses' reported
collaboration was associated with a reduced risk of a negative outcome; perceived
collaboration by the nurses in the other two reus or from physicians had no such
association. Unit-level collaboration held an exact rank order correlation with pa-
tient outcomes. The study was limited by the small sample size and the use of a
combined endpoint, rather than reporting of separate data for mortality and reu
readmission.
The EURieUS I study of 89 reus in 12 European countries supported the con-
cept that improving teamwork between reu physicians and nurses could positively
impact reu mortality. Lower levels of task differentiation and greater levels of de-
centralized decision-making and organizational commitment were associated with
improved SAPS II adjusted mortality. Interestingly, no difference was found be-
tween open versus closed culture reus [32]. While limited in number, these studies
suggest that human factors play a role in determining reu outcomes.
An interesting study by Sexton and colleagues used the eMAQ survey instru-
ment noted above and modified it for use in operating rooms and reus [33, 34].
These derivative survey instruments were then applied to an reu in a large, urban
US teaching hospital and 12 operating rooms in five countries. eMAQ data from 40
different airlines in 25 countries served as a comparison cohort [34]. Most striking
was the response to the item "Even when fatigued, I perform effectively during crit-
ical times", to which 60% of medical staff agreed, versus only 26% of pilots. Differ-
ences between nurses and physicians were also noted, with 77% of intensivists re-
porting high levels of teamwork with nurses, while only 40% of nurses reported
high levels of teamwork with doctors. While these results were only from a single
reu, this nearly 2-fold difference in perception suggests a large disconnect between
intensivist perception of teamwork and reality. Supportive of this hypothesis was
that over half of the intensive care respondents stated that decision making should
include more team member input, despite the fact that 94% of reu staff advocated
a flat hierarchal system that invited input from junior colleagues.
Attitudes about error and safety were equally striking. Only 33% of medical re-
spondents said that errors were handled appropriately in their hospital, 25% re-
ported that they were not encouraged to report safety concerns, and more than
50% reported that they found it difficult to discuss mistakes. Incredibly, one out of
three reu respondents did not acknowledge that they made errors at all. The
authors concluded that medical staff's difficulty in discussing, or even admitting,

errors, combined with differing perceptions of teamwork and denial of the effect of
stress and fatigue on performance posed a serious potential problem.
Dr. Sexton went on to develop a Safety Attitudes Questionnaire (SAQ), derived
from the ICU version of the CMAQ [35]. The SAQ was designed to assess six
"safety attitude" domains: teamwork climate [18, 36], job satisfaction [37], percep-
tions of morale [38], safety climate [39-41], working conditions [24, 42], and stress
recognition [43, 44]. Safety climate refers to the perception of a strong organiza-
tional commitment to patient safety. These domains were chosen based on previous
research in medicine and other industries that demonstrated associations with im-
proved outcomes or productivity. The SAQ was then applied to 106 ICUs of the
United Kingdom's Intensive Care National Audit and Research Centre (ICNARC),
and matched with these units' APACHE II data, outcomes from 18 089 patients, and
annual nurse turnover rates.
This work is notable for psychometrically validating the first aviation-based hu-
man factors survey instrument on a large number of ICUs. Preliminary data suggest
an association between safety attitude scores, risk-adjusted mortality and nurse turn-
over. A complete analysis is currently being developed. Future work by the authors
will further refine this instrument by applying it to other national ICU databases.
I How Can Human Factors in the ICU be Improved?

If we accept that human factors influence ICU outcomes, how can they be im-
proved? Unfortunately, limited information is available to guide us in this regard. A
unique approach was illustrated by Clemmer and colleagues, who applied the prin-
ciples of the legendary quality improvement expert, W. Edwards Deming, to a sin-
gle 12-bed mixed ICU [45]. Dr. Clemmer noted that of Deming's 14 points, 12 fo-
cused on the importance of creating a work environment that prioritized collabora-
tion, empowerment and safe relationships [46]. Starting in 1992, a highly detailed
quality improvement process was collaboratively created with input from ICU lea-
dership, personnel and hospital administrators. Consensus was achieved amongst
all stakeholders regarding a 5-year vision for their ICU, educational workshops
were held to teach providers the Deming principles, and possibly most importantly,
flexible, multidisciplinary teams of the 'front line' ICU providers were created to
target specific areas for improvement. These teams were given the authority and
autonomy to define a standard practice protocol, build a consensus among those
the protocol would affect, revise it based on colleagues' input and pilot testing, and
then create a long-term monitoring system.
Results from 1991 and 1995 were then compared, during which time severity of
illness as measured by the Computerized Severity Index methodology substantially
increased. Despite this, significant improvement in both targeted areas (e.g., use of
enteral feeding, acute respiratory distress syndrome [ARDS] survival, reduction in se-
dation and paralytics) as well as non-targeted areas (laboratory, blood gas and radi-
ology usage) was achieved. The authors hypothesized that a cultural change of in-
creased collaboration and empowerment was produced from the formal quality im-
provement projects and had a passive effect on all areas of ICU care, beyond those
specifically targeted for improvement. Dr. Clemmer and colleagues have distilled their
approach into five principles {Table 1); patient safety guidelines developed by Dr.
Helmreich and colleagues provide a useful comparison (Table 2) [47-49].
Table 1. Collaborative Quality Improvement in the ICU. Adapted from [47] with permission
Methods for Fostering Cooperation

Develop a shared purpose
Create an open environment
Include all who share the common purpose and encourage diverse viewpoints
Learn how to negotiate agreement
Insist on fairness and equity in applying rules
Table 2. Improving patient safety. Adapted from [49] with permission
Patient Safety Guidelines

Understand the organization's history and issues
Continuously gather accurate data on current practices to identify error-inducing conditions and
threats
Promote a safety culture that recognizes the inevitability of error and actively identifies and reduces
latent threats
Train staff in teamwork, decision-making, and error management
I Provide regular feedback, reinforcement and ongoing training
A more focused project recently demonstrated the utility of a collaborative wean-

ing plan [SO]. Through the use of a bedside weaning board and flowsheet, de-
creases in ICU length of stay (LOS) and length of ventilator time were achieved. No
weaning protocols were utilized. The authors hypothesized that these interventions
may have led to increased communication and collaboration among the ICU per-
sonnel, resulting in the observed weaning improvements. Furthermore, the multi-
disciplinary development of the weaning board and flowsheet may have, in and of
itself, sparked greater teamwork between ICU personnel. Positive results attributed
to the use of ICU protocols might also be partly due to such a mechanism,
although an alternative hypothesis that well-designed, mandatory protocols reduce
the effects of poor human factors is also possible (e.g., 'I may not want to bother
giving a detailed report on a patient, but if a protocol mandates it, I will').
Related work has been done in emergency departments (ED) by the MedTeams
Research Consortium. Part of a for-profit consulting company, MedTeams offers
teamwork training to ED personnel. Derived partly from aviation safety and mili-
tary practices, their teamwork system focuses on creating small work teams and
teaching teamwork behaviors, skills, and habits. In a retrospective study of 54 ED
malpractice incidents, MedTeams estimated that an average of 8.8 teamwork failures
occurred per case and that more than half of the resulting deaths and permanent
disabilities could have been avoided [51]. Teamwork training has been demon-
strated to favorably impact on ED effectiveness and medical error rates [52].
Conclusion
In summary, there is a growing body of evidence that human factors have impor-
tant effects on both patient outcomes and nurse turnover rates. Whether referred to
as collaboration, safety attitudes, caregiver interaction or process factors, attention
to this organizational aspect of intensive care may be of significant value to reus.
Relative to the efforts focused on the technical and organizational aspects of inten-
sive care through the Leapfrog Group, credentialing committees, fellowship curricu-
lum development, and other worthy endeavors, it is not clear what is being done to
optimize human factors in the ICU. Though direct application of organizational
practices from aviation and other industries may not be appropriate, it is incum-
bent upon medicine to explore which aspects can be of benefit to our patients.
However, it must be emphasized that whatever approach is taken, there is no sub-
stitute for sincerely committed leadership, without which any attempt to foster im-
proved human factors will rapidly degenerate into hackneyed truisms and mocked
mission statements. Future outcomes research should consider separately control-
ling for human factors, in addition to the more commonly measured variables of
disease severity, physician staffing patterns, workload and patient-to-nurse ratios.
References
1. Kohn LT, Corrigan JM, Donaldson MS (eds) (1999) To Err Is Human: Building a Safer
Health System. Committee on Quality of Health Care in America. Institute of Medicine,
Washington
2. The Leapfrog Group (Last updated Nov, 2000) Factsheet: ICU Physician staffing. The Leap-
frog Group website. URL http://www.leapfroggroup.org. The Leapfrog Group, Accessed
December, 2002
3. De Lange S, Van Aken H, Burchardi H (2002) ESICM Statement: European Society of Inten-
sive Care Medicine statement: Intensive care medicine in Europe - structure, organisation
and training guidelines of the Multidisciplinary Joint Committee of Intensive Care Medi-
cine (MJCICM) of the European Union of Medical Specialists (UEMS). Intensive Care Med
28:1505-1511
4. Brilli RJS (2001) Critical care delivery in the intensive care unit: Defining clinical roles and
the best practice model. Crit Care Med 29:2007-2019
5. Helmreich RL, Foushee HC, Benson R, Russini W (1986) Cockpit resource management:
exploring the attitude-performance linkage. Aviat Space Environ Med 57:1198-1200
6. Klinect JR, Wilhelm JA, Helmreich RL (1999) Threat and error management: Data from
line operations safety audits. In: Proceedings of the Tenth International Symposium on
Aviation Psychology. The Ohio State University, Columbus, pp 683-688
7. Greenfield LJ (1999) Doctors and nurses: a troubled partnership. Ann Surg 230:279-288
8. Doering LV (1999) Nurse-physician collaboration: at the crossroads of danger and opportu-
nity. Crit Care Med 27:2066-2067
9. Billings CE, Reynard WD (1984) Human factors in aircraft incidents: results of a 7-year
study. Aviat Space Environ Med 55:960-965
10. Wiegmann DA, Shappell SA (1999) Human error and crew resource management failures
in Naval aviation mishaps: a review of U.S. Naval Safety Center data, 1990-1996. Aviat
Space Environ Med 70:1147-1151
11. Cooper GE, White MD, Lauber JK (1980) Resource management on the flightdeck: Pro-
ceedings of a NASA/Industry Workshop, NASA Conference Publication No. CP-2120 ed.
NASA - Ames Research Center, Moffet Field
12. Helmreich RL, Foushee HC (1993) Why crew resource management? Empirical and theore-
tical bases of human factors in training and aviation. In: Wiener E, Kanki BG, Helmreich
RL (eds) Cockpit Resource Management. Academic Press, San Diego, pp 3-45
13. Pizzi L, Goldfarb Nl, Nash DB (2001) Crew resource management and its applications in
medicine. In: Making Health Care Safer: A Critical Analysis of Patient Safety Practices. Evi-
dence Report/Technology Assessment Number 43. AHRQ Publication No. 01-E058. Agency
for Healthcare Research and Quality, Rockville, pp 501.:..509
14. Helmreich RL (1984) Cockpit management attitudes. Hum Factors 26:583-589
15. Helmreich RL, Foushee HC, Benson R, Russini W (1986) Cockpit resource management:
exploring the attitude-performance linkage. Aviat Space Environ Med 57:1198-1200
16. Gregorich SE, Helmreich RL, Wilhelm JA (1990) The structure of cockpit management atti-
tudes. J Appl Psychol 75:682-690
17. Foushee HC (1984) Dyads and triads at 25000 feet: Factors affecting group process and air-
crew performance. Am Psychol 39:885-993
18. Knaus WA, Draper EA, Wagner DP, Zimmerman JE (1986) An evaluation of outcome from
intensive care in major medical centers. Ann Intern Med 104:410-418
19. Shortell SM, Rousseau DM, Gillies RR, Devers KJ, Simons TL (1991) Organizational assess-
ment in intensive care units (ICUs): construct development, reliability, and validity of the
ICU nurse-physician questionnaire. Med Care 29:709-726
20. Shortell SM, Zimmerman JE, Rousseau DM, et al (1994) The performance of intensive care
units: does good management make a difference. Med Care 32:508-525
21. Mitchell PH, Shannon SE, Cain KC, Hegyvary ST (1996) Critical care outcomes: linking
structures, processes, and organizational and clinical outcomes. Am J Crit Care 5:353-363
22. Gifford BD, Zammuto RF, Goodman EA (2002) The relationship between hospital unit cul-
ture and nurses' quality of work life. J Healthc Manag 47:13-25
23. Anonymous (2001) Perspectives. Work environment a top issue in nurse retention. Med
Health 55:7-8
24. Aiken LH, Clarke SP, Sloane DM, Sochalski J, Silber JH (2002) Hospital nurse staffing and
25. Tarnow-Mordi WO, Hau C, Warden A, Shearer AJ (2000) Hospital mortality in relation to
staff workload: a 4-year study in an adult intensive-care unit. Lancet 356:185-189
26. Needleman J, Buerhaus P, Mattke S, Stewart M, Zelevinsky K (2002) Nurse-staffing levels
and the quality of care in hospitals. N Engl J Med 346:1715-1722
27. Joint Commission on Accreditation of Healthcare Organizations (2002) Health care at the
crossroads: Strategies for addressing the evolving nursing crisis. JCAHO, Oakbrook Terrace
28. Steinbrook R (2002) Nursing in the crossfire. N Engl J Med 346:1757-1766
29. Baggs JG (1994) Development of an instrument to measure collaboration and satisfaction
about care decisions. J Adv Nurs 20:176-182
30. Baggs JG, Ryan SA, Phelps CE, Richeson JF, Johnson JE (1992) The association between in-
terdisciplinary collaboration and patient outcomes in a medical intensive care unit. Heart
Lung 21:18-24
31. Baggs JG, Schmitt MH, Mushlin AI, et al (1999) Association between nurse-physician colla-
boration and patient outcomes in three intensive care units. Crit Care Med 27:1991-1998
32. Miranda DR (1998) Organisation and Management of Intensive Care: A Prospective Study
in 12 European Countries. Springer, Berlin
33. Helmreich RL, Schaefer H-G (1994) Team performance in the operating room. In: Bogner
MS (ed) Human Error in Medicine. Laurence Erlbaum, Hillsdale, pp 225-253
34. Sexton JB, Thomas EJ, Helmreich RL (2000) Error, stress, and teamwork in medicine and
aviation: Cross sectional surveys. Br Med J 320:745-749
35. Sexton JB (2002) A matter of life or death: Social, psychological and organizational factors
related to patient outcomes in the intensive care unit (PhD dissertation). The University of
Texas, Austin
36. Vincent C, Taylor-Adams S, Stanhope N (1998) Framework for analysing risk and safety in
clinical medicine. Br Med J 316:1154-1157
37. Aiken LH, Clarke SP, Sloane DM, et al (2001) Nurses' reports on hospital care in five coun-
tries. Health Aff (Millwood) 20:43-53
38. Itoh K, Andersen HB (1999) Motivation and morale of night train drivers correlated with
accident rates. In: Karwowski W, Mondelo P, Mattila M (eds) Proceedings of the Interna-
tional Conference on Computer-Aided Ergonomics and Safety. Barcelona, Spain. May 19-
21, 1999. CABS, (CD-rom)
962 D. T. Huang et al.: Human Factors and ICU Outcomes
39. Sexton JB, Klinect JR (2001} The link between safety attitudes and observed performance
in flight operations. In: Jensen RS (ed) Proceedings of the Eleventh International Sympo-
sium on Aviation Psychology. The Ohio State University, Columbus
40. Dedobbeleer N, Beland F (1991} A safety climate measure for construction sites. J Safety
Res 22:97-103
41. Niskanen T (1994} Assessing the safety environment in work organization of road mainte-
nance jobs. Accid Anal Prev 26:27-39
42. Arnetz BB, Akerstedt T, Anderzen I (1990} Sleepiness in physicians on night call duty.
Work and Stress 4:71-74
43. Reason JT (1990} Human Error. Cambridge University Press, New York
44. Buckley TA, Short TG, Rowbottom YM, Oh TE (1997) Critical incident reporting in the in-
tensive care unit. Anaesthesia 52:403-409
45. Walton M (1990) Deming Management at Work. Perigee Books, New York
46. Clemmer TP, Spuhler VJ, Oniki TA, Horn SD (1999} Results of a collaborative quality im-
provement program on outcomes and costs in a tertiary critical care unit. Crit Care Med
27:1768-1774
47. Clemmer TP, Spuhler VJ, Berwick DM, Nolan TW (1998) Cooperation: the foundation of
improvement. Ann Intern Med 128:1004-1009
48. Helmreich RL (2000} On error management: lessons from aviation. Br Med J 320:781-785
49. Helmreich RL, Musson DM, Sexton JB (2001} Applying aviation safety initiatives to medi-
cine. Focus on Patient Safety 4:1-2
50. Henneman E, Dracup K, Ganz T, Molayeme 0, Cooper C (2001} Effect of a collaborative
weaning plan on patient outcome in the critical care setting. Crit Care Med 29:297-303
51. Risser DT, Rice MM, Salisbury ML, Simon R, Jay GD, Berns SD (1999} The potential for
improved teamwork to reduce medical errors in the emergency department. The MedTeams
Research Consortium. Ann Emerg Med 34:373-383
52. Simon R, Salisbury M, Wagner G (2000} MedTeams: teamwork advances emergency depart-
ment effectiveness and reduces medical errors. Ambul Outreach 21-24
The Risk of Nursing in an Error Prone Environment
J. M. Binnekade, M. B. Vroom, and J. Kesecioglu
I Introduction
In the Netherlands, the availability of intensive care unit (ICU) nurses is seriously
threatened by a tight job market and future perspectives look even more worri-
some. The availability of ICU nurses is an important factor in maintaining an ac-
ceptable level of quality of care [1-4]. Unfortunately, many ICUs are confronted
with a rapid turnover within their nursing team resulting in a loss of experience.
In addition, working under pressure in a complex environment may introduce er-
rors [5]. As a result, the quality of care may become compromised as nurses per-
form and control the majority of tasks in direct patient care [6, 7]. Under these
conditions, an objective indicator of nursing care quality would be very useful,
especially when this indicator is able to detect deterioration in quality before it be-
comes apparent. The difficulty of such a tool is the fact that quality needs to be ex-
pressed in a quantitative manner. Therefore, a new instrument was developed, pro-
viding quantitative measures adjustable to the specific working environment.
I The Measurement of Quality of Nursing Care

