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GREEN FEILD SURGERY Scientificprinciplespracticemulhollandgreenfieldssurgery5thedition 141230131431 Conversion Gate01
GREEN FEILD SURGERY Scientificprinciplespracticemulhollandgreenfieldssurgery5thedition 141230131431 Conversion Gate01
GREENFIELDS
SURGERY
Volume 1
Ronald V. Maier, MD
Keith D. Lillemoe, MD
Jay L. Grosfeld Professor and Chairman
Department of Surgery
Indiana University School of Medicine
Surgeon-in-Chief
Indiana University Hospital
Indianapolis, Indiana
Gerard M. Doherty, MD
N.W. Thompson Professor of Surgery
Head, Section of General Surgery
Chief, Division of Endocrine Surgery
University of Michigan
Ann Arbor, Michigan
Diane M. Simeone, MD
Lazar J. Greenfield Professor of Surgery and
Molecular & Integrative Physiology
Chief, Division of Gastrointestinal Surgery
Associate Chair of Research
University of Michigan
Ann Arbor, Michigan
2010024548
DISCLAIMER
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errors or omissions or for any consequences from application of the information in this book and
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new or infrequently employed drug.
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10 9 8 7 6 5 4 3 2 1
To my loving family.
M.W.M.
To my wife, Cheryl, and our children, Chris, Shannon,
Becky, and Heather for your love and support and to the
surgical residents who have always stimulated me to stay
one step ahead.
K.D.L.
To my wonderful family: Faith, Kevin, and Megan.
G.M.D.
To Lauren, Michael, and Anna, for all you sacrifice
for me.
R.V.M.
Dedicated to the continual pursuit of Scientific
knowledge to improve the lives of our patients.
D.M.S.
To my family, Nancy, Rivers, Walker, Joe, and Antione,
who remains supportive of my vocation as a surgeon
G.R.U.
CONTRIBUTORS
Keith D. Aaronson, MD
Ariel L. Barkan, MD
Associate Professor
Department of Internal Medicine
Division of Cardiovascular Medicine
University of Michigan
Ann Arbor, Michigan
Barbara L. Bass, MD
Sanjeev Aggarwal, MD
Professor
Department of Surgery
Weill Medical College of Cornell University
New York, New York;
Carolyn and John F. Bookout Chair
Department of Surgery
The Methodist Hospital
Houston, Texas
B. Timothy Baxter, MD
N. Scott Adzick, MD
Surgeon in Chief
Department of Surgery
Childrens Hospital of Philadelphia
Philadelphia, Pennsylvania
Professor
Department of Surgery
University of Nebraska Medical Center
Staff Surgeon
Department of Surgery
Nebraska Methodist Hospital
Omaha, Nebraska
John J. Aiken, MD
Private Practice
Restoration Foot and Ankle
Owasso, Oklahoma
Gorav Ailawadi, MD
Michael Belkin, MD
Assistant Professor
Department of Surgery
University of Virginia
Charlottesville, Virginia
Steven A. Ahrendt, MD
Reginald Alouidor, MD
Assistant Professor of Surgery
Tufts University School of Medicine
Springfield, Massachusetts
Subodh Arora, MD
Associate Professor of Surgery
George Washington University
Washington, DC
Ali Azizzadeh, MD
Assistant Professor
Cardiothoracic and Vascular Surgery
University of Texas at Houston Medical School
Medical Director, Vascular Laboratory, Staff Vascular Surgeon
Memorial Hermann Hospital
Houston, Texas
Carlo Bellabarba, MD
Assistant Professor
Departments of Orthopaedics and Neurosurgery
University of Washington
Seattle, Washington
Christopher K. Bichakjian, MD
Assistant Professor
Department of Dermatology
University of Michigan
Ann Arbor, Michigan
Timothy R. Billiar, MD
The George Vance Foster Professor and Chair
Department of Surgery
Presbyterian University Hospital
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania
vi
Contributors
John D. Birkmeyer, MD
John L. Cameron, MD
Professor of Surgery
The Johns Hopkins University
Baltimore, Maryland
C. Richard Boland, MD
Chief
Department of Internal Medicine, Division of Gastroenterology
Baylor University Medical Center
Dallas, Texas
Edward L. Bove, MD
Helen and Marvin Kirsch Professor
Professor and Section Head, Cardiac Surgery
C.S. Mott Childrens Hospital
Ann Arbor, Michigan
Tony Capizzani, MD
Department of Surgery
University of Michigan Health System
Ann Arbor, Michigan
Assistant Professor
Department of Orthopaedics
University of Washington
Seattle, Washington
Robert S. Bresalier, MD
Darrell L. Cass, MD
Professor of Medicine
Department of Gastrointestinal Medicine and Nutrition
University of Texas, MD Anderson Cancer Center
Houston, Texas
Assistant Professor
Michael E. DeBakey Department of Surgery and
Department of Pediatrics
Baylor College of Medicine
Co-Director, Texas Center for Fetal Surgery
Houston, Texas
Richard J. Bransford, MD
Steven R. Buchman, MD
Professor, Plastic Surgery
Chief, Pediatric Plastic Surgery
Director, Craniofacial Anomalies Program
University of Michigan Health System
Ann Arbor, Michigan
Eileen M. Bulger, MD
Associate Professor
Department of Surgery
University of Washington School of Medicine
Associate Director
Emergency Surgical Services
Harborview Medical Center
Seattle, Washington
Paul S. Cederna, MD
Associate Professor and Associate Chair
Department of Surgery
University of Michigan
Associate Chief of Staff
Office of Clinical Affairs
University of Michigan Health System
Ann Arbor, Michigan
Samuel Cemaj, MD
Assistant Professor
Department of Surgery
Creighton University Medical Center
Omaha, Nebraska
William F. Chandler, MD
Professor
Department of Neurosurgery
University of Michigan
Ann Arbor, Michigan
Andrew C. Chang, MD
Assistant Professor of Surgery
Section of Thoracic Surgery
University of Michigan
Ann Arbor, Michigan
Jens R. Chapman, MD
Assistant Professor
Department of Surgery
Johns Hopkins University School of Medicine
Director of Liver Transplant
Comprehensive Transplant Center
Johns Hopkins Hospital
Baltimore, MD
Contributors
Randall M. Chesnut, MD
Eric J. Devaney, MD
Robert E. Cilley, MD
Professor of Surgery and Pediatrics
Department of Surgery
Penn State University College of Medicine
Chief, Division of Pediatric Surgery
Department of Surgery
Milton S. Hershey Medical Center
Hershey, Pennsylvania
G. Patrick Clagett, MD
Professor and Chairman, Division of Vascular and
Endovascular Surgery
Department of Surgery
University of Texas Southwestern Medical Center
Dallas, Texas
Joseph Cuschieri, MD
Associate Professor
Department of Surgery
University of Washington School of Medicine
Harborview Medical Center
Seattle, Washington
Michael C. Dalsing, MD
Director of Vascular Surgery
Indiana University School of Medicine
Indianapolis, Indiana
E. Patchen Dellinger, MD
Professor and Vice Chairman, Surgery
Associate Medical Director and Chief of General Surgery
University of Washington School of Medicine
Seattle, Washington
Eric J. DeMaria, MD
Director
Duke Health System Weight Loss Surgery Program
Durham, North Carolina
vii
Gerard M. Doherty, MD
N.W. Thompson Professor of Surgery
Head, Section of General Surgery
Chief, Division of Endocrine Surgery
University of Michigan
Ann Arbor, Michigan
Matthew O. Dolich, MD
Associate Clinical Professor
Department of Surgery
University of California Irvine
Irvine, California
Matthew J. Eagleton, MD
Assistant Professor
Department of Vascular Surgery
Cleveland Clinic Lerner College of Medicine of Case Western
Reserve University
Staff, Vascular Surgery
The Cleveland Clinic Foundation
Cleveland, Ohio
Jonathan L. Eliason, MD
Assistant Professor
Department of Surgery
University of Michigan Health System
Ann Arbor, Michigan
Jean C. Emond, MD
Thomas S. Zimmer Professor
Department of Surgery
Director of Transplantation Services
Department of Surgery
New York HospitalColumbia University Medical Center
New York, New York
Anthony L. Estrera, MD
Assistant Professor and Director, Cardiovascular Intensive Care Unit
Cardiothoracic and Vascular Surgery
University of Texas at Houston
Memorial Hermann Hospital
Houston, Texas
Mary E. Fallat, MD
Professor and Division Director of Pediatric Surgery
Department of Surgery
University of Louisville
Chief of Surgery and Trauma
Kosair Childrens Hospital
Louisville, Kentucky
Emily Finlayson, MD
Assistant Professor
Division of General Surgery
University of California San Francisco
San Francisco, California
viii
Contributors
A. Mark Gillinov, MD
Professor
Department of Surgery
Creighton University Medical Center
Omaha, Nebraska
Yuman Fong, MD
Murray F. Brennan Chair in Surgery
Chief, Gastric and Mixed Tumor Service
Department of Surgery
Memorial Sloan-Kettering Cancer Center
Professor of Surgery
Cornell University Medical College
New York, New York
Douglas L. Fraker, MD
Jonathan E. Rhoads Professor of Surgery
Department of Surgery
University of Pennsylvania
Philadelphia, Pennsylvania
Chris E. Freise, MD
Associate Professor of Surgery
Transplant Division
University of California, San Francisco
San Francisco, California
Eric R. Frykberg, MD
Professor
Department of Surgery
University of Florida College of Medicine
Chief, Division of General Surgery
Shands Jacksonville Medical Center
Jacksonville, Florida
Joseph M. Galante, MD
Assistant Professor
Department of Surgery
University of California Davis Medical Center
Davis, California
Robert D. Galiano, MD
Assistant Professor
Department of Surgery
Northwestern University Feinberg School of Medicine
Attending Surgeon
Department of Surgery
Northwestern Memorial Hospital
Chicago, Illinois
Paul G. Gauger, MD
Professor
Department of Surgery, Division of Endocrine Surgery
University of Michigan
Ann Arbor, Michigan
Nicole S. Gibran, MD
Professor of Surgery
University of Washington
Director, University of Washington Burn Center
Harborview Medical Center
Seattle, Washington
Matthew A. Goettsch, MD
Department of Surgery
Creighton University Medical Center
Omaha, Nebraska
Jason S. Gold, MD
Assistant Professor of Surgery
Department of Surgery (Brigham and Womens
Hospital)
Harvard Medical School
Boston, Massachusetts
Staff Surgeon
Department of Surgical Service
VA Boston Healthcare System
West Roxbury, Massachusetts
Ahmet Gurakar, MD
Medical Director, Liver Transplantation
The Johns Hopkins University School of Medicine
Baltimore, Maryland
Jonathan W. Haft, MD
Assistant Professor
Department of Cardiac Surgery
University of Michigan
Ann Arbor, Michigan
Peter K. Henke, MD
Associate Professor of Surgery
Section of Vascular Surgery
University of Michigan
Ann Arbor, Michigan
Contributors
Ronald B. Hirschl, MD
Timothy M. Johnson, MD
Richard A. Hodin, MD
Gregory J. Jurkovich, MD
Professor
Department of Surgery
Harvard Medical School
Surgical Director, Crohns and Colitis Center
Department of Surgery
Massachusetts General Hospital
Boston, Massachusetts
Professor
Department of Surgery
University of Washington
Chief, Trauma Service
Harborview Medical Center
Seattle, Washington
Richard A. Hopper, MD
Assistant Professor
Department of Plastic Surgery
University of Washington
Division Chief
Department of Pediatric Plastic Surgery
Seattle Childrens Hospital
Seattle, Washington
Thomas J. Howard, MD
Willis D. Gatch Professor of Surgery
Department of Surgery
Indiana University School of Medicine
Indianapolis, Indiana
David B. Hoyt, MD
Executive Director
American College of Surgeons
Chicago, Illinois
Tam T. Huynh, MD
Assistant Professor
Cardiothoracic and Vascular Surgery
University of Texas at Houston Medical School
Memorial Hermann Hospital
Houston, Texas
Ajay Jain, MD
Assistant Professor
Department of Surgery
University of Maryland
Chief, Section of Surgical Oncology
Department of Surgery
Baltimore VA Medical Center
Baltimore, MD
Craig M. Jarrett
Research Fellow
Department of Thoracic and Cardiovascular Surgery
Cleveland Clinic
Cleveland, Ohio
Larry R. Kaiser, MD
President
University of Texas Health Sciences Center
Alkek-Williams Chair
Cardiothoracic and Vascular Surgery
University of Texas Medical School at Houston
Houston, Texas
Eugene P. Kennedy, MD
Assistant Professor of Surgery
Thomas Jefferson University
Philadelphia, Pennsylvania
Lawrence T. Kim, MD
Professor
Department of Surgery
University of Arkansas for Medical Sciences
Chief
Department of Surgery
Central Arkansas Verterans Healthcare System
Little Rock, Arkansas
Tari A. King, MD
Associate Professor
Department of Surgery
Weill Medical College of Cornell
Associate Attending, Jeanne A Detrek Junior Faculty Chair
Memorial Sloan-Kettering Cancer Center
New York, New York
ix
Contributors
Lauren Kosinski, MD
Peter H. Lin
Assistant Professor
Department of Surgery
Medical College of Wisconsin
Froedtert Memorial Lutheran Hospital
Milwaukee, Wisconsin
Professor of Surgery
Chief, Division of Vascular Surgery
Michael E. DeBakey Department of Surgery
Baylor College of Medicine
Houston, Texas
Alexander S. Krupnick, MD
Virginia R. Little, MD
Instructor of Surgery
University of Washington School of Medicine
Seattle, Washington
John C. Kucharczuk, MD
Associate Professor of Surgery
University of Pennsylvania
Philadelphia, Pennsylvania
Professor of Pathology
Mayo Clinic College of Medicine
Consultant at Mayo Clinic
Rochester, Minnesota
G. Matthew Longo, MD
Vibha Lama, MD
Assistant Professor
Department of Internal Medicine
University of Michigan Health System
Ann Arbor, Michigan
Wendy B. Landman, MD
Department of Radiology
Brigham and Womens Hospital
Boston, Massachusetts
Kirk A. Ludwig, MD
The Vernon O. Underwood Professor
Department of Surgery
Medical College of Wisconsin
Chief of Colorectal surgery
Department of Surgery
Froedtert Memorial Lutheran Hospital
Milwaukee, Wisconsin
Michael P. LaQuaglia, MD
Robyn R. Macsata
Professor
Department of Surgery
Weill-Cornell Medical School
Chief
Department of Pediatric Surgerical Service
Memorial-Sloan Kettering Cancer Center
New York, New York
W. Anthony Lee, MD
Robert D. Madoff, MD
Professor
Department of Surgery
University of Minnesota
Minneapolis, Minnesota
Steven K. Libutti, MD
Professor, Departments of Surgery and Genetics
Director
Montefiore-Einstein Center for Cancer Care
Montefiore Medical Center
Bronx, New York
Keith D. Lillemoe, MD
Jay L. Grosfeld Professor and Chairman
Department of Surgery
Indiana University School of Medicine
Surgeon-in-Chief
Indiana University Hospital
Indianapolis, Indiana
Jules Lin, MD
Assistant Professor
Section of Cardiothoracic Surgery
Department of Surgery
University of Michigan Health System
Ann Arbor, Michigan
David K. Magnuson, MD
Assistant Professor of Surgery and Pediatrics
Case Western Reserve University
Chief, Division of Pediatric Surgery
Rainbow Babies & Childrens Hospital
Cleveland, Ohio
Raja S. Mahidhara, MD
Assistant Professor of Surgery
Section of Thoracic Surgery
University of Michigan Health System
Ann Arbor, Michigan
Ronald V. Maier, MD
Jane and Donald Trunkey Professor and Vice-Chairman
of Surgery
University of Washington
Surgeon-in-Chief
Harborview Medical Center
Seattle, Washington
Contributors
Michael R. Marvin, MD
Professor
Cardiothoracic and Vascular Surgery
Center for Clinical Research and Evidence-Based Medicine
Center for Biotechnology
University of Texas at Houston Medical School
Houston, Texas
Jeffrey B. Matthews, MD
Professor and Chairman
Dean for Clinical Affairs
Department of Surgery
University of Chicago
Surgeon-in-Chief
Department of Surgery
University of Chicago Hospital
Chicago, Illinois
Matthew T. Menard, MD
Co-Director of Endovascular Surgery
Division of Vascular and Endovascular Surgery
Brigham and Womens Hospital
Instructor in Surgery
Harvard Medical School
Boston, Massachusetts
Robert M. Merion, MD
Professor of Surgery
Department of Surgery
University of Michigan
Attending Transplant Surgeon
Department of Surgery
University of Michigan Health System
Ann Arbor, Michigan
Fabrizio Michelassi, MD
Lewis Atterbury Stimson Professor and Chairman
Department of Surgery
Weill Medical College of Cornell University
Surgeon-in-Chief
New York Presbyterian Hospital-Weill Cornell Medical Center
New York, New York
Tomislav Mihaljevic, MD
Staff
Department of Thoracic and Cardiovascular Surgery
Cleveland Clinic
Cleveland, Ohio
Barbara S. Miller, MD
Assistant Professor
Department of Surgery
Staff Physician
Division of Endocrine Surgery
University of Michigan
Mathew C. Miller, MD
Assistant Professor
Department of Otolaryngology
University of Rochester Medical Center
Rochester, New York
Eugene Minevich, MD
Professor
Department of Surgery
Division of Pediatric Urology
Cincinnati Childrens Hospital
Cincinnati, Ohio
Rebecca M. Minter, MD
Assistant Professor Surgery
Assistant Professor of Medical Education
Department of Surgery
University of Michigan Medical School
University of Michigan Health System
Ann Arbor, Michigan
Gregory L. Moneta, MD
Professor and Chief
Division of Vascular Surgery
Oregon Health & Science University
Portland, Oregon
Mark D. Morasch, MD
Associate Professor of Surgery
Division of Vascular Surgery
Northwestern University Feinberg School
of Medicine
Attending Surgeon
Division of Vascular Surgery
Northwestern Memorial Hospital
Chicago, Illinois
Arden M. Morris, MD
Assistant Professor of Surgery
Section of General Surgery
Division of Colorectal Surgery
University of Michigan
Ann Arbor, Michigan
Monica Morrow, MD
Professor of Surgery
Weill Medical Collge of Cornell University
Chief, Breast Surgical Service
Department of Surgery
Memorial Sloan-Kettering Cancer Center
New York, New York
xi
xii
Contributors
Thomas A. Mustoe, MD
Mary F. Otterson, MD
Professor
Department of Surgery
Medical College of Wisconsin
Physician
Department of Surgery
Froedtert Memorial
Milwaukee, Wisconsin
George B. Mychaliska, MD
Assistant Professor
Department of Pediatric Surgery
University of Michigan
Ann Arbor, Michigan
Christopher J. Myers, MD
Durham, North Carolina
Attila Nakeeb, MD
Associate Professor
Department of Surgery
Indiana University School of Medicine
Attending Surgeon
Indiana University Hospital
Indianapolis, Indiana
Shawn J. Pelletier, MD
Assistant Professor
Department of Surgery
Division of Transplant Surgery
University of Michigan Health System
Ann Arbor, Michigan
Jeffrey H. Peters, MD
Professor of Surgery
University of Toronto Faculty of Medicine
Toronto, Canada
Santhat Nivatvongs, MD
Professor of Surgery
Mayo Clinic College of Medicine
Rochester, Minnesota
Richard G. Ohye, MD
Assistant Professor, Departments of Surgery and
Pediatrics and Communicable Diseases
Surgical Director, Pediatric Cardiac Transplantation
Director, Pediatric Cardiovascular Surgery Fellowship Program
University of Michigan
Ann Arbor, Michigan
Grant E. OKeefe, MD
Rebecca P. Petersen, MD
Seattle, Washington
Allan Pickens, MD
Assistant Professor of Surgery
Section of Thoracic Surgery
University of Michigan Health System
Ann Arbor, Michigan
Professor of Surgery
Department of Surgery
University of Washington School of Medicine
Harborview Medical Center
Seattle, Washington
Professor
Department of Surgery
University of Maryland
Director, Surgical Care
Baltimore VA Medical Center
Baltimore, Maryland
Keith T. Oldham, MD
Henry A. Pitt, MD
Jeffrey L. Platt, MD
Professor Surgery
Professor of Microbiology and Immunology
Department of Transplantation Biology
University of Michigan
Ann Arbor, Michigan
Thomas H. Quinn, MD
Contributors
Steven E. Raper, MD
Matthew R. Rosengart, MD
Associate Professor
Department of Surgery
University of Pennsylvania
Attending Surgeon
Department of Surgery
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania
Assistant Professor
Department of Surgery
University of Pittsburgh School of Medicine
Pittsburgh, Pennsylvania
Philip A. Rascoe, MD
Department of Surgery
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania
Grace S. Rozycki, MD
Daniel J. Reddy, MD
Professor
Department of Surgery
Wayne State University School of Medicine
Vascular Surgeon
Department of Surgery
John D. Dingell VA Medical Center
Detroit, Michigan
Timothy W. Rutter, MD
Associate Professor
Department of Anesthesiology
University of Michigan
Ann Arbor, Michigan
Rishindra M. Reddy, MD
Michael S. Sabel, MD
Assistant Professor
Department of Surgery
University of Michigan
Ann Arbor, Michigan
Amy B. Reed, MD
Hazim J. Safi, MD
Taylor S. Riall, MD
Department of Surgery
New York-Presbyterian Hospital
New York, New York
Assistant Professor
Department of Surgery
University of Texas Medical Branch
Galveston, Texas
Barrie S. Rich, MD
Ben Samstein, MD
Thomas T. Sato, MD
Assistant Professor
Department of Surgery
University of Massachusetts Medical School
Worcestor, Massachusetts
xiii
xiv
Contributors
Willam P. Schecter, MD
Professor of Surgery
Department of Surgery
Pennsylvania State University College of Medicine
Breast Disease Team Leader
Breast Care Center
Penn State Hershey Medical Center
Hershey, Pennsylvania
Randall P. Scheri, MD
Assistant Professor
Department of Surgery
Duke University
Durham, North Carolina
Assistant Professor
Division of Urology
Department of Surgery
The University of Texas Medical School at Houston
Houston, Texas
Richard D. Schulick, MD
Associate Professor of Surgery, Oncology, Gynecology and Obstetrics
Johns Hopkins Medical Institutions
Baltimore, Maryland
Federico G. Seifarth, MD
Department of Pediatric Surgery
Cleveland Clinic
Cleveland, Ohio
Curtis A. Sheldon, MD
Professor of Surgery
Department of Urology
University of Cincinnati
Director
Department of Pediatric Urology
Cincinnati Childrens Hospital
Cincinnati, Ohio
David I. Soybel, MD
Associate Professor of Surgery
Harvard Medical School
Staff Surgeon
Department of Surgery
Brigham & Womens Hospital
Boston, Massachusetts
Sunita D. Srivastava, MD
Assistant Professor
Section of Vascular Surgery, Department of Surgery
Cleveland Clinic Lerner College of Medicine of Case Western University
Staff, Department of Vascular Surgery
The Cleveland Clinic Foundation
Cleveland, Ohio
Matthew J. Sideman, MD
Sharon L. Stein, MD
Alexander D. Shepard, MD
Diane M. Simeone, MD
Lazar J. Greenfield Professor of Surgery and Molecular &
Integrative Physiology
Chief, Division of Gastrointestinal Surgery
Associate Chair of Research
University of Michigan
Ann Arbor, Michigan
Peter Stock, MD
Professor
Surgical Director, Pediatric Renal Transplant Program
Surgical Director, Pancreas Transplant Program
Department of Surgery
San Francisco, California
Aurna Subramanian, MD
Contributors
Randall S. Sung, MD
Kevin E. Taubman, MD
Assistant Professor
Department of Surgery
University of Oklahoma-Tulsa
Tulsa, Oklahoma
Theodoros N. Teknos, MD
Professor and David E. and Carole H. Schuller Chair
in Head and Neck Oncologic Surgery
Director
Division of Head and Neck Surgery
Department of Otolaryngology
Ohio State University Medical School
Columbus, Ohio
Kevin K. Tremper, MD
Thomas W. Wakefield, MD
S. Martin Lindenauer Professor of Surgery
Department of Surgery, Section of Vascular Surgery
University of Michigan
Ann Arbor, Michigan
Thomas J. Watson, MD
Associate Professor
Department of Surgery
University of Rochester
Rochester, New York
Mitchell R. Weaver, MD
Department of Surgery
Henry Ford Hospital
Detroit, Michigan
Sharon M. Weber, MD
Professor
Department of Surgery
Chief, Surgical Oncology
University of Wisconsin Medical School
Madison, Wisconsin
Richard H. Turnage, MD
Theordore H. Welling, MD
Assistant Professor
Department of Surgery
University of Michigan Health System
Ann Arbor, Michigan
Douglas J. Turner, MD
Hunter Wessells, MD
Assistant Professor
Department of Surgery
University of Maryland
Baltimore, Maryland
Edward E. Whang, MD
Assistant Professor of Surgery
Department of Surgery
Brigham and Womens Hospital
Harvard Medical School
Boston, Massachusetts
Elizabeth C. Wick, MD
Thomas K. Varghese, Jr., MD
Assistant Professor
Department of Surgery
Universtiy of Washington
Director of Thoracic Surgery
Department of Surgery
Harborview Medical Center
Seattle, Washington
Assistant Professor
Department of Surgery
Johns Hopkins Medicine
Baltimore, Maryland
xv
xvi
Contributors
David H. Wisner, MD
Brett Yamane, MD
Department of Surgery
University of Wisconsin Hospital and Clinics
Madison, Wisconsin
Amy D. Wyrzykowski, MD
Assistant Professor
Department of Surgery
Emory University
Associate Director
Surgical Intensive Care Unit
Grady Memorial Hospital
Atlanta, Georgia
Charles J. Yeo, MD
Samuel D. Gross Professor and Chairman
Department of Surgery
Thomas Jefferson University
Chief
Department of Surgery
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania
Nicholas J. Zyromski, MD
Assistant Professor of Surgery
Indiana University School of Medicine
Indianapolis, Indiana
PREFACE
xvii
ACKNOWLEDGMENTS
K.D.L.
I appreciate the efforts of the faculties and residents at the
University of Michigan, Washington University, and UCSF
with whom I have had the privilege to work.
G.M.D.
xix
CONTENTS
Contributors v
Preface xvii
Acknowledgments
. . . . . . . . . . . 327
Eileen M. Bulger
xix
Volume 1
PART ONE :
SCIENTIFIC PRINCIPLES
21 Neck Injuries
. . . . . . . . . . . . . . . . . . . . . . . . . . . 48
5 Hemostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
. . . . . . . . . . . . . . . . . . . . . . . . 132
. . . . . . . . . . . . . . . . . . . . . . 423
. . . . . . . . . . . . . . . . . . . . . . . . . 431
Mary E. Fallat
E. Patchen Dellinger
8 Shock . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
William P. Schecter
29 Trauma in Pregnancy
Joseph Cuschieri
. . . . . . . . . . . . . . . . . . . . . . 450
. . . . . 189
11 Burns
. . . . . . . . . . . . . . . . . . . . . . . . . 414
Benjamin W. Starnes
27 Pediatric Trauma
. . . . . . . . . . . . . . . . . . . . . 405
26 Orthopaedic Trauma
. . . . . . . . . . . . . . . . . . . . . . . 385
25 Vascular Trauma
7 Surgical Infections
23 Abdominal Trauma
24 Genitourinary Trauma
6 Inflammation
...............9
Steven E. Raper
4 Wound Healing
. . . . . . . . . . . . . . . . . . . . . . . . . . . . 359
Saman Arbabi
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
Nicole Gibran
. . . . . . 456
Grant E. OKeefe
32 Terrorism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 486
Eric R. Frykberg
13 Cancer
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
Steven K. Libutti
Volume 2
SECTION B: TRANSPLANTATION & IMMUNOLOGY
33 Transplantation Immunology . . . . . . . . . . . . . . . . 497
Jeffrey L. Platt and Marilia Cascalho
35 Renal Transplantation
. . . . . . . . . . . . . . . . . . . . . 531
PART TWO:
SURGICAL PRACTICE
SECTION A: TRAUMA
Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
Ronald V. Maier
38 Pulmonary Transplantation
. . . . . . . . . . . . . . . . . 576
xxi
xxii
Contents
. . . . . . . . . . . . . . . . . . . . . . . . . . 609
Cholangitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 981
SECTION D: ESOPHAGUS
Keith D. Lillemoe
41 Esophageal Anatomy
62 Biliary Neoplasms
. . . . . . . . . . . . . . . . . . . . . . . . 998
Volume 3
42 Esophagus: Tumors
Elizabeth C. Wick
Michael W. Mulholland
Michael W. Mulholland
45 Morbid Obesity
. . . . . . . . . . . . . . . . . . . . . . . 935
59 Hepatic Neoplasms
. . . . . . . . . . . . . . . . . . . . . . . . . . 713
66 Ulcerative Colitis
. . . . . . . . . . . . . . . . . . . . . . . . 1056
Emily Finlayson
Rebecca M. Minter
Arden Morris
. . . . . . . . . . . . . . . . . . . . . . 737
. . . . . . . . . . . . . . . . 748
49 Crohn Disease
. . . . . . . . . . . . . . . . . . . . . . . . . . . 772
SECTION J: HERNIA, ACUTE ABDOMEN, AND SPLEEN
. . . . . . . . . . . . . . . . . . 1159
SECTION G: PANCREAS
73 The Spleen
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1212
Douglas L. Fraker
. . . . . . . . . . 837
55
. . . . . . . . . 857
. . . . . . . . . . . . . . . . . . . . 873
Richard D. Schulick
76 Parathyroid Glands
. . . . . . . . . . . . . . . . . . . . . . 1303
77 Adrenal Gland
. . . . . . . . . . . . . . . . . . . . . . . . . . 1325
. . . . 888
Gerard M. Doherty
Contents
. . . . . . . . . . . . . . . . 1706
Gorav Ailawadi
Volume 4
. . . . . . . . 1719
. . . 1449
85 Pericardium . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1505
Jules Lin
87 Endovascular Treatment
of Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1537
SECTION O: PEDIATRICS
103 Surgical Physiology of Infants and Children . . . . 1803
Federico G. Seifarth and David K. Magnuson
. . . . . . . . . . . . . . . . . . 1842
. . . . . . . . . . . . . . . 1768
Amy B. Reed
. . . . . . . . . . . . . . . . . . . . . . 1853
G. Patrick Clagett
90 Cerebrovascular
91 Upper Extremity
Arterial Disease
xxiii
. . . . . . . . . . . . . . . . . . . . . . . . . 1598
Mark D. Morasch
Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1608
Gilbert R. Upchurch, Jr., Peter K. Henke,
John E. Rectenwald, Jonathan L. Eliason, and James C. Stanley
. . . . . . . . . . . 2018
Sandra L. Wong
. . . . . . . . . . . . . . . . . . . . 1999
. . . . . . . . . . . . . . . . . . . . . 1983
Index
I1
LIST OF ALGORITHMS
Algorithm 3.1
Management of the total parenteral nutrition (TPN) patient who becomes septic. . . . . . . . . . . . . . . . . .43
Algorithm 5.1
Algorithm 7.1
Algorithm 8.1
Algorithm 8.2
Algorithm 9.1
Algorithm 9.2
Algorithm 9.3
Algorithm 12.1
Decision aid for preoperative cardiac evaluation prior to noncardiac surgery. . . . . . . . . . . . . . . . . . . .247
Algorithm 12.2
Algorithm 17.1
Field Triage Decision Scheme: The National Trauma Triage Protocol . . . . . . . . . . . . . . . . . . . . . . . . . .318
Algorithm 18.1
Algorithm 18.2
Algorithm 19.1
Glasgow Coma Scale (GCS) triage guide for initial evaluation of head injury. . . . . . . . . . . . . . . . . . . .341
Algorithm 19.2
Prehospital evaluation and treatment of a patient with severe traumatic brain injury. . . . . . . . . . . . . .343
Algorithm 19.3
Evaluation and treatment of the patient with severe traumatic brain injury
on arrival at the trauma center. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .344
Algorithm 19.4
Algorithm 23.1
Algorithm 23.2
Algorithm 24.1
Algorithm 24.2
Algorithm 24.3
Algorithm 31.1
Algorithm 35.1
Stepwise approach to the management of decreased low urine output posttransplant . . . . . . . . . . . . . .537
Algorithm 38.1
Algorithm 41.1
Algorithm 42.1
Algorithm 42.2
Algorithm 42.3
Algorithm 44.1
Algorithm 45.1
Algorithm 46.1
Algorithm 48.1
Algorithm 48.2
Algorithm 52.1
Algorithm 54.1
Algorithm 55.1
Algorithm 57.1
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .901
Algorithm 57.2
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .902
xxv
xxvi
List of Algorithms
Algorithm 58.1
Algorithm 59.1
Algorithm 59.2
Algorithm 59.3
Algorithm for the management of colorectal cancer with hepatic metastases . . . . . . . . . . . . . . . . . . . . .947
Algorithm 60.1
Algorithm 61.1
Algorithm for diagnosis and management of bile duct injury associated with
laparoscopic cholecystectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .984
Algorithm 64.1
Algorithm 64.2
Algorithm 64.3
Algorithm 65.1
Algorithm 66.1
Algorithm 68.1
Algorithm 68.2
Algorithm 69.1
Algorithm 72.1
Algorithm 74.1
Algorithm 74.2
Algorithm 74.3
Algorithm 74.4
Algorithm 77.1
Algorithm 77.2
Algorithm 77.3
Algorithm 78.1
Algorithm 78.2
Algorithm 78.3
Algorithm 79.1
Algorithm 79.2
Algorithm 79.3
Algorithm 80.1
Algorithm 80.2
Algorithm 80.3
Algorithm 80.4
Algorithm 80.5
Algorithm 84.1
Algorithm 85.1
Algorithm 88.1
Algorithm 92.1
Algorithm 94.1
Algorithm 101.1
Algorithm 101.2
Algorithm 102.1
Algorithm 102.2
Algorithm 108.1
. . . . . . . . . . . . . . . . . . . .1249
PART ONE
SCIENTIFIC PRINCIPLES
K E Y
During a residency in surgery, the successful surgeon-to-be
advances from a novice, who must follow rules to achieve
good outcomes, to becoming proficient, which means that
accumulated knowledge and experience allows him/her to
respond correctly to situations in a more automatic and
effortless manner.
2 Real learning (more than just memorization for the short
term) occurs when information becomes stored in long
term memory. Learning with understanding occurs when
the student or resident has accumulated sufficient knowl-
P O I N T S
edge in long-term memory that he/she recognizes familiar
patterns in the new situations that are encountered.
3 Reading is a critical tool for acquiring surgical knowledge.
Reading that leads to deep understanding can be facilitated
by conscious strategies before, during, and after reading that
increase the likelihood that information will be retained in
long-term memory and be accessible when needed.
4 The student of surgery can and should develop conscious
strategies for assessing the extent to which their reading
results in deep comprehension of the educational material.
SCIENTIFIC PRINCIPLES
PROFICIENCY IN SURGERY
Some readers fall asleep while reading, or find themselves having to reread a paragraph several times. Others commit to
Surface Versus Deep Structured
studying for a block of time, only to start hours later because
they found other things to do. Active reading requires a perLearning Approaches
sons full attention. Even with the best of intentions, a readers
The retention of information in long-term memory is affected
success can be compromised if concentration is lacking. It is
by a students approach to learning. Individuals have tendenimportant to minimize or eliminate visual or auditory distraccies to use either a surface or deep structured approach to
tions and to improve the study environment if there is poor
reading and studying, although any given individual may
lighting, clutter, or uncomfortable seating. Internal distractors
change his or her approach at times. Readers who take a sur(hunger, performance anxiety, sleepiness, etc.) require attenface approach read on autopilot, not processing or fully
tion as well. In order to use study time well, keen and consisthinking about the information being read. These individuals
tent concentration are needed.8,9
may go through the motions of highlighting sections in the 3
Table 1.1 demonstrates a three-step reading approach designed
text, but they dont carefully choose key points. These learners
to promote deep structured learning.10 In the first stage, learners
tend to memorize facts indiscriminately, treat what is being
prepare before reading by activating their prior knowledge and
read as unrelated bits of information, and find difficulty in
setting themselves up to read with a purpose. The second stage
later explaining what they read in their own words.5 Surface
suggests ways to process the information while reading and make
readers glean satisfaction from the number of pages covit personally meaningful. The last step reinforces the need to revisit
ered, but then have difficulty remembering the content
and rehearse what was read to better transfer the information
because the words were never translated into personally meanfrom short-term to long-term memory.
ingful information. Surface-level readers search for facts that
might appear on the test but not for the meaning of the text. A
surface approach leads to temporary and superficial engageBefore Reading: Activate Prior Knowledge
ment with the educational material and does not promote
long-term retention or understanding because little active
There is a well-established correlation between prior knowledge
thinking occurred during reading. A negative association has
and reading comprehension.11,12 Before reading new material,
been reported between the surface study approach and exam
the learner should carefully reflect on what he or she already
performance. This approach is common in learners who are
knows about the topic and how it relates to other subjects
stressed, have performance anxiety, have little interest in the
already studied. Prior knowledge is the foundation upon which
topic, possess limited time management skills and try to read
new information is built. A person with a high level of prior
too much in too little time, or lack the ability to discriminate
knowledge on a given topic can comprehend what is being read
between essential and less important concepts, thereby missing
in less time and with less effort than a person who has limited
the forest for the trees and drowning in information
experience or knowledge about the subject. Prior knowledge
overload.6
helps learners construct concepts and make meaning out of what
In contradistinction, deep structured learners are motivated
is being read.13,14 By activating existing knowledge about a topic
by natural curiosity and a genuine need to know. Their purbefore reading more about it, the learner can identify knowledge
pose for reading is to acquire information that is considered
gaps and then actively read with the clear aim to fill them. Sevrelevant and personally meaningful. They take control of their
eral strategies exist for activating ones prior knowledge, includown learning and seek to fully understand a topic. They recing reflection and recording, interactive discussions, question
ognize when they understand what is being read, and also recand answer development, hypotheses development, and deciding
ognize when they need more or different information to fully
what information about the subject matters the most.
comprehend the material. These learners mentally engage with
the information they read by questioning the material, asking
Reflection and Recording. One of the simplest methods is
themselves about key points, analyzing the material for relato bring to mind the subject and note what you know about it.
tionships with what they already know through experience or
You can revisit existing knowledge by listing the chapter headprior knowledge, and identifying underlying principles to
ings and subtitles and documenting what you already know. For
guide their thinking. A deep structured learning approach is an
example, assume that a chapter entitled Shock lists eight subactive, integrative process. It results in learners translating the
titles: pathophysiology, evaluation of shock, classification of
words, charts, and other forms of information into an orgahemorrhage, treatment of hemorrhagic shock, resuscitative flunized mental picture. This deep and structured approach leads
ids, special situations, experimental resuscitative fluids, and
to long-term retention.7
complications of shock. The process of briefly recording what
TA B L E 1 . 1
STRATEGIES TO ACHIEVE DEEP STRUCTURED READING
BEFORE READING
DURING READING
AFTER READING
Take notes:
Pictorial: Flow charts, maps,
diagrams
Verbal: Cornell method
Combined: Virtual Web page
design
Rehearse:
Periodic reviews
Self-assessment
Summarize
SCIENTIFIC PRINCIPLES
Interactive Discussion with Others. Some people activate prior knowledge best through verbal exchange with
others. Talking with a colleague about a specific topic can help
highlight key points to be studied, highlight lessons learned
through personal experiences, and clarify ones understanding
about the topic. These discussions can also yield important
questions about the topic that require attention as well as
provide an organizational structure for thinking about the
subject.
Prediction or Hypothesis Development. Learners benefit from making predictions about various aspects of a topic by
tapping into what they already know and predicting how it
relates to the subject under study. For example, if reading
about rectal cancer, the reader might predict that multimodality therapy is frequently employed, based on his or her preexisting knowledge of pelvic anatomy and lymphatic drainage
and past experience with other gastrointestinal malignancies.
By hypothesizing answers to key knowledge gaps, readers can
test their assumptions through focused reading.
Visual Notes. Visual notes help learners organize information because they show relationships and hierarchies of concepts. Types of graphic organizers include tables, pictures,
flowcharts, mind maps, and diagrams.16 Graphic organizers are
often already published in the text and serve to highlight the
importance of the information. Reading the published version,
however, is less useful than constructing your own because creating your own version requires more information processing.
Nevertheless, it can be useful to copy graphic organizers from a
book to carry in a lab coat pocket to review during windows of
available time or access when a clinical opportunity arises.
Another strategy is to omit the data in parts of the published
graph and later fill in the blanks to further reinforce understanding and retention.
Tables are useful for comparing and contrasting common
types of details across variables. For example, a table would be
helpful to learn about the various imaging techniques for pancreatic cancer. The column headings might include Name of
Test, Cost, Risks, Sensitivity, Specificity, and Positive Predictive Value. This approach allows you to extract
information from the books narrative and place it in the correct
location in the table format. The finished table enables you to
compare and contrast the tests and create a big picture view
of the multiple factors involved in choosing an optimal diagnostic tool.
A flowchart is a picture of the separate steps of a process in
sequential order. Translating the material you read into a flowchart helps you think through ifthen scenarios and can
uncover your incorrect or unclear decision pathways. After
reading a segment of a chapter on a particular disease entity,
you can, for example, draw a scheme for working up a jaundiced patient or create an algorithm for the treatment of pulmonary embolus.
Mind maps, sometimes referred to as concept maps, relate
facts or ideas to other facts or ideas. Relationships and patterns across information are easily seen in mind maps. A mind
map is a structured graphic display of an individuals conceptual scheme within a well-circumscribed domain.17,18 There
are various approaches to developing mind maps, but most
methods share similar steps. The first step, the brainstorming
stage, occurs by drawing or writing the topic in the center of
the page (Fig. 1.2). If the chapter under study is about gastroesophageal reflux disease (GERD), the reader would write the
word GERD in the middle of a large sheet of blank paper.
Lines are then drawn from the center topic outwardly to represent the main ideas or categories that are written or illustrated in the reading. Subheadings from the book could be
used for these spokes, or the reader can choose his or her
own collection of key ideas. For example, one spoke might have
printed on it Diagnosis and a second spoke may contain the
word Treatment. A third spoke might be Epidemiology,
and a fourth might read Complications. Given that our minds
dont think in a linear fashion, mind or concept maps enable
readers to build branches and subbranches onto the main spokes
or build more main spokes, depending on what they are thinking
at the time. Any number of branches can be added to the major
spoke lines. Learners continue to build their maps as their
thoughts and search and find mental association powers are
FIGURE 1.2. A basic mind map dealing with the topic of gastroesophageal
reflux.
Endoscopy
24 Hour pH monitoring
Epidemiology
Diagnosis
GERD
Complications
Stricture
Fundoplication
SCIENTIFIC PRINCIPLES
Treatment
Barretts esophagus
? Prevention
unleashed. Mapping allows for free-flow thinking and spontaneous thought and decreases the chances of premature closure
about a topic or subtopic, which typically happens when using
an outline approach.
Once the initial brainstorming map is completed, the organizational stage needs to occur. In this phase, readers redo
their mind maps, sequencing the branches in sort of meaningful order. During this phase, readers may see hierarchies or new
associations that can serve as a basis for organizing or modifying the maps branches or subbranches. Additional details on
how to construct mind maps are published elsewhere.19
Other types of graphic organizers include diagrams or pictures. The latter can be helpful, for example, in summarizing a
segment of a chapter that describes anatomy. Anatomic pictures can either be drawn or copied from the Internet or other
printed source and used to note structures. Creating graphics
helps readers activate background knowledge, strengthens
metacognitive skills, strengthens their ability to construct
meaning from the printed word, and reinforces understanding.
Verbal Notes. Research suggests that underlining (or highlighting) while reading leads to greater understanding than
reading alone, but writing notes while reading is significantly
better for retention than underlining. Creating summaries in
your own words of the material you read is critical to converting learning into memory. If notes cant be done easily,
then the information is not well enough understood to be
incorporated for the long term. One note-making system
worth considering is the Cornell method.15 This method, pictured in Figure 1.3, provides a format for condensing and
organizing notes. It makes use of paper with a 2.5-inch margin on the left and a 6-inch area on the right in which to write
notes. While reading, you write cue words in the left margin
and key phrases or points in the right. Later, when reviewing
notes, you can view the cue word while simultaneously covering up the key phrases to discern whether you can extemporaneously come up with the key points. For example, while
studying the principles of tumor biology, cue words in the left
margin might read how cancers develop, role of the host,
clinical staging, etc. The bottom 2 inches of the page are
used to write summary information or to note areas that need
additional study. Templates for the Cornell method note formats and instructions about how to use them can be found on
the Internet.
Combined Methods. There are many ways you can interact with the material you read, be it verbally or visually. With
todays technology, you could set up a Web page for your reading notes. The Web page could include visual and verbal notes,
all organized using a structure that makes sense to you.
2.0
6.5
CUES
NOTES
Keywords
Questions
Concise sentences
Pictures/diagrams
9.0
SUMMARY
2.0
FIGURE 1.3. The Cornell method for note taking (see also Pauk W,
Owens R. How to Study in College, 8th ed. Boston, MA: Houghton
Mifflin Company Publishers; 2005).
TA B L E 1 . 2
SUMMARY OF POSSIBLE STRATEGIES FOR MAXIMIZING
READING COMPREHENSION
Select reading materials of appropriate difficulty, suitable
for academic progress and purpose
Identify sources of potential personal bias or error in
judging reading comprehension
Do massed re-reading to improve fluency and/or
immediate recall
Use deep structured reading approach to improve
understanding and retention
Discuss reading content with colleagues to gauge your level
of understanding
Use self-assessments such as review guides or question
banks
Select self-assessment materials that are similar in
format and difficulty to your targeted purpose for
reading
During self-assessments, stop and reflect on
justifications for answering questions
9. Furnham A, Gunter B, Peterson E. Television distraction and the performance of introverts and extraverts. Appl Cogn Psychol 2006;8:705711.
10. Straker K, Kelman E. Vital Skills: Study Strategies Every Nursing Student
Must Know. Houston, TX: Karista Press; 2007.
11. Maquire E, Frith C, Morris RG. The functional neuroanatomy of comprehension and memory: the importance of prior knowledge. Brain 1999;122:
18391850.
12. McNamara D, Kintsch W. Learning from texts: effects of prior knowledge
and text coherence. Discourse Process 1996;22:247288.
13. Spires H, Donley J. Prior knowledge activation: inducing engagement with
information texts. J Educ Psychol 1998;90:249260.
14. Kendou P, Van den Broek P. The effects of readers misconceptions on comprehension of scientific text. J Educ Psychol 2005;97:235245.
15. Pauk W, Owens R. How to Study in College, 8th ed. Boston, MA:
Houghton Mifflin Company Publishers; 2005.
16. Kelman E, Straker K. Study Without Stress: Mastering Medical Sciences.
Thousand Oaks, CA: Sage Publishers; 2000.
17. Allen D, Tanner K. Approaches to cell biology teaching: mapping the
journeyconcept maps as signposts of developing knowledge structures.
Cell Biol Educ 2003;2:133136.
18. Diwaker V, Ertmer P, Nour A. Helping students learn veterinary physiology through the use of concept maps. J Vet Med Educ 2007;34:652657.
19. Buzan T, Buzan B. The Mind Map Book. London, UK: BBC Publishers; 2006.
20. Ericsson K, Kintsch W. Long-term memory. Psychol Rev 1995;102:211245.
21. Trabasso T, Bouchard E. Teaching readers how to comprehend text strategically. In: Block CC, Pressley ME, eds. Comprehension Instruction:
Research-Based Best Practices. New York: Guilford Press; 2002:176200.
22. Ryan MP. Monitoring text comprehension: individual differences in epistemological standards. J Educ Psychol 1984;76:248258.
23. Croskerry P. Cognitive forcing strategies in clinical decisionmaking. Ann
Emerg Med 2003;41:110120.
24. Croskerry P. The importance of cognitive errors in diagnosis and strategies
to minimize them. Acad Med 2003;78:775780.
25. Hacker DJ. Self-regulated comprehension during normal reading. In:
Hacker DJ, Dunlosky J, Graesser AC, eds. Metacognition in Educational
Theory and Practice. Mahwah, NJ: Erlbaum; 1998:165191.
26. Zhao Q, Linderholm T. Adult metacomprehension: judgment processes
and accuracy constraints. Educ Psychol Rev 2008;20:191206.
27. Griffin TD, Wiley J, Thiede KW. Individual differences, rereading, and selfexplanation: concurrent processing and cue validity as constraints on
metacomprehension accuracy. Mem Cognit 2008;36:93103.
28. Callender AA, McDaniel MA. The limited benefits of rereading educational texts. Contemp Educ Psychol 2009;34:3041.
29. Austin Z, Gregory P, Chiu S. Use of reflection-in-action and self-assessment to promote critical thinking among pharmacy students. Am J Pharm
Educ 2008;72:18.
References
1. Carraccio C, Benson B, Nixon LJ, et al. From the educational bench to the
clinical bedside: translating the Dreyfus developmental model to the learning of clinical skills. Acad Med 2008;83:761767.
2. Sousa DA. How the Gifted Brain Learns. Thousand Oaks, CA: Corwin
Press; 2003:2225.
3. Schmidt H, Norman G, Boshuizen HP. A cognitive perspective on medical
expertise: theory and implications. Acad Med 1990;65:611621.
4. Mayberry J. Residency reform Halsted-style. JACS 2003;197:433435.
5. Entwistle N. Styles of Learning and Teaching: An Integrated Outline of
Educational Psychology for Students, Teachers, and Lecturers. New York:
Wiley and Sons; 1981.
6. Ferguson E, James D, Madeley L. Factors associated with success in
medical school: systematic review of the literature. BMJ 2002;324:
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IN SURGERY
STEVEN E. RAPER
K E Y
P O I N T S
K E Y
Intermediary metabolismas the metabolic manipulation
and balancing of ingested carbohydrate, fat, and protein
ultimately can process all nutrients to acetyl coenzyme A
(CoA) for energy production in the citric acid cycle.
2 Glucose must always be available for brain function; if not
available directly from the diet, it can be mobilized for a
brief period from glycogen stores and then derived from
proteins in the liver and kidneys.
3 Free fatty acids are a direct source of energy catabolized by
cardiac and skeletal muscle.
4 Hepatic protein synthesis, when excess amino acids are
available, includes albumin, fibrinogen, and apolipoproteins and can reach 50 g per day.
1
P O I N T S
The citric acid cycle includes a series of mitochondrial
enzymes that transform acetyl CoA into water, carbon
dioxide, and hydrogen-reducing equivalents; the hydrogen-reducing equivalents are then transformed into adenosine triphosphate (ATP) by the electron transport chain.
Each molecule of acetyl CoA that enters the citric acid
cycle yields 12 molecules of ATP.
6 Biotransformation of potentially toxic, often hydrophobic,
compounds into hydrophilic, excretable compounds
occurs mainly in the liver by the cytochromes P-450, the
uridine diphosphate-glucuronyl (UDP-glucuronyl) transferases, the glutathione (GSH) S-transferases, and the sulfotransferases.
SCIENTIFIC PRINCIPLES
10
INTERMEDIARY METABOLISM:
AN OVERVIEW
[D]o You Have a More Exciting
Word for Metabolism?*
CARBOHYDRATE METABOLISM
The products of intestinal carbohydrate digestion are glucose
(80%) and fructose and galactose (20%). Fructose and galactose are rapidly converted to glucose, and the body uses glucose as the primary molecule for transport and uptake of carbohydrates by cells throughout the body. Blood glucose levels
are tightly regulated by the liver despite wide fluctuations in
dietary intake. About 90% of portal venous glucose is
removed from the blood by liver cells through carrier-facilitated
diffusion. Large numbers of carrier molecules on the sinusoidal domain of the hepatocyte are capable of binding glu-
Glucose-6-phosphate
FIGURE 2.1. The chemical reactions of glycogenesis and glycogenolysis. Glucose-6-phosphatase allows hepatic glucose to be transported
out of the hepatocyte for use in other tissues. Glucose-6-phosphate, in
red, plays a central role in carbohydrate metabolism.
11
ATP + Mg
Hexokinase (glucokinase)
ADP + Pi
Glucose 6-phosphate
SCIENTIFIC PRINCIPLES
Fructose 6-phosphate
ATP + Mg2+
Phosphofructokinase
ADP + Pi
Fructose 1,6-biphosphate
Protein
Dihydroxyacetone
phosphate
Glyceraldehyde 3-phosphate
NAD+ + Pi
NADH + H+
1,3-biphosphoglycerate
ADP + Pi
ATP + Mg2+
3-phosphoglycerate
Glycogen P
Glycogen P
2-phosphoglycerate
H2 O
Phosphoenolpyruvate
ADP + Pi
Pyruvate kinase
ATP + Mg2+
Pyruvate
Glycolysis
Glycolysis is the pathwayin all mammalian cellsby which
glucose is converted to pyruvate or lactate (Fig. 2.3). The glycolytic pathway is interesting in that glucose can be metabolized in the presence (aerobic) or absence (anaerobic) of oxygen. The aerobic conversion of glucose to pyruvate has three
effects: (a) a net gain of two ATP molecules, (b) generation of
two reducing equivalents of the nicotinamide adenine
nucleotide (NADH H), or (c) conversion of pyruvate to
acetyl CoA with subsequent degradation of acetyl CoA in the
citric acid cycle (see later). The conversion of glucose to pyruvate is regulated by three enzymes: hexokinase (glucokinase),
phosphofructokinase, and pyruvate kinase, which are nonequilibrium reactions and as such, functionally irreversible.
Under anaerobic conditions, NADH H cannot be reoxidized by transfer of reducing equivalents through the electron
transport chain to oxygen. Instead, pyruvate is reduced by the
NADH H to lactate. Glycolysis takes place in the cytoplasm, in contrast to the citric acid cycle, which is a mitochondrial process. During times of glucose excess, as in the fed
state, hepatic glycolysis can generate energy in the form of
ATP, but the oxidation of ketoacids is a preferred hepatic
energy source.
In erythrocytes, a unique variant of glycolysis enhances
oxyhemoglobin dissociation. The first site in glycolysis for
generation of ATP is bypassed, leading to the formation of
2,3-bisphosphoglycerate by an additional enzyme called bisphosphoglycerate mutase. Kinetics of the mutase present in
erythrocytes allow the presence of high concentrations of
2,3-bisphosphoglycerate to build up. The 2,3-bisphosphoglycerate displaces oxygen from hemoglobin, allowing a shift of
the oxyhemoglobin dissociation curve to the right.
Gluconeogenesis
There is an absolute minimum requirement for glucose in
humans. Below a certain blood glucose concentration, brain
dysfunction causes coma and death. When glucose becomes
scarce, as in the fasting state, glycogenolysis occurs. Once
glycogen stores have been depleted, the liver and kidneys are
capable of synthesizing new glucose by the process of gluconeogenesis. Glucagon is produced in response to low blood
sugar levels and stimulates gluconeogenesis. Gluconeogenesis
is not a simple reversal of the glycolytic pathway. In glycolysis,
as noted previously, the conversion of glucose to pyruvate is a
one-way reaction. As a result, four separate, functionally irreversible enzyme reactions are required to convert pyruvate
into glucose (Fig. 2.4). These enzymes are pyruvate carboxylase,
12
Pyruvate carboxylase
Gluconeogenesis
in liver
Blood
Glycolysis
in muscle
ADP + Pi
Glucose
Oxaloacetate
GTP
Phosphoenolpyruvate
carboxykinase
GDP + CO2
Phosphopyruvate
Glucose
2~P
6~P
Pyruvate
Pyruvate
NADH
NAD+
2-phosphoglycerate
3-phosphoglycerate
ATP
Lactate
Lactate
FIGURE 2.5. The Cori cycle, an elegant mechanism for the hepatic
conversion of muscle lactate into new glucose. Pyruvate plays a key
role in this process.
ADP + Pi
1,3-biphosphoglycerate
NADH + H+
NAD+
Pi
Dihydroxyacetone
phosphate
Glyceraldehyde 3-phosphate
ADP + Pi
ATP + Mg2+
Fructose 1,6-biphosphate
H2O
Fructose 1,6-biphosphatase
Pi
Phosphogluconate Pathway
When glucose enters the liver, glycogen is formed until the
hepatic glycogen capacity is reached (about 100 g). If excess
glucose is still available, the liver converts it to fat by the phosphogluconate pathway (also known as the pentose phosphate
pathway) (Fig. 2.6). The cytosolic phosphogluconate pathway
Fructose 6-phosphate
Glucose 6-phosphate
H2O
Pyruvate kinase
Glucose-6-phosphate
Pi
Glucose
FIGURE 2.6. The phosphogluconate pathway. One of the major purposes of this pathway is to generate reduced nicotinamide adenine dinucleotide, which can serve as an electron donor and allow the liver to
perform reductive biosynthesis.
13
can completely oxidize glucose, generating CO2 and nicotinamide adenine dinucleotide phosphate (NADPH) through
what is known as the oxidative phase. Hydrogen atoms
released in the phosphogluconate pathway combine with oxidized nicotinamide adenine dinucleotide phosphate (NADP)
to form reduced nicotinamide adenine dinucleotide phosphate
(NADPH H).2 The oxidative phase is present only in tissues, such as the adrenal glands and gonads, that require
reductive biosyntheses such as steroidogenesis or other forms
of lipid synthesis. Essentially, all tissues contain the nonoxidative phase, which is reversible and produces ribose precursors
for nucleotide synthesis. In erythrocytes, the phosphogluconate pathway provides reducing equivalents for the production of reduced glutathione by glutathione reductase. Reduced
glutathione can remove hydrogen peroxide, which increases
the conversion of oxyhemoglobin to methemoglobin and subsequent hemolysis.
are absorbed directly into the portal circulation and are avidly
taken up by the liver. Free fatty acids in the circulation are noncovalently bound to albumin and are transferred to the hepatocyte cytosol by way of fatty acidbinding proteins. Fatty acid
CoA esters are synthesized in the cytosol after hepatic uptake
of fatty acids. These fatty acid CoA esters can be converted into
triglyceride, transported into mitochondria for the production
of acetyl CoA and reducing equivalents, or stored in the liver as
triglycerides. The rate-limiting step in the synthesis of triglyceride is the conversion of acetyl CoA to malonyl CoA. Malonyl
CoA, in turn, inhibits the mitochondrial uptake of fatty acid
CoA ester, favoring triglyceride synthesis. The liver also contains
dehydrogenases that can unsaturate essential dietary fatty
acids. Structural elements of all tissues contain significant
amounts of unsaturated fats, and the liver is responsible for the
production of these unsaturated fatty acids. As another example, dietary linoleic acid is elongated and dehydrogenated to
the prostaglandin precursor arachidonic acid.
3
Under basal conditions, most free fatty acids are catabolized for energy by cardiac and skeletal muscle. Under conditions of adipocyte lipolysis, the liver can take up and metaboLIPID METABOLISM
lize fatty acids. Although fatty acid synthesis occurs in the
cytosol, fatty acid oxidation occurs in the mitochondria. Fatty
Lipid Transport
acid CoA esters bind carnitine, a carrier molecule, and in the
absence of cytosolic malonyl CoA, they enter the mitochonLipid transport throughout the body is made complicated by
dria, where they undergo -oxidation to acetyl CoA and
the fact that lipids are insoluble in water. To overcome this
reducing equivalents (Fig. 2.7). Acetyl CoA can then take one
physicochemical incompatibility, dietary triglycerides are first
of the following routes: (a) enter the tricarboxylic acid cycle
split into monoglycerides and fatty acids by the action of
and be degraded to carbon dioxide, (b) be converted to citrate
intestinal lipases. After absorption into the small intestinal
for fatty acid synthesis, or (c) be converted into 3-hydroxy-3cells, triacylglycerols are re-formed and aggregate into chymethylglutaryl CoA (HMG-CoA), a precursor of cholesterol
lomicrons, which then enter the bloodstream by way of the
and ketone bodies. The mitochondrial hydrolysis of fatty acids
lymph. Chylomicrons are removed from the blood by the liver
is a source of large quantities of ATP. The conversion of stearic
and adipose tissue. The capillary surface of the liver contains
acid to carbon dioxide and water, for instance, generates 136
large amounts of lipoprotein lipase, which hydrolyzes triglycmolecules of ATP and demonstrates the highly efficient storage
erides into fatty acids and glycerol. The fatty acids freely difof energy as fat. By a process called -oxidation, acetyl CoA
fuse into the hepatocytes for further metabolism. Similar to
molecules are cleaved from fatty acids. The acetyl CoA is then
chylomicrons, very low-density lipoproteins (VLDLs) are synmetabolized through the citric acid cycle under normal cirthesized by the liver and are the main vehicle for transport of
cumstances.
triacylglycerols to extrahepatic tissues. The intestines and liver
In times of unrestrained lipolysis, such as starvation, unconare the only two tissues capable of secreting lipid particles. In
trolled diabetes, or other conditions of triglyceride mobilization
addition to chylomicrons and VLDLs, there are two other
from adipocyte stores, ketone bodiespredominantly 3major groups of plasma lipoproteins: low-density lipoproteins
hydroxybutyrate and acetoacetateare formed in hepatic mito(LDLs) and high-density lipoproteins (HDLs). LDLs and
chondria from free fatty acids and are a source of energy for
HDLs contain predominantly cholesterol and phospholipid.
extrahepatic tissues. Ketogenesis is regulated predominantly by
The structure of all classes of lipoproteins is similar. There
the rate of mobilization of free fatty acids. Once in the liver
is a core of nonpolar lipids, either triacylglycerols or cholesmitochondria, the relative proportion of acyl CoA destined to
teryl esters, depending on the particular lipoprotein. This nonundergo -oxidation is limited by the activity of an enzyme,
polar core is coated with a surface layer of amphipathic phoscarnitine palmitoyltransferase-1. Lastly, there are mechanisms
pholipid or cholesterol oriented so that the polar ends are in
that keep the levels of acetyl CoA entering the citric acid cycle
contact with the plasma. A protein component is also present.
constant, so that only at high mitochondrial levels will acetyl
The A apolipoproteins occur in chylomicrons and HDLs. The
CoA be converted to ketone bodies. Even the brain, in times of
B apolipoproteins come in two forms: B-100 is the predomistarvation, can use ketone bodies for half of its energy requirenant apolipoprotein of LDLs, whereas the shorter B-48 is
ments. At some point, however, the ability of liver to perform located in chylomicrons. The C apolipoproteins can transfer
oxidation may be inadequate. Under such circumstances,
between VLDLs, LDLs, and HDLs. Apolipoprotein D and E
hepatic storage of triglyceride or fatty infiltration of the liver can
also exist. Apolipoproteins have several functions in lipid
be significant, leading to the development of nonalcoholic
transport and storage. Some, such as the B apolipoproteins,
steatohepatitis (NASH). Triglyceride storage by itself does not
are an integral part of the lipoprotein structure. Other
appear to be a cause of hepatic fibrosis, but fatty infiltration
apolipoproteins are enzyme cofactors, such as C-II for lipopromay be a marker for the derangement of normal processes by
tein lipase. Lastly, the apolipoproteins act as ligands for cell
alcohol or drug toxicity, diabetes, or long-term total parenteral
surface receptors. As an example, both B-100 and E serve as
nutrition. A specific type of microvesicular fatty accumulation is
ligands for the LDL receptor.3,4
also seen in a variety of diseases, such as Reye syndrome, morbid obesity, and acute fatty liver of pregnancy.
Cholesterol Metabolism
Cholesterol is an important regulator of membrane fluidity
and is a substrate for bile acid and steroid hormone synthesis.
SCIENTIFIC PRINCIPLES
14
FIGURE 2.7. Diagram of hepatic fatty acid metabolism. Both dietary and newly synthesized fatty acids are
esterified and subsequently degraded in the mitochondria for energy, first as reducing equivalents, then
adenosine triphosphate via the electron transport chain.
Acetyl CoA
HCO3, ATP
Acetyl CoA carboxylase
Palmitic acid
or
Steric acid
NADP +
or
Oleic acid
Esterification
Triglycerides and phospholipids
VLDL, LDL
Adipose triglyceride
Fatty acid-FABP
Lipolysis
or
esterification
Citrate
Acetyl CoA
Citrate acid cycle
CO2
Phospholipids
The three major classes of phospholipids synthesized by the
liver are lecithins, cephalins, and sphingomyelins. Although
most cells in the body are capable of some phospholipid synthesis, the liver produces 90%. Phospholipid formation is
controlled by the overall rate of fat metabolism and by the
availability of choline and inositol. The main role of phospholipids of all types is to form plasma and organelle membranes.
The amphiphilic nature of phospholipids makes them essential
for reducing surface tension between membranes and surrounding fluids. Phosphatidylcholine, one of the lecithins, is
the major biliary phospholipid and is important in promoting
the secretion of free cholesterol into bile. Thromboplastin, one
of the cephalins, is needed to initiate the clotting cascade. The
sphingomyelins are necessary for the formation of the myelin
nerve sheath.
15
PROTEIN METABOLISM
Formation and Catabolism of Plasma Proteins
4
FIGURE 2.9. The enterohepatic circulation of bile acids. The primary bile acids,
cholic acid and chenodeoxycholic acid, are
synthesized in the liver from cholesterol.
Deoxycholic acid and lithocholic acid are
formed in the colon (blue lines) during
bacterial degradation of the primary bile
acids. All four bile acids are conjugated
with glycine or taurine in the liver. Most of
the lithocholic acid is also sulfated, which
decreases reabsorption and increases fecal
excretion. Bile acids are absorbed passively
in the epithelium of the small and large
intestine and actively in the distal ileum.
SCIENTIFIC PRINCIPLES
16
TA B L E 2 . 1
CLASSIFICATION
AMINO ACID
PRECURSOR
Arginine
Alanine
Pyruvate
Histidine
Asparagine
Oxaloacetate
Isoleucine
Aspartate
Oxaloacetate
Leucine
Cysteine
Methionine
Lysine
Glutamate
-Ketoglutarate
Methionine
Glutamine
-Ketoglutarate
Phenylalanine
Glycine
3-Phosphoglycerate
Threonine
Hydroxyproline
-Ketoglutarate
Tryptophan
Hydroxylysine
Lysine
Valine
Proline
-Ketoglutarate
Serine
3-Phosphoglycerate
Tyrosine
Phenylalanine
Amino
acids
NH3
Glutamate
NH3
L-glutamine
L-glutamine
Urea
Ornithine
H2O
Arginine
Carbamoylphosphate
+ 2ADP
Citrulline
Fumarate
Argininosuccinate
+ AMP
Aspartate + ATP
FIGURE 2.10. The urea cycle. Ammonia entering the urea cycle is
derived from protein and amino acid degradation in tissues (endogenous) and the colonic lumen (exogenous).
Glucose-6-Phosphate
Acetyl CoA
Citrate synthase
Oxaloacetate
Acetyl-CoA + H2O
CoA
Citrate
H2O
Cis-aconitate
H 2O
Isocitrate
NAD
CO2 + NADH + H+
CoA + NAD
CO2 + NADH + H+
Succinyl-CoA
Pi + ADP
ATP + CoA
Succinate
FAD
FADH2
Fumarate
H 2O
Malate
NAD
NADH + H+
Oxaloacetate
FIGURE 2.12. The citric acid cycle. Reduced nicotinamide adenine
dinucleotide and reduced flavin adenine dinucleotide, formed in the
citric acid cycle, are subsequently oxidized in mitochondria by means
of the electron transport chain to generate adenosine triphosphate.
Acetyl coenzyme A plays a key role.
FIGURE 2.11. Summation of the key regulatory molecules used by the liver during diverse
metabolic functions. Essentially, any compound
found in the body can be synthesized in the liver
from glucose-6-phosphate, acetyl coenzyme A,
or pyruvate. As a consequence of the inability
of mammalian liver to convert acetyl coenzyme
A to pyruvate, fats cannot be converted to carbohydrates.
BIOTRANSFORMATION
Biotransformation is defined as the intracellular metabolism of
endogenous organic compounds (e.g., heme proteins and
SCIENTIFIC PRINCIPLES
Pyruvate
17
18
Sulfotransferases
The sulfotransferases catalyze the transfer of sulfate groups from
3-phosphoadenosine-5-phosphosulfate (PAPS) to compounds
such as thyroxine, bile acids, isoproterenol, -methyldopa, and
acetaminophen. They are located primarily in the cytosol.
Although many P-450 derivatives can be further conjugated
by either the sulfotransferases or the glucuronyl transferases,
a limited ability of the liver to synthesize PAPS makes glucuronidation the predominant mechanism.
Cytochromes P-450
The cytochromes P-450 are named for their ability to absorb
light maximally at 450 nm in the presence of carbon monoxide. These enzymes are bound to the ER and collectively catalyze reactions by using NADPH and oxygen. The P-450
isozymes present in mammalian liver catalyze reactions such
as oxidation, hydroxylation, sulfoxide formation, oxidative
deamination, dealkylation, and dehalogenation. Such reactions allow further phase II conjugation with polar groups
such as glucuronate, GSH, and sulfate. The cytochromes P450 can also create potentially toxic metabolites. Drugs such
as acetaminophen, isoniazid, halothane, and the phenothiazines can be converted into reactive forms that cause cellular
injury and death. The cytochromes also are responsible for the
formation of organic free radicals, reactive metabolites that
can directly attack and injure cellular components or act as
haptens in the generation of an autoimmune response. Several
of the most potent known carcinogens are aromatic hydrocarbons, which are modified by cytochromes P-450.
Glutathione S-transferases
The GSH transferases are more selective in the biotransformations they perform. GSH conjugation occurs only with
compounds that have electrophilic and potentially reactive
centers. The role of GSH conjugation catalyzed by the GSH Stransferases is demonstrated by acetaminophen. In metabolism of this drug, cytochromes P-450 create an electrophilic
center that reacts with protein thiol groups or GSH.10 The
presence of GSH S-transferase allows the preferential detoxifi-
METAL METABOLISM
Iron uptake appears to occur by two distinct processes: (a)
receptor-mediated endocytosis of irontransferrin complexes
and (b) facilitated diffusion across the plasma membrane.
More iron is taken up and stored by the liver than by any other
organ, with the exception of the bone marrow. Transferrin is
synthesized in the liver and has specific plasma membrane
receptors on a number of different tissues. After endocytosis,
the transferrin and iron dissociate and the transferrin and
transferrin receptor return to the cell surface for recycling. A
pathway appears to involve the dissociation of iron and transferrin at the plasma membrane and subsequent internalization
by carrier-mediated diffusion. Once internalized, iron is stored
and forms a complex with apoferritin. Each apoferritin molecule is capable of storing several thousand iron molecules. The
ironapoferritin complex, called ferritin, is responsible for
iron storage under physiologic conditions. Iron storage in a
protein-bound form is essential because free iron can catalyze
free radical formation, leading to cell injury.12
Copper is transported to the liver bound to albumin or histidine and enters the hepatocytes by a process of facilitated
Glycine
-ALA
Porphobilnogen (PBG)
Synthase
Succinyl CoA
19
(4-PBG)
-ALA
Hydroxymethylbilane
Heme proteins
Fe2+
Protoporphyrin IX
Uroporphyrinogen III
Uroporphyrinogen I
Protoporphyrinogen IX
Coproporphyrinogen III
Coproporphyrinogen I
Uroporphyrin
(excretion)
Coproporphyrin
(excretion)
FIGURE 2.13. The heme biosynthetic pathway. Inherited defects of each of the heme biosynthetic enzymes except -aminolevulinic
acid synthase have been described and lead to the clinical disorders known as the porphyrias.
INTERMEDIARY METABOLISM
AND SPECIALIZED CELL
FUNCTION
Once understood, the general principles of intermediary
metabolism can be used to understand cell biology in specialized cell types. Several examples, not intended to be all-inclusive,
are discussed to demonstrate how biochemical pathways influence cellular function.
Hepatocyte-specific Measures
of Liver Reserve
To refine traditional estimates of liver reserve, such as the clinically based Childs-Pugh classification and cross-sectional
imaging to quantitate liver volume, functional tests have been
developed that measure the ability of an individual liver to
carry out specific biochemical tasks and correlate this functional capacity with perioperative morbidity and mortality.13
Although myriad functional studies have been described, sev-
SCIENTIFIC PRINCIPLES
Heme
20
SUMMARY
The basics of intermediary metabolism have changed little over
the past decade. Knowledge of the fundamental biochemical
reactions by which substrates are metabolized, however, is being
exploited at an ever-accelerating rate to support and perhaps
enhance specialized cellular function. Variations on basic metabolic themes in individual cell types allow the development of
References
1. Lodish H, Berk A, Zipursky LS, et al., eds. Molecular cell biology. New
York: WH Freeman; 2004:301350.
2. Berg J, Tymoczko J, Stryer L, eds. Biochemistry. 5th ed. New York:
WH Freeman; 2002:551576.
3. Havel RJ, Hamilton RL. Hepatocytic lipoprotein receptors and intracellular lipoprotein catabolism. Hepatology 1988;8:1869.
4. Mayes PA. Lipid transport and storage. In: Murray RK, Granner DK,
Mayes PA, et al., eds. Harpers biochemistry. 25th ed. New York:
McGraw-Hill; 2000:268.
5. Bonifacino JS, Weissman A. Ubiquitin and the control of protein fate in
the secretory and endocytic pathways. Annu Rev Cell Dev Biol 1998;14:
19.
6. Brosnan JT. Interorgan amino acid transport and its regulation. J Nutr
2003;133(6 Suppl 1):2068S2072S.
7. Berg J, Tymoczko J, Stryer L, eds. Biochemistry. 5th ed. New York:
WH Freeman; 2002:665692.
8. Morris SM Jr. Regulation of enzymes of the urea cycle and arginine
metabolism. Annu Rev Nutr 2002;22:87.
9. Kornberg H. Krebs and his trinity of cycles. Nat Rev Mol Cell Biol 2000;
1:225.
10. Lee T, Li L, Ballatori N. Hepatic glutathione and glutathione S-conjugate
transport mechanisms. Yale J Biol Med 1997;70:287300.
11. Gross U, Hoffmann GF, Doss MO. Erythropoietic and hepatic porphyrias.
J Inherit Metab Dis 2000;23:641.
12. Hentze MW, Muckenthaler MU, Andrews NC. Balancing acts: molecular
control of mammalian iron metabolism. Cell 2004;117:285.
13. Mullin EJ, Metcalfe MS, Maddern GJ. How much liver resection is too
much? Am J Surg 2005;190:8797.
14. Minagawa M, Makuuchi M, Takayama T, et al. Selection criteria for
repeat hepatectomy in patients with recurrent hepatocellular carcinoma.
Ann Surg 2003;238:703710.
15. Ercolani G, Grazi GL, Calliva R, et al. The lidocaine (MEGX) test as an
index of hepatic function: its usefulness in liver surgery. Surgery 2000;127:
464471.
16. Lebel S, Nakamichi Y, Hemming A, et al. Glycine conjugation of paraaminobenzoic acid (PABA): a pilot study of a novel prognostic test in
acute liver failure in children. J Pediatr Gastroenterol Nutr 2003;36:
6271.
17. Doenst T, Bugger H, Schwarzer M, et al. Three good reasons for heart surgeons to understand cardiac metabolism. Eur J Cardiothoracic Surg 2008;
33:862871.
18. Lopaschuk GD. Optimizing cardiac fatty acid and glucose metabolism as
an approach to treating heart failure. Semin Cardiothorac Vasc Anesth
2006;10(3):228230.
19. Wang W, Lopaschuk GD. Metabolic therapy for the treatment of ischemic
heart disease: reality and expectations. Expert Rev Cardiovasc Ther
2007;5:11231134.
20. Liu Q, Docherty JC, Rendell JC, et al. High levels of fatty acids delay the
recovery of intracellular pH and cardiac efficiency in post-ischemic
hearts by inhibiting glucose oxidation. J Am Coll Cardiol 2002;39:
718725.
21. Taegtmeyer H. Clinical trials report. Metabolic modulation as a principle
for myocardial protection. Curr Hypertens Rep 2003;5:443444.
22. Leibiger IB, Leibiger B, Berggren P-O. Insulin signaling in the pancreatic
beta cell. Ann Rev Nutr 2008;28:233251.
23. Suckale J, Solimena M. Pancreas islets in metabolic signalingfocus on
the beta cell. Front Biosci 2008;13:71567171.
24. Schuit F, De Vos A, Farfari S, et al. Metabolic fate of glucose in purified
islet cells. Glucose-regulated anaplerosis in beta cells. J Biol Chem 1997;
25;272(30):1857218579.
K E Y
1
3
4
5
6
7
Nutrition support is indicated in surgical patients if they are significantly malnourished prior to surgery, if they are expected to
remain NPO (non per os, nothing by mouth) for more than 5
days postoperatively, or if they are critically ill.14 The main feature of metabolism in the surgical patient is the presence of the
inflammatory response. The inflammatory response is critical to
survival from surgical or traumatic injury, yet it poses challenges
in the nourishment of these patients. If the surgical injury is not
sufficient to produce an inflammatory response, nutrition support
in surgery is similar to that in simple starvation. Well-nourished
patients with short-term undernutrition or mild inflammatory
stress and limited weight loss do not have increased risk of complications during their surgical convalescence related to their
nutritional status.14 However, as America becomes more obese,
good nutrition does not equate to a body weight above the
ideal. In an Italian study, body mass index (BMI) and waist circumference were directly associated with systolic and diastolic
blood pressure values. Processed meat, potatoes, and wine, typically consumed in the unhealthy American diet, were directly
associated with increased blood pressure.5
1
The goal of nutrition support is to minimize protein loss
and to provide key nutrients to maintain immune and other
critical functions during and after surgical or traumatic injury.
This chapter addresses the areas of nutritional assessment,
metabolism, and therapy including the nutritional response to
inflammation.
BASIC NUTRITIONAL
METABOLIC PRINCIPLES
Body Composition
Total body mass is composed of aqueous and nonaqueous
components. The nonaqueous portion is made up of bone
P O I N T S
8
9
10
11
12
13
21
SCIENTIFIC PRINCIPLES
22
O2
CO2
Fuel
ATP
Work
Urea
TA B L E 3 . 1
CLASSIFICATION
kg
kcal VALUE
Fat
14
125,000
Skeletal muscle
24,000
Other
24,000
23
Glycogen
Muscle
0.15
600
Liver
0.075
300
Free glucose
0.02
80
Carbohydrate
The basic unit of carbohydrate metabolism in humans is glucose. Nearly all dietary carbohydrate is converted to glucose,
and glucose is the form of carbohydrate for oxidation. The
human body has a constant need for glucose oxidation in the
central nervous system and blood cells. A glucose supply of
approximately 12 hours is available as liver glycogen, which is
sufficient to cover glucose needs between meals. In periods of
fasting extending beyond the glycogen supply, the body converts amino acids to glucose, recycles the available glucose,
and eventually induces ketone production from fat, which can
substitute for some but not all of the bodys glucose need.
Resumption of glucose intake completely reverses these metabolic adaptations. In surgical nutrition, the inflammatory
Protein
Protein is a key nutrient in surgical nutrition and differs from
carbohydrate and fat because it contains nitrogen. Twenty different amino acids are dietarily essential, and the quality of a
food protein is determined by its content of these 20 amino
acids. Proteins can be categorized structurally as amino acids,
peptides, and proteins. The human gastrointestinal (GI) tract
can absorb amino acids and small peptides, and must digest
intact proteins into these smaller sizes for absorption. Protein
is not stored by the body. All protein is functional.
Absorbed amino acids pass first through the liver, where
portions are extracted for synthesis of circulating proteins.
The branched-chain amino acids (leucine, isoleucine, and
valine) are untouched by the liver and so are transported to
and extracted by muscle. Dietary and endogenous amino acids
eventually mix and distribute into intracellular and extracellular amino acid pools, where they are available upon demand
for further metabolism. Excess amino acids are degraded and
their carbon skeletons are oxidized to produce energy or are
incorporated into glycogen or free fatty acids. In addition to
SCIENTIFIC PRINCIPLES
Lipid
Protein
24
Nutrition Assessment
Metabolism is altered to varying degrees by surgical injury. In
many cases, these alterations are adaptive, short-lived, and
sustainable by a previously well-nourished person, even if
they are denied food for a few days after surgery. However, in
patients with preexisting malnutrition or with sufficiently
severe metabolic insult in response to surgical injury or infection, early resumption of a nutrient supply is important in
maximizing their recovery and minimizing their complication
risk.14 The aim of nutrition assessment is to identify the
patient in need of early resumption of metabolic support and
to determine the nutrient requirements to be fed to the
patient.
2
Starvation versus Inflammation as the Cause of Malnutrition. Starvation and systemic inflammatory response
result in erosion of the fat-free mass and body weight (malnutrition) and are indicators for nutrition support if present.14 In
starvation, the main features are reduced or absent nutrient
intake with gradual loss of lean mass and body fat, preservation of serum protein levels, and reversal of the metabolic
response upon feeding. The usual causes of starvation are
functional (dysphagia, nausea, emesis, malabsorption) and
psychosocial (food insecurity, social isolation, depression).
The main metabolic features of inflammatory response are
elevated metabolic rate (hypermetabolism and hypercatabolism), an acute-phase protein response, and reduced sensitivity
of the metabolic state to reversal by feeding. Impaired intake
might also be present with an inflammatory response (i.e., the
anorexia of illness). Inflammatory response is often the cause
of malnutrition in patients with recent acute illness or chronic
illness (e.g., cardiac cachexia, cancer cachexia).
Subjective Global Assessment. Subjective global assessment is a valid way to determine whether tissue erosion has
occurred and whether the etiology is starvation or inflammation.11,12 Subjective global assessment utilizes several types of
information, including physical examination, weight history,
recent nutrient intake, gastrointestinal symptoms, and history
of disease. The patient is classified as class A (not malnour-
SCIENTIFIC PRINCIPLES
25
26
TA B L E 3 . 2
CLASSIFICATION
NONOBESE
OBESE
Harris-Benedict
69
64
Owen
73
51
WHO
69
57
Mifflin-St. Jeor
82
70
threshold is not met, a longer 30-minute measurement accepting a 10% coefficient of variation is accurate. These guidelines
cover other aspects of measurement including environmental
conditions, body posture, physical motion, feeding state, and
interpretation of respiratory quotient.16
the presence of inflammatory response (Table 3.4).20 Interestingly, the expenditure of kilocalories is only minimally
increased after elective surgery. The largest increase in energy
expenditure occurs in patients with severe multiple trauma or
major thermal injury. However, the average-sized adult who
sustains even a major burn rarely increases his or her energy
expenditure to more than 3,000 kcal/day.
Overfeeding
While the provision of enough calories is beneficial, giving too
many calories can overfeed the patient. Excess calories, especially in the form of sugars, lead to lipogenesis and hepatic
steatosis interfering with hepatic function. To avoid overfeeding,
critically ill patients may not fit the factors used to estimate their
energy requirements and require indirect calorimetry to more
accurately measure energy expenditure. There are two major
consequences of overfeeding, hypophosphatemia and steatosis.
Nutrition Interventions
Elective Patients. Most patients undergoing elective operations
are adequately nourished. Unless the patient has suffered significant preoperative malnutrition (subjective global assessment
class C) or has a major intraoperative or postoperative complication, intravenous solutions containing 5% dextrose may be
administered for 5 to 7 days before the return of feeding with no
detrimental effect on outcome. Therefore, the increased cost of
feedings and the potential complications associated with intravenous nutrition cannot be justified. On the other hand, malnourished patients should not be left unfed for more than a day
or two after surgery. Assessment of nutritional status therefore
should be completed early so that this information can be integrated into decision making and nutrition care planning. Enteral
feeding is preferred to parenteral nutrition in patients who cannot resume an oral diet. Standard high-protein feeding formulas
are adequate. Choice of product and volume of feeding are based
on the results of the nutrition assessment. Most tube feedings
today are manufactured with water-soluble dietary fiber, and the
use of this nutrient should be standard in the feeding of surgical
patients. If fluid intake must be limited, there are standard feeding formulas with a calorie concentration of 2.0/mL.
Critical Care. Timing and feeding route are primary considerations in nutrition intervention in the critically ill surgical
TA B L E 3 . 3
CLASSIFICATION
ACCURACY RATES OF METABOLIC RATE EQUATIONS IN CRITICALLY ILL PATIENTS (PERCENTAGE OF INDIVIDUAL ESTIMATES
FALLING WITHIN 10% OF MEASURED)
YOUNG
EQUATION
ALL
(n 202)
NONOBESE
(n 52)
ELDERLY
OBESE
(n 47)
NONOBESE
(n 52)
OBESE
(n 51)
Mifflin-St. Jeor
25
23
21
21
35
ACCP
35
44
34
50
12
Ireton-Jones
46
33
49
50
51
Swinamer
54
61
51
60
43
Faisy
53
65
72
37
39
Brandi
55
61
55
61
41
Penn State
67
69
70
77
53
TA B L E 3 . 4
27
CLASSIFICATION
METABOLIC RATES OF CRITICALLY ILL PATIENTS CATEGORIZED BY REASON FOR ADMISSION VS. FEVER STATUS
(MEASURE OF RESTING ENERGY EXPENDITURE/HARRIS-BENEDICT ESTIMATE OF RESTING METABOLIC RATE)
Tmax 38C
Tmax 38C
Trauma
145 22
123 14
134 23
Surgery
138 22
125 14
132 22
Medical
139 20
125 20
132 20
141 24
124 17
No significant difference among the reasons for admission, the difference by fever status p 0.0001, and no significant fever reason for admission
interaction.
Data from Frankenfield DC, Smith JS, Cooney RN, et al. Relative association of fever and injury with hypermetabolism in critically ill patients. Injury
1997;28:617.
SCIENTIFIC PRINCIPLES
FEVER STATUS
28
Alterations in Fat Metabolism. To support the hypermetabolism, increased gluconeogenesis, and interorgan substrate
flux, stored triglyceride is mobilized and oxidized at an accelerated rate. Glucose administration poorly attenuates this
lipolysis, which may be the result of continuous stimulation of
the sympathetic nervous system. Although mobilization and
use of free fatty acids are accelerated in injured subjects, ketosis during brief starvation is blunted, and the accelerated protein catabolism remains unchecked. If unfed, severely injured
patients rapidly deplete their fat and protein stores. Such malnutrition increases their susceptibility to added stresses of
hemorrhage, surgery, and infection and may contribute to
organ system failure, sepsis, and death.
TA B L E 3 . 5
DIFFERENCES BETWEEN ELECTIVE SURGERY AND ACCIDENTAL INJURY
INSULT
ELECTIVE OPERATION
Tissue damage
Hypotension
Pain/fear/anxiety
Generally present
Infectious complications
29
changes. Patients are assessed prior to surgery by anesthesiologists and surgeons to determine the need for preoperative
nutritional support or additional medical consultation.
Hydration prior to surgery is common, as is the administration
of prophylactic antibiotics and drugs to relieve anxiety and
fear. In the operating theater, the surgical site is prepped in
a sterile fashion to minimize contamination, and numerous
physiologic responses (i.e., blood pressure, pulse, urine output) are continually monitored. Blood and blood products are
invariably available. During the operation, tissues are carefully
dissected and incised to minimize tissue trauma; tissues are
reapproximated with care when possible. Appropriately
selected pharmacologic agents are used to block undesirable
cardiovascular responses, and specific techniques such as
epidural or local block anesthesia or patient-controlled analgesia are effective in minimizing postoperative pain. As a consequence, the physiologic responses to elective surgery are generally of a lesser magnitude than those following major
SCIENTIFIC PRINCIPLES
30
demands and the cell is forced to switch to anaerobic metabolism, leading to lactic acidosis.
Tissue Damage
Injury of body tissues appears to be the most important factor
setting the stress response into motion. Hypovolemia and starvation do not initiate a hypermetabolic/hypercatabolic response
unless they result in infection or tissue injury. For example,
prolonged underperfusion may lead to ischemia, cellular
death, and the release of toxic products that can initiate the
stress response. Afferent neural pathways from the wound
signal the hypothalamus that injury has occurred; tissue
destruction is generally sensed in the conscious patient as pain.
Efferent pathways from the brain are immediately triggered
and stimulate a number of responses designed to maintain
homeostasis.
SCIENTIFIC PRINCIPLES
muscle. This response provides key nutrients to support cellular metabolism at a time when food cannot be acquired. The
primary metabolic component of the acute-phase response
affected by IL-6 is a qualitative alteration in hepatic protein
synthesis with a resulting alteration in plasma protein composition. Characteristically, proteins acting as serum transport
and binding molecules (albumin, transferrin) are reduced in
quantity, and acute-phase proteins (fibrinogen, C-reactive protein) are increased. Acute-phase proteins are elaborated, in
part, for the purpose of reducing the systemic effects of tissue
damage. While the true physiologic role of many of the acutephase proteins remains unclear, many act as antiproteases,
opsonins, or coagulation and wound-healing factors, and they
likely inhibit the generalized tissue destruction that is associated with the local initiation of inflammation. For example,
increases in fibrinogen enhance thrombus formation, while
antiproteases reduce tissue damage caused by proteases
released by dead or dying cells. C-reactive protein has been
hypothesized to have a scavenger function and its serum level
can be a measure of the inflammatory response. This acutephase response normally confers a significant survival advantage following injury and infection.
31
32
The pattern of physiologic changes elicited in response to surgical stress results from the specific interaction of an individual
patient with the stressful stimulus. The host must be capable of
transmitting and integrating injury signals, both neural and
humoral, and then mounting an appropriate response that
requires the interaction of a number of organ systems. The
nature, intensity, and duration of the stress are fundamental
determinants of both the host mediators activated and the
physiologic changes observed. The responses that follow a
minor elective operation are similar to those observed during a
comparable, brief period of fasting and bed rest. On the other
hand, major thermal injury results in a prolonged period of
hypermetabolism and a severe drain on the bodys energy and
protein stores, resolving only with wound closure and resolution of the sepsis that may have developed. Thus, there are
profound metabolic differences between the bodys response
to simple starvation and major stress (Table 3.6).
Body Composition
Body composition is a major determinant of the metabolic
responses observed during surgical illness. Posttraumatic
nitrogen excretion is directly related to the size of the body
protein mass. The balance of nitrogen intake versus output
from the body serves as a marker of protein metabolism. The
net loss of a certain amount of nitrogen from the body implies
the net breakdown of the corresponding amount of protein. In
women, the size of the skeletal muscle mass is about one-half
that of age-matched men; thus, it is the muscular young man
in whom nitrogen losses are most marked after injury, and it is
the elderly, sedentary woman in whom they are the least
marked.8
Age
Many of the changes in the metabolic responses to surgical illness that occur with aging can be attributed to alterations in
body composition and to longstanding patterns of physical
activity. Although weight remains more or less stable, fat mass
tends to increase with age while muscle mass tends to decrease.
The loss of strength that accompanies immobility, starvation,
and acute surgical illness may have marked functional consequences. The capacity of muscle to serve as an energy source
may be limited during prolonged illness in the elderly patient,
and muscle strength may rapidly become inadequate for respiratory and other vital muscle function.
After the limited stress of elective operation, increases in
energy expenditure are independent of age. Endocrine responses
to elective operation and to trauma appear intact in older
patients in terms of plasma cortisol levels and urinary excretion
of adrenaline, noradrenaline, and 17-hydroxycorticosteroids.
The prevalence of cardiovascular and pulmonary diseases
increases with age. Diminished arterial compliance, impaired
vasoconstriction, altered autonomic function and sensitivity to
catecholamines, and decreased baroreflex sensitivity may all
impair the maintenance of cardiovascular homeostasis during
acute surgical illness. Thus, the delivery of oxygen to the tissues may be impaired in the elderly and may be inadequate
when oxygen demands are highest.
Gender
Observed differences between the metabolic responses of men
and women in general reflect differences in body composition.
Lean body mass, expressed as a proportion of body weight, is
TA B L E 3 . 6
METABOLIC DIFFERENCES BETWEEN THE RESPONSE TO SIMPLE STARVATION AND
TO INJURY
SIMPLE STARVATION
SEVERE INJURY
Presence of mediators
Fat
Mixed
Hepatic ureagenesis
Gluconeogenesis
Muscle proteolysis
33
SCIENTIFIC PRINCIPLES
34
Hypermetabolism. Oxygen consumption is usually elevated in the infected patient. The extent of this increase is
related to the severity of infection, with peak elevations reaching 50% to 60% above normal. Such responses often occur in
the postoperative and postinjury periods secondary to severe
pneumonia, intra-abdominal infection, or wound invasion. If
the patients metabolic rate is already elevated to a maximal
extent because of severe injury, no further increase occurs. In
patients with only slightly accelerated rates of oxygen consumption, the presence of infection causes a rise in metabolic
rate that appears additive to the preexisting state. A portion of
the increase in metabolism may be ascribed to the increase in
reaction rate associated with fever (Q10 effect). Calculations
suggest that the metabolic rate increases 10% to 13% for each
elevation of 1C in central temperature. On resolution of the
infection, the metabolic rate returns to normal.
Altered Glucose Dynamics. The observation that glucose
production is increased in infected patients appears to be additive to the augmented gluconeogenesis that occurs following
injury. For example, uninfected burn patients have an accelerated glucose production rate approximately 50% above normal; with the onset of bacteremia in similar individuals, hepatic
glucose production increases to twice basal levels. Glucose
dynamics following infection are complex, and profound hypoglycemia and diminished hepatic glucose production have also
been described in both animals and human patients. Studies in
animals and in human patients show that deterioration in gluconeogenesis is associated with more progressive stages of infection and may be related to alterations in splanchnic blood flow.
Alterations in Protein Metabolism. Accelerated proteolysis, increased nitrogen excretion, and prolonged negative
nitrogen balance occur following infection, and the response
pattern is similar to that described for injury. Amino acid
efflux from skeletal muscle is accelerated in patients with sepsis, and this flux is matched by accelerated visceral amino acid
uptake. In infected burn patients, splanchnic uptake of amino
acids is increased 50% above rates in uninfected burn patients
with injuries of comparable size. These amino acids serve as
glucose precursors and are used for synthesis of acute-phase
proteins. Studies in animals have demonstrated that an
increase in hepatic amino acid uptake during systemic infection is due to an increase in the activities of specific amino acid
transporters that reside in the hepatocyte plasma membrane.
Severe infection is often associated with a hypercatabolic
state that initiates marked changes in interorgan glutamine
metabolism (Fig. 3.8). The cycle may begin with a breakdown
in the gut mucosal barrier resulting in microbial translocation.
Bacteria and their endotoxins stimulate macrophages to release
cytokines, which activate the pituitary/adrenal axis. The release
of cortisol stimulates glutamine synthesis and release by tissues
such as the lungs and skeletal muscle. The bulk of the glutamine is taken up by the liver at the expense of the gut. Acidosis
frequently occurs in the patient with sepsis, and this stimulus
serves as a signal for accelerated glutamine uptake by the kidney. Glutamine liberates an ammonia ion that combines with a
hydrogen ion and is excreted in the urine, thus participating in
acidbase homeostasis. Because the glutamine arises from
skeletal muscle proteolysis, this complication of sepsis is yet
another stimulus of heightened skeletal muscle breakdown.
35
Alterations in Fat Metabolism. Fat is a major fuel oxidized in infected patients, and the increased metabolism of
lipids from peripheral fat stores is especially prominent during
a period of inadequate nutritional support. Lipolysis is most
probably mediated by the heightened sympathetic activity that
is a potent stimulus for fat mobilization and accelerated oxidation. Serum triglyceride levels reflect the balance between
rates of triglyceride production by the liver and use and storage by peripheral tissues. Marked hypertriglyceridemia has
been associated with gram-negative infection on occasion, but
plasma triglyceride concentrations are usually normal or low,
indicating enhanced clearance by other organs. Infected
patients cannot convert fatty acids to ketones efficiently in the
liver, and hence do not adapt to starvation like fasted,
unstressed individuals. It has been suggested that the low
ketone levels of infection may be a consequence of the hyperinsulinemia associated with catabolic states.
Changes in Trace Mineral Metabolism. Changes in balance of magnesium, inorganic phosphate, zinc, and potassium
generally follow alterations in nitrogen balance. Although the
iron-binding capacity of transferrin is usually unchanged in
early infection, iron disappears from the plasma, especially
during severe pyrogenic infections; similar alterations are
observed with serum zinc levels. These decreases cannot be
totally accounted for by losses of the minerals from the body.
Rather, both iron and zinc accumulate within the liver, and this
accumulation appears to be another host defense mechanism.
The administration of iron to the infected host, especially early
in the disease, is contraindicated because increased serum iron
concentrations may impair resistance. Unlike iron and zinc,
copper levels generally rise, and the increased plasma concentrations can be ascribed almost entirely to the increase in ceruloplasmin produced by the liver.
Respiratory Insufficiency. A common problem associated with systemic infection is oxygenation and elimination
of carbon dioxide in patients with a compromised pulmonary status. Patients often require intubation and vigorous ventilatory support, and hypermetabolism is a common
feature of their illness. Hypermetabolism is accompanied by
increased oxygen consumption, which drives carbon dioxide
production as more substrate must be oxidized to support
the hypermetabolic response. Within this model, composition of diet (carbohydrate vs. fat) is relatively unimportant in
determining the carbon dioxide burden (carbohydrate at respiratory quotient [RQ] 1.0 releasing more CO2 than fat at
RQ 0.7). Avoidance of overfeeding is the primary concern in
SCIENTIFIC PRINCIPLES
36
containing 14 g arginine, 14 g glutamine, and 3 g -hydroxy-methylbutyrate (an analog of leucine) has shown that such
supplementation can increase the fat-free mass of cachectic
cancer patients (stage IV solid tumors) and patients with stage
III AIDS.45,46
OTHER METHODS OF
MODIFYING THE CATABOLIC
RESPONSE TO SURGERY AND
CRITICAL ILLNESS
Besides nutritional intervention, other methods to modify the
physiologic and biochemical response to operation have been
studied in an effort to reduce the magnitude of the stress
response and to provide insight into possible mechanisms.
Regional anesthetic techniques block afferent signals from the
wound and interrupt sympathetic nervous efferent signals to
the adrenal gland and possibly the liver, reducing the apparent
magnitude of the stress response. Others have studied stress
responses in sympathectomized animals by blocking the efferent limb of the neuroendocrine reflex response. These reports
indicate that central nervous system blockade interrupts afferent signals stimulated by operative procedures.
More recent studies have documented the safety and efficacy of long-term exogenous recombinant growth hormone
(GH) administration.47 GH stimulates protein synthesis during
hypocaloric feedings and increases retention of sodium and
potassium by the kidney. The potential synergistic effects of
specialized nutrition in combination with GH require further
study. Cyclooxygenase inhibitors such as aspirin and ibuprofen attenuate the symptoms and endocrine responses that
occur with critical illness without altering cytokine elaboration. It is anticipated that researchers may eventually be able
to selectively block the deleterious effects of excessive
cytokines yet preserve their beneficial effects.
Research Findings
One of the difficulties in applying the research on nutritional
modulation of the inflammatory response is that research protocols target particular diseases, and so results are often not
generalizable (i.e., a study that shows an improvement in body
composition and quality of life in cancer patients cannot be
generalized to patients with congestive heart failure).
Although novel approaches to the management of the
inflammatory response are becoming clinical realities,48 the
current standard of supplemental macro- and micronutrients
should not be ignored. Akner and Cederholm23 reviewed the
literature and found that in 60% of 36 randomized controlled trials, standard supplementation of nutrient intake
improved function/morbidity, and in 80% of 41 randomized
controlled trials, standard supplementation improved
anthropometric variables. However, this leaves a large percentage of studies in which standard support of calorie, protein, and micronutrient intake did not have a positive effect.
The intriguing question is whether in these negative studies a
more targeted form of nutrition support would have had the
desired effect.
CHOICE OF NUTRITION IN
SURGICAL PATIENTS: ENTERAL
OR PARENTERAL?
Although the physiologic advantage of enteral nutrition is
apparent, preoperative nutritional repletion via the enteral
37
NUTRITION AS
PRIMARY THERAPY
1. Patients with enterocutaneous fistulas (parenteral preferred
but enteral could be used with a low-output fistula)
Patients with gastrointestinal-cutaneous fistulas represent the
classic indication for TPN. In such patients, oral intake of
food almost invariably results in increased fistula output,
which can lead to metabolic disturbances, dehydration, and
death. Several comprehensive reviews have concluded that
total parenteral nutrition clearly impacts the treatment and
course of disease for patients with GI fistulas. The following
conclusions can be drawn from studies evaluating the use of
TPN in patients with enterocutaneous fistulas: (a) TPN
increases the spontaneous closure rate of enterocutaneous fistulas, but does not markedly decrease the mortality rate in
patients with fistulas (improvements in mortality are mainly
due to improved surgical and metabolic care); (b) if spontaneous closure of the fistula does not occur, patients are better
prepared for operative intervention because of the nutritional
support they received; and (c) certain fistulas (radiated
bowel) are associated with a higher failure rate of closure
than others and should be treated more aggressively surgically after a defined period of nutritional support (unless closure occurs).
2. Patients with short bowel syndrome (parenteral)
Prospective randomized trials designed specifically to examine
the impact of TPN on patients with short bowel syndrome
have not been initiated, mainly because such patients have no
choice but to receive TPN. Most of these patients, who would
have certainly died prior to the availability of TPN, now survive for long periods of time on home parenteral nutrition. In
selected patients with residual small intestine (at least 18
inches), postresectional hyperplasia may develop with time
such that they can tolerate enteral feedings. Studies by
Wilmore and colleagues39 have demonstrated that the requirement for TPN could be decreased or even eliminated in
patients with short gut syndrome by providing a nutritional
regimen consisting of supplemental glutamine, growth
hormone, and a modified high-carbohydrate, low-fat diet.
There was a marked improvement in the absorption of nutrients with this combination therapy and a decrease in stool output. In addition, TPN requirements were reduced by 50%, as
were the costs associated with care of these individuals. Discontinuation of the growth hormone did not increase TPN
needs in these patients once they had undergone successful gut
rehabilitation.
3. Patients with hepatic failure (enteral preferred)
Individuals with liver disease may be malnourished because of
excessive alcohol intake, diminished food intake, or an inflammatory state from viral infection. These individuals are protein
depleted yet are intolerant of protein because of their tendency
to become encephalopathic with a high nitrogen intake.
SCIENTIFIC PRINCIPLES
38
One of the best studies to date evaluating the efficacy of preoperative TPN was published by the Veterans Affairs Total Parenteral Nutrition Cooperative Study Group.53 More than 3,500
patients requiring mainly elective abdominal surgery were
entered into this prospective randomized trial. They were initially screened for evidence of malnutrition using subjective criteria and/or by determining their Nutritional Risk Index Score,
which included objective criteria such as percentage of weight
loss and serum albumin level. The patients were further divided
into categories assigning them to one of four groups: well nourished, borderline malnourished, moderately malnourished, or
severely malnourished. Patients in each malnourished category
were randomized to receive at least 7 days of preoperative TPN
or to proceed with surgery without preoperative TPN. Patients
randomized to receive TPN received 1,000 kcal/day in excess of
calculated caloric requirements. Lipid was provided on a daily
basis. One criticism of this study was that patients were allowed
to eat in addition to receiving parenteral feedings.
Analysis of the data from this study indicated that there
was no difference in short-term or long-term complications
between groups. Infectious complications including pneumonia, abscess, and line sepsis were statistically significantly
higher for patients receiving TPN.54 Noninfectious complications (impaired wound healing) were significantly lower only in
those patients receiving TPN who were in the severely malnourished group (15% weight loss and serum albumin 2.9 mg).
This study strongly suggests that preoperative TPN should be
provided only to severely malnourished patients who cannot
be nourished by the enteral route. Contraindications to the use
of preoperative TPN include patients requiring emergency
operation and those who are only mildly or moderately malnourished. In such patients, TPN should be continued postoperatively only if the GI tract cannot be utilized for tube feedings. Nasojejunal or jejunostomy tubes should also be considered
in patients undergoing major upper abdominal procedures in
whom it is anticipated that oral feedings may not be resumed
for 7 to 10 days after surgery.
39
TA B L E 3 . 7
COMPOSITION OF A STANDARD CENTRAL VENOUS SOLUTION
10% Amino acid solution
50% Dextrose solution
Fat emulsion
Electrolytes vitamins minerals
Total volume
500 mL
500 mL
50 mL
1,050 mL
Amino acids
Dextrose
Total N
Dextrose kcal
mOsms/L
50 g
250 g
50/6.25 8 g
250 g 3.4 kcal/g 840 kcal
2,000
Composition
Range of concentrations
Sodium (mEq/L)
60
0150
Potassium (mEq/L)
40
080
Acetate (mEq/L)
50
50150
Chloride (mEq/L)
50
0150
Phosphate (mEq/L)
15
030
Calcium (mEq/L)a
4.5
020
Magnesium (mEq/L)
515
Generally added as calcium gluconate or calcium chloride: one ampule of calcium gluconate 1 g of
calcium 4.5 mEq.
FIGURE 3.9. Technique for insertion of a subclavian catheter (see text for details).
SCIENTIFIC PRINCIPLES
Volume
40
810
2040b
60
1.01.5
1.21.7
mg TE
g
g
g
Vitamin E (tocopherol)
Vitamin K (phylloquinone)
mg
mg
mg
mg
Pantothenic acid
Folic acid
Vitamin B12
Biotin
100200
3.0
0.4
b
Unknown
1.5
18
20
75
20
Unknown
400
5,000
DAILY
REQUIREMENT OF
THE MODERATELY
INJURED
Unknown
2.5
40
40
100
10
10
300
20
Unknown
400
5,000
DAILY
REQUIREMENT
OF THE SEVERELY
INJURED
20
100
10
10
100
15
400
10,000
AMOUNT
PROVIDED
BY ONE
VITAMIN PILL
60
0.4
15
4.0
40
3.6
3.0
100
0c
10a
200
3,300 (retinol)
DAILY AMOUNT
PROVIDED BY STANDARD
INTRAVENOUS
PREPARATIONS
2.02.2
g
Niacin
47 (adults)b
1319
g
mg
200
IU
Vitamin D (ergocalciferol)
1,760 (women)
3,300 (men)
IU
UNIT
RECOMMENDED
DIETARY ALLOWANCE
FOR DAILY
ORAL INTAKE
Vitamin A (retinol)
VITAMIN
VITAMIN REQUIREMENTS
TA B L E 3 . 8
41
TA B L E 3 . 9
MINERAL AND TRACE ELEMENT REQUIREMENTS
Zinc
15
SUGGESTED DAILY
INTRAVENOUS
INTAKE (mg)
2.55.0a
Copper
23
0.51.5
1.0
Manganese
2.55.0b
0.150.8
0.5
Chromium
0.050.2b
0.010.015
0.1
Iron
8 (women)10 (men)
The use of lipids in TPN was developed to meet the requirement for essential fatty acids (linoleic acid) and the full caloric
needs in hypermetabolic patients, recognizing the complications associated with infusing large amounts of dextrose.
Intravenous fat emulsions are composed of soy or safflower
oils (vegetable fat emulsions), which contain primarily longchain triglycerides (LCTs) composed of fatty acids with 16and 18-carbon chain lengths. The provision of fat provides
essential linoleic acid, inhibits lipogenesis from carbohydrates,
and lowers the RQ, which may benefit patients with respiratory compromise. However, the high content of n-6 polyunsaturated fatty acids (in particular, linoleic acid) in these emulsions may have harmful effects on pulmonary and immune
function.55 Standard intravenous fat emulsions may alter the
cell membrane phospholipid composition of cells of the reticuloendothelial system, resulting in changes in membrane fluidity such that clearance of bacteria and toxins is impaired. In
addition, n-6 polyunsaturated fatty acids may alter the local
production of eicosanoids and cytokines such that chemotaxis
is negatively impacted. Newer nutritional methods of modifying the catabolic response to injury and infection propose the
use of the n-3 fatty acids, which may decrease eicosanoid
biosynthesis and thereby diminish the vasoconstriction,
platelet aggregation, and immunosuppression that may occur
when n-6 derivatives are administered. Studies suggest that
n-3 fatty acids may be of benefit to the critically ill patient.
Omega-3 fatty acids have been added to enteral formulas, but
are not in parenteral formulas available in the United States.
Fat is an important fuel source for critically ill patients. Septic and injured patients preferentially utilize endogenous fat as
an energy source, which appears to be related in part to the
effects of counterregulatory hormones on stimulating fat mobilization. These patients have a relative unresponsiveness to the
administration of carbohydrates in that free fatty acid mobilization is only marginally decreased and free fatty acid oxidation is not suppressed, as in pure starvation. Glucose infusion above energy expenditure in a hormonal milieu that favors
fat mobilization and oxidation only leads to hepatic steatosis.
SCIENTIFIC PRINCIPLES
MINERAL
RECOMMENDED DIETARY
ALLOWANCE FOR DAILY
ORAL INTAKE (mg)
42
TA B L E 3 . 1 0
COMPLICATIONS ASSOCIATED WITH THE USE OF TPN
COMPLICATION
CAUSE
TREATMENT
Pneumothorax
Air embolism
Catheter embolization
Venous thrombosis
Catheter malposition
MECHANICAL
METABOLIC
Hyperglycemia
Hypoglycemia
Hyperglycemic, hyperosmolar
nonketotic coma (HHNC)
Hyperchloremic metabolic
acidosis
Azotemia
Hypertriglyceridemia
Hypophosphatemia
Inadequate administration of
Increase administration
Hypocalcemia
electrolyte in question
Hypomagnesemia
Hypokalemia
Bleeding
Vitamin K deficiency
Administer Vitamin K
Line sepsis
SEPTIC
CXR, chest radiograph; IJ, internal jugular; TPN, total parenteral nutrition.
Gut-specific Nutrients. It is now clear that the composition of the diet, as well as the route of delivery, plays an
43
Infection resolves:
Continue central
venous feeding
ALGORITHM 3.1
ALGORITHM 3.1. Management of the total parenteral nutrition (TPN) patient who becomes septic.
nal mucosa is the overall stimulation of DNA synthesis as evidenced by thymidine incorporation.
TECHNIQUES OF ENTERAL
NUTRITIONAL SUPPORT
Enteral feeding causes the gut to release trophic factors, which
improves intestinal mucosal integrity and reduces bacterial
transmigration even if caloric goals are not met. It has also
been associated with a decrease in postoperative infection
rates and a significant increase in collagen deposition at anastomotic sites, increasing wound strength.60,61 Therefore, it
should always be considered first over parenteral feeding in the
surgically ill patient.
SCIENTIFIC PRINCIPLES
44
Technique of Percutaneous
Endoscopic Gastrostomy
FIGURE 3.10. Use of a feeding tube bridle for patients who are prone
to extubate the feeding catheter.
TECHNIQUES OF PARENTERAL
NUTRITIONAL SUPPORT
Parenteral nutrition has several advantages over enteral nutrition. Delivery access is much simpler and reliable, nutrition
does not have to be discontinued for further surgical procedures, and patients meet caloric goals consistently. However,
intravenous feeding is not without serious complications and is
associated with increased morbidity, including bacteremia, and
prolonged ventilator dependency.60 Even so, it still remains a
valuable adjunct in caring for the critically ill patient.
SCIENTIFIC PRINCIPLES
this reason and can also be used in patients where transillumination of the stomach is difficult or in patients who have
had a subtotal gastrectomy with a small residual stomach.65
45
46
ACKNOWLEDGMENTS
We would like to thank Drs. Brian Cicuto and Melissa Boltz
for their contributions to the Techniques section.
References
1. Kattelman KK, Hise M, Russell M, et al. Preliminary evidence for a medical nutrition therapy protocol: enteral feedings for critically ill patients.
J Amer Diet Assoc 2006;106:12261241.
2. Kreyman KG, Berger MM, Deutz NEP, et al. ESPEN guidelines on enteral
nutrition: intensive care. Clin Nutr 2006;25:210223.
3. ASPEN Board of Directors and the Clinical Guidelines Taskforce. Guidelines for the use of parenteral and enteral nutrition in adult and pediatric
patients. JPEN J Parenter Enteral Nutr 2002;26:(Suppl 1):1SA138SA.
4. Heyland DK, Khaliwal R, Drover JW, et al. Canadian critical care clinical
practice guidelines for nutrition support in mechanically ventilated, critically ill patients. JPEN J Parenter Enteral Nutr 2003;27:355373.
5. Masala G, Bendinelli B, Versari D, et al. Anthropometric and dietary determinants of blood pressure in over 7000 Mediterranean women: the European Prospective Investigation into cancer and NutritionFlorence cohort.
J Hypertens 2008;26:21122120.
6. Cohn SH, Vaartsky D, Yasumura S, et al. Compartmental body composition based on total body nitrogen, potassium, and calcium. Am J Physiol
1980;239:E524E530.
7. Frankenfield DC, Cooney RN, Smith JS, et al. Age-related differences in
the metabolic response to injury. J Trauma 2000;48:49.
8. Frankenfield DC, Rowe WA, Cooney RN, et al. Limits of body mass index
to detect obesity and predict body composition. Nutrition 2001;17:26.
9. Frankenfield DC, Cooney RN, Smith JS, et al. Bioelectrical impedance
plethysmographic analysis of body composition in critically injured and
healthy subjects. Am J Clin Nutr 1999;69:426.
10. Ravasco P, Camilo ME, Gouveia-Oliveira A, et al. A critical approach to
nutritional assessment in critically ill patients. Clin Nutr 2002;21:7377.
11. Baker JP, Detsky AS, Wesson DE, et al. Nutritional assessment. A comparison of clinical judgment and objective measures. N Engl J Med 1982;306:
969972.
12. Lupo L, Pannarale O, Altomare D, et al. Reliability of clinical judgment in
evaluation of the nutritional status of surgical patients. Br J Surg 1993;80:
15531556.
13. Povoa P. C-reactive protein: a valuable marker of sepsis. Intensive Care
Med 2002;28:235243.
14. Frankenfield DC, Smith JS, Cooney RN. Accelerated nitrogen loss after
traumatic injury is not attenuated by achievement of energy balance. JPEN
J Parenter Enteral Nutr 1997;21:324.
15. Scheinkestel CD, Kar L, Marshall K, et al. Prospective, randomized trial to
assess caloric and protein needs of critically ill, anuric, ventilated patients
requiring continuous renal replacement therapy. Nutrition 2003;19:
909916.
16. Compher C, Frankenfield DC, Keim N, et al. Best practice methods to
apply to measurement of resting metabolic rate in adults: a systematic
review. J Am Diet Assoc 2006;106:881903.
17. Frankenfield DC, Rowe WA, Smith JS, et al. Validation of several established equations for resting metabolic rate in obese and non obese people.
J Am Diet Assoc 2003;103:1152.
18. Frankenfield D, Smith JS, Cooney RN. Validation of 2 approaches to predicting resting metabolic rate in critically ill patients. JPEN J Parenter
Enteral Nutr 2004;28:259.
19. Frankenfield DC, Coleman A, Alam S, et al. Analysis of estimation methods for resting metabolic rate in critically ill adults. JPEN J Parenter
Enteral Nutr 2009;33:2736.
20. Frankenfield DC, Smith JS, Cooney RN, et al. Relative association of fever
and injury with hypermetabolism in critically ill patients. Injury 1997;28:
617.
21. Pontes-Arruda A, Aragao AMA, Albuquerque JD. Effects of enteral feeding with eicosapentaenoic acid, gamma linolenic acid, and antioxidants in
mechanically ventilated patients with severe sepsis and septic shock. Crit
Care Med 2006;34:23232333.
22. Cuthbertson DP. Q J Med 1932;1:233.
23. Akner G, Cederholm T. Treatment of protein-energy malnutrition in
chronic non-malignant disorders. Am J Clin Nutr 2001;74:6.
24. Kotler DP. Cachexia. Ann Intern Med 2000;133:622.
25. Kaysen G, Eisenrich JP. Characteristics and effects of inflammation in endstage renal disease. Semin Dial 2003;16:438.
26. Espat NJ, Moldower LL, Copeland EM. Cytokine-mediated alterations in
host metabolism prevent nutritional repletion in cachectic cancer patients.
J Surg Oncol 1995;58:77.
27. Shulze PC, Gielen S, Adams V, et al. Muscular levels of proinflammatory
cytokines correlate with a reduced expression of insulin like growth factor
in chronic heart failure. Basic Res Cardiol 2003;98:367.
28. Debigar R, Cot CH, Maltais F. Peripheral muscle wasting in chronic
obstructive pulmonary disease. Am J Respir Crit Care Med 2001;164:
1712.
29. Chrousos GP. The hypothalamic-pituitary-adrenal axis and immunemediated inflammation. N Eng J Med 1995;332:1351.
30. Steinborn W, Anker SD. Cardiac cachexia: pathophysiology and clinical
implications. Basic Appl Myol 2003;13:191.
31. Anker SD, Coats AJS. Cardiac cachexia. A syndrome with impaired survival and immune and neuroendocrine activation. Chest 1999;115:836.
32. Fontana L, Weiss EP, Villareal DT, et al. Long-term effects of calorie or
protein restriction on serum IGF-1 and IGFBP-3 concentration in humans.
Aging Cell 2008;7:681687.
33. Bessey PQ, Watters JM, Aoki TT, et al. Combined hormonal infusion simulates the metabolic response to injury. Ann Surg 1984;200:264.
34. Souba WW. Cytokines: key regulators of the nutritional/metabolic
response to critical illness. Curr Probl Surg 1994;31:577.
35. Sena MJ, Utter GH, Cushieri J, et al. Early supplemental parenteral nutrition is associated with increased infectious complications in critically ill
trauma patients. J Am Coll Surg 2008;207:459467.
36. Dissanaike S, Pham T, Shalhub S, et al. Effect of immediate enteral feeding
on trauma patients with an open abdomen: protection from nosocomial
infection. J Am Coll Surg 2008;207:690697.
37. Petrov MS, van Santvoort HC, Besselink MGH, et al. Enteral nutrition and
the risk of mortality and infectious complications in patients with severe
acute pancreatitis. Arch Surg 2008;143:11111117.
38. Bagga D, Wang L, Farius-Eisner R. Differential effects of prostaglandin
derived from n-6 and n-3 polyunsaturated fatty acids on COX-2 and IL-6
secretion. Proc Natl Acad Sci U S A 2003;100:1751.
39. Scholz H. Prostaglandins. Am J Physiol Regul Integr Comp Physiol 2003;
285:R512.
40. Wigmore Sj, Fearon KC, Maingay JP, et al. Down-regulation of the acutephase response in patients with pancreatic cancer cachexia receiving
oral eicosapentaenoic acid is mediated via suppression of interleukin-6.
Clin Sci 1997;92:215.
41. Barber MD, McMillan DC, Preston T, et al. The metabolic response to
feeding in weight-losing pancreatic cancer patients and its modulation by
a fish oil-enriched nutritional supplement. Clin Sci 2000;98:389.
42. Barber MD, Ross JA, Fearon KC, et al. Fish oil-enriched nutritional supplement attenuates progression of the acute phase response in weight-losing patients with advanced pancreatic cancer. J Nutr 1999;129:1120.
43. Barber MD, Ross JA, Fearon KC, et al. The effect of an oral nutritional
supplement enriched with fish oil on weight loss in patients with pancreatic
cancer. Br J Cancer 1999;81:80.
44. Gogos CA, Ginopoulis P, Salsa B, et al. Dietary omega-3 polyunsaturated
fatty acids plus vitamin E restore immunodeficiency and prolong survival
for severely ill patients with generalized malignancy. Cancer 1998;82:395.
45. May PE, Barber A, DOlipio D, et al. Reversal of cancer-related wasting
using oral supplementation with a combination of beta-hydroxybeta-methylbutyrate, arginine, and glutamine. Am J Surg 2002;183:
471.
46. Clark RH, Feleke G, Din M, et al. Nutritional treatment for acquired
immunodeficiency virus-associated wasting using beta-hydroxybeta-methylbutyrate, glutamine, and arginine: a randomized, doubleblind, placebo-controlled study. JPEN J Parenter Enteral Nutr 2000;24:133.
47. Jiang ZM, He GZ, Zhang SY, et al. Low-dose growth hormone and
hypocaloric nutrition attenuates the protein-catabolic response after major
operation. Ann Surg 1989;210:514.
48. Fong Y, Marano MA, Barber A, et al. Total parenteral nutrition and bowel
rest modify the metabolic response to endotoxin in humans. Ann Surg
1989;210:449.
49. Ziegler TR, Young LS, Benfell K, et al. Clinical and metabolic efficacy of
glutamine-enriched parenteral nutrition following bone marrow transplantation: a double-blind randomized controlled trial. Ann Intern Med
1992;116:821.
50. Byrne TA, Persinger RL, Young LS, et al. A new treatment for patients with
the short bowel syndrome: growth hormone, glutamine, and a modified
diet. Ann Surg 1995;222:243.
51. Alexander JW, MacMillan BG, Stinnert JD, et al. Beneficial effects of
aggressive protein feeding in severely burned children. Ann Surg 1980;192:
505.
52. Abel RM, Beck CH, Abbott WM, et al. Improved survival from acute renal
failure following treatment with intravenous essential L-amino acids and
glucose: results of a prospective, double-blind study. N Engl J Med 1973;
288:695.
53. Buzby GP and The Veterans Affairs Total Parenteral Nutrition Cooperative
Study Group. Perioperative total parenteral nutrition in surgical patients.
N Engl J Med 1991;325:525.
47
SCIENTIFIC PRINCIPLES
K E Y
1
4
5
6
P O I N T S
8
9
10
48
49
SCIENTIFIC PRINCIPLES
FIGURE 4.1. Timeline of phases of wound healing with dominant cell types and major physiologic events.
TA B L E 4 . 1
PLATELET GRANULES AND MEDIATORS OF
PLATELET AGGREGATION
PLATELET GRANULES
Granules: Contain Platelet-specific Proteins
Platelet factor 4
-Thromboglobulin
Platelet-derived growth factor
Transforming growth factor-
Dense Granules
Adenosine diphosphate
Serotonin
Calcium
MEDIATORS OF PLATELET AGGREGATION
Thromboxane A2
Thrombin
Platelet factor 4
50
FIGURE 4.2. Schematic representation of wound healing processes. ADP, adenosine diphosphate; FGF, fibroblast growth factor; KGF, keratinocyte growth factor;
PAF, platelet-activating factor; PDGF, platelet-derived
growth factor; PF4, platelet factor 4; TGF, transforming
growth factor; TNF-, tumor necrosis factor-; TXA2,
thromboxane A2. (continued)
51
SCIENTIFIC PRINCIPLES
Proliferative Phase
2
The proliferative phase begins with the formation of a provisional matrix of fibrin and fibronectin as part of initial clot
formation. Initially, the provisional matrix is populated by
macrophages; however, by day 3, fibroblasts appear in the
fibronectinfibrin framework and initiate collagen synthesis.
Fibroblasts proliferate in response to growth factors to
become the dominant cell type during this phase. Growth factors produced by macrophages simultaneously induce angiogenesis, which induces the ingrowth and proliferation of
endothelial cells, forming new capillaries. The process of neovascularization is driven in large part by the local tissue
hypoxia present in the wound center, which in turn is orchestrated by the hypoxia-inducible factor-1 (HIF-1). This master
transcription factor functions as the switch that turns on
angiogenic processes, metabolic adaptations to hypoxia, an
increase in iron transport, and erythropoiesis, functioning
across local, regional, and systemic levels to restore blood flow
to an injured area. Initially, the angiogenic cascade unleashed
by HIF-1 results in a hypervascular network, which will be
pruned later. This neovascularity is visible through the epithelium and gives the wound a pink or purple-red appearance.
Capillary ingrowth provides the fibroblasts with oxygen and
nutrients to sustain cell proliferation and support the production of the permanent wound matrix. This matrix is composed
52
FIGURE 4.3. A: Type I collagen showing triple helix and intramolecular cross-links. B: Intermolecular cross-links provide tensile
strength. C: Assembly of collagen fibrils, fibers, and fiber bundles.
TA B L E 4 . 2
COLLAGEN TYPES
TYPE
I
PROPERTY OF
AGGREGATE UNIT
TISSUE
DISTRIBUTION
Rigid fibrils
II
Rigid fibrils
III
Elastic fibrils
IV
Sheet
Basement membrane
Fibril
Widespread
VI
Beaded filaments
Widespread
VII
Anchoring fibrils
Interface of basement
membrane and
underlying stroma
VIII
Sheet
Descemet membrane
IX
Fibril
Hyaline cartilage
Sheet
Hypertrophic cartilage
XI
Fibril
Hyaline cartilage
XII
Fibril
Similar to type I
53
rates of synthesis and degradation continue throughout remodeling, there is no further change in total collagen content.4 Tensile strength gradually increases as random collagen fibrils are
replaced by organized fibrils with more intermolecular bonds.
During the initial phase of wound healing, there is a relative
abundance of type III collagen in the wound. With remodeling,
the normal adult ratio of 4:1 (type I to type III) collagen is
restored. Under normal wound healing conditions, the capillary density gradually diminishes, and the number of fibroblasts is reduced. The wound loses its pink or purple vascular
color and becomes progressively pale. The collagen undergoes
constant remodeling. New collagen is formed, and collagen
degradation by specific collagenases is ongoing. Collagenase
activity is balanced against new production of collagen to produce a steady state. As equilibrium is achieved, the collagen
fibrils align themselves in a longitudinal arrangement as dictated by stress placed on the wound. Scars never achieve the
degree of order achieved by collagen in normal skin or tendons, but they do increase in strength for 6 months or longer,
eventually reaching 70% of the strength of unwounded skin
(Fig. 4.4).
The other important component of the extracellular matrix
is the ground substance or proteoglycans. These substances are
composed of a protein backbone with long hydrophilic carbohydrate side chains. The hydrophilic nature of these molecules
accounts for much of the water content of scars. In the early
immature wound, there is a disproportionately large amount
of proteoglycans (particularly hyaluronic acid). During the
maturation phase, the proteoglycan content returns to a level
that closely approximates that of normal skin.
Until recently, the extracellular matrix (predominantly collagen and proteoglycans) was thought to be inert. It is becoming increasingly clear, however, that extracellular matrix signals certain cells through cell attachment receptors (integrins)
and serves as a reservoir for growth factors. Via integrin receptors, the extracellular matrix influences intracellular signal
transduction with an impact on cell motility and migration,
FIGURE 4.4. Relation of the rate of collagen synthesis to the gain of tensile strength of rat skin wounds. (Adapted from Madden JW, Peacock
EE Jr. Studies on the biology of collagen during wound healing. 1. Rate of collagen synthesis and deposition in cutaneous wounds of the rat.
Surgery 1968;64:288.)
SCIENTIFIC PRINCIPLES
54
Epithelialization
55
SCIENTIFIC PRINCIPLES
Clinical Implications
Optimal Outcomes from Surgical Closure. This review
of normal wound healing has numerous practical implications
to the care of wounds and surgical incisions in order to ensure
uncomplicated, expeditious healing as well as produce an optimal scar. Meticulous hemostasis reduces the inflammation and
phagocytosis necessary to clear the wound of blood. The use
of electrocautery should be judicious. Electrocautery results in
a band of tissue necrosis that varies in thickness in relation to
56
57
(collagen, fibronectin, basement membrane proteins, and glycosaminoglycans) is composed of structural elements that are
not inert. They function as an essential substrate, with adhesion molecules regulating intercellular communication. The
cellular occupants of the matrix express specific receptors
that recognize amino acid sequences on the matrix proteins.
This allows for cellular attachment at specific sites, cell locomotion, and intracellular signal transduction. Rapid epithelialization is therefore dependent on an optimal matrix, synthesized by the underlying granulation tissue, as well as on
optimal delivery of nutrients and oxygen by an adequate
blood supply. The rate of epithelialization is also inversely
related to the degree of bacterial presence in the wound, a
variable that is directly related to the quality of the granulation tissue present.
Inflammatory cells in open wounds, especially the macrophages, release growth factors. Growth factors enhance migration and proliferation of fibroblasts and endothelial cells in
wounds. In an open wound, this leads to the formation of
granulation tissue, the cobblestonelike pink surface of healthy
new tissue. The ability of an open wound to form granulation
tissue is governed by the blood supply to the tissue and the relative absence of devitalized tissue and bacteria. Therefore,
wounds that form granulation tissue should heal or be
amenable to surgical closure with flaps or skin grafts. Wounds
that do not form granulation tissue are very likely to be recalcitrant to all treatments except those directed at the underlying
cause of the failure to form granulation tissue, that is, vascular
bypass to restore adequate blood flow to an ischemic extremity wound or a vigorous surgical dbridement to clear the
wound of contaminating bacterial pathogens that impair the
development of healthy granulation tissue and impede epidermal migration.
Dbridement deserves mention, as it is frequently underutilized in clinical care. It is a simple technique that is unglamorous in comparison to other more complex surgical operations, yet is essentially critical to ensuring healing in a
contaminated surgical wound. Dbridement is a term that
refers to clearance of tissue that is unnecessary and counterproductive to healing, and in practical terms usually refers to
bacteria and necrotic, devitalized tissue. Dbridement can take
the form of nonsurgical techniques, such as autolytic, enzymatic, or biologic approaches, or alternatively a surgical technique can be used. The astute clinician will tailor the degree of
dbridement necessary to achieve the desired outcome while
minimizing removal of healthy healing tissue. The importance
of dbridement is most clearly seen in chronic wounds, which
will be more fully discussed later. The process of dbridement
removes bacteria and their products, which serve to propagate
a counterproductive hyperinflammatory phase and which
divert metabolic resources away from the healing wound. In a
chronic wound, bacterial critical colonization often will result
in a hyperinflammatory loop that is best short-circuited by a
judicious dbridement, allowing the wound to progress
toward healing (Fig. 4.6).8
Wound Contraction
Wound contraction is an important event that contrasts the
healing of open wounds with closed incisions. When open
wounds contract, the surrounding skin is pulled over the
wound to reduce its size. This can occur much faster than
epithelialization. In addition to increasing the speed of wound
closure, another advantage is that the open wound is resurfaced by the normal sensate skin surrounding the wound.
Most animals are loose skinned, meaning that the skin (epithelium, dermis, subcutaneous fat) is only loosely attached to the
underlying muscle fascia. Some animal wounds heal almost
entirely by contraction; for example, a 2-cm ulcer heals to a
SCIENTIFIC PRINCIPLES
B
FIGURE 4.6. The inflammatory cascade in wound repair. A: In healthy patients with adequate tissue perfusion, the
inflammatory burst is self-limited as reactive oxygen species (ROS) serve to clear bacteria from the wound bed to enable
progression to the later phases of wound healing. Since the bacteria are cleared from the wound, the production of ROS
and proteases is self-limited, minimizing bystander cellular damage. B: In a setting of regional hypoxia or other comorbidities, bacteria are not efficiently cleared, partly due to an ineffective oxidative burst, which requires oxygen. Bacteria
will continue to accumulate in a biofilm state and a level of critical colonization or frank infection will result, leading to
an amplified and/or prolonged inflammatory state with further tissue damage and persistent hypoxia as neovascularization is impaired. (Reproduced with permission from Thorne CM. Grabb and Smiths Plastic Surgery, 6th ed. Philadelphia,
PA: Lippincott Williams & Wilkins; 2006, Figure 3.1.)
Clinical Features
Basic principles of wound care should be tailored to assist
the mechanisms elaborated earlier, leading to more rapid
healing. Although many varieties of wound care are practiced, Winter and Scales10 first recorded that epithelialization is more rapid under moist conditions than dry conditions. Without dressings, a superficial wound, or one with
minimal devitalized tissue, forms a scab or crust. The scab
forms when blood and serum coagulate, dry, and form a
protective moisture barrier over the open wound (Fig. 4.7).
Epithelialization occurs with controlled clot proteolysis and
migration of the epithelium under the clot. If the wound is
kept moist with an occlusive dressing, however, and the exudate does not become infected, then epithelial migration is
optimized. A skin graft donor site, for example, epithelializes several days faster under an occlusive dressing than a
dry dressing. In addition, the pain of an open wound or skin
graft donor site is dramatically reduced under an occlusive
dressing.
Moist healing can be achieved by occlusive dressings,
ointments or creams, or continually moistened dressings.
The traditional wet to dry dressing, however, if truly left to
dry, simply produces desiccation and necrosis of the surface
layer of the wound, delaying epithelialization. Although
wet to dry dressings can be effective for dbridement of
wound exudate, they are generally less desirable than a
moist healing environment combined with effective cleaning of the wound (i.e., water irrigation or a tailored surgical
dbridement).
Role of Oxygen
Oxygen is necessary for normal metabolic cellular function,
but in wounds with actively proliferating and metabolically
stimulated cells, it is even more critical. PMNs require ambient
PO2 levels of 25 mm Hg to produce superoxide radicals, which
serve an essential role in bacterial killing. The enzyme system
that generates superoxide and its derivative oxidant products
functions optimally at PO2 levels greater than 50 mm Hg. Collagen synthesis is also highly dependent on an adequate tissue
oxygen tension. A fresh wound is initially avascular and is
always hypoxic relative to the surrounding tissues. In the center of a new wound, the tissue PO2 can drop to near zero. After
angiogenesis and the delivery of oxygenated blood, the tissue
PO2 quickly rises. Generally, the tissue oxygen tension in a
wound is lower than that of surrounding normal tissues. Atherosclerosis of major arteries, small vessel disease from other
causes, impaired oxygen delivery, local scarring with fibrosis,
and other events may reduce local tissue PO2 levels from normal (about 40 mm Hg) to less than 25 mm Hg. If so, tissue
hypoxia results in significantly impaired wound healing. In the
postoperative patient, suboptimal skin perfusion due to even
modest hypovolemia, smoking-related arteriopathy, or excess
circulating epinephrine can result in a low tissue PO2. Subcutaneous tissue oxygen levels have been correlated clinically
with surgical complication rates. Supplemental oxygen, optimal fluid administration, pain control, and arterial reconstruction all have potential roles in the effort to enhance the tissue
PO2. Oxygen delivery to tissue is the primary determinant of
healing; anemia alone is not specifically detrimental to wound
healing.11
SCIENTIFIC PRINCIPLES
59
60
FIGURE 4.7. Rapid epithelialization occurs in a moist environment. Desiccation delays healing by causing tissue necrosis in the exposed wound.
The scab ultimately forms a moisture barrier, and epithelialization occurs from the wound edge and any remaining dermal appendages.
Hyperbaric oxygen therapy (HBO) can achieve high oxygen levels in most wounds for the duration of the treatment,
usually 1.5 hours at a time. The patient is placed in the hyperbaric chamber and is exposed to 2 to 2.5 atmospheres of
pressure and 100% oxygen. Although oxygen is a necessary
component in aerobic metabolism, it may also act as a signaling molecule for growth factor production. There is extensive
clinical experience suggesting clinical efficacy of HBO, but
conclusive prospective randomized trials have not been conducted. It is clear that HBO can raise the PO2 in ischemic
wounds, but the indications, length of treatment, and number
of treatments are still empiric. Based on the success of a number of retrospective studies, the usage of HBO in recent years
has become widespread, particularly with diabetic foot ulcers
and wounds that have been irradiated.
The role of oxygen as a therapeutic agent has been in part
stimulated by an increased understanding of the role of oxygen
in intracellular signaling. Previously, oxygen was thought to
play an essential role in oxidative metabolism, but oxygen sensors were thought to be limited to the kidney (erythropoietin
synthesis), the carotid body, and other specialized organs.
However, there has been a great deal of interest, in recent years,
in the existence in every cell of signal transduction pathways in
response to hypoxia. These pathways are mediated by the master transcription factor HIF-1 that is transported to the nucleus
and binds to the promoter region to activate synthesis of many
genes including growth factors and hormones such as VEGF,
erythropoietin, and stromal cellderived factor (SDF). Therefore, there is a plausible role for intermittent oxygen therapy
to induce signal transduction and improve wound healing.
The amount of oxygen necessary to result in a therapeutic
effect is unknown, but in the acute surgical situation there are
data indicating a beneficial effect from supplemental oxygen in
the immediate postoperative period. For the treatment of
chronic wounds, placing the wound in an enriched oxygen
environment has had some anecdotal interest.12 Another
Role of Edema
In normal tissue, each cell is only a few cell diameters away
from the nearest capillary and receives nutrients and oxygen by
diffusion. However, with inflammation, venous insufficiency,
or any other causes of edema formation, the sequestered extracellular and extravascular fluid increases the diffusion distance
for oxygen and results in a lower tissue PO2. In the case of
lower extremity venous insufficiency, the chronic protein leak
from the capillaries results in pericapillary deposition. This
cuffing is a further barrier to oxygen and nutrient diffusion
and possibly functions as a site of nonspecific binding of
growth factors, making them less available to the wound environment. The importance of edema control is often underestimated. Even in extremities that are not noticeably swollen, elevation and other methods of edema control (elastic wraps,
compression stockings, and sequential compression machines)
can be of substantial benefit. The most important therapeutic
maneuver in the healing of leg ulcers associated with venous
insufficiency is edema control with leg elevation, compression
stockings or compressive dressings, and, in severe cases, intermittent or sequential compression devices.
CHRONIC WOUNDS
61
SCIENTIFIC PRINCIPLES
62
Edema is detrimental to wound healing and is often undertreated, in part because of difficulties in patient education.
Edema can be a factor in virtually any ulcer of the lower extremity, although venous insufficiency is the most important.
Because patients often have personal habits that are hard to
modify, this can be a refractory problem. Patients often object to
compression stockings, the most effective method for limiting
edema. This leaves intermittent leg elevation, elastic wraps, and
elevation of the foot of the bed as alternative measures. The critical factor is getting the patient to realize that leg swelling must
be avoided, and so in the course of the day, each patient must
modify behavior sufficiently to treat this problem.
There are at least 150 dressing products commercially available at present. These include multiple topical antibiotics, irrigants, and dbriding agents. Although PDGF (Regranex) and
tissue engineered living cell constructs (Apligraf and Dermagraft) have been shown to decrease healing times in certain
wounds, standard treatment, which adheres to the principles
outlined earlier, may be successfully applied to the vast majority of wounds. There are many good alternative treatments,
but to avoid confusion, they should be judged according to the
following criteria:
1.
2.
3.
4.
TA B L E 4 . 3
FACTORS THAT CONTRIBUTE TO WOUND ISCHEMIA
Poor arterial inflowatherosclerosis
Poor venous flowvenous stasis
Smoking
Radiation
Edema
Diabetes mellitusaccelerates atherosclerosis, microvascular
dysfunction
Vasculitis
Fibrosischronic scarring
Pressurepressure sores or decubitus ulcer
SCIENTIFIC PRINCIPLES
63
64
Other Local Conditions. Peripheral arterial occlusive disease secondary to atherosclerosis can be a primary cause of
impaired healing and may also be a cofactor with the other
conditions discussed. In addition, conditions such as vasculitis, prolonged pressure, lower leg venous insufficiency, and tissue fibrosis affect wound healing through the mechanism of
local tissue ischemia.
Leg Ulcers. Leg ulcers are perhaps the most common type of
chronic ulcer. The underlying disease process is most often
local tissue ischemia. The underlying cause of this local tissue
ischemia should be identified and appropriate treatment initiated. About 90% of leg ulcers in the United States are secondary
to venous insufficiency (valvular incompetence) (Fig. 4.9).