Quality of care is defined as the degree to which health services for individuals and
populations increase the likelihood of desired health outcomes [8]. The likelihood
of desired health outcomes increases when nurses use protocols representing good
clinical practice. 'Ideal nursing care' can be defined simply as the formal care de-
scriped in standards, protocols and guidelines. This 'ideal nursing care' is consider-
ed to be the goal; deviation from this standard (i.e., error) can be considered as
the .variable characteristic quantifying the quality of care. An observable error re-
lated to nursing behavior can be measured if this error is unequivocally defined.
According to this line of reasoning, error is the k-ey concept in the construct to
measure quality of nursing care.
I Error and Nursing

An error is defined as a planned action, which fails to achieve the desired goal. Ba-
sic error types are planning failures, visible execution failures, or invisible memory
failures [9-11]. An error is by definition unexpected and is never planned or de-
sired. This is in contrast to an intentional deviation from a protocol, which is con-
964 J. M. Binnekade et al.
sidered to be a violation. Errors can occur in someone's mind, can be unobservable

planning failures, or observable errors once action has been taken.
Errors can take several forms:

I error of omission, an appropriate step is left out in the process. For instance, a
blood gas sample was not taken following extubation
1 error of insertion, an inappropriate step is added into the process. For example a
wedge pressure balloon is inflated while the external pacemaker wire is still in
place via the right ventricular lumen of the Swan-Ganz catheter
I error of repetition, an inappropriate step is added into the process that is nor-
mally appropriate. For instance, a drug was administered twice because it was
not registered appropriately the first time
I error of substitution, the appropriate step, object or time is replaced by an inap-
propriate one. For example, an incorrect drug was administration due to unclear
handwriting.
It is common to discuss errors in medical settings in terms of their consequences,

especially injury or death. However, this does not provide information concerning
th~ underlying. cause of the error. Fortunately, in our clinical experience, most er-
rors are recognized before an adverse event occurs. For instance, a nurse can select
a wrong ampoule. but replace it immediately with the right one. Also, safety nets or
barriers are created in order to reduce errors, for instance by using checklists, re-
gistration systems or double checks of medication dosage. A high nursing work-
load, however, will reduce the aforementioned corrective attention and evoke the
bypassing of the barriers in order to gain time.
I Objectives of the Instrument
The objective was to develop an instrument to assess error and safety aspects of
ICU nursing performance. This instrument had to:
I be based on a clear construct strongly related to the quality of nursing care
1 generate an overall figure of quality based on a valid cross-section of direct and
indirect nursing care
I be reliable and sensitive for changes in quality
I be capable of measurement independent of the time, nurses, or patients involved
I be applicable without the active cooperation of the nurses.
From a practical point of view we only used visible predefined consequences of

protocol errors due to nursing activities. A meaningful measure is not generated by
simply counting all predefined protocol deviations, but by prioritizing the possible
deviations (i.e., possible protocol violations) by the degree to which they i:educe a
patient's safety. These selected errors were labeled 'critical nursing situations'. 'Crit-
ical' stands for a condition that possibly turns into an adverse event (Fig. 1). 'Nurs-
ing' depicts the domain and 'situation' describes a set of observable circumstances.
An error is not synonymous with an adverse event or an accident. Similarly, an ac-
cident may occur without a preceding error. An accident is an unplanned, unex-
pected, and undesired event, usually with an adverse outcome.
We assume that there is a limited but unknown set of potential critical nursing
situations in ICU practice. Since many of these critical nursing situations will be-
The Risk of Nursing in an Error Prone Environment 965
- - - - - - Dire<tion of work proce11 - -- -- - -
~ O"""'b" •~•. f.•.d~O<•• from pro~d
1 - - - - - Ri1k e1timation - - - - - - ,
' - - - - - - - Preventive measure1 revise protocol
Fig. 1. Model of error occurrence. 1) Barriers to error such as hourly monitoring of vital signs and check-
lists. 2) A factor can change circumstances producing the opportunity for sequential errors to cause an
accident. 3) Risk estimation is based on the known relation between a visible error and an accident.
4) Accidents that can be related to the occurrence of error will lead to preventive behavior or revising of
protocols
come visible at some point during nursing care, a systematic observational

approach independent of the ongoing care process can be used to quantify these
situations. Neither the nurse nor the patient is the subject of the observation, only
the environment of the patient. This enables the nurses to remain blinded for the
observed items in order to avoid bias. Based on these assumptions we composed a
Critical Nursing Situation Index (CNSI).
I The "Critical Nursing Situation Index" (Appendix)
The CNSI consists of a list of predefined errors that stem from deviations of ICU
nursing protocols. All unambiguous strict orders were collected from the standards
and protocols for which the nurse was responsible and translated into deviations of
care. Each error was formulated into a short observational statement, describing
the manifestation of an error. For instance, the admission protocol contains a direc-
tive stating that all patients transferred from other hospitals must have bacterial
cultures taken in order to prevent the spread of multiresistant bacteria. The proto-
col states: take standard bacterial cultures on admission if the patient is transferred
from another hospital. This can be translated into a negative statement: 'No inven-
tory of bacterial cultures upon transfer from another hospital is made'. In practice,
this statement can be true (an error occurred), false (no error occurred), or not ap-
plicable (as the patient was not transferred from another hospital). Another exam-
ple: 'The humidifying system of the respirator is not functioning (is switched off)'.
This observed item can be scored as true (the situation is present), false (the situa-
tion is not present), or not applicable (because this patient is not mechanically ven-
tilated). The risk associated with this error is that a patient is being ventilated with
dry air, which can cause serious sputum thickening and subsequent atelectasis.
The index represents a cross-section of the ICU-nursing care domain [12]. The
final index contains 84 descriptions of critical nursing situations in:
I basic ICU nursing care (14 items);
I care of mechanical ventilation (20 items);
1 care of intravenous lines (10 items);
I administration of fluids (5 items);
1 monitoring of cardiac rhythm and circulation (8 items);
I administration of medication (10 items);
I the care of enteral nutrition (6 items);
I hygienic care and control of devices (11 items) (see Appendix).
New items can be added to the database and items that are no longer of interest
can be removed. The intention was to collect a sufficient number of items in order
to be able to compose new forms after a study was completed and the items were
made public for the nursing team. Each new series of CNSI observations would be
conducted with a different set of observational items.
I Use and Interpretation of CNSI Scores

Each selected patient is observed for all items on a CNSI-form. Observation is
made a small distance from the bed. During these observations, the nurses are
neither questioned about the care nor about the condition of the observed patient.
The nurses are informed about the objective of the observations, but for reasons of
information-bias they must be kept unaware of the precise content of the items un-
til the study has finished. It is also advisable to observe patients in random se-
quences and time periods. Consequently, it is possible that a patient is observed
more than once, but this is irrelevant as the focus of the index is the actual nursing
care and not the specific condition of the individual patient.
CNSI figures can be calculated for one patient, or/and summarized for groups of
patients observed for a limited time period. The scores are summarized for true
items, false items, items at risk (true and false items) and items not applicable. The
sum of the true items reflects the number of critical nursing situations, whereas
the pooled sum of the true and false items determines the number of items at risk.
The quotient of true items and items at risk is the cumulative incidence (CI). Dif-
ferences in NSCI quality scores, for example between two different ICUs are calcu-
lated by the ratio of the CI rates and can be expressed in a Relative Risk estimate.
Risk difference (CI of group A - CI group B) will express the magnitude (increase
or decrease) of the change. In addition, by means of the CNSI, associations be-
tween changes in nursing workload and quality of nursing performance can be
documented [12].
I Conclusion
The advantage of the CNSI is the composition of items forming a cross-section of
ICU-nursing care for the detection of errors. Observing nursing care provides an
estimate of the quality of care under specific circumstances. Raising or lowering
CNSI scores from subsets of patients under different circumstances can provide im-
portant feedback about the impact of (organizational) changes.
The CNSI is simple to use and has encouraging metric properties in which the
assessment is closely related to direct patient care [12]. The CNSI is not meant to
judge the individual nurse but to detect weaknesses in the safety and quality of
care of patients in the ICU. Raising or lowering CNSI scores from subsets of pa-
tients under different circumstances can therefore provide important feedback
about the impact of (organizational) changes. The instrument can be easily ad-
justed to changes in the daily practice of the ICU and has the ability to be a tool
by which we can continuously investigate and improve the quality of our care.
References
1. Tarnow-Mordi WO, Hau C, Warden A, Shearer AJ (2000) Hospital mortality in relation to
staff workload: a 4-year study in an adult intensive care unit. Lancet 356:185-189
2. Servellen G, Schultz MA (1999) Demystifying the influence of Hospital Characteristics on
Inpatient Mortality Rates. J Nurs Adm 29:39-47
3. Aiken LH, Smith HL, Lake ET (1994) Lower medicare mortality among a set of hosptials
known for good nursing care. Med Care 32:771-787
4. Taunton RL, Kleinbeck SVM, Stafford R, Woods CQ, Bott MJ (1994) Patient outcomes. Are
they linked to registered nurse absenteeism, separation, or workload? J Nurs Adm
24(4S):48-55
5. Berwick DM. Taking action to improve safety: How to increase the odds of success. (http://
www.mederrors.org/1998/html/keynote.html)
6. Donchin Y, Gopher D, Olin M, et al (1995) A look into the nature and causes of human er-
rors in the intensive care unit. Crit Care Med 23:294-300
7. Giraud T, Dhainaut JF, Vaxelaire JF, et al (1993) Iatrogenic complications in adult intensive
care units: a prospective two center study. Crit Care Med 21:40-51
8. Glance LG, Osler TM, Dick A (2002) Rating the quality of intensive care units: is it a func-
tion of the intensive care unit scroring system? Crit Care Med 30:1976-1982
9. Reason J (1990) Human Error. Cambridge University Press, Cambridge
10. Norman DA (1988) To err is human. In: The Psychology of Everyday Things. Basic Books,
11. Runciman WB, Sellen A, Webb RK, et al (1993) Errors, Incidents and Accidents in Anaes-
thetic Practice. Anaesth Intensive Care 21:506-519
12. Binnekade JM, Mol BA de, Kesecioglu J, Haan RJ de (2001) The Critical Nursing Situation
Index for safety assessment in intensive care. Intensive Care Med 27:1022-1028
I Appendix: The Critical Nursing Situations Index (CNSI)

84 items: each item scores 'true~ 'false' or 'not applicable'
Basic ICU nursing care (14 items)
1. No inventory of bacterial cultures upon transfer from another hospital
2. Bacterial culture delayed for more than 2 hours (despite written arrangement)
3. No risk of pressure score assessment
4. Entrance to the isolation room is not marked as such
5. Patient's eyes are clearly contaminated
6. Incorrect use of Galsgow Coma scale
7. Patient is not mobilized according to instructions
8. Patient's position is not in agreement with instructions
9. No defecation for more than 3 days, no intervention (day 4)
10. No collection of urine production for assessment of fluid balance

11. No records of earlier shift (48 hrs)
12. No records on family or relatives
13. No records on patient's length and body weight on the ICU chart (all ICU
charts)
14. No up-to-date temperature list (past 48 hrs)
Mechanical ventilation (20 items)

15. Discrepancy between registration and actual tuning of mechanical ventilation
16. No hourly intrinsic PEEP during pressure-controlled ventilation
17. No manual inflation according to protocol
18. No endotracheal suction according to protocol
19. No clear marking of changes in tuning of mechanical ventilation
20. Relocation of endotracheal tube not according to protocol
21. No blood gas sample taken within 1 hour after removal of endotracheal tube
22. Inhalation therapy during mechanical ventilation not in agreement with in-
structions
23. Change of patient's position is bed not according to protocol
24. Visible condensate between the tubal connection and the endotracheal tube
25. Condensate piled up in tubes
26. Visible condensate in the heated wire (inspiration) tubes
27. Humidifying system does not function (is switched off)
28. No pulsoximetric and capnographic monitoring of patient in the prone position
29. No connection to a closed endotracheal suction system of patient in the prone
position
30. No water set with connected oxygen tubing in basic ICU set-up (backup in case
of malfunctioning ventilator)
31. No complete (and functioning) endotracheal suction system in basic ICU set-
up
32. No sterile NaCl solution for endotracheal flush in basic ICU set-up
33. Incorrect flow tuning during mechanical ventilation in assisted spontaneous
breathing
34. Maximum pressure tuning of mechanical ventilation exceeds prescribed limits
Intravenous lines (infusion and measurement; 10 items)

35. No record of introduction of central venous line
36. No record of introduction of arterial line
37. Swan Ganz catheter in situ for more than 4 days
38. Central venous line in situ for more than 6 days
38. Arterial access in situ for more than 6 days
40. One or more (red) caps missing on arterial access
41. One or more caps missing on the Swan Ganz catheter

42. One or more caps missing on peripheral line
43. Empty flush bag in line pressure system
44. Insufficient pressure on flush bag
Administration of fluids (5 items)

45. No six-hourly assessment of fluid balance
46. Packed cell bag is connected to the patient without PC number registration
47. Packed cell bag is not checked and endorsed by a second nurse
48. Flush system is not or incorrectly measured on the fluid balance of the ICU
chart
49. Not all infusions of the patient are recorded on the ICU chart
Cardiac rhythm and circulation (8 items)

50. No routine ECG made on admission
51. Arterial blood pressure not checked against sphygmomanometric pressure
(past 24 hours)
52. No hemodynamic profile made of patient with a Swan Ganz catheter
53. Incorrect monitoring of cardiac rhythm (frequency)
54. Sound alarm for heart rhythm is permanently switched off
55. Sound alarm for pressure curves is permanently switched off
56. Alarm margins of hearth rhythm and arterial pressure not adequately adjusted
57. Reference point and pressure device not installed at the correct height
Medication (10 items)

58. Prescribed medication(s) not administered or endorsed
59. Prescribed IV medication for prolonged administration not connected
60. Discrepancy between actual and prescribed ml/hour for IV medication
61. Connected prolonged IV medication not recorded on the ICU chart
62. Prepared IV medication not double-checked and endorsed according to protocol
63. No supportive continuous flush infusion in patient with cardiogenic medica-
tion
64. Unused lumina of infusion lines are not capped
65. IV medication connected with wrong lumen
66. IV medication for solitary infusion combiend with other medication
67. IV medication combined with an intermittent flush instead of a continuous flush
Enteral nutrition (6 items)

68. No record of introduction feeding tube
69. No retention measurement during gastric tube feeding
970 J. M. Binnekade et al.: The Risk of Nursing in an Error Prone Environment
70. Intake of prescribed tube feeding less than 75% without specific reason
71. Duodenal tube not flushed according to instructions
72. Change of tube feeding exceeds allowed time
73. Patient is in horizontal position while receiving gastric tube feeding
Hygiene and control of parts and devices (11 items)

74. Vacuum device of thoracic drain leaks air
75. Waterseal of thoracic drain device is missing or insufficient
76. Inhalation devices not renewed according to protocol
77. Closed endotracheal suction system not renewed according to protocol
78. Mechanical ventilation equipment not changed according to protocol
79. Infusion system for total parenteral feeding not renewed according to protocol
80. Bandage of central intravenous line not renewed according to protocol
81. Bandage of arterial line not renewed according to protocol
82. Intravenous and intra-arterial pressure lines not renewed according to protocol
83. Standard infusion systems not renewed according to protocol
84. Bandages of introduction sites for infusion not renewed according to protocol
Identifying the Patient-at-Risk:
Technology and ICU Outreach Services
D. C. Scales, J. Granton, and W. J. Sibbald
I Introduction
The provision of intensive care to critically-ill patients is a very costly endeavor. In-
tensive care units (ICUs) account for approximately 10% of inpatient acute care
beds in the United States [1, 2], and this proportion is expected to increase as our
population ages [3].
Intensive care medicine has traditionally been described as "advanced and
highly specialized care provided to patients whose conditions are life threatening"
and that is administered within "specially equipped care units" [4]. However, there
has been a recent movement to expand the conventional model of 'intensive care'
to encompass the provision of expertise in critical care medicine to patients who
are not yet (or are no longer) admitted to the ICU [5].
This movement has been in part driven by the publication in 2000 of the United
Kingdom Department of Health report, "Comprehensive Critical Care. A review of
Adult Critical Care Services" [6]. This document attempted to develop a framework
for the future organization and delivery of health care for the nation. Among the
principle tenets of this policy was that health care providers should strive to pro-
vide 'Comprehensive Critical Care', defined as the "complete process of care for the
critically-ill which focuses on the level of care that individual patients need rather
than on beds and buildings".
The impact of this initiative has been far-reaching. Most National Health Service
(NHS) hospitals in the United Kingdom have introduced or are in the process of
implementing the 'Comprehensive Critical Care' approach to health care delivery.
Special 'outreach teams' have been developed to provide specialized care outside of
the ICU, and to attempt to identify patients at risk [7]. With earlier intervention, it
is hoped that these outreach teams will help avert admissions to ICUs, facilitate dis-
charges from ICUs, and to share critical care skills across the acute care areas [8].
In the United States, the Leapfrog initiative has also caused institutions and pro-
viders to examine how critical care services are provided. The Leapfrog group re-
presents more than 90 public and private organizations that purchase health care
on behalf of their employees. The group has recommended that all hospitals should
strive to ensure that the ICU is staffed by a full-time, specially-trained critical care
physician for at least 8 hours daily [9]. The impetus for this recommendation stems
from mounting evidence that patient outcomes are better if dedicated intensivists
are involved in the care of critically-ill patients [10-12]. Faced with a nationwide
shortage of intensive care specialists [3], many hospitals will experience difficulty
meeting the objectives outlined by the Leapfrog Group. Some of the strategies that
have been proposed to deal with this deficit of intensivists include the implementa-
972 D. C. Scales et al.
tion of telemedicine solutions and 'virtual ICUs' to attempt to increase the number
of patients cared for by specialists.
Patients-at-Risk
There is a growing body of evidence to suggest that many seriously ill patients may
receive sub-optimal care on the hospital wards prior to their admission to the ICU.
This is often the result of a lack of awareness of, misinterpretation of, or misman-
agement of clinical signs of life threatening dysfunction of the airway, breathing, or
circulation [13].
Most survivors of in-hospital cardiopulmonary resuscitation will be admitted to
the ICU. In one observational study, as many as 5.8% of patients admitted to the
ICU from the hospital ward received CPR prior to ICU admission, but this group
accounted for 30% of all deaths [14]. It has been well demonstrated that patients
admitted to the ICU following cardio-respiratory arrest often will have displayed
premonitory signs prior to their acute deterioration [15-20]. Up to 80% of these
patients suffer severe (and perhaps unrecognized) physiologic deterioration in the
hours before their arrest.
In a study by McGloin and colleagues [21], blinded assessors judged that sub-
optimal care had been provided prior to the admission to the ICU in 32 of 87
(37%) patients. The mortality amongst this cohort was shown to be significantly
higher than in a group of 'well-managed' patients.
In 1998, McQuillan and colleagues conducted a prospective, confidential inquiry
into the quality of care of 100 consecutive patients prior to their admission to the
ICU [13]. Using structured interviews and questionnaires which were subsequently
reviewed by two blinded external intensivists these researchers demonstrated that
54% of these patients were perceived to have received sub-optimal care between the
time of hospital admission and admission to the ICU. The in-hospital mortality of
this group was greater than that of the cohort of patients that were judged to have
received adequate care, although the difference did not reach statistical significance
(48 vs 25%, p =0.07). Of interest, the assessors felt that 69% of the patients who
had received sub-optimal care had been admitted to the ICU late. The authors con-
cluded that major causes of sub-optimal care included failure of organization, lack
of knowledge, failure to appreciate clinical urgency, lack of supervision, and failure
to seek advice. They went on to suggest the implementation of a medical emer-
gency team that could respond pre-emptively to the clinical signs of life threatening
dysfunction of airway, breathing, and circulation.
Clearly a strong argument can be made for developing strategies to identify
patients-at-risk for deterioration. In so doing, pre-emptive interventions aimed at
averting admission to intensive care may be implemented, or alternatively appropri-
ate and timely admission to the ICU can be arranged [22]. Although several meth-
ods of achieving these goals have been described, it is the implementation of medi-
cal emergency teams or 'ICU outreach teams' that has recently gained the most
popularity.
Identifying the Patient-at-Risk: Technology and ICU Outreach Services 973
I The Medical Emergency Team