Venous ulcers lead to local tissue ischemia by increased venous
pressure, which lowers the transcapillary perfusion pressure,
and by leg edema. Initial treatment should be directed to
cleansing and dbriding the wound of proteinaceous exudate
and limiting the edema and protein loss with compression
dressings and elevation. A common treatment has been the
Unna boot, a paste bandage that is absorptive, limits edema,
and can be changed weekly. This allows the physician to control treatment with weekly visits. If this dressing is made compressive by adding an elastic wrap, it is highly effective in
reducing edema, absorbing exudate, and providing an occlusive wound environment. Its limitations are that it requires
weekly visits and precludes normal showering or bathing.
Another alternative that has become standard in many venous
leg ulcer studies is the four-layered compression garment, in
which multiple layers result in effective compression over
many days. With effective compression, over 50% of venous
ulcers can be healed within a 3- to 4-month period. Compression garments or elastic wraps with frequent dressing changes,
thorough cleaning, and an occlusive dressing can be equally
65
SCIENTIFIC PRINCIPLES
FIGURE 4.10. Diabetic ulcer of the heel. These lesions are noted at
sites of pressure, such as the heel in this patient. (Reproduced with permission from Goodheart HP. Goodhearts Photoguide of Common
Skin Disorders, 2nd ed. Philadelphia, PA: Lippincott Williams &
Wilkins; 2003.)
66
Antibiotics. The role of antibiotics in wound care is controversial. All open wounds are colonized with bacteria. Only
when the surrounding tissue is invaded (cellulitis) are systemic
antibiotics clearly indicated. Antibiotics may be useful in other
situations, such as when the granulation tissue has a high bacterial count or in a case of reduced resistance to bacteria, such
as in a diabetic foot ulcer, but these situations are not clearly
defined. The routine use of systemic antibiotics for chronic
wounds should be avoided to reduce the development of resistant bacterial strains within the wound.
Topical antibiotics are frequently used and can be useful.
The ointment vehicle may help keep the wound moist, and the
bacteria count in a wound may be lowered as a result. With
most antibiotics, however, resistant organisms emerge quickly
and development of allergic, hypersensitivity reactions are
common. Most topical antibiotic ointments should be limited
to 3 weeks of therapy to avoid developing a rash or other signs
of inflammation as a result of the antibiotic ointment, not bacteria. The expense is substantial, and the benefits are not well
demonstrated. Silver sulfadiazine, frequently used for burn
care, is also useful for chronic wounds. Its broad spectrum of
activity, the lack of relevant drug-resistant plasmids in bacteria, and its low cost make it a good choice.
In recent years, silver-impregnated dressings have become
available and achieved widespread acceptance. They have
the antibacterial activity of silver ions without the potential
for allergy with sulfadiazine, combine a powerful broadspectrum antibacterial activity without the problems of drug
resistance, and have the absorptive activities of many dressings. However, although widely used, questions such as the
concentration of silver needed for efficacy await better evidence before their routine use can be justified.
Dbriding Agents. Collagenases have been used to dbride
wounds for 20 years and can be a highly effective adjunct in the
treatment of chronic wounds with necrotic tissue. These agents
may be used after surgical dbridement to help clean a wound
and to avoid a painful mechanical dbridement. Currently, only
one enzymatic agent is approved for reimbursement in the
United States. Another method of wound dbridement involves
EXCESSIVE SCARRING
Many factors are involved in the formation of an ideal scar.
The most important of these are (a) accurate alignment of
sharply incised tissue parallel to the natural lines of resting skin
tension, (b) closure of the wound without tension on the epidermis and without underlying dead space, and (c) primary
healing without complications such as infection or dehiscence.
The patients genetic makeup and the location of the wound
on the body are also important factors. The more negative factors that are associated with a particular wound, the more
likely it will form a scar that is less than ideal. In general terms,
the three main factors associated with an adverse scar include
genetic predisposition, tension, and inflammation. From an
evolutionary viewpoint, wound healing has been programmed
to be rapid and exuberant to minimize the problems of an open
wound. As part of the aging process, the proliferative phase of
wound healing becomes less exuberant, and although wound
healing is slower, scars are improved (see the remodeling phase
67
TA B L E 4 . 4
CLASSIFICATION
COMPOSITION
INDICATIONS
FUNCTIONS
EXAMPLES
Films
Semiocclusive
(semipermeable)
polyurethane or copolyester
Op-site
Bioclusive
Tegaderm
Visulin
Nondraining primarily
closed wounds
Blisterfilm
Acute or chronic
partial- or fullthickness wounds
Absorbs fluid
Cutinova Hydro
Duoderm
Stage I to IV decubitus
ulcers
Protects wounds
Restore
Intrasite
Encourages granulation
J&J ulcer
dressing
Promotes reepithelialization
Comfeel
Ultec
Acute or chronic
partial-thickness
wounds with
minimal exudate
Vigilon
Geliperm
Elastogel
Intrasite gel
Decreases pain
Does not adhere to wound
Foams
Either hydrophilic or
hydrophobic
Acute or chronic
partial-thickness
wounds that are
highly secreting and
require mechanical
dbriding
Dbrides
Cutinova Plus
Lyofoam
Allevyn
AquaphorGauze
Nonadherent
Acute or chronic
partial-thickness
wounds with
minimal or
moderate exudate
Chronic full-thickness
wounds with large
amounts of exudate
Spand-Gel
Geliperm
Nonocclusive
Usually polyurethane or gel
film coated
High absorbency
Impregnates
Absorptive powders
and pastes
Promotes reepithelization
Adaptic
Biobrane
Envisan paste
Bard
absorption
Dressing
Duoderm
granules
Hydrogran
Hollister
Exudate
Absorber
Compiled by M.C. Crossland, RN, Wound Healing Center, Medical College of Virginia, Richmond, VA.
SCIENTIFIC PRINCIPLES
WOUND DRESSINGS
68
FIGURE 4.11. Keloids. A: This lesion is growing well beyond the border of cesarean section scar. B: The ear lobes are a common location.
(Reproduced with permission from Goodheart HP. Goodhearts Photoguide of Common Skin Disorders, 2nd ed. Philadelphia, PA: Lippincott
Williams & Wilkins; 2003.)
section). The distinctions between an unsightly scar, a hypertrophic scar, and a true keloid can be confusing. An accurate
diagnosis of most scars can be made by clinical observation and
the history of the lesion.
Keloids
True keloids are uncommon and occur predominantly in darkskinned people with a genetic predisposition for keloid formation.7 In most cases, the gene appears to be transmitted in an
9 autosomal dominant pattern. The primary difference between
a keloid and a hypertrophic scar is that a keloid extends
beyond the boundary of the original tissue injury. It behaves as
a benign tumor and extends into or invades the normal surrounding tissue. This creates a scar that is larger than the original wound (Fig. 4.11).
Histologically, keloids contain an overabundance of collagen. The absolute number of fibroblasts is not increased, but
the production of collagen continually outpaces the activity of
collagenase, resulting in a scar of ever-increasing dimensions.
The cause of keloid formation is unknown. Immunoglobulin
G levels are increased, which suggests possible autoimmune
stimulation resulting in a chronic inflammatory response with
continued collagen deposition.
The treatment of keloids is difficult. The cause of keloids is
unknown, and the underlying disorder is not resolved by any
specific therapy. Some improvement is usually seen with excision followed by intralesional steroid injection.24 In unresponsive cases, excision followed by a short course of radiotherapy
has been successful, but the resulting scar is unpredictable and
may potentially be worse. Keloids typically develop several
months after injury and rarely, if ever, subside. Although many
therapies have been tried, with anecdotal reports of success,
none is ideal, and recurrence is frustratingly common.25
develop within the first month after wounding and often subside gradually (Fig. 4.12).
Improvement of hypertrophic scars may be obtained with
pressure garments, topical silicone gel sheeting applications, or
reexcision and closure.6,26 Reexcision and closure should be
considered if conditions of the closure can be improved. This
is especially true for wounds that originally healed by secondary intention or were complicated by infection: that is,
wounds that were adversely affected by prolonged inflammation. Simple reexcision and closure is unlikely to improve a
Hypertrophic Scars
Hypertrophic scars are histologically similar to keloids. They
contain an overabundance of dermal collagen. Hypertrophic
scars, however, respect the boundaries of the original injury
and do not extend into normal unwounded tissue. They have
less genetic predisposition, but hypertrophic scars also occur
more frequently in Asian and African skin. They are often seen
on the upper torso and across flexor surfaces. They usually
69
role that such cells play in tissue repair is currently being elucidated, and the potential of these cells to augment healing in disease states such as diabetes, as well as in clinical states associated
with impaired healing such as advanced age, holds tremendous
promise for all fields of surgery.30
Unsightly Scars
Tissue-derived stem cells also play a role in healing. It is likely
that epithelial stem cells and dermis-resident cells have previA wound that is closed under tension or without adequate or
ously unappreciated functions in wound repair. The potential of
accurate alignment, or a wound that runs across the lines of
other tissue-derived stem cells, such as adipose tissuederived
natural skin tension, is often unsightly. Surgical excision and
stem cells, in tissue repair is currently an area of intense research.
closure with attention directed to correcting the underlying
cause of the unsightly scar usually results in improvement. 10 The directed manipulation of stem and progenitor cells will
likely define future advances in regenerative medicine, which is a
When reexcising either a hypertrophic scar or an unsightly scar
direct offshoot of wound healing science.
from other causes, reclosure with attention to relieving mechanical tension by the use of semipermanent or permanent intradermal sutures and everting wound closure, followed by treatment with taping and/or silicone gel sheeting, and judicious use
References
of injected intralesional steroids can result in substantial
improvement in the quality of the scar in a high percentage of
1. Singer AJ, Clark RA. Cutaneous wound healing. N Engl J Med 1999;341:
cases.
738.
2. Leibovich SJ, Ross R. The role of the macrophage in wound repair: a study
with hydrocortisone and antimacrophage serum. Am J Pathol 1975;78:71.
3. Cross KC, Mustoe TA. Growth factors in wound healing. Surg Clin North
Am 2003;83:531546.
4. Madden JW, Peacock EE. Studies on the biology of collagen during wound
healing. I. Rate of collagen synthesis and deposition in cutaneous wounds
of the rat. Surgery 1968;64:288.
5. Ruoslahti E. Stretching is good for a cell. Science 1997;276:13451346.
6. Mustoe TA. Editorial: treatment of scars and keloids. BMJ 2004;328:
13291330.
7. Mustoe TA, Cooter R, Gold M, et al. International clinical guidelines for
scar management. Plast Reconstr Surg 2002;110:560572.
8. Galiano RD, Mustoe TA. Wound care. In: Thorne CH, ed. Grabb and
Smiths Plastic Surgery, 6th ed. Philadelphia, PA: Lippincott Williams and
Wilkins; 2006.
9. Peacock EE Jr. Wound Repair, 3rd ed. Philadelphia, PA: WB Saunders;
1984:2332.
10. Winter GD, Scales JT. Effect of air drying and dressings on the surface of a
wound. Nature 1963;197:91.
11. Jonsson K, Jensen JA, Goodson WH, et al. Tissue oxygenation, anemia,
and perfusion in relation to wound healing in surgical patients. Ann Surg
1991;214:6.
12. Davidson JD, Mustoe TA. Commentary. Oxygen in wound healing: more
than a nutrient. Wound Repair Regen 2001;9:175177.
13. Mustoe TA. Understanding chronic wounds: a unifying hypothesis on their
pathogenesis, and implications for therapy. Am J Surg 2004;187:S65S70.
14. James GA, Swogger E, Wolcott R, et al. Biofilms in chronic wounds.
Wound Repair Regen 2008;16:37.
15. Gross A, Cutright DE, Bhaskar SN. Effectiveness of pulsating water jet
lavage in treatment of contaminated crushed wounds. Am J Surg 1972;
124:373.
16. Seifter E, Rettura G, Padawer J, et al. Impaired wound healing in streptozotocin diabetes: prevention by supplemental vitamin A. Ann Surg 1981;
194:42.
17. Ehrlich P, Tarver H, Hunt TK. Inhibitory effect of vitamin E on collagen
synthesis and wound repair. Ann Surg 1972;175:235.
18. LaVan FB, Hunt TK. Oxygen and wound healing. Clin Plast Surg 1990;17:
463.
19. Carver N, Leigh IM. Synthetic dressings. Int J Dermatol 1992;31:10.
20. Mustoe TA, Pierce GF, Thomason A, et al. Accelerated healing of incisional wounds in rats induced by transforming growth factor-. Science
1987;237:1333.
21. Brown GL, Nanney LB, Griffen J, et al. Enhancement of wound healing by
topical treatment with epidermal growth factor. N Engl J Med 1989;321:
76.
22. Argenta LC, Morykwas MJ. Vacuum-assisted closure: a new method for
wound control and treatment: clinical experience. Ann Plast Surg 1997;38:
563577.
23. Moues CM, Vos MC, van den Bemd GJ, et al. Bacterial load in relation to
vacuum-assisted closure wound therapy: a prospective randomized trial.
Wound Repair Regen 2004;12:1117.
24. Griffith H. The treatment of keloids with triamcinolone acetonide. Plast
Reconstr Surg 1966;38:202.
25. Lawrence WT. In search of the optimal treatment of keloids: report of a
series and a review of the literature. Ann Plast Surg 1991;27:164.
26. Ahn ST, Monafo WW, Mustoe TA. Topical silicone gel: a new treatment
for hypertrophic scars. Surgery 1989;106:781.
27. Khouri RK, Mustoe TA. Trends in the treatment of hypertrophic scars.
Adv Plast Reconstr Surg 1991;8:129.
28. Mast BA, Diegelmann RF, Krummel TM, et al. Scarless wound healing in
the mammalian fetus. Surg Gynecol Obstet 1992;174:441.
29. Siebert JW, Burd AR, McCarthy JG, et al. Fetal wound healing: a biochemical study of scarless healing. Plast Reconstr Surg 1990;85:503.
30. Gurtner GC, Werner S, Barrandon Y, et al. Wound repair and regeneration. Nature 2008;453:314.
SCIENTIFIC PRINCIPLES
scar that was closed with proper alignment and that healed
primarily without complications.27
CHAPTER 5 HEMOSTASIS
PETER K. HENKE AND THOMAS W. WAKEFIELD
K E Y
At the same time that thrombin forms, natural anticoagulant mechanisms oppose further thrombin formation and
help to localize thrombin activity to areas of vascular
injury. Just as thrombin generation is key to coagulation,
antithrombin is the central anticoagulant protein.
2 The endothelial cell acts as a nonthrombogenic surface, and
inflammation tips the balance to the procoagulant state.
3 Thrombosis and inflammation are closely linked, and may
perpetuate each other. Leukocytes and chemokines are
involved with normal deep venous thrombosis resolution.
1
BASIC CONSIDERATIONS
Coagulation is an essential homeostatic mechanism for survival
and involves tightly controlled processes to maintain vascular
integrity including thrombosis localization, amplification, and
neutralization. These coordinated steps occur at the vessel,
cellular, and subcellular level. Understanding of pathologic
thrombosis and its basic hemostatic processes is essential for
surgeons. Thrombosis, directly or indirectly, is the underlying
leading cause of death in the world.
Platelets form the initial hemostatic plug and are locally activated and aggregation induced (Fig. 5.1). Platelet aggregation is
mediated by receptors that are part of the mammalian integrin
family. This family includes the 1 family, mediating platelet
interaction with cells, collagen, fibronectin, and laminin; the 2
family (LeuCAM), present on leukocytes mediating interactions
between leukocytes and other cells important in inflammation;
and the 3 family (cytoadhesion), including the megakaryocytespecific glycoprotein (Gp) IIb/IIIa receptor and the vitronectin
receptor present on platelets and other cells.1 Platelet aggregation is mediated by GpIIb/IIIa, which binds fibrinogen, von
Willebrand factor (vWF), fibronectin, vitronectin, and thrombospondin to activated platelets. These high-density receptors
are hidden on inactivated platelets and become exposed on the
surface of activated platelets.
Once stimulated, activated platelets contract, with externalization of negatively charged procoagulant phospholipids,
including phosphatidylserine and phosphatidylinositol (termed
platelet factor 3).2 This allows for the coagulation proteins to
assemble on the surfaces of platelets, accelerating the coagulation reaction.3,4 Platelet membranes contribute critical surfaces
for coagulation complex assembly. During platelet activation,
granules release their contents of calcium, serotonin, adenosine
diphosphate (ADP), and adenosine triphosphate3 and membranes are exposed that are rich in receptors for factors Va and
VIIIa,5,6 as well as fibrinogen, vWF, and ADP, a potent activator of other platelets. vWF is responsible for platelet adhesion
through binding to GpIb,7 whereas fibrinogen forms bridges
between activated platelets by binding to GpIIb/IIIa on adjacent stimulated platelets.8 The GpIIb/IIIa receptor contains a
binding site for the tripeptide sequence arginine-glycine-aspartic acid (RGD), which is common to many of the receptor proteins. Unstimulated platelets can also attach to immobilized
70
P O I N T S
Heparin agents are the primary anticoagulants for acute
venous and arterial thrombosis, while a vitamin K antagonist is standard for long-term anticoagulation.
5 Factor VIII and IX deficiency states are involved in hemophilia A and B and von Willebrand disease.
6 Heparin-induced thrombocytopenia (HIT) occurs in 0.6%
to 30% of patients in whom heparin is given; severe thrombocytopenia associated with thrombosis (HITTS) is much
less frequent. Cessation of heparin is critical.
4
Chapter 5: Hemostasis
Granulation
Recruitment
release
(ADP, TXA2)
vWF
Aggregation
(hemostatic plug)
Endothelium
Basement
membrane
Collagen
important, through thrombin with negatively charged surfaces.16 Factor XIa activates factor XI autocatalytically and
also catalyzes the conversion of factor IX to IXa. After activation, factor VIIIa dissociates from vWF and assembles with
factors IXa and X. Factor IXa, factor X, ionized calcium, and
thrombin-activated factor VIII (VIIIa) then assemble on the
platelet surface in a complex called the Xase complex to catalyze the activation of factor X to Xa3 (Fig. 5.3). Factor Xa
then shunts into the prothrombinase complex for further
amplification of thrombin formation. The importance of a
mechanism of factor XI activation independent of the contact
activation system is apparent because patients deficient in
those factors of the contact activation system, including factor
XI, bleed, whereas patients deficient in factor XII, prekallikrein,
and high-molecular-weight kininogen do not usually bleed.15
The contact activation system is the most important coagulation
process involved in extracorporeal bypass circuits, including
cardiopulmonary bypass and extracorporeal membrane oxygenation (ECMO).
NATURAL ANTICOAGULANT
MECHANISMS
1
Extrinsic Pathway
Intrinsic Pathway
Fibrin
TF
FXII
FXI
FIX
FVIIa
Thrombin
TF FVIIa
TF
TF
FXa
FVa
FVIII
FIX
FVIIIa
FXIa
FVa
TF pre-mRNA
TF mRNA
Platelet
Blood
SCIENTIFIC PRINCIPLES
Platelet
adhesion Shape
change
71
72
Intrinsic Pathway
Extrinsic Pathway
XII
Tissue injury
(Hageman Factor)
HMWK collagen
Kallikrein
Prekallikrein
Tissue Factor
(Thromboplastin)
XIIa
XI
XIa
XII
IX
XIa
VIII
Tissue Factor
VIIIa
Thrombin
(IIa)
X
Ca2+
XIIa
Ca2
Xa
V
Phospholipid
surface
Ca2+
Active
Inactive
FIBRINOLYSIS
In addition to natural anticoagulants such as protein C and S,
physiologic clot formation is balanced by a contained process
of clot lysis, which prevents thrombus formation from proceeding outside of the injured area (Fig. 5.5). The central fibrinolytic enzyme is plasmin, a serine protease generated by the
proteolytic cleavage of the proenzyme plasminogen. Its main
substrates include fibrin, fibrinogen, and other coagulation
factors. Plasminogen, tissue plasminogen activator (tPA), and
2-antiplasmin (2-AP) become incorporated into the fibrin
clot as it forms.3 Plasminogen activators are serine proteases
that activate plasminogen, by cleavage of a single argininevaline peptide bond, to the enzyme plasmin. Plasminogen activation provides localized proteolytic activity.2628 In fact,
thrombin promotes tPA release from endothelial cells as well
as the production of plasminogen activator inhibitor-1 (PAI-1)
from endothelial cells.29,30
The major categories of plasminogen activators include
exogenous factors, such as streptokinase; endogenous factors,
such as tPA and urokinase; and intrinsic factors, such as factor
XII, prekallikrein, and high-molecular-weight kininogen.3
These later factors of the contact system are more important in
Ca2+
Va
Thrombin
(IIa)
XIII
Ca2+
II
IIa
(Prothrombin)
(Thrombin)
XIIIa
Ca2+
Fibrinogen
(I)
Fibrin
(Ia)
Cross-linked
Fibrin
Common Pathway
Chapter 5: Hemostasis
Intrinsic Pathway
XII
Prekallikrein
HMWK
Contact
activation
Extrinsic Pathway
XII
Platelet adhesion,
activation,
aggregation
vWF-co
73
FIGURE 5.4. Antithrombin is a primary anticoagulant. Note that antithrombin complexes with IIa to inhibit
fibrin polymerization, as well as factor Xa, and inactivates factor Va and
VIIIa.
VII
SCIENTIFIC PRINCIPLES
TF
IX
XI
XIIa
TF-VIIa (complex)
VIIIa-IXa
(Xase complex)
Xa
IXa
XIII
VIIIa-IXa
(Xase complex)
Fibrinogen
ATIII-IIa
II
FPA
FPB
Fibrin polymers
XIIIa
XIIIa
Fibrin
2-antiplasmin
2-antiplasmin/plasmin complexes
Free plasmin
Plasminogen
Activator
Inhibitors (PAI)
Thrombin
Tissue
Plasminogen
Activator
(tPA) and
Urokinase
Plasminogen
Platelets
Plasmin
Fibrin clot
Endothelium
74
Anti
Pro
Endothelium
Endothelium
PGI2 Vasodilation
NO
tPA/uPA
Thrombolysis
ERPC
APC
TFPI
Anticoagulation
TM
IL-1O Anti-inflammatory
Resting state
ENDOTHELIUM
AND HEMOSTASIS
Through its ability to express procoagulants and anticoagulant factors, vasoconstrictors and vasodilators, and key cell
adhesion molecules and cytokines, the endothelial cell is a key
regulator of hemostasis34 (Fig. 5.6). Vascular endothelium
maintains a vasodilatory and local fibrinolytic state in which
coagulation, platelet adhesion and activation, and leukocyte
activation are suppressed.
Endothelial products that are vasodilatory include adeno2 sine, nitric oxide (NO), and prostacyclin (PGI2).35 A nonthrombogenic endothelial surface is maintained by four main
mechanisms including endothelial production of thrombomodulin and subsequent activation of protein C, endothelial
expression of surface heparan- and dermatan-sulfate, constitutive expression of TFPI by endothelium (which is markedly
accelerated in response to heparin), and local production of
tPA and urokinase plasminogen activator (uPA).34,36 Finally,
the elaboration of NO and interleukin (IL)-10 by endothelium
inhibits leukocyte adhesion and activation.35
During states of endothelial disturbances such as injury, a
prothrombotic and proinflammatory state of vasoconstriction
is supported by the endothelial surface. Endothelial release of
platelet-activating factor (PAF) and endothelin-1 promotes
vasoconstriction.36 Endothelial cells increase production of
vWF, TF, PAI-1, and factor V to augment thrombosis with
exposure to prothrombotic stimuli. Finally, in response to
endothelial injury, endothelial cells are activated, resulting in
increased surface expression of cell adhesion molecules (such
as P- or E-selectin), and promotes leukocyte adhesion and activation. This initiates and amplifies inflammation and thrombosis.
Vaso
TM2
constriction Endothelin-1
Inhibits
thrombolysis
PAH-1
Procoagulant vWF
proteins
TF
Initiate
P-selectin
coagulation,
inflammation
Systemic inflammation
local injury
THROMBOSIS, INFLAMMATION,
AND RESOLUTION
After venous thrombosis, an acute to chronic inflammatory
response occurs in the vein wall and thrombus, leading to
thrombus amplification and organization and vein recanalization (often at the expense of vein wall and vein valvular damage). Initially, there is an increase in neutrophils in the vein wall
followed by monocytes/macrophages. Cytokines, chemokines,
and inflammatory factors (e.g., tumor necrosis factor [TNF])
facilitate inflammation. The ultimate response of the vein wall
depends on proinflammatory and anti-inflammatory mediator
balance at the interface between the leukocyte, activated
platelet, and endothelium.37
Selectins (P- and E-selectin) have been found to be intimately involved in this process38 (Fig. 5.7). Selectins are the
first upregulated glycoproteins on activated platelets and endothelial cells. The P-selectin receptor is P-selectin glycoprotein
ligand-1 (PSGL-1). This receptor, expressed on leukocytes,
facilitates the initial rolling of inflammatory cells along stimulated vascular endothelium. Interactions between P-selectin
and PSGL-1 mediate leukocyteendothelial cell and leukocyte
platelet interactions.
PSGL-1 has the greatest affinity for P-selectin and lesser
affinity for E-selectin and L-selectin. The role of P-selectin in
venous thrombosis has been suggested by the study of a mouse
with high circulating levels of P-selectin, the Delta CT
mouse.39 This mouse has a normal phenotype but expresses
circulating plasma P-selectin threefold to fourfold higher than
wild-type mice. These mice are hypercoagulable based on clotting tests, and a receptor antagonist against the P-selectin
receptor (rPSGL-Ig) will reverse the hypercoagulability. Consistently, wild-type mice administered soluble P-selectin become
P-/E-selectin
Expressed on
surface:PSGL-1
1.
Injury
2.
Stasis
Activation of
TF:FVII
complex
Procoagulant
syndromes
3.
Microparticles
(procoagulant)
75
Fibrin
deposition
4.
Thrombus
amplification
Early
< 8day
The first cell type in the thrombus is the neutrophil (polymorphonuclear leukocytes [PMNs]). Although PMNs may
cause vein wall injury, they are essential for early thrombus
resolution by promoting both fibrinolysis and collagenolysis.45,46 In a rat model of stasis DVT, neutropenia was associated with larger thrombi at 2 and 7 days and was correlated
with increased thrombus fibrosis and significantly lower
thrombus levels of both uPA and MMP-9.47 Neutropenic
cancer patients are not protected from DVT, and multiple
neutropenic episodes are associated with recurrent VTE in
patients with malignant disease who required filter placement due to a failure of, or contraindication to, anticoagulation.48
The monocyte is likely the most important cell for later
DVT resolution. Monocyte influx into the thrombus peaks at
day 8 after thrombogenesis and correlates with elevated monocyte chemotactic protein-1 (MCP-1) levels,49 which has been
associated with DVT resolution.50 Targeted deletion of the CC
receptor-2 (CCR-2 KO) in the mouse model of stasis thrombosis was associated with late impairment of thrombus resolution, probably via impaired MMP-2 and MMP-9 activity. We
also found that CCR-2 KO mice with stasis thrombosis supplemented with exogenous interferon- had full restoration of
thrombus resolution, in part due to recovery of MMP-2 and
MMP-9 activities, and without an increase in thrombus monocyte influx.51
Late
> 9day
Thrombus
L1
Proinflam factors
Thrombus
Time
TGF
PMN
MMP-9
UPA
Mechanical
stretch
IL13
TGF
Monocytes
MMPs
Plasmin
activators
Collagenolysis
Elastinolysis
Collagen accumulation
VSMC proliferation
MMP2
MMP9
SCIENTIFIC PRINCIPLES
Chapter 5: Hemostasis
76
ARTERIAL VERSUS
VENOUS THROMBOSIS
Thrombosis in the arterial system occurs somewhat differently
than in the venous system (Fig. 5.9). The elements required for
the initiation of venous thrombosis were described by Virchow
as stasis, endothelial injury, and hypercoagulability of the blood.
In the arterial circulation, endothelial injury (whether acute or
chronic) is key to thrombosis. This is most clearly demonstrated
by the typical atherosclerotic plaque. In advanced lesions, the
lipid core of the plaque is rich in inflammatory cells, cholesterol
crystals, and TF (generated by activated macrophages within the
plaque).56 Plaque ulceration exposes highly thrombogenic lipid
to the bloodstream, activating coagulation and platelet aggregation and leading to the deposition of clot.57 Platelet deposition
occurs at the apex of stenosis, the point of maximal shear force.
A platelet-rich thrombus is observed in arterial thrombus,
while in contrast, venous blood stasis and changes in its composition (leading to hypercoagulability) incite the formation of
thrombus from local procoagulant events, including small
endothelial disruptions at venous confluences, saccules, and
valve pockets. Hypercoagulable states have classically been
highly associated with VTE, but do play a role in cardiovascular
disease as well. For example, both factor V Leiden and
Vessel wall
Endothelium
Rupture
of plaque
Platelet
Altered
vessel wall
Smooth
muscle cell
Atherosclerotic
plaque
Foam cell
Tissue Factor
Cholesterol
Necrotic core
Abnormal
blood flow
Increased
coagulability
Altered
vessel wall
Chapter 5: Hemostasis
TA B L E 5 . 1
TA B L E 5 . 3
ANATOMIC LOCATION OF VTE DUE TO
HYPERCOAGULABLE STATES
FREQUENCY (%)
Factor V Leiden
2060
Hyperhomocysteinemia
10
PT G20210A
46
Protein C deficiency
35
Protein S deficiency
23
Dysfibrinogenemia
13
Antithrombin
12
Dysplasminogenemia
1
PT, prothrombin.
PROCOAGULANT STATES
Refer to Tables 5.1 to 5.3 and Algorithm 5.1.
ACQUIRED
PROCOAGULANT STATES
Most thrombotic clinical episodes have a proximate cause,
although environmental risks and genetic predispositions to
thrombosis may account for many of the VTE that manifest
clinically. Risk factors for arterial thrombosis are primarily
related to atherosclerosis, and are detailed elsewhere.
The most common risk factors for venous thrombosis are
prior DVT, malignancy, immobility, intravenous catheters,
increased age, major surgery, trauma, infections such as pneumonia and urinary tract infection, and certain cytotoxic
chemotherapy regimens.5961 Certain medications such as oral
contraceptives and hormonal replacement therapies also
increase the risk of VTE.
Of primary importance to surgeons is how to best estimate
perioperative VTE risk and apply appropriate prophylaxis.
TA B L E 5 . 2
SEVERITY OF VTE DUE TO HYPERCOAGULABLE STATES
High risk for thrombosis
AT deficiency
Protein C deficiency
Protein S deficiency
HIT/HITTS
Antiphospholipid antibody syndrome
Lower risk for thrombosis
Factor V Leiden
Hyperhomocysteinemia
PT G20210A
Dysfibrinogenemia
Dysplasminogenemia
Elevated factors VIII, IX, and XI
AT, antithrombin; HIT, heparin-induced thrombocytopenia; HITTS,
heparin-induced thrombocytopenia and thrombosis syndrome; PT,
prothrombin; VTE, venous thromboembolism.
Arterial
Elevated fibrinogen
Abnormal platelet aggregation
Atherosclerosis
Lipoprotein(a)
Both arterial and venous
Hyperhomocysteinemia
HITTS
Antiphospholipid antibody
Elevated PAI-1
Venous
AT
Protein C
Protein S
Factor V Leiden
PT G20210A
Dysfibrinogenemia
Elevated factors XI, IX, and VIII
AT, antithrombin; HITTS, heparin-induced thrombocytopenia and
thrombosis syndrome; PAI-1, plasminogen activator inhibitor; PT,
prothrombin; VTE, venous thromboembolism.
Lupus Anticoagulant/Antiphospholipid
Syndrome (Antiphospholipid Antibody)
This condition, despite its name, is a prothrombotic state and
deserves expanded discussion. The antiphospholipid antibody
syndrome consists of an elevated antiphospholipid antibody
titer in association with thrombosis, recurrent fetal loss, thrombocytopenia, and livedo reticularis.64,65 Strokes, myocardial
infarction, visceral infarction, and extremity gangrene may also
occur. Although the lupus anticoagulant has been noted often
in patients with systemic lupus erythematosus (SLE), it does
occur in patients without SLE. It may also be induced in
patients by medications, cancer, and certain infections.66
This syndrome is associated with antiphospholipid antibodies
that are most commonly immunoglobulin G (IgG). Antiphospholipid antibody syndrome is a particularly virulent hypercoagulable state that results in arterial and venous thrombosis at 5- to
16-fold greater risk.6668 A number of possible thrombotic mechanisms have been suggested, including inhibition of prostacyclin
synthesis or release from endothelial cells,69 inhibition of APC by
thrombin/TM,70 elevated PAI-1 levels,67 platelet activation,71
endothelial cell activation,72 and interference with the endothelial cellassociated annexin V anticoagulant activity.73 Increased
SCIENTIFIC PRINCIPLES
77
78
Patients with:
Strong family history
Young patients with
thrombosis without
obvious cause
Multiple episodes of
thrombosis without
underlying anatomic
abnormality
Thrombosis in unusual
locations
Procoagulant
screen
ALGORITHM 5.1
ALGORITHM 5.1. Coagulation analysis.
TF expression on monocytes and low free protein S plasma levels have also been found with the antiphospholipid syndrome
and a history of thrombosis.74
At least one third of patients with lupus anticoagulants
have a history of one or more thrombotic events, 70% or more
being VTE.75 Graft thrombosis has been observed in 27% to
50% of patients positive for antiphospholipid antibody.76,77
The diagnosis should be suspected in someone with a prolonged activated partial thromboplastin time (aPTT) with other
standard coagulation tests normal, along with the presence of
an increased antiphospholipid or anticardiolipin antibody titer
and elevation of 2-glycoprotein I.3,78 The prolongation in the
aPTT is strictly a laboratory phenomenon. The dilute Russell
viper venom time confirms the presence of a lupus anticoagulant.
There is imperfect agreement between diagnostic tests for
this abnormality. Approximately 80% of patients with a prolonged aPTT will have a positive antiphospholipid antibody,
but only 10% to 50% of patients with a positive antiphospholipid antibody will have a prolonged aPTT.79 Patients with
both tests positive are reported to have the same thrombotic
risk as those with either test alone.
Heparin followed by warfarin has been recommended for
the treatment of the antiphospholipid syndrome.66,75 For
recurrent fetal loss, heparin or low-molecular-weight heparin
(LMWH) use through pregnancy is recommended. In patients
with lupus anticoagulants, heparin is monitored by antifactor
Xa levels.
INHERITED
PROCOAGULANT STATES
Defects with High Risk for Thrombosis
Antithrombin Deficiency. AT is a serine protease inhibitor
(SERPIN) of thrombin, kallikrein, and factors Xa, IXa, VIIa,
Chapter 5: Hemostasis
79
Age:
Sex:
Wgt:
lbs Hgt:
inches
Please see Following Page for Prophylaxis suggestions and Safety Considerations
A
FIGURE 5.10. A Caprini risk factor score sheet is shown here as an example of a preoperative risk factor scoring
system. (continued)
SCIENTIFIC PRINCIPLES
80
Risk
Level
Prophylaxis Regimen
0-1
< 10%
Low Risk
No specific measures;
early ambulation
10-20%
Moderate Risk
3-4
20-40%
High Risk
5 or more
40-80%
1-5%
mortality
Highest Risk
Pharmacological: LDUH,
LMWH*, Warfarin*
or FXa I* alone or in
combination with IPC
Legend
IPC Intermittent
Pneumatic Compression
LDUH Low Dose
Unfractionated Heparin
LMWH Low Molecular
Weight Heparin
FXa I Factor Xa Inhibitor
Date:
B
FIGURE 5.10. (Continued)
be prevented by initiating warfarin therapy under the protection of systemic heparin anticoagulation or a direct thrombin
inhibitor.
81
is a connection between fibrinolysis and VTE.123,128,129 Additionally, PAI-1 is upregulated by thrombin, endotoxin, and IL1, explaining the elevated circulating levels of PAI-1 during
infections.130 Lipoprotein(a), associated with LDL, has both
atherogenic and prothrombotic properties.131133 It prevents
plasminogen from binding to cells or fibrin and inhibits fibrinolysis.134 Elevated levels of lipoprotein(a) have been associated with VTE in childhood; it is a weak thrombotic risk
factor in adults.135
When an individual with thrombosis presents with one of
the previously mentioned abnormalities, standard anticoagulation is necessary.136,137
Elevated Procoagulant
Factors: VIII, IX, and XI
Elevated prothrombotic factors have only recently been associated with primary and recurrent VTE.83,139 A dose-response
effect has been observed, and elevated factor VIII has been best
studied.139141 Factor VIII:C above the 90th percentile is associated with a five times increased risk of VTE.141,142 Factor
VIII:C elevation is also affected by blood type and race. Elevation of factor XI above the 90th percentile is associated with a
twofold increase in VTE, independent of other hypercoagulability factors.143 Similar increases in VTE risk have been
observed with elevated factor IX.144 Acquired and environmental factors precipitate VTE in patients with elevation of
these factors, as opposed to inherited deficiencies of AT, protein C, and protein S that confer higher VTE risk.145
The diagnosis is made by the direct measurement of these
factors with activity assays. If VTE occurs with one of these
factors elevated, standard anticoagulant management should
be undertaken.137
SCIENTIFIC PRINCIPLES
Chapter 5: Hemostasis
82
BLEEDING DISORDERS
Although the surgeon deals more often with procoagulant
states than bleeding disorders, it is important to recognize
these disorders when they occur.
Platelet Disorders
Platelet disorders are another important cause of bleeding.
Inherited defects of platelet receptors include defects of
GpIIb/IIIa (Glanzmann thrombasthenia), characterized by
impaired platelet binding to vWF, fibrinogen, and fibronectin.
In patients with defects in GpIb (Bernard-Soulier syndrome),
the absolute number of platelets is decreased, the platelets are
larger, and platelet aggregation and adhesion are abnormal.3
Acquired deficits occur in uremia; both GpIb and GpIIb/IIIa
receptors are defective, resulting in impaired adhesion and
aggregation. Acquired deficits also occur in patients who previously received platelet transfusions and then acquire immunemediated antiplatelet antibodies.
Abnormalities in Fibrinolysis
Abnormalities in fibrinolysis may play a role in abnormal
bleeding disorders. Genetic or acquired deficiencies in 2-AP
may be associated with bleeding, whereas deficiencies in factor
XIII (fibrin stabilizing factor) may lead to highly lysable clot.
2-AP deficiency is treated with e-aminocaproic acid or
tranexamic acid. Homozygous patients with factor XIII deficiency and less than 1% of normal plasma activity often show
bleeding from the umbilical cord at birth, bleeding after
trauma or surgery, and delayed bleeding 24 to 36 hours later.3
Intracranial bleeding also has been noted. Screening test
results include a shortened euglobulin lysis time.3 A specific
assay for factor XIII activity exists. Treatment consists of fresh
frozen plasma, cryoprecipitate, and factor XIII concentrates.
PHARMACOLOGIC AND
NONPHARMACOLOGIC
INTERVENTIONS
Heparin, Factor Xa, and
Direct Thrombin Inhibitors
4
Heparin, discovered by Jay McLean in 1916, is a heterogeneous mixture of sulfated polysaccharide molecules of varying
molecular weights, ranging from 2 to 40 kD. Heparin is
obtained from beef lung or porcine intestine. Heparin accelerates the inhibition of thrombin and other serine proteases by
AT. Heparin also directly binds and inhibits coagulation proteases and is important for the selective inhibitor of thrombin,
heparin cofactor II.154 After bolus injection, heparins half-life
is approximately 90 to 120 minutes, although the half-life
depends on the amount injectedthe more injected, the longer
the half-life. Activated factor X and activated factor II are
most sensitive to the heparinAT complex. Heparin is cleared
through the reticuloendothelial system and does not cross the
placental barrier. Heparin is reversed with protamine sulfate
by direct irreversible binding between the compounds.
Clinical use of heparin is for prophylaxis of, and treatment
of, venous and arterial thrombosis.155 In monitoring heparin,
an aPTT 1.5 to 2.0 times control or a TCT two times control
reflects adequate anticoagulation. Activated clotting times
(ACTs) in a range of 150 to 200 seconds also suggest adequate
anticoagulation. The use of low-dose unfractionated heparin
(UFH) therapy is most commonly used for VTE prophylaxis.63
Because of the bleeding complications caused by UFH,
LMWH for venous thrombosis prophylaxis and treatment is
83
now primary.63 Standard heparin is a mixture of polysaccharide molecules that vary in size from 2 to 40 kD. The anticoagulant effect is primarily centered over the lower end of the
molecular-weight spectrum. Standard UFH is able to inhibit
thrombin because it is large enough to make a ternary complex
between itself, thrombin, and AT. LMWH is not large enough
to make this complex because the minimum chain length necessary for formation of such a ternary complex is 18 saccharide units. LMWH demonstrates less AT activity, but for inhibition of factor Xa, such a ternary complex is not necessary.
Thus, LMWH preparations are able to inhibit factor Xa. Each
LMWH preparation has its own antifactor Xatoantifactor
IIa (thrombin) ratio, depending on its size and molecular
weight.157 Most commercially available LMWH preparations
have ratios between 4:1 and 2:1. Because the bleeding potential of heparin is related largely to its AT activity, LMWH has
a lower bleeding potential. In addition, LMWH preparations
have less antiplatelet activity and less risk for heparin-induced
thrombocytopenia (HIT).
The LMWH preparations have other advantages over standard UFH. These include an improved pharmacokinetic profile due to reduced nonspecific binding to plasma proteins, less
lipolysis, a half-life that is not dose dependent, more constant
antifactor Xa inhibition, less interference with protein C activation, less complement activation and interference with
appropriate platelet aggregation, less risk for osteoporosis,
and a lower level of fibrin monomer production.156 High and
sustained plasma antifactor Xa levels exist for greater than
16 hours after LMWH administration in therapeutic doses,
and its excretion is primarily renal. There is no available agent
effective for complete LMWH reversal as measured by antifactor Xa levels,157 although clinically the bleeding potential of
LMWH can be reversed by protamine sulfate.
LMWH is the primary therapy for VTE. A number of level
1 evidence studies and meta-analyses have compared LMWH
with UFH in the treatment of VTE.158,159 Together, these studies demonstrate a lower risk of major bleeding, a lower risk of
recurrent thromboembolic events, and a lower risk of death
than with UFH. Even for nonmassive pulmonary embolism
(PE), LMWH appears at least equivalent if not superior to
UFH, but much more convenient.160 It is not necessary to
monitor LMWH with coagulation testing except in specific situations such as renal failure, pregnancy, or morbid obesity,
and most dosage schemes use either fixed-dose or weightadjusted dosing given subcutaneously. Because there is no need
for coagulation testing, outpatient treatment has become a
reality.
LMWH has also been studied in unstable angina156 and has
been found superior to placebo and equivalent or superior to
UFH when evaluating the outcomes of death or myocardial
infarction, without any increase in major bleeding.
The most common complication of heparin therapy is
bleeding. The risk of hemorrhage is increased in the elderly; in
postmenopausal women; and in patients with preexisting
abnormalities of coagulation, thrombocytopenia, and uremia.
Long-term therapy may be associated with alopecia and osteoporosis; osteoporosis has been found in patients receiving
large doses of heparin for longer than 6 months.
Reversal of heparin anticoagulation with protamine sulfate
may be associated with adverse hemodynamic and hematologic side effects, including hypotension, bradycardia, pulmonary artery hypertension or hypotension, declines in oxygen consumption, leukopenia, and thrombocytopenia.161,162
Immunologic reactions may occur in patients with prior exposure to protamine, especially in diabetic patients taking NPH
insulin that contains protamine or those previously exposed to
protamine. Unfortunately, no other effective and safe agent for
heparin neutralization exists, and in those situations when
heparin must be reversed, such as at the completion of major
aortic reconstructions and cardiopulmonary bypass, protamine must be given. Although it has been suggested that the
SCIENTIFIC PRINCIPLES
Chapter 5: Hemostasis
84
rate of administration is the most crucial factor in protaminerelated reactions, declines in hemodynamic parameters and
oxygen consumption still occur with slow administration.162
The specific factor Xa inhibitor pentasaccharide fondaparinux (Arixtra, GlaxoSmithKline, Parsippany, NJ) potentiates approximately 300-fold factor Xa neutralization by AT. It
has a half-life of 17 hours and does not bind to plasma proteins. It is primarily excreted through the kidneys. Large
prospective randomized studies for both DVT and PE treatment have been conducted suggesting efficacy and safety similar to LMWH.163 In orthopedic surgery, this agent is superior
to the best currently available DVT prophylaxis using LMWH.
In fact, in hip fracture and knee reconstruction surgery, this
agent has decreased the incidence of DVT by greater than 50%.
In a meta-analysis of more than 7,000 patients, fondaparinux
significantly decreased the odds of VTE as compared to
LMWH with no difference in critical bleeding, although major
bleeding was slightly greater.164166 There is no good reversal
drug for this agent, and this has been one of the factors that
has prevented its wider adoption into the medical and surgical
communities.
Oral Xa inhibitors are currently being developed. Rivaroxaban (BAY 59-7939), one such inhibitor, showed promising
results in phase 2 trials when compared to enoxaparin for the
prevention of VTE in those undergoing major orthopedic
surgery.167 Trials are currently under way in additional treatment applications.
Direct thrombin inhibitors have been developed for both
oral and parental use, particularly in HIT. Unlike heparin, the
direct thrombin inhibitors have the ability to inactivate fibrinbound thrombin.168 Direct thrombin inhibitors such as argatroban and lepirudin (hirudin analogue) have also been shown
to be effective anticoagulants in patients with HIT and are
dosed via the aPTT.169 Argatroban has a relatively short halflife, is cleared by the liver, and is safe to use in those with renal
insufficiency. Conversely, lepirudin is cleared renally, has a
slightly longer half-life, and is the preferred anticoagulant in
patients with hepatic insufficiency. A third parental thrombin
inhibitor, bivalirudin is used in patients with unstable angina
who are undergoing percutaneous cardiac intervention and
cardiac surgery.
Although early trials with ximelagatran, a direct oral thrombin inhibitor, were not successful owing to the hepatic toxicity,
a new agent in the same family, dabigatran, has promising data
supporting its efficacy and safety. Results of a large phase 2 trial
comparing dabigatran to enoxaparin for VTE prevention in
those undergoing hip replacement demonstrated noninferiority
to enoxaparin.170
Other new alternative agents are in various stages of development, such as oral heparins, oral factor IIa and Xa
inhibitors, P-selectin inhibitors, factor VIIa inhibitors, TFPIs,
and PAI-1 inhibitors.170 These agents, available now and in the
future, will likely revolutionize the whole field of thrombosis
prophylaxis and treatment.
Heparin-induced Thrombocytopenia
and Thrombosis Syndrome
6
A specific complication of heparin deserves detailed discussion. HIT occurs in 0.6% to 30% of patients in whom heparin
is given, although severe thrombocytopenia associated with
thrombosis (HITTS) occurs much less frequently.171,172
Approximately one half of HIT patients have thrombosis that
is noted clinically or by duplex imaging. In an analysis of 11
prospective studies, the incidence was reported to be 3%, with
thrombosis in 0.9%.173 Although earlier morbidity and mortality rates of 61% and 23% had been reported,70 with early
diagnosis and appropriate treatment, these rates have declined
to 6% and 0%, respectively.174 HIT is caused by a heparindependent IgG antibody that, when bound to platelet factor 4
(PF4), induces platelet aggregation in part by inducing MP formation.175,176 The antibody may not be heparin specific, as the
degree of sulfonation of the heparinlike compound has been
suggested to be critical for this aggregation.177 Both porcine
and bovine UFH as well as LMWH have been associated with
HIT.178 The syndrome usually begins 3 to 14 days after
heparin is begun. Both arterial and venous thromboses have
been reported, and even small exposures to heparin (heparin
coating on catheters) can cause the syndrome.171,179
The diagnosis should be suspected when a patient experiences a 50% or greater decline in platelet count, when there is
a fall in platelet count below 100,000/mL during heparin therapy, or in any patient who experiences thrombosis during
heparin administration.180 The syndrome may be difficult to
diagnose as many hospitalized patients have multiple reasons
for low platelet counts, and vigilance is important. A platelet
count should be checked about every 2 days when on heparin
therapy.
The laboratory diagnosis of HIT/HITTS is made by a number of assays. The serotonin release assay (SRA) was the gold
standard. An enzyme-linked immunosorbent assay (ELISA)
test detecting the antiheparin antibody in the patients plasma
directed against the heparinPF4 complex is now commonly
used.171 This assay is less specific but easier to perform and
interpret than the serotonin assay.
When the diagnosis is made (clinically), cessation of
heparin is mandatory. This includes removing heparin from
intravenous catheters and flushes.179 Warfarin should not be
administered until an adequate alternative anticoagulant has
been started to prevent venous limb gangrene development.181
LMWH preparations have high rates of cross-reactivity with
the HIT antibody and therefore should not be merely substituted for UFH in patients with HIT.182
A number of anticoagulants are now available to substitute
for patients with this diagnosis. The direct thrombin inhibitors
hirudin (lepirudin/Refludan) and argatroban are the treatments of choice and are U.S. Food and Drug Administration
approved for this indication.180,183 These agents show no
cross-reactivity to heparin antibodies.
Warfarin
Warfarin oral anticoagulant therapy remains the standard for
long-term treatment of arterial and venous thromboembolism.
Warfarin interferes with the vitamin Kdependent clotting factors II, VII, IX, and X and proteins C and S. In the liver, these
factors are -carboxylated in a reaction catalyzed by the
reduced form of vitamin K. During this reaction, 10 to 12 glutamic acid residues are converted to -carboxyglutamic acid
residues. When these factors are released from the liver, they
are secreted as active proteins.3 The carboxyglutamic acid
residues are responsible for these proteins binding to phospholipid membranes and the formation of the Xase and prothrombinase complexes on activated platelet surfaces. Warfarin prevents the reduction of vitamin K once it has functioned as a
cofactor for the -carboxylation.
Because of variations in the thromboplastins used for the
prothrombin time (PT) determinations in various countries, the
international normalized ratio (INR) system, in which the sensitivity of thromboplastins has been standardized, was developed.184 Using this system, the proper range for treatment of
most thrombotic diseases by warfarin is an INR of 2 to 3.
Major complications of warfarin therapy include bleeding,
recurrent thrombosis, and skin necrosis. Patients at highest
risk for bleeding on warfarin include the elderly, patients with
gynecologic or urologic disorders, women after childbirth, and
patients given large warfarin loading doses. A specific complication of warfarin is skin necrosis, which occurs more
frequently in patients with protein C deficiency. This usually
involves full-thickness skin sloughing over fatty areas such as
Chapter 5: Hemostasis
Antiplatelet Agents
Antiplatelet agents are used to prevent cardiovascular events
such as coronary and peripheral arterial thrombosis. Platelet
aggregation can be inhibited by several mechanisms, including
(a) blocking cyclooxygenase, the first step in converting arachidonic acid to thromboxane and prostacyclin; (b) blocking
thromboxane synthase, the enzyme leading to thromboxane
A2; (c) blocking the thromboxane A2 receptor; (d) increasing
intraplatelet levels of cyclic adenosine monophosphate (cAMP)
or guanosine monophosphate (GMP), which inhibit the exposure of the platelet GpIIb/IIIa receptor; and (e) directly blocking
the platelet receptor GpIIb/IIIa.
Aspirin inhibits cyclooxygenase, and thus both thromboxane and prostacyclin. In clinical situations, the use of lower
doses of aspirin in an attempt to inhibit thromboxane generation but preserve prostacyclin generation is theoretical, and
may have some efficacy. Dipyridamole (Persantine; Boehringer
Ingelheim, Ridgefield, CT), inhibits the uptake of adenosine
into platelets, endothelial cells, and red blood cells. This leads
to increased platelet cAMP levels through a local increase in
adenosine concentration, inhibiting platelet aggregation.
Additionally, it also inhibits phosphodiesterase, the enzyme
that normally degrades cAMP, leading to higher levels of
cAMP, and augments the increase in cGMP produced by nitric
oxide. Thienopyridines work by ADP receptor blockade, interfering with subsequent GIIb/IIIc fibrinogen binding.187 In addition, monoclonal antibodies to GpIIb/IIIa itself or synthetic
peptide blockers of this receptor containing the RGD sequence
or the fibrinogen -chain carboxyl-terminal sequence directly
inhibit the function of this receptor. Receptor blockage is the
most specific way to inhibit aggregation, and when the GpIIb/
IIIa receptor is blocked, even high concentrations of agonists
cannot stimulate platelets.
Because of ticlopidine-associated neutropenia, an analogue
of ticlopidine, clopidogrel, was developed. This thienopyridine
compound is not associated with the same degree of neutropenia and has been shown to reduce the composite endpoints of
stroke, myocardial infarction, and death in patients with vascular disease.2 It is mandatory treatment for patients in whom
a drug-eluting stent has been placed in the coronary arterial
circulation and is used for periprocedural protection in those
patients undergoing peripheral angioplasty and stenting.
Direct inhibitors of the GpIIb/IIIa receptor were first developed as murine-derived monoclonal antibodies. The compound C7E3Fab (ReoPro; Eli Lilly, Indianapolis, IN), a human
chimeric monoclonal antibody directed at GpIIb/IIIa, is the
first agent of this class to become clinically available.2 Its receptor binding is nonspecific and it binds to other cell surface integrins. Other agents include RGD mimics that are competitive
antagonists to the GpIIb/IIIa receptor, including the cyclic peptide eptifibatide (Integrilin; Key Pharmaceutical, Kenilworth,
NJ) and the parenteral nonpeptide mimetics tirofiban
(Aggrastet; Merck & Co., West Point, PA) and lamifiban.188 All
studies to date with these agents have involved coronary interventions.
Fibrinolytic Agents
Fibrinolytic agents are direct or indirect activators of plasminogen, the inactive proteolytic enzyme of plasma that binds to fibrin during the formation of thrombus. Fibrin-bound plasminogen is more susceptible to activation than is free plasminogen in
plasma. Streptokinase isolated from group C -hemolytic streptococci and acylated plasminogenstreptokinase (APSAC) act
through a streptokinaseplasminogen complex; urokinase,
single-chain urokinase-type plasminogen activator (SCU-PA),
and recombinant tPA act directly on plasminogen without an
intermediate drugplasminogen complex189 (Fig. 5.11). tPA
(originally isolated from a melanoma cell line and now produced through recombinant DNA technology), APSAC, and
SCU-PA are termed fibrin selective because of their high ratio
of activity for fibrin-bound plasminogen compared with circulating plasminogen. For therapeutic uses, tPA or recombinant
plasminogen activator (rPA) is primarily used, and the others
are of historical significance only. tPA has a fibrin-binding site
and a catalytic site that are widely separated from each other.
This separation allows tPA to be activated to its fibrin target,
thus establishing its fibrin-specific nature. Evidence-based recommendations for agent and indications are continually
updated.190,191
Bleeding complications associated with fibrinolytic agents
are related to the invasive procedures associated with drug
delivery. Factors associated include hypofibrinogenemia and
fibrin degradation products. The latter inhibit fibrin polymerization and, in combination with a decrease in the clotting factors V and VIII (from excess plasmin not neutralized by 2AP), inhibit the ability of blood to clot. Although coagulation
tests in general do not correlate well with bleeding, a fibrinogen level less than 100 mg/dL is associated with an increased
risk and severity of bleeding.
Platelets are both inhibited and stimulated by fibrinolytic
agents. Because fibrinogen is a necessary cofactor for ADPinduced platelet aggregation, low fibrinogen levels aggravate a
platelet defect. At the same time, plasminogen bound to
platelets leads to impaired adhesion and a decrease in their ability to aggregate. Plasmin-induced cleavage of adhesive proteins,
such as thrombospondin, fibronectin, and fibrin, also disrupts
the bonds that hold platelet aggregates together.
Despite these mechanisms that decrease the clotting ability
of blood during fibrinolytic therapy, it has been found that
these agents promote reocclusion in up to 30% of cases early
after thrombolysis through platelet activation, suggesting that
platelet activation occurs early after lysis and platelet inhibition occurs later.1 In addition, increased synthesis of endothelial cell PAI-1 has been demonstrated experimentally after
treatment with tPA, another mechanism that could potentially
contribute to early thrombotic reocclusion if the patients are
not heparinized.192
Thrombolytic therapy for peripheral arterial applications is
commonly used, especially when the agents are given via
catheter infusion, and is a standard treatment for acute limb
ischemia and peripheral bypass graft occlusion.193 Several
studies suggest its efficacy and safety for acute limb ischemia
as comparable to surgery.194,195 After thrombolytic therapy has
reopened an occluded vessel or graft, however, radiologic or
surgical correction of the lesion responsible for the thrombosis
SCIENTIFIC PRINCIPLES
the breasts and buttocks but can also occur in other anatomic
distributions such as the extremities and digits.
Warfarin should be continued for at least 3 months after
an initial episode of DVT or arterial thromboembolism.
Detailed guidelines for level of anticoagulation and duration
are updated every 3 to 5 years.63 Currently, 3 months of anticoagulant treatment is indicated for a provoked VTE event,
while consideration of bleeding and thrombosis risk needs to
be determined and a longer duration used if an unprovoked
event occurred. Male gender, antiphospholipid syndrome,
prior DVT, and thrombophilias all increase the risk of recurrence and support prolonged anticoagulation. Conversely,
Asian race and a normal D-dimer at 1 month after ceasing
anticoagulation support limited anticoagulation. Data that
support prolonged therapy for unprovoked DVT include a
recent multicenter trial comparing low-dose warfarin (INR
1.5 to 2.0) to placebo with 4-year follow-up.185 Another study
suggested that full-dose warfarin (INR 2.0 to 3.0) was superior to low-dose warfarin in these same patients without a difference in bleeding, suggesting that unprovoked DVT requires
long-term oral anticoagulation of some still-to-be-defined
duration.186
85
86
FIGURE 5.11. Sites of action of plasminogen activators on plasminogen. APSAC, acylated plasminogenstreptokinase; Plgn,
plasminogen; SCU-PA, single-chain urokinase plasminogen activator; SK, streptokinase; TPA, tissue plasminogen activator;
UK, urokinase.
must be addressed for long-term success.196 The use of intraoperative thrombolytic therapy has been advocated for situations in which complete clot evacuation cannot be accomplished (as may occur in up to 40% of patients undergoing
balloon embolectomy with an embolectomy catheter for acute
arterial occlusion) or when the distal vasculature is occluded
and precludes appropriate inflow patency.197
Complications associated with thrombolytic therapy for
arterial thrombosis include bleeding, rethrombosis, embolization treated with further thrombolytic therapy, and sepsis
from prolonged catheter placement. The most recent innovation in intra-arterial thrombolytic therapy involves lacing the
entire length of the thrombus with high-dose tPA before continuous infusion and then using pulse-spray techniques, sometimes in conjunction with mechanical dissolution.198
Indications for DVT and PE thrombolytic therapy remain
controversial.197 Thirteen studies of thrombolytic therapy for
acute DVT have been compiled from the literature.199 In these
studies, patients were assessed with venography. Of those
patients treated with anticoagulants, only 4% had complete
lysis and 14% revealed partial lysis. In contrast, 45% of
patients treated with thrombolytic agents showed significant or
complete clot lysis and an additional 18% revealed partial lysis.
Importantly, catheter-directed thrombolysis for iliofemoral
DVT is associated with significantly improved quality of life
over time.200 Thrombolytic therapy in PE has been extensively
studied. Early studies evaluated the use of either urokinase or
streptokinase. Although both agents rapidly lysed clot and
improved pulmonary hemodynamics, there was no difference in
patient mortality rate or recurrence rate of PE compared with
heparin alone.201,202 As a general guide, thrombolytic therapy
for PE should be considered when there is angiographically documented lobar or greater PE causing acute pulmonary hypertension and right ventricular failure with hemodynamic compromise; lesser degrees of PE should be treated with standard
heparin or LMWH anticoagulation.63,203 Fibrinolytic therapy
may also have a role and has been suggested for use in upper
extremity effort thrombosis, catheter-induced venous thrombosis, and superior vena caval thrombosis. Contraindications to
thrombolytic therapy, whether regional or systemic, are well
defined (Table 5.4).
TA B L E 5 . 4 INDICATIONS/CONTRAINDICATIONS
CONTRAINDICATIONS TO THROMBOLYTIC THERAPY
ABSOLUTE
Neurosurgery within 3 mo
Active internal bleeding
Recent (2 mo) cerebrovascular accident
Intracranial disease
Recent gastrointestinal bleeding
RELATIVE
Major
Recent (10 d) major surgery, obstetric delivery, or
organ biopsy
Left heart thrombus
Active peptic ulcer or gastrointestinal abnormality
Recent major trauma
Uncontrolled hypertension (systolic 180 mm Hg;
diastolic 110 mm Hg)
Recent eye surgery
Minor
Minor surgery or trauma
Recent cardiopulmonary resuscitation
Atrial fibrillation with mitral valve disease
Bacterial endocarditis
Hemostatic defects (i.e., renal or liver disease)
Diabetic hemorrhagic retinopathy
Pregnancy
CONTRAINDICATIONS TO STREPTOKINASE
Known allergy
Recent streptococcal infection
Previous therapy within 6 mo
Table adapted from TASC II. J Vasc Surg. 2007;45:S45.
Dextran
Dextran is a high-molecular-weight polysaccharide produced
from sucrose by Leuconostoc mesenteroides. Fractionation and
hydrolysis produce a product with an average molecular
weight of either 40 kD (dextran-40 [Rheomacrodex; Medisan,
Parsippany, NJ]) or 70 kD (dextran-70). Dextran-40 has been
studied in detail for its ability to augment patency of difficult
lower extremity bypass grafts in the early postoperative period.
Dextran-40 acts as a volume expander, causing hemodilution,
decreasing blood viscosity, decreasing platelet adhesiveness,
reducing factor VIII activity, and increasing the lysability of
clots.204 In addition, dextran has been found to coat endothelial
cell surfaces, decreasing their electronegativity.
LABORATORY MONITORING
OF COAGULATION AND
ANTICOAGULATION
Tests of Platelet Function
Platelet tests include peripheral platelet counts, bleeding times,
and platelet aggregation. Usually, a platelet count of
50,000/mL or more ensures adequate hemostasis, whereas
counts less than 10,000/mL are dangerous and may lead to
spontaneous bleeding. Thrombocytosis is considered to exist
when the platelet count exceeds 500,000/mL, although in
some cases (especially those involving myeloproliferative disorders or following splenectomy), counts may be greater than
1,000,000/mL.3 Bleeding time assays assess the ability of
platelets to form hemostatic plugs and are usually shorter than
8 minutes. A bleeding time between 8 and 15 minutes most
often reflects a low plasma level of vWF, the use of antiplatelet
drugs, the presence of lupuslike antibodies, or a factor XI deficiency.3 A bleeding time greater than 15 minutes is clearly prolonged and indicates severe platelet functional impairment,
very low levels of vWF, or a fibrinogenemia and severe factor
V deficiency. Many of the platelet functions are best assessed
with the platelet function analyzer (PFA-100; Dade Behring,
Germany), available in most hospitals.205
Coagulation Tests
Coagulation tests include PT (intrinsic and extrinsic pathways
and fibrinogen), aPTT (contact and intrinsic pathway), TCT
(fibrinogen conversion to fibrin), and ACT (whole blood and
platelets). The only abnormality that causes an isolated elevation in PT with all of the other test results normal is factor VII
deficiency. In addition, the PT is sensitive to small decreases in
factor V levels. The aPTT identifies abnormalities of the contact and intrinsic phases of coagulation. Conditions that cause
a prolonged aPTT include the presence of heparin; deficiencies
in factors VIII, IX, and XII; and the presence of lupuslike anticoagulants.3 aPTT values have variably been shown to correlate with heparin dosages and serum heparin levels, and levels
of 0.2 IU/mL or greater usually correlate with an aPTT of
1.5 times normal or greater.
The TCT is a measurement of the time it takes for exogenously added thrombin to turn plasma fibrinogen into fibrin
clot. As such, it is extremely sensitive to levels of heparin and is
an excellent means of measuring the level of heparin-induced
anticoagulation. The beauty of the TCT is that it is not specific
for any disease condition; thus, it may be used to differentiate
factor deficiencies from the presence of heparin or to separate
lupus anticoagulant from abnormalities in fibrinogen levels.3
The ACT is a measurement of the ability of whole blood to
clot and as such is an available technique for monitoring
87
Tests of Fibrinolysis
Tests of fibrinolysis are less well characterized. The euglobulin
lysis test time is a crude screening test for problems with fibrinolysis.3 Patients with accelerated fibrinolysis are often found
to have a deficiency of 2-AP (of which the total amount normally is only half of the total plasmin that can be generated) or
the fibrin clot-stabilizing factor XIII.3 A deficiency of PAI-1
also may lead to accelerated fibrinolysis. During normal clot
formation and breakdown, the D-dimer fragment of fibrinogen is a marker for ongoing thrombosis and physiologic fibrinolysis, whereas for fibrinogenolysis, the two D fragments that
are produced are not cross-linked into the D-dimer form.3
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173. Cancio LC, Cohen DJ. Heparin-induced thrombocytopenia and thrombosis. J Am Coll Surg 1998;186(1):7691.
174. Almeida JI, Coats R, Liem TK, et al. Reduced morbidity and mortality
rates of the heparin-induced thrombocytopenia syndrome. J Vasc Surg 1998;
27(2):309314; discussion 315316.
175. Kelton JG, Smith JW, Warkentin TE, et al. Immunoglobulin G from
patients with heparin-induced thrombocytopenia binds to a complex of
heparin and platelet factor 4. Blood 1994;83(11):32323239.
176. Walenga JM, Jeske WP, Messmore HL. Mechanisms of venous and arterial thrombosis in heparin-induced thrombocytopenia. J Thromb Thrombolysis 2000;10(suppl 1):1320.
177. Greinacher A, Michels I, Mueller-Eckhardt C. Heparin-associated thrombocytopenia: the antibody is not heparin specific. Thromb Haemost 1992;
67(5):545549.
CHAPTER 6 INFLAMMATION
K E Y
1
The concept of inflammation has undergone considerable revision since the initial description of the four cardinal signs and
symptoms by Celsus in the first century AD: rubor et tumor
cum calor et dolore, redness and swelling with heat and pain.1
Centuries lapsed before John Hunter postulated that inflammation provides a survival mechanism to preserve the host.
Ironically, he commented that an exuberant inflammatory
response could be deleterious; the pathologic sequelae of excessive inflammation (i.e., acute respiratory distress syndrome
[ARDS], multiple organ dysfunction syndrome [MODS]) are
encountered more frequently as technology affords survival of
the initial insult.1 The 19th century witnessed milestone contributions to our understanding of this process. Rudolph Virchow detailed the cellular pathology of inflammation, Julius
Cohnheim provided microscopic details of the acute phases of
inflammation (vasodilatation, edema formation, and leukocyte
emigration), and Elie Metchnikoff described the events of
phagocytosis.13 The evidence culminated into a cellular and
humoral concept of inflammation, both of which were deemed
critical in host defense against foreign pathogens.
In the 20th century, technologic advancements in molecular
biology and biochemistry facilitated more detailed investigation and enabled the rapid expansion of knowledge of the
many interwoven facets of the inflammation process. Evidence
P O I N T S
inflammation, in particular systemic cytokine concentrations, in reducing mortality. Yet only one, activated protein
C, has been approved by the U.S. Food and Drug Administration for use, and studies are ongoing to confirm its
benefit.
The complement system is integral to both innate and
adaptive immunity and has the capacity to independently
eliminate organisms and facilitate host defense by marking
foreign particles for phagocytosis through opsonization.
Additional systems, including the vascular (i.e., vasodilatation, adhesion receptors, kinin cascade) and neuroendocrine (i.e., adrenocorticotropic hormone, arginine vasopressin, corticotropin-releasing hormone), integrate with
the immune system, sharing similar mediators and their
receptors, to orchestrate an intense, coordinated response
to any injurious/septic insult.
Our immune system differentiates pathogens and damaged
cells from self using evolutionarily ancient sets of recognition
molecules called pattern recognition receptors, which bind
conserved molecular structures found in large groups of
pathogens, termed pathogen-associated molecular patterns
(PAMPs), an example being the Toll-like receptors (TLRs).
Danger-associated molecular patterns are the endogenous
equivalent of PAMPS, represent danger signals or alarmins,
and share many characteristics similar to cytokines. They
may be released following nonprogrammed cell death, such
as necrosis, or secreted as mediators by immune cells, under
which circumstance they may facilitate the inflammatory
response.
91
SCIENTIFIC PRINCIPLES
92
INNATE VERSUS
ADAPTIVE IMMUNITY
1
CELLULAR COMPONENTS
Neutrophils
Neutrophils are integral to both innate and humoral immunity, providing the initial defense against invading viral, bacterial, and parasitic pathogens. This importance is underscored
by the fact that 55% to 60% of the hematopoietic output of
bone marrow is dedicated to the production of neutrophils.5
On exiting the marrow they circulate for 7 to 10 hours before
taking up residence in the tissues for 1 to 2 days (Table 6.1).6,7
They are uniquely sensitive to minute concentration gradients
of microbial products and inflammatory mediators and
rapidly accumulate at sites of infection, where they ingest and
dispose of a wide array of pathogens with their vast microbicidal armamentarium. This pathogenicity, however, carries with
it an implicit capacity for host injury and, accordingly, neutrophil function must be tightly regulated.
TA B L E 6 . 1
LEUKOCYTE SUBSETS
CELL
NEUTROPHIL
MONOCYTE
LYMPHOCYTE
EOSINOPHIL
BASOPHIL
Size (m)
13
1620
916
1216
15
Differential (%)
4075
26
2045
16
1
Life span
6 h to 7 d
1 d to years
Months to years
8 to 12 d
1 year
Activators
G-CSF, IL-8
M-CSF, GM-CSF,
IFN-, TNF-
G-CSF, IL-5
G-CSF, IL-3
G-CSF, granulocyte colony-stimulating factor; IL, interleukin, M-CSF, macrophage colony-stimulating factor; TH, helper T cell; TNF, tumor necrosis
factor.
Modified from Burkitt G, Young B, Heath JW, eds. Wheaters Functional Histology: A Text and Colour Atlas, 3rd ed. Edinburgh, New York: Churchill
Livingstone; 1993.
Chapter 6: Inflammation
1
Integrin
Tight adhesion
41
L2
M2
High-affinity
integrin
Selectin
Integrin
ligand
Emigration
PECAM-1
41
L2
M2
4
Ig-family
E-selectin
P-selectin
1 ICAM-1,2
VCAM-1
Cytokines
PECAM-1
Ig-family
ICAM-1
VCAM-1
Chemokines
Macrophage
engulfing pathogen
FIGURE 6.1. Leukocyte recruitment. 1. Circulating leukocytes express integrins in a low-affinity conformation. 2. Exposure to activated endothelium leads to rolling, which is mediated by L-selectin and
P-selectin on the neutrophil and E-selectin on endothelium. 3. Leukocyte exposure to cytokines released
by macrophages phagocytosing pathogens induces a high-affinity integrin conformation integrins. Tight
leukocyteendothelial adhesion involves integrin engagement with counterligand expressed on the
endothelium. 4. Subsequent exposure to chemokines leads to diapedesis, which is further mediated by the
family of 1 and 2 integrins. (Redrawn from Abbas AK, Lichtman AH. Cellular and Molecular
Immunology. Philadelphia: Saunders; 2003.)
phagocytosis. Mac-1 also binds fibrinogen, heparin, and factor X and is implicated in neutrophil phagocytosis-induced
apoptosis, a process essential for resolution of the inflammatory process (vide infra). The very late antigen 4 (VLA-4) binds
vascular cellular adhesion molecule 1 (VCAM-1) and may
provide an additional mechanism for tight adhesion. In addition to providing mechanical anchorage, these receptors interact with the cytoskeleton and other structural proteins and signaling cascades and are thought to represent a biochemical
link between the external environment and intracellular signal
transduction cascades that induce a cellular phenotype more
appropriate for the current environment (Box A. Integrin signaling).1315
Once tightly adhered, neutrophils must diapedese between
endothelial cells and across the basement membrane to arrive
at the focus of inflammation. Platelet/endothelial cell adhesion
molecule 1 (PECAM-1) and integrin-associated protein are
integral to transmigration (Fig. 6.1).13,14,16,17 PECAM-1 is concentrated along the intercellular junctions of endothelial cells,
and both leukocyte and endothelial PECAM-1 appear to be
essential for neutrophil and monocyte diapedesis. Other candidate receptors include the 1 integrins, or VLAs, which possess affinity for many constituents of the extracellular matrix,
including laminin, fibronectin, and collagens, and the 3 family of integrins including glycoprotein (Gp) II/III and the vitronectin receptor.4 Further directions for migration to the
focus of inflammation are delivered by the concentration
gradients of chemotactic factors, including complement C5a,
IL-8, leukotriene B4 (LTB4), and the bacterial product formylmethionyl-leucyl-phenylalanine (fMLP).1820
The clinical significance of even minor derangements in any
aspect of this process is evident in the disease leukocyte adhesion deficiency, characterized by complete absence of CD18,
and therefore all 2 integrins. Patients usually succumb to
recurrent skin and mucosal infections within the initial
10 years of life.4
SCIENTIFIC PRINCIPLES
Selectin
Rolling
L-selectin
PSGL-1
ESL-1
93
94
BOX A
pathway that utilizes toxic proteinases.25 These two components are compartmentalized into four distinct granules or
vesicles that also contain adhesion molecules and important
inflammatory mediators (Table 6.2).26 They are mobilized in a
hierarchical fashion in response to gradual elevations in the
intracellular calcium level, which parallels their respective contents and the current needs of the cell.27
Primary, or azurophil (affinity for the dye azure A), granules
target the destruction of phagocytosed organisms (Table 6.2).
The myeloperoxidase (MPO) within these granules generates
hypochlorous acid from products generated by nicotinamide
adenine dinucleotide phosphate (NADPH) oxidase and also
imparts the characteristic greenish color of pus.9,27 Other
Chapter 6: Inflammation
95
TA B L E 6 . 2
NEUTROPHIL GRANULES AND SECRETORY VESICLES
AZUROPHIL
GRANULES
SPECIFIC
GRANULES
GELATINASE
GRANULES
SECRETORY
VESICLES
Myeloperoxidase (MPO)
Lysozyme
Gelatinase
Plasma proteins
Lysozyme
Phospholipase A2
Lysozyme
Cathepsins
Gelatinase
2-Microglobulin
Elastase
Collagenase
Acetyltransferase
Proteinase 3
Lactoferrin
Azurocidin
TNF
BPI
2-Microglobulin
Defensins
Histaminase
iNOS
Heparinase
1-Antitrypsin
uPA
SCIENTIFIC PRINCIPLES
MEMBRANE
-Mannosidase
Sialidase
Acid mucopolysaccharide
-Glycerophosphatase
Elastase
CYTOSOL
CD63
CD68
Mac-1
Mac-1
Mac-1
SNAP proteins
SNAP proteins
SNAP proteins
CD15
Cytochrome b558
Cytochrome b558
CD66
fMLP R
CR1
CD67
CD14
Cytochrome b558
DAG-deacylating
enzyme
Fibronectin R
uPA R
fMLP R
CD45
Laminin R
uPA R
Vitronectin R
C1q R
Thrombospondin R
fMLP R
uPA R
BPI, bactericidal/permeability-increasing protein; CD, cluster of differentiation; CR1, complement
component C3b; DAG, diacylglycerol; fMLP, N-formylmethionyl-leucyl-phenylalanine; iNOS, inducible
nitric oxide synthase; R, receptor; TNF, tumor necrosis factor; uPA, urokinase-type plasminogen activator.
Modified from Faurschou M, Borregaard N. Neutrophil granules and secretory vesicles in inflammation.
Microbes Infect 2003;5:13171327.
96
TA B L E 6 . 3
MAJOR ROS AND THEIR METABOLISM
ROS MOLECULE
Superoxide (O2)
ENZYMATIC DEFENSE
SYSTEMS
MAIN SOURCES
PRODUCTS
Superoxide dismutase
H2O2 O2
Activated phagocytes
Superoxide reductase
H2O2
Xanthine oxidase
Flavoenzymes
Hydrogen peroxide (H2O2)
Glutathione peroxidase
H2O GSSG
NADPH oxidase
Catalase
H2O O2
Glucose oxidase
Peroxiredoxins
H2O
Glutathione/TrxR
GSNO
Xanthine oxidase
Hydroxyl radical (O2)
NADPH, nicotinamide adenine dinucleotide phosphate; ROS, reactive oxygen species; TrxR, thioredoxin.
Modifed from Nordberg J, Arner E. Reactive oxygen species, antioxidants, and the mammalian thioredoxin system. Free Radic Biol Med 2001;31:
12871312.
Oxidative Burst and Oxidant Metabolites. The generation of toxic oxygen metabolites or reactive oxygen species
(ROS) is the cardinal characteristic of the neutrophil, but may
also be produced by the monocyte/macrophage. Their essential
antimicrobial properties are equally destructive to host tissues
and implicated in the pathophysiology of many inflammatory
disorders (Table 6.3). Counterintuitive to their role in cell
destruction, recent evidence also supports a role of ROS in
intracellular signal transduction.32
A free radical is any species possessing one or more
unpaired electrons; the valence is irrelevant. They are categorized under the broader term ROS, which encompasses all molecules capable of radical formation. Despite a very brief existence (1011 to 106 seconds), extensive damage may occur
through the induction of free radical chain reactions. Species
operant during both physiologic and pathophysiologic inflammation include the following: the superoxide anion (O2), the
hydroxyl radical (OH), hydrogen peroxide (H2O2), and singlet
oxygen, as well as the reactive nitrogen intermediates nitric
oxide (NO) and peroxynitrite (ONOO) (Table 6.3). In addition to their antimicrobial properties, ROS may modulate the
immune response by activating inflammatory cells and inducing proinflammatory cytokine secretion.33,34
2
Implicit with the capacity for pathogen elimination, however, is the potential for destruction of host tissues. Hence,
numerous regulatory mechanisms provide temporal and spatial control of the ROS production. The NADPH oxidase complex itself exists in a disassembled state, and only upon cell
activation and the need for ROS production are the subunits
approximated and enzymatic function restored.35 In addition,
high plasma and tissue concentrations of proteinase inhibitors
provide continuous surveillance and systemic control. However, such regulation is incomplete as evidenced by such diseases as rheumatoid arthritis, chronic obstructive pulmonary
disease, and autoimmune vasculitis, which are the consequence of damage due to neutrophil-derived products.35
NADPH oxidase is a heteromeric complex composed of six
subunits: flavocytochrome b558, the electron transporting
apparatus, which is subdivided into Gp91(phox) and
p22(phox); the cytosolic complex p40(phox), p47(phox), and
p67(phox); and the oxidase factor rac-2 (Fig. 6.2).35 Microorganisms or high concentrations of chemoattractants bind to
cell surface receptors and initiate oxidase activation, heralded
by phosphorylation of p47(phox). Cytochrome b558 (Gp91
and p22), which exists within the plasmalemma and the
2O2
Gp91
rac-2
P22
Gp91
P67
P47
+
+
NADP + H
P40
rac-2
Rho GDI
P22
2O2 + NADPH
P
P47
P67
P40
Rho GDI
rac-2
P67
P47
P40
Other mechanisms of superoxide production include uncoupling of the xanthine dehydrogenase system, uncoupling of
mitochondrial and endoplasmic reticulum electron transport
chains, and nonenzymatic reactions such as autooxidation of
hemoglobin.37,38
Superoxide is relatively weak and of low bactericidal potency.
However, its membrane permeability and role as a reactant in
reactions yielding highly toxic products confers upon it a high
potential for cellular and tissue damage.36
Superoxide can spontaneously or enzymatically (superoxide dismutase) dismutate into hydrogen peroxide35,36:
2H O2 H2O2 O2
It can also be converted to the more potent hydroxyl radical through the metal-catalyzed Haber-Weiss reaction35,36:
H2O2 O2 Fe3 O2 OH OH Fe2
or through the Fenton equation35,36:
H2O2 Fe2 Fe3 OH OH Hb-Fe2 H2O2
Hb-Fe3 OH OH
Under physiologic conditions, lactoferrin found in neutrophil-specific granules provides the iron catalyst for the
Haber-Weiss reaction. In the Fenton reaction, superoxide or
other biologic reducing agents such as lactate or ascorbate
donate electrons to generate the ferrous ions required to react
with hydrogen peroxide to produce the hydroxyl radical.35,36,39
The hydroxyl anion is highly reactive and induces DNA
strand breaks and base hydroxylations leading to adenosine
triphosphate (ATP) depletion and gene mutations. It can
attack lipid side chains of membrane phospholipids to form
hydrogen peroxide and lipid hydroperoxides in a process
called lipid peroxidation. These products can disrupt membrane function, serve as substrates for the production of cytotoxic aldehydes, or uncouple calcium-ATPase and increase
cytosolic calcium concentration. Recent data also support a
mechanism by which oxidation of critical sulfhydryl residues
on the ryanodine receptors induce an open configuration
and a leak of intracellular endoplasmic reticulum (ER) calcium
into the cytosol.40 This elevation of cytosolic calcium activates
calcium-dependent proteases and phospholipases that propagate cellular damage.39
Superoxide can react with nitric oxide to produce peroxynitrite (ONOO) and hydroxyl radical36,41:
97
H+
2O2
Superoxide
dismutase
H2O2
Catalase
H2O2
HOCl
GSH
NADP
Glutathione
peroxide
Glutathione
reductase
GSSG
NADPH
H2O
Taurine
SCIENTIFIC PRINCIPLES
Chapter 6: Inflammation
98
Regulation of Inflammation. In addition to the previously described mechanisms for controlling the inflammatory
response of neutrophils, there is substantial evidence supporting the role of apoptosis in resolving the inflammatory
response (Box B).45 Within 90 minutes of phagocytosis, over
250 genes are induced, of which more than 30 encode proteins
integral to at least three distinct apoptotic pathways.45 These
observations suggest that the mechanism inducing apoptosis is
BOX B
Mononuclear Phagocytes
Monocytes circulate for about 1 to 2 days; thereafter, they
constitutively hone to a particular tissue to differentiate into
macrophages possessing a phenotype specific to the resident
tissue (dendritic cells, Kupffer cells) (Table 6.1).4,46,47 Resident
macrophages are typically found at interfaces with blood (liver
and spleen) and with lymph, where they can readily detect,
ingest, and destroy invading organisms.39 Mononuclear cells
function as antigen-presenting cells in T-cellmediated adaptive immune responses, presenting antigen in the appropriate
context to effector T cells. They provide service integral to
both innate and adaptive immune responses. Evidence also
supports their role in providing an alarm both locally and
systemically through the release of intracellular proteins (i.e.,
high-mobility group box 1 protein [HMGB1]) expressing
damage-associated molecular patterns (DAMPs) that can
function as a danger signal (see later).
Recruitment
Monocytes are recruited and emigrate to foci of inflammation
utilizing similar mechanisms of adhesion and diapedesis as
described for neutrophils (Fig. 6.1). PAF; C5a; the CC
chemokines, regulated on activation, normally T-cell expressed
and secreted (RANTES); macrophage inflammatory protein
(MIP)-1; and chemokines of the membrane cofactor protein
(MCP) family are potent monocyte-macrophage chemotaxins.48,49 The selectin family of adhesion receptors mediates the
initial tethering of monocytes to endothelial cells.18 Firm adhesion to the endothelium involves the interactions of 1 and 2
integrins on monocytes with the endothelial adhesion molecules ICAM-1 and VCAM-1.18
99
receptor dissociate, and the receptor is recycled to the cell surface.24 This early endosome undergoes a series of maturation
steps in which it is acidified (pH 5.5 to 6.0). This acidification
is requisite for optimal protease and hydrolase activity involved
in pathogen killing. It may also be integral for phagosome maturation as titrating the acidity inhibits phagosomelysosome
fusion.24 Ultimately, the endosome fuses with a lysosome,
which is characterized by its extreme acidity (pH 5.0) and
elevated concentration of proteases.24 Lysosomes are the terminal destination of phagocytosed material to be degraded.
After fusion, MPO released into phagosomes can react with
hydrogen and halides to yield toxic hypohalous acids, superoxide anion, hydrogen peroxide, and hydroxyl radical (Table 6.3).
Macrophages may also use peroxidase generated by adjacent
neutrophils, eosinophils, and monocytes and acquired through
endocytosis to generate these ROS. In addition to supporting
the inflammatory response, macrophages also play an important immunoregulatory role in inflammation by scavenging
apoptotic neutrophils at sites of inflammation.39
SCIENTIFIC PRINCIPLES
Chapter 6: Inflammation
100
TA B L E 6 . 4
MONOCYTE/MACROPHAGE PRODUCTS
PRODUCT
FUNCTIONS
Enzymes
Lysozyme
Antimicrobial
Urokinase
Collagenase
ACE
Vasopressor
Cytokines
Multiple
IL-1
Multiple
TNF-
Interferon /
Acute-phase response
IL-6
Anti-inflammatory
IL-10
IL-12, IL-18
Neutrophil chemoattraction
IL-8
Fibroblast growth
FGF
Granulocyte, macrophage
differentiation
GM-CSF
Chemoattractant
MIP-1/
Monocyte recruitment
MCP-1
RANTES
Monocytes stimulated with GM-CSF and IL-4 or IL-13 differentiate toward DCs. Maturation of the DC requires TNF- or
LPS stimulation.39 Epidermal Langerhans cells, after encountering antigen, migrate through the lymphoid organs and differentiate into mature DCs and acquire the capacity to provide
the costimulatory signal. DCs are particularly effective at presenting viral antigen. They present antigen in the context of
both MHC I and MHC II and thereby induce both a TH1 and
TH2 response, respectively. DCs can also present antigens
derived from apoptotic cells in the context of MHC class I.5860
Macrophages present antigenic peptides from ingested
pathogens that persist in the phagosomes. These peptides, usually of bacterial origin, are expressed in conjunction with MHC
class II molecules. B cells, by contrast, bind specific soluble molecules (insect toxins, venom, and allergens) via immunoglobulin. This is endocytosed, processed, and presented on surface
MHC II.39,6062
Lymphocytes
Complement proteins
Coagulation
Coagulation factors
Localization, migration
Adhesion, matrix
molecules
Iron transport
Fibronectin,
proteoglycan
Transport proteins
Vitamin transport
Inflammation
Transferring
Inflammation
B12-binding protein
Platelet activation
Bioactive lipids
Antimicrobial
Cyclooxygenase
Antimicrobial
Lipo-oxygenase
Antibacterial
PAF
Reactive oxygen
intermediates
Superoxide,
hydrogen
peroxide
oxygen singlet
Reactive nitrogen
intermediates
NO, nitrates, nitrites
Defensins
ACE, angiotensin-converting enzyme; FGF, fibroblast growth factor;
GM-CSF, granulocyte/macrophage colony-stimulating factor; IL,
interleukin; MCP, membrane cofactor protein; MIP, macrophage
inflammatory protein; NO, nitric oxide; PAF, platelet-activating
factor; RANTES, regulated on activation, normally T-cell expressed
and secreted; TNF, tumor necrosis factor.
Modified from Gordon S. Development and distribution of mononuclear
phagocytes: relevance to inflammation. In: Gallin JL, Snyderman R, eds.
Inflammation: Basic Principles and Clinical Correlates, 3rd ed.
Philadelphia, PA: Lippincott Williams & Wilkins; 1999.
101
SCIENTIFIC PRINCIPLES
Chapter 6: Inflammation
102
LAT
TCR
PIP2
DAG
Ras-GDP
Ras-GTP
P
PKC
Sos
Grb-2
Lck
P
PLC1
IP3
Inactive
ZAP-70
Ras-GTP
Active
Raf
P
MEK-1
Cystolic Ca2+
Cellular response
P
ERK 1,2
103
SCIENTIFIC PRINCIPLES
Chapter 6: Inflammation
BOX C
specific stimulation of a large proportion of the T-cell population. An overwhelming activation of all arms of the immune system ensues and underlies much of the pathophysiology of toxic
shock syndrome. Intravenous immunoglobulin (IVIG), by binding this antigen, is thought to be of therapeutic benefit.
Eosinophils
Eosinophils are marrow-derived granulocytes that share some
properties of neutrophils and are involved in the eradication of
helminthic infections and allergen reaction (Table 6.1). IL-3,
GM-CSF, and IL-5 promote eosinophil differentiation, the
induction of effector functions, and survival by inhibiting apoptosis.76 They emigrate through inflamed endothelium and upon
exiting release inflammatory mediators and toxic agents from
cytoplasmic granules. They generate superoxide anion and
hydrogen peroxide, though less efficiently than neutrophils.
Eosinophils act in conjunction with basophils and mast cells as
primary effectors in allergy and inflammation. They express IgE
receptors and stimulate histamine release from basophils and
mast cells through major basic protein (MBP). They can also
regulate basophil and mast cell function by releasing enzymes
that inactivate histamine and slow-reacting substance of anaphylaxis (SRS-a). Upon exiting the marrow, their intravascular
half-life is but a few hours; thereafter, they enter the mucosa of
the lung, gastrointestinal, and genitourinary tracts.39,76
104
Granules. Eosinophils possess a compartmentalized armamentarium of toxic substances to assist in the elimination of organisms, in particular helminths. Their specific granules contain
GM-CSF and MBP, the latter of which is cytotoxic to parasites
and normal cells and is a stimulus for histamine release from
mast cells and basophils.78 The granule matrix contains
eosinophil peroxidase (EPO), eosinophil-derived neurotoxin,
lysosomal enzymes, catalase, TNF-, transforming growth
factor- (TGF-), and eosinophilic cationic proteins that stimulate formation of transmembrane pores to increase target cellular
permeability.79 EPO is released extracellularly on target cell surfaces where it generates hydrogen peroxide and hydrogen
halides. Approximately 30% of oxygen consumed by stimulated
eosinophils is utilized in the formation of halogenating species.
Thiocyanate may be the major halide for the EPO-H2O2 system.80 If ingested by a neighboring phagocyte, EPO can combine
with H2O2 and halides to form hypohalous acids. EPO also stimulates neutrophil aggregation and adhesion to endothelial cells.
Although they express Fc receptors for IgG, IgA, and IgE, they
are relatively insensitive to activation by antigen-mediated crosslinking of these receptors. However, they can kill microorganisms
by antibody-dependent cell-mediated cytotoxicity (ADCC).4,39
The primary targets of eosinophils are extracellular parasites. The size of these pathogens prohibits phagocytosis, and
their integument is relatively resistant to the microbicidal products of neutrophils and macrophages; however, they can be
killed by MBP, which is released after cross-linking of Fc-bound
IgE coating the parasite. The TH2 response to parasitic invasion
produces IL-4, IL-5, and IL-13. IL-4 stimulates the production
of specific IgE antibodies, which opsonize helminths. IL-5 activates eosinophils, which bind to the IgE-coated helminths via Fc
receptors. Activated eosinophils then release their granule contents and generate reactive oxygen species and hypohalous
acids. EPO also stimulates neutrophil aggregation and adhesion
to endothelial cells. The sparse uncompartmental granules contain Charcot-Leyden crystals and have lysophospholipase activity. Finally, eosinophils produce and release lipid mediators such
as PAF, prostaglandins, and leukotrienes, which probably contribute to the process of allergic diseases.4,81,82
Mature basophils constitute only 0.5% to 1% of the circulating leukocytes, and mast cells primarily reside fixed in connective tissue. Engagement of IgE-bound antigen with the
high-affinity IgE antibody receptor, FcR, provides the primary stimulus for basophil and mast cell activation and
degranulation. In addition, diverse agents such as contrast
media, opiates, anaphylatoxins, chemokines, and neuropeptides may serve as activators. Basophils and mast cells elaborate both preformed and newly synthesized inflammatory
mediators. The main basophil proteoglycan is chondroitin sulfate A, whereas mast cells contain heparin, chondroitin sulfate,
and chondroitin sulfate E and also store neutral proteases.84
The lipid mediators LTB4, LTC4, and prostaglandin D2 (PGD2)
are synthesized de novo in response to stimulation. The
leukotrienes are powerful vasoconstrictors, bronchoconstrictors, and chemoattractants for neutrophils and eosinophils.
PGD2 inhibits platelet aggregation and is chemotactic for neutrophils. Both basophils and mast cells synthesize and secrete
histamine. Histamine, or 2-(4-imidazolyl)-ethylamine, is formed
by the carboxylation of histidine. It is stored in preformed
granules at acid pH as a complex with proteins and proteoglycans. Mast cells carry greater quantities of histamine than do
basophils. The classic vasoactive properties of arteriolar
dilatation, increased vascular permeability, and bronchoconstriction are mediated by the H1 receptors. H2 receptors are
involved in modulation of the immune response and stimulating gastric output and mucus secretion. H3 receptors participate in neuroconduction.39,84,85
Platelets
Though classically considered in the context of hemostasis,
platelets are integral to both normal and pathologic inflammation and link the processes of hemostasis, inflammation, and
tissue repair. They are activated in a variety of inflammatory
conditions, such as rheumatoid arthritis and inflammatory
bowel disease, a testimony to their role in inflammation.86
Upon activation, they release factors that enhance vascular
permeability, chemokines, microbicidal proteins, and mitogens for endothelial cells, smooth muscle cells, and fibroblasts.
They assist leukocytes in promoting the inflammatory reaction
and killing microbes by providing an adhesive surface to facilitate emigration, by stimulating adhered leukocytes, and by
further modulating chemokine synthesis (Table 6.5).86,87
Humans possess about 150 to 400 109 platelets per liter
of blood.86 Thrombopoiesis is regulated by thrombopoietin
(TPO) as well as a variety of other peptides (IL-3, IL-4, IL-6,
IL-7, and IL-11). In fact, human IL-11 is clinically used to
stimulate thrombopoiesis in patients undergoing chemotherapy.88 After release from the marrow, they circulate with a
half-life of approximately 12 days. Interferon- is inhibitory
for megakaryocyte growth, and the elevated levels induced
with some viral and inflammatory conditions may explain the
relative thrombocytopenia observed in these conditions.86,89
TA B L E 6 . 5
PLATELET-DERIVED MEDIATORS
Chemoattractants
C5a
12-HETE
PAF
-Granule proteins
PDGF
PF-4
RANTES
Growth Factors
Transforming growth factors- and -
Fibroblast growth factor
PDGF
Antimicrobial activity
Cationic bactericidal protein
IgE-mediated oxidant production by platelets directed at
schistosomes
Vascular Reactions
Prostaglandin E2
Prostaglandin I2
Prostaglandin F2
Serotonin
PDGF
Serotonin
PAF
Cationic proteins
Vascular endothelial growth factor
HETE, hydroxyeicosatetraenoic acid; IgE, immunoglobulin E; PAF,
platelet-activating factor; PDGF, platelet-derived growth factor; PF-4,
platelet factor 4; RANTES, regulated on activation, normally T-cell
expressed and secreted.
From Klinger MHF, Jelkmann W. Role of blood platelet in infection
and inflammation. J Interferon Cytokine Res 2002;22:913922.
link to other platelets, leukocytes, and the endothelium. Possibly the immobilization on the vessel wall of activated platelets
with induced P-selectin biochemically and functionally promotes the adhesion of neutrophils to endothelial cells.86,89
Platelets are a primary source of chemoattractants for neutrophils. Neutral proteinases released from stimulated platelets
cleave complement factor C5, liberating the chemoattractant
C5a. PDGF binds strongly to the extracellular matrix, providing a long-acting source of chemoattractant. Platelet factor 4
(PF4) is a cationic protein that penetrates the vascular wall and
is a chemoattractant. Activated platelets also bind monocytes
via P-selectin and PSGL-1 and induce the expression and secretion of MCP-1 and IL-8. Thrombospondin released from activated platelets mediates monocyte binding to platelets.
Together these substances promote leukocyte margination,
activation, and recruitment to the sites of injury.39
105
Noncellular Components
Cytokines. Cytokines are soluble protein mediators secreted
by the cells of the innate and adaptive immunity in response to
microbes and other antigens, including intra- and extracellular
proteins, and mediate many of the functions of these cells
(Table 6.6). They regulate and influence the host response to
both pathogen-associated molecular patterns (PAMPs; i.e.,
SCIENTIFIC PRINCIPLES
Chapter 6: Inflammation
106
TA B L E 6 . 6
CYTOKINES
CYTOKINE
RECEPTOR
SIGNAL
TRANSDUCTION
CELLULAR
SOURCE
TRAFS
Mo/M
, MC, Ba,
Eo, NK, B, T, F, Ep
TARGETS
EFFECTS
Endothelium
c inflammation,
coagulation, adhesion
molecules
INNATE/EARLY CYTOKINES
TNF-
TNF R
Death domains
PMN
Many cells
c activation
c apoptosis
c fever, APP, catabolism
IL-1
Ig family
IRAK
Mo/M
, B, EC,
Ep, F
Endothelium
PMN
Mo
c inflammation,
coagulation, adhesion
molecules
c activation and
emigration
c activation and
emigration
c shock, fever, APP
production
Chemokines/IL-8
7 trans-membrane G protein
Mo/M
, T, PMN,
F, EC, Ep
PMN
T
c activation, adherence,
and migration
Mo/M
c emigration
EC
c emigration
Ba
c adhesion molecules
c histamine release
IL-12
Type I
JAK/STAT
T
NK
TH1 differentiation,
interferon- synthesis,
c cytolytic activity
JAK/STAT
All
All
Antiviral, antitumor,
increases MHC I activates
T, M
, NK cells
IL-10
JAK/STAT
Mo/M
, T, B, MC
Mo/M
T IL-12, costimulators,
MHC II
B, NK, MC
T TH1 differentiation
Differentiation
c antibody-producing cells
Mo/M
APP synthesis
IL-6
Type II
Type I
JAK/STAT
Mo/M
, B, F, EC,
Ep
E
IL-15
IL-18
Type I
Ig family
JAK/STAT
NK
Proliferation
Proliferation
IRAK
T, NK
c interferon-
JAK/STAT
T activation and
proliferation, Fas
apoptosis
ADAPTIVE/LATE CYTOKINES
IL-2
Type I
B
NK
c proliferation, antibody
synthesis
c proliferation and
activation
Mo/M
activation
IL-4
Type I
JAK/STAT
T, Ba, MC
T
B
Mo/M
Chapter 6: Inflammation
107
TA B L E 6 . 6
CYTOKINE
RECEPTOR
SIGNAL
TRANSDUCTION
IL-5
Type I
JAK/STAT
Interferon-
Type II
JAK/STAT
CELLULAR
SOURCE
T, NK
TARGETS
EFFECTS
M
activation
IgG secretion
TH1 differentiation
c MHC I and II
c antiviral
c fever, anorexia, shock,
capillary leak
c APP synthesis,
inflammatory cytokine
induction
TGF-
All
T T proliferation and
effector functions
T M
function
T proliferation
c matrix protein synthesis
Lymphotoxin
TNF R
TRAFs
PMN
Recruitment and
activation
Mo/M
T M
function switching
to isotype IgE
Death domains
IL-13
Type I
JAK/STAT
B
EC
APP, acute-phase protein; B, B cell; Ba, basophil; EC, endothelial cell; Ep, epithelial cell; F, fibroblast; IL, interleukin; IRAK, IL-1Rassociated kinase;
JAK/STAT, Janus kinase/signal transducer and activator of transcription; MC, mast cell; MHC, major histocompatibility complex; Mo, monocyte;
M
, macrophage; NK, natural killer; PMN, polymorphonuclear leukocyte; T, T cell; TNF, tumor necrosis factor; TRAF, tumor necrosis factor
receptorassociated factor.
Modified from Abbas AK, Lichtman AH. Cellular and Molecular Immunology, 5th ed. 2003:179, 181182.
acute and chronic bacterial, viral, fungal, and parasitic infections) and DAMPs (i.e., trauma, burns, allograft rejection,
ischemia/reperfusion injury, and autoimmune disease). They
govern lymphocyte differentiation during adaptive immunity
and activate effector cells of both arms of inflammation to
eliminate microbes. Cytokines play important roles in tumor
biology as well as angiogenesis. Though essential for a normal
immune response, excessive cytokine release underlies a variety of pathophysiologic inflammatory states such as acute
respiratory distress syndrome (ARDS) and multiple organ dysfunction syndrome (MODS).9396
Cytokine secretion is brief, and as they typically are not
stored preformed, necessitates transcription and de novo synthesis, which is also transient as the messenger RNA is unstable. Their functions are pleiotropic and redundant, which has
been interpreted as a teleologic safety mechanism. However,
such protective characteristics greatly limit the therapeutic
5 utility of either cytokine administration or blockade. In fact,
over 30 randomized controlled clinical trials have been conducted to assess the efficacy of agents modulating inflammation, in particular systemic cytokine concentrations, in reducing mortality. Yet only one, activated protein C, has been
approved by the U.S. Food and Drug Administration (FDA)
for use, and studies are ongoing to confirm its benefit.97
Cytokines often influence the synthesis and actions of other
cytokines, such as IL-1induced T-cell IL-2 production; this
interaction may be synergistic (additive or multiplicative) or
antagonistic. They may function in an autocrine, paracrine, or
SCIENTIFIC PRINCIPLES
CYTOKINES (Continued )
108
TNF-RI
TNF-RII
Death
domain
DD
TRA
R
I
P
F
A
D
D
TRADD
TRAF
IB kinase
P
SAP kinase
Caspase 8
precursor
Active JNK
IB
NF-B
Caspase 8
Caspase 3
Jun
IB
NF-B
Fos
Active AP-1
NF-B
P
Apoptosis
Gene transcription
Inflammatory mediators
IB
1. Binding of LPS/LBP
with CD14
2. Association of
CD14/LPS
with TLR4
CD14
TLR4
MyD88
5. Activation of TRAF6
TRAF6
IRAK
IB kinase
P
3. Recruitment of
MyD88 and IRAK
P
MAP kinase
6a. Activation
of MAPK
8a. Translocation to
nucleus and
transcription
109
Jun
Fos
Jun
Fos
P
IB
IB
NF-B
NF-B
7b. Phosphorylation of
IB- or IB-
8b. Dissociation
and degradation
of IB- or IB-
Active AP-1
NF-B
9b. Translocation to
nucleus and
transcription
Gene transcription
Inflammatory mediators
P
IB
SCIENTIFIC PRINCIPLES
Chapter 6: Inflammation
110
cells. TNF- and IL-1 are key molecules for inducing IL-8. It is
chemotactic for all granulocytes and influences nearly every
aspect of neutrophil function. It stimulates neutrophil degranulation, phagocytosis, transendothelial migration, and shedding of L-selectin, upregulation of 2 integrins, and augments
superoxide production. It is also a potent angiogenic factor. It
binds to both CXCR1 and CXCR2, receptors that also engage
the chemokines GCP-2, GRO-, and ENA-78. ENA-78 is a
potent neutrophil chemotaxin produced by the endothelium in
response to TNF- or IL-1, neutrophils, or monocytes. Studies
have demonstrated that ELR-containing CXC chemokines are
angiogenic, whereas those lacking this motif are angiostatic.39,93,119121
The interferon-influenced chemokines IP-10 and Mig do not
target neutrophils, and the ELR motif is absent. They induce
IFN- production and may play a more prominent role in mediating the inflammatory response to viral infections and autoimmune disorders. Mig is chemotactic for tumor-infiltrating lymphocytes, activated T cells, and monocytes and promotes CTL
activity. IP-10 is chemotactic for monocytes, T cells, and NK
cells and augments T-cell adhesion. Both chemokines bind the
CXCR3 receptor found on IL-2activated T cells. IFN- attenuates the expression of both IL-8 and ENA-78, and hence may
serve as an important mechanism to the control and regulate
inflammation.39,93 Stromal cellderived factor-1 (SDF-1) is the
only known ligand for the CXCR4 receptor and in the presence
of IL-7 stimulates proliferation of preB-cell clones and growth
of bone marrow B progenitor cells. The receptor has gained
much interest since it was identified as a coreceptor for human
immunodeficiency virus type 1 (HIV-1). Platelet factor 4 and
neutrophil-activating protein-2 are CXC chemokines of platelet
origin. PL-4 has angiostatic properties and inhibits the growth
of various cancer cell lines in a manner that appears to be
related to its angiostatic properties. It binds heparin with high
affinity to stimulate coagulation.39
The CC chemokines recruit monocytes, granulocytes, T
cells, NK cells, and dendritic cells. RANTES is produced by
stimulated T cells, platelets, and endothelial cells and is constitutively produced in resting T cells, which implies a homeostatic function. MIP-1 and MIP-1 are produced by activated T
cells and are chemotactic for neutrophils, monocytes, eosinophils, basophils, and T lymphocytes. They are also mitogenic
for hematopoietic progenitor cells and upregulate TNF-,
IL-1, and IL-6. The MCP family of chemokines influences the
recruitment of monocytes and T cells. Their influence upon the
function of these target cells is dictated by the cells specific
profile of receptor expression. MCP-1 is produced by nonlymphocytic cells (endothelial cells, epithelial cells, fibroblasts,
smooth muscle cells, macrophages, and mast cells). Binding to
CCR1 enhances chemotaxis, whereas activation of CCR2
increases the release of intracellular substances such as histamine and leukotrienes from basophils.39
Lymphotactin is the only member of the C chemokine family and is produced by CD8 lymphocytes, thymocytes, and
NK cells and, to a lesser degree, by DCs and activated mast
cells. It selectively recruits lymphoid cells.39
Fractalkine is the sole CX3C chemokine and is produced by
endothelium. In its membrane-bound form it may act as a
solid-phase adhesion molecule, but upon cleavage serves as a
soluble chemoattractant for lymphoid cells and monocytes.39
Interleukin-12 (Natural Killer Cell Stimulatory Factor, Cytotoxic Lymphocyte Maturation Factor). IL-12 is integral in the
innate immune response (Table 6.6). It is produced early during innate immune reactions against intracellular microbes
and stimulates subsequent adaptive responses that confer further host protection against these pathogens; hence, it is an
important link between innate and adaptive immune responses. IL-12 is critical for initiating a sequence of responses
involving macrophages, NK cells, and T lymphocytes that results
in the eradication of intracellular microbes. It is primarily
3. Phosphorylation
of STATs
111
to fuel the reaction in a positive feedback mechanism. Ultimately, IFN activates macrophages to kill and degrade phagocytosed microbes. IL-12 potentiates bacterial LPS-induced
macrophage TNF- production. IL-12 antagonists reduce mortality in experimental models of LPS-induced septic shock; however, there is no evidence of their efficacy in human clinical
trials.4
CD4 helper T lymphocytes, under the influence of IL-12,
differentiate into TH1 cells, which subsequently activate
phagocytes in cell-mediated immunity. It enhances the
cytolytic functions of activated NK cells and CD8 CTLs, and
suppresses TH2 cell differentiation and effector activity. The
inhibition of TH2 and IL-4 activity confers antiallergic properties to IL-12. IL-12 knockout mice demonstrate diminished
IFN- production and defective TH1 cell development and cellmediated immunity against intracellular organisms.4,39
Interleukin-6. IL-6 regulates the acute-phase response to
inflammation, characterized by altered thermoregulation (i.e.,
fever), perturbation in nitrogen balance (i.e., cachexia and
catabolism), and the generation of the acute-phase reactants of
innate immunity by the liver (Tables 6.6 and 6.7).93,124 It functions in both innate and adaptive immunity to enable the host
to recover. Despite in vitro data demonstrating that a variety of
cells can produce IL-6, the most prominent in vivo sources of
IL-6 are monocytes and macrophages stimulated with LPS or
IL-1 or TNF-stimulated fibroblasts and endothelial cells.125
Steroids inhibit the induction of IL-6. The receptor for IL-6
consists of cytokine-binding protein and a signal-transducing
subunit, which belong to the type I cytokine receptor family. It
signals through the JAK/STAT pathway (Fig. 6.7).4
In conjunction with IL-1 and TNF-, IL-6 regulates the systemic manifestations of the acute-phase response.124 It potentiates the immune response by inducing B-cell differentiation and
activating T cells. It interacts with TNF- to enhance T-cell
proliferation and promotes neutrophil activation and accumulation. In adaptive immunity, IL-6 stimulates the growth of B
TA B L E 6 . 7
ACUTE-PHASE PROTEINS
2. Recruitment
of STATs to
receptor
ACUTE-PHASE PROTEIN
P
4. Dimerization
P
5. Translocation to nucleus
and transcription and
gene induction
FUNCTION
INCREASE
C-reactive protein
Opsonin
Serum amyloid A
Apolipoprotein
1-Acid glycoprotein
Platelet inhibitor
Fibrinogen
2-Macroglobulin
Antiprotease
1-Protease inhibitor
Antiprotease
1-Antichymotrypsin
Antiprotease
Haptoglobulin
Antioxidant
Hemopexin
Antioxidant
Ceruloplasmin
Antioxidant
C3
Complement
Factor b
Complement
C1 inhibitor
Complement
C4b-binding protein
Complement
Mannose-binding lectin
Complement
DECREASE
Albumin
Transport
Prealbumin
Transport
Transferrin
Transport
SCIENTIFIC PRINCIPLES
Chapter 6: Inflammation
112
Chapter 6: Inflammation
Interferons (Type I). Type I interferons possess potent antiviral and antitumor properties (Table 6.6). It is from this ability
to interfere with viral infection that the name is derived. They
are subcategorized into and interferons. Mononuclear
phagocytes are the major source of interferon-, whereas
many cell types produce interferon-. The most potent stimulus inducing the synthesis and release of either is viral infection, particularly double-stranded RNA produced during viral
replication. Other inducers include IL-1, TNF-, LPS, and
antigen-activated T cells. Both groups bind to the same cell
surface receptor and induce similar responses by signaling
through the JAK/STAT pathway (Fig. 6.7).
These cytokines provide the first line of defense against
viral infection and promote cell-mediated immunity against
intracellular pathogen. They are secreted from virally infected
cells to protect neighboring uninfected ones by inducing the
synthesis of a number of enzymes that interfere with viral
RNA or DNA transcription and viral replication. Through
enhanced expression of class I MHC molecules, the type I
interferons facilitate recognition of class Iassociated viral
antigens on infected cells by CTLs and increase the efficiency
of CTL-mediated killing. Type I interferon stimulates the
development of TH1 cells by promoting these cells to express
IL-12 receptor. They can also stimulate B-cell development,
proliferation, and immunoglobulin heavy chain switching
from IgM to IgG.150152 Knockout mice lacking the receptor
for these cytokines are susceptible to viral infections. Interferons are currently in clinical use for hepatitis B and C infection,
multiple sclerosis, chronic myelocytic leukemia (CML), and
Kaposi sarcoma.150152
Interleukin-10 (Cytokine Synthesis Inhibiting Factor). IL-10
inhibits activated macrophages and antigen-presenting cells
and functions in a counterregulatory mechanism to suppress
innate immune reactions (Table 6.6). It is produced mainly by
macrophages, and hence functions by negative feedback. T
lymphocytes, particularly the TH2 subset, B cells, and some other
nonlymphoid cells produce IL-10, in response to a variety of
stimuli including LPS, TNF-, IL-2, IL-4, and IL-13.
IL-10 binds to a type II (interferon) receptor. Though the
manner by which it effects curtailment of the inflammatory
response is unknown, its presence inhibits NK-B activation
and the generation of inflammatory mediators perhaps by
inhibiting, in some manner, the activation of signal transduction cascades and gene activation in proinflammatory pathways.4,153
IL-10 terminates many of the functions of activated
macrophages and participates in reestablishing homeostasis as
the infection resolves. It downregulates proinflammatory
cytokine (TNF-, IL-1, IL-6, and IL-8) production, suppresses
IL-12 production, and inhibits IFN- production and the
innate and cell-mediated immune responses.4,56,93 It represses
the expression of costimulators and class II MHC molecules
on antigen-presenting cells, thereby terminating T-cell activation and inhibiting cell-mediated immunity.4 In neutrophils it
inhibits cytokine release, superoxide generation, migration,
and even survival.154 In combination with IL-4, it inhibits
IFN- release and IL-12 production to limit differentiation
and function of TH1 cells, favoring a TH2 profile.56
IL-10 knockout mice develop inflammatory bowel disease,
which is hypothesized to result from unregulated macrophage
reaction to enteric microbes.155 In observational studies of
ARDS or MODS, serum IL-10 levels were often elevated, and
those patients with the highest systemic concentrations died.153
It is unclear whether this is actually a pathologic response or
merely a marker of disease severity. Contemporary belief is that
SCIENTIFIC PRINCIPLES
113
114
Transforming Growth Factor-. TGF- is a homodimer synthesized and secreted by activated T cells, macrophages, and 6 The complement system is integral to both innate and adaptive
immunity. It has the capacity to independently eliminate
many other cells (Table 6.6). It is primarily immunosuppresorganisms and to facilitate host defense by marking foreign
sive and inhibits the proliferation and activation of lymphoparticles for phagocytosis through opsonization. Many pathocytes and other leukocytes. It promotes wound healing by
physiologic inflammatory diseases, immune complex diseases,
increasing extracellular matrix protein synthesis and stimulatischemia/reperfusion injury, and ARDS are considered conseing mononuclear cell and fibroblast influx.162164 Though the
quences of aberrant function of this system.168171
family consists of three closely related isoforms, most cells uti-
The system consists of three pathways composed of approximately 30 serum and cell surface proteins that interact with one
another and with other molecules of the immune system in a
highly coordinated fashion. These cascades involve the sequential proteolytic activation of zymogens to generate enzymes with
proteolytic activity. This mechanism for activation amplifies the
response because each individual enzyme activated can cleave
numerous zymogens in the next step and generate multiple activated enzyme molecules. Ultimately, the products of complement
activation adhere to microbial cell surfaces or to antibody-bound
microbes and other antigens to directly or indirectly eliminate
these pathogens. Temporal and spatial regulation to the focus of
infection is ensured both by the transience of activation of these
enzymes in the absence of microbes or antigens and by several
circulating proteins that provide surveillance.168,170
The complement cascade is divided into three distinct pathways: the classical pathway (humoral immunity), which is
activated by antibody bound to antigen; the alternative pathway (innate immunity), in which complement is activated by
components of microbial cell surfaces; and the mannose/lectin
pathway (innate immunity), which is activated by a plasma
lectin that binds to mannose residues on microbes. Despite differences in which the cascade is activated, all three complement pathways ultimately result in the cleavage of C3 and
share the same subsequent late cascade.168,170
The alternative pathway functions in the absence of antibody and is phylogenetically the oldest pathway (Fig. 6.8). Bacteria, viruses, fungi, and parasites all function as stimuli. Initial
activation begins with the cleavage of C3 and the stable attachment of its product C3b to the microbial surface. Bound C3b
binds factor B, which is subsequently cleaved by a plasma serine
protease called factor D to generate Bb. The C3bBb complex is
called the alternative pathway C3 convertase and functions to
cleave more C3. In doing so the convertase serves as an amplification step in both the classical and alternative pathways. Properdin prolongs the half-life of C3 convertase by delaying the
release of Bb from C3bBb. C3b is the recognition component of
the alternate pathway and is responsible for the opsonization of
bacteria. C3a in conjunction with C5a and C4a induces acute
inflammation by activating mast cells and neutrophils. These
inflammatory mediators play a significant role in increasing
blood vessel permeability, vasodilatation, edema formation,
neutrophil adhesion and activation, chemotaxis, and the release
of toxic oxygen species and lysosomal enzymes from phagocytic
cells. The binding of another C3b to this complex generates the
alternative pathway C5 convertase, C3bBb3b.4,168,170
Alternate pathway
Pathogen
C3 convertase
C3b
1
C3b
Bb
Late pathway
C5 convertase
C3b
C5
B
C3
C3
Classical pathway
Pathogen
C5 convertase
C3 convertase
2
C6,7,8
3
C9
C4
C2
C3
115
Membrane attack
complex (MAC)
SCIENTIFIC PRINCIPLES
Chapter 6: Inflammation
116
Lipid Mediators
Eicosanoids. Eicosanoids are 20-carbon lipid inflammatory
mediators derived from membrane arachidonic acid that are
involved in numerous homeostatic processes and inflammation. These lipid mediators are not stored in tissues, but are
synthesized de novo within seconds in response to a variety of
stimuli, including mechanical trauma, or specific cytokines,
growth factors, and other mediators (Fig. 6.9). Although most
cells are capable of producing eicosanoids, neutrophils and
macrophages are the predominant source during inflammation. They are rapidly degraded in the circulation, which limits their role primarily to that of autocrine and paracrine mediators of local inflammatory changes.176178
The liberation of the precursor molecule, arachidonic acid,
is the major rate-limiting step. The family of PLA2, in particular type IV cytosolic PLA2, is responsible for eicosanoid production; cells lacking type IV PLA2 are devoid of eicosanoid
synthesis.179 Many PLA2 are transcriptionally regulated by
IL-1 and TNF-, whereas others are regulated by the MAPK
pathway and by calcium-dependent translocation to membranes. Once formed, arachidonic acid metabolism proceeds
along one of two pathways.176178
Cyclooxygenase Pathway (Prostaglandins). Cyclooxygenase catalyzes the initial step of a series of reactions that
converts arachidonic acid to prostanoids (Fig. 6.9). There are
two isoforms, COX1 and COX2; the former is constitutively
expressed, whereas COX2 is inducible. COX2 is considered
more important during inflammatory processes such as fever,
hyperalgesia, and edema formation. Either enzyme catalyzes
the conversion of arachidonic acid to the endoperoxidase
PGG2, which is subsequently converted to PGH2. PGH2 serves
as the precursor to numerous specific prostaglandins. All of
these products possess very short half-lives and are rapidly
inactivated.179,180
Prostaglandins mediate their effects through G-protein signaling (Table 6.8). Prostacyclin (PGI2) is produced by the
endothelium as a potent vasodilator and inhibitor of platelet
aggregation and adhesion, characteristics that enhance tissue
perfusion. PGI2 inhibits neutrophil chemotaxis and activation
and interacts synergistically with PGE2 to increase vascular
permeability through the bradykinin pathway. PGE2 is the
predominant anti-inflammatory prostaglandin and is produced
by nearly all inflammatory cells. It is produced in response to IL1 and mediates the hypothalamic fever response and synergizes
Phospholipids
Glucocorticoids
Arachidonic acid
2
15
5-HPETE
PGG2
NSAIDs
17
10
PGH2
12-HPETE
12-HPETE
16
5-HETE
12-HETE
117
5(6)-Epoxytetraene
4
TXA4
LTA4
Lipoxin A4
11
5
PGI2
LTB4
Lipoxin B4
12
PGE2
18
LTC4
Lipoxin C4
13
PGD2
19
LTD4
Lipoxin D4
20
14
PGF2
LTE4
Lipoxin E4
with bradykinin and histamine to mediate pain. It is a bronchodilator, inhibits both IL-1 production and T-cell responsiveness to IL-1, and at low concentrations suppresses TNF- production. It also inhibits neutrophil chemotaxis and activation
and TH1 lymphocyte proliferation.179,180 There is some suggestion from animal studies that PGE2, PGE1, and PGI2 may be
beneficial in response to sepsis through their endogenous counterregulatory properties. Administration of each of these has
been shown to improve survival in several animal models of
hypovolemic and traumatic shock, though clinical trials have
failed to identify benefit.180 PGD2 is a potent bronchoconstrictor
that inhibits neutrophil chemotaxis and activation. TXA2,
PGG2, and PGH2 oppose the actions of prostacyclin by promoting platelet aggregation and inducing bronchoconstriction.
TXA2 produced by platelets and macrophages is a powerful
vasoconstrictor that induces neutrophil accumulation and
increases vascular permeability.176178,181 There is substantial
evidence that TXA2 plays a significant role in early acute-phase
organ injury.180
TA B L E 6 . 8
PROSTANOID EFFECTS
PGG2
PGH2
PGI2
PGE2
TXA2
Chemotaxis
Bronchial resistance
Platelet aggregation
SCIENTIFIC PRINCIPLES
Chapter 6: Inflammation
118
associates with the perinuclear membrane protein 5-LOactivating protein (FLAP) to catalyze the formation of 5hydroperoxyeicosatetraenoic acid (5-HPETE). 5-HPETE is
subsequently converted to LTA4 by the combined efforts of a
dehydrase and 5-LO. LTA4 serves as the precursor for either
LTB4 or LTC4. LTC4 can in turn be successively hydrolyzed to
the dipeptide derivative LTD4 and the LTE4. Additional LO
activity results in the production of 12-HPETE, 12-HETE, and
15-HPETE. These compounds exhibit biologic activity, although
they are not as potent as the leukotrienes or prostaglandins.
The leukotrienes are inactivated by oxidation followed by
dehydration.177179,181,182
The major lipoxygenase product of neutrophils is LTB4,
though macrophages may also synthesize this compound. This
compound is potently chemotactic for both neutrophils and
eosinophils, and by upregulating endothelial cell surface adhesion molecules promotes leukocyte recruitment. It increases
vascular permeability, either directly or through interaction
with neutrophils and endothelial cells. LTB4 has also been
shown to induce hyperalgesia.92,179
LTC4, LTD4, and LTE4 comprise the family of slow-reacting
substances of anaphylaxis (SRSA), compounds synthesized by
mast cells during anaphylactic reactions. LTC4 is the major
eicosanoid product of eosinophils and the only mast cellderived
product of LO. These three leukotrienes are potent vasoconstrictors and the most powerful bronchoconstrictors in humans,
being three orders of magnitude more potent than histamine.
They also increase vascular permeability and are vasodilatory in
skin.43,179
Lipoxins are biosynthesized by several routes in a tissuespecific manner. Current evidence implicates the eosinophil. A
5(6)-epoxytetraene intermediate can be formed by 5-LO activity on 15-HPETE. This reaction when carried out in blood vessels requires the interaction between platelets and neutrophils.
On mucosal surfaces, 12-LO and 5-LO activity on LTA4 can
result in formation of this lipoxin intermediate through
leukocyteepithelial interactions. The 5(6)-epoxytetraene
intermediate is then converted to lipoxin A4, lipoxin B4, or
lipoxin C4, the last of which serves as the precursor for lipoxins D4 and E4.90,183,184
Though many of the functions of lipoxins have yet to be elucidated, they appear to counterregulate the actions of
leukotrienes. They inhibit leukotriene production by downregulating 5-LO as 15-LO is upregulated. The anti-inflammatory
cytokines IL-4 and IL-13 further contribute to suppression of
inflammatory responses by enhancing 15-LO activity. In addition to inhibiting synthesis, lipoxins inhibit the actions of LTB4
and LTD4. Lipoxins A4 and B4 are potent vasoactive compounds,
though this effect is tissue specific for lipoxin B4, as it induces
vasoconstriction in some tissue beds. Lipoxins influence smooth
muscle and vascular tonus by increasing NO and prostacyclin
production, increasing arachidonate release, and reversing
endothelin-induced vasoconstriction. Counterinflammatory
functions of lipoxin A4 include inhibition of leukotrienes, fMLP,
and other chemoattractants. Lipoxin A4 also downregulates
LTB4-mediated delayed-type hypersensitivity reactions.90,183185
A large number of anti-inflammatory drugs, many of which
are in clinical use, act by interfering with eicosanoid synthesis.
The anti-inflammatory properties of corticosteroids are mediated at least in part by the inhibition of PLA2 through the
induction of lipocortin. They have been shown to selectively
inhibit COX2 activation without affecting COX1. NSAIDs
block the synthesis of both prostaglandins and thromboxanes
by inhibiting COX activity. In contrast to the other NSAIDs,
aspirin inhibits COX in an irreversible manner, and restoration
of platelet function necessitates the administration of platelets.
Recently aspirin, by either acetylating COX2 or by inducing
the oxidation of arachidonic acid by cytochrome P450 or 5LO, has been shown to stimulate the formation of 15R-HETE
in endothelial or epithelial cells. These 15-epilipoxins exhibit
higher potency in suppressing inflammation because of their
Platelet-activating Factor
PAF is a heterogeneous mixture of 1-0-alkyl-2-acetyl-snglycero-3-phosphocholines that plays a prominent role in both
physiologic and pathologic inflammatory states. It does not
exist preformed, but is rapidly produced by activated cells.
Synthesis involves either the remodeling of membrane phospholipids by PLA2, usually more important under inflammatory conditions, or de novo synthesis as occurs in resting cells.
De novo synthesis is regulated by substrate availability and
involves a constitutively active enzyme that produces PAF in
small basal amounts.187 The membrane phospholipid precursor is present in high amounts in neutrophils. Other cells that
can synthesize PAF include platelets, basophils, monocytes,
eosinophils, mast cells, and vascular endothelial cells. Similar
to eicosanoid production, the synthesis of PAF is initiated by
calcium-dependent activation of PLA2, which yields 1-0-alkylsn-glycerophosphocholine (lyso-PAF); subsequent acetylation
generates PAF. PAF may be released from the cell, or it may be
converted back to lyso-PAF by an acetylhydrolase and to the
precursor ether-phosphatidylcholine.187
The actions of PAF are mediated by G-protein activation. As
the name implies, PAF induces platelet aggregation and degranulation, yet also possesses many other critical functions for
inflammation. Its vasoactive properties include vasodilation
and increased permeability, and it is an equally potent bronchoconstrictor. PAF enhances arachidonic acid metabolism,
leading to increased leukocyte motility, degranulation, and free
radical formation. PAF plays an integral role in promoting
activation and adherence of inflammatory cells to the endothelium.188 During the early inflammatory response, activated
endothelial cells synthesize and express PAF on the cell surface.
Leukocytes tethered by selectins to the endothelium are activated by endothelial PAF, which results in the induction of tight
integrin-dependent adhesion and subsequent emigration and
chemotaxis toward the inflammatory focus. Acyl-PAF, the
major acetylated lipid from mast cells, basophils, and endothelial cells, is a less potent derivative of PAF that likely plays a
similar role in the regulation of neutrophil recruitment. PAF
also promotes platelet and neutrophil aggregation, thereby
contributing to the prothrombotic state of acute inflammation.
In circumstances of persistent pathologic stimuli, PAF may be
liberated systemically, thereby causing the sequelae of an excessive inflammatory response. As a mediator of sepsis, PAF augments endotoxin-induced hypotension and neutrophil and
platelet accumulation in the lungs. There is evidence that the
NO-induced hypotension in experimental models of endotoxemia is mediated by PAF.189 PAF infusion leads to a shock state
that is similar to septic shock in that there is tissue hypoperfusion despite adequate fluid resuscitation. In animal studies, PAF
has been shown to contribute many manifestations of sepsis
including coronary vasoconstriction, reduced cardiac contractility, reduced preload, peripheral vasodilation, pulmonary
vasoconstriction, increased microvascular permeability, gastrointestinal hemorrhage, and thrombocytopenia.180 Two
prospective randomized, placebo-controlled trials of PAF inhibition in sepsis have suggested a benefit.180
PAF acetylhydrolase, an enzyme regulated by dexamethasone, estrogen, and PAF itself, is the enzyme responsible for
degradation of PAF.
Chapter 6: Inflammation
Tissue
Factor XI
Kallikrein
Plasmin
Intracellular
enzymes
HMWK
Factor XIIa
Hageman factor
Factor XIIa
HMWK
Prekallikrein
Kallikrein
HMWK
Pro-kallikrein
FIGURE 6.10. Kinin pathway. (Modified from Proud D, Kaplan AP. Kinin
formation: mechanisms and role in
inflammatory disorders. Annu Rev
Immun 1988;6:49.)
Factor XIa
LMWK
Coagulation
cascade
Bradykinin
Coagulation
cascade
Kallikrein
Cellular
kininogenase
Lysyl bradykinin
(Kallidin)
Carboxypeptidase N
DES-ARG
bradykinin
Bradykinin
ACE proteinases
Inactive
metabolites
Kinins
Kinins (i.e., bradykinin and lysyl bradykinin) are small
vasoactive peptides generated during the inflammatory response
(Fig. 6.10). Three mechanisms of kinin formation are operant
during inflammation: (a) plasma proteins, (b) tissue proteins,
and (c) cellular proteinases.190193
SCIENTIFIC PRINCIPLES
Plasma
119
120
Neuropeptides
Neuropeptides may provide the neuroendocrine link between
psychological stress and inflammatory diseases such as psoriasis and inflammatory bowel disease. Like cytokines, their
7 actions are pleiotropic and redundant. Neuropeptides execute
their inflammatory and immunomodulatory effect by binding
to specific G-proteincoupled receptors on the surfaces of target cells, and the resultant effect may be proinflammatory,
anti-inflammatory, or both. For example, substance P mediates the hypothalamic fever response to PGE2 induced by IL-1
and TNF-, whereas adrenocorticotropic hormone (ACTH),
arginine vasopressin (AVP), and -melanocytestimulating
hormone (-MSH) suppress it. The pituitary peptides prolactin, corticotropin-releasing hormone (CRH), and AVP have
been shown to augment immune responses by enhancing TH1
activity.39,197,198
Tachykinins are important proinflammatory neuropeptides
that mediate pain and vasodilatation and promote the classic
inflammatory signs of erythema and edema. Substance P stimulates monocyte and neutrophil influx and neutrophil phagocytosis. Its inflammatory effects appear to be mediated by the
proinflammatory cytokines TNF- and IL-1 from mast cells,
monocytes, macrophages, bone marrow, and endothelial cells.
During allergic inflammation, substance P stimulates histamine release from mast cells. As an effector of immune function, substance P promotes T-cell proliferation and antibody
production. Substance P released locally by nerve terminals is
important in mediating the perception of pain.39,190
CRH induces the release of IL-1, IL-6, and superoxide
anion from macrophages and regulates its own proinflammatory effects through cortisol release. Cortisol downregulates
production of proinflammatory cytokines such as IL-1, TNF-,
and IL-2; metalloproteinases; and inducible nitric oxide synthase (iNOS), and through this negative feedback loop,
inhibits the production of CRH as well as ACTH and AVP.
AVP, growth hormone, and prolactin are other important
proinflammatory neuropeptides.39,197,198
Vasoactive intestinal peptide (VIP) and its homologues display both proinflammatory and anti-inflammatory effects. VIP
is widely distributed throughout the central and peripheral
nervous systems and serves as a chemoattractant for
macrophages, neutrophils, and T cells, and may play an
important role in granulomatous reactions. VIP stimulates the
release of histamine, and IL-5 and is a potent vasodilator. It
inhibits IL-6, TNF-, and IL-12 release and iNOS expression
in activated macrophages. VIP has also been shown to stimulate the production of the anti-inflammatory cytokine IL-10 by
macrophages and inhibit T-lymphocyte proliferation and IL-2
and IFN- production.199
Somatostatin and -MSH are primarily anti-inflammatory
in action. Somatostatin, which colocalizes with substance P in
sensory nerves, inhibits IgE formation and NK cell activity.
-MSH inhibits leukocyte chemotaxis and IFN- production
and downregulates TH1 activity. ACTH, calcitonin, and endorphin are other neuropeptides with predominantly antiinflammatory properties.39
Calcitonin gene-related peptide (CGRP) is an immunomodulator that inhibits the activity of T cells and macrophages, in
part through the induction of IL-10. It also is an inhibitor of
antigen presentation. CGRP promotes vasodilatation and neutrophil influx and synergizes with bradykinin and histamine to
promote edema formation.
hemoglobin and other endogenous substances; thus, it functions primarily in a paracrine and autocrine fashion. The
enzyme NO synthase (NOS) catalyzes the formation of NO
and citrulline from the substrates L-arginine and oxygen.50,201203 NOS contains prosthetic groups for flavin-adenine
dinucleotide, flavin mononucleotide, tetrahydrobiopterin, iron
protoporphyrin IX, and zinc. Three isoforms of NOS have
been identified. The calcium-dependent constitutive isoforms,
neuronal NOS (nNOS) and endothelial NOS (eNOS), generate
the small amounts of NO necessary for those processes maintaining physiologic homeostasis, such as neurotransmission
and endothelial regulation of vascular tone. The expression of
iNOS, however, requires stimulation and produces larger, sustained amounts of NO with both cytoprotective and cytotoxic
properties. This distinction is not absolute, as certain cell populations express low basal levels of iNOS, and constitutive
NOS transcripts can be enhanced by certain stimuli such as
shear stress and hypoxia.50,201203
Many of the physiologic effects of NO are mediated by the
activation of soluble guanylate cyclase. Increased levels of
intracellular cyclic guanosine monophosphate trigger a reduction in calcium concentration and promote vascular smooth
muscle relaxation and the inhibition of platelet aggregation
and adhesion. The cellular response to NO also likely involves
multiple signal transduction mechanisms including the MAPK
pathway.
Inflammation secondary to endotoxemia, hemorrhagic
shock, and ischemia/reperfusion are associated with increased
NO production by iNOS. iNOS, first described in macrophages,
can be expressed in essentially any cell type in response to
immunologic stimuli, and unlike nNOS and eNOS, does not
depend on elevations in intracellular calcium levels for its activity.50,201203 Important activators of iNOS upregulation include
LPS, IL-1, TNF-, and IFN-. Expression is primarily transcriptionally regulated, although stabilization of iNOS mRNA
also appears to play a role. IFN- stabilizes iNOS mRNA,
whereas TGF- can destabilize it. Transcription of the iNOS
gene is controlled by NF-B, IFN-responsive element, and
TNF-responsive element. Induction of iNOS can be inhibited
by glucocorticoids, thrombin, macrophage deactivation factor, PDGF, IL-4, IL-8, IL-10, and IL-13.50,201203 Dexamethasone may inhibit iNOS induction by impairing the DNAbinding capacity of NF-B and by increasing levels of
I-B.204,205
The endothelial dysfunction and vascular hyporeactivity
characteristic of septic shock is mediated in part by iNOS production of NO.206 NO has been shown to be the effective
mediator of the negative myocardial inotropy of TNF-, IL-6,
and IL-2 and the TNF-induced vasodilatation in the systemic and microcirculations.207 NO may indirectly increase
prostaglandin production by increasing the catalytic activity of
cyclooxygenase and decrease leukotriene production by
inhibiting 5-lipoxygenase.208 NO plays an autoregulatory role
in the TH1 subset of TH cells by limiting their own proliferation.209
NO can mediate tissue injury in inflammation by modulating organ perfusion, mediating interactions with neutrophils,
contributing to proinflammatory signaling, and regulating
apoptosis.210 Whereas eNOS primarily regulates perfusion
during homeostasis, both eNOS and iNOS modulate organ
flow in pathophysiologic states. Basal NO production from
eNOS prevents the adherence of neutrophils to the endothelium and inhibits chemotaxis under physiologic conditions.
Animal studies have demonstrated that pharmacologic inhibition of iNOS or genetic deletion of iNOS attenuates neutrophil
accumulation in organs after ischemia/reperfusion injury.211
Conversely, similar experiments in endotoxemia implicate an
antiadhesive role for iNOS, suggesting that the effect of
induced NO on neutrophil accumulation is insult specific.210
Activated neutrophils can be stimulated by fMLP, PAF, and
LTB4 to produce NO. NO produced by neutrophils at sites of
121
SCIENTIFIC PRINCIPLES
Chapter 6: Inflammation
122
DAMPs, the endogenous equivalent of PAMPs, represent danger signals or alarmins and share many characteristics similar
to cytokines.227 DAMPs may be released following nonprogrammed cell death, such as necrosis, and under such circumstances tend to elicit inflammation. By contrast, programmed
cell death (i.e., apoptosis) incorporates mechanisms such as
acetylation to minimize the release of these mediators and any
subsequent inflammatory response. Cells of the immune system
also can be induced to secrete these mediators.227 This secretion
may occur by specialized secretion systems or by the classical
ER-Golgi secretion pathway.227 Under these circumstances,
DAMPs may facilitate the inflammatory response by aiding the
recruitment of innate immune cells, most notably dendritic
cells. In doing so, they indirectly orchestrate the subsequent
adaptive immune response and facilitate tissue repair.227 The
prototypical alarmin, HMGB1, has already been discussed.
Here we briefly discus mediators recently added to this list.
123
are viable and fertile, they display a wide range of defects. Most
of these defects are subtler than expected, leading to the suggestion that other receptors with overlapping function might exist.
Signaling appears to necessitate clustering into a particular
orientation, which facilitates binding of cytosolic signaling complexes.95,235 Its ligands include products of nonenzymatic glycosidation (e.g., advanced glycation end-products or AGEs), the
amyloid- precursor protein, the S100/calgranulin family of
proinflammatory cytokinelike mediators, and HMGB1, and its
expression is upregulated at sites of diverse pathologies including
atherosclerosis and Alzheimer disease. In fact, RAGE-mediated
cellular stimulation is thought to increase expression of the receptor itself, thereby generating a positive feedback mechanism
and perpetuating the proinflammatory state.95,235,236
Recent studies demonstrate the activation of multiple signal
transduction cascades subsequent to ligand binding, including
the MAPK family (p38, ERK1/2, and JNK) and Rho GTPases
(cdc42 and rac).236 Like TLRs and IL-1R, RAGE engagement
leads to NF-B activation, suggesting that both receptor usage
and signaling pathways evoke similar responses when cells are
activated by PAMPs and DAMPs. It is currently hypothesized
that RAGEligand interaction induces a new heightened basal
state of activation. With a superimposed stimulus, cellular perturbation is magnified. Rather than returning to homeostasis,
cellular signal transduction mechanisms favor augmented dysfunction.95,235
Studies have implicated RAGE to be an important receptor
during various acute and chronic inflammatory processes as
well as tumor biology. RAGE expression and function directly
correlated with tumor growth in RAGE-transfected C6 glioma
cells. In a murine tumor model, in mice treated with soluble
RAGE, which functions as a decoy, there was a reduction in
lung metastases, cellular invasion, and expression of matrix
metalloproteinases.236
RAGE has also been identified as a receptor for S100A12,
a member of the S100/calgranulin family of proinflammatory
mediators. Endothelial cells cultured with S100A12 displayed
RAGE-dependent expression of VCAM-1 and tissue factor.
Mononuclear phagocytes displayed S100A12-RAGE chemotaxis, expression of tissue factor, and elaborated IL-1 and
TNF-. In vivo studies of delayed-type hypersensitivity
demonstrated reduced inflammatory response when mice were
treated with anti-RAGE F(ab)2, anti-S100 F(ab)2, or soluble
RAGE. Treated animals also displayed reduced NF-B activation and IL-1 and TNF- expression.236
The angiopathy of diabetes is thought to be consequent to
inflammatory processes generated by elevated glucose concentrations. Hyperglycemia has been demonstrated to activate
numerous signaling cascades. One process that might mediate
these effects is through the nonenzymatic formation of
AGEs.95,235,236 AGERAGE interactions on endothelium lead
to the expression of procoagulant tissue factor and VCAM-1
and macrophage-released tissue factor. Animals treated with
soluble RAGE showed decreases in atherosclerotic lesion area
and number and a marked reduction in lesion complexity. Also,
treated animals had reduced expression of adhesion molecules,
tissue factor, MCP-1, and matrix metalloproteinases.95,235,236
CD91
The immunologic properties of HSPs were discovered by their
ability to elicit antitumor immunity. It was later discovered
that this antigenic specificity was determined by the peptides
they chaperoned. APCs can bind and internalize HSPpeptide
complexes derived from virus-infected cells or tumors and represent them on MHC class I molecules. In addition, APC
engagement of HSPpeptide complexes induces maturation,
the expression of costimulatory molecules, and the induction
and release of cytokines (TNF-, IL-1, IL-12, IL-6, GM-CSF,
MIP-1, RANTES, and NO).237,238
SCIENTIFIC PRINCIPLES
Chapter 6: Inflammation
124
CD91 had been identified as a receptor for the serum protein 2-macroglobulin, a natural protease inhibitor that, like
HSPs, is found across many species. In fact, 2-macroglobulin
is the evolutionary precursor of the C3 complement component. By binding pathogen proteases utilized during invasion
and shuttling them for endocytosis, 2-macroglobulin hinders
pathogen invasion.237,239
However, such a method of host defense would be ineffective for intracellular pathogens that gain access by alternative
means, such as mimicking host proteins and developing ligands for host receptors. Hence, another method of signaling
danger is necessary. It is currently thought that upon cell
death, HSPs contained within the cell transfer information
regarding the infected intracellular environment to CD91.
This large cell surface receptor, complexed with the HSPs, is
internalized and delivers antigen into the classical MHC class
I pathway. The MHCs bind and present them to CD8 T cells.
On recognizing nonself, T cells are induced to proliferate and
mediate killing. This mechanism could be generalized to implicate CD91 and HSP interactions in the recognition of all cellular stress that culminates in injury and death.239
CD91 was first identified by Binder et al. as the receptor for
Gp96 and then by Basu et al. as a common receptor for other
HSPs (HSP70, HSP90, and calreticulin).240,241 This large multidomain 600-kD protein possesses multiple binding sites for
at least 32 ligands. The binding of this receptor to many members of the HSP family has been corroborated by several independent functional and structural studies.239
Several in vivo studies suggest a physiologic relevance for
HSPCD91 interaction. Mice immunized with tumor-derived
Gp96peptide complexes reject a subsequent tumor challenge. If
CD91 antiserum is mixed with the HSP-peptide inoculum, the
mice fail to reject the tumors. Binder et al. noted that blocking of
CD91 completely inhibits the phenomenon of re-presentation of
peptides that are carried or chaperoned by HSPs, suggesting that
not only is CD91 a receptor for HSPs, but it may also be the sole
receptor involved in antigen re-presenting.238,241
HSPs have been shown to chaperone antigenic peptides
(tumor, viral, minor histocompatibility antigens) from all cellular compartments. The HSPs thus appear to be a universal
mechanism for antigen capture, and they permit a high-efficiency
antigen uptake through a receptor-mediated mechanism.
Evidence that HSPpeptideCD91 interactions serve to signal cellular stress is beginning to culminate. Basu et al. demonstrated that HSP70, HSP90, Gp96, and calreticulin are released
from cells as a result of necrotic cell death, but not apoptotic
cell death.240 Similarly, Melcher et al. reported that tumor cells
undergoing necrotic death are highly immunogenic as compared to those undergoing apoptotic death.242 Actual necrosis
may be unnecessary as stressed cells and cancer cells have been
reported to express cell surface HSP molecules, which may activate APCs. Zheng et al. observed that physical contact of
tumor cells artificially engineered to express cell surface HSPs
with immature DCs elicits a powerful maturation of DCs.243
Other Heat Shock Protein Receptors. CD40 was reported as a
receptor for HSP70 when anti-CD40 antibodies were observed
to inhibit macrophage chemokine secretion in response to
mycobacterial HSP70. Subsequently, Becker et al. noted the
association of recombinant GST-tagged CD40 with murine
HSP70.244,245 They further demonstrated enhanced binding after
the APCs were stimulated with LPS. As LPS induces expression
of a number of cell surface molecules, the authors concluded that
CD40 mediates recognition and binding of HSP70.246
CD36 has been implicated as a receptor for Gp96. Transfection of CD36 into CD36-negative cells has been shown to
enhance Gp96 binding. In addition, CD36/ macrophages have
a 52% reduction in Gp96 binding compared with wild-type
controls, suggesting some role for CD36 as an HSP receptor.246
LOX-1, a member of the same scavenger superfamily as
CD91 and CD36, has been postulated to be an additional
125
SCIENTIFIC PRINCIPLES
Chapter 6: Inflammation
126
Mediators of the Acute-phase Response. Bacterial products such as LPS are probably the most potent activators of tissue macrophages, the initiators of the acute-phase response.
LPS, through its interactions with LPS-binding protein, CD14,
and Toll-like receptors, induces macrophage synthesis of ROS,
including NO; lipid derivatives such as PGE2, thromboxane A2,
and PAF; and acute-phase cytokines. The primary signals
inducing synthesis of acute-phase cytokines in the absence of
bacterial infection may be free radicals, prostaglandins, or
modified proteins acting like foreign materials.39
Acute-phase cytokines can be proinflammatory (IL-1, TNF-,
IFN-, IL-8) or anti-inflammatory (IL-10, IL-4, IL-13, TNF-).
However, it is IL-6 and IL-6type cytokines that are most
critical in the acute-phase response. IL-6 is the major inducer
of acute-phase protein synthesis and, together with IL-1 and
TNF-, is responsible for the systemic features classically associated with the acute-phase response (fever, anorexia, leukocytosis, and hormonal changes).39
In addition to the aforementioned cytokines, IFN- is a
potent inducer of complement components. The anti-inflammatory cytokine TGF- stimulates synthesis of antiproteases,
urokinase, and negative acute-phase proteins. IL-4 is inhibitory
to some acute-phase proteins. Growth factors, including hepatocyte growth factor and TGF-, are also able to modulate the
synthesis of acute-phase proteins. Glucocorticoids augment the
response to cytokines, and insulin attenuates the cytokineinduced rise in acute-phase proteins.39
Effects of the cytokines are influenced by cytokine receptors, receptor antagonists, and hormones. IL-1RA competes
with IL-1 and attenuates the acute-phase response in vivo. Soluble receptors for IL-1 and TNF- act as antagonists. In contrast,
soluble receptors for IL-6 act as agonists.
Regulation of Acute-phase Cytokines and Proteins.
Several major families of transcription factors participate in
the upregulation of acute-phase cytokines and proteins, the
most important being NF-IL-6, AP-1, and NF-B.260 NF-IL6
participates in the induced expression of the cytokines IL-1,
TNF-, IL-6, and IL-8, among others. Activation of cytokine
gene expression by NF-B is probably the most important
pathway. The triggering of IL-6 in monocytes in vitro by IFN-
involves a change in the amount of the phosphorylated transcription factor Sp1, together with the induction and activation of IFN-regulatory factor.
All known acute-phase proteins are regulated primarily at
the transcriptional level. Activation of TNF- and IL-1 receptors triggers signaling pathways that activate transcription factors AP-1 and NF-B. Many type I acute-phase protein genes
contain response elements for NF-B, NF-IL-6, and AP-1.
Acute-phase protein responses to IL-6 are mediated through
the JAK/STAT signal transduction pathway. In addition, both
IL-1 and IL-6 signal transduction mechanisms activate the
MAPK pathway that activates transcription factor NF-IL-6,
linking the IL-1 and IL-6 pathways.
Reperfusion Injury
Prolonged tissue ischemia produces irreversible injury and cell
death. Timely restoration of perfusion may salvage some tissue, though paradoxically can induce injury as well. Reperfusion injury is the damage caused by the restoration of blood
flow in previously ischemic tissue (i.e., myocardial ischemia,
transplantation, vascular surgery). Injury is the direct consequence of activation of the inflammatory response, especially
complement activation and neutrophil recruitment. Components of the complement cascade promote tissue damage
through the generation of anaphylatoxins and by the formation of the MAC. Invading neutrophils injure tissue through
the generation of ROS and the release of proteolytic enzymes.
Recent evidence points to TLR4 as a sensor of tissue stress
probably through the release of DAMPs from ischemic cells.32
TLR4 stimulation leads to the activation of local and systemic
inflammation in both warm and cold reperfusion. This inflammation contributes to tissue damage in this setting.
Alterations in the microvascular endothelium are central to
the pathophysiologic process of reperfusion injury. Early loss of
constitutive NO production facilitates neutrophil adherence
and the upregulation of cell adhesion molecules such as Pselectin, and inhibits vasorelaxation and perfusion.261 Low
oxygen tension induces the conversion of xanthine dehydrogenase to xanthine oxidase. Reperfusion and reoxygenation yield
the formation of superoxide anion and H2O2 and induce oxidant injury. Neutrophils and other cellular effectors are progressively recruited and activated, releasing ROS, cytokines,
and NO, further contributing to increased vascular permeability and tissue injury. PAF released by neutrophils activates circulating platelets and promotes vascular plugging. Platelets
also release factors that enhance plateletneutrophil adhesion.
Both cell types also release vasoconstricting agents that can further exacerbate no-reflow. Capillary plugging by neutrophils
and platelets can impair local blood flow and cause the noreflow phenomenon.39
Neutrophils mediate direct toxicity to the surrounding tissue through the elaboration of ROS and granule contents. Peroxynitrite formed by the reaction of NO and superoxide can
contribute directly to tissue injury during reperfusion. Neutrophil granule proteases such as elastase, collagenase, and
gelatinase alter the vascular permeability and are highly
destructive to local tissue. The significance of the neutrophil in
mediating these effects is apparent in neutrophil depletion studies demonstrating attenuated tissue injury compared with subjects with normal numbers of neutrophils.262 Animal studies
using blocking monoclonal antibodies to selectins and 2 integrins show improved organ function ischemia/reperfusion.263
The mechanism by which complement is activated with
reperfusion is not completely understood. Ischemia may alter
the cells plasma membrane or through the exposure of basement membrane or subcellular organelle components, creating
a complement-activating surface. Alternatively, binding of natural antibody may lead to induction of these cascades.171
Complement activation has been shown to occur in the setting
of therapeutic thrombolysis. The generation of plasmin-dependent fibrinolytic agents and plasmin after tissue plasminogen
activator administration has been associated with complement
activation.264
Anaphylatoxins are important effectors of complementmediated injury. They alter vascular permeability and induce
smooth muscle cell contraction and the release of histamine
from mast cells and basophils. C3a and C5a are potent
chemoattractants especially for neutrophils. C5 can be activated by oxygen free radicals, which are abundant. The subsequent generation of the MAC perturbs the maintenance of
vital ion gradients, induces cell lysis, and facilitates neutrophil
recruitment. In addition, it can induce the expression of
numerous inflammatory mediators, including cytokines (TNF-,
IL-1, IL-8), ROS, prostaglandins, leukotrienes, and cell surface
adhesion molecules.265
127
metabolism, and end-organ failure. The metabolic and nutritional sequelae of this activated cytokine milieu includes fever,
catabolism, cachexia, and altered fat, glucose, and trace mineral metabolism.
SIRS is counteracted by the concomitant induction of an
anti-inflammatory response termed the compensatory antiinflammatory response syndrome (CARS).269 Many of the
proinflammatory mediators that participate in SIRS modulate
the immune function of lymphocytes and mononuclear cells.
Proinflammatory mediators can inhibit their own synthesis or
enhance the synthesis of natural antagonists by negative feedback mechanisms. Thus, at any given time, the clinical manifestation is SIRS, CARS, or an intermediate, mixed inflammatory
response syndrome. The spectrum of features that characterize
these syndromes has been termed CHAOS (cardiovascular
shock, homeostasis, apoptosis, organ dysfunction, and
immune suppression). Studies employing a variety of specific
anticytokine agents have failed to observe an improvement in
the outcome of patients with SIRS or sepsis. However, two
studies of immunomodulation have noted significant effects in
septic populations. The PROWESS study of activated protein
C underscores the importance of the coagulation cascade during inflammation. This randomized controlled trial noted a
19.6% relative reduction and a 6.1% absolute reduction in
mortality for those patients with severe sepsis who received
activated protein C.270 Another study used a combination of
corticosteroid and mineralocorticoid replacement for those
patients with sepsis who had relative adrenal insufficiency as
defined by a less than 10 unit increase in cortisol after a
Cortrosyn stimulation test. They documented a 33% related
reduction and 10% absolute reduction in the risk of death for
those patients who received steroids.271
Chronic Inflammation
There are no clear boundaries between an acute and a chronic
inflammatory response. In general, if the source of an acute
inflammatory process is incompletely eliminated, a state of
chronic inflammation eventually ensues. Chronicity is usually
not characterized by the signs classically associated with acute
responses, such as swelling, heat, or redness. Pain is minimal if
not absent. Microscopically, a mononuclear cell infiltrate predominates (lymphocytes, monocytes, plasma cells) with proliferation of fibroblasts and vascular elements.
Many agents can create a state of chronic inflammation,
including persistent infectious agents, remnants of dead organisms, foreign bodies, and metabolic byproducts. Ultimately,
chronicity of inflammation is a result of the immune response
to a persistent antigen. Furthermore, a chronic inflammatory
response can develop in the absence of a preceding acute
response, such as infections with agents of low toxicity such as
mycobacterium and treponema. CD4 T cells and macrophages are the primary cellular orchestrators of the chronic
inflammatory response.272 TH1 cell-mediated immunity (CMI)
responses are protective against most microbes and usually
result in the elimination of the pathogen. If the microbe persists, the ongoing TH1 response results in inflammatory tissue
injury. Cytokines and growth factors released by T lymphocytes and macrophages stimulate proliferative responses. Neutrophils and eosinophils contribute to the release of proteolytic
enzymes and oxygen derivatives. Eosinophilia occurs with
chronic parasitic infections and hypersensitivity conditions.
Fibroblasts are actively recruited by chemoattractants such as
fibrin, collagens, and cytokines. Local IL-1 stimulates fibroblast proliferation and collagen production. Irreversible tissue
damage can occur through the replacement of normal
parenchyma with fibrous connective tissue. Fibroblasts can
release metalloproteinases that degrade normal tissue, further
contributing to tissue destruction. Mast cells are elevated in
chronic conditions and may play a part in cell-mediated
SCIENTIFIC PRINCIPLES
Chapter 6: Inflammation
128
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SCIENTIFIC PRINCIPLES
Chapter 6: Inflammation
K E Y
Surgical infections require surgical intervention, that is,
source control, which refers to a mechanical or anatomic
procedure to drain an abscess, relieve an obstruction, repair
a perforation, or resect dead, ischemic, or inflamed tissue or
foreign body to promote resolution.
Source control is combined with empiric antibiotic therapy
that is later modified based on microbiologic susceptibility
patterns.
Empiric antibiotic therapy requires knowledge of the current patterns of pathogens involved and antibiotic susceptibility within the institution and, even, specific units, such as
the intensive care unit.
Surgical site infections are dependent on numerous factors,
including extent of contamination, hemostasis, tissue handling, length of operation, tissue hypoxia, patient temperature,
and glucose control, in addition to minimizing comorbidities.
Antibiotic prophylaxis should be dosed to maintain adequate tissue concentrations during the period of potential
contamination, starting approximately 1 hour or less prior
to surgery; repeated after one to two half-lives during prolonged operations, with increased doses in large patients;
and stopped within 24 hours postoperatively if not immediately at the end of the operation. Choose a first-generation
cephalosporin if no anaerobes are expected and add
metronidazole if anaerobic activity is likely. Consider vancomycin only if there is a history of methicillin-resistant
Staphylococcus aureus (MRSA) colonization or infection,
for a dialysis patient or a patient with recent hospitalization or antibiotic treatment, or if there is a high rate of
MRSA surgical site infections in your institution.
6 With peritonitis, antibiotics active against aerobic gramnegative organisms prevent early mortality and those active
against anaerobic organisms prevent abscesses. Thus, broadspectrum antibiotics are needed.
7 Necrotizing soft tissue infections are hard to diagnose, present with external skin changes underrepresenting the
extent of underlying disease, and have potential for major
tissue loss and high morbidity and mortality.
P O I N T S
132
133
TREATMENT
DIAGNOSIS
Although details specific to the diagnosis of specific surgical
infections and other infections in surgical patients are covered
in those individual sections, some items of diagnosis are common to all. Some relatively straightforward infections such as
superficial SSIs or subcutaneous abscesses are properly treated
by simply opening the wound or draining the abscess without
the use of antimicrobial agents and do not require routine cul2 ture. However, most surgical infections require at least the initial use of antimicrobial agents that are most effective if active
against the primary pathogens involved. If initial treatment is
clearly successful, then knowledge of the specific pathogens
and their susceptibilities is not critical for the treatment of that
patient. However, when the patient does not respond as
expected, then knowledge of the pathogens and their susceptibilities can be extremely useful, and this information will not
be available unless the appropriate cultures were obtained
prior to initiating antibiotic therapy.
SCIENTIFIC PRINCIPLES
134
TA B L E 7 . 2
CLASSIFICATION
TA B L E 7 . 1
Clean
Clean-contaminated
Contaminated
Dirty
ALL
Clean
1.0
2.3
5.4
2.1
Clean-contaminated
2.1
4.0
9.5
3.3
Contaminated
3.4
6.8
13.2
6.4
Dirty
3.1
8.1
12.8
7.1
All
1.5
2.9
6.8
13.0
2.8
2.1
1.7
1.8
1.0
Maximum ratio
one risk point for each of (a) contaminated or dirty wound, (b)
American Society of Anesthesiologists (ASA) class 3 or higher,
and (c) duration of operation exceeding the 75th percentile for
that operation.9 Thus, an operation may fall into one of four
classes between 0 and 3. Table 7.29 demonstrates the increased
precision of this system compared with the older system that
refers only to wound class. This system can be used to roughly
compare the performance of a hospital or surgical department
against the NNIS database by comparing expected with
observed infection rates.10 Of course, much more precise risk
data can be developed for single operative procedures through
analysis of large databases in which the heterogeneity imposed
by multiple different procedures is eliminated.11,12
Many other factors that influence the risk of SSI have been
proposed, and a relatively complete summary of these factors
is provided in a publication by the Hospital Infection Control
Practices Advisory Committee (HICPAC) of the CDC.6 Some
of these are summarized in Table 7.3, which lists the category
1 recommendations that are readily influenced by the surgeon.
It is likely that the majority of these are important in most
operative procedures, although most have been generated
through analysis of single procedures or limited classes of procedures and have not been reproduced in all cases. Many, such
as the patients weight and smoking status or the presence of
an infection at a distant site, are modifiable prior to scheduled
operation. Others, such as age or underlying immune disorders, cannot be improved. Some, such as diabetes, cannot be
eliminated, but recent information suggests that tight control
of perioperative glucose levels can greatly reduce the risk associated with this diagnosis.1315
WOUND CLASSIFICATION
DEFINITION
CLASSIFICATION
CLASS
WOUND CLASS
Prevention
4
Preventing SSIs is clearly a prime responsibility of any operating surgeon. Although many surgeons think first of prophylactic antibiotics for prevention, and these are clearly important,
antibiotics are most effective when they complement maximal
efforts for prevention by other means. Two classic papers on
surgical prophylaxis, each of which demonstrated the superiority of prophylactic antibiotics to placebo in randomized
prospective trials, also demonstrated an increased infection
TA B L E 7 . 3
TREATMENT
CDC, Centers for Disease Control and Prevention; SSI, surgical site
infection.
a
These items are required by Occupational Safety and Health
Administration (OSHA) regulations and are not actually supported by
class 1 data.
From Mangram AJ, Horan TC, Pearson ML, et al. Guideline for
prevention of surgical site infection, 1999. Hospital Infection Control
Practices Advisory Committee. Infect Control Hosp Epidemiol.
1999;20:250278, with permission.
135
SCIENTIFIC PRINCIPLES
136
TA B L E 7 . 4
RESULTS
PLACEBO (%)
NNTa
35
Colon
412
2448
Other (mixed) GI
46
1529
49
Vascular
14
717
1017
Cardiac
39
4449
23
Hysterectomy
116
1838
36
Craniotomy
0.53
412
929
0.51
29
12100
3.5
5.2
58
GI, gastrointestinal.
a
Approximate number needed to treat (NNT) to avoid one surgical site infection.
TA B L E 7 . 5
137
MANAGEMENT
SUMMARY OF PUBLISHED GUIDELINES ON ANTIMICROBIAL PROPHYLAXIS FOR OPERATIONS TARGETED FOR SURVEILLANCE
IN THE NATIONAL SURGICAL CARE IMPROVEMENT PROJECT (SCIP)
Cardiothoracic surgery
PROPHYLACTIC ANTIBIOTIC
RECOMMENDATION
COMMENTS
Cefazolin
Cefuroxime
Vancomycin
If -lactam allergy:
Vancomycin
Clindamycin
Vascular surgery
Cefazolin
or hip or knee arthroplasty Cefuroxime
Vancomycin
If -lactam allergy:
Vancomycin
Clindamycin
Colon surgery
Parenteral:
Cefazolin
Cefotetan
Cefoxitin
Cefuroxime
Ampicillin-sulbactam
If -lactam allergy:
Clindamycin plus an aminoglycoside
or a quinolone or aztreonam
OR
Metronidazole plus an aminoglycoside
or a quinolone
OR
Clindamycin monotherapy
OR
Metronidazole monotherapy
Adapted from Bratzler DW, Houck PM. Antimicrobial prophylaxis for surgery: an advisory statement from the national surgical infection prevention
project. Clin Infect Dis 2004;38:17061715, with permission. Available at: http://www.qualitynet.org/dcs/ContentServer?cid1137346750659&
pagenameMedqic%2FContent%2FParentShellTemplate&parentNameTopicCat&cMQParents. Accessed December 1, 2008.
SCIENTIFIC PRINCIPLES
OPERATIONS
138
earliest signs were fever, diarrhea, and vomiting. Erythroderma and hypotension were also present. Often, local signs of
wound infection were initially absent. Drainage and irrigation
of the wound in combination with a systemic antistaphylococcal antibiotic is recommended.
Although most wound infections are diagnosed within 2
weeks after the procedure, diagnosis may occasionally be considerably delayed. This is more likely when a significant
amount of tissue covers the operative site such as abdominal
incisions in morbidly obese patients. Because many patients
have some fever in the first several days after a major operative
procedure even without infection, fever is not a specific sign of
postoperative infection (Fig. 7.1).51 Many surgeons want to
continue prophylactic antibiotics or to restart antibiotics in cases
with early postoperative fever, but this is unlikely to be helpful.
In addition, SSI cannot be treated without opening the incision. If antibiotics are given for an SSI without opening the
wound, this can result in a delay in diagnosis and definitive
treatment, additional morbidity, and additional complications
such as wound dehiscence.
Therapy
The most important treatment for an SSI is to open the incision and evacuate the infected material. Antimicrobial agents
are needed only when a patient exhibits a significant systemic
response to the infection or when there is clinical evidence for
Operation
Fever in first 48 hr
Unlikely to
represent
wound infection
Systemic illness
No systemic illness
Wound drainage
No wound
infection, observe
Gram stain to
rule out streptococcal
and clostridial infection
Either found
Erythema
or
induration
Wound
normal
to exam
Open wound
Temp <38C
WBC <12,000
Erythema <5 cm
Dressing changes,
no antibiotics
Temp >38C
WBC >12,000
Erythema >5 cm from incision
with induration or any necrosis
Begin antibiotics
and dressing changes
None
Clean wound, trunk,
head, neck, extremity
Open wound,
dbride, start
penicillin
Seek other
sources of
fever
Start cefazolin
or oxacillin
Wound of perineum or
operation on
GI tract or female
genital tract
Start cefotetan or
ampicillin/sulbactam
ALGORITHM 7.1
ALGORITHM 7.1. Managing potential surgical site infections. (Adapted from Dellinger EP. Post-operative wound infections. In: Schlossberg D,
ed. Clinical Infectious Disease. New York: Cambridge University Press; 2008:769773.)
100
Fevers (%)
80
Undiagnosed
60
Wound infection
40
Respiratory
20
0
1
>7
Days
FIGURE 7.1. Percentage of all postoperative fevers occurring on the
indicated day following an operative procedure. Lines indicate the percent of fevers occurring on each day attributable to the cause indicated. (After Dellinger EP. Approach to the patient with postoperative
fever. In: Gorbach S, Bartlett J, Blacklow N, eds. Infectious Diseases.
Philadelphia, PA: Lippincott Williams & Wilkins; 2004:817823.)
INTRA-ABDOMINAL INFECTIONS
Prevention
Most intra-abdominal infections are the result of spontaneous
disease including such conditions as appendicitis, diverticulitis, obstructed or perforated carcinomas, or inflammatory
bowel disease. Here, prevention depends on early diagnosis
and treatment of the underlying condition. However, an
increasing proportion of intra-abdominal infections from
series published in the past few decades have been postoperative, reflecting the increasing number of operative procedures
performed, the increasing risk status of the patients, and the
complexity of the operations performed. In the case of postop-
139
Diagnosis
Intra-abdominal infections are usually divided into peritonitis, a
poorly localized infection of the peritoneal space, or intraabdominal abscess, a localized infection within the abdomen.
Peritonitis can be relatively local within one quadrant or region
of the abdomen, as in early gangrenous or perforated appendicitis, or diffuse in two or more abdominal quadrants. Diffuse peritonitis has a worse prognosis than peritonitis localized to one
quadrant.52 Abscesses may occur within the free peritoneal space
in the subphrenic regions, lateral gutters, pelvis, or interloop
within the intestinal folds, or they may occur in the retroperitoneum or within a solid organ (visceral) such as liver or spleen.
Peritonitis has traditionally been divided into primary and secondary peritonitis, and in recent years the concept of tertiary
peritonitis has been proposed. Primary peritonitis describes
those patients with ascites due either to hepatic cirrhosis or to
nephrotic syndrome who develop infected ascites presumably
secondary to bacteremia and without evidence for perforation or
underlying GI tract pathology. If the diagnosis of primary peritonitis can be made, these patients are best treated with antimicrobial agents alone and without operation. Because of their
severe underlying disease, they are at high risk for poor outcome.
Secondary peritonitis refers to peritoneal infection that occurs
secondary to another underlying disease such as bowel perforation. Tertiary peritonitis is a condition first recognized toward
the end of the last century and describes patients who continue
to have evidence of poorly localized intra-abdominal infection
after initial operative and antimicrobial treatment of secondary
infection. At subsequent interventions, these patients tend to
have evidence of diffuse inflammation without bowel perforation, and cultures return a variety of bacteria that are not common pathogens in the peritoneum such as coagulase-negative
staphylococci, Candida sp., enterococcus, and Pseudomonas
sp.53 The categorization of secondary intra-abdominal infection
can also be divided into spontaneous infection, those cases arising from underlying disease, and postoperative infection, occurring after operative intervention or other procedures or trauma.
Recent series show that approximately 66% of intra-abdominal
infections are spontaneous and 34% are postoperative.52
The diagnosis of intra-abdominal infection is almost
always first suggested by abdominal pain. This supplemented
with a directed history and an exam demonstrating abdominal
tenderness strengthens the case. Fever and elevated WBC
count are often present, but early cases of appendicitis and
diverticulitis will sometimes present with normal temperature
and/or WBC count. In patients with diffuse peritonitis such as
follows freely perforated bowel or ulcer, the diagnosis is usually made by clinical examination, and this can be followed by
resuscitation and operative management without additional
sophisticated studies. With abscess, however, the clinical picture
is often less straightforward and the addition of cross-sectional
imaging techniques, particularly CT scanning, can be very
helpful, whereas radionuclide scans have limited usefulness in
the diagnosis of intra-abdominal abscess.
SCIENTIFIC PRINCIPLES
140
The initial antimicrobial treatment of intra-abdominal infection is always empiric. The diagnosis is made clinically, and
antimicrobial therapy is started when the diagnosis is made
and while the patient is being prepared for the source control procedure. Cultures should be taken in the operating
room or radiology suite, but bacterial identification will not
be available for at least a day for aerobic and facultative
species and for at least 2 days or more for anaerobes. Susceptibility data will not be available for an equivalent
amount of time after that. Accordingly, the first 2 to 5 days
of treatment are empiric and will be completed without specific susceptibility data. The potential bacterial flora of peritonitis is complex. At least 400 different bacterial species
can be identified in the human colon.60 Despite this, clinical
NECROTIZING SOFT
TISSUE INFECTIONS
Necrotizing soft tissue infection refers to a spectrum of surgical infections that involve tissue necrosis but are not localized
or walled off as abscesses are. These include clostridial infections, which are rare, and nonclostridial infections. Historically, a great variety of labels have been applied to the nonclostridial infections, and in some cases attempts are made to
distinguish one from another (Table 7.7).75 However, these
TA B L E 7 . 6
TREATMENT
CLASSIFICATION
Gangrenous erysipelas
Necrotizing erysipelas
Hemolytic streptococcal gangrene
Nonclostridial crepitant cellulitis
Nonclostridial gas gangrene
Synergistic necrotizing cellulitis
Bacterial synergistic gangrene
Necrotizing fasciitis
Necrotizing cellulitis
Fournier gangrene
141
Diagnosis
The most important aspect for effective treatment of necrotizing soft tissue infections is early diagnosis. Delay in diagnosis
affects outcome adversely. The following physical signs are
strongly suggestive of necrotizing infection and merit exploration of the wound in the operating room: any skin necrosis,
crepitus, gas in tissue detected by radiologic examination, bullae, or ecchymosis. Other suggestive criteria include marked,
or woody, edema beyond the area of inflammation or progression of the infection despite apparently appropriate
antimicrobial therapy. Although necrotizing soft tissue infections have a reputation for progressing very rapidly, and many
do, leading to potential early death, they can also be more
indolent and simply persist until diagnosed and dbrided.79
The diagnostic significance of infection-associated gas is
worth an explanation. When aerobic and facultative bacteria
are able to use oxidative metabolic pathways, they produce
CO2 as do mammals. CO2 is highly soluble and is readily carried away by blood flow in perfused tissue. However, when
facultative and anaerobic bacteria are forced to use nonoxidative metabolic pathways, they rely on fermentation, denitrification, or deamination. These processes produce nitrogen and
hydrogen, which are relatively insoluble and accumulate in the
surrounding tissue. Thus, the presence of gas in tissue with
infection implies anaerobic metabolism, which is incompatible
with living host tissue. This implies that the infection is in nonperfused, dead tissue and requires dbridement or drainage.
The persistent difficulty of diagnosis using signs and symptoms
has led clinicians to search for other aids to diagnosis. Multiple
reports examining the role of ultrasound, CT scans, and magnetic
resonance imaging suggest that these techniques have increased
sensitivity for detecting abnormalities in affected tissues but are
not specific and frequently are unhelpful in distinguishing
between soft tissue infections that require operative intervention
from those that do not.79,80 In addition, biopsy and frozen section
examination of affected tissues have been suggested.81 However,
if enough suspicion exists to do a biopsy, most experienced surgeons can recognize the extent of the process and need for
dbridement visually when the incision is made.79
Treatment
Operative management of these infections requires exposure
of all affected tissue. This usually necessitates incision through
uninvolved skin for a significant distance. Necrotic tissue
should be dbrided, and involved areas must be exposed, but
this does not necessarily require excision of overlying tissues
unless they are rendered ischemic by the incisions. Careful
planning of incisions should be able to avoid this in most cases.
On an extremity, amputation may be required for a clostridial
infection, and, although this is uncommon for nonclostridial
soft tissue infections, amputation may still be lifesaving
and should not be delayed if indicated. Intraoperatively, lack
SCIENTIFIC PRINCIPLES
142
OTHER NOSOCOMIAL
INFECTIONS IN
SURGICAL PATIENTS
Surgical patients are also susceptible to a number of nonsurgical nosocomial infections during hospitalization. The appropriate care of these patients demands an understanding of the
prevention and treatment of these infections.
tional education program to emphasize the importance of insertion technique has been shown to lower infection rates.87 Skin
preparation with a chlorhexidine solution results in lower infection rates than preparation with povidone-iodine solutions.88 All
intravascular devices are susceptible to infection, and the risk
increases the longer the catheter is in place. However, changing
central lines on a particular schedule does not decrease infection
risk.89,90 The final risk is related to the number of days that any
catheter is in place. Subclavian central venous catheters have a
lower risk of infection than internal jugular catheters. Recommendations for the use of antimicrobial-coated catheters are not
well established because one must balance the risk of line infection against the risk of additional antimicrobial exposure to the
patient and to the environment. When the local rate of infection
is high, they are probably justified.90 The single most impressive
effort in reducing central lineassociated infections has been a
program that bundles all of these components together, uses a
checklist, and empowers all members of the medical/surgical
team to take responsibility for adherence to the bundle.91
The diagnosis of catheter-related bloodstream infection is
made by isolating the same organism from the bloodstream
and from a semiquantitative culture of the catheter tip. To
make a diagnosis of catheter-related bloodstream infection
without removing the catheter, draw simultaneous cultures
through the line and from a different peripheral source. A line
infection is indicated when the quantitative culture of the line
is equal or greater than five times the peripheral quantity or
when the line culture turns positive 2 hours or more before the
peripheral culture. When the diagnosis is made, the catheter
should be removed. Bacteremia should be treated by a specific
antimicrobial agent and, for S. aureus, gram-negative rods, or
fungi, should be continued for 10 to 14 days.92 For coagulasenegative staphylococci, the most common pathogen, duration
of treatment can be limited to the period of systemic response
after removal of the catheter.
Pneumonia
Pneumonia is less common than SSI and UTI on surgical services but when it occurs is a major source of morbidity and
mortality. Prevention of postoperative pneumonia is best
accomplished by policies and procedures that emphasize the
early extubation of ventilated patients, the use of noninvasive
positive-pressure ventilation when feasible, and elevation of
the head of the bed for ventilated patients. Diagnosis can be
made by physical examination and chest radiograph in the
spontaneously breathing postoperative patient. The diagnosis
can be much more challenging in the ventilated ICU patient.
These patients often have abnormal chest films and physical
findings as well as fever and leukocytosis in the absence of
pneumonia. In addition, all patients with an endotracheal tube
for more than a few days are likely to have bacteria in tracheal
aspirates independent of infection. Overtreatment of suspected
infection is common, and restriction of treatment for patients
without demonstrated pneumonia improves outcome.93 On the
other hand, delayed, specific treatment of true infection
increases mortality.94,95 For this reason, procedures that produce
a more specific diagnosis of pneumonia and that help to rule out
the diagnosis when pneumonia is not present, such as bronchoalveolar lavage and protected specimen brush cultures, have
an important role in the care of ventilated ICU patients.9698
Cultures of expectorated sputum or of simple endotracheal
aspirates are very nonspecific and of little use in diagnosing
pneumonia. When pneumonia is diagnosed, treatment duration
should be limited. Usually 7 to 8 days is sufficient.99
urinary catheters placed in the operating room. A primary preventive measure for UTI is to use urinary catheters only when
actually necessary due to the location of the operative procedure or the length and complexity of the operation. When a
catheter is required it should be removed as soon as possible,
often at the end of the operative procedure or on the first postoperative day. When a catheter must be left in place, a closed
system should always be used. The risk of UTI doubles on any
day when the integrity of a closed system is violated.
In a patient without a catheter, the diagnosis of UTI is traditionally made when a quantitative culture shows greater
than 105 organisms per milliliter of urine. In patients with
catheters, much lower colony counts may represent true infection. Attempts to clear bacteriuria when the catheter is in place
usually fail. If the patient is symptomatic, specific antimicrobial treatment should be followed by a catheter change. If the
patient is not symptomatic, specific antimicrobial treatment
should be given after the catheter has been removed.
PATHOGENS
As noted in the beginning of this chapter, most surgical infections are caused by endogenous microorganisms that gain
access to the body after violation of an epithelial barrier. Specific
pathogens are identified through culture in the microbiology
laboratory, but earlier information can be obtained through
examination of a Gram-stained smear of material taken from
the infected site. Gram-positive cocci are very commonly found
in soft tissue infections and can represent Staphylococcus sp.,
either S. aureus or coagulase-negative staphylococci, or streptococcal species. Coagulase-negative staphylococci are the most
common pathogens found in catheter-related bloodstream
infections but cause serious infections in other locations rarely.
S. aureus possess virulence characteristics that enable them to
invade healthy tissues and form abscesses and are usually significant when recovered. Extensive use of -lactam antibiotics has
led to the emergence of MRSA in many areas, and recently some
strains of vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA) strains have emerged. In the
first decade of the 21st century a new strain of MRSA has
become common in the community in patients not recently
exposed to the health care system. This is called communityacquired MRSA and is frequently characterized by a new virulence feature, the Panton-Valentin leucocidin that appears to
stimulate more tissue necrosis. This organism has been associated with necrotizing soft tissue infections similar to those previously only associated with -hemolytic streptococci.
-Hemolytic streptococci, especially from group A, have
significant virulence properties that allow them to invade uninjured or minimally injured tissues to cause severe soft tissue
infections as previously discussed in the section on necrotizing
soft tissue infections. They are uncommon surgical pathogens
otherwise. Group D streptococci, or enterococci, are frequently recovered from intra-abdominal infections, but studies
fail to demonstrate superior outcomes when antimicrobial regimens are directed toward enterococci. However, this species can
clearly cause severe disease in immune-compromised patients,
especially liver transplant patients. In this setting the occurrence
of vancomycin-resistant enterococci (VRE) in recent years has
presented a very difficult treatment challenge.
Facultative gram-negative rods, which can grow in either aerobic or anaerobic environments, are commonly associated with
surgical infections, especially those arising from intra-abdominal
sources. These include the familiar genera Escherichia, Proteus,
Klebsiella, Enterobacter, Morganella, Providencia, and Serratia.
These pathogens are most commonly treated with advancedgeneration cephalosporins, expanded-spectrum penicillins, carbapenems, or fluoroquinolones. In recent years, a number of
these pathogens have developed extended-spectrum -lactam
enzymes (ESBLs) capable of inactivating even third-generation
143
ANTIMICROBIAL AGENTS
Antimicrobial agents are used in combination with source control and other treatment modalities to prevent or resolve surgical
infections. The goal should be to use these agents when they are
required and to withhold them when they are not. Overuse of
antimicrobial agents contributes to bacterial resistance and limits their effectiveness when they are needed. They should be used
in a manner that ensures therapeutic levels at the site of infection
for the appropriate duration. Pharmacodynamic principles of
antibiotic use differ for different classes of drugs. The factors
that go into an antibiotics effectiveness include its minimal
SCIENTIFIC PRINCIPLES
144
TA B L E 7 . 8
CLASSIFICATION
ANTIBIOTICS
Penicillin class
Carbapenems
The original
Imipenem/cilastatin
Penicillin G
Antistaphylococcal
Meropenem
Ertapenem
Methicillin
Doripenem
Nafcillin
Fluoroquinolones
Oxacillin
Ciprofloxacin
Levofloxacin
Ampicillin
Gatifloxacin
Amoxicillin
Moxifloxacin
Aminoglycosides
Carbenicillin
Gentamicin
Ticarcillin
Tobramycin
Piperacillin
Amikacin
Netilmicin
Ampicillin/sulbactam
Amoxicillin/clavulanate
Chloramphenicol
Ticarcillin/clavulanate
Clindamycin
Piperacillin/tazobactam
Metronidazole
Cephalosporin class
First generation
Vancomycin
Cephalothin
Quinupristin/dalfopristin
Cefazolin
Linezolid
Cephalexin
Daptomycin
Cephradine
Tigecycline
Second generation
Antifungal drugs
Cefuroxime
Amphotericin
Cefoxitin
Fluconazole
Cefmetazole
Voriconazole
Cefotetan
Caspofungin
Third generation
Cefotaxime
Ceftizoxime
Ceftriaxone
Cefoperazone
Ceftazidime
Cefepime
MRSA, methicillin-resistant Staphylococcus aureus.
Anidulafungin
Micafungin
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CHAPTER 8 SHOCK
K E Y
Shock is the clinical syndrome that results from inadequate
tissue perfusion from numerous causes: hypovolemic, cardiogenic, extracardiac obstructive, and distributive.
Hypovolemic shock due to ongoing blood and/or plasma
loss leads to progressive cardiovascular deterioration,
ultimate hypotension, oliguria, confusion, irreversible cell
injury, and death.
Cardiogenic shock results in decreased tissue perfusion due
to intrinsic pump failure.
Extracardiac obstructive shock attenuates pump function
due to external compression of inflow and outflow (tamponade, tension pneumothorax, etc.).
Septic and traumatic shock, forms of distributive shock,
are systemic inflammatory responses to infection or tissue
injury with cellular breakdown, producing severe hypotension requiring massive volume resuscitation and high risk
of multiple organ failure and death.
6 Complications of an episode of shock include ischemiareperfusion injury from oxidant stress; potential secondary
immunosuppression with enhanced nosocomial infection
risk; hypothermia and coagulopathy; and multiple organ
failure syndrome, including abdominal compartment syndrome.
7 Treatment of shock involves aggressive volume resuscitation with control of the underlying etiology and careful
monitoring of adequacy of end-organ perfusion to avoid
under- and overresuscitation.
3
4
P O I N T S
EVALUATION OF SHOCK
Shock is easily recognized by even the most inexperienced
caregiver after the compensatory mechanisms have been overcome (Table 8.1). However, it is more difficult to recognize the
147
SCIENTIFIC PRINCIPLES
JOSEPH CUSCHIERI
148
TA B L E 8 . 1
SHOCK RECOGNITION
ORGAN SYSTEM
SIGN/SYMPTOM
CAUSE
CNS
Tachycardia
Adrenergic stimulation
Atrial/ventricular
dysrhythmias
Coronary ischemia
Hypotension
Hypotension
Decreased CVP
Hypovolemia
Circulatory
Cardiac
Systemic
Respiratory
Increased CVP
Tachypnea
Cyanosis
Hypoxia
Renal
Oliguria
Skin
Cool, clammy
Vasoconstriction
Warm, dry
Vasodilation
CNS, central nervous system; CVP, central venous pressure; SVR, systemic vascular resistance.
These biochemical changes associated with the hypoperfusion of shock occur even with compensation. Because of the
potential difficulties in diagnosing compensated shock, an
arterial and/or venous blood gas analysis including base deficit
and lactate should be obtained for every patient suspected of
being in shock. Additionally, any patient with a lactate of
4 mmol/L or base deficit of 6 mEq/L should be considered
to be in shock until proven otherwise.13,16,17
Although each of these factors can be used to characterize
shock, no single measurement has been determined to be optimal or when used singly to be always accurate for identification and treatment of shock. Currently, other measurements
are being investigated that demonstrate promise. These markers include measurements of central and mixed venous oxygen
saturations, end-diastolic cardiac volume indices, and specific
noninvasive end-organ tissue oxygen saturations.1823
TYPES OF SHOCK
Although several different classifications for shock have been
described, the most currently widely accepted classification of
shock was proposed by Weil and Shubin in 1971.6 This classification divides the shock syndrome into four distinct categories (Table 8.2). Despite this separation, however, there is
considerable overlap between the categories, with some
patients presenting with more than one factor at the same time.
Given this overlap, it is helpful to evaluate the hemodynamic
pattern in order to elucidate the etiology and manage the patient
(Table 8.3).
Hypovolemic Shock
2
149
SCIENTIFIC PRINCIPLES
Chapter 8: Shock
150
TA B L E 8 . 2
CLASSIFICATION SYSTEM AND CAUSES OF SHOCK
CLASSIFICATION
ETIOLOGY
Hypovolemic
Hemorrhagic
CAUSE
Trauma
Gastrointestinal
Nonhemorrhagic
Cardiogenic
Myocardial
Ischemia
Infarction
Contusion
Cardiomyopathy
Myocarditis
Pharmacologic/toxic (beta-blockers,
calcium channel blockers, tricyclic
antidepressants, anthracycline)
Metabolic (hypophosphatemia,
hypocalcemia, acidosis)
Valve failure
Infection
Injury
Ruptured papillary muscle
Stenosis
Arrhythmias
Ischemia
Pharmacologic/toxic
Metabolic
Extracardiac obstructive
Extrinsic compression
Mediastinal tumors
Pulmonary embolism
Air embolism
Tumors (myxoma)
Proximal aortic dissection
Aortic coarctation
Acute pulmonary hypertension
Tamponade
Pericarditis
Distributive
SIRS related
Trauma
Sepsis
Pancreatitis
Burns
Anaphylactic/
anaphylactoid
Venoms
Neurogenic
Toxic/pharmacologic
Drugs
Vasodilators
Benzodiazepines
Endocrine
Adrenal insufficiency
Thyroid
Myxedema
Chapter 8: Shock
151
TA B L E 8 . 3
HEMODYNAMIC PATTERNS IN SHOCK
TYPE
CO
SVR
PAOP
CVP
SvO2
Left ventricular MI
N, c
Right ventricular MI
N, T
Pericardial tamponade
Pulmonary embolism
Hypovolemic
Extracardiac obstructive
Distributive
Early
c, N, T
c, N, T
N, c
N, c
N, c
N, c
c, N, T
Late
CO, cardiac output; CVP, central venous pressure; MI, myocardial infarction; N, normal; PAOP,
pulmonary artery occlusion pressure; SvO2, mixed venous oxygen saturation; SVR, systemic vascular
resistance.
TA B L E 8 . 4
CLASSIFICATION OF HEMORRHAGIC SHOCK
CLASS I
CLASS II
CLASS III
CLASS IV
Up to 750
7501,500
1,5002,000
2,000
Up to 15
1530
3040
40
Heart rate
100
100
120
140
Blood pressure
Normal
Normal
Decreased
Decreased
Pulse pressure
Normal
Decreased
Decreased
Decreased
Respiratory rate
1420
2030
3040
35
30
2030
515
Minimal
Mental status
Normal
Mildly anxious
Anxious and
confused
Confused and
lethargic
Fluid replacement
Crystalloid
Crystalloid
Crystalloid and
blood
Crystalloid and
blood
SCIENTIFIC PRINCIPLES
Cardiogenic
152
Distributive Shock
Distributive shock occurs in a state of inappropriate oxygen
utilization associated with the systemic inflammatory response
syndrome (SIRS). Classically, SIRS is triggered by sepsis, but
SIRS is associated with other immune processes including
trauma, pancreatitis, and other types of tissue injuries. However, other types of distributive disturbances can occur unrelated to inflammation that may be directly due to loss of vascular tone from spinal cord injury, endocrine dysfunction, or
anaphylaxis.
peripheral vasomotor impairment present, but can be misclassified if not appropriately evaluated. Early septic shock is distinguished by peripheral vasodilation, flushed and warm
extremities, and a compensatory elevation in cardiac output.
Although an increase in venous capacitance diminishes venous
return to the heart, cardiac output is maintained via tachycardia and the decrease in afterload due to systemic vasodilation.
Late septic shock is characterized by impaired myocardial
contractility due to local and systemic release of cardiac depressants, worsening peripheral perfusion, vasoconstriction, extremity mottling, oliguria, and hypotension. Peripheral oxygen utilization may be severely impaired by bacterial toxins, such as
lipopolysaccharide (LPS) and the inflammatory products of the
hosts own immune response, resulting in metabolic dysfunction and acidosis despite a high systemic oxygen delivery. This
inappropriate oxygen utilization and systemic shunting lead
not only to confusion regarding the adequacy of resuscitation,
but also to progressive cell death. Together, both systemic hypoperfusion and the altered tissue metabolism create a vicious cycle
that propagates the inflammatory response initiated in reaction
to the initial infectious challenge leading to progressive cellular
injury.
Due to both volume deficits and cardiovascular dysfunction,
persistent perfusion deficits are common and contribute significantly to multiple organ failure and mortality. In fact, the fluid
volume required for treatment may exceed that required for
treatment of other forms of shock due to persistent microvascular endothelial capillary leak. As a result of this profound
leak, interstitial and total body fluid balances become extreme,
leading to the potential development of marked hypoxia and
the abdominal compartment syndrome.
Although appropriate early resuscitation and cardiovascular support are essential to the treatment of septic shock, as
important are early infection source control and appropriate
administration of antimicrobials. In fact, numerous investigators have demonstrated that even a few hours delay in initiation of antimicrobial therapy is associated with a significant
increase in mortality.29
Septic Shock
Traumatic Shock
Septic shock is defined as a SIRS response to infection in conjunction with arterial hypotension, despite adequate fluid resuscitation.27 It occurs when bacterial products interact with cells
of the immune system, leading to elaboration of mediators that
cause circulatory disturbances and direct and indirect cell damage leading to the clinical manifestations of SIRS (Table 8.5).28
Hemodynamic changes are defined as early (warm or hyperdynamic) or late (cold or hypodynamic). These stages are primarily characterized by the degree of ventricular contractility and
TA B L E 8 . 5
SYSTEMIC INFLAMMATORY RESPONSE SYNDROME
Systemic inflammatory response syndrome: The systemic
inflammatory response to a variety of severe clinical
inflammatory factors is manifested by two or more of the
following conditions:
Temperature 38C or 36C
Heart rate 90 bpm
Respiratory rate 20 breaths/min or PaCO2 32 mm Hg
WBC count 12,000 cells/mm3, 4,000 cells/mm3, or
10% immature (band) forms
bpm, beats per minute; PaCO2, partial pressure of arterial carbon
dioxide; WBC, white blood cell count.
Neurogenic Shock
Neurogenic shock is defined as failure of the nervous system to
provide effective peripheral vascular resistance, resulting in
inadequate end-organ perfusion. Warm, flushed, flaccid extremities; paraplegia; confusion; oliguria; and hypotension are the
classic clinical findings. Injury to the proximal spinal cord, with
interruption of the autonomic sympathetic vasomotor pathways, disrupts basal vasoconstrictor tone to peripheral veins
and arterioles. Profound vasodilation of all microvascular beds
below the level of cord injury diminishes venous return to the
heart, reduces cardiac output, and precipitates hypotension.
Injuries at or above the fourth thoracic vertebrae may disrupt
sympathetic enervation to the heart, resulting in significant
bradycardia and severe decompensation.
Similar to the initial therapy for shock resulting from hypovolemia, treatment of the relative hypovolemia due to vasodilation of neurogenic shock requires intravenous volume resuscitation. Restoration of the pathologically expanded intravascular
space improves preload and cardiac output and may reverse
hypotension. However, maintenance of adequate hemodynamics
often requires vasopressor support in an effort to avoid the
administration of excessive fluids. CVP monitoring to assess cardiac preload should be considered as a means of determining
adequate and nonexcessive filling pressures, as loss of vasomotor capacity within the pulmonary circulation predisposes these
patients to pulmonary edema. As spinal cord injury is often
associated with other traumatic injuries, the diagnosis of isolated neurogenic shock must be a process of exclusion.
This condition should not be confused with spinal shock.
Spinal shock is defined as a loss of sensation accompanied by
motor paralysis with initial loss but gradual recovery of spinal
reflexes following spinal cord injury. The reflexes caudal to the
spinal cord injury are hyporeflexic or absent, while those rostral
are unaffected. No circulatory compromise is associated with
this condition; thus, it should not be considered a shock state.
Hypoadrenal Shock
The role of adrenocortical hormones in providing resistance to
shock is well recognized. The reduction in effective blood volume and changes in blood chemistry that occur after adrenalectomy are similar to those of shock and hemorrhage.
Adrenalectomized animals have markedly diminished tolerance to both trauma and hypovolemia. Adrenal cortical hormones also play a key role in maintaining normal capillary
tone and permeability. In recent years, the concept of functional or relative adrenal insufficiency has received increasing
attention as a cause of unrecognized shock and hypoperfusion.
Most critically ill patients have elevated cortisol levels, but
some have low concentrations in relation to the degree of
stress imposed by their disease. Administration of physiologic
doses of steroids to correct this insufficiency may result in stabilization of hemodynamics and possible survival benefits.33
However, the concept of routine administration of physiologic
doses of steroids has been questioned and thus routine and
indiscriminate use is not recommended.34
Diagnosis of hypoadrenal shock is difficult, as classic signs
of Addison disease are absent. The only clinical clues may be
153
PHYSIOLOGIC RESPONSE
TO HYPOVOLEMIA
Common to each shock state is usually an initial decrease in
circulating intravascular volume. This reduction is due directly
to fluid loss or secondarily to fluid redistribution. This reduction in circulating fluid volume initiates both a rapid and sustained compensatory response. Within minutes, a rapid compensatory response occurs primarily due to adrenergic output.
Sustained responses, in contrast, occur slower and result in
intravascular fluid reabsorption and renal conservation of
water and electrolytes (Algorithm 8.1).
Rapid Response
Hypovolemia results in the initial secretion of epinephrine and
norepinephrine from the adrenal gland due to decreased afferent impulses from arterial baroreceptors. Catecholamine
release is acute, and limited to the first 24 hours following the
onset of hypovolemia. This results in vasoconstriction, tachycardia, and increased myocardial contractility. Adrenergicinduced vasoconstriction of the systemic capacitance of small
veins and venules shifts blood back to the central venous circulation, thus increasing right-sided filling pressures. Left-sided
filling and pressure are augmented by pulmonary vasoconstriction. Concomitantly, vasoconstriction occurs in the skin, kidneys, and viscera, effectively shunting blood to the heart and
brain. Adrenergic-induced vasoconstriction increases cardiac
filling and causes increased contractility and reflex tachycardia,
all of which combine to increase stroke volume and cardiac
output.
Adrenergic-mediated vasoconstriction affects arterioles, preand postcapillary sphincters, and small veins and venules. Due
to this specific vasoconstriction, decreased hydrostatic pressure
distal to the precapillary sphincter occurs that leads to reabsorption of interstitial fluid [water, sodium (Na), and chloride
(Cl)] into the vascular space. This functions to restore circulating blood volume and is known as transcapillary refill.37
Sustained Response
Sustained compensatory responses include the release of
vasoactive hormones and fluid shifts from the interstitium and
SCIENTIFIC PRINCIPLES
Chapter 8: Shock
154
Hypovolemia
Decreased arterial
Barorecptor activity
CNS
response
RAPID
SUSTAINED
Pituitary release
increased ACTH and
AVP
Peripheral vasoconstriction
increased cardiac activity
Arterial vasoconstriction
Na/water retention
Increased cortisol
Na/water retention
ALGORITHM 8.1
ALGORITHM 8.1. Neurohormonal response to hypovolemia.
ORGAN-SPECIFIC
COMPENSATORY
RESPONSES TO SHOCK
Cardiac and Microvascular Response
Cardiovascular physiology is profoundly affected by shock
(Table 8.3). Reduced stroke volume is caused by an absolute
or relative loss of preload. Intrinsic neuroendocrine and renal
compensatory responses, along with additional intravenous
fluid, are needed to increase ventricular end-diastolic volume.
Restoration of adequate preload alone is often sufficient to
return cardiac output to levels required to overcome peripheral perfusion deficits. However, some cases are complicated
by acquired myocardial contractility derangements. Contractile function under these conditions is less a function of preload and more related to intrinsic myocardial dysfunction.
A defining characteristic of shock is compromise of microvascular perfusion. Far from being a passive conduit, the microvasculature actively participates in the response to shock. Arteriolar
vessels are innervated by sympathetic nerves, as are small veins
and venules. The vasoconstriction of hypovolemic shock and the
vasodilation of septic and neurogenic shock are a result of these
autonomic responses. The majority of the circulating blood volume
resides in the venous system, and normal physiologic compensation mechanisms rely on this venous blood pool as an autotransfusion reservoir. Collapse of underperfused veins passively propels
blood toward the heart, while -adrenergic venoconstriction
actively mobilizes the venous pool. Profound peripheral vasoconstriction via -adrenergic, vasopressin, angiotensin II, and
endothelin-1 stimulation of arteriolar and precapillary smooth
muscle sphincters selectively diminishes perfusion to dermal,
renal, muscle, and, significantly, splanchnic vascular beds to preserve perfusion of critical central organs, primarily the central
nervous system (CNS) and myocardium.38
The capillary endothelial monolayer maintains a semipermeable barrier between the intra- and extraluminal spaces and
is compromised by shock.39 Circulating inflammatory mediators and byproducts of infection (LPS, thrombin, tumor necrosis factor alpha [TNF-], interleukin [IL]-1, nitric oxide, and
endothelin-1) generated in response to traumatic or septic
shock have been shown to induce and sustain endothelial capillary leak. Although the exact mechanisms of endothelial
monolayer dysfunction are unclear, the only available therapies to reverse microvascular decompensation are timely
restoration of peripheral perfusion, rapid elimination of infectious and necrotic tissue, and pharmacologic and mechanical
support of cardiopulmonary function.40,41
Neuroendocrine Response
The neuroendocrine reaction to shock consists of involuntary
responses by the hypothalamus, autonomic nervous system,
and secretory endocrine glands and is directed toward restoration of tissue perfusion and a redirected utilization of metabolic substrates. The autonomic response is initially triggered
by hypoxia, hypotension, or hypovolemia detected by aortic
and carotid baroreceptors and chemoreceptors (Algorithm 8.2).
Subsequently, sympathetic vasoconstriction of specific vascular
beds, induced by direct synaptic release of norepinephrine,
results in redistribution of circulating blood volume from tissue of low metabolic activity to more metabolically demanding organs. Cardiac output, diminished by loss of preload, is
ATLS/ACLS PROTOCOL
OBTAIN ABG
PAC
YES
Cl 3.8
L/min/m2
YES
CVP > 15
MAP > 60
NO
NO
NO
NO
Consider uncontrolled
bleeding
CONSIDER
VASOPRESSOR
Consider uncontrolled
bleeding
Consider TTE
tamposade/cardia
e dysfunction
YES
YES
Treat
cardiac
disease
Crystalloid and/or
PRBCs until
PCWP > 15, HCT > 30
Resuscitate until
HCT 30 and CVP 15
Preload
optimized
based on
starling
curve
YES
VS unstable
or
unresolving
acidosis
NO
YES
CVP < 15
or
HCT < 30
PAC
ALGORITHM 8.2
ALGORITHM 8.2. Shock resuscitation algorithm.
NO
YES
NO
Monitor
Monitor CI
for
deterioration
SCIENTIFIC PRINCIPLES
155
Chapter 8: Shock
156
Immunoinflammatory Response
Many shock-inducing events, particularly those associated
with septic or traumatic shock, simultaneously trigger a massive systemic inflammatory response. Although inflammatory
mediators (TNF-, ILs, chemokines, etc.) play an integral role
in the recovery of local tissue to trauma and infection, an uncontrolled systemic inflammatory response contributes to organ
failure. Immunologically active cells involved in the systemic
inflammatory response include nucleated blood cells (monocytes,
polymorphonuclear leukocytes [PMNs]) and platelets, microvascular endothelial cells, and tissue macrophages. These cells generate and secrete scores of signal-amplifying inflammatory
mediators ranging in complexity from individual molecules
(nitric oxide) to large multisubunit, extensively modified proteins (TNF-, IL-1, etc.). Even transient systemic elevation of
any of these mediators has profound physiologic consequences.
Local tissue destruction, microbial contamination, and infection similarly activate the coagulation cascade and induce platelet
aggregation and release of numerous platelet-, endothelial-, and
clot-derived vasoactive mediators. Persistent, profound, and recurring microvascular hypoperfusion of the splanchnic and other
organs likewise causes local tissue ischemia, parenchymal cell injury,
microvascular coagulation, activation of inflammatory cells, and
release of inflammatory mediators. Circulating monocyte, lymphocyte, and PMN adherence to activated endothelium results in
extraluminal transmigration of these inflammatory cells into tissues remote from the area of injury. This hyperdynamic immunologic response, with continued generation of proinflammatory
mediators, is responsible for the progression of SIRS toward
MODS.4245
Regulation of the systemic inflammatory response has been
an active area of shock research for several decades. Elimination of particular inflammatory mediators from the systemic
circulation, or inhibition of particular cellcell interactions in
experimental animal systems, has been shown to improve outcomes after shock resuscitation.4648 However, to date, all
efforts to regulate the SIRS response with therapeutic elimination or supplementation of specific proinflammatory and antiinflammatory mediators have proven ineffective or even harmful in humans. This lack of efficacy may relate to inadequacy
of current animal models of shock, sepsis, and organ failure or
to inadequate understanding of the full spectrum and interactive nature of key elements that regulate this syndrome. Unfortunately, the network of inflammatory mediators and affected
cells is so complex and redundant that no single agent is likely
to be effective at interrupting this response. As a result, there is
probably no single common pathway likely to respond to a
silver bullet approach.
Pulmonary Response
The lung is the organ system most sensitive to systemic insult
and injury and is frequently the first organ to fail in the progression to MODS. ARDS represents a high-mortality form of
pulmonary insufficiency that is often precipitated by sepsis or
traumatic shock. It is triggered and perpetuated by the numerous inflammatory mediators created in the hypoperfused
microvasculature elsewhere in the body.4951
Interstitial edema and subsequent reduced compliance
result in diminished tidal volume and tachypnea, compromising gas exchange. Surfactant abnormalities contribute to alveolar collapse, resulting in loss of functional residual capacity
Renal Response
Direct sympathetic-induced renal vasoconstriction increases
afferent arteriole resistance in response to shock. This effect is
reinforced by elevated circulating angiotensin II and catecholamines. The resulting decrease in renal blood flow and
glomerular filtration rate (GFR), along with elevated circulating aldosterone and vasopressin (ADH), produce oliguria and
prerenal azotemia. Acute tubular necrosis (ATN) may result
from prolonged decreases in renal cortical blood flow, as well
as from toxins generated during sepsis. Oliguric renal failure,
like the pulmonary insufficiency of ARDS, is a common component of MODS.
Distinguishing low urine output due to oliguric renal failure
from the oliguria of decreased renal perfusion pressure can be
aided by analyzing urine sodium and osmolality. Renal hypoperfusion usually results in urine sodium of less than 20 mEq/L
with an osmolality of greater than 400 mOsm/kg, whereas
acute tubular injury impairs sodium reabsorption and is associated with a low urinary osmolality. A fractional excretion of
sodium of less than 2% may also help determine whether the
cause is renal or prerenal.
Early detection of abnormal kidney function is critical to
prevent progression to renal injury. Abnormal renal function
can be detected as a decline in creatinine clearance. The correlation between a creatinine clearance based on a 24-hour collection and a sample collected over a shorter interval is poor. However, the 24-hour value represents an average value over that
time. A sample obtained over a shorter period may reflect the
time in question and allow timely recognition and treatment of
renal dysfunction.
Hepatic Response
Ischemic injury to liver is not apparent early during shock.
However, the liver plays an important role in the regulation of
shock and subsequent tissue injury through both the release of
acute-phase reactants and lack of clearance of potential toxic
agents. As shock continues, hepatic necrosis occurs, leading to
the release of aspartate aminotransferase and alanine aminotransferase. Continued shock results in attenuated synthesis of
coagulation factors, albumin and prealbumin. Although progressive ischemia can occur, leading to complete loss of glycogen
stores and marked hypoglycemia, this condition is rare without
preexisting liver disease, significant direct liver injury, or hepatic
artery occlusion.
Chapter 8: Shock
LOSS OF COMPENSATORY
RESPONSES TO SHOCK
If shock is prolonged, the arteriolar and precapillary sphincters become refractory and relax, while the postcapillary
sphincter remains in spasm. Therefore, the capillary hydrostatic pressure increases, and Na, Cl, and water are moved into
the interstitium, leading to depletion of intravascular volume.
Cellular membrane function is also impaired with prolonged shock. The normal negative membrane potential
approaches neutrality, leading to increased permeability and
interstitial flooding by K. This is caused, at least in part, by a
decrease in the normal function of the adenosine triphosphatedependent Na-K membrane pump that is a result of
cellular hypoxia. The loss of the membrane potential difference leads to cellular swelling due to an intracellular influx of
Na and fluid.
In addition to these cellular effects, severe and prolonged
shock results in the development of progressive organ dysfunction. Although the mechanisms responsible are incompletely understood, it appears that the vital organs, in particular the lung early on, are limited in their ability to protect
themselves during shock. As a result, direct endothelial injury
occurs, resulting in leakage of various inflammatory mediators,
which in turn results in accumulation of interstitial fluid and
subsequent reduction in nutrient and gaseous diffusion. This
condition, along with progressive microcirculatory thrombosis, is responsible for the late organ dysfunction characteristic
of uncompensated shock.
COMPLICATIONS OF SHOCK
Ischemia-Reperfusion Injury
6
Second-hit Phenomena
Patients who have been successfully resuscitated from shock are
at risk for what is referred to as the second-hit phenomenon. A
single episode of severe or prolonged shock may precipitate
organ failure, but, in addition, the initial insult may prime the
inflammatory response, resulting in an augmented or prolonged
response to a subsequent insult such as an infection, a second
episode of blood loss, or major surgery.55 For example, after the
primary event, circulating neutrophils demonstrate enhanced
superoxide anion production, increased endothelial cell adherence, augmented cytokine response, and increased cytotoxicity.
Not only do circulating innate immune cells demonstrate this
priming effect, but tissue-fixed cells, in particular the macrophage,
demonstrate altered phagocytosis and augmented cytokine
release.56 This dysfunctional response leads to not only diminished microbial clearance and enhanced risk of nosocomial
infection but also increased host tissue injury and subsequent
development of MODS.
SCIENTIFIC PRINCIPLES
unique host-specific responses have been identified as important determinants of the outcome of sepsis and septic shock.
Genetic predispositions in an individuals immunoinflammatory response may dictate whether infection is adequately or
inadequately countered. These differences in response may be
partially explained by single nucleotide polymorphisms (SNPs)
in the genetic sequences for various inflammatory mediators.
These subtle nucleotide variations may affect the transcription
or translation of associated genes or the secretion or function
of the corresponding proteins.
The recognition that genetic background may regulate the
response to severe sepsis and septic shock has led to the identification of an array of genetic markers associated with enhanced
risk of septic mortality. These SNPs are in genes encoding proteins involved in pathogen recognition (toll-like receptors 2, 4,
and 5; CD14; and mannose-binding lectin), cytokine expression (TNF-, IL-1, IL-6, and IL-10), and several other genes
involved in mediating and controlling the innate immune
response and the inflammatory cascade.53,54
Investigation into genetic polymorphisms should provide
important insights into the pathophysiology of shock. SNP
identification leading to early diagnosis of individuals at risk of
developing or dying from the complications of shock may allow
therapies to become more preemptive and effectively targeted.
157
158
Hypothermia
Hypothermia (core temperature 35C) is common during
shock. In addition to immobilization, both prehospital and
postadmission exposure can lead to conductive, convective,
and evaporative heat loss, which should all be minimized. In
addition, the administration of room temperature intravenous
fluids and of cold-stored blood also contributes to hypothermia.59 Hypothermia increases fluid requirements and independently increases acute mortality rates.60
As the core temperature decreases, the rate of oxygen consumption also decreases, to approximately 50% of normal at
28C. The decrease in oxygen consumption is accompanied by
increased production of acid metabolites. A leftward shift in
the oxyhemoglobin dissociation curve also occurs with
hypothermia but is partially compensated by the acidosis.
Central nervous system effects progress from confusion and
loss of manual dexterity to obtundation and frank coma as the
core temperature decreases from 35C to 26.5C. The heart
rate decreases to approximately half of baseline at 28C, with
a concomitant decrease in cardiac output. All cardiac electrical
conduction intervals are prolonged, consistent with the
changes in heart rate, and both atrioventricular dissociation
and refractory ventricular fibrillation occur at 28C. Other
potential physiologic effects include ileus and pancreatitis
(from cold enzyme activation) at temperatures lower than
35C.
Compensatory responses to hypothermia include increased
excretion of catecholamines, resulting in doubling of the basal
metabolic rate, and increased production of thyroid hormones, further increasing the basal metabolic rate to five times
baseline. Shivering can increase heat production as well, but it
represents a significant energy expenditure, and has been
shown to be inhibited during episodes of hypotension or
hypoxemia.61 Compensatory responses to hypothermia are
lost at temperatures below 30C or 31C, and a state of complete poikilothermy is reached.
The treatment for hypothermia is rewarming. The core temperature should be obtained on admission of the trauma
patient. Patients whose core temperatures are 33C to 35C can
be treated with passive rewarming, warm blankets, and hot
Coagulopathy
Coagulopathy is a frequent problem complicating shock, especially in those patients who have received large volumes of
crystalloid solution and blood for resuscitation. Although this
problem is incompletely understood, it is clear that coagulation defects during shock are multifactorial. The presence of
shock, the fluid volume required for resuscitation, the presence
of hypothermia, and preexisting diseases all influence the likelihood and severity of coagulopathy.62
A major factor in coagulopathy is usually due to the dilutional thrombocytopenia that occurs after massive volume
resuscitation. Although bleeding times can be prolonged with
platelet counts less than 100,000 cells/mL, platelet counts of
50,000 cells/mL or greater are usually adequate for surgical
hemostasis. Dilutional thrombocytopenia becomes more likely
with infusions of more than one blood volume. Each unit of
platelets administered increases the platelet count by 10,000 to
15,000 cells/mL. Control of surgically remediable hemorrhage
is prudent before platelet transfusion to prevent the loss of the
transfused platelets.
Dilution of other coagulation factors also plays a role in
development of coagulopathy. Factors V and VIII are the most
labile in banked blood, but levels of less than 10% of normal
for factors VII, X, XI, XII, and XIII are all associated with
abnormalities in hemostasis, as demonstrated by prolonged
partial thromboplastin time and prothrombin time. Fresh
frozen plasma can be administered as a source of all the soluble coagulation factors. The administration of cryoprecipitate
may be necessary as a concentrated source of factor VIII and
fibrinogen, particularly if adequate hemostasis is not obtained
with the use of fresh frozen plasma.
Recent support has emerged for the use of recombinant activated factor VIIa. Although developed initially for use in hemophiliacs who developed inhibitors to factor VIII, anecdotal evidence has suggested that recombinant activated factor VIIa may
serve to quickly reverse hemorrhage-induced coagulopathy.63
However, currently no definitive data exist on which patients
may benefit, and therefore further studies are required before
routine use can be advocated.
Finally, evidence has suggested that coagulopathy and hemorrhage can be minimized following massive blood loss if early
aggressive use of fresh frozen plasma is administered. Military
data demonstrate that significant early coagulopathy is present
after massive injury, even before blood component therapy is
begun. Both civilian and military experience with a 1:1 ratio of
packed red blood cells to fresh frozen plasma has been associated with reduced mortality.6466 However, this practice has
been associated with an increase in the development of ARDS
and organ dysfunction due to poorly defined mechanisms.67
Thus, generalization of this data to all patients with hemorrhage
other than the massively injured should be performed with caution until further prospective evidence is available.
TREATMENT
Fluid Therapy
Early investigators of hemorrhagic shock noted that decreased
CVP and a reduction in total body oxygen delivery (DO2) were
key early findings. If the decrease in oxygen delivery was
severe or prolonged, a reduction in total body oxygen consumption ensued. After adequate fluid resuscitation, oxygen
delivery and consumption increased above the baseline value
for several hours, as if the body was paying back an oxygen
debt. Failure of the patient to achieve this hyperdynamic
response to resuscitation was almost always fatal. Because
early death from shock appeared to be explained by the
dynamics of oxygen delivery and utilization, therapy focused
on restoring hemodynamics and oxygen transport with fluid
and inotropes.
The provision of additional fluid beyond the amount of
blood loss was associated with improved survival in both clinical and experimental studies of hemorrhagic shock, leading to
widespread acceptance of aggressive fluid infusion. However,
some researchers have recently described a significant increase
in mortality associated with crystalloid overresuscitation and
have postulated that excessive fluid administration increases
the clinical risk of ARDS, MODS, increased intracranial pressure, and abdominal compartment syndrome.6870 Because
massive volumes of fluid are only provided to patients with
severe shock, it is unclear if it is the excessive fluid or the associated underlying shock that increases the risk of ARDS, organ
failure, or death after massive fluid resuscitation.
7
A minimum of two large-bore (14- to 16-gauge) intravenous catheters should be established in adults. Isotonic fluid
is then infused at the same time as blood is obtained for arterial blood gas analysis, screening, and typing. Fluid can be
infused up to 200 mL/min through a 14-gauge catheter and up
to 220 mL/min through a 7-French catheter. A fluid challenge
of 10 to 25 mL/kg is administered to the hypotensive patient and
the response is assessed (i.e., 2,000 mL or 40% of blood volume of a 70-kg man). This therapeutic challenge is an effective
trial in determining the amount of preexisting or continuing
volume loss. If the blood pressure returns to normal and is stabilized, the volume loss was relatively small, and the only
treatment required may be infusion of isotonic fluid.
If the increase in blood pressure is transient after fluid bolus,
then hemorrhage or continued fluid losses are severe and ongoing. Additional crystalloid is administered, and the need for
blood transfusion is assessed. Patients who continue to require
large amounts of fluid and blood to support perfusion usually
have ongoing hemorrhage and require surgical intervention.
No response or a minimal response to apparently adequate
infusions of crystalloid solution and blood indicates exsanguinating hemorrhage and the need for urgent surgery.
Crystalloids. Balanced salt solutions are the most commonly used resuscitative fluids, and their use to restore extracellular volume significantly decreases the transfusion requirement after hemorrhagic shock. Lactated Ringer solution is
isotonic, readily available, and inexpensive. It rapidly replaces
the depleted interstitial fluid compartment and does not aggravate any preexisting electrolyte abnormalities. Previous investigations have shown that administration of lactated Ringer
solution does not lead to aggravation of the lactic acidosis that
is present in shock.71 In fact, animal models have demonstrated that the use of blood plus lactated Ringer solution
results in a more rapid return to normal lactate and pH than
dose shed blood alone. As volume and perfusion are restored,
lactate is mobilized and metabolized to bicarbonate in a single
159
Colloids. Colloids have the theoretic advantages of increasing the colloid oncotic pressure and requiring smaller volumes
for resuscitation than crystalloids.76 Colloids commonly used
for volume expansion in hypovolemia include albumin, dextran 70, dextran 40, and hydroxyethyl starch. Although each
has unique individual characteristics, currently there is little
justification for the routine addition of colloids to balanced
salt solutions for volume replacement during shock.
Albumin solutions have been used during resuscitation to
increase colloid oncotic pressure and, hypothetically, to protect the lung from interstitial edema; however, there is a relatively rapid flux of albumin across the pulmonary capillary
membranes and relatively rapid clearance through the pulmonary lymphatics. In fact, colloid albumin infusion has been
demonstrated to prolong the resuscitation phase and delay
postresuscitation diuresis. Additionally, albumin may serve to
depress circulating immunoglobulin levels and suppress albumin synthesis.
Dextran 40 and dextran 70 are polysaccharides with molecular weights of 40 and 70 kD, respectively. Dextran 40 (10%)
is hyperoncotic and initially exerts a volume-expanding effect.
However, because of its lower molecular weight, it is more
rapidly excreted. Thus, dextran 40 is commonly used in cases
of peripheral vascular disease and hyperviscosity syndromes.
Dextran 70, conversely, is provided as a 6% solution and does
not exert a hyperoncotic effect. The volume expansion is
somewhat greater than the amount infused, and because of its
large molecular size the effect is maintained for up to 48 hours.
The dextran preparations, however, cause decreased platelet
adhesiveness and decreased factor VIII activity. They also
carry an incidence of allergic reaction of up to 5% and anaphylaxis of 0.6%.76
Hydroxyethyl starch is an amylopectin with volumeexpanding effects for approximately 36 hours. It has side
effects similar to those of dextran, but with less frequency. The
incidence of anaphylaxis is 0.006%. A new hydroxyethyl
starch, pentastarch, has a lower molecular weight and fewer
hydroxyethyl groups than hydroxyethyl starch. Pentastarch
has a shorter duration of action (2.5 hours) and has been
reported to have even fewer side effects.77,78
The controversy regarding use of crystalloids versus colloids in resuscitation has not been resolved. Both types of solutions can restore circulating volume. The effects of the solutions on pulmonary function are at issue and are summarized
as follows: (a) the use of crystalloid solutions decreases plasma
oncotic pressure, thereby leading to lung edema at lower
SCIENTIFIC PRINCIPLES
Chapter 8: Shock
160
Permissive Hypotension
Elevation of systemic arterial pressure in patients with disruption of the arterial system or major solid organ injury, especially after penetrating trauma, may cause acceleration of
hemorrhage, disrupt natural clotting mechanisms, and cause
dilution of clotting factors. Laboratory and clinical evidence
support judicious use of intravenous fluids until hemorrhage is
controlled by surgery, angiography, or direct pressure for penetrating trauma.80 Fluid resuscitation for patients with multisystem blunt trauma, especially with concomitant traumatic
brain injury, represents a more complicated decision process,
as maintaining cerebral perfusion pressure is a competing priority. Avoidance of both excessive fluid administration and
prolonged hypoperfusion is best achieved in all patients not by
maintenance of a marginal blood pressure, but by rapid surgical or angiographic intervention to control bleeding.
Transfusion
Anemia prompts clinical concerns because it may signify blood
loss or hematologic disease, but it rarely causes tissue
ischemia. The hemoglobin level that causes concern should
depend on the adequacy of other mechanisms involved in oxygen delivery such as arterial oxygen saturation and cardiac
output, the specific clinical situation, and the organ systems
most at risk, balanced against the risk of transfusion. Clinical
evidence suggests that hemoglobin values above 7 mg/dL are
adequate in most patients, including the critically ill, but this
has not been explored during shock. In one prospective randomized trial in critically ill patients, it was clearly demon-
Type O Blood. Type O (universal donor) blood is immediately available without a cross match. Because type O blood
contains no AB cellular antigens, administration of packed red
blood cells is relatively safe in patients of any blood type.
Males should be transfused type O Rh-positive blood, while
prepubescent females and females of childbearing age should
be given type O Rh-negative blood to avoid sensitization that
would complicate future pregnancies. The administration of
more than 4 units of type O blood to a nonO-blood-type
patient, however, theoretically can result in an admixture of
blood type. A pretransfusion blood specimen should be sent to
the blood bank when the patient is admitted, and type-specific
blood should be transfused as soon as it is available.
Type-specific Blood. Type-specific blood is available from
most blood banks within 5 to 10 minutes of receipt of the
blood specimen, while the patient is being resuscitated with
balanced salt solutions. Although not cross matched, this
blood can be administered safely, as demonstrated in both military and civilian experiences.82
TA B L E 8 . 6
COMPARISON OF BLOOD AVAILABILITY
BLOOD
TYPING
ANTIBODY
SCREEN
CROSS
MATCH
TIME
Type O
No
No
No
Immediate
Type specific
Yes
No
No
10 min
Yes
Yes
Yes
2030 min
Yes
Yes
Yes
4560 min
Endpoints of Resuscitation
Endpoints of resuscitation can be categorized as either global
or regional indicators of perfusion. Blood pressure and pulse
are global measures and are relatively poor determinants of the
adequacy of tissue oxygenation. They must also be interpreted
in the context of patient age and preexisting medical conditions. Tachycardia is a component of SIRS and does not always
resolve with increased preload. Arterial pressure is maintained
by myriad compensatory mechanisms, even in the face of a significant volume deficit, and interpretation is complicated by
highly variable baseline pressures, age, and preexisting medical conditions.
Base deficit and serum lactate are also global indicators of
perfusion and may help in the detection of patients who are in
otherwise compensated shock. Acidosis arising from regional
tissues may not be apparent in peripheral blood samples, as is
frequently the case in patients with intestinal ischemia, in whom
systemic acidosis is a late finding. An elevated base deficit and
lactate can be caused by electrolyte abnormalities, accelerated
glycolysis or pyruvate production, and/or decreased clearance
by the liver. They may also reflect dysfunction caused by a
period of hypoperfusion that has already resolved and that does
not need further treatment. A positive response toward correction, however, is indicative of appropriate resuscitation.
A pulmonary artery catheter (PAC) has obvious appeal as a
monitor because ensuring adequate oxygen delivery is paramount in the treatment of shock (Algorithm 8.2). A progressive
decline in systemic oxygen delivery (DO2) results in an increase
in the oxygen extraction ratio, evident as a reduction in pulmonary mixed venous oxygen saturation. When DO2 is
reduced below the level needed to maintain normal tissue metabolic activity, anaerobic metabolism occurs. This is evident as a
decrease in total body oxygen consumption (VO2). Adequate
resuscitation requires eliminating any pathologic decrease in
VO2 by restoring oxygen delivery to an adequate level. In clinical practice, however, there is no precise level of VO2 that can
be used as an endpoint, as tissue oxygen needs vary according
to the patients condition, level of sedation, body temperature,
and other factors, and are affected by endogenous and exogenously administered catecholamines.
Oxygen consumption may be especially difficult to interpret in patients with late-stage sepsis because acquired defects
in mitochondrial respiration may prevent utilization of oxygen, resulting in decreased consumption and progressive acidosis despite normal or high DO2.
The adequacy of resuscitation can also be assessed by measurement of end-organ function and perfusion, in addition to
global measures. Blood flow to the most vital organs (brain
and heart) is preserved during shock at the expense of flow to
the skin, muscles, gut, and, ultimately, kidneys. Detection of
ischemia in less vital organs could theoretically identify patients
in compensated shock who have otherwise normal global indicators.
Low urine output (0.5 to 1.0 mL/kg per hour) is an indicator of inadequate end-organ perfusion, but inappropriate urine
output may initially be maintained by peripheral venoconstriction and maintenance of cardiac output due to tachycardia. The
use of gastric tonometry to measure intramucosal pH has highlighted the uneven recovery from shock by visceral organs.
Persistent visceral hypoperfusion, as demonstrated by intramucosal acidosis despite correction to normal hemodynamics, is
161
associated with organ failure and poor outcomes. Unfortunately, direct measurement of visceral hypoperfusion, as well
as hypoperfusion in other regional vascular beds, requires use
of technically challenging, labor-intensive devices that often
produce variable unreliable results and has not yet had widespread application. Presently, the goal of therapy is to restore
tissue perfusion, both global and regional as measured by
organ function, and to normalize cellular metabolism while
avoiding excessive use of fluids and inotropes.
Recently, several biomarkers, in addition to base deficit and
lactate, have demonstrated potential promise. Among the most
promising is procalcitonin for the early recognition of sepsis.
However, in addition to being significantly elevated during sepsis, procalcitonin has recently been demonstrated, similar to
lactate and base deficit, to be prognostic of outcome from
hypovolemia based on rate of clearance.86 Thus, this biomarker along with potential others may lead to early recognition and treatment of shock.
MONITORS
Central Venous Pressure
CVP is determined by a number of factors, the most important
of which are venous volume and venous compliance. Cardiac
output and arterial dilation modulate CVP by affecting central
venous volume, whereas sympathetic venoconstriction and
thoracic and intra-abdominal pressure primarily affect central
venous compliance. A variety of conditions can raise CVP
despite a normal or even low cardiac preload. High ventilator
pressures, expiratory airway obstruction, tension pneumothorax, cardiac tamponade, and obesity are additional nonvolumedependent causes of a relatively elevated CVP.
Circulating catecholamines cause vasoconstriction, with
maintenance of venous pressure despite reduced circulating
volume. In such cases, fluid therapy may reduce the intensity of
vasoconstriction by reducing tone, with no net change in CVP.
Following the change in CVP in response to a fluid challenge
may be the only way to accurately estimate preload in some
patients. Although an elevated CVP does not guarantee adequate
preload, a low CVP is a reliable indicator of hypovolemia. Inspiratory stridor is the only condition that can falsely reduce CVP
and mimic hypovolemia by significantly reducing intrapleural
pressure.
SCIENTIFIC PRINCIPLES
Chapter 8: Shock
162
PHARMACEUTICAL SUPPORT
Therapeutic adjustments of preload and afterload form the
basis of treatment strategies in all forms of shock. Optimal
volume resuscitation should always precede measures to augment the contractile function of the heart. Inotropic augmentation of cardiac output may therefore be required when
restoration of venous preload fails to provide sufficient cardiac
output to satisfy tissue oxygen demands. The effect of
inotropic agents depends on the specific adrenergic receptor
affinity, chronotropic effects, and demands placed on myocardial oxygen consumption of the individual agents (Table 8.7).
Vasodilators reduce demands on the myocardium and augment cardiac function via reduction in systemic vascular resistance (SVR) or afterload or by dilating the venous system and
reducing cardiac preload. Afterload reduction may preserve
stroke volume in the face of a failing myocardium, whereas
TA B L E 8 . 7
PHARMACODYNAMICS OF INOTROPIC/VASOCONSTRICTOR AGENTS
SITES OF ACTION
HEART
1
HEART
2
Renal
Hepatic
Hepatic
DRUG
METABOLISM
Isoproterenol
VESSELS
HEMODYNAMIC RESPONSE
VESSELS
2
RENAL
PERFUSION
/
0/
0/
0/
Low dose
CO SVR BP
/
0/
1 mg/250 mL
12 g/min
initially
Dobutamine
250 mg/250 mL
3 g/kg/min
initially
Dopamine
200 mg/250 mL
Low dose
High dose
25 g/kg/min
low dose
0/
High dose
2050 g/kg/min
high dose
Epinephrine
Renal
Renal
/
Renal
2 mg/250 mL
2 g/min initially
Norepinephrine
4 mg/250 mL
4 g/min initially
Phenylephrine
(alpha), vasoconstrict peripheral arterioles; 1 (beta-1) myocardial inotropy, chronotropy, enhance atrioventricular conduction; 2 (beta-2)
chronotropy, vasodilate mesenteric/skeletal bed, bronchodilation; dopaminergic, vasodilate mesenteric/renal bed.
BP, blood pressure; CO, cardiac output; SVR, systemic vascular resistance.
Epinephrine. Epinephrine, the endogenous adrenal catecholamine, is released physiologically in response to stress. It
has a broad spectrum of systemic actions, including significant
cardiovascular effects. When epinephrine is administered as a
pharmacologic agent (0.01 to 0.05 g/kg per minute), 1adrenergic effects predominate, causing increased stroke volume, heart rate, and contractility, along with modest 2-receptor
stimulation. At higher infusion rates, -adrenergic receptors are
stimulated, which overcome 2-mediated peripheral vasodilation, resulting in an increase in blood pressure and SVR. Renal
and splanchnic vasoconstriction, cardiac dysrhythmias, and
increased myocardial oxygen demands limit the prolonged use
of high-dose epinephrine. Transient increases in serum lactate
have also been noted, possibly due to impaired regional blood
flow. Epinephrine should be considered as a potential shortterm agent for use in patients with impaired cardiac function
not responsive to other agents such as dobutamine.
163
therefore appropriate for use in patients who remain hypotensive despite dopamine administration or as a dopamine alternative. Combined - and -stimulation typically results in an
increase in afterload and renal glomerular perfusion pressure,
with preservation of cardiac output. Despite the potential for
renal vasoconstriction, as a result of its effects on mean arterial pressure, norepinephrine is associated with an increase in
urine output and creatinine clearance in hypotensive, and particularly septic, patients. A primary concern is to ensure adequate volume resuscitation prior to utilization due to risk of
severe tissue damage from excessive vasoconstriction on the
hypovolemic patient.
with potent -adrenergic effects. From a cardiovascular standpoint, both cardiac and peripheral effects are significant. Stimulation of cardiac 1-receptors prompts an increase in contractility, heart rate, and conduction velocity. The chronotropic
response, however, may predominate. These activities, in conjunction with peripheral vasodilation, generate significant
increases in cardiac output and pulse pressure. Isoproterenol
greatly increases myocardial oxygen demand and limits coronary filling due to tachycardia. As a result, indications for isoproterenol are limited to patients with hemodynamically significant bradyarrhythmias while preparations are made for
electrical pacing.
Vasopressin. Vasopressin acts directly on V1 receptors in vascular smooth muscle to cause vasoconstriction and increases the
reactivity of vascular smooth muscle to catecholamines. Release
of endogenous vasopressin is a normal physiologic response to
shock. After septic or prolonged hemorrhagic shock, circulating
vasopressin levels are decreased, possibly due to depletion of
hypophyseal secretory stores. This relative deficiency may play a
role in causing refractory hypotension. Vasopressin has minimal
effects on normotensive patients, but in patients with septic
shock it is effective in increasing SVR and mean arterial pressure.
Vasopressin does not have inotropic properties but has potent
splanchnic and coronary vasoconstrictors. It has been associated
with decreased cardiac output due to myocardial ischemia and
increased afterload and may worsen metabolic acidosis in patients
in shock by causing splanchnic ischemia. As a result, early use of
vasopressin at only physiologic concentrations to minimize associated other pressor use may be indicated.
Amrinone and Milrinone. Amrinone and milrinone are
noncatecholamine inotropes with cardiovascular effects similar
to dobutamine, but with minimal chronotropic activity. As
steroidlike phosphodiesterase antagonists, they increase smooth
muscle cyclic adenosine monophosphate (cAMP) and alter calcium metabolism. Cardiac contractility, stroke volume, heart
rate, and cardiac output are increased, while a concomitant
reduction in afterload offsets cardiac workload. The increase in
cardiac performance with minimal demands on myocardial
oxygen consumption offers some utility in the treatment of cardiogenic shock or as a potential alternative to dobutamine infusion. Both agents have a relatively long half-life of nearly 3
hours and should therefore be used with caution in patients at
risk of developing hypotension, a major risk in the critically ill
patient.
SCIENTIFIC PRINCIPLES
Chapter 8: Shock
164
Vasodilators
Vasodilators are used as a means to augment cardiac function
through optimization of preload and afterload, both of which
reduce demands on the myocardium. The failing ventricle
responds to afterload reduction with significant increases in
stroke volume. The reason for this is that the compromised
myocardium is working past the plateau and on the down slope
of the Starling curve. As a result, afterload reduction with
vasodilator agents may allow cardiac output to increase, resulting in improved oxygen delivery.
Nitroprusside. Nitroprusside is a balanced but potent arterial and venous smooth muscle vasodilator. It causes a reduction in afterload that increases cardiac output and has a less
prominent venodilatory effect that reduces pulmonary venous
pressure and preload. Hypotension may limit its use, particularly in the presence of contractility deficits or inadequate preload. Infusions (3 g/kg per minute) continued for greater
than 48 hours require monitoring of serum thiocyanate levels
and arterial pH to detect complications of cyanide toxicity.
Miscellaneous Therapeutics
Corticosteroids. In septic shock, ACTH resistance may
diminish the normal cortisol response. Also, peripheral tissue
resistance to corticosteroids may develop through proinflammatory-induced downregulation of normal corticosteroid
receptors. Initial clinical trials showed no reduction in mortality when short courses of high-dose corticosteroids were used
as adjuncts in the treatment of septic shock. However, recent
studies utilizing low or physiologic doses (300 mg/day) of
hydrocortisone for a longer duration (5 days) of treatment
have demonstrated a beneficial impact on mortality, particularly in septic patients.33 Currently, routine use of ACTH stimulation tests is not advocated since they provide little more
than prognostic information.35 Given that hypoadrenal shock
complicates various shock states, routine use is considered, but
given the lack of proven benefit in other multicenter trials, use
is currently not widely advocated without caution.34
Future Therapies
When initiating therapy for shock, the clinician does not know
whether therapy has been started early, when salvage is still possible, or late, after irreversible changes have occurred within the
cell and death is inevitable. Failure to respond to fluids, inotropes,
and vasopressors with restoration of normal oxygen consumption and aerobic metabolism probably represents a defect in cellular and subcellular function in critical organ systems. There are
many active areas of investigation that reflect the progression of
our understanding of shock that have been outlined in this chapter and that have begun to move the field beyond the basics of
fluid resuscitation and hemodynamic monitoring.
Efforts to control ischemia-reperfusion injury include controlled reperfusion with carbon monoxide or other compounds
to reduce oxidative stress. Induced hypothermia may interrupt
generation of harmful byproducts of ischemia and enable
restoration of circulation and repair of structural injuries in a
cellular environment where hypoxia is no longer critical. Additional biomarkers, such as procalcitonin, may allow earlier
diagnosis and treatment of sepsis and shock.86 New biosensors
using near-infrared light may enable transcutaneous identification of critical limitations of blood flow and enable clinicians to
more accurately target areas of regional hypoperfusion.91 A
search for agents that optimize circulation in the microvascular
system by preventing activation of the endothelium may enable
resuscitative efforts to restore oxygen to cells as needed to maintain normal respiration and provide critical nutrients. Ultimately,
further understanding of functional genomics may enable clinicians to target transcription and translational events triggered by
shock and thus alter outcome.
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care physician staffing on patients with septic shock in a university hospital medical intensive care unit. JAMA 1988;260(23):34463450.
90. Dhainaut JF, Yan SB, Margolis BD, et al. Drotrecogin alfa (activated) (recombinant human activated protein C) reduces host coagulopathy response in
patients with severe sepsis. Thromb Haemost 2003;90(4):642653.
91. Hopf HW. Molecular diagnostics of injury and repair responses in critical
illness: what is the future of monitoring in the intensive care unit? Crit
Care Med 2003;31(suppl 8):S518S523.
K E Y
Critical care units provide monitoring to identify and guide
intervention prior to life-threatening physiologic deterioration and utilize advanced technology to support failing
organs until treatment and recovery can occur.
2 Oxygen delivery to tissues must match cellular metabolic
needs. To prevent cellular failure, adequate tissue oxygenation relies on oxygen-carrying capacity of blood (hemoglobin), loading of oxygen (gas exchange), and cardiac output
(heart function).
3 When oxygen delivery is inappropriate to meet demand,
fluid administration is often used to increase cardiac output through an increase in stroke volume. Conventional
static indices of assessing fluid responsiveness are inferior
to dynamic indices.
4 Respiratory dysfunction involves inadequate gas exchange,
ventilation, or both. Oxygenation requires matching pulmonary perfusion to alveolar ventilation, whereas CO2
excretion relies primarily only on ventilation. Ventilator
support should be tailored to individual needs, and the
P O I N T S
ORGANIZATIONAL
STRUCTURE OF THE
INTENSIVE CARE UNIT
A significant proportion of patients under the care of surgeons
receive some form of critical care during their hospital stay.
The exposure to the intensive care unit (ICU) may take one of
5
6
167
SCIENTIFIC PRINCIPLES
168
saturated, is 16 mL/dL; hence, the normal arteriovenous difference in O2 content (avO2 difference) is 4 mL/dL. Expressed
mathematically:
DO2 CI
CaO2
where: CaO2 1.36
Hsb 0.0031
PaO2 CI stroke
volume
heart rate and, therefore,
VO CI
(CaO CvO )
2
Hemodynamic Assessment
When DO2 falls below the level of VO2, VO2 becomes supply
monitoring (and subsequent manipulation) of CI that is most
challenging. The cardiac output is a product of the stroke voldependent and a state of anaerobic metabolism occurs.
Preload
FIGURE 9.2. The concept of preload-recruitable stroke volume is
demonstrated. If the ventricle is on the steep part of the Starling curve
(A), then a given increase in preload will lead to a significant increase in
stroke volume. By contrast, on the flatter part of the curve (B), the
stroke volume increases marginally if at all with the same increase in
preload. Dynamic indices of preload-recruitable stroke volume are more
accurate than static indices in identifying where on this curve the patient
is at any point in time.
DYNAMIC INDICES
169
SCIENTIFIC PRINCIPLES
Stroke volume
170
up
SPV
Airway pressure
45 mm H2O
Line of reference
down
Arterial pressure
0
120 mm Hg
2 sec
End-expiratory
pause
PPmax
PPmin
0
5 seconds
FIGURE 9.3. Demonstration of cyclic systolic (A) and pulse pressure variation (B) during the respiratory cycle of a mechanically ventilated
patient. Systolic pressure variation (A) is demonstrated along with the reference line and end inspiration, from which down can be determined. Pulse pressure variation is demonstrated in B. The pulse pressure is greatest at the end of the inspiratory period and at least several
beats later (during the expiratory period). (From Michard F, Teboul JL. Using heart-lung interactions to assess fluid responsiveness during
mechanical ventilation. Crit Care 2000;4:282289, with permission.)
Systolic pressure variation (SPV) is the difference between maximal and minimal values of systolic blood pressure during one
positive-pressure mechanical breath (Fig. 9.3). SPV is divided
into two components: up and down. Up is the difference
between the maximal value of systolic pressure over a single
respiratory cycle and the reference systolic pressure. Down is
the difference between the reference systolic pressure and the
minimal value of systolic pressure over a single respiratory
cycle. In either case the reference systolic pressure is that pressure measured during an end-expiratory pause. SPV greater
than 11% or down greater than 5 mm Hg has been most
strongly associated with fluid responsiveness.23
Pulse pressure variation has also been used as a dynamic
index of fluid responsiveness and is directly proportional to
left ventricular stroke volume (Fig. 9.3). Pulse pressure variation is measured as follows:
PP (%) 100
(PPmax PPmin)
(PPmax PPmin)/2
171
FIGURE 9.5. The PaO2 values achieved at variable levels of FiO2 and
variable levels of shunt. These calculations assume normal hemoglobin and a venous saturation of 75%. (After Bartlett RH. University of
Michigan Critical Care Handbook. Boston, MA: Little, Brown; 1996.)
opening directly into the left side of the heart. This phenomenon, combined with the normal minor V/Q mismatch associated with shallow breathing at rest and positional effects on
pulmonary blood flow, results in a normal arterial PO2 of 90
to 100 mm Hg and a normal SaO2 of 98%. The extent to
which various degrees of transpulmonary shunting affect arterial oxygenation is shown in Figure 9.5. The shunt fraction is
actually calculated by assuming that the blood in capillaries in
those alveolar units that are functioning normally is fully saturated and oxygenated. In addition, it is assumed that the blood
passing through areas of transpulmonary shunt is identical to
venous blood. With these assumptions, the fraction of blood
passing through the shunt can be calculated as the O2 content
of blood leaving the capillaries of normal alveoli minus the O2
content of arterial blood divided by the O2 content of blood
leaving normal alveoli minus the O2 content of venous blood.
Obviously, the effect of the O2 content of venous blood in
the shunt calculation is considerable; when O2 delivery is
decreased because of low cardiac output or a low Hgb concentration, the venous saturation falls and the shunt fraction is
increased. It is not generally appreciated that the reductions in
mixed venous oxygen saturation as a result of inadequate cardiac output or severe anemia might lead to profound hypoxemia refractory to increases in the fraction of inspired oxygen
(FiO2). This effect occurs only in the presence of some degree of
intrapulmonary shunting and is not evident in patients with
normal lungs. For example, if one assumes there is some degree
of shunt due to atelectasis, blood perfusing the atelectatic lung
mixes with blood perfusing the more normal lung, so that
overall pulmonary venous oxygen content is significantly lowered. Increasing the inspired O2 to 100% may result in a large
increase in PO2 in the blood leaving the normal lung but little
increase in arterial oxygen saturation because the pulmonary
venous blood from normal alveoli was already maximally
saturated. The large increase in PO2 is associated with a small
increase in O2 content because the O2 that raises the PO2
(e.g., from 100 to 500 mm Hg) does increase the small amount
dissolved in plasma. However, the oxygenation of the arterial
blood is an average of the O2 content of blood from the two
areas of lung, not an average of the PO2. Therefore, systemic
hypoxia persists regardless of the FiO2. This physiology
should be kept in mindat times improvements in arterial
oxygen saturation may only be gained through increasing O2
by improving CI or Hgb concentration, both of which would
serve to increase the mixed venous oxygen saturation.
SCIENTIFIC PRINCIPLES
172
TA B L E 9 . 2
CALORIC VALUE OF METABOLIC SUBSTRATES
kcal/g
kcal/L O2
RQ
Carbohydrate
4.0
5.0
1.0
Fat
9.5
4.7
0.7
Protein
4.8
4.5
0.8
The shunt fraction can be calculated for any FiO2, but such
a calculation will also include components of diffusion block
and V/Q mismatch when the FiO2 is less than 1. The level of
lung dysfunction can be similarly estimated by calculating the
alveolararterial (Aa) gradient for O2 or the PaO2 divided by
the FiO2. The Aa gradient is calculated as follows:
AaO2
173
Pulmonary Mechanics
The interrelations of gas volumes and pressures in ventilation
are referred to as pulmonary mechanics. How these volumes
and pressures relate depend on pulmonary compliance. The
standard compliance or volumepressure curve, shown in Figure 9.8, is drawn by measuring volume and pressure at stages
of lung deflation after total inflation. Volumepressure curves
for normal lungs in three different patients are shown in
Figure 9.8. Notice that the curve for a normal 35-kg child is
the same as that for an adult with major atelectasis. (It would
be similar after pneumonectomy in an adult.) This emphasizes
the point that the functional lung in acute respiratory failure is
smaller, but not necessarily stiffer. Computed tomographic
studies of patients with ARDS support this concept. The lung
injury in ARDS is heterogeneous such that, in the presence of
normal tidal volumes, the relatively few alveoli that remain
ventilated might very well be overdistended.29 These findings
have significant implications for iatrogenic injury and ventilatory strategies in these patients.
In the example shown in Figure 9.8, inflation of the normal
lung with 500 mL of gas requires a pressure of 8 cm H2O and
SCIENTIFIC PRINCIPLES
174
Mechanical RX
Systemic RX
Fluid Status
Treat pneumothorax,
hydrothorax
Large ET tube
Tracheostomy?
Bronchoscopy?
Bronchodilators?
Rx ascites
Consider PE if PA
systolic >40
Ventilation
TV 810 mL/kg
rate 1012
hTV, rate (<35)
to PaCo2 3540
Limit: Pplat 30
Oxygenation
FIO2 as needed
PEEP 5
h PEEP to SaO2 >90%
h FIO2 to SaO2 >90%
Limit: FIO2 1.0
PaCo2 40
SaO2 >90%
PRBC to Hgb >70 mg/dL
h CO to SvO2 >70
>Dry weight
Diurese
Limit: iCO
Pplat 30
Dry weight
PaCo2 40
Stable
Maximize O2
delivery
PaCo2 >45
h rate then TV
(Limit: Pplat 30)
i VCo2
Paralysis
PaCo2 >45
Limit: pH <7.2
Consider
bicarbonate
infusion
Decrease Vo2
Nutrition
Treat infection
Sedation
Consider
paralysis
Positive nitrogen
balance
Adequate calories
SaO2 <90
SvO2 <70
SaO2 >90
SvO2 >70
hFIO2 0.61.0
Prone position?
Nitric oxide?
HFOV?
Wean
FIO2 to 0.4
PEEP to 5
ALGORITHM 9.1
ALGORITHM 9.1. Management of respiratory failure. ET, endotracheal; PA, pulmonary artery; PCWP, pulmonary capillary wedge pressure;
PE, pulmonary embolism; PEEP, positive end-expiratory pressure; PRBC, packed red blood cells; TV, tidal volume. (Modified from Bartlett RH.
University of Michigan Critical Care Handbook. Boston, MA: Little, Brown; 1996.)
Ventilator Strategies. Endotracheal intubation and mechanical ventilation provide vital support yet are associated with
disadvantages, including a greater risk of pneumonia and
aggravation of alveolar injury, respectively. Additionally, there
is increasing evidence that the manner by which patients are
ventilated and weaned might have significant effects on outcome. For example, in a large randomized controlled trial,
patients with ARDS or acute lung injury (a form of hypoxemic
respiratory failure, Table 9.330) ventilated with lower tidal volumes (6 mL/kg) had a significantly lower mortality than those
ventilated at higher tidal volumes (12 mL/kg).31 Clinical and
experimental studies suggest that higher tidal volumes lead to
ventilator-induced lung injury (by means of overdistending
alveoli), which incites a secondary greater local and systemic
inflammatory response. Patients ventilated with lower tidal volumes also had significantly lower ventilatory pressures (plateau
pressures 30 cm H2O); thus, it is unclear which offered benefitthe lower tidal volumes or the lower plateau pressures.
Most centers have since adopted this lung-protective ventilatory strategy.
A frequent point of controversy in managing the hypoxemic patient is the relative merits of using high levels of PEEP
and lower levels of FiO2 or using lower levels of PEEP with a
correspondingly higher FiO2. By convention, many intensivists
use higher levels of PEEP to maintain the FiO2 less than 0.6,
believing that higher levels of oxygen might induce hyperoxic
lung injury. However, results from a randomized controlled
trial comparing a high PEEP strategy with a high FiO2 strategy
demonstrated similar outcomes.32 Given these data, the risks
and benefits of using PEEP should be assessed for each patient
depending on the nature of his or her underlying lung disease
and associated conditions (e.g., low cardiac output state, high
intracranial pressure, unilateral lung disease).
Refractory hypoxemia in the critically ill patient often presents a significant challenge. Two common approaches to
assist in the management of these patients are prone positioning and high-frequency oscillatory ventilation (HFOV). Prone
positioning requires that the patient be cared for in this position, typically for as few as 4 to as many as 24 hours a day for
as long as 1 to 10 days, depending on the clinical response.
This approach results in improved ventilation due to the triangular shape of the rib cage (wider posteriorly) and a reduction
in atelectasis by reversing the compressive effects of the heart and
TA B L E 9 . 3
RECOMMENDED CRITERIA FOR ACUTE LUNG INJURY AND ACUTE RESPIRATORY DISTRESS SYNDROMEa
PULMONARY ARTERY
WEDGE PRESSURE
TIMING
OXYGENATION
CHEST RADIOGRAPH
Acute onset
PaO2/FiO2 300
regardless of PEEP level
18 when measured or no
clinical evidence of left atrial
hypertension
Acute respiratory
distress syndrome
(ARDS)
Acute onset
PaO2/FiO2 200
regardless of PEEP level
18 when measured or no
clinical evidence of left atrial
hypertension
SCIENTIFIC PRINCIPLES
175
176
Energy Sources
The major sources of energy are carbohydrates (including
ketones and alcohols) and fats. In addition, protein can be oxidized through gluconeogenesis and is often a significant source
of energy in critically ill patients. The goal of nutritional support
is to supply energy from sources other than protein, so that
endogenous and exogenous protein can be used for anabolism
rather than catabolism. In normal volunteers and surgical
patients, the breakdown of protein is decreased by giving the
177
Metabolic Requirements
The typical expenditures of energy and protein in normal subjects
and critically ill patients are shown in Figure 9.10. Protein and
energy requirements are continuous. These are met by endogenous sources during fasting or through exogenous treatment
(nutrition). Energy expenditure is referred to as the basal metabolic rate, or the basal energy expenditure. The term basal metabolic rate describes the energy required to maintain cell integrity
in the resting state and at thermoneutrality. The latter term means
an ambient temperature, usually close to 80F (28C), at which
the heat loss and the need for increased heat production to maintain the body temperature are minimal. The basal energy expenditure (BEE) decreases with advancing age and varies with sex
and body size. It is a function of cellular metabolism and hence of
the body cell mass. The basal energy expenditure (in kilocalories)
TA B L E 9 . 4
PREDICTED INCREASE IN CALORIC REQUIREMENTS AS A
FUNCTION OF STRESSOR
PHYSIOLOGIC STRESS
STRESS FACTOR
Operation
1.1
1.25
1.5
Thermal injury
10% BSA
1.25
20%30% BSA
1.5
40% BSA
1.75
50% BSA
2.0
SCIENTIFIC PRINCIPLES
178
Protein Metabolism
Estimating and Measuring Protein Requirements. In
normal protein metabolism, a continuous excretion of nitrogen (mostly as urea) equivalent to about 50 g of protein each
day is matched by a protein intake of 50 g/d. The rate of protein synthesis and breakdown is about 300 g/d, with most
endogenous amino acids being recycled into new protein. In
starvation, protein catabolism continues (although at a slower
rate) without a corresponding protein intake, leaving the
patient in a negative protein balance. This protein flux is most
conveniently measured as nitrogen flux; consequently, the condition is commonly referred to as negative nitrogen balance.
During critical illness, the rate of protein catabolism generally
increases while intake stops, so that a significant negative
nitrogen balance results. It is convenient to think of this protein breakdown as necessary to produce critically required glucose through gluconeogenesis when other carbohydrate stores
have been exhausted.
Protein Sources. The fact that the nitrogen balance is negative does not mean that protein synthesis stops or slows down.
On the contrary, the synthesis of new cells, inflammatory cells,
collagen, coagulation factors, antibodies, and scores of other
proteins occurs at an accelerated rate during critical illness.
Amino acids derived from muscle tissue or other somatic and
visceral proteins become the building blocks for protein in
healing tissue and host defenses. Thus, the site of a traumatic
or surgical wound or an area of acute inflammation diverts
protein from other body tissues. Proteins that would otherwise
strengthen the diaphragm or myocardium or participate in
host defense processes are less available, thus significantly
compromising the patient. A large part of the goal of nutritional management is to provide sources of energy so that
endogenous proteins are not required for energy (i.e., protein
sparing) and to supply exogenous proteins so that all the needs
of protein synthesis can be met without a breakdown of
endogenous sources. Although oversimplified, a convenient
number to remember for the basal protein requirement is 0.8
g/kg per day. The average critically ill surgical patients might
require 1.5 g/kg per day, whereas patients with severe thermal
Fat Metabolism
In a normal 80-kg man, about 1,000 cal are readily available as
glycogen and other stored carbohydrates, 24,000 cal are available as protein, and approximately 140,000 cal are stored as fat.
A 10,000-cal deficit accrued over 5 to 6 days of semistarvation in
a critically ill patient is considered a severe, acute energy deficit.
This seems paradoxical given the large amount of calories stored
as fat. However, the problem of a 10,000-cal deficit is not the
loss of a few kilograms of fat but rather the protein catabolism
commonly associated with an energy deficit of this size.
With the exception of essential fatty acids, the critically ill
patient has little need for the administration of exogenous
lipid. If the entire nonprotein caloric requirement were administered solely as carbohydrate, glycemic control and CO2 retention (or a need for a higher minute ventilation) would be the
only potential adverse effects. Thus, lipid is provided to prevent
essential fatty acid deficiency and minimally as a source of nonprotein calories.
There is significant debate regarding the value of administering intravenous fat emulsions in patients requiring parenteral
nutritional support. Selected studies report an increased risk of
infection and other complications, including potential lung toxicity from released fatty acids, compared to patients not receiving
lipid emulsions.55 It is entirely possible that the improved outcomes in the patients not receiving lipids were related to the
withholding of these fat infusions or due to the hypocaloric
nutritional regimen (underfeeding) these patients received, which
simplifies glycemic control along with all of its inherent benefits.
a systemic inflammatory response leads to depletion of endogenous antioxidants, including vitamins E and C. In this regard,
there is evidence to suggest that high doses of vitamins E and C
might improve outcome and lower the risk of multiple organ
failure in critically ill surgical patients.56 Adequate levels of
other vitamins are readily available in commercially prepared
formulations used for enteral or parenteral administration.
Mineral and trace metals must be managed more carefully
than vitamins because a deficiency can occur more quickly and
overdose can be deleterious. Calcium, phosphorus, and magnesium are lost continuously through the urine, stool, gastric
juices, and other drainage. Although large body stores (particularly of calcium and phosphorous) are available, functional
deficiency can develop rapidly. Enteral and parenteral feeding
must include these elements and serum levels of calcium, phosphorus, and magnesium should be measured at regular intervals.
In addition, zinc, copper, chromium, selenium, and manganese
must be supplied to patients who are supported with enteral or
parenteral feeding for more than 2 weeks.
Nutritional Support
6
179
Yes
No
Needs TPN
Full feeding
>2000 kcal
<2000 kcal
Central line
Peripheral?
Full feeding
ALGORITHM 9.2
ALGORITHM 9.2. Nutritional management. RQ, respiratory quotient; TPN, total parenteral nutrition. (Modified from Bartlett RH. University
of Michigan Critical Care Handbook. Boston, MA: Little, Brown; 1996.)
SCIENTIFIC PRINCIPLES
180
TA B L E 9 . 5
EFFECTORS AND MECHANISMS OF STRESS-INDUCED
HYPERGLYCEMIA
MEDIATOR
Cortisol
INCREASED
PERIPHERAL
INSULIN
RESISTANCE
INCREASED
HEPATIC
GLUCOSE
PRODUCTION
Glucagon
Growth hormone
X
X
Norepinephrine
Epinephrine
TNF-
IL-1
181
TA B L E 9 . 6
CLASSIFICATION OF ACUTE KIDNEY INJURY (RIFLE CLASSIFICATION)
RIFLE CATEGORY
GFR CRITERIAa
RISK
5%
INJURY
14.7
FAILURE
36.5
LOSS
47.6
END-STAGE KIDNEY
DISEASE
Either GFR (glomerular filtration rate) or urine output criteria might be used to define the RIFLE classification.
TA B L E 9 . 7
STANDARD MEASUREMENTS IN THE DIAGNOSIS
OF RENAL FAILURE
TEST
PRERENAL
PARENCHYMAL
Urine osmolarity
(mOsm)
500
250350
U/P osmolality
1.5
1.1
U/P creatinine
20
10
Urine sodium
20
40
FENa
1%
3%
SCIENTIFIC PRINCIPLES
ICU MORTALITY
182
General Care
With nonoliguric ARF, the treatment may differ little from
that required for identical patients with normal renal function.
The management of fluids, solutes, and nutrition is usually
unaffected by nonoliguric ARF, although the BUN may be elevated. The extent of renal dysfunction is limited and almost
always reversible. The use of renal replacement therapies (and
their inherent complications) is rarely necessary.
Oliguria and anuria pose several management difficulties. In
the absence of normal urine output, problems of fluid overload
can lead to anasarca, pulmonary edema, and congestive heart
failure. The pharmacokinetics of drugs becomes difficult to
predict as a result of decreased elimination and increased volume of distribution. In light of these risks, the volume status of
patients with ARF must be carefully monitored. Fluid intake
and output must be precisely tabulated, and the body weight
should be measured daily. Pulmonary artery catheterization
may be necessary to monitor the fluid status of these patients
more closely. Treatment options for hypervolemia consist of
fluid restriction or fluid removal with some form of RRT. Fluid
restriction, however, limits the administration of intravenous
medications and may preclude adequate nutrition.
ARF can create severe derangements in electrolyte and
acidbase physiology. Serum electrolytes should be measured
at least daily. Of all the electrolyte abnormalities that can
occur with ARF, hyperkalemia is the most serious. Under the
conditions of hypercatabolism and tissue necrosis that characterize these patients, large amounts of potassium may be generated and accumulate during a short period of time. Acute
hyperkalemia causes a decrease in cardiac excitability, which
can ultimately result in asystole. The removal of potassium
must be accomplished with RRT or ion exchange resins. Other
electrolyte abnormalities, such as hyponatremia, hyperphosphatemia, hypocalcemia, and metabolic acidosis, are common
in ARF and must be monitored closely. Treatment consists of
appropriate additions or restrictions of intravenous solutions
and effective use of RRT.
Platelet dysfunction and coagulopathy are often associated
with ARF. A reproducible platelet defect can be demonstrated
experimentally with a BUN of 100 mg/dL. This defect can be
transiently reversed with administration of desmopressin
(DDAVP). Platelet transfusion in this clinical setting will be
ineffective because the transfused platelets will rapidly acquire
the same dysfunction at the patients platelets. Anemia also
accompanies ARF in surgical patients. In addition to the loss
of blood during hemorrhage or operation, the production of
erythropoietin has been shown to decrease in direct proportion to the decrease in renal function.
183
Oliguria
Bladder catheter
Ultrasound
Confirm by urine
electrolytes
and clearance
Polyuria
Oliguria
Dx: no nephrons functional
Expect azotemia
Full nutrition
Intermittent hemodialysis
as needed for
solute clearance
Full nutrition
Intermittent hemodialysis
as needed for volume
and solute control
Multiple-organ failure
Full nutrition
Continuous renal replacement therapy
ALGORITHM 9.3
ALGORITHM 9.3. Management of acute renal failure. CAVH, continuous arteriovenous hemofiltration; CAVHD, continuous arteriovenous
hemodialysis; PD, peritoneal dialysis.
SCIENTIFIC PRINCIPLES
Blood volume
Cardiac output
Inotropes
184
TA B L E 9 . 8
PROPOSED CRITERIA FOR INITIATION OF RENAL
REPLACEMENT THERAPY IN CRITICALLY ILL PATIENTS
WITH ACUTE RENAL FAILURE
Pulmonary edema
Unable to meet nutritional requirements due to volume load
(pulmonary edema)
Oliguria: urine output 200 mL in 12 h
Anuria: urine output 50 mL in 12 h
Hyperkalemia: potassium concentration 6.5 mmol/L
Severe acidemia: pH 7.0
Azotemia: urea concentration 30 mmol/L
Uremic encephalopathy
Uremic neuropathy/myopathy
Uremic pericarditis
Plasma sodium abnormalities: concentration 155 mmol/L
or 120 mmol/L
Hyperthermia
Drug overdose with dialyzable toxin
Adapted from Lameire N, Van Biesen W, Vanholder R. Acute renal
failure. Lancet 2005;365:417430.
PROGNOSTICATION
AND INTENSIVE CARE
UNIT OUTCOME
8
185
TA B L E 9 . 9
ADVANTAGES OF INTERMITTENT HEMODIALYSIS AND CONTINUOUS RENAL
REPLACEMENT THERAPY
INTERMITTENT HEMODIALYSIS
CONTINUOUS RENAL
REPLACEMENT THERAPY
Advantages
Better hemodynamic stability
Lower cost
Disadvantages
Availability of dialysis staff
Greater cost
TA B L E 9 . 1 0
SCORING SYSTEMS IN THE ICU
PROGNOSTIC SCALES:
SEVERITY OF ILLNESS
Uses
Prognostication; risk
stratification
Timing of
ascertainment
Selection of
variables
Physiologic measures
Worst values
Selected to maximize
predictive capacity
Maximize prediction
Maximize description
Calibration
SCIENTIFIC PRINCIPLES
186
TA B L E 9 . 1 1
ORGAN DYSFUNCTION SCORING: THE MARSHALL MULTIPLE ORGAN
DYSFUNCTION SCORE
ORGAN SYSTEM
Respiratory (PaO2/FiO2)
300
226300
1.1
1.22.3
151225
76150
75
2.43.9
4.05.6
5.7
1.1
1.23.5
3.67.1
7.214.1 14.2
Cardiovascular (PARa)
10.0
10.115.0
15.120.0
20.130.0 30.0
120
81120
5180
2150
20
15
1314
1012
79
Adapted from Marshall JC, Cook DJ, Christou NV, et al. Multiple organ dysfunction score: a reliable
descriptor of a complex clinical outcome. Crit Care Med 1995;23:1638.
Outcome Measures
Organ failure is a relatively frequent occurrence in critically ill
patients and has resulted in attempts to describe and quantify
organ dysfunction. This is a difficult process because organ
failure is dynamic and represents a broad spectrum of disease.
Which organ systems to include and which measures one
should use to quantitate organ dysfunction remain controversial. Most scores focus on six organ systems: respiratory, cardiovascular, hematologic, central nervous system, renal, and
hepatic. These outcome measures have conceptual appeal for
several reasons. First, they provide an estimate of baseline
severity for entry into clinical trials, whereas serial evaluation
might provide information on mortality risk. With these
organ dysfunction measures, the burden of disease experienced by the patient throughout the course of ICU stay is captured. By contrast, with prognostic scoring systems there is
but an early snapshot of the patients physiologic status,
whereas information regarding the remainder of the patients
course is lost.
The most commonly used outcome measures include the
Sequential Organ Failure Assessment (SOFA) Score and the
Multiple Organ Dysfunction (MOD) Score or Marshall Score,
both of which capture data on the six aforementioned sys-
ETHICS IN THE
INTENSIVE CARE UNIT
The availability of advanced technologies to prolong life in the
ICU has resulted in a number of controversies centered on
their appropriate use. The controversies have developed under
the guise of the technologic imperative, implying that the
availability of technology requires that this technology be used.
To counter the technologic imperative, physicians have often
invoked the concept of futility to limit its inappropriate use,
resulting in confusion and, at times, conflict when caring for
critically ill patients.
In the strictest sense, true medical futility occurs rarely and
signifies interventions that simply should not be offered. For
example, we do not offer ongoing medical care to a patient
who meets criteria for brain death. The majority of interventions that physicians judge to be futile are not truly futile. They
should more accurately be considered inadvisable or inappropriate because the chances of achieving the intended goal are
exceedingly low, their benefits are controversial, or their costs
are excessively great. Implicit in this definition is a clear understanding of the real or perceived therapeutic endpoint; that is,
it is meaningless to say an intervention is futile without specifying the goal of the intended therapy. Conflicts arise when
there are disagreements about the intended goal, whether the
desired goal is appropriate, and whether the probability of
success is sufficiently great. In this sense, there are both qualitative (value-driven) and quantitative (probabilistic) aspects to
the understanding and application of futility in the ICU.
Quantitative futility describes a clinical situation in which
the application of an intervention has a very low probability of
producing a satisfactory outcomeusually survival. There
have been a large number of prognostic scoring systems developed to compare outcomes in large groups of patients.
References
1. Brilli RJ, Spevetz A, Branson RD, et al. Critical care delivery in the intensive care unit: defining clinical roles and the best practice model. Crit Care
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K E Y
The human body is conceptualized as composed of at least
four compartments: water, protein, fat, and bone ash.
2 Sodium (extracellular fluid [ECF]) and potassium (intracellular fluid [ICF]) are the dominant cations and, whereas
composition varies between ECF and ICF, overall concentration of solutes in these fluids is identical.
3 Osmolality is kept constant by tight regulation of water
balance by osmoreceptor-induced control of antidiuretic
hormone and thirst.
4 Effective circulating volume is sensed by volume receptors
(capacitance vessels, atria, hepatic, and central nervous
system) and pressure receptors (aortic arch, carotid, and
intrarenal) that alter sodium and water balance mediated
by renin-angiotensin, aldosterone, atrial natriuretic peptide, dopamine, and renal prostaglandins.
BODY FLUIDS
Total Body Water and
Body Fluid Compartments
Traditionally, most scientists used a two-compartment model
of tissues within the body: the fat compartment and the fat1 free or lean tissue compartment. Over the past 20 years, technology has added significantly to our knowledge of body composition, and more complex models have been developed, the
simplest of which is the four-compartment model. In this
model, the fat-free mass is actually composed of three separate
compartments: water, protein, and bone ash. The remaining
compartment is fat, which is considered to be triglycerides,
because adipose tissue, a more general descriptor, also contains small amounts of water. Total body water (TBW) is
defined as the total volume of water within the body. TBW has
traditionally been measured using indicator dilution techniques in which radioactive tracers such as deuterium oxide
(D2O) were given to subjects and a steady state allowed to
develop before measurements of the D2O in the plasma were
made. More recently, other techniques have added greatly to
our ability to measure TBW content as well as the content of
P O I N T S
Water losses involve both sensible (measurable) via urine,
stool, and sweat and insensible (unmeasurable) via evaporative loss from both the skin and respiratory tract.
6 Goals of fluid therapy are to normalize hemodynamic
parameters and body fluid electrolyte concentrations and
can be achieved with crystalloids (preferable) or colloids,
both correcting deficits and matching ongoing or expected
losses.
7 The major cations (Na, K, Ca2, and Mg2) should be
monitored and replaced, recognizing unique distributions
and impact of various diseases.
8 Acidbase balance is carefully buffered within very narrow
limits. Acidbase disturbance and compensation are frequently mixed, involving respiratory and metabolic-renal
responses.
189
SCIENTIFIC PRINCIPLES
ACIDBASE BALANCE
190
TA B L E 1 0 . 1
BODY FLUID COMPARTMENTS
BODY
WEIGHT (%)
TOTAL BODY
WATER (%)
Total
60
100
Intracellular
40
67
Extracellular
20
33
Intravascular
15
25
Interstitial
Transcellular
the ECF compartment and multiplies this by the known quantity of 40K measured in a serum sample, the ICF can then be calculated by subtracting this total from the TBK.
The ECF compartment is subdivided into the intravascular
and interstitial spaces. The intravascular space accounts for
25% of the ECF and contains the plasma volume, which is
approximately 8% of the TBW or 5% of body weight. Interstitial water volume is calculated as ECFintravascular space
volume and constitutes approximately 25% of TBW, or 15%
of body weight. The interstitial space extends from the blood
vessels to the cells themselves and includes the complex
ground substance making up the acellular tissue matrix. The
water in this space exists in free and bound phases. The free
phase contains water that is freely exchangeable with intravascular, lymphatic, and intracellular water and that is in a constant state of flux. The bound or gel phase is much less freely
exchangeable and is composed of water that hydrates matrix
materials such as glycosaminoglycans and mucopolysaccharides. The transcellular space, a third and smaller component
of ECF, consists of water that is separated from other compartments by endothelial and epithelial barriers, including
cerebrospinal, ocular, and synovial fluids, as well as fluid in the
gastrointestinal (GI) tract. Under normal circumstances, fluid
in the transcellular space is not easily exchangeable with that
in other compartments.
TA B L E 1 0 . 2
ELECTROLYTE CONCENTRATIONS OF INTRACELLULAR AND EXTRACELLULAR
FLUID COMPARTMENTS
EXTRACELLULAR FLUID (mEq/L)
PLASMA
INTERSTITIAL
INTRACELLULAR
FLUID (mEq/L)
Cations
Na
K
Ca2
2
Mg
140
146
12
150
107
103
114
Anions
Cl
HCO3
24
27
SO2
4
HPO3
4
116
16
40
Protein
Organic anions
10
191
SCIENTIFIC PRINCIPLES
192
sodium is calculated to fall 1.5 mEq/L, without an actual alteration of body sodium content. The osmotic diuresis caused by
the elevated glucose level tends to normalize the serum sodium
if adequate hydration is maintained. Some patients with uncontrolled diabetes also have marked hyperlipidemia. Because of
this, the concentration of measured sodium falls. This condition is termed pseudohyponatremia.
Plasma osmolality (Posm) is an excellent measure of total
body osmolality. Osmolality differentials between fluid compartments are only transient because fluid shifts maintain isosmotic conditions. Sodium is the predominant extracellular
cation; thus, estimates of Posm can be made by simply doubling
the serum sodium concentration (serum [Na]):
Posm (mOsm/L) 2 serum[Na]
Because glucose and BUN may make significant contributions to Posm in certain disease states, this formula is modified
for glucose and for BUN:
Posm (mOsm/L) 2 serum[Na] glucose/18 BUN/2.8
Discrepancies of greater than 15 mOsm/L between calculated Posm and Posm measured in the clinical laboratory may be
the result of the presence of other osmotically active particles,
such as mannitol, ethanol, or ethylene glycol, or of a reduced
fraction of plasma water secondary to high levels of myeloma
proteins or hypertriglyceridemia.
Osmoregulation
3
Osmolality of body fluids stays fairly constant at approximately 285 to 295 mOsm/L as the result of tightly regulated
water balance. Osmoreceptor cells in the paraventricular and
supraoptic nuclei of the hypothalamus exert central control
over the thirst mechanism and antidiuretic hormone (ADH)
secretion from the posterior pituitary. In the presence of excess
free water, ECF osmolality falls toward 280 mOsm/kg H2O,
thirst is inhibited, and ADH levels decline. In the absence of
ADH, the permeability of renal collecting tubules to water is
decreased, causing free water reabsorption to decrease and
excretion to increase. Urine osmolality (Uosm) can decline to
100 mOsm/kg H2O (Fig. 10.2). As excess free water is eliminated, Posm begins to rise. Conversely, free water depletion
causes an increase in Posm. As Posm approaches 295 mOsm/kg
H2O, thirst is stimulated as is ADH secretion. As ADH levels
rise to approximately 5 pg/mL, the renal collecting tubules
become maximally permeable to water. Water is reabsorbed
from the collecting ducts in response to the concentration gradient developed in the renal medullary interstitium. Thus, the
final concentration of urine depends on both the permeability
of the collecting ducts (controlled by ADH secretion) and the
concentration of the medullary interstitium. Maximal Uosm
may approach 1,200 mOsm/kg H2O. The net effect of these
mechanisms is to promptly return high or low Posm to normal.
The high sensitivity of the osmoreceptors and the responsiveness of the ADH feedback system ensure that even small
changes in Posm result in marked alterations in urine concentration. This relation can be expressed as follows:
Urine osmolality 95 plasma osmolality
FIGURE 10.2. The relation of plasma antidiuretic hormone (arginine vasopressin, or AVP) secretion to plasma (A) and urine (B) osmolality in healthy adults in varying states of water balance. (Reproduced with permission from Robertson GL, Berl T. Water metabolism. In:
Brenner BM, Rector FC Jr, eds. The Kidney. Philadelphia, PA: WB Saunders; 1986:392.)
193
FLUID BALANCE
Sodium Concentration and Water Balance
Changes in TBW content are reflected by changes in the extracellular solute concentration. Because sodium is the primary
extracellular cation and potassium is the predominant intracellular cation, the serum [Na] approximates the sum of the
exchangeable total body sodium (Nae) and exchangeable TBK
(Ke) divided by TBW:
Volume Control
Changes in volume are detected both by osmoreceptors, which
detect changes in Posm, and baroreceptors, which are sensitive
to changes in pressure. The osmoreceptors are responsible for
the day-to-day fine-tuning of volume, whereas the baroreceptors contribute relatively little to the control of fluid balance
under normal conditions.4 As mentioned previously, large
changes in circulating volume (10% to 20% blood volume
loss) can modify the osmoregulation of ADH secretion. Cardiac atrial baroreceptors control volume by means of sympathetic and parasympathetic neural mechanisms, whereas atrial
natriuretic peptide (ANP) released by atrial myocytes in
response to atrial wall distention may influence sodium-linked
volume control by inhibition of renal sodium reabsorption.
Baroreceptor Modulation of Volume Control. Effective circulating volume describes that portion of the extracellular volume that perfuses the organs of the body and affects
the baroreceptors. The effective circulating volume normally
Serum[Na ] Na e Na e /TBW
corresponds to the intravascular volume. However, in disease
states such as congestive heart failure and arteriovenous fisBecause total body solute content (Nae Ke) remains reltula, where a smaller percentage of intravascular volume than
atively stable over time, changes in TBW content result in
normal is available for organ perfusion, effective circulating
inversely proportional changes in serum Na (Fig. 10.4). Thus,
volume is reduced.
Changes in the effective circulating volume are sensed by
4
volume receptors in the intrathoracic capacitance vessels and
atria, pressure receptors of the aortic arch and carotid arteries,
intrarenal baroreceptors, and hepatic and cerebrospinal volume receptors. These stretch receptors respond to changes in
pressure and circulating volume and, through a complex system of neural and hormonal actions, alter sodium and water
balance in the kidneys. Hormonal effects are mediated by the
renin-angiotensin system, aldosterone, ANP, dopamine, and
the renal prostaglandins.
Baroreceptor Function. The low-pressure baroreceptors
FIGURE 10.4. Relation between serum [Na] and the ratio of (Nae
Ke) to total body water (TBW). (Reproduced with permission from
Edelman IS, Liebman J, OMeara MP, et al. Interrelationships between
serum sodium concentration, serum osmolarity and total exchangeable sodium, total exchangeable potassium and total body water. J Clin
Invest 1958;37:1236.)
SCIENTIFIC PRINCIPLES
194
terone release is also stimulated by increased potassium levels, adrenocorticotropic hormone, endothelins, and prostaglandins.
Atrial and Renal Natriuretic Peptides. ANP is synthesized and
released by atrial myocytes in response to atrial wall distention. As mentioned previously, small changes in right atrial
pressure produce large increases in plasma levels of ANP.7,8
There is evidence that ANP has a direct inhibitory effect on
renal sodium reabsorption, which is probably maximal at the
level of the medullary collecting tubules. Although pharmacologic doses of ANP can cause changes in both renal blood flow
and glomerular filtration rate, physiologic levels do not appear
to have any major effect on these parameters. Other active
fragments of the ANP prohormone have been found to have
natriuretic activity. The best described is urodilatin, also
known as renal natriuretic peptide. Urodilatin is a peptide
with ANP-like activity that was first isolated from human
urine. It is synthesized and luminally secreted by cortical collecting tubule cells. Like ANP, it is released in the kidney
tubules in response to atrial distention and saline loading. It is
at least twice as potent as ANP, acting in the distal nephron to
cause a rise in intracellular cyclic guanosine monophosphate,
leading to sodium, chloride, and water diuresis. ANP and
other peptides may play an important role in controlling
intravascular volume and water and electrolyte secretion.9
Renal Prostaglandins. Renal prostaglandins appear to play a
role in volume control, although under normal physiologic
conditions, this role may be minimal. Disease states such as
sepsis and jaundice, or the induction of anesthesia, may make
the contribution of the prostaglandins more pronounced.
Prostaglandin E2 (PGE2) and prostaglandin I2 (PGI2) appear
to be the predominant prostaglandins produced in the kidney.
PGE2 is produced primarily by the interstitial cells of the renal
medulla. The release of PGE2 has been shown to depend on
increases in interstitial pressure, which can be induced by
changes in renal perfusion, ureteral obstruction, or alterations
in oncotic pressure. Under these conditions, PGE2 increases
sodium excretion in the absence of changes in glomerular filtration rate. PGE2 antagonizes the action of vasopressin (ADH)
and inhibits ADH-induced sodium reabsorption along the
medullary collecting duct and thick ascending limb. PGI2 is produced by the glomeruli and endothelial cells of the kidney and is
present in the greatest concentrations in the renal cortex. PGI2 is
195
TA B L E 1 0 . 3
WATER LOSSES IN A 60- TO 80-kg MAN
AVERAGE
DAILY
VOLUME (mL)
MINIMAL
DAILY
VOLUME (mL)
Sensible losses
Urinary
8001,500
Intestinal
0250
Sweat
300
0
0
Endothelins. Endothelins are peptide vasoconstrictors that are
involved in volume and pressure regulation. Endothelin is proInsensible losses
duced and released by endothelial and other cells act on adjaLungs and skin
600900
600900
cent smooth muscle cells. In addition to increasing peripheral
resistance, endothelin infusion has a direct inotropic effect on
Adapted from Shires GT, Canizaro PC. Fluid and electrolyte
the myocardium. In contrast to its vasoconstrictive effects,
management of the surgical patient. In: Sabiston DC, ed. Textbook of
endothelin stimulates the release of other vasoactive mediaSurgery. Philadelphia, PA: WB Saunders; 1986:77, with permission.
tors, particularly endogenous vasodilators like nitric oxide,
which act to limit its intense vasoconstrictor effect.
Endothelin exerts a complex influence on sodium and
water exchange through varied interactions with many other
hormones that govern fluid and electrolyte balance. One net
only because of disease but also because perioperative fluid
effect of endothelin is a decrease in the filtered load of sodium
replacement may sidestep some of these homeostatic mechain the kidney. This results in inhibition of water reabsorption
nisms. Although it is important to recognize and correct disand decreased sodium excretion. Endothelin increases ANP
ease, trauma, and stress-related abnormalities, it is equally
secretion, activates ACE, and inhibits renin release by the juximportant to understand normal fluid and electrolyte balance
taglomerular apparatus. At low doses, endothelin-1 produces
and to avoid iatrogenic perturbations of these systems.
a dose-dependent natriuresis and diuresis. Endothelin also
modulates the biosynthesis of aldosterone, thereby inhibiting 5 Normal Water Exchange. Water losses are both sensible
water reabsorption through aldosterone-controlled mecha(measurable) and insensible (unmeasurable). Sensible losses
nisms. Vasopressin-mediated water reabsorption is also inhibinclude losses through urine, stool, and sweat. Table 10.3 sumited. Endothelin appears to have complex interactions with
marizes the normal sensible and insensible losses encountered
other regulators of renal perfusion and handling of water and
in a 24-hour period. The volumes of these losses may vary conelectrolytes, which has stimulated research to evaluate the considerably. Urinary loss usually varies in proportion to intake
tribution of endothelin to the pathophysiology of various
plus other losses. The minimal amount of water needed to
renal diseases.11
excrete normal metabolic waste products is approximately
300 mL/d.
Nitric Oxide. Nitric oxide is a short-lived free radical proWater loss in stool is usually small, on the order of 150 mL/d,
duced from L-arginine by nitric oxide synthases. Although this
but may increase markedly in disease conditions. The GI tract
substance has numerous biologic functions that are beyond the
has a net secretory action down to the level of the jejunum, and
scope of this chapter, including regulation of vascular tone and
the reabsorptive capacity of the remainder of the small and large
tissue blood flow,12 its effects in the kidney as they relate to
intestines keeps water loss by this route to a minimum. Bowel
fluid and electrolyte homeostasis deserve mention. Nitric
obstruction, severe diarrhea, and enterocutaneous fistulas are
oxide is produced in renal smooth muscle cells, mesangial
examples of conditions that may increase GI losses of water and
cells, tubules, and endothelial cells and participates in the regelectrolytes.
ulation of renal hemodynamics and renal handling of water
Sweat does not usually account for much of the daily water
and electrolytes. Nitric oxide and PGI2 each independently
loss. Sweating is an active process involving the secretion of a
cause renal vasodilation in response to a variety of stimuli.
hypotonic mixture of electrolytes and water, and it should be
Nitric oxide is important in the regulation of medullary (vasa
differentiated from the insensible water loss of evaporation
recta) blood flow. Pressure-dependent sodium excretion is
from the skin.
ablated by inhibitors like L-NG-monomethyl-arginine and
Insensible water loss is the evaporatory loss of water from
restored with L-arginine. Nitric oxide also contributes to tububoth the skin and the respiratory tract (see Table 10.3). Evaploglomerular feedback, which modulates the delivery and
oratory skin losses are determined by the body surface area
reabsorption of sodium and chloride in the renal tubules.
and temperature of the patient, as well as by the relative
Nitric oxide synthase in macula densa cells is activated by
humidity of the environment. Evaporation through the skin
tubular solute reabsorption to release nitric oxide as a vasodifunctions as a mechanism for heat loss and is proportional to
lating component of the tubuloglomerular feedback response.
calories expended. Approximately 30 mL of water is lost for
Nitric oxide also participates in regulating renin release by the
every 100 kcal expended. Respiratory exchange depends on
juxtaglomerular apparatus. Finally, nitric oxide produced in
the ambient temperature and the relative humidity as well as
the proximal tubule may mediate the effects of angiotensin on
on the rate of air exchange. Respiratory water loss is also
tubular reabsorption.12
energy dependent; thus, at normal respiratory rates, 13 mL of
water is lost for every 100 kcal expended. Overall, normal
insensible water losses average approximately 8 to 12 mL/kg
per day. Insensible water loss increases 10% for each degree of
Normal Water and Electrolyte Exchange
body temperature above 37.2C (99F). In addition, patients
The bodys normal homeostatic mechanisms control both the
with tracheostomies who breathe unhumidified air lose addivolume and composition of the fluid compartments such that
tional free water. Conversely, patients who are on respirators
a remarkably stable internal milieu is maintained. Surgical
or who breathe air that is 100% humidified have no respirapatients are prone to fluid and electrolyte abnormalities, not
tory losses and may gain free water.
SCIENTIFIC PRINCIPLES
196
TA B L E 1 0 . 4
ELECTROLYTE CONTENT OF COMMONLY USED INTRAVENOUS CRYSTALLOID SOLUTIONS
ELECTROLYTE (mEq/L)
SOLUTION
Na
K
Ca2
Mg2
Cl
...
0.9% NaCl
154
154
0.45% NaCl
77
77
0.33% NaCl
56
56
0.2% NaCl
34
34
Lactated Ringer
130
109
28
3.0% NaCl
513
513
5.0% NaCl
855
855
197
resuscitative solution in a variety of clinical settings with variable results. Coagulopathy and bleeding complications have
been widely reported after administration of highly substituted,
high-molecular-weight HES.25,26 This appears to be associated
with reduced factor VIII and von Willebrand factor levels, a
prolonged partial thromboplastin time, and impaired platelet
function.27 Because of its long half-life, coagulopathy does not
quickly reverse after cessation of HES administration. Reports
of renal insufficiency or renal failure after HES 450/0.7, HES
250/0.45 (Pentaspan), and HES 200/0.62 administration add
to the concerns regarding overuse of these volume expanders,
particularly in patients with preexisting renal impairment.