Several units in different countries have now implemented services that strive to
identify patients-at-risk of deterioration. Although the function of these services is
similar, the names given to these teams have varied; they have been called 'Medical
Emergency Teams' [23], 'Patient-at-Risk Teams' [24], and 'ICU outreach services'
[25, 26]. An illustration of the manner in which such a service might improve pa-
tient care is shown in Fig. 1. The results of the observational studies examining the
effectiveness of these services at improving patient care have been encouraging. Bu-
ist and colleagues demonstrated a reduction in the rate of unexpected cardiac ar-
rest following the implementation of a Medical Emergency Team (3.77 arrests per
1000 deaths in 1996 to 2.05 per 1000 deaths in 1999, p < 0.001). The mortality rate
following unexpected cardiac arrest also decreased after the service was introduced,
and this reduction persisted even after adjustment for case-mix (adjusted odds ra-
tio 0.52, 95% C.I. 0.36-0.74) [23]. When Goldhill and colleagues retrospectively ex-
amined the impact of their own patient-at-risk team, they found that patients were
less likely to have required cardiopulmonary resuscitation (CPR) before intensive
care admission if they had been seen by the service (3.6% of patients seen by the
team received CPR vs 30.4% of those not seen, p < 0.005) [24] . A reduction in post-
ICU, in-hospital mortality was observed by Young and colleagues following the im-
plementation of an ICU outreach service, though this trend did not reach statistical
significance (7.8% mortality in 6 months following implementation of the service
vs 12.8% in preceding 6 months, p=0.068) [25].
The ICU
outreach
team
Fig. 1. Use of a medical emergency team to improve patient care

97 4 D.C. Scales et al.
I The Need for Improved Monitoring and Detection Strategies
If early intervention by a medical emergency team is to be successful, a sensitive

method of identifying patients-at-risk of deterioration must first be implemented.
This presents several challenges. Primary care nurses or physicians working on the
ward must be relied upon to detect changes in a patient's status that might foresha-
dow deterioration. However, these physicians and nurses often may not have re-
ceived suitable training in the care of seriously ill patients and may consequently
be poorly prepared to identify 'critical changes' in a patient's status. Most of the
hospitals that have implemented medical emergency teams have used a set of pre-
defined physiologic parameters to identify patients at risk for deterioration (Ta-
ble 1). However, the sensitivity, specificity, and accuracy of these parameters have
not been proven [26].
Goldhill and colleagues, in discussing their own 'patient-at-risk team' acknowl-
edged that the physiologic criteria used to notify the team might have been unsatis-
factory [24]. Some patients admitted to ICU fulfilled none of the pre-specified crite-
ria that were intended to indicate the need for a response.
It may be that a reliance on pre-defined physiologic criteria to identify patients-
at-risk of deterioration is an approach that is too rigid, and that inclusion of more
subjective or qualitative parameters may improve sensitivity. Daffurn and collea-
gues examined the response of nurses to the implementation of a medical emer-
gency team in Australia [27]. Using a questionnaire administered to nurses, these
researchers were able to demonstrate that the majority of calls placed to the medi-
cal emergency team were triggered by obvious patient distress, whereas a change
in observations prompted the call for help in only 2.8% of cases. In a related study,
Cioffi and colleagues further explored the shortcomings of a reliance on changes in
physiologic parameters to patients-at-risk [28]. According to this group, nurses of-
ten identified the need to call for help based on 'feelings they had about patients -
a gut feeling, a sixth sense'. It may be that individual physiologic variables do not
adequately predict the potential for further deterioration, whereas a health care
Table 1. Example of parameters used to identify patients-at-risk of deterioration prior to activation of a

Medical Emergency Team. (Adapted from [23))
Criteria for calling medical emergency team
Airway
Respiratory distress Neurology
Threatened airway Any unexplained decrease in consciousness
Breathing Agitation or delerium
Respiratory rate > 30/min Repeated or prolonged seizures
Respiratory rate <6/min Other
Sa02 < 90% on oxygen Concern about patient
Difficulty speaking Uncontrolled pain
Circulation Failure to respond to treatment
Blood pressure < 90 mmHg Unable to obtain prompt assistance
Heart rate> 130 min
worker's ability to form a global, subjective assessment based on past experiences

may be far more powerful and accurate.
I Bridging the Gap: Innovation and Technology

Although there have been remarkable advances in computer technology, monitoring
techniques, and decision-making support software over the last several decades, the
penetration of these advances into the field of health care has been relatively lim-
ited and slow. Monitoring techniques in use today in most hospitals and institu-
tions have changed very little in the past three decades. Indeed, outside of the set-
ting of the ICU, the available monitoring devices are usually limited to remote tele-
metry to provide surveillance for arrhythmias, automated blood pressure monitor-
ing devices, and pulse oximeters for determining saturation of hemoglobin with
oxygen. Through the use of these simple monitoring techniques along with more
advanced monitoring aids such as 'smart-alarms' and neural network technology,
we believe it should now be possible to substantially improve patient care. In par-
ticular, with rapidly improving decision-support programs and integrative software
tools and neural networks, computers might soon facilitate practitioners in the
identification of patients-at-risk for deterioration and even help replicate a global
assessment or that elusive 'sixth-sense'.
The technology is now available to enable monitoring of patients' vitals signs
and physiologic parameters from remote locations. Closed-circuit television can
similarly be utilized to enable health care workers to visually monitor a patient
from other locations in the hospital (for example, the physician's office) or even a
different institution. As will be discussed below, the availability of these techniques
for remote monitoring has prompted some physicians to advocate for the develop-
ment of 'virtual ICUs' that would enable the continuous monitoring techniques
typically only available within the ICU to be used on patients still on the general
ward.
Several barriers exist to more widespread implementation of currently available
monitoring techniques to patients outside of the ICU. These include the high costs
involved, the need to train personnel in the use of these monitoring techniques
(particularly for telemetry), and the perception from health care professionals that
the use of these monitoring aids may not translate into improved patient outcomes.
The latter barrier may be particularly relevant given the observed shortcomings of
a reliance on changes in an individual physiologic parameter to detect a change in
a patient's status.
I The Virtual ICU

A model of care utilizing remote monitoring and provision of care has been de-
scribed already by Celi and colleagues [29]. This group and their commercial enter-
prise, VISICU, have developed a system for the remote monitoring of patients ad-
mitted to an ICU. Their approach has been marketed as a method of enabling care
to be provided to patients 24 hours per day, 7 days a week using a remote, intensi-
vist-led, multidisciplinary team (eiCU team). Telemedicine, video conferencing, and
integrated clinical information technologies allow the remote eiCU to be in direct
voice and video communication at any time with the staff of participating hospi-
tals. The system could potentially increase the number of patients admitted to reus
that can be cared for by a limited number of intensivists. In the context of the
aforementioned Leapfrog initiative, this is of particular relevance. Only an esti-
mated 23.1 o/o of the patients that are admitted to reus in the United States are
cared for by a full-time intensivist [3]. The first operational eieU was installed at
Sentara Healthcare in Norfolk, VA and according to numerous press releases it ap-
pears to have been greeted with considerable enthusiasm. Sentara has reported that
mortality rates at Norfolk General decreased by 25o/o during the first half of
2001 following the institution of the ereu [31].
The VISieU group has published an observational study examining the impact
of the use of telemedicine and remote intensivist input on the outcomes of patients
admitted to a surgical reu in a 450-bed hospital that did not have on-site intensi-
vist support [31]. The participating intensivists provided patient care exclusively
from their homes using cameras and data transmission equipment. Following a 16-
week trial program, they observed that severity adjusted reu mortality decreased
during the intervention by a range of 46 to 68o/o compared to two baseline time
periods (p < 0.05 for both comparisons). They attributed the decreased mortality to
a reduction in the incidence of reu complications. Total reu costs were also re-
duced by between 25 and 31 o/o when compared to the two baseline periods
(p = 0.03 ). The authors concluded that technology-enabled remote care could be
used to provide continuous reu patient management and to achieve improved clin-
ical and economic outcomes when on-site intensivist coverage is not available.
These conclusions will need to be confirmed by other centers employing this
approach to health care delivery. As with all interventions of this type, applying the
methodology of a randomized, controlled-clinical trial may not be feasible.
Similar remote monitoring technology may someday be used to improve the qual-
ity of care provided on general hospital wards. The incorporation of integrative soft-
ware employing smart alarms and possibly the use of neural network technology
could substantially improve the ability to identify patients-at-risk of deterioration.
A 'virtual reu' could be established within the hospital to provide a central hub for
monitoring patients admitted to hospital wards but outside of the actual IeU.
Smart Alarms - Their Time has Come
Most monitoring systems currently in use are equipped with alarms to notify the
clinician that a particular threshold for the parameter being monitored has been
reached. However, most of these alarms are quite simple and are designed to react
only to supra-normal or sub-normal values for a parameter. As an example, an
automated blood pressure monitor can be set to alarm if the systolic or mean
blood pressure is either too low or too high. Similarly, telemetry monitors may
identify tachyarrhythmias occurring at a certain rate, or may be set to alarm if
ventricular ectopy is detected. It has been observed that as the number of new
monitoring devices available increases, so does the number of these simple alarms
[32]. eonj:erns have been raised regarding the potential hazards of this growing 'or-
chestra of alarms'; specifically, as the number of alarms increases so may the risk
for errors. A recent study .by ehambrin and colleagues estimated that a typical
nurse working in an reu might contend with one alarm every 37 minutes [33].
These simple alarm systems, while certainly helpful when used in the proper
context, are still likely too primitive to enable the detection of subtle changes in a
patient's overall status. As an example, patients presenting with sepsis may initially
have preserved blood pressure while still demonstrating evidence of the systemic
inflammatory response (SIRS). Although derangements of other physiologic param-
eters (for example, respiratory rate and pulse) might be detected in this situation,
these abnormalities may not be sufficient, when viewed in isolation, to enable a
health care provider to properly identify the patient as being at risk for deteriora-
tion. Only when the blood pressure subsequently falls might the clinician infer that
the patient has developed septic shock and attempt to arrange a transfer to a more
appropriate setting for treatment and observation. A growing body of literature
suggests that early, protocol-driven response to septic shock may substantially im-
prove patient outcomes [34]. This highlights the need for early detection of pa-
tients-at-risk.
Many of the devices in use today now incorporate more complex algorithms for
detecting concerning trends in a patient's physiology. However, an integrated
approach to the many monitoring devices in use is clearly lacking [32]. There is a
need for 'smart alarms' that incorporate more intelligent data processing algorithms
to synthesize the many parameters being monitored in a given patient. Systems
with such capabilities are widely available in technology used in other sectors, such
as the automobile and aeronautic industry. However, the implementation of more
integrative software to the health care industry has been surprisingly slow.
In the example of the patient with sepsis and systemic inflammatory response, a
'smart-alarm' system could be progra,mmed to react to subtle changes in physiolog-
ic parameters before the threshold for a particular parameter has been reached. A
slight rise in heart rate accompanied by an increase in respiratory rate over a given
time period might be interpreted as a concerning trend, and a clinician might be
warned earlier of .the changes, allowing timely intervention. Software in these
'smart-alarms' should be developed to analyze patterns of physiologic changes to
assist the clinician in diagnosis. By incorporating several monitored variables in
the algorithm, a computer should even be able to be programmed to provide diag-
nostic support. In this latter regard, the development of neural network technology
may be particularly promising.
I Neural Network Technology
Neural networks have been described as "statistical pattern-recognition machines

composed of simple nonlinear processors connected into networks" [35]. This tech-
nology attempts to create a form of artificial intelligence that can provide a better
approximation of the human decision-making process than can conventional com-
puter analysis aids. A detailed description of neural network theory is beyond the
scope of this discussion, but has been well reviewed elsewhere [35-37].
In practice, most clinical decisions are based on several pieces of data, each as-
signed different weights and considered together in the context of the particular
clinical situation. Experienced physicians are more likely to make correct diagnoses
than novices because they are able to incorporate into their decision all of their
past experience. Attempts to simulate this process artificially become very difficult
using. conventional programming techniques, requiring complex algorithms, ad-
vanced statistical techniques, and often many assumptions. In contrast, neural net-
works may be well suited to medical decision-making given the ability of this tech-
nology to be modified by experience; the neural network is 'trained' by the infor-
mation that it receives. The power of these tools to simulate 'pattern-recognition'
may be particularly important in interpreting changes in physiologic parameters.
Although experience using neural networks in critical care is still somewhat lim-
ited, they have been used with success in other medical domains. To date, most of
the application of neural network technology to health care has been to assist in
diagnosis, staging (especially of cancer), and prognostication [36]. Within the field
of intensive care medicine, attempts have been made to apply neural network tech-
nology to help estimate risk of adverse outcome [38].
The application of neural networks to physiologic monitoring has been limited.
Swiercz and colleagues have been attempting to use neural networks to improve the
monitoring and interpretation of intracranial pressure (ICP) waveforms [39]. It re-
mains to be seen whether or not the application of this technology to ICP monitor-
ing will translate into improved outcomes. Spencer and colleagues have attempted
to use neural networks to automate the discovery, recognition and prediction of he-
modynamic patterns in real-time [40]. Their preliminary work suggests that their
neural network may be able to predict several hemodynamic patterns before they
completely unfold in time. Leon and Lorini trained neural networks to analyze flow
and pressure waveforms from ventilators, and found that their system could cor-
rectly recognize ventilation mode (pressure support vs spontaneous breathing) in
all of the 433 test waveforms [41].
It is expected that as this technology evolves it will become much more powerful
and useful at interpreting physiologic trends. We have already alluded to some of
the shortcomings of the alarm and monitoring systems that are currently available.
If neural networks are able to predict trends with accuracy through pattern recog-
nition, they may become valuable components of future monitoring systems. How-
ever, rigorous evaluations of neural networks and 'smart alarms' are lacking, and
must be considered before these new technologies and systems are introduced into
widespread use.
I A Vision of the Future
It has become clear that outcome following intensive care admission is often depen-
dent on the system through which critical care is provided. Factors relating to care
prior to intensive care admission may be as important in determining outcome as
is the quality of care provided within the unit. Patients seem to do better if care in
ICU is coordinated by a specialist with critical care training, and if this specialist is
available around-the-clock. Similarly, improvements in outcome may be seen if pa-
tients-at-risk are identified early so that pre-emptive intervention or timely referral
to ICU can occur.
The provision of care to patients who are seriously-ill or 'at-risk' in the future is
likely to be quite different than the current standard. We envision the widespread
use of monitoring devices for patients outside of the ICU. These monitoring
devices will be equipped with 'smart-alarms', possibly using neural network tech-
nology, which can detect subtle trends and changes in several physiologic parame-
ters in real-time. These devices will be able to detect patterns predicting a risk of
deterioration with much greater accuracy than the fairly crude simple alarms in
use today.
The devices employed to provide surveillance to patients on the hospital wards
will likely be monitored from a remote location, a 'virtual ICU', by a practitioner
with training in intensive care medicine. Video links and telemedicine solutions
will ensure adequate communication between this individual, possibly an ICU
nurse, and the nurses on the ward. When a concerning pattern is detected by the
neural network that is monitoring a patient, the nurse will notify the ward team as
well as the medical emergency team. If the neural network technology and its abil-
ity to accurately predict physiologic perturbations have been adequately validated,
the need for extensive training of nurses to man the remote monitors will have
been eliminated. This could translate into significant cost savings; presently, the
cost to train a nurse to correctly interpret output from remote cardiac telemetry
monitors is substantial.
Once the medical emergency team has been activated, the trained nurse and/or
physician will descend upon the ward to assess the patient-at-risk. This may result
in early intervention to remedy the physiologic derangement that triggered the
smart-alarm, or alternatively the patient may be transferred to the ICU. Once ad-
mitted to the unit, the patient would receive 24-hour continuous monitoring by
similar smart alarms with neural network support. The output of these monitors
would be available throughout the day to the intensivist on-duty, who could review
any trends or changes in a patient's status from outside the ICU, if necessary.
The potential cost-savings of such a system could be substantial. Improved mon-
itoring of patients will assist with the earlier detection of those at-risk. This will
lead to earlier intervention and consequent improvements in patient outcomes.
Complication rates will decrease and the frequency of medical errors will decline.
Consequently, mortality rates will decrease and average length of hospital stay will
be reduced. With the introduction of interpretive alarm technology, the need to ex-
pend resources training nurses to monitor each individual alarm will no longer be
present.
Of course, before any of these envisioned changes should be implemented, each
must be properly validated. For many of these innovations, further development of
the technology is required. Ideally, randomized, controlled clinical trials should be
conducted to ensure that this new vision does improve upon currently available
monitoring techniques and devices, or at the very least provides a similar standard
of care. And, although a reduction in overall cost is certainly an admirable goal,
the priority must remain (above all else) to enact an improvement in patient out-
come.
I Conclusion
There has recently been an important shift from the traditional model of providing
critical care as hospitals and health care workers strive to provide 'Comprehensive
Critical Care'. This involves delivering optimal care to seriously-ill patients, regard-
less of their physical location within the hospital. In our view, an important com-
ponent of this model of care will include advanced monitoring techniques,
equipped with responsive smart-alarms and integrative neural network technology
to identify patients-at-risk of deterioration. A central 'virtual ICU' will coordinate
the monitoring of such patients, and if concerning trends are detected, a medical
emergency team will be enacted. A physician specially trained in critical care medi-
cine will oversee the care of patients admitted to the ICUs, and provide 24-hour
support, 7-days per week via teleconferencing and electronic data transmission.
The implementation of these strategies should result in substantial cost savings as
a result of reduced rates of complications and medical error, decreased length of
hospital stays, and a decreased need to train nurses in the operation of multiple
simple alarms. More importantly, these innovations should translate into improved
patient outcomes and decreased hospital mortality rates.
References
1. Groeger JS, Storsberg MA, Halopern NA, et al (1992) Descriptive analysis of critical care
units in the United States. Crit Care Med 20:846-883
2. Halpern NA, Bettes L, Greenstein R (1994) Federal and nationwide intensive care units and
healthcare costs: 1986-92. Crit Care Med 22:2001-2007
3. Angus DC, Kelley MA, Schmitz RJ, White A, Popovich Jr J (2000) Current and projected
workforce requirements for care of the critically ill and patients with pulmonary disease.
Can we meet the requirements of an aging population? JAMA 284:2762-2770
4. CancerWeb Medical Dictionary. http://cancerweb.ncl.ac.uk/omd
5. Hillman K (1999) Health systems research and intensive care. Intensive Care Med 25:1353-
1354
6. Death of Health (2002) Comprehensive Critical Care. A Review of Adult Critical Care
Services. Department of Health, London
7. Young C, Millo JL, Salmon J (2002) Reduction in post-ICU, in-hospital mortality following
the introduction of an ICU nursing outreach service. Crit Care 6:P247(abst)
8. Southampton General Hospital, NHS (2002) Outreach: purpose of the outreach service.
www.suht.nhs. uk/ criticalcare/icu/generaUoutreach.html
9. The Leapfrog Group for patient safety (2002) Rewarding higher standards. www.leapfrog-
group.org
10. Blunt MC, Burchett KR (2000) Out-of-hours consultant cover and case-mix adjusted mor-
tality in intensive care. Lancet 356:735-736
11. Vincent JL (2000) Need for intensivists in intensive care units. Lancet 356:695-696
12. Pronovost PJ, Jencks M, Dorman T, et al (1999) Organizational characteristics of intensive
care units related to outcomes of abdominal surgery. JAMA 281:1310-1312
13. McQuillan P, Pilkington S, Allan A, et al (1998) Confidential inquiry into quality of care
before admission to intensive care. Br Med J 316:1853-1858
14. Goldhill DR, Sumner A (1998) Outcome of intensive care patients in a group of British in-
tensive care units. Crit Care Med 26:1337-1345
15. Sax FL, Charlson ME (1987) Medical patients at high risk for catastrophic deterioration.
16. Franklin C, Mathew J (1994) Developing strategies to prevent in-hospital cardiac arrest:
analyzing responses of physicians and nurses in the hours before the event. Crit Care Med
22:244-247
17. Schein RMH, Hazday N, Pena M, Ruben BH, Sprung CL (1990) Clinical antecedents to in-
hospital cardiopulmonary arrest. Chest 98:1388-1392
18. Bedell SE ( 1991) Incidence and characteristics of preventable iatrogenic cardiac arrest.
JAMA 265:2815-2820
19. Dubois RW (1988) Preventable deaths; who, how often, and why? Ann Intern Med 109:582-
589
20. George Jr AL (1989) Prearrest morbidity and other correlates of survival after in hospital
cardiac arrest. Am J Med 87:28-34
21. McGloin H, Adam S, Singer M (1997) The quality of pre-ICU care influences outcome of
patients admitted from the ward. Clin Intensive Care 8:104 (abst)
22. Garrad C, Young D (1998) Suboptimal care of patients before admission to intensive care
is caused by a failure to appreciate or apply the ABCs of life support. Br Med J 316:1841-
1842
Identifying the Patient-at-Risk: Technoloqy and ICU Outreach Services 981
23. Buist MD, Moore GE, Bernard SA, Waxman BP, Anderson JN, Nguyen TV (2002) Effects of
a medical emergency team on reduction of incidence and mortality from unexpected car-
diac arrests in hospital: preliminary study. Br Med J 324:1-5
24. Goldhill DR, Worthington L, Mulcahy A, Tarling M, Sumner A (1999) The patient-at-risk
team: identifying and managing seriously ill ward patients. Anaesthesia 54:853-860
25. Young C, Millo JL, Salmon J (2002) Reduction in post-ICU, in-hospital mortality following
the introduction of an ICU nursing outreach service. Crit Care 6:247 (abst)
26. Smith G (2000) To M.E.T. or not to M.E.T. - that is the question. Care of the Critically Ill
16:198-199
27. Daffurn K, Lee A, Hillman KM, Bishop GF, Bauman A (1994) Do nurses know when to
summon emergency medical assistance? Intensive Crit Care Nurs 10:115-120
28. Cioffi J (1994) Nurses' experiences of making decisions to call emergency assistance to
their patients. Crit Care Med 22:189-191
29. Celi LA, Hassan E, Marquardt C, Breslow M, Rosenfeld B (2001) The eiCU: It's not just tel-
emedicine. Crit Care Med 29:N183-N189
30. News segment: Szabo L. Virtual ICU draws national attention. The Virginian Pilot, June 13,
2002
31. Rosenfeld BA, Dorman T, Breslow MJ, et a! (2000) Intensive care unit telemedicine: Alter-
nate paradigm for providing continuous intensivist care. Crit Care Med 28:3925-3931
32. Friesdorf W, Buss B, Gobel M (1999) Monitoring alarms - the key to patient's safety in the
ICU? Intensive Care Med 25:1350-1352
33. Chambrin MC, Ravaux P, Calvelo-Aros D, Jaborska A, Chopin, Boniface B (1999) Multi-
centric study of monitoring alarms in adult intensive care unit (ICU): a descriptive analy-
34. Rivers E, Nguyen H, Havstad S, et a! (2001) Early goal directed therapy in the treatment of
severe sepsis and septic shock. N Eng! J Med 345:1368-1377
35. Penny W, Frost D (1996) Neural networks in clinical medicine. Med Decis Making
116:386-398
36. Lisboa PJG (2002) A review of evidence of health benefit from artificial neural networks in
medical intervention. Neural Networks 15:11-39
37. Cross SS, Harrison RF, Kennedy RL (1995) Introduction to neural networks. Lancet
346:107 5-1079
38. Wong LS, Young JD (1999) A comparison of ICU mortality prediciton using the APACHE
II scoring system and artificial neural networks. Anaesthesia 54:1048-1054
39. Swiercz M, Mariak Z, Lewko J, Chojnacki K, Kozlowski A, Piekarski P (1998) Neural net-
work technique for detecting emergency states in neurosurgical patients. Med Bioi Eng
Comput 36:717-722
40. Spencer RG, Lessard CS, Davilla F, Etter B (1997) Self-organizing discovery, recognition
and prediction of haemodynamic patterns in the intensive care unit. Med Bioi Eng Comput
35:117-123
41. Leon MA, Lorin FL (1997) Ventilation mode recognition using artificial neural networks.
Comput Biomed Res 30:373-378
Multimedia Medical Education and E-Learning
M. Antonelli, G. Bello, and M.A. Pennisi
Introduction
The progress in communication systems opens new horizons for the diffusion of a
new form of knowledge, with extraordinary opportunity to transmit words, meaning,
sounds, images, and information. New technologies have led to a change in the usual
way of access to knowledge and learning. In the course of history, every technological
innovation has been received with fear or suspicion: the diffusion of writing found a
reluctant Socrates, defender of the supremacy of the word and the dialogue against
writing, that he considered as "inhuman". Plato makes him say in the Phaedrus:
"Writings will lead to the forgetfulness in learners' souls, and they will disregard
their memories ... You give your disciples not the truth but only the resemblance
of the truth ... they will appear to be omniscient and will know nothing" [1].
I Computer-Assisted Learning
In 1946, the first computer, ENIAC (electronic numerical integrator and computer),
was developed at the University of Pennsylvania [2]. Since then, using computers to
improve learning has been a focus for medical training. Combining computers with
other modern digital technologies has allowed the development of many educa-
tional tools [3-5]. The easy access to Internet and the World Wide Web has encour-
aged the latest explosion of interest in computer-assisted learning.
The use of a computer as a 'teaching machine' has growing importance and of-
fers various options:
the possibility of personalizing a learning course, with self-teaching programs,
that take into account the different abilities of learners
I the opportunity of using the machine as a support to practice the theory learnt
in traditional courses
I the simulation of real situations and settings, otherwise unavailable because of
costs, time, or danger
analysis of results of individual tests, with suggestions of possible corrections.
The multimedia systems for teaching represent an evolution in traditional teaching

that combines techniques and different tools. Programs containing texts, sounds
and images allow virtual interaction and direct communication with teachers. The
'user' can memorize and send videos or images to other individuals connected to
the system, or dialog with persons whose image is visualized on the computer screen.
Multimedia Medical Education and E-Learning 983
I Virtual Reality and Simulators

The new technologies have given life to virtual reality [6-11], the term referring to
the fact that the interaction is with a 'synthetic' environment that exists only in the
computer. In the more advanced concept of virtual reality, the representation of the
environment is almost 'felt' by the eyes and ears through goggles, visors and head-
phones.
The association of the 'fast Internet' (broadband) and of robotic science [12-16]
will give us the possibility of operating at a distance of thousands of miles in tele-
presence. The 'customer', connected to the robot by means of the broadband Inter-
net, and equipped with stereoscopic helmets will receive the images and make the
robot repeat his/her own movements.
Even though the potential effects of this approach are interesting, in practice,
virtual reality simulators are at the moment quite limited in capability or extremely
expensive.
In recent years, several companies have developed computer-controlled patient
simulators to be used in medical training. The introduction of the Human Patient
Simulator (Medical Education Technologies, Inc™), has enabled instructors to re-
create realistic patient scenarios in a standardized fashion [17].
The Simulator is a life-size, computer-controlled manikin that breathes, has a
heart beat, and includes sophisticated models of physiology and pharmacology that
permit an accurate representation of human responses. This manikin offers, for the
first time, learning opportunities to practitioners in a wide range of health care
fields. Users can interact with the 'patient' by performing physical examinations,
cardiopulmonary resuscitation and defibrillation, airway manipulation, trauma pro-
cedures, and intravenous drug and fluids injections.
Using the Human Simulator, clinicians can develop and refine skills in monitor-
ing and diagnostic or therapeutic procedures far more rapidly and safely than
when traditional teaching methods are used. This instrument can also be used to
collect information during the evaluation process. The use of simulation permits
the assessment of a candidate's preparation, their approach to clinical situations
and problems, and their accuracy in recording medical information.
Simulation has many advantages as a training tool [18]:

I no risk for the patient
situations and events involving uncommon but serious problems can be experi-
enced by the participant
I actual complex devices can be used
1 errors can be allowed to occur whilst in a clinical setting they would need im-
mediate intervention of an expert
simulation can be frozen at any moment to discuss the situation and its manage-
ment
recording, replay, and critique of performance are facilitated, because there are
no issues of patient safety or confidentiality.
The Bristol Medical Simulation Centre (BMSC) offers a simulation training specifi-
cally designed for the needs of medical and healthcare professionals, paramedics
and the emergency services. Medical emergencies such as anaphylaxis, acute myo-
cardial infarction, major hemorrhage and shock can be simulated in the Centre's
984 M. Antonelli et al.
operating room· using ,the advanced Human Patient Simulator. The facilities can
also be used for personnel tutorial training in various disciplines and specialities.
Simulation scenarios are designed according to the needs of each group of partici-
pants, allowing every delegate to try the relevant procedures, both simple and com-
plex.
I Multimedia Films
The ability to consult scientific reviews through the network, free of charge or con-
ditioned by a subscription, is a consolidated reality. This type of communication
has increased remarkably the possibilities of real time update and exchange of in-
formation in the scientific community.
The opportunity now exists to attach real multimedia motion pictures to scien-
tific papers. The use of films has contributed to making the understanding of con-
tents more incisive and motivated, especially when diagnostic-therapeutic proce-
dures are described.
I PACEP and PACT

The Pulmonary Artery Catheterization Education Project (PACEP, http://www.pacep.
org) is an educational program co-sponsored by several organizations and designed
to allow the clinician to use the pulmonary artery catheter (PAC) in a safe and com-
petent fashion. This is a Web-based educational tool that demonstrates how to use the
use and interpret information obtained from the PAC in the clinical environment. The
content has been divided into modules to facilitate progressive learning of partici-
pants and includes the ability to add information on new technologies and therapies.
Patient Centred Acute Care Training (PACT, http://www.esicm.org/PACTI) is one
of the multimedia training programs established by the ESICM (European Society
of Intensive Care Medicine). It is a distance learning program with a primary aim
of improving and harmonizing the quality of intensive care training.
I Danger of Imbalance?
In multimedia education, there is the danger of an imbalance, of creating a two lev-

el society, in which only one part of the population has access to the newer net-
works and can enjoy their benefits. The danger, therefore, is to create a divided
world, with a large part of the population left at the margins of progress and
knowledge. The resultant inadequacy of professional formation and a scanty knowl-
edge of technological innovations might compromise integration into active clinical
life, causing a type of functional "returned illiteracy".
Umberto Eco, an Italian semiologist, perceived the risk of creating immense masses
of "technological proletariat", made up by those who are excluded from the com-
puter sciences [19]. On the other hand, it is worth underlining how the simplified
use of the technologies has facilitated the process of education.
I Continuing Medical Education

The rapid and ongoing development of medicine and the continuous growth of
technological innovations make it increasingly difficult for doctors to keep up-to-
date and competent. For this reason, a series of Continuing Medical Education
(CME) schemes have been developed in many countries throughout the world [20-
26]. CME involves organized and controlled theoretical and practical training, with
the aim of keeping the medical profession as updated as possible. These activities
are promoted by scientific or professional bodies, hospitals, and any other health
organization specifically dedicated to training and education.
CME implies the evaluation of each training activity, with the best professional
guarantees of quality. CME is also a form of 'memento' for caregivers about the
need for a continuous updating of their clinical background.
Nowadays, attendance at refresher courses and retraining schemes is a doctor's
duty, as established in the deontological code of many countries and represents a
citizen's right to receive diligent and updated medical assistance. This is even more
important as the public is more and more informed about the opportunities of
treatment and prevention.
In the European Union (EU), the treaty of Maastricht promotes the development
of e-learning and the formulation of operating schemes (art. 126). In the 1996 pub-
lication of the White Paper on education and training, the EU outlined the Europe-
an way to a 'computer-literate society', with a warning of the inadequacies of scien-
tific and technical education in Europe.
I E-Learning
E-learning is training via digital networks. It involves a type of technology that
coniugates the main features of global communication: diffusion of knowledge and
ease of access. The information available on the networks is used for training a
large number of people at a lower cost than that of traditional methods. The e-
learning and the traditional educational approach have however common pathways
(Fig. 1).
E-learning has the following characteristics:

I Remote access: E-learning allows learners to benefit from a training course that
they could not personally attend. Learners can overcome the obstacle of the dis-
tance from a learning center, adapting their study time to their own schedule, free
from a rigid academic timetable, and modulating their learning process to their
own abilities. E-learning implements audio and video programs, and personal
computer networks, enabling students to interact with one another and with tea-
chers.
I Digital format: the structural and functional requisite of digital communication.
The transmission of a cognitive content is accomplished through the use of
images, graphics, videos and sounds that together form the multimedia commu-
nication: a compendium of integrated systems.
I E-learning offers the opportunity of a constant updating of educational courses
in 'real time'.
I The information is collected in an electronic document with different areas, con-
nected to one another, configured in a way that allows free consultation and use.
Journals, text books etc. I

~ ~ ,--------,
I Information I I Internet
~
/ [ Qualified teachers I~
Traditional education - Online education

(lessons, tutorials, laboratories etc.) - (computers, Internet, virtual reality, simulators etc.)
~ /
I Data acquisition I
~--~/--~ := I~~~--~
Oral or w ritten examinations and practical tests Computerized evaluation tests
Evaluation
Fig. 1. Significant phases of formative pathways: traditional and online
Users can put together their own learning course, which is open to the most var-
ied logical associations, without being forced into a rigid sequential structure,
and self-verifying the reached level of learning.
I Flexibility: learning techniques elaborated by e-learning can be easily adapted to
the specific requirements, learning pace, and abilities of the learner. Learners
are in the position to attend the courses whenever they whish logging on from
their preferred location.
I Management: e-learning simplifies course organization avoiding the traditional
teaching structures and staff. The evolution of the Internet platform contributes
to a more efficient management of the contents. In particular, the LCMS (learn-
ing content management systems), constitutes the last generation of these plat-
forms and has a more flexible and functional approach than in the past.
I An on-line medical learning activity has an intrinsic entrepreneurial-corporate
view, with criteria of efficacy (relationship between results obtained and pur-
poses) and efficiency (relationship between results and financial, human, logistic
and time resources).
I An indispensable requisite of advanced multimedia is the use of the broadband.
This technology allows a significant increase in the speed of electronic transmis-
sion of information.
Traditional education is unfortunately exposed to the risk of fossilization. E-learn-

ing appears to be a profitable method to rapidly adjust and adapt professional
training.
In the medical world, the areas which have shown the highest application for e-
learning are: dentistry [27-29] and nursing [30-33]. The user interacts with the
computer and other users through a multitude of media, actively participating in

the process of knowledge and never being passive. The amount of time dedicated
to learning can be handled in a number of ways: a student can follow an entire
educational session or divide the overall duration into several short units, optimiz-
ing time and attention.
Teaching diagnostic or therapeutic procedures is a complex and difficult task. In
these cases the impact of a traditional explanation is low. Multimedia technologies
can compensate for the inadequacies in the language.
The Cisco systems (www.cisco.com/edu/emea) are the major producers of tele-
communication apparatuses. The data about learning collected by Cisco's experi-
ence are interesting:
I traditional formation is insufficient
I people remember 90% of what they do and only 10% of what they read
I e-learning is the fastest way to increase the know-how and skill.
According to IDC Research, leaders in monitoring the information and communi-

cation technology (ICT) market, the European e-learning market is expected to
grow in turnover by 51 o/o per year: turnover is currently 666.8 million Euros, and
will rise to 3.6 billion Euros in four years' time. The Netherlands, Sweden and Great
Britain are the European Countries where the greatest development is foreseen;
these countries record the highest Internet penetration rate in Europe and the high-
est percentage of English-speaking people. Southern Europe will follow with some
delay.
E-learning initiatives are offered by various training categories: the pure players
who only operate on-line (such as skillpass or Individual Training), traditional
companies with e-learning opportunities (Elea, Isvor, Sfera), consultancy firms
(Kpmg, Nusia), content providers that provide the contents of the courses (Opera
multimedia, Giunti, NetG), ICT companies (Italdata, Linfa, Microsoft, IBM), as well
as business schools.
However, the information found on the digital webs sometimes is not informa-
tive at all. The danger, therefore, is the poor quality of e-learning. The use of Inter-
net for learning purposes imposes the need for qualified teachers and trainers who
use scientifically reliable material. Furthermore, e-learning requires teachers who
have specific skills and know-how in ICT, teaching in accordance with the nature
and form of the new systems.
E-learning can be intended as an effective operational methodology that inte-
grates modern technologies with traditional classroom tuition and training
(blended solutions). This implies that every training measure should produce supe-
rior results, which can be made immediately operational.
I Comparison between Two Methods of Teaching