Hextend, a balanced 6% hetastarch (molecular weight
[MW] 720,000) in lactated Ringer solution, has been forwarded as a much-improved alternate resuscitation product as
compared to 6% hetastarch in saline. In a phase III trial of
Hextend and 6% hetastarch in saline, Hextend was found to
be as effective for resuscitation but without adversely affecting
the coagulation profile.28 Although the safety profile of this
alternative colloid resuscitative fluid appears to be better than
that of 6% hetastarch in saline, the data regarding its safety in
situations of massive resuscitation are not clear. In a recent
study using an experimental model of traumatic brain injury,
Hextend was found to reduce fluid requirements, eliminate the
need for mannitol, and improve neurologic outcome as compared to crystalloid and mannitol resuscitation. Furthermore,
it had no adverse effect on coagulation.29 In another recent
experimental report, Hextend was found to have no significant
platelet-inhibitory effects.30
Low-molecular-weight, low-substituted (MW 130 kD; DS
0.4) HES (Voluven) has recently been introduced and demonstrated to have a far smaller effect on coagulation than other
HES solutions.31 In addition, there is evidence that renal impairment does not occur after administration of HES 130/0.4, in
contrast to the high-molecular-weight, highly substituted HES
solutions.32 Although numerous reports now suggest that this
type of alternative HES is a very good option when plasma volume expansion is indicated, the safety of wide use of largevolume Voluven administration remains to be demonstrated.
SCIENTIFIC PRINCIPLES
198
develop hemoglobin-based oxygen-carrying (HBOC) solutions, and the results of recent clinical trials with these substances have been encouraging.36 In the future, these solutions
may prove beneficial when volume expansion in conjunction
with increased oxygen-carrying capacity is required and will
avoid the immunologic consequences of allogenic blood transfusions.
CORRECTION OF
VOLUME ABNORMALITIES
Volume Excess
Clinical manifestations of volume excess may occur with excessive parenteral volume administration, particularly in at-risk
patients such as the elderly and those with cardiac disease. Volume overload can occur if appropriate adjustments to fluid therapy are not made. Possible manifestations of volume overload
are weight gain, elevated central venous pressure (CVP), pulmonary congestion or edema, and peripheral edema. Intravascular volume excess is treated by volume restriction and use of
loop diuretics.
199
TA B L E 1 0 . 6
ELECTROLYTE CONCENTRATIONS IN GASTROINTESTINAL SECRETIONS
ELECTROLYTE (mEq/L)
Salivary
RATE
(mL/d)
Na
K
Cl
...
H
50
20
40
30
1001,000
100
10
140
30
1,000
Gastric
Basal
Stimulated
30
10
140
100
Bile
140
100
Pancreatic
140
75
1,000
Duodenum
140
80
1002,000
Ileum
140
70
1002,000
Colon
60
70
15
patients with chronic disorders, patients who experience significant volume shifts, or patients who require long-term parenteral fluid therapy, these electrolytes should be measured
and corrected by the most practical route. If the enteral route
is unavailable, these are administered in parenteral nutrition
solutions along with trace elements, vitamins, and appropriate
caloric sources.
REPLACEMENT OF
ONGOING FLUID LOSSES
Once volume deficits have been replaced and maintenance fluids have been calculated and given, the overall fluid balance of
the patient can be maintained by replacement of fluid losses
beyond those considered to be maintenance. Ongoing losses
from nasogastric tubes, stomas, fistulas, and other measurable
sources are recorded during the course of care and can be
replaced in fairly straightforward fashion. The electrolyte contents of these fluids can be estimated or measured and used to
guide the choice of replacement fluid type (Table 10.6).
4,200
5001,000
ELECTROLYTES
Volume excess or deficits are often isotonic but may be accompanied by changes in extracellular sodium concentration and
osmolality. The mechanisms controlling normal osmoregulation
SCIENTIFIC PRINCIPLES
SECRETION
200
TA B L E 1 0 . 7
CAUSES OF THE SYNDROME OF INAPPROPRIATE
ADH SECRETION
Tumor hypersecretion of ADH
Lung
Pancreas
Bladder
Prostate
CNS disorders
Head trauma
Neurosurgical interventions
Brain tumors
Alcohol withdrawal
Stroke
Other
Infection
Medication induced
may be affected by the same processes responsible for controlling volume. Volume depletion is the most common disorder of
volume status encountered in surgical and trauma patients.
These patients usually present with isotonic dehydration (Fig.
10.6A). In this condition, the volume lost is isotonic with
plasma. Examples of isotonic volume deficits include blood
loss, third-space losses, and GI losses. Volume depletion may
also be accompanied by hypo-osmolar conditions (hypotonic
dehydration; see Fig. 10.6B) and is often iatrogenic and the
result of incomplete volume resuscitation with hypotonic solutions. Dehydration associated with hyperosmolar states (hypertonic dehydration; see Fig. 10.6C) is infrequent and usually
indicates impaired consciousness and thirst mechanisms or a
patients inability to drink or obtain water. As mentioned previously, volume excesses often occur some time after hospitalization rather than at presentation. The most frequent concentration defect associated with volume excess is hyponatremia.
Hyponatremia
Causes. Hyponatremia may result from direct sodium loss or
from dilution of sodium by excessive free water under hypovolemic, euvolemic, or hypervolemic conditions. Hyponatremia
is frequently seen in the postoperative or postinjury period
when ADH is elevated as a component of the normal stress
response to injury. Inflammatory and stress cytokines such as
C-reactive protein, interleukin-6, interleukin-1, and tumor
Fatigue
Muscle cramps
TA B L E 1 0 . 8
SYMPTOMS OF HYPONATREMIA
Central nervous system
Headaches
Confusion
Delirium
Coma
Seizures
Gastrointestinal
Anorexia
Nausea
Vomiting
Musculoskeletal
201
Weakness
TA B L E 1 0 . 9
CAUSES OF HYPERNATREMIA
VOLUME
STATUS
CAUSE
Low
Normal
High
SCIENTIFIC PRINCIPLES
202
Uosm V
Posm
where CH2O free water clearance rate, Cosm osmolar clearance rate, V urine flow rate, and Uosm and Posm urine and
plasma osmolalities, respectively.
The Uosm and Posm can be estimated by the total sodium and
potassium concentrations. Therefore,
CH2O V
(UNa Uk) V
[Na]s
where UNa and UK urinary sodium and potassium concentrations, respectively. A positive number signifies net free
water loss and adds to the water requirement, whereas a negative number indicates free water absorption and is subtracted
from the water requirement. Thus, the total water requirement
to achieve the desired decrease in serum [Na] is the sum of
the calculated water deficit plus the calculated insensible water
loss plus the urinary free water clearance.
203
TA B L E 1 0 . 1 0
CAUSES OF HYPOKALEMIA
SCIENTIFIC PRINCIPLES
204
205
SCIENTIFIC PRINCIPLES
parathyroidectomy with autonomous parathyroid transplantation. Hypercalcemia secondary to tumor secretion of hormonal
mediators may be controlled by extirpation of the tumor. In the
presence of metastatic bone disease, inhibition of bone resorption with mithramycin or calcitonin may yield good results. In
addition, hypercalcemia due to metastatic breast carcinoma or
hematologic malignancies may respond to steroid therapy.
Intravenous administration of bisphosphonates has been shown
to be extremely effective and safe for treatment of patients with
hypercalcemia associated with cancer.40 Patients with renal failure benefit from dialysis using a low-calcium dialysate.
Hypocalcemia
Causes. Hypocalcemia secondary to hypoparathyroidism can
complicate thyroid or parathyroid surgery by either inadvertent total parathyroidectomy or loss of parathyroid function
due to devascularization. This has been reported to occur in as
many as 2% to 3% of patients undergoing total thyroidectomy, although this figure appears to be declining. After resection of a parathyroid adenoma, hypocalcemia can occur
because of atrophy of the remaining glands. Calcium replacement therapy may be required until the remaining glands
resume normal function.
Hypocalcemia can also complicate acute pancreatitis owing
to calcium precipitation into the peripancreatic tissues. In
addition, pancreatic and small-bowel fistulas may result in loss
of calcium-rich fluid. Longstanding vitamin D deficiency secondary to malnutrition, malabsorption, or lack of exposure to
sunlight can lead to hypocalcemia. Renal failure can lead to a
deficiency in 1,25-dihydroxyvitamin D3 and result in diminished intestinal absorption of calcium. Severe magnesium deficiency can also lead to hypocalcemia because of suppression of
PTH levels.
Clinical Features. Serum calcium levels below 8 mg/dL may
be associated with symptoms and signs that are primarily
206
Magnesium. Total body content of magnesium in the average adult is 2,000 mEq, half of which is confined to bone. Most
of the remaining magnesium is distributed in the intracellular
space. Less than 1% of total body magnesium is located in the
extracellular space, at concentrations of 1.4 to 2 mEq/L (or 1.7
to 2.3 mg/dL). Sixty percent of this magnesium exists in the
ionized form, 25% is in the protein-bound state, and the
remainder is complexed with nonprotein anionic species.
Approximately 25 mEq/d of magnesium is consumed in the
diet, a variable amount of which is absorbed by the small
intestine. Magnesium absorption may be influenced by the levels of 1,25-dihydroxyvitamin D3. Bone stores constitute the
other major source of available magnesium, although regulation of magnesium exchange with bone is poorly understood.
Magnesium is excreted primarily by the kidneys. Approximately 40% of the filtered magnesium is reabsorbed in the
proximal tubule, predominantly in the ascending limb of Henle.
Thus, loop diuretics cause a marked increase in magnesium
excretion. Magnesium excretion is also increased by hypermagnesemia, hypercalcemia, metabolic acidosis, and phosphate
depletion. Conversely, magnesium excretion is decreased by
metabolic alkalosis.
Hypermagnesemia
Causes. Because of the ability of the kidneys to excrete large
magnesium loads, hypermagnesemia rarely occurs if renal
function is normal. In chronic or acute renal failure, administration of magnesium-containing antacids or laxatives is frequently the cause of hypermagnesemia. Severe burns, crush
injuries, and other causes of rhabdomyolysis may lead to high
magnesium levels due to the release of magnesium from
injured tissues. Severe metabolic acidosis, extracellular volume
depletion, and renal insufficiency with creatinine clearances
below 30 mL/min may also cause hypermagnesemia.
Clinical Features. Neuromuscular function is depressed by
hypermagnesemia because of the inhibition of synaptic acetylcholine release. Loss of deep tendon reflexes can occur with
magnesium levels above 8 mg/dL. Paralysis and eventually
coma can develop if levels exceed 12 to 18 mg/dL. Hypotension or even cardiac arrest can occur if levels exceed 18 mg/dL.
Treatment. Magnesium-containing medications must be
avoided in patients with hypermagnesemia. Calcium antagonizes the effects of magnesium, and infusion of 5 to 10 mEq of
ACIDBASE BALANCE
Definitions
An acid is defined as a chemical that can donate a hydrogen ion
(H), for example, HCl and H2CO3, and a base is a chemical
that can accept a H, for example, OH and HCO3.
Ampholytes are both acids and bases; an example is H2PO4,
which can donate a H to become HPO42 but can also accept
H to become H3PO4. Because HCl is a strong acid that almost
completely dissociates, Cl is not considered a base. Bases are
commonly anions, but neutral substances can also function as
bases (e.g., ammonia and creatinine). Some chemicals do not fit
the classic definition of an acid, although they retain acidic
properties when dissociated in water. For example, when CaCl2
is dissolved in water, the Ca2 accepts OH to form Ca(OH)2.
Because [H] [OH] in water remains constant at 10 to 14,
the consumption of OH by Ca2 results in increased dissociation of water. Consequently, the concentration of hydrogen ions
increases, and CaCl2 dissolved in water is an acidic solution.
The concentration of hydrogen ions [H] determines the
acidity of a solution. The pH is the negative logarithm of [H]
expressed in moles per liter (mol/L). The concentration of H
in biologic systems is in the range of nanomoles (109 mol) per
liter (nmol/L). When
[H] 40 nmol/L 4 1010 mol/L
then
pH log[H] (7.4) 7.4
Buffer Systems
Buffers are chemicals in solution that tend to minimize
changes in pH that would otherwise occur after the addition of
acid or alkali. If a strong acid is added to the salt of a weak acid
and a strong base, the reaction produces another salt and a
weak acid:
HCl NaHCO3 S NaCl H2CO3
Thus, the decrease in pH that would have occurred in the
absence of NaHCO3 is minimized. Conversely, if a strong base
is added to a weak acid, the base is neutralized:
NaOH H2CO3 S NaHCO3 H2O
Anion Gap
The anion gap is defined as follows:
Anion gap [Na] ([Cl] [HCO3])
Normally, the difference between the serum [Na] and the
sum of the chloride and bicarbonate anion concentrations is a
reflection of the sum of the serum proteins, sulfate anions, inorganic phosphates, and organic acids present in low concentrations. The anion gap is usually 12
2 mEq/L. Variances from
the normal may be caused by a change in unmeasured anions or
cations. Calculation of the anion gap may help define both simple and mixed forms of acidbase disturbances. Acidosis associated with a high anion gap is usually secondary to increases in
endogenously produced acids (e.g., lactic acidosis or ketoacidosis), decreases in renal excretion of acid, or ingestion of toxins.
SCIENTIFIC PRINCIPLES
When
207
208
TA B L E 1 0 . 1 1
HCO3 AND PCO2 DERANGEMENTS IN PRIMARY AND SECONDARY
ACIDBASE DISTURBANCES
PRIMARY
SECONDARY
pH
HCO3
Metabolic acidosis
Metabolic alkalosis
Respiratory acidosis
Respiratory alkalosis
DISORDER
The first two mechanisms are relatively infrequent and usually produce only mild, self-limiting metabolic acidosis; however, aggressive overresuscitation of surgical or trauma
patients with normal saline solution may result in a dilutional
acidosis. Most clinically significant metabolic acidosis is
related to net loss of bicarbonate, which occurs when consumption due to either loss or titration is greater than bicarbonate generation. Under normal circumstances of ingestion
of the average amount of protein in the American diet,
approximately 70 mEq of acid is generated daily. The major
source of acid production is sulfuric acid from the metabolism
of sulfur-containing amino acids. In addition, normal physiologic processes result in the generation of organic acids, the
titration of which consumes bicarbonate. Although the resulting organic anions are further metabolized with regeneration
of bicarbonate, urinary excretion of some organic anions
occurs and results in net loss of bicarbonate.
These sources of acid gain are partially offset by net GI
absorption of metabolizable anions, such as citrate, which are
metabolized to yield bicarbonate. The remainder of the excess
acid is balanced by renal excretion of acid with simultaneous
generation of bicarbonate. A decrease in body bicarbonate
content may therefore be the result of a primary increase in net
acid generation, termed extrarenal acidosis, or a primary
reduction in renal acid excretion, termed renal acidosis.
In extrarenal acidosis, the normal compensatory mechanism is increased renal excretion of acid, usually as ammonia,
with generation of bicarbonate. This mechanism is sensitive to
decreases in bicarbonate concentration and has the capacity to
generate large amounts of bicarbonate.
In contrast, renal acidosis is not as readily compensated
because the renal abnormality is the primary mechanism. The
level to which serum bicarbonate concentration decreases
depends on several factors, including the magnitude of the disparity in acid production and acid excretion as well as its
duration. In general, the development of renal acidosis is slow
but progressive, whereas the development of extrarenal acidosis is rapid but usually self-limiting. Despite persistent net loss
of bicarbonate, extracellular bicarbonate concentration may
stabilize at a subnormal level rather than continue to decrease.
This may be due to bone buffering, which has the capacity to
buffer as much as 28 to 37 mEq/d of acid.
Mechanisms Resulting in Decreased Body Bicarbonate Content
Increased Production of Organic Acids. Increased protein
intake and tissue catabolism resulting in greater metabolism of
sulfur-containing amino acids can lead to generation of
increased amounts of sulfuric acid. With normal kidney function, any decline in serum bicarbonate concentration stimulates
renal acid excretion, which can compensate nearly completely
for the increase in acid production.
Administration of Exogenous Acid. Ingestion of a sufficient
quantity of exogenous acid can exceed renal compensatory
PCO2
HCO3
PCO2
T
c
209
SCIENTIFIC PRINCIPLES
210
Metabolic Alkalosis
Causes. Sustained metabolic alkalosis occurs only if extracellular bicarbonate concentration is increased and renal
excretion of excess bicarbonate is inhibited. Extracellular
bicarbonate concentration increases can occur through several mechanisms. In surgical patients, loss of HCl is a frequent cause of metabolic alkalosis, most commonly due to
vomiting or nasogastric drainage in the face of gastric outlet
obstruction. External loss of gastric acid results in a net gain
in bicarbonate (generated by equimolar gastric secretion of
HCl), which causes the alkalosis. Although the kidney can
excrete excess bicarbonate, this must be accompanied by
excretion of sodium. Renal excretion of sodium is limited in
the face of the volume depletion that also occurs with external losses of gastric secretion. As volume depletion progresses, sodium is conserved in exchange for hydrogen, and
urine will become acidic, even in the presence of severe metabolic alkalosis. This phenomenon is referred to as paradoxic
aciduria.
Increased extracellular bicarbonate concentration can
occur with administration of either bicarbonate or precursors
of bicarbonate, such as lactate, citrate, or calcium carbonate,
or as a result of increased renal production of bicarbonate.
Conditions in which acid excretion exceeds endogenous acid
production and in which the renal threshold for bicarbonate
reabsorption is increased can result in metabolic alkalosis.
Respiratory Compensation. The major compensatory mechanism in metabolic alkalosis is respiratory because the presence
of the metabolic alkalosis implicates renal dysfunction in
either generating or failing to excrete increased amounts of
bicarbonate. Hypoventilation is limited by the development of
hypoxemia, which stimulates ventilation, and PCO2 rarely
exceeds 60 mm Hg (Table 10.12). Among the four major types
of acidbase disorders, this compensatory mechanism is the
least effective. For a given degree of metabolic alkalosis, the
following equation can be used to predict the compensatory
increase in PCO2:
dPCO2 0.7 d[HCO3 ]
5
where dPCO2 expected increase in PCO2 given the measured
increase in serum bicarbonate concentration.
TA B L E 1 0 . 1 2
CALCULATIONS FOR ESTIMATING THE COMPENSATORY RESPONSES TO PRIMARY
ACIDBASE DISTURBANCES
TYPE OF DISORDER
Metabolic acidosis
COMPENSATION REQUIREMENT
TIME
dPCO2
d[HCO3 ]
1.2
2
1224 h
dPCO2
d[HCO3 ]
0.7
5
1224 h
Minutes
d[HCO3 ]
35 d
Minutes
d[HCO3 ]
23 d
Metabolic alkalosis
dPCO2 0.4
3
dPCO2 0.5
2.5
SCIENTIFIC PRINCIPLES
211
212
Familiarity with the acidbase disorders associated with various clinical situations and the expectation of mixed abnormalities allows appropriate interpretation of arterial blood gases
and serum electrolyte determinations. A summary of the calculations for estimating the compensatory responses and timing
of these responses is presented in Table 10.12.43
References
1. Kehayias JJ, Valtuena S. Neutron activation analysis determination of
body composition. Curr Opin Clin Nutr Metab Care 1999;2:453463.
2. Forbes G. Body Composition: overview. J Nutr 1999;129(1):270S272S.
3. Pietrobeloi A, Wang Z, Heymsfield SB. Techniques used in measuring
human body composition. Curr Opin Clin Nutr Metab Care 1998;1:
439448.
4. Briggs JP, Sawaya BE, Schnerman J. Disorders of salt balance. In: Kokko
JP, Tannen RL, eds. Fluid and Electrolytes. Philadelphia, PA: WB Saunders;
1990:70.
5. Thompson CA, Tatro DL, Ludwig DA, et al. Baroreflex responses to acute
changes in blood volume in humans. Am J Physiol 1990;259:R792R798.
6. Stockand JD. New ideas about aldosterone signaling in epithelia. Am J
Physiol Renal Physiol 2002;51:F559F576.
7. Boland DG, Abraham WT. Natriuretic peptides in heart failure. Congest
Heart Fail 1998;4:2333.
8. Falcao LM, Fausto P, Luciano R, et al. BNP and ANP as diagnostic and
predictive markers in heart failure with left ventricular systolic dysfunction. J Renin Angiotensin Aldosterone Sys 2004;5:121129.
9. Schrier R, Abraham W. Mechanisms of disease: hormones and hemodynamics in heart failure. N Engl J Med 1999;341:577585.
10. Wait RB, Kahng KU. Renal failure complicating obstructive jaundice. Am
J Surg 1989;157:256263.
11. Naicker S, Bhoola KD. Endothelins: vasoactive modulators of renal function in health and disease. Pharmacol Ther 2001;90(1):6168.
12. Roland CB, Aihua D, Mark L, et al. The complex role of nitric oxide in the
regulation of glomerular filtration. Kidney Int 2002;61:782785.
13. Ruttmann TG, James MFM, Lombard EM. Haemodilution induced
enhancement of coagulation is attenuated in vitro by restoring antithrombin III to predilution concentrations. Anaesth Intensive Care 2001;29:
489493.
14. Ng KFJ, Lam CCK, Chan LC. In vivo effect of haemodilution with saline
on coagulation: a randomized controlled trial. Br J Anaesth 2002;88:
475480.
15. Ruttmann TG, James MFM, Finlayson J. Effects on coagulation of intravenous crystalloid or colloid in patients undergoing peripheral vascular
surgery. Br J Anaesth 2002;89:226230.
16. De Lorenzo C, Calatzis A, Welsch U, et al. Fibrinogen concentrate reverses
dilutional coagulopathy induced in vitro by saline but not by hydroxyethyl
starch 6%. Anesth Analg 2006;102:11942000.
17. Koustova E, Standon K, Gushchin V, et al. Effects of lactated Ringers solution on human leukocytes. J Trauma 2002;53:872878.
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19. Wade CE, Kramer GC, Grady JJ, et al. Efficacy of 7.5% saline and 6%
dextran-70 in treating trauma. A meta-analysis of controlled clinical studies. Surgery 1997;122:609616.
20. Doyle J, Davis D, Hoyt D. The use of hypertonic saline in the treatment of
traumatic brain injury. J Trauma 2001;50:367383.
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213
SCIENTIFIC PRINCIPLES
CHAPTER 11 BURNS
NICOLE GIBRAN
K E Y
1
2
3
Burns should be triaged to a burn center with a multidisciplinary care team according to American Burn Association
criteria.
Burn depth evolves over 72 hours, making early surgical
decisions difficult.
Inhalation injury constitutes three types of injuryupper
airway thermal burns, chemical pneumonitis, and carbon
monoxide toxicityand with a thermal injury is associated with increased mortality.
Fluid resuscitation during the first 24 to 48 hours after
injury must be titrated to urine output (30 mL/h for adults;
1 to 1.5 mL/kg per hour for children 20 kg) and mean
arterial blood pressure (60 mm Hg).
Prophylactic systemic antibiotics other than tetanus prophylaxis are contraindicated.
MANAGEMENT PHILOSOPHY
Whereas the coordinated care provided by a burn center may
primarily benefit patients with complicated life-threatening large
burn injuries, excellent multidisciplinary management of smaller
burns bears long-term beneficial impact on patient outcome
both aesthetic and functional. The focused systematic approach
of an organized burn center allows for early surgical excision
and closure of burn wounds, critical care support, patient and
family psychosocial support, patient and family education, continuous long-term rehabilitation, reentry into society, and recon1 structive surgical needs.1 Therefore, patients with burns that
meet American Burn Association criteria (Table 11.1) for transfer to a burn center soon after initial assessment are likely to benefit from a multidisciplinary specialized burn care plan. (Guidelines for the Operations of Burn Centers [pp. 7986], Resources
for Optimal Care of the Injured Patient: 2006, Committee on
Trauma, American College of Surgeons.)
With modern burn care, survival with an excellent quality of
life should be expected for most patients with severe burns. Predicting mortality is difficult in burned patients. There remain no
reliable formulas for predicting burn survival in spite of the easily remembered Age % total body surface area burn mortality formula.2 In one statistical evaluation, age over 60 years,
full-thickness burn size over 40% total body surface area
214
P O I N T S
6
7
8
10
TA B L E 1 1 . 1
AMERICAN BURN ASSOCIATION CRITERIA FOR PATIENT
TRANSFER TO A BURN CENTER
215
TA B L E 1 1 . 2
RISK FACTORS FOR BURN INJURIES
Alcohol and drugs
EPIDEMIOLOGY
Because burns are an unreported disease, the annual incidence
of thermal injuries is unknown. However, extrapolation from
SCIENTIFIC PRINCIPLES
216
BIOLOGY OF SKIN
BURN PATHOPHYSIOLOGY
D
FIGURE 11.1. Zone of injury correlates with burn depth. A, B: The central zone of coagulation (a) represents a full-thickness
burn (as shown in C); the surrounding zone of stasis (b) represents a partial-thickness burn (as shown in D) that may extend
into the reticular dermis (deep partial thickness) or the papillary dermis (superficial partial thickness). The peripheral zone
of hyperemia (c) correlates with a superficial or first-degree burn and might be similar to a sunburn.
217
lar cells synthesize cytokines, including interleukins,1721 monocyte chemoattractant protein-1,22 and tumor necrosis factor.23,24 Before margination into the wound bed, neutrophils
adhere to endothelial cell adhesion molecules and plug the capillaries, thereby inducing further cytokine release and potential
tissue ischemia. In burn wounds, the zone of stasis represents
ischemic tissue that may convert to a zone of coagulation with
neutrophil-mediated reperfusion injury. Whereas inhibition of
the neutrophil-endothelial adherence in deep dermal rabbit
contact burns speeds healing,25 these studies have not been verified in human burn patients.
Granulation tissue, with its capillary arcades, is wellrecognized clinical evidence that a wound is healthy and is ready
for closure. However, normal excisional wound closure occurs
with angioinhibition,26,27 suggesting that secondary wound
repair may not require angiogenesis. Skin grafts and tissue flaps
do require angiogenesis for engraftment. Whereas delivery of
oxygen and nutrients to a skin graft by imbibitionor diffusionsuffices for a few days, skin graft take requires neovascularization, which occurs by inosculation, the linkage between
existent capillaries in the graft and in the wound bed. Excessive
wound granulation actually hinders burn wound healing as it
prevents migration of the epithelial tongue; many burn surgeons
dbride the granulation tissue in a healing burn before applying
a skin graft to maximize graft take because of the associated bacterial contamination and exuberant inflammatory response.
Excessive granulation tissue has been associated with increased
hypertrophic scar formation in the healed wound.28,29
An epithelialized burn equals a healed burn. Full-thickness
wounds heal from the wound edges (Fig. 11.2A), but an
advancing epithelial tongue can migrate for approximately 1 cm
before it stops migrating and heaps up at the wound edge.
In contrast, partial-thickness wounds heal from epidermal
SCIENTIFIC PRINCIPLES
218
tion, inadequate tissue perfusion, and, ultimately, risk of multiappendages (i.e., hair follicles, sweat glands, and sebaceous
organ dysfunction. Therefore, patients with large burns require
glands) in the wound bed (Fig. 11.2B). Whereas completion of
continuous intravenous replacement to compensate for the
this process by no means represents the end of burn wound
capillary leak. The leak associated with a burn larger than 30%
healing, epithelialization restores the three protective barrier
TBSA (or smaller if there is concomitant inhalation injury) can
functions of the outer layer of the skin: fluid maintenance, temcause clinically significant interstitial edema in soft tissues
perature regulation, and prevention of microbial or toxin invaincluding muscle compartments, the lungs, and the abdomen.
sion. Epithelialization may also represent an essential transiThe potential morbidity from the edema includes compartment
tion in the wound inflammatory state. Growing evidence
syndrome in injured and noninjured extremities, abdominal
suggests that epidermaldermal interactions regulate cutaneous
compartment syndrome, and pulmonary edema leading to
morphogenetic processes such as fetal skin development and
development of adult respiratory distress syndrome. Careful
wound repair.30 Just as the epidermis responds to mesenchymeattention to fluid status of the acutely injured burn patient can
derived mediators,31 activated keratinocytes in the advancing
avoid resuscitation failures including inadequate and excessive
epidermal tongue may secrete cytokines and growth factors to
resuscitation.
promote dermal inflammation.32,33 Once cellcell contact is
achieved with complete wound epithelialization, release of the
inflammatory mediators may stop. Evidence for epidermal
influence on dermal inflammatory responses includes clinical
INITIAL EVALUATION
observations that partial-thickness wound coverage with viable
allograft eliminates granulation tissue formation and promotes
A burn patient is a trauma patient and should be addressed
healing.34 Because it takes time for a mature basement memwith the same organized approach to serious injuries that
begins with the primary survey to assess airway, breathing,
brane to develop, epithelialized wounds undergo epidermolysis
and circulation. A systematic early comprehensive secondary
(blistering) until the anchoring structures mature.
survey is mandatory, especially for burn patients with associWhereas clinicians consider an epithelialized wound to be
ated trauma such as seen in motor vehicle collisions. Evidence
healed, long-term dermal and subcutaneous fibrogenesis
suggests that even a small burn injury significantly worsens
may be the most critical determinants of long-term wound
prognosis in patients with multiple injuries and high injury
appearance and cutaneous tensile strength. Deposition of fibrin,
severity scores.42 Therefore, close coordination between the
thrombin, fibronectin, and vitronectin into the site of injury
promotes cellular migration and proliferation for angiogenesis
trauma and burn teams is indicated, especially during the resusand fibrogenesis. As fibroblasts migrate into the wound from
citative phase of response to injury.
the margins, they synthesize collagen. The result is deposition
Since workup of a trauma patient is covered extensively in
of collagen III and subsequently collagen I in a dense mat that
Chapter 17, this section focuses on elements of the workup
is characteristic of dermal scar. As collagen I fibrils are crossrelevant to evaluation of the burn component of the injuries.
linked into cables, dermal breaking strength increases but never
Expeditious transfer of a critically burned patient to a burn
meets that of uninjured skin. Matrix remodeling begins with
ICU is essential to avoid hypothermia and resuscitation comfibrin clot dissolution and ends with a mature wound 12 to
plications; this mandates rapid evaluation in the emergency
24 months later. Matrix metalloproteinases (MMPs) have been
department. Table 11.3 is an example of a transfer protocol
implicated in keratinocyte migration,35 angiogenesis,36 and derthat outlines initial management of the burn patient prior to
transfer to a burn center.
mal matrix remodeling.37,38 Expression levels of MMPs appear
A crucial part of the initial evaluation of the extent of burn
to be decreased in hypertrophic scars.39
injury is estimation of the size and depth of the burn. This is the
Contraction, resulting from centrifugal forces in the center
basis for subsequent fluid resuscitation and care plans. Because
of the wound, constitutes an important wound closure mechanism. Myofibroblasts, specialized fibroblasts characterized by 2 the zones of injury in a burn wound evolve for up to 72 hours
(see earlier discussion on the zones of injury), burn depth deterintracellular smooth muscle actin filaments,29 may contribute
mination at the initial examination can be erroneous. Although
to this means of closure. A pathologic extension of wound
numerous burn depth indicators have been investigated,
contraction over joints is a contracturea debilitating scarincluding laser Doppler flow meters, intravenous fluorescein,
ring process that compromises return to function in many
burn wound biopsy, thermography, light reflectance, magnetic
patients with large burns. Constant attention to stretching,
resonance imaging, and intravenous dyes,4345 no technology
exercising, and splinting can minimize contracture development, but surgical release of the tight bands may be necessary
has been more accurate than an experienced burn surgeon.
to restore normal function of the extremities, neck, or mouth.
Therefore, many indeterminate burns must be in a wait and
Just as the dermis undergoes changes, the epidermis also
watch plan to determine whether the burn will heal within
evolves after injury. Melanocytes migrate from the wound edge
3 weeks or whether excision and grafting will be necessary to
and from epidermal appendages soon after the epithelial cells
close the wound.
(Fig. 11.2C). Patients must be informed that pigmentation in
Two simple formulas exist to estimate burn size. The rule of
healed burn wounds can be unpredictable and may result in
nines (Fig. 11.3) provides an anatomic estimate in which each
either increased or decreased melanin. Most clinicians advise
arm is considered to be 9% TBSA, each leg 18%, the anterior
patients that exposure to ultraviolet rays exacerbates pigmentatrunk 18%, the posterior trunk 18%, and the head 9%; this
tion changes in the wound. Use of topical bleaching agents should
method underestimates head size in children. Another easy
also be discouraged. Patients with healing partial-thickness
method involves using the patients full palm, including digits,
wounds complain of pruritus. Hypertrophic scars, which are
to represent 1% TBSA. First-degree burns should not be
classically very pruritic, have increased numbers of sensory
included in the calculation of burned areas. Soot should be
nerves compared to normal scars and uninjured skin.40,41
gently cleaned from the patient since it often misleads an unfamiliar evaluator and erroneously increases the estimated burn
size.
Initial assessment of the burn patient requires few laboraSYSTEMIC RESPONSE
tory or radiologic studies. Patients with a history of exposure
to noxious fumes should have partial pressure of arterial oxyTO BURN INJURY
gen (PaO2), partial pressure of arterial carbon dioxide
(PaCO2), pH, and carboxyhemoglobin (CO) percentage deterCutaneous inflammatory cells release mediators from the
injured tissue to drive the systemic response to cutaneous thermined. Patients with isolated burns without other injuries
mal injury, leading to accelerated intravascular volume deplerarely need blood products during the resuscitative phase of
219
TA B L E 1 1 . 3
6.
7.
8.
9.
10.
their care but a routine blood sample can be sent to the blood
bank as a type and screen. Routine hematology and chemistry
profiles have limited use, but baseline electrolyte levels and
renal function (blood urea nitrogen [BUN], creatinine), hematocrit, white blood cell count, and platelet count should be
established. The efficacy of following laboratory values such
as base deficits and lactic acid levels has not been established
in burn patients. Urinalysis may be helpful to diagnose myoglobinuria in patients with electrical injuries or deep thermal
burns, but if the urine appears clear, treatment is not warranted. Need for radiographic assessments must be based on
mechanism of injury, but a baseline chest radiograph is sufficient for an isolated burn without other evidence of trauma.
AIRWAY ASSESSMENT
AND MANAGEMENT
3
SCIENTIFIC PRINCIPLES
220
TA B L E 1 1 . 4
CARBOXYHEMOGLOBIN LEVEL CORRELATIONS WITH
PATIENT SYMPTOMS
CARBOXYHEMOGLOBIN
LEVEL (%)
10
SYMPTOMS
None
1525
Nausea, headache
3040
Confusion, stupor,
weakness
4060
Coma
60
Death
Inhalation Injury
Inhalation injury complicates approximately one third of all
major burns. Whereas isolated inhalation injuries do not result
in high mortality, they significantly increase mortality in patients
with cutaneous burns.4651 Presumably, the combined injuries
lead to recurrent or persistent bacteremia from the burn wound
that potentiates the pulmonary injury. Unfortunately, no reliable long-term outcome data exist about late sequelae related to
inhalation injury.
TA B L E 1 1 . 5
CARBON MONOXIDEHEMOGLOBIN HALF-LIFE WITH
OXYGEN TREATMENT
CARBOXYHEMOGLOBIN
HALF-LIFE
TREATMENT
MODALITY
4h
Room air
4560 min
100% oxygen
20 min
TA B L E 1 1 . 6
PRODUCTS OF COMBUSTION THAT CAN BE PREDICTED TO
CAUSE SIGNIFICANT PULMONARY PARENCHYMAL INJURY
PRODUCT OF
COMBUSTION
FLUID RESUSCITATION
Most patients undergo resuscitation without difficulty. However, approximately 15% of patients with thermal injuries
fail resuscitation66 in spite of significant attention to improving
Carbon dioxide
fluid management of the burn patient.67 Vascular access
Petroleum products
Carbon monoxide, nitrogen
should be obtained early during the evaluation before swelling
(gasoline, kerosene, propane,
oxide, benzene
obscures venous markings. Two large-bore peripheral intraplastics)
venous (IV) lines should provide adequate prehospital venous
Wood, paper, anhydrous
Nitrogen oxides (NO, NO2)
access; since the early burn is not contaminated with bacteria,
ammonia
these IV lines can be placed through eschar, but care should be
taken to secure them well. For children, intraosseous cannulae
Polyvinyl chloride (plastics)
Hydrogen chlorine
can provide temporary lifesaving resuscitation, but intraWool, silk, polyurethane
Hydrogen cyanide
venous access should be obtained as soon as possible.
(nylon)
Multiorgan failure due to inadequate resuscitation and
decreased tissue perfusion was a common cause of death in
Wood, cotton, paper
Aldehydes
burn patients before formulas were developed to estimate
Polyurethane (nylon)
Ammonia
fluid needs.68 Several proposed fluid resuscitation formulas
estimate fluid requirements in the patient with large burns,
suggesting that no one formula satisfactorily estimates fluid
requirements for all patients. It is essential to remember that
each of these formulas estimates fluid needs. However, fluid
and bronchial obstruction. Tracheobronchial mucosal damage
volumes should be constantly adjusted based on patient physand loss of ciliary clearance of the debris induce parenchymal
iologic responses during resuscitation (urine output, alert
inflammation, which leads to exudate formation and microsensorium, and blood pressure). Patients may require more or
vascular permeability, and ultimately50 may progress to pulless fluid depending on the size and depth of burn (deeper
monary edema, pneumonia, or acute respiratory distress synburns often are associated with a greater inflammatory
drome (ARDS). Significant inhalation of aerosolized toxins
response and higher fluid needs), presence of inhalation injury,
can reduce myocardial contractility and cause resuscitation
associated injuries, or comorbidities. Other clinical indicators
failure. Whereas diagnosis of lower airway inhalation injury
of higher volume requirements include mechanical ventilation
can be confirmed by bronchoscopy, a scoring system to correand high base deficit.69
late degree of pulmonary injury and outcome has yet to be
133
58
One of the commonly used resuscitation formulas has been
developed. Xenon
ventilation-perfusion scan has also
the Baxter (or Parkland) formula, which calls for 3 to 4 mL of
been used for diagnosis but often underdiagnoses the extent of
crystalloid per percentage TBSA burned over 24 hours. Half
injury and does not change the clinical outcome.59 Therefore,
of this volume is delivered during the first 8 hours after injury;
these technologies may help with documentation of a clinical
the other half is delivered over the subsequent 16 hours. If a
diagnosis but they are not crucial to subsequent management.
patient receives all of the 24-hour estimated volume during
Given the high rate (up to 50%) of pneumonia46 in patients
the first 2 hours after injury, that fluid will likely leak into the
with lower airway inhalation injuries, successful treatment
interstitial extracellular tissues and the patient still must
requires aggressive pulmonary toilet and frequent chest physreceive the estimated hourly crystalloid volumes to maintain
iotherapy.
intravascular volumes. The reliability of the Parkland formula directly depends on an accurate initial assessment of
burn depth and size as described earlier. The trend since BaxAcute Respiratory Distress Syndrome
ter originally proposed this formula has been to administer
more fluid than patients require. Some studies report volARDS is an independent risk factor for death in burn
umes approaching 8 mL/kg per percent TBSA burn,70 but
patients.60,61 Understanding of ARDS pathophysiology and
whether this impacts long-term outcome is difficult to
management has improved since its initial description in the
demonstrate.71
late 1960s,62 but 40% to 70% of patients with ARDS still die.
Reliable clinical resuscitation endpoints include maintainARDS is defined by the clinical findings of pulmonary 4
ing a mean arterial blood pressure greater than 60 mm Hg and
edema, hypoxemia, diffuse pulmonary infiltrates, and reduced
urine output of 30 mL/h for adults. Pediatric fluid requirelung compliance; radiographic findings may be nonspecific.
ments often exceed formula estimates72 likely due to less-wellHistologically, ARDS has diffuse alveolar epithelial damage,
developed renal concentrating abilities. Therefore, the urinary
microvascular permeability, and subsequent inflammatory cell
output goal for infants and very young children (20 kg)
infiltration into the lung parenchyma; interstitial and alveolar
should be 1.5 mL/kg per hour. Large-volume crystalloid
edema; hyaline membrane formation; and, ultimately, fibrosis.
boluses should be restricted to hypotensive episodes and
The development of ARDS is often presaged by high fluid
should be accompanied by an increase in the hourly volume by
resuscitation requirements reflecting increased microvascular
10%. Decreased urine output for 1 to 2 hours does not require
permeability and leading to increased pulmonary edema.
a large-volume crystalloid bolus and should be managed by
ARDS commonly develops within 7 days after injury. Burn
increasing the hourly resuscitation fluid rate by 10%. Stabipatients with inhalation injury have as much as a 73% incilization of the flux of mediators and closure of capillary leaks
dence of respiratory failure (defined by hypoxemia, pulmonary
occur gradually 12 to 48 hours after the burn injury. As capilinfections, or prolonged ventilator support) and a 20% incilary leak resolves, the amount of fluids needed to maintain
dence of ARDS compared to burn patients without inhalation
these endpoints should progressively decrease and the IV rate
injury, who have a 5% incidence of respiratory failure and a
generally can be slowly weaned by 10% per hour. Most burn
2% incidence of ARDS.63 Advanced age may also be a risk facpatients do not require pulmonary arterial pressure monitoring
tor for development of ARDS.64 Acute lung injury rarely develOrganic matter
Carbon monoxide
SCIENTIFIC PRINCIPLES
SOURCE
221
222
early postburn neutropenia, but this is more likely related margination of neutrophils due to the overall inflammatory response
to injury rather than to the topical agent. The neutropenia is typically self-limited and rarely requires a change in antimicrobial
therapy. Patients with sulfa allergies typically do not have adverse
223
FIGURE 11.5. Escharotomies can be useful for improving chest-wall compliance and relieving extremity compartment syndromes but are very unaesthetic unless a fascial excision will be necessary. A: For torso escharotomies,
incisions across the infraclavicular and subcostal chest
that connect the anterior axillary incisions facilitate ventilation, especially in children. B: Extremity escharotomies
are performed with the limb in its anatomic position along
the medial and lateral axes. C: Hand escharotomies should
be placed in the spaces between the metacarpals.
SCIENTIFIC PRINCIPLES
224
TA B L E 1 1 . 7
ADVANTAGES AND DISADVANTAGES OF ANTIMICROBIAL TOPICAL AGENTS
ANTIMICROBIAL
AGENT
COVERAGE
ADVANTAGES
DISADVANTAGES
Silver sulfadiazine
Broad spectrum,
especially Pseudomonas
Soothing
Mafenide acetate
Broad spectrum,
including clostridium
Good eschar
penetration
Excellent for both
treatment and
prophylaxis
Silver nitrate
Broad spectrum
Excellent prophylaxis
Bacitracin
Gram-positive bacteria
Expensive
Often delivered in combination
with neomycin and polymyxin B,
which are nephrotoxic
Mupirocin
Methicillin-resistant
Staphylococcus
Excellent for
methicillin-resistant
Staphylococcus
Very expensive
Silver-impregnated gauze
Broad coverage
Hides wound
Can cause discomfort when dried
Nonadhesive and slips from
wound
The beneficial impact of early excision and grafting on outcomes following thermal injuries has been remarkable. Because
of this change in therapy from a nonoperative to an operative
225
FIGURE 11.7. A: Fascial excision limits bleeding but results in suboptimal aesthetic outcomes and should be avoided if possible. If necessary
because of burn depth, care can be taken to tack down the edges to minimize the ledge that interferes with function. B: Tangential excision requires
serial tissue removal until the wound bed has diffuse punctate bleeding; ideally this allows a thin pearly white dermal layer to remain in the wound
bed.
FIGURE 11.8. Traditional widely meshed skin grafts leave hypertrophic interstices long after the wounds are mature.
SCIENTIFIC PRINCIPLES
226
TA B L E 1 1 . 8
ADVANTAGES AND DISADVANTAGES OF SKIN
SUBSTITUTES
DERMAL
SUBSTITUTES
EPIDERMAL
SUBSTITUTE
Pros
Useful with
limited donor sites
Replaces epidermis
Fewer donor sites
Cons
Expensive
Prone to infection
Requires completely
viable wound bed
Requires fastidious
postoperative wound
care
Expensive
Prone to infection
Prone to sheering
Prolonged
immobilization
with delayed
rehabilitation
Prolonged length
of stay
meticulous surgical excision and postoperative care to minimize infection.99 A topical antimicrobial agent is usually necessary postoperatively; if neodermal quantitative cultures
demonstrate more than 106 colony-forming units, directed systemic antibiotics might also be indicated. A significant advantage is the rapid healing and minimal scarring in ultra-thin
donor sites (Fig. 11.9C).
Another promising dermal substitute is AlloDerm (LifeCell,
Woodlands, TX), a cryopreserved human dermal allograft.100
The advantage of this product is the native mesenchymal
structure without the allogenic cellular components that cause
allograft rejection. This dermal substitute requires immediate
autografting since there is no outer barrier.
METABOLIC AND
NUTRITIONAL SUPPORT
Patients with major thermal injury develop a hypermetabolic
state characterized by increased basal metabolic rate, increased oxygen consumption, negative nitrogen balance, and
weight loss. Subsequently, these patients have increased caloric
requirements101 to prevent delayed wound healing, decreased
immune competence, and cellular dysfunction.
Protein catabolism in a 60-kg patient with a large burn may
result in loss of 150 to 200 g of nitrogen per day. Nitrogen
excreted in the urine can be measured, but large amounts of
nitrogen lost from wounds are insensible. Therefore, measured
227
TA B L E 1 1 . 9
NUTRITIONAL ASSESSMENT OF BURN PATIENTS
Moderate burn
Large burn
NITROGEN LOSS
FROM WOUNDS
(g/kg/d)
10
0.02
1130
0.05
19
Supplemental enteral
feeding if oral intake is
insufficient
31
0.12
45
NUTRITIONAL NEEDS
Oral intake only
Glucose Management
Hyperglycemia negatively impacts wound healing and
increases morbidity and mortality in critically ill patients, even
those without underlying diabetes mellitus.118 Increased risk of
infection, reduced skin graft take, and higher mortality119 underscore the importance of maintaining blood sugars between 80 to
120 mg/dL.118 In spite of the initial excitement about the beneficial effect of tight glucose control on outcomes of critically
injured patients, increasing data suggest that very tight control
does not improve outcomes in trauma patients120 and should
be studied prospectively in burn patients.121
Albumin
Hypoalbuminemia typically persists in burn patients until the
wounds are healed. Patients with large burns typically have
serum albumin levels of 1.7 g/dL and rarely exceed 2.5 g/dL.109
Administration of exogenous albumin to attain serum levels
above 1.5 g/dL does not appear to impact length of stay, complication rate, or mortality.122
Nutritional Supplementation
Enteral Nutrition
Prolonged ileus and stress ulcers in burn patients have been
largely eliminated by early feeding.114 Multiple studies have
shown that patients with major thermal injury can receive adequate calories soon after injury. At the University of Washington Burn Center, tube feeding is started a median of 5 hours
after admission (unpublished quality improvement data).
Benefits of gastric feeding versus duodenal feeding continue
to be debated. Although feeding distal to the pylorus theoreti-
Studies to determine benefits of specialized nutritional supplements such as arginine, glutamine, and omega-3 fatty
acids in burn patients are contradictory.123125 However,
there are reports that anabolism can be promoted in burn
patients with metabolically active agents such as insulin,
recombinant human growth factor, the anabolic steroid
oxandrolone, and propranolol.126 Oxandrolone in particular
has been reported to improve weight gain and functional
recovery in burn survivors.127 Propranolol has now been
fairly well characterized as having a beneficial effect in
SCIENTIFIC PRINCIPLES
Small burn
WOUND SIZE
(% TBSA)
228
pediatric patients128 and should be investigated in a multicenter trial for adults. Early administration of the antioxidants
-tocopherol and ascorbic acid reduces the incidence
of organ failure and shortens ICU length of stay in critically
ill trauma patients.77 Whereas a multicenter study will be
necessary to demonstrate similar results in burn patients, the
potential benefit and the low cost make antioxidant supplementation an attractive low-risk intervention for burn
patients at risk for multiorgan dysfunction.
INFECTION
PAIN MANAGEMENT
229
Genital Burns
Genital burns should be investigated for suggestion of abuse or
neglect. A burned foreskin must be reduced to a normal
SCIENTIFIC PRINCIPLES
230
Chemical Injuries
Regardless of whether a chemical burn is alkali or acid, the initial treatment should be copious irrigation with tap water for
30 minutes. Cement and concrete powder or powdered lye
should be brushed dry from the patient since contact with water
activates the aluminum hydroxide. For eye burns, topical oph-
Tar Injuries
Tar is often heated to more than 300F and commonly causes
a deep burn, especially if the source is the mother pot.
Adherent tar can be initially cooled by tap water irrigation to
limit the progression of the injury. It can be easily removed
from the skin (Fig. 11.12) with a lipophilic solvent such as
Medi-Sol (The Orange-sol Group of Companies, Gilbert, AZ).
Once the wound is exposed, it can be treated like other thermal injuries with topical antimicrobial ointments until the
need for surgery is determined.
NONACCIDENTAL
BURN INJURIES
Neglect and abuse affect enough children that providers
should consider these diagnoses in any child that has burns. If
there is any question that either contributes to the injury, the
child should be admitted to the hospital for further assessment.9 If expert opinion suggests that the injuries are suspicious, they should be filed with the appropriate local agency.
Radiographic evaluation of the head, ribs, and long bones
231
FIGURE 11.12. A: Congealed tar should be removed with a lipophilic solvent to determine whether there is a burn underneath. B: Cleaning
wounds thoroughly with Medi-Sol is safe and essential for correctly determining an accurate burn size.
NONBURN CONDITIONS
COMMONLY CARED FOR
IN BURN CENTERS
SCIENTIFIC PRINCIPLES
232
FIGURE 11.13. A: Toxic epidermal necrolysis (TEN), a severe variant of erythema multiforme major, causes distinct blisters and a characteristic
Nikolsky sign (arrow) of normal-appearing skin sloughing between the bullae. B: Scalded skin with diffuse erythema appears more diffuse and
when the skin sloughs, the underlying epidermis is often healed. C: Graft versus host disease can be confused in appearance with TEN, but history of a recent transplant (solid or hematologic) is pathognomonic. D: Removal of the sloughed skin and protection of the underlying viable
wound bed by applying a biologic dressing such as xenograft improves survival in patients with TEN.
paucity of white blood cells and assume -hemolytic streptococcal infection if there are abundant gram-positive cocci.
Plans should be made to reexplore the wound within 24 hours
of the original operation; this may be sooner if the patient
undergoes clinical deterioration or if the white blood cell count
increases. Broad-spectrum antibiotics should be continued
FIGURE 11.14. Purpura fulminans resulting from meningococcemia or streptococcemia causes patchy cutaneous necrosis on many body surfaces
(A), but especially the digits (B).
233
FIGURE 11.15. A: Necrotizing soft tissue infections must be differentiated from cellulitis based on systemic physiology. B: Wide surgical dbridement of all involved tissues is the mainstay of treatment for this life-threatening tissue infection, even if it exposes vital structures.
hypertrophic scar formation, our understanding of the pathophysiology is very limited; this basic lack of knowledge is aggravated by the absence of an animal model of scar hypertrophy.
However, recent studies suggest that the female red Duroc pig
generates a fibroproliferative scar160 that parallels many clinical,
histologic, and biochemical findings in human hypertrophic
scar tissues.
The ability to regulate development of hypertrophic scars is
limited, as is treatment for the symptoms. Custom-fit compression garments are worn within 2 weeks of wound healing and
often continue until the wounds mature at 1 or 2 years after
injury. Topical silicone anecdotally improves hypertrophic scar
size and symptoms, but the mechanism is not clear and skin
irritation and rashes can accompany use. Intradermal steroid
injection has also been described but is very painful and unreliable in the management of hypertrophic scarring; furthermore,
the wound size that can be treated is limited by the risk of systemic steroid effects. Patients with persistent symptomatic
hypertrophic scarring that limit function or activities of daily
living often require excision and primary wound closure or
wound closure with sheet autografts or tissue flaps. Patients
who have survived large burns may require several sequential
reconstructive procedures during the first few years after injury
to attain optimal cosmetic and functional results.
TA B L E 1 1 . 1 0
SIGNS AND SYMPTOMS OF NECROTIZING SOFT
TISSUE INFECTION
White blood cell count 20,000
Thin, gray drainage
Marked induration
Edema of entire limb
Hyponatremia (Na 135 mEq/L)
Skin blistering/sloughing
Skin necrosis
Crepitus/soft tissue gas on radiography
Pain out of proportion to skin findings
Sepsis (tachycardia, hypotension, high fluid requirements)
If patient meets any of these criteria, consider early surgical
consultation.
SCIENTIFIC PRINCIPLES
234
REHABILITATION AND
RECONSTRUCTION
As survival following major burns has improved, more emphasis has been placed on functional recovery, societal reintegration, and return to school or work. In the early 1990s, the
National Institute of Disability and Rehabilitation Research
(NIDRR; http://www.ed.gov/offices/osers/nidrr), whose mission is to generate, disseminate, and promote new knowledge
to improve independent living options for disabled persons,
recognized that burn survivors would likely benefit from organized rehabilitation model systems that had been established
for survivors of traumatic brain injuries. Since then, the
NIDRR has continuously funded projects to advance knowledge in burn rehabilitation by providing multicenter grants to
four centers of excellence.
Physical function requires continual participation of burn
occupational and physical therapists from the time of the acute
injury until long after discharge from the hospital. Initially,
therapists are involved with twice-daily passive or active
range-of-motion exercises of all joints and positioning and
splinting of the hands, extremities, or neck. In patients with
small burns or in those with almost healed large injuries, therapy involves strengthening, ambulation, active and passive
range of motion, performance of activities of daily living, and,
in older adolescents and adults, development of work-related
skills and, if necessary, development of adaptive skills with
modified utensils or prosthetic devices. Therapists often provide the essential human bridge between inpatient and outpatient care.
Posttraumatic stress, anxiety, or depression frequently
manifests after severe burns. Whereas burns that involve the
hands or face can be anticipated to induce these symptoms,
they cannot be otherwise predicted based on burn size or location. Preinjury psychiatric conditions, family dysfunction, or
substance abuse further complicate psychosocial recovery. The
major impact that psychological recovery has on the burn
patients ability to recover functionally underscores the need
for coordinated participation of burn psychologists and social
workers in the multidisciplinary care of burn patients. These
staff members typically interact with the patient, family, and
local outpatient support services throughout hospitalization
and assist with coordinating discharge plans.
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119. Gore DC, Chinkes D, Heggers J, et al. Association of hyperglycemia with
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120. Shin S, Britt RC, Reed SF, et al. Early glucose normalization does not
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125. Herndon DN. Nutritional and pharmacological support of the metabolic
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126. Demling RH, DeSanti L. Oxandrolone induced lean mass gain during
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128. Jeschke MG, Norbury WB, Finnerty CC, et al. Propranolol does not
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129. Karyoute SM, Badran IZ. Tetanus following a burn injury. Burns Incl
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130. Horvath EE, Murray CK, Vaughan GM, et al. Fungal wound infection
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131. Wahl WL, Brandt MM, Ahrns KS, et al. Venous thrombosis incidence in
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132. Rue LW 3rd, Cioffi WG Jr, Rush R, et al. Thromboembolic complications
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135. Sharar SR, Carrougher GJ, Selzer K, et al. A comparison of oral transmucosal fentanyl citrate and oral oxycodone for pediatric outpatient wound
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137. Martin-Herz SP, Patterson DR, Honari S, et al. Pediatric pain control practices of North American burn centers. J Burn Care Rehabil 2003;24:
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150. Bird PE, Harrington DT, Barillo DJ, et al. Elder abuse: a call to action.
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152. Assin WD. Multiple cigarette burn wounds in a chronic paranoid schizophrenic. S Afr Med J 1996;86:1437.
153. Barillo DJ, Hallock GG, Mastropieri CJ, et al. Utilization of the burn unit
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156. Imahara SD, Holmes JHT, Heimbach DM, et al. SCORTEN overestimates
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epidermal necrolysis treated in U.S. burn centers at the end of the twentieth century. J Burn Care Rehabil 2002;23:8796.
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159. Warner PM, Kagan RJ, Yakuboff KP, et al. Current management of purpura
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animal model of hypertrophic scarring and the potential role of the cones
of skin. Burns 2003;29:649664.
K E Y
1
2
The state of general anesthesia is a combination of hypnosis, amnesia, analgesia, and muscle relaxation. This state can
be achieved by administration of single or multiple anesthetic
agents via inhalational or intravenous routes. Historically,
anesthesia was achieved by inhaling volatile anesthetic vapors
that produced each of these conditions in proportion to the
concentration achieved in the central nervous system. Anesthesia can also be achieved by using a balance of multiple
pharmacologic agents, each targeted to produce a specific
effect. These are the hypnotic/sedatives, analgesics, and neuromuscular blocking agents. As the concentration of hypnotic/
sedative and analgesic agents increases, cardiovascular and
respiratory functions may be progressively blunted. For this
P O I N T S
10
11
12
237
SCIENTIFIC PRINCIPLES
MANAGEMENT
238
Intravenous Sedatives/Hypnotics
Several commonly used intravenous sedative/hypnotic medications can also be used in lieu of an inhalational anesthetic to
achieve the hypnotic component of the state of anesthesia. A
constant intravenous infusion of these medications is used to
achieve and maintain a blood concentration that results in the
loss of consciousness and prevents recall. Unlike the inhalational agents, there currently is no ability to measure the
patients expired or blood concentration of these intravenous
agents. As a result, the infusion rate is titrated to effect by
observing patient movement (if muscle relaxants are not used
concurrently) and hemodynamic responses to procedural stimuli. Of note, the sedative/hypnotic intravenous agents do not
possess clinically useful muscle relaxant or analgesic properties
and must be combined with other agents to deliver a balanced anesthetic. The most commonly used intravenous agent
for maintenance of anesthesia is propofol, a lipid-soluble substituted isopropyl phenol that produces hypnosis and sedation
through interactions with -aminobutyric acid (GABA), the
TA B L E 1 2 . 1
COMMON INHALATION AGENTS: MINIMUM ALVEOLAR CONCENTRATIONS AND EFFECTS
AGENT
Nitrous oxide
MINIMUM ALVEOLAR
CONCENTRATION (%)
105
STRENGTHS
WEAKNESSES
Analgesia
Sympathetic stimulation
Isoflurane
1.15
Pungent odor
Pungent odor
Causes coughing
High vapor pressure (Boiling point
23.5C)
Requires special pressurized
vaporizer
High cost
Sevoflurane
1.71
Moderate cost
Less pungent
primary inhibitory neurotransmitter of the central nervous system. When administered as a continuous infusion, propofol can
achieve minimal levels of sedation, deep sedation, or general
anesthesia. Additional details regarding the use and side effects
of propofol are discussed later. Other classic agents such as benzodiazepines can also be used as maintenance infusions, but do
not enable the rapid return to consciousness that propofol
offers. A novel, highly specific 2-receptor agonist, dexmedetomidine, has recently demonstrated an exciting role as an intravenous sedative/hypnotic that also has analgesic effects. In the
perioperative setting, it is currently limited to use as an adjunct
to propofol and inhalational anesthetics.
Muscle Relaxants
2
239
TA B L E 1 2 . 2
COMMON NEUROMUSCULAR BLOCKING DRUGS AND REVERSAL AGENTS
MUSCLE RELAXANT
INTUBATING
DOSE (mg/kg)
INFUSION DOSE
(mg/kg/min)
1.0
100a
STRENGTHS
WEAKNESSES
DEPOLARIZING
Succinylcholine
NONDEPOLARIZING
Long acting (1 h)
Pancuronium
0.1
0.3
No histamine release
Tachycardia
Slow onset
Long duration
Intermediate acting (1 h)
Cisatracurium
0.2
0.1
Spontaneous degradation,
not affected by renal or
liver disease
Vecuronium
0.1
No cardiovascular effects
Rocuronium
0.8
10
Moderate cost
SCIENTIFIC PRINCIPLES
240
TA B L E 1 2 . 3
a
TIME TO PEAK
EFFECT (min)
DOSE
USE WITH
COMMENTS
ANTICHOLINESTERASES
Edrophonium
Neostigmine
Pyridostigmine
12
35
1012
0.51.0 mg/kg
0.040.07 mg/kg
0.20.3 mg/kg
0.008 mg/kg
(0.50.6 mg/70 kg)
Neostigmine
Pyridostigmine
ANTICHOLINERGICS
Glycopyrrolate
Atropine
0.0070.02 mg/kg
(0.051.5 mg/70 kg)
Edrophonium
241
TA B L E 1 2 . 4
ANALGESICS
POTENCY
SEDATION DOSE
DURATION
INFUSION DOSE
0.020.1 mg/kg IV
27 h
0.51 mg/kg IV
3060 min
Morphine
Fentanyl
Sufentanil
1
100
1,000
Not recommended
Alfentanil
25
1020 mg/kg IV
1015 min
Remifentanilb
Not recommended
10 min
0.10.2 mg/kg/min
Ketamine
2550 mg/kg/min
80 mg/kg/min
1.02.0 mg/kg IM
IM, intramuscular; IV, intravenous.
a
May produce apnea.
b
Will produce apnea.
c
Produces pain on injection that can be reduced by treatment with 20 mg of lidocaine IV.
Propofol
Propofol is a lipid-soluble substituted isopropyl phenol that
produces a rapid induction of anesthesia in 30 seconds followed by awakening in 4 to 8 minutes after a single bolus.
Intravenous propofol can effectively produce total anesthesia
(for less stimulating procedures), including amnesia, some
4 analgesia, and some degree of muscle relaxation. Propofol is
unique because it is rapidly cleared through hepatic metabolism to inactive metabolites in a way that the patient becomes
alert soon after cessation of the infusion. However, as the
duration and dose of the maintenance infusion is increased,
the time to return of consciousness is also significantly
increased. This context-sensitive half-life of propofol must be
incorporated into expectations of a quick wake-up. Propofol has direct antiemetic properties and is a valid alternative
to inhalational anesthetics in patients who have demonstrated
a history of prolonged, refractory postoperative nausea and
vomiting. It has an important role in intensive care units when
used as a continuous infusion sedative at dosages of 25 to
50 g/kg/min. However, prolonged infusions have been associated with a lethal metabolic derangement known as propofol infusion syndrome, characterized by a profound metabolic
acidosis and cardiovascular compromise.4 Propofol can produce significant hypotension when IV induction doses are
administered. It also produces significant pain on injection in
peripheral veins. Pain can be diminished or eliminated by pretreatment with IV lidocaine via the vein to be used for propofol administration. Propofol is insoluble in aqueous solution
and therefore comes dissolved in a lipid emulsion that has the
associated risk of bacterial contamination. Once a vial of
propofol is opened, it is not recommended that it be used after
6 hours.
Ketamine
Ketamine is a phencyclidine derivative that produces anesthesia characterized by dissociation between the thalamus and
SCIENTIFIC PRINCIPLES
OPIOIDS
242
TA B L E 1 2 . 5
ANXIOLYTICS AND AMNESICS (BENZODIAZEPINES)
NAME
DOSE (mg/kg)
DURATION (h)
Midazolam (Versed)
0.5
STRENGTHS
WEAKNESSES
Water soluble
Acute respiratory
depression
Short duration
Good for sedation for
short procedures
Diazepam (Valium)
0.1
Intermediate duration
Irritation on IV injection
Phlebitis
Acute respiratory
depression after IV
overdose
Lorazepam (Ativan)
0.020.08
68
Long duration
4590 min
BENZODIAZEPINE REVERSAL
Flumazenil
(Romazicon)
IV, intravenous.
Local Anesthetics
Local anesthetics constitute a class of drugs that temporarily
block nerve conduction by binding to neuronal sodium channels. As the concentration of the local anesthetic increases
around the nerve, autonomic transmission will be blocked
first, followed by sensory transmission, and then motor nerve
transmission. These drugs can be injected locally into tissue to
produce a field block, around peripheral nerves to produce a
specific dermatomal block, around nerve plexuses to produce
a major conductive block, or into the subarachnoid or
epidural space to produce extensive neuroaxial blockade. All
the methods have been used to assist in the provision of an
alternative form of balanced anesthesia by supplementing
analgesia and muscle relaxation.
Adverse consequences associated with the use of local anesthetics fall into three categories: acute central nervous system
toxicity due to excessive plasma concentration, hemodynamic
and respiratory consequences due to excessive conduction
block of the sympathetic or motor nerves, and allergic reactions. Whenever a local anesthetic is injected, there can be
inadvertent intravascular injection or an overdose of the drug
because of rapid uptake from the tissues. All can produce
seizures. Complications can be minimized by withdrawing
before injection to avoid an intravascular injection and limiting dosages to the safe range (Table 12.6).
When local anesthetics are administered for a spinal or
epidural block, they produce a progressive blockade of the
sympathetic nervous system, which produces systemic vasodilation. Sympathetic nerves travel along the thoracolumbar
region with the first four thoracic branches, including the cardiac sympathetic accelerators. A sympathetic blockade of this
entire region produces profound systemic vasodilatation and
bradycardia. This condition is referred to as total sympathectomy, and the hypotension that ensues is usually below the
minimal cerebral perfusion pressure required to maintain consciousness. Affected patients are bradycardic, hypotensive,
unconscious, and usually apneic. This disastrous situation is
easily remedied if treated quickly with a vasopressor (phenyl
ephrine or ephedrine) and atropine. If not treated promptly, the
situation proceeds to cardiac arrest. In this emergency situation,
the treatment of high doses of epinephrine is 10 to 40 /kg, or
1 to 4 mg for an adult. The doses of epinephrine are higher
than in a usual cardiac arrest because of the total sympathectomy.5 Because the level of sympathetic block is two to
six dermatomal levels higher than the sensory block, it is often
difficult to obtain a high spinal sensory level without approaching a total sympathectomy.
Local anesthetics are chemically divided into two groups,
esters and amides. The esters (2-chloroprocaine and tetracaine) produce metabolites that are related to p-aminobenzoic
acid and have been associated with allergic reactions. Amides
(lidocaine and bupivacaine) are rarely associated with allergic
reactions. If an allergic reaction does occur, it is most likely
due to the preservative (methyl paraben) used in multidose
vials of lidocaine.
243
TA B L E 1 2 . 6
LOCAL ANESTHETICS
MAXIMUM SINGLE
DOSE (mg)
DURATION (h)
COMMENTS
Lidocaine
500
1a
Fast onset
Ropivacaine
200
412a
Bupivacaine
200
412a
Exaggerated
cardiotoxicity
with IV injection
Slow onset
Long duration
ESTERS
2-Chloroprocaine
1,000
0.51a
Fast onset
Lowest toxicity
Tetracaine
80
0.51
Slow onset
IV, intravenous.
a
Addition of 100 g of epinephrine (0.1 mL of 1:1,000) lowers the toxicity and increases the duration of
the local anesthetic.
b
Metabolism to paraaminobenzoic acid may cause allergic reactions.
SCIENTIFIC PRINCIPLES
AMIDES
244
Class I
TA B L E 1 2 . 7
SEDATION SCALE
SEDATION SCALE
Class III
Class IV
DESCRIPTION
The preprocedure evaluation should include current medications, coexisting disease, and a brief physical examination
including an evaluation of the airway. The most common drug
used to provide sedation is midazolam. This is a fast-onset, relatively short-acting benzodiazepine that can be easily titrated
to produce a sedated yet cooperative arousable state. It is usually given to adults in incremental doses of 1 mg (0.01 mg/kg in
children). Narcotics such as fentanyl even in small doses act
synergistically with benzodiazepines to cause a more sedated
state with a much higher incidence of apnea. To assess the
effect of the drug, a validated sedation scale can be of value.
The scale used at the University of Michigan is presented in
Table 12.7.9
TA B L E 1 2 . 8
STANDARD AIRWAY EXAMINATION FOR NONANESTHESIOLOGISTS
EXAM ELEMENT
CONCERNING FINDINGS
Mouth opening
Mallampati classification
Mandibular protrusion
Neck anatomy
Beard
RISKS ASSOCIATED
WITH ANESTHESIA
7
Cardiovascular Diseases
Hypertension. Hypertension is the most common preexisting medical disease in patients presenting for surgery and is a
major risk factor for renal, cerebrovascular, peripheral vascular, and coronary artery diseases, as well as congestive heart
failure (CHF). It is particularly associated with lipid disorders,
245
Coronary Artery Disease. Much of the anesthetic preoperative evaluation has historically been focused on the detection and treatment of coronary artery disease. Coronary artery
disease is present in about 25% of patients who undergo
surgery each year.21 It is the leading cause of death in the
United States and continues to be a major cause of postoperative morbidity and mortality.22 The goal of the preoperative
cardiac evaluation is to identify patients who are at increased
risk of perioperative cardiac morbidity and ensure that their
chronic conditions are optimized. Although perioperative cardiac events are the leading cause of death following anesthesia
and surgery, it has been difficult to define patient characteristics that accurately predict a high risk of adverse outcome.23 It
has been even more difficult to modify that risk effectively.24
Preoperative CHF is clearly a significant risk factor, as is recent
myocardial infarction or unstable angina (Table 12.9). Diabetes mellitus, atherosclerotic vascular disease, and hypertension also appear to confer risk, although less than with CHF
or unstable angina. Perioperative risk in patients with valvular
heart disease varies with the severity of the disease as represented by CHF, pulmonary hypertension, and dysrhythmias.
Dysrhythmias are also a concern in the presence of coronary
artery disease. Age and stable angina remain controversial as
predictors of perioperative risk, with equal numbers of supporting and refuting studies. The value of revascularization
remains controversial as well. In patients without significant
pulmonary disease, the ability to climb two flights of stairs
without stopping or experiencing symptoms of angina or
shortness of breath is considered a good practical test of cardiac reserve. Unfortunately, many patients with ischemic heart
disease have concomitant pulmonary disease or other medical
problems that limit their activity. A history of myocardial
infarction is important information. Large retrospective studies have found that the incidence of reinfarction is related to
the time elapsed since the previous myocardial infarction.2527
The incidence of reinfarction appears to stabilize at about 6%
SCIENTIFIC PRINCIPLES
246
TA B L E 1 2 . 9
CLINICAL PREDICTORS OF INCREASED PERIOPERATIVE
CARDIOVASCULAR RISK (MYOCARDIAL INFARCTION,
HEART FAILURE, DEATH)
MAJOR
Unstable coronary syndromes
Acute or recent MIa with evidence of important ischemic
risk by clinical symptoms or noninvasive study
Unstable or severeb angina (Canadian class III or IV)c
Decompensated heart failure
Significant arrhythmias
High-grade atrioventricular block
Symptomatic ventricular arrhythmias in the presence of
underlying heart disease
Supraventricular arrhythmias with uncontrolled ventricular
rate
TA B L E 1 2 . 1 0
CARDIAC RISKa STRATIFICATION FOR NONCARDIAC
SURGICAL PROCEDURES
High (reported cardiac risk often 5%)
Emergent major operations, particularly in the elderly
Aortic and other major vascular surgery
Peripheral vascular surgery
Anticipated prolonged surgical procedures associated with
large fluid shifts and/or blood loss
Intermediate (reported cardiac risk generally 5%)
Carotid endarterectomy
Head and neck surgery
Intraperitoneal and intrathoracic surgery
Orthopedic surgery
Prostate surgery
Intermediate
Endoscopic procedures
Superficial procedures
Cataract surgery
Breast surgery
Advanced age
Abnormal ECG (left ventricular hypertrophy, left bundlebranch block, ST-T abnormalities)
Rhythm other than sinus (e.g., atrial fibrillation)
Low functional capacity (e.g., inability to climb one flight of
stairs with a bag of groceries)
History of stroke
Uncontrolled systemic hypertension
ECG, electrocardiogram; MI, myocardial infarction.
a
The American College of Cardiology National Database Library
defines recent MI as 7 d but
1 mo (30 d); acute MI is within 7 d.
b
May include stable angina in patients who are unusually sedentary.
c
Campeau L. Grading of angina pectoris. Circulation 1976;54:522.
after 6 months. The highest rate of reinfarction occurs in the 0to 3-month period. Mortality from reinfarction, for patients
undergoing noncardiac surgery (Table 12.10), has been
reported to be between 20% and 50% and usually occurs
within the first 48 hours after surgery.
Perioperative cardiac adverse event risk reduction has
undergone significant changes over the past decade. Previous
retrospective studies demonstrating value to coronary revascularization spurred aggressive preoperative coronary artery disease identification and management. However, recent data
have questioned the value of coronary revascularization
among asymptomatic patients in not only the perioperative
period, but also in the general medical population.28,29 The
most recent American College of Cardiology (ACC)/American
Heart Association (AHA) guidelines reserve preoperative
coronary revascularization for patients demonstrating asymptomatic left main coronary artery disease, three-vessel disease,
reduced ejection fraction, unstable angina, or acute myocardial
infarction.30 Furthermore, large retrospective and prospective
studies have demonstrated that the institution perioperative
beta blockade also bears significant risks that must be weighed
against possible benefits.31,32 As a result, the most recent 8
247
Step 1
No
Active cardiac
conditions*
Step 2
No
Low risk
surgery
Step 3
Yes
(Class I,
LOE C)
Yes
(Class I,
LOE B)
Operating room
Perioperative surveillance
and postoperative risk
stratification and risk
factor management
Consider
operating room
Yes
(Class I,
LOE B)
SCIENTIFIC PRINCIPLES
Proceed with
planned surgery
No
Step 4
Step 5
Yes
(Class I, LOE B)
Proceed with
planned surgery
No or unknown
3 or more clinical
risk factors
Vascular
surgery
Intermediate
risk surgery
1 or 2 clinical
risk factors
Vascular
surgery
No clinical
risk factors
Intermediate
risk surgery
Class I,
LOE B
Class IIa,
LOE B
Consider testing if it will
change management
Proceed with
planned surgery
ALGORITHM 12.1
ALGORITHM 12.1. Decision aid for preoperative cardiac evaluation prior to noncardiac surgery. This decision tree for preoperative evaluation
takes into account not only the patients physical status but also the severity of the surgical procedure. ACC, American College of Cardiology;
AHA, American Heart Association; LOE, level of evidence.
Pulmonary Disease
Pulmonary disease is classically divided into acute and chronic
restrictive and obstructive disease. Restrictive disease is
defined by processes that reduce lung volumes, and obstructive
disease is characterized by reduced flow rates on pulmonary
function tests.
Obstructive diseases are present in patients with forced
expiratory volume in 1 second (FEV1)/forced vital capacity
(FVC) ratios of less than 50%. Obstructive pulmonary disease
can be either chronic or acute (asthma). In either case, the
reversible component of obstruction should be reversed before
elective surgery. Patients are maintained on bronchodilator
medications, and those with chronic secretions are appropriately hydrated and receive therapy to mobilize secretions. In
patients with reactive airway disease, the endotracheal tube
can induce severe bronchospasm. Even in patients who are
well treated preoperatively, reactive bronchospasm can complicate anesthetic induction and the emergence from anesthesia. The principal method used to prevent or diminish this
foreign bodyinduced bronchospasm is intubation of the
patient at a deep level of anesthesia when reflexes are blunted.
248
Obesity
Obesity causes a host of problems on both sides of the surgical
drapes. Obesity is defined as a body mass index greater than or
equal to 30 kg/m2. Body mass index (BMI) can be easily calculated by dividing the patients weight in kilograms by the
square of his or her height in meters. The pathophysiologic
changes associated with morbid obesity (BMI 40 kg/m2)
affect the respiratory, cardiovascular, and gastrointestinal systems. Patients have an external restrictive disease that reduces
functional residual capacity and worsens with the supine position. Breathing effort increases and ventilation becomes
diaphragmatic and position dependent. Obese patients frequently desaturate at night and have a high incidence of sleep
apnea. Because of increased blood volume and frequent desaturations, obese patients can develop pulmonary hypertension
and right-sided heart failure. Obese individuals have a high
incidence of coronary artery disease. Because of size alone, they
have increased cardiovascular demands with limited cardiac
reserve and exercise tolerance. Obese patients have a high incidence of hiatal hernia and gastroesophageal reflux, increasing
the risk for aspiration on induction and emergence from anesthesia. Issues as mundane as venous access can cause significant
problems in this patient group.
A significant concern of the anesthesiologist is gaining adequate control of the airway. The combined problems of aspiration risk, rapid desaturation caused by reduced functional
residual capacity and increased oxygen demand, and technical
difficulties associated with intubation due to anatomic fat
deposits make intubation a high-risk procedure. If problems
occur, there can be significant technical difficulties in obtaining
a rapid cricothyrotomy. For these reasons, a nasal or oral
awake intubation can be useful. Patients should receive prophylactic administration of H2-receptor antagonists and a
nonparticulate antacid to improve the pH of gastric contents.
If intubations are to be done after induction of anesthesia, they
should be performed in a rapid sequence using cricoid pressure. To prevent aspiration on emergence, obese patients
should be extubated when fully awake, preferably in the sitting position. Regional anesthetics can be very useful when
peripheral procedures are planned. Unfortunately, morbidly
obese patients can develop pulmonary failure just by lying flat,
making it difficult to use epidural or spinal anesthetics for
abdominal procedures. Epidural analgesics for postoperative
pain management allow earlier extubation and ambulation of
these patients.38
Diabetes Mellitus
The incidence of diabetes mellitus (DM) is rising, particularly
type 2 DM in the elderly. This is a systemic disorder that has
particular relevance for the anesthesiologist and surgeon
because of its effect on the vascular, renal, nervous, and
immune systems. Patients with DM should be investigated
for the presence of concomitant coronary artery disease,
peripheral vascular occlusive disease, renal failure, and autonomic and peripheral neuropathy. Problems with cardiovascular instability, fluid balance, and aspiration due to gastroparesis should be expected. In addition, these patients are
more prone to infection and have problems with temperature
control. The management of the diabetic state in these
patients is important and complicated. Hypoglycemia during
the anesthetic state is a feared complication because of challenges in prompt diagnosis. Oral hypoglycemic agents such
as glipizide should be stopped prior to surgery and hyperglycemic situations treated with short-acting intravenous or
subcutaneous insulin during the perioperative period. Brittle
diabetics, those prone to ketoacidosis or hypoglycemia,
should probably be admitted the night before surgery or at
least scheduled as the first case of the day. Insulin-dependent
diabetics for same-day admission or outpatient surgery
should take one half of their usual morning dose of long-acting insulin. After the establishment of an IV line, laboratory
blood samples are drawn and infusion of dextrose is started.
Additional insulin is then given according to the results of
frequent (every 1 to 2 hours) blood sugar monitoring. Alternatively, simultaneous IV infusion of dextrose and insulin
may be used to keep the blood sugar in the range of 120 to
180 mg/dL. Again, these patients, whenever possible, should
be done as the first case of the day to interfere as little as possible with the diabetic regimen.
2. For patients on LMWH (once a day dosing), needle placement should occur at least 12 hours after the last LMWH
dose. For patients receiving higher dosing (e.g., enoxaparin
1 mg/kg twice a day), placement should occur at least 24
hours after the last LMWH dose.
3. It is recommended that patients who have an indwelling
epidural catheter will receive LMWH only when there is an
extreme risk of deep vein thrombosis (DVT) and there is
frequent monitoring of the patients neurologic status
(every hour); the catheter should not be removed within 12
hours of the last dose.
4. Following removal of an epidural catheter, LMWH dosing
should not occur for at least 2 hours.41
TA B L E 1 2 . 1 1
PREDICTORS OF POSTOPERATIVE ACUTE KIDNEY INJURY
AFTER GENERAL SURGERY PROCEDURES
Age 56 y
Male sex
Emergency surgery
Intraperitoneal procedures
Preoperative renal insufficiency (serum creatinine 1.2 mg/dL)
Ascites
Active congestive heart failure
Diabetes mellitus requiring oral hypoglycemic or insulin therapy
PREOPERATIVE EVALUATION
TA B L E 1 2 . 1 2
RESULTS
70a
0.1%/0.5%
0.4%/2%
0.8%/4%
Renal failure
0.2%/1%
0.9%/2%
Abdominal surgery
0.3%/2%
1%/6%
2%/9%
3%/12%
0.7%/3%
3%/13%
6%/24%
0.9%/4%
4%/17%
7%/30%
2%/8%
2%/32%
16%/50%
6%/26%
22%/60%
37%/76%
Figures are for elective surgery (first number) and emergency surgery (second number).
From Pedersen T, Eliasen K, Henriksen E. A prospective study of mortality associated with anesthesia and surgery: risk indicators of mortality in
hospitals. Acta Anaesthesiol Scand 1990;34:176, with permission.
SCIENTIFIC PRINCIPLES
249
250
TA B L E 1 2 . 1 3
CLASSIFICATION
DESCRIPTION
PS-1
PS-2
PS-3
PS-4
PS-5
PS-6
A declared brain-dead patient whose organs are being removed for donor purposes
251
TA B L E 1 2 . 1 4
SIMPLIFIED STRATEGY FOR PREOPERATIVE TESTING
Estimated energy requirements for various activities
4 METs
4 METs
or workup? Is medical treatment of these problems optimized? If not, what needs to be done and how long will it
take?
In addition, the patients medication regimen should be
reviewed to ensure that appropriate medications are continued
or discontinued in the days and hours leading up to an elective
procedure. In general, diuretics and ACE-I/ARB medications
should not be taken the day of surgery. Several important
classes of medications should be continued per the patients
normal regimen: chronic pain therapy (including opioids),
beta-blockers, statins, and proton pump inhibitors. The decision regarding anticoagulant therapy is a complex one that
must take into account the indication for therapy, the likelihood and impact of surgical bleeding, and the risk of perioperative thrombosis. Insulin and oral hypoglycemic agents
should be continued at a reduced dose given the fasting state of
10 the surgical patient. Patients receiving chronic pain or opioid
addiction therapy with buprenorphine (Subutex, Suboxone)
can be particularly challenging to manage in the postoperative
period and should be immediately referred to their primary
care physician and an anesthesiologist to create a pain management plan prior to the day of surgery. Buprenorphine is
mixed opioid agonist/antagonist that tightly binds at the
receptor and has a long and varied half-life (24 to 60 hours). It
can inhibit the analgesic benefits of traditional opioids in the
postoperative period, resulting in uncontrolled pain, decreased
patient satisfaction, and the potential for adverse events due to
the need for very high doses of opioids.43 A management protocol used at the University of Michigan is demonstrated in
Algorithm 12.2.
An obvious problem that concerns anesthesiologists is the
potential of a difficult intubation. This can be assessed as discussed earlier (see Fig. 12.1 and Table 12.8). Even if a patient
has no medical problem, the possibility of a difficult airway
warrants that the patient be seen preoperatively and evaluated.
These patients can always be approached by an awake fiberoptic
technique, but this takes planning and can cause a significant
delay if there is no prior warning.
MONITORING THE
SURGICAL PATIENT
One of the more obvious changes in anesthesia care has been the
routine use of an array of electronic monitoring devices to provide continuous surveillance of physiologic status. Because the
art and science of anesthesiology involves titrating pharmaco-
Monitors of Oxygenation
Pulse oximetry has been called the most significant advance
in patient monitoring to date. This device continuously, noninvasively, and inexpensively provides arterial hemoglobin
saturation (SaO2) and peripheral pulse by measuring light
absorption in a manner similar to that of a laboratory
cooximeter. A laboratory cooximeter shines light through a
cuvette filled with a blood sample. Each hemoglobin species
absorbs light in direct proportion to its concentration (BeerLambert law). A cooximeter requires one wavelength of light
for each hemoglobin species to be measured, that is, one
wavelength for oxyhemoglobin and one for reduced hemoglobin. To measure other hemoglobins, such as carboxyhemoglobin or methemoglobin, the device requires four wavelengths of
light.
The traditional pulse oximeter uses two wavelengths of
light, one red and one infrared, that shine through a tissue bed,
usually a finger. Opposite the light sources is a photodiode that
measures the transmitted light intensity. A large proportion of
the light absorbed as it passes through the tissues is not associated with arterial blood but with other components of the tissue, such as skin, muscle, bone, and venous blood. Therefore,
the device analyzes only the pulsatile component of absorption
and assumes that anything that pulses within the tissue bed is
arterial blood, hence the name pulse oximeter. Actually, the
pulse oximeter measures the ratio of the pulsatile component
of red light absorbed to the pulsatile component of the
infrared light absorbed. This ratio changes with SaO2. The
exact relation between this ratio and SaO2 has been empirically determined from volunteer studies and is programmed
into the electronics of the oximeter. If any artifacts occur in a
pulsatile nature, they may be erroneously integrated into the
equation, causing erroneous SaO2 estimates.
Several things should be remembered when interpreting a
pulse oximeters output. First, the device measures SaO2 and
not arterial oxygen tension (PaO2). The PaO2 must drop
below 80 mm Hg before any significant change in SaO2
occurs. As the PaO2 drops below 60 mm Hg, the SaO2 rapidly
falls as the inflection point of the sigmoidal oxyhemoglobin
SCIENTIFIC PRINCIPLES
1 MET
252
Circulation Monitors
Ventilation Monitors
variability. As a result, patients may rarely experience awareness under anesthesiaa state characterized not only by
consciousness but also by recall of intraoperative events. The
laypress and public have increased their scrutiny of this perioperative event.
First, appropriate expectations and effective communication of the anesthetic are required. Recent literature has
demonstrated that patients undergoing regional anesthesia are
as likely to report unpleasant awareness as patients undergoing a general anesthetic.48 This is despite the reality that loss
of consciousness is only a goal of general anesthesia. Clearly,
anesthesiologists must communicate the anesthetic plan and
expectations more accurately.
Second, several level of consciousness monitors have been
developed in hopes of providing the anesthesiologist with
additional objective data to guide their assessment and
actions. The current generation of monitors generally uses
electroencephalographic (EEG) analysis to provide the clinician with an assessment of the relative depth of anesthesia
achieved. Several commercially available monitors such as
the bispectral index (BIS) from Aspect Medical Systems and
Entropy from General Electric Healthcare are in common
clinical use. Data evaluating the value of these EEG-based
monitors in reducing awareness are conflicting, with several
large trials producing varying results.49,50 As a result, the
ASA has not adopted awareness monitors as a standard of
care and leaves the decision to use such monitoring technology to each provider, patient, and situation.51 Further large,
randomized studies comparing EEG-based monitoring techniques to routine clinical care in a typical general surgery
population are currently under way and may provide valuable data.
253
POSTOPERATIVE ACUTE
PAIN MANAGEMENT
Postoperative pain is an inevitable consequence of surgery. Its
severity is site dependent (Table 12.18), but the magnitude of
the pain experienced by individual patients after similar surgical procedures is influenced by a multitude of factors. Variation in patient experience has been clearly demonstrated by
several authors and is reflected in deficiencies in postoperative
pain control.58 The recognition of this clinical problem has
prompted interest in underlying pain mechanisms and in innovative ways to alleviate postoperative suffering.
In 1965, the crucial role of nociceptive C fiber feedback
behavior and its modulation by cells in the substantia gelatinosa of the dorsal horn was recognized.59 Repetitive stimulation of these fibers by cellular mediators, such as kinins and
catecholamines, promotes neural excitation, prolongs repetitive firing, and lowers the threshold to further excitation. As a
SCIENTIFIC PRINCIPLES
254
TA B L E 1 2 . 1 5
STANDARDS FOR POSTANESTHESIA CARE
STANDARDS
a
CRITERIA TO BE FULFILLED
Standard I
Standard II
Standard III
Standard IV
Standard V
255
TA B L E 1 2 . 1 6
POSTANESTHESIA RECOVERY SCOREa
PARAMETER
SCORE
Unable to move
RESPIRATION
Breathes deeply and coughs
Dyspnea, hypoventilation
Apneic
CIRCULATION
Blood pressure equals 80% of preanesthetic level
CONSCIOUSNESS
Fully awake
Arousable
Unresponsive
COLOR
Pink
Pale, blotchy
Cyanotic
Patients should score at least 7 before discharge from the postanesthesia care unit.
FIGURE 12.2. Major postanesthesia care unit complications by percentage of occurrence and number of patients experiencing each
complication. Nausea and vomiting were the most frequently observed complications. ROMI, rule out myocardial infarction. (Reproduced with permission from Hines R, Barash PG, Watrous G, et al. Complications occurring in the postanesthesia care unit: a survey.
Anesth Analg 1992;74:505.)
SCIENTIFIC PRINCIPLES
ACTIVITY
256
TA B L E 1 2 . 1 7
DIFFERENTIAL DIAGNOSIS OF DELAYED EMERGENCE
METABOLIC ABNORMALITIES
Hypoxia
Hypercarbia
Hypoglycemia
Hypotension
Hypothermia
Hyponatremia
DRUG EFFECTS
Muscle relaxants
Opioids
Barbiturates
Benzodiazepines
Ketamine
Anticholinergics
Inhalational anesthetics
NEUROLOGIC INJURY
Ischemia
Mass lesions
Seizure disorders
FIGURE 12.3. Surgical procedures in which peripheral nerve blockade can provide postoperative pain relief.
result, C fibers do not show fatigue, and the stage is set for
continuous pain. Counterirritation of large afferent activity
has been shown empirically to have beneficial effects. The
gate-control theory provides an explanation for the inhibition of C fibermediated pain. Serotonergic and enkephalinergic descending inhibitory pathways modulate activity in
the dorsal horn before information is relayed to the
somatosensory cortex through the spinothalamic tract. The
common observation that pain is worse at night, when less
sensory information is processed, and that it decreases with
TA B L E 1 2 . 1 8
257
TA B L E 1 2 . 1 9
PROBLEMS THAT CAN OCCUR DURING PATIENTCONTROLLED ANALGESIA (PCA) THERAPY
OPERATION
NO
ANALGESIC
NEEDED (%)
THREE OR MORE
ANALGESIC
INJECTIONS (%)
82
Inguinal hernia
52
Appendectomy
25
10
Lower abdominal
surgery
18
40
PATIENT ERRORS
Upper abdominal
surgery
10
4565
OPERATOR ERRORS
Misprogramming PCA device
Failure to clamp or unclamp tubing
TA B L E 1 2 . 2 0
EXAMPLE OF ORDERS FOR PATIENT-CONTROLLED ANALGESIA (PCA)
1. Patient is to be initiated on PCA with
standard monitoring protocol.
2. Drug selection
3. Loading initial dose (start PRN for pain)
Maximum total loading dose
4. Pump setting PCA dose
Morphine
1 mg/mL
Hydromorphone
0.2 mg/mL
25 mg
0.20.5 mg
10 mg
1 mg
12 mg
0.10.2 mg
Lockout interval
610 min
610 min
4-Hour limit
3045 mg
45 mg
University of Michigan Hospitals online order form Acute Pain Service, Patient Controlled Analgesia
Standard Orders.
SCIENTIFIC PRINCIPLES
258
TA B L E 1 2 . 2 1
OPIOID PROTOCOLS IN EPIDURAL OPIATE ANALGESIA
MORPHINEa
FENTANYLb
Length of onset
Duration
More prone
Less prone
Indication
Dose
Yes
Minimal to
no pain
Elective
Surgery
Preoperatively
Surgical Team:
Assess anticipated
post-operative
pain and opioid
requirements
Off buprenorphine
Assess the amount of time since the last dose of buprenorphine
If 5 days off buprenorphine, treat with traditional opioids
Surgeons should contact the physician prescribing buprenorphine
and ensure that they are aware of surgery
No
After post-op pain normalizes, the patient may work with their
physician to reinstitute buprenorphine therapy
Yes
Moderate to
severe pain
No
ALGORITHM 12.2a
ALGORITHM 12.2. Algorithm for managing a patient on chronic buprenorphine therapy. APS, acute pain service; ICU, intensive care unit; PCA,
patient-controlled anesthesia; NSAIDs, nonsteroidal anti-inflammatory drugs. (continued)
Minimal to
no pain
No
Urgent/
Emergent
Surgery
Preoperatively
Assess anticipated
post-operative
pain and opioid
requirements
Moderate to
severe pain
Yes
No
Off buprenorphine
Anticipate patients course will be similar to opioid tolerant patient
Surgeons should ensure appropriate outpatient follow-up
ALGORITHM 12.2b
ALGORITHM 12.2. (Continued)
the acute surgical pain (see Table 12.4). The use of nonopioid
and nonpharmacologic treatments is essential in the management of acute postoperative pain in this patient population.
Peripheral nerve blockade, aggressive use of acetaminophen
and nonsteroidal anti-inflammatory agents, and novel agents
such as dexmedetomidine may be necessary to minimize the
adverse effects associated with uncontrolled postoperative
pain. As mentioned earlier, these patients may need to be evaluated by an anesthesiologist prior to the day of surgery. This
should be an institutional requirement for patients on chronic
buprenorphine therapy, as demonstrated in Algorithm 12.2.
References
1. Calverly R. Anesthesia as a specialty: past, present and future. In: Barash
P, Cullen B, Stoelting R, eds. Clinical Anesthesia Philadelphia, PA: JB
Lippincott, 1992.
SCIENTIFIC PRINCIPLES
Yes
259
260
34.
35.
36.
37.
38.
39.
40.
41.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
CHAPTER 13 CANCER
K E Y
P O I N T S
Few medical diagnoses carry with them the fear and dread that
a diagnosis of cancer brings to the patient. Historically, Hippocrates is credited with first distinguishing between benign and
malignant tumors. Hippocrates described invasive carcinoma
using the Greek term for crab, karkinos, based on the similarities between the invasive tongue of solid tumors and the claws
of the crab. Karkinos forms the root for the term carcinoma.
The word cancer is derived from the Latin, cancrum, for crab.
The term has come to represent a constellation of malignant processes involving a host of tissue types, each with differing potentials for invasion and metastases. Each pathologic
type of cancer has different approaches for its diagnosis and
management. However, there are certain basic characteristics
that define the transition from normal cell division and proliferation into abnormal, unregulated growth and invasion,
which is the hallmark of cancer. The breadth and depth of
information regarding the processes involved in the development, diagnosis, and treatment of cancer are complex; this
chapter gives an overview to provide a basis for further investigation and discovery.
are prostate (25%), lung and bronchus (15%), and colon and
rectum (10%). In women, the most common cancers by incidence are breast (26%), lung and bronchus (14%), and colon
and rectum (10%). In both men and women, lung and
bronchial cancers continue to account for the largest number
of cancer-related deaths (31% men; 26% women). This is followed by prostate cancer in men (10%) and breast cancer in
women (15%) accounting for the second most common histologies resulting in death. Colon and rectal cancer remains
the third most common cause of cancer-related deaths in both
men (8%) and women (9%) (Table 13.1). Although the overall incidence of cancer, as well as mortality due to cancer,
decreased between 1994 and 2008, for several tumor types
there has been either an increase in incidence or relatively little
change over that time. For example, melanoma of the skin
increased in incidence among men from 3% to 5% and among
women from 3% to 4% between 1994 and 2008. The incidence of thyroid cancer increased from 2% to 4% between
1994 and 2008 for women, in whom thyroid cancer occurs
more frequently than in men (3:1). Despite the decline in incidence and associated death among common cancer types in
both men and women, cancer continues to pose a significant
cost to the United States in both human and financial terms.
In 2003, cancer cost the United States an estimated $189.5
billion. Roughly one third of these costs were due to direct
medical costs, and more than two thirds were related to nonmedical costs, including lost productivity and lost workdays.
The Centers for Disease Control and Prevention (CDC) has
estimated that cancer screening and early detection could
reduce colorectal cancer deaths by 30%, breast cancer deaths
by 16%, and cervical cancer deaths by 60%. Further, it is estimated that in the year 2003, more than 180,000 cancer deaths
were due to the consequences of tobacco use. Although the
connection between cigarette smoking and lung cancer is an
obvious and well-established one, smoking plays a role in
approximately 30% of all other cancer deaths (e.g., kidney,
oral, bladder). As newer and more effective adjuvant therapies,
most notably, biologic agents, are developed and validated,
these costs will undoubtedly increase.
Major efforts are under way in cancer prevention. Some
causative agents, such as tobacco, are obvious. Other factors
that influence the development of cancer include genetic predisposition, diet and exercise, and environmental factors. For
EPIDEMIOLOGY
The earliest recorded writings related to cancer were made in
the Edwin Smith Papyrus in Egypt around 1600 BC. Since that
time and throughout recorded history, references are made to
various malignancies of the bone and soft tissue that were
attributed to sources as varied as vital humors and parasites.
Cancer affects approximately 9.6 million Americans, and a
total of 1.4 million new cancer diagnoses and 570,000 cancerrelated deaths are expected in the United States in the year
2008. For persons younger than the age of 85, cancer is the
leading cause of death in the United States and has been since
1999. Although overall mortality rates from cancer have
declined in both men and women, the rate of decline in deaths
due to heart disease has been much more rapid (Fig. 13.1).
Between 1995 and 2004, the cancer incidence rates in men
stabilized, while the incidence rates in women have stabilized
between 1999 and 2004. The overall death rate due to cancer
has continued to decease in men since 1990 and in woman
since 1991. Cancers differ in men and women by both type
and incidence. The most common cancers in men by incidence
261
SCIENTIFIC PRINCIPLES
STEVEN K. LIBUTTI
262
FIGURE 13.1. Age-adjusted death rates from cancer and heart disease. (Jemal A, et al. CA Cancer J Clin 2008;58:7196.)
ETIOLOGY
At its most basic, cancer can be defined as abnormal cell
growth. Often described as a foreign invader in the body, it is
more accurate to think of cancer as the bodys own cellular
1.
2.
3.
4.
5.
6.
263
TA B L E 1 3 . 1
THE 10 LEADING CANCER TYPES FOR THE ESTIMATED NEW CANCER CASES AND DEATHS, BY GENDER, FOR THE
UNITED STATES IN 2008
MALES
CANCER
FEMALES
INCIDENCE
CANCER
INCIDENCE
Prostate
186,320
(25%)
Breast
182,460
(26%)
114,690
(15%)
100,330
(14%)
77,250
(10%)
71,560
(10%)
Urinary bladder
51,230
(7%)
Uterine corpus
40,100
(6%)
Non-Hodgkin lymphoma
35,450
(5%)
Non-Hodgkin lymphoma
30,670
(4%)
34,950
(5%)
Thyroid
28,410
(4%)
33,130
(4%)
27,530
(4%)
25,310
(3%)
Ovary
21,650
(3%)
Leukemia
25,180
(3%)
21,260
(3%)
Pancreas
18,770
(3%)
Leukemia
19,090
(3%)
All sites
745,180
100%
All sites
692,000
100%
ESTIMATED DEATHS
Lung and bronchus
90,810
(31%)
71,030
(26%)
Prostate
28,660
(10%)
Breast
40,480
(15%)
24,260
(8%)
25,700
(9%)
Pancreas
17,500
(6%)
Pancreas
16,790
(6%)
12,570
(4%)
Ovary
15,520
(6%)
Leukemia
12,460
(4%)
Non-Hodgkin lymphoma
9,370
(3%)
Esophagus
11,250
(4%)
Leukemia
9,250
(3%)
Urinary bladder
9,950
(3%)
Uterine corpus
7,470
(3%)
Non-Hodgkin lymphoma
9,790
(3%)
5,840
(2%)
8,100
(3%)
5,650
(2%)
294,120
100%
All sites
271,530
100%
All sites
a
Excludes basal and squamous cell skin cancers and in situ carcinoma except urinary bladder. Estimates are rounded to nearest 10.
Adapted from Jemal A, et al. CA Cancer J Clin 2008;58:7196.
Evading
apoptosis
Insensitivity
to antigrowth
signals
Sustained
angiogenesis
Tissue invasion
and metastasis
SCIENTIFIC PRINCIPLES
264
Each of these capabilities is placed in the perspective of current research efforts in the sections that follow.
CANCER BIOLOGY
The basic unit of tissues and organs is the cell. The control of
cell growth and differentiation is the focal point in understanding the processes involved in malignant transformation.
Cells normally grow, divide, perform necessary functions to
maintain homeostasis, and die in a programmed fashion
throughout most tissues and organs. A cancer cell is one that
has alterations in this carefully controlled program that lead to
the phenotype of cancer. Hanahan and Weinbergs model
describes four of the six functional capabilities, which directly
relate to changes within the cell itself. These are the acquired
ability for self-sufficient growth, insensitivity to antigrowth
signals, ability to evade apoptosis, and limitless replicative
potential. The other two functional capabilitiessustained
angiogenesis and tissue invasion and metastasesinvolve
changes not only within the individual cancer cell but also in
the interaction and relationship with other host elements.
Inhibition of Differentiation
by Notch Signaling
Another major pathway influencing HLH-regulated cellular
differentiation involves the Notch signaling pathway. Notch
signaling appears to play a critical role in regulating cellular
differentiation during both normal development and malignant transformation. The pathway is highly conserved, with
homologous components in Caenorhabditis elegans, Drosophila, zebrafish, mice, and humans (Table 13.2). Four human
Notch family members have been identified. Notch proteins
TEL-PDGFR
APC
-catenin
c-src
BCR-ABL
c-Myc
Nucleus
-catenin
Tcf
c-myc
FIGURE 13.3. The c-myc gene is a central oncogenic switch for oncogenes and the tumor suppressor adenomatous polyposis coli (APC).
The APC tumor suppressor protein mediates the degradation of catenin. The Wnt oncoprotein is shown activating its receptor, which
results in the stabilization of free -catenin, which sustains activating
mutations in human cancers; -catenin is a cofactor for the transcription factor Tef. Tef activates c-myc expression through specific DNA
binding sites. The oncogenic fusion protein TEL-PDGFR hypothetically activates c-src, as does native PDGFR, resulting in the activation
of c-myc. The BRC-ABL oncoprotein likewise requires c-myc for its
activity. (Adapted from Dang CV. c-Myc target genes involved in cell
growth, apoptosis, and metabolism. Mol Cell Biol 1999;19:1.)
DFR
cad
TK
RCC1
Telomerase
Cell cycle
Apoptosis
DNA metabolism
Cell
growth
DNA dynamics
DFR
Energy metabolism
ECA39
elF2alpha
elF4E
MrDb
Macromolecular
synthesis
TA B L E 1 3 . 2
CONSERVED COMPONENTS OF THE NOTCH SIGNALING PATHWAY
CAENORHABDITIS
ELEGANS
Notch receptors
Lin-12
DROSOPHILA
MAMMALS
Notch
Notch1 Notch3
Glp-1
Extracellular ligands
(DSL proteins)
Lag-2
Notch2 Notch4
Delta
Apx-1
Delta-1
Delta-1
Delta-like 1 (Dll-1)
Delta-like 3 (Dll-3)
Serrate
Jagged1 (Serrate1)
Jagged2 (Serrate2)
Intracellular effectors
Lag-1
CBF-1/RBP-J
Deltex
Deltex
NFB
Target genes
Processing molecules
Modifiers
SUP-17
bHLH
bHLH
Groucho
TLE
Kuzbanian
Kuzbanian
Fringe
Lunatic fringe
Manic fringe
Radical fringe
Numb
Numb
Numb-like
Disheveled
Disheveled 1,2,3
SCIENTIFIC PRINCIPLES
Wnt
receptor
265
266
FIGURE 13.5. Notch signaling inhibits lineage-specific cellular differentiation. Ligands presented by
adjacent differentiated cells lead to
Notch receptor activation. Following
intramembrane cleavage of Notch by
-secretase, the intracellular domain
of Notch (Notch-IC) translocates to
nucleus and cooperates with RBP-J
(mammalian homologue of Drosophila Suppressor of Hairless) to induce
HES-1. HES-1 represses transcription
of lineage-specific transcription factors, including neurogenin 3, myoD,
and the achaete-scute homologue
(ASH). Activation of Notch signaling
thereby maintains cells in an undifferentiated, stem celllike state.
Differentiated
cell
Delta
Notch
-secretase
Undifferentiated
stem cell
NotchIC
Nucleus
RBP-J/Su(H)
HES 1
Lineage-specific factors:
ngn3
myoD
ASH
Transformation from the normal phenotype to invasive malignancy appears to involve a loss of normal tumor suppressive
and growth inhibitory responses as well as the acquisition of
inappropriate proliferative signals. The presence of inappropriate proliferative signals has been well documented in most
malignancies and includes overexpression of peptide growth
factors (transforming growth factor [TGF-], amphiregulin,
heparin-binding EGF) and of growth factor receptors (e.g.,
HER2/neu). Alternatively, there may be mutational activation
Cyclin B
Mitogenic signals
cdc2
M
GO
Cyclin D
RB
E2F
Cyclin A
cdc2
G2
G1
Cyclin D
cdk4/6
R-point
Cyclin E
cdk2
Cyclin A
cdc2
RB
cdk4/6
p21WAF1
p15INK4B
p27KIP1
p16INK4A
E2F
Anti-mitogenic signals
SCIENTIFIC PRINCIPLES
267
268
Cyclin A,B
+ CDK1
M
G2
G1
Cyclin D's
+ CDK4,6
S
pRb
phosphorylation
Cyclin A
+ CDK2
Cyclin E
+ CDK2
FIGURE 13.7. The cell cycle clock. This version of the cell cycle
shows where the retinoblastoma protein (pRB) is either phosphorylated or dephosphorylated to regulate cell cycle transit.
Activated
Basal
Repressed
P
pRB
pRB
E2F DP
E2F DP
P P
pRB
P P
pRB
E2F DP
E2F DP
Cyclin D
Cyclin E
Cyclin A
Mitogen stimulation
p27
269
G0
G1
G2-M
G1
G2-M
G0
protein functions as an important transcription factor mediating expression of a variety of genes whose products may
directly regulate growth arrest or apoptosis. Growth arrest
induced by p53 may enable a cell to repair DNA that has been
damaged. Alternatively, p53 also functions to induce apoptosis to prevent propagation of a cell lineage containing mutated
DNA sequences.
Expression of p53 may be induced by either DNA damage
or by inappropriate mitogenic signaling. An example of an
important p53-responsive gene product involved in cell cycle
arrest is the cyclin kinase inhibitor protein p21Cip1. Several
p53-responsive gene products appear to be involved in the
apoptotic response. These include Bax, Fas/Apo, Killer/Dr5,
and the redox regulator gene products known as PIGs (p53induced genes). The expression of Mdm2 is also induced on
activation of the p53 gene. Mdm2 is a negative feedback regulator of p53 whose function is to target p53 for rapid degradation. Interestingly, one of the two products of the INK4a/ARF
locus, p14ARF inhibits the function of Mdm2, thereby stabilizing and activating p53 and promoting cell cycle arrest and
apoptosis in response to inappropriate mitogenic signals. The
other product of the INK4a/ARF locus is p16Ink4a, the important inhibitor of CDKs 4 and 6, and a mediator of G1 cell
cycle.
The protein product of the Myc proto-oncogene also regulates both cell proliferation and apoptosis in cell culture systems.
Myc expression is capable of preventing cells from exiting the
cell cycle and of promoting continuous cell cycle progression.
Expression of Myc also inhibits differentiation in certain cell
types. Similar to the situation in which inappropriately
increased E2F triggers apoptosis, inappropriate Myc expression can also trigger apoptosis. Both increased E2F and Myc
increase the expression of the ARF protein (p14 and p19), and
as described previously, increased expression of ARF stabilizes
p53, leading to both growth arrest and apoptosis.
There is a growing list of additional proteins that are
involved in sensing and repairing DNA damage, or in ensuring
correct chromosomal segregation during mitosis. Loss of function of these important genomic caretaker systems appears
to be common in cancer cells, and this loss facilitates genomic
instability with the accumulation of additional genetic lesions.
The cumulative genetic mutations lead to tumor cells with
selective advantages for aggressive biologic behavior including
invasiveness and metastatic capacity, resistance to immunosurveillance, resistance to apoptosis, and the ability to resist cancer therapeutic interventions.
SCIENTIFIC PRINCIPLES
270
Positive growth
factors:
EGF
TGF
FGF
PDGF
TGF-
+
Positive
growth
factors
Autocrine/paracrine
effects:
Fibroblastoid change
Altered cell adhesion
Increased migration
TGF-
+++
+++
Positive
growth
factors
spindle cell phenotype in transgenic mice expressing high levels of TGF- in the skin. The TGF-induced epithelial to
mesenchymal transition in Ha-rastransformed mammary
epithelial cells involves disrupted cellcell adhesion and the
loss of epithelial cell polarity in addition to causing the cells to
become more spindle shaped and invasive. The loss of cell
polarity in response to TGF- appears to be the result of a disruption of ZO-1 and F-actin proteins comprising the tight
junctions in mammary epithelial cells.
There also is an important regulatory interaction between
the TGF- and cyclooxygenase-2 (COX-2) pathways. Forced
overexpression of COX-2 in the nontransformed RIE-1 cells
results in downregulation of the TRII, and forced overexpression of COX-2 in a human colon cancer cell line results in
increased secretion of TGF-1 from those cells. TGF- synergistically enhances the expression of COX-2 in conditionally
Ha-rastransformed RIE-1 cells, and the increase in COX-2
expression by TGF- in the context of ras transformation
occurs primarily through a marked increase in the stability of
the COX-2 mRNA.
The predominant effect of TGF- appears to be dependent
on the context of the responding cell. Thus, the divergent
effects of TGF- in carcinogenesis may depend on the proliferative capacity and state of differentiation of the epithelial cell,
both of which may be altered during the process of neoplastic
transformation. Clearly, TGF- signaling has an important
tumor suppressive role; however, after transformation has
occurred, TGF- effects may be detrimental and may actually
promote tumor cell survival, invasion, and metastasis. Recent
work suggests that these effects may involve TGF- regulation
of COX-2 and other pathways that may contribute to tumor
cell aggressiveness.
Tumor Angiogenesis
4
271
ing a blood supply. Models have been developed that demonstrate the importance of VEGF in tumorigenesis. Using a transgenic mouse model of pancreatic islet carcinoma (RIP1-Tag2),
Hanahan et al. demonstrated that five VEGF lineage genes are
expressed in normal islets and throughout islet tumorigenesis.
When this group produced an islet beta cellspecific knockout
of VEGF-A, the resulting islets in these animals had reduced
vascularity but retained their normal physiology. In RIP1-Tag2
mice in which most of the oncogene expressing cells had
deleted the VEGF-A gene, both angiogenic switching and
tumor growth were disrupted, as was the degree of neovessel
formation. This elegant work demonstrates the crucial role of
VEGF in angiogenesis. Although such experimental work is
compelling, clinical data support this notion further.
A humanized mouse monoclonal antibody against VEGF
(bevacizumab, Avastin, Genentec, Inc.) has recently completed
phase III clinical trials and has received Food and Drug Administration (FDA) approval based on its activity in patients with
colon cancer. In a prospective randomized phase III trial in
renal cancer, James Yang et al. demonstrated that systemic
administration of anti-VEGF antibody to patients with
metastatic renal cell carcinoma resulted in a significant prolongation in the time to disease progression when compared with
patients receiving a placebo. Herb Hurwitz et al. combined
anti-VEGF antibody with a three-drug chemotherapy regimen
consisting of 5-fluorouracil (5FU), leucovorin, and irinotecan
for patients with metastatic colorectal carcinoma and compared this combination with the three-drug chemotherapy regimen alone. The addition of the anti-VEGF antibody to the
standard chemotherapy regimen resulted in an improved
response rate and an improved disease-free and overall survival. This clear relationship between blockade of factors
known to induce tumor vasculature leading to antitumor
effects seen clinically in patients underscores the importance of
the angiogenic process in human tumors.
To gain a better understanding of the complex relationships
between tumor cells and the surrounding stromal cells, including the endothelium, a basic understanding of the molecular
processes involved in endothelial cell growth and differentiation is important. Indeed, regulation of vessel growth and proliferation is an important component of normal homeostatic
mechanisms. Following embryogenesis and tissue formation,
the growth of new blood vessels in normal tissues is carefully
controlled and regulated. In addition to VEGF, there are a
number of other regulatory cytokines, both initiators of vessel
formation and inhibitors, that are regulated in a careful balance. An understanding of this balance may allow a more
informed selection of targets for future cancer therapies. In
addition to VEGF, other stimulatory cytokines have been
shown to play an important role in a tumors ability to recruit
a vasculature. Among these, acidic fibroblast growth factor
(aFGF) and basic fibroblast growth factor (bFGF) as well as
placental-derived growth factors play important roles.
In addition to a careful balance of cytokines, integrin signaling plays an important role in regulating angiogenesis.
When quiescent blood vessels are compared to activated or
actively proliferating blood vessels, the panel of expressed
integrins differs. Integrins such as v3, which plays an
important role in endothelial cell adhesion to vitronectin (a
component of the extracellular matrix), is differentially
expressed in the vasculature of certain tumors when compared
to other histologies and to normal tissues. Endothelial cells differ in their expression of various surface proteins depending
on the tissue in which they reside. Work by investigators such
as Pasqualini and Arap has demonstrated the diversity of
endothelial cells and underscores the important observation
that not all endothelial cells are the same.
In landmark studies using phage display techniques,
Pasqualini and Arap have demonstrated that endothelial cells
have unique surface markers that define their differences based
on their tissue of origin. These so-called endothelial cell zip
SCIENTIFIC PRINCIPLES
272
TA B L E 1 3 . 3
ENDOGENOUS NATURALLY OCCURRING
ANGIOGENESIS INHIBITORS
Angiostatin/other plasminogen kringles
IP-10
Antithrombin (cleaved)
METH-1 and -2
Endostatin
MIG
Fibronectin fragments
p16
PEX
p53
16-kD Prolactin
Canstatin
Prothrombin kringle-2
PEDF
Maspin
Platelet factor-4
Restin
Vasostatin
Proliferin-related
protein
PSA
Arresten
Protamine
IFNs
Retinoic acid
TIMPs
Soluble FGF
receptor
1,25-(OH)2-vitamin D
2-Methoxyestradiol
Angiopoietin-2
EMAP-II
gro-
TGF-1
TNF-
Troponin I
TSP-1 and -2
THE FUTURE OF
CANCER THERAPY
Throughout the 20th century, the standard approaches for the
treatment of cancer included surgical resection, radiation therapy, and chemotherapy. Although advances in specific technical applications and in combinations of therapies were made,
these three broad modalities remained the foundation of therapeutic approaches. This section focuses on novel strategies
for treating cancer that may serve to complement and in some
cases replace the traditional paradigm of surgery, radiation,
and chemotherapy.
SCIENTIFIC PRINCIPLES
273
274
TA B L E 1 3 . 4
MOLECULAR TARGETS AND THE AGENTS DEVELOPED TO
MODULATE THEM
TARGET
AGENT
MANUFACTURER
Bcr-abl
Gleevec
Novartis
HER2 (neu)
Herceptin
Genentech
Ras
R11577
VEGF
Avastin
Genentech
VEGF
VEGF Trap
Regeneron
EGFR
Iressa
AstraZeneca
EGF
ABX-EGF
Abgenix
Cyclindependent
kinase
Flavopiridol
Aventis
Protein
linase C
Affinitak
Isis Pharmaceuticals
Gene Therapy
5
275
SCIENTIFIC PRINCIPLES
with prostate adenocarcinoma using direct injection of an adenovirus expressing hsv-tk followed by ganciclovir exposure.
These studies have demonstrated the safety of this strategy,
although studies to evaluate efficacy are still under way.
The future of gene therapy for cancer is dependent on several important lines of investigation. Improved vectors are
needed that minimize toxicity, allow for specific targeting,
decrease the hosts immune response or prevent a host immune
response, and can be produced efficiently for clinical use. The
judicious selection of the appropriate genes to deliver in such a
strategy is dependent on further investigation into the molecular pathways that are important to the malignant phenotype.
Immunotherapy
Harnessing the bodys immune system to attack cancer is an
attractive strategy and area of investigation. Tumors express
antigens that are often different from the antigens expressed
by the normal cells. There are two main approaches for the use
of immunotherapy to treat patients with cancer. The first
involves the use of vaccine therapy to stimulate the bodys
native immune system, mainly antigen-presenting cells and
lymphocytes, to react specifically against the tumor antigens
resulting in tumor regression. The second is the transfer of
lymphocytes isolated from the patients tumor tissue (tumor
infiltrating lymphocytes [TILs]) that have been selected for
their immunoreactivity against the patients tumor.
Vaccine therapy may utilize peptides derived from the protein sequence of the cancer antigen, gene therapy with vectors
carrying a coding sequence for the peptide or antigen, or, alternatively, the delivery of whole tumor lysate providing a variety
of antigenic stimuli. Once vaccinated, the protein or peptide is
processed by antigen-presenting cells in the context of the
patients class I major histocompatibility complex (MHC)
molecule, thus stimulating a lymphocyte response to the
tumor.
276
TA B L E 1 3 . 5
ANTIANGIOGENIC GENE THERAPY: GENES AND VECTORS
GENE
DELIVERY VECTOR
FINDINGS
Angiostatin
Adeno-associated virus
Cationic liposome:
DNA complex
In vitro transfection
In vitro transfection
Retrovirus
Adenovirus
Adenovirus
Cationic liposome:DNA
complex
Adeno-associated virus
In vitro transfection
Stable transfection of mouse and human tumor cell lines inhibited formation of
lung and liver metastases in mice.
Cationic liposome:DNA
complex
Adenovirus
Adenovirus
IL-4
IL-10
In vitro transfection
Endostatin
In vitro transfection
Transfection of human prostate cancer cells inhibited their growth in nude mice
IL-12
IFN-a
TIMP-1
In vitro retroviral
transduction
Adenovirus
TIMP-2
In vitro transfection
TSP-1
Liposome:DNA complex
p16
Adenovirus
Pretreatment with virus inhibited the ability of glioma cells to induce angiogenesis
in a dorsal air sac model in nude mice.
p53
Liposome:DNA complex
Liposome:DNA complex
PF-4
Adenovirus
Coinjection of adenovirus with glioma cells under renal capsule of nude mice
inhibited tumor growth and vascularity.
EMAP-II
Vaccinia
From Feldman AL, Libutti SK. Progress in antiangiogenic gene therapy of cancer. Cancer 2000;89:1181.
277
SCIENTIFIC PRINCIPLES
278
TA B L E 1 3 . 6
PREDICTORS OF MORTALITY AND SURVIVAL FOLLOWING
RESECTION OF HEPATIC COLORECTAL METASTASES
PROGNOSTIC
FACTOR
p VALUE
RR DEATH
Disease-free interval
12 mo
0.002
1.56
Tumor number 1
0.01
1.56
0.05
1.45
Size 5 cm
0.01
1.46
0.05
1.34
5-y SURVIVAL
(%)
MEDIAN
OS
57
74
57
73
47
50
16
30
15
Axillary vein
Gastroduodenal
artery
Temperature
probe
Superior
mesenteric vein
Outflow
Perfusion
circuit
Inferior vena cava
Saphenous vein
Inflow
Veno-veno
bypass
FIGURE 13.13. A view of the retrohepatic vena cava following dissection for an isolated hepatic perfusion.
279
Gastroduodenal
artery
Temperature
probe
Superior
mesenteric vein
Veno-veno
bypass cannula
A
B
FIGURE 13.14. Complete portal dissection for isolated hepatic perfusion.
Vascular clamp
on common
hepatic artery
SCIENTIFIC PRINCIPLES
280
FIGURE 13.15. Magnetic resonance imaging of the liver for a patient with colorectal cancer metastatic to the liver before (top) and after (bottom) an isolated hepatic perfusion (IHP).
(Fig. 13.16). The filtered blood is then returned via the internal
jugular vein to maintain venous return. A phase I trial was
recently completed at the NCI demonstrating a safe dose of
melphalan that can be delivered in this fashion. A multicenter
phase III trial is now under way to evaluate the utility of this
approach for metastatic melanoma (cutaneous and ocular) to
the liver compared to best standard therapy.
Regional therapy can be applied to other locations in the
body such as the limb (isolated limb perfusion for melanoma
or sarcoma) and the peritoneal cavity. Peritoneal carcinomatosis secondary to a number of histologies including colorectal
Blood flow
Filters
Delcath
double-balloon
catheter
Flow probe
Pump head
FIGURE 13.16. Schematic diagram (A) and fluoroscopic image (B) depicting the technique of percutaneous hepatic perfusion.
281
Thermister
Reservoir
Heat exchanger
weight loss, ascites, and bowel obstruction. These complications can lead to death and there are no effective systemic
treatment options. Although agents such as cisplatin and carboplatin as well as paclitaxel (Taxol) and doxorubicin (Adriamycin) have been used to treat this condition, response rates
are low (20%) and survival is poor. The technique of contin-
FIGURE 13.18. Intraoperative photo demonstrating significant carcinomatosis involving the mesentery of the small bowel.
SCIENTIFIC PRINCIPLES
Pressure
monitor
282
FIGURE 13.19. Computed tomography scan of a patient with ascites from peritoneal mesothelioma before (top) and after (bottom) a tumor
debulking and continuous hyperthermic peritoneal perfusion.
CANCER DETECTION
AND BIOMARKERS
Methods to enable more accurate early detection of cancer are
an active area of investigation. Some of these methods are
amenable to cancer screening, allowing assessment of large
populations of at-risk patients to detect disease at its earliest
possible time. Other methods are best applied to patients who
have already been treated for their cancer and are being followed for signs of recurrence. This section highlights three
areas that illustrate the possibilities for early cancer detection.
Imaging
Standard imaging techniques such as CT, MRI, and ultrasound
have been applied to patients as a means of both screening and
follow-up. Standard plain radiographs have also been used in
this setting. As CT scans and MRIs have become more
advanced with higher resolution and shorter scanning times,
the sensitivity for lesion detection has been dramatically
improved. One example has been the development of both CT
and magnetic resonance (MR) colonography.
Colonography has been proposed as a means to screen
patients for colon polyps and tumors in an effort to avoid the
need for an optical endoscopic colonoscopy. Virtual colonoscopy
using CT scanning was evaluated as a screening procedure for
colorectal neoplasia in asymptomatic adults at the National
Naval Medical Center in Bethesda, Maryland. A total of 1,233
asymptomatic adults (mean age 58 years) underwent a sameday CT colonography as well as an optical colonoscopy. The
radiologist used a three-dimensional endoluminal display for
the detection of polyps on the virtual colonoscopy. The physicians performing the optical colonoscopy did not know the
results of the virtual colonoscopy for the initial examination.
The sensitivity and specificity of virtual colonoscopy compared
to optical colonoscopy were then compared to the findings of a
final unblinded optical colonoscopy, which was used as the reference standard.
Sensitivity of the virtual colonoscopy for adenomatous
polyps was 94% for polyps greater than 8 mm in diameter and
283
SCIENTIFIC PRINCIPLES
FIGURE 13.20. Fluorodeoxyglucose positron emission tomography scan demonstrates a recurrent colon cancer in
the bed of a previous right hemicolectomy that was not detected on computed tomography scan in a patient with a
rising serum carcinoembryonic antigen.
on specific expression of receptors or pathways. In combination with molecular therapies, such imaging methods may
allow for noninvasive monitoring of the activity of targeted
agents.
A number of preclinical models have been developed to test
molecular imaging strategies. Weissleder et al. have designed a
number of noninvasive methods for imaging the activity of
enzymes and pathways to predict the efficacy of molecular
agents. One example is their use of iron oxide nanoparticles
cross-linked to Cy-3 and Cy-5 fluorescent dyes. Using cathepsin-B cleavable linking peptides, activity can be measured via
cleavage and determination of the ratio of the various fluorophores. By using fluorophores as well as iron particles, both
fluorescent imaging and MRI of the tissue in question can be
performed.
Specific tissue receptors can also be imaged noninvasively.
Tumor vasculature is known to have an increased expression
of integrins such as v3. Using RGD cyclic pentapeptides
labeled with PET positron emitters, tissues with enhanced v3
expression can be imaged. Such techniques can be used to locate
areas of increased tumor neovascular density and can also be
utilized to follow the targeting or activity of v3-specific
agents.
these genes from a variety of sources capable of yielding substrate RNA. Using linear RNA amplification techniques, even
the smallest samples of RNA from fine-needle aspirates
(FNAs) or microdissected tissues can be utilized for profiling.
Gene expression profiling can be used to answer a variety of
questions including the differences in gene expression pathways between malignant and normal tissues. Expression profiles can also be determined in tissues prior to and following
therapies to better understand mechanism of action of a treatment. Recently, genomics approaches have been validated for
the stratification of women with breast cancer for treatment
with adjuvant therapy. Such approaches are useful in determining which patients may benefit from adjuvant chemotherapy or hormonal therapy and which patients will not, thereby
avoiding unnecessary toxicity in patients unlikely to benefit
from the therapy.
Complex bioinformatics software programs have been
developed to allow a more thorough analysis of the data sets
obtained through these studies. The National Institutes of
Health (NIH) Center for Information Technology and the NCI
have posted a series of bioinformatics tools to allow investigators to better study and understand the results of their microarray experiments. This Web site can be found at http://nciarray.
nci.nih.gov/.
One example of the utility of microarray approaches for
the diagnosis of cancer is the differentiation of benign versus
malignant thyroid lesions. Approximately 10 million new thyroid lesions are diagnosed each year in the United States. Only
5% of these lesions are malignant. Although fine-needle aspiration has been utilized in an attempt to identify those patients
with a thyroid cancer who require further management,
straightforward cytologic examination of FNA samples often
leads to indeterminate or nondiagnostic studies. A molecular
method for distinguishing benign from malignant thyroid
lesions would be helpful in identifying those patients who
would most benefit from a surgical intervention.
Utilizing cDNA microarray, our group compared expression profiles of thyroid cancers (papillary thyroid cancers and
follicular variant papillary thyroid cancers) to benign thyroid
284
Proteomics
Genes mainly code for proteins that perform the various structural and functional roles in the cell. Proteins undergo a series
of modifications to perform these jobs, most importantly
glycosylation and phosphorylation. Although cDNA and
oligonucleotide microarrays can determine levels of gene
expression, they cannot elucidate the modifications that take
place at the protein level.
Proteomics, or the direct study of proteins, allows for not
only a quantification of the levels of proteins present in tissues
but also a determination of the phosphorylation status of these
proteins. Serum proteomics is an exciting new technology,
which holds promise for the diagnosis of cancer from a sample
of blood. Such an approach is now being applied to clinical
samples.
Based on the assumption that patients harboring a malignancy have circulating proteins in their serum that are not present in unaffected patients, serum proteomics endeavors to distinguish a biosignature profile of human cancer. By taking
samples from a population of patients with cancer and comparing the proteomic profile of their serum to that of a population of people without cancer, a pattern can be elucidated
that identifies the at-risk population. The novelty of this
approach is that, unlike investigating single specific biomarkers such as CEA for colon cancer or CA 199 for pancreas cancer, a serum proteomic approach requires no hypotheses about
which proteins will be important to identify. In fact, thousands
of proteins can be queried and utilized to form the biosignature. The most informative of these can be determined using
various bioinformatics strategies to reduce the number to a
manageable assay.
Applying this approach to patients with ovarian cancer,
high-resolution spectral data have been obtained that demonstrated a specific pattern capable of distinguishing patients
with stage I ovarian cancer from patients with more advanced
ovarian cancer, as well as from normal healthy controls. As
these techniques improve, they will no doubt be applied to
other tumor histologies and will add to the armamentarium of
diagnostic tests available to the clinician.
CLINICAL TRIALS
As knowledge increases regarding the pathways involved in
tumorigenesis, novel agents will be identified that show
promise in treating cancer. Although much can be learned
about these agents in preclinical models, the ultimate evaluation of a new cancer therapeutic requires carefully conducted
clinical trials.
Clinical trials involve the participation of patient volunteers. These volunteers agree to participate in studies that pose
specific scientific questions to find improved strategies to prevent, diagnose, screen for, or treat a particular disease process.
There are a number of types of clinical trials.
Prevention trials are designed to evaluate strategies or
therapies aimed at preventing the development of cancer.
These studies are most often conducted with healthy patient
285
TA B L E 1 3 . 7
BEST OVERALL RESPONSE CALCULATIONS BASED ON RECIST CRITERIA
NONTARGET
LESIONS
NEW LESIONS
OVERALL
RESPONSE
CR
CR
No
CR
CR
Incomplete response/SD
No
PR
PR
Non-PD
No
PR
SD
Non-PD
No
SD
PD
Any
Yes or no
PD
Any
PD
Yes or no
PD
Any
Any
Yes
PD
CR, complete response; PD, progressive disease; PR, partial response; RECIST, response evaluation criteria
in solid tumors; SD, stable disease.
SCIENTIFIC PRINCIPLES
TARGET
LESIONS
286
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P O I N T S
K E Y
Commonly used quality indicators, including both volumeand risk-adjusted outcomes, readily identify groups of hospitals and surgeons with superior outcomes. They are not
reliable in profiling performance for individual providers,
however.
2 In surgery, the most familiar process compliance strategy is
the pay-for-performance program of the Surgical Care
Improvement Project, which aims to increase adoption of
evidence-based practices related to perioperative care.
3 Current process measures do not reliably identify hospitals
or surgeons with better outcomes. Higher leverage measures, including those that reflect important aspects of surgical decision making or operative performance, are needed.
1
P O I N T S
Although prophylactic strategies aimed at avoiding complications in the first place are obviously important, rescuing patients once a complication has occurred may be even
more critical in reducing current variations in hospital mortality rates.
5 Outcomes measurement and feedback may provide early
benefits by capitalizing on the surgical Hawthorne effect,
but they do not inform hospitals or surgeons about how best
to improve.
6 The optimal strategy for improving surgical quality may
depend on political realities, the clinical context, and which
outcomes stakeholders hope to improve.
4
287
SCIENTIFIC PRINCIPLES
288
TA B L E 1 4 . 1
CHARACTERISTICS OF THREE DIFFERENT MODELS FOR REDUCING VARIATION AND IMPROVING SURGICAL MORTALITY
SELECTIVE REFERRAL
PROCESS COMPLIANCE
OUTCOMES MEASUREMENT
Goal/mechanism
Examples
Inexpensive, expedient
Traction with patients
and payers
Disadvantages
Highly polarizing
(for providers)
Hard to identify best
providers (at individual level)
these include specific processes aimed at reducing rates of surgisurgeons with superior outcomes. For example, data readily
cal site infection, postoperative cardiac events, venous thromobtained from administrative data, including procedure volume
boembolism, and ventilator-associated pneumonia.
and hospital mortality, not only describe past performance, but
Efforts aimed at improving compliance with specific
also forecast future performance with many procedures.13
processes of care are considerably less polarizing than selective
Unfortunately, such measures are considerably less useful
referral. In theory, anyone can win. To the extent that surin discriminating performance among individuals, in part
geons can play to the quiz, process-based pay-for-perforbecause provider-specific outcomes are statistically unstable.
mance programs have the potential to achieve rapid and signifiFor example, Krumholz et al. used clinical data from the
cant improvements in many aspects of perioperative care. At the
Cooperative Cardiovascular Project to assess the usefulness of
University of Michigan Hospital, for example, the proportion of
the HealthGrades hospital ratings for acute myocardial infarccolorectal surgery patients receiving an appropriate antibiotic
tion (based primarily on risk-adjusted mortality rates from
within 60 minutes prior to incision increased virtually overnight,
Medicare data).14 Relative to one-star (worst) hospitals, fivefrom 70% to over 95%, following implementation of a pay-forstar (best) hospitals had significantly lower mortality (16% vs.
performance program by one of its major private payers. Studies
22%, p 0.001) after risk adjustment with clinical data. Howin primary care suggest that pay-for-performance programs may
ever, the HealthGrades ratings poorly discriminated among
be particularly effective in improving process compliance among
any two individual hospitals. In only 3% of head-to-head
poor performers and thus reducing overall variation.16,17
comparisons did five-star hospitals have statistically lower
mortality rates than one-star hospitals.
Nonetheless, the extent to which process compliance will
Selective referral strategies have other downsides. Strategies 3 improve surgical outcomes remains uncertain. Studies to date
that displace patients from their usual site of care and regular
have generally failed to demonstrate a strong relationship
physicians may interfere with coordination of care. They tend to
between provider performance and specific process measures
be highly polarizing, dividing hospitals and surgeons into winand patient outcomes. For example, based on data suggesting
ners and losers. In alienating the latter, a price of selective referthat patients in whom more nodes are detected seem to have a
ral may be lost opportunities for engaging physicians in other
more favorable prognosis after cancer surgery, many pay-fortypes of quality improvement efforts. And finally, selective referperformance programs recently began rewarding hospitals for
ral improves outcomes exclusively to the extent that it steers
examining at least 12 lymph nodes from the surgical specimens
care away from poor performers. It provides no mechanism for
of patients undergoing colectomy for colon cancer. In a recent
helping other hospitals and surgeons improve their outcomes.
study, hospitals varied widely in their success in achieving the
12-node minimum.18 However, hospitals scoring well on this
process measure had virtually identical 5-year survival rates as
those scoring poorly. In another study by Hawn et al.,19 hospiPROCESS COMPLIANCE
tals compliance with SCIP-1 (proportion of patients receiving
2 Another approach to improving surgical outcomes is to encourappropriate antibiotics within 60 minutes of surgical incision)
had little relation to their rates of surgical site infection. Such
age hospitals and surgeons to increase their compliance with
studies highlight the complexity of surgical care and the limitaprocesses of care associated with better outcomes. This model is
tions of focusing on a small number of discrete steps.
best represented by ongoing pay-for-performance programs of
Even if current process compliance strategies were successboth public and private payers. For example, payers are linking
ful in reducing rates of specific complications, it is not certain
hospital reimbursement to satisfactory adherence to evidencethat they would also reduce mortality, arguably the most
based practices related to perioperative care, as defined by the
important end result of many major procedures. To explore
Surgical Care Improvement Project (SCIP), a joint effort of the
this issue empirically, we recently assessed hospital compliance
Centers for Medicare and Medicaid Service (CMS) and the Cenwith several process measures targeted by the Surgical Care
ters for Disease Control and Prevention.15 At the present time,
80
70
60
Low
Medium
High
No report
50
40
30
20
10
0
Abdominal aortic
aneurysm repair
Coronary artery
bypass grafting
Pancreatic resection
Improvement Project, as compiled by CMSs Hospital Compare Program. Process compliance varied widely across hospitals (56% in the lowest vs. 91% in the highest hospital tercile).
However, hospital compliance with SCIP process measures
had no significant relationship with perioperative mortality for
high-risk surgery (Fig. 14.1).
Although prophylactic strategies aimed at avoiding complica4
tions in the first place have obvious appeal, rescuing patients
once a complication has occurred may be even more critical in
reducing mortality. In a large study of Medicare patients by Silber et al., hospital mortality with specific procedures seemed to
be primarily related to failure to rescue (the likelihood of mortality given a complication), and only weakly correlated with
complication rates.20 We conducted a similar analysis based on
data from the American College of Surgeons National Surgical
Quality Improvement Program. Participating hospitals were
ranked and sorted according to their risk-adjusted mortality
rates. Hospitals in the best quintile had mortality rates of only
2.2%, versus 7.2% in the highest-mortality quintile. As seen in
Figure 14.2, high-mortality hospitals had only slightly higher
overall complication rates (odds ratio 1.2, p 0.001) than lowmortality hospitals. However, their failure-to-rescue rates were
markedly higher (odds ratio 3.2, p 0.001).
Patients(%)
SCIENTIFIC PRINCIPLES
100
90
289
290
SUMMARY
Selective referral, process compliance, and outcomes measurement reflect different philosophies on how best to improve sur6 gical quality and have distinct advantages and disadvantages.
The optimal strategy may depend on political realities, the
clinical context (e.g., which procedure), and which outcomes
stakeholders hope to improve.9 As currently configured, selective referral strategies may be best applied to relatively uncommon procedures for which outcomes vary dramatically across
hospitals and surgeons (e.g., esophagectomy, pancreatic resection). Process compliance strategies are currently focusing on
low-hanging fruitimproving adherence to a small number
of evidence-based practices in perioperative care. They may
not be effective in reducing surgical mortality, but they may
ultimately prove successful to reducing adverse events important to patients (e.g., surgical site infection). Finally, outcomes
measurement effortsthe major thrust of professional organizationsare likely to improve outcomes to the extent that
they can capitalize on the surgical Hawthorne effect. In addition to spurring quality improvement at the local level, these
efforts may ultimately provide a platform for public reporting
and provider accountability in surgery.
Each of the three strategies would benefit from advances in
quality measurement and improvement. Selective referral could
be improved by measures that more reliably capture
performance for individual hospitals and surgeons. Optimal
measures would not only describe past performance, but also
forecast future outcomes for patients and payers trying to identify the best hospitals and surgeons for specific procedures. As
described elsewhere, individual measures of structure (including procedure volume), process of care, and outcomes have
major limitations in reflecting provider-specific quality.26 Composite quality measures, which empirically combine information from several quality domains, appear very promising and
may soon become the standard in selective referral.27,28 Simple
composites combining procedure volume and operative mortality have already been adopted by the Leapfrog Group.
Effective process compliance strategies await higher-leverage
processes of care on which to base them. A better understanding of mechanisms underlying variation in surgical mortality
and other important outcomes is essential for identifying such
practices. For example, which types of clinical events and complications account for differences in mortality across hospitals?
Which specific processes of care and organizational factors
explain different rates of these clinical events? Previous research
provides only preliminary answers to these basic questions.
High-leverage processes of care may ultimately prove harder to
codify than the perioperative processes that SCIP and payers
are now focusing upon, and may involve those related to preoperative decision making (e.g., which patients to operate on in
the first place) and surgeon proficiency in the operating room.
To fully realize their potential, outcomes measurement
strategies need a more potent effecter arm. Performance
feedback may be the essential first step, but hospitals and surgeons need more guidance on what they can do to improve.
As described earlier, a better understanding of mechanisms
underlying variation and suboptimal outcomes will be crucial
in this regard. In the meantime, professional organizations
should develop better systems for developing and disseminating practice guidelines, providing expert-based consultative
services to underperforming providers, and educating surgeons about the principles of continuous quality improvement.
Regardless of the underlying improvement strategy, payers
and professional organizations should ensure that surgical quality is not defined too narrowly. At the present time, each is focusing almost exclusively on measures of technical quality around the
surgical episode. However, a large body of evidence suggests that
the use of surgery varies even more widely across providers
than do the outcomes of surgery. Despite the practical and methodologic challenges involved, policy approaches to improving
References
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a Safer Health System. Washington, DC: National Academy Press; 1999.
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surgical adverse events in Colorado and Utah in 1992. Surgery 1999;
126(1):6675.
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5. OConnor GT, Plume SK, Olmstead EM, et al. A regional prospective
study of in-hospital mortality associated with coronary artery bypass
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6. Dudley RA, Johansen KL, Brand R, et al. Selective referral to high volume
hospitals: estimating potentially avoidable deaths. JAMA 2000;283:
11591166.
7. Halm EA, Lee C, Chassin MR. Is volume related to outcome in health
care? A systematic review and methodologic critique of the literature. Ann
Intern Med 2002;137:511520.
8. Houghton A. Variation in outcome of surgical procedures. Br J Surg
1994;81:653660.
9. Birkmeyer NJ, Birkmeyer JD. Strategies for improving surgical quality
should payers reward excellence or effort? N Engl J Med 2006;354(8):
864870.
10. Fink A, Campbell DJ, Mentzer RJ, et al. The National Surgical Quality
Improvement Program in non-Veterans Administration hospitals: initial
demonstration of feasibility. Ann Surg 2002;236:344353.
11. Rowell KS, Turrentine FE, Hutter MM, et al. Use of national surgical quality improvement program data as a catalyst for quality improvement. J Am
Coll Surg 2007;204:12931300.