In order to compare the efficacy of so-called 'formal' ('face-to-face') teaching with
on-line training, we have recently carried out a study. In this study, we evaluated
the results obtained from two groups of doctors randomly assigned to attend a tra-
ditional course on the management of the airway or to attend the same educational
course on-line, in a multimedia fashion.
The traditional course was arranged with theoretical-practical lessons held by
specialized teachers. The multimedia educational path was set up on-line through
the Catholic University Internet platform, realized using the multimedia platform
of Blackboard provided by the Blackboard Inc™ (Washington DC, USA). The plat-
form allows the integration of traditional teaching with new multimedia tools, and
allows teachers and students to participate in the courses through any computer
connected to Internet. This type of platform is flexible, able to manage several
courses at the same time, and can be accessed through a browser after connection
to Internet. The platform includes different applications: course management, com-
munication between participants and between participants and teachers, question-
naires for student assessment, statistical control of the sites visited by the students
during the course, direct access to news, research instruments, links, forums, and
selected automatic services.
The participants could access the course at any time by introducing their user's
name and password in the home-page of the platform. During the course, every stu-
dent could ask questions on the various topics by sending an e-mail to the teachers.
The contents of both courses, traditional and on-line, were the same. The proce-
dures in the on-line course were supported by films and videos, previously regis-
tered. Before and after the course, every student underwent a quantitative written
and a practical test. This allowed the evaluation of individuals' basic knowledge
and of the impact of the two methodologies on the grade of learning.
Each of the two participating groups was composed of five doctors belonging to
the emergency department and ten doctors from the Department of Intensive Care.
The final results showed that both methods had similar efficacy with comparable
improvement in practical skill and knowledge. The traditional method, however, re-
quired the participation of more teachers, the specific allocation of the resources,
higher financial support, and less fun for the participants.
I Conclusion
In the field of training, ongoing technological innovations need to be critically
evaluated. The proposal of multimedia teaching as an alternative and not as a com-
plement to traditional learning appears promising but, at the moment, unrealistic.
We believe that the human component of the educational process is fundamental to
transmit not only cognitive contents, but also to share values, behaviors, traditions
and ideas.
Recommended Web sites related to multimedia education (accessed November,

2002)
http:/I europa.eu.int/comm/education/elearning/index.html
http:/ /www.cisco.com/warp/public/ 10/wwtraining/elearning/
http:/ /www.expresslearning.com/
http:/ /www.imsglobal.org/index.cfm
I References
1. Plato, Phaedrus 275a-b (translated by the authors)
2. Winegrad D, Atsushi A (1996} A short history of the second American revolution. U Penn
Almanac 42:4-7
3. Entwisle G, Entwisle DR (1963} The use of a digital computer as a teaching machine. J
Med Educ 38:803-812
4. Nanson EM (1977} The potential of an educational computer in medical education. Aust N
Z J Surg 47:545-547
5. Norman GR, Schmidt HG (1992} The psychological basis of problem-based learning: A re-
view of the evidence. Acad Med 67:557-565
6. Seymour NE, Gallagher AG, Roman SA, et al (2002) Virtual reality training improves oper-
ating room performance: results of a randomized, double-blinded study. Ann Surg
236:458-63
7. Rowe R, Cohen RA (2002} An evaluation of a virtual reality airway simulator. Anesth An-
alg 95:62-66
8. Colt HG, Crawford SW, Galbraith 0 3rd (2001} Virtual reality bronchoscopy simulation: a
revolution in procedural training. Chest 120:1333-1339
9. Kalawsky RS (1993} The Science of Virtual Reality and Virtual Environments. Addison-
Wesley, Workingham
10. Freeman KM, Thompson SF, Allely EB, Sobel AL, Stansfield SA, Pugh WM (2001) A virtual
reality patient simulation system for teaching emergency response skills to U.S. Navy medi-
cal providers. Prehospital Disaster Med 16:3-8
11. Reznek M, Harter P, Krummel T (2002) Virtual reality and simulation: training the future
emergency physician. Acad Emerg Med 9:78-87
12. Chitwood WR Jr, Nifong LW (2000} Minimally invasive videoscopic mitral valve surgery:
the current role of surgical robotics J Card Surg 15:61-75
13. Schurr MO, Buess G, Neisius B, Voges U (2000} Robotics and telemanipulation technolo-
gies for endoscopic surgery. A review of the ARTEMIS project. Advanced Robotic Telema-
nipulator for Minimally Invasive Surgery. Surg Endosc 14:375-381
14. Buess GF, Schurr MO, Fischer SC (2000) Robotics and allied technologies in endoscopic
surgery. Arch Surg 135:229-235
15. Swaminathan R, Wheeler M (2000} Robotics into the millennium. J Clin Pathol 53:22-26
16. Ballantyne GH (2002} Robotic surgery, telerobotic surgery, telepresence, and telementoring.
Surg Endosc 16:1389-1402
17. Gordon JA, Pawlowski J (2002} Education on-demand: the development of a simulator-
based medical education service. Acad Med 77:751-752
18. Gaba DM, DeAnda A (1988} A comprehensive anesthesia simulation environment: Re-creat-
ing the operating room for research and training. Anesthesiology 69:387-394
19. Eco U (1995} Nomenclatura e democrazia elettronica. Interview held on September 21,
1995. SMAU, Milan
20. Friedewald VE Jr, Roberts WC (2002} The Personal Professor: continuing medical educa-
tion meets the new media. Am J Cardiol 90:620-621
21. Mazmanian PE, Davis DA (2002) Continuing medical education and the physician as a
learner: guide to the evidence. JAMA 288:1057-1060
22. Casebeer L, Bennett N, Kristofco R, Carillo A, Centor R (2002} Physician Internet medical
information seeking and on-line continuing education use patterns. J Contin Educ Health
Prof 22:33-42
23. Carriere MF, Harvey D (2001} Current state of distance continuing medical education in
North America. J Contin Educ Health Prof 21:150-157
24. Zimitat C (2001} Designing effective on-line continuing medical education. Med Teach
23:117-122
25. Holmer AF (2001} Industry strongly supports continuing medical education. JAMA
285:2012-2014
26. Knox AB, Underbaake G, McBride PE, Mejicano GC (2001} Organization development stra-
tegies for continuing medical education. J Contin Educ Health Prof 21:15-23
990 M. Antonelli et al.: Multimedia Medical Education and E-Learning
27. Spallek H, Pilcher E, Lee JY, Schleyer T (2002) Evaluation of web-based dental CE courses.
J Dent Educ 66:393-404
28. Clark GT (2001) Education problems and Web-based teaching: how it impacts dental edu-
cators? JAm Coli Dent 68:25-34
29. Schleyer TK (1999) On-line continuing dental education. JAm Dent Assoc 130:848-854
30. Thurmond VA (2002) Considering theory in assessing quality of web-based courses. Nurse
Educ 27:20-24
31. Kozlowski D (2002) Using on-line learning in a traditional face-to-face environment. Com-
put Nurs 20:23-30
32. Ambrosiadou V, Compton T, Panchal T, Polovina S (2000) Web-based multimedia course-
ware for emergency cardiac patient management simulations. Stud Health Techno! Inform
77:578-582
33. Mills AC (2000) Creating Web-based, multimedia, and interactive courses for distance
learning. Comput Nurs 18:125-131
End-of-Life Care in the Intensive Care Unit:
Toward a New Concept of Futility
D. Crippen
From the fool's gold mouthpiece

The hollow horn plays wasted words
Proves to warn
That he not busy being born
Is busy dying.
Bob Dylan
I Introduction
A high proportion of patients who die in hospitals do so in some form of intensive

care unit (ICU) [1]. As medical care is made available to growing populations, the
number of patients who develop critical illness increases. Accordingly, more titrated
treatment needs to be provided, in an environment that facilitates such care. Nor-
mally, only patients with a strong potential to benefit from the services of an ICU
992 D. Crippen
are admitted to one [2]. In a perfect system, no one would die in an ICU, except as
a result of an unexpected decompensation [3]. Many intensivists believe that pa-
tients who fail to respond to intensive care should be quickly transferred to home
or hospice to die [4].
But the reality is that prospective patients with organ system failure are given
the benefit of any doubt. It frequently seems reasonable to institute aggressive treat-
ment for a time to see whether the disease will respond. Experience has shown that
it is difficult to determine prospectively who will benefit from titrated critical care.
In most acute illnesses, time is needed to see whether aggressive treatment will im-
prove the patient's condition. Decisions to place patients on life support are usually
hastened by expectations heightened by the emergent nature of the proceedings.
Physicians are prepared to use life-sustaining technology when the benefit seems to
outweigh the risk and when there is a reasonable chance of a desirable outcome. If,
however, the patient's organ system failure is not reversible, life support serves no
further useful function. When it appears that death, not meaningful life, is being
prolonged, physicians must be prepared to remove life support.
I Life and Death in Intensive Care
Physicians are quick to put patients on life support and hope for the best. Some-
times the worst occurs. Patients may become dependent on mechanical life-support
devices, unable to survive without them but maintaining a poor quality of life with
them. A controversy has arisen regarding life-supporting technology; increasingly,
patients and their families are becoming more assertive in deciding when to re-
move it [5]. These situations are predictable in Western society, where rights of the
individual are traditionally favored over rights of the masses [6]. The courts have
repeatedly affirmed a competent patient's authority to regulate his or her medical
treatment, regardless of the patient's reasoning [7]. When the patient becomes inca-
pacitated, family surrogates are usually granted a great deal of power to dictate
treatment options, because of their proximate knowledge of what the patient would
have wanted before he or she became incompetent [8]. This position is based on
the idea that any attempt to introduce paternalism into surrogate decision-making
is ethically unacceptable.
One would think that rational patients and their families would be loathe to con-
tinue support of vital signs after a reasonable trial demonstrated that the ICU bene-
fit of ICU care had passed the point of diminishing returns, but patients and fami-
lies sometimes do continue such support. Increasingly, surrogates request that dy-
ing patients be kept on life support after the medical team concludes that there is
no chance of reanimation [9]. Current concepts of autonomy inevitably breed con-
flicts over who should assume ultimate responsibility for doing what to whom in
the technology-filled ICU. Life-support technology can produce the appearance of
viability when in reality there would be no viability if the machines were removed.
Some families believe that if life-support systems can maintain vital signs for a day
or a week, reanimation is possible by indefinite maintenance. These opinions are
frequently supported by articles in the popular press, anecdotes about patients who
awakened after years of coma. On the other side of the conflict are critical care
physicians, who are frustrated by the esthetic, ethical, and clinical conundrum of
maintaining warm cadavers [10].
End-of-Life Care in the Intensive Care Unit: Toward a New Concept of Futility 993
Critical care physicians sometimes try to reason with recalcitrant surrogates

on the basis of medical futility. The concept of futile medical treatment goes back
to the time of Hippocrates, who allegedly advised physicians "to refuse to treat
those who are overmastered by their diseases, realizing that in such cases
medicine is powerless" [11, p 496]. However, in today's arena of expensive techno-
logical medical support systems, it is difficult to say that an intervention is futile.
One must always ask, "Futile in relation to what?" One end of the spectrum is the
concept of absolute futility. As stated in the Hastings Center guidelines on the
termination of life-sustaining treatment: "If a treatment is clearly futile in achieving
its physiological objective and so offers no physiological benefit to the patient,
the professional has no obligation to provide it" [12]. For example, a woman who
had a lumpectomy and radiation therapy for breast cancer 5 years ago is admitted
to an ICU and has terminal metastatic disease everywhere. She then says not only
does she want intensive care, she wants a bilateral mastectomy for completeness.
Would a rational physician grant her the mastectomy just because she desires it?
Probably not. The treatment is futile because it will not achieve the desired objec-
tive.
However, on the other end of the spectrum, treatment that achieves an estheti-
cally or clinically undesirable end point but "works" is not necessarily futile. If a
patient with a progressively fatal disease demands to be intubated and to die on
mechanical ventilation, rational physicians do not have a strong authority to resist
that request [13]. Intubating the patient will indeed prolong his or her vital signs
(an arguable definition of life) and is, therefore, not futile by the strict definition;
if it postpones death, it is effective treatment, never mind that it will only prolong
the dying process in a more uncomfortable mode. The physiological objective of
mechanical ventilation is to maintain adequate ventilation and oxygenation in the
presence of respiratory failure. The physiological objective of cardiopulmonary re-
suscitation is to maintain adequate cardiac output and respiration in the presence
of cardiorespiratory failure. Mechanical ventilation is not futile if it passes air into
the lungs of a patient who will never breathe on his or her own again. Cardiopul-
monary resuscitation is not futile if it facilitates spontaneous circulation in even a
terminally ill patient. If desired (for whatever reason), treatment that prolongs vital
signs cannot be withheld on the basis of futility. It can only be proscribed on the
basis of medical inappropriateness, a term that means different things to different
people.
Critical care providers commonly complain that resources are 'wasted' on ICU
patients for whom treatment is deemed futile - patients predicted to do poorly in
the context of continued aggressive care [14]. A substantial amount of literature
supports the premise that such care is expensive. Scheffler [15] found a nonlinear,
U-shaped relationship between use of resources and probability of survival. At one
end of the spectrum, an increasing amount of therapeutic intervention generated a
decreasing mortality rate. At the other end, 40o/o of resources were used to prolong
life temporarily in 9o/o of the patient population, and the mortality increased as the
number of therapeutic interventions increased. Detsky et al. [16] found that pa-
tients with the highest hospital expenses (on average) fell into two groups: survi-
vors who had been predicted on admission to have a poor chance of survival, and
non-survivors who had been predicted on admission to have a good chance of sur-
vival. Patients with the lowest charges were found to be non-survivors who were
predicted on admission not to survive and survivors who were predicted on admis-
sion to survive.
994 D. Crippen
But whether intensive care is expensive out of proportion to a patient's benefit is an

open question [17]. There is no substantive evidence that spending money in ICUs for
terminally ill patients has an effect on the resources available for patients with better
chances of survival. The motivations of the health care insurance industry with regard
to financing futile therapies are also relatively unknown. Is the maintenance of warm
cadavers in reus expensive out of proportion to the benefit to the patients and their
surrogates? The argument has been made that futile care does not use up enough
scarce resources to compel abridgement of patient autonomy [18]. Although it may
be true that beds in the ICU are relatively scarce, it is an open question whether pa-
tients' occupation of those beds for care that will not make the patients better ac-
counts for a significant proportion of the cost of medical care in the United States.
Similarly, futility cannot be determined by computing the statistical probability
of an undesirable outcome [19]. Any statistical cutoff point chosen as the threshold
for determining futility is usually relative. No matter what point is selected, there
is a potential for an unpredicted survivor. Society does not like to hear about pa-
tients who could have been successfully treated falling through cracks; the public
and the courts use vast quantities of scarce resources to avoid that possibility. Even
if a statistical cutoff point for determining futility could be decided on, physicians
are often highly unreliable in estimating the likelihood of success for a therapeutic
intervention. Statistical inferences about what might happen to groups of patients
do not permit accurate predictions of what will happen to the next individual. In
addition, the tendency to remember cases that are unusual or bizarre predisposes
physicians to make decisions on the basis of 'miraculous' cures or unexpected tra-
gedies in their practices.
The best-publicized aspect of futility may be its effect on the allocation of scarce
resources. In most countries, physicians do not manage end-of-life care on the ba-
sis of the expectation that patients might get better if enough resources are spent
on them for a long enough period [20]. Physicians practicing in resource-chal-
lenged locales do not buy much into the concept of giving moribund patients the
benefit of the doubt. In deciding whether to accept patients for resource-intensive
care, these physicians consider the amount of resources that must be removed from
other patients requiring them. The physicians have been more or less empowered
by their health care underwriters to prioritize admissions in terms of potential
benefit, not necessarily in terms of patient desire [21]. Conversely, physicians in re-
source-rich countries buy heavily into the concept of individual patient autonomy
and the right to unlimited medical care on demand [22].
In India, demand for medical services greatly exceeds supply [23]. Like most de-
veloped nations, India has a free national health service. This situation necessitates
resourceful management because expending resources on one patient may affect
others. And in such a system, there is both great benefit and great detriment. Pa-
tients who cannot afford to pay for additional care feel the effects of rationing, and
those who can afford to pay have access to world-class care. Prospective patients
must plan very effectively for their care. It is necessary to set limits at the micro-
management level - the level of the consumer rather than of the provision system.
Nursing home patients with dementia in the terminal stages are not admitted to an
ICU, because that luxury cannot be afforded. Limits are placed on the duration of
intensive care. If there is not clear evidence of progressive benefit, intensive care is
withdrawn quickly, so that the patient's family does not lose precious resources or
go flat broke. Family conferences are held daily and include discussions about how
cash reserves are holding up.
In the United Kingdom, effective prioritization is necessary for resources to be