12. The Leapfrog Group. The Leapfrog Group fact sheet. Available at:
http://www.leapfroggroup.org/about_us/leapfrog-factsheet. Accessed
December 1, 2008.
13. Birkmeyer JD, Dimick JB, Staiger DO. Operative mortality and procedure
volume as predictors of future hospital performance. Ann Surg 2006;243:
411417.
14. Krumholz HM, Rathore SS, Chen J, et al. Evaluation of a consumeroriented internet health care report card: the risk of quality ratings based
on mortality data. JAMA 2002;287(10):12771287.
15. Gold JA, Gold JA. The surgical care improvement project. Wis Med J
2005;104(1):7374.
16. Rosenthal MB, Dudley RA. Pay-for-performance: will the latest payment
trend improve care? JAMA 2007;297(7):740744.
17. Rosenthal MB, Frank RG, Li Z, et al. Early experience with pay-forperformance: from concept to practice [see comment]. JAMA 2005;294(14):
17881793.
18. Wong SL, Ji H, Hollenbeck BK, et al. Hospital lymph node examination
rates and survival after resection for colon cancer [see comment]. JAMA
2007;298(18):21492154.
19. Hawn MT, Itani KM, Gray SH, et al. Association of timely administration of prophylactic antibiotics for major surgical procedures and surgical site infection. J Am Coll Surg 2008;206(5):814819; discussion
921.
20. Silber JH, Rosenbaum PR, Williams SV, et al. The relationship between
choice of outcome measure and hospital rank in general surgical procedures: implications for quality assessment. Int J Qual Health Care 1997;9(3):
193200.
21. Shahian DM, Edwards FH, Ferraris VA, et al. Quality measurement in
adult cardiac surgery: part 1conceptual framework and measure selection. Ann Thorac Surg 2007;83(suppl 4):S3S12.
22. Khuri SF, Daley J, Henderson W, et al. Risk adjustment of the postoperative mortality rate for the comparative assessment of the quality of surgical care: results of the National Veterans Affairs Surgical Risk Study. J Am
Coll Surg 1997;185:315327.
23. Birkmeyer JD, Shahian DM, Dimick JB, et al. Blueprint for a new American
College of Surgeons: National Surgical Quality Improvement Program. J
Am Coll Surg 2008;207:777782.
24. OConnor GT, Plume SK, Morton JR, et al. Results of a regional prospective study to improve the in-hospital mortality associated with coronary
artery bypass grafting. JAMA 1996;275:841846.
25. Dimick JB, Welch HG, Birkmeyer JD. Surgical mortality as an indicator of
hospital quality: the problem with small sample size. JAMA 2004;292(7):
847851.
26. Birkmeyer JD, Birkmeyer NJ, Dimick JB. Measuring the quality of surgical
care: structure, process, or outcomes? J Am Coll Surg 2004;198:626632.
27. OBrien SM, Shahian DM, DeLong ER, et al. Quality measurement in
adult cardiac surgery: part 2statistical considerations in composite measure scoring and provider rating. Ann Thorac Surg 2007;83:S13S26.
28. Staiger DO, Dimick JB, Baser O, et al. Empirically derived composite measures of surgical performance. Med Care 2009;47:226233.
K E Y
1
P O I N T S
6
10
and composites. The chapter then closes with recommendaWith growing recognition that the quality of surgical care
tions for selecting the right measure and a description of
varies widely, good measures of performance are in high
emerging techniques that address some of the limitations of
demand. Patients and their families need accurate information
existing quality measures.
to help them choose the safest hospitals for surgery.1 Employers and payers need reliable measures for their value-based
purchasing programs.2 Motivated in part by these external
OVERVIEW OF
pressures, clinical leaders need better measures to guide their
quality improvement efforts.3
CURRENT MEASURES
Despite a broadening array of measures, there remains con4,5
siderable uncertainty about which measures are most useful.
An ever-broadening array of performance measures has been
Current measures are remarkably heterogeneous, encompass- 1 developed for assessing surgical quality. Over the past few
years, the National Quality Forum (NQF) has emerged as the
ing different elements of health care structure, process, and
leading organization endorsing quality measures. Table 15.2
outcomes. With the proliferation of value-based purchasing,
includes surgical quality measures endorsed by the NQF.
which requires a global assessment of quality, there has been a
Many other organizations, including the Joint Commission
rapid growth in the use of composite measures.6 Although
and the Centers for Medicare and Medicaid Services (CMS),
each of these types of performance measures has strengths,
rely on endorsement by the NQF before applying a measure to
each is also associated with conceptual, methodologic, and/or
practice. The number of measures relevant to surgery endorsed
practical problems (Table 15.1).
by the NQF has grown rapidly. Many of these new measures
This chapter provides an overview of existing quality indiare part of CMSs Surgical Care Improvement Program (SCIP),
cators followed by a review of the main strengths and limitawhich includes process measures related to prevention of
tions of each type of measure: structure, process, outcomes,
291
SCIENTIFIC PRINCIPLES
OF SURGICAL CARE
292
TA B L E 1 5 . 1
EXAMPLES, STRENGTHS, AND LIMITATIONS OF DIFFERENT APPROACHES TO MEASURING SURGICAL PERFORMANCE
Structure
Process
EXAMPLE
STRENGTHS
LIMITATIONS
Strong relationship to
important outcomes
Outcome
Risk-adjusted mortality
Risk-adjusted morbidity
TA B L E 1 5 . 2
OVERVIEW OF CLINICAL PERFORMANCE MEASURES RELEVANT TO SURGERY THAT HAVE
BEEN ENDORSED BY THE NATIONAL QUALITY FORUM (NQF) AS OF AUGUST 2007
DIAGNOSIS OR PROCEDURE
PERFORMANCE MEASURE
293
TA B L E 1 5 . 3
OVERVIEW OF PERFORMANCE MEASURES CURRENTLY USED FOR SURGERY
DEVELOPER/
ENDORSER
PERFORMANCE MEASURE
LF
Hospital volume
AHRQ, LF
AHRQ
LF
Carotid endarterectomy
Hospital volume
AHRQ
Hospital volume
AHRQ
Pancreatic resection
Hospital volume
AHRQ, LF
AHRQ
Hospital volume
AHRQ
AHRQ
AHRQ
Craniotomy
AHRQ
Cholecystectomy
Laparoscopic approach
AHRQ
Appendectomy
AHRQ
AHRQ, Agency for Healthcare Research and Quality; LF, Leapfrog Group.
Structure
Health care structure refers to fixed attributes of the system in
which patients receive care. Many structural measures describe
hospital-level attributes, such as the resources or staff coordination and organization (e.g., nurse-to-patient ratios, hospital
teaching status). Other structural measures reflect attributes of
individual physicians (e.g., subspecialty board certification,
procedure volume).
Process of Care
Process of care measures are the clinical details of care provided to patients. Although long the predominant quality indicators for medical care, their popularity in surgery is growing
rapidly. Perhaps the best example of the trend toward using
SCIENTIFIC PRINCIPLES
DIAGNOSIS OR
PROCEDURE
294
6.0
5.0
4.0
4.1
4.0
3.4
3.4
3.2
3.0
3.0
2.7
2.9
2.0
1.0
0.0
Hospital volume
Risk-adjusted mortality
A
Pancreatic cancer resection
for acute myocardial infarction explained only 6% of the observed variation in risk-adjusted mortality for acute myocardial infarction.12
Although few analogous studies have been done in surgery,
there are some reasons to believe that existing process measures
explain very little of the variation in important surgical outcomes. First, most process measures currently used in surgery
relate to secondary outcomes. While none would dismiss the
value of prophylactic antibiotics in reducing risks of superficial
wound infection, this process is not related to the most important adverse events of major surgery, including death.
Second, process measures in surgery often relate to complications that are very rare. For example, there is consensus that
venous thromboembolism prophylaxis is necessary and important. The SCIP measures, endorsed by the NQF, include the use
of appropriate venous thrombosis prophylaxis. However, pulmonary embolism is very uncommon, and improving adherence to these processes will therefore not avert many deaths.
Until we understand which processes of care account for those
adverse events leading to death, process measures will have
limited usefulness in surgical quality measurement.4,1113
15.0
13.0
11.0
Outcomes
11.0
9.5
9.0
7.9
7.1
7.0
5.0
3.0
4.5
4.4
3.0
2.2
1.0
1.0
Hospital volume
Risk-adjusted mortality
B
FIGURE 15.1. Ability of hospital rankings based on 20032004 mortality rates and hospital volume to predict risk-adjusted mortality in
20052006. Data shown for abdominal aortic aneurysm repair (A)
and pancreatic cancer resection (B). Source: National Medicare data.
295
FIGURE 15.2. Big problems with small samples: the proportion of hospitals in the United
States with sufficient caseloads (sample size) to
reliably use mortality rates to measure quality.
100%
90%
80%
60%
40%
33%
8%
2%
0%
Coronary Craniotomy Pediatric
bypass
heart
surgery
surgery
1%
identifying poor-quality outliers is an important function of outcomes measurement, focusing on this goal alone significantly
underestimates problems with small sample sizes. Discriminating among individual hospitals with intermediate levels of performance is even more difficult.
Another significant limitation of outcomes assessment is
the expense of data collection. Reporting outcomes requires
the costly collection of detailed clinical data for risk adjustment. For example, it costs over $100,000 annually for a private sector hospital to participate in the NSQIP. Because of the
expense of data collection, the American College of Surgeons
(ACSs) NSQIP currently collects data on only a sample of
patients undergoing surgery at each hospital. Although this
sampling strategy decreases the cost of data collection, it exacerbates the problem of small sample size with individual procedures. As discussed in the next chapter, changes in the next
iteration of the NSQIP are aimed at reducing the expense of
data collection without compromising the risk adjustment.
COMPOSITE MEASURES
3
1%
SCIENTIFIC PRINCIPLES
25%
20%
100
Risk-adjusted mortality rates (%)
296
90
80
70
60
50
40
30
20
10
0
Before
adjusting for
reliability
After
adjusting for
reliability
8.2
8.5
7.7 8.0
7.0
6.4
6.3
5.6
6.3
5.2
4
2
0
Hospital volume
Mortality
Composite
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11591166.
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of prophylactic antibiotics for major surgical procedures and surgical site
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Affairs NSQIP: the first national, validated, outcome-based, risk-adjusted,
and peer-controlled program for the measurement and enhancement of the
quality of surgical care. National VA Surgical Quality Improvement Program. Ann Surg 1998;228:491507.
15. Fink AS, Campbell DA Jr, Mentzer RM Jr, et al. The National Surgical
Quality Improvement Program in non-Veterans Administration hospitals:
initial demonstration of feasibility. Ann Surg 2002;236:344353.
16. Dimick JB, Welch HG, Birkmeyer JD. Surgical mortality as an indicator of
hospital quality: the problem with small sample size. JAMA 2004;292:
847851.
17. OBrien SM, Shahian DM, DeLong ER, et al. Quality measurement in adult
cardiac surgery: part 2statistical considerations in composite measure
scoring and provider rating. Ann Thorac Surg 2007;83(suppl 4):S13S26.
18. AHRQ Inpatient Quality Indicators Composite Measure. Draft technical
report. Available at: http://qualityindicators.ahrq.gov/news/AHRQ_IQI_
Composite_Draft.pdf. Accessed June 27, 2007.
19. Staiger DO, Dimick JB, Baser O, et al. Empirically derived composite measures of surgical performance. Med Care 2009;47(2):226233.
20. Hofer TP, Hayward RA, Greenfield S, et al. The unreliability of individual
physician report cards for assessing the costs and quality of care of a
chronic disease. JAMA 1999;281:20982105.
21. Zaslavsky AM, Beaulieu ND, Landon BE, et al. Dimensions of consumerassessed quality of Medicare managed-care health plans. Med Care 2000;
38:162174.
22. Adult Coronary Artery Bypass Graft Surgery in the Commonwealth of
Massachusetts. Fiscal Year 2006 Report, October 1, 2005September 30,
2006. Available at: http://www.massdac.org/reports/CS%20FY2006.pdf.
Accessed June 17, 2010.
23. Casparie AF. The ambiguous relationship between practice variation and
appropriateness of care: an agenda for further research. Health Policy 1996;
35:247265.
24. Bynum JP, Bernal-Delgado E, Gottlieb D, et al. Assigning ambulatory patients
and their physicians to hospitals: a method for obtaining population-based
provider performance measurements. Health Serv Res 2007;42:4562.
25. Fisher ES, Staiger DO, Bynum JP, et al. Creating accountable care organizations: the extended hospital medical staff. Health Aff (Millwood) 2007;
26:w44w57.
SCIENTIFIC PRINCIPLES
% Mortality (2002-03)
10
297
K E Y
P O I N T S
IMPORTANT DEFINITIONS:
SAFETY VERSUS QUALITY
month. Imagine the public outcry this would produce, the laws
that would be quickly passed, and the boon to train travel that
would result. But this is not what has happened in medicine.
The government response has been weak at best, and the medical community has been slow to acknowledge, and even
slower to respond, to the safety imperative.
THE PROBLEM
By now, all are familiar with the report issued by the Institute
of Medicine (IOM) in 2000 entitled To Err Is Human.1 The
report was an exhaustive review of the status of safety in our
nations hospitals. The bottom linewhich served as a burning platform for the patient safety movementwas the
astonishing calculation that between 44,000 and 98,000
Americans died annually in hospitals as the result of preventable medical error. The report produced a flurry of outrage from consumer groups and denials and refutations from
medical groups, but when the dust settled, what was left was
the recognition, by all groups, that something was seriously
wrong in our medical care delivery system.
Comparisons are often made between the safety of airline
travel and medical care. One airline disaster every 2 or 3 years
produces calls for new regulation, better airports, more frequent mechanical checks, and earlier retirement for pilots. But
consider medical care. If even the lower number of preventable
deaths extrapolated by the IOM report (44,000 annually) were
seen as accurate, and one accepted that an average of 350 passengers were on board every major commercial aircraft flight,
deaths from medical error would be equivalent of 63 separate
midair collisions per year in the airline industry, or five per
298
CULTURE
Culture is defined as how we do things around here. That is,
there is a certain level of acceptance for what goes on in a
given hospital. That acceptance is based on two precepts,
which in the past have not been challenged. One precept is that
medical errors exist because humans will always make mistakes. While superficially true, this statement fails to
acknowledge that modern human factors engineering strategies can militate against commonly encountered errors. A concrete example of how human factors engineering can be
brought into play involves something as simple as a connector
for medical tubing. If the connector is designed such that it is
not possible to connect an O2 line to a CO2 valve, a potentially
catastrophic mistake becomes impossible. More globally,
work hour restrictions for medical trainees, which reduce
fatigue, could be expected to result in fewer errors by
exhausted and stressed doctors. To date, human factors engineering has not been brought into the delivery of medical care
effectively. While humans will always be capable of making
mistakes, the number of mistakes will be reduced if design is
targeted to what we know about human fallibilities.
The second precept accounting for complacency is the
notion that a medical error is the result of poor individual performance rather than an imperfect system of care. If an individual made the error, in isolation, the only thing to do about
it would be to fire the hapless caregiver, or immerse him or her
in intensive remedial education. The problem with this
approach is that it doesnt apply to the next hapless caregiver
faced with the same situation. And so, since there is a high
turnover in most medical environments, mistakes continue to
happen, caregivers continue to be fired, and nothing really
changes. This sequence has been ingrained in the medical culture, and is why the medical community has been slow to
respond to the safety crisis.
299
Systems Failures
SCIENTIFIC PRINCIPLES
Error
300
18,000
All events
Temporary harm
Permanent harm
16,000
15,680
14,108
14,000
12,000
11,005
10,000
8,000
6,706
6,000
3,511
4,000
2,000
3,455
4,668
3,891
3,189
0
1999
44
2000
2001
2002
2003
417
2004
1,381
788
66
2005
76
2006
1,880
128
2007
Calendar Year
Voluntary reporting includes near-misses as well as events that result in patient harm
Increased reporting with low rate of permanent harm events is desired
Goal enhance patient safety and improve quality of care; events mutually exclusive
both the short and long term. The long-term solution is an electronic one; the short-term solution is a paper-based handoff
tool. This effort was a direct result of information gained from
the safety culture survey.
A second way we use the safety culture survey data is to
identify specific hospital units that are struggling with a dispirited or complacent attitude toward the safety effort. Such problems often result from poor nurse leadership, disruptive physicians, or a lack of perceived resources. Armed with information
about the safety culture (or lack of it), the institution can implement a focused strategy customized to the problem. Figure 16.3
shows results from our survey arranged by individual nursing
unit, demonstrating certain units in need of help with error
reporting and, conversely, units where the culture is good and
institutional resources are not needed. A third source of information derived from the survey comes from narrative comments entered by individual caregivers. This is a very rich
source of information and, since it is anonymous, often draws
a fine line under issues that are hard to talk about in any other
forum. Issues of suspected physician impairment, abusive
behavior, or lack of leadership skills are sometimes identified.
Two important questions regarding safety culture and our
efforts to improve it remain. First, using the AHRQ tool, have
we seen an aggregate improvement over the past two survey
intervals? Many safety initiatives have been instituted over this
period of time, and yet the aggregate culture data havent shown
much change. We interpret this information to mean that much
more work needs to be done, and that changing a culture is a
hard thing to do, akin to changing direction of an aircraft carrier. Also, over the period of time we have been studying our
culture, our institutional activity has gone up dramatically, the
complexity of our patients has increased, and nursing turnover
has been high. Under these circumstances, no change in the
safety culture data might be viewed more optimistically.
A second question is, Are there individual strategies we
have used that influence the safety culture positively? If so, we
could use these strategies more broadly. The answer to this
question is yes. Patient safety rounds have been an important
strategy that has improved the safety culture. Over the course
301
70%
60%
56% 57%
50%
45%
40%
33%
39%
49%
65%
53%
41%
29% 30%
30%
20%
36%
48%
60%
25%
17% 17%
19%
10%
0%
77%
70%
67%
58%
60%
50%
50%
40%
40%
35%
30%
20%
10%
0%
Organizational
Learning/Quality
Improvement
Feedback and
Communication
About Error
Nonpunitive
Response
to Error
SCIENTIFIC PRINCIPLES
80%
80%
302
80
60
40
20
No BSI 31%
No BSI 44%
DEVELOPING CONSENSUS
The NQF works closely with the Joint Commission. When the
NQF has reached consensus on a specific safety practice, this is
often translated into a Joint Commission requirement for hospital accreditation, in this setting recognized as Joint Commission patient safety goals. These goals are more specific than
consensus guidelines and have more bite to them, in that all
hospitals need to fulfill these requirements in order to be
TA B L E 1 6 . 2
UNIVERSITY OF MICHIGAN PROTOCOL FOR PREVENTION
OF VENTILATOR-ACQUIRED PNEUMONIA (VAP)
Hand washing/hand sanitizing
Chlorhexidine oral rinse prior to intubation, then q12h on
09002100 schedule
Oral care with swabs q23h
Head of bed elevated 3045 degrees on all patients at all
times, unless medically contraindicated
Extubate earlyas soon as safely possible
Turn off tube feedings when placing patients flat for
turning or for procedures, unless small-bore feeding tube
postpyloric
Endotracheal tube tape changed every 48 h
Minimal use of saline lavage
Change ventilator tubing only when soiled
Staff education and updates on VAP
10.00
8.00
6.00
4.00
2.00
0.00
8
-0
ay
M 8
-0
ar
M
08
nJa 7
-0
ov
N 7
0
pSe
7
l-0
Ju 7
-0
ay
M 7
-0
ar
M
07
nJa 6
-0
ov
N 6
0
pSe
6
l-0
Ju 6
-0
ay
M 6
-0
ar
M
06
nJa
Month/Year
TA B L E 1 6 . 3
NATIONAL QUALITY FORUM SAFE PRACTICES
TA B L E 1 6 . 4
SURGICAL CARE IMPROVEMENT PROGRAM (SCIP) PROCESS
AND OUTCOME MEASURES
Infection (INF)
SCIP INF 1: Prophylactic antibiotic received within 1 h
prior to surgical incision
SCIP INF 2: Prophylactic antibiotic selection for surgical
patients
SCIP INF 3: Prophylactic antibiotics discontinued within
24 h after surgery end time (48 h for cardiac patients)
SCIP INF 4: Cardiac surgery patients with controlled
6 a.m. postoperative blood glucose
SCIP INF 6: Surgery patients with appropriate hair
removal.
SCIP INF 7: Colorectal surgery patients with immediate
postoperative normothermia
Venous Thromboembolism (VTE)
SCIP VTE 1: Surgery patients with recommended venous
thromboembolism prophylaxis ordered
SCIP VTE 2: Surgery patients who received appropriate
venous thromboembolism prophylaxis without 24 h prior
to surgery to 24 h after surgery
SCIENTIFIC PRINCIPLES
303
304
TA B L E 1 6 . 5
AGENCY FOR HEALTHCARE RESEARCH AND QUALITY
PATIENT SAFETY INDICATORS
1. Hospital-level patient safety indicators
Complications of anesthesia
Death in low-mortality DRGs
Decubitus ulcer
Failure to rescue
Foreign body left in during procedure
Iatrogenic pneumothorax
Selected infections due to medical care
Postoperative hip fracture
Postoperative hemorrhage or hematoma
Postoperative physiologic and metabolic derangements
Postoperative respiratory failure
Postoperative pulmonary embolism or deep vein
thrombosis
Postoperative sepsis
Postoperative wound dehiscence in abdominopelvic
surgical patients
Accidental puncture and laceration
Transfusion reaction
Birth traumainjury to neonate
Obstetric traumavaginal delivery with instrument
Obstetric traumavaginal delivery without instrument
Obstetric traumacesarean delivery
IMPLEMENTATION STRATEGIES
Establishing a safe culture is important, and emphasizing an evidence base and consensus guidelines is important, but ensuring
implementation of what is known to be safe practice is critical
and may be the most difficult of all safety strategies to accomplish. Several strategies have been helpful in our environment.
305
TA B L E 1 6 . 6
BEFORE INDUCTION
OF ANESTHESIA
SIGN IN
TIME OUT
SIGN OUT
mandatory for nursing; no judgment is required. If the parameters are exceeded, the RRT is activated. This relieves some of the
anxieties experienced by nurses in the past about communication
with physicians, particularly at odd hours. In our center, activation of the RRT results in the timely arrival of an experienced
surgical intensive care unit nurse and a respiratory therapist. If
the conditions are found to warrant it, a hospitalist is called. This
occurs in 15% of cases. There is controversy in the literature as
to whether the RRT effort actually is effective.11 However, the
concept has so much face validity that most hospitals have
accepted it as an important strategy to improve a safety culture.
An interesting, and entirely unexpected, offshoot of the
RRT has been the process, by the RRT team, of visiting nursing floors on a shift-by-shift basis prior to any RRT activation.
This process lets the team become more familiar with patients
who might subsequently warrant RRT activation. Visits often
foster a discussion among caregivers and family as to whether
any intervention is appropriate or warranted.
Developing Collaborative
Groups of Hospitals
Under conditions where motivated hospitals get together to
discuss safety, the result is often a more consistent implementation of safety practices and better results. The development
of a collaborative group directed at safety and/or quality
allows for comparative evaluation of quality and safety, and
often results in a spirit of friendly competition, which
improves the aggregate level of safety.
A prominent example of such collaboration was mentioned
previously, the Michigan Hospital Associationsponsored
Keystone Initiative. Here, evidence-based practice for the care
of patients in the ICU was monitored and found to be low
across the state. A protocol was adopted for over 100 ICU
groups, which included elevation of the head of the bed 30
degrees, ulcer prophylaxis, regular respiratory weaning trials,
and a central line insertion protocol, with line maintenance
involving chlorhexidine patches. When the latter protocol was
implemented, a profound drop in the incidence of bloodstream
infections across the state was seen, and the estimated cost savings exceeded $160 million.6
In a different example, 34 Michigan hospitals formed the
Michigan Surgical Quality Collaborative. These hospitals,
SCIENTIFIC PRINCIPLES
306
DEVELOPING A TAXONOMY
FOR PATIENT SAFETY
Ultimately, comparative data on the safety of patient care in this
country will be available to the public, much in the same way
that the safety of retail products, medications, and automobiles
is currently reported. For any reporting system to be valuable
and fair, the definitions of safety events need to be refined and
agreed upon. It is not possible to compare the safety of different
hospitals if definitions used are not standardized. Many
national organizations are working on this topic. The WHO has
recently developed an International Classification for Patient
Safety designed to define, harmonize and group patient
safety concepts into an internationally agreed upon classification in a way that is conducive to learning and improve patient
PART TWO
SURGICAL PRACTICE
SECTION A
TRAUMA
GENERAL CONSIDERATIONS
RONALD V. MAIER
Injury is an epidemic in America, killing 150,000 and hospitalizing 3.0 million while costing more than $250 billion per year. Trauma is the leading cause of death to age
45 years, the fourth leading cause of death overall, and
the leading contributor to years of potential life lost before
age 65 overall. The major causes of injury-related death, in
decreasing order, are motor vehicle crashes, penetrating
trauma, falls, and burns.
2 Trauma deaths occur at three time periods following
injury, each having a unique pattern and etiology: 50% at
the scene, 30% within the golden hour or acute resuscitation phase, and 20% delayed from several days to several
weeks after injury.
3 Modern trauma care is derived from the care of wounds
and casualty management developed during major wars,
and trauma systems are based on military experiences of
improved survival in injured personnel produced by rapid
transport to definitive care.
4 Trauma systems require a lead agency with designating
authority, a formal verification process utilizing American
1
EPIDEMIOLOGY
Injury has been a frequent cause of death in the United States
since accurate statistics were first collected in the middle of the
19th century. With decreases in infectious diseases and the
industrialization of society, injury has become a leading public
health concern, which shows little sign of abating (Table 17.1).
1 In the United States, more than 3 million people are hospitalized annually as a result of unintentional injury, and approximately 35 to 40 million emergency department visits occur
for the evaluation and treatment of injuries.1 According to the
most recent Centers for Disease Control and Prevention
National Center for Injury Prevention and Control (CDCNCIPC) statistics, 163,750 deaths resulted from injury in the
United States in 2006 (Fig. 17.1).2 Unintentional injuries
account for about three fourths of these deaths (121,599 in
2006), and nearly one half of these were caused by motor
vehicle crashes (MVCs), including occupant, pedestrian, and
motorcyclist. Falls, occurring primarily among the elderly, are
the second major cause of death from unintentional injuries. In
2002, there were 3,482 unintentional drownings and 14,050
burn injuries, with 2,670 deaths. Intentional injuries are
responsible for just over 40,000 deaths per year, of which 66%
are suicides and 34% homicides. Firearms account for 60% of
all suicides and 72% of all homicides.3 Injury causes not only
mortality but also significant morbidity. Each year, 37 million
people are treated in emergency departments for injury and
approximately 10% will require hospitalization.2 It is estimated that the direct costs associated with fatal and nonfatal
injuries total over $60 billion per year.3 However, the overall
impact of injury on society exceeds $250 billion per year due
P O I N T S
College of Surgeons or similar standards, a limit on the
number of centers based on patient needs, and triage criteria
to deliver the right patient to the right hospital at the right
time. The impediments of distance, discovery, training, and
maintenance of expertise make rural trauma care a remaining major challenge.
5 Scoring systems allow objective quantification of the injury
to assess impact on outcome and to track differences in
outcome, both serially within an institution and between
institutions and regional systems.
6 Traumatic injury results in deformation and structural
damage of tissue dependent on the kinetic energy transferred to the host, which, in turn, is dependent on the mass
and, to a much greater extent, the velocity of the injuring
force. Varying mechanisms of injury produce predictable
patterns of damage.
7 The interdisciplinary science of injury control requires a
team approach that involves surgical and medical specialists, epidemiologists, statisticians, biomechanical engineers,
public health practitioners, and economists.
309
TRAUMA
K E Y
310
TA B L E 1 7 . 1
SIGNIFICANT HISTORICAL DEVELOPMENTS RELATED TO TRAUMA CARE
PERIOD OR PERSON
CONTRIBUTION
Greek medicine
Roman Empire
Civil War
World War I
Principle of dbridement and delayed closure for wounds more than 8 h old
Established primary closure for wounds 8 h old only
Field ambulance mechanized with automobile availability
Recognition that shock was due to blood or fluid loss and use of seawater to replace
blood volume
World War II
Korean War
Vietnam War
More damage control operations, flying critical care air transport (CCAT)
Optimal utilization of blood components: ratio of red blood cells to fresh frozen
plasma to cryoprecipitate
The impact of injury in children younger than 15 is also significant. The leading causes of injury in this group are MVCs,
burns, drowning, falls, and poisoning. Injury in this age group
leads to a significant number of deaths, disabilities, days of
missed school, medical costs, and missed workdays for parents. Adolescents are also at increased risk for injury. In fact,
more adolescents die from injuries than from all other diseases
combined (Fig. 17.1).8 Of all deaths in this age group, 40% are
caused by intentional injuries, such as homicide and suicide.9
Considering only adolescents 15 to 19 years of age, one fourth
of the deaths are caused by firearms.10
Alcohol ingestion is a major cause of fatal vehicular crashes.
Although significant progress has been made in the prevention
of drinking and driving, 32% of all traffic fatalities in 2007
were still alcohol related.11 More importantly, 60% of the time
that a child passenger dies in a car crash, the driver was intoxicated.11 In addition, other commonly abused drugs, such as
marijuana and cocaine, have been implicated in 18% of MVCrelated fatalities.12 Thus, those who participate in injury
research and prevention must take into account both the unique
characteristics of the specific target population and other important epidemiologic factors such as alcohol and drug use.
Although its position as the leading killer of young people
has not changed, the overall mortality rate of trauma has gradually decreased during the past two decades. Prevention efforts
311
Rank
<1
1-4
5-9
10-14
15-24
25-34
35-44
45-54
55-64
65+
All Ages
Congental
Anomalies
5,819
Unintentional
Injury
1,610
Unintentional
Injury
1,044
Unintentional
Injury
1,214
Unintentional
Injury
16,229
Unintentional
Injury
14,954
Unintentional
Injury
17,534
Malignant
Neoplasms
50,334
Malignant
Neoplasms
101,454
Heart
Disease
510,542
Heart
Disease
631,636
Short
Gestation
4,841
Congenital
Anomalies
515
Malignant
Neoplasms
459
Malignant
Neoplasms
448
Homicide
5,717
Suicide
4,985
Malignant
Neoplasms
13,917
Heart
Disease
38,095
Heart
Disease
65,477
Malignant
Neoplasms
387,515
Malignant
Neoplasms
559,888
SIDS
2,323
Malignant
Neoplasms
377
Congenital
Anomlies
182
Homicide
241
Suicide
4,189
Homicide
4,725
Heart
Disease
12,339
Unintentional
Injury
19,675
Chronic Low.
Respiratory
Disease
12,375
Cerebrovascular
117,010
Cerebrovascular
137,119
Maternal
Pregnancy
Comp.
1,683
Homicide
366
Homicide
149
Suicide
216
Malignant
Neoplasms
1,644
Malignant
Neoplasms
3,656
Suicide
6,591
Liver
Disease
7,712
Unintentional
Injury
11,446
Chronic Low.
Respiratory
Disease
106,845
Chronic Low.
Respiratory
Disease
124,583
Unintentional
Injury
1,147
Heart
Disease
161
Heart
Disease
90
Heart
Disease
163
Heart
Disease
1,076
Heart
Disease
3,307
HIV
4,010
Suicide
7,426
Diabetes
Mellitus
11,432
Alzheimers
Disease
71,660
Unintentional
Injury
121,599
Placenta
Cord
Membranes
1,140
Influenza &
Pneumonia
125
Chronic Low.
Respiratory
Disease
52
Congenital
Anomlies
162
Congenital
Anomlies
460
HIV
1,182
Homicide
3,020
Cerebrovascular
6,341
Cerebrovascular
10,518
Diabetes
Mellitus
52,351
Diabetes
Mellitus
72,449
Respiratory
Distress
825
Septicemia
88
Cerebrovascular
45
Chronic Low.
Respiratory
Disease
63
Cerebrovascular
210
Diabetes
Mellitus
673
Liver
Disease
2,551
Diabetes
Mellitus
5,692
Liver
Disease
7,217
Influenza &
Pneumonia
49,346
Alzheimers
Disease
72,432
Bacterial
Sepsis
807
Perinatal
Period
65
Influenza &
Pneumonia
40
Cerebrovascular
50
HIV
206
Cerebrovascular
527
Cerebrovascular
2,221
HIV
4,377
Suicide
4,583
Nephritis
37,377
Influenza &
Pneumonia
56,326
Neonatal
Hemorrhage
618
Benign
Neoplasms
60
Septicemia
40
Septicemia
44
Influenza &
Pneumonia
184
Congenital
Anomlies
437
Diabetes
Mellitus
2,094
Chronic Low.
Respiratory
Disease
3,924
Nephritis
4,368
Unintentional
Injury
36,689
Nephritis
45,344
10
Circulatory
System
Disease
543
Cerebrovascular
54
Benign
Neoplasms
38
Benign
Neoplasms
38
Complicated
Pregnancy
179
Influenza &
Pneumonia
335
Septicemia
870
Viral
Hepatitis
2,911
Septicemia
4,032
Septicemia
26,201
Septicemia
34,234
FIGURE 17.1. Ten leading causes of death, United States, 2006, all races, both sexes. (Data from the National Center for Injury Prevention and Control Department within the Centers for Disease Control and Prevention. 10 Leading Causes of Death, United States, 2006, All
Races, Both Sexes. http://webapp.cdc.gov/sasweb/ncipc/leadcaus10.html.)
TRAUMA
Age Groups
312
MILITARY HERITAGE
AND DEVELOPMENT
OF TRAUMA SYSTEMS
3
313
TRAUMA
314
TA B L E 1 7 . 2
TRAUMA CENTER DESIGNATION LEVELS IN THE UNITED STATES
TRAUMA
CENTER LEVELS
ESTIMATED
NUMBER
DESCRIPTION
Typically located in large urban environments, major cities. Provides full spectrum of
trauma care 24 h/d with 24-h availability of in-house surgeon. Acts as a community
leader in trauma research, education, and prevention. Expected to admit 1,200
trauma, 20% of whom are severely injured.
190
263
Must have the capability to manage the initial care of most injured patients. General
surgeon must be promptly available for major resuscitation. Will have transfer
agreements in place to rapidly transfer patients to higher levels of care. Will have
educational programs for physicians, nurses, and allied health care workers.
251
Provides initial evaluation and assessment of injured patients in rural and urban
environments. Requires 24-h coverage by a physician (level 4 only). No specific
requirement for surgeon or availability of specialists. Most injured patients will require
transfer to larger facilities. Will have transfer agreements in place to rapidly transfer
patients to higher levels of care as appropriate.
450
4/5
Data from U.S. Department of Health and Human Services. A 2002 National Assessment of State Trauma System Development. Washington, DC:
Emergency Medical Services Resources and Disaster Readiness for Mass Casualty Events; 2003. Table from Nathens AB, Brunet FP, Maier RV.
Development of trauma systems and effect on outcomes after injury. Lancet 2004;363:17941801, with permission from Elsevier.
be in place to facilitate interfacility transfer from outlying centers. A QA program, both at the hospital level and at the system level, is critical to ensure optimal patient outcomes.
Within a center, these QA programs allow for the evolution of
evidence-based care protocols, whereas at the system level,
they ensure adequate triage and the integrity of the triage and
interfacility transfer process. These and other critical trauma
system components were identified by West et al.29 and then
expanded by Bazzoli et al.30 (Table 17.3)30 Many have advocated that both injury prevention and postacute hospital care
(e.g., rehabilitation) be included under the conceptual umbrella
of the trauma system to better reflect the entire continuum
needed for optimal trauma care.31
TA B L E 1 7 . 3
ESSENTIAL TRAUMA SYSTEM COMPONENTS
Presence of a lead agency with legal authority to designate
trauma centers
Use of a formal process for trauma center designation
Use of American College of Surgeons (or similar) standards
for trauma center verification
Use of an out-of-area survey team for trauma center
designation
A mechanism to limit the number of designated trauma
centers in a community based on community need
Written triage criteria that form the basis for bypassing
nondesignated centers
Presence of ongoing monitoring systems for quality
assurance (e.g., trauma registry)
Statewide availability of trauma centers
From Nathens AB, Brunet FP, Maier RV. Development of trauma
systems and effect on outcomes after injury. Lancet 2004;363:
17941801, with permission from Elsevier.
TRAUMA SYSTEM
IMPLEMENTATION AND
EFFECTIVENESS IN THE
UNITED STATES
Progress in the implementation of organized systems of care in
the United States has been difficult and is still limited in many
areas. A major ongoing restraint is that the funding required to
support the design, implementation, and maintenance of a wellintegrated, coordinated regional system of trauma care is lacking. This is paradoxical in the face of the enhanced awareness
and threat of terrorism, which virtually always involves mass
casualties requiring the resources of the trauma care system.
However, despite this chronic relatively limited funding, progress
has been made; 38 states have implemented, or are in the process
of implementing, organized systems of trauma care (Fig. 17.3).32
Several lines of evidence suggest that an organized system of
trauma care reduces mortality from injury. West and Trunkey33
evaluated the preventable death rate caused by trauma in San
Francisco County, California, where a single institution was
responsible for all major trauma care, with the death rate in
Orange County, California, where more than 40 centers managed trauma patients. In San Francisco County, only 1% of
deaths were considered preventable, whereas almost three
quarters of all deaths in Orange Country were potentially salvageable. Subsequently, Orange County implemented a trauma
system and demonstrated an eightfold reduction in the rate of
preventable death as patients were triaged and cared for at designated trauma centers.34 Population-based studies have also
been used to evaluate the benefits of regional trauma centers.
For example, Rutledge et al.35 demonstrated that counties with
designated trauma centers in North Carolina had a 20% reduction in per capita trauma deaths compared with counties without trauma centers, whereas Nathens et al.36 demonstrated that
states with an organized system of trauma care reduced MVCrelated mortality by 10%. These results have been confirmed
by MacKenzie et al. in the only prospective study analyzing
Ranking of states
according to West criteria
Meets less than 3 criteria (4)
Meets 3-6 criteria (25)
Meets all criteria (25)
No authority to designate (12)
FIGURE 17.3. Regional trauma system in the United States as of
2002. States are ranked by the number of trauma system components
implemented in their region. (From U.S. Department of Health and
Human Services. A 2002 National Assessment of State Trauma System
Development, Emergency Medical Services Resources, and Disaster
Readiness for Mass Casualty Events. 2003. From ftp://ftp.hrsa.gov/
hrsa/trauma/nationalassessment.pdf. Accessed November 2004.)
injured patients cared for in level 1 trauma centers versus community hospitals where a 25% reduction in mortality was
shown.23 However, these benefits are not achieved instantaneously, taking as long as a decade following enacting legislation to become manifest.37,38 It is likely that, after formal legislative implementation of the trauma system, a gradual change
in care delivery and the process of quality improvement leads
to better outcomes. Presumably, prehospital protocols improve
such that the patients are more appropriately triaged to centers
with adequate resources, whereas the trauma centers themselves evolve as they begin to commit an appropriate proportion of their resources to trauma and become more experienced
due to increased volumes and thus capable of providing more
optimal care.3941
TRAUMA
315
316
%
%
Popn
Land
82.62% 24.08%
700 miles
an adequate level of experience despite adequate training. Simuniformly consistent across states and within regions. For
ilarly, physicians working in rural environments have limited
example, the availability of trauma centers varies greatly
exposure to the major trauma patient. Together, these data
across states, ranging from 0.9 to 6.6 centers per million popsupport the premise that enhanced training (with subsequent
ulation, and 25% of the land mass of America is not within
maintenance of skills), combined with mandatory time in the
1 hour of a level 1 or 2 trauma center (Fig. 17.4).28,48 In addition,
field, provides the best opportunity for optimal outcomes.
many of the states have not fulfilled many of the key compoGiven these impediments to providing adequate and timely
nents of trauma system design to ensure that populations
trauma care, some rural states have implemented inclusive
within more sparsely populated regions have access to hightrauma systems such that virtually all hospitals are required to
level trauma care (Fig. 17.3); thus, rural access to trauma care
participate as designated trauma centers to the extent that
remains a major challenge in trauma system design.
their resources allow.45 This approach is in contrast to exclusive systems, where most injured patients are transported to
relatively few centers, which may be at great distance. Each
SCORING SYSTEMS AND INJURY
region must decide the appropriate balances of patient needs
AND OUTCOME ASSESSMENTS
and resources available. At a minimum, the structure of an
inclusive system must ensure that the initial receiving hospital 5 Many scoring systems have been developed in an effort to
will have a plan as well as appropriate human material
match injuries and trauma patients to allow comparison
resources in place to provide initial, emergent management of
within and among institutions. Although all provide considerthe severely injured patient. In addition, once patients are
able help, none is perfect. The impetus for injury severity scorassessed by the receiving center, they must be transferred as
ing systems is provided by the need to identify and classify
indicated to higher-level trauma centers for definitive care.
severely injured patients in the prehospital phase, predict morTo facilitate this process, many hospitals (designated as
tality, assess outcome results, and improve communication.
level 3, 4, or 5 trauma centers) have interfacility transfer proOutcome analyses based on these parameters are a major
tocols and agreements with level 1 or level 2 centers to expeobjective of these types of scoring systems.50 These systems
dite the transfer process. In the rural settings, these lower-level
also permit tracking of patient outcomes within an institution
trauma centers play a critical role in initial stabilization and
over time.
46
triage. Although conceptually sound, the efficacy of this
One simple way to classify trauma patients is to place them
approach is unproved. For example, when rural centers were
into three groups according to severity of injury: (a) those
designated in Oregon, evidence showed clearly that the distripatients with injuries that are rapidly fatal, (b) those with
bution of trauma patients within the system changed; however,
injuries that are potentially fatal, and (c) those with injuries
no significant measurable improvements in overall outcome
that are not fatal. The first group includes patients who have
were evident in this limited population of the most severely
exsanguinating injuries, massive head injuries, high cervical
47,48
injured patients.
spinal cord transection, or major airway disruption producing
death in less than 10 minutes. Of traumatic injuries, 5% and
half of all injury-related deaths fall within this category. The
third group, which accounts for 80% of trauma patients,
SUMMARY
includes patients with injuries that are minor or confined to
soft tissue and isolated extremity fractures. Significant risk to
There is clear evidence that trauma system implementation
life is seldom seen in this group and urgent treatment is not
reduces injury-related mortality.23,3436 However, despite
essential. These patients survive without significant disability
increasing trauma system implementation across the United
even if prolonged delays occur before definitive therapy. The
States, approximately one third of major trauma victims are
real impact of improved prehospital care and organized
not cared for at regional trauma centers.49 The reasons for this
trauma systems is on the second category of patients (15% to
are multifactorial; however, it is likely that access is not
317
TA B L E 1 7 . 4
REVISED TRAUMA SCORE COMPONENTS
SYSTOLIC BLOOD
PRESSURE (mm Hg)
RESPIRATORY RATE
(Breaths/Min)
CODED
VALUE
1315
89
1029
912
7689
29
68
5075
69
45
149
15
20% of the total): those who can be saved and morbidity minimized if effective medical care is provided quickly. It is for this
group that trauma systems and scoring have been developed.41
TA B L E 1 7 . 5
ABBREVIATED INJURY SCALE SCORING SYSTEM
FOR ABDOMINAL INJURIES
SCORE
INJURY EXAMPLES
TRAUMA
GLASGOW
COMA SCALE
318
< 14 or
< 90 or
< 10 or > 29
(< 20 in infant < one year)
Yes
No
No
Falls
Adults: > 20 ft. (one story is equal to 10 ft.)
Children: > 10 ft. or 2-3 times the height of the child
High-Risk Auto Crash
Intrusion: > 12 in. occupant site; > 18 in. any site
Ejection (partial or complete) from automobile
Death in same passenger compartment
Vehicle telemetry data consistent with high risk of injury
Auto v. Pedestrian/Bicyclist Thrown, Run Over, or with
Significant (> 20 MPH) Impact
Motorcycle Crash > 20 MPH
Yes
No
Age
Older Adults: Risk of injury death increases after age 55
Children: Should be triaged preferentially to pediatric-capable
trauma centers
Anticoagulation and Bleeding Disorders
Burns
Without other trauma mechanism: Triage to burn facility
With trauma mechanism: Triage to trauma center
Time Sensitive Extremity Injury
End-Stage Renal Disease Requiring Dialysis
Pregnancy > 20 Weeks
EMS Provider Judgment
Yes
No
ALGORITHM 17.1
ALGORITHM 17.1.
BIOMECHANICS OF INJURY
6
319
Energy Transfer
The severity of any injury is directly proportional to the
amount of kinetic energy transferred to the tissues, whether by
a projectile or by blunt impact. Kinetic energy (KE) is a function of the mass (M) of an object and its velocity (V):
KE (M V)/2
Changes in velocity alter the kinetic energy transfer more
significantly than changes in mass. This fact becomes critical
when assessing the extent of damage from high-velocity and
low-velocity gunshot wounds. Likewise, a small child and a
large adult, though significantly different in size and weight,
are subjected to similar levels of energy transfer in a highspeed vehicular collision, the primary determinant being velocity rather than mass.
Cavitation
Cavitation occurs as tissue impacted by a moving body
recoils from the point of impact, away from the object. The
resulting transient tissue cavity can be caused by rapid acceleration or deceleration. Extreme strain occurs at points of
anatomic fixation during the formation of these temporary
cavities. Forces can be produced both along the longitudinal
axis (tensile or compression strain) and across the transverse
axis (shear strain). These types of forces cause deformity,
tearing, and soft tissue failure or fracture. With penetrating
trauma, transfer of kinetic energy from the projectile causes
transient cavitation. A permanent cavity is produced by tissue displacement and destruction. Cavitation is the cause of
tissue damage and loss beyond the immediate course of the
projectile.
TRAUMA
320
TA B L E 1 7 . 6
PREDICTABLE INJURY PATTERNS RESULTING FROM THE
UP-AND-OVER COMPONENT OF FRONTAL IMPACT
Rib fractures, pulmonary contusion, flail chest, and
myocardial contusion from anterior chest-wall
compression against the steering wheel
Hollow abdominal viscera and solid organ compression,
resulting in intestinal perforation and lacerations of the
mesentery and solid organs, with accompanying
hemorrhage
After the anterior chest stops intrathoracic organs continue
to move, resulting in shear injuries such as lacerations of
the aorta or liver
Shear injuries to the kidneys and other solid viscera
Injury to the brain from direct compression with scalp
lacerations, skull fractures, and cerebral contusions, or
from deceleration and shear stress, which cause diffuse
axonal injury and cerebral contusion or subdural
hematoma
Acute neck flexion, hyperextension, or both, causing a
cervical spine injury
MOTORCYCLES
Motorcycle injuries involve four types of impacts: frontal, angular, ejection, and rear-end collision. In a frontal impact, the center
of gravity is above and behind the front axle as the motorcycle
tips forward and the rider travels over the handlebars. Injuries to
the head, chest, or abdomen occur, depending on which part of
the anatomy strikes the handlebars. If the riders feet are placed
on the pegs, the upper leg strikes the handlebars on forward
motion, causing bilateral midshaft femur fractures. Angular or
lateral impact from another vehicle or the ground when laying
the bike down to avoid a collision generally results in crush
injuries of the lower extremities. With ejection, the rider is
thrown into the air until the head, chest, or extremities strike
another object. Injury occurs at the point of impact, and, just as
with the occupant ejected from the automobile, the potential for
severe injury is high. This mechanism of injury is frequent and
contributes importantly to the extraordinary injury potential for
motorcycle riders.
In rear-end collisions, the motorcycle is usually at a stop
when it is hit by a second vehicle from behind. The injury pattern is that of rapid acceleration with hyperextension and subsequent crush injuries on sudden stop.
PEDESTRIANS
Two general patterns are seen in motor vehicle versus pedestrian impacts, depending on whether the pedestrian is an adult
or a child. In adults, the initial impact is often by the car
bumper, producing fractures to the tibia and fibula. As the victim falls over the moving vehicle, the pelvis and upper femur
are struck by the front of the vehicles hood, and the abdomen
and thorax continue onto the top of the hood. The secondary
strike can result in fractures of the femur or pelvis and produce
serious intra-abdominal or intrathoracic injury. Injury to the
head depends on whether the patients head strikes the car
hood or is protected with the arms. A third impact occurs as
the victim falls away, striking the ground. This impact commonly leads to head injury as well.
In children, the initial impact is predictably higher and may
produce injury to the pelvis or upper femur. The second impact
occurs when the front of the hood strikes the thorax. The final
impact may not occur on top of the hood but rather as the
TRAUMA
321
322
TA B L E 1 7 . 7
Vertebral
compression
fractures
Lower extremity
fractures
Calcancals
fractures
FIGURE 17.6. Hyperflexion and axial loading injury after a fall.
child is dragged underneath the vehicle. As the child falls backward, multiple impacts with the ground, underside of the vehicle, and wheels are possible, so virtually any type of injury may
occur. Because of the potential for forceful impact and the
direct blow to the middle torso, any child struck by a vehicle
must be considered to have potentially severe crush injuries.
FALLS
Falls result in multiple impacts. Energy transfer is a result of
the velocity that develops during the fall, so the height of the
fall usually determines the magnitude of injury. Falls from
more than three times the height of the victim, or from more
than 20 feet, are considered severe. The surface on which the
victim lands and its degree of compressibility (e.g., water vs.
concrete) also have an effect on the energy transfer and the
types of shear and tensile strain that occur. A typical injury
pattern after falls in which the victim lands on his or her feet is
transaxial and includes bilateral calcaneal fractures, lower
extremity fractures, and multiple compression fractures of the
thoracic and lumbar spine (Fig. 17.6). Of increasing importance are low-level falls (ground level falls [GLFs]) in the very
elderly where the presence of significant comorbidities and
medications (such as Coumadin) greatly enhance the risks of
complications and mortality, even with relatively minor
injuries.
GENERAL ANATOMIC
CONSIDERATIONS IN
BLUNT INJURY
The first and second ribs, sternum, scapula, and femur are
considered to be some of the strongest and least vulnerable
bones in the body. Therefore, fractures of these bones are indicators of severe trauma. Clear association exists between first
and second rib fractures and injuries to the head, chest, and
abdomen. Similarly, fractures to the sternum, though unusual,
have a relatively high frequency of associated myocardial con-
ASSOCIATED INJURY
Fracturetemporal, parietal
bone
Epidural hematoma
Maxillofacial fracture
Sternal fracture
Cardiac contusion
Fractured scapula
Pulmonary contusion
Lacerated liver
Lacerated spleen
Fractured pelvis
Fractured humerus
Supracondylar humerus
fracture
BIOMECHANICS OF
PENETRATING INJURIES
Penetrating trauma involves the transfer of energy to a relatively small tissue area. The velocity of a gunshot wound is
exceedingly high compared with any type of blunt trauma.
The kinetic energy [KE (M V)/2] of a bullet disrupts and
fragments cells and tissues, moving them away from the path
of the bullet. The actual size of the area of impact is determined by three factors: profile, tumble (spin and yaw), and
fragmentation.
The profile, or frontal area, of a knife, screwdriver, or smooth
bullet is that of a pointed missile. If the missile is crushed or
deformed as a result of impact, the frontal area changes shape
and disperses the impact over a wider tissue area, producing
more rapid and greater energy exchange to the tissue and
therefore greater injury. A knife or jacketed bullet does not
323
TA B L E 1 7 . 8
MUZZLE VELOCITY, KINETIC WEIGHT OF PROJECTILE, AND APPROXIMATE MAXIMUM
KINETIC ENERGY OF FREQUENTLY USED FIREARMS
DESCRIPTION
(CALIBER)
PROJECTILE
WEIGHT (g)
MUZZLE
VELOCITY (ft/s)
KINETIC
ENERGY (ft/lb)
29
1,000
72
263
Pistols
.22 Short
.38 Special
158
870
9-mm Luger
125
1,150
440
.45
250
860
410
.357 Magnum
158
1,430
695
.44 Magnum
240
1,470
1,150
40
1,150
150
55
3,200
1,248
170
2,200
1,830
Rifles
.56-mm M-16
.30-30 Winchester
High-Energy Weapons
The essential difference between high-energy weapon wounds
and the typical civilian gunshot wounds is that their projectiles
produce a much larger cavity or pressure cone than low- and
medium-velocity missiles. The temporary cavity extends well
beyond the actual bullet tract, producing a wider injury. The
vacuum created by the cavitation pulls clothing, bacteria, and
other debris from the surrounding areas into the wound, creating the additional risk of contamination. The proliferation
of semiautomatic weapons also has resulted in an increased
number of wounds a victim may experience. Instead of a single gunshot wound, the surgeon may be faced with multiple
wounds in multiple body locations.
Shotgun Injuries
Blast injuries caused by close-range shotgun fire (10 to 15 ft.)
constitute devastating injuries composed of extensive tissue
destruction. Besides specific organ injury, blast injuries due to
wadding from the shell and extensive foreign body contamination have the highest potential for secondary infection. These
injuries, in general, should be surgically explored, devitalized
tissue should be extensively dbrided, and the wounds should
be left open and packed with sterile dressing that should be
changed; the wounds should be reviewed serially for additional dbridement in the operating room.57
GENERAL ANATOMIC
CONSIDERATIONS OF
PENETRATING INJURIES
Evaluation of each entrance and exit wound helps to assess but
does not confirm the number of projectiles, their courses, and
which organs are at risk of injury. Close-range entrance
TRAUMA
.22 Long
324
325
Prevention; 2005.
6. Baker SP. The Injury Fact Book, 2nd ed. New York: Oxford University
Press; 1992.
7. Rice DP, Mackenzie EJ, Centers for Disease Control, Johns Hopkins University, School of Hygiene and Public Health, Injury Prevention Center.
Cost of Injury in the United States: A Report to Congress, 1989. San
Francisco, CA; Baltimore, MD: Institute for Health & Aging, University of
California Injury Prevention Center, School of Hygiene and Public Health,
Johns Hopkins University; 1989.
8. Centers for Disease Control and Prevention. Injury Mortality: National
Summary of Injury Mortality Data 19841990. Atlanta, GA: Centers for
Disease Control and Prevention; 1993.
9. Runyan CW, Gerken EA. Epidemiology and prevention of adolescent
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10. Fingerhut LA, National Center for Health Statistics. Firearm Mortality
Among Children, Youth, and Young Adults 134 Years of Age, Trends
and Current Status: United States, 198590. Hyattsville, MD: U.S.
Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Center for Health Statistics; 1993.
11. National Highway Traffic Safety Administration (NHTSA). Traffic Safety
Facts 2007: Alcohol. Washington, DC: NHTSA; 2008.
12. National Highway Traffic Safety Administration (NHTSA). The Incidence
and Role of Drugs in Fatally Injured Drivers. Washington, DC: NHTSA;
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38. Nathens AB, Jurkovich GJ, Cummings P, et al. The effect of organized systems of trauma care on motor vehicle crash mortality. JAMA 2000;283:
19901994.
39. OKeefe GE, Jurkovich GJ, Copass M, et al. Ten-year trend in survival and
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409415.
40. Peitzman AB, Courcoulas AP, Stinson C, et al. Trauma center maturation: quantification of process and outcome. Ann Surg 1999;230:87
94.
41. Gruen RL, Jurkovich GJ, McIntyre LK, et al. Patterns of errors contributing to trauma mortality: lessons learned from 2594 deaths. Ann Surg 2006;
244(3):371380.
42. Rogers FB, Shackford SR, Osler TM, et al. Rural trauma: the challenge for
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43. Baker SP, Whitfield RA, ONeill B. Geographic variations in mortality
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44. Grossman DC, Kim A, Macdonald SC, et al. Urban-rural differences in
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46. Grossman DC, Hart LG, Rivara FP, et al. From roadside to bedside: the
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47. Mann NC, Hedges JR, Mullins RJ, et al. Rural hospital transfer patterns before and after implementation of a statewide trauma system.
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48. Clay Mann N, Mullins RJ, Hedges JR, et al. Mortality among seriously
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643653.
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Medicine; 1990.
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RESUSCITATION CARE
EILEEN M. BULGER
P O I N T S
A multidisciplinary team of specialists, led by the captain
of the ship, usually a trauma surgeon, is available in level
1 and 2 trauma centers to provide coordinated optimal
care for any and all injuries.
5 Trauma assessment and care are provided in a logical, consistent manner. The primary survey identifies and simultaneously treats life-threatening injuries, including airway loss,
inadequate ventilation, ongoing hemorrhage, and central
nervous system damage. The secondary survey identifies all
other injuries, including those with potential long-term
disability.
4
among different ALS systems regarding the procedures permitCare of the injured patient begins in the prehospital setting
ted and medications allowed for use by an EMT-P.1,2
with a tightly integrated multidisciplinary emergency medical
An area of frequent controversy in the literature involves
service (EMS) system. The goal of the EMS system is to pro- 2
the philosophy of rapid transport (scoop and run) versus
vide immediate access to lifesaving medical care. This care
field stabilization (stay and play) for the injured patient.3
usually entails the use of a first-response team, such as the fire
department or other public safety personnel with the capabilThe choice of approach for the individual patient often
ity of providing basic life support (BLS) within minutes of an
requires complex judgments. Decisions made by experienced
injury. When available, a rapid transport team capable of proon-scene EMTs, communicating online with trauma center
viding advanced life support (ALS) moves the injured patient
control that will receive the patient, provide the best patient
to a trauma center where a multidisciplinary team meets the
outcome.4,5 The procedures performed and the time invested
patient to continue resuscitation, identify injuries, and provide
depend on factors such as the patients hemodynamic stability,
expeditious therapy, with the aim of completing all of these
level of consciousness, complexity of extrication, distance
processes within 1 hour (called the golden hour). The goal of
from the receiving trauma center, and experience of the prehosthe EMS system is to assess for life-threatening injuries, initipital personnel. Injured patients who are at risk for progressive
ate emergency care, and transport the injured patient as expedeterioration from continued hemorrhage are better served
ditiously and safely as possible to the nearest appropriate
with stabilization procedures done en route rather than at the
trauma center.
scene.4
Nationally standardized training programs for EMTs, both
BLS and ALS, have become popular. These programs, Basic
Trauma Life Support (BTLS) and Prehospital Trauma Life
Support (PHTLS), provide EMS personnel a curriculum to
PREHOSPITAL CARE
assist in making these complex decisions.
Personnel
1
327
TRAUMA
K E Y
328
329
TRIAGE
Another key decision that needs to be made in the prehospital
environment is to select the appropriate facility to receive the
patient. The Centers for Disease Control and Prevention
recently convened an expert panel to revise the Field Triage
Decision Scheme for transport to a designated trauma center
(Fig. 18.2).53 This decision tree is based on four steps in the
evaluation process. Step 1 involves an initial evaluation of
physiologic status and level of consciousness including Glasgow Coma Scale (GCS) score, systolic blood pressure, and respiratory rate. Step 2 focuses on specific injury patterns likely to
require trauma center care. Step 3 addresses the mechanism of
injury, and Step 4 considers the extremes of age and other mitigating comorbidities. If at any point in the algorithm the
patient meets the suggested criteria, then transport to a designated trauma center is recommended. This algorithm has been
endorsed by the American College of Surgeons Committee on
Trauma.
RESUSCITATION PHASE
Development of trauma centers and trauma systems has produced documented improvement in survival of multiply
injured patients in numerous reports.5458 Trauma centers are
hospitals committed to the total care of the trauma patient,
24 hours a day. Multidisciplinary trauma teams consist of
TRAUMA
330
<14 or
<90 or
<10 or >29 (<20 in infant <1 year)
YES
NO
YES
Take to a trauma center. Steps 1 and 2 attempt to identify
the most seriously injured patients. These patients should be
transported preferentially to the highest level of care within
the trauma system.
NO
Falls
Adults: >20 ft. (one story is equal to 10 ft.)
Children: >10 ft. or 2-3 times the height of the child
High-Risk Auto Crash
Intrusion: >12 in. occupant site; >18 in. any site
Ejection (partial or complete) from automobile
Death in same passenger compartment
Vehicle telemetry data consistent with high risk of injury
Auto vs. Pedestrian/Bicyclist Thrown, Run Over, or with
Significant (>20) Impact
Motorcycle Crash >20
YES
Transport to closest appropriate trauma center which,
depending on the trauma system, need not be the highestlevel trauma center.
NO
Assess special patient or
system considerations
Age
Older adults: Risk of injury death increases after age 55
Children: Should be triaged preferentially to pediatric-capable
trauma centers
Anticoagulation and Bleeding Disorders
Burns
Without other trauma mechanism: Triage to burn facility
With trauma mechanism: Triage to trauma center
Time-Sensitive Extremity Injury
End-Stage Renal Disease Requiring Dialysis
Pregnancy >20 Weeks
EMS Provider Judgment
YES
Contact medical control and consider transport to a trauma
center or a specific resource hospital.
NO
Transport according to protocol
FIGURE 18.2. Field triage decision scheme. (Reprinted with permission from American College of Surgeons Committee on Trauma. Resources
for the Optimal Care of the Injured Patient. Chicago, IL: American College of Surgeons; 2006:22).
The trauma team consists of members from different disciplines, each of whom sees the patient from a particular point
of view. Of necessity, the team must have a single captain of
the ship whose responsibility it is to organize and prioritize
treatment efforts. In a well-orchestrated team, the team leader
integrates and coordinates several tasks simultaneously. In
most level 1 and 2 trauma centers, the team captain is a general surgeon trained in trauma care. In the ideal situation, the
trauma surgeon should be present when the patient arrives. In
many rural and nonacademic level 3 trauma centers, the initial
team captain is an emergency physician, with a general surgeon assuming the role on arrival. Academic institutions with
both emergency medicine and surgical residency programs
have the obligation of training both specialties to assume the
role of trauma team leadership.
Although responsibilities vary between institutions, anyone
involved in the resuscitation of trauma patients must master
several procedures: all types of airway management, including
cricothyroidotomy; establishment of vascular access through
both percutaneous and open approaches; decompression of the
pleural space using needle or tube thoracostomy; and decompression of the pericardial space by pericardiocentesis, subxiphoid window, or emergency thoracotomy.
The first priority of the trauma team is to repeat the assessment of the airway, breathing, circulation, and level of consciousness of the patient. This assessment is referred to as the
primary survey. Although in reality the primary survey is performed in a simultaneous fashion, it is described here in its
individual components and their appropriate priorities.
The first priority is reassessment of the airway. Airway
obstruction often responds to simple maneuvers such as suctioning, chin lift, jaw thrust, or placement of an oropharyngeal
airway. Protection of the cervical spine with in-line immobilization is imperative during these maneuvers. Persistence of respiratory insufficiency requires endotracheal intubation. Unsuccessful intubation necessitates emergent cricothyroidotomy.
Occasionally, the anatomy does not allow cricothyroidotomy,
as can occur with laryngeal fracture. In these cases, a formal tracheotomy must be performed. After an airway is established, a
physician auscultates the chest to confirm air exchange, confirms return of carbon dioxide via the endotracheal tube, and
331
TRAUMA
332
TA B L E 1 8 . 1
DIAGNOSIS
To voice
To pain
None
VERBAL RESPONSE
Oriented
Confused
Inappropriate words
Incomprehensible sounds
None
MOTOR RESPONSE
Obeys commands
Withdraw (pain)
Flexion (pain)
Extension (pain)
None
GCS SUBTOTAL
315
Secondary Survey
The secondary survey is directed at specific identification of
suspected and unsuspected injuries. It consists of a thorough
physical examination that includes observation and palpation
of the entire body for evidence and characterization of injury.
However, performance of the secondary survey depends on the
results of the primary survey and the patients response to initial resuscitative efforts. The secondary survey for a patient in
hemorrhagic shock unresponsive to initial resuscitative efforts
during the primary survey consists only of rapid identification
of the bleeding site and rapid transport to the operating room
for definitive control of hemorrhage. At the other end of the
spectrum, a completely stable patient with relatively minor
injuries undergoes a complete physical examination with confirmatory laboratory and radiographic tests before initiation
of the treatment phase. The secondary survey can be interrupted at any time if a patients status deteriorates. Adjuvants
to the secondary survey include radiographic examinations
and laboratory testing. For the purposes of description, the
secondary survey is discussed by its individual components.
333
Yes
ATLS protocol
for evaluation
and management
No
Mechanism of injury
Blunt trauma
Penetrating trauma
Absent
SOL in ED
Absent
DOA
No
SOL absent
Less than 5 minutes
Present
Present
Absent
SOL in ED
Yes
Present
No
Yes
Take patient to OR
for definitive treatment
ALGORITHM 18.1
ALGORITHM 18.1. Emergency thoracotomy for penetrating trauma. ED, emergency department; ATLS, Advanced Trauma Life Support;
SOL, signs of life; DOA, dead on arrival; EDRT, emergency department resuscitative thoracotomy; OR, operating room. (Adapted from Boyd M,
Vanek VW, Bourguet CC. Emergency room resuscitative thoracotomy: when is it indicated? J Trauma 1992;33:714721.)
some combination of angiography, triple endoscopy (pharyngoscopy, laryngoscopy, and esophagoscopy), radiographic contrast study, computed tomography (CT) scan, and observation.61 Injuries encompassing the area from the cricoid cartilage
to the angle of the mandible are usually explored. Angiography
is mandatory for injuries between the cricoid cartilage and the
clavicle and for injuries between the angle of the mandible and
the base of the skull. Radiographic evaluation of the cervical
spine should include anteroposterior, lateral, and odontoid
views. A CT scan is often used to evaluate suspected bony
injuries, and careful flexion and extension films may be necessary to rule out potentially unstable ligamentous injuries of the
cervical spine.
TRAUMA
EDRT
334
radiograph should be evaluated for widening of the mediastinum (more than 8 cm on a 40-inch anteroposterior chest
radiograph), apical capping of the lung with extrapleural
blood, tracheal displacement, depression of the left main-stem
bronchus, loss of the aortic window, deviation of the nasogastric tube, and loss of the paraspinous stripe. Each of these findings suggests the presence of a mediastinal hematoma, which is
often associated with a transection of the aorta. Patients with
a significant mechanism of injury and suspicion of mediastinal
hematoma on chest radiography should undergo diagnostic
evaluation with either CT angiography or arch aortography to
rule out transection of the aorta. In some centers, transesophageal echocardiography has also been reported to identify these injuries.
Evidence of a ruptured diaphragm on chest radiograph
includes the presence of the nasogastric tube or bowel above
the normal plane of the diaphragm. If the patient has a diagnosis of ruptured diaphragm and respiratory distress, consideration should be given to careful placement of a chest tube.
Placement of the chest tube to water seal instead of suction
minimizes the negative intrathoracic pressure and prevents
further herniation. These patients should undergo expeditious
exploratory laparotomy to repair the defect and address the
commonly associated intra-abdominal injuries.
Management of penetrating injuries to the chest depends
on the trajectory of the missile. Wounds confined to one lung
or pleural cavity are usually treated by chest tube placement
alone, with reexpansion of the lung. If the missile may have
traversed the mediastinum, further evaluation is necessary,
potentially including bronchoscopy, esophagoscopy, and aortography. Echocardiography is used to rule out pericardial
blood and heart injury. False-negative studies have occurred
when blood in the pericardium decompresses through the
injury into the pleural space. However, echocardiography may
be a sufficient screening tool if there are no clinical signs or
symptoms of cardiac injury and no hemothorax. Gunshot
wounds below the nipple line, the upper limit of diaphragm
excursion, place the abdominal cavity at risk and thus require
abdominal exploration as well.
intra-abdominal injury that may eventually require laparotomy, but the major source of hemorrhage causing the
hypotension is likely elsewhere (chest or pelvis).66
In the hemodynamically stable patient, the lack of specificity
of the DPL and FAST could lead to nontherapeutic and therefore unnecessary laparotomies. For this reason, CT has become
routine for the evaluation of the abdomen in hemodynamically
stable patients. Injuries that often have subtle findings during
the first several hours after injury but may be found on a
delayed CT scan include duodenal rupture, pancreatic transection, and blunt rupture of the intestine. Similarly, laboratory
evaluations that may be helpful include liver enzyme levels and
serial serum amylase levels with serial determinations in highrisk patients.
The workup for patients with penetrating abdominal
injuries depends on the missile. Gunshot wounds to the
abdomen are an indication for exploratory laparotomy
because 90% to 95% of these patients have intra-abdominal
injuries. The occasional patient with a tangential subcutaneous wound can be evaluated by laparoscopy or even CT to
determine whether peritoneal penetration injury has
occurred.67 Stab wounds to the abdomen are often evaluated
initially by local exploration of the wound. If the wound traverses the anterior fascia, then the patient can be evaluated by
DPL or laparoscopy and should undergo exploratory laparotomy if the results are positive. A lower threshold for a positive
RBC count is often set for stab wound injuries because the
DPL is designed simply to confirm peritoneal penetration and
not significant bleeding. Stab wounds to the flank and back are
best evaluated by a triple-contrast CT scan and serial observation.68,69 CT scan findings that mandate exploratory laparotomy include significant retroperitoneal hematoma, free air,
extravasation of contrast material, and free intraperitoneal
fluid.
335
Mechanism
(blunt torso trauma)
Immobolize in field
(backboard)
Rapid transport
Unstable pelvis
(PASG or sheet wrap)
ED evaluation
Pelvic radiograph
DPL/abdominal CT
Hemodynamically
unstable
(~4 Tx or
Hct ~25)
Hemodynamically
stable
Urgent definitive
stabilization
External fixation
ORIF
Angiography
embolization
ALGORITHM 18.2
SUMMARY
The ideal trauma system consists of a prehospital care team
that quickly and safely transports an injured patient to a
trauma center where a multidisciplinary trauma team immediately begins resuscitation of the patient. Treatment of
immediately life-threatening injuries begins during transport
and continues after arrival at the trauma center. Rapid initial
evaluation, followed by a more detailed secondary survey,
allows identification of injuries while therapy is simultaneously begun. The primary survey focuses on identification and
simultaneous treatment of life-threatening injuries, including
airway obstruction, mechanical factors in the chest that
impair ventilation, and control of hemorrhage. The next priority is assessment and intervention for neurologic injuries
including traumatic brain injury and spinal cord injury. Once
these issues have been addressed, the secondary survey is performed to identify all other injuries. The secondary survey is
interrupted as necessary to treat life-threatening and limbthreatening injuries as they are identified. If interruption
becomes necessary, the secondary survey is completed at a
later time.
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EPIDEMIOLOGY
In the field of trauma, other than for exsanguinating injuries,
brain trauma is the injury most commonly responsible for
mortality, accounting for about half of deaths at the scene. The
injuries are generally blunt, occurring most frequently in
motor vehicle crashes (MVCs). As many as two thirds of all
MVC victims sustain some degree of brain injury. Complications from closed head injuries are the single largest cause of
morbidity and mortality in patients who reach the hospital
alive. Of patients who require long-term rehabilitation, head
trauma is usually the primary injury.
These data are generally applicable to children as well.
Although the mechanisms vary, head injuries are the major cause
of morbidity and mortality in childhood trauma victims, accounting for an annual mortality rate of 1 per 1,000 in this age group.
Recently, with the aging of the population, a new spectrum of
brain injury is blossoming, consisting of persons aged 60 years or
older whose primary mechanism of injury is a fall. These patients
have less inherent neurologic plasticity, limiting their recovery
potential. As well, they often have significant comorbidities and
may be on one or more anticoagulants. Management of these
patients often takes a course differing from that optimal for the
younger population.
In the mid-1990s, gunshot wounds surpassed other mechanisms as the most common cause of brain injuries.1 Because of
a case mortality ratio of approximately 94%, however, they
continue to represent only a fraction of the brain injuries that
come to definitive hospital care. In addition, because civilian
gunshot wounds to the head are frequently isolated injuries,
their spectrum of care varies more toward individual neurosurgical management.
PATHOPHYSIOLOGY
1
P O I N T S
Computed tomography is the diagnostic test of preference
and should be used serially in settings of increased risk of
progression of TBI.
6 Initial increases in ICP are treated by removal of mass lesions
(blood collections or edematous injured brain), cerebrospinal
fluid drainage, mild hyperventilation (PaCO2 30 to 35 mm
Hg), or hyperosmolar therapy using mannitol or hypertonic
saline to decrease edema. Hyperventilation should be avoided
early (PaCO2 35 to 38 mm Hg) and used cautiously (PaCO2
30 to 35 mm Hg) later to treat unresponsive elevated ICP.
7 Refractory ICP elevation may be treated medically with
more aggressive hyperventilation (PaCO2 30 mm Hg),
barbiturates, or hypothermia, generally guided by aggressive,
multimodality monitoring. Decompressive craniectomy
constitutes an effective surgical treatment for refractory
intracranial hypertension.
Primary Injury
Energy transfer to the head causes direct disruption of neurons,
glia cells, and microvasculature localized at the area of impact.
As the brain rebounds within the skull, it is also vulnerable to
impact with the opposite inner table. Therefore, countercoup
injury to the contralateral brain is relatively common, in some
cases being the more severe site of damage.
Particularly when the mechanism includes rotational forces,
head trauma can result in widespread disruption of white
matter axons throughout the brain, producing the condition
termed diffuse axonal injury (DAI). Such injuries often damage
a large number of widely distributed neurologic systems. When
such injuries involve ascending pathways in both hemispheres
or in the brainstem, the result is a depressed level of consciousness. The brain is also subject to torsion injury resulting
from rotation around the fixed brainstem. This type of injury
can damage the reticular activating system, producing unconsciousness.
Intracranial hemorrhage can take many forms. Direct laceration of epidural arteries from impact fractures or bleeding
from fracture lines produces epidural hematomas, which damage the brain by compression. Disruption of bridging subdural
veins and bleeding from cortical tissue damage produces a
subdural hematoma, which is generally associated with disruption of underlying brain tissue. Intracerebral contusions,
lacerations, and hematomas are caused by direct tissue disruption with associated vascular injury, producing neuronal damage and intraparenchymal bleeding.
Penetrating injury damages the brain through tissue injury
caused directly by the projectile and, in the case of projectiles
337
TRAUMA
K E Y
338
with relatively high velocity, result in disruption of neural tisIntracranial Pressure. ICP is a function of the aggregate
sue at a greater distance from the track via cavitation injury. In
volumes of brain, cerebrospinal fluid (CSF), and blood within
survivors, the extent and degree of the cavitation injury
the fixed intracranial compartment. Mild or slow expansion of
(related linearly to the mass and in a squared fashion to the
one or two of these compartments can be buffered by comvelocity of the projectile) are often the primary determinant of
pensatory decreases in either the CSF or blood compartments
outcome. Another source of morbidity is vascular injury, pro(into the spinal subarachnoid space or the venous sinuses,
ducing aneurysms, pseudoaneurysms, and other vascular
respectively). When this buffering capacity is exceeded, the
anomalies that may present immediately or be delayed.
compliance of the brain is compromised and small additional
Whether a projectile or direct impact causes contusion,
increases in any intracranial compartmental volume will prosubdural hematoma, epidural hematoma, or diffuse axonal
duce marked elevations in ICP.
injury, little can be done therapeutically to change the magni- 3
Intracranial hypertension is considered deleterious via two
tude or location of the primary injury once it has occurred. As
somewhat separable mechanisms: herniation and ischemia.
such, most of our present care focus is on secondary injuries.
Herniation occurs when a pressure gradient exists across an
incomplete barrier, such as the tentorium, falx cerebri, or
foramen magnum. It is deleterious because of the tissue damage that occurs and direct compression of adjacent vessels.
Secondary Injury
Transtentorial herniation, the most recognized form, is maniSecondary brain injuries result from events occurring after the
fest by anisocoria, motor posturing, autonomic disturbances,
primary insult, either from the direct consequences of the
and death. The specter of herniation is the major determinant
process initiated by the primary injury or from deleterious
of the absolute threshold of ICP management, which is gener2 exogenous influences. The occurrence and magnitude of secally accepted as 20 to 25 mm Hg (although this range has not
ondary insults are often the determining factor in outcome
been well determined empirically). A major unanswered quesfrom brain injury. In contrast to primary injuries, secondary
tion is how ICP should be managed when separated from perinsults are amenable to medical management and even prevenfusion, both in terms of measuring the probability of herniation; they are the focus toward which the medical treatment of
tion and in determining whether there are detrimental effects
brain injury is primarily directed.
of elevated pressure per se. It is hoped that ongoing research in
Primary tissue injury initiates a variety of biochemical
the area of cerebral compliance will produce clinically useful
processes, including free radicalmediated lipid peroxidation,
information regarding these issues.
excitotoxic super-activation of glutamate-aspartate neuroThe second deleterious aspect of intracranial hypertension
transmitter systems, and alterations in membrane receptor
is elevated resistance to cerebral blood flow (CBF), resulting in
and ionic channel characteristics, among others. A variety of
or exacerbating ischemia. This resistance can be very roughly
genomic processes are also activated, including apoptotic cell
approximated by cerebral perfusion pressure (CPP), which is
death, which is a focus of much current research. These
defined as the difference between mean arterial blood pressure
processes can proceed for significant periods of time following
and ICP:
primary injury and often are self-sustaining. The goal of the
CPP mean arterial pressure ICP
numerous clinical trials involving treatment of patients with
brain trauma with various pharmacologic agents is to deterUnder normal circumstances, cerebral pressure autoregulamine the means by which these processes may be attenuated or
tion maintains CBF stable over a wide range of CPP (approxireversed. Unfortunately, to date, no clinically useful tools have
mately 50 to 150 mm Hg) (Fig. 19.1). Following injury to the
been obtained from such research.
brain, this autoregulation is generally disrupted. This disrupThe primary external secondary injury processes occurring
tion can be complete, resulting in a pressure-passive system.4
following brain injury are hypotension and hypoxia. HypotenMore frequently, the disruption is incomplete, characterized
sion is the number one treatable determinant of severe head
by a normal sigmoid shape but with abnormal elevation of the
injury. A single episode of systolic blood pressure less than
lower breakpoint above the normal value of 50 mm Hg (sig90 mm Hg occurring during the period from injury through
moid dashed line). A probable consequence of this disruption
resuscitation doubles the mortality and significantly increases
is that a CPP that is satisfactory for uninjured patients may be
the morbidity of any given brain injury.2 Furthermore, an early
associated with a lower CBF following head trauma (range of
hypotensive episode strongly increases the probability of later
hypoperfusion).
intracranial hypertension. For these reasons, rapid and comIn a pressure-passive system, cerebral blood volume (CBV)
plete restoration of blood pressure is the most important goal
will increase in proportion to CPP. In such an instance, the
in the resuscitation of the brain-injured patient. The old saw of
goal is to keep the CPP just above the level of cerebral
keeping the brain injury patient dry by restricting fluids has
ischemia, thereby minimizing iatrogenic intracranial hypertenbeen found to be completely erroneous and has been abansion driven by increased CBV. In the situation of incomplete
doned. Also for this reason, the somewhat unconventional
disruption, the goal is to keep CPP within the range of
suggestion of using pressors as temporizing agents during volautoregulation, because this not only avoids ischemia but
ume resuscitation has been incorporated into brain injury
also may decrease ICP if autoregulatory vasoconstriction in
care.2
response to increased CPP serves to decrease CBV.
Hypoxia (apnea or cyanosis in the field or a partial presConfounding this situation are reports that CBF may be
sure of arterial oxygen [PaO2] 60 mm Hg) is also an indedisproportionately depressed during the early postinjury
pendent predictor of poor outcome.2,3 The frequency and
period. It is particularly critical, therefore, that CPP be supmagnitude of hypoxia have been notably decreased by modported assiduously from the first point of patient contact.
ern airway management techniques, particularly early endoBecause hyperventilation causes vasoconstriction, thereby
tracheal intubation and assisted ventilation, in addition to
decreasing CBF, the use of hyperventilation during this early
ensuring adequate oxygen-carrying capacity through the
period is somewhat more hazardous than after the first 24 to
avoidance of anemia.
48 hours.
Another important source of secondary injury is pyrexia.
The preceding physiologic reasoning supported the increase
Fever is correlated with poorer outcome both by degree and
in use of cerebral perfusion pressure therapy, wherein CPP was
duration.3 Although the precise mechanism of this effect
elevated to 70 mm Hg or higher throughout the course of
remains unclear, increased metabolism and the resultant metaintracranial hypertension. The efficacy of CPP therapy has
bolic recruitment of additional blood flow (and blood volume)
been suggested by studies without internal controls reporting
is presumed to play a role.
decreased morbidity and mortality associated with CPP therapy
339
as compared to historical controls that practiced more conventional ICP-based therapy. The result of such reports was
that CPP-based therapy at significantly elevated values became
widely accepted as standard practice.
Subsequent reports, however, suggested that such acceptance might have been premature. Potential errors in selecting
the historical control groups against which CPP-based therapy
results were compared have prevented differentiating the
effects of artificially increasing CPP from those of simply avoiding in-hospital hypotensive episodes. When control groups are
selected to address this deficiency, it becomes apparent that
CPP-based therapy may simply be a proxy for avoidance of
transient ischemia.5 Such a possibility is further supported by
analysis of data from the National Institutes of Health (NIH)funded North American Brain Injury Study on Hypothermia,
which suggested that dips of CPP below 60 mm Hg are much
more highly correlated with outcome than the efficacy of maintaining CPP above 70 mm Hg.6 In addition, it appears that elevating CPP may increase the duration of intracranial hypertension.7,8 This might be caused by the elevation of hydrostatic
forces favoring the formation of vasogenic edema, thereby
iatrogenically prolonging brain swelling and ICP elevation.
Finally, the results of a prospective randomized investigation of
CPP-based versus ICP-based management suggest that there is
no overall difference in outcome between the two strategies,
with the major effect of CPP-based therapy being the alteration
in the mode of exitus from early, ICP-related deaths to delayed
mortality from systemic complications (especially acute respiratory distress syndrome [ARDS]).9 Such considerations imply
that, although attention to CPP (and, thus, cerebral perfusion)
is important, the proper method of managing CPP remains to
be determined. It is clear, however, that routinely elevating CPP
to values above 70 mm Hg is not associated with improved
outcome.10 This is reflected in the most recent revision of the
Guidelines for the Management of Severe Brain Injury wherein
the recommended CPP threshold has been decreased to 60 mm
Hg based on an updated evidence review.11
Ultimately, the goal of managing blood pressure and CBF is
to maintain a level of perfusion that meets the metabolic
demands of the cell. The major problem with managing traumatic brain injury (TBI) based on pressure measurements is
that alterations in cerebral metabolism will be missed. This
may be of significant importance because the usual course of
TRAUMA
340
CLINICAL ASSESSMENT
The objectives during early clinical assessment of the patient
with head injury are multiple and must be accomplished simultaneously. These include establishing adequate oxygenation,
ventilation, and circulatory stability and evaluating the extent
of brain injury while treating ICP elevations. Although some
evidence indicates that systemic hypotension may infrequently
be the result of a head injury, always initially presume that
hypotension in a trauma patient is the result of hypovolemia.
It is a significant error to withhold volume resuscitation in a
misdirected effort to control cerebral edema.
During initial assessment, mental status changes cannot be
presumed to be the result of drugs or alcohol, although routine
toxicology screening is appropriate. It should be presumed
341
Admission GCS
GCS >12
GCS 912
GCS <9
Complete evaluation
Always severe
ALGORITHM 19.1
ALGORITHM 19.1. Glasgow Coma Scale (GCS) triage guide for initial evaluation of head injury. For the motor scale, the best response for any
limb is recorded.
Pupils
Pupillary asymmetry, dilation, or loss of light reflex in an
unconscious patient usually reflects herniation because of the
mass effect from intracranial hemorrhage ipsilateral to the
dilated pupil. The probability of an intracranial mass lesion
can be roughly approximated given the degree of anisocoria
(1 mm or 3 mm), the mechanism of injury ( motor vehicle crash), and age (Fig. 19.2).21 Occasionally, pupillary signs
may indicate direct second or third nerve injury or trauma to
the globe, but this must always be a diagnosis of exclusion. An
unequal and nonreactive pupil is the cardinal sign that herniation is occurring, and rapid lowering of ICP is essential. An
TRAUMA
that any change in mental status or the neurologic examination in general, or any evidence of herniation (e.g., anisocoria),
suggests an expanding intracranial mass lesion. Under such
circumstances, therapeutic ICP reduction becomes the first priority and diagnostic imaging or surgical decompression must
be accomplished emergently.
Do not assume that apparent neurologic unresponsiveness
represents a lack of sensitivity to pain. Noxious stimuli, such
as placement of urinary drainage catheters, nasogastric tubes,
or IV catheters, can precipitate ICP peaks during resuscitation.
These procedures should be done quickly and efficiently, optimally after sedation. Endotracheal intubation is particularly
likely to induce herniation in borderline cases. Whenever practical, consider premedication with analgesics, sedatives, or IV
or endotracheal lidocaine before airway instrumentation.
With regard to the brain injury, several critical assessments
are necessary and should be precisely recorded because trends
4 are at least as important as any single observation. The three
key parameters are level of consciousness, pupillary reflexes
and size, and the motor examination.
342
Motor Examination
The motor system is examined for asymmetry, abnormal posturing, or lack of movement. Hemiparesis, paraparesis, or
quadriparesis suggests a cervical or thoracolumbar spine fracture with spinal cord injury. Hemiparesis secondary to brainstem herniation from the mass effect may be either ipsilateral
or contralateral to the side of the dilated pupil or an intracranial mass lesion.21 Hemiparesis may also result from significant brain contusion. In the unconscious patient, a painful
stimulus should be used to evaluate motor function. All four
extremities should be examined and the results noted, because
only the response of the best limb will be reflected in the GCS
score.
INITIAL TREATMENT
Evidence-based Medicine and the
Management of Traumatic Brain Injury
The publication of the first edition of the Guidelines for the
Management of Severe Brain Injury in 1996 represented a significant step in standardizing the management of TBI based on
published, peer-reviewed literature.22 This document represents
the application of a strict evidence-based process to 14 topics
relevant to TBI care. Following an exhaustive, explicitly
defined literature search covering each topic, the recovered literature was carefully classified along a three-point continuum
of scientific rigor. As such, each article was ranked as class I,
class II, or class III and the analysis of the scientific basis of each
topic was predicated on the most scientifically rigorous (highest
literature class) reports available. This process produced a set
of standards, guidelines, and options for treatment where standards (based on class I evidence) represent principles with a
high degree of clinical certainty, guidelines (based on class II
evidence) reflect principles with a moderate degree of clinical
certainty, and options (based on class III evidence) reflect principles for which unclear clinical certainty exists. By specifically
defining the scientific foundation on TBI management issues,
the Guidelines for the Management of Severe Brain Injury provided an unbiased reference focused on facilitating scientific
management of TBI.
Since the initial publication of the Guidelines for the Management of Severe Brain Injury, it has undergone updating and
revision10,11 encompassing more recently published data and
revising earlier practice recommendations where indicated as
well as expanding the scope of covered topics. The same evidence-based process has also been applied in the generation of
other sets of brain injury guidelines. The Guidelines for the Prehospital Management of Traumatic Brain Injury were published
in 2002,20 spawning the training efforts mentioned previously.
In 2001, the Guidelines for the Management of Penetrating
Brain Injury were published.23 The Guidelines for the Management of Pediatric Brain Injury were published in 2003.18 The
Guidelines for the Surgical Management of Traumatic Brain
Injury were published in 2001.24 In light of the need for responsiveness of all evidence-based reports to the publication of new
literature, the Brain Trauma Foundation has established a
process to ensure that all of these reports are regularly updated
and expanded through the Neurosurgical Evidence-based Medicine Center at the University of Washington.
Wherever applicable, the findings contained in these guidelines have been incorporated into this text. For details, the
reader is referred to the source documents.
343
ABC(D)s
Isotonic or hypertonic fluid
resuscitation to
normal blood pressure
GCS 8?
Ventilate to
PaCO2 3538 mm Hg
Sedate per protocol
Yes
No
Maintain blood pressure
Hyperventilate to
PaCO2 3035 mm Hg
Euvolemic?
No
Mannitol,
0.25 g/kg,
IV bolus
Immobolize
spine
No mannitol
ALGORITHM 19.2
ALGORITHM 19.2. Prehospital evaluation and treatment of a patient with severe traumatic brain injury. Signs of increased ICP is the decision point for determining the necessity of intracranial pressure (ICP)-lowering therapy. These signs include pupillary abnormalities, motor posturing, or neurologic deterioration not related to medications. The order of steps is determined by the risk-benefit ratio for individual treatment
maneuvers. This algorithm should be viewed as expert opinion and used as a framework, which may be useful in guiding an approach to field
management of such patients. ( R.M. Chesnut, MD., FCCM, reproduced with permission.)
Algorithm 19.3 is based on the Guidelines for the Management of Severe Brain Injury10,11,22 for evaluation and treatment
of the severe TBI patient from arrival at the trauma center
prior to the placement of an ICP monitor. As with any trauma
patient, the first step is Advanced Trauma Life Support (ATLS)
resuscitation. When appropriate, brain-specific therapies are
incorporated into the treatment course. Brain-friendly initial
ICU management should lead directly to monitoring of ICP.
Elevating the head of the bed (reverse Trendelenburg position
in the absence of clearance of the axial skeleton) has been shown
to generally lower the CPP in the absence of adequate volume
resuscitation.29 Because this may elevate the ICP per se, it is not
advised until complete resuscitation has been accomplished.
The confusion and agitation often attendant to head injury
often can drive intracranial hypertension and renders sedation
desirable. Therefore, patients with suspected head injury
should generally receive sedatives and analgesics whenever possible. Particularly in the TBI patient, the difference between
sedation and analgesia should be kept in mind and the two
agents titrated specific to their respective indications. Shortacting agents are preferable in the interest of following the neurologic examination.
In addition to eliminating any possibility of spontaneous
ventilation and mandating complete ventilatory control, pharmacologic relaxation has the undesirable effect of limiting the
neurologic examination to the pupils and the CT scan. Its use
in the absence of evidence of herniation, therefore, should be
TRAUMA
Yes
344
Trauma evaluation
Emergency
diagnostic
studies
Operating
theater
CT scan
Measure ICP
Bolt
Ventriculostomy
Air ventriculogram?
Operating
theater
Yes
Surgical lesion?
No
Intensive care unit
Sedation
Relaxation PRN
Elevate head of bed
(euvolemia)
Neutral head position
General measures
Maintain SaO2 >94%
Maintain electrolytes
Maintain normothermia
Maintain normal glucose
Treat intracranial hypertension
Monitor ICP
ALGORITHM 19.3
ALGORITHM 19.3. Evaluation and treatment of the patient with severe traumatic brain injury on arrival at the trauma center. The order of steps
is determined by the risk-benefit ratio for individual treatment maneuvers. This algorithm should be viewed as expert opinion and used as a
framework, which may be useful in guiding an approach to initial hospital management of such patients prior to the initiation of ICP monitoring.
( R.M. Chesnut, MD., reproduced with permission.)
Radiographic Priorities
5
observed with sequential examinations and radiographic evaluation may be unnecessary unless the results determine whether
the patient can be discharged from the hospital. In contrast,
however, a cogent argument can be made for the liberal application of CT scanning to even patients with minimal evidence of
TBI as a method of making safe, efficient, and economic triage
decisions.30 In any instance, evidence of neurologic deterioration or the occurrence of a situation wherein the neurologic
examination cannot be followed (e.g., the need for general anesthesia) mandates CT scanning, intraoperative ICP monitoring,
or both. General indications for neurologic imaging (generally,
CT scanning) are listed in Table 19.1.
Patients with moderate or severe injuries require prompt
neurosurgical consultation and rapid radiographic evaluation
using the CT scanner. Hemodynamically stable patients with
significant neurologic deterioration should go to the CT scanner immediately following ATLS resuscitation. In hemodynamically unstable patients who require immediate surgical intervention to sustain intravascular volume, lifesaving exploratory
thoracotomy or laparotomy must take precedence. In such
cases, it is a mistake to delay further investigation of the
intracranial compartment pending the end of the case and
transport to the CT scanner. A number of methods can be
employed to evaluate the intracranial compartment during
such lifesaving, extracranial surgery, including insertion of an
TA B L E 1 9 . 1
345
DIAGNOSIS
TRAUMA
346
347
DEFINITIVE MANAGEMENT
Surgical Decompression and Outcome
Skull Fracture (Including Basal Skull Fractures).
TRAUMA
Depressed skull fractures are easily seen on plain frontal or lateral skull films and on CT. The mechanism of injury is usually
a direct blow to the skull by a blunt object. Closed depressed
skull fractures that are comminuted and those with a fragmented outer margin displaced beneath the inner table have
characteristically been treated surgically, although growing
evidence indicates that many may be treated nonoperatively if
there is no neurologic dysfunction or CT evidence of underlying tissue injury. Open fractures are also generally treated surgically, although, again, growing evidence indicates that fresh,
noncomminuted fractures without neurologic deficit, CSF or
brain extrusion, gross contamination, or underlying tissue
injury can be closed and treated with prophylactic antibiotics.
When surgery is indicated, the goals are to dbride the injury,
accomplish secure CSF containment, restore cosmetic contours, and close the wound in a manner to ensure healing.
Basilar skull fractures are usually diagnosed with CT imaging or on clinical evidence, as they are poorly visualized on
plain films. Clinical signs include otorrhea or rhinorrhea, subcutaneous ecchymoses overlying the mastoid region (Battle
sign), bilateral periorbital ecchymoses (raccoon eyes), or
hemotympanum. A basilar skull fracture may involve the
paranasal sinuses, piriform sinus, petrous bone, sphenoid
sinus, or sella turcica. Injuries to adjacent structures, such as
the seventh or eighth cranial nerves, brainstem, and carotid or
basilar arteries, are not uncommon. These are generally visualized with CT scanning, although special protocols may be
required. If vascular injury is suggested (such as by fracture
lines involving the carotid canal), CT or catheter angiography
should be considered. In the acute CSF leak, no specific therapy is indicated. The leak should not be tamponaded unless it
is brisk. Antibiotics should not be administered solely for prophylaxis of meningitis. Most CSF leaks stop spontaneously
with minimal treatment (e.g., elevating the head of the bed).
Leaks that continue more than 72 hours generally require temporary CSF diversion (e.g., via lumbar drainage or ventriculostomy). CSF drainage that does not respond to diversion will
require surgery. Although most instances of rhinorrhea cease
without surgery, the most common operation for persistent
CSF leaks is exploration of the floor of the frontal fossa. The
goal of such surgery is to identify the dural defect (often associated with herniation of a small tongue of brain tissue) and
either close it primarily, patch it, or otherwise isolate the subarachnoid compartment from the skull base.
348
Surgical Management of Traumatic Brain Injury24 can be summarized as follows: in general, patients with any lesion greater
than 50 mL in volume should be treated operatively. Additionally, patients who have parenchymal mass lesions and
signs of progressive neurologic deterioration referable to the
lesion, medically refractory intracranial hypertension, or signs
of mass effect on CT scan should be considered for surgery.
Patients with GCS scores of 6 to 8 should be treated operatively if they have frontal or temporal contusions greater than
20 mL in volume with either midline shift over 5 mm or cisternal compression on CT scan.
Patients with parenchymal mass lesions may be managed
nonoperatively if they do not show evidence for neurologic
compromise, have controlled ICP, and have no significant
signs of mass effect on CT scan. Such patients should be managed with intensive monitoring and serial imaging. Surgery
should be readdressed if difficulties with control of intracranial hypertension lead to consideration of second tier therapies (e.g., hypothermia or barbiturate coma) so as to avoid the
secondary complications of such therapy. In all nonoperatively
treated patients with parenchymal mass lesions, surgery
should be considered before reaching the medical point of
failure.
Surgical management may involve decompression to
make room for the lesion-induced swelling, evacuation and
dbridement of the offending lesions, or a combination.
Because evacuation of such lesions does not always eliminate
the development of intracranial hypertension, extensive craniotomy with expansible duraplasty and without replacing the
bone flap should be considered at the time of operation.
Penetrating Injuries. Penetrating injuries to the brain present several unique management problems, including the prophylaxis and treatment of intracranial infection, the possibility
of epilepsy, and the risk of occult vascular injuries. The recommendations regarding the management of penetrating
TA B L E 1 9 . 2 INDICATIONS/CONTRAINDICATIONS
INDICATIONS FOR NONOPERATIVE MANAGEMENT OF
COMPOUND DEPRESSED SKULL FRACTURES
No clinical or radiographic evidence of:
349
TRAUMA
350
MEDICAL MANAGEMENT
General Measures
351
TRAUMA
352
Monitor ICP
Maintain
CPP >60 mm Hg
ICP <20 mm Hg?
Consider
hypertonic saline
No
Ventricular drainage
if available
ICP <20 mm Hg?
No
Hyperventilation to
PaCO2 30-35 mm Hg
Consider
hypertonic saline
May repeat mannitol
if serum osmolarity
<320 mOsm/L &
patient is euvolemic
Consider optimized
hyperventilation if
JvSO2 indicates
hyperemia
Consider
decompressive
craniectomy
No
No
No
Consider hyperthermia
Consider other
second-tier therapies
Second-tier therapy
ALGORITHM 19.4
ALGORITHM 19.4. Treatment of established intracranial hypertension, based on the Guidelines for the Management of Severe Brain Injury. The
order of steps is determined by the risk-benefit ratio for individual treatment maneuvers. This algorithm should be viewed as expert opinion
and used as a framework, which may be useful in guiding an approach to elevated ICP.
woods for such rebound until the serum sodium has returned
to within normal limits. As such, we generally leave the ICP
monitor in place and caution against major, nonemergent surgical cases.
Hyperventilation is generally effective in lowering ICP. As
noted, however, it works on the arterial side, via vasoconstriction-induced decreases in CBV, which allows the possibility of
inducing ischemia by embarrassing CBF. At present, no clinically applicable method exists for measuring CBV, and it is
unclear how often elevated CBV per se is a primary physiologic abnormality in intracranial hypertension. Therefore,
lowering CBV to treat intracranial hypertension includes risks
that need be minimized.
In keeping with the Guidelines for the Management of
Severe Brain Injury, hyperventilation (PaCO2 35 mm Hg)
should be avoided during the first 24 hours following TBI.11
Thereafter, if intracranial hypertension continues, hyperventilation to PaCO2 values between 30 and 35 mm Hg may be
considered. Whenever hyperventilation is used, and certainly
when PaCO2 values of less than 30 mm Hg are targeted, methods of monitoring the effects on CBF or flow-perfusion matching should be considered, such as quantitative CBF measurement, jugular venous saturation monitoring, or following
cerebral tissue oxygen saturation.
7
When ICP control does not respond to these management
steps, second-tier therapies should be considered. These
include barbiturate therapy, hypothermia, decompressive
craniectomy, and optimized hyperventilation (among other
approaches). The details of the choice between second-tier
agents are beyond the scope of this chapter. In general, the
choice should be based on and directed using as much multimodality monitoring as is available, because the risk-benefit
ratio of most of these treatments is very narrow.
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2. Chesnut RM, Marshall LF, Klauber MR, et al. The role of secondary brain
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216222.
3. Jones PA, Andrews PJ, Midgley S, et al. Measuring the burden of secondary insults in head-injured patients during intensive care. J Neurosurg
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4. Lang EW, Chesnut RM. A bedside method for investigating the integrity
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5. Chesnut RM. Avoidance of hypotension: conditio sine qua non of successful severe head-injury management. J Trauma 1997;42:S4S9.
6. Clifton GL, Miller ER, Choi SC, et al. Fluid thresholds and outcome from
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7. Chesnut RM. Hyperventilation versus cerebral perfusion pressure management: time to change the question. Crit Care Med 1998;26:
210212.
8. Cruz J. The first decade of continuous monitoring of jugular bulb oxyhemoglobin saturation: management strategies and clinical outcome. Crit
Care Med 1998;26:344351.
9. Robertson CS, Valadka AB, Hannay HJ, et al. Prevention of secondary
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20862095.
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10. Bullock R, Chesnut RM, Clifton G, et al. Guidelines for the management
of severe head injuryrevision. J Neurotrauma 2000;17:457627.
11. Bratton S, Bullock R, Carney N, et al. Guidelines for the management of
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12. Robertson CS, Cormio M. Cerebral metabolic management. New Horiz
1995;3:410422.
13. Kiening K, Unterberg A, Bardt T, et al. Monitoring of cerebral oxygenation
in patients with severe head injuries: brain tissue PO2 versus jugular vein
oxygen saturation. J Neurosurg 1996;85:751757.
14. van Santbrink H, Maas AI, Avezaat CJ. Continuous monitoring of partial
pressure of brain tissue oxygen in patients with severe head injury. Neurosurgery 1996;38:2131.
15. Edwards P, Arango M, Balica L, et al. Final results of MRC CRASH, a
randomised placebo-controlled trial of intravenous corticosteroid in
adults with head injuryoutcomes at 6 months. Lancet 2005;365:1957
1959.
16. Kaufmann AM, Cardoso ER. Aggravation of vasogenic cerebral edema by
multiple-dose mannitol. J Neurosurg 1992;77:584589.
17. Chesnut RM, Gautille T, Blunt BA, et al. Neurogenic hypotension in
patients with severe head injuries. J Trauma 1998;44:958963; discussion
963964.
18. Adelson PD, Bratton SL, Carney NA, et al. Guidelines for the acute medical management of severe traumatic brain injury in infants, children, and
adolescents. Pediatr Crit Care Med 2003;4:S1S71.
19. Marion DW, Carlier PM. Problems with initial Glasgow Coma Scale
assessment caused by prehospital treatment of patients with head injuries:
results of a national survey. J Trauma 1994;36:8995.
20. Gabriel EJ, Ghajar J, Jagoda A, et al. Guidelines for prehospital management of traumatic brain injury. J Neurotrauma 2002;19:111174.
21. Chesnut RM, Gautille T, Blunt BA, et al. The localizing value of asymmetry in pupillary size in severe head injury: relation to lesion type and location. Neurosurgery 1994;34:840845; discussion 845846.
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25. Vassar MJ, Fischer RP, OBrien PE, et al. A multicenter trial for resuscitation of injured patients with 7.5% sodium chloride. The effect of added
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26. Vassar MJ, Perry CA, Gannaway WL, et al. 7.5% sodium chloride/dextran
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27. Vassar MJ, Perry CA, Holcroft JW. Prehospital resuscitation of hypotensive trauma patients with 7.5% NaCl versus 7.5% NaCl with added
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29. Rosner MJ, Coley IB. Cerebral perfusion pressure, intracranial pressure,
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four hours. N Engl J Med 1981;304:15111518.
TRAUMA
K E Y
Maxillofacial trauma is directly related to social structure,
geography, and economics. Facial injury patterns vary
according to age, risk taking, and daily activities.
2 Facial trauma is common (up to one third of all multisystem trauma patients), is frequently associated with lifethreatening injuries, and should provide a warning of
potential concomitant airway, central nervous system, and
orthopedic injuries.
3 Initial management of maxillofacial trauma follows
Advanced Trauma Life Support (ATLS) principles and
1
P O I N T S
involves airway management, control of hemorrhage, and
rapid identification of injuries with significant morbidity,
ocular injury, cerebrospinal fluid leakage, neurologic damage, and malocclusion.
4 Structured history and physical examination and computed tomography scanguided diagnosis with reconstruction of major facial buttress damage using open reduction
and internal fixation in a timely fashion are critical to optimize final functional and esthetic outcome.
354
the established Advanced Trauma Life Support (ATLS) protocols. Rarely is facial trauma itself directly life threatening;
however, as mentioned earlier, it should be viewed as a strong
indicator of a significant mechanism of injury with associated
injuries. Within the ATLS algorithms, there are considerations
specific to maxillofacial injuries.
Airway Management
Airway compromise in maxillofacial injuries can result from
direct laryngeal injury, foreign bodies (including aspirated teeth
and bone fragments), or active bleeding from an upper airway
source. Treatment of the compromised airway is complicated
by the likelihood that 10% of facial trauma patients have cervical spine injuries.7 As initial treatment, any blood clots
should be suctioned from the oropharynx, and a finger sweep
used to remove foreign material from the oral airway. Comminuted fractures of the mandible can lead to loss of support of
the hyomandibular complex and consequent ptosis and
retroposition of the tongue. Manual anterior traction on the
mandible symphysis will often temporarily resolve this obstruction until definitive control of the airway can be achieved.
For definitive control of the airway, an artificial oral or nasal
airway is often possible, but the use of blind nasal intubation
should be carried out with caution. Nasal intubations can exacerbate bleeding from the nasal and nasopharyngeal regions, and
the tube may be inadvertently placed into the cranial fossa in the
obtunded patient with a comminuted skull base fracture. In the
case of severe maxillofacial injuries such as a gunshot wound to
the face, intubation is often easier than expected, since the missing or pathologically mobile jaws allow an unprecedented view
of the glottis. As with all facial trauma patients, those with significant maxillofacial injury should have a secured airway early
in the trauma assessment. The secondary swelling that occurs
over the first few hours following the trauma can impede, or in
some cases prevent, oral intubation.
Emergent tracheotomy is rarely indicated except in the
unusual circumstance of laryngeal fracture or the inability to
intubate orally due to massive bleeding or swelling. Semielective tracheostomy in the operating room is reserved for those
cases with expected prolonged intubation due to massive soft
tissue and bony injuries or impaired consciousness.
Massive Hemorrhage
The elaborate vascularity of the head and neck can result in
rapid significant blood loss. Fortunately, the location of the
injuries allows sufficient access for direct pressure to control
the hemorrhage. Efforts should be made when possible to
expose and visualize the source of bleeding prior to suture ligature or cautery in order to avoid collateral damage to adjacent structures, primarily neural structures.
Nasopharyngeal bleeding is common in maxillofacial injuries.
The blood supply to the nose arises from both the internal and
external carotid systems. The external carotid artery supplies the
internal maxillary artery, whose sphenopalatine branch supplies
the posterior nasal septum and lateral nasal walls, and the facial
artery, whose superior labial branch supplies the anterior inferior
nasal cavity. The internal carotid artery gives off the ophthalmic
artery, which in turn supplies the anterior and posterior ethmoidal arteries that perfuse the superior and anterior nasal septum. The most common site of epistaxis is at the Kiesselbach
plexus at the confluence of the anterior ethmoidal and superior
labial arteries. Anterior bleeding is best controlled by formal anterior nasal packing of half-inch gauze coated with antibiotic ointment. The tail of the gauze is left exposed, and with the aid of a
nasal speculum, good lighting, and bayonet forceps, the gauze is
carefully layered and packed back and forth along the nasal floor
until the roof is reached. The direction of packing is directly posterior, then inferior. Prefabricated nasal packing is also available.
355
Ocular Injury
Direct injury to the eyeball should be suspected in all patients
with orbital fractures or lacerations to the periorbital region.
One prospective study reported a 29% incidence of ocular
injury in 49 patients with orbital fractures.9 Pain, decreased
vision, and the appearance of spots before the eyes are all
highly suggestive of globe damage. During the neurologic
phase of trauma assessment, a brief clinical ophthalmologic
examination should be performed. This would include visual
acuity, pupillary response to light and accommodation,
extraocular range of motion, globe position, and turgor. If
there are any abnormal findings on the examination, an immediate ophthalmologic consult should be obtained for examination of the retina and ocular pressures. Injuries that may
require immediate ophthalmologic treatment or result in permanent sequelae include corneoscleral lacerations, lens dislocation, major hyphema, acute glaucoma, and retinal detachment.
Blindness at the time of presentation is fortunately rare, but
is an extremely poor prognostic factor for future sight. Patients
with light perception at the time of presentation but who then
demonstrate progressive loss of vision during the trauma
assessment must be treated aggressively. The most common
etiology of this presentation is traumatic optic neuropathy
secondary to optic nerve compression from a retrobulbar
hematoma, a bone fragment, or edema. The management of progressive vision loss remains controversial, for it is unclear which
patients benefit from emergent optic nerve decompression. If the
eyeball is tense, then immediate lateral canthotomy is indicated
to release the confining force of the lids. If there is a clear source
of compression visualized on computed tomography (CT),
immediate operative decompression is indicated.10 All other
patients are treated with high-dose steroids.11
TRAUMA
356
Neurologic Injury
Injury to the muscles of facial expression or the seventh cranial
nerve can be particularly debilitating, due to their importance
in interpersonal interactions. The most common cause of
facial nerve injury is fracture of the temporal bone in the
intraosseous canal.13 Penetrating injury to the facial branches
of the seventh nerve requires exploration and repair, whereas
nonpenetrating injury is observed for recovery over a period of
3 to 6 months. Injury to the middle branches of the nerve distal
to the parotid (zygomatic and buccal) can be masked by crossinnervation with other branches. The marginal mandibular
(lower lip depressors) and temporal (brow elevation) branches
have the least degree of cross-innervation, and therefore more
commonly result in functional problems.
COMPUTED TOMOGRAPHY
DIAGNOSIS OF MAXILLOFACIAL
FRACTURES: THE FACIAL
BUTTRESSES
Occlusion
The functional units of the face are held together and stabilized by several vertical and horizontal skeletal buttresses
Occlusion is the contact of the posterior masticating (chewing)
(Fig. 20.1). These buttresses represent regions of relatively
and anterior incising (cutting) surfaces of the maxillary and
dense bone that serve to support the functional units of the
mandibular teeth. Malocclusion is an indicator of orthogface in an optimal relation and define the form of the face by
nathic fracture and/or dental injury. The maxillary teeth
projecting the overlying soft tissue envelope.14 Additionally,
should overlap the mandible teeth in normal occlusion in three
the facial buttresses stabilize the face to the cranial base and
ways: (a) overjet describes the horizontal projection of
determine the proper relationship between these two importhe upper front teeth in front of the lower teeth, (b) overbite
4 tant structural units. Conceptualizing and describing maxillodescribes the vertical overlap of the upper front teeth over the
facial fractures according to the involved buttresses is useful
lower teeth, and (c) the posterior maxillary arch should
because they are directly related to the definitive surgical treatbe wider than the mandible arch on both sides by the space of
ment. Each buttress can be visualized on the craniofacial CT
one cusp. Typical malocclusion patterns seen following fracscan. There are four transverse and four paired vertical buttures include an anterior open bite (gap between the upper and
tresses. Due to the reliance of facial form and function on these
lower front teeth), that indicates the fractured maxilla is
buttresses, as well as the mechanical force exerted on them, the
impacted upward or that both condyles of the mandible have
craniofacial trauma surgeon typically treats any significant
collapsed; a posterior open bite (gap between the upper and
buttress displacement using anatomic reduction and rigid
lower back teeth) often associated with a unilateral condylar
internal fixation.
fracture; or a posterior cross-bite (back teeth lateral or medial
As structural units that support the face, the buttresses
to the normal arch form) that indicates either a mandible fracmust
either directly or indirectly interface with the skull base
ture or a comminuted fracture of the maxilla and palate. These
or
cranium
as a stable reference. From superior to inferior, the
malocclusion patterns indicate that surgical intervention is
transverse
facial
buttresses are as follows:
indicated.
Missing or fractured teeth should be documented. If a tooth
is missing, the oral cavity and airway should be carefully
checked for the foreign body. Securing the tooth to an adjacent
one with a wire can often salvage a loose or dislocated tooth.
If a tooth is fractured with unstable fragments, the fragments
should be removed to prevent entrance into the airway.
FIGURE 20.1. Illustration of adult skull demonstrating the four paired vertical and four transverse buttresses, all existing in areas of relative increased bone
thickness.
Vertical buttresses
Lateral maxillary
(plus lateral
orbital wall)
Medial maxillary
(plus medial
orbital wall)
Posterior maxillary
(pterygomaxillary)
Posterior vertical
Transverse buttresses
Upper transverse
maxillary (plus
orbital floor)
Lower transverse
maxillary (plus
palate)
Upper transverse
mandibular
Lower transverse
mandibular
PATTERNS OF INJURY
Naso-orbito-ethmoid Fractures
NOE fractures involve the central upper midface between the
eyes, disrupting the confluence of the medial maxillary buttress
with the upper transverse maxillary buttress. Fractures of the
NOE complex can be one of the most difficult fracture patterns to accurately repair. Failure to restore the sagittal projection of this region and correct the rotation of the frontal
process of the maxilla (superior portion of the medial maxillary buttress) will result in a lack of upper nasal projection and
telecanthus (increased distance between the inner corner of the
eyes), both of which are difficult to correct as a secondary
operation. The eyelids insert around the lacrimal fossa
through the medial canthal tendon. If the tendon insertion is
not returned to its correct position, the patient loses the normal shadow definition on either side of the nose, the medial
corner of the palpebral fissure drifts laterally, and the eyes
appear too far apart. If the distance between the medial canthi
is greater than 30 mm, a NOE pattern should be suspected.
By definition, NOE fractures include damage to the ethmoid sinus and walls. If there is bilateral comminution and
Maxillary Fractures
With the exception of alveolar and palate fractures, maxillary
fractures are commonly described according to the classification described by Rene LeFort in 190116 (Fig. 20.3). LeFort
fractures involve a separation of all or a portion of the maxilla
TRAUMA
357
358
Mandible Fractures
from the skull base. For this to occur, the posterior vertical
maxillary buttress at the junction of the posterior maxillary
sinus with the pterygoid plates of the sphenoid must be disrupted. This can either be through the posterior walls of the
sinus or through the plates themselves as seen on axial CT
images. Once a pterygomaxillary disjunction has been diagnosed, the remaining facial buttresses are inspected to determine the class of LeFort fracture. If the inferior portions of
both the lateral and medial maxillary buttresses are fractured,
a LeFort I fracture has occurred, and the maxillary arch
(lower transverse maxillary buttress) will move in relation to
the rest of the face and skull. If the inferior lateral maxillary
buttress (zygomaticomaxillary suture) and the superior
medial maxillary buttresses (frontomaxillary sutures) are
fractured, then the entire maxilla will move in relation to the
skull base as a LeFort II fragment. If the upper transverse
(zygomatic arch), superior lateral (frontozygomatic), and
superior medial (maxillofrontal) maxillary buttresses are fractured, then craniofacial separation has occurred as a LeFort
III pattern, with the entire face moving in relation to the skull
base.
For all LeFort fractures, the maxillary dental arch is
mobile; therefore, the patient must be placed in maxillomandibular fixation prior to plating of the fractures. All buttresses can be plated with the exception of the buttress common to all LeFort patternsthe pterygomaxillary posterior
vertical buttress. Similar to zygomatic fractures, if there is
severe comminution of a buttress, bone grafting may be
required.
Unlike the rest of the facial buttresses, isolated mandible fractures are typically diagnosed with plain radiograph series. In a
trauma patient with multiple injuries, however, the diagnosis is
often made on CT scan imaging as a disruption of the mandible
arch. Fractures can occur at any point on the mandible including, in decreasing order of frequency, the body, angle, condylar neck, symphysis and parasymphysis, ramus, and alveolar
ridge. The condyles are best visualized on coronal images.
Many condylar fractures are not directly fixated because of the
difficulty accessing this region surgically as a result of the
proximity of the facial nerve, as well as the risk of iatrogenic
temporomandibular joint (TMJ) dysfunction. If there are
bilateral condylar neck fractures associated with a severely
comminuted LeFort fracture, one condyle is typically exposed,
reduced, and plated in order to reestablish a stable vertical
buttress for reestablishing facial height. Intracapsular condylar
injuries have a high risk of ankylosis and are treated conservatively with early range of motion if occlusion can be established.
SUMMARY
Maxillofacial injuries in a trauma victim should be considered
an indicator of associated severe injuries. The initial evaluation within the ATLS protocol includes special considerations
of airway management, ocular assessment, control of bleeding, identification of CSF leaks, and neurologic injury. The
definitive treatment of maxillofacial injuries, following a
structured history and physical examination, includes identification of damage to the facial buttresses on CT imaging.
Displaced buttress fractures require open reduction and internal fixation in a timely fashion to minimize secondary soft tissue contracture and optimize the final functional and esthetic
outcome.
References
1. Gassner R, Tuli T, Hachl O, et al. Cranio-maxillofacial trauma: a 10 year
review of 9,543 cases with 21,067 injuries. J Craniomaxillofac Surg 2003;
31(1):5161.
359
K E Y
The numerous vital structures in the neck are concentrated
in a small anatomic area at risk of injury, unprotected by
bone or dense muscular covering.
2 Anatomically, in addition to large bilateral anterior and posterior triangles, the anterior neck is divided into three zones:
zone I, extending from the sternal notch to the cricoid cartilage; zone II, from the cricoid cartilage to the angle of the
mandible; and zone III, from the angle of the mandible to
the base of the skull.
P O I N T S
3
TRAUMA
360
ANATOMY
2
The neck is classically divided into a number of anatomic triangles (Fig. 21.1). The two large anterior and posterior triangles are particularly important in neck trauma. Wounds to the
FIGURE 21.2. Proximity of cranial nerves to the carotid arteries of the neck. Trauma resulting in cranial nerve deficits in this
region is often associated with vascular injury.
361
ferred. If cervical spine injury has not been excluded, hyperextension of the neck must be avoided. Two-man intubation
with in-line cervical traction is the preferred alternative to
nasotracheal intubation.
A massive pharyngeal or neck hematoma can totally
occlude the airway, making direct intubation impossible.
Attempts at blind nasotracheal intubation can further aggravate mucosal or laryngeal injury, and an emergency surgical
airway (cricothyroidotomy or tracheostomy) is required.
Occasionally, blunt laryngeal trauma is so severe as to disrupt
and occlude the airway. The preferred method of controlling
the airway in this setting is controversial, but provisions for a
surgical airway must be at hand. Options include primary
tracheostomy or a single attempt at endoscopically assisted
endotracheal intubation. Temporization with transtracheal
needle-jet insufflation can be a valuable adjunct in these settings, and mandatory in the young child.
Concurrent with airway control is awareness of potential
cervical spine injury, particularly in unconscious patients who
FIGURE 21.3. Zones of the neck. The junction of zones I and II is
have sustained blunt head and neck trauma. The head and
variously described as being at the cricoid cartilage or at the top of the
neck should be supported in the neutral position until this posclavicles. The important implication of a zone I injury is the greater
potential for intrathoracic great vessel injury.
sibility is excluded radiographically and by physical examination. In the emergency room, support of the head and neck
during manipulation or procedures is best accomplished by a
strong, steady assistant rather than by collars, sandbags, or
tape. The lateral cervical spine film is an essential component
cation,4 zone I is defined as extending from the sternal notch to
of the initial evaluation of patients with either blunt or penethe lower border of the cricoid cartilage (Fig. 21.3). Injuries
trating neck trauma, both to assess the bony cervical spine and
here carry the highest mortality rate because of the risk of
to evaluate soft tissues for edema or malplaced air.
major vascular and intrathoracic injury. Zone II is the central
The initial management subsequent to control of the airand largest portion of the neck. It extends from the top of zone
way follows the ABC guidelines of trauma care advocated by
I to the angle of the mandible. Zone II injuries are most comthe Advanced Trauma Life Support course of the American
mon but carry a lower mortality rate than either zone I or III
College of Surgeons, with particular attention directed at adeinjuries, because injury is usually apparent and exposure of
quacy of ventilation, treatment of shock, and baseline neurovital structures is readily accomplished. Zone III is that part of
logic examination. Patients with blunt neck trauma often have
the neck above the angle of the mandible. The risk of injury to
concomitant thoracic injuries, and penetrating neck wounds
the distal carotid artery, salivary glands, and pharynx is greatmay follow a caudal trajectory, injuring lung or intrathoracic
est in this zone. Exposure in this region can be particularly
great vessels, particularly if the entrance is in zone I.5 Rapid
difficult.
physical examination of the thorax is therefore part of the iniThe other major anatomic landmark in the neck is the
tial evaluation of neck trauma patients and should include
platysma muscle. This thin, broad muscle lies just beneath the
inspection, palpation, and auscultation. Pneumothorax must
skin and covers the entire anterior triangle and anteroinferior
be treated rapidly by needle decompression or tube thoracosaspect of the posterior triangle. Wounds that fail to penetrate
tomy, or both, and treatment should not necessarily be delayed
the platysma are considered superficial and do not warrant
for radiographic confirmation, particularly in the unstable
extensive evaluation. Wounds that penetrate the platysma
patient. Major neck hemorrhage is treated with direct presmust be considered a serious surgical problem that mandates
sure. Blind clamping of vessels is discouraged to avoid inadhospital admission and further evaluation.
vertent injury to adjacent nerves or esophagus. Adequate
peripheral intravenous access is required in all patients with
neck trauma and usually requires at least two peripheral intravenous catheter lines of 16 gauge or larger contralateral to the
side of greatest neck injury. Blood is drawn for typing and
INITIAL MANAGEMENT
cross matching and routine laboratory evaluations, and fluid
resuscitation is initiated based on the degree of shock and
The same priorities for initial care of the multiply injured
anticipated hemorrhage. A rapid yet thorough neurologic
patient apply to the management of isolated neck trauma. Airexamination is also part of the initial management, with parway control remains the primary tenet of initial trauma care,
ticular attention to the patients level of consciousness and the
and it takes precedence over all other aspects of the evaluation
status of cranial and brachial plexus nerves. Changes in the
and resuscitation. If injury involves the airway itself or surresults of neurologic examination are key indicators of progresrounding structures, this management task takes on special
sive injury.
significance. Rapid inspection for air movement, crepitus,
After the initial resuscitation, a complete physical examinahoarseness, and subcutaneous emphysema is the first step. 3
tion is performed to detect associated injuries and to better
Supplemental oxygen should always be administered, and adedefine the extent of neck trauma. Close visual inspection of the
quate lighting and suction are essential. If spontaneous ventineck alerts the physician to the possibility of underlying
lation appears adequate, close observation and pulse oximetry
injuries and the mechanism of injury. For example, an oblique
monitoring are suggested, because acute decompensation can
4- to 6-cm bruise on the neck of a restrained passenger in a
occur with little warning. If spontaneous respirations are inadmotor vehicle accident should alert the physician to the possiequate, if blood or other material obstructs the airway, or if
bility of blunt cervical vascular trauma from a seat belt injury.
progressive cervical swelling from hemorrhage threatens to
Neck wounds should not be probed for fear of dislodging a
occlude the airway, emergency intubation is necessary. Proclot and reinstituting hemorrhage. The neck should be palcrastination converts a simple intubation into a difficult and
pated with attention to normal anatomic landmarks and areas
bloody emergency tracheostomy. Direct visualization of the
of tenderness. Crepitus or subcutaneous emphysema indicates
vocal cords and oral endotracheal intubation are usually pre-
TRAUMA
362
TA B L E 2 1 . 1
DIAGNOSIS
DIGESTIVE TRACT
Shock
Hemoptysis
Active bleeding
Dysphagia or odynophagia
Large or expanding
hematoma
Hematemesis
Pulse deficit
Subcutaneous emphysema
AIRWAY
NEUROLOGIC
Dyspnea
Stridor
TA B L E 2 1 . 2
MANDATORY OPERATION COMPARED WITH SELECTIVE
MANAGEMENT OF PENETRATING NECK TRAUMA
MANDATORY
SELECTIVE
Number of series
11
24
Number of patients
1,653
2,540
Mortality rate
(range)
5.85%
(0.3%11.0%)
3.75%
(0%9.8%)
Cases explored
Patients
Outcome
Hoarseness
Dysphonia or voice change
Subcutaneous emphysema
injury to the trachea, esophagus, or lung until proven otherwise. Never assume that a penetrating skin wound itself is
responsible for subcutaneous air. If the patient is able to talk,
determine the presence of hoarseness, dysphagia, or dysphonia. Hemoptysis and hematemesis are also signs of tracheal or
esophageal injury. Table 21.1 lists the clinical signs of significant injury that usually mandate neck exploration to exclude
or treat vascular, airway, esophageal, or nerve injuries.
All patients with blunt or penetrating neck trauma should
have a chest radiograph to rule out thoracic trauma. Stable
patients should have soft tissue neck films to look for retropharyngeal hematoma, tracheal narrowing or deviation, retained
missile fragments and pathways, and subcutaneous or retropharyngeal air. Computed tomography (CT) of the neck is particularly helpful in blunt trauma to evaluate laryngeal structures to
look for laryngeal fractures. Patients with blunt neck trauma
whose neurologic examination is inconsistent with findings on
head CT should undergo studies to evaluate for cervical vascular injury.
SELECTIVE VERSUS
MANDATORY EXPLORATION
There is uniform agreement that all unstable patients and all
patients with clinical signs of significant neck injury require
prompt exploration. All other patients with wounds that penetrate the platysma should at least be admitted to the hospital
and observed. Controversy exists, however, in the management of asymptomatic, stable patients with penetrating neck
4 injury. Two distinct schools of thought exist, one advocating
mandatory surgical exploration of all wounds that penetrate
the platysma2,6,7 and the other favoring a more selective
approach.812 A comprehensive review of selective versus
mandatory operative management published in 1991 documents similar rates for injury incidence, overall mortality, and
delayed complications, as well as similar hospital costs, but
with a significant reduction of negative neck explorations in
the selective management group13 (Table 21.2). Most recent
studies have advocated some type of selective management in
a clinical setting with explicit guidelines and expertise in the
appropriate use of various diagnostic modalities.1417
Advocates of a mandatory exploration policy cite the low
morbidity and negligible mortality rate after negative neck
exploration as justification for the high rate of negative findings
1,492 (90.2%)
1,596 (62.8%)
Positive explorations
803 (53.8%)
1,117 (70.0%)
Cases observed
161 (9.8%)
Delayed exploration
3 (1.9%)
944 (37.2%)
20 (2.1%)
System injured
Arterial injuries
213 (12.9%)
303 (11.9%)
Venous injuries
310 (18.8%)
459 (18.0%)
Esophagus or
pharynx
163 (9.9%)
191 (7.5%)
Larynx or trachea
150 (9.1%)
181 (7.1%)
363
TRAUMA
364
OPERATIVE EXPLORATION
Of patients with penetrating neck trauma (depending on mechanism), 25% to 50% present with obvious signs of injury requiring prompt operation. An additional 10% to 20% of patients
without clinical signs of injury are discovered to have significant
vascular, esophageal, or airway injury on further diagnostic testing. A physician treating patients with neck trauma must be
capable of performing a complete neck exploration and repair of
vascular and aerodigestive injuries. Neck exploration should be
performed in the operating room under general endotracheal
anesthesia. In the hemodynamically stable patient with a patent
airway, intubation can be deferred until laryngoscopy and bronchoscopy have been performed. A nasogastric tube is usually
passed to ensure an empty stomach. Preparation and draping of
the patient before induction of anesthesia allows control of hemorrhage if the patient starts to gag at the time of placement of the
endotracheal tube. The chest is also auscultated before surgery,
and a chest radiograph is routinely performed, because penetrating injuries may follow a downward path with pleural penetration. A pneumo-thorax may not develop until positive-pressure
ventilation is applied, and it may initially present as unexplained
hypotension during anesthesia.
The incision is planned to allow full exposure of the tract of
the injury (Fig. 21.4). The oblique incision along the anterior
border of the sternocleidomastoid muscle is preferred for unilateral and high (zone III) injuries, whereas the transverse collar incision is preferable for bilateral or neck-traversing
wounds. Extension of either neck incision into a median sternotomy affords excellent exposure of the thoracic great vessels. Proximal and distal control of the major vessels potentially involved must also be considered in the length and
position of the incision, and the patient is always surgically
prepared for a possible median sternotomy. The tract of the
injury is followed to its depth, systematically examining each
structure in or near the tract.
MANAGEMENT OF
SPECIFIC INJURIES
Blood Vessels
Blood vessels are the most commonly injured structures in the
neck. Major arterial and venous injuries occur in 18% and
26% of penetrating neck wounds, respectively.48 There has
been an increase in reported blunt carotid injuries, most likely
due to better recognition.4951 Most recent studies report an
incidence rate of 1% to 2% for blunt cervical vascular injuries.
The initial diagnosis, however, remains a difficult one and must
always be suspected with an appropriate mechanism of injury.
Carotid Artery
In one of the largest series reported in English literature, 85 blunt
carotid injuries were recognized in 67 patients over 11 years in a
level I trauma center.51 Motor vehicle crashes were the most
common injury mechanism (82%), followed by motorcycle
crashes (7%) and assaults (6%). All but two of the patients had
associated injuries, and combinations of blunt carotid injury
with closed head and cervical spine injuries occurred in 48% and
6% of patients, respectively. The initial physical examination
demonstrated neurologic examination that was not compatible
with brain CT in 34% and soft tissue injury in the anterior neck
in 14% of the patients. A neurologic deficit developed subsequent to hospital admission in 43% of the patients. The average
interval from injury to definitive diagnosis was 53 hours, highlighting the point that, although its recognition is often delayed,
blunt carotid trauma must be suspected in patients who develop
focal neurologic signs or symptoms after a latent interval. In a
multicenter review, 29% of patients developed significant neurologic deficits more than 12 hours after admission.41 Other physical findingsexpanding hematoma, audible bruit, pulsatile
neck mass, palpable thrill, Horner syndrome, or any neurologic
symptom not explained by other injuriesmay be absent at the
initial examination. Cervical vascular injury should be suspected
in trauma patients with neurologic deficit not explained by head
CT. Because some evidence suggested improved outcome with
early diagnosis,41,50,51 a high index of suspicion must exist if the
mechanism of injury involves a direct blow to or compression of
the neck, basilar skull fracture, cervical hyperextension and rotation, or blunt bilateral perioral fractures. Table 21.3 lists screening criteria for blunt cerebrovascular injury in asymptomatic
trauma patients.27,30
The mortality rate remains high with blunt carotid injury,
ranging from 20% to 40%, with permanent neurologic impairment in 25% to 80% of survivors.41,5052 There is a reasonably
good neurologic outcome, better than 55%, for an uncomplicated arterial dissection and a uniformly poor outcome, with
365
Vertebral Artery
TA B L E 2 1 . 3
DIAGNOSIS
Traumatic injury to the vertebral artery, once only rarely diagnosed, is now more commonly identified because of the liberal
application of neck angiography after both penetrating and
blunt neck injuries. Blunt vertebral artery injuries occur more
commonly than blunt carotid injuries, probably because of the
close association of bony and ligamentous structures. Mechanisms reported to cause vertebral artery injury are remarkably
diverse, including hyperextension and rotation, direct blows,
chiropractic manipulation, yoga exercises, volleyball, and even
head banging to heavy metal rock music.63,64 Unilateral vertebral artery occlusion seldom results in a neurologic deficit,
despite a 15% incidence of congenital unilateral hypoplastic
vertebral arteries.65 Treatment of blunt vertebral artery injury
with thrombosis usually is nonoperative: systemic anticoagulation (if possible) is recommended to avoid further propagation
TRAUMA
366
367
TRAUMA
FIGURE 21.7. Frontal view (A) and three-quarters view (B) of the larynx.
368
Nerves
The preoperative determination of level of consciousness and
lateralizing gross motor or sensory deficits is required in all
patients; a more detailed neurologic examination of the
brachial plexus, deep cervical plexus, phrenic nerve, and cranial nerves should be performed in all but the most unstable
patients. A hypoglossal or spinal accessory nerve injury is particularly easy to miss unless a preoperative neurologic examination is performed. The vagus nerve can be evaluated by
examination of the vocal cords. Primary dbridement and
repair of all severed or lacerated named nerves is preferred,
with the use of fine interrupted nonabsorbable sutures on the
perineurium. Repair of a single recurrent nerve injury is controversial. An avulsed recurrent laryngeal nerve (blunt laryngotracheal disruption) should be implanted into the posterior
cricoarytenoid muscle.79 If a motor nerve deficit is apparent,
an expendable sensory nerve such as the great auricular can be
interposed as a nerve graft to allow anastomosis without tension. If the patients condition precludes primary repair, the
nerve ends should be marked with silver clips or nonabsorbable colored sutures. Secondary repair several weeks after
injury is advised.
References
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3. Sankaran S, Walt AJ. Penetrating wounds of the neck: principles and some
controversies. Surg Clin North Am 1977;57:139150.
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5. Flint LM, Snyder WH, Perry MO, et al. Management of major vascular
injuries in the base of the neck. An 11-year experience with 146 cases.
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6. Bishara RA, Pasch AR, Douglas DD, et al. The necessity of mandatory
exploration of penetrating zone II neck injuries. Surgery 1986;100:
655660.
7. Jones RF, Terrell JC, Salyer KE. Penetrating wounds of the neck: an analysis of 274 cases. J Trauma 1967;7:228237.
8. Ayuyao AM, Kaledzi YL, Parsa MH, et al. Penetrating neck wounds.
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12. Merion RM, Harness JK, Ramsburgh SR, et al. Selective management of
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13. Asensio JA, Valenziano CP, Falcone RE, et al. Management of penetrating
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14. Biffl WL, Moore EE, Rehse DH, et al. Selective management of penetrating neck trauma based on cervical level of injury. Am J Surg 1997;174:
678682.
15. Irish JC, Hekkenberg R, Gullane PJ, et al. Penetrating and blunt neck
trauma: 10-year review of a Canadian experience. Can J Surg 1997;40:
3338.
16. Klyachkin ML, Rohmiller M, Charash WE, et al. Penetrating injuries of
the neck: selective management evolving. Am Surg 1997;63:189194.
17. Sofianos C, Degiannis E, Van den Aardweg MS, et al. Selective surgical
management of zone II gunshot injuries of the neck: a prospective study.
Surgery 1996;120:785788.
18. Carducci B, Lowe RA, Dalsey W. Penetrating neck trauma: consensus and
controversies. Ann Emerg Med 1986;15:208215.
19. Hirshberg A, Wall MJ, Johnston RH Jr, et al. Transcervical gunshot
injuries. Am J Surg 1994;167:309312.
20. Sclafani SJ, Cavaliere G, Atweh N, et al. The role of angiography in penetrating neck trauma. J Trauma 1991;31:557562; discussion 562563.
21. Inaba K, Munera F, McKenney M, et al. Prospective evaluation of screening multislice helical computed tomographic angiography in the initial
evaluation of penetrating neck injuries. J Trauma 2006;61:144149.
22. Munera F, Cohn S, Rivas LA. Penetrating injuries of the neck: use of helical computed tomographic angiography. J Trauma 2005;58:413418.
23. Gonzalez RP, Falimirski M, Holevar MR, et al. Penetrating zone II neck
injury: does dynamic computed tomographic scan contribute to the diagnostic sensitivity of physical examination for surgically significant injury?
A prospective blinded study. J Trauma 2003;54:6164; discussion 6465.
24. Richardson JD, Flint LM, Snow NJ, et al. Management of transmediastinal gunshot wounds. Surgery 1981;90:671676.
25. Weigelt JA, Thal ER, Snyder WH 3rd, et al. Diagnosis of penetrating cervical esophageal injuries. Am J Surg 1987;154:619622.
26. Gracias VH, Reilly PM, Philpott J, et al. Computed tomography in the
evaluation of penetrating neck trauma: a preliminary study. Arch Surg
2001;136:12311235.
27. Biffl WL, Moore EE, Offner PJ, et al. Optimizing screening for blunt cerebrovascular injuries. Am J Surg 1999;178:517522.
28. Rogers FB, Baker EF, Osler TM, et al. Computed tomographic angiography as a screening modality for blunt cervical arterial injuries: preliminary
results. J Trauma 1999;46:380385.
29. LeBlang SD, Nunez DB Jr. Helical CT of cervical spine and soft tissue
injuries of the neck. Radiol Clin North Am 1999;37:515532, vvi.
30. Miller PR, Fabian TC, Croce MA, et al. Prospective screening for blunt
cerebrovascular injuries: analysis of diagnostic modalities and outcomes.
Ann Surg 2002;236:386393; discussion 393395.
31. Nunez DB Jr, Torres-Leon M, Munera F. Vascular injuries of the neck and
thoracic inlet: helical CT-angiographic correlation. Radiographics 2004;
24:10871098; discussion 10991100.
32. Munera F, Soto JA, Nunez D. Penetrating injuries of the neck and the
increasing role of CTA. Emerg Radiol 2004;10:303309.
33. Munera F, Soto JA, Palacio DM, et al. Penetrating neck injuries: helical CT
angiography for initial evaluation. Radiology 2002;224:366372.
34. Biffl WL, Egglin T, Benedetto B, et al. Sixteen-slice computed tomographic
angiography is a reliable noninvasive screening test for clinically significant
blunt cerebrovascular injuries. J Trauma 2006;60:745751; discussion
751752.
35. Eastman AL, Chason DP, Perez CL, et al. Computed tomographic angiography for the diagnosis of blunt cervical vascular injury: is it ready for
primetime? J Trauma 2006;60:925929; discussion 929.
36. Utter GH, Hollingworth W, Hallam DK, et al. Sixteen-slice CT angiography in patients with suspected blunt carotid and vertebral artery injuries.
J Am Coll Surg 2006;203:838848.
37. Berne JD, Reuland KS, Villarreal DH, et al. Sixteen-slice multi-detector
computed tomographic angiography improves the accuracy of screening
for blunt cerebrovascular injury. J Trauma 2006;60:12041209; discussion 12091210.
38. Malhotra AK, Camacho M, Ivatury RR, et al. Computed tomographic
angiography for the diagnosis of blunt carotid/vertebral artery injury: a
note of caution. Ann Surg 2007;246:632642; discussion 642643.
39. Davis JW, Holbrook TL, Hoyt DB, et al. Blunt carotid artery dissection:
incidence, associated injuries, screening, and treatment. J Trauma 1990;
30:15141517.
40. Mascalchi M, Bianchi MC, Mangiafico S, et al. MRI and MR angiography
of vertebral artery dissection. Neuroradiology 1997;39:329340.
41. Cogbill TH, Moore EE, Meissner M, et al. The spectrum of blunt injury to
the carotid artery: a multicenter perspective. J Trauma 1994;37:473479.
42. U-King-IM JM, Trivedi RA, Graves MJ, et al. Contrast-enhanced MR
angiography for carotid disease: diagnostic and potential clinical impact.
Neurology 2004;62:12821290.
43. Ho KY. MR angiography of carotid arteries. JBR-BTR 2004;87:2932.
44. Hathout GM, Duh MJ, El-Saden SM. Accuracy of contrast-enhanced MR
angiography in predicting angiographic stenosis of the internal carotid
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
369
TRAUMA
K E Y
P O I N T S
Thoracic injuries account for 25% of immediate traumarelated deaths, second only to head and spinal cord injuries.1
For those who survive the initial trauma, an additional 25%
will die within the first year from complications.2 Initial
assessment and treatment of patients with thoracic trauma
consists of the primary survey and intervention, resuscitation
of vital functions, detailed secondary survey, and definitive
care.
Major thoracic injuries can be grouped together as the
2 fatal 14 (Table 22.1). The lethal six (airway obstruction,
tension pneumothorax, open pneumothorax, flail chest with
pulmonary contusion, massive hemothorax, and cardiac tamponade) are immediate life-threatening injuries that should be
corrected as they are being identified during the primary
3 survey. The hidden eight (simple pneumothorax, hemothorax,
pulmonary contusion, tracheobronchial tree injury, blunt cardiac
injury, traumatic aortic disruption, traumatic diaphragmatic tear,
and esophageal rupture) are potentially life-threatening injuries
that should be detected during the secondary survey with subsequent definitive treatment.
TREATMENT OF INJURIES
DURING THE PRIMARY SURVEY
Airway Assessment
The first priority in treating trauma patients is airway management. Trauma personnel rarely see acute airway injuries
presenting to the emergency department (ED), which is likely
the result of the high fatality rate at the scene secondary to
aspiration of blood, secretions, and debris causing an acute
BREATHING
airway obstruction. Acute management of the airway should
Complete exposure of the patients chest and neck allows for
follow the guidelines proposed and updated regularly by the
assessment of breathing and the neck veins. Signs of chest
American College of Surgeons Committee on Trauma for
injury or hypoxia include increased respiratory rate or change
Advanced Trauma Life Support (ATLS). The cornerstones of
in breathing pattern.
airway management are adequate oxygenation, ventilation,
and protection from aspiration. Airway patency and air
exchange should be assessed by listening for air movement at
the patients nose, mouth, and lung fields; inspecting the
Tension Pneumothorax
oropharynx for airway obstruction; and observing for intercostal and supraclavicular muscle retractions. Orotracheal 4 Tension pneumothorax develops secondary to a bronintubation with appropriate cervical spine immobilization and
chopleural fistula (BPF) acting as a one-way valve, allowing for
direct laryngoscopy is the most common important first step in
air entry into the pleural space from a defect in the lung
370
TA B L E 2 2 . 1
CLASSIFICATION OF MAJOR THORACIC INJURIES (FATAL 14)
A. Injuries identified during the primary survey
(lethal six)
i.
ii.
iii.
iv.
v.
vi.
Airway obstruction
Tension pneumothorax
Open pneumothorax
Flail chest with pulmonary contusion
Massive hemothorax
Cardiac tamponade
Simple pneumothorax
Hemothorax
Pulmonary contusion
Tracheobronchial tree injury
Blunt cardiac injury
Traumatic aortic disruption
Traumatic diaphragmatic tear
Esophageal rupture
371
Open Pneumothorax
Chest wall defects that are significantly large can remain open
and result in an open pneumothorax. Such wounds usually
FIGURE 22.1. A 27-year-old patient with history of a 200-lb bag of fertilizer falling onto the back of the neck with subsequent hyperextension
and disruption of the cervical trachea. A: Patients airway is stabilized with an endotracheal tube placed into the distal trachea. B: Primary repair
of the cervical trachea is performed with interrupted 40 Vicryl sutures.
TRAUMA
372
FIGURE 22.2. A: Simple pneumothorax: air collects between the lung and chest wall. B: Tension pneumothorax: air collects between the lung
and chest wall, with associated mediastinal shift. This leads to compression of venous structures and subsequent decreased venous return to the
heart.
preventing air entry through the chest wall. When the patient
exhales, the open end of the dressing allows air to escape from
the pleural space. A chest tube is placed remotely from the
wound.
The next priority is to address any underlying intrathoracic
injuries. If definitive surgical intervention is needed, an attempt
is made to make the thoracotomy in such a fashion to preserve
blood supply and muscle mass of the chest wall adjacent to the
defect. After repair of intrathoracic injuries and dbridement of
devitalized tissue, the next step is to plan the definitive closure
of the wound. In the interim, aggressive wound dbridement,
drainage of pneumothorax and/or hemothorax, and simple
packing are appropriate.3 A dreaded complication of chest
Rib
Rib
Lung
Lung
FIGURE 22.3. Occlusive dressing for open pneumothorax: an open pneumothorax occurs when there is a pneumothorax associated with a
chest wall defect such that the pneumothorax communicates with the exterior. Treatment entails placing an occlusive dressing as well as an
intercostal drain (chest tube). The occlusive dressing is airtight on three sides. A: Inspiration: the occlusive dressing prevents air entry into the
chest. B: Expiration: air escapes from the wound and exits at the inferior aspect of the dressing.
pulmonary parenchyma, injury. Although chest wall instability leads to paradoxical motion of the chest wall during inspiration and expiration, the major difficulty in flail chest is the
injury to the lung (pulmonary contusion). Additional restriction in chest wall movement from the associated pain further
exacerbates hypoxia.
There has been intense debate about the role of surgical
intervention for flail chest. In the preventilator era, intervention centered on external fixation techniques such as external
strapping, the placement of sandbags, or even external fixation
combined with traction.5 The significant rate of complications,
prolonged bed rest needed for fracture union, and high failure
rates led to early ventures in internal fixation. However, the
use of positive-pressure mechanical ventilation (internal splinting) led to the observation of adequate stabilization in most
patients, and hence the enthusiasm for surgical intervention
waned. Only select patients who had persistent flail despite
mechanical ventilation had a variety of attempted rib fracture
repairs done with plates, wires, and intramedullary techniques.
Recently, two randomized trials suggested that patients may
FIGURE 22.4. Pathophysiology of flail chest. A: Inspiratory phase: chest wall collapses inward, causing air to
move out of the bronchus of the involved lung into the
trachea and bronchus of the uninvolved lung, causing a
shift of mediastinum to the uninvolved side. B: Expiratory phase: chest wall balloons outward so that air is
expelled from the lung on the uninvolved side and
enters the lung on the involved side with an associated
shift of mediastinum to the involved side.
TRAUMA
wounds is necrotizing infection.4 These infectious complications need wide local dbridement and reconstruction. Most
chest wall defects can be closed with viable autogenous tissue,
usually through rotation of local flaps of the pectoral muscle,
latissimus dorsi, or rectus abdominus. Collaboration between
trauma surgeons, plastic surgeons, and thoracic surgeons is
often helpful in these complex cases. Extensive injuries may
dictate the need for mesh reconstruction with either Gore-Tex
or methyl methacrylate.
373
374
larity. Neck veins should be noted for distention. Cardiac contusions can lead to arrhythmias, which can be exacerbated
with hypoxia and acidosis. Major thoracic injuries that affect
circulation should be addressed during the primary survey,
such as massive hemothorax and cardiac tamponade.
Massive Hemothorax
CIRCULATION
After acute life-threatening airway and breathing issues are
addressed during the primary survey, the patient is assessed for
hypovolemia. The pulse is noted for its quality, rate, and regu-
Cardiac Tamponade
Cardiac tamponade is more often seen in penetrating injuries
than blunt. Filling of the pericardium with blood can occur
with injuries to the heart, great vessels, or pericardial vessels.
Regardless of the mechanism, the collection of blood in the
pericardium can result in tamponade physiology. Only a relatively small amount of blood in the relatively fixed fibrous sac
(i.e., the pericardium) is needed to restrict cardiac activity and
impair cardiac filling. Rising intrapericardial pressure causes
hemodynamic instability and decreased cardiac perfusion,
classically described in three phases.12 In the first phase, rising
pericardial pressure restricts ventricular diastolic filling and
reduces subendocardial blood flow.13 In this phase cardiac output is maintained by compensatory tachycardia, increased systemic vascular resistance, and elevated ventricular filling pressure. In the second phase, rising pericardial pressure further
compromises diastolic filling, stroke volume, and coronary
perfusion, resulting in diminished cardiac output. Initial signs
of shock such as anxiety, diaphoresis, and pallor become evident in this phase. In the third phase, compensatory mechanisms fail as the intrapericardial pressure approaches the ventricular filling pressure. Cardiac arrest results as profound
coronary hypoperfusion occurs.
Signs of cardiac tamponade may be difficult to detect.
Becks triad of muffled heart sounds, jugular venous distention, and pulsus paradoxus is present in only 15% of patients
who are later judged to have tamponade.14 Differences in
blood pressure greater than 10 mm Hg suggest accentuation of
the physiologic drop in pressure associated with inspiration.
Pulsus paradoxus can be difficult to detect in a noisy emergency room with a tachypneic patient. However, chest radiography can occasionally but unreliably demonstrate a widened
4th
intercostal
space
increased myocardial demand, increasing acidosis from malperfusion, and risk of paraplegia.
In a patient with a penetrating chest injury who develops
profound hypotension and cardiac arrest following endotracheal intubation and positive-pressure ventilation, a bronchovenous air embolism should be suspected. The traumatic
alveolar-venous communication leads to migration of the air
embolism to the coronary circulation, with resultant myocardial ischemia and shock. The associated low pulmonary venous
pressure from intrathoracic blood loss and high bronchoalveolar pressure from positive-pressure ventilation increase the gradient for air transfer across the bronchovenous channels.20
Immediate thoracotomy with pulmonary hilar cross-clamping
prevents further pulmonary venous embolism. The pericardium is opened, and with the patient in Trendelenburg
position, air trapped in the ventricles is removed by aspiration.
Cardiac massage may also dissolve air present in the coronary
arteries. Aspiration of the aortic root is also done to remove
any additional accumulated air.
Analysis of the literature on EDT indicates that the success
rates approach 35% in the patient arriving in shock with penetrating cardiac wounds and 15% for all penetrating wounds.18
In contrast, the results of EDT are poor in the setting of blunt
trauma, with a survival of only 1% to 2%. Patients undergoing
cardiopulmonary resuscitation (CPR) prior to arrival in the ED
should be stratified based on the type of injury and transport
time to assess the potential utility of EDT.
TREATMENT OF
INJURIES DURING THE
SECONDARY SURVEY
The secondary survey includes detailed physical examination,
a chest radiograph (ideally upright, injuries permitting), arterial blood gas measurements, pulse oximetry, and ECG monitoring. The chest radiograph is examined for adequate lung
expansion, presence of fluid, widening of the mediastinum,
mediastinal shift, and loss of anatomic detail. Multiple rib
fractures and fractures of the first and second ribs are indicative of a severe force delivered to the chest. Unlike the previously described immediate life-threatening conditions, injuries
detected during the secondary survey are not obvious on physical examination. A high degree of suspicion is needed, along
with appropriate studies.
TRAUMA
cardiac shadow. Central venous pressure (CVP) reflecting elevated pressures can lead to the diagnosis, but may be absent
due to hypovolemia. Elevated CVP and pulseless electrical activity (PEA) are nonspecific signs. Prompt diagnosis and evacuation of pericardial blood are indicated for patients who do not
respond to the usual measures of resuscitation for hemorrhagic
shock and have the potential for cardiac tamponade. Methods
that are rapid and accurate in assessing cardiac injuries include
focused sonogram in trauma (FAST) and echocardiography.15
The presence of a pericardial effusion is diagnostic. However,
its absence does not necessarily rule out injury.16 Specifically,
echocardiography cannot reliably rule out cardiac injury in the
setting of an associated left pleural effusion. This occurs due to
the effusion obscuring the pericardium or the effusion occurring as a result of a pericardial tear and escape of blood from
the pericardium into the pleural space. In this circumstance,
the pericardial sac may be empty.
In the first two phases of cardiac tamponade, patients may
be aggressively managed with definitive airway control and volume resuscitation, and may be temporized with an attempted
pericardiocentesis. However, definitive intervention requires
taking the patient to the OR for a pericardial window or immediate median sternotomy. A pericardial window is typically performed through the subxiphoid approach, although there is a
role for thoracoscopy in the stable patient with an associated
hemothorax or if the abdominal route is to be avoided in the
case of intra-abdominal contamination.17 When the diagnosis
is highly likely due to pattern or injury, hemodynamic
responses, and/or ultrasound (FAST) results, a primary median
sternotomy may be indicated prior to further physiologic deterioration for both definitive diagnosis and treatment. In the
third phase of tamponade, patients have profound hypotension
and should undergo ED thoracotomy (EDT) for evacuation of
pericardial blood. Following the release of tamponade, the
source of bleeding is directly controlled.
375
376
suggested a chest tube be placed for those with two or more rib
fractures. In another prospective study,25 8 out of 15 patients
on positive-pressure ventilation required chest tubes, with
three of these patients having developed tension pneumothoraces. The authors thus recommended chest tubes to be placed
for all patients with occult pneumothoraces and requiring
positive-pressure ventilation. In contrast, Brasel et al. in a
prospective study of 44 patients found that neither size nor
positive-pressure ventilation correlated with the development
of clinically significant pneumothorax that needed a chest
tube.26 Thus, the treatment of an occult pneumothorax should
be done in the context of the whole patient. In the stable
patient an occult pneumothorax may be observed, but in those
with multiple injuries, it would be wiser to place a chest tube.
Serial examinations in those patients observed include repeat
chest radiographs at 6 and 24 hours.
Currently, the standard treatment for a traumatic pneumothorax found on the screening AP chest radiograph is
placement of a chest tube to allow for reexpansion of the lung
and apposition of visceral and parietal pleurae. Supplemental
oxygen may be tried to enhance reabsorption of the pneumothorax, but it is unlikely that high inspired oxygen tensions
(60%) will provide any more benefit than O2 given by nasal
prongs.27
SIMPLE PNEUMOTHORAX
A pneumothorax is one of the most common traumatic
injuries, with a reported prevalence of 20% in patients arriving alive to trauma centers.21 There are three types of pneumothoraces: simple, open, and tension. A simple pneumothorax is a collection of air trapped in the pleural space. The most
common cause is air leaking into the pleural space as a result
of a parenchymal lung injury. Open pneumothorax occurs
when wounds of the chest wall allow air to enter the pleural
space from the outside. A tension pneumothorax occurs when
air collects in the pleural space under pressures exceeding
atmospheric pressure. This pressure collapses the affected lung
and is transmitted to the mediastinal structures, leading to a
shift of the heart and great vessels away from the side of the
pneumothorax.
The etiology of a pneumothorax differs in blunt and penetrating trauma. Pneumothoraces following blunt trauma may
occur from (a) a sudden increase in intrathoracic pressure
leading to ruptured alveoli and air leak, (b) rib fractures lacerating the lung, (c) deceleration injuries tearing the lung, or (d)
blunt forces directly crushing and disrupting alveoli. In penetrating trauma, the etiology is the direct laceration of lung
parenchyma.
A definitive diagnosis is made on chest radiography (Fig.
22.7). Associated findings include subcutaneous emphysema,
decreased breath sounds, and overlying chest wounds. With
the increased use of computed tomography (CT) in the evaluation of the trauma patient, it is apparent that pneumothoraces
can be missed on supine anteroposterior (AP) chest radiography. This rate of missed pneumothorax has been estimated to
be as high as 20% to 35%. The patients symptoms and physiologic response to the pneumothorax is significantly more
important than the apparent size and should dictate the
urgency of treatment.
There is debate regarding the management of patients
whose pneumothorax is visible only on CT and not on a chest
radiography. The reported incidence of these occult pneumothoraces is between 2% and 8% of all blunt trauma patients.22,23
In one retrospective study, the size of the occult pneumothorax
was correlated with the need for a chest tube, and recommendation was made for chest tube placement in all pneumothoraces greater than 5 80 mm in size.24 These authors also
HEMOTHORAX
Hemothorax is the collection of blood within the pleural
space. This can occur as a result of pulmonary parenchymal
lacerations, intercostal artery or vein laceration, or disruption
of major pulmonary or bronchial vessels. Because parenchymal tears result in low-pressure pulmonary vessel injury, they
usually stop bleeding with chest tube intervention and full
expansion of the lung. The presence of retained blood in the
chest can lead to complications such as empyema and restrictive fibrothorax. Early evacuation of hemothorax is thus ideal.
The vast majority of hemothoraces can be drained with chest
tube placement alone. Chest tubes fail to completely evacuate
a hemothorax in approximately 5% of cases.28 Conditions
that can increase the chance of complications in retained fluid
collections include prolonged ventilation, pleural disruption,
the development of pneumonia, and other distant sites of
B
FIGURE 22.7. A: Chest radiograph demonstrating simple pneumothorax. B: Resolution of pneumothorax after chest tube placement.
TA B L E 2 2 . 2
SIGNS OF PULMONARY CONTUSION
TRAUMA
377
378
TRACHEOBRONCHIAL
TREE INJURY
Disruption or injury to a major bronchus or trachea is a rare
potentially fatal condition that is often overlooked on initial
assessment. It has been reported to occur in 1% to 3% of motor
vehicle collisions, and more than 80% die in the field.42,43 Those
who reach the hospital alive have a high mortality rate from
associated injuries. The injury, alone or in combination, is in the
distal trachea within 2 cm of the carina in 76% of cases and in
the right main stem within 2 cm of the carina in 43%. Approximately 50% of the injuries are circumferential.44 In contrast,
penetrating injuries involve the cervical trachea in greater than
80% of cases.
A high degree of suspicion is needed to detect these injuries
in a timely manner. Clinical signs include subcutaneous emphysema, continuous large air leaks seen in chest tubes, and hemoptysis.45 Although a chest radiograph is nonspecific, a pneumothorax, cervical emphysema, or pneumomediastinum may be
present. A chest CT scan is more sensitive for detecting pneumomediastinum, and occasionally a fallen lung sign may be
present, where the lung is seen to fall away from the hilum.46 A
persistent pneumothorax, despite a well-placed chest tube, and
a continuous air leak throughout the entire respiratory cycle are
also signs of a possible tracheobronchial disruption.
The first priority is airway control. Orotracheal intubation
with appropriate cervical spine precautions and direct laryngoscopy is typically an appropriate first step in securing the airway. Caution should be used in the setting of maxillofacial
trauma or suspicion of laryngeal trauma. Flexible bronchoscopy
plays a role in the diagnosis and management of the injured airway. It can be used even in the most difficult airway while maintaining cervical spine immobilization. It allows for the accurate
placement of distal tubes in the airway that can act as a stent for
the disrupted trachea or mainstem bronchi. The status of the larynx can be assessed and a decision made to continue with the
tube insertion over the bronchoscope versus aborting intubation
and proceeding with a definite surgical airway. Tracheostomy is
preferred over a cricothyroidotomy, as the latter can lead to com-
plete airway separation and loss of ability to intubate in this setting. A smooth-end endotracheal tube such as an Armoured
wired endotracheal tube of at least 8.0 French should be used.
Adequate suctioning and bronchoscopy are possible with the 8.0
size, and the smooth-end reinforced tube reduces the risk of
aggravating the airway tear, is easier to place, can be passed
across the injury site, and can be manipulated during surgery. On
occasion, the distal airway must be intubated through the operative field to allow for adequate exposure.
A patient who deteriorates after intubation, ventilation, and
appropriate chest tube placement and subsequently develops a
massive air leak should have immediate bronchoscopy. The
timing and type of definitive repair depend on the site, extent,
and association with other injuries. The proximal two thirds of
the trachea is best approached via a low collar incision. This
also allows access to the esophagus and cervical vessels in case
of associated injury. The collar incision can be extended down
into the manubrium with an upper sternal split (T incision)
for greater exposure of the middle third of the trachea, as well
as facilitate control of the proximal innominate artery and
vein. If there is any suspicion of injury to a great vessel, the
ascending aorta, or the heart, median sternotomy should be
employed.43 The distal one third of the trachea and right mainstem bronchus is best approached by a right posterolateral thoracotomy via the fourth or fifth intercostal space. A left posterolateral thoracotomy through the fourth or fifth intercostal
space gives one access to the left mainstem bronchus and the
proximal left subclavian artery, descending thoracic aorta, and
lower esophagus. However, the very proximal left mainstem is
difficult to expose and requires mobilization of the arch by
dividing the ligamentum arteriosum.47
Repair of simple lacerations of the trachea and bronchi are
repaired primarily using interrupted sutures of 30 polyglactin
910 (Vicryl) to reestablish mucosal-to-mucosal continuity.
Dbridement of devitalized tissues should be performed with
caution to leave the greatest amount of trachea available for
repair. Suture lines performed through the chest are reinforced
with pedicled flaps of pleura or pericardium wrapped around
the anastomosis. Alternatively, intercostal muscle can be used.
Repairs made through the neck are reinforced using mobilized
strap muscles. In the case of more complex injuries involving
complete transection of the trachea, the trachea can be mobilized anteriorly and around the hila to allow for structures to
shift superiorly. Care is taken to avoid lateral dissection as
much as possible, as the vascular supply enters on the sides.
Interrupted 30 Vicryl sutures are placed after careful dbridement. Pericartilaginous sutures are placed on the rigid portion
of the trachea, and simple interrupted sutures are placed on
the membranous portion (Fig. 22.1). At the end of the procedure, the patients chin may be sutured to the anterior chest to
prevent the patient from extending the neck and stressing the
suture line (guardian stitch). This stitch is left in for 1 week
and removed after confirmation of integrity of the suture line
is done by flexible bronchoscopy. Distal airway injuries associated with lobar destruction can be managed by lobectomy.45
Stricture and dehiscence occur in 3% of patients following tracheobronchial reconstruction, with stricture often presenting
as new-onset wheezing. If the stricture is limited, dilation and
temporary stenting can allow remodeling and thus provide a
permanently patent and functioning airway.
TRAUMATIC
AORTIC DISRUPTION
Patients involved in high-energy blunt trauma involving rapid
deceleration (such as a motor vehicle crash at speeds over 40
miles per hour or a fall from a height of 10 feet) are at signifi-
TA B L E 2 2 . 3
CHEST RADIOGRAPHY FINDINGS ASSOCIATED WITH A
MAJOR VASCULAR INJURY IN THE CHEST
Widened mediastinum
Obliteration of the aortic knob
Deviation of the trachea to the right
Depression of the left mainstem bronchus
Elevation of the right mainstem bronchus
Obliteration of the aortopulmonary window (space
between the aorta and pulmonary artery)
Deviation of the nasogastric tube (esophagus) to the right
Widened paratracheal stripe
Widened paraspinal interfaces
Presence of a pleural or apical cap
Left hemothorax
Fractures of the first rib, second rib, or scapula
cant risk for blunt aortic injury (BAI). BAIs cause immediate
death from aortic transection in 80%. In a minority of
patients, the adventitia and mediastinal structures contain the
rupture, allowing the patient to survive the ambulance transport to the ED. In patients who survive to reach the hospital,
the most common site of disruption is just distal to the origin
of the left subclavian artery at the ligamentum arteriosum.
This site is the juncture of the mobile aortic arch and immobile
descending thoracic aorta, additionally tethered by the intercostal arteries. In a sudden deceleration, the descending aorta
stops with the rest of the body, while the heart and aortic arch
continue to move forward. Shear force develops at the juncture of these two segments of aorta, creating a tear.56
Specific signs and symptoms of traumatic aortic disruption
are frequently absent. A high index of suspicion prompted by
noting the mechanism of injury (rapid deceleration) and findings on chest radiography should be maintained, and the
patient appropriately assessed. Findings on chest radiography
that indicate a likelihood of major vascular injury in the chest
are shown in Table 22.3. Any abnormality on chest radiography should be followed by a CT scan of the chest. A normal
CT scan essentially rules out BAI.5759 An equivocal CT scan
should be followed by angiography to exclude aortic injury in
those where suspicion of injury remains.60 Transesophageal
echocardiography (TEE) can be used in those patients too
unstable for chest CT. TEE has a high sensitivity and specificity
for BAI and can be performed either in the ED or in the OR. It
also has utility in assessing valvular incompetence and pericardial effusions.
When BAI is diagnosed, the goal of management is to prevent propagation of adventitial dissection and subsequent free
rupture by controlling the shearing forces exerted on the aorta.
This is accomplished by lowering the heart rate with a betablocker and decreasing the blood pressure with intravenous
nitroprusside or nitroglycerin in those cases where the betablocker alone is not sufficient. Intravenous esmolol, due to its
rapid action and short half-life, is an ideal beta-blocker to use
as an initial agent. Beta blockade should be initiated prior to
any other blood pressurereducing medications, as other drugs
may result in a compensatory elevation in heart rate and
thereby increase the shearing force. In patients in whom betablockers are contraindicated, a calcium channel blocker such
as diltiazem can be used. The goal is to maintain a heart rate
below 100 and a systolic blood pressure around 100 mm Hg.61
Surgical options include thoracotomy with open repair or
interposition graft, and endovascular stenting. Surgery should
not be delayed if clinical or radiographic signs of impending
rupture are present such as reaccumulating hemothorax, rapid
enlargement of a pseudoaneurysm, or contrast extravasation.
Surgery should also ideally be done early in those patients who
are hemodynamically stable without other major injuries, as
TRAUMA
379
380
TRAUMATIC
DIAPHRAGMATIC INJURY
The true incidence of diaphragmatic injuries is hard to estimate because of missed and delayed diagnosis. A query of the
National Trauma Data Bank (NTDB) of 952,242 patients
from 565 trauma centers during the years 2000 to 2004
revealed an overall incidence of 0.63% (n 6,038). Thirtyfive percent occurred from blunt trauma and 65% from penetrating diaphragmatic injuries.68 The frequency, however, may
be even higher, as one prospective study where all patients
admitted with left-sided penetrating thoracoabdominal trauma
were evaluated with laparoscopy demonstrated 26 out of 110
(24%) patients with a diaphragmatic injury.69
There are several possible mechanisms for diaphragm rupture: increased abdominal pressure from forceful impact that
causes stretching with avulsion or, more commonly, lacerations;
or fractured ribs that can perforate the muscle.70 Tears tend to
be in a radial orientation along the posterolateral aspect of the
diaphragm. Diagnosis is easiest on the left when herniated
bowel enters into the chest. Severe associated injuries occur in
greater than 50% of cases. The liver and spleen are the most
commonly associated injury. Diaphragmatic injury may be associated with epigastric and abdominal pain, referred shoulder
pain, shortness of breath, or shock. However, some patients are
asymptomatic, and initial chest radiography may be nondiagnostic, particularly if the patient is on positive-pressure ventilation. CT allows for the production of sagittal and coronal reformatting, which appears to improve accuracy. In one large series,
the sensitivity for CT in diagnosing left-sided diaphragmatic
tears was 78% and for right-sided tears was 50%, with 100%
specificity.71 Accuracy is poor in the absence of visceral herniation. Right-sided injuries are more difficult to diagnose because
the liver and diaphragm have a similar appearance on CT (Fig.
22.8). Coexisting injuries, atelectasis, and aspiration can also
obscure the diaphragm and decrease sensitivity.
Often diaphragmatic injuries are found incidentally during
laparotomy or thoracotomy to treat coexistent injuries. Treat-
ESOPHAGEAL RUPTURE
Diagnosis, management, and outcome for traumatic esophageal
perforations are affected by etiology, location, and duration
between event and intervention. In trauma, there is a tendency for
the diagnosis to be delayed.72 Esophageal injury lacks specific
symptoms and generally occurs in multiple trauma, making it difficult to diagnose. Historically, injuries diagnosed greater than 24
hours after injury were treated with diversion. In recent times, the
trend has changed to intervention based on the clinical stability of
the patient, underlying esophageal pathology, and quality of the
mediastinal tissues. There is now an emphasis on primary repair
when possible, with some form of tissue reinforcement.
Traumatic injuries, which tend to involve the cervical esophagus in younger patients, have a mortality rate ranging from
9% to 19%.72 The most common traumatic injury occurs following penetrating neck injury, accounting for more than 80%
of all traumatic perforations. Only 0.5% to 5% of penetrating
neck injuries, however, are associated with esophageal involvement. Blunt trauma patients rarely sustain esophageal rupture;
when they do occur, it is mostly in the cervical area, typically
caused by a sudden blow to the anterior hyperextended neck.
Virtually all thoracic traumatic perforations are a consequence
of penetrating trauma. Transmediastinal gunshot wounds
involving low-velocity missiles that course close to the spine
can result in through-and-through injuries.
Signs of injury may include blood in the nasogastric aspirate,
subcutaneous cervical air, and neck hematoma, but none is sensitive.72,73 Initial symptoms of cervical perforations may be simply hoarseness, spitting up blood, subcutaneous air, or anterior
tracheal deviation. Untreated, fever, erythema, swelling, increasing crepitus, airway distress, and, finally, frank abscess formation occur. Infection often spreads along the precervical plane to
involve upper mediastinal structures, leading to signs and symptoms of mediastinitis. Patients who present with zone II injuries
that are associated with penetration of the platysma should be
considered at risk for esophageal injury. Thoracic perforations
typically have a subtle initial presentation but can quickly
progress to mediastinitis, empyema, and septic shock.
Plain radiography may reveal pneumomediastinum, pleural
effusion, mediastinal contour changes (which progress with
inflammation), or gas bubbles in the nasogastric tube or
esophagus, if a tracheoesophageal communication exists. CT
scans may show subtle air leaks at the site of perforation,
although the sensitivity of such findings is unclear. Pneumomediastinum without a clear cause is an indication for further
assessment by a contrast study. Diagnosis is primarily made by
contrast study. Although many radiologists favor Gastrografin
studies, 15% of perforations can be missed with this type of
study alone. Dilute or thin barium studies are thus preferred as
the initial diagnostic study. A contrast study confirms the
location of the leak and the side toward which the leak is
going, and also demonstrates other pathology such as strictures that may need to be addressed.
Esophagoscopy and contrast studies are complementary in
the trauma setting. Esophagoscopy can miss 15% to 40% of
traumatic injuries, but when combined with contrast studies
the sensitivity approaches 90% to 100%. Ideally, flexible
esophagoscopy should be performed in the OR, as definitive
intervention can be done when an injury is found.
The principles of surgical intervention include control of the
leak, dbridement of all devitalized tissues, wide drainage, and
nutritional support. Broad-spectrum antibiotic coverage is
essential.79 Ideally, primary repair should be done whenever
possible. Additional reinforcement with tissues such as pleura,
381
TRAUMA
382
SPECIAL THORACIC
TRAUMA ISSUES
Sternal Fractures
5
Because of the force required, the degree of sternal fracture displacement correlates with the risk for associated thoracic injury,
although even nondisplaced fractures carry a significant risk.74,75
Commonly associated injuries include rib fractures, blunt cardiac injury, hemopericardium, spinal fracture, hemothorax, and
pneumothorax. Sternal fractures usually result from a highenergy direct blow to the anterior chest wall. Typically these
fractures occur during a motor vehicle crash when the drivers
chest strikes the steering column or rapid deceleration causes an
occupants chest to slam against the cross-shoulder seatbelt.
As with rib fractures, management is primarily supportive.
Most fractures are transverse, involve the sternal manubrial
junction or upper one third of the sternum, and stabilize with
pain control. Unstable fractures, fractures associated with
chronic pain, or those associated with infection (indicated by
new sternal click in the setting of fever or erythema) require
operative intervention. Options include wires in figure-of-eight
fashion, plates, or both (Fig. 22.9). Longitudinal fractures may
require closure similar to that for closing a sternotomy incision. Sternal fractures complicated by mediastinal abscess may
require serial widespread dbridement and irrigation, followed
by eventual closure with muscle or omental flaps.76
Rib Fractures
Rib fractures represent the most frequent chest injury. Patients
with three or more rib fractures, especially elderly patients, are
at significant risk for complications, such as pulmonary contusion and pneumonia, even in the absence of other injuries. In a
multivariate analysis of 17,308 patients with rib fractures, age
and Injury Severity Score were independent risk factors for
development of pneumonia and mortality, with the incidence of
pneumonia in this study being 6%, with an overall mortality of
4%.80 These findings support the concept of aggressive pain
management for patients with rib fractures to prevent atelectasis and to improve functional residual and vital capacity and
the ability to clear secretions. Although the initial therapy for
rib fractures has been supportive, the outcome of a strictly nonoperative approach may at times not be ideal. Rib fracture
repair has had waxing and waning enthusiasm among select
centers for over 50 years, but the operative indications have not
yet been clearly established. Potential indications for rib fracture repair include flail chest; painful, movable rib fractures
refractory to conventional pain management; chest wall deformity/defect; rib fracture nonunion; and during thoracotomy for
other traumatic indication.5 Rib fracture repair can at times be
technically challenging secondary to the human ribs relatively
thin cortex and its tendency to fracture obliquely. Many techniques of rib fracture repair have been described, including
using wire sutures, intramedullary wires, staples, and various
plates made of metal or absorbable materials (Fig. 22.10). Multicenter randomized trials are needed to firmly establish optimal guidelines in dealing with these common injuries.
Empyema
Posttraumatic empyema is likely to require surgical intervention because the blood and infection create a vigorous inflammatory reaction and early aggressive management of retained
or contaminated hemothorax may reduce morbidity.77,78
FIGURE 22.9. A: Computed tomography scan demonstrating transverse sternal fracture. B: Sternal plating performed using the titanium
locking plates (Sternal Fixation SystemSynthes CMF, West Chester,
Pennsylvania).
TRAUMA
383
FIGURE 22.10. A: Exposure of rib fracture via cutdown technique. B: U-plate theoretically overcomes the inherent softness of the human rib by
grasping the rib over its superior margin and by securing the plate with anterior-to-posterior locking screws that do not rely on screw purchase
in bone (Acute Innovations Rib-Loc Plating System, Portland, Oregon). C: Securing the U-plate in place over the fractured rib. D: Final position
of U-plate on fixed rib.
SUMMARY
Thoracic trauma is common in the multiply injured patient and
is a significant source of morbidity and mortality. The ability to
recognize injuries in a timely manner can be lifesaving. The primary survey includes management of airway obstruction, tension
pneumothorax, open pneumothorax, flail chest and pulmonary
contusion, massive hemothorax, and cardiac tamponade. The
secondary survey includes identification and initial treatment of
potentially life-threatening injuries such as simple pneumothorax, hemothorax, pulmonary contusion, tracheobronchial tree
injury, blunt cardiac injury, traumatic aortic disruption, traumatic diaphragmatic injury, and blunt esophageal injury. A
deliberate and systematic approach in this patient population is
essential in delivering effective care.
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P O I N T S
Within the broad scope of trauma care, the knowledge to comprehensively manage abdominal trauma is the sine qua non of
the trauma surgeon. Most civilian abdominal injuries are
caused by blunt trauma secondary to high-speed automobile
crashes, although penetrating injuries are common in urban
environments. The inability to appropriately manage abdominal injuries accounts for most of the preventable deaths that
follow multiple trauma. Failure to recognize occult abdominal
hemorrhage and to control bleeding from intra-abdominal
organs leads to significant morbidity, and such injuries
account for approximately 10% of the traumatic deaths that
occur annually in the United States.
ANATOMIC CONSIDERATIONS
The abdomen is defined by the diaphragm at its superior
aspect and by the infragluteal fold at its caudal aspect; it
includes the entire circumference of the torso. Abdominal
injury is often accompanied by trauma to other sites, such as
the central nervous system, the chest, and the musculoskeletal
system. The pattern of extra-abdominal injury can often pre1 dict the abdominal organs at risk of injury. To simplify the initial trauma evaluation, the abdomen can be divided into four
areas: intrathoracic abdomen, true abdomen, pelvic abdomen,
and retroperitoneal abdomen (Fig. 23.1). With the exception
of the true abdomen, all of these areas are difficult to assess by
physical examination alone.
The intrathoracic abdomen is the portion of the upper
abdomen that lies beneath the rib cage (Fig. 23.1A). Bony and
385
TRAUMA
K E Y
386
387
PENETRATING INJURY
2
BLUNT TRAUMA
Automobile crashes are the cause of at least 60% of all traumatic injuries. Table 23.2 shows the frequency with which
TA B L E 2 3 . 2
FREQUENCY OF ORGAN INJURY IN BLUNT ABDOMINAL
TRAUMA IN ADULTS
ORGAN
OCCURRENCE (%)
Liver
30
Spleen
25
Retroperitoneal hematoma
13
Kidney
Urinary bladder
Intestine
Mesentery
Pancreas
Diaphragm
Urethra
Vascular
PREHOSPITAL CARE
TA B L E 2 3 . 1
FREQUENCY OF ORGAN INJURY IN PENETRATING
ABDOMINAL TRAUMA
ORGAN
OCCURRENCE (%)
Liver
37
Small bowel
26
Stomach
19
Colon
17
Major vascular
13
Retroperitoneal
10
10
Spleen
Diaphragm
Kidney
Pancreas
Duodenum
Biliary system
Other
Little can be done outside a hospital for patients with abdominal injuries. For penetrating wounds, sterile dressings should be
applied and the patient should be carefully monitored. Foreign
bodies embedded in the trunk should not be removed because
major bleeding can follow. Evisceration is best left undisturbed
except for application of a moist sterile dressing and protection
of the eviscerated organ from further injury. General principles
of stabilization and evaluation should be followed, including
ensuring an adequately functioning airway, inserting intravenous lines (preferably in the upper extremity), beginning
fluid resuscitation, and providing rapid transport to a trauma
center. Recent controversy surrounding the issue of the value of
fluid resuscitation in the early posttraumatic period has arisen.
In blunt trauma, aggressive volume resuscitation to return
toward normal vital signs and level of consciousness is generally indicated, though a preoccupation with fluid resuscitation
at the scene should not delay rapid transport to a trauma center. In penetrating abdominal trauma, smaller resuscitation volumes to achieve a systolic blood pressure only greater than 70
to 80 mm Hg may improve outcomes and diminish total blood
loss.1 The prehospital application of the pneumatic antishock
garment in the treatment of abdominal trauma is rarely indicated and may lead to increased blood loss from injury manipulation and delay in transfer and impair pulmonary and cardiac function due to upward pressure on the diaphragm and
increase in afterload.
TRAUMA
388
HOSPITAL RESUSCITATION
AND DIAGNOSIS
Diagnosis and treatment should proceed concurrently according to established protocols. A functioning airway must be
established, particularly in the comatose patient, before evaluation of the abdomen occurs. If necessary, an endotracheal
tube is placed and assisted ventilation is begun. Upper extremity, large-bore intravenous catheters are initiated, and resuscitation is begun with a balanced salt solution (e.g., lactated
Ringer or normal saline). Early crystalloid resuscitation is
mandatory, especially in the presence of a head injury, despite
theoretic considerations that instillation of intravenous fluids
increases bleeding and causes a dilutional coagulopathy.2
When operative intervention is indicated, however, it should
not be delayed by overzealous and prolonged attempts at fluid
resuscitation.
LABORATORY STUDIES
3
PHYSICAL EXAMINATION
The objective of the physical examination in abdominal
trauma is to rapidly identify the patient who needs laparotomy. Precise definition of specific organ injury is unnecessary.
In addition, the specificity and sensitivity of physical examination alone, however, are not adequate to make these determinations. Associated injuries often cause tenderness and spasm
in the abdominal wall and make diagnosis difficult. Lower rib
fractures, pelvic fractures, or abdominal wall contusions can
mimic the signs of peritonitis.
In patients with gunshot wounds, no presumptions should
be made about entrance and exit wounds. Unfounded presumptions can lead to inaccurate estimations about the number of times a patient was shot and the course of the bullets. If
time permits, radiographs should be obtained to determine the
location of any bullets or bullet fragments that remain in
the patient. Penetrating wounds should be marked with
radiopaque clips to allow radiographic delineation of the injury
tract.
Because the primary manifestation of blunt solid organ
injury is hemorrhage, the patient should be monitored closely
during the initial assessment, and continuing or refractory
shock is presumed to result from continuing or massive hemorrhage. The patient should be examined from head to toe for
signs of blunt trauma and for penetrating wounds. Small abrasions or areas of ecchymosis suggest significant local intra-
The hematocrit is the primary blood study of value in the initial evaluation of a patient with abdominal trauma. Leukocyte
counts, serum creatinine, glucose, serum amylase/lipase, and
serum electrolyte determinations are often obtained for reference but usually have little value in the immediate management period, but are critical for serial assessments and trending the results.
The diagnosis of massive hemorrhage is usually obvious
from hemodynamic parameters, and the hematocrit merely
confirms the diagnosis. Iatrogenic dilutional anemia is common and, in the presence of hemodynamic stability, is well tolerated. In the less severely injured, serial hematocrits showing
a persistent downward trend identify ongoing bleeding requiring operative or angiographic intervention. Urinalysis confirms the presence of microscopic hematuria. For blunt
trauma, radiographic evaluation (usually by CT) of the kidneys and bladder should be initiated if the patient has gross
hematuria or microscopic hematuria and shock (systolic blood
pressure 90 mm Hg in an adult) at any point during the prehospital or emergency department course.
The serum amylase is insensitive and nonspecific as a
marker for major pancreatic or enteric injury. Injuries to the
head and face commonly cause increased plasma amylase concentrations. Serum lipase levels are not elevated by facial
trauma and are possibly more specific than amylase levels.
Sensitivity and specificity of lipase levels, however, especially
in the early postinjury period, are still relatively low. Sensitivity and specificity of both the amylase and lipase improve with
RADIOGRAPHIC EVALUATION
Radiologic studies of potential value in the evaluation of
abdominal trauma include a chest radiograph, retrograde urethrography and cystography, CT scans, ultrasound, and
angiography. In addition, all injuries from penetrating trauma
should be evaluated with a plain radiograph with the use of
radiodense markers on the wound sites to allow evaluation of
the missile trajectory. With blunt trauma, an anteroposterior
film of the pelvis can delineate pelvic fractures not detectable
on physical examination. The initial pelvic film or chest radiograph can also demonstrate fractures of the thoracic or lumbar spine. A transverse fracture of the vertebral bodies, or
Chance fracture, should increase the search for serious blunt
intestinal injury. The value of plain abdominal films after blunt
trauma is extremely limited and they should not be routinely
obtained.
Of greater value are CT scans, ultrasound, and angiogra4
phy. CT has real value in the accurate assessment of solid
organ injuries, particularly of the liver, kidney, and spleen;
contrast-enhanced CT has great accuracy in the delineation of
intra-abdominal bleeding. The accuracy of CT scan in evaluation of hollow viscus injury is somewhat more limited, but
improvements in CT technology have led to increasing sensitivity of CT in the detection of the more subtle signs of injury
to the intestine.3,4 CT is also highly specific in the evaluation
of retroperitoneal injuries and is the single most useful and
informative diagnostic study for patients with abdominal
trauma.
CT scanning can also be used on occasion for penetrating
injuries when it is uncertain whether the track of the knife or
bullet violated the retroperitoneum or the peritoneal cavity.
Such an approach is most useful in patients with back and
flank wounds but is also occasionally helpful in patients with
anterior wounds if it is likely that the knife did not reach the
peritoneal cavity or the bullet traversed a tangential path.
Patients with any signs of peritonitis or hemodynamic instability after penetrating trauma are obviously not candidates for
diagnostic CT scanning, nor is any trauma patient displaying
hemodynamic instability.
Angiography is reserved for specific situations, such as suspected aortic or renal arterial injuries, or ongoing hemorrhage
from pelvic, hepatic, or splenic injuries. It is not considered an
initial screening investigation.
Laparoscopy has been used for both diagnosis and treatment of trauma patients.5 Although limited to evaluation of
the diaphragm in blunt trauma, after penetrating trauma
laparoscopy is helpful when it is unclear whether the peritoneum has been penetrated. In patients in whom peritoneal
penetration is seen, the use of laparoscopy to further explore
the peritoneal cavity and repair injuries is more controversial.
The adequacy of abdominal exploration, particularly examination of the bowel and retroperitoneum, has been questioned, and repair of large injuries through the laparoscope
can be tedious. In patients with a lower chest wound, however,
laparoscopy can identify both peritoneal penetration and
diaphragmatic injury. An isolated diaphragmatic injury or
associated nonbleeding liver laceration is one area in which
repair of the diaphragm through the laparoscope has proved
feasible. Of note, when laparoscopy is used in patients with
potential diaphragmatic injury, the positive pressure in the
peritoneal cavity can lead to tension pneumothorax if the chest
is not adequately vented.
DIAGNOSTIC PERITONEAL
LAVAGE AND ABDOMINAL
ULTRASOUND
Diagnostic peritoneal lavage and focused abdominal sonography for trauma (FAST) are standard techniques to detect significant intra-abdominal hemorrhage after blunt trauma.
FAST is less useful after penetrating trauma for potential
intestinal injury.
The specific indications for DPL or FAST in blunt trauma
include the following:
Unconscious patient with question of potential abdominal
injury
Patient with a high-energy injury, suspected intra-abdominal injury, and equivocal physical findings
Patient with multiple injuries and unexplained shock
Patient with major noncontiguous or thoracoabdominal
injuries
Patient with spinal cord injury
Intoxicated patient in whom abdominal injury is suspected
Patient who has a suspected intra-abdominal injury with
equivocal diagnostic findings and who will be undergoing prolonged general anesthesia for another injury,
making continued reevaluation impossible
Relative contraindications to DPL but not to FAST are previous abdominal operations, pregnancy, and morbid obesity.
Obvious peritonitis is a contraindication to either study. If the
patient is hemodynamically stable, CT scan is prudent, and if
the patient is unstable, immediate exploratory laparotomy,
rapid abdominal tap, or FAST to confirm gross hemoperitoneum is indicated.
Diagnostic peritoneal lavage is not generally useful for
patients with abdominal gunshot wounds, most of whom
require laparotomy.6 If local exploration of a stab wound suggests penetration of the fascia or peritoneum, DPL can help
distinguish significant and insignificant injuries. It is most sensitive in the diagnosis of hemoperitoneum, but significant
hemoperitoneum does not necessarily accompany hollow viscus lacerations. In blunt trauma, DPL is considered positive if
10 mL of grossly bloody aspirate is obtained before instillation
of lavage fluid or (of much less importance) if the siphoned
lavage fluid has more than 100,000 red blood cells (RBCs) per
milliliter (equal to 20 mL of blood). Evaluation of lavage fluid
in stab wounds should be based on a more sensitive protocol.
In general, more than 1,000 RBCs/mL is considered a positive
DPL, and laparotomy should follow. In both cases, presence of
bile, amylase, bacteria, or particulate matter should indicate
visceral injury and need for laparotomy.
Diagnostic peritoneal lavage and CT scan are both satisfactory tests for the diagnosis of visceral injury after blunt
abdominal trauma. DPL has some advantages, including
rapidity, higher sensitivity, lower cost, and immediate interpretation (Table 23.3). The major disadvantages are a 1% to 3%
risk of iatrogenic intraperitoneal injury and the high sensitivity
of the test. The high sensitivity can lead to nontherapeutic
laparotomies (i.e., when there are no injuries requiring repair).
False-positive DPL findings may result from traversing a pelvic
hematoma that has dissected into the anterior infraumbilical
abdominal wall if an infraumbilical approach is used in a
patient with a pelvic fracture. A pelvic radiograph should be
obtained before DPL, and if a pelvic fracture is present, the
incision is placed cephalad to the umbilicus.
Before DPL, the bladder should be emptied with a Foley
catheter. The abdomen is prepared with povidone-iodine solution and draped with sterile towels. The infraumbilical midline is
infiltrated using lidocaine with epinephrine, and a 3-cm incision
is carried down to the linea alba. This is opened, and a peritoneal
TRAUMA
389
390
TA B L E 2 3 . 3
DIAGNOSIS
COMPUTED
TOMOGRAPHY
1%
False-negative result
5%20%
False-positive result
5%12%
5%
Time to complete
5 min
55 min
Cost
$125
$900
Hemodynamic instability:
DPL or FAST
Laparotomy
Grossly positive lavage
Positive FAST
Negative DPL
Indeterminate DPL
(50,000100,000 RBCs/mL) (<50,000 RBCs/mL)
or FAST
or FAST
Laparotomy
ALGORITHM 23.1
ALGORITHM 23.1. Diagnosis of blunt abdominal trauma.
CT scan
CT scan or
observation
Negative
Positive
Find cause
of instability
Laparotomy or
find cause of
instability
Find cause of
instability
391
Laparotomy
Fascial violation
or equivocal
No fascial violation
Diagnostic laparoscopy
Observation
Peritoneal violation
Exploratory
laparotomy
No peritoneal violation
Discharge after recovery
from anesthesia
ALGORITHM 23.2
TRAUMA
392
toneal injury and because the lack of adhesions makes reduction of the abdominal viscera back into the peritoneal cavity
relatively easy. Defects discovered at a later date can be
addressed satisfactorily by a transthoracic approach, which
facilitates lysis of adhesions.
SPECIFIC INJURIES
Diaphragm
Spleen
Injuries to the diaphragm after blunt trauma involve predominantly the left hemidiaphragm. All diaphragmatic injuries
must be repaired to avoid the long-term potential for herniation, incarceration, and strangulation of abdominal viscera.
Strangulation can occur months or even years after the injury
if the hole in the diaphragm is not diagnosed and treated. The
diagnosis of diaphragm injury should be suspected if respiratory distress and radiologic evidence of pleural effusion are not
relieved by tube thoracostomy or if an upright radiograph
demonstrates obvious visceral herniation into the thorax (Fig.
23.2). Chest radiograph (CXR) findings in patients with blunt
diaphragmatic rupture are sometimes subtle, particularly in
the face of positive-pressure ventilation, and may appear only
as a blurring of the costophrenic angle or the line of the
hemidiaphragm. Serial CXRs may demonstrate evidence of
delayed herniation. Low-thoracic (below the level of the nipples) penetrating injuries should be presumed to have traversed the diaphragm. During exploratory laparotomy, the
entire diaphragmatic surface should be exposed and directly
visualized. Linear lacerations can be repaired with a simple
running suture or interrupted horizontal mattress sutures,
whereas larger lacerations and tissue deficits occasionally
require repair with prosthetic material or resuspension of the
diaphragm to higher ribs. Exploration of acute traumatic
diaphragmatic rupture is usually accomplished through the
abdomen because of the high risk for associated intraperi-
Liver
The liver, the largest organ in the abdominal cavity, is commonly damaged in blunt and penetrating abdominal trauma as
well as in thoracoabdominal injuries. Some series have found
that the incidence of liver injuries exceeds that of injuries to
the spleen. In any case, the two together account for approximately 75% of all blunt intra-abdominal injuries. Trauma sufficient to lacerate the liver is often associated with injuries to
other organs. Spontaneous hemostatic mechanisms are sufficiently effective that approximately 85% or more of patients
with liver injuries can be managed nonoperatively.
Patients with significant liver injuries usually have a history of major blunt energy transfer to the right thorax or
upper abdomen. Physical findings may be minimal because
early bleeding may not cause peritoneal irritation or abdominal distention. Any patient with unexplained persistent or
recurrent hypotension after blunt abdominal trauma must be
considered at risk for a severe liver injury. DPL or FAST is
most helpful in quickly establishing the diagnosis of hemoperitoneum, and if the results are positive, laparotomy is
appropriate. In hemodynamically stable patients or patients
who respond well to resuscitation, the presence of a liver
injury may be suspected based on physical examination or
ultrasound. A CT scan with intravenous contrast is indicated
to illustrate the magnitude of injury and the presence of associated injuries. The injury should be graded according to the
American Association for the Surgery of Trauma (AAST)
Liver Trauma Scale. The grade of liver injury, the presence of
active extravasation (or blush), and a rough estimate of the
amount of free fluid pres-ent should be noted. However, the
decision to proceed to laparotomy is not determined by the
grade of injury but should be based on the patients clinical
response to resuscitation and the presence of other injuries,
real or suspected. While earlier recommendations considered
a severity grade (AAST grade IV or V) to be an indication for
laparotomy, the relatively high mortality of operation and the
proven success of nonoperative management do not support
this approach.
Liver injuries seen on CT scan in hemodynamically stable
patients can be treated nonoperatively as long as the patient
is followed closely and the possibility of associated hollow
viscus or pancreatic injury is borne in mind.20 Penetrating
injuries isolated to the liver can be managed in a similar
manner as blunt injuries.21 If active contrast extravasation is
demonstrated, angiographic embolization should be considered along with the need for operative intervention,
although it is not proven whether embolization improves
outcomes. However, since active extravasation has been
identified in patients without a blush on CT, embolization
may be considered in all patients with significant bleeding.22
Overall reported success of nonoperative management is
greater than 90% in most series. When broken down by
grade of injury, the success rate of nonoperative management for injuries grades I through III approaches 95%. In
stable patients with ongoing bleeding, angiographic
embolization as an adjuvant to a protocol of nonoperative
management may lower the number of blood transfusions
and the number of operations.
Patients with grades III through V liver injuries are generally admitted to the intensive care unit for monitoring of vital
signs and serial hematocrit determinations. Patients with
grades I and II injuries may be appropriate for a ward bed with
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393
394
FIGURE 23.5. Intracaval shunt used for retrohepatic venous injuries, combined with a
Pringle maneuver for isolation of the retrohepatic vena cava for operative repair.
TRAUMA
placed over the raw surface and left in place to preserve hemostasis when the packs are removed. For packing to be successful, it should be used early, before coagulopathy has become
too severe. A system to evacuate fluid in a closed system
should be constructed, or, more commonly, a commercial
device is applied (wound vac). Subsequent operative removal
of the packs 24 to 72 hours later can be accompanied occasionally by resection and suture ligation as needed. After
hemostasis has been achieved, the area may be drained,
although this may not diminish the incidence of biloma.
Inability to control bleeding by any of the previously
described techniques suggests significant retrohepatic vena
caval or adjacent hepatic vein bleeding. Early consideration
should be given to complete vascular isolation or the placement of an intracaval shunt. This approach is rarely necessary
and should be undertaken only if packing has not controlled
hemorrhage from the liver and appropriate expertise is available (Fig. 23.5). To accomplish this, the midline laparotomy
incision is extended into the chest, either by a right anterior
thoracotomy or, preferably, by a median sternotomy. Infrahepatic (cephalad to the renal veins) and suprahepatic (usually
intrapericardial) control of the vena cava is obtained. A shunt
or other large conduit (chest tube or endotracheal tube) is then
395
396
Stomach
The stomach is vulnerable to penetrating injuries of the upper
abdomen and lower chest. The upper abdominal viscera
underlie the lower ribs to a level as high as the fourth intercostal space during full expiration. The stomach is injured in
5% to 10% of patients with penetrating abdominal trauma.
Hematemesis or blood found on aspiration of the stomach
with a nasogastric tube is a finding suggestive of gastric
injury. Although many patients with blood in the stomach
after penetrating abdominal trauma have a gastric injury, the
absence of blood in the gastric aspirate does not rule out such
an injury.
At laparotomy, adequate exposure requires mobilization
and visualization of the entire stomach. Most of the anterior
surface of the stomach can be adequately visualized without
extensive mobilization by grasping the edge of the greater
curve of the stomach with fingers or Babcock clamps, and the
stomach is pulled down and spread. Exposure of the gastroesophageal junction can be difficult if the flare of the costal
margin is narrow or if the left lobe of the liver is in the way.
Improved exposure is accomplished with extension of the midline incision as high as possible by creating a paraxiphoid
extension. The left hepatic lobe is retracted to the right after
division of the left triangular ligament. Mobilization of the
gastroesophageal junction, encirclement with a tape or drain,
and caudal traction into the operative field improves visualization and the performance of any necessary repairs. The posterior wall of the stomach should also be examined for the presence of injuries, particularly if there is an injury on the anterior
surface. The posterior stomach is exposed by opening the gastrocolic ligament bluntly to the left of the midline approximately halfway between the stomach and the transverse colon
in a relatively avascular area. The lesser sac is entered and the
posterior wall of the stomach examined.
Injuries to the stomach are usually easy to repair, primarily
in two layers, with an inner layer of 30 or 40 absorbable
sutures followed by an outer layer of 30 or 40 permanent
Lembert sutures. Because of the ample blood supply and large
lumen of the stomach in all areas except the gastroesophageal
junction and pylorus, there is minimal concern for excessive
inversion and luminal compromise. On rare occasions, especially after shotgun wounds, large injuries of the stomach may
require resection. Injuries to the pylorus are rare. If viable tissue is present, it should be closed with a Heineke-Mikulicz
pyloroplasty; a concomitant vagotomy is not necessary.
Because of the stomachs position high in the abdomen,
penetrating injuries to the stomach are frequently associated
with lacerations of the diaphragm. During spontaneous ventilation, there is negative pressure in the pleural cavity and positive pressure in the abdomen, and the resultant pressure gradient causes movement of gastric fluid and particulate matter
from the abdomen into the chest. The degree of contamination can be deceptive in the operating room because most
occurs before the institution of positive-pressure ventilation
and laparotomy. Because even small amounts of contamination can result in an empyema, combined injuries to the stomach and diaphragm require the pleural cavity to be lavaged
before closure of the diaphragm. The diaphragmatic laceration should be enlarged enough to allow lavage from the
abdomen. The course of the phrenic nerve in the diaphragm
should be borne in mind, and enlargement of the diaphragmatic laceration should be done either radially or as peripherally as possible. Occasionally, adequate lavage is difficult
because of the amount of pleural contamination or if enlargement of the diaphragmatic laceration cannot be done without
risk of de-nervation. In such instances, the patient should be
closely followed postoperatively for evidence of the development of an empyema or undergo prophylactic videoassisted thora-scopic surgery (VATS) to lavage the chest. If
empyema develops, it can usually be managed with a VATS
approach.24
Blunt injuries to the stomach are rarer than penetrating
injuries. The stomach is large, distensible, and mobile. A great
deal of force is necessary to cause a blowout of the gastric
wall. As a consequence, the mortality rate from associated
injuries is high in patients with blunt stomach injuries.
Blowout injuries of the stomach also tend to be large and the
stomach is more likely to be full at the time of the injury. Thus,
blunt trauma injuries are often associated with significant
intraperitoneal contamination. Principles of operative exposure and repair are the same as for penetrating injuries.
Duodenum
Penetrating Injuries. Because of the retroperitoneal location of the duodenum close to a number of other viscera and
major vascular structures, isolated penetrating injuries to the
duodenum are rare. The need for abdominal exploration is
usually dictated by associated injuries, and the diagnosis of
duodenal injury is usually made in the operating room.25 With
blunt trauma, gastrointestinal (GI) contrast CT scans are frequently diagnostic.
Diagnosis and treatment of duodenal injuries in the operating room depend on adequate exposure. Exposure is obtained
by incising the lateral peritoneal reflection of the duodenum
and mobilizing the duodenum from right to left with a combination of blunt and cautery dissection. This technique is
known as the Kocher maneuver, and it can be carried well
across the midline to the level of the abdominal aorta, providing exposure of the underlying vena cava and aorta. Entry into
the lesser sac by way of the gastrocolic ligament provides
exposure of the caudal aspect of the first portion of the duodenum and the medial aspect of the second portion. Exposure of
the third and fourth portions of the duodenum, if necessary, is
carried out by incising the ligament of Treitz and mobilizing
the right colon from right to left so that the right colon and
small intestine can be elevated (Cattell maneuver). With this
combination of maneuvers, the entire duodenum can be mobilized and exposed for evaluation of any injury. It is critical to
identify all injuries at the time of the initial exploration,
because overlooked injuries are associated with a significant
increase in subsequent morbidity.
TA B L E 2 3 . 4
397
DIAGNOSIS
Grading systems have been devised to characterize duodenal injuries. Although useful for research purposes, the
specifics of the grading systems are less important than several
simple aspects of the duodenal injury (Table 23.4). Most penetrating injuries to the duodenum are simple lacerations that
can be repaired primarily. Such repairs should be done in two
layers, with an inner absorbable layer of 30 or 40 sutures
followed by an outer layer of 30 or 40 permanent Lembert
sutures. The closure should be oriented transversely, if possible, to avoid luminal compromise, but transverse orientation is
not as critical in the duodenum as it is in the rest of the small
intestine. The biliary tract does not require drainage in such
cases unless an associated biliary tract injury is present, and
the duodenum does not require tube decompression, although
both of these maneuvers have been advocated in the past. The
periduodenal area should be drained with closed suction
drainage.
Injuries that encompass as much as 40% or 50% of the
duodenal wall can be successfully closed primarily. Primary
repair of injuries larger than this, however, can lead to luminal compromise. If the duodenum has been transected or
almost transected, the edges should be dbrided and a twolayer primary anastomosis done without tension after mobilization of the duodenum, provided that the transection is
not close to the ampulla of Vater. Large injuries of the duodenum can be reinforced with a jejunal patch by bringing up
a loop of jejunum and laying it onto the area of injury so
that the serosa of the jejunum buttresses the duodenal repair
(Fig. 23.6). Alternatively, a Roux-en-Y duodenojejunostomy
can drain a large defect internally. If there are severe associated injuries to the pancreas or biliary tract, pancreaticoduodenectomy may be necessary. The morbidity associated
with pancreaticoduodenectomy is substantial, and this operation is indicated only if the extent of injury is so great that
the necessary resection has, in essence, been done by the
injury.
Some duodenal repairs are tenuous. This is a particular
problem if there is associated pancreatic injury, raising concern about the digestive action of activated pancreatic
enzymes on the repair. Pyloric exclusion defunctionalizes the
duodenum and protects the repair from activated pancreatic
enzymes until it has had time to heal. A gastrotomy along the
greater curvature of the stomach provides access to the
pylorus, which is closed with a large running nonabsorbable
suture or, alternatively, the pylorus is stapled shut. GI continuity is restored by a gastrojejunostomy (Fig. 23.7). Tube
decompression of the duodenum may be performed in
extreme duodenal injuries, but the biliary tract does not
require decompression except in cases of an associated biliary
tract injury. As with all duodenal injuries, the periduodenal
area should be externally drained to control postoperative
leak as a controlled fistula. With creation of a gastrojejunal
anastomosis and no concomitant procedure to decrease gastric acid production, H2 blockers or proton pump inhibitors
should be given in the postoperative period to prevent mar-
TRAUMA
Blunt Injuries. Blunt injuries to the duodenum are less common and more difficult to diagnose than penetrating injuries.
They can occur in isolation or with pancreatic injury. The need
for immediate abdominal exploration is frequently not obvious. Because the duodenum is located in the retroperitoneum,
findings on physical examination of the abdomen may be subtle except in cases of associated intra-abdominal injuries.
Nonetheless, the physical examination is still one of the best
methods for determining the presence of a duodenal injury.
This is particularly true if the admission examination is indeterminate, emphasizing the need for serial abdominal examinations.
398
The serum amylase concentration is helpful in the diagnosis of blunt duodenal injuries; however, the test lacks sensitivity. The duodenum is retroperitoneal, the concentration of
amylase in the fluid that leaks is variable, and amylase concentrations often take hours, even days, to increase after injury.
Serial determinations of serum amylase are better than a single, isolated determination on admission, but sensitivity is still
not good and delays are inherent in serial determinations.
Upper GI series and CT scans with GI contrast are reasonably sensitive for the presence of duodenal injury after blunt
trauma. Performance of these tests requires a stable patient
without any other obvious indications for abdominal exploration. An advantage of CT over upper GI series is that the rest
of the retroperitoneum and peritoneal viscera are also visualized. With either study, extravasation of contrast material
from the duodenum constitutes an absolute indication for surgical intervention and repair.
Operative exposure and repair of the duodenum after blunt
trauma are the same as for penetrating injuries. Crush injuries
are more common after blunt trauma and occasionally require
extensive resection, but the injuries can be treated frequently
by simple techniques of repair if they are diagnosed in a timely
fashion.
Intramural hematoma of the duodenum is a rare injury specific to patients with blunt trauma. It is most common in children after isolated localized force to the upper abdomen (e.g.,
bicycle handlebar ends). Intramural hematomas occur when the
Pancreas
Penetrating Injuries. Penetrating injuries to the pancreas
are usually diagnosed in the operating room.26 The pancreas is
located in the retroperitoneum, surrounded by a number of
other viscera and major vascular structures. As a result, an isolated injury to the pancreas is unusual, and patients with penetrating pancreatic trauma usually have obvious indications
for abdominal exploration. Preoperative serum amylase and
lipase concentrations are not helpful; they are elevated only in
a few patients with penetrating pancreatic injuries.
On abdominal exploration, signs of pancreatic injury
include a projectile path that passes near the pancreas, a central hematoma in the upper abdomen, and injuries to the duodenum, vena cava, suprarenal aorta, or mesenteric vessels. In
all these instances, the pancreas should be thoroughly
explored.
The anterior surface of the pancreas is visualized by entry
into the lesser sac of the peritoneal cavity. This is done in the
same fashion as outlined previously for exposure of the posterior aspect of the stomach, with division of the gastrocolic ligament in a relatively avascular area to the left of the midline.
A thin layer of peritoneum overlies the anterior surface of the
pancreas at this point, and complete visualization of the surface sometimes requires incision of this layer.
The tail of the pancreas can be more fully visualized, especially in its posterior aspect, by mobilization of the spleen and
the tail of the pancreas as a unit. This is accomplished by incision of any lateral attachments of the spleen to the abdominal
wall and mobilization of the spleen with blunt dissection laterally to medially by development of the plane between the anterior surface of the left kidney and the posterior aspect of the
spleen. This brings the spleen into the abdominal wound and
elevates the posterior aspect of the pancreatic tail for inspection. The posterior aspect of the body of the pancreas is visualized by opening the avascular area at the inferior margin of
the body and tail of the pancreas with a combination of sharp
and blunt dissection. The pancreas can then be mobilized
inferiorly to superiorly. This maneuver is also important to
mobilize the pancreas in preparation for distal pancreatic
resection.
The posterior aspect of the head of the pancreas can be
exposed by an extensive Kocher maneuver. In combination
with entry into the lesser sac, this also allows for bimanual palpation of the pancreatic head, with one hand placed on the
anterior surface of the pancreas through the hole in the lesser
399
sac and the other hand placed behind the pancreas in the plane
developed by the Kocher maneuver.
In the evaluation of penetrating pancreatic injuries, an
important key to operative management is whether a ductal
injury is present. Transduodenal intraoperative pancreatography has been recommended. The advantage of this maneuver
is that it allows for more definitive determination of the type of
operative intervention that should be undertaken. The major
disadvantage is that it necessitates entry into the duodenum
when there is no associated duodenal injury, which turns simple pancreatic injuries into combined pancreaticoduodenal
injuries, with an attendant significant increase in potential
postoperative morbidity. A further argument against intraoperative pancreatography is that most injuries to the pancreas
can be adequately evaluated and decisions made about appropriate operative treatment without radiographic examination
of ductal anatomy. In rare circumstances in which the patients
condition permits and the necessary equipment and expertise
are available, the use of intraoperative endoscopic retrograde
cholangiopancreatography (ERCP) provides an excellent
option.
The operative management of penetrating pancreatic
injuries depends on both the location and severity of the
injury.27 With respect to location, injuries can be subdivided
into those of the head, body, and tail of the pancreas. With
respect to severity, injuries can be classified by the degree of
parenchymal disruption and the presence or absence of ductal
injury.
Contusions of the pancreas, regardless of location, should
be either simply observed or drained. The optimal type of
drainage is a matter of some debate, and a variety of different
drainage methods have been espoused. The type of drain used
after pancreatic injury is probably not as important as ensuring that adequate drainage has been effected. If drains are
used, they should be left in place for at least 5 to 7 days to
ensure that a drain tract develops. Pancreatic fistulas can
develop on a delayed basis 3 to 7 days after injury, and if the
drains are removed before that time, drainage may be inadequate. The morbidity rate for patients with undrained pancreatic secretions is much greater than for those with drained
pancreatic secretions.
The timing of drain removal should be based on both the
amount and character of the pancreatic drainage. Drain outputs in excess of 150 to 200 mL/d are suggestive of pancreatic
fistulas. Determinations of drain amylase concentration are
helpful, but amylase concentrations within a few days of
injury, even if very high levels (50,000 IU/L), do not correlate with the development of a pancreatic fistula or other complications. Determinations at 7 days after injury correlate with
the persistence of a pancreatic fistula or other pancreatic complication only if the level is higher than 100,000 IU/L, whereas
the negative predictive value of a concentration below
100,000 IU/L is poor and does not rule out the presence or
subsequent development of a pancreatic complication.
Treatment of major parenchymal disruptions depends on
location and the presence of ductal injury. Injuries to the body
or tail of the pancreas should be evaluated for possible ductal
disruption. It can be difficult to determine definitively whether
an injury has occurred to the duct by inspection of the
parenchymal injury. If a ductal injury is obvious or likely, the
distal pancreas should be resected and the proximal pancreas
and pancreatic duct oversewn. Distal resection can include up
to 80% of the gland, if necessary. Subsequent endocrine or
exocrine insufficiency is rare if the pancreas is normal. If a ductal injury is not present or is unlikely, the pancreas should be
drained. Major parenchymal disruptions of the head of the
pancreas should be drained, regardless of the presence of ductal disruption, because the morbidity of pancreaticoduodenectomy or attempts at internal drainage is greater than the morbidity of simply draining the area of injury. If a pancreatic
fistula develops, drains can control it. If the fistula does not
TRAUMA
400
Small Intestine
Penetrating Injuries. Because the small intestine occupies
more volume in the peritoneal cavity than any other organ, it
is the intra-abdominal viscus most frequently injured by penetrating abdominal trauma. The severity of injury ranges from
trivial rents in the bowel serosa or mesentery to massive perforation or devascularization injuries requiring extensive
resection.
Diagnosis of small-bowel injury can be made by a number
of methods. Physical examination of the abdomen reveals peritoneal signs in many patients with penetrating small-bowel
injuries. Patients with gunshot wounds routinely undergo
laparotomy. Recently, some have advocated that all patients
with penetrating abdominal trauma, including gunshot
wounds, who do not exhibit signs of peritonitis or hemodynamic instability should undergo abdominal CT.30 If CT is performed, free air or stranding is an indication for early laparotomy due to the likelihood of bowel injury. However, for
abdominal gunshot wounds, most trauma surgeons continue
to limit this approach to only very limited tangential or right
upper quadrant trajectories.
401
TRAUMA
402
that segment also should be resected. Caution should be exercised in using stapled anastomoses in trauma patients if extensive bowel wall edema is present. With normal intestinal wall
thickness, however, stapled anastomoses are particularly useful when time is of the essence and should be constructed in a
side-to-side, functional end-to-end fashion.
Knife wounds to the small intestine are usually easy to
manage and rarely require extensive dbridement or resection.
On rare occasions, a large rent in the small bowel mesentery
results in enough devascularization to require resection of a
segment of intestine.
Minor mesenteric lacerations should be treated with suture
ligation of bleeding points and closure of the rent. Major lacerations with devascularization should be treated with resection and primary anastomosis. Small-bowel anastomoses,
when properly done and after adequate dbridement of devitalized tissue, have an excellent rate of healing even with
severe associated injuries, shock, and peritonitis.
Shotgun wounds to the abdomen from close range are often
associated with massive tissue destruction, which should be
dbrided and anastomosis completed as appropriate. Mediumor longer-range shotgun wounds sometimes result in a diffuse
pattern of shot injury, creating multiple small perforations of
the small intestine. In such instances, the general principles
outlined should be followed and obvious areas of injury
repaired. It is sometimes impossible to ensure closure of all the
numerous areas of perforation, and planned repeat laparotomy may be required to rule out occult injuries.
On rare occasions, injuries to the small intestine occur in
patients who are hemodynamically unstable as a result of associated injuries. In such instances, the small intestine can be
treated most expeditiously by application of the gastrointestinal anastomosis stapler as necessary to remove the injured
areas of bowel as a damage control technique. A second
operation is planned and definitive anastomosis is deferred
with the stapled ends of the intestine returned to the abdomen
until the second procedure is performed.
6
nized for all of these findings, then the sensitivity of CT is actually quite high. If these findings are present, the CT may be
repeated in 4 to 6 hours to evaluate for progression of the
injury.32 A follow-up DPL can also be valuable if there are concerns about radiation or contrast. If the patient is fully evaluable and does not have any signs or symptoms of injury, these
studies may be obviated for careful serial exams. If abdominal
pain or tenderness is present, a follow-up study is prudent.
Optimally, the intestinal injury should be identified within 6 to
8 hours. Intervention greater than 12 to 24 hours will have a
substantial increase in morbidity and mortality. Blunt injuries
to the small intestine are most common in either the proximal
jejunum or the distal ileum, probably because the intestine is
fixed at these two points and more vulnerable to shear and
stretch injuries. Multiple injuries to the small intestine from
blunt trauma occur in approximately 25% of cases. Second or
even third areas of injury should be carefully sought if a blunt
intestinal injury is discovered on abdominal exploration.
After the suspicion of blunt intestinal or other intraabdominal injury has been raised and the decision to explore
the abdomen has been made, the basic principles of abdominal
exploration and operative management of blunt small-bowel
injuries are the same as for penetrating injuries. Because of the
nature of the mechanism of injury, the perforations are usually
amenable to primary repair. Mesenteric rents that cause devascularization and require resection are relatively more common
after blunt injury than after penetrating injury. The radiologic
and physical findings associated with these types of injuries are
initially more subtle, but become obvious after the devascularized bowel perforates. This may lead to a delay in laparotomy
and definitive control.
TA B L E 2 3 . 5
403
MANAGEMENT
TRAUMA
TA B L E 2 3 . 6
ZONES OF THE PERITONEUM
ZONE
LOCATION
ASSOCIATED INJURIES
Central
retroperitoneum
Pancreaticoduodenal injuries
or major abdominal vascular
injury
Pelvis
Pelvic fractures
Retroperitoneal Hematoma
The optimal management of retroperitoneal hematoma
depends on a number of factors, including its cause, its loca7 tion, and the presence of associated injuries. The retroperitoneum can be divided into anatomic zones for purposes of
decision making (Fig. 23.8 and Table 23.6). Retroperitoneal
404
Zone 3 retroperitoneal hematomas in patients with penetrating injuries should be explored to exclude major vascular
injuries. Bleeding from iliac vessels can be challenging and
have a significant mortality. Venous control with direct pressure and dissection allows exposure for diagnosis, ligation, or
repair. Arterial injuries are controlled proximally and occasionally require distal control below the inguinal ligament due
to extensive collateral blood flow. Patients with zone 3
hematomas secondary to blunt trauma usually have associated
pelvic fractures. If found at laparotomy, exploration of the
hematoma can be hazardous and difficult to control and is
avoided. There is often combined extensive injury to the rich
presacral venous plexus and arterial circulation. Incision of the
peritoneum releases the tamponade, and dissection within the
hematoma can produce catastrophic bleeding. Discrete bleeding points rarely can be identified. Exploration of these
hematomas is associated with an increased requirement for
transfusion and a higher mortality rate. Pelvic packing is useful for substantial hematomas, with a return to the operating
room in 24 to 72 hours for pack removal. Zone 3 hematomas
found on CT or clinically suspected that are associated with
hemodynamic instability are best managed with angiographic
embolization and/or, less commonly, external pelvic fixation.
Recently, extraperitoneal packing through a Pfannenstiel incision has been described as an exigent option, particularly if
angiography is not available.36
References
1. Bickell WH, Wall MJ Jr, Pepe PE, et al. Immediate versus delayed fluid
resuscitation for hypotensive patients with penetrating torso injuries. N
Engl J Med 1994;331:11051109.
2. Geeraedts LM Jr, Kaasjager HA, van Vugt AB, et al. Exsanguination in
trauma: a review of diagnostics and treatment options. Injury 2009;40(1):
1120.
3. Malhotra AK, Fabian TC, Katsis SB, et al. Blunt bowel and mesenteric
injuries: the role of screening computer tomography. J Trauma 2000;48:
9911000.
4. Killeen KL, Shanmuganathan K, Poletti PA, et al. Helical computed
tomography of bowel and mesenteric injuries. J Trauma 2001;51:2636.
5. Villavicencio RT, Aucar JA. Analysis of laparoscopy in trauma. J Am Coll
Surg 1999;189:1120.
6. Moore E, Moore J, Van Duzer-Moore S, et al. Mandatory laparotomy for
gunshot wounds penetrating the abdomen. Am J Surg 1980;140:847851.
7. Rozycki GS, Ballard RB, Feliciano DV, et al. Surgeon-performed ultrasound for the assessment of truncal injuries: lessons learned from 1,540
patients. Ann Surg 1998;228:557567.
8. McKenny MG, Martin L, Lentz K, et al. 1,000 Consecutive ultrasounds
for blunt abdominal trauma. J Trauma 1996;40:607612.
9. Branney SW, Moore EE, Cantrill SV, et al. Ultrasound based key clinical
pathway reduces the use of hospital resources for the evaluation of blunt
abdominal trauma. J Trauma 1997;42:10861090.
10. Shackford SR, Rogers FB, Osler TM, et al. Focused abdominal sonogram
for trauma: the learning curve of nonradiologist clinicians in detecting
hemoperitoneum. J Trauma 1999;46:553564.
11. Wherrett LJ, Boulanger BR, McLellan BA, et al. Hypotension after blunt
abdominal trauma: the role of emergent abdominal sonography in surgical
triage. J Trauma 1996;41:815820.
12. Luchette FA, Borzotta AP, Croce MA, et al. Practice management guidelines for prophylactic antibiotic use in penetrating abdominal trauma: the
EAST Practice Management Guidelines Work Group. J Trauma 2000;48:
508518.
13. Kirton OC, ONeill PA, Kestner M, et al. Perioperative antibiotic use
in high-risk penetrating hollow viscus injury: a prospective randomized,
double-blind, placebo-control trial of 24 hours versus 5 days. J Trauma
2000;49: 822832.
14. Rotondo MF, Schwab CW, McGonigal MD, et al. Damage control: an
approach for improved survival in exsanguinating penetrating abdominal
injury. J Trauma 1993;35:375382.
15. Suliburk JW, Ware DN, Balogh Z, et al. Vacuum-assisted wound closure
achieves early fascial closure of open abdomens after severe trauma. J
Trauma 2003;55:11551160.
16. Schurr MJ, Fabian TC, Gavant M, et al. Management of blunt splenic
trauma: computed tomographic contrast blush predicts failure of nonoperative management. J Trauma 1995;39:507512.
17. Thaemert BC, Cogbill TH, Lambert PJ. Nonoperative management of
splenic injury: are follow-up computed tomographic scans of any value?
J Trauma 1997;43:748751.
18. Peitzman AB, Heil B, Rivera L, et al. Blunt splenic injury in adults: multiinstitutional study of the Eastern Association for the Surgery of Trauma.
J Trauma 2000;49:177189.
19. Davidson RN, Wall RA. Prevention and management of infections in
patients without a spleen. Clin Microbiol Infect 2001;7:657660.
20. Croce MA, Fabian TC, Menke PG, et al. Nonoperative management of
blunt hepatic trauma is the treatment of choice for hemodynamically stable
patients: results of a prospective trial. Ann Surg 1995;221:744753.
21. Demetriades D, Hadjizacharia P, Constantinou C, et al. Selective nonoperative management of penetrating abdominal solid organ injuries. Ann Surg
2006;244(4):620628.
22. Brown CV, Kasotakis G, Wilcox A, et al. Does pelvic hematoma on admission computed tomography predict active bleeding at angiography for
pelvic fracture? Am Surg 2005;71(9):759762.
23. Polanco P, Leon S, Pineda J, et al. Hepatic resection in the management of
complex injury to the liver. J Trauma 2008;65(6):12641269.
24. Scherer LA, Battistella FD, Owings JT, et al. Video-assisted thoracic
surgery in the treatment of posttraumatic empyema. Arch Surg 1998;133:
637642.
25. Levison MA, Peterson SR, Sheldon GF, et al. Duodenal trauma: experience
of a trauma center. J Trauma 1984;24:475480.
26. Wisner DH, Wold RL, Frey CF. Diagnosis and treatment of pancreatic
injuries: an analysis of management principles. Arch Surg 1990;125:
11091113.
27. Patton JH, Lyden SP, Croce MA, et al. Pancreatic trauma: a simplified
management guideline. J Trauma 1997;43:234240.
28. Lucas CE. Diagnosis and treatment of pancreatic and duodenal injury.
Surg Clin North Am 1977;57:4965.
29. Fulcher AS, Turner, MA, Yelon JA, et al. Magnetic resonance cholangiopancreatography (MRCP) in the assessment of pancreatic duct trauma
and its sequelae: preliminary findings. J Trauma 2000;48:10011007.
30. Shanmuganathan K, Mirvis SE, Chiu WC, et al. Penetrating torso trauma:
triple-contrast helical CT in peritoneal violation and organ injurya
prospective study in 200 patients. Radiology 2004;231(3):775784.
31. Wisner DH, Chun Y, Blaisdell FW. Blunt intestinal injury: keys to diagnosis and management. Arch Surg 1990;125:13191322.
32. Ekeh AP, Saxe J, Walusimbi M, et al. Diagnosis of blunt intestinal and
mesenteric injury in the era of multidetector CT technologyare results
better? J Trauma 2008;65(2):354359.
33. Velmahos GC, Constantinou C, Tillou A, et al. Abdominal computed
tomographic scan for patients with gunshot wounds to the abdomen
selected for nonoperative management. J Trauma 2005;59(5):11551160.
34. Stone HH, Fabian TC. Management of perforating colon trauma: randomization between primary closure and exteriorization. Ann Surg 1979;
190:430436.
35. Demetriades D, Murray JA, Chan L, et al.; Committee on Multicenter
Clinical Trials. American Association for the Surgery of Trauma. Penetrating colon injuries requiring resection: diversion or primary anastomosis? An AAST prospective multicenter study. J Trauma 2001;50(5):
765775.
36. Osborn PM, Smith WR, Moore EE, et al. Direct retroperitoneal pelvic
packing versus pelvic angiography: a comparison of two management protocols for haemodynamically unstable pelvic fractures. Injury 2009;40(1):
5460.
P O I N T S
Ureteral injuries due to external violence are rare and
require a heightened index of suspicion due to lack of consistent physical findings.
5 Injuries to the bladder require prompt diagnosis, with
intraperitoneal injuries necessitating surgical repair.
6 Initial management of urethral injuries varies based on location (anterior vs. posterior) and severity, the most severe
requiring urinary diversion with a suprapubic tube.
7 Primary open reconstruction of posterior urethral injuries
secondary to pelvic fracture is discouraged, and primary
endoscopic realignment should be undertaken only by a
surgeon experienced with this technique.
4
405
TRAUMA
K E Y
406
TA B L E 2 4 . 1
CLASSIFICATION
AMERICAN ASSOCIATION FOR THE SURGERY OF TRAUMA (AAST) ORGAN INJURY SCALES FOR URINARY TRACT
INJURED
STRUCTURE
Kidneya
Uretera
Bladder
Urethra
AAST
GRADE
CHARACTERISTICS OF INJURY
II
III
Laceration 1.0 cm parenchymal depth of renal cortex without collecting system rupture or
urinary extravasation
IV
Parenchymal laceration extending through renal cortex, medulla, and collecting system with
urinary extravasation; injury to main renal artery or vein with contained hemorrhage
II
50% transection
III
50% transection
IV
II
III
IV
II
Stretch injury with elongation of urethra, but without extravasation of urethrography contrast
material
III
Partial disruption with extravasation of urethrography contrast material at injury site with
visualization in the bladder
IV
Complete transection with 2 cm urethral separation or extension into the prostate or vagina
detecting urologic injury and is inferior to CT.12,13 Renal arterial angiography is rarely used diagnostically but therapeutically is indicated to treat isolated, symptomatic (early or late)
renal bleeding, arteriovenous fistula, or pseudoaneurysm using
embolization.14
Most injuries can be managed nonoperatively.3,15 Grade I
3
and II injuries often require no further management. The bulk
of blunt grade III and nonvascular grade IV injuries can be
managed expectantly. Select penetrating injuries in hemodynamically stable patients can be managed on observation
protocols as well.16 The absolute indications for renal exploration include hemodynamic instability secondary to renal
hemorrhage, expanding or pulsatile retroperitoneal hematoma at laparotomy, and pedicle avulsion. Furthermore, in
patients undergoing laparotomy for concomitant intraperitoneal injuries, exploration should be considered for deep
grade III or IV lacerations, with or without devitalized kidney
fragments, because the incidence of complications from nonoperative management can potentially be reduced.10,17 If renal
exploration is contemplated or necessary, demonstration of
contralateral renal function is important in the event ipsilateral nephrectomy is performed. In patients in whom immediate laparotomy is performed without preoperative imaging,
407
Hemodynamically stable
Hemodynamically unstable or
expanding, pulsatile hematoma
One shot I.V. pyelogram (IVP).
Blunt trauma
Adult, microscopic
hematuria and no shock
Discharge from ED
Repeat urinalysis in 3 wks
Penetrating trauma
Grade I or II
Laparotomy indicated
ALGORITHM 24.1
ALGORITHM 24.1. Evaluation and management of suspected kidney injury.
managed and explored kidneys should be managed angioThe capsule of the kidney is routinely left intact for closure folgraphically, because nephrectomy is likely with exploration.
lowing renal reconstruction. During renal exploration, sharp
Late complications are uncommon and include renin-mediated
dbridement, hemostasis, collecting system repair, and pledhypertension from chronic renal ischemia, arteriovenous malgeted, bolstered closure of the renal capsule using absorbable
formations, and segmental arteriolar pseudoaneurysm.
suture is performed. A perinephric suction drain is placed
away from the repair in the retroperitoneum and removed
when drainage subsides, usually less than 50 mL/d. If concern
exists regarding the nature of the drainage, an aliquot of fluid
Ureter
can be sent for creatinine concentration to evaluate for the
4 Ureteral injuries are rare (1%), with fewer than 10 (due to
presence of urine.
In the case of renal artery thrombosis, surgical revascularexternal causes) presenting annually in busy trauma centers.25
ization is rarely helpful because of the time delay from injury
As these injuries often present without clear signs or sympto revascularization. Intervention is commonly limited to
toms, many are missed at the initial assessment and delayed
patients with solitary kidney or bilateral injuries.22,23 An
diagnosis is common (Algorithm 24.2).26 The most common
emerging therapy is vascular stent placement through the
source of injury to the ureter is iatrogenic during hysterecinjury or thrombus; however, most series are limited and
tomy. These injuries occur with ligation of the infundiburesults mixed.24 Venous injuries often result in massive bleedlopelvic ligament where the ureter crosses the uterine artery.27
ing and may require nephrectomy. Isolated proximal left renal
In the adult population, penetrating injuries, gunshot wounds
vein injuries can potentially be managed by controlling and
followed distantly by stab wounds, are the most frequent
oversewing the caval stump because left renal vein collateral
source of injury associated with external violence.28,29 A high
drainage is present via the gonadal, adrenal, and lumbar veins.
degree of suspicion should accompany the evaluation of peneRight renal venous injury requires repair, if feasible, or
trating wounds and injury should be suspected when organs
nephrectomy due to lack of collateral circulation.
anatomically related to the ureter sustain injury: iliac vessels,
Frequent clinical monitoring for ongoing bleeding is essenbladder, sigmoid colon, and lumbar spine or transverse
tial.6 Postoperative complications of ileus, urinoma, atelectasis,
processes. Significant deceleration and hyperextension mechanisms can result in blunt avulsion as well. In children, the
and infection can occur. Secondary bleeding of nonoperatively
TRAUMA
408
409
Patient is stable
Patient is unstable
CT w/ delayed cuts
Normal Studies
Abnormal Studies
Observation
Perform laparotomy
ALGORITHM 24.2
ALGORITHM 24.2. Evaluation and management of suspected ureteral injury.
Ureteropelvic
Junction
Reanastomosis
Distal Ureter
Short defects: reimplantation
Long defects: vesicopsoas
hitch or Boari flap
reimplantation
TRAUMA
410
FIGURE 24.3. Techniques of ureteral repair. A: End-to-end ureteroureterostomy. B: Vesico-psoas hitch reconstruction with reimplantation performed by suturing of the bladder to psoas tendon after mobilization of both obliterated
umbilical, plus or minus contralateral superior vesical, pedicles, avoiding the genitofemoral nerve. C: Boari flap
performed using a tubularized bladder flap based on the ipsilateral superior vesical artery. D: Transureteroureterostomy (TUU). For all repairs the principles include tension-free, watertight, stented, spatulated, mucosa-to-mucosa
anastomosis using absorbable suture with drain placement.
Urethra
TRAUMA
411
412
No extravasation
Positive Extravasation
Penetrating injury
Blunt injury
Penetrating injury
Blunt injury
Associated injuries,
high-velocity gunshot
wound, or bony fractures.
Place suprapubic cystostomy tube and rule out bladder injury.
Planned laparotomy: explore bladder and place open suprapubic tube.
Planned orthopedic fracture reconstruction or presence of rectal injury:
perform primary realignment of posterior urethral injury and remove
suprapubic tube
Change tube at one month, then monthly until surgical reconstruction.
ALGORITHM 24.3
ALGORITHM 24.3. Evaluation and management of suspected urethral injury.
References
1. Peden M, Scurfield R, Sleet D, et al. World Report on Road Traffic Injury
Prevention. Geneva, Switzerland: World Health Organization; 2004.
2. Clarke DE, Fantus RJ, eds. National Trauma Data Bank Annual Report.
Chicago: American College of Surgeons; 2007.
3. Wessells H, Suh D, Porter JR, et al. Renal injury and operative management in the United States: results of a population-based study. J Trauma
2003;54(3):423430.
4. Krieger JN, et al. Urological trauma in the Pacific Northwest: etiology, distribution, management and outcome. J Urol 1984;132(1):7073.
5. Baverstock R, Simons R, McLoughlin M. Severe blunt renal trauma: a 7year retrospective review from a provincial trauma centre. Can J Urol
2001;8(5):13721376.
6. Santucci RA, et al. Evaluation and management of renal injuries: consensus statement of the renal trauma subcommittee. BJU Int 2004;93(7):
937954.
7. Wright JL, et al. Renal and extrarenal predictors of nephrectomy from the
National Trauma Data Bank. J Urol 2006;175(3 Pt 1):970975; discussion
975.
8. Shariat SF, et al. Evidence-based validation of the predictive value of the
American Association for the Surgery of Trauma kidney injury scale. J
Trauma 2007;62(4):933939.
9. McAndrew JD, Corriere JN Jr. Radiographic evaluation of renal trauma:
evaluation of 1103 consecutive patients. Br J Urol 1994;73(4):352
354.
10. Corriere JN Jr, McAndrew JD, Benson GS. Intraoperative decision-making
in renal trauma surgery. J Trauma 1991;31(10):13901392.
11. Morey AF, et al. Single shot intraoperative excretory urography for the
immediate evaluation of renal trauma. J Urol 1999;161(4):10881092.
12. McGahan JP, et al. Use of ultrasonography in the patient with acute renal
trauma. J Ultrasound Med 1999;18(3):207213; quiz 215216.
13. Perry MJ, Porte ME, Urwin GH. Limitations of ultrasound evaluation in
acute closed renal trauma. J R Coll Surg Edinb 1997;42(6):420422.
14. Hagiwara A, et al. The role of interventional radiology in the management
of blunt renal injury: a practical protocol. J Trauma 2001;51(3):526
531.
15. Hammer CC, Santucci RA. Effect of an institutional policy of nonoperative treatment of grades I to IV renal injuries. J Urol 2003;169(5):
17511753.
16. Wessells H, et al. Criteria for nonoperative treatment of significant penetrating renal lacerations. J Urol 1997;157(1):2427.
17. Husmann DA, et al. Major renal lacerations with a devitalized fragment
following blunt abdominal trauma: a comparison between nonoperative
(expectant) versus surgical management. J Urol 1993;150(6):1774
1777.
413
TRAUMA
3
4
A large body of literature currently exists regarding the management of traumatic vascular injuries with traditional open
surgical techniques. Likewise, there is an evolving literature on
the management of vascular trauma with endovascular techniques. Over the past several decades, catheter-based and
endovascular techniques have been used with increasing frequency for the management of trauma. This is particularly
true for the management of solid organ injury and vascular
injuries resulting from pelvic fracture. The endovascular management of vascular trauma seems particularly appealing in
the management of blunt truncal injuries, especially in the setting of severe concomitant brain and lung injury. Extremity
and neck injuries are currently best handled by traditional
methods of surgical proximal and distal control, the exception
to this being base-of-skull injuries where there is no ability for
distal vessel control and watershed areas between the trunk
and extremities where surgical management for the unfamiliar
surgeon can be quite difficult. This chapter reviews current literature with regard to broad principles of both open and
endovascular management of traumatic vascular injuries with
regions being broadly defined as neck, trunk, and extremity.
EPIDEMIOLOGY OF VASCULAR
INJURY: DISTRIBUTION
OF INJURIES
P O I N T S
The ascending aorta and innominate and right subclavian
arteries are best approached by median sternotomy. The
proximal left subclavian artery and descending thoracic
aorta are best approached via left thoracotomy.
7 Left colon mobilization is useful for exposure of the paravisceral aorta, left renal artery, infrarenal aorta, and left
iliac artery. Similarly, the inferior vena cava, right renal
artery, infrarenal aorta, and right iliac artery can be
approached by an extensive Kocher maneuver and mobilization of the right colon.
8 Endovascular repair of traumatic thoracic aortic disruption is associated with lower mortality and lower rates of
paraplegia than traditional open repair.
6
PHYSIOLOGIC CONSEQUENCE
OF VASCULAR INJURY
The principal physiologic consequence of vascular injury results
from either profound hemorrhage with associated metabolic consequences of total body ischemia or end-organ ischemia of the
vascular bed fed by the injured vessel. Factors affecting ischemic
tolerance include the nature of injury (complete vs. incomplete
disruption), adequacy of collateral blood flow, underlying metabolic state, associated injuries, sensitivity of the end organ to
ischemia, and the time required to repair the injury. The brain is
the most sensitive tissue to ischemia due to the high basal energy
requirements and the absence of robust glycogen stores. Warm
brain ischemia lasting longer than 6 minutes results in irreversible
injury. Other than bone, skeletal muscle is probably most resistant to ischemia. Peripheral nerves and muscle can tolerate up to
6 hours of ischemia without permanent damage.
Tissue ischemia causes anoxic cell death. Restoration of
oxygen-rich blood flow after ischemic injury produces a reperfusion injury mediated by oxygen-free radicals.2 These oxygen-free
radicals initiate multiple proinflammatory processes, including
lipid peroxidation, which causes diffuse injury to the microvasculature resulting in increased permeability, edema formation,
and an increase in interstitial pressure. This overall process ultimately leads to stasis within the microvasculature, worsening
ischemia, and cell lysis, including rhabdomyolysis. The resultant
tissue destruction causes hyperkalemia, metabolic acidosis, and
myoglobin-induced renal failure and may ultimately prove fatal.
414
TRAUMA
K E Y
TRAUMA
415
416
TREATMENT
Lateral repair
Patch angioplasty
Primary end-to-end
anastomosis
Interposition graft
Extra-anatomic bypass
Suture ligation
vessel thrombosis in the early postoperative setting. After adequate dbridement, the vessels should be flushed with a
heparinized saline solution both proximally and distally. A
tension-free repair should then ensue. Options for repair are
many and are listed in Table 25.1. As a general rule, the most
often utilized vascular procedures are ligation and interposition bypass graft. With combined injuries, arterial repair
should precede venous repair except when venous repair
requires little effort. This is to minimize ischemic burden from
an already severely injured vascular bed.
The temptation to reconstruct, repair, or even ligate an arterial injury in the setting of a highly contaminated wound
should be thoroughly resisted. Recent studies have shown that
a high failure rate ensues due to infection and subsequent
thrombosis.11 In a contaminated wound, every effort should be
made to perform adequate dbridement and then reassess for
adequate collateral macroperfusion with every means available. If ligation of a major artery is required, distal embolectomy should be routinely performed followed by distal infusion
or systemic administration of heparin to preserve collateral circulation.12 If feasible, patients should undergo abdominal
decompression, prophylactic fasciotomy, observation, and then
definitive revascularization once control of wound sepsis has
been accomplished. Alternatively, routing of bypass grafts
through uncontaminated fields offers the best chance for success in the management of these challenging injuries.
Key to the success of vascular repair is appropriate use of
available conduit for reconstruction. It is widely held that the
best alternative conduit for reconstruction is autologous
saphenous vein. The saphenous vein is the workhorse for vascular surgeons and can be used in multiple locations. It is
important to remember the concept of directional flow within
veins and thus reverse or turn around the saphenous vein prior
to using it as a conduit for revascularization. The saphenous
vein may also be used as patch material or refashioned in the
form of a panel or spiral graft for reconstruction of larger vessels. The saphenous vein should always be recovered from the
uninvolved extremity. This is done to provide maximal venous
drainage from the injured extremity should the deep system be
involved or the patient develop deep vein thrombosis in the
postoperative period. Proximal saphenous vein can still be utilized in the rare patient presenting with upper extremity vascular injury and bilateral major traumatic below-knee injuries.
The repair of extremity venous injuries has been controversial. Data from Dr. Norman Rich and the Vietnam Vascular Registry supports an effort at repair of most major venous injuries if
possible.13,14 The decision to repair versus ligate a major extremity venous injury depends on the available resources, existing
comorbidities, coexistent injuries in the same patient, and, of
course, the hemodynamic stability of the patient. Rich retrospectively demonstrated a lower incidence of chronic venous insufficiency and postphlebitic syndrome in those patients undergoing
venous repair as opposed to ligation in the lower extremity.13
However, the same general principles do not hold true for venous
injuries in the upper extremity, where ligation is better tolerated
with minimal chronic morbidity.
OPERATIVE MANAGEMENT
OF SPECIFIC REGIONS
Management of Vascular Injury in the Neck
Injuries to the neck have been notoriously difficult to manage.
A clear anatomic division of the neck into zones has allowed a
selective approach to penetrating neck trauma. Zone I lies
below the cricoid cartilage, and zone III lies above the angle of
the mandible. Zone II, which is between I and III, has classically been managed with immediate exploration and direct
evaluation of the aerodigestive tract and the carotid and jugular vessels. The most commonly injured structures in the neck
are the blood vessels, with the incidence of major vascular
trauma following penetrating neck trauma being 20%.15 Physical examination and determination of hard signs predict those
patients with significant injuries who might benefit from
immediate exploration.16 Direct surgical repair remains the
gold standard for injuries in all zones, but endovascular
approaches are appealing in that some of these injuries can be
remotely approached from within the thoracic inlet and base
of the skull, thus avoiding the morbidity of the required extensive surgical exposure. Unique advantages for an endovascular
approach to the extracranial cerebrovascular system include
avoidance of general anesthetic and the ability to monitor neurologic status during the intervention.
Penetrating zone I and III injuries that require immediate
operative intervention are not candidates for a purely
endovascular approach. However, endovascular techniques
may be utilized in a hybrid fashion to support the standard
open repair of these injuries. Zone I injuries with hard signs of
vascular injury may have an enlarging hematoma at the thoracic inlet, high chest tube output, or shock. These injuries
notoriously involve the great vessels. Immediate control
involves a high anterior thoracotomy, sternotomy, or clavicular resection to obtain adequate proximal control. Once the
patient is prepared in the operating room, an occlusion balloon can be rapidly utilized from the groin to provide endoluminal proximal control of the great vessels, allowing conduct
of a surgical exposure in a more controlled fashion and possibly avoiding sternotomy for proximal exposure. With an
occlusion balloon in place, an arteriogram will help locate the
injury and allow for operative planning. After the injury is
exposed, a vascular clamp replaces the occlusion balloon, or,
alternatively, if proximal vessel length is not adequate, the
occlusion balloon remains in place for repair.
In patients with soft signs of a cervical vascular injury and
hemodynamic stability, there is ample time for further evaluation. Arteriography may identify an intimal flap, dissection,
pseudoaneurysm, complete or partial transection, or thrombosis. Operative repair of these lesions has been shown to reduce
overall mortality and stroke rates for both penetrating and
blunt trauma as compared to observation or ligation.17 However, several centers have found that early anticoagulation
alone also improves overall neurologic status and mortality in
a cohort of patients with high internal carotid artery trauma
who did not undergo operative repair and were able to tolerate anticoagulation with heparin.1820
TRAUMA
TA B L E 2 5 . 1
417
418
FIGURE 25.3. A: Axial computed tomography angiography (CTA) image of blunt aortic injury. B: Oblique sagittal CTA image of the same injury.
C: Follow-up CTA reconstruction after successful stent graft repair.
blunt abdominal trauma.44 Long-term follow-up is not available for iliac stenting in the setting of injury from blunt arterial trauma; however, one would surmise that long-term
patency rates are not too dissimilar and perhaps better than
those from standard iliac artery angioplasty and stenting.
Injury to the vena cava is a rare event, occurring in 0.5% to
5% of penetrating injuries and 0.6% to 1% of blunt abdominal injuries.45 Despite their rarity, injuries to the vena cava represent 30% to 40% of all abdominal vascular injuries and are
commonly associated with a mortality as high as 50%.46
TRAUMA
advocated using the Injury Severity Score (ISS) to guide therapy.27 A predicted mortality based on an ISS of greater than
100% should elicit an approach to simply supporting the
patient with conservative measures, including long-term control of blood pressure with beta-blocking agents and other
antihypertensive agents as required in the resistant patient.
419
420
INDICATIONS/CONTRAINDICATIONS
Tense compartments
Prophylactic
POSTOPERATIVE MANAGEMENT
Patients who have undergone repair of vascular injuries from
trauma should be monitored in the intensive care unit for at
least the first 24 hours after surgery. This should include electrocardiographic monitoring and pulse oximetry, particularly
because hemorrhagic shock and reperfusion of an ischemic
limb may result in systemic physiologic derangements such as
hypoxia, hyperkalemia, and acidosis. Acidosis, anemia, and
hypothermia should be aggressively corrected. For isolated
extremity vascular injuries, mild coagulopathy may be tolerated after revascularization as long as continued bleeding is
minimal. Patients may have substantial hypothermia, tissue
edema, and vasospasm in the injured limb, making palpation
of pulses difficult. Hypothermia should therefore be aggressively corrected and evaluation of vascular status should rely
on Doppler evaluation with ABIs rather than palpable pulses.
During this early postoperative period, palpation for distal
pulses and search for Doppler signals should occur hourly.
Any change at the completion of the surgical repair in pulse or
particularly Doppler signals from the baseline examination
warrants an investigation, either by rechecking ABIs and/or
performing an arteriogram. Patients who had heavily contaminated wounds on initial presentation should have a planned
return trip to the operating room within 24 hours for repeat
irrigation and dbridement of wounds.
MILITARY-SPECIFIC
APPLICATIONS
The modern battlefield has a staunch reputation of being
unclean, noisy, and lacking valuable resources.69 In addition,
high-kinetic-energy injuries such as those resulting from high
explosives, munitions, and high-velocity missiles often cause
soft tissue destruction that is not routinely seen in civilian settings. Extremity injuries predominate, representing 50% to
70% of all injuries treated during Operation Iraqi Freedom,
and exsanguination from extremity wounds is the leading preventable cause of death on the modern battlefield.70 Recent
advances in military medicine have translated into a greater
percentage of wounded soldiers surviving during Operations
Enduring and Iraqi Freedom than in any other previous
American conflict.70 Despite the relative lack of proper angiographic equipment on the modern battlefield, some surgeons
are challenging this standard and attempting to perform
damage control endovascular procedures in the field. This
technology cannot be ignored for future military conflicts.
OUTCOMES
Outcomes after vascular injury are time dependent, necessitating
a sense of urgency in overall management. The results of expeditiously treated vascular injuries are encouraging. Mortality rates
are highest when associated with truncal vascular injuries and
mostly involve the aorta or its primary branches. Most often,
however, the mortality is related to other associated injuries.
The ultimate outcome measure for lower extremity vascular
trauma is the functional limb preservation rate. Amputation
rates after peripheral vascular trauma continue to decrease,
with several modern series reporting rates of less than 2%. This
decrease in amputation rate probably relates to a shortening of
the duration of ischemia by improvements in evacuation, rapid
diagnosis and treatment, and the use of intraluminal shunts.
Early amputation is more likely if a delay in diagnosis occurs or
there has been a significant blunt component (crush) to the
injury. Late amputation is not well documented but is typically
done for intractable pain, complex wound issues, disability, or
chronic infection, which frequently includes osteomyelitis.
Long-term functional outcome is not dependent on the durability of the vascular repair but, alternatively, on the integrity of
the neuromuscular and skeletal elements.72
CONCLUSIONS
The application of endovascular technology to the management
of penetrating and blunt traumatic vascular injuries represents
an exciting and significant advance in modern trauma centers.
Utilization of these techniques to stabilize a patient in extremis
or to serve as a bridge to future elective procedures represents
an attractive alternative with potentially lower morbidity and
mortality rates than conventional open surgical management. It
is of the utmost importance that these procedures be carried out
by experienced providers in a committed trauma center environment conducive to such repair. A wide variety of imaging
equipment as well as endovascular inventory must be readily
available for the successful management of these injuries.
Surgeons should emphasize the use of endovascular surgery
as a modern damage control technique.73 Likewise, training
paradigms for the credentialing of qualified trauma surgeons
should include exposure to basic endovascular techniques. It is
likely that in one or two decades, all endovascular procedures
relating to trauma will be performed by trauma specialists.
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51. Bosse MJ, MacKenzie EJ, Kellam JF, et al. A prospective evaluation of the
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53. Granchi T, Schmittling Z, Vasquez J, et al. Prolonged use of intraluminal
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P O I N T S
Compartment syndromes are defined as inadequate tissue
perfusion to meet oxygen requirements resulting from
increased pressure in a confined anatomic space. The earliest reliable sign is excessive pain to passive or active movement of muscles in the compartment. Pressure monitoring
with pressure differences between the compartment and
diastolic pressure of less than 30 mm Hg require urgent
operative decompression.
5 Major joint dislocations such as of the hip, femoral neck
fracture, open fractures with contamination, talar neck
fracture with dislocation, and thoracic fracture dislocations
are common injuries with potential for long-term disability
that require aggressive early intervention.
6 Spinal cord injuries are leading causes of long-term morbidity and mortality. Aggressive prevention programs, adequate
recognition and resuscitation to optimize perfusion, and
timely decompression and stabilization are required to optimize recovery. The use of steroids in the management of
spinal cord injuries is no longer the standard of care.
4
ment of deformed limbs, palpation of pulses, and detailed neuThe initial resuscitation phase of an acutely traumatized
rologic examination.6 While maintaining full spine precaupatient aims to identify and treat the immediately lifethreatening conditions with priorities placed on maintaining
tions using the multiperson team technique, a formal logor restoring airway, breathing, and circulation. Injuries to the
roll turn remains a standard procedure for full clinical
head, chest, and abdomen receive undisputed priority in
trauma assessment at the earliest feasible time with full palparationale-based trauma assessment and treatment algorithms.
tion of the axial spine from the occiput through the coccyx and
1 Musculoskeletal injuries, which have more than a 70% incidenotation of direct or indirect injury signs. Open injuries and
dence in multiply injured patients and a high potential for
penetrating wounds are evaluated for their impact on the
considerable long-term morbidity, if not addressed properly,
patients vital functions and limb viability and then are dressed
play an important role in successful trauma management.1
sterilely and splinted until definitive care is rendered. Appropriate antibiotic management for open fractures and tetanus
Systematic and effective incorporation of musculoskeletal
immunization should be administered in the emergency settreatment algorithms in trauma assessment and care can play
ting. A systematic neurologic examination and documentation
a crucial role in improving long-term patient outcomes and
are preferably performed consistent with the published standecreasing mortality. On a conceptual basis, orthopaedic
dards recommended by the American Spinal Cord Injury Assoinjuries can be differentiated into the three general impact
ciation, including perianal and rectal examination for presence
categories: (a) life-threatening injuries, (b) limb-threatening
of blood, voluntary contraction, sensation, tone, and reflexes.7
injuries, and (c) injuries with adverse long-term functional
implications.
For all trauma patients a protocol for secondary and tertiary
To minimize the effects of musculoskeletal injuries on the
evaluation should be in place to minimize the occurrence and
care of trauma patients, implementation of a protocolized
impact of delayed injury recognition. This is particularly
approach to diagnosis is helpful. Since approximately 75% of
important for patients with cognitive impairment and patients
missed injuries are orthopaedic in nature, a systematic muscuwho have been removed from the normal trauma care evalualoskeletal systems evaluation is recommended.25 Inadequate
tion algorithm because of exigent circumstances.
visualization of the region of injury or failure to perform a formal secondary or tertiary trauma survey are the most common
causes of delay in diagnosis.
LIFE-THREATENING INJURIES
Initial musculoskeletal assessment of an acutely injured
patient ideally is performed concurrently with the other comMusculoskeletal trauma may directly or indirectly lead to
ponents of the trauma patient evaluation, including serial doc- 2 patient demise on an acute, subacute, or delayed basis. Acutely
umentation of vital signs and mental status and an anteroposlife-threatening conditions may arise from large-scale blood
terior radiograph of the pelvis, a lateral radiograph of the
loss seen with major arterial injuries in conjunction with long
cervical spine, and an anteroposterior roentgenogram of the
bone fractures, pelvic ring disruption, or spine fracture dislochest. Preferably, formal musculoskeletal systems assessment
cations. Subacute life-threatening circumstances may result
and initial care take place during the exposure of the patient,
from occult blood loss with delayed recognition and response.8
with palpation of the trunk and all extremities, manual realignDelayed patient loss of life may occur as either a direct or
423
TRAUMA
K E Y
424
indirect result of musculoskeletal injuries. Secondary pulmonary deterioration and sepsis after multiple fractures are
leading causes of such delayed patient loss of life. Although the
exact cause of posttraumatic sepsis and pulmonary deterioration remains incompletely understood and is likely multifactorial,
the timing and technique of resuscitation and musculoskeletal injury treatment, including factors such as the duration of
recumbence and immobility, undoubtedly play a considerable role in the onset and prevention of these serious
events.911
Injuries to the musculoskeletal system may be of sufficient
severity to cause acutely life-threatening hemodynamic instability because of hypovolemia or neurologic alterations. Injuries
with disruption of vascular structures leading to acute or subacute hypovolemia include pelvic ring disruptions, multiple long
bone fractures, traumatic forequarter or hindquarter amputations, scapulothoracic dissociations, and upper- to midthoraciclevel fracture dislocations, as well as any form of distractive
spinal column injury.1215 The blood loss in each of these injuries
may be occult if the injury is closed. The source of bleeding may
be of arterial, venous, or combined origin, which can dissect
along soft tissue planes even at low pressures into larger recesses
such as the retroperitoneal pelvis, thigh, chest, or lumbodorsal
fascia plane. Thus, constant suspicion of this third-spacing
phenomenon in conjunction with severe musculoskeletal
injuries remains a major differential diagnosis of hypovolemia.
Diagnostic modalities such as computed tomography (CT)
scans or even plain radiographs can assist in identifying such
abnormal fluid collections. Aggressive countermeasures in this
setting may include simple bedside measures such as temporary
pressure dressings, pelvic sheet application, and limb realignment and splinting.16
A major factor affecting mortality in musculoskeletal injury
has arisen with the increasing care challenges for injuries to the
elderly. The adverse relationship between survival beyond 1 year
following trauma for patients 80 years or older in the presence
of numerous comorbidities and certain injuries, such as hip fractures, type 2 odontoid fractures, and fractures in ankylosing
spinal conditions, has become an increasingly well-documented
public health concern. Large-scale outcome studies continue to
define the role of early aggressive multidisciplinary management
versus more palliatively directed management options for this
increasingly aged segment of the population.1720
However, currently for these two large populationsthe
multiply injured secondary to high kinetic forces and the very
FIGURE 26.1. A: Application of pelvic sheet to provide external stability and reduce pelvic volume. B: Pelvic sheet in place swaddling patients
pelvis with application of pressure over both iliac wings and trochanteric area. The clamps are applied as cephalad, caudal, and lateral as possible to prevent obfuscation of subsequent imaging. Should groin access be necessary, the sheet may be fenestrated without significant compromise
of the pelvic binding ability.
amputations; and closed disruptive injuries such as scapulothoracic dissociation.21 Because bleeding commonly comes from
arterial sources, emergent embolization following attempts at
closed injury reduction and application of nonconstrictive
compression dressings will frequently significantly reduce further blood loss. However, emergent operative intervention to
control bleeding may have to be considered, especially in the
presence of proximal limb or forequarter amputations.14
Scapulothoracic dissociation injuries can be commonly identified on chest radiographs but may elude casual observation
due to postinjury reduction. A combination of arterial injuries
with venous bleeding in addition to brachial plexus disruption may pose a significant source of hemorrhage. If technically feasible, application of a chestarm compressive spica
dressing may limit fluid extravasation into the soft tissue
planes of the torso. Should these measures prove unsuccessful, interventional angiography can prevent ongoing arterial
bleeding. Surgical exploration of the injured shoulder girdle
in a patient with known scapulothoracic dissociation is prone
to significant hemorrhage in the acute setting and is not advisable.12,13
Spine Injuries
Life-threatening conditions may arise from several types of
spinal column injuries. Upper cervical spinal cord or brainstem
injury may be caused by bony or ligamentous disruption from
the craniocervical junction through the C4 level. Patients with
craniocervical injuries in particular are at risk for anoxia due to
loss of respiratory drive secondary to concurrent brainstem or
upper cervical cord injury. A particular worry in dealing with all
spinal injuries is the potential for occult or underdiagnosed
extent of spinal trauma, with potential for devastating consequences due to the delay in diagnosis. There are several potential spinal conditions typically overlooked. Spinal dislocations
or ligamentous injuries may not be recognized on initial imaging
tests because of a partial rebounding mechanism leading to a
spontaneous, yet inherently unstable, skeletal reduction. Distractive spine injuries are especially worrisome due to their
highly unstable nature and high propensity for associated neurovascular injury.22 Other patients affected by critical but often
occult or underappreciated spinal injuries are individuals whose
425
FIGURE 26.2. A: Initial lateral cervical radiograph of a young man after a motorcycle crash. He presented with paraplegia and neurogenic shock.
Once the shock was under control, the next phase in care was rapid closed reduction of the cervical spine. B: Postreduction radiograph. Patient
went on to definitive surgical stabilization at 48 hours after resuscitation and stabilization.
TRAUMA
426
TA B L E 2 6 . 1
COMPARISON OF NEUROGENIC AND
HEMORRHAGIC SHOCK
PARAMETER
HEMORRHAGIC
SHOCK
NEUROGENIC
SHOCK
Blood pressure
Heart rate
Urine output
Skin
Pale, clammy
Warm, pink
Mental status
Anxious
Normal
Central venous
pressure
LIMB-THREATENING INJURIES
Although the majority of orthopaedic injuries in trauma
patients are not life-threatening, they may be a significant
source of morbidity.33 This is particularly true when the injury
may directly lead to loss of limb or, if unrecognized or undertreated, result in poor long-term outcomes due to diminished
function or chronic pain.34 Injuries in which survival of the
limb is immediately threatened include disruption of the major
arterial blood supply, due to open fractures, from high-energy
or penetrating trauma (Figs. 26.3 and 26.4). Furthermore, any
FIGURE 26.3. External fixation may be thought of as portable traction. This method can rapidly stabilize any extremity and allow for
patient mobilization while awaiting definitive internal stabilization.
427
TRAUMA
Vascular Injuries
After realignment of deformed limbs in a trauma patient, any
potentially injured limb should have its vascular and neurologic status evaluated. Diagnosis of clinically significant vascular injury may be made by using the systolic ABI and/or confirming such by angiography if indicated. An ABI of greater
than 0.9 is considered low risk for arterial injury, and immediate arteriography is not indicated.35 In contrast, delay in the
diagnosis of vascular injury following limb trauma with a
warm ischemia time of 6 hours or more leads to a markedly
increased rate of amputation.37 Extremity trauma typical for
an increased risk of vascular injury includes any penetrating
428
TA B L E 2 6 . 2
TA B L E 2 6 . 3
1
1
POINTSa
PARAMETER
SKELETAL/SOFT TISSUE INJURY
Low energy (stab, simple fracture,
civilian GSW)
1.9
1
10
12
Knee dislocation
1640
29
LIMB ISCHEMIA
Pulse reduced or absent, perfusion normal
1*
2*
3*
SHOCK
injury, open fracture, or high-energy long bone fracture as evidenced by history or fracture pattern. Certain anatomic locations have a higher prevalence for arterial injury due to direct
proximity of bone or vascular tethering to surrounding fascial
structures.37 For instance, displaced fractures to the supracondylar femur and proximal humerus, knee dislocations, and
scapulothoracic dissociations are all at an inherently greater
risk of concurrent vascular injury through either direct laceration or by distractive intimal damage (Table 26.2).
Hypotensive transiently
Persistent hypotension
AGE (y)
30
3050
50
Mangled Extremity
3
SCORING SYSTEM
429
temporary external fixation can expedite stabilization to permit improved mobility and care of patients with serious
extremity trauma. Similar to the injured abdomen, the role of
damage control surgery in orthopaedics, with limitation to
only the most critical injuries and in an expedited approach,
has become a popular concept and appears to be life and organ
sparing in many cases; however, it remains subject to further
validation.
Compartment Syndrome
TRAUMA
430
fixation of fractures can then be safely performed after appropriate soft tissue management has occurred, which can also
ultimately aid soft tissue healing.29,30
Displaced fractures of the talar neck with or without dislocation of the talar body are associated with a poor prognosis. Urgent reduction of the fracture or dislocation should be
undertaken as soon as the diagnosis is made. If skin viability
is compromised by underlying bone fragments and is not
improved by closed reduction, immediate open reduction and
fixation should occur. Although the presence of a talar neck
fracture has been considered an indication for urgent operative reduction and stabilization in the past due to the potential for AVN, more recent studies have indicated that emergent surgical intervention may not affect the incidence of
AVN. Operative dbridement of open wounds and internal fixation of these injuries should be performed at the earliest reasonable time.4850 Delay of reduction of peritalar fractures or
dislocations can be expected to lead to soft tissue breakdown,
greatly increasing subsequent reconstruction challenges.
Neglect of these fractures is associated with a higher incidence
of AVN of the talus, subsequent severe arthrosis, and longterm disability.
Neurologic Injury
The presence of a neurologic deficit can be a major source of
poor outcomes. Annually, there are approximately 11,000
new spinal cord injuries in the United States. While life
expectancy of patients following thoracolumbar spinal cord
injury and even higher levels of quadriplegia approximates
that of their respective age cohorts, this injury entity still lacks
an evidence-based proven treatment of choice. On the whole,
no other condition affects patient outcome as profoundly as
6 spinal cord injury. At present, spinal cord injury therapeutic
protocols follow four basic philosophies: (a) minimize the
occurrence of preventable spinal cord injuries through education of the population at large and high-risk target groups
specifically; (b) avoid secondary spinal cord injury or progression of injury through minimizing the occurrence of missed
spinal column injuries; (c) optimize chances for spinal cord
recovery through a number of measures including adequate
resuscitation, timely decompression and stabilization of the
spine, and pharmacologic measures aimed at reduction of
swelling of neural membranes; and (d) implement a formal
spinal cord rehabilitation program at the earliest possible
time.51 Highly publicized reports on breakthrough successes of
treatment, including systemic hypothermia or stem cell therapies, are currently based more on opportunistic media reporting rather than objective medical evidence.52
Recovery from spinal cord injury is a highly variable and
somewhat unpredictable occurrence. Injury mechanism, age,
and health of the patient are major factors influencing the outcomes of spinal cord injury. To date there are no reproducible
methods to achieve spinal cord regeneration. Pharmacologic
treatment with methylprednisolone had been a widely followed practice in North America after several prominent studies. However, its ongoing routine use has become increasingly
controversial due to questions about the study methodology
and potential for serious adverse effects of treatment.53,54
More than a decade after its widespread implementation, it
has become apparent that the recommended high-dose intravenous application of 30 mg/kg methylprednisolone bolus
given over 1 hour followed by a drip of 5.4 mg/kg per hour
over 23 hours has not produced the anticipated dramatic
change in the fate of most spinal cord injury patients. The
administration of intravenous methylprednisolone has become
a treatment option rather than a standard of care.54 Unfortunately, for the foreseeable future there are no medical or cellular treatment regimens for spinal cord injury available outside
of controlled clinical trials.
SUMMARY
The diagnosis and management of musculoskeletal injuries in
the multiply injured patient population are often complex.
Early recognition of injuries leads to diminished morbidity
(both early and long term), earlier stabilization of patient
hemodynamics, decreased length of stay in the intensive care
setting, decreased rates of transfusion, earlier patient mobilization, and decreased mortality.55 Improved understanding of
how each organ injury complex of multisystem trauma impacts
overall patient well-being will improve patient outcomes
through enhanced, appropriate collaborative care and communication by the many specialists needed for an optimal outcome. While orthopaedic consultation may be readily available
at major level I trauma centers, this is an increasing challenge in
the greater community. Similarly, there is a significant trend
toward improved survival in multiply injured patients and
patients with concurrent thoracolumbar injuries when care is
provided at level I centers. Overall, the orthopaedist treating
multisystem trauma must understand the basics of general
surgery trauma care, and the trauma surgeon needs to recognize, stabilize, and involve the orthopaedic surgeon early in the
case of musculoskeletal trauma to optimize appropriate management and minimize morbidity and mortality.
References
1. Court-Brown CM. Care of accident victims. Br Med J 1989;298:115.
2. Davis JW, et al. The etiology of missed cervical spine injuries. J Trauma
1993;34:342.
3. Hanson DA, et al. Cervical spine injury: a clinical decision rule to identify
high-risk patients for helical CT screening. Am J Roentgenol 2000;174:713.
4. Soundappand SV, et al. Role of an extended tertiary survey in detecting
missed injuries in children. J Trauma 2004;57:114.
5. Brooks A, et al. Missed injury in major trauma patients. Injury 2004;35:407.
6. Stephen DJG, et al. Early detection of arterial bleeding in acute pelvic
trauma. J Trauma 1999;47:638.
7. American Spinal Injury Association. Standards of ASIA Standards for
Neurological and Functional Classification of Spinal Cord Injury, Revised
1992. Chicago, IL: American Spinal Injury Association; 1992.
8. Evers BM, et al. Pelvic fracture hemorrhage: priorities in management.
Arch Surg 1989;124:422.
9. Pape HC, et al. The timing of fracture treatment in polytrauma patients:
relevance of damage control orthopedic surgery. Am J Surg 2002;183:622.
10. Hildebrand F, et al. Damage control: extremities. Injury 2004;35:678.
11. Olson SA. Pulmonary aspects of treatment of long bone fractures in the
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12. Johansen K, et al. Traumatic scapulothoracic dissociation: a case report.
J Trauma 1991;31:147.
13. Ebraheim NA, et al. Scapulothoracic dissociation (closed avulsion of the
scapula, subclavian artery, and brachial plexus): a newly recognized variant, a new classification, and a review of the literature and treatment
options. J Orthop Trauma 1987;1:18.
14. Hovius SE, et al. Acute management of traumatic forequarter amputations: case reports. J Trauma 1991;31:1415.
15. Dendrinos G, et al. Traumatic hemipelvectomy: a case report and comments on associated injuries. Acta Orthop Trauma Surg 1992;111:293.
16. Routt ML, et al. Circumferential pelvic anti-shock sheeting: a temporary
resuscitation aid. J Orthop Trauma 2002;16:45.
17. Empara JP, Dargent-Molina P, Brart G. Effect of hip fracture on mortality
in elderly women: the EPIDOS prospective study. J Am Geriatr Soc 2004;
52(5):685690.
18. Chapman JR, Bransford R. Geriatric spine fractures an emerging health
care crisis. J Trauma 2007;62(suppl 6):S61S62.
19. Smith HE, Kerr SM, Maltenfort M, et al. Early complications of surgical
versus conservative treatment of isolated type II odontoid fractures in
octogenarians: a retrospective cohort study. J Spinal Disord Tech 2008;
21(8):535539.
20. Haas B, Jurkovich GJ, Wang J, et al. Survival advantage in trauma centers:
expeditious intervention or experience? J Am Coll Surg 2009;208:2836.
21. Vale FL, et al. Combined medical and surgical treatment after acute spinal
cord injury: results of a prospective pilot study to assess the merits of
aggressive medical resuscitation and blood pressure management. J Neurosurg 1997;87:239.
22. Grant GA, et al. Risk of early closed reduction in cervical spine subluxation injuries. J Neurosurg 1999;90(suppl 1):13.
23. Hawryluk GW, Rowland J, Kwon BK, et al. Protection and repair of the
injured spinal cord: a review of completed, ongoing, and planned clinical
trials for acute spinal cord injury. Neurosurg Focus 2008;25(5):E14.
24. Krengel WF, et al. Early stabilization and decompression for incomplete
paraplegia due to thoracic-level spinal cord injury. Spine 1993;18:2080.
25. McHenry TP, Mirza SK, Wang JJ, et al. Risk factors for respiratory failure
following operative stabilization of thoracic and lumbar spine fractures.
J Bone Joint Surg Am 2006;88(5):9971005.
26. Chipman JG, Deuser WE, Beilman GJ. Early surgery for thoracolumbar
trauma decreases complications. J Trauma 2004;56:5257.
27. Frangen TM, Zilkens C, Muhr G, et al. Odontoid fractures in the elderly:
dorsal C1/C2 fusion is superior to halo-vest immobilization. J Trauma
2007;63(1):8389.
28. Gosselin RA, et al. Antibiotics for preventing infection in open limb fractures. Cochrane Database Syst Rev 2004;(1):CD003764.
29. Verhelle N, et al. How to deal with bone exposure and osteomyelitis: an
overview. Acta Orthop Belg 2003;69:481494.
30. Gustilo RB, et al. The management of open fractures. J Bone Joint Surg
Am 1990;72:299.
31. Bone LB, et al. Early versus delayed stabilization of femoral fractures: a
prospective randomized study, 1989. Clin Orthop Relat Res 2004;422:
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32. Al-Arabi YB, Nader M, Hamidian-Jahromi AR, et al. The effect of timing
of antibiotics and surgical treatment on infection rates in open long bone
fractures: a 9 year prospective study from a general hospital. Injury 2007;
38(8):900905.
33. Myerson MS, et al. Morbidity after crush injuries to the foot. J Orthop
Trauma 1994;8:343.
34. Bondurant FJ, et al. The medical and economic impact of severely injured
lower extremities. J Trauma 1988;28:1270.
35. Mills WJ, et al. The value of the ankle-brachial index for diagnosing arterial injury after knee dislocation: a prospective study. J Trauma 2004;56:
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36. Klineberg EO, et al. The role of arteriography in assessing popliteal artery
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37. Subasi M, et al. Popliteal artery injuries associated with fractures and dislocations about the knee. Acta Orthop Belg 2001;67:259.
38. MacKenzie EJ, et al. Functional outcomes following trauma-related lowerextremity amputation. J Bone Joint Surg Am 2004;86-A(8):16361645.
Erratum in: J Bone Joint Surg Am 2004;86-A(11):2503.
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39. Johansen K, et al. Objective criteria accurately predict amputation following lower extremity trauma. J Trauma 1990;30:568.
40. Hansen ST Jr. Salvage or amputation after complex foot and ankle trauma.
Orthop Clin North Am 2001;32(1):181186.
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42. McQueen M, et al. Compartment monitoring in tibial fractures. The pressure threshold for decompression. J Bone Joint Surg Br 1996;78:99.
43. Heckman MM, et al. Compartment pressure in association with closed tibial
fractures. The relationship between tissue pressure, compartment, and the
distance from the site of the fracture. J Bone Joint Surg Am 1994;76:1285.
44. Brostrom LA, et al. Acute compartment syndrome in forearm fractures.
Acta Orthop Scand 1990;61:50.
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48. Vallier HA, et al. Talar neck fractures: results and outcomes. J Bone Joint
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50. Hawkins LG. Fractures of the neck of the talus. J Bone Joint Surg Am 1970;
52:991.
51. McLain RF. Functional outcomes after surgery for spinal fractures: return
to work and activity. Spine 2004;29(4):470477; discussion Z6.
52. Kwon BK, Mann C, Sohn HM, et al. Hypothermia for spinal cord injury.
Spine J 2008;8(6):859874.
53. Bracken MB. Methylprednisolone and acute spinal cord injury: an update
of the randomized evidence. Spine 2001;26(suppl 24):S47S54.
54. Coleman WP, et al. A critical appraisal of the reporting of the National
Acute Spinal Cord Injury Studies (II and III) of methylprednisolone in
acute spinal cord injury. J Spinal Disord 2000;13(3):185199.
55. Meek RN. Delaying emergency fracture surgery fact or fad. J Orthop
Trauma 2006;20(5):337340.
EPIDEMIOLOGY
1
Unintentional injury is the leading cause of death among children ages 14 years and under in the United States and remains
P O I N T S
7
10
11
TRAUMA
432
of cancer, stroke, heart disease, and acquired immunodeficiency syndrome (AIDS) than injury.
Injury prevention is the most effective method of reducing
death in children and adolescents.2 The science of injury prevention is complex and involves societal decisions that trade
safety for other benefits. For example, individual states have
chosen both to raise the speed limit past 55 miles per hour to
reduce travel time and to rescind motorcycle helmet laws to
preserve individual freedom, rather than to protect the populace from increased death and disability due to vehicular
crashes.2 Health care workers can ultimately play a pivotal
role in injury prevention by carefully documenting and collecting data regarding how injuries occur, which will serve dual
roles of identifying populations at risk and providing compelling evidence to lawmakers in support of effective injury
prevention legislation.
Trauma registries are one way to show trends or patterns of
specific injuries and to use cumulative data to build a case for legislation. The National Pediatric Trauma Registry (NPTR)3 and
the National Trauma Registry of the American College of Surgeons (NTRACS)4 are examples of national registries that have
identified and can elucidate areas to target for prevention initiatives. The predominant mechanism of injury varies by age, with
inflicted injuries most common in infants, falls more common in
young children, pedestrian injuries in toddlers and elementary
school-age children, and motor vehicle trauma in adolescents.
Disparities in clinical and functional outcome have also been
identified using registry data, providing opportunities for targeted initiatives. For example, worse outcome at discharge has
been documented in black children after traumatic brain injury
(TBI) compared with equivalently injured white children.5,6
Other disparities in pediatric trauma care deserve mention.
Mortality rates for all types of trauma are greater in rural parts
of the country than in cities and suburbs. The reasons for this
are protean and include longer times from injury to definitive
care,7 in-hospital delays to definitive treatment,8 less time for
injury prevention education in schools and primary care
offices, and socioeconomic and ethnic factors. Other associations have been identified that increase susceptibility to
trauma. Children with behavioral disorders such as attentiondeficit hyperactivity disorder (ADHD) have one and one-half
times the odds of sustaining a variety of injuries from multiple
causes than those without behavioral disorders, even after
controlling for known demographic correlates.9 Sometimes
age works in favor of youth, with less morbidity after highlevel falls in those 14 years of age and younger.10
The trimodal mortality curve described in adults is not
seen in children. Children who die from injury do so either at
the scene or within a few hours of hospital admission. Late
deaths due to sepsis or organ failure are rare.11 After injury
control, prompt recognition and emergent treatment of lifethreatening injuries are the most important ways to decrease
death and disability caused by pediatric trauma. Whether or
not outcome for a pediatric trauma victim is affected if care is
rendered at a childrens versus adult trauma center remains a
somewhat controversial and unanswered question.12
PREHOSPITAL CARE
Pediatric runs represent approximately 10% of all prehospital
emergency calls in the United States. Although educational
courses such as Pediatric Education for the Prehospital Professional (PEPP)13 and Pediatric Advanced Life Support (PALS)14
have augmented the knowledge base of some prehospital
providers, the recommended amount of pediatric training
included in the U.S. Department of Transportation National
Highway Traffic Safety Administration Emergency Medical
Technician-Paramedic National Standard Curriculum is temporally limited and basic. The adequacy of prehospital airway
management and the ability to obtain venous access in chil-
dren by individual providers are associated with proper training, experience, skill maintenance, and online and offline medical oversight for prehospital care services.15,16
A goal of pediatric prehospital care is to prevent secondary
brain injury associated with hypoxia or hypotension by controlling the airway and striving for normocapnia and normotension with appropriate fluid resuscitation. All ambulances must be equipped with pediatric equipment in various
sizes, including blood pressure cuffs, masks, endotracheal
tubes, and intravenous (IV) access devices.17 Prehospital care
of injured pediatric patients for short transports may be limited to maintaining spinal precautions, assurance of an adequate airway, administration of oxygen, and rapid transport
to definitive care. Placement of a definitive airway and establishment of IV or intraosseous (IO) access is recommended for
longer transport times.
An inclusive trauma system must provide for the needs of
injured children as well as adults, with triage by the prehospital provider to the closest appropriate facility with the capabilities of caring for major trauma. This may be a free-standing
pediatric trauma center or a regional trauma center with a verified pediatric component.18 The receiving center must have
the necessary personnel and equipment to care for the injured
child, as outlined in Resources for Optimal Care of the Injured
Patient: 2006 by the American College of Surgeons Committee
on Trauma.19 Despite evidence for improved outcomes of
severely injured children admitted to high-level trauma centers, almost one third of children with severe TBI fail to receive
care in such centers and regionalization efforts in many parts
of the country are still in their infancy.20
INITIAL RESUSCITATION
AND EVALUATION
Preparation is the key to a successful pediatric trauma resuscitation. In institutions using a team approach, interventions
may be done simultaneously (i.e., for airway and circulation).
The best protection for the airway in the child who is
breathing spontaneously is maintenance of a superior and
anterior position of the midface (sniffing position), while keeping the cervical spine immobilized. If the airway is inadequate,
it can be opened with a gentle jaw thrust. The mouth is cleared
of blood and foreign material and supplemental oxygen is
used. In a young child, respiratory compromise can result from
gastric dilatation or from compression of the diaphragm by
intra-abdominal blood or air, necessitating the use of a gastric
tube. The tube should be inserted orally if there is concern for
a basilar skull or midface fracture.
Children with obvious respiratory distress, those with a
Glasgow Coma Scale (GCS) score of less than or equal to 8, or
those who arrive in shock must have immediate tracheal intubation. The proper-size endotracheal tube can be estimated by
choosing one that corresponds to the diameter of the childs
small finger or the external nares or using an appropriate reference as a guide. An excellent approach is the use of colorcoded drawers containing all of the equipment necessary for a
certain-size child and using a length-based pediatric resuscitation tape to estimate the childs weight.21 In children younger
than 8 years, nasotracheal intubation is avoided because of the
more anterior and cephalad positioned airway, relatively large
adenoids and tonsils, a soft short trachea, and the potentially
serious complications associated with blind nasal passage.
After preoxygenation, a pharmacologically assisted intubation
using a neuromuscular blocker and a sedative is performed,
unless the child has a GCS of 3 or has arrested. A chest radiograph should be obtained to confirm proper position of the
endotracheal tube. If the airway cannot be secured by the most
senior person in the resuscitation room, a temporizing needle
cricothyrotomy is placed and jet insufflation initiated until an
433
TRAUMA
FIGURE 27.1. Child with multiple dog bites on face, extremities, and torso.
434
MANAGEMENT OF
SPECIFIC INJURIES
Neurologic and Extracranial Head Trauma
Traumatic brain injury is the leading cause of traumatic death
and disability in children. The annual clinical burden remains
high, with 50,658 TBI-associated hospitalizations in 2000 and
a corresponding financial burden of $1 billion.36 Unfortunately, the majority of the proinflammatory response caused
by TBI occurs within 6 hours of injury, making early treatment
initiatives challenging. Multiple pathways contribute to the
endpoint of hypoxic ischemic injury, and a host of clinical trials evaluating single-modality translational treatment strategies have yielded uniformly disappointing results with no
intervention resulting in improved outcome.37 The National
Institutes of Health (NIH) is currently promoting prospectively designed studies that will employ multiple therapeutic
agents in combination. Emerging strategies that may be considered include hypertonic saline resuscitation, hypothermia,
and cellular therapeutics (bone marrow progenitor cell therapy).38 Each has its own inherent benefits, risks, and complications, and hypertonic saline and hypothermia ideally need to
be started very soon after injury. Most treatments for TBI are
TA B L E 2 7 . 2
CLASSIFICATION
VERBAL SCORE
Persistently irritable
Restless, agitated
None
435
TRAUMA
FIGURE 27.2. A: Scalp wound with underlying open frontal skull fracture. B: Bone window computed
tomography image showing comminuted frontal skull fracture, pneumocephaly, and multiple additional
skull fractures. C: A small frontal contusion is seen beneath the skull fracture.
best with outcome. Except for the most minor cases, a head
CT scan is performed in all children with evidence of neurologic injury (Fig. 27.2). For those with severe TBI, serial scans
ordered for increased ICP and neurologic deterioration best
correlate with the need for operative intervention.43
Secondary measures to treat TBI in children include evacuation of an intracranial space-occupying hematoma, normalization of intracranial pressure (ICP), maintenance of tissue
oxygenation, external ventricular drainage, and decompressive craniectomy in rare cases of conservative treatment failure.44,45 Although mass lesions from hemorrhage requiring
surgical intervention are relatively uncommon in children,
cerebral edema is common and deserves treatment. Children
with a GCS score of 8 or less and those with evidence of cerebral edema on CT scan are best managed with sedation, paralysis, endotracheal intubation, and mechanical ventilation to
keep the PaCO2 at approximately 35 mm Hg. Prophylactic
hyperventilation has the potential to reduce cerebral blood
flow to damaged or marginal brain tissue to ischemic levels. In
a retrospective cohort analysis of significant pediatric TBI
done after publication of the 2003 acute TBI medical manage-
436
Spinal Trauma
437
FIGURE 27.4. A: Abdominal computed tomography image showing grade V splenic rupture with extravasation of contrast. B: Ruptured spleen.
TRAUMA
Abdominal Trauma
438
GRADING
439
FIGURE 27.6. A: Jejunal hematoma and perforation at the ligament of Treitz resulting from child maltreatment. This child presented in hypovolemic shock and had a damage-control laparotomy. B: The abdomen was treated open for several days using a conventional, commercially
available pediatric silo.
TRAUMA
FIGURE 27.5. A: Ecchymosis of the abdominal wall resulting from improperly positioned seatbelt on the torso of a small child. B: Deserosalized
segment of jejunum containing enterotomy.
440
441
TA B L E 2 7 . 5
MEASURE
DEFINITION
PURPOSE
Missed intubation
Unplanned extubation
Unintentional extubation by
patient or provider
Extubation within 24 h
of rapid-sequence
intubation (excluding
operative procedures)
Hypocapnia or
hypercapnia
Overventilation or
underventilation, especially
in the first 12 h after injury
Resuscitation volumes
Unplanned operation
following nonoperative
management
Unplanned hypothermia
Nosocomial pneumonia
Missed injury
From
INJURY PREVENTION
Public health experts recommend that injury prevention
efforts focus on injuries that are common, severe, and readily
preventable. Examples include mechanisms likely to result in
head or spinal cord injuries, where there is a high mortality or
hospitalization rate and a long-term disability rate and effec11 tive countermeasures exist. The Emergency Medical Services
for Children (EMSC) program emphasizes a step-by-step
approach to injury prevention by establishing goals and objectives with measurable outcomes (Table 27.6).115
TRAUMA
442
TA B L E 2 7 . 6
PREVENTION
References
1. Mendelson K, Fallat M. Pediatric injuries: prevention to resolution. Surg
Clin North Am 2007;87:207228.
2. Brussoni M, Towner E, Hayes M. Evidence into practice: combining the
art and science of injury prevention. Inj Prev 2006;12:373377.
3. Tepas JJ 3rd. The national pediatric trauma registry: a legacy of commitment to control of childhood injury. Semin Pediatr Surg 2004;13:126132.
4. National Trauma Registry of the American College of Surgeons
(NTRACS). www.dicorp.com. Accessed Feb 14, 2010.
5. Haider A, Efron D, Haut E, et al. Black children experience worse clinical
and functional outcomes after traumatic brain injury: an analysis of the
National Pediatric Trauma Registry. J Trauma 2007;62:12591263.
6. Martin C, Falcone R Jr. Pediatric traumatic brain injury: an update of
research to understand and improve outcomes. Curr Opin Pediatr 2008;
20:294299.
7. Svenson JE, Spurlock C, Nypaver M. Factors associated with the higher traumatic death rate among rural children. Ann Emerg Med 1996;27:625632.
8. Esposito TJ, Sanddal ND, Dean JM, et al. Analysis of preventable pediatric
trauma deaths and inappropriate trauma care in Montana. J Trauma
1999;47:243253.
9. Brehaut JC, Miller A, Raina P, et al. Childhood behavior disorders and
injuries among children and youth: a population based study. Pediatrics
2003;111(2):262269.
10. Demetriades D, Murray J, Brown C, et al. High-level falls: type and severity of injuries and survival outcome according to age. J Trauma 2005;58:
342345.
11. Calkins C, Bensard DD, Moore EE, et al. The injured child is resistant to
multiple organ failure: a different inflammatory response? J Trauma
2002;53(6):10581063.