available to the widest population. Daniels [24] looked at the difference in alloca-
tion of scarce resources in the United Kingdom and the United States. Annually,
the British spend less than half what Americans spend on medical care, but the for-
mer provide access to the system for all citizens, and all British citizens know in
advance what limitations are in effect. Advance planning is not only possible but
mandatory. Because all patients have equal access within this closed system, re-
sources must be allocated with judgment regarding which resources are most bene-
ficial for the entire group. Introduction of beneficial new procedures must be
weighed against the benefits of alternatives. Although an added service or proce-
dure might help one group of patients, its cost might be high enough to deny other
patients services. Because distributing resources most equitably within the system
provides the most care to the largest population, indiscriminately saying yes to de-
mands might be unjust. Physicians do not directly or indirectly benefit from deliv-
ering care at lower cost; thus, the incentive to provide care is limited.
Conversely, medical care in the United States is provided in an open system [24].
No prospective medical budget determinations or estimates of cost-effectiveness are
made. All varieties of medical care are equally funded in theory, but there is a catch.
Instead of determining how much should be allotted to services, the United States
health care system prospectively allows all services and then denies reimbursement
for some after they have been rendered. This unusual tack has several implications.
Caregivers are placed in the position of expending resources that may not be replen-
ished, on the whims of gatekeepers and because of technicalities. Another implication
is that there is no real way to determine whether resources expended will be replen-
ished until after the fact, which makes prospective planning difficult if not impossible.
Accordingly, resource allocation in the United States proceeds according to a table of
organization that is poorly responsive to need and sensitive to demand.
The United States is the only country that routinely accepts patients for intensive
care on the basis of open-ended desires that a high-tech care plan will cure them
[25]. The reimbursement system (the system of reimbursement for medical ser-
vices) creates an incentive to treat anyone for anything as long as a bill can be sent
to a third party that knows little or nothing about the treatment. Patients in the
United States believe they deserve free health care by right of living in an affluent
society that can afford it. Because of the emotional incentive to individualize deliv-
ery of critical care services according to principles of individual autonomy, users of
these services have a stronger incentive to use resources than conserve them. The
notion is evolving that treatment is futile only when vital signs cannot be sup-
ported by further manipulation. American health care providers are concerned
about this trend. Critical care providers in the United States know that moribund
patients supported by life-sustaining machinery in an ICU are different from per-
sistently vegetative patients supported by a feeding tube in nursing homes. It is
possible to give the former a thin veneer of life, but underneath there is only a
shell. The cost of that support is high and is unfairly borne by a tax base that has
more important priorities. Accordingly, futility seems to be a poor measure to use
when determining allocation of critical care resources, because it is subject to bias,
bias that makes its meaning different to different parties
However, if one chooses to move away from the traditional strict definition of
medical futility, there may be other rubrics more applicable. It may be effective to
consider other more pragmatic measures to apply futility to real patients and real
situations It is not unreasonable to reject the economic argument regarding futility,
996 D. Crippen
on the grounds that no one has proven that finances matter in the grand scheme,
that maximizing care for all comers generates a marginally improved outcome, even
for a diminishing population, and that each unexpected survivor generates more
value than the sum of the other inequities. There is another possible argument for
redefining futility, an argument that centers on patient comfort. Maintaining vital
signs in the context of multiple organ system failure (MOF) can be associated with
profound and unrelenting discomfort, with no hope of resolution except at death
[26]. Such care is not in keeping with the Hippocratic Oath and mandates a differ-
ent look at traditional patient autonomy. If these revised considerations are valid,
the decision to limit futile care is no longer an economic issue but an issue of pa-
tient comfort during the dying process.
Evidence suggests that maintenance of moribund but awake patients on life sup-
port is uncomfortable and that the sedation required to ameliorate this discomfort
destroys the chance of a positive quality of life [27]. Intensive care that serves only
to preserve a dying patient's vital signs is indeed given. An increasing number of
patients or surrogates want "everything done" because some ground might be
gained. "Giving up;' means benefit - however marginal - will not be possible. And
miracles occasionally happen. But this approach means making patients profoundly
uncomfortable for the sake of wildly speculative long shots.
Agitated, uncomfortable patients are a fact of life in critical care [28]. Before the
technological revolution in critical care medicine, agitation and discomfort were re-
latively minor issues. Little could be done for critically ill patients beyond making
them as comfortable as possible and observing them for treatable decompensations.
Modern ICUs can keep a patient with organ system failure alive, but only by pinn-
ing the patient firmly to the bed with tubes and appliances in every orifice. This
results in discomfort, to say the least. And this discomfort is firmly rooted in al-
tered physiology induced by the high-stress environment of the ICU, an alteration
called brain failure [29]. Physical discomfort plus distorted and interrupted meta-
bolic homeostasis, endocrine insufficiency, acute and chronic cardiopulmonary de-
compensations, poor tissue perfusion, polypharmacy, and disruption of the sleep-
wake cycle due to immobilization cause varying degrees of brain failure. Brain fail-
ure is as relevant as renal or hepatic failure and produces profound problems that
are difficult or impossible to ameliorate without chemical and physical restraint.
Brain failure is the physiological basis of true delirium. Delirium resulting from
adrenergic and dopaminergic hyperfunction is characterized by global disorders of
cognition and wakefulness and by impairment of psychomotor behavior [29]. Ma-
jor cognitive functions such as perception, deductive reasoning, memory, attention,
and orientation are globally disordered. Excessive motor activity frequently accom-
panies severe cases of delirium. When this occurs, the resulting constellation of
symptoms is called agitated delirium. This syndrome is not uncommon after ex-
tremely stressful ICU stays, especially if the patient experienced untreated pain, an-
xiety, or delirium during a previous admission.
Therefore, normally beneficial responses are detrimental to the patient in the ar-
tificial, intensive care environment, and the only way to block them is to dull them
with central nervous system-depressing medication, which in turn blocks the pa-
tient's view and experience of his or her world.
The intensive care environment is a repository for hemodynamic and metabolic
stress factors that facilitate brain failure and delirium [30]. The limbic and cortical
regions innervated by the locus coeruleus are thought to be involved in the ela-
boration of adaptive responses to stress [31]. Stress produces a heightened sense of
End-of-life Care in the Intensive Care Unit: Toward a New Concept of Futility 997
free-floating fear and anxiety, which precipitates increased norepinephrine turnover

in the limbic regions (hippocampus, amygdala, locus coeruleus) and cerebral cor-
tex. Panic attacks, insomnia, accentuated startle reflex, autonomic hyperarousal,
and hypervigilance are characteristics of noradrenergic hyperfunction. Patients
who find themselves in the same environment in which they previously experienced
stress show increased responsiveness to excitatory stimuli. Repeated exposure to
stress that does not increase noradrenergic activity in control animals increases
norepinephrine release in animals previously exposed to the same kind of stress.
Dopaminergic enervation of the medial and dorsolateral prefrontal cortex appears
to be particularly affected by repetitive stress.
These activated neurotransmission-modulated humoral factors resulting from
psychological and physical trauma may promote responses such as anxiety, panic,
hypervigilance, exaggerated startle reflexes, and paranoia when an intensive care
environment is entered [32]. For example, patients who have undergone traumatic
emergency endotracheal intubation and mechanical ventilation in the past may ex-
perience conditioned fear and recollect immobilization stress [33]. In ICU patients,
the sensitizing factor may result from hemodynamic and metabolic decompensa-
tions due to multiple system insufficiency. Behavioral sensitization to stress may
also involve 'memory imprinting' alterations in noradrenergic function. This sensi-
tization is thought to be the mechanism of posttraumatic stress disorder, originally
recognized in Vietnam veterans but now considered a sequel of other prolonged,
inordinately stressful event- such as an unpleasant stay in an ICU [34].
These compensations (and decompensations) represent evolutionary adaptive re-
sponses critical for survival in an uncertain and potentially dangerous environment.
These compensatory responses were presumably created when there were no high-
tech surrogates for naturally induced environmental stress. The highly stressful en-
vironment of the ICU leads to loss of orientation to time and place. Monotonous
sensory input (e.g., from repetitive and noisy monitoring equipment), prolonged
immobilization (especially with indwelling life-support hardware), frequently inter-
rupted sleep, and social isolation contribute to the onset of brain dysfunction. Pa-
tients in the artificial intensive care environment undergo stress but no natural en-
vironmental threat, so the response is not only wasted but also detrimental. Sus-
taining vital signs during a death spiral perpetuates global and multilevel discom-
fort in helpless patients, who can neither communicate their discomfort nor make
it stop. They must be sedated to give the superficial appearance of comfort.
Is the argument regarding futility a money issue or a patient-comfort issue? Ar-
guing that 'futile' care should be limited to save money suggests an interest in
skimping on the basis of prioritization, a concept not universally accepted. To limit
care on the basis of financial issues prompts criticism, particularly by minorities
and disabled individuals. If futility is a money issue, time will tell who is willing to
continue underwriting 'futile' care. However, if 'medically inappropriate' care
causes pain, suffering, and discomfort, the money issue (if it exists) is not relevant.
If futility is a patient-comfort issue, it is unreasonable to force physicians to go
against their expert judgment when families insist on maintaining prolonged dis-
comfort for reasons that are defensible only in emotional terms. Life support for
dying patients does not equal comfort care. Comfort measures that ameliorate suf-
fering during the dying process result in an end of life that is more in keeping with
physicians' mandates to avoid harming patients as a primary goal.
If one advocates a definition of futility that precludes maintaining helpless pa-
tients in agony, futile care must be defined as 'medically inappropriate treatment'.
998 D. Crippen
Futility should be defined in terms of the number of organ systems that have failed,
the length of time they have failed, the number of life-support machines needed to
maintain viability in the face of deteriorating hemodynamics, and the inability to
maintain comfort.
In a perfect world, there would be a balance of everything in life and death. But
where there cannot be a balance because of fundamental incompatibilities, there
must be a consensus. Accumulating evidence suggests that critical care providers
render high-quality medical care to critically ill patients from many countries. The
United States stands out for its tolerance of resource utilization predicated on pa-
tient desire rather than on demonstrated efficacy. It has not been shown that end-
of-life care is 'better' in the United States than in the rest of the global village. End-
of-life situations are a reality in intensive care, and critical care physicians need
some maxim to follow in these situations. The fundamental maxim for ICU patients
should be comfort. There is convincing evidence that some patients will die no
matter what treatment they receive in an ICU. Medically inappropriate care causes
pain, suffering, and discomfort. Technological life support for patients predicted to
die does not equal comfort care. Current definitions of futility ('inability to sustain
vital signs in a warm cadaver') have unintended adverse consequences in intensive
care. A new definition of futile treatment is needed ('medically inappropriate care')
to improve comfort care at the end of life.
Conclusion
"The success of Intensive Care is not to be measured only by the statistics of sur-
vival, as though each death were a medical failure.. . It is to be measured by the
quality of lives preserved or restored and by the quality of the dying of those in
whose interests it is to die, and by the quality of the human relationships in each
death" [35].
References
1. Dragsted L, Qvist J ( 1992) Epidemiology of intensive care. Int J Techno! Assess Health Care
8:395-407
2. Wu AW, Damiano AM, Lynn J, et a! (1995) Predicting future functional status for seriously
ill hospitalized adults. The SUPPORT prognostic model. Ann Intern Med 122:342-350
3. Teno JM, Fisher E, Hamel MB, et a! (2000) Decision-making and outcomes of prolonged
ICU stays in seriously ill patients. J Am Geriatr Soc 48:S70-S274
4. Lynn J, Harrell F Jr, Cohn F, Wagner D, Connors AF Jr (1997) Prognoses of seriously ill
hospitalized patients on the days before death: implications for patient care and public pol-
icy. New Horiz 5:56-61
5. Prendergast TJ (1997) Resolving conflicts surrounding end-of-life care. New Horiz 5:62-71
6. Cassell EJ (1986) Autonomy in the intensive care unit: the refusal of treatment. Crit Care
Clin 2:27-40
7. Fama AJ (1980) Classification of critically ill patients: a legal examination. St Louis Univ
Law J 24.:514-533
8. Teres D (1993) Trends from the United States with end of life decisions in the intensive
care unit. Intensive Care Med 19:316-322
9. Burrows R (1994) Removal of life support in intensive care units. Med Law 13:489-500
10. Crippen D, Levy M, Truog R, Whetstine L, Luce J (2000) Debate: what constitutes 'termin-
ality' and how does it relate to a living will? Crit Care 4:333-338
11. Yeager AL (2002) On Hippocrates. Either help or do not harm the patient. Br Med J
325:496
12. Truog RD (1999) Death: merely biological? Hastings Cent Rep 29:4
13. Kelly DF {2002) Medical futility in American health care. In: Crippen D, Kilcullen JK, Kelly
DF (eds) Three Patients: International Perspective on Intensive Care at the End of Life.
Kluwer Academic Publishers, Boston, pp 7-23
14. Engelhardt HT Jr, Rie MA {1986) Intensive care units, scarce resources, and conflicting
principles of justice. JAMA 255:1159-1164
15. Scheffler R {1982) Severity of illness and the relationship between intensive care and survi-
val. Am J Public Health 72:449-454
16. Detsky AS, Stricker SC, Mulley AG, Thibault GE {1981) Prognosis, survival, and the expen-
diture of hospital resources for patients in an intensive-care unit. N Engl J Med 305:667-
672
17. Pronovost P, Angus DC (2001) Economics of end-of-life care in the intensive care unit. Crit
Care Med 29:N46-N51
18. Angus DC, Sirio CA, Clermont G, Bion J {1997) International comparisons of critical care
outcome and resource consumption. Crit Care Clin 13:389-407
19. Chelluri L, Pinsky MR, Donahoe MP (1993) Long-term outcome of critically ill elderly pa-
tients requiring intensive care. JAMA 269:3119-3123
20. Crippen D {2002) Discussion of the medical aspects of futility. In: Crippen D, Kilcullen JK,
Kelly DF (eds) Three Patients: International Perspective on Intensive Care at the End of
Life. Kluwer Academic Publishers, Boston, pp 189-203
21. Vincent JL {1998) Information in the ICU: are we being honest with our patients? The re-
sults of a European questionnaire. Intensive Care Med 24:1251-1256
22. Crippen D (1999) Regionalization, prioritization, and sailing ships in the year 2010. New
Horiz 7:218-228
23. Crippen D {2000) The devolution of critical care in the U.S. Cost Qual 6:17-19
24. Daniels N (1986) Why saying no to patients in the United States is so hard: cost contain-
ment, justice, and provider autonomy. N Engl J Med 314:1380-1383
25. Crippen D, Whetstine L (1999) ICU resource allocation: life in the fast lane. Crit Care
(Lond) 3:R47-R51
26. Weiser B (1983) As they lay dying, part 1: The doctor's agony: deciding to end life-saving
therapy. Washington Post April17:A1, A16
27. Crippen D (2000) Life-threatening brain failure and agitation in the intensive care unit.
Crit Care 4:81-90
28. Szokol JW, Vender JS {2001) Anxiety, delirium, and pain in the intensive care unit. Crit
Care Clin 17:821-842
29. Crippen D (1995) Understanding the neurohumoral causes of anxiety in the ICU: clinical
consequences include agitation, brain failure, delirium. J Crit Illn 10:550-555, 559-560
30. Donchin Y, Seagull FJ {2002) The hostile environment of the intensive care unit. Curr Opin
Crit Care 8:316-320
31. Van den Berghe G {2002) Neuroendocrine pathobiology of chronic critical illness. Crit Care
Clin 18:509-528
32. Scragg P, Jones A, Fauvel N {2001) Psychological problems following ICU treatment. Anaes-
thesia 56:9-14
33. Jones C, Griffiths RD, Humphris G, Skirrow PM {2001) Memory, delusions, and the devel-
opment of acute posttraumatic stress disorder-related symptoms after intensive care. Crit
Care Med 29:573-580
34. Stoll C, Kapfhammer HP, Rothenhausler HB, et al (1999) Sensitivity and specificity of a
screening test to document traumatic experiences and to diagnose post-traumatic stress
disorder in ARDS patients after intensive care treatment. Intensive Care Med 25:697-704
35. Dunstan GR (1985) Hard questions in intensive care. A moralist answers questions put to
him at a meeting of the Intensive Care Society, Autumn, 1984. Anaesthesia 40:479-482
Subject Index
Aerosol medications 305

Afterload 299, 512
Abcbtimab 396, 401, 455 Age 164, 176, 177, 360
Abdominal Agitation 348
- pressure 294 Airway epithelium 3
- sepsis 90 - management 679
- surgery 344, 367, 384 - occlusion pressure 297
Absorptive atelectasis 248 - pressure 296
Acetaminophen 352, 848 - - release ventilation (APRV) 245, 264
Acetate 741 - resistance 259, 295
Acetylcholine 539, 765 Alarms 671, 976
Acidosis 39, 138, 548, 591, 597, 711, 807, Albumin 67, 568, 832
887 Albuterol 307
Acinetobacter 179, 204, 221 Alcohol 86, 839
Acquired immunodeficiency syndrome Alcoholism 177
(AIDS) 152 Aldosterone 588, 906
Activated partial thromboplastin time Alfentanil 350
(aPTT) 121 Alkalosis 567
- protein C (APC) 124, 129, 536 Alpha 2 agonists 352
Activity energy expenditure (AEE) 914 Alteplase 416
Acute brain injury 701 Alveolar recruitment 267
- coronary syndromes 391 Amiloride 307
- lung injury (ALI) 3, 12, 40, 513, 701, 707 Arninoglycosides 185, 308, 335, 766, 780
- myocardial infarction (AMI) 412, 428, Ammonia 740
447, 454, 874 Amphetamines 815
- - ischemia 427 Amphotericin B 199
- normovolemic hemodilution (ANH) 597, Amylase 823
615 Anaerobes 180
- renal failure 164, 596, 639, 663 Anaerobic glycolysis 575
- respiratory distress syndrome (ARDS) 3, Analgesia 348
12, 86, 231, 243, 265, 307, 317, 318, 322, Androgens 863, 891
331, 355, 366, 374, 546 Anemia 588
- - failure 164, 243 Anesthesia 41, 244, 361, 370
- tubular necrosis (ATN) 637 Angiogenesis 22
- phase proteins 102 Angiography 747
Adenosine 12, 587 Angioplasty 396, 403, 419, 420, 448
- triphosphate (ATP) 465, 575, 884 Angiopoietin 24
Adhesion molecules 779 Angiotensin 589, 903
Adrenal gland 906 - converting enzyme (ACE) 11, 80, 405,
- hemorrhage 78 451, 876
- insufficiency 897 Antacid drugs 716
- steroids 891 Anterior pituitary 905
Adrenocorticotropic hormone (ACTH) 868, Antibiotics 42, 82, 156, 165, 167, 199, 203,
903, 904 219, 308, 335, 372, 766, 831, 834, 853
1002 Subject Index
Anticholinesterase 770 Bilevel positive airway pressure (BiPAP) 247,