12. Ochoa C, Choski N, Upperman J, et al. Prior studies comparing outcomes
from trauma care at childrens hospitals versus adult hospitals. J Trauma
2007;63:S87S91.
13. American Academy of Pediatrics. Pediatric Education for the Prehospital
Professionals, 2nd ed. Sudbury, MA: Jones and Bartlett.
14. American Heart Association. Pediatric Advanced Life Support. Provider
Manual. 2006.
15. Nicholl J, Hughes S, Dixon S, et al. The costs and benefits of paramedic
skills in pre-hospital trauma care. Health Tech Assess 1998;2:173.
16. Paul TR, Marias M, Pons PT, et al. Adult versus pediatric prehospital
trauma care: is there a difference? J Trauma 1999;47:455459.
17. American College of Surgeons Committee on Trauma, American College
of Emergency Physicians, National Association of EMS Physicians, Pediatric Equipment Guidelines Committee EMSC Partnership for Children
Stakeholder Group, American Academy of Pediatrics. Equipment for
ambulances. Bull Am Coll Surg 2009;94:2329.
18. Potoka DA, Schall LC, Gardner MJ, et al. Impact of pediatric trauma centers on mortality in a statewide system. J Trauma 2000;49:237245.
19. American College of Surgeons, eds. Resources for Optimal Care of the
Injured Patient. Chicago, IL: American College of Surgeons; 2006.
20. Hartman M, Watson R, Linde-Zwirble W, et al. Pediatric traumatic brain
injury is inconsistently regionalized in the United States. Pediatrics 2008;
122:e172e180.
21. Luten R, Wears RL, Broselow J, et al. Managing the unique size-related
issues of pediatric resuscitation: reducing cognitive load with resuscitation
aids. Acad Emerg Med 2002;9(8):840847.
22. Holmes JF, Goodwin HC, Land C, et al. Coagulation testing in pediatric
blunt trauma patients. Ped Emerg Care 2001;17(5):324328.
23. Capraro A, Mooney D, Waltzman M. The use of routine laboratory studies as screening tools in pediatric abdominal trauma. Ped Emerg Care
2006;22:480484.
24. Swischuk L. Emergency pediatric imaging: changes over the years (part 1).
Emerg Radiol 2005;11:193198.
25. Westra S, Wallace E. Imaging evaluation of pediatric chest trauma. Radiol
Clin North Am 2005;43:267281.
26. Chwals WJ, Robinson AV, Sivit CJ, et al. Computed tomography before
transfer to a level I pediatric trauma center risks duplication with associated increased radiation exposure. J Ped Surg 2008;43:22682272.
27. Partrick DA, Bensard DD, Moore EE, et al. Ultrasound is an effective
triage tool to evaluate blunt abdominal trauma in the pediatric population.
J Trauma 1998;45:5763.
28. Rogovik AL, Rostami M, Hussain S, et al. Physician pain reminder as an
intervention to enhance analgesia for extremity and clavicle injuries in
pediatric emergency. J Pain 2007;8:2632.
29. Oliver RC, Fallat ME. Traumatic childhood death: how well do parents
cope? J Trauma 1995;39:303307.
30. Oliver RC, Sturtevant JP, Scheetz JP, et al. Beneficial effects of a hospital
bereavement intervention program following traumatic childhood death.
J Trauma 2001;50(3):440448.
31. Jurkovich GJ, Pierce B, Pananen L, et al. Giving bad news: the family perspective. J Trauma 2000;48:865873.
32. Kirshblum S, Fichtenbaum J. Breaking the news in spinal cord injury. J
Spinal Cord Med 2008;31:712.
33. Meyers TA, Eichhorn DJ, Guzzetta C, et al. Family presence during invasive procedures and resuscitation. Am J Nurs 2000;100:3241.
34. OBrien MM, Creamer KM, Hill EE, et al. Tolerance of family presence
during pediatric cardiopulmonary resuscitation: a snapshot of military and
civilian pediatricians, nurses, and residents. Ped Emerg Care 2002;18(6):
409413.
35. Hanson C, Strawser D. Family presence during cardiopulmonary resuscitation: Foote Hospital emergency departments nine-year perspective. J
Emerg Nurs 2002;18:104106.
36. Schneier A, Shields B, Hostetler S, et al. Incidence of pediatric traumatic
brain injury and associated hospital resource utilization in the United
States. Pediatrics 2006;118:483492.
37. Hutchison J, Ward R, Lacroix J, et al. Hypothermia therapy after traumatic brain injury in children. N Engl J Med 2008;358:24472456.
38. Walker P, Harting M, Baumgartner J, et al. Modern approaches to pediatric brain injury therapy. J Trauma 2009;67:S120S127.
39. Adelson PD, Bratton SL, Carney NA, et al. Guidelines for the acute medical management of severe traumatic brain injury in infants, children and
adolescents. Pediatr Crit Care Med 2003;4(3)(suppl):S1S18.
40. Badjatia N, Carney N, Crocco TJ, et al. Guidelines for prehospital management of traumatic brain injury 2nd edition. Prehosp Emerg Care 2007;
12:S152.
41. Gausche M, Lewis R, Stratton S, et al. Effect of out-of-hospital pediatric
endotracheal intubation on survival and neurological outcome: a controlled clinical trial. JAMA 2000;283:783790.
42. Samant U IV, Mack C, Koepsell T, et al. Time of hypotension and discharge outcome in children with severe traumatic brain injury. J Neurotrauma 2008;25:495502.
43. Figg R, Stouffer C, Vander Kolk W, et al. Clinical efficacy of serial computed tomographic scanning in pediatric severe traumatic brain injury.
Pediatr Surg Int 2006;22:215218.
44. Meier U, Zeilinger FS, Henzka O. The use of decompressive craniectomy for
the management of severe head injuries. Acta Neurochir 2000;76: 475478.
443
TRAUMA
444
END-OF-LIFE DECISIONS
WILLIAM P. SCHECTER
DEFINITION OF
GERIATRIC TRAUMA
P O I N T S
Elderly trauma victims are often undertriaged despite the
increased risk of death and disability associated with
advanced age.
6 Long-term survival after cardiopulmonary resuscitation in
the elderly is unusual.
7 Withholding or withdrawing life support is the most common event preceding death in the intensive care unit.
8 Decisions to limit critical care must be made in the best
interests of the individual patient.
Comorbidities
Comorbidities are more common in the elderly population and
are associated with an increased risk of death following injury.
Eighty percent of patients over age 65 have at least one comorbidity and 5% have at least two.1 The increased relative risk of
death with cirrhosis is 4.5, coagulopathy 3.2, chronic heart
disease 1.8, chronic obstructive pulmonary disease 1.8, and
diabetes 1.2.8 In addition, renal disease and malignancy
increase the risk of death following injury.9,10
Injury Severity
PREDICTORS OF MORBIDITY
AND MORTALITY
445
TRAUMA
K E Y
446
Effect of Beta-Blockers
Twenty percent of elderly patients with coronary artery disease and 10% with hypertension take beta-blockers,15 which
inhibit their ability to respond to hypovolemia with tachycardia. Geriatric trauma patients often may not fulfill hemodynamic criteria for trauma team activation despite significant
injury.16 Preinjury beta blockade is associated with an
increased risk of death.17
Effect of Anticoagulation
Splenic Injury
Although nonoperative management of hemodynamically stable patients with splenic injury is now standard care,48 this
approach must be used with caution in geriatric patients
because of decreased physiologic reserve in the event of sudden
hemorrhage. The success rate of nonoperative management of
Skeletal Injury
Rib Fractures. Rib fractures are serious injuries in elderly
patients and are associated with significant morbidity and
mortality rates. The risk of pneumonia after isolated thoracic
trauma in geriatric patients is three times the risk in younger
patients.55,56 The mortality rate associated with one to two rib
fractures is 12% but is approximately 40% if more than six
rib fractures are present.57
Chest-wall analgesia and pulmonary toilet are important in
the management of rib fractures.58 Parenteral opiates should be
used with caution because of the risk of respiratory depression.
Intercostal nerve blockade with local anesthetics effectively
controls chest-wall pain, but unfortunately the duration of
anesthesia is limited.59 Epidural analgesia is probably the most
effective method of pain control after rib fracture60 and may be
associated with a reduction in mortality rate.56 Elderly patients
with rib fractures should be admitted to the hospital, be monitored carefully, and receive chest-wall analgesia.
OUTCOME FROM
CARDIOPULMONARY
RESUSCITATION IN THE ELDERLY
INTENSIVE CARE IN
GERIATRIC TRAUMA
WITHHOLDING AND
TRAUMA
447
448
SUMMARY
An increasing number of geriatric patients will require care as
a result of injury. Physiologic changes due to aging and multiple comorbidities both increase the geriatric patients susceptibility and adversely affect the physiologic response to injury.
Public and professional injury prevention education efforts
have the potential to reduce the risk of injury in the elderly.
Aggressive evaluation and treatment of the geriatric trauma
patient are essential to minimize potentially preventable death
and complications. In spite of all efforts, many desperately ill
geriatric trauma patients require prolonged intensive care, presenting medical, rehabilitation, and ethical challenges to the
trauma team.
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K E Y
1
5
6
P O I N T S
Fetal evaluation includes fundal height measurement and
recording heart tones, heart rate, and movement. Focused
abdominal sonogram for trauma is an excellent noninvasive, radiation-free method of evaluating the mother,
uterus, and fetus.
8 Trauma may require urgent transfusion, which should be
type O, Rh-negative blood.
9 Liberal but judicious use of radiographic studies is advised
for the evaluation of the pregnant trauma patient. An
imaging study deemed necessary should not be withheld
for fear of potential hazard to the fetus.
10 Although the myometrium is relatively elastic, the placenta is not, predisposing it to shear forces at the uteroplacental interface, which may lead to abruptio placentae. Abruptio placentae is the most common cause of
fetal demise following trauma and may present as an
occult process.
7
TA B L E 2 9 . 1
451
MANAGEMENT
CHANGE
IMPLICATION
Neurologic
Cardiovascular
Genitourinary
Laboratory values
Hypercoagulable stage
Cardiovascular
Maternal blood volume (plasma and erythrocytes) begins to
increase during the first trimester but expands most rapidly
TRAUMA
452
Pulmonary
INITIAL ASSESSMENT
453
TA B L E 2 9 . 2
DIAGNOSIS
EXAMINATION
MEAN
MAXIMUM
EXPOSURE
DOSE
(mGy)
(mGy)
1.4
4.2
0.01
0.01
1.7
10
Lumbar spine
1.7
10
Pelvis
1.1
Skull
0.01
0.01
Thoracic spine
0.01
0.01
FLUOROSCOPIC EXAMINATIONS
Upper gastrointestinal
1.1
Barium enema
6.8
5.8
24
COMPUTED TOMOGRAPHY
After patient stabilization, several diagnostic modalities are
Abdomen
8.0
49
used to define the extent and type of injury for the mother and
8 fetus. Initially, laboratory studies are obtained. If blood is
Chest
0.06
0.96
urgently needed, type O, Rh-negative blood is chosen. EvaluaHead
0.005
0.005
tion of the abdomen may be performed by ultrasound, comLumbar spine
2.4
8.6
puted tomography (CT) scan, or diagnostic peritoneal
lavage.44 Reliance on ultrasound to evaluate both the mother
Pelvis
25
79
and the fetus obviates the need to perform a CT scan in some
cases and can provide valuable information on fetal motion,
Adapted from Sharp C, Shrimpton JA, Bury RF. Diagnostic Medical
heart tones, location, and placement. If diagnostic peritoneal
Exposures. London: National Radiology Board; 1998.
lavage is elected, the open, supraumbilical technique is recommended.
9
Liberal but judicious use of radiographic studies is
advised for the evaluation of the pregnant trauma patient. An
skull fracture or intracerebral hemorrhage. Pelvic fractures in
imaging study deemed necessary should not be withheld for
the gravid patient may cause extensive maternal retroperifear of potential hazard to the fetus. Factors contributing to
toneal hemorrhage as a result of engorged pelvic veins.
the sequelae of prenatal exposure to ionizing radiation are
Uterine rupture is a catastrophic and fortunately rare comthe stage of development, the exposure time, the dose delivplication of blunt abdominal trauma. The incidence is approxered, and the dose absorbed. The absorbed radiation dose
imately 0.6%.39 Fetal mortality approaches 100% and associvaries according to many factors, including instrument
ated maternal mortality is 10%.22
model, desired image quality, and distance from the radioac- 10
Abruptio placentae is the most common cause of fetal
tive source. The roentgen (R) is the unit of exposure, and the
death after maternal injury. This carries a 30% to 70% rate of
centigray (cGy) or rad is the unit of absorbed dose. Approxfetal death and a 1% maternal mortality rate. Over 50% plaimate absorbed fetal doses for radiographic tests are precental separation invariably results in fetal demise.48 Abruptio
sented in Table 29.2. There is no medical justification for terplacentae can occur in the absence of obvious abdominal
45
minating pregnancy in women exposed to 5 cGy or less. A
injury, because maternal shock is a far greater stimulus for
0.1% increase in the rate of spontaneous abortion during
abruption than are the mechanical forces of trauma disrupting
the first 2 weeks of development follows a dose of 10 cGy,
the placenta.38 Abruptio placentae is more common in the
and there is a 1% increase in congenital abnormalities at the
presence of hypertension, diabetes mellitus, advanced age,
46
same dose. Another concern is the potential for late neomultiparity, and maternal use of tobacco or cocaine. Abruptio
plasia development. The risks for radiation-induced cancer
placentae presents with vaginal bleeding (in 80% of cases),
after in utero exposure during the second and third trimesters
abdominal pain, disseminated intravascular coagulation due
are estimated to be 1 in 15,000 children if exposed to 1 mGy
to thromboplastin release, and inexplicable maternal hypo47
x-radiation. If the fetus receives 50 mGy, the risk is
volemia. It invariably occurs within 48 hours after trauma,
increased to 1 in approximately 300 children. Prudent judgand pregnant patients who are at risk should be monitored
ment and foresight by the physician should ensure that speaccordingly.
cific radiographic studies are ordered and accurately perThe pregnant patient with minor injury should be observed
formed to avoid repetition.
for several hours. Most patients with insignificant trauma do
not require admission unless specific signs and symptoms, such
as vaginal bleeding, abdominal cramps, or leakage of amniotic
fluid, are present. In one series, only 1 of 11 patients had
BLUNT TRAUMA
symptoms after minor trauma, and pregnancy outcome was
Motor vehicle crashes remain the chief cause of blunt trauma
successful.6 Occult abruptio placentae has been reported after
in the pregnant patient. As pregnancy progresses, the uterus
motor vehicle accidents in which the patient displayed only
becomes more vulnerable, rising out of the protective bony
subtle clinical signs and symptoms. Because placental separapelvis, and it absorbs most of the impact of blunt abdominal
tion can occur with rapid deceleration injuries, a three-point
trauma. These factors often result in direct fetal injury, usually
restraint system appropriately applied is recommended for
TRAUMA
DIAGNOSTIC MODALITIES
454
PENETRATING TRAUMA
TA B L E 2 9 . 3
TREATMENT
OPERATIVE MANAGEMENT
General anesthesia is preferred for the gravid patient with multisystem injury. The risks of anesthesia are related to the physiologic changes that accompany pregnancy. For example,
because aspiration is more likely, rapid-sequence induction
with cricoid pressure is preferred. Both thiopental and etomidate are good induction agents in pregnancy. As a general rule,
ketamine should be avoided as it increases uterine tone and
may decrease placental perfusion. Both depolarizing and nondepolarizing neuromuscular blocking agents cross the placenta.
This must be remembered because if delivery is required, the
infant will be hypotonic and apneic. Volatile agents should be
used, if tolerated, as they relax the uterine smooth muscle and
blunt the maternal catecholamine response, both of which
improve uterine perfusion.53
The standard vertical midline incision is used for maternal celiotomy. Adequate visualization of viscera is mandatory, and the pregnant uterus should not interfere with
abdominal exploration or repair of an injury. If labor ensues,
vaginal delivery is almost always encouraged. Even early in
the postoperative period, vaginal delivery is still preferred
and does not appear harmful to the mother or the neonate.
Cesarean section prolongs the operative time and increases
blood loss, generally by approximately 1 L. Indications for
cesarean section during celiotomy for trauma are listed in
Table 29.3.
If fetal delivery is cesarean, the uterus is incised longitudinally. After the amniotic membranes are ruptured, the fetus is
delivered, and the placenta is removed. The uterus is closed in
a running-locking fashion using large, absorbable suture.
Once the uterus is evacuated, postpartum hemostasis begins.
In cases of uterine atony, bimanual compression of the uterus
and the intravenous administration of oxytocin are begun. In
addition, the surgeon should examine the uterus and cervix for
any lacerations and ensure that the uterus is thoroughly evacuated. Other measures to control severe hemorrhage include
intravenous methyl ergonovine, or intramyometrial injection
of 15-methyl prostaglandin F2a. For the most part, massive
hemorrhage associated with emergent cesarean section in the
injured women is associated with a pelvic fracture. Packing of
the pelvis or embolization of the internal iliac arteries may be
needed as well.
Successful outcome of a postmortem cesarean section
depends on the duration of the gestation and the time interval
between maternal death and delivery. Under optimal conditions, at 26 to 28 weeks gestation, the estimated fetal survival
CARDIOPULMONARY
RESUSCITATION
The enlarged uterus compresses the vena cava, resulting in a
25% decrease in cardiac output as a result of decreased venous
return. To improve the effects of cardiopulmonary resuscitation
(CPR), patients before 24 weeks gestation can be maintained
in the supine position but with manual displacement of the
uterus laterally. After 24 weeks gestation, a procedure table
with a 30-degree left lateral tilt is helpful, although CPR is
only 80% effective when performed with the patient in this
position. Emergent cesarean section may be needed if the
patient does not respond to CPR within approximately 5 minutes.56,57 Morris et al. found that if the fetus is viable (presence
of fetal heart tones) and is at least 26 weeks gestation, emergent cesarean section is justified; they found that infants who
met these criteria had a survival rate of 75%.58
TOXEMIA OF PREGNANCY OR
PREECLAMPSIA (PREGNANCYINDUCED HYPERTENSION)
Any traumatized pregnant patient presenting with seizures or
coma should have head injury excluded. Toxemia of pregnancy
should also be included in the differential diagnosis. In the
455
severe state, eclampsia is manifested by hypertension, pulmonary edema, elevated liver function enzymes, proteinuria
(i.e., HELLP syndrome), and seizure activity. The pathophysiologic cause is vasospasm, which affects hepatic, renal, cerebral,
and placental blood flow. Despite the presence of pulmonary
edema, intravascular volume depletion is often present, and a
fluid challenge may be appropriate. Rapid control of the hypertension is achieved with hydralazine.59 However, elevated
maternal oxygen consumption disrupts uterine vascular oxygen supply and maternal equilibrium, resulting in fetal distress.
Smoother control of reduction in blood pressure and myocardial oxygen consumption is accomplished by achieving volume
expansion before vasodilation. Inotropic support, in combination with vasodilator treatment, maximizes oxygen delivery
and affects afterload reduction. Magnesium sulfate has a slight
hypotensive effect but does not decrease systemic vascular
resistance.
THROMBOEMBOLISM
INTERPERSONAL VIOLENCE
Although motor vehicle crashes and falls are the most common causes of trauma during pregnancy, reports indicate that
4% to 17% of pregnant women are victims of interpersonal
violence.24 In fact, this number may be underestimated
because population-based prevalence estimates are often
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12. Biester EM, Tomich PG, Esposito TJ, et al. Trauma in pregnancy: normal
revised trauma score in relation to other markers of maternofetal status
a preliminary study. Am J Obstet Gynecol 1997;176:12061212.
13. Connolly A, Katz VL, Bash KL, et al. Trauma and pregnancy. Am J Perinatol 1997;14:331336.
14. Weiss HB, Songer TJ, Fabio A. Fetal deaths related to maternal injury.
JAMA 2001;286:18631868.
15. Weiss HB, Lawrence B, Miller T. Prevalence and risk of hospitalized pregnant occupants in car crashes. In: Annual Proceedings/Association for the
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16. Cunningham FG, MacDonald PC, Gant NF, et al., eds. In: Williams
Obstetrics, 20th ed. Norwalk, CT: Appleton & Lange; 1997:191225.
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18. Whittaker PG, MacPhail S, Lind T. Serial hematologic changes and pregnancy outcome. Obstet Gynecol 1996;88:33.
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24. Gonick B. Intensive care monitoring of the critically ill pregnant patient.
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in late pregnancy: III. Unreliability of the sphygmomanometric method in
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26. Greiss FC, Anderson SG. Effect of ovarian hormones on the uterine vascular bed. Am J Obstet Gynecol 1970;107:829.
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MANAGEMENT
GRANT E. OKEEFE
K E Y
Adequate resuscitation is critical to avoid ongoing occult
hypoperfusion and subsequent complications by using a
protocol for physiologic endpoints, including central venous
pressure.
2 Hypothermia occurs due to ongoing heat loss and metabolic failure requiring large amounts of energy production
and thus oxygen consumption. There is no proven benefit
for hypothermia in traumatic brain injury (TBI) outcomes.
3 Coagulopathy is common and due to both dilution and consumption while being aggravated by hypothermia. Early
empiric replacement of coagulation components reduces
mortality.
P O I N T S
TBI is a major cause of injury-related death, with care
directed at avoiding secondary brain injury, control of elevated intracranial pressure, and early recognition of treatable mass lesions.
5 Elevated intra-abdominal pressure (abdominal compartment
syndrome) causes a tense distended abdomen, hypoxia, oliguria despite adequate volume, and impaired cardiac output,
requiring decompression and an open abdomen in severe
cases.
6 Acute lung injury and acute respiratory distress syndrome
require adequate, frequently higher levels of positive
end-expiratory pressure; low tidal volumes; and moderate
4
STABILIZATION AND
SECONDARY SURVEY (INITIAL
24 HOURS POSTINJURY)
This phase is often a continuation of emergency department or
operating room stabilization of vital functions and the ongoing diagnosis and management of life-threatening injuries. In
other circumstances, resuscitation is complete, but secondary
or tertiary surveys to search for occult injuries are undertaken, optimal support of vital organ function is continued,
and careful monitoring for deterioration is required.
Hemodynamic Resuscitation:
Monitoring and Targets
Tissue injury, local and global ischemia, and hypoxia are wellknown contributors to subsequent multiple organ dysfunction
syndrome (MODS), nosocomial infection, and other complications after severe injury.5,6 The duration and degree of shock
both increase the risk for subsequent organ dysfunction and
severe nosocomial infection after various types of trauma
1 (blunt, penetrating, and burn injury).6,7 Therefore, rapid and
adequate resuscitation is a critical component of the initial ICU
care of trauma patients. However, there are no definitive markers of adequate resuscitation. Arterial base deficit and arterial
lactate concentration are good indicators of the severity of
injury and are a function of the degree and duration of shock.
However, they correlate poorly with other real-time measures
of tissue perfusion. Excessive attempts to normalize these values
may lead to overresuscitation. Serum lactate concentrations and
base deficit often remain elevated for hours after perfusion is
appropriately restored, in part because they reflect adrenergic
Hypothermia
stimulation of Na-K/ATPase, which increases lactate production unrelated to tissue hypoxemia.8,9 In addition, other bio- 2 Hypothermia (core temperature 34.5C) is less common in
chemical or physiologic markers may only be obtained by invatrauma patients arriving in the ICU than it was in the past. This
sive means, which are not warranted in most cases.
is likely due to more aggressive prevention in the emergency
Therefore, and in recognition of the limitations of these
department, radiology suite, and operating room. However, it
physiologic endpoints, this early phase should initially be
remains a preventable and treatable situation that contributes
TRAUMA
457
458
TA B L E 3 0 . 1
HEMODYNAMIC RESUSCITATION PARAMETERS DURING
INITIAL 24 HOURS AFTER INJURY
Urine output: 30 mL/kg/h
Hemoglobin: 1215 g/dL
Heart rate: 100/min
Arterial blood pressure: 120 mm Hg
Central venous pressure: 1015 mm Hg
Cardiac index: 3.54.0 L/min/m2
Oxygen delivery: 500550 mL O2/min/m2
Mixed venous oxyhemoglobin saturation: 65%
Central venous oxyhemoglobin saturation: 70%
to complications and death. Thermoregulation is compromised 3 Hemostatic Abnormalities. Coagulopathies are common
in critically injured trauma patients and their cause is multifacin severely injured patients by shock and failure of cellular
torial (Table 30.2). It is evident that hemorrhage accompanied
metabolism. Hypothermia from metabolic failure is often exacby crystalloid and red blood cell transfusion results in dilution
erbated by external heat loss through the four general mechaof coagulation factors, yet the implications of this dilution are
nisms of energy transfer: (a) radiation, (b) convection, (c) evapnot clear. Correlation between the amount of blood transfused
oration, and (d) conduction.18 Minimizing heat loss through
and specific factor levels or the global measures of coagulation
careful attention to the patients environment is central to pre(activated partial thromboplastin time [aPTT], prothrombin
venting hypothermia and its consequences. In theory, the pretime [PT]) are relatively low, and coagulopathy after non
vention of hypothermia simply requires the elimination or mintrauma-related blood loss alone seems to generally occur after
imization of heat loss by these four mechanisms. This primarily
rather large transfusions (10 to 12 units of packed red blood
involves keeping the patient covered and dry. Warm air concells).25,26 The effect of pure dilution on platelet counts is even
tains little heat (specific heat 0.25 kcal/kg per C) and is of
less clear, with wide variations in the incidence of thrombocylittle help in warming a cold patient. However, a warm air envitopenia being reported. Basing coagulation factor replacement
ronment or warm air circulating blanket is an excellent way to
and platelet transfusion needs on predictive formulas is generprevent heat loss.
ally inaccurate.27
A considerable amount of energy and, therefore, oxygen is
18,19
A number of other factors have been linked to hemostatic
required to warm a hypothermic patient.
The amount of
abnormalities after trauma. Tissue trauma leads to platelet
energy required to warm a hypothermic patient by 3C (34C
aggregation and activation of coagulation. Variable induction
to 37C, for example) is substantial and can be a significant
of these processes depending on the nature and severity of the
metabolic stress. Based on the following formula, where spetrauma likely explain the lack of correlation of measured
cific heat of the human body is 0.83 kcal/kg per C:
hemostatic deficits with blood loss, resuscitation, and blood
transfusion volumes. For example, traumatic brain injury can
Q (heat) mass (in kg) 0.83 kcal/kg/C
result in coagulopathy that is independent of blood loss and
[Temp1 Temp2 (
Temp)]
transfusion volumes.28 The exact mechanism is uncertain and
Q (heat) 70 kg 0.83 kcal/kg/C [37C 34C]
likely more complicated than release of brain tissue thrombo 181 kcal
plastins, as has been previously theorized. Marked reductions
in circulating fibrinogen concentrations (50 mg/dL) are often
It will take 181 kcal of energy to return the patient to 37C.
seen, suggesting that hyperfibrinolysis plays an important role.
A patient would have to double his or her oxygen consumption
Extremity injuries, including fractures and extensive soft tissue
for 3 hours (or increase it by 50% for 6 hours) in order to gentrauma, expose circulating coagulation factors and platelets to
erate this amount of heat. Patients in shock or recovering from
subendothelial collagen and tissue factor. However, clinically
shock are unable to meet such a high metabolic demand and
significant coagulopathies are unlikely to occur solely as the
should be actively warmed, rather than having to rely on their
result of tissue trauma and require additional contributing facown metabolism (termed passive warming). A number of techtors. The effect of hypothermia on hemostasis is significant
niques for actively rewarming patients are available. These
include overhead radiant heat warmers, whose effectiveness
requires that they be placed relatively close to the patient
(within 70 cm) and that the patient be fully exposed to the radiTA B L E 3 0 . 2
ant heat, rather than covered by a blanket, in which case the
blanket is warmed. Not surprisingly, risk of thermal injury is
FACTORS CONTRIBUTING TO COAGULOPATHY IN TRAUMA
significant. Body cavity lavage (pleural or peritoneal) can
potentially transfer large amounts of energy, but may not be
Dilution of coagulation factors
practical in the multiply injured patient or due to the significant
logistic challenges. Airway warming with heated, humidified
Hypothermia (impaired enzyme activity, platelet dysfunction,
oxygen transfers relatively little energy, similar to increasing
enhanced fibrinolysis)
ambient temperature in general, and should not be relied upon
Acidosis
for treatment of hypothermia. The most effective method for
Tissue trauma (brain injury, fractures, soft tissue injuries)
rewarming is full cardiopulmonary bypass, which has been
used successfully in severely hypothermic trauma victims.
Preexisting hemostatic defects (von Willebrand disease,
Although a heparin-bonded system avoids the need for syshemophilia, chronic liver disease)
temic anticoagulation, limited availability and overall impleMedications (warfarin, antiplatelet agents)
mentation technical challenges hamper its usefulness.20,21
repeat CT scan. This is the only practical method for the prompt
identification of patients in whom surgically correctable mass
lesions develop during the initial phase of care.
Important additional and avoidable causes of secondary
brain injury include hypotension, hyperthermia, seizure activity, hyperglycemia, and hypoxemia. Taken together, these contribute to deterioration in the severity of brain function and
are often preventable. Hypotension at any point (even brief
time periods) approximately doubles the likelihood of death
from a given brain injury and must be avoided.33,34 Posttraumatic seizures increase cerebral metabolic rate, may increase
ICP, and may cause important secondary brain injury. Prevention with intravenous phenytoin for the first 7 days after injury
is indicated and effective.35 Normocapnia (partial pressure of
arterial carbon dioxide [PaCO2] 35 to 40 mm Hg) should be
maintained to avoid cerebral vasoconstriction and concomitant
hyperfusion. However, brief, but not excessive, hyperventilation (keep PaCO2 25 mm Hg) as a temporizing measure to
treat sudden increases in ICP or herniation may be necessary
while preparing for definitive treatment (craniotomy, ventriculostomy for cerebrospinal fluid drainage, etc.).
Mechanical Ventilation
This will be discussed in more detail elsewhere, but there are a
number of important considerations in the delivery of mechanical ventilation during this resuscitative and diagnostic phase.
First, abnormal gas exchange, leading to hypoxemia, commonly
exists in patients who are being resuscitated from hemorrhagic
shock. Pulmonary edema may arise more as a consequence of
overly aggressive crystalloid resuscitation than the transiently
increased endothelial permeability consequent to shock. Transient hypoxemic respiratory failure is observed in trauma
patients and may reflect a somewhat different pathophysiologic
process than that which exists in the more prolonged hypoxemic respiratory failure seen with subsequent acute lung injury
(ALI) and acute respiratory distress syndrome (ARDS).36 However, the goals of support at this point are primarily to ensure
adequate resuscitation from shock, support oxygen delivery,
and prevent any ongoing oxygen insufficiency. Therefore, it is
important to distinguish the approach to mechanical ventilation
in these first hours from the approach used once the patient has
been successfully resuscitated and may have developed moderate to severe ALI. Initial ventilator settings aim to achieve adequate ventilation and oxygenation. This typically requires a
minute ventilation of greater than or equal to 12 L/min and
employs a fairly traditional approach. This includes volumecontrolled ventilation, with a tidal volume of 8 to 10 mL/kg, a
rate of 18 to 22 breaths/min, positive end-expiratory pressure
(PEEP) of at least 5 to 10 cm H2O, and a fraction of inspired
oxygen (FiO2) greater than or equal to 50%. Contrary to limits
imposed for treatment of ALI or ARDS, it is appropriate to
accept end-inspiratory static (Pst) pressures up to 40 cm H2O
and not aggressively limit tidal volume to 6 mL/kg and static
pressures to less than 30 cm H2O during this initial phase.
Rarely, circumstances occur in the severely injured patient
that require unconventional ventilation strategies. These
patients may be profoundly hypoxemic despite high FiO2 concentrations and elevated PEEP and/or may have a massive air
leak due to severe parenchymal or airway injury. These patients
have typically received a massive volume of fluid during the
acute resuscitation, have sustained severe thoracic trauma,
and/or often both. There are no established proven best
approaches to managing these patients. However, some principles can apply. First, large air leaks require treatment at this
stage only if they are significantly affecting patient oxygenation
due to diversion of the inspired gas away from gas-exchanging
alveoli. Bronchoscopy should be considered to identify proximal airway injuries, but patient instability may preclude both
bronchoscopy and definitive operative management. Therefore,
TRAUMA
459
460
regardless of the anatomy of the injury, in these severely hypoxemic patients, initial treatment options are often nonsurgical.
Approaches include maneuvers to minimize air leak, such as
high-frequency oscillatory ventilation (HFOV) and single-lung
isolation (double-lumen endotracheal tube or bronchial blockers) to support effective gas exchange.
intra-abdominal pressures. One causal factor that seems common to all cases of ACS is the use of very aggressive crystalloid
resuscitation, including attempts to reach elevated O2 delivery to
reverse a perceived oxygen debt. Therefore, attempts to achieve
supranormal endpoints (cardiac index of 4 L/min per m2 or
oxygen delivery index of 600 mL/min per m2), which often
require the excessive resuscitation volumes that contribute to
ACS, should be avoided.11
Elevated intra-abdominal pressure (intra-abdominal hypertension) leading to pulmonary, renal, or cardiac dysfunction is
termed the abdominal compartment syndrome (ACS). According to most studies, death is almost certain if greatly excessive
pressure is not relieved.37 Intra-abdominal hypertension can be
defined as an intra-abdominal pressure of greater than or equal
to 20 cm H2O.38 Experimental data indicate that hepatic arterial, portal venous, and hepatic microcirculatory blood flow are
markedly reduced when intra-abdominal pressure is increased
to greater than or equal to 20 cm H2O.39 Typically, it is observed
after severe abdominal trauma that requires celiotomy and control of intra-abdominal hemorrhage.40,41 It has also been
described in the setting of intra-abdominal injuries that were
initially managed nonoperatively (e.g., severe liver or kidney
injuries).42 In addition, excessive large-volume resuscitations,
even in the absence of any direct abdominal trauma, can also
lead to ACS.12,43,44
The diagnosis often begins with a triad of clinical findings:
(a) tense, distended abdomen; (b) increased end-inspiration
airway pressures; and (c) oliguria despite appropriate volume
resuscitation. Additional clinical measurements, particularly
those that reflect poor cardiac performance, may be helpful in
making the diagnosis. Signs consistent with ACS are a reduced
cardiac output, elevated systemic vascular resistance, and elevated pulmonary capillary wedge pressure with simultaneous
low or normal calculated estimates of end-diastolic volumes.
The addition of corroborative findings from invasive hemodynamic monitoring may help clarify the diagnosis and direct the
appropriate treatment.
Bladder pressure is the most widely used surrogate for
intra-abdominal pressure. It is measured with the patient
supine, by distending the bladder with 100 mL of sterile saline.
The drainage tubing is then occluded, and an 18-gauge needle
inserted sterilely and connected to the pressure transducer
through the aspiration port on the catheter tubing. An adequate pressure tracing is indicated by visible respiratory variation, which is usually less than 5 to 10 mm Hg.45 The mean
pressure should be used as an estimate of the intra-abdominal
pressure, although this aspect of the procedure is not well characterized. A simpler method (although not validated) involves
filling the bladder with 100 mL of sterile saline and elevating
the clear tubing vertically above the pubic symphysis. The
height of the fluid column is measured and converted to mm
Hg (1.3 cm H2O 1 mm Hg).
Established ACS with associated organ dysfunction is treated
with surgical decompression of the abdomen.38 In contrast, elevated intra-abdominal pressures, regardless of the actual measured value, in the absence of physiologic derangement is not an
indication for decompressive celiotomy. Similarly, high intrathoracic pressures and marked FiO2 and PEEP requirements are not
necessarily sufficient to warrant decompression. Progressive
renal dysfunction (oliguria, rising creatinine) despite adequate
preload and ongoing resuscitation should warrant abdominal
decompression. Persistent shock, particularly when vasopressor
agents are needed to supplement fluid resuscitation, also warrants decompressive celiotomy. There are no absolute thresholds
for airway pressure, urine output, or arterial blood lactate that
indicate or contraindicate decompressive celiotomy. Of note,
ACS can occur in patients whose fascia has not been definitively
closed, but where some other technique of temporary abdominal
closure has been performed and is sufficient to generate excessive
461
TRAUMA
462
better general supportive care, particularly adequate resuscitation, or due to specific preventative measures is uncertain. Nevertheless, trauma patients in the ICU receiving mechanical
ventilation for over 48 to 72 hours constitute a high-risk group
in whom the risk for upper gastrointestinal hemorrhage is
reported to be from 4% to 12%.68,69 Histamine-2receptor
antagonists may be the most effective agent for preventing
upper gastrointestinal hemorrhage in the ICU, and many practitioners choose them for prophylaxis.70,71 However, nosocomial pneumonia and, in trauma patients, other nosocomial
infections as well are increased in patients receiving histamine2 antagonists when compared to those given sucralfate.72,73
The use of sucralfate avoids gastric acid neutralization and the
potential systemic effects of histamine-2receptor antagonists.
Proton pump inhibitors markedly suppress gastric acid secretion but are no more effective than other agents in reducing
clinically relevant hemorrhage from stress gastritis. Once
enteral nutrition via the stomach has been initiated and shown
to be tolerated, there is no proven benefit to continuing any of
the gastric-protective interventions.
Pain Relief
Approaches to pain relief and sedation assume great importance in this phase of care of the critically ill trauma patient. In
particular, adequate pharmacologic relief of thoracic pain due
MANAGEMENT OF INFECTIOUS
to multiple rib fractures may be critical to avoiding intubation
COMPLICATIONS
and to hastening liberation from mechanical ventilation and
extubation. It appears that, when possible, thoracic epidural
(8 DAYS AND BEYOND)
analgesia results in fewer cases of nosocomial pneumonia and
fewer days of mechanical ventilation than systemically adminInfectious complications can occur earlier in the postinjury
istered opioid analgesia.74 Given the multiple painful stimuli
period, but they assume heightened importance as patients
remain in the ICU beyond the first week. At this point, preexperienced by trauma patients in the ICU (fractures, surgical
vention, surveillance, rapid diagnosis, and effective treatment
incisions, lacerations, contusions, etc.), it is reasonable to conbecome an important focus of the critical care team.
sider regional analgesia not just for those with multiple rib
fractures. However, contraindications to the use of epidural
analgesia are commonly encountered and include severe traumatic brain injury, spinal fracture, coagulopathy, or any injury
Nosocomial Pneumonia
that would preclude appropriate positioning for accessing the
epidural space. While sedation is critical to optimize patient 8 Pneumonia is the most common pulmonary complication and
rest and recovery, overdosing and deposition of active byprodthe most common infection in trauma victims. It most often
ucts can lead to prolonged oversedation and inability to extuoccurs in association with tracheal intubation, and when assobate in a timely fashion. All patients receiving sedation should
ciated with mechanical ventilation is referred to as ventilatorundergo a sedation holiday every 24 hours, allowing the
associated pneumonia (VAP). Posttraumatic VAP occurs due
patient to return to baseline mentation and permit serial daily
to a combination of factors including alterations in host
monitoring of overall neurologic status.
defense mechanisms and concomitant colonization with pathogenic bacteria. Taken together, recumbent positioning and
translaryngeal intubation facilitate microaspiration of secretions that have pooled in the hypopharynx. Although gastric
Venous Thromboembolic Disease
bacterial colonization may lead to oropharyngeal and tracheal
colonization, oropharyngeal colonization frequently precedes
7 Venous thromboembolic disease (VTE), which can manifest as
both gastric and tracheal colonization.69 Alterations in host
deep venous thrombosis (DVT) or pulmonary embolism (PE),
is common after trauma and can have serious or fatal conseinnate immune mechanisms likely contribute to the risk for
quences. Pulmonary embolism is the most devastating manifespneumonia by impairing cellular immune responses to aspitation and an important cause of posttraumatic death. Both
rated bacteria. Examples of alterations in host innate immune
can occur at any time after injury, and many occur as early as
mechanisms that exist in critically ill patients include reducthe initial 48 hours.75 In particular, spinal cord injuries and
tions in immune cell expression of bacterial antigen receptors
(Toll-like receptors 2 and 4) and alterations in intracellular siglower extremity and severe pelvic fractures are strong risk facnalling (decreased nuclear factor-B heterodimer formation)
tors for VTE.76 However, patients without these injuries are
leading to reduced cytokine responses.85,86
also at risk for thromboembolic complications. Other important risk factors include increasing age, immobility, and the
Posttraumatic nosocomial pneumonia is caused by a range
need for blood transfusions.76,77 That most trauma patients are
of gram-negative and gram-positive organisms. Pseudomonas
species and Staphylococcus aureus are the two most common
at risk and that both DVT and PE can occur early pose difficult
pathogens and together are responsible for up to 40% of
practical problems to apply effective prevention strategies due
cases.87,88 Multidrug-resistant bacteria are becoming a greater
to the high risk for ongoing or secondary bleeding and associated complications.
challenge. Both gram-negative organisms, such as Acinetobacter
Low-molecular-weight heparin is more effective than unfracspecies, and gram-positive organisms, such as methicillin and
tionated heparin for prophylaxis and should be used in patients
vancomycin-resistant staphylococci and enterococci, have
in high-risk groups. One large randomized trial demonstrated
emerged as important pathogens.
that proximal DVT risk was approximately 30% lower in
Prevention strategies reduce the incidence of VAP. For
patients receiving low-molecular-weight heparin (30 mg twice
example, elevating the head of the bed to 45 degrees effectively
463
which cultures of the blood and of the catheter reveal the same
pathogen), and exit site infections (in which there is local
catheter site evidence of infection without positive blood or
catheter cultures).97 Approximately 10% of critically ill
patients will develop a vascular catheterrelated infection during their ICU stay, and this translates into approximately 9
infections per 1,000 patient-days.97 In the absence of infection
at the site of insertion, the diagnosis of catheter-related infections is difficult. Options for diagnosing catheter-related infections include culture of a catheter segment or of blood drawn
through the catheter alone or simultaneously with blood drawn
from a peripheral vein. These specimens can be quantitatively,
semiquantitatively, or qualitatively cultured. In general, quantitative catheter segment cultures are the most accurate (highest combined sensitivity and specificity) for the diagnosis of
infection. Unpaired quantitative culture of blood (drawn via
the vascular catheter alone, without paired peripheral samples) is slightly less accurate.98 Therefore, when infection is
suspected but the insertion site is not inflamed or draining, the
catheter should be removed for intratissue catheter segmental
culture or blood should be drawn from the catheter for quantitative culture.98
Preventative strategies can lower the incidence of catheterrelated infections in the ICU. Full sterile barriers are appropriate for insertion of central venous catheters and reduce subsequent infection rates, but they may not be required for the
insertion of peripheral arterial catheters.99,100 Chlorhexidine
gluconate results in fewer bloodstream infections in comparison to povidone-iodine when used for insertion site preparation.101 Using a silver-impregnated antimicrobial subcutaneous
cuff attached to central venous catheters or antibiotic-impregnated catheters decreases the incidence of catheter infections.
However, while impregnating catheters with antimicrobials
(rifampin-minocycline) may reduce the risk of catheter-related
infections, antibiotic resistance can develop.
Hyperglycemia does not seem to be an important risk factor for catheter-related infections. However, TPN administration is a risk factor for catheter-related and other bloodstream
infections. Avoiding unneeded TPN use and preventing even
short periods of excessive caloric intake will help reduce the
incidence of these infections.102,103
Other Infections
Other infections are less common in trauma patients but are
still of considerable importance and reflect the spectrum of
infections seen in other cohorts of critically ill patients. Wound
and urinary tract infections, intra-abdominal abscesses, and
less commonly considered complications such as Clostridium
difficile colitis and acalculous cholecystitis must be considered
in the days to weeks after injury. Any patient developing diarrhea or a rapidly rising white blood cell count, particularly following or during a course of antibiotic therapy, should have a
stool specimen sent for C. difficile toxin and, in the critically
ill, metronidazole begun empirically.
Fungal infections are uncommon but are serious complications in critically ill trauma victims. They typically develop
after a prolonged ICU course in patients who have received
multiple antibiotics for nosocomial bacterial infections. They
are responsible for 5% to 17% of bloodstream infections in
critically ill patients and various Candida species are responsible for the majority of these infections.104106 Candidemia
refers to the growth of Candida from blood cultures, and systemic candidiasis refers to the situation in which microabscesses are present in multiple organs and tissues and are
extremely difficult to eradicate.
The single most relevant risk factor for the development of
candidemia in nonneutropenic trauma patients is the use of
broad-spectrum antibiotics. Colonization with Candida organisms is another important risk factor that can be useful in identifying the highest-risk patients.105,107 Fungal infections acquired
TRAUMA
464
in the ICU are an important risk factor for death in critically ill
patients in general as well as in trauma patients.104 Although
antifungal prophylaxis with fluconazole seems safe and may
reduce the incidence of invasive fungal infections in high-risk
surgical patients, it is typically not indicated in trauma
patients.107 The diagnosis of candidemia is challenging, and the
clinical presentation is neither sensitive nor specific for fungal
infection. However, invasive Candida infections can occur
without cultures being positive. Therefore, treatment is often
empiric, based on a high clinical suspicion, typically in a patient
colonized by Candida with sepsis who is not responding to
antibiotic therapy. Treatment is generally with fluconazole or
another azole antifungal agent. Candida glabrata and Candida
krusei should be considered resistant to fluconazole, and resistance to amphotericin has been documented to occur.108 Therefore, if these organisms are suspected or determined to be
responsible for infection, amphotericin or one of the agents in
the echinocandin class should be used as initial therapy.
Voriconazole is a newer azole antifungal that is effective against
azole-resistant Candida species. It is an acceptable alternative
to amphotericin and the echinicadins.109,110
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58485859.
TRAUMA
K E Y
1
Of 3,000 species of snakes worldwide, only 375 are venomous, with approximately 20 deaths per year in the United
States caused by snakebites compared with 100,000 species
of Hymenoptera that cause approximately 40 deaths per
year, mostly as a result of severe anaphylactic reactions.
Snakebite morbidity is a result of venom composition, time
of year, size of snake, and depth and amount of envenomation. Venoms consist of numerous (up to 30 or more) proteins that disrupt endothelial cells and blood flow, produce
neuromuscular blockade, or generate a coagulopathy via
procoagulants. Coral snake venom also has direct neurotoxins and cardiotoxins.
Snakebites induce immediate pain, edema, and erythema at
the site, and spread at greater than 30 cm/h indicates severe
envenomation. Initial incision and suction provides little
benefit, as does a proximal tourniquet, which may cause
harm. Use of purified ovine antivenin is effective and has
replaced equine antivenin with its associated risk of serum
sickness.
Spider bites produce toxicity by local tissue necrosis
(brown recluse and hobo spiders) and painful muscle contractions (black widow spider) in the United States. Deaths
may be caused by stinging Hymenoptera, including bees
(particularly aggressive Africanized bees), fire ants, and
scorpions.
Hypothermia risk is high in the severely injured patient as
a result of exposure, loss of normal protective metabolism
(i.e., shivering), rapid massive infusion of cold fluids/blood,
and open thoracic and abdominal cavities.
Loss of protective responses to hypothermia occurs between
33C and 30C with an initial intensive sympathetic-type
reaction with tremulousness, profound vasoconstriction,
tremendous increases in oxygen consumption, and accelerated heart rate and minute ventilation.
ENVENOMATION
Snakes and Snakebites
1
466
P O I N T S
Hypothermia affects both blood gases and coagulation
parameters with increased PAO2 and decreased PCO2,
whereas coagulopathy is aggravated as a result of platelet
dysfunction and impaired enzyme activity. However, both
blood gases and coagulation parameters should be assessed
at 37C because if the arterial blood gas value is normal at
37C, it will be acceptable at lower temperatures, whereas
coagulopathy at 37C requires blood component therapy
separate from warming to correct the cold-induced coagulopathy.
8 Hypothermia increases risk of mortality at every level of
injury. And, although hypothermia delays mortality in
experimental shock models, there is no improvement in
outcome when applied to severe traumatic brain injury,
and patients rapidly rewarmed require less resuscitation
volume and have improved survival.
9 Hypothermia is treated either passively by preventing further losses and allowing endogenous rewarming or actively
either externally by use of warm blankets, heating pads, or
lights and immersion in warm water or internally by core
rewarming, which includes heated intravenous fluids;
heated peritoneal, thoracic, gastric, bladder, or colonic
lavage; heated moist inhaled air; extracorporeal circulatory rewarming (continuous arteriovenous rewarming), or
closed circuit intravascular countercurrent heat exchange
devises.
10 Frostbite involves ice crystal formation and unpredictable
loss of tissue. Early definitive rewarming (avoiding refreezing) by submersion in 40C to 42C water is preferable
with subsequent meticulous care, possible early thrombolytic therapy, and awaiting demarcation and avoidance
of early dbridement to optimize outcomes and tissue
salvage.
7
467
TA B L E 3 1 . 1
GENUS
COMMON NAME
CHARACTERISTICS
RANGE
Agkistrodon
Bothrops
Crotalus
Rattlesnakes
Lachesis
Bushmaster
Sistrurus
North America
Trimeresurus
Rattlesnakes
Asia
TRAUMA
468
FIGURE 31.1. Characteristics of snakes that differentiate poisonous pit vipers from harmless snakes.
TA B L E 3 1 . 2
CLASSIFICATION
II
III
IV
DESCRIPTION OF BITE
Visible bite but no envenomation; swelling/
erythema around the fang mark 2.5 cm;
minimal pain and tenderness; no systemic
symptoms
TA B L E 3 1 . 3
ENZYMES OF SNAKE VENOMS
Proteolytic enzymes
Arginine ester hydrolase
Thrombinlike enzyme
Hyaluronidase
Collagenase
Phospholipase A2 (A)
Phospholipase C
Lactate dehydrogenase
Phosphomonoesterase
Phosphodiesterase
Acetylcholinesterase
RNase
DNase
5-Nucleotidase
L-Amino
acid oxidase
469
edema, pulmonary edema and hemorrhage, significant interstitial fluid sequestration, and hypotension. Other venom proteins
appear to induce a neuromuscular blockade or coagulopathy.
Procoagulant venom factors seem to dominate, primarily exerting their effect late in the clotting cascade by activating factor
X or prothrombin or by directly converting fibrinogen to fibrin.10 Tissue destruction is aided by several different proteins.
L-Amino acid oxidase causes extensive tissue destruction and
splits fibrinogen, leading to platelet trapping and unstable clot
formation, thus contributing to the genesis of disseminated
intravascular coagulation (DIC). Phospholipase A2 causes
hydrolysis of lecithin at the C-2 position, resulting in the formation of lysolecithin. This event alters the permeability of
erythrocyte membranes and muscle cell plasma membranes,
leading to hemolysis and tissue edema. Hyaluronidase induces
the lysis of ground substance and thereby aids in the distribution of the venom throughout body tissues.
The Elapidae snake venom also contains specific and unique
neurotoxins and cardiotoxins, which have a more direct effect
on the neuroactivity of the prey. Coral snake venom directly
blocks action of acetylcholine receptor sites that do not appear
to be responsive to neostigmine. This blockade results in ptosis, dysphagia, and slurred speech and can lead to seizures,
coma, and death within 8 to 72 hours. While coral venom is
extremely toxic, there has been only one confirmed death in
the United States from a coral snake bite in the past 40 years,
the victim delaying medical attention; alcohol was involved.10a
TRAUMA
470
venom-binding portion of immunoglobulin G. CroFab (Crotalidae Polyvalent Immune Fab [Ovine]; Fougera, Melville,
New York) is a sterile, nonpyrogenic, purified, lyophilized
preparation of ovine Fab (monovalent) immunoglobulin fragments obtained from the blood of healthy sheep immunized
with one of the following North American snake venoms:
Crotalus atrox (western diamondback rattlesnake), Crotalus
adamanteus (eastern diamondback rattlesnake), Crotalus scutulatus (Mojave rattlesnake), and Agkistrodon piscivorus (cottonmouth or water moccasin). To obtain the final antivenin
product, the four different monospecific antivenins are mixed.
Each monospecific antivenin is prepared by fractionating the
immunoglobulin from the ovine serum, digesting it with
papain, and isolating the venom-specific Fab fragments on ion
exchange and affinity chromatography columns.33
CroFab is standardized by its ability to neutralize the lethal
action of each of the four venom immunogens following intravenous injection in mice. The potency of the product varies
with each batch; however, a minimum number of mouse LD50
neutralizing units against each of the four venoms is included
in every vial of final product. A schema for using CroFab to
treat snakebites is given in Algorithm 31.1. This product is
roughly five times more potent than the older equine Crotalidae polyvalent antivenin; it has rapidly replaced the equine
antivenin once widely used against all North American crotalids, primarily because of fewer allergic reactions.5,29,30 Recurrence of the effects of venom after an initial response to
antivenin has been well recognized, hence the subsequent
smaller doses 6, 12, and 18 hours following an effective initial
response. As the algorithm illustrates, however, the equine
antivenin may still have a role in the patient who is a nonresponder to CroFab, and an equine antivenin remains the most
effective antivenin for coral snake bites.
The occurrence of anaphylaxis during or after administration of any antivenin mandates immediate cessation of therapy
and countermeasures, including antihistamines (oral diphenhydramine), epinephrine infusion, and/or corticosteroids. The
adequacy of the airway and volume status must be ensured.
The risk of continuing antivenin must be weighed against the
potentially fatal consequences of severe envenomation. Concomitant administration of intravenous antihistamine and epinephrine in small, titrated microdrip doses to prevent the most
severe manifestations of systemic anaphylaxis has been described
in an allergic patient in whom antivenin therapy was deemed
essential. This technique requires close physician observation
because there are risks from both anaphylaxis and the treatment itself.
The other major complication of any antivenin therapy is
serum sickness. Serum sickness occurs in approximately 50%
to 75% of all patients treated with an equine-based antivenin
but only 16% with the ovine source of antivenin.5,24 Serum
sickness is a type III hypersensitivity reaction in which soluble
antigenantibody complexes are deposited diffusely in the
presence of antigen access. In 26 patients who were treated
with a total of 507 vials of Crotalidae antivenin, there was a
23% incidence of immediate hypersensitivity reaction and a
50% incidence of serum sickness.24 Of patients who received
more than eight vials of antivenin, 83% experienced serum
sickness compared with 38% of patients who received fewer
than eight vials. Serum sickness symptoms of urticaria, itching,
nephritis, and arthralgia can occur at any time up to 3 weeks
after antivenin therapy. The exact number of vials of antivenin
required to induce serum sickness is unknown, but it appears
that increasing amounts of antivenin lead to a higher incidence
of serum sickness, with almost universal occurrence after the
administration of 7 to 10 vials of antivenin. The treatment for
serum sickness is systemic corticosteroids in decreasing doses
over a 7- to 14-day period.
Treatment of snakebites with antivenin has changed with
the more widespread use of the ovine polyvalent CroFab. As
illustrated in Algorithm 31.1, patients with a suspected or
471
Yes
No
Yes
No
Yes
No
ALGORITHM 31.1
ALGORITHM 31.1. Treatment of snakebite envenomation with antivenin. (Adapted from Gold BS, Dart RC, Barish RA. Bites of venomous
snakes. N Engl J Med 2002;347:347356; and Cribari C. Management of Poisonous Snakebites. Chicago, IL: American College of Surgeons
Committee on Trauma Poster; 2004.)
confirmed envenomation are recommended to receive an initial four to six vials of CroFab. If signs and symptoms of
envenomation are controlled, additional vials are administered
in a delayed fashion to prevent recurrence of symptoms. However, if the initial treatment fails to control envenomation, an
additional four to six vials of CroFab are repeated twice, and
then consideration should be given to using the older
Wyeth-Ayerst polyvalent equine antivenin. The estimated initial amount of Crotalidae antivenin needed should correlate
with the presenting clinical grade of envenomation. The package insert for Wyeth-Ayerst Crotalidae Antivenin Polyvalent
provides detailed instructions for preparing, administering,
and dosing this agent.
Although early surgical excision of the bite wound has been
advocated by some, most authorities regard antivenin as the
primary therapy and reserve surgery for the occasional compartment syndrome or dbridement of necrotic tissue at the
site of the bite several days after envenomation. Unless deep
intramuscular envenomation has occurred and antivenin therapy has been delayed, fasciotomy is rarely required. Because
the musculature and deep compartments of the hand are
relatively superficial, however, intramuscular penetration may
occur at these sites. Myonecrosis and interstitial edema may
cause enough compartmental hypertension in these sites that
linear finger fasciotomy and digital release are helpful. Fasciotomy may help reduce the ischemic tissue damage caused by
increased pressure but does not alleviate the myonecrosis
caused by the direct toxic effect of the venom.31,32 Noninvasive
arterial studies may help select patients who require special
surgical intervention for ischemia.33
TRAUMA
472
Crocodile and alligator attacks on humans are not uncommon in certain parts of the world. Saltwater crocodiles (Crocodylus porosis) are formidable predators in northern Australia.
They are the largest of 23 species of crocodilians and
are indigenous to southeast Asia and northern Australia. They
are significantly larger than North American alligators or Nile
crocodiles, averaging 5 meters in length versus 3 to 3.5 meters.
The largest recorded was 8.5 meters in length and weighed 2
tons.39a Injuries sustained are primarily from the forceful jaws,
conical teeth, and heavy skull, resulting in mangled extremities
infected with gram-negative water-borne organisms. While
humans are usually not strong enough to force open a crocodile
jaw, the strategy of applying forceful pressure to the reptiles
eyes may be more than folklore. Of course, shooting the beast
or beating it with a large stick may also provoke a release of the
victim. Prevention is the best form of treatment.
473
30
the size of the skin lesion and limiting the need for surgical
dbridement,49,50 whereas other studies demonstrate no benefit
in animal models,51 and no prospective study in humans supports
its use.52 The most common dose is 50 to 100 mg (0.7 mg/kg)
twice daily for 3 days to 2 weeks, although it is not approved for
this use by the U.S. Food and Drug Administration. One controlled trial of dapsone, electric shock therapy, or no therapy in
guinea pigs injected with 30 mg of spider venom demonstrated
efficacy of dapsone in reducing lesion induration and necrosis
area 72 hours after envenomation.53 Electric shock therapy had
no benefit. Hyperbaric oxygen treatment of model envenomation in rabbits and pigs also failed to demonstrate any effect on
lesion healing time or superficial appearance, although hyperbaric
treatments seemed to have decreased the amount of undermining
necrosis visualized histologically on day 24 after envenomation.54,55 A trial of hyperbaric oxygen, dapsone, and cyproheptadine in rabbits also failed to demonstrate any significant
difference in lesion size, ulcer size, or histopathologic ranking
up to 10 days after injection of toxin.55 Local injections of lidocaine, phentolamine, and systemic steroids and antihistamines
have been widely used in the past but have no demonstrable
benefit. Systemic corticosteroids probably have a role only in
the rare case of systemic loxoscelism, which has minimal skin
changes but produces massive hemolysis.44 Surgical excision of
the lesion itself has no clear benefit.56
Commercial antivenin for the brown recluse spider is not
available in the United States, although a rabbit antivenin for
L. laeta is available in South America.39 Equine-derived
antivenin has been shown effective in mice and rabbits, and
pepsin treatment to isolate the F(ab)2 monoclonal fragment
has been attempted. However, studies to date fail to demonstrate any advantage to antivenin, with or without dapsone,
particularly if there is a few-hour delay in administering the
antivenin. In areas where Loxosceles spiders are endemic, vaccination might hold promise.60
Few living creatures invite such poetic fascination and fear as
the black widow spider. Its name, coloring, carnivore diet, and
the disconcerting habit of the female eating her sexual partner
invite such fascination. And although both the male and female
spider possess potent venom, only the female is dangerous to
humans because the male is smaller and thus its bite cannot penetrate human skin. The mature female has a black body,
approximately 6 mm in diameter, with a characteristic red hourglass mark on the ventral aspect of the thorax. This mark is not
always present and may consist only of two red dots. The black
widow prefers a dry, protected, dimly lit area with access to flies
TRAUMA
474
TYPE
SETTINGS
Accidental
Therapeutic
Drug induced
Central nervous
system dysfunction
Hypothalamic
dysfunction
Metabolic
Hypoglycemia, hypothyroidism,
hypoadrenalism, malnutrition
Dermal dysfunction
Burns, erythrodermas
Traumatic
1200
1000
800
600
400
200
0
Year
FIGURE 31.3. Number of hypothermia-related deaths by year in the
United States, 19792002. (After Hypothermia-related deaths
United States, 20032004. MMWR Morb Mortal Wkly Rep 2005;54:
173175.)
TRAUMA
79
19
81
19
83
19
85
19
87
19
89
19
91
19
93
19
95
19
97
19
99
20
01
Hypothermia
19
ENVIRONMENTAL INJURIES
TA B L E 3 1 . 4
Number
475
476
Rate
Male
Female
Death rate
<1
14
510 9
-1
15 4
-1
20 9
-2
25 4
-3
35 4
-4
45 4
-5
55 4
-6
65 4
-7
75 4
-8
4
>8
5
Number
occurred in males (Fig. 31.4), but the overall death rate (0.5
per 100,000 population) was the same for both males and
2.5
females. Hypothermia-related deaths are commonly reported
by states with characteristically milder climates that experi2.0
ence rapid temperature changes (e.g., North Carolina [0.4]
and South Carolina [0.4]) and by western states that have high
1.5
elevations and experience considerable changes from daytime
1.0
to nighttime temperatures (e.g., Arizona [0.3]). States with the
greatest overall death rates caused by hypothermia are Alaska,
0.5
New Mexico, North Dakota, and Montana.
The physiologic response to hypothermia is one of
0.0
transitional changes, with few exact temperature-dependent
responses (Fig. 31.5). Broadly speaking, the transition from a
safe zone of hypothermia (in which physiologic adaptations
Age group (yrs)
to heat loss are working) to a danger zone of hypothermia
(in which shivering is abolished, metabolism decreases, and
FIGURE 31.4. Number and rate (per 100,000 population) of
heat loss is passively accepted) occurs between 33C and 30C.
hypothermia-related deaths, by age group and gender, in the United
States, 19792002. (After Hypothermia-related deaths United States, 6 The initial effects of hypothermia mimic intense sympathetic
stimulation, with tremulousness, profound vasoconstriction,
20032004. MMWR Morb Mortal Wkly Rep 2005;54:173175.)
and tremendous increases in metabolic rate, oxygen consumption, and minute ventilation.77
The initial cardiovascular response includes tachycardia,
followed by progressive bradycardia, which starts at approximately 34C and results in a 50% heart rate decrease at 28C.
90
80
70
60
50
40
30
20
10
0
477
TRAUMA
478
TA B L E 3 1 . 5
CLASSIFICATION
TEMPERATURE
Mild hypothermia
36C34C (96.8F93.2F)
Moderate hypothermia
34C32C (93.2F89.6F)
Severe hypothermia
32C (89.6F)
Hypothermia appears to occur primarily in victims of relatively severe trauma. Little and Stoner,109 reporting on a
heterogeneous group of 82 trauma patients, observed that
hypothermia occurred only in those patients with an ISS greater
than 12. Skin temperature fell from 32.0C to 31.7C, whereas
core temperature fell from 37.3C to 36.5C. Hypothermia did
not occur in less severely injured patients, and shivering, which
should be expected, was noted in only one of the hypothermic
patients. Mild degrees of injury have, in fact, been associated
with small elevations in core body temperature, particularly
when the shivering response mechanism has not been
abated.73,110
The detrimental effect of hypothermia in the human trauma
victim is contrasted by a large body of experimental evidence
in animals, suggesting that hypothermia has a protective role in
shock. This extensive body of literature is reviewed elsewhere,73
but in general, animals subjected to combined hypothermia
and shock (hemorrhage, burn, blunt trauma) usually survive
longer than similarly injured but actively warmed animals.
Blalock and Mason111 were among the first in modern times to
recognize the ability of hypothermia to prolong survival times
after shock, but they emphasized that the overall survival rate
was unchanged, an observation reaffirmed in 2003.112 However, other investigators have shown increases in both survival
times and survival rates in a number of animal models of induced
hypothermia after hemorrhagic shock.113,114 The protective
effects of hypothermia in preventing ischemiareperfusion injury
have been described in a number of models, including muscle,
intestine, and rabbit ear.115118
Hypothermia has also been suggested to protect the traumatically injured brain. The use of therapeutic hypothermia
in a patient with traumatic brain injury was first reported in
1943119 and sporadically over the ensuing two decades.120
More recently, a randomized, multicenter, controlled trial of
core body hypothermia in trauma patients with severe closed
head injury (Glasgow Coma Scale scores of 3 to 7) was conducted.121 Select trauma patients with severe head injury were
intentionally cooled within 6 hours of injury to 32C to 33C
for 48 hours after injury and then rewarmed. The outcome
was poor (defined as severe disability, a vegetative state, or
death) in 57% of the patients in both groups. Mortality was
28% in the hypothermia group and 27% in the normothermia group (p 0.79). The patients in the hypothermia group
had more hospital days with complications than the patients
in the normothermia group. The authors concluded that
treatment with hypothermia is not effective in improving outcomes in patients with severe brain injury. Other authors have
also reported higher rates of pneumonia and diabetes
insipidus in a small study of induced hypothermia in severely
head-injured patients (Glasgow Coma Scale scores of 3 to 7)
with no effect on neurologic outcome.122 Evidence further
supporting the harmful effect of hypothermia in the trauma
patient is provided by a prospective randomized trial of rapid
rewarming versus conventional rewarming of 57 multipletrauma patients.123 In this study, trauma patients who were
rapidly rewarmed with continuous arteriovenous rewarming
from less than 34.5C to greater than 36C required less
resuscitation fluid volume and had a lower early mortality
rate than those rewarmed more slowly. Failure to rewarm in
either group was uniformly fatal. The survival rate at 3 days
after injury was 82% in the rapid rewarm group versus 62%
in conventionally managed patients. Approximately 50% of
the patients in both groups had a severe head injury, defined
as a head Abbreviated Injury Severity score of 3 or greater. In
this well-controlled study, maintenance of hypothermia not
only failed to confer an advantage but also was detrimental to
early survival.
The role of hypothermia in the injured patient remains unresolved. It is apparent that the physiologic consequence of
severe trauma is a drop in core body temperature. It remains
unclear, however, whether this response is a protective response
479
to shock or the result of diminished heat production caused by 9 Treatment. Rewarming techniques are usually classified as
failing metabolism. The frequent presence of lactic acid accupassive external rewarming, active external rewarming, or
mulation in cold, seriously injured patients supports the latter
active core rewarming.132 Passive external rewarming simply
hypothesis. Clinical studies indicate that even mild hypotherimplies allowing spontaneous rewarming to occur with the
mia in the trauma patient is predictive of a poor outcome.
patient removed from a hypothermic environment and is usuHypothermia does diminish metabolic demands and oxygen
ally used only for the mildly hypothermic patient. Active exterconsumption in anesthetized patients, but the price appears to
nal rewarming techniques include surrounding the patient
be malfunction of enzymes and physiologic systems necessary
with warm blankets or heating pads, infrared heating lights, or
to recover from injury.
immersion in warm water. Active core rewarming includes
The systems most affected by hypothermia in victims of
heated intravenous fluids, as well as heated peritoneal or thoinjury are those involved in clotting. Reports of coagulation
racic lavage; heated gastric, bladder, or colonic lavage; heated
abnormalities in patients with apparently normal clotting
and water-saturated inhaled air; and extracorporeal circulafactor levels surfaced shortly after the introduction of
tory rewarming. Blood rewarming is currently limited to a
hypothermic cardioplegia for cardiac surgery.124,125 Although
maximum temperature of 42C by the American Association
hemodilution with volume expanders deficient in clotting
of Blood Banks, but rewarming to 49C with inline microwave
factors and platelets is the usual cause of nonsurgical bleedblood rewarmers has been reported as safe, as has intravenous
ing, cold platelets are known to undergo morphologic
fluid rewarming to 65C.133,134
changes that affect adherence, including loss of shape, cytoThe advantages and disadvantages of each technique are
plasmic swelling, and dissolution of cytoplasmic microregularly debated, particularly regarding the role of external
tubules necessary for normal motility.126 Platelet activation is
versus core rewarming. It is clear, however, that the rate of heat
also associated with activation of cell membrane phospholitransfer to the hypothermic patient is greatest using active core
pases that hydrolyze phospholipids to arachidonic acid, a
rewarming, particularly extracorporeal circulation rewarming.
precursor to prostaglandin endoperoxides and thromboxane
This may be a critical factor in surgical patients for whom
A2, a potent vasoconstrictor necessary for normal platelet
rapid restoration of clotting and cardiac function is necessary.
aggregation127 Valeri et al.128 induced systemic hypothermia
The technique of rewarming the hypothermic victim by
to 32C in baboons, but kept one forearm warm using heatextracorporeal circulation has been described by numerous
ing lamps and a warming blanket. Simultaneous bleeding
authors, based primarily on small personal experiences.81,82
time measurements in the warm and cold arm were 2.4 and
This technique has appeal in cases of primary accidental
5.8 minutes, respectively. This effect, which was reversible
hypothermia, in which maintenance of circulation, correction
with rewarming, appeared to be mediated by cold-induced
of hypoxia, and replenishment of intravascular volume may
slowing of the enzymatic reaction rates. A recent report sugplay a role as large as correcting the temperature change itself.
gests that bleeding observed at mildly reduced temperatures
The need for systemic anticoagulation has, however, generally
(33C to 37C) results primarily from a platelet adhesion
limited the usefulness of full cardiopulmonary bypass rewarmdefect and not reduced enzyme activity or platelet activation;
ing in the trauma patient.
however, at temperatures below 33C, both reduced platelet
A simplified technique of extracorporeal active core
function and enzyme activity likely contribute to the coagurewarming is continuous arteriovenous rewarming (CAVR).135
lopathy,129 perhaps helping to explain why 32C is such a
This technique makes use of the patients own blood pressure
critical temperature for survival in the coagulopathic injured
to drive an extracorporeal circuit through an efficient but
patient.
small countercurrent heat-exchange device (Sims Level 1,
As with blood gases, clinical tests of coagulation are temRockland, Massachusetts). Systemic anticoagulation is not
perature standardized to 37C. Fibrometers contain a thermal
necessary if the tubing is heparin bonded and trauma patients
block that heats the plasma and reagents to 37C before initiare relatively anticoagulated. The relative ease of use made this
ating the assay. Thus, tests of coagulation reflect clotting facdevice widely applicable in rewarming severely hypothermic
tor deficiencies but are corrected for any potential effect of
patients with an intact circulation and, in a prospective ranhypothermia on clotting factor function. A detailed study of
domized trial of rewarming trauma patients, demonstrated its
the kinetic effects of hypothermia on clotting factor function
efficacy by improved surival.123 Unfortunately, as of 2007, the
130
has been undertaken by Reed et al., who performed clotting
single manufacturing company for the tubing needed for
tests (PT, PTT, and thrombin time) on reference human
CAVR halted production.
plasma-containing normal clotting factor levels at temperaDirect intracirculation rewarming can be accomplished with
tures ranging from 25C to 37C. The results showed a signifcommercially available devices that employ an intravena caval
icant slowing of all coagulation tests at temperatures below
countercurrent heat exchange device (InnerCool Therapies,
35C that was proportional to the degree of hypothermia. The
San Diego, California; Alsius Corporation, Irvine, California).
prolongation of clot formation occurred at clinically relevant
While initially developed to cool patients for neurosurgical
levels of hypothermia and was equivalent to that seen in norprocedures and for induced resuscitative hypothermia followmothermic patients with significant clotting factor depletion.
ing cardiac arrest, rewarming can be accomplished by simply
For example, assays conducted at 35C, 33C, and 31C prochanging the temperature of the closed-loop circulating fluid.
longed the PTT to the same extent as would occur in a eutherRequirements are the commercial bedside console and specialmic patient with reductions in factor IX levels to 66%, 32%,
ized endovascular temperature control catheter, inserted via the
and 7% of normal, respectively.
femoral vein to the vena cava via an 11- to 12-French introClotting factor supplementation is not the answer to a
ducer. Preliminary data on rewarming cold patients suggest
hypothermia-induced coagulopathy; rewarming is. However,
that rewarming can occur rapidly, up to 3C per hour.123a
in many seriously injured patients, clotting factor depletion
The use of body cavity lavage with warm solutions is a simexists in conjunction with hypothermia. A potentiating effect
ple, less invasive method of accomplishing active core rewarmof hypothermia on coagulation dysfunction occurs in plasma
ing; however, rewarming rates with body cavity lavage vary
of patients with deficient clotting factor levels, although there
greatly based on initial core temperature, dialysate temperature,
does not appear to be synergy between the two conditions.131
infusion rate, and dwell time. Several studies support the notion
Hypothermic, coagulopathic trauma patients still benefit from
that active core rewarming by peritoneal lavage is preferable
coagulation profile testing. If prolongation of PT and PTT is
to active external rewarming.136 Moss74 examined three techevident in plasma warmed to 37C, clotting factor replacement
niques of rewarming hypothermic and cardiac-arrested dogs,
is indicated. If PT and PTT are near normal, rewarming alone
concluding that both peritoneal lavage (55C dialysate) and
reverses the clinically relevant coagulopathy.
partial extracorporeal circulation were faster than active external
TRAUMA
480
rewarming with a heating blanket.74 A frequently stated disadvantage of external rewarming is that the peripheral tissues are
rewarmed in advance of the still cool core, resulting in
peripheral vasodilation. In the presence of inadequate volume
resuscitation, this rewarming method may result in vascular collapse (rewarming shock) and a subsequent fall in central temperature (afterdrop) as the cold peripheral blood returns to
the core. Volume contraction caused by vasoconstriction, cold
diuresis, and cellular swelling coupled with inadequate fluid
resuscitation may be a more appropriate explanation for circulatory collapse during rewarming.
The thermodynamic principles of heat transfer to the
hypothermic patient are reviewed in greater detail elsewhere,
but a sense of rewarming rates and quantity of heat transferred
by various techniques is instructional.132,137 Ventilating a patient
with a core temperature of 32C with water-saturated air at
41C results in a maximum heat transfer rate of 9 kcal/h. For
comparison, basal metabolic heat generation produces approximately 70 kcal/h, and shivering produces up to 250 kcal/h.
Given the specific heat of the body (0.083 kcal/kg per C),
58 kcal is required to raise the temperature of a 70-kg patient
by 1C. Thus, more than 6 hours would be required to warm
a 32C patient using 41C humidified inspired air.
Heat transfer rates using body cavity lavage can be similarly
calculated based on the specific heat of water (1 kcal/kg per C).
If 1 L of 44C water infused into a body cavity dwells long
enough to exit at 40C, 4 kcal of heat will have been transferred to the patient. Thus, over 14 L of fluid is needed to
increase core temperature by 1C. However, warming becomes
less efficient as the patient rewarms because a longer dwell time
is required to reduce the temperature of the infusate to 40C.
Warming by cardiopulmonary bypass or continuous arteriovenous rewarming is the most efficient method of core heating. With flow rates of 15 to 30 L/h, it is possible to deliver
120 to 240 kcal/h if the reinfused blood is heated to 40C, a
rate of heat transfer over 10 times that of the other methods.
In each case, the urgency with which rewarming must be
accomplished depends on how adversely the hypothermia is
affecting the patient. With the exception of extracorporeal circulatory methods, most rewarming techniques serve primarily
to prevent further loss of endogenously generated heat and are
ineffective in circumstances during which rapid rewarming is
indicated. Early and direct attention to the mechanisms of heat
loss is necessary to optimize prevention of heat loss and the
metabolic and hemorrhagic complications associated with
hypothermia in surgical patients.
TA B L E 3 1 . 6
CLASSIFICATION
CLASSIFICATION OF FROSTBITE
DEGREE
DESCRIPTION OF FROSTBITE
First
Second
Third
Fourth
Treatment
Prehospital or field care of the victim of cold injury should
focus on removing the patient from the hostile environment
and protecting the injured body part from further damage.
Rubbing or exercising the affected tissue does not augment
blood flow and risks further cold injury or mechanical
trauma. Because repeated bouts of freezing and thawing
worsen the injury, it is preferable for the patient with frostbite of the hands or feet immediately to seek definitive shelter and care rather than rewarm the tissue in the field and
risk refreezing. Although the initial symptoms may be mild
and overlooked by the patient, severe pain, burning, edema,
and even necrosis and gangrene may appear with rewarming. With severe injury the range of motion progressively
decreases and edema becomes prominent. The injury may
progress to numbness and, eventually, to loss of all sensation
in the affected tissue.
The emergency room treatment of a frostbite victim should
first focus on the basic ABCs (airway, breathing, and circulation) of trauma resuscitation and then systemic hypothermia
481
should be identified and corrected. Most patients are dehydrated, and resuscitation with warm fluids is an important
part of early management. Fractures are often accompanied by
frostbite in mountaineers, and although manipulation may be
required to treat vascular compromise, open reduction is hazardous, and application of traction should be delayed until
after postthawing edema has been assessed.
Rapid rewarming is the goal. Gradual, spontaneous
rewarming is inadequate, particularly for deeper injuries, and
rubbing the injured part in ice or snow often delays warming
and results in marked tissue loss.152 Rapid rewarming should
be achieved by immersing the tissue in a large water bath of
40C to 42C (104C to 108F). The water should feel warm,
but not hot, to the normal hand. The bath should be large
enough to prevent rapid loss of heat, and the water temperature should be maintained. Dry heat is not advocated because
it is difficult to regulate, and the result of using excessive
heat is often disastrous. The rewarming process should
take approximately 30 to 45 minutes for digits, with the
affected area appearing flushed when rewarming is complete
and good circulation has been reestablished. Narcotics
are required because the rewarming process can be quite
painful.
The skin should be gently but meticulously cleansed and air
dried and the affected area elevated to minimize edema. A
tetanus toxoid booster should be administered as indicated by
immunization history. Sterile cotton is placed between toes or
fingers to prevent skin maceration and extreme care taken
to prevent infection and avoid even the slightest abrasion. The
affected tissue should be protected by a tent or cradle, and
pressure spots must be prevented. In one review, infection
developed in 13% of urban frostbite victims, but one half of
these infections were present at time of admission.145 Most
clinicians reserve antibiotics for identified infections.153
After rewarming, the treatment goals are to prevent further
injury while awaiting the demarcation of irreversible tissue
destruction. All patients should be hospitalized and affected
tissue gently cleansed once or twice a day in warm (38C)
whirlpool baths, with some clinicians adding an antiseptic
such as chlorhexidine or an iodophor to the bath. Based on the
findings of arachidonic acid metabolites in the blisters of frostbite victims, some authors advocate the use of topical aloe vera
(thromboxane inhibitor) and systemic ibuprofen or aspirin.
Heggers et al.154 report on a nonrandomized trial in which 56
patients treated with these agents, plus prophylactic penicillin,
had less tissue loss, a lower amputation rate, and a shorter
hospital stay than 98 patients treated with warm saline, silver
sulfadiazine, or Sulfamylon dressings (Bertek Pharmaceuticals,
Research Triangle Park, North Carolina).154 Another report
on frostbite treatment in rabbits demonstrated improved tissue viability when systemic pentoxifylline and topical aloe
vera cream were used.155 Uninfected blebs should be left
intact because they provide a sterile biologic dressing for 7 to
10 days and protect underlying epithelialization. After resolution of edema, digits should be exercised during the whirlpool
bath and physical therapy begun. Tobacco, nicotine, and
other vasoconstrictive agents must be withheld. Weight bearing is prohibited until complete resolution of edema.
Numerous adjuvants have been suggested and tried in an
effort to restore blood supply to frostbitten areas. The intense
vasoconstrictive effect of cold injury has focused attention on
increased sympathetic tone. Sympathetic blockade and even surgical sympathectomy continues to be advocated by some
authors based on the theory that it releases the vasospasm that
precipitates thrombosis in the affected tissue.156,157 This method
of treatment has produced inconsistent results and is difficult to
evaluate clinically, with no prospective randomized trials available. Although sympathectomy appears to mollify the pain,
hyperhidrosis, and vasospasm of cold injuries, it may increase
vascular shunting and adversely affect healing. In one series, a
more proximal demarcation of injury in sympathectomized
TRAUMA
482
FIGURE 31.6. Digital angiography of a 19-year-old woman who sustained bilateral lower extremity frostbite following vehicle breakdown.
A: The image demonstrates poor distal perfusion to the left toes. B: Following administration of tissue plasminogen activator via bilateral femoral
catheters, angiography demonstrates return of perfusion. All 10 of her toes were saved. (Reproduced with permission from Bruen KJ, Ballard JR,
Morris SE, et al. Reduction of the incidence of amputation in frostbite injury with thrombolytic therapy. Arch Surg 2007;142:546553.)
TA B L E 3 1 . 7
AMPUTATION OUTCOMES OF PATIENTS TREATED WITH TISSUE PLASMINOGEN ACTIVATOR (tPA) COMPARED WITH ALL
OTHER PATIENTS BY FROSTBITE
EXTREMITIES REQUIRING
AMPUTATION, NO. (%)
AGENT
NO. OF
PATIENTS
NO. OF
INVOLVED
EXTREMITIES
NONE
PROXIMAL
No agenta
26
57
25 (45)
14 (25)
13
10 (77)
32
70
35 (50)
tPA administration,
24 h
Total
a
0
14 (20)
DIGITS
ONLY
18 (29)
3 (23)
21 (30)
NO. OF DIGITS
AMPUTATED/TOTAL
DIGITS INVOLVED (%)
97/234 (41)
6/59 (10)b
103/293 (35)
January, amputate in June. The natural history of a fullthickness frostbite injury is the gradual demarcation of the
injured area with dry gangrene or mummification clearly
delineating nonviable tissue. Often the permanent tissue loss is
much less than originally suspected. In an Alaskan series, only
10.5% of patients required amputation, usually involving only
phalanges or portions of phalanges.141 The need for emergency
surgery is unusual, but vigilance should be maintained during
the rewarming phase for the development of a compartment
syndrome requiring fasciotomy. Open amputations are indicated in patients with persistent infection and sepsis that is
refractory to dbridement and antibiotics. Mills161 convincingly demonstrated that of all the factors in the treatment of
frostbite that may influence outcome, premature surgical intervention by any means, in any amount, was by far the greatest
contributor to poor results.
The use of technetium-99m methylene diphosphonate
bone scanning has shown some promise in the early detection of eventual bone and soft tissue viability,162 as has the
use of magnetic resonance imaging.163 Technetium-99m
triple-phase scanning (at 1 minute, 2 hours, and 7 hours)
performed beginning 48 hours after admission has been used
to assess early tissue perfusion and viability, in an attempt to
define the extent of fatally damaged tissues and to allow for
early dbridement and wound closure.164,165 The utility of
this diagnostic modality continues to evolve, however, with
one recent study suggesting that the moderate to severe
frostbite lesion identified by technetium-99m scans can be
hibernating (viable) tissue, which can show improvement
up to 6 months following injury.153,166
Frostbitten tissues seldom recover completely. Some degree
of cold insensitivity invariably remains. Hyperhidrosis (in up
to 72% of patients), neuropathy, decreased nail and hair
growth, and a persistent Raynaud phenomenon in the affected
part are frequent sequelae to cold injury.167 The affected tissue
remains at risk for reinjury and should be carefully protected
during any cold exposure. As mentioned previously, chilblain
(or chronic pernio) is a specific form of a dermopathy secondary to cold-induced skin vasculitis. Treatment with antiadrenergic agents (prazosin hydrochloride, 1 to 2 mg/d) or calcium channel blockers (nifedipine, 30 to 60 mg/d) and careful
protection from further exposure are often helpful.139,167
However, few therapies afford significant relief to the chronic
symptoms after tissue freeze injury, although - and -adrenergic
blocking agents, calcium channel blockers, topical and systemic steroids, and a host of home remedies have been tried
with occasional individual success.
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485
TRAUMA
CHAPTER 32 TERRORISM
ERIC R. FRYKBERG
K E Y
1
P O I N T S
Dispersal of radioactive agents has severe theoretical risk
but is primarily a psychological and panic effect. Penetration by ionizing radiation causes severe damage but is limited in range (square of the distance), and containment is
relatively easy and nontransmittable. Care is supportive,
treating dermal burns and gastrointestinal and hematopoietic damage.
7 Terrorist attacks are, by far, implemented most commonly
using conventional weapons and confirm the need of a system to treat the casualties of bombings. The magnitude of
energy achieved, the ease of technology required, and cost
effectiveness support an ongoing increase in risk of mass
casualties.
8 Explosion injuries are caused by the primary blast
waveinduced disruption of organs with airliquid interfaces (lung, bowels, eyes, and ears); secondary blast injury
from flying objects, particularly shrapnel placed in bombs
and suicide bomber body parts; tertiary blast injury from
displacement of the victims body; and quaternary blast
injury from indirect causes such as building collapse.
9 Response to mass casualty events requires triage of victims
to effectively utilize resources, including the paradigm shift
from greatest good for the individual to greatest good for
the greatest number, with need for preemptive planning,
coordination, and practice of an Incident Command System to respond optimally.
6
THE CHALLENGE
486
487
TRAUMA
488
TA B L E 3 2 . 1
AGENTS
TREATMENT/ANTIDOTE
Pulmonary irritants
Benzene
Decontamination, hypochlorite,
dimercaprol
Nerve agents
Blood agents
Cyanide
should be involved in the planning and management of chemthat exploded in the World Trade Center in New York City in
ical terrorist disasters.
1993 contained enough cyanide to contaminate the entire
building, but it was destroyed by the blast.23 In 1995, the
gaseous release of the nerve agent sarin in the Tokyo subway
system caused 12 deaths and 5,000 injuries, representing the
NUCLEAR/RADIOLOGIC
first terrorist use of this agent on a civilian population.24
The initial phase of response to intentional chemical
WEAPONS
attacks, as well as biologic and radiologic attacks, is known as
consequence detection. Early detection is essential if casualties
Dispersal of radioactive substances poses a significant potenand death are to be minimized and can occur from either the
tial for a terrorist attack because of the theoretical damage
discovery of the source of environmental release or exposure,
that could be inflicted on large populations, although such a
or the diagnosis of the afflicted casualties. Patterns of large
deliberate attack on civilian populations has never occurred
numbers of patients with similar symptom clusters must be
outside of war. These agents also carry the potential of widerecognized, which requires a knowledge of the classic sympspread psychosocial effects and panic caused by the mystique
toms of chemical poisoning, including coughing and choking
that is associated with radiation among the general populafrom pulmonary agents such as chlorine and phosgene, dry
tion. The dangers of these agents are largely overestimated,
mouth and mucous membranes, seizures, eye irritation, and
however, and result from poor understanding of radiation
the cholinergic symptoms of nerve agent poisoning described
biology. These misperceptions are as common among health
by the mnemonic DUMBBELS (diarrhea, urination, miosis,
care providers as among the lay public and represent a major
bronchospasm, bronchorrhea, emesis, lacrimation, and salivabarrier to effective management. In fact, major radiation expotion).
sure from a terrorist attack should be easier to manage than
The response phase that involves organization and cleanup
biologic or chemical events because of easy detection methods
of the disaster scene and medical and psychological treatment
with Geiger counters and dose-rate meters; the large number
of the casualties is termed consequence management. The
of hospital, industrial, and government personnel who reguidentified source of contamination and exposure must be neularly deal with radiation; and the well-known clinical effects
tralized to prevent further damage. Health care workers must
that can be monitored with simple laboratory tests.25,26
wear personal protective equipment to prevent their exposure
Radiation is categorized as nonionizing and ionizing, and
to hazardous materials (HAZMAT), including the prevention
may consist of particles or waves, each of which has specific
of inhalation of toxic fumes from off-gassing that may emanate
implications for injury in mass casualty scenarios. Nonionizfrom the tissues or clothing and belongings of afflicted
ing radiation, such as infrared and visible light, has little if any
victims.
6 injurious effects on living organisms. Ionizing radiation repreTriage and decontamination of casualties must be estabsents the major radiologic threat from terrorist events, as it
lished outside the hospital, and away from the disaster scene,
causes damage to living cells and tissues from its direct energy
to prevent health care providers and hospital facilities from
as well as from the indirect effects of the unstable and toxic
being contaminated and rendered useless for further treatment
hyperoxide molecules it creates. These effects are long term, as
of casualties. Decontamination should furthermore take place
they continue far beyond the time of exposure. -Rays and
at a site that is uphill and upwind from the scene for this purx-rays, which are examples of wave radiation, have high tissue
pose. A hot zone must be established for contaminated casualpenetrance and cause the greatest tissue damage, especially to
ties, to be clearly demarcated from the warm zone, where
rapidly dividing cells (gastrointestinal tract and bone marrow).
decontamination takes place, and the cold zone, where casualNeutrons are particles that behave much like - and x-rays as
ties are considered fully decontaminated and ready to undergo
they also have high penetrance with severe tissue damage.
re-triage and medical treatment. All casualties must undergo
(Helium nuclei) and (electrons) particle radiation have low
decontamination as early as possible to minimize adverse
tissue penetrance and damage potential and are easily
effects. Simply removing their clothing and showering with
shielded, but cause highly lethal damage if ingested or if they
soap and water removes more than 90% of all contaminating
gain access through open wounds.25
agents, a process known as gross decontamination. The more
The major factors that determine the severity of radiation
intensive technical decontamination then follows for specific
exposure are time, distance, and shielding. The absorbed radiforms of exposure, such as hypochlorite solutions for mustard
ation dose rapidly decreases with shortened duration of expoagents, and copious eye irrigation with saline solution. Poison
sure and with the square of the distance from the source, so
control centers, public health officials, pharmacologists, and
that quadrupling the distance reduces the dose rate to one
toxicologists are important resources and personnel who
sixteenth of the original exposure. In doses of less than 1 Gy
489
TRAUMA
490
TA B L E 3 2 . 2
RESULTS
YEAR(S)
EXPLOSIVE AGENT
(*BUILDING COLLAPSE)
1970s
TNT, dynamite
1980
TNT
Beirut airport
1983
Ammonium nitrate(*)
Paris bombings
1986
TNT
1993
Ammonium nitrate
1994
Ammonium nitrate(*)
Oklahoma City
1995
Ammonium nitrate(*)
Atlanta Olympics
1996
TNT
1998
TNT(*)
2000
TNT
2001
2001present
TNT, C-4
2003
Ammonium nitrate(*)
2004
TNT
2005
TNT
most prominent and most likely threat for which civilian populations must be prepared in the future. This has important
implications for the role of surgeons in disaster planning and
management because the casualties of explosive disasters will
be afflicted predominantly with traumatic injuries for which
surgical expertise and support are necessary. The technology
required for large-scale casualty generation and lethality with
this mechanism is easily learned, and its cost effectiveness is
unsurpassed by any other method.31,32 These factors have
resulted in a dramatic worldwide increase in frequency of
these incidents with each passing year (Table 32.2).7
Historical Perspective
An analysis of two major accidental explosions of the 20th
century serves to demonstrate the devastation of civilian populations that can result from large-magnitude explosive agents
and provides important lessons in the planning for and prevention of their disastrous consequences. On December 6,
1917, in Halifax harbor, Nova Scotia, the Belgian ship Imo
collided with the French munitions ship Mont Blanc, causing a
fire on the top deck of Mont Blanc from the ignition of 35 tons
of benzene. Hundreds of first-responder city firefighters and
civilian onlookers then flocked to the scene. After 15 minutes,
the fire ignited a cargo below decks consisting of 2,300 tons of
picric acid, 10 tons of gun cotton, 300 rounds of ammunition,
and 200 tons of trinitrotoluene (TNT). The ensuing explosion,
the largest nonnuclear manmade explosion ever to occur, was
followed by a 150-foot tidal wave, which leveled more than
2.5 km2 of the city, blew the ship 1 mile high and vaporized it,
threw its 1,100-pound anchor 2 miles away and a cannon
3.5 miles away, shattered windows 100 km away, and was
heard in Boston. The resulting smoke plume rose 4 miles into
the air. This delayed explosion wiped out the hundreds of curious citizens and firefighters who initially responded to the fire.
There were 2,000 deaths, 9,000 injured, and more than
20,000 left homeless in a city with a population of only
50,000, and all medical facilities were destroyed.33
In the port of Texas City, Texas, on April 16, 1947, the
freighter Grand Camp caught fire, again attracting the entire
491
Pressure
Atmospheric
pressure
Time
FIGURE 32.1. The Friedlander curve demonstrating the pressure
characteristics of a blast wave over time.
TRAUMA
492
TA B L E 3 2 . 3
RESULTS
IMPACT OF BUILDING COLLAPSE ON THE OUTCOME OF THE 1995 TERRORIST BOMBING IN OKLAHOMA CITY, OKa
CASUALTY
LOCATION
NO. SURVIVORS
NO. SURVIVORS
HOSPITALIZED
153 (87%)
22
18 (82%)
10 (5%)
176
32 (18%)
163 (45%)
198
50 (25%)
NO. CASUALTIES
NO. DEAD
Collapsed
175
Uncollapsed
186
Total
361
Includes only 361 casualties inside the Alfred P. Murrah Federal Building stratified by portion of building in which they were located.
Adapted from data in Mallonee S, Shariat S, Stennies G, et al. Physical injuries and fatalities resulting from the Oklahoma City bombing. JAMA
1996;276:382387.
Errors of Triage
The accuracy of triage could certainly affect the ultimate outcome of surviving casualties. Improper assignment to a
delayed category of critically ill or injured casualties who
require urgent care, termed undertriage, is the most important
493
TA B L E 3 2 . 4
RESULTS
NO. OVERTRIAGE
(%)b
34
3 (9)
9 (75)
1 (33)
1970s
339
113 (33)
29 (20)
5 (4)
Old Bailey,
London, U.K.63
1973
160
4 (2.5)
15 (79)
1 (25)
Guildford pubs,
U.K.43
1974
64
22 (34)
2 (8.3)
Birmingham,
U.K.65
1974
119
9 (8)
12 (57)
2 (22)
Tower of
London, U.K.64
1974
37
10 (27)
9 (47)
1 (10)
Bologna train
station, Italy50
1980
218
48 (22)
133 (73.5)
11 (23)
Beirut,
Lebanon55
1983
112
19 (17)
77 (80)
7 (37)
AMIA building,
Buenos Aires,
Argentina54
1994
200
14 (7)
47 (56)
4 (29)
Oklahoma City,
OK3
1995
597
52 (9)
31 (37)
5 (10)
294 (16)
364 (53)
37 (12.6)
YEAR
Cu Chi,
Vietnam67
1969
Craigavon,
Northern
Ireland66
Total
NO.
SURVIVORS
1,880
NO. CRITICAL
MORTALITY (%)c
TRAUMA
EVENT
BE
40%
CC
Critical Mortality
AMIA
30%
9/11
PB
20%
Bol
OC
10%
OB
Mad
TL
CA
GP
0%
0%
20%
40%
60%
80%
100%
Overtriage
FIGURE 32.2. Relationship of overtriage to critical mortality rate in
survivors of major terrorist bombings, from data in Table 34.4 (r
0.92). GP, Guildford pubs U.K.; CA, Craigavon, Northern Ireland;
OC, Alfred P. Murrah Federal Building, Oklahoma City, OK, U.S.; TL,
Tower of London, U.K.; BP, Birmingham pubs, U.K.; AMIA, AMIA
building, Buenos Aires, Argentina; Bol, Bologna train terminal, Italy;
OB, Old Bailey, London, U.K.; CC, Cu Chi, Vietnam; BE, Beirut airport, Lebanon. (Adapted from Frykberg ER. Medical management of
disasters and mass casualties from terrorist bombings: how can we
cope? J Trauma 2002;53:201212.)
494
80
Surge
capacity
60
40
20
10
15
20
the outcome of these casualties. The abundant published information on the hospital management of terrorist bombing casualties can be extrapolated to the expected demands from disasters of all kinds.31,32,36,68
Hospitals must restrict access of casualties to all but those
most seriously injured in order to conserve their scarce
resources and allow them to be applied to those most in need.
No casualty should be allowed into a hospital before being
both decontaminated and triaged. The three hospital resources
most in demand in this setting are the emergency room (ER)
where casualties are first received and evaluated, the operating
room (OR), and the intensive care unit (ICU). Each of these
units should have a designated controller, who is not involved
directly in medical care but is responsible for the proper
admission, movement, and disposition of all casualties to optimize rapid and efficient casualty handling. Casualties should
always move forward through hospital spaces, never returning
or going backward, thereby minimizing traffic gridlock and
confusion.36,40,60,61,69,70
Developing the space to accommodate the added casualty
load, or surge capacity, is the first thing that a hospital must
accomplish following a mass casualty event, and this must be
done within a matter of minutes. More important is the provision of the ability to care for the casualties brought into this
space (i.e., nurses; special needs such as dialysis, pediatric,
geriatric, and burn care; and surgical specialists), or surge
capability, without which the space and beds alone are of no
TA B L E 3 2 . 5
COMPLICATIONS
SURGE
CAPACITYb
OVERTRIAGE
LOADc
4.7
25
4.6
1.6
50
3.8
3.8
75
2.7
8.1
RESULTS
TA B L E 3 2 . 7
COMPLICATIONS
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SECTION B
TRANSPLANTATION & IMMUNOLOGY
CHAPTER 33 TRANSPLANTATION
IMMUNOLOGY
JEFFREY L. PLATT AND MARILIA CASCALHO
Development of the vascular anastomosis and immunosuppression were the key technologic advances that
allowed clinical application of transplantation.
2 The condition of the donor and ischemia and reperfusion
of the transplant impact directly on grafts and on the
immune response to grafts.
3 The genetic relationship between the recipient and the
donor determine the outcome of a transplant, especially
susceptibility to rejection.
4 Transplantation provokes immune responses by T cells
and B cells.
1
P O I N T S
Modern immunosuppressive agents and regimens effectively prevent acute rejection.
6 The impact of T-cell and B-cell responses on a graft
depends to the greatest extent on whether a transplant consists of cells, tissues, or an organ.
7 Transplanted organs but not transplanted cells and tissues
are susceptible to various types of humoral rejection; all
transplants are susceptible to cellular rejection.
8 Chronic rejection is the most common cause of loss of
organ transplants.
Transplantation refers to the transfer of living cells, tissues, or 1 injured organ with a healthy one. Ultimately, the vascular
anastomosis was one of two advances critical to the clinical
organs from one individual to another. Envisioned from a theoapplication of organ transplantation, the other advance being
retical perspective throughout history, transplantation has been
the discovery of immunosuppression.
attempted surgically since the early years of the twentieth cenSuccessful application of the vascular anastomosis for transtury. Today, transplantation is the preferred method to replace
plantation of the kidneys was reported by Alexis Carrel in 1908.2
the function of the heart, lungs, kidneys, liver, and bone marrow
and, in some circumstances, the islets of Langerhans of the panCarrel was awarded a Nobel Prize in 1912 for having developed
creas. Applications may soon be expanded if transplantation of
the vascular anastomosis and using it to launch the field of transstem cells or the derivatives of stem cells become part of cliniplantation. However, Carrels collaborator, Charles Guthrie,
cal practice. Transplants have shed light on such fundamental
actually perfected the technique of vascular suture, which Carrel
principles of biology and immunology as the genetic differences
applied.3,4,5
between individuals in a population, the principle that organs
The outcome of the first transplants is illustrated in Figure
are integral biologic structures, the major histocompatibility
33.1.5 Although Carrel claimed the transplants to be successful,
complex, and tolerance. Many terms have been applied to
all of the recipients died during the ensuing 5 weeks. This
transplants based on the genetic relationship between the
result contrasts with the outcome of transplants performed
source and recipient of transplants. Some of these terms are
into the same animals from which the kidneys were harvested,
listed and defined in Table 33.1.
termed autografts. These results illustrate several points. Organs
transplanted into unrelated individuals (allotransplants) almost
invariably fail, while organs transplanted into oneself or into a
genetically identical recipient, an isograft, survive indefinitely.
THE VASCULAR ANASTOMOSIS
This chapter will consider the biologic reasons why transplanted
AND FIRST LESSONS OF
tissues and organs fail.
TRANSPLANTATION
497
TRANSPLANTATION
K E Y
498
other damage. Ischemia-reperfusion injury to the heart (myocardial infarction) and brain (stroke) are leading causes of death
and disability. Organs differ in the extent to which they are damaged by ischemia-reperfusion. Lung, liver, and heart are more
susceptible than kidney. The risk of severe ischemia-reperfusion
injury limits the time that organs can be preserved prior to
transplantation and hence the matching of organs to the recipients most in need.
The mechanisms by which ischemia-reperfusion injures tissues remain uncertain. Table 33.2 lists some factors implicated
in the pathogenesis of ischemia-reperfusion injury. Inhibition
or absence of these factors can prevent or decrease ischemiaperfusion injury. Since inhibition of many different factors
decreases or eliminates ischemia-reperfusion injury, those factors must function in series or in a limiting way in parallel,
with injury critically dependent on the sum of independent
insults. How these factors orchestrate the pathology and
pathophysiology of ischemia-reperfusion injury is a question
of central importance in the field of transplantation.
The factors that initiate ischemia-reperfusion injury remain
unclear and are the focus of much inquiry. Surgical harvesting
deprives organs and tissues of the flow of blood. Severe injury
and/or prolonged deprivation of blood cause changes in small
blood vessels that prevent re-establishment of perfusion, a
condition referred to as no reflow, and directly cause necrosis.7
Mild injury and shorter periods of ischemia cause transient
changes in structure and function. Deprivation of oxygen
might initiate many of the reversible changes in ischemiareperfusion injury.8 Reperfusion of a graft also contributes to
tissue injury, perhaps to a greater extent than ischemia.
Nearly every factor that contributes to tissue injury can
also protect against it.9,10 For example, activation of complement in subtoxic amounts causes cells to acquire resistance to
toxic amounts of complement.11 Similarly, while inhibiting
interleukin-1 (IL-1) decreases ischemia-reperfusion injury,
treatment with IL-1 in advance of reperfusion protects against
damage.12,13 This antithesis of injury and protection suggests
that ischemia-reperfusion injury may cause damage in some
circumstances but may be protective in others. As only one
example, ischemia-reperfusion injury may help to sequester the
TA B L E 3 3 . 1
TERMINOLOGY OF TRANSPLANTATION
TERM
DEFINITION
Autograft
Transplant to oneself
Allograft
Homograft
Allograft
Isograft
Xenograft
Heterograft Xenograft
FIGURE 33.1. Method (A) and outcome (B) of the initial successful transplants reported by Carrel in 1908.2 All recipients died
over a period of weeks. In contrast, a few autografts performed by
the same surgeon functioned for years. The difference between the
outcome of autografts and allografts illustrates the preeminence of
the immunologic barrier to transplantation. ([A] from Carrel A.
Originally published in The Journal of Experimental Medicine.
1908;10:98140.)
Carrel (1908)
Survival Rates
0.8
0.6
0.4
0.2
0
A
10
15
20
25
30
Days After Transplantation
35
40
Normal
Isograft 3hr
499
GENETIC DETERMINANTS
3
MECHANISM
Hypoxia
Hypoxia-inducible factor
Complement
Natural antibodies
Activate complement
Oxidants
Apoptosis
Disrupts endothelium
Toll-like receptors
Cell adhesion
molecules
T cells
Unknown
TRANSPLANTATION
FIGURE 33.2. Impact of ischemia-reperfusion on the structure of a graft. The figure depicts heparan sulfate, a sugar that supports most of the normal functions of blood vessels, by silver staining in a normal
heart (left) and in hearts transplanted heterotopically into genetically identical guinea pigs (middle and
right). The micrograph on the right is from a recipient in which complement was inhibited by treatment
with cobra venom factor (CVF). The figure shows that transplantation under optimal surgical conditions
causes loss of all detectable heparan sulfate in a complement-dependant manner.
FIGURE 33.3. The outcome of transplants incompatible at strong and weak histocompatibility loci. The
figure shows that incompatibility of strong histocompatibility genes causes rapid and universal rejection of
allografts. Incompatibility of weak histocompatibility
genes causes rejection to occur in some but not all
transplants and at a relatively slow rate. Prior exposure to a transplant incompatible for a weak gene
causes the response to be universal and more rapid.
The locus of the strong histocompatibility genes is
called the major histocompatibility complex.
Percent Survival
500
Minor Histocompatibility
Antigen
0.5
Repeated
Transplants
of Minor Antigen
Major Histocompatibility
Antigen
0
Day Day Day Day Day Day Day Day Day Day Day Day Day
0
2
5
8
11
14
17 20 23
26 29
32
64
later found to be a complex of genes called the major histocompatibility complex (MHC). Transplants matched for
MHC might still undergo rejection, albeit at a slower tempo;
this type of rejection was attributed to weaker histocompatibility antigens, later called minor antigens.
In 1958, Jean Dausset discovered that human patients who
had received multiple transfusions of blood were subject to
transfusion reactions, and contained in their serum antibodies
specific for leukocyte alloantigens.24 These antigens, ultimately
called human leukocyte antigens (HLAs), were encoded by
genes analogous to the murine H-2 genes.
The field of histocompatibility has struggled to address the
nature of the genetic determinants of tissue individuality, the
factors that condition recipient immune responses to foreign
tissues, and the mechanisms mediating those responses. A central question has been whether antigens encoded by MHC
(MHC antigens) function only as passive targets of immune
responses or whether MHC antigens participate in some way
in the physiology of the immune system.25 Another question
has been what distinguishes the strong histocompatibility
barrier posed by antigens encoded by MHC versus the weaker
barrier posed by minor antigens. Yet another question concerned the nature of MHC genes and the proteins they encode
that enable this system to confer uniqueness to each member
of an outbred population. Only recently have answers to these
questions emerged and the biologic role of histocompatibility
determinants in the initiation and regulation of immune
responses in normal animals been determined.
TRANSPLANTATION
MHC class I molecules consist of a 45-kD chain and 2microglobulin, a 12-kD glycoprotein not encoded by the
MHC complex (Fig. 33.4A). The MHC class I molecule has
four extracellular domains, a transmembrane region, and a
cytoplasmic tail. Each MHC class I molecule has a groove
that harbors an antigenic peptide. Correct folding of the class
I MHC proteins depends on the presence of the peptide. The
peptide and polymorphic regions of the 1 and 2 domains
bind to the T-cell receptor. A nonpolymorphic region of the 3
domain binds to CD8.
The peptides presented by MHC class I molecules are 8 to
10 amino acids in length and join the MHC class I molecule
during assembly in the endoplasmic reticulum.33 The peptides
derive from degradation of cytoplasmic proteins by proteasomes made up of low-molecular-proteins encoded in the class
II region of HLA in close linkage with genes encoding the peptide transporters for both class I and class II molecules and by
other proteases. These transporters carry the peptides into the
endoplasmic reticulum where the class I assembly takes
place.24 The major transporter of peptide destined to associate
501
FIGURE 33.4. A: Human leukocyte antigen (HLA) class I molecule. The polymorphic heavy chain (45 kD) of the class I polypeptide is noncovalently bound to the invariant light chain, 2-microglobulin (12 kD). The heavy chain consists of five domainsthree extracellular
domains (1, 2, and 3), a transmembrane domain, and a cytoplasmic domain. The 1 and 2 domains contain the most polymorphic residues
responsible for antigen binding and form the side walls of the peptide-binding groove; the transmembrane portion anchors the molecule to the
plasma membrane; and the 2-microglobulin stabilizes the conformation of the extracellular domains. B: Human leukocyte antigen (HLA)
class II molecule. The two chains, (29 kD) and (34 kD), are noncovalently associated and are made up of four domainstwo extracellular domains, a transmembrane domain, and a cytoplasmic domain. Most of the allelic variance is contained in the chain. The peptidebinding site is believed to be in the groove between the 1 and 1 domains.
502
segment C with one each of a number of V, D, and J gene segments in the case of chains and V and J segments in the case
of chains. Much of the diversity of the TCR repertoire is
engendered by the inexact selection of the ends of the segments
to be so spliced (i.e., from junctional diversity). The joining of
various V, D, and J segments to form a T-cell antigen receptor
gene could yield 1012 to 1016 specificities. However, from the
repertoire of cells bearing TCRs actually assembled (1012
different cells), a much smaller repertoire (109), which can
bind to self-MHC proteins plus peptide, is selected to proceed toward maturity. This process ensures that all T cells can
recognize self-MHC. Fashioning of the final T-cell repertoire
in the thymus is also based on the general rule that the T cells
that recognize peptides complexed with MHC class II molecules express CD4 glycoproteins; T cells that recognize MHC
class I molecules express CD8 glycoproteins. The final T-cell
repertoire is also fashioned by elimination of thymocytes with
TCRs that bind too aggressively to self-MHC, a process called
negative selection.
ANTIGEN PROCESSING
AND PRESENTATION
FIGURE 33.5. T-cell receptor (TCR) complex in the cell membrane
composed of TCR , CD3, CD4, and CD8 chains.
the presence of invariant chain or Ii, which stabilizes the tertiary structure until it is replaced by a peptide. The invariant
chain also directs the traffic of MHC class II proteins from the
endoplasmic reticulum to a specialized endosomal compartment known as the MHC class II compartment. There, the
invariant chain is degraded, leaving class IIassociated invariant chain peptide (CLIP) in the peptide-binding groove. CLIP
is replaced by peptides of 12 to 24 amino acids, the replacement being facilitated by HLA-DM.35,36
The peptides bound to MHC class II molecules originate
with intact cells, cellular debris, and proteins taken up by
phagocytosis into phagosomes.37 Phagosomes fuse with lysosomes and the contents are degraded. Peptides generated in
phagolysosomes vary greatly in propensity for loading in
MHC class II. Not only is the size of the peptide important,
but also the presence of certain amino acids at critical points,
which allow binding to the antigen-binding cleft. So important
is this discrimination of peptides that the genes encoding
MHC class II were originally called immune response genes.
MHC class II antigens lacking a peptide are not expressed on
the cell surface.38 Absence of free MHC class II antigens
ensures that peptides in the extracellular environment are not
inadvertently presented.
T-cell Receptors
T cells recognize foreign antigens via cell surface glycoproteins
called T-cell antigen receptors (TCRs). The TCR is a heterodimer
consisting of and chains, each approximately 40 to 45 kD
and resembling immunoglobulins in three-dimensional structure (Fig. 33.5). TCRs reside in complexes with co-receptor
proteins including CD3 and CD4 or CD8 that facilitate cellular signaling. While TCRs resemble immunoglobulins, they do
not bind to free antigens as immunoglobulins do but only
bind to antigens that are associated with MHC class I or class
II molecules. TCR genes are assembled in T-cell precursors in
the thymus by recombination of a constant region gene
Recognition of foreign antigen by T cells begins with the processing and presentation of antigen by antigen-presenting
cells.39 Phagocytic cells of all types, especially dendritic cells
and B cells, process and present antigen. Antigen-presenting
cells engulf and digest antigens (Fig. 33.6). Because cells generate many different peptides from endogenous proteins and
proteins ingested into cells, relatively few peptides from any
given source and of any given sequence will be presented on
the cell surface at any point in time. Since activation of a T cell
requires at least 200 peptides of a given type to be presented,
effective presentation of peptide to a T cell capable of recognizing it is highly improbable.40 Thus, under normal conditions, antigen-presenting cells do not effectively present peptides in association with MHC. Effective presentation of
antigenic peptides requires activation of antigen-presenting
cells, typically by cytokines or products of tissue injury. Activated antigen-presenting cells migrate to lymph nodes, the
architecture of which brings T cells and antigen together at the
same place and the same time, heightening expression levels of
MHC class I and class II proteins and increasing peptide stability in those protein complexes.41 Activated antigen-presenting cells also express costimulatory molecules such as CD80
and CD86 and produce cytokines that provide additional signals to T cells.
T-CELL ACTIVATION
Activation of T cells generally requires two signals, one delivered by the T-cell antigen receptor and proteins of the TCR
complex and one by a costimulatory receptor.42 The binding of
the TCR to MHC molecules is enhanced by CD8 for MHC
class I molecules and by CD4 for MHC class II molecules.
CD8 and CD4 in complex with TCR deliver signals that
amplify TCR stimulation. Besides signals generated by the
TCR complex, T cells receive costimulatory signals from
receptors such as CD28. Costimulatory signals overlap and in
part complement the signals generated by the antigen receptor
complex.43,44 Signals delivered by the antigen receptor and by
costimulatory receptors can be suppressed by stimulation of
controlling receptors such as cytotoxic T-lymphocyte antigen-4
(CTLA-4). Both types of signals are modified further by other
signals, such as those delivered by cytokines.
The biochemistry of T-cell activation and control is complex, but the biologic impact can be summarized as follows.
Moderate signals delivered through the TCR complex in the
503
IMMUNOLOGIC MEMORY
Protective immune responses by T cells and B cells generally
reflect immunologic memory. The first encounter with foreign
antigen may or may not activate nave T cells, with activation
occurring over an extended period of time (weeks). Consequently, defense against microorganisms and toxins on first
encounter depends on innate immunity. Defense against subsequent encounters with microorganisms and toxins can be
dominated by immunologic memory, which is more rapid, specific, and effective than innate immunity. The vigorous and
reliable memory response to minor transplantation antigens
was described earlier. For cellular immunity, memory resides
TRANSPLANTATION
FIGURE 33.6. Antigen processing and presentation. Endogenously synthesized or intracellular proteins (e.g., viral gene products) are degraded
into peptides that are transported to the endoplasmic reticulum. These peptides bind to class I major histocompatibility complex (MHC) molecules and are transported to the surface of the antigen-presenting cell. CD8 T cells recognize the foreign peptide bound to class I MHC by way
of the T-cell receptor complex. Exogenous antigen (e.g., bacterial) is endocytosed and broken down into peptide fragments in endosomes. Class
II molecules are transported to the endosome in association with the invariant chain, bound to the peptide, and delivered to the surface of the
antigen-presenting cell, where they are recognized by CD4 cells.
504
TA B L E 3 3 . 3
COMPARISON OF IMMUNE RESPONSE TO AN ALLOGRAFT
WITH IMMUNE RESPONSE TO A MICROORGANISM
ALLOGRAFT
MICROORGANISM
(BCG)
Frequency of
response
100%
50%
Frequency of
T cells
Up to 1/10
1/100,000
Kinetics of
immunity
814 d
36 wk
Impact on tissue
Destruction
Minimal
While the immune response to transplantation exhibits features typical of all immune responses (generalized, systemic,
specific, and characterized by memory), the immune response
to transplantation also exhibits features that set it apart from
other adaptive immune responses (Table 33.3). Considering
how very limited the genetic diversity within a species is, and
considering that the immune system probably evolved to protect against microbial organisms, one might predict that
immune responses to transplants would be idiosyncratic and
weak in comparison to immune responses to microorganisms.
But such a prediction proves wrong. The immune response to
transplantation is universal (occurring in every unmanipulated
recipient), rapid, and quite severely destructive.47 In contrast,
immune responses to bacteria, viruses, fungi, vaccines, and
other antigens, including minor histocompatibility antigens,
occur sporadically, over periods of weeks or months, and do not
generally destroy the targeted cells. The difference between the
immune response to allografts and to all other antigenic challenges could reflect the peculiar way in which antigens encoded
by the major histocompatibility complex are presented, or it
could reflect unanticipated immunologic memory.48,49
The mechanism by which T cells recognize allogeneic cells
might explain the universal, rapid, and highly destructive allogeneic response. T cells can recognize allogeneic cells directly;
T cells recognize intact allogeneic MHC expressed on allogeneic
antigen-presenting cells. By direct recognition, a T cell can
engage a large fraction of a given MHC on antigen-presenting
cells.50,51 Hence, direct recognition activates up to 30% of
T cells.52 In contrast, T cells recognize other antigens, such as
toxins and bacterial and viral proteins, as degraded foreign peptides associated with MHC on autologous antigen-presenting
cells. When T cells indirectly recognize antigen on autologous antigen-presenting cells, only a small fraction of MHC
complexes on the autologous cells contain a given peptide.
Hence, indirect recognition activates only a small fraction of
1% of T cells; in some cases no activation ensues.
Grafts consisting of allogeneic cells and tissues are fed by
blood vessels of the recipient, and the immunologic reaction
seems to be directed mainly against these blood vessels.5254
Recognition of these blood vessels must involve the indirect
pathway. Yet these grafts are rejected universally, rapidly, and
severely. Eliminating allogeneic MHC from the surface of all
donor cells does not prevent or slow the course of allograft
rejection.55
If peptides of allogeneic MHC presented indirectly can eventuate powerful rejection reactions, then the immune system
might recognize peptides of allogeneic MHC differently than
other proteins. The immune system is predisposed to respond
aggressively to allogeneic MHC.55 Heightened immunogenicity
of MHC-derived peptides indicates that peptides from MHC
efficiently load on MHC complexes.56,57 MHC with MHCderived peptides also interacts distinctly with T-cell receptors.
REGULATION OF
ALLOIMMUNE RESPONSES
The immune system must potentially recognize all microorganisms, every species of animal and plant, toxins of many
types, and cells with histocompatibility antigens foreign at one
or only a few amino acids. Given this diversity of recognition
and destructiveness, how autoreactivity is avoided has been a
question of importance for more than 100 years.61,62
Freemartins are fraternal twins in cattle.63 Freemartins have
two kinds of erythrocytes, those that bear blood group antigens of autologous hematopoietic cells and those that bear the
blood group antigens of the twin, thus making the freemartin
hematopoietic chimeras. The existence of such chimerism
shows that blood and hematopoietic precursor cells have been
exchanged between twins sharing the same placenta. Such
chimerism results from the failure to mount an immunologic
response against the foreign blood cells; this failure is evidence of induced acceptance of a genetically distinct intrauterine graft, in other words, tolerance.64 Thus, the discrimination
between self and non-self is learned and not just inherited.
Today, one can think of tolerance at molecular, cellular, and
systemic levels, yet the mechanism that avoids self-reactivity,
or at least injury from self-reactivity, is incompletely known. A
few aspects pertinent to transplantation immunology are mentioned and are summarized in Table 33.4. For T cells, the first
and most important steps in avoiding self-reactivity take place
in the thymus. Positive selection ensures that thymocytes bearing receptors that bind to anything other than MHC die. Negative selection destroys thymocytes that recognize self-MHC,
TA B L E 3 3 . 4
MECHANISMS OF PERIPHERAL TOLERANCE
MECHANISM
EXAMPLE
Peripheral deletion
Conditional responses
Anergy
Suppression
Regulatory T cells
Accommodation
TRANSPLANTATION
Besides efficient loading, peptides from MHC might be recognized in some special way. This idea may explain the distinct
structure of TcRs bound to MHC-peptide complexes.
As still another explanation for the universal, rapid, and
severe response to allotransplantation, one might postulate that
the allogeneic response is actually a manifestation of immunologic memory. Generally, a protective response occurs weeks and
sometimes months after the first exposure to antigen, if it occurs
at all, and full protection is only exhibited upon re-exposure to
antigen. On the other hand, responses on first exposure to cells
bearing allogeneic MHC can be detected within a few days. The
speed and intensity of the allogeneic response thus resembles the
speed and intensity of the response on re-exposure to antigen.
Consistent with this possibility, many of the T cells that respond
to allogeneic cells in human adults are memory T cells.58 This
explanation would place alloimmune responses within the
framework of conventional immune responses. Some T-cell
clones for peptides of cytomegalovirus and intestinal flora also
respond to allogeneic MHC. Allogeneic grafts in the newborn
sometimes generate immunity and sometimes do not. Consistent
with the concept, newborn mice do not reject tumor grafts
acutely but can still be primed to generate second set responses,
as if the antigens were minor rather than major.60
One practical implication of the difference in antigen recognition in alloimmune versus conventional responses is that
alloimmune responses can be detected in cell cultures if allogeneic antigen-presenting cells are mixed with allogeneic T
cells. For conventional antigens, primary responses are not
detected in cell culture systems; only memory responses can
be detected in this way.
The rapid kinetics of alloimmune responses probably reflects
several factors. To the extent that peptides play a nominal role
as antigenic targets, antigen-presenting cells of the donor are
fully able to evoke alloimmune responses without antigen
uptake processing and presentation. The large number of cells
committed to alloimmune responses limits the amount of T-cell
proliferation needed before a sizable response is achieved. Especially important, the effecter functions of the alloimmune
response follow directly from activation of nave T-cells.
505
506
INDUCTION OF TOLERANCE
The induction of tolerance for transplantation has been a central goal of transplantation immunology for five decades.81,82
How to accomplish this goal without exerting undue toxicity
has been difficult. Two general approaches have been proposed.
One approach to inducing allogeneic tolerance involves
elimination of mature lymphocytes and other hematopoietic
cells and provision of hematopoietic stem cells of the would-be
transplant source, which would potentially rebuild an immune
system lacking responsiveness to the hematopoietic cell source.
If the source (transplant donor) is fully allogeneic, the approach
should fail.83 The thymus of the treated individual would select
T cells, the function of which are restricted to the MHC of the
treated individual, while the antigen-presenting cells would
express incompatible MHC. In practice, however, the approach
could work since fully allogeneic human thymus is capable of
selecting T cells cross-reactive with allogeneic MHC.84 Regardless, the problem of incompatible MHC can be overcome by
administering hematopoietic stem cells of both the donor and
the recipient.85 The main deterrent to applying this approach to
tolerance resides in the need to eliminate mature T cells and B
cells. In the absence of mature lymphocytes, especially memory
cells, the treated individual lacks the ability to protect against
infection and the thymus of the mature individual may allow
this defect to be repaired only slowly, if at all.
Another approach to inducing tolerance involves administration of inhibitors of costimulation, such as blockers of
CD80, CD86, CD40, and CD40 ligand.68,86 This approach
prevents nave T cells from being activated but avoids the
eradication of memory lymphocytes and hence maintains
acquired host defense. However, full tolerance is not induced
and in some experimental model systems ongoing treatment is
needed. The limitations may prove even more challenging
because the approach does not inhibit memory T cells to any
great extent and because T cells that protect against some
infectious agents such as cytomegalovirus also recognize HLA.
B CELLS IN TRANSPLANTATION
B cells develop in the fetal liver and in the bone marrow of adult
mammals from multipotent hematopoietic stem cells. In contrast
to T cells, B cells are produced continuously throughout life.
The most important feature of B-cell development is the assembly of a functional B-cell receptor, which is a membrane-bound
507
TRANSPLANTATION
508
B-CELL TOLERANCE
Humoral tolerance defines specific absence of a humoral
immune response following an adequate stimulus in an individual fully able to respond to other immune stimuli. This definition has three critical parts. First, tolerance refers to the
immune response and not its impact. Second, the stimulus
must be adequate to induce a perceptible response; all foreign
proteins are not immunogenic. Third, nonresponsiveness must
be specific for the tolerizing antigen; absence of response in an
immunosuppressed or immune-incompetent subject may not
reflect tolerance.
Clonal deletion, receptor editing, and anergy establish tolerance in immature B cells or when the autoantigen is present
during development. Elimination of self-reactive B cells is
called clonal deletion. Membrane-bound antigens and complex
autoantigens, such as DNA, that possess repetitive epitopes,
with the potential to cross-link the B-cell receptor, induce central and/or peripheral deletion of antigen-specific B cells.103
Bone marrow B cells may also become self-tolerant by
receptor editing. Receptor editing postulates that low-affinity/
avidity self-antigen binding on immature B cells induces rerearrangements of the immunoglobulin genes changing the cell
specificity from self to non-self and presumably rescuing it
from death. This salvage mechanism was first postulated to
occur in immature B cells in the bone marrow.
Tolerance to soluble autoantigens is achieved by functional
inactivation of self-reactive B cells. Anergic B cells express
decreased amounts of surface IgM and have decreased responsiveness to B-cell receptormediated stimulation and shortened
lifespan. Anergic B cells undergo apoptosis induced by Fas.
The mechanisms that establish tolerance of immature B cells
are less efficient at precluding antibody production from mature
B cells, as well illustrated by the fate of ABO-incompatible cardiac grafts in human subjects. While spontaneous tolerance
occurs to A and B blood group antigens in infants with cardiac
transplants, the same does not occur later in life. Infants lack the
ability to produce antipolysaccharide antibodies including
antiblood group antibodies. Thus, without preexisting antibodies, the newborn becomes tolerant probably through deletion of B cells committed to producing antiblood group antibodies upon exposure to a graft carrying these antigens. In
contrast, adults who receive organ transplants carrying foreign
blood group antigens continue to make antiblood group antibodies because mature B cells are not susceptible to mechanisms
that would eradicate or inactivate immature B cells.
B-CELL MEMORY
The raison dtre of adaptive immunity is immunologic memory, and memory was the first feature of the immune system
to be recognized. B-cell memory is characterized by a faster
and more effective antibody response following a repeated
antigen encounter, and is manifested by heightened clearance
IMPACT OF IMMUNITY
ON TRANSPLANTS
Why the alloimmune response is more destructive than other
immune responses is not fully understood. Alloimmune
509
Donor
Tissue
Cell Transplant
Primary
Non-Function
Cellular
Rejection
Antibody-mediated
Rejection
Tissue Transplant
Organ
Transplant
Cellular
Rejection
Chronic
Rejection
Accommodation
Organ Transplant
A
Hyperacute
Rejection
FIGURE 33.8. A: The origin of blood vessels in cell, tissue, and organ grafts. Both cell and tissue grafts are fed at least in part by blood vessels
of the recipient. Organ grafts depend entirely on blood vessels of the donor. The consequences of this difference are shown in panels B and C.
B: Cell and tissue transplants. Fed by blood vessels of the recipient, cell and tissue transplants are susceptible mainly to early nonfunction, perhaps
owing to ischemia and cellular rejection. Antibodies and complement of the recipient penetrate poorly through blood vessel walls and hence do
not injure these grafts. C: Organ transplants. An organ transplant is fed entirely by vessels of the transplant donor. Consequently, antibodies
made by the recipient can bind to the blood vessel walls and cause injury manifest as hyperacute or acute vascular rejection and chronic rejection. Under some circumstances antibodies can cause an organ graft to resist immunological injury. This condition is called accommodation.
HYPERACUTE REJECTION
Hyperacute rejection occurs within 24 hours of reperfusion and
is characterized by immediate loss of graft function and by a
pathologic picture of interstitial hemorrhage, thrombosis, and
varying extents of inflammation. Hyperacute rejection is thought
to be caused by antidonor antibodies binding to blood vessels
and activating the complement system in a newly transplanted
organ. The development of hyperacute rejection depends
absolutely on the activation of complement, and inhibition of
complement nearly always prevents hyperacute rejection.73
Anti-HLA antibodies most often cause hyperacute rejection
of clinical allografts. Hyperacute rejection occurs in up to
80% of the kidneys transplanted into recipients with cytotoxic
antibodies detected by cytotoxic cross match78 (Fig. 33.9).
Hyperacute rejection is now observed rarely because assays for
anti-HLA antibodies identify subjects at risk and transplantation is avoided. FACS methods are especially sensitive but they
may also exclude from transplantation recipients with very
low levels of anti-HLA antibodies or noncomplement-fixing
antibodies who might safely receive a transplant.109 The lymphocytotoxic cross match illustrated in Figure 33.9 is less sensitive, but a positive result may predict hyperacute rejection
with more confidence.
Antibodies directed at blood group A and B antigens in a
graft can also cause hyperacute rejection. Gleason reported that
46% of ABO-incompatible allografts never gained function and
at 12 months only 1 of 24 ABO-incompatible renal transplants
continued to function, whereas only 9% of a large group of
ABO-compatible grafts did not show early function.110 Whether
antiblood group antibodies cause hyperacute rejection
depends on such factors as the antibody levels and the affinity
and susceptibility of the graft to injury. For example, the A2
antigen interacts less well with anti-A antibodies; hence, organs
expressing A2 transplanted into recipients of blood group O are
less susceptible to destruction by humoral responses.111
TRANSPLANTATION
510
Some antibodies can activate complement through the alternative pathway.117,118 Hyperacute rejection can occur independent of antidonor antibodies, and these cases may reflect activation of the alternative or lectin pathways as might occur with
ischemic injury.119,120 Prolonged preservation and high perfusion pressures in allografts can cause lesions that are pathologically similar to those found in hyperacute rejection.121,122
ANTIBODY-MEDIATED
REJECTION
ABO-incompatible organs vary in susceptibility to hyperacute rejection, liver transplants being less susceptible than kidney or heart transplants. The 3-year graft survival rate for
ABO-compatible liver grafts and ABO-incompatible grafts is
remarkably similar, 39% and 36%, respectively.112 Differences
in the size of the vascular beds may explain the varying susceptibility, as a given amount of antibody and complement
would be deposited less densely in the liver than in a smaller
organ such as the kidney. The liver also intrinsically resists
injury by complement.73,113
Hyperacute rejection sometimes occurs in recipients lacking detectable antidonor antibodies. In some cases, antibody
capable of causing rejection is present in the blood but is not
detected by assays in which leukocytes are used as the target.
For example, the major histocompatibility complex class
Irelated chain A is not expressed on leukocytes but is
expressed on endothelial cells, and antibodies against that antigen have been postulated to cause some cases of hyperacute
rejection in recipients with a negative cross match.114,115 Similarly, antibodies against yet undefined endothelial antigens
have also been linked to rejection of transplants between
HLA-identical sibling transplants.116 In other cases, the recipient may truly lack antidonor antibodies and the alternative or
lectin pathways without the involvement of antibody may activate complement.
Antibody-mediated rejection is a vexing condition.123,124 Previously known as humoral rejection and before that as acute
vascular rejection, antibody-mediated rejection has been
considered very difficult and expensive to reverse. Most cases
appear to be caused by antibodies and therefore the term antibody-mediated rejection is used.
Antidonor antibodies such as those directed at MHC
antigens likely trigger antibody-mediated rejection. The timing of antibody-mediated rejection after transplantation
depends mainly on when antidonor antibodies are produced. In the absence of immunosuppression, antibodymediated rejection can begin within 24 hours of transplantation and proceed over days if the recipient is sensitized to
donor antigen. In immunosuppressed recipients, antibodymediated rejection usually appears weeks or months after
transplantation.
Evidence of antibody-mediated rejection can be found in
20% to 30% of episodes of acute rejection, but the diagnosis of antibody-mediated rejection is sometimes challenging.125 Although antibodies specific for the donor are sometimes found in the circulation, such antibodies are not often
found at high levels. The absence of antidonor antibodies
does not exclude antibody-mediated rejection, because an
organ graft can absorb tremendous amounts of antibody,
leaving little or none in the blood.126 Also, the antibodies
found in the blood may be of lower affinity and thus may not
represent the antibodies bound to the graft and those that
cause tissue injury.
Because of the limited value of measuring antidonor antibodies, pathologists have turned to the detection of C4d as
diagnostic evidence of antibody-mediated rejection.127 C4d
deposits in peritubular capillaries of transplant recipients with
circulating donor-specific antibodies strongly suggest that C4d
is a specific and reliable indication of antibody-mediated rejection following kidney transplantation.128 Formed by cleavage
of C4b covalently bound to target cells, C4d is functionally
inert and hence a relatively enduring footprint of complement
activation. Since C4 can be cleaved during activation of the
classic pathway, the presence of C4d on the endothelium of a
graft is taken as evidence that antidonor antibody has bound
to that site. C4d is also generated during activation of the
lectin pathway; hence, it might be found in some conditions in
which antidonor antibodies do not exist. C4d can also be
CHRONIC REJECTION
8
ACCOMMODATION
Accommodation refers to acquired resistance of an organ graft
to humoral injury. Accommodation was first described and later
named based on observations of the outcome of ABO-incompatible kidney transplants.72,73,141 In the mid-1980s, several
investigators observed that if antiblood group antibodies were
removed from the circulation at the time of transplantation,
kidneys transplanted across blood group A or blood group B
barriers could survive and function.70,71 This suggested that
incompatibility of blood groups was not an absolute barrier to
transplantation and prompted the question of how these kidneys survived. Some recipients had antibodies specific for donor
blood groups and the transplanted kidneys continued to express
donor antigen, but graft injury and compromise of function did
not occur. This observation suggested that the survival of the
graft must reflect some change in the graft itself. Accommodation may be more frequent than currently assumed.142 Healthy
organs can absorb antidonor antibodies in large amounts,
removing these antibodies from the circulation, and hence more
recipients may make antidonor antibodies than surveys of the
prevalence of antibodies would suggest.
Accommodation might reflect a change in the properties of
the antibody or the antigen. Both of these mechanisms have
been observed in experimental models. Under some conditions, the Ig subclass of antidonor antibodies does not efficiently fix complement and may even block the binding of
complement-fixing antibodies.142,143 In other conditions, carbohydrate antigen may be shed or undergo biochemical
change and therefore might be less avidly bound.144146
While these models may apply in some cases, most studies
suggest that accommodation reflects resistance to injury.
Exposure of an organ to heme induces heme oxygenase, which
can protect the organ against lethal injury by various toxins.147
Xenografts and allografts with accommodation express a number of protective, antiapoptotic genes.148,149 Products of these
genes may prevent cells of the graft from undergoing apoptosis
that otherwise would be triggered by humoral immunity. Consistent with this concept, exposure to xenoreactive antibodies
induces expression of antiapoptotic genes in endothelial cells.150
Anti-HLA antibodies likewise induce such genes.151 Further
understanding of how accommodation is induced and by what
mechanisms it is manifest and maintained could have a profound impact on transplantation in general and perhaps on
other fields.
CELLULAR REJECTION
All allografts are subject to cellular rejection, and the clinical
application of transplantation depends absolutely on suppressing
TRANSPLANTATION
511
512
CONCLUDING REMARKS
This chapter reviews the immunology of transplantation as it
is practiced in the first decade of the 21st century and elucidated over the past century. However, the practice of transplantation may soon change, as transplants consisting of stem
cells, stem cell derivatives, and engineered tissues are used.
Stem cells interact with the immune system in ways, very different from mature cells and organs. These differences will
become important as surgeons turn increasingly to regenerative medicine and novel approaches to organ replacement for
the treatment of disease.
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ABO blood groups. Surgery 1986;100:342348.
113. Collins BH, Chari RS, Magee JC, et al. Mechanisms of injury in porcine
livers perfused with blood of humans with fulminant hepatic failure.
Transplantation 1994;58:11621171.
114. Zou Y, Mirbaha F, Lazaro A, et al. MICA is a target for complementdependent cytotoxicity with mouse monoclonal antibodies and human
alloantibodies. Hum Immunol 2002;63:3039.
115. Zwirner NW, Marcos CY, Mirbaha F, et al. Identification of MICA as a
new polymorphic alloantigen recognized by antibodies in sera of organ
transplant recipients. Hum Immunol 2000;61:917924.
116. Kalil J, Guilherme L, Neumann J, et al. Humoral rejection in two HLA
identical living related donor kidney transplants. Transplant Proc 1989;
21:711713.
117. Devine DV, Rosse WF. Regulation of the activity of platelet-bound C3 convertase of the alternative pathway of complement by platelet factor H.
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118. Lutz HU, Jelezarova E. Complement amplification revisited. Mol Immunol
2006;43:212.
119. Vakeva AP, Agah A, Rollins SA, et al. Myocardial infarction and apoptosis after myocardial ischemia and reperfusion: role of the terminal complement components and inhibition by anti-C5 therapy. Circulation
1998;97:22592267.
120. Zhou W, Farrar CA, Abe K, et al. Predominant role for C5b-9 in renal
ischemia/reperfusion injury. J Clin Invest 2000;105:13631371.
121. Spector D, Limas C, Frost JL, et al. Perfusion nephropathy in human transplants. N Engl J Med 1976;295:12171221.
122. Cerra FB, Raza S, Andres GA, et al. The endothelial damage of pulsatile
renal preservation and its relationship to perfusion pressure and colloid
osmotic pressure. Surgery 1977;81:534541.
123. Takemoto SK, Zeevi A, Feng S, et al. National conference to assess
antibody-mediated rejection in solid organ transplantation. Am J Trans
2004;4:10331041.
124. Solez K, Colvin RB, Racusen LC, et al. Banff 05 meeting report: differential diagnosis of chronic allograft injury and elimination of chronic allograft nephropathy (CAN). Am J Trans 2007;7:518526.
125. Mauiyyedi S, Colvin RB. Humoral rejection in kidney transplantation:
new concepts in diagnosis and treatment. Curr Opin Nephrol Hypertens
2002;11:609618.
126. Parker W, Lin SS, Platt JL. Antigen expression in xenotransplantation:
how low must it go? Transplantation 2001;71:313319.
127. Feucht HE, Felber E, Gokel MJ, et al. Vascular deposition of complementsplit products in kidney allografts with cell-mediated rejection. Clin Exp
Immunol 1991;86:464470.
128. Collins AB, Schneeberger EE, Pascual MA, et al. Complement activation in
acute humoral renal allograft rejection: diagnostic significance of C4d
deposits in peritubular capillaries. J Am Soc Nephrol 1999;10:2208
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129. Bustos M, Saadi S, Platt JL. Platelet-mediated activation of endothelial
cells: implications for the pathogenesis of transplant rejection. Transplantation 2001;72:509515.
130. Miyata Y, Platt JL. The role of complement in acute vascular rejection:
lessons from the inhibition of C1rs activity. Transplantation 2002;73:675.
131. Marcum JA, Rosenberg RD. Anticoagulantly active heparan sulfate proteoglycan and the vascular endothelium. Semin Thromb Hemost 1987;13:
464474.
132. Ihrcke NS, Wrenshall LE, Lindman BJ, et al. Role of heparan sulfate in
immune system-blood vessel interactions. Immunol Today 1993;14:
500505.
133. Saadi S, Platt JL. Transient perturbation of endothelial integrity induced by
natural antibodies and complement. J Exp Med 1995;181:2131.
134. Saadi S, Platt JL. Endothelial cell responses to complement activation. In:
Volanakis JE, Frank MM, eds. The Human Complement System in Health
and Disease. New York: Marcel Dekker, Inc.; 1998:335353.
135. Brunn GJ, Saadi S, Platt JL. Differential regulation of endothelial cell activation by complement and interleukin 1alpha. Circ Res 2006;98:793800.
136. Brunn GJ, Saadi S, Platt JL. Constitutive repression of IL-1alpha in
endothelial cells. Circ Res 2008;102:823830.
137. Mauiyyedi S, Pelle PD, Saidman S, et al. Chronic humoral rejection: identification of antibody-mediated chronic renal allograft rejection by C4d
deposits in peritubular capillaries. J Am Soc Nephrol 2001;12:574582.
138. Piazza A, Poggi E, Borrelli L, et al. Impact of donor-specific antibodies on
chronic rejection occurrence and graft loss in renal transplantation: posttransplant analysis using flow cytometric techniques. Transplantation
2001;71:11061112.
139. Lederer SR, Kluth-Pepper B, Schneeberger H, et al. Impact of humoral
alloreactivity early after transplantation on the long-term survival of renal
allografts. Kidney Int 2001;59:334341.
140. Platt JL, Vercellotti GM, Dalmasso AP, et al. Transplantation of discordant
xenografts: a review of progress. Immunol Today 1990;11:450456.
141. Bannett AD, McAlack RF, Raja R, et al. Experiences with known ABOmismatched renal transplants. Transplant Proc 1987;19:45434546.
142. Saadi S, Holzknecht RA, Patte CP, et al. Complement-mediated regulation
of tissue factor activity in endothelium. J Exp Med 1995;182:18071814.