Anticoagulants ll5, 129, 131, 672 264, 283
Antidiuretic hormone 588 Bilirubin 617
Anti -endotoxin therapies 65 Biofilm 215
Anti-factor Xa activity 123 Bioimpedance 483
Anti-inflammatory response 652 - cardiography 529
Antimicrobial resistance 204 Bivalirudin 395
Antioxidant 732 Blood culture 165, 180, 188, 194
Antithrombin 82, 124, 125, 130, 132, 394, - velocity 502
595 -volume 589
Antithrombotic agents 418 Bloodstream infection 204, 927
Aortic blood flow 484, 501 Body mass index (BMI) 832
- - velocity 495 Bone marrow 26
- regurgitation 483 - - transplant (BMT) llO, 188
Apoptosis ll1, 431, 545, 546, 680, 726 Botulism 781
Arachidonic acid metabolites 863 Bradykinin 11
Arginine 97 Bronchiectasis 167, 309
Arrhythmias 416, 494, 642, 802 Bronchiolitis obliterans and organizing
Arterial pressure 39, 447, 500, 506 pneumonia (BOOP) 179, 183
Artificial oxygen carriers 615 Bronchoalveolar lavage (BAL) 8, 40, 94, 166,
- support 854 181, 190, 220, 243, 321, 372, 715, 925
Aspergillus 167, 189 Bronchodilators 275, 305
Asphyxia 801 Bronchoscopy 166, 180, 223, 770
Aspiration 371, 682 Bronchospasm 309
Aspirin 395 Bubble humidifier 258
Asthma 306, 367 Burns 238, 545, 599
Asynchrony 439
Atelectasis 274, 335, 367, 368, 769
Atherosclerosis 67
Atomic absorption spectrophoto- Calcium 610, 702, 832
metry 464 - channel blockers 406, 816
Atrial natriuretic factor 588 Cancer llO, 188
Automated weaning strategies 267 Candida 184, 188, 209, 214, 221
Automatic tube compensation (ATC) 268 Candidemia 189
Autonomy 994 Capacitance vessels 588
Auto-PEEP 291 Capillaroscopy 538
Autopsy 190, 705 Capillary perfusion 538
Autoregulation 638 - surface area 14
Axonal polyneuropathy 782 Carbohydrate-deficient transferring
Azathioprine 773 (CDT) 89
Carbon dioxide (C0 2 ) 550, 619, 679, 710
- monoxide poisoning 800
Carboxyhemoglobin 801
Bacteremia 158, 214 Cardiac arrest 461, 472, 929
Bacterial translocation 610 - index 341
Bactericidal permeability increasing (BPI) - output 39, 101, 379, 448, 450, 481, 485,
protein 71 494, 508, 576, 578, 588, 637
Bag-valve-mask (BVM) ventilation 691 - preload 491
Barbiturates 705 - surgery 141, 201, 368, 429, 596, 936
Baroreceptors 585 Cardiogenic shock 416, 421, 447, 885
Barotrauma 277, 288, 696, 807, 929 Cardiomyopathy 438
Base deficit 832 Cardiopulmonary bypass (CPB) 341, 368,
- excess 567 374, 447, 539, 599
Bcl-2 protein 729 - resuscitation (CPR) 973, 993
Benzodiazepines 813 Cariporide 463
Beta blockade 405 Carnitine palmitoyltransferase (CPT) 885
Bicarbonate 574 Caspase-8 547
Subject Index 1003
Catecholamines 343, 586, 640, 714, 780 Congestive heart failure (CHF) 295, 298,
Cathepsin B 825 359
Catheter-related infection 209, 927 Continuing medical education 985
CD11b/CD18 3 Continuous hemofiltration 853
Cecal ligation and perforation (CLP) 37 - positive airway pressure (CPAP) 244, 259,
Cellulitis 212 369, 451
Central venous catheter 152 - renal replacement therapies (CRRT) 649,
- - oxygen saturation (Scv0 2 ) 343 663
- - pressure (CVP) 486, 492 Contractility 511, 512
Cephalosporin 169, 221 Contraction asynchrony 437
Cerebral artery Doppler 850 Contrast-enhanced CT scan 833
- blood flow (CBF) 590, 701, 710, 747, Coronary angiography 453
761 - artery bypass graft (CABG) 355, 399, 427,
-- volume (CBV) 748, 750 432, 463, 887
- edema 849, 851, 854 - - disease (CAD) 428
- hypoxia 710 Corticosteroids 113, 115, 308, 717, 863, 904
- ischemia 710, 725, 730 Corticotropin releasing factor (CRF) 868,
- metabolic rate for oxygen (CMR0 2 ) 703, 907
851 -- hormone (CRH) 903
- perfusion pressure (CPP) 350, 759 Cortisol 430, 891
- vasospasm 755 Cost-effectiveness 995
Cerebrospinal fluid (CSF) 752, 782 Costs 157
Cerulein 824 Countershock 472
Chemokine 826, 829 C-reactive protein (CRP) 79, 829, 833, 839
Chemoprophylaxis 83 Creatine kinase (CK) 782, 805
Chemoreceptor 247 Creatinine 596, 641, 908
Chest compressions 475 - kinase 415
- wall impedance 529 Cricoid pressure 687, 693
Chlorhexidine 201 Cricothyroidotomy 695
Chronic bronchitis 256 Critical illness myopathy (CIM) 777
- obstructive pulmonary disease -- polyneuromyopathy (CIPNM) 777
(COPD) 167, 177, 272, 274, 280, 295, 305, - nursing situation index (CNSI) 965, 966
306, 312, 370 Cryoprecipitate 82
Ciprofloxacin 202 Cryptococcus 189
Cirrhosis 639, 556 Crystalloids 594
Citrulline 98 Cyclic adenosine monophosphate
Clindamycin 155 (cAMP) 901
Clonidine 352, 717 Cyclooxygenase 349, 852
Clopidogrel 396 Cystic fibrosis 51, 256
Closing pressure 243 Cytochrome a3 802
Clostridium difficile 221 - c 547, 732
Club drugs 811 - P450C17 891
Coagulation 594, 618, 650 Cytokines 99, 176, 608, 650, 653, 779, 826,
Coagulopathy 136, 773 863, 893
Collagen 93 Cytomegalovirus (CMV) 184
Colloids 598 Cytopathic hypoxia 564
Colonization 149, 188, 190, 211, 927
Community-acquired pneumonia (CAP) 89,
162, 175
Complement 112, 649 Danaparoid 126
Compliance 244, 313 Dead space 261, 288, 310, 916
Complications 793 Defibrillation 472
Computed tomography (CT) 705, 747, 805, Dehydration 817
831 Dehydroepiandrosterone (DHEA) 861, 891
Computer 982 Delirium 996
Computerized physician order entry Deoxyhemoglobin 554
(CPOE) 937 Dexmetetomidate 770
1004 Subject Index
Diabetes 176, 431, 873 Endothelium 11, 829

Dialysate 665 - bound enzyme activity 17
Diaphragm 281, 284 Endotoxemia 202, 609
Diaphragmatic denervation 783 Endotoxic shock 874
- dysfunction 784 Endotoxin 3, 36, 65, 99, 131, 221, 342,
Diaspirin cross linked hemoglobin 654
(DCLHb) 616 - binding columns 69
Diastolic dysfunction 469, 493 Endotracheal intubation 697
Diffuse alveolar damage (DAD) 232 - tube 266, 268, 326, 691
Diffusion 266 End-systolic pressure-volume relation
Dilated cardiomyopathy 492 (ESPVR) 436
Diltiazem 406 - - volume (ESV) 442
2,3 diphosphoglycerate (DPG) 626, 882 Energy 427
Disseminated intravascular coagulation - balance 912, 915
(DIC) 78, 111, 124, 816 Eosinophils 182
Dobutamine 81, 342, 343, 452, 579, 638, Epidermal growth factor (EGF) 23
916 Epinephrine 81, 344, 472, 473, 640
Dopamine 81, 429, 451, 638, 639, 896 Epithelial neutrophil-activating protein 78
Dopaminergic agonists 637 (ENA-78) 830
Dopexamine 343, 344 - permeability 545
Doppler imaging 444 Epithelium 257
Double indicator dilution technique 513 Erlangen Micro-lightguide spectrophotometer
Duffy antigen/chemokine receptor (EMPHO) 555
(DARC) 51 Erythropoietin 588
Dynamic hyperinflation 273, 296, 306, 510 Esmolol 442
Dysoxia 564 Esophageal Doppler 484, 526
Dyspnea 233 - pressure 283
- resection 938
Esophagectomy 367, 558
Estrogen 863, 891
Echocardiography 184, 299, 380, 445, 450, - receptor (ER) 866
487, 491, 494, 510 Ethyl pyruvate 604
Ecstasy 816 Excitatory amino acids 803
Edema 7 Exercise testing 381, 384
- clearance 644 Expiratory flow limitation 272, 273
Edrophonium 767 Extracorporeal circuits 123, 430
Ejection efficiency 442 - membrane oxygenation (ECMO) 81
- fraction (EF) 521 Extravascular lung water (EVLW) 486,
Elastance 440 508
£-learning 985 Extubation 929
Elective surgery 595
Electrocardiogram (EKG) 805
Electromagnetic flowmetry 482, 485
Electromyogram (EMG) 768 Face mask 260
Electrophysiological testing 786 Factor V Leiden gene 51
Emergency surgery 617 - VII 136
Empyemia 373 Fas ligand 547
Encephalopathy 743, 847 Fenoldopam 644
Endocarditis 179, 215, 523 Fentanyl 349
End-of-life 991 Fever 219, 225, 773, 913
Endoscopic retrograde cholangiopancreato- Fiberoptic intubation 692
graphy (ERCP) 824 - catheter 748
Endothelial cell 3, 59, 111, 869 Fibrin 138
- - replacement 21 Fibrinolytic therapy 393, 452
- damage 650 Fibroblast growth factor (FGF) 23
- progenitor cell (EPC) 21 Fibronectin 79
Endothelin 12, 536, 464, 639 Fibroscopy 716
Subject Index 1005
Fibrosis 181 - macrophage colony-stimulating factor

Fick principle 509, 525, 575 (GM-CSF) 27, 193
Fine needle aspiration (FNA) 831, 841 Growth-related oncogene-alpha
Fluid balance 717 (GRO-a) 830
- challenge 486 Guidewire exchange 212
- responsiveness 491, 511 Guillain-Barre syndrome 781
Flumazenil 812 Gut mucosal hypermeability 609
Flunitrazepam 812
Fluorescein flowmetry 748
Fluorodeoxyglucose (FDG) 741
Fluoroquinolones 169, 178, 185 Handwashing 159
Flutamide 865 Hantavirus 179
Free fatty acids (FFA) 88, 427, 885 Harris-Benedict equation 912
Fresh frozen plasma 82, 113 Head trauma 504, 704, 710, 742
Functional residual capacity (FRC) 273, 296, Health policy 950
313 Heart failure 43 7
Fungal infections 223 - rate 586
- pneumonia 189 Heat and moisture exchanger (HME) 261,
Fungi 182 703
Furosemide 780 - shock proteins (HSP) 726
Fusidic acid 154 Helium 312
Futility 991 Helmet 260
Helper cells 624
Hematocrit 620
G
Hemodiafiltration 665
Gammaglobulin 70 Hemodialysis 152, 668
Gamma-hydroxybutyrate (GHB) 811, 812 Hemodynamic instability 667
Gas flow 259 - monitoring 508, 521
- temperature 256 Hemoflltration 82, 653, 667
Gastric intramucosal pH (pHi) 342, 565, Hemoglobin 343, 553, 567, 574, 615, 623,
597, 620 625, 630
- tonometry 540, 565, 598 - solutions 616
Gastrointestinal bleeding 672 Hemolytic uremic syndrome (HUS) 109
- perfusion 345 Hemophilias 137
Gene modified mice 35 Hemorrhage 139, 393, 419, 843, 862
- transfer 29 Hemorrhagic shock 605
Genes 48 Hemostasis 594
Genetic factors 46, 356 Hemothorax 373
Glasgow Coma Scale 685, 711, Heparin 82, 120, 129, 130, 131, 216, 394,
- score 833 397
Global ejection fraction (GEF) 512 - induced thrombocytopenia 125
- end-diastolic volume (GEDV) 508 Hepatic failure 142
Glucagon 430 - surgery 142
Glucocorticoids 177, 898 Hepatitis 818, 847
Glucose 427, 780, 873 Hibernating myocardium 449
- insulin-potassium (GIK) 428 High density lipoprotein 71
Glutamate receptors 733 - flux membranes 671
Glutamine 98 - frequency oscillation (HFO) 288
Glutathione 91, 94, 352 - - ventilation (HFV) 264, 266, 695
Glycemia 785 - mobility group (HMG) protein 609
Glycerol 761 - volume hemofiltration (HVHF) 853
Glycolysis 431, 881 - risk surgical patients 341
Glycoprotein (GP) 11/llla inhibitors 395, Hirudin 126, 394
396, 419 Histiocytosis X 183
Glycopyrolate 690 Homeostasis 867
Granulocyte colony stimulating factor Hormones 861, 863
(G-CSF) 24, 88 Human factors 955
1006 Subject Index
- immunodeficiency virus (HIV) 48, 110, Indomethacin 852

150, 168, 180, 623 Infant respiratory distress syndrome
- leukocyte antigen (HLA) 48, 779 (IRDS} 317
Humidification 255 Infection 624
Hybridization reaction 56 - control 159
Hydrogen peroxide (H 2 0 2 } 193, 604 Infectious complications 830
Hydroxyethyl starches (HES} 138, 595 Inflammation 99, 830
Hydroxyl radicals (OH-) 741 Inflammatory phase 823
Hyperbaric oxygen (HBO) therapy 805, Inotropic agents 342, 428, 439
806 Inspiratory muscles 295
Hypercapnia 292, 576, 679, 703, 707, 876 Insulin 427, 610, 887
Hyperchloremic acidosis 597 - therapy 429
Hyperemia 557 - like-growth-factor-! (IGF-1} 876
Hyperglycemia 430, 873, 887 Integrins 3
Hyperlactatemia 883 Intercellular adhesion molecule-!
Hypernatremia 915 ICAM-1) 3, 66
Hypertension 640 Interferon (IFN) 4, 191, 610
Hyperthermia 817 Interleukin (IL) 79
Hyperthyroidism 766 - 1 4, 356, 828
Hypertonic crystalloids 598 - - receptor antagonist (IL-lra) 650
- saline 852 - 6 177, 828, 833
Hyperventilation 711, 713, 852 - 10 37, 779, 829
Hypoalbuminemia 599, 780 Intermittent positive pressure ventilation
Hypocalcemia 81 (IPPV) 244
Hypoglycemia 81, 854 International normalized ratio (INR} 352,
Hyponatremia 152, 818, 904 395
Hypotension 349, 359, 599, 683, 706 Interstitial base excess 569
Hypothalamus 866, 901 Intraabdominal pressure (lAP) 492, 844
Hypothermia 41, 138, 706, 758, 806, 849, Intraaortic balloon counterpulsation pump
852 (IABP) 360, 450, 452
Hypoventilation 714 Intracardiac shunt 515
Hypovolemia 349, 451, 494, 585, 594, 830 Intracerebral hemorrhage 754, 850
Hypoxemia 291, 299, 357, 361, 577 Intracranial hypertension (ICH) 701, 713,
Hypoxia 546, 548, 579, 631, 679, 680, 801 849
- pressure (ICP) 350, 679, 701, 707, 710,
758, 850, 978
Intramucosal C0 2 tension 597
Iatrogenic events 923, 827 Intrathoracic pressure 248, 492
ICU outreach services 971 Intrinsic positive end-expiratory pressure
Ileus 643 (PEEPi) 267, 274, 280, 296, 308
Iloprost 311 Intubation 680, 769
Imipenem 185 Inverse ratio ventilation (IRV} 264
Immune function 86 lpratropium 303
Immunodepression 868 Iron 589
Immunoglobin 70, 113, 773, 785 Ischemia 28, 881, 885
Immunomodulatory effect 632 - reperfusion (1/R) 101, 546, 604
Immunonutrition 102 Ischemic brain 728
Immunoparalysis 831 - contracture 465
Immunostimulator 895 - myocardium 464
Immunosuppression 188, 209, 348, 370, - preconditioning 725
706 - tolerance 725, 731
Immunosuppressive agents 110, 167 Isolation 371
Immunotherapy 773
Incentive spirometry 369, 371
Indicator-dilution techniques 12, 13
Indirect calorimetry 912 Jaundice 847
Indocyanine green (ICG} 557, 747, 854 Jehovah's Witnesses 631
Subject Index 1007
Jugular bulb oxygen saturation (Sjv02 ) 747,

759, 850
Macrolide 169, 185
Macrophage 5, 37, 193, 827, 861
- inflammatory protein (MIP)-2 193
Ketamine 811, 815 Magnetic resonance imaging (MRI) 702,
Ketones 611 758, 805
Kupffer cells 863, 868 - - spectroscopy 747
Major surgery 138
Malaria 51
Malnutrition 102
Labeled water 740 Malondialdehyde (MDA) 605
Lactate 564, 570, 578, 580, 848, 883 Mannitol 712, 818, 851
- dehydrogenase (LDH) 805 Mannose binding lectin (MBL) 51
- pyruvate (L:P) ratio 886 Mask ventilation 687
Lactic acidosis 382, 565, 884 Matrix metalloproteinases (MMPs) 93
Lamifiban 397 Maximal expiratory flow-volume (MEFV)
Laparotomy 839 curve 272
Laryngoscope 682, 689 Mechanical ventilation 42, 166, 247, 264,
Laser Doppler flowmetry 537, 556, 564 274, 280, 295, 299, 305, 328, 333, 356, 357,
Left atrial pressure 591 371, 701, 710, 717, 778, 785, 924
- bundle branch block (LBBB) 441 Mediators 323, 714, 853
- ventricular ejection effectiveness 436 Medical emergency team 973
- - - fraction 299 Meningitis 78
--- time 503 Meningococcal disease 51, 76, 793
- - end-diastolic area (LVEDA) 492, 510 Meropenem 185
- - - volume (LVEDV) 484 Mesenteric ischemia 604
- - relaxation 493 Meta-analysis 201, 203
Legionella 166, 168, 177, 185 Metabolic acidosis 577
Length of stay 923, 938, 959 - autoregulation 710
Leukocytosis 219, 225 Methicillin resistant Staphylococcus aureus
Leukoreduction 624 (MRSA) 149, 179, 204, 215, 221
Leukotrienes 639 Methylene chloride 801
Lidocaine 690 Microarray 50, 55
Lipase 823 Microcirculation 589, 597
Lipid-A analogs 71 Microsatellite mapping 60
- monoclonal antibodies 68 Microspheres 740
Lipopolysaccharide (LPS) 4, 22, 36, 59, 65, Microvascular alterations 535
608, 649 Milrinone 81, 452
- binding protein (LBP) 67 Minimal inhibitory concentration (MIC) 309
Lithium (Li) 521 Mitochondria 611, 874, 875, 883
- dilution technique 527 Mitochondrial damage 547
- indicator 485 - permeability transition 463
Liver failure 847 Mitogen-activated protein kinase
- transplantation 142, 558, 916 (MAPK) 609, 826
Low density lipoprotein (LDL) 17, 27 Mitral flow 493
- molecular weight (LMW) heparin 394, Mixed venous oxygen saturation (Sv02 ) 299,
419 522, 619
Lung abscesses 373 Molecular adsorbent recycling system
- Injury Score (LIS) 233 (MARS) 855
- mechanics 311, 317 Monoamine oxidase (MAO) 816
Lymphocytes 50, 100, 182 Monoclonal antibodies 70
Lysergic acid diethylmide (LSD) 811 Morbidity 223, 342, 385, 631
Lysostaphin 155 Morphine 349, 406, 451
Mortality 91, 125, 130, 169, 193,199, 203, 222,
231, 295, 322, 344, 395, 405, 428, 455, 617,
631, 712, 713, 784, 839, 923, 925, 935, 946
1008 Subject Index
Multimedia medical education 982 Nuclear factor kappa-B (NF-KB) 8, 611, 826,
Multimodal monitoring 760 874
Multiple organ failure (MOP) 131, 231, 342, Nursing 939, 963, 986
362, 579, 912 Nutrition 716
Multi-resistant bacteria 924 Nutritional support 915
Mupirocin 153, 159
Murine models 35
Muscle biopsy 783 0
Myasthenia gravis 781 Oligonucleotides 56
Myasthenic crisis 765 Oliguria 450
Mycoplasma 177, 178 Oncotic pressure 331, 589
Myelinolysis 779 Opioids 41, 349
Myeloid differentiation factor 88 Optic nerve ultrasound 85 1
(MYD-88) 72 Optodes 749
Myeloperoxidase 193 Organ failure 66
Myocardial depressant factor 591 Orthogonal polarization spectral (OPS)
- infarction 392, 523 imaging 537, 557, 564
- ischemia 377, 378, 384, 448, 632 Orthopedic surgery 159, 617
- oxygen consumption (MV0 2 ) 436 Osmolality 712
- reperfusion 452 Osmolarity 666
- stunning 427, 449 Outcomes 936, 945, 953
Myoglobin 415, 802 Oxygen 805
- consumption (V0 2 ) 298, 379, 381, 575,
741, 913
N - delivery (D02 ) 39, 341, 382, 448, 481, 521,
N-acetylcysteine (NAC) 83, 611, 826 553, 615, 630, 679
Near infrared spectroscopy 747 - extraction 578, 630
Necrosectomy 838 - free radicals 345, 547
Necrotizing myopathy (NM) 777 - saturation 554
Neonates 267, 317, 945 - therapy 256
Neoplasms 179, 183 - transport 299
Neostigmine 768 Oxygenation 334
Nerve biopsies 783
Neural network technology 977 p
Neurogenic pulmonary edema 705, 714
Neuromechanical coupling 282 Pain 348
Neuromuscular abnormalities 776 Pancreatitis 655, 823, 838
- blockade 706, 777, 916 Papaverine 752
Neuropathy 782 Partial C0 2 re-breathing 483
Neuroprotective strategies 725 - liquid ventilation (PLV) 313
Neutropenia 167 - ventilatory assist 283
Neutrophils 86, 181 Patient -to-nurse ratios 960
Nitrates 406 - ventilator interaction 284
Nitric oxide (NO) 11, 97, 292, 310, 374, 515, Peak expiratory force 772
535, 589, 617, 854, 884, 914 Pediatric cardiac surgery 946
- - synthase 726 - intensive care 791, 945
Nitrogen balance 100 - - - transport 793
Nitroglycerin 101, 539 - Risk of Mortality (PRISM) score 791, 948
N-methyl-D-aspartate (NMDA) antago- Pendelluft 290
nists 850 Penicillin 168
Non-invasive positive pressure ventilation - binding protein 2 (PBP-2) 69
(NPPV) 255, 259, 312, 769 Percutaneous transluminal coronary angio-
Non-steroidal anti-inflammatory drugs 351 plasty (PTCA) 403
Norepinephrine 12, 640 Perfluorocarbon (PFC) 313, 615, 619
Normoglycemia 776 Periodic hyperinflation 24 7
Nosocomial infection 199, 219, 223, 923, 940 Perioperative risk 433
- pneumonia 176, 183, 188, 366, 370, 925 Peritonitis 36
Subject Index 1009
Permeability 328 Process 935

Permissive hypercapnia 291 Prolactin 863, 896
Pethidine 351 Promoter 47
Pharmacists 941 Prone positioning 292, 717
Phorbol myristate acetate (PMA) 17 Prophylaxis 155, 200
Phosphodiesterase inhibitors 452 Proportional assist ventilation (PAY) 269
Phosphofructokinasse (PFK) 881 Prostacyclin (PGI 2 ) 310
Phospholipids 321 Prostaglandin 11, 351
Physician staffing 937 - E1 (PGE 1) 12
Piperacillin-tazobactam 185 - E2 650
Plasma exchange 113 Prostatectomy 625
Plasmafiltration 656 Protamine 121
Plasmapharesis 82, 773, 853 Protected specimen brush (PSB) 166, 181,
Plasmin-antiplasmin (PAP) complexes 651 190, 372, 925
Plasminogen activator inhibitor Protein 101
(PAl) 51-52, 80, 398, 874 - c 82
Plateau pressure 248 - kinase C (PKC) 874
Platelet 115, 391, 596 Providone-iodine 155
- activating factor (PAP) 639, 649, 827, 829 Pseudocyst 838
- aggregability 404 Pseudomonas 179, 185, 215
-count 619 Pseudomonas aeruginosa 167, 210, 221
Pleural effusion 368 Psychosis 803
- pressure 275, 282, 516 Pulmonary artery catheter (PAC) 374, 383,
Pneumocystis carinii 166, 179 481, 486, 521, 578, 984
Pneumonia 78, 163, 175, 200, 331, 369, 704, - - catheterization 522
715, 718 - - occlusion pressure (PAOP) 486
Polymerase chain reaction (PCR) 57, 79, - - wedge pressure 234
180 - edema 299, 307, 486, 513, 598
Polymicrobial sepsis 38 - function testing 367
Polymorphisms 47 - hyperinflation 273
Polymorphonuclear neutrophils (PMN) 654, - hypertension 311, 515, 683
877 - vascular permeability index (PVPI) 514
Polymyxin B 71 Pulse contour analysis 485, 527
Polyneuropathy 777 - pressure 511
Polysporin 154 - - variation (PPV) 486, 511
Polytrauma 499 Purpura fulminans 51
Positive end-expiratory pressure (PEEP) 40, Pyridostigmine 770
233, 243, 264, 275, 332, 516, 558, 703, 469, Pyruvate 604, 881
794 - dehydrogenase (PDH) 884
- emission tomography (PET) 737, 747
Postoperative cardiac failure 378
- care 843
- complications 935 Quality 923, 934, 963
- respiratory management 366 - of life 157, 992
Post-resuscitation myocardial dysfunc-
tion 469
Preconditioning 885
Pregnancy 110, 238 Radiocontrast nephropathy 644
Pre-hospital thrombolytic therapy 420 Radioisotopes 738
Preload 510 Ramipril 406
Preoperative assessment 378 Randomized controlled trial (RCT) 225, 235
Pressure assist 269 Rationing 994
- control 264 Reactive oxygen species (ROS) 91, 193, 341,
- slope 269 604, 732,
- support 245, 268 Receptor for advanced glycated end products
- - cycle adjusters 269 (RAGE) 874
- regulated volume control (PRVC) 266 Recruitment 291, 312
1010 Subject Index
- maneuvers 246 Septic shock 28, 49, 97, 231, 495, 538, 561,
Red blood cell (RBC) 623, 631 574, 578, 596, 639, 655, 793, 883, 898, 908
Reflectance spectrophotometry 553 Serotonin 12
Regional phase angle 442 Serratia 204
- wall motion abnormalities (RWMA) 437 Severe head injury 705
Regionalization 941 Sex steroids 861, 864
Remifentanil 349, 350 Sigh 243
Renal blood flow 637 Single nucleotide polymorphism (SNP) 59,
- failure 114, 360, 368, 853 357
- function 596 Single photon emission computed tomogra-
- perfusion pressure 638 phy (SPECT) 752
- protection 63 7 Sleep apnea 877
- replacement therapy 780 Slow low efficient daily dialysis
- vasodilators 644 (SLEDD) 664
Renin 588 Smoking 367, 404
- angiotensin system 638 Sodium-hydrogen exchanger 461
Renovascular resistance 639 Soluble TNF receptors 828
Reperfusion 412, 418, 433, 462 Spatial resolved spectroscopy (SRS) 753
- injury 803 Spectrophotometer 556
Resin 658 Spermine 97
Respiratory acidosis 297 Splanchnic blood flow 579
- alkalosis 802 - perfusion 97
- chain 727 Splenectomy 115
- failure 355 Staphylococci 209
- insufficiency 792 Staphylococcus aureus 149
- muscle 280 Statins 404
- quotient 580 Status asthmaticus 306
- syncytial virus (RSV) 793 Stenotrophomonas 221
Resting energy expenditure (REE) 913 Stents 29
Restriction fragment length polymorphism Steroids 167, 179, 765, 773, 779
(RFLP) 60 Streptococcus pneumoniae 166, 168, 177
Reticuloendothelial system (RES) 619 Stroke 420, 758
Reverse transcription-polymerase chain reac- - volume 444, 521, 526, 527
tion (RT-PCR) 728 - - variation (SVV) 486, 495, 512
Rifampicin 83, 154, 155 -work 436
Right arterial pressure 493 Strong ion difference (SID) 566
- ventricular dysfunction 447 Subarachnoid hemorrhage (SAH) 703, 747,
ejection fraction (RVEF) 487 759
- - end-diastolic volume (RVEDV) 510 Subdural space 752
- - failure 184 Sublingual capnometry 540
Ringer's lactate solution (RLS) 605 Suction bulb 697
RNA polymerase 47 Sufentanil 348
Rounds 938 Superoxide 874
Surfactant 87, 248, 311, 317, 331, 878
s Synchronized intermittent mandatory ventila-
tion (SIMV) 248, 283
Salbutamol 305 Systemic inflammatory response syndrome
SAMU 416 (SIRS) 641, 852
Sedation 770 - lupus erythematosis (SLE) 766, 897
Seizures 115, 814 - vascular resistance (SVR) 521, 587
Selective decontamination of the digestive Systolic dysfunction 464
tract (SDD) 199, 716 - fraction (SF) 494
Sellick maneuver 687 - pressure variation (SPV) 486
Sepsis 22, 35, 46, 86, 97, 99, 129, 220, 322,
536, 578, 609, 631, 649, 650, 852, 881, 883,
913, 917
Subject Index 1011
I Translocation 88, 194, 830

Transplantation 21
T lymphocytes 861 Transpulmonary pressure (Ptp) 248, 273
Tachycardia 494, 591 - thermodilution 508
Telemedicine 939 Transtentorial herniation 761
Telemetry 975 Transtracheal Doppler 484
Temperature 255 Trauma 86, 136, 141, 341, 599
Tenecteplase 417 - hemorrhage 896
Terbutaline 305 Traumatic brain injury (TBI) 761, 861
Therapeutic Intervention Scoring System Tricarboxylic acid (TCA) cycle 604, 741,
(TISS) 956 884
Thermodilution 481, 508, 527 Tricuspid regurgitation 482, 493
Thick filament myopathy (TFM) 777 Troponin 415, 432, 805
Thienopyridine derivatives 395 Trypsinogen 825
Thiopental 705 - activation peptide (TAP) 834
Thoracic bioimpedance 522 Tumor necrosis factor (TNF)-a 4, 37, 79, 88,
Thrombelastography (TEG) 595 177, 356, 547, 670, 779, 826, 863
Thrombin 79, 138
- inhibitors 394
- antithrombin (TAT) complexes 651
Thrombocytopenia 109, 124, 394 Ultrafiltration 654, 655
Thromboelastrography 140 Unplanned extubation 372
Thromboembolism 131 5' untranslated region (UTR) 48
Thrombolytic therapy 412 Urinary antigen detection 166
Thrombomodulin 79 - infections 202
Thrombophlebitis 215
Thrombosis 121, 126, 392, 595
Thrombotic episodes 143
- microangiopathy 109 Vaccines 52, 70, 158
- thrombocytopenic purpura Vagal tone 585
(TTP) 109 Vancomycin 185, 215
Thromboxane 639 Vascular endothelial growth factor
Thymoma 765 (VEGF) 22
Ticlopidine 395 - repair 29
Tirofiban 396, 401 Vasculitis 190
Tissue base excess 564 Vasculogenesis 24
- factor (TF) 131, 137, 392 Vasoactive drugs 309
- hypoxia 576 - intestinal peptide (VIP) 868
- oxygenation 553 Vasoconstriction 901
- plasminogen activator (tPA) 393 Vasodilation 590, 617
Tobramycin 199, 205 Vasodilators 539
Tolerance 726 Vasopressin 588, 589, 590, 639, 818, 901
Toll like receptor 4 (TLR4) 67 Vasospasm 706
Total lung capacity (TLC) 369 Velocity 526
Toxicology 811 - time integral (VTI) 494
Tracers 739 Veno-arterial PC0 2 gradient 564, 574
Tracheal gas insufflation (TGI) 264, 266 Venous admixture (QvaiQ) 245
Tracheostomy 372, 373, 693 - pulmonary flow 494
Transbronchial biopsies 183, 190 - return 587
Transcranial Doppler (TCA) 747 - thromboembolism 121
Transdiaphragmatic pressure 282 Ventilation/perfusion (V/Q) mismatch-
Transesophageal echocardiography ing 368
(TEE) 215, 491, 521, 526 Ventilator associated pneumonia (VAP) 46,
Transforming growth factor beta 176, 199, 220, 264, 308, 362, 704, 714, 924
(TGF-p) 23 - induced lung injury (VILI) 243, 364, 277,
Transfusion 358, 418, 535, 617, 623, 630 288, 311, 332
- risks 624 Ventilators 796
1012 Subject Index
Ventricular arrhythmias 468

- fibrillation 463, 464, 472
- function 379 Warfarin 395
Verapamil 406 Weaning 267, 295, 372, 717, 781
Videoscopic-assisted techniques 375 White blood cells 4
Vincristine 113 Work of breathing 248, 274, 297, 451, 913
Viral pneumonia 334
Virtual ICU 975
- reality 983
Vital capacity 769, 774, 781, 875 Xenon dilution technique 747
Volume support 267
- therapy 594
Volutraurna 40
von Willebrand factor (vWF) 22, 111

B. Beck-Schimmer, R. C. Schimmer, T. Pasch (Auth.), Jean-Louis Vincent MD, PHD, FCCM, FCCP (Eds.) - Intensive Care Medicine - Annual Update 2003-Springer-Verlag New York (2003)

Uploaded by

Document Information

Original Description:

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

B. Beck-Schimmer, R. C. Schimmer, T. Pasch (Auth.), Jean-Louis Vincent MD, PHD, FCCM, FCCP (Eds.) - Intensive Care Medicine - Annual Update 2003-Springer-Verlag New York (2003)

Uploaded by

Copyright:

Available Formats

INTENSIVE

Head, Department of Intensive Care

With 176 Figures and 96 Tables

ISBN 978-1-4757-5550-3 ISBN 978-1-4757-5548-0 (eBook)

Printed on acid-free paper.

©Springer-Verlag Berlin Heidelberg 2003

Role of Epithelial ICAM-1 in Endotoxin-Induced Lung Injury 3

Pulmonary Endothelium-Bound Enzymes in the Normal

Endothelial Cell Replacement Therapy in the Critically Ill 21

Sepsis: Mechanisms and Therapy

Reconciling Clinical Criteria and the Use

Human Genetics and Human Sepsis:

Microarray Technology in Sepsis: Tool or Toy . . . . . . . . . . . . 55

Update on Anti-Endotoxin Therapies 65

An Update of Childhood Meningococcal Sepsis . . . . . . . . . . . 76

The Effect of Alcohol Consumption on Risk of Sepsis

Supplementing Arginine during Sepsis:

Severe Thrombotic Microangiopathy in Critically Ill Patients . 109

Heparin in the Treatment of Critically Ill Patients

Endogenous Anticoagulants and the Role of Heparin

Is Recombinant Activated Factor VII a Universal Hemostatic? . 136

Nasal Carriage of Staphylococcus aureus: Associated Risks

Current Dilemmas in the Management of Adults

Evaluation of Non-Resolving and Progressive Pneumonia ... . 175

Candida in Lung Specimens from Non-Neutropenic ICU

A Reappraisal of Selective Decontamination

Management of Catheter-Related Sepsis in the ICU ... ..... 209

Empiric Antibiotics in Critical Illness: Do they Help or Harm? 219

Acute Respiratory Failure

Mortality Rates in Patients with ARDS:

Sigh in Acute Respiratory Failure . . . . . . . . . . . . . . . . 243

The Conditioning of Medical Gases during Spontaneous

Recent Innovations in Mechanical Ventilatory Support . . . . . 264

Expiratory Flow Limitation in Mechanically Ventilated Patients 272

Respiratory Muscle Unloading during Mechanical Ventilation . 280

High Frequency Oscillation (HFO): Physiological Basis

Withdrawal from Mechanical Ventilation in Patients

Inhalation Therapy during Mechanical Ventilation . . . . . . . 305

Trials of Surfactant Replacement Therapy in Patients

Surfactant Therapy: Beyond a Rescue Therapy for ARDS . . . . 331

High Risk Surgical Patients: Why We Should Pre-Optimize ... 341

Pain Control in the Intensive Care Unit . . . . . . . . . . . . . 348

Respiratory Failure Post-Coronary Bypass Surgery ......... 355

Postoperative Respiratory Management . . . . ... . . . . . .366

Myocardial Ischemia or Cardiac Failure:

Acute Coronary Syndromes .... . .................... 391

Pre-Hospital Reperfusion Strategies to Optimize Outcomes

Glucose, Free Fatty Acids, and Insulin Following

Quantifying Left Ventricular Ejection Effectiveness . . . . . . . 436

Cardiogenic Shock ................................ 447

Inhibition of the Sarcolemmal Sodium-Hydrogen Exchanger:

Immediate Defibrillation for Out-of-hospital Ventricular

Cardiac Output Monitoring: Will New Technologies Replace

Assessment of Cardiac Preload and Volume Responsiveness

Early Transesophageal Echo Doppler Approach in Trauma:

Management of Circulatory and Respiratory Failure

Minimally Invasive Hemodynamic Monitoring . . . . . . . . . . . 521

Microvascular Alterations in Patients with Circulatory Failure 535

Critical Tissue Oxygen Thresholds for the Induction

Reflectance Spectrophotometry and Tissue Oxygenation

The Case for Tissue Base Excess . . . . . . . .... . . . . . . 564

Clinical Use of Venoarterial PC0 2 Difference in Septic Shock . 574