143. McCurry KR, Kooyman DL, Alvarado CG, et al. Human complement regulatory proteins protect swine-to-primate cardiac xenografts from
humoral injury. Nat Med 1995;1:423427.
144. Cozzi E, Yannoutsos N, Langford GA, et al. Effect of transgenic expression
of human decay-accelerating factor on the inhibition of hyperacute rejection of pig organs. In: Cooper DKC, Kemp E, Platt JL, et al., eds. Xenotransplantation: The Transplantation of Organs and Tissues Between
Species. Berlin, Germany: Springer; 1997:665682.
145. Pruitt SK, Kirk AD, Bollinger RR, et al. The effect of soluble complement
receptor type 1 on hyperacute rejection of porcine xenografts. Transplantation 1994;57:363370.
146. Lin SS, Weidner BC, Byrne GW, et al. The role of antibodies in acute vascular rejection of pig-to-baboon cardiac transplants. J Clin Invest
1998;101:17451756.
147. Nath KA, Balla G, Vercellotti GM, et al. Induction of heme oxygenase is a
rapid, protective response in rhabdomyolysis in the rat. J Clin Invest
1992;90:267270.
148. Bach FH, Ferran C, Hechenleitner P, et al. Accommodation of vascularized xenografts: expression of protective genes by donor endothelial
cells in a host Th2 cytokine environment. Nat Med 1997;3:
196204.
149. Hancock WW, Buelow R, Sayegh MH, et al. Antibody-induced transplant
arteriosclerosis is prevented by graft expression of anti-oxidant and antiapoptotic genes. Nat Med 1998p;4:13921396.
150. Delikouras A, Fairbanks LD, Simmonds AH, et al. Endothelial cell cytoprotection induced in vitro by allo- or xenoreactive antibodies is mediated
by signaling through adenosine A2 receptors. Eur J Immunol 2003;33:
31273135.
151. Jindra PT, Zhang X, Mulder A, et al. Anti-HLA antibodies can induce
endothelial cell survival or proliferation depending on their concentration.
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152. Rocha PN, Plumb TJ, Crowley SD, et al. Effector mechanisms in transplant rejection. Immunol Rev 2003;196:5164.
153. Alegre ML, Florquin S, Goldman M. Cellular mechanisms underlying acute
graft rejection: time for reassessment. Curr Opin Immunol 2007;19: 563568.
154. Mintz B, Silvers W. Intrinsic immunological tolerance in allophenic
mice. Science 1967;158:14841487.
155. Sutton R, Gray D, McShane P, et al. The specificity of rejection and the
absence of susceptibility of pancreatic islet B cells to nonspecific immune
destruction in mixed strain islets grafted beneath the renal capsule in the
rat. J Exp Med 1989;170:751762.
156. Saadi S, Holzknecht RA, Patte CP, et al. Endothelial cell activation by
pore forming structures: pivotal role for IL-1. Circulation 2000;101:
18671873.
157. Rosenberg AS, Singer A. Cellular basis of skin allograft rejection: an in
vivo model of immune-mediated tissue destruction. Ann Rev Immunol
1992;10:333358.
158. Platt JL, LeBien TW, Michael AF. Interstitial mononuclear cell populations
in renal graft rejection: identification by monoclonal antibodies in tissue
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159. Platt JL, Grant BW, Eddy AA, et al. Immune cell populations in cutaneous
delayed-type hypersensitivity. J Exp Med 1983;158:12271242.
P O I N T S
Much of the injury to transplanted organs occurs not during the period of ischemia but during organ reperfusion.
2 The general attributes of an acceptable organ donor include
pronouncement of donor death, previously good general
health, and relative hemodynamic stability from the time of
the precipitating event leading to death until organ procurement is complete.
3 The following requirements must be met to make a firm
diagnosis of brain death: the presence of reversible
causes of coma should be excluded; clinical criteria
PATHOPHYSIOLOGY OF ORGAN
PRESERVATION INJURY
function of membrane-bound enzymes. Physicochemical membrane changes induced by hypothermia result in increased permeability, which in turn adds to the burden of maintaining a stable intracellular environment and contributes to cell swelling.
Organ preservation solutions have historically therefore been
hypertonic to minimize these alterations.
Structural Integrity
The cell membrane plays a crucial physical protective role and
provides an active interface with the extracellular environment. Receptors, ion regulation, and enzyme systems linked to
the cell membrane complex contain extracellular, transmembrane, and intracellular components essential to their function. The interrelation of such systems with the membrane
itself is highly dependent on a stable configuration of the lipid
bilayer and on tight control of temperature, pH, and osmolarity. Organ ischemia and preservation disrupt all these relations. Lowering the temperature through the phase transition
of lipids results in profound changes in conformation and stability of the membrane in addition to drastically altering the
Ionic Composition
The foregoing membrane changes are compounded by crippling of the Na-K-adenosine triphosphatase (ATPase) pump
caused by the lack of ATP production and by generation of
excess hydrogen ion resulting from anaerobic metabolism during ischemia. When the Na-K-ATPase pump is paralyzed,
potassium diffuses down its concentration gradient to the
extracellular environment while sodium, normally present at a
low concentration in the cell, pours in. Modern preservation
solutions have typically had electrolyte compositions similar
to that inside the cell with high potassium and low sodium
concentrations. Osmotic gradients are, therefore, minimized,
and the cellular ionic charge remains relatively constant.
Hydrogen ion production continues in ischemic organs and
may result in cellular damage. Intracellular pH gradually falls
without replenishment of buffering capabilities, and under
conditions requiring a switch from aerobic to anaerobic glycolysis, the production of lactic acid also increases. The liver
appears to be especially susceptible to this type of injury. A
plausible mechanism has been described whereby glucokinase
in the liver phosphorylates glucose (endogenous or provided in
preservation solution) to glucose-6-phosphate.3 The normal
metabolic pathway for glucose-6-phosphate results in production of pyruvate and ultimately lactate by lactic dehydrogenase
(Fig. 34.1). Unlike the kidney, the hepatic isozyme of lactic
dehydrogenase, M4, functions particularly well under acidotic
conditions in the presence of high concentrations of lactic acid.
These biochemical differences underlie the range of acceptable
cold ischemia time for various organs.
Calcium ion permeability is increased with ischemia, and
a rapid influx of calcium may overwhelm mitochondrial
buffering capacity. There is increased activity of calmodulin,
a cytoplasmic calcium-binding protein, and a cascade of
enzyme activation events, including the upregulation of
515
TRANSPLANTATION
K E Y
516
Cellular Energy
The energy requirements of aerobic cells are provided by a combination of the enzymatic breakdown of glucose (glycolysis) and
by the process of cellular respiration, encompassing the transfer
of electrons from organic molecules to molecular oxygen (electron transport and oxidative phosphorylation) (Fig. 34.2).
Hypothermia results in decreased metabolic rate and slows the
rate at which enzymes degrade cellular components, but metabolism is not completely suppressed. It has been calculated that
cooling from 37C to 0C results in a 12-fold reduction of cellular metabolism.1 Although metabolism is slowed and utilization of cellular energy stores is slowed, ATP and adenosine
diphosphate (ADP), the major sources of cellular metabolic
Reperfusion Injury
energy, are gradually depleted during hypothermia. This depletion is presumably a result of residual energy requirements that 1 It is apparent that much of the injury to transplanted organs
exceed the capacity of the cell to produce ATP.
occurs not during the period of ischemia per se but upon
During ischemia and organ preservation, the glycolytic
organ reperfusion. This realization has led to many advances
pathway is sidetracked to lactate production as the Krebs triin organ preservation. Furthermore, some of the events
carboxylic acid cycle and mitochondrial respiration are
that occur during reperfusion may result in enhanced
517
This allows the intracellular concentration of these metabolites to rise. Upon reperfusion, oxygen is suddenly available
and metabolism proceeds rapidly, resulting in a dramatic and
sudden production of reactive oxygen intermediates. The cellular defenses against peroxidation are overwhelmed and
injury occurs.8
Agents that reduce oxygen free radical generation, or scavenge them once they are formed, have been used to determine
the contribution of these molecular species to preservationrelated reperfusion injury and have the ability to decrease peroxidation due to oxygen free radicals during reperfusion.
Allopurinol, an inhibitor of xanthine oxidase, has been
shown to have protective effects when used before the
ischemic insult in a variety of experimental systems. Unfortunately, allopurinol has other effects, such as vasodilatation
and preservation of the purine nucleotide pool, making it a
less-than-ideal agent for defining oxygen free radical effects.
Other studies using superoxide dismutase have clearly
demonstrated a role for oxygen radicals in reperfusion injury
in transplantation.9 Similarly, desferrioxamine, an iron chelator, removes an essential metal cofactor for the generation of
the extremely reactive hydroxyl radical, resulting in decreased
oxidative injury.
Indirect evidence of oxygen free radical effects rests on the
documentation of lipid peroxidation. In this process, interaction of highly reactive oxygen species with polyunsaturated
fatty acids in the cell membrane starts a chain reaction that
may ultimately destroy cellular integrity and result in cell
death. The products of this reaction can be measured by several different assays. The magnitude of lipid peroxidation
appears to be inversely related to levels of glutathione, which
functions as an endogenous free radical scavenger. Glutathione
and other agents that protect against peroxidation are, therefore, useful in organ preservation solutions to attenuate reperfusion injury.
Production of oxygen free radicals also initiates production
of prostaglandins including leukotriene B4 by direct activation
of phospholipase A2. This chemoattractant causes leukocyte
adherence to vascular endothelium. These neutrophils may
contribute to local injury by plugging the microcirculation and
by degranulation, resulting in proteolytic damage to the
organ.
Cytokine-mediated Effects
Cytokines are a recently described group of intercellular messenger molecules that may be produced in a variety of normal
TRANSPLANTATION
518
CONTEMPORARY
CLINICAL PRACTICE
The science of transplantation has developed rapidly during
the past 40 years. Improved understanding of the immune
response to allografts and better appreciation of the complexity of organ ischemia and preservation-related injury have
contributed to greatly improved graft and patient survival
results. Most solid organ transplants are now performed as
the therapeutic option of choice, and in many cases transplantation offers the only definitive treatment for a given disease
entity. As a result, an ever-widening list of indications for solid
organ transplantation has emerged, placing increasing pressure on an already limited supply of donor organs. As of
December 2006, there were 93,820 patients awaiting deceased
donor organ transplantation in the United States, almost double the number listed in 1997.13 Each year, more patients are
placed on the waiting lists than are transplanted, resulting in
thousands of waiting list deaths and increasing waiting time.
519
TRANSPLANTATION
520
Pathophysiology
Brain Death
3
Etiology. Any condition that results in an overwhelming cerebral insult may be sufficient to cause brain death. In general,
these conditions fall into the broad categories of subarachnoid
or intracerebral hemorrhage, direct cerebral trauma, primary
malignancy of the central nervous system, and other rare and
miscellaneous entities. Subarachnoid hemorrhage may result
from rupture of an intracranial aneurysm. Other cerebrovascu-
Spouse
Adult son or daughter
Either parent
Adult brother or sister
Guardian
Any other person authorized to dispose of the body
is different from other kinds of death. Obviously, the distinction is intended to differentiate this modality of dying from
cardiac death but not to indicate that the person is any less
dead. Phrases such as keeping the organs alive so they can be
transplanted are as misleading and confusing as they are
incorrect.
According to the Uniform Anatomical Gift Act, a signed
and witnessed organ donor card is a legally binding indication
of the decedents wishes, but throughout North America and
most European countries, the familys consent is routinely
obtained before organ procurement. Although it is desirable
that the entire family be in agreement about donating, the legal
next of kin is required to agree to the donation and grant
signed permission (Table 34.1).
Donor Maintenance
Tissue Perfusion. Most donors are maintained with a miniThe Organ Procurement and Transplantation Netmum of fluids to prevent increased cerebral edema, and, therework and the Coordination of Surgical Teams. When
fore, one of the first priorities in donor maintenance should be
brain death has been declared, the person has been identified
the prompt restoration of intravascular volume. Depending on
as a suitable organ donor, and permission has been given by
the duration of the donors underlying illness, this process may
the next of kin, the logistics of organ procurement must be
require from 3 to 10 L of volume resuscitation. In general, the
arranged. Since passage of the National Organ Transplantadosage of pressor agents required to support blood pressure
tion Act, a national Organ Procurement and Transplantation
can be progressively decreased as the central venous pressure is
Network (OPTN) has been organized. The federal contract for
raised to 10 to 12 cm H2O. Crystalloid may be used, and lacthis important function is held by the United Network for
tated Ringer solution is often given because its slightly lower
Organ Sharing (UNOS). The OPTN is responsible for the fair
sodium concentration counteracts the concentrating effects of
and equitable distribution of deceased donor organs throughdiabetes insipidus. If the latter condition has resulted in severe
out the United States. The 50 states and U.S. territories and
hypernatremia, the addition of free water may be necessary.
possessions are divided into 11 regions (Fig. 34.4). Within
Colloid and blood should be used to restore and maintain
each region, federally certified local organ procurement orgaosmotic pressure and normovolemia. The hematocrit should
nizations (OPOs) are responsible for maintaining the list of
be kept around 35 volume percent to replace traumatic losses 4 potential recipients for their catchment area. All transplant
and to maintain oxygen-carrying capacity. Enough volume
candidates within the United States are entered into a comshould be administered to achieve a urine output of at least
puter system, and an allocation system is used to determine the
100 mL/h and a systolic arterial pressure of 90 to 120 mm Hg.
appropriate potential recipient for a given donor organ. In
Higher levels of arterial blood pressure are usually unnecesgeneral, offers are made first to candidates listed with transsary because the loss of sympathetic tone accompanying brain
plant centers in the local OPO service area, then to suitable
death facilitates tissue perfusion at lower pressure.
candidates in the region, and finally to any candidate in the
If diabetes insipidus is severe, exogenous vasopressin must
nation. In each case, priority is ordered by the existing allocabe given. Available in a variety of forms, desmopressin acetate,
tion system designed for that organ.30 An important exception
a synthetic analog of 8-arginine vasopressin, appears to have the
to these general rules relates to renal transplant recipients who
least splanchnic vasoconstrictive effect compared with its antishare six antigens with the donor. These kidneys are automatdiuretic action. This agent can be given by a variety of routes,
ically shared nationwide even if suitable local recipients are
including intranasally, subcutaneously, or intravenously. The
available.
usual dosage is 20 g intranasally or 2 to 4 g intravenously or
Recipients of the various organs may reside in geographisubcutaneously.
cally distant locations. Because the recipient transplant teams
must be given considerable detailed information about the
Oxygenation and Ventilation. Arterial blood gases should
donor to decide whether to use a particular organ for a parbe checked regularly and appropriate adjustments of the venticular recipient, a finite period of time is required to assemble
tilator made to optimize gas exchange and acidbase balance.
the necessary donor retrieval teams. A national computerized
Oxygen supply should be adequate to maintain an arterial
system (DonorNet) provides all relevant medical informaoxygen saturation of greater than 95% and mixed venous oxytion simultaneously to multiple prospective accepting progen saturation above 70%. Low levels of positive end-expiratory
grams. The coordinating OPO contacts accepting teams,
pressure may facilitate achieving a balanced oxygen supply
facilitates logistical arrangements and communications for
and demand.
travel to the donor hospital, and makes arrangements for the
TRANSPLANTATION
TA B L E 3 4 . 1
521
522
FIGURE 34.4. The 50 United States are divided into 11 regions of approximately equal populations for purposes of administration of
organ procurement, distribution, and educational objectives.
523
TRANSPLANTATION
FIGURE 34.5. A complete midline incision from suprasternal notch to pubis is made for multiple organ procurement. The sternum is split. If necessary, cruciate
abdominal incisions are added to facilitate exposure of
the intra-abdominal organs.
524
FIGURE 34.7. A: The left triangular ligament is divided and the left lateral segment of the liver is retracted to
expose the esophagus and aortic hiatus. B: The pars flaccida of the lesser omentum is widely opened after
checking for the presence of a replaced left hepatic artery arising from the left gastric artery. C: After division
of the diaphragmatic crura, the supraceliac aorta is encircled at the level of the diaphragm.
525
TRANSPLANTATION
FIGURE 34.8. A: Standard hepatic arterial anatomy, with the artery arising as a single vessel as a branch
of the celiac axis. B: Aberrant hepatic arterial anatomy, with a replaced right hepatic artery arising from
the superior mesenteric artery and ascending posterior to the common bile duct and anterolateral to the
portal vein. C: A replaced left hepatic artery arising from the left gastric artery is usually visible and palpable crossing the pars flaccida of the lesser omentum from the lesser curvature of the stomach. D: A completely replaced common hepatic artery arising from the superior mesenteric artery.
526
527
and vein emerging from the uncinate process are ligated and
divided, and a cylinder of aorta is removed encompassing the
superior mesenteric artery and celiac axis. The distal superior
mesenteric artery and vein provide blood supply to the small
intestinal graft, which is removed next. The liver and pancreas are separated as a bench procedure, retaining the celiac
FIGURE 34.11. Preparation of the heart for cardioplegia. Minimal dissection is necessary. The venae cavae are encircled, and
the aorta is separated from the pulmonary artery.
TRANSPLANTATION
vena cava and adjacent to the bare area of the liver is divided.
The infrahepatic inferior vena cava is divided just cephalad to
the left renal vein. The liver and pancreas unit is now attached
only by the distal superior mesenteric vessels coursing to the
small bowel and by the aortic origins of the superior mesenteric artery and celiac axis. The superior mesenteric artery
528
FIGURE 34.12. In situ perfusion set-up. A: A cannula is placed into the portal vein through the inferior mesenteric vein for portal venous
perfusion. B: A needle is placed in the aortic root for perfusion of the coronary arteries with cardioplegia solution. C: A cannula is placed
in the distal aorta for retrograde perfusion with cold preservation solution. Another cannula is placed in the distal vena cava for venous
decompression and exsanguination.
axis with the liver (Fig. 34.13). The splenic artery is divided
at its origin. This vessel and the superior mesenteric artery
are reconstructed with a bifurcated donor iliac artery graft.
The portal vein is divided about 1 cm from the pancreas.
The common bile duct is divided at the superior edge of the
pancreas.
The kidneys are also removed en bloc. The ureters are given
wide berth to avoid devascularization and are divided near
their entrance into the bladder. Dissection is carried out posterior to the aorta and vena cava in the plane of the prevertebral
fascia. Once removed, the left renal vein is divided flush with
the vena cava (Fig. 34.14). The aorta is opened in the midline
to identify the orifices of the renal arteries from within the
lumen. In this way, multiple renal arteries can be readily identified and kept on a single aortic Carrel patch. Once the
abdominal and thoracic organs have been removed, a sampling of lymph nodes and spleen is taken for tissue typing and
cross match testing. The chest and abdomen are closed, and
standard postmortem care is given.
529
FIGURE 34.13. The liver and pancreas are removed en bloc. Separation of the two organs is accomplished as a bench procedure. The
celiac axis is retained with the liver, dividing the splenic artery just beyond its origin. The gastroduodenal artery is ligated and divided.
The portal vein is divided approximately 1 cm from the superior edge of the pancreas, and the common bile duct is divided just superior
to its entrance into the pancreas.
FIGURE 34.14. The kidneys are removed en bloc and separated on the back bench. Safe division is ensured by viewing the kidneys posteriorly. The aorta is divided between the paired lumbar arteries, and renal arterial orifices can be viewed directly from within the aortic
lumen. This avoids any hilar dissection with the accompanying risk of injury to renal arteries. The left renal vein is divided at its entrance
to the inferior vena cava, leaving the entire vena cava with the shorter right renal vein.
TRANSPLANTATION
waiting an additional 5 minutes after cessation of effective cardiac function and pronouncement of death before proceeding
with organ procurement.
At this point, the organs are rapidly cooled by infusing cold
preservation fluid via the previously placed cannula. Simultaneously, the abdomen and chest are opened and a standard
organ procurement procedure is carried out. Growing experience demonstrates that outcomes of kidneys transplanted from
DCD donors are comparable with those from brain-dead
donors, with the exception of a higher incidence of delayed
graft function.34 However, DCD livers have been noted to
develop ischemic-type biliary strictures, and significantly
worse outcomes from livers from DCD versus brain-dead
donors have been reported.35
530
TA B L E 3 4 . 2
COMPOSITION OF HYPOTHERMIC ORGAN
PRESERVATION SOLUTIONS
COMPONENT
Euro-Collins Solution
KH2PO4
K2HPO4
KCl
NaHCO3
Glucose
2.05 g
7.4 g
1.12 g
0.84 g
35 g
100 mmol
25 mmol
5 mmol
30 mmol
5 mmol
3 mmol
100 IU
40 IU
8 mg
1 mmol
HTK Solution
NaCl
KCl
KH-2-ketoglutarate
MgCl2
Histidine hydrochloride
Histidine
Tryptophan
Mannitol
CaCl2
15 mmol
9 mmol
1 mmol
4 mmol
18 mmol
180 mmol
2 mmol
30 mmol
0.015 mmol
Heart and Lungs. Cardiac preservation has changed relatively little in recent years. Crystalloid cardioplegia solution is
used at 4C, and 4 hours is the generally accepted limit of cold
ischemia. For this reason, donor and recipient operations must
be finely coordinated. Recently, machine perfusion preservation has been explored as an alternative to simple cold storage,
but this modality is still considered experimental.
A comprehensive review of pulmonary preservation has
recently been published.42 Hypothermia is used along with
intracellular-type solutions such as Euro-Collins or UW solution. Pulmonary inflation is also important. The optimal vascular perfusate for the lungs remains unknown, however, and
results with pulmonary transplantation are still limited by deficiencies in the quality and duration of preservation.
Small Bowel. Transplantation of small bowel segments with
or without concomitant liver transplant is being performed
more commonly as a definitive treatment for short-gut syndrome. Preservation of the bowel is generally performed with
UW solution or HTK solution.43 Since most small bowel procurements are from donors that have multiple transplantable
organs, standard in situ intra-aortic preservation techniques
are used. The current limit of cold ischemia time for small
bowel is approximately 12 hours.44
References
1. Belzer FO. Evaluation of preservation of the intra-abdominal organs.
Transplant Proc 1993;25:25272531.
2. McLaren AJ, Friend PJ. Trends in organ preservation. Transpl Int 2003;
16:701708.
3. Belzer FO, Southard JH. Principles of solid-organ preservation by cold
storage. Transplantation 1988;45:673676.
4. Simonson MS, Dunn MJ. Endothelins: a family of regulator peptides.
State-of-the-art lecture. Hypertension 1991;17:856863.
5. Wilhelm SM, Simonson MS, Robinson AV, et al. Cold ischemia induces
endothelin gene upregulation in the preserved kidney. J Surg Res 1999;85:
101108.
6. Southard JH, Senzig KA, Belzer FO. Effects of hypothermia on canine kidney mitochondria. Cryobiology 1980;17:148153.
531
K E Y
The major barriers to successful renal transplantation
include ABO compatibility and the HLA system.
2 Before a renal transplant is undertaken, histocompatibility
of the donor and recipient are determined.
3 Methods to expand the donor pool of kidneys include the
use of donation after cardiac death and expanded criteria
donors.
4 The etiology of kidney disease resulting in end-stage failure,
and the necessity for transplantation is led by glomerulonephritis, diabetes, and hypertension.
1
P O I N T S
5
6
7
8
9
TRANSPLANTATION
532
IMMUNOLOGY OF RENAL
TRANSPLANTATION
The immunologic response to allografted tissue is well defined
and under the influence of both T-cell and B-cellderived
reactions. The cells and cytokines responsible for rejection
vary with time posttransplant (hyperacute, acute, and chronic
rejection) and have a differential response to currently available immunosuppressive agents.
1
The major barriers to successful renal transplantation
include ABO compatibility and the human leukocyte antigen
(HLA) system. In general, renal transplantation is done between
ABO-compatible donor and recipients using the same guidelines
as for blood transfusion. However, because of the shortage of
donors, cadaver kidneys are nearly always used in recipients of
identical blood type. Recently, ABO-incompatible living-donor
transplants have been performed on an experimental basis secondary to excessive wait times for ABO-compatible deceaseddonor transplants.1,2
The HLA system is made up of well-defined antigens present on most cell types that are genetically determined for each
patient and are termed the major histocompatibility complex.
These genes reside on chromosome 6 and are distributed in a
Mendelian fashion to offspring. The HLA system includes several loci, but the most commonly characterized are the HLAA, HLA-B, and HLA-D regions. Given that each human has
two alleles for each locus, there are six potential HLA antigens
of clinical significance. These are characterized using tissue
typing techniques and can be used to determine the degree of
matching between a donor and potential recipient, i.e., oneantigen match to six-antigen match. Improved results of graft
survival are seen when the degree of matching reaches the sixantigen level, and long-term results may be better with matching to a lesser degree.
Class I antigens include the HLA antigens A, B, and C,
whereas class II antigens include the D and DR loci. Class I
antigens act as targets for cytotoxic T lymphocytes, and class II
antigens are important for antigen presentation. Class II antigens are also responsible for triggering lymphocyte proliferation in the mixed lymphocyte culture system.
2
Before a renal transplant is undertaken, histocompatibility
of the donor and recipient are determined. Standard testing
consists of two procedures. Donors and recipients first undergo
tissue typing, which involves characterization of their respective HLA type. Recipient serum is tested against a panel of antigens that contain the known HLA types, to identify anti-HLA
antibodies. The sensitivity for detecting anti-HLA antibodies
continues to improve, and newer technology uses single antigen
beads to detect antibodies against a specific HLA antigen. The
amount of reactivity that a potential recipient has against a
panel of HLA antigens is indicative of the degree of sensitization. Based on the number of anti-HLA antibodies detected, a
calculated percent reactive antibodies (cPRA) can be estimated.
A cPRA of 70% would suggest that the potential recipient
would have anti-HLA antibodies against 70% of the potential
donor pool. Sensitization to HLA antigens occurs as a result of
previous exposure to foreign HLA antigen either from pregnancy, previous blood transfusion, or a previous organ transplant. A patient who is highly sensitized is more difficult to
transplant because of the greater likelihood of having antibodies to a potential donor.
The second test performed prior to transplantation is commonly known as the final cross-match. Several recipient serum
samples collected at different times are mixed with donor
lymphocytes in a culture system. This assay will detect preformed cytotoxic antibodies that would result in a hyperacute
rejection if the transplantation were performed (see Rejection,
later). A more sensitive method of detecting these antibodies
uses a fluorescent activated cell scanner and is commonly used
when evaluating potential recipients who are highly sensitized
or receiving second transplants. In the near future, many transplant centers will be adopting a virtual cross-match based
on the detection of anti-HLA antibodies present in a given
recipient. The most sensitive technology will be used to detect
the presence of anti-HLA antibodies in a given recipient. Based
on these antibodies, each recipient will have a list of unacceptable donor antigens. Compatability with each donor will be
determined in the absence of the final cross-match by eliminating a potential donor based on the presence of unacceptable
antigens. This strategy facilitates an expedited transplant and
minimization of cold ischemia times, as it avoids the additional time and expense associated with the final cross-match.
Widespread acceptance of the virtual cross-match will require
further confirmation that all donor antigens are sufficiently
identified using the single antigen bead technology.
Living Donors
The first long-term success in renal transplantation over
50 years ago involved a live donor transplant between twin
brothers. The number of living donors has increased significantly in the last few years, in part as a result of the increased
use of the laparoscopic technique for donor nephrectomies.
For the first time, in 2001 the number of living donors
exceeded the number of deceased donors, although deceased
donor transplants still represent the majority of kidney transplants done today.4 This trend toward increased live donation
may also be the result of the excessive waiting times for
deceased donor transplants, now more than 7 years for blood
type O and B recipients in many parts of the United States.
Despite initial concerns about the safety and efficacy of the
laparoscopic technique for the donor procedure, morbidity
and mortality rates (0.03%) remain low and comparable with
those of the open technique.5,6
The evaluation of a potential living kidney donor begins
with a brief overall assessment of physical condition because
Deceased donor
Year
2
20
0
20
01
00
20
19
99
19
98
97
96
19
93
19
19
96
19
97
19
98
19
99
20
00
20
01
20
02
19
95
19
93
19
94
10,000
19
20,000
94
30,000
19
9
40,000
Living donor
8000
7000
6000
5000
4000
3000
2000
1000
0
19
50,000
Number of transplants
Number of patients
9000
Year
FIGURE 35.1. The growth in the number of patients awaiting transplant (A) has exceeded the relatively stagnant rate of deceased donor kidney
transplants leading to progressively increasing waiting times over the last decade. Living donors have had a slight increase, which may be in
part due to the introduction of the laparoscopic donation procedure. There has been an increase in the proportion of recipients aged 50 years
and older on both the wait list and receiving transplants (B). (Adapted from Wolfe RA, Merion RM, Roys EC, et al. Trends in organ donation
and transplantation in the United States, 19982007. Am J Transplant 2009;9:869878, with permission.)
TRANSPLANTATION
533
534
TA B L E 3 5 . 1
ETIOLOGY
535
The procedure is most commonly done through a transperievaluated by a hepatologist to determine the risks of immunotoneal approach, although some surgeons prefer to remain
suppression causing progression to end-stage liver disease.
retroperitoneal. Once the operative space is expanded with
Potential kidney recipients with evidence of advanced liver
carbon dioxide gas and the scope is inserted, two to three addidisease should be evaluated for a combined liver and kidney
tional ports are placed to allow for the passage of instruments
transplant. For patients with less advanced liver disease, conto dissect the kidney (Fig. 35.2). Some centers also favor the
sideration could be given to interferon therapy before prouse of a gastight hand-port, which allows placement of the
ceeding with kidney transplantation to provide the opportunity
surgeons hand in the operative space to assist in exposure and
for viral clearance. Kidney transplantation was previously
to have available if sudden bleeding is encountered. Once the
contraindicated in people with HIV infection secondary to
kidney vessels are transected and the vessel stumps are conconcerns of exacerbating an already immunologically comprotrolled by laparoscopic staples, the kidney can be removed
mised state. Recent advances in antiretroviral therapy and the
through a 2- to 3-inch incision, which can be placed in a posiability to provide effective prophylaxis against opportunistic
tion that leaves minimal scarring and avoids cutting muscle tisinfections has prompted several centers to perform transplansue. Most commonly this is via a Pfannenstiel incision, and
tation in people with end-stage renal disease and HIV infecrecently the use of natural orifice approaches (NOTES) has
tion. Early results suggest that progression of HIV to AIDS has
been described. Donors who undergo the laparoscopic procenot been seen following transplantation and immunosuppresdure typically have reduced pain medicine requirements, have
sion, with early allograft success rates comparable to those in
a slightly shorter hospital stay, and are able to return to their
nonHIV-positive recipients.14 Potential patients with a previusual activities sooner.5,6
ous history of tuberculosis or conversion to purified protein
derivative positivity should be evaluated for active disease.
The safety of this relatively new procedure has been estabColonoscopy, mammography, and Pap smear should be
lished, in addition to the demonstration that kidneys recovered
performed as dictated by age-specific standard guidelines. For
through a laparoscopic approach function as well as kidneys
most malignancies, with the exception of nonmelanoma skin
removed in an open operation. It is important that there seems
cancers and early-stage renal cancers, a disease-free interval of
to have been an increased interest in live donation, coincident
5 years is recommended before kidney transplantation.
with the introduction of the laparoscopic procedure, suggestFor patients with congenital abnormalities as the cause of
ing that this procedure has removed some of the disincentives
renal failure, a complete workup of the genitourinary systems
of the donation process.
is necessary, including urodynamics and voiding cystourethrograms. These studies are particularly important in children
with end-stage disease resulting from posterior urethral valves,
Recipient Operative Procedure
to ensure that the bladder will serve as an adequate conduit for
the kidney transplant. For patients with severe reflux disease 5 The kidney transplant is heterotopically placed in the extraperiand chronic pyelonephritis, native nephroureterectomy may
toneal iliac fossa. Although this is a less technically demanding
be required to prevent posttransplant infection secondary to
procedure than either liver or pancreas transplants, attention to
chronic reflux into the native ureters. For patients with inadedetail is imperative to optimize immediate graft function and
quate bladder capacity and function, pretransplant reconstrucavoid technical complications resulting in loss of the kidney
tive procedures such as ileal augmentation or ileal conduits
transplant.
may be required.
The operation is initiated by exposure of the iliac fossa
For patients with suspected clotting disorders based on a
through a curvilinear incision and can be done on either the
previous history of thromboembolic events (frequent clotting
right or left side. The incision extends from 1 cm above the
problems with dialysis access) or diseases associated with an
symphysis pubis to approximately 2 cm lateral to the anterior
increased frequency of clotting disorders (i.e., lupus), a hemailiac spine (Fig. 35.3). The fascia is divided along the lateral
tologic workup is necessary to determine the necessity for antiborder of the rectus sheath, and the contents of the peritoneal
coagulation at the time of the transplant. This workup should
cavity are reflected cephalad and medially, exposing the iliac
include a determination of serum levels of protein C, protein S,
vessels in the retroperitoneum. Lymphatics overlying the iliac
anticardiolipin antibody, factor V Leiden, antithrombin III
vessels are ligated and divided to prevent the development of
levels, and the G20210 A prothrombin gene mutation.
lymphoceles. In males, the spermatic cord is secured with a
vessel loop and can be retracted away from the operative field.
In females, the round ligament is suture ligated and divided.
The inferior epigastric artery and vein are typically divided to
Living Donor Nephrectomy:
prevent potential compression of the transplanted ureter.
Placement of a mechanical retractor should avoid compression
Open and Laparoscopic
of the iliac artery and vein as well as the femoral nerve to prevent neurapraxias.
A living kidney donor operation is a unique surgical procedure
The living or deceased donor kidney is inspected for the
for two reasons. First, the donor has no medical reason to be
presence of multiple vessels, duplication of the urinary collectin the operating room, and the process is driven only by his or
ing system, and parenchymal abnormalities. The artery and
her willingness to help another person with the gift of donavein are dissected from surrounding structures to provide the
tion. Second, the removed tissue must be in perfect condition
necessary length for transplantation. In the case of multiple
because it will be reimplanted into the recipient. These two
arteries, a decision must be made as to whether to perform ex
features, therefore, necessitate that the donor operation is
vivo reconstruction to achieve a single implantable conduit
done safely and done well. The original donor operation was
versus implanting the vessels separately. This decision is in
done through a generous flank incision, allowing for good
part dependent on the quality of the recipient vessels and an
exposure and careful dissection of the renal vessels. Unfortuassessment as to whether the anastomosis of multiple vessels
nately, this flank approach generally left a large incision, with
directly into the recipient would require an unacceptable
its accompanying morbidity, pain, and sometimes adverse cosperiod of warm ischemia to the kidney. In general, in an adult
metic result. The development of the laparoscopic procedure
the anastomosis of the renal artery and vein are performed in
to remove kidneys has revolutionized the field, although its inian end-to-side fashion to the external iliac vessels, although
tial introduction was met with trepidation because of concerns
occasionally the presence of atherosclerotic disease requires
over donor safety. With the explosive growth and disseminatransplantation to the common iliac vessels. In children who
tion of this procedure, it has now become the standard for
weigh less than 20 kg, or for third transplants in adults, an
donor nephrectomy.
TRANSPLANTATION
536
12 mm port
for stapler
11 mm ports
Extraction
incision
Camera port
A
The reimplantation of the ureter is most frequently performed through an extravesicular technique. Following positioning of the revascularized kidney in the iliac fossa and
assurance of hemostasis, the ureter is shortened to permit a
tension-free anastomosis with adequate blood supply to the
distal ureter. In men, the ureter is placed under the spermatic
cord to prevent ureteral obstruction. The bladder is distended
with an antibiotic solution to identify a suitable area for
ureteral implantation on the dome of the bladder, and a
B
Muscular layer
Mucosa
Beveled ureter
Rectus
border
Ureter
External iliac
vein and artery
Bladder
FIGURE 35.3. A: Curvilinear iliac fossa incision used for the kidney transplant recipient procedure. B: Vascular anastomoses completed
between the recipient external iliac artery and vein and donor renal artery and vein. Insets: ureteral anastomosis performed using the external
ureteroneocystostomy technique.
COMPLICATIONS
Early Graft Dysfunction
Most kidneys begin to function right after implantation, especially in the case of a living donor. When the initial function
537
No initial urine
or
Drop in urine output
Hypovolemic
Euvolemic or overloaded
Diuretic challenge
Saline bolus
Urine improved?
Yes
Continue fluid
No
No
Urine improved?
Doppler ultrasound
Yes
Continue fluid
consider lasix
infusion
Yes
Delayed graft function
Minimize fluids
assess dialysis needs
early biopsy
ALGORITHM 35.1
ALGORITHM 35.1. Stepwise approach to the management of decreased low urine output posttransplant.
TRANSPLANTATION
538
Technical Complications
6
IMMUNOSUPPRESSION,
REJECTION, AND
IMMUNOSUPPRESSIVE
COMPLICATIONS
Immunosuppression
Major advances in the ability to block immune-mediated
destruction of the kidney have taken place in the past few
years, resulting in a significant decrease in the incidence of
acute rejection and improvement in long-term allograft
survival rates. 13 This advance is the result of numerous
agents that have been added during the past decade to the
Flap
External iliac
vein and artery
539
Stenotic ureter
Mobilized bladder
TRANSPLANTATION
Double J stent
540
Immunosuppressive Complications
It would be nave to assume that the intensification of
immunosuppressive regimens resulting in decreased acute and
chronic rejection rates can be accomplished without sequelae.
Infections and malignancy remain significant complications
associated with long-term immunosuppression and are the driving force for drug-minimization strategies. Early infections
during the perioperative period are commonly iatrogenic and
involve bladder infections or intravenous catheter use. Higher
doses of immunosuppressive drugs used in the early postoperative period predispose patients to these infections and emphasize the importance of maintaining sterility during Foley
catheter placement and insertion of intravenous catheters.
Pneumonia related to mechanical ventilation and poor postop-
100
90
80
70
60
50
67
54
53
40
38
32
30
LD92
LD02
SCD92
SCD02
ECD92
ECD02
20
n
9,859
23,404
31,338
28,440
1,709
5,223
t1/2
12.0
17.9
10.2
11.3
8.0
6.6
19
541
suppressive agents has resulted in marked decreases in the incidence of acute rejection, which it is hoped will translate to
prolongation in the long-term function of kidney transplants.
Newer strategies in immunosuppressive regimens that minimize nephrotoxic cyclosporine and tacrolimus by adding nonnephrotoxic agents will also benefit the long-term function of
transplanted kidneys. The effect of ischemia-reperfusion injury
on both early and late graft function, as well as its impact on
the development of chronic rejection and transplant glomerulopathy, is an area of active research, and potential therapeutic
interventions to minimize this injury are being evaluated. The
induction of tolerance to foreign antigen remains the holy
grail of transplantation. A paucity of tolerizing regimens
have been applied clinically, although the use of donor bone
marrow or stem cells will likely have a future role in achieving
the elusive goal of transplantation tolerance.
10
1
3
4
5
6
7
Years posttransplant
10
to monoclonal lymphomas has required chemotherapy. CD20positive lymphomas have been successfully managed with rituximab, an anti-CD20 antibody, with no significant side
effects.
References
1. Tanabe K, Tokumoto T, Ishida H, et al. Excellent outcome of ABOincompatible living kidney transplantation under pretransplantation
immunosuppression with tacrolimus, mycophenolate mofetil, and steroid.
Transplant Proc 2004;36:21752177.
2. Takahashi K, Saito K, Takahara S, et al. Excellent long-term outcome of
ABO-incompatible living donor kidney transplantation in Japan. Am J
Transplant 2004;4:10891096.
3. Meier-Kriesche HU, Kaplan B. Waiting time on dialysis as the strongest
modifiable risk factor for renal transplant outcomes: a paired donor kidney
analysis. Transplantation 2002;74:13771381.
4. Rosendale JD. Organ Donation in the United States: 19982002. In:
Cecka JM, Terasaki PI, eds. Clinical Transplants 2003. Los Angeles: UCLA
Immunogenetics Center; 2004:6576.
5. Melcher M, Carter JT, Posselt A, et al. More than 500 consecutive laparoscopic donor nephrectomies without conversion or repeated surgery. Arch
Surg 2005;140(9):835839.
6. Nogueira JM, Jacobs SC, Haririan A, et al. A single center comparison of
long-term outcomes of renal allografts procured laparoscopically versus
historic controls procured by the open approach. Transpl Int 2008;21(9):
908914.
7. Cooper JT, Chin LT, Krieger NR, et al. Donation after cardiac death: the
University of Wisconsin experience with renal transplantation. Am J
Transplant 2004;4:14901494.
8. Bromberg J, Gill J. Heavy LYFTing: KASting Pearls Before Swine. Am J
Transplant 2009;9:14891490.
9. Warren DS, Zachary AA, Sonnenday CJ, et al. Successful renal transplantation across simultaneous ABO incompatible and positive crossmatch
barriers. Am J Transplant 2004;4:561568.
10. Jordan SC, Tyan D, Stablein D, et al. Evaluation of intravenous
immunoglobulin as an agent to lower allosensitization and improve transplantation in highly sensitized adult patients with end-stage renal disease:
report of the NIH IG02 trial. J Am Soc Nephrol 2004;15:32563262.
11. Metzger RA, Delmonico FL, Feng S, et al. Expanded criteria donors for
kidney transplantation. Am J Transplant 2003;3(suppl 4):114125.
12. Port FK, Bragg-Gresham JL, Metzger RA, et al. Donor characteristics associated with reduced graft survival: an approach to expanding the pool of
kidney donors. Transplantation 2002;74:12811286.
13. Cecka JM. The OPTN/UNOS Renal Transplant Registry. In: Cecka JM,
Terasaki PI, eds. Clinical Transplants 2003. Los Angeles: UCLA Immunogenetics Center; 2004:112, 14.
14. Roland ME, Barin B, CarlsonL, et al. HIV-infected liver and kidney transplant recipients: 1- and 3-year outcomes. Am J Transplant 2008;8(2):
355365.
15. Vincenti F. Immunosuppression minimization: current and future trends in
transplant immunosuppression. J Am Soc Nephrol 2003;14:19401948.
16. Vincenti F, Kirk AD. Whats next in the pipeline. Am J Transplant 2008;
8(10):19721981.
17. Morath C, Mueller M, Goldschmidt H, et al. Malignancy in renal transplantation. J Am Soc Nephrol 2004;15:15821588.
18. Wynn JJ, Distant DA, Pirsch JD, et al. Kidney and pancreas transplantation. Am J Transplant 2004;4(suppl 9):7280.
TRANSPLANTATION
K E Y
The main indication for liver transplantation is end-stage
liver disease, defined as the clinical scenario in which a
pathologic process or multiple processes have resulted in a
damaged liver that has minimal function and no potential
for recovery.
2 The Organ Procurement and Transplantation Network
uses the Model of End-stage Liver Disease (MELD) score
as a method of prioritizing liver transplant recipients. The
MELD score is an integer value based on three objective
laboratory studies: creatinine, bilirubin, and the international normalized ratio.
3 The degree of preoperative debilitation and the complexity
of the operative procedure make complications following
hepatic transplantation very common.
4 Approximately 2% to 10% of transplanted livers function so poorly in the immediate postoperative period
P O I N T S
6
7
542
TA B L E 3 6 . 1
FORMULAS TO CALCULATE MELD AND PELD SCORES
MELD score 0.957 Loge (Creatinine [mg/dL]) 0.378
Loge (Total bilirubin [mg/mL]) 1.120
Loge (INR) 0.643
543
TA B L E 3 6 . 2
URGENT LISTING CRITERIA FOR LIVER TRANSPLANTATION
Status 1A
TRANSPLANTATION
544
DISEASE-SPECIFIC INDICATIONS
AND OUTCOMES
While the MELD score assessment plays a critical role in evaluating and listing patients who might benefit from liver transplantation, patients who develop liver diseasespecific complications, regardless of MELD, are also appropriate to consider
for liver transplantation. Some of these complications along with
other liver-specific metabolic diseases are listed in Table 36.3.
Hepatitis C is the most common disease for which liver
transplantation is currently performed in the United States
(33%) (Fig. 36.1). Alcoholic liver disease, NASH, and
cholestatic liver diseases are the next most common ranging
from 10% to 14% of cases. However, this trend is believed to
be changing with a greater proportion of liver transplants
being performed for NASH (Fig. 36.2).5 Outcomes following
liver transplantation are best for pediatric patients with biliary
atresia, while patients with cholestatic liver diseases experience
the best survival among adults (Fig. 36.3). Patients with
hepatitis C or HCC experience worse survival secondary to
disease recurrence. Disease-specific indications, outcomes, and
considerations will be discussed in the following sections.
TA B L E 3 6 . 3
LIVER DISEASE COMPLICATIONS AND LIVER-SPECIFIC
METABOLIC DISEASES
Complications:
Ascites
Encephalopathy
Refractory variceal hemorrhage or portal gastropathy
Hepatocellular carcinoma
Hepatopulmonary syndrome (HPS)
Portopulmonary hypertension (PPHTN)
Fulminant hepatic failure (FHF)
Metabolic diseases:
Wilson disease
1-Antitrypsin disease
Familial amyloidosis
Urea cycle enzyme deficiencies
Glycogen storage disease
Tyrosemia
Primary oxaluria
10%
33%
7%
4%
1%
6%
14%
4%
9%
12%
Hepatitis C
Hepatitis B
Alcohol
Cryptogenic/NASH
Cholestatic
Hepatocellular Carcinoma
Other Malignancies
Metabolic
Pediatric Diseases
Miscellaneous
FIGURE 36.2. Changing incidence of liver transplantation for nonalcoholic steatohepatitis (NASH), hepatocellular carcinoma (HCC), and hepatitis C. (Reproduced with permission from OLeary JG, Lepe R,
Davis GL. Indications for liver transplantation. Gastroenterology 2008;134:17641776.)
4000
Cryptogenic/NASH
Number of patients
3500
HCC
Hepatitis C
3000
545
2500
2000
1500
1000
2006
2005
2004
2003
2002
2001
2000
1999
1998
1997
1996
1995
1994
1993
1992
500
Year
categories. It has also become understood that determining worthiness for receiving a lifesaving organ by making a judgment
about past behavior is neither ethical nor possible.
Today, the same methods of determining suitability for
transplantation are used for patients with alcoholic liver disease as with other diagnoses with one proviso. Unlike other disorders that tend to be universally progressive, alcohol-induced
liver injury frequently regresses following cessation of alcohol
consumption as long as cirrhosis is not yet present. Patients
with a history of recent alcohol abuse should therefore be
observed for a minimum of 6 months to ensure that their
Viral Hepatitis
Most patients who become infected with hepatitis B develop
an immunologic response to the virus that results in complete
1.0
0.9
TRANSPLANTATION
0.8
Portion surviving
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
2
PBC
PSC
HEP C
ALD
HEP B
5
Years
Autoimmune
Cancers
Metabolic
Fulminant
Other
546
TA B L E 3 6 . 4
TNM CLASSIFICATION AND STAGING OF
HEPATOCELLULAR CARCINOMA
CLASSIFICATION
T1
T2
T3
T4a
T4b
N0
N1
M0
M1
STAGE GROUPING
Stage I
T1
Stage II
T2
Stage III
T3
Stage IV A1
T4a
Stage IV A2
T4b
Stage IV B
remainder of the recipient candidate pool. However, in the latest review of outcomes of liver transplantation as reported by
the SRTR,4 the adjusted 3-year survival rate for HCC patients
was 74% and was statistically lower than non-HCC recipients
(81%) during the MELD era, suggesting that the allocation
policy may need further refinements.
Other primary tumors of the liver include hepatoblastoma,
cholangiocarcinoma, and primary sarcoma. Hepatoblastoma
occurs primarily in children with resection or transplantation
being used as potential curative options.30 Transplantation is
utilized for patients who are unresectable because of bilobar
disease or hilar location. Hepatoblastoma can respond partially to chemotherapy, but complete and sustained tumor
regression is uncommon. Patients are often treated with
chemotherapy until the time of transplantation to prevent
extrahepatic growth prior to the definitive treatment. Hepatoblastoma is relatively unique among liver tumors in that longterm survival has been reported even in children who have had
distant metastatic spread.
Cholangiocarcinoma has historically been considered a
contraindication to transplantation because 5-year survival
rates have been reported at less than 20%. Recently, success
similar to other recipients has been reported for patients who
have limited disease (2.5 cm, no lymph node disease) and
have received neoadjuvant therapies. However, more investigations are required as transplantation following this regimen
has been associated with increased vascular complications.31
Although there are anecdotal reports of long-term survival
following transplantation for primary sarcoma of the liver, the
majority of experiences indicate that transplantation is not a
curative therapy for this condition. Liver transplantation is
generally not appropriate for patients who have secondary
(metastatic) hepatic malignancy, because long-term survival
rates are very poor due in part to the observation that
immunosuppression promotes tumor growth. The possible
exception to this rule is patients who have metastatic carcinoid
that is limited to the liver. This tumor grows very slowly and
local cure of the primary tumor is frequently possible. A subset of patients who have a period of years without evidence of
Biliary Atresia
Biliary atresia is a congenital disorder of infants that is characterized by biliary obstruction resulting from obliteration or
discontinuity of the extrahepatic biliary system resulting in
progressive hyperbilirubinemia, cirrhosis, and hepatic failure.
The etiology is unknown yet is the most common indication for
hepatic transplantation in pediatric patients. Standard treatment
includes creation of a portoenterostomy (Kasai procedure), if
this can be done before 3 months of age. After this point, success
rates diminish markedly. Response to the portoenterostomy
TA B L E 3 6 . 5
KINGS COLLEGE CRITERIA FOR LIVER TRANSPLANTATION
ACETAMINOPHEN
NONACETAMINOPHEN
pH 7.3
Grade 34
encephalopathy
PT 100 s
(INR 6.5)
Cr 3.4 mg/dL
TRANSPLANTATION
tumor growth anywhere else but in the liver will have longterm disease-free survival following liver transplantation.32
547
548
Budd-Chiari Syndrome
LIVER TRANSPLANTATION:
SURGICAL PROCEDURE
Anesthetic Management
Other Considerations
Surgical Technique
Transplantation of the liver is among the most technically
demanding surgical procedures. During induction and placement of the appropriate monitoring lines by the anesthesiology
team, the donor liver is prepared on the back table for implantation (Fig. 36.4). Bench preparation includes resection of the
donor diaphragm and adrenal gland off of the bare area of
the liver and vena cava. Meticulous ligation of tributaries from
the vena cava (adrenal vein, phrenic vein, and lumbar branches)
is performed. The artery is dissected free from the Carrel patch
of the aorta up to the gastroduodenal artery. Dissection near
the right or left hepatic arteries is avoided to prevent unnecessary injury. The portal vein is circumferentially dissected free.
The gallbladder may be removed at this stage or following
reperfusion. Tissues surrounding the common bile duct are left
intact to avoid injury of the blood supply.
Following this, the recipients abdomen and bilateral groins
are prepped and draped in a standard fashion. The most commonly used incision is a bilateral subcostal incision with a
midline extension to the xiphoid process (Fig. 36.4B). After
dividing the fascia, ascites, which can occasionally be present
in a large volume, is evacuated. The ligamentum teres hepatis
is carefully divided between clamps and ligated because a large
recannulized umbilical vein is often present in patients with
severe portal hypertension. After dividing the falciform ligament with cautery, a mechanical retractor is used to retract the
bilateral costal margins anteriorly and superiorly for excellent
exposure of the upper abdomen. The abdominal cavity and
liver are then inspected for any abnormalities including unsuspected malignancy, particularly within the cirrhotic liver, which
is a risk factor for hepatocellular carcinoma. Following this,
liver transplantation occurs in three stages: (a) recipient hepatectomy, (b) anhepatic phase, and (c) postrevascularization.
FIGURE 36.4. A: The donor liver after excision and before transplantation. B: Bilateral subcostal incision with a
subxiphoid extension.
TRANSPLANTATION
thrombocytopenia and extensive venous collaterals. Intraoperative coagulopathy may be worsened during the anhepatic
phase of the procedure. Finally, liver transplantation involves
extensive dissection of major vascular structures including the
inferior vena cava, portal vein, and hepatic artery, all with an
inherent risk for torrential bleeding.
Intraoperatively, coagulation is monitored by frequent determination of standard parameters including prothrombin time,
partial thromboplastin time, platelet count, and fibrinogen.
Abnormalities of these laboratory values associated with intraoperative bleeding are often corrected with fresh frozen plasma,
platelets, or cryoprecipitate. Normal coagulation is also helped
by maintaining normal pH, calcium levels, and normothermia.
Intraoperative thromboelastography (TEG) can facilitate decision making by rapidly identifying which components of the
coagulation cascade are deficient or by identifying the presence of
a fibrinolytic state. However, the device for TEG can be fragile
and overly sensitive, which may limit its practical use in the clinical setting. The decrease in excessive bleeding in the modern era
of liver transplantation has led to many programs abandoning
the routine use of TEG. While the administration of recombinant
factor VII intraoperatively can rapidly and effectively stop nonsurgical bleeding, its use has a theoretical risk of postoperative
thrombotic complications including hepatic arterial thrombosis.
In addition, no definitive data have been demonstrated to
decrease the need for intraoperative blood transfusions.47,48
Therefore, its use is only recommended in emergent situations.
Following reperfusion of the donor liver, a fibrinolytic state
may be encountered. This is related to the lack of production
of fibrinolysis inhibitors during the anhepatic phase and the
inability of the liver to metabolize profibrinolytic compounds.
This state may be identified either by thromboelastography,
recurrence of bleeding where hemostasis had been previously
obtained (such as the wound edge), or extensive and refractory
bleeding after revascularization. This state may be treated with
the use of antithrombolytic agents including -aminocaproic
acid, tranexamic acid, or aprotinin. Because therapy with
antithrombolytic agents has been associated with intravascu-
549
550
Recipient Hepatectomy
During the recipient hepatectomy phase, the liver is mobilized
from its ligamentous attachments and the porta hepatis is
skeletonized. Attention is first directed to dissecting and skeletonizing the structures of the portal triad. The peritoneum
overlying the portal triad is divided with electrocautery near
the liver edge. The right and left hepatic arteries are dissected
free, ligated, and divided, leaving adequate length to form a
branch patch for the arterial anastomosis. The proper hepatic
artery is also dissected free to the level of the gastroduodenal
artery allowing enough length for clamping during the anastomosis. Because portal venous flow of blood to the liver may be
hepatofugal (away from the liver), division of the artery may
leave the patient functionally anhepatic. If a prolonged period
of time is expected for mobilization of the liver, such as when
extensive adhesions are present, the artery may be dissected
free but left in continuity to allow whatever synthetic capacity
the native liver has to continue. A replaced or accessory right
hepatic artery, which arises as a branch off the superior mesenteric artery and travels in a posterior position to the common
bile duct and lateral to the portal vein, can usually be palpated
if present and can be ligated and divided. When the replaced
right hepatic artery is relatively large and the proper hepatic
artery is diminutive in size, the replaced right hepatic artery
can be left long and used for arterial inflow for the donor liver.
A replaced or accessory left hepatic artery arises from the left
gastric artery if present and can be identified by inspection of
the pars flaccida of the lesser omentum along the lesser curvature of the stomach (Fig. 36.5).
Conceptually, the common bile duct and common hepatic
duct should be dissected free with as much length as possible
and without injuring the blood supply to the bile duct. Leaving the recipient bile duct as long as possible allows the
length of the donor bile duct, which may have a tenuous
blood supply, to be shorter and still avoid tension at the time
of anastomosis. This is accomplished by first ligating and
dividing the cystic duct. The common bile duct and common
hepatic duct are then circumferentially dissected free leaving
the surrounding tissue to preserve the bile duct blood supply.
The common hepatic duct is then ligated as close to the
native liver as possible.
Once the bile duct and the hepatic artery are freed from
surrounding tissues, the portal vein can be easily approached
FIGURE 36.5. A replaced left hepatic
artery usually arises as a branch of the
left gastric artery, traversing the pars
flaccida of the lesser omentum from left
to right toward the left lobe of the liver.
clamped before division to make sure that adequate cardiac filling and blood pressure can be maintained. If the patient
becomes hypotensive during test clamping, the clamp should be
removed and additional volume or pressor support can be
administered. Occasionally, patients will require venovenous
bypass, but its use is no longer routine at most centers.
If necessary, venovenous bypass can be accomplished from
both the portal vein and inferior vena cava simultaneously, or a
single cannula in either the portal vein or the inferior vena cava
may be used (Fig. 36.6). There are several accepted methods of
placing cannulas for venovenal bypass. Cannulas may be
placed percutaneously in the internal jugular vein and femoral
vein prior to beginning the procedure. These cannulas are
advanced into the superior and inferior vena cava, respectively.
Alternatively, one or both of the bypass cannulas may be placed
by cutdown on the axillary and/or greater saphenous vein.
Inferior vena caval and mesenteric blood is delivered to the
superior vena cava by a centrifugal pump. The cannulas, tubing, and centrifugal pump head are heparin bonded to reduce
the chance of thrombus formation and subsequent embolism
without the use of anticoagulation. Flow rates of 1 to 2 L/min
are usual.
Once venovenous bypass has been established or the decision to forego bypass has been made, the recipient hepatectomy is completed. If still intact, the portal vein is divided as
high in the hilum as possible. Three methods are commonly
used for orthotopic liver transplantation: (a) the bicaval technique, (b) the piggyback technique, and (c) cavocavostomy
(side-to-side caval technique).
1. For the bicaval technique, the recipient liver is excised en
bloc with the retrohepatic inferior vena cava after caval
clamps have been placed in a suprahepatic and infrahepatic
position. The hepatic veins are divided within the substance
FIGURE 36.6. Setup for venovenous
bypass during hepatic transplantation.
Cannulas are placed into the portal
vein to decompress the splanchnic bed
and inferior vena cava (through the
greater saphenous vein) to decompress
the lower extremities and kidneys during the anhepatic phase of the transplantation. A centrifugal pump is used
to deliver bypassed blood to the central
circulation by means of a cannula
passed into the axillary vein.
TRANSPLANTATION
551
552
FIGURE 36.7. A: The diseased recipient liver is removed by incising the liver
below the level of the hepatic veins. B: The hepatic veins are then opened to
form a large suprahepatic cuff for anastomosis. The suprahepatic vena caval
anastomosis: posterior suture line (C) and anterior suture line (D).
553
TRANSPLANTATION
FIGURE 36.8. Cavocavostomy. A: The recipient right and junction of the middle and left hepatic veins are stapled and the inferior vena
cava is left in continuity. B: The supra- and infrahepatic vena cavae are stapled and a venotomy is made longitudinally on the posterior
aspect of the donor liver. C: A side-to-side caval anastomosis is performed with a running suture.
554
(Fig. 36.8). Venting can be performed from either the suprahepatic donor vena cava or the medial wall of the anastomosis.
During the caval anastomosis, the donor liver may be perfused
with cold fluid via a cannula placed within the donor portal
vein to wash out the preservation solution and to help maintain
the cold temperature of the liver. This step is not required but
may be considered if the liver was preserved with a solution
containing a high concentration of potassium or if a prolonged
warm ischemic time is anticipated.
Once the caval anastomosis or anastomoses are completed,
either the portal anastomosis, arterial anastomosis, or both can
be performed prior to reperfusion. In theory, reperfusion with
arterial blood would limit the extent of warm ischemia to the
biliary tree, which, unlike the remainder of the liver, receives its
blood supply exclusively from the arterial blood and not along
with portal venous blood. However, neither sequence has been
clearly shown to be an advantage over the other, so the choice
is made based on the surgeons preference and the patients
anatomy. Most commonly, the portal venous anastomosis is
completed and the liver is reperfused. If portal bypass has been
used, the portal limb of the venovenous bypass circuit is
removed. The portal anastomosis is usually performed in an
end-to-end fashion using a running technique. To avoid narrowing, an air knot is used when the suture is tied.
At the time of revascularization, flow is restored to the liver
through the portal vein and/or the hepatic artery. The first several hundred milliliters of blood may be vented through the
infrahepatic vena cava and the knot can be tied completing the
caval anastomosis. Alternatively, the caval clamp can be
flashed and the anastomosis inspected for bleeding and
repaired if present. If blood is not vented through the infrahepatic cava, portal blood should be restored gradually to
minimize cardiac irritability, bradycardia, and hypotension, all
of which routinely result from cold blood circulating through
the donor liver and going directly into the right atrium. Close
coordination between the surgeon and anesthesiologist is necessary during this phase as hypotension and bradycardia are
routinely encountered and cardiac arrest may rarely occur. If
venovenous bypass has been used during the anhepatic phase,
it can now be discontinued.
Once hemostasis is obtained and the patient has stabilized,
attention can now be turned toward the arterial anastomosis if
it has not already been performed. Conceptually, the arterial
anastomosis can be performed in one of two ways. The anas-
555
graft consisting of the donor common and external (or internal) iliac artery. A partially occluding aortic clamp can either be
placed in a supraceliac or infrarenal position and the common
iliac artery is sutured in an end-to-side fashion to the recipient
aorta. The donor Carrel patch can then be sutured in an endto-end fashion to the external iliac artery of the conduit.
Postrevascularization Phase
Following revascularization, the liver should assume a normal
color and consistency within several minutes. If the liver
remains pale or is overly soft, problems with portal inflow
should be considered. Alternatively, if the liver becomes ede-
In the 1980s, the waiting list mortality for small, pediatric liver
candidates was relatively high because the number of suitably
sized small liver donors was inadequate. As a result, techniques to reduce the size of an adult liver, based on Couinauds
segmental anatomy (Fig. 36.13), were developed so that the
left lobe, left lateral segment, or even a single segment could be
used for a recipient more than 10 times smaller by weight than
the donor.54,55 During the early experience, the donor hepatectomy was performed in a standard fashion and the liver was
brought back to the recipient hospital. The needed segments of
the liver were cut down on the back table with the organ on
ice, the vessels were left intact to the future transplant graft,
and the remainder of the liver was discarded. Techniques have
now developed so that both sides of the liver can be transplanted into two recipients, either a child and an adult or two
adults.56,57 In addition, the liver may be split in situ at the
donor hospital, allowing coagulation of the cut edge of the
liver so that bleeding is minimized following reperfusion. Perfusion to both sides of the liver can be inspected prior to flushing, ensuring that blood flow to all segments of each future
graft has been preserved. Because of technical and practical
issues, both the cut-down technique and in situ splitting of the
liver are still employed. Split liver transplantation has been
TRANSPLANTATION
556
RHV
R Hepatic
ducts x 2
557
RPV
RHA
Living donor liver transplantation was progressively developing in the United States until a well-publicized donor mortality
occurred.59 Living donor liver transplantation now accounts
for approximately 5% of all liver transplants performed in the
United States. In Japan and other areas of the Far East, where
deceased donor transplantation has developed more slowly
because of cultural difficulties with the concept of brain death,
living donor transplant is the rule rather than the exception.
A
Left hepatic
vein
Bile ducts
(segments
II and III)
Left hepatic
artery
Left portal
vein
TRANSPLANTATION
Proper
hepatic
artery
B
Left hepatic vein
Segment II
Inferior
vena cava
Bile ducts to
segments
II and III
Roux-en-Y
loop
Left
portal vein
Portal vein
Segment III
Left hepatic
artery
Hepatic
artery
Aorta
558
Right
hepatic vein
Donor liver
Right hepatic
artery
Right
portal vein
Right hepatic
artery
Inferior
vena cava
Right
portal vein
Right
bile duct
Portal vein
Roux-en-Y loop
FIGURE 36.16. Right lobe (segments V to VIII) living donor transplantation. A: Donor operation. B: Recipient operation completed.
is necessary to prevent edema of inadequately drained segments of the liver possibly leading to small-for-size syndrome.
Therefore, any accessory veins greater than 5 mm in diameter
should be reconstructed either by direct anastomosis to the
vena cava or by using an interposition graft. In addition,
the lengths of the portal vein, hepatic artery, and bile duct on
the donor graft are considerably shorter than those available
from a deceased donor. Therefore, during the recipient hepatectomy, considerable care should be given to preserving the
length of the recipient bile duct as well as the right and/or left
hepatic artery and portal vein that are intended for future
anastomosis.
4
COMPLICATIONS
3
Primary Nonfunction
About 2% to 10% of transplanted livers function so poorly in
the immediate postoperative period that death is likely in the
absence of retransplantation. This circumstance is referred to
as primary nonfunction. Most cases of primary nonfunction
likely occur as a result of ischemic injury, occurring either in
the donor or the recipient,60 or from poor preservation. Donor
factors known to predispose to primary nonfunction include
allograft steatosis, advanced donor age, and prolonged cold
ischemic time. In addition, donor race and the need for portal
vein reconstruction have also been demonstrated to be risk
factors for primary nonfunction.61
Early evidence for primary nonfunction includes poor bile
production of the liver intraoperatively, refractory acidosis,
progressive coagulopathy, and hepatic encephalopathy. In a
short period of time, these early signs are often followed by
acute renal insufficiency and eventually cardiopulmonary collapse. Serial factor V levels may be helpful to determine if a
liver allograft is functioning in a patient who has received a
massive transfusion of fresh frozen plasma. In this setting, the
INR may reflect transfused coagulation factors rather than
factors emphasized by the liver graft. Fresh frozen plasma contains relatively little factor V because this factor is relatively
unstable in cold storage. Therefore, a steady increase in the
factor V level suggests production by the liver rather than
transfusion with fresh frozen plasma.
Liver transplant recipients in the United States with primary nonfunction, currently defined as those who were transplanted within 7 days and are anhepatic or those who have
developed an aspartate transaminase above 3,000 along with
an INR above 2.5 and/or acidosis, can be relisted as a status
1A. Patients listed as a status 1A receive regional priority over
less ill patients and frequently wait only a period of a few days
for an appropriate donor to become available. Despite this
preferential listing for retransplantation, primary nonfunction
is associated with a mortality rate of more than 50%.61
559
Postoperative Hemorrhage
Postoperative hemorrhage requiring laparotomy occurs in
approximately 5% to 15% of liver transplant recipients. Postoperative bleeding should be suspected in any liver recipient
during the immediate posttransplant period who develops
tachycardia, volume-dependent hypotension, oliguria, and
abdominal distention. Because many liver transplant recipients
may have had a large volume of ascites preoperatively (sometimes more than 10 to 20 L), a considerable amount of bleeding may occur before developing an abdominal compartment
syndrome. In general, attempts to correct coagulopathy should
be made and reexploration should occur in patients with
refractory hypotension, abdominal compartment syndrome,
or ongoing need for blood transfusion. At exploration, a specific bleeding point often cannot be identified, suggesting that
bleeding may be related more to coagulopathy than failure of
surgical hemostasis. Therefore, waiting until coagulopathy is
corrected before reexploration may be wise, assuming that the
recipient is otherwise reasonably stable.
artery thrombosis is higher in pediatric recipients and recipients of living donors or split livers. Other risk factors include
receiving a liver from a donor who is significantly smaller than
the recipient, the need for reconstructive arterioplasty in the
presence of nonstandard donor anatomy, acute rejection within
the first week posttransplant, placement of cytomegalovirus
(CMV)-positive organs into CMV-negative recipients, and a
recipient history of smoking.62 The association between rejection and hepatic artery thrombosis may be the result of a
decrease in hepatic arterial flow that occurs when the liver is
swollen and edematous or of release of procoagulations into
the microcirculation in association with the inflammatory
injury of graft rejection.
Hepatic artery thrombosis can occur in the early period,
arbitrarily defined as within 30 days, or late posttransplant
period. Early hepatic artery thrombosis is usually identified
within the first 10 days posttransplant. The diagnosis is suspected in the setting of unexpectedly high liver enzymes, an
elevation in liver enzymes rather than a gradual decline, or
poor synthetic function during the first week to 10 days posttransplant. Other signs of biliary ischemia from hepatic arterial thrombosis include the development of biliary leaks, strictures, or intrahepatic abscesses. Doppler ultrasonography is
usually used to confirm flow within the extrahepatic and intrahepatic arteries. If inappropriate waveforms or no flow is identified, the diagnosis can be confirmed by angiography or reexploration. At exploration, flow can be restored within the
TRANSPLANTATION
560
FIGURE 36.18. Bile leak (arrow) from the choledochocholedochostomy after hepatic transplantation.
561
Intra-abdominal Sepsis
Intra-abdominal sepsis presents as diffuse peritonitis or localized abscess and occurs in about 5% of patients who undergo
liver transplantation. The most common cause of peritonitis is
leakage of the biliary anastomosis. Abscesses may also develop
spontaneously in the right upper quadrant or elsewhere in the
abdomen. Most isolated infected fluid collections can be managed by percutaneous placement of drains guided by ultrasound or computed tomography (CT) scanning, along with
broad-spectrum intravenous antibiotics. Generalized infected
ascitic fluid is managed with paracentesis and antibiotics.
Surgical drainage may be necessary if leakage of enteric contents is suspected based on the finding of extravasated oral
contrast in the peritoneal cavity on CT scan, or if the patient
does not respond to percutaneous drainage.
Neurologic Complications
The liver is relatively resistant to injury from recipient antibodies, regardless of whether they are present at the time of
transplant or develop later. This is very different compared
with renal and cardiac recipients who experience rapid graft
destruction, termed hyperacute rejection, if performed in a
patient who has complement fixing antibodies directed against
the donor organ in significant concentrations at the time of
transplantation. Hepatic graft injury from preexisting antibodies directed at donor ABO determinants does occur, but in
a much less pronounced fashion than in the context of renal
transplantation. The overall results of ABO-incompatible liver
transplants are somewhat inferior to those of ABO-compatible
transplantations, but only by about a 10% to 20% decrease in
1-year graft survival rates compared to ABO-compatible
grafts. Some of this decrease in graft survival rate may be due
to the fact that ABO-incompatible transplants are usually performed only in dire circumstances where the patient is so ill
that he or she may not survive the wait for a compatible organ.
Because preformed antibodies do not seem to be clinically
important, most transplantation programs do not perform
prospective cross matches between recipient serum and donor
cells before transplantation, and determination of recipient
and donor HLA type is no longer considered mandatory.
Why the liver is less susceptible to antibody-mediated
destruction than the kidney is not clearly understood. One factor may be the vastly different microcirculation that the liver
has compared with the kidney, with a preponderance of sinusoidal channels and a smaller capillary network. It is probable
that antibody-mediated injury affects blood flow through the
delicate capillary network of the kidney more than it does liver
sinusoids. In addition, each hepatocyte is exposed to two sinusoidal channels, presumably permitting survival if only one
sinusoid is occluded. Finally, differences in HLA antigen
expression are known to exist in the two organs, with the kidney the more antigenic of the two.
TRANSPLANTATION
Antibody-mediated Rejection
562
FIGURE 36.19. Acute rejection of a liver transplant. A: A portal tract is expanded by a polymorphous inflammatory infiltrate consisting of large
and small lymphocytes, plasma cells, macrophages, and neutrophils. The bile ducts (arrows) are damaged and inflamed. B: A central vein from
the same biopsy exhibits endothelialitis, characterized by swollen endothelial cells and infiltrating lymphocytes. (Reproduced with permission
from Thung SN, Gerber MA. Histopathology of liver transplantation. In: Fabry TL, Klion FM, eds. Guide to Liver Transplantation. New York:
Igaku-Shoin Medical Publishers; 1988.)
563
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56. Emond JC, Whitington PF, Thistlethwaite JR, et al. Transplantation of two
patients with one liver. Analysis of a preliminary experience with splitliver grafting. Ann Surg 1990;212(1):1422.
57. Humar A, Khwaja K, Sielaff TD, et al. Technique of split-liver transplant
for two adult recipients. Liver Transpl 2002;8(8):725729.
58. Marcos A, Fisher RA, Ham JM, et al. Right lobe living donor liver transplantation. Transplantation 1999;68(6):798803.
59. Miller C, Florman S, Kim-Schluger L, et al. Fulminant and fatal gas gangrene of the stomach in a healthy live liver donor. Liver Transpl 2004;
10(10):13151319.
60. Strasberg SM, Howard TK, Molmenti EP, et al. Selecting the donor liver:
risk factors for poor function after orthotopic liver transplantation. Hepatology 1994;20(4 Pt 1):829838.
61. Oh CK, Sawyer RG, Pelletier SJ, et al. Independent predictors for primary
non-function after liver transplantation. Yonsei Med J 2004;45(6):
11551161.
62. Pungpapong S, Manzarbeitia C, Ortiz J, et al. Cigarette smoking is associated with an increased incidence of vascular complications after liver
transplantation. Liver Transpl 2002;8(7):582587.
63. Bhattacharjya S, Gunson BK, Mirza DF, et al. Delayed hepatic artery
thrombosis in adult orthotopic liver transplantationa 12-year experience. Transplantation 2001;71(11):15921596.
64. Furuta S, Ikegami T, Nakazawa Y, et al. Hepatic artery reconstruction in
living donor liver transplantation from the microsurgeons point of view.
Liver Transpl Surg 1997;3(4):388393.
65. Stahl RL, Duncan A, Hooks MA, et al. A hypercoagulable state follows
orthotopic liver transplantation. Hepatology 1990;12(3 Pt 1):553558.
66. Parrilla P, Sanchez-Bueno F, Figueras J, et al. Analysis of the complications
of the piggy-back technique in 1,112 liver transplants. Transplantation
1999;67(9):12141217.
67. Borsa JJ, Daly CP, Fontaine AB, et al. Treatment of inferior vena cava anastomotic stenoses with the Wallstent endoprosthesis after orthotopic liver
transplantation. J Vasc Interv Radiol 1999;10(1):1722.
68. Frazer CK, Gupta A. Stenosis of the hepatic vein anastomosis after liver
transplantation: treatment with a heparin-coated metal stent. Australas
Radiol 2002;46(4):422425.
69. Feller RB, Waugh RC, Selby WS, et al. Biliary strictures after liver transplantation: clinical picture, correlates and outcomes. J Gastroenterol
Hepatol 1996;11(1):2125.
70. Wiesner RH, Batts KP, Krom RA. Evolving concepts in the diagnosis,
pathogenesis, and treatment of chronic hepatic allograft rejection. Liver
Transpl Surg 1999;5(5):388400.
71. Axelrod DA, Guidinger MK, McCullough KP, et al. Association of center
volume with outcome after liver and kidney transplantation. Am J Transplant 2004;4(6):920927.
Since 1964, cardiac transplantation has evolved from a sensational, perilous experiment to become conventional therapy for
end-stage heart disease, the paradigm of successful but expensive high-tech medicine. This remarkable transformation
stemmed from fundamental surgical innovations supported by
incremental improvements in the diagnosis and management of
common problems. Current challenges revolve around donor
supply and allocation, improving long-term outcomes, developing alternative therapies, and related ethical issues.
HISTORICAL PERSPECTIVE
Based on significant contributions by many surgical pioneers,18 the first clinical heart transplant was performed in
1964 by Hardy, who attempted to salvage a man dying from
cardiogenic shock by replacing his heart with one from a chimpanzee.9 Then, before the concept of brain death achieved wide
social or legal acceptance, in 1967 Christian Barnard et al. captured the imagination of the world with the first operative survival, using the heart of a resuscitated cadaveric donor.10 This
case, and many others that were performed shortly thereafter,
demonstrated not only the physiologic capacity of the transplanted human heart allograft to support the recipients circulation but also the difficulty of managing subsequent immunologic and infectious complications. After a worldwide flurry of
activity, generally dismal outcomes at many prominent cardiac
surgery centers made clear the need for more thoughtful
approaches to what was clearly a difficult constellation of problems beyond effective circulatory support.
A few pioneering programs persisted in cautious clinical
application supported by parallel laboratory investigation.
Recognizing the need for a more sensitive and specific diagnostic technique to diagnose rejection, Phillip Caves, working
P O I N T S
565
TRANSPLANTATION
K E Y
566
CANDIDATE EVALUATION
End-stage heart failure is the primary indication for heart
transplantation in adults, with coronary artery occlusive disease and myopathy of various etiologies each accounting for
about 45% of cases. Congenital heart disease is the primary indication for infants, whereas myopathy predominates in older
children.
The heart transplant evaluation process seeks to identify
2
patients for whom no other reasonable treatment options exist
and who are at higher risk of death without transplant than
with it, while excluding those whose comorbid conditions are
likely to significantly limit length or quality of life. In 1993, a
National Institutes of Health consensus conference developed
recipient selection guidelines for cardiac transplantation, based
on objective criteria known to predict poor outcome without
transplantation17; these guidelines (Tables 37.1 through 37.3)
continue to evolve in the context of improving heart failure
therapy.1820 Among patients with heart failure symptoms,
maximal oxygen consumption (MVO2) is more sensitive and
specific than ejection fraction in gauging prognosis, and
blunted cardiac output response to exercise may further stratify patients into high- and low-risk groups.18
When no clear survival advantage is apparent for transplantation or an alternative management strategy, quality of
life and other subjective factors are weighed. Contemporary
studies defining relative risks, along with basic considerations
in the medical management of end-stage heart failure, are well
summarized in recent reviews.19,20
TA B L E 3 7 . 1
INDICATIONS FOR HEART TRANSPLANT
General indications
End-stage heart disease without lower-risk alternative
Absence of any noncardiac condition likely to:
TA B L E 3 7 . 2
SELECTION CRITERIA FOR STRATIFYING RISK AND
SURVIVAL RESULTS
Survival benefit established
MVO2 10 mL/kg/min
Class IV CHF symptoms despite maximal medical therapy
Requiring mechanical circulatory support
Refractory angina without therapeutic alternative
Refractory ventricular arrhythmia without alternative
Survival benefit likely
MVO2 1014 with blunted CO response to exercise
Instability of fluid balance or renal function despite
documented compliance
EF 20% with class III HF symptoms on maximal medical
therapy
Survival benefit not established
MVO2 1014 with preserved CO response to exercise
MVO2 14, EF 20% without other indication
History of CHF or arrhythmia, controlled with medical
therapy
Quality-of-life considerations may influence selection of
recipients for whom survival benefit is not established.
CHF, congestive heart failure; CO, carbon monoxide; EF, ejection
fraction; MVO2, maximal oxygen consumption.
DONOR SELECTION
AND MANAGEMENT
The ideal donor is a young, previously healthy individual without cardiac disease or hypertension, who is well matched in size
to the intended recipient and whose hemodynamics have been
carefully managed during the evolution of his or her lethal central nervous system (CNS) injury. Some programs have advocated use of older donors, donors who may transmit infection
or malignancy to the recipient, and grafts with hypertensive
myocardial hypertrophy for particular recipients.21 Some
aggressive programs have even proposed that hemodynamically
significant coronary stenoses can be bypassed at the time of
transplant.22 These approaches to donor selection are associated
with less favorable short- and long-term outcomes,15,23,24 but
the increased risk may be considered acceptable for patients in
whom the short-term prognosis is poor without transplant.
Donor management requires skill and experience to successfully address the complex physiologic perturbations associated with brain death. Reflex hypertensive and hypotensive
responses to intracranial pressure changes, fluid and electrolyte imbalances consequent to the diabetes insipidus from
pituitary death, and additional stresses related to hemorrhage,
trauma, and surgery often cause hemodynamic and metabolic
instability, which may injure a previously healthy heart. The
neurohumoral milieu of CNS catastrophe may also adversely
affect other fundamental cell regulatory functions, such as
those dependent on thyroid hormone. Despite controversy
regarding the mechanisms involved, thyroid hormone is often
administered to the donor as a continuous infusion, hoping to
correct a sick euthyroid syndrome and optimize cardiac
metabolism prior to explant. Although evidence to date is
largely anecdotal, inotrope requirements can often be reduced
after thyroid infusion is begun, and donor hemodynamic
567
TA B L E 3 7 . 3
CONTRAINDICATIONS TO CARDIAC TRANSPLANTATION
Absolute contraindications
High pulmonary vascular resistancea
MATCHING DONOR
TO RECIPIENT
TRANSPLANTATION
RECIPIENT MANAGEMENT
BEFORE TRANSPLANT
Age over 65
568
HEART PROCUREMENT
OPERATIVE RECIPIENT
MANAGEMENT
Timing of the recipient operation requires careful coordination with the procurement team. Anesthesia is induced after
the donor heart is visually inspected and found suitable.
Venous access is obtained, which will permit rapid volume
resuscitation and invasive cardiac monitoring after the new
heart is implanted. Prior cardiac surgery may complicate coordination of operative timing and is associated with increased
risk of bleeding.
If appropriate, Coumadin effects are reversed with fresh
frozen plasma and vitamin K. Aprotinin or -aminocaproic
acid are often used to inhibit fibrinolysis and prevent coagulopathic bleeding after prior cardiac surgery or associated with
hepatic congestion. Increased inotropic infusion, antiarrhythmic agents, or mechanical circulatory support may be required
FIGURE 37.1. Native cardiectomy and donor graft preparation. A: Recipient pericardium after institution of cardiopulmonary bypass and ascending aortic occlusion, with caval snares secured. The diseased native heart can then be safely
excised by transecting the recipient aorta and pulmonary artery, and the atria divided as appropriate for the intended
implant technique. Shown is the right atrial incision for the traditional Lower/Shumway right atrial cuff. B: Posterior view
of the explanted donor heart, indicating various incisions used for atrial cuff preparation. Donor atrial cuff incisions made
in preparation for traditional Lower/Shumway biatrial implant are indicated by the heavy white dashed line. The superior
vena cava (SVC) is ligated or oversewn. Right and left pulmonary vein (light white dashed line) and superior vena cava
(black dashed line) incisions are indicated for the total atrioventricular implant technique. For the bicaval technique, the
donor SVC (black dashed line) and inferior vena cava are retained as for the total atrioventricular technique (Fig. 37.4), and
the donor left atrial cuff trimmed as for the traditional biatrial approach (heavy white dashed line).
569
TRANSPLANTATION
570
571
Hypertension and hyperlipidemia are prevalent due to predisfunction, and this drug has recently been approved by the U.S.
position in the recipient patient population and as side effects
Food and Drug Administration for clinical use.38 Poor function of either or both ventricles may necessitate institution of 6 of various immunosuppressive agents. Prophylaxis against
opportunistic infections includes agents targeted at common
mechanical support as a bridge to graft recovery or to retransprotozoal and viral pathogens (Table 37.4). Surveillance biopplantation.
sies are performed according to a scheduled routine, and addiPostoperatively, ventilator and inotropic support is
tional biopsies are performed to exclude rejection in the event
weaned, immunosuppression is instituted, and diuretic and
of hemodynamic instability or unexplained fever. Typically,
antihypertensive agents are initiated as necessary. Isopropatients are able to leave the hospital within 10 days of uncomterenol is continued for about 5 days and replaced with theoplicated operation, to be followed regularly in outpatient clinic.
phylline if needed to sustain a resting heart rate over 70. The
Monitored physical rehabilitation facilitates optimal cardiofirst surveillance endomyocardial biopsy is performed 7 to 10
vascular and musculoskeletal recuperation,48 and occupational
days after surgery and repeated as an outpatient procedure
about every 2 weeks for the first 3 months. Patient and carerehabilitation may offer important psychological and social
giver education with regard to medication schedules and physbenefits.
iologic monitoring facilitates early discharge for patients without complications. Biologic monitoring of peripheral blood
gene or protein expression and electrical approaches to moniCOMPLICATIONS
tor the immune response to the graft have shown promise to
3941
supplant routine invasive monitoring.
Complications of antirejection therapy relate primarily to the
side effects of the specific immunosuppressive agents currently
used. Infections tend to occur in patients with the greatest
degree of preoperative debility and malnutrition, or in conIMMUNOSUPPRESSION
junction with additional stressors such as perioperative bleeding or hepatorenal dysfunction. Bacterial pathogens are comThe goal of immunosuppressive therapy is to prevent immunemon in the first several weeks, particularly in the lung and
mediated injury to the graft while minimizing associated com5 plications, including opportunistic infection. Most programs
related to surgical or vascular access sites. Opportunistic viral
and fungal infections usually predominate later. Increasingly
employ a triple-drug regimen, including a calcineurin
effective prophylaxis for cytomegalovirus and herpes infections
inhibitor, an antimitotic agent, and steroids. This approach
has markedly reduced the morbidity associated with these comallows each individual drug to be used within its therapeutic
mon pathogens. When infection occurs, immunosuppression is
window (Table 37.4). Some centers add antibody induction
tapered as aggressively as possible based on myocardial biopsy
with anti-CD3, polyclonal antilymphocyte serum, or antiinterresults.
leukin-2 (anti-IL-2) receptor antibodies.4247 The mechanisms of
Acute rejection occurs in the majority of patients and is
action and side effect profiles of these agents are well described
graded histologically according to standardized criteria develin an earlier section of this chapter.
oped by the International Society for Heart and Lung TransMedical management after heart transplantation is focused
plantation (ISHLT). When detected at an early histologic stage
on anticipation and prevention of common complications.
TRANSPLANTATION
FIGURE 37.4. Total atrioventricular transplant technique. A: Recipient pericardial well after preparation of bilateral pulmonary vein
pedicles and caval cuffs, for total atrioventricular heart transplant. B: Construction of left pulmonary vein anastomosis. As with other
left atrial anastomotic approaches, atrial walls or vein cuffs are everted to minimize exposure of thrombogenic fat or muscle to the
blood.
572
TA B L E 3 7 . 4
TYPICAL IMMUNOSUPPRESSIVE PROTOCOL AND ASSOCIATED MEDICAL TREATMENT
FOLLOWING ADULT HEART TRANSPLANTATION
Calcineurin inhibitors:
Side effects:
Cyclosporine
FK506
Antimitotic agents:
Side effects:
Glucocorticoids:
Azathioprine
12 mg/kg/d qd
Mycophenolate mofetil
Side effects:
Antiprotozoal:
Antiviral:
Antihypertensives:
Antilipid agents:
(ISHLT grade 1, Fig. 37.5) in an asymptomatic patient on surveillance biopsy, rejection will often respond to augmented
oral steroids and/or an increased dose of calcineurin inhibitor.
When a higher grade of rejection is found (Fig. 37.6), when the
infiltrate fails to resolve in response to initial interventions, or
in the setting of depressed cardiac function or shock, high-dose
intravenous steroids are administered and antilymphocyte
therapy often added. Inotropic or mechanical support is instituted as needed in hopes of rescuing graft and patient. Antibody-mediated vascular rejection is a controversial entity
that, when documented by immunohistochemical techniques,
may warrant introduction of cyclophosphamide or other
agents with increased activity against B cells.
FIGURE 37.5. International Society for Heart and Lung Transplantation grade 1Rdiffuse interstitial or focal perivascular infiltrate with
rare or absent myocyte damage is characteristic of mild acute cellular
rejection.
FIGURE 37.6. International Society for Heart and Lung Transplantation grade 3Rmultifocal cellular infiltrate with focal myocyte necrosis,
typical of severe acute cellular rejection.
573
2005-06
80
2000-04
70
60
1995-99
1990-94
50
40
1985-89
30
20
10
1980-84
0
0.5
2
3
4
Years after transplant
FIGURE 37.8. Heart Transplant Survival, 19802006. Survival following heart transplantation in recipients, grouped by era of operation, analyzed by the Kaplan-Meier method. Operative survival
accounts for much of the steady improvement in outcomes over the
past two decades. The subsequent rate of attrition appears to have
changed little over the past 20 years, likely reflecting the effect of competing influences such as an older recipient population and improving
patient management strategies. (Figure created from data provided by
the United Network for Organ Sharing, including follow-up information available as of 12/10/09.) Current demographics and statistics
may be found at International Society for Heart and Lung Transplantation website (www.ishlt.org).
typical rapid ventricular response. Most other agents traditionally used to treat atrial arrhythmias depress AV node conduction or myocardial contractility, particularly undesirable
side effects in a recent heart recipient. Amiodarone is generally
better tolerated, controls heart rate and promotes conversion
to sinus rhythm, and has been used widely in this circumstance.
Among patients who survive beyond the first year, the pridecreased by about 15% between 1997 and 2004 despite a
mary limits to long-term survival are cardiac allograft vascusteady increase in average donor age.15,24 A recent trend
lopathy (CAV) and malignancy15,16,24 (Fig. 37.7). Current
upward in U.S. heart transplant activity (from 2,000 to 2,200
understanding of the pathogenesis of CAV is incomplete.4951
cases annually) may reflect the influence of the Health
Widely presumed to be a consequence of chronic rejection,
Resources and Services Administration organ donor initiathis process has an incidence of approximately 5% per year.
tive,15,55,56 implementation in 2006 of a donor allocation algoCAV may cause progressive insufficiency of coronary flow,
rithm that emphasizes disease acuity over proximity to donor
myocardial infarction, and ultimately death. Recent research
hospital or other factors.
has drawn attention to the importance of donor stress associOperative survival in adults has improved over the past 20
ated with brain death and ischemia/reperfusion injury in the
years to above 90%, and both patient and graft 1-year surincidence and severity of CAV in animal models.52 In contrast
vival rates exceed 87%15,16 (Fig. 37.8). The most important
to the usual pattern of focal proximal lesions in conventional
risk factors for death within the first year include previous
atherosclerosis, coronary arteries are diffusely involved, and
transplant, increased donor age (with age older than 60 conconventional revascularization techniques are not generally
ferring greater risk than age older than 45), need for ventilator
feasible. In the future, new immunosuppressive or antiproliferor left ventricular assist device support before transplant, and
ative agents may prevent this process or delay its progression.53 Both CAV and increased risk of malignancy would 8 recipient age older than 60. Among common complications,
rejection and infection together account for most of the morlikely be prevented if efforts to accomplish durable tolerance
tality during the first year and contribute approximately
are successful, but this obstacle is proving stubborn.54
equally (Table 37.5). Beyond the first year, malignancy, including posttransplant lymphoproliferative disease, and chronic
rejection emerge as prominent additional factors limiting longRESULTS
term survival. Extrapolating from current early results, more
7 Due to a decline in the number of donor hearts that are considthan 50% of recent recipients can expect to be alive 10 years
after transplant, with actuarial graft half-life over 12
ered acceptable, the number of heart transplants performed
years.16,24,27
worldwide has declined, from a peak of about 4,070 in 1995 to
Repeat heart transplantation accounts for less than 2% of
fewer than 3,200 reported in each year since 2000, a 20%
all heart transplants done. When performed within the first 6
decrease. While some decrease in reporting from European cenmonths, typically for early failure of the first graft, 1-year surters may have resulted from the absence of an incentive to convival is less than 50%. When performed later, usually for cartribute to international registries, reported U.S. activity
diac allograft vasculopathy, 1-year survival is over 80%, and
which is federally mandated by organ allocation regulations
TRANSPLANTATION
574
TA B L E 3 7 . 5
COMPLICATIONS FOLLOWING HEART TRANSPLANTATION
Primary graft failure (5%)
Technical (inadequate tissue preservation; reperfusion
injury)
Immunologic (hyperacute rejection)
Donor selection (myocardial, valvular, or coronary
obstructive disease in donor)
Technical
Size mismatch (too large, too small)
Bleeding (surgical, medical)
Anastomotic (narrowing, aneurysm, disruption)
Infection
Bacterial (various)
Viral (herpes, cytomegalovirus, Epstein-Barr virus)
Protozoal (toxoplasmosis, Nocardia)
Fungal (Candida, Aspergillus)
Rejection
Acute (cellular, humoral, mixed) (24%34% within first
year)
Chronic (cardiac allograft vasculopathy) (53% by 10 years)
Treatment effects
The heart transplant community has taken the lead in standardizing patient selection and management guidelines and has
established policies for equitable organ allocation. Those given
an opportunity to receive the gift of life are chosen from a
much larger population who might benefit. Recipient candidacy decisions are made by a multidisciplinary group based on
objective and subjective input from many individuals who
come to know the patient and family in depth. Some recipient
selection criteria are fundamentally arbitrary: age is retained as
a criterion because of the limited supply of donor organs and
based on the consensus view that younger patients deserve preferred access. Recipient selection criteria only become unfair if
they are applied unequally or inconsistently at different programs or between various regions of the country.
Some of the most difficult decisions made by the heart
transplant team involve medically marginal candidates with
outstanding and effective social support or medically suitable
candidates with marginal social support. While the majority of
such patients will do well, outcomes in either case can, on
average, be expected to fall below outcome benchmarks. For
every marginal patient transplanted, a candidate who meets all
the criteria may die. Thus, the right decision for an individual patient is difficult or impossible to know in advance and
may conflict with the best interests of the population of potential recipients.
CURRENT ISSUES
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18. Chomsky DB, Lang CC, Rayos GH, et al. Hemodynamic exercise testing.
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K E Y
Long-term survival after lung transplant is lower in comparison to outcomes in the transplantation of other solid
organs. The lack of effective medical therapy for acute and
chronic rejection remains a barrier.
2 Candidates for pulmonary transplantation have significant
functional impairment that interferes with activities of
daily living. In patients with restrictive or obstructive disease, abnormal gas exchange is the major problem and
essentially all require supplemental oxygen. In patients with
pulmonary vascular disease, the manifestations of right
ventricular failure predominate.
3 A paradigm shift in the allocation of donor lungs has
decreased lung waitlist times and waitlist mortality. The
effect of the Lung Allocation Score on short-term and longterm mortality remains to be seen.
1
INTRODUCTION
With nearly 18,000 lungs implanted, pulmonary transplantation comprises only 4% of the organs transplanted in the
1 United States between 1988 and 2008. Since the first lung
transplant was performed in 1963,1 outcomes for this operation have improved dramatically, but even with advances in
immunosuppression, surgical technique, and perioperative
and posttransplant care, long-term survival following pulmonary transplantation remains less than that of other solid
organ transplant recipients. The major problems limiting
durable pulmonary transplantation have been infection, acute
rejection, impaired anastomotic healing,2 and chronic rejection, manifested in lung transplant recipients as the onset of
bronchiolitis obliterans.3
In the lung, unlike other solid organs, systemic arterial
blood supply is limited to the bronchial arteries. Because the
P O I N T S
Advances in donor management and lung preservation
have been shown (a) to minimize lung injury, (b) to increase
the number and quality of recoverable donor lungs, and (c)
likely to be responsible for the dramatic increase in the
number of lung transplants performed over the last 10
years.
5 It is believed that posttransplant lung injury results not only
from the ischemic insult and the host immunologic response
but also from reperfusion of the ischemic organ and other
mediators of nonalloimmune-related injury.
6 Airway anastomotic healing remains a concern following
transplantation but has been ameliorated by improvements
in operative technique and postoperative management.
7 By the end of the first year after transplantation, approximately 80% of recipients report no limitations in activity.
4
bronchial artery anatomy and caliber vary greatly, most transplant surgeons have not advocated reanastomosis of these vessels primarily to avoid prolonged total organ ischemia time,
particularly when bilateral sequential transplantation is
planned. Consequently, the bronchial anastomosis is more profoundly ischemic after transplantation and susceptible to airway dehiscence, typically within 3 weeks after transplantation.
The combination of anastomotic ischemia and other factors
such as infection and post-reperfusion edema hampered initial
efforts to develop successful clinical programs in pulmonary
transplantation.
The first combined heart and lung transplantation was performed successfully in 1981, but this procedure currently is
rarely performed, with only 50 or fewer performed annually in
the United States since 2000. Combined cardiac and pulmonary transplantation introduced a series of new problems
related to transplanting two organs, including those associated
with heart transplantation, especially accelerated coronary
577
TRANSPLANTATION
578
TA B L E 3 8 . 1
INDICATIONS/CONTRAINDICATIONS
TA B L E 3 8 . 2
INDICATIONS/CONTRAINDICATIONS
ABSOLUTE CONTRAINDICATIONS
Recent malignancy other than nonmelanoma skin cancer
COPD
Active sepsis
Pulmonary hypertension
DLCO 39%
RELATIVE CONTRAINDICATIONS
CF
Age 65
Mechanical ventilation
Hypercapnia
Osteoporosis
Pulmonary hypertension
PAH
Disease-Specific Indications
Disease-specific indications for lung transplantation are listed
in Table 38.2.
Idiopathic Pulmonary Fibrosis. Usual interstitial pneumonia (UIP) is the pathologic correlate of IPF and is the most
common subtype of interstitial pneumonia. Pulmonary fibrosis
Cystic Fibrosis/Bronchiectasis/Infection-related Endstage Lung Disease. Cystic fibrosis (CF) is the third most
common indication for lung transplantation, accounting for
20% of lung transplants performed in 2006, with most recipients undergoing bilateral transplantation.11 Colonization of the
airway with resistant organisms is common in these patients
and is not an absolute contraindication to transplantation,
although overt sepsis is an absolute contraindication to transplantation. Single-institution studies have identified colonization with Burkholderia cepacia genomovar III (redesignated as
Burkholderia cenocepacia) to be associated with a 30% to
40% increase in posttransplant mortality, although this finding
has not been validated in a multi-institutional setting.
Among patients with pulmonary disease due to cystic fibrosis, the time course of respiratory deterioration is highly variable. As a consequence, the criteria for pulmonary transplantation in this population have been difficult to define by risk
modeling, although deterioration of FEV1 to below 30% of
predicted remains an indication for referral to evaluation,
although not for immediate listing.22,23 Other factors to consider include increasing oxygen requirement, hypercapnia, and
pulmonary hypertension.24
Diagnosis code
Functional status
Diabetes
Assisted ventilation
Supplemental oxygen
FVC% predicted
PA systolic
PA mean
PA wedge
PCO2
Highest
Lowest
Change %
Six-min walk
Creatinine
FVC, forced vital capacity; PA, pulmonary artery.
http://www.unos.org/resources/frm_LAS_Calculator.asp
STAGING
TRANSPLANTATION
has been the second most common indication for lung transplantation, accounting for 28% of single-lung transplants and
14% of bilateral lung transplants since 1995.11 In 2006, IPF
accounted for 32% of all lung transplants performed.
Although the options for effective medical therapy of
patients with IPF are limited and patient mortality is high with
median survival of 3 to 4 years following diagnosis, patients
experience a varying clinical course, with some patients progressing rapidly and others following a more indolent deterioration. Risk factors for poor survival include a pathologic
diagnosis of UIP (vs. other type of interstitial pneumonia),
severe fibrosis by high-resolution computed tomography, the
presence and severity of pulmonary hypertension, and acute
pulmonary exacerbations.
Assessment of pulmonary function and exercise capacity
also can be used to identify subgroups of patients with pulmonary fibrosis at higher risk for mortality. A baseline DLCO
of less than 39% and greater than 10% decrement of DLCO
or forced vital capacity (FVC) over a 6- to 12-month period
are associated with an increased risk of death.19,20 Oxygen
desaturation and shorter walk distance during 6-minute walk
testing independently predicted increased mortality in patients
diagnosed with pulmonary fibrosis.21
579
580
DONOR CONSIDERATIONS
Donor Selection
The shortage of acceptable donors for lung transplantation is
highlighted by the observation that although the number of lung
transplants has steadily increased (1,465 in 2007) and waitlist
times and waitlist death rates have decreased, the total number
of registrants on the wait list has remained the same.28 The reasons that fewer lungs are offered or accepted compared to other
organs is manifold. Death from head injury or bleeding may
lead to neurogenic pulmonary edema, while chest trauma can
result in contusion or pneumothorax. All brain-dead donors are
intubated and at risk for aspiration and nosocomial pneumonia,
especially if there is a prolonged interval between hospitalization and declaration of brain death. Finally, hemodynamic instability, whether from herniation or trauma, often results in significant volume resuscitation that can contribute to acute lung
injury.
Bronchoscopy allows for direct examination of the
bronchial tree and for microbiologic examination of bronchial
secretions, the results of which may influence later treatment
of the recipient. Chest radiography and computed tomography
are useful to evaluate for effusions or pulmonary infiltrates,
consolidation, and contusion that might be contributing to
donor hypoxemia. Unlike other solid organ transplants, lungs
are unique in carrying a relatively high risk of intrinsic infection (i.e., pneumonia) following transplant. Infiltrates typically
preclude donor candidacy. A small infiltrate in one lung without evidence of purulent secretions may still allow this lung to
be used in conjunction with a contralateral normal lung in a
bilateral lung transplant. Moreover, a pulmonary infiltrate
does not necessarily preclude use of the contralateral lung for
single-lung transplant.29 Not infrequently, the lungs of a particular donor may not be suitable because of infiltrates when
all other organs are acceptable. Because all brain-dead patients
have endotracheal tubes and are on mechanical ventilation,
there is a high likelihood that the airway is either colonized
with bacteria or that there is ongoing invasive pulmonary infection. With pulmonary infection, an infiltrate often is present on
the screening chest radiograph.
Aspiration at the time of the insult that resulted in brain
death is a common cause of pulmonary infiltrates in potential
donors. Signs of aspiration may not be evident on a chest radiograph for 24 to 48 hours, underscoring the importance of the
bronchoscopic examination when evaluating donor candidacy.
Characteristic early bronchoscopic evidence of aspiration
includes erythematous tracheobronchial mucosa, purulent secretions, and occasionally the presence of food particles.
Major pulmonary contusion resulting from blunt chest
trauma also may eliminate lungs from donor consideration,
but minor to moderate contusions unilaterally are often
acceptable. Evaluating the full extent of contusion at the time
of donor retrieval can be difficult because the interval from
injury to determination of brain death and donation may be
short. Although the detrimental effect on gas exchange caused
by a pulmonary contusion is usually transient, further bleeding into the lung parenchyma could occur if cardiopulmonary
bypass is required to perform the transplantation. Pulmonary
edema may occur as a result of massive head injury and may
be exacerbated by donor management protocols directed at
maintaining satisfactory nonpulmonary organ perfusion and
function.
The well-recognized limitation of donor organ availability is
compounded by the relatively fewer usable lungs per donor.
Criteria for an acceptable donor lung are particularly stringent,
as listed in Table 38.4.30 This consensus statement highlights
the dearth of data available to validate these criteria. Multiple
single-institution retrospective reports looking at extended
criteria donors (those who do not meet one or more ideal criterion) have been published with conflicting results on nearly
every single criterion with respect to postoperative, short, and
long-term outcomes. Clinically, these selection criteria provide
an overall gestalt of the quality of the donor. If one aspect of the
donor is marginal, the donor lungs can still be acceptable; however, when multiple criteria are not met, the risk of transplanting such lungs might be increased. There are several caveats
that have come into standard practice. Although leukocytes
or occasional bacteria on sputum Gram stain can be acceptable,
the presence of gross pus or fungal elements confers a high risk
of perioperative complications.31 In the annual report of lung
transplant outcomes, increasing donor age modestly increased
the risk of 5-year mortality.11 Analysis of a large cohort of more
than 750 lung and heartlung recipients demonstrated significantly worse long-term survival with ischemic times greater than
330 minutes. Hazard ratios for death were threefold higher in
patients with ischemic times of 8 hours and nearly eightfold
higher when ischemia reached 10 hours.32 The detrimental
effects of older donor age and longer ischemic times appear to
be additive.33
TA B L E 3 8 . 4
MANAGEMENT
581
Donor Management
Pulmonary toilet
Restrict IV fluids
Diurese to CVP 4-8 mmHg
Elevate head of bed 30
Lung protective ventilation
Plateau pressure < 30 cm H2O
Tidal volume 4-8 ml/kg
Re-evaluate ABG
Recruitment Maneuvers
PEEP 15 cm H2O for 2 hours
Intraoperative Evaluation
Bronchoscopy
Examine lungs for contusions,
nodules, or injuries
ABG
Pulmonary vein gases if indicated
ALGORITHM 38.1
Donor Management
4
Lung Preservation
Unlike the kidney, liver, or pancreas, immediate acceptable
function of the transplanted lung is vital for survival of the
recipient. Primary graft dysfunction occurs in 10% to 25% of
TRANSPLANTATION
582
TRANSPLANTATION OPERATION
The decision to proceed with single-lung or bilateral lung transplantation depends on several factors, including the etiology of
respiratory insufficiency and donor lung availability. Patients
with chronic infection, such as those with cystic fibrosis or
immunoglobulin deficiency disorders, require replacement of
both lungs. Single-lung transplantation can be considered for
patients with restrictive physiology (pulmonary fibrosis), particularly if there is no evidence of secondary pulmonary hypertension.
In patients with end-stage obstructive lung disease, specifically
emphysema, early in the pulmonary transplantation experience,
it became evident that single-lung transplantation was associated
with altered physiology arising from hyperventilation of an
overly compliant native emphysematous lung left in situ. Air
trapping in the overly compliant native lung, combined with
the resultant mediastinal shift, resulted in a significant ventilation and perfusion mismatch, as well as poor expansion and
compromised function of the transplanted lung. Despite such
concerns, it also has been demonstrated that single-lung transplantation not only is an acceptable operation for patients with
emphysema but also may be the operation of choice for
patients older than 50 years.44 In contrast, bilateral lung transplant recipients appear to have greater improvement of FEV1
and 6-minute walk testing when compared with single-lung
transplant recipients, at 1-year follow-up.45
Bilateral lung transplantation, when indicated, has been
simplified by the development and refinement of the sequential
lung transplant procedure rather than en bloc double-lung
operation, which required a tracheal anastomosis with cardiopulmonary bypass and resulted in significant perioperative
cardiac morbidity and mortality.46 Bilateral sequential lung
transplant can be approached either by median sternotomy or
bilateral thoracotomies and with or without cardiopulmonary
bypass depending on the indication for transplantation. A
bilateral thoracosternotomy incision (clamshell) permits easier completion of the recipient pneumonectomies than median
sternotomy, but the clamshell incision tends to be more painful.
A candidates past history of chest operations does not alone
preclude eligibility for bilateral lung transplantation.
In patients with pulmonary hypertension, single-lung transplantation historically had been felt to be adequate to unload the
right ventricle, reduce pulmonary artery pressure, and thus lead
to improved right ventricular function (Table 38.5). Currently,
TA B L E 3 8 . 5
COMPLICATIONS
PRETRANSPLANT
POSTTRANSPLANT
58 mm Hg
16 mm Hg
Systolic
94 mm Hg
28 mm Hg
25%
52%
4 L/min
7 L/min
1,302 dyne/cm5/s
161 dyne/cm5/s
OPERATIVE TECHNIQUE
Single-lung Transplantation
The performance of the donor operation does not vary because
one always attempts to use both lungs, either for single-lung
replacement on two recipients or for distribution in another
transplant medical center. This practice provides the most efficient use of limited donor organs. In the recipient operation, a
standard fourth intercostal space posterolateral thoracotomy
is performed. In patients with emphysematous disease, musclesparing axillary thoracotomy can be performed, but this
approach might not afford suitable exposure for patients who
have significant volume loss due to severe pulmonary fibrosis,
previous thoracotomy, or pleurodesis. The hilar dissection
(Fig. 38.1) differs from that of a pneumonectomy in that the
main pulmonary artery should be mobilized and divided distal
to the origin of the first segmental trunk and the pulmonary
veins should be divided at the main segmental tributaries as
they return to the superior or inferior veins. Care should be
taken to preserve lymphatic and areolar tissue at the point of
division of the mainstem bronchus in order to maintain its vascular supply. When the donor lung arrives in the operating
room, the recipient pneumonectomy is performed by dividing
the hilar vessels as far distally as possible and the bronchus at
the level of the upper lobe take-off.
The implantation procedure begins with construction of an
anastomosis between the donor and recipient bronchus. Endto-end anastomosis, with running suture approximation of the
TRANSPLANTATION
583
584
RESULTS
IMMUNOSUPPRESSION
Immunosuppression is initiated in the immediate perioperative
period and continued for the rest of the recipients life. UNOS
registry data show that regimens typically include a calcineurin inhibitor, either cyclosporine or tacrolimus; a purine
synthesis antagonist, either azathioprine or mycophenolate
mofetil; and a corticosteroid, either methylprednisolone (intravenous) or prednisone (oral). In a recent open-label randomized trial of 90 patients who received either cyclosporine or
tacrolimus,55 subjects who were treated with tacrolimus experienced significantly less acute rejection. Lymphocytic bronchitis was less frequent among patients receiving tacrolimus. In
addition, fewer (but not statistically significant) patients developed stage 0-p bronchiolitis obliterans syndrome. These investigators used a composite endpoint including cumulative acute
rejection score, cumulative lymphocytic bronchitis score, or
the development of bronchiolitis obliterans syndrome stage
0-p (10% or greater decrease in FEV1). No difference in graft
survival was noted. Although diabetes was slightly more
prevalent among subjects treated with tacrolimus, there were
no differences observed between the two treatment groups in
terms of hypertension, chronic renal disease, posttransplant
malignancy, or total number of infections.
In other solid organs, use of induction (perioperative) antithymocyte regimens appears to be salutary in reducing both acute
and chronic rejection. There are limited data supporting the use
of such agents in lung transplantation. In a study of 44 patients
randomized to conventional triple-drug immunosuppression
585
COMPLICATIONS
Complications resulting from pulmonary transplantation occur
frequently, may be severe, and occasionally result in death.
Intraoperative complications include technical problems with
the vascular or bronchial anastomoses, injury to the phrenic or
recurrent laryngeal nerves, and myocardial infarction. Early
postoperative complications include primary graft dysfunction,
infection, and problems with airway healing and acute rejection. The most common late complications are infection and
bronchiolitis obliterans (chronic rejection). Intra-abdominal
complications are not uncommon. Wound infection is noted
rarely. Noninfectious, nonpulmonary complications related to
immunosuppression are common. The cumulative prevalence
within 5 years after transplant of hypertension, renal insufficiency, hyperlipidemia, and diabetes is 85.3%, 37.0%, 53.6%,
and 35.5%, respectively.11 Finally, there is a three- to fourfold
higher risk of malignancy in patients after transplant.60
Causes of recipient death can be categorized according to the
time frame in which they occur. Early deaths (sooner than 30
days following transplant) most commonly result from primary
graft failure (28.2%).11 Infection is the second most common
cause of early death (20.3%), followed by heart failure
(11.1%). Rejection accounts for 4.3% of deaths in the early
posttransplantation period. Hemorrhage and airway dehiscence
each are responsible for 8.3% of early postoperative deaths.
Infection accounts for about 39.5% of deaths within the first
year of transplant (after 90 days). About one third of deaths
result from manifestations of chronic rejection and obliterative
bronchiolitis, the single biggest impediment to long-term survival following lung transplantation. Respiratory failure and
malignancy are the next most common causes of late mortality.
Despite the major strides made in the operation itself and early
postoperative care, the complications resulting from chronic
immunosuppression continue to plague transplant patients.
TA B L E 3 8 . 6
STAGING
GRADE
RADIOGRAPHIC
INFILTRATE CONSISTENT
WITH PULMONARY
EDEMA
PaO2/
FiO2
300
Absent
300
Present
200300
Present
200
Present
Rejection
With few exceptions, acute rejection episodes occur soon after
transplantation, usually between posttransplantation days 5
and 7. Often, two or three rejection episodes occur within the
first month. Mild temperature elevation, perihilar fluffy infiltrates, or a minimal decrease in blood oxygenation as measured by arterial oxygen tension may herald rejection. Because
rejection occurs so frequently during this period, the distinction between infection and rejection may be difficult. Often,
the distinguishing factor between these two entities is that
rejection responds positively to the administration of corticosteroids. Treatment of early rejection episodes involves the use
of bolus corticosteroid administration given on 3 consecutive
days. Within 12 to 18 hours after the first corticosteroid dose,
symptoms relating to rejection usually resolve, including clearing of infiltrates on chest radiograph.
The diagnostic experience using transbronchial biopsy to
diagnose and monitor rejection at some centers after cardiopulmonary transplantation is impressive, but the number
of biopsies required to maximize specificity is large. One group
recommends obtaining 18 separate transbronchial biopsy
specimens to achieve 95% specificity. The risks and potential
complications of transbronchial lung biopsy do not justify its
routine performance because suspected rejection episodes
respond so well to corticosteroids. Transbronchial lung biopsy
can be used when the issue of rejection versus infection is not
TRANSPLANTATION
586
Infection
587
patients is related to a human major histocompatibility complex (human leukocyte antigen)A2 antigen mismatch. Others
postulate that CMV infection or early lung injury, such as that
arising from primary graft dysfunction,75 may be implicated.
Once diagnosed, it is imperative to increase immunosuppression to prevent what is usually an insidiously progressive disorder. Unfortunately, in patients who have developed obliterative
bronchiolitis and then undergo retransplantation, the pathology can recur in the newly transplanted lungs. Obliterative
bronchiolitis remains the major problem in patients surviving for
greater than 2 years following transplantation. Overall, longterm survival for lung transplantation is not likely to improve
significantly until effective strategies for the prevention and
treatment of obliterative bronchiolitis and bronchiolitis obliterans syndrome are identified.
TA B L E 3 8 . 7
INDICATIONS/CONTRAINDICATIONS
Emphysema
SINGLE
LUNG (%)
DOUBLE
LUNG (%)
53.0
23.0
1-Antitrypsin
8.5
9.5
Cystic fibrosis
2.3
31.0
24.0
9.7
Primary pulmonary
hypertension
1.1
7.6
Retransplant
2.0
1.7
Idiopathic pulmonary
fibrosis
Adapted with permission from Trulock EP, Edwards LB, Taylor DO,
et al. The Registry of the International Society for Heart and Lung
Transplantation: twenty-first official adult heart transplant report
2004. J Heart Lung Transplant 2004;23:804815.
FIGURE 38.4. Mean values for ventilation and perfusion for patients
undergoing single-lung transplantation for emphysema. Note the
ventilation-perfusion mismatch that occurs, as expected, after transplantation.
TRANSPLANTATION
POSTTRANSPLANTATION
PHYSIOLOGY
588
FIGURE 38.5. Comparison of percentage of predicted forced expiratory volume in 1 second in 14 patients undergoing single and 10
patients undergoing bilateral sequential pulmonary transplantation
for chronic obstructive pulmonary disease.
FUTURE CONSIDERATIONS
Pulmonary transplantation has slowly evolved from an experimental therapy to standard of care for patients with respiratory
failure, although many fewer patients undergo these operations
compared with other solid organ transplants. Donor availability remains a limiting issue and will likely continue to be an
obstacle despite efforts to improve both donor management
and organ procurement efforts at a societal level. Lung volume
reduction surgery has demonstrated some benefit in a select
group of COPD patients but has not had as significant an
impact on quality of life as lung transplant has for patients with
emphysema. Questions about long-term impact and preservation of lung function remain to be answered. Other considerations including posttransplantation quality of life and costutility analyses also will likely impact the application of this
therapy despite the accomplishments of the past 40 years.
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213218.
73. Trulock EP, Edwards LB, Taylor DO, et al. Registry of the International
Society for Heart and Lung Transplantation: Twenty-second Official Adult
Lung and Heart-Lung Transplant Report2005. J Heart Lung Transplant
2005;24(8):956967.
74. Sato M, Keshavjee S. Bronchiolitis obliterans syndrome: alloimmunedependent and -independent injury with aberrant tissue remodeling. Semin
Thorac Cardiovasc Surg 2008;20(2):173182.
75. Daud SA, Yusen RD, Meyers BF, et al. Impact of immediate primary lung
allograft dysfunction on bronchiolitis obliterans syndrome. Am J Respir
Crit Care Med 2007;175(5):507513.
76. Starobin D, Shitrit D, Steinmetz A, et al. Quantitative lung perfusion following single lung transplantation. Thorac Cardiovasc Surg 2007;55(01):
4852.
77. Mason DP, Rajeswaran J, Murthy SC, et al. Spirometry after transplantation: how much better are two lungs than one? Ann Thorac Surg 2008;
85(4):11931201.
78. Gerbase MW, Spiliopoulos A, Rochat T, et al. Health-related quality of life
following single or bilateral lung transplantation: a 7-year comparison to
functional outcome. Chest 2005;128(3):13711378.
79. Oelberg DA, Systrom DM, Markowitz DH, et al. Exercise performance in
cystic fibrosis before and after bilateral lung transplantation. J Heart Lung
Transplant 1998;17(11):11041112.
80. Schwaiblmair M, Reichenspurner H, Muller C, et al. Cardiopulmonary
exercise testing before and after lung and heart-lung transplantation. Am J
Respir Crit Care Med 1999;159(4):12771283.
81. Reinsma GD, ten Hacken NHT, Grevink RG, et al. Limiting factors of
exercise performance 1 year after lung transplantation. J Heart Lung
Transplant 2006;25(11):13101316.
82. Bavaria JE, Kotloff R, Palevsky H, et al. Bilateral versus single lung transplantation for chronic obstructive pulmonary disease. J Thorac Cardiovasc
Surg 1997;113(3):520527.
TRANSPLANTATION
TRANSPLANTATION
RANDALL S. SUNG
K E Y
The Diabetes Control and Complications Trial demonstrated that tight control of blood glucose and minimization of hemoglobin A1C delays the progression of secondary complications of diabetes.
2 Recipients with functioning pancreas transplants have normal glycemic control without the need for exogenous
insulin, and pancreas transplantation has a beneficial
impact on diabetic complications.
3 Most pancreas transplants are performed in patients with
end-stage renal disease, either concomitant with or following a kidney transplant.
PATHOPHYSIOLOGY
The classic pathophysiology of diabetes is that of insulin secretory failure in type 1 diabetes and peripheral insulin resistance
in patients with type 2 diabetes. However, the etiology, epidemiology, and pathogenesis of diabetes is much more complex
than is reflected in early characterizations of the disease. Type 1
diabetes is classically described as an autoimmune disorder
manifest by destruction of -cells, with proinsulin being the
590
P O I N T S
4
5
6
7
8
SECONDARY COMPLICATIONS
OF DIABETES
TRANSPLANTATION
591
592
Patient Selection
Pancreas transplantation is usually performed in patients with
type 1 diabetes. The diagnosis of type 1 diabetes is relatively
straightforward for most individuals. A history of juvenile or
young adult onset, diabetic ketoacidosis, a lean body habitus,
and a low insulin requirement (0.7 units/kg) all support the
diagnosis of type 1 diabetes. In contrast, older age of onset,
obesity, an interval of treatment with diet or oral agents, or
high insulin requirements are all suggestive of type 2 diabetes.
A subset of adult-onset diabetics will display characteristics
otherwise associated with type 1 diabetes, including absence of
insulin production. Whether these individuals are properly
classified as type 1 or type 2 diabetics may be subject to debate,
but these individuals may certainly benefit from pancreas transplantation. Individuals with type 1 physiology but adult age of
onset and low but detectable C-peptide secretion (so-called
type 1.5 diabetics) may also be considered for pancreas
transplantation. Approximately 5% of pancreas transplant
recipients are reported as having type 2 diabetes, and outcomes
for these recipients are similar to those with type 1 diabetes.20
These are likely to be highly selected individuals without significant insulin resistance; most type 2 diabetics would not
be considered candidates. Some type 1 diabetics may develop
Simultaneous KidneyPancreas
Transplantation
SPK from a deceased donor is the most commonly performed
pancreas transplant option, with the number exceeding all
other types combined. An SPK transplant has the advantage of
requiring only one operation for both transplants. Since
alloreactivity against the transplanted pancreas tends to be
concordant with activity against the kidney, pancreas rejection
may be heralded by signs of kidney rejection, which are more
sensitive and present earlier. Consequently, SPK pancreas outcomes have been historically superior to those of solitary pancreas transplants.
TRANSPLANTATION
593
594
PTA
PAK
SPK
1,000
FIGURE 39.3. Number of U.S. simultaneous pancreaskidney (SPK), pancreas after kidney transplantation (PAK), and pancreas transplantation
alone (PTA) transplants performed by year. (Data
from Scientific Registry of Transplant Recipients.
2007 Annual Report. Rockville, MD: Health Resources and Services Administration, Department
of Health and Human Services; 2008.)
500
1997
1998
1999
2000
2001 2002
Year
2003
2004
2005
2006
TRANSPLANTATION
Number of Transplants
1,500
595
596
Donor Evaluation
4
Procurement Technique
The importance of the pancreatic procurement cannot be
overstated. It is thought by many pancreas transplant surgeons
to be more critical to the success of the transplant than the
recipient procedure. Because the pancreas is susceptible to
traumatic injury, it must be carefully dissected and manipulated to avoid injury to the pancreatic parenchyma. Typically
the pancreas is procured along with the liver and kidneys. This
is performed in standard fashion through a midline incision
that extends from the sternal notch to the pubic symphysis.
After a generous Kocher maneuver, mobilization of the right
colon, and isolation of the distal and supraceliac aorta to prepare these vessels for clamping, the pancreas is mobilized. This
is most commonly achieved by entering the lesser sac, dividing
the gastrocolic omentum. This dissection continues with division of the short gastric vessels and the avascular gastrosplenic
ligament. The pancreas is dissected from the pancreatic bed
using the spleen as a handle. The tail is lifted from the pancreatic bed using blunt dissection and the occasional use of electrocautery. The proximal jejunum is dissected at the ligament
of Treitz. An antibiotic and/or Betadine-containing solution is
frequently instilled into the duodenum through a nasogastric
tube for decontamination. The duodenum is divided both at the
ligament of Treitz and at the pylorus using a stapler. Division of
the middle colic vessels permits exposure of the proximal small
Splenic vein
Portal vein
Gastroduodenal
artery
Superior
pancreaticoduodenal
artery
Common bile duct
FIGURE 39.4. Back-table preparation of the pancreas. Before transplantation, the pancreas must be prepared
in a slush-filled basin to maintain cold
preservation. Preparation includes
unifying the arterial blood supply of
the pancreas by anastomosis of the
donor external iliac artery to the superior mesenteric artery and the donor
internal iliac artery to the splenic
artery. The donor common iliac artery
is used for anastomosis to the recipient
iliac artery. During back-table preparation, donor splenectomy is performed.
Recipient Operation
The pancreas transplant is typically performed through a midline incision, although a lower quadrant incision similar to a
kidney transplant incision may be used. The recipient should
receive broad-spectrum antibiotics preoperatively. The pancreas transplant, for systemic venous drainage, is placed in the
iliac fossa, preferably on the right side. After dissection of the
iliac artery and vein, the portal vein is anastomosed in an endto-side fashion to the external iliac vein. The common iliac
vein or distal inferior vena cava may also be used; the recipient
vein segment should be mobile enough for the portal vein to
reach without tension. The common iliac artery component of
the donor Y-graft is then anastomosed in an end-to-side fashion to either the recipient external iliac artery or common iliac
artery; the distal aorta can also serve as the site of anastomosis. A pancreas placed on the left side in the recipient may be
placed either medial or lateral to the sigmoid colon. Multiple
variations have been described.
Because of concerns about the systemic hyperinsulinemia
that invariably develops with systemically drained pancreas
transplants, portal venous drainage is also utilized (Fig. 39.5).
As 50% of insulin is removed with the first pass through the
liver, systemic drainage leads to elevated peripheral insulin levels, which is not observed following portal venous drainage.
Since hyperinsulinemia has been associated with dyslipidemia
TRANSPLANTATION
Splenic artery
597
598
FIGURE 39.5. Simultaneous pancreaskidney transplantation performed with drainage of the pancreatic exocrine secretions into the proximal jejunum (enteric drainage). This technique has been adopted by most
transplant centers in the United States for simultaneous pancreaskidney
transplants. For solitary pancreas transplantation, some centers still
utilize bladder drainage to allow monitoring of the urinary amylase.
Note that the donor portal vein drains into the recipient superior
mesenteric vein (portal venous drainage), preventing peripheral hyperinsulinemia. Many centers continue to place the pancreas in the pelvis,
combining enteric drainage and systemic venous drainage. This placement requires enteric anastomosis to a more distal segment of jejunum
or ileum.
and accelerated atherosclerosis, portal venous drainage theoretically ought to decrease cardiovascular risk compared with
systemic drainage.43 Portal drainage is associated with stimulation of the insulinlike growth factor I (IGF-I)/growth hormone (GH) axis, contributing to glucose control despite lower
insulin levels.44 However, despite a nearly 10-year experience
with the procedure, no effect on cardiac morbidity or mortality has been shown, although equivalent graft and patient survival has been demonstrated.45,46
Although the type of venous drainage typically depends on
the preferences of individual surgeons or transplant centers,
the decision to perform portal or systemic drainage may also
depend on the anatomy of an individual patient. Patients with
multiple previous abdominal operations or who have a thickened mesentery may be more suited for systemic venous
drainage. Alternatively, patients who have had multiple transplants or other operations on the iliac vessels may be candidates for portal venous drainage.
For portal venous drainage the superior mesenteric vein is
dissected out just below the transverse mesocolon.47 The right
common iliac artery is almost completely dissected. An end-toside anastomosis of the donor portal vein to the recipient superior mesenteric vein is performed with the duodenum oriented
superiorly and the tail pointed inferiorly. The iliac artery graft
Immunosuppression
The immunogenicity of a pancreas transplant is considered to
be greater than the majority of solid organ transplants because
of the extensive lymphoid component of the gland. In addition, the difficulty in diagnosing rejection compared to other
solid organ transplants makes the choice of immunosuppression perhaps more significant for pancreas transplants. Most
centers use some form of triple maintenance therapy utilizing
a calcineurin inhibitor, an antiproliferative agent, and steroids,
although steroid-free regimens are becoming more common.
According to data from the Scientific Registry of Transplant
Recipients, 92% of kidneypancreas recipients in 2006
received tacrolimus as maintenance therapy, compared to only
6% who received cyclosporine.31 Mycophenolate mofetil is the
antiproliferative agent of choice in pancreas transplantation,
although the use of sirolimus has increased from virtually nil
in 1999 to nearly 16% in 2006. The use of steroids for combined kidney transplantation is also decreasing; whereas in
1999, 97% of kidneypancreas recipients received steroids as
part of initial maintenance immunosuppression, this has
decreased to 67% in 2006. This pattern of usage is similar to
that employed for solitary pancreas transplantation, either
PTA or PAK.
The use of induction therapy to inhibit lymphocyte function is common. Two large randomized multicenter trials utilizing diverse agents such as T-celldepleting antibody induction (OKT3, ATGAM, and thymoglobulin) and interleukin-2
(IL-2) receptor antibody inhibition (daclizumab and basiliximab) showed a reduction in the incidence of acute rejection
but failed to demonstrate a significant effect on patient or graft
survival.52,53 Despite this modest impact on overall graft outcome, 83% of kidneypancreas transplant recipients received
induction therapy in 2006.31 Of these, approximately three
quarters received thymoglobulin; the remaining were split
between antiIL-2 receptor and Campath induction therapy.
For pancreas after kidney transplants, fewer recipients
received induction (78%), with a similar proportion receiving
thymoglobulin over antiIL-2 receptor agents or Campath.
The International Pancreas Transplant Registry (IPTR) has
demonstrated a lower risk of pancreas graft loss in all categories of pancreas transplantation with the use of tacrolimus,
and also demonstrated similar associations with the use of
mycophenolate mofetil.36 Consistent with the multicenter trials, IPTR analyses also fail to demonstrate a beneficial effect of
induction therapy on patient and graft survival.
Several groups have reported excellent intermediate-term
patient and graft outcomes utilizing steroid minimization protocols.5456 These protocols generally employ an induction
agent (usually a depleting T-cell antibody or Campath),
tacrolimus, and either mycophenolate mofetil or sirolimus.
Steroids are given for a maximum of 3 days. These steroid
minimization protocols, as in kidney transplantation, aim to
avoid the significant short- and long-term side effects associated with corticosteroids. Regimens employing maintenance
monotherapy have also been successfully employed, although
long-term outcomes are not yet established.57
Complications
Thrombosis of the pancreas transplant is the most common
cause of graft loss in the early postoperative period. Why pan-
599
TRANSPLANTATION
600
has the morbidity associated with bladder drainage. Occasionally a fluid collection or leak that presents late can be treated
with percutaneous CT-guided drainage.62 In addition, drainage
of infection without primary repair of the duodenal leak has
been successfully employed in situations where inflammation is
so profound that the leak could not be primarily repaired.
However, the morbidity associated with these duodenal fistulas dictates that these options be employed only when definitive repair is not possible.
In contrast to renal transplantation, the complications of
pancreas transplantation can be severe and life threatening if
not properly managed. Even in the most experienced centers,
occasional patients who suffer extended intensive care unit
stays and even death are not unusual. This is a consequence of
both the tenuous medical status of longstanding diabetics and
the substantial morbidity of pancreas transplant complications.
Therefore, given the limited survival benefit of pancreas transplantation, particularly compared with kidney transplantation, patients should be counseled frankly about the potential
magnitude of these complications so that they have a realistic
expectation of outcomes. Even with honest discussion and
informed consent, most individuals will elect pancreas transplantation, and many will pursue multiple pancreas transplants even with a history of significant complications from
previous pancreas transplants.
TA B L E 3 9 . 1
Recurrent Autoimmunity
Selective -cell destruction in pancreas transplants may occur in
a pattern similar to the insulitis seen in type 1 diabetes. This pattern is histologically distinct from cellular rejection. Although
recurrent autoimmunity has been documented in both immunosuppressed pancreas transplant recipients and nonimmunosuppressed living donor recipients from identical twin siblings,
well-documented case series have been infrequent. A variety of
CLASSIFICATION
PROPOSED BANFF CLASSIFICATION FOR GRADING PANCREAS ALLOGRAFT ACUTE CELLULAR REJECTION
GRADE
II
III
SEVERITY
FINDINGS
Normal
Absent inflammation or inactive septal, mononuclear inflammation not involving ducts, veins,
arteries, or acini. There is no graft sclerosis. The fibrous component is limited to normal septa and
its amount is proportional to the size of the enclosed structures (ducts and vessels). The acinar
parenchyma shows no signs of atrophy or injury.
Indeterminate
Septal inflammation that appears active but the overall features do not fulfill the criteria for mild
cell-mediated acute rejection
Mild
(a) Active septal inflammation (activated, blastic lymphocytes eosinophils) involving septal
structures: venulitis (subendothelial accumulation of inflammatory cells and endothelial damage
in septal veins), ductitis (epithelial inflammation and damage of ducts); neural/perineural
inflammation and/or (b) focal acinar inflammation: no more than two inflammatory foci per
lobule with absent or minimal acinar cell injury
Moderate
(a) Multifocal (but not confluent or diffuse) acinar inflammation (three or more foci per lobule)
with spotty (individual) acinar cell injury and drop-out and/or (b) minimal intimal arteritis
Severe
(a) Diffuse (widespread, extensive) acinar inflammation with focal or diffuse multicellular/
confluent acinar cell necrosis and/or (b) moderate or severe intimal arteritis and/or (c) transmural
inflammation: necrotizing arteritis
From Drachenberg CB, Odorico J, Demetris AJ, et al. Banff schema for grading pancreas allograft rejection: working proposal by a multi-disciplinary
international consensus panel. Am J Transplant 2008;8(6):12371249.
601
associations have been suggested with autoantibodies to glutamic acid decarboxylase (GAD-65) and islet cells (IA-2), but
patterns of autoantibody expression have not proven reliable
enough to establish their etiologic relevance or prognostic value.
100
90
80
SPK
PTA
PAK
100
90
Graft Survival (%)
80
70
70
60
50
40
30
20
10
0
3 months
1 year
3 years
5 years
60
50
40
30
20
10
0
3 months
1 year
3 years
5 years
TRANSPLANTATION
SPK
PTA
PAK
602
registrants on the waiting lists for PAK and PTA had better
survival rates than recipients who underwent these procedures.76 Subsequently, another group, using a similar cohort
but different analytical methods, reported better survival
rates for recipients of solitary pancreas transplantation than
registrants on the waiting list.78 These discrepancies are in
part related to the differing methodologies used in the two
studies with respect to deaths among those removed from the
waiting list and to variability in the year-to-year death rates
on the waiting list. In contrast, both studies demonstrated a
conclusive benefit for SPK recipients compared with remaining on the waiting list, which illustrates the importance of
restoration of kidney function in this population, as with kidney6 alone transplant. While opinions on the specific benefit of the
pancreas transplant differ in light of the differing conclusions
of these two studies, together the studies indicate that any survival benefit conferred by the pancreas transplant is likely to
be modest.
ISLET TRANSPLANTATION
Overview
603
associated with islet transplants, which are not routinely reimbursed by insurers.99 As a result, the volume of islet transplants has contracted in the past few years.100
Islet Isolation
The precise separation of the islets from the other tissues of the
pancreas (exocrine cells, lymphatics, vascular structures) is
perhaps the most important determinant of successful islet
transplantation (Fig. 39.8). One of the limitations of islet isolation is the difficulty in getting a large number of high-quality
islets, and consistent success in islet isolation is a combination
of science, art, and experience. Although a variety of methods
have been utilized, most currently employ some modification
of the semiautomated method described by Ricordi in 1988.101
This method combines mechanical distention with enzymatic
digestion of the pancreas. After cleaning the pancreas of surrounding fat, the pancreatic duct is cannulated with an angiocatheter and the pancreas is distended and loaded with warm
collagenase solution, which digests the pancreas.102 The pancreas is then placed into a sterile chamber, which also contains
a number of stainless steel or glass spheres. Additional collagenase solution is added, and the chamber is attached to a
shaking apparatus or agitated by hand. The collagenase solution is recirculated and kept at 37C as the chamber is agitated. Agitation of the chamber allows the spheres to continue
to disrupt the structural integrity of the pancreas as it digests.
Following digestion, the separation of islets from nonislet tissue is performed via density gradient centrifugation. After suspension in culture media, islets are counted and assessed for
sterility, purity, viability, and functional capacity. As islet isolation in the United States is regulated by the U.S. Food and
Drug Administration, stringent product release criteria are in
place to ensure the quality of the transplanted islets. The percentage of islet isolations that result in a transplantable preparation varies widely among centers, between 25% and 70%,
and depends on both donor selection practices and the experience and expertise of the particular center.
Patient Selection
Candidates for islet transplantation are selected in a similar
manner as for whole-organ pancreas transplantation. Islet
transplantation is currently limited to adult type 1 diabetics
with progressive diabetic complications who have failed inten-
Transplant Techniques
The portal circulation of the liver is currently the preferred site
for islet transplantation (Fig. 39.9).111 This can be performed
by a minilaparotomy, with infusion of the islets into a peripheral mesenteric vein. However, most centers utilize interventional radiology techniques, avoiding both a surgical incision
and general anesthesia. Percutaneous transhepatic portal vein
catheterization is done under ultrasound and fluoroscopic
guidance, with usually a small-gauge (4-French) catheter. The
islets are infused into the portal vein through the catheter by
either gravity from an infusion bag or by hand injection, and
the islets lodge in the hepatic parenchyma. Portal vein pressure
is monitored intermittently throughout the procedure. Following infusion of the islets, hemostasis is usually achieved using
a combination of coils and Gelfoam. Recipients receive
heparin in the islet preparation, systemically during the procedure, and in the perioperative period as prophylaxis against
portal vein thrombosis, a now rare but serious complication.
TRANSPLANTATION
FIGURE 39.8. Isolated, purified human islets. Islets are stained red
with diphenylthiocarbazone. (Adapted from Robertson PR. Islet
transplantation as a treatment for diabetes: a work in progress. N Engl
J Med 2004;350:694705.)
604
Pancreas
Central vein
Branch of
portal vein
Collagenase
digestion
Islets within
sinusoids
Liver
Exocrine
fragments
Purified
islets
Transplantation of purified
islets into liver through a
percutaneous catheter
Perioperative Care
Although islet transplantation is in theory an outpatient procedure, it is not uncommon for recipients to receive a few days of
inpatient care for monitoring purposes. Immediately following
the islet transplant, patients are maintained on bed rest for a
short interval and monitored for bleeding. Liver function tests
are monitored, and a liver ultrasound is frequently done to assess
portal venous flow and to check for hematoma. It has been
demonstrated that intensive glycemic control with insulin in the
immediate posttransplant period is beneficial for islet function.112 Hence, many centers will give insulin postoperatively to
keep the serum glucose tightly controlled, in order to rest the
islets. Additional adjuncts to prevent nonspecific inflammation
may include antioxidants such as vitamin E, antibodies against
tumor necrosis factor-, pentoxifylline, and others.
Immunosuppression
regulation to hypoglycemia is diminished, actual hypoglycemic events are rare.113 However, islet recipients have significantly more diminished -cell reserve than do recipients of
whole-pancreas transplants, which may account for their
reduced long-term survival.114 Analyses of the impact on diabetic complications and mortality await further experience.
Complications
Morbidity from islet transplantation is substantial but much
less than for whole-pancreas transplantation. The most common serious complication is bleeding (1% to 5%). Most cases
of bleeding can be managed nonoperatively with adjustments in
anticoagulation, though occasionally laparotomy is required.
The side effects of immunosuppression, such as hyperlipidemia
and mouth ulcers in sirolimus-containing regimens, are much
more common and can significantly affect quality of life.115
Renal insufficiency is an uncommon but serious consequence.98
Transient elevations of portal venous pressure during islet infusion and elevations of liver function tests following infusion are
common and usually well tolerated.116,117 Recently, the demonstration of late steatosis has raised concerns about chronic liver
disease; to date, this has not occurred.118 Cytomegalovirus
infection is rare. Sensitization to alloantigen does occur,
although perhaps to a lesser extent than for whole-organ transplants.98 Mortality is virtually nil.
Graft Failure
Graft failure appears to occur earlier than for wholepancreas transplants. This may be related to a lower initial
islet mass or the inability to histologically diagnose and treat
islet rejection, since the islets are scattered about the liver
parenchyma. Attempts to identify immunologic markers of
rejection or recurrent autoimmunity, or metabolic indicators
of impending graft failure are not of sufficient predictive
value for clinical application.124,125 Recipients with prior
graft function who have returned to insulin are candidates
for retransplantation. In fact, some centers have used transplanted islets from isolations where yields are insufficient for
a primary transplant as retransplants, where the islet requirement may be less.
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role of percutaneous biopsy and standardized histologic grading of rejection. Arch Surg 1997;132:5257.
64. Bartlett ST, Schweitzer EJ, Johnson LB, et al. Equivalent success of simultaneous pancreas kidney and solitary pancreas transplantation. A prospective trial of tacrolimus immunosuppression with percutaneous biopsy. Ann
Surg 1996;224:440452.
65. Sutherland DER, Gruessner RWG, Dunn DL, et al. Lessons learned from
more than 1,000 pancreas transplants at a single institution. Ann Surg 2001;
233(4):463501.
66. Carpenter HA, Engen DE, Munn SR, et al. Histologic diagnosis of rejection by using cystoscopically directed needle biopsy specimens from dysfunctional pancreatoduodenal allografts with exocrine drainage into the
bladder. Am J Surg Pathol 1990;14:837846.
67. Atwell TD, Gorman B, Larson TS, et al. Pancreas transplants: experience
with 232 percutaneous US-guided biopsy procedures in 88 patients. Radiology 2004;231:845849.
68. Kayler LK, Merion RM, Rudich SM, et al. Evaluation of pancreatic allograft dysfunction by laparoscopic biopsy. Transplantation 2002;74:
12871289.
69. Drachenberg CB, Odorico J, Demetris AJ, et al. Banff schema for grading pancreas allograft rejection: working proposal by a multi-disciplinary
international consensus panel. Am J Transplant 2008;8(6):1237
1249.
70. Humar A, Khwaja K, Ramcharan T, et al. Chronic rejection: the next
major challenge for pancreas transplant recipients. Transplantation 2003;
76:918923.
71. Ricart MJ, Malaise J, Moreno AN, et al.; the Euro-SPK Study Group.
Cytomegalovirus: occurrence, severity, and effect on graft survival in
simultaneous pancreaskidney transplantation. Nephrol Dial Transplant
2005;20(suppl 2):ii25ii32.
72. Axelrod D, Leventhal JR, Gallon LG, et al. Reduction of CMV disease
with steroid-free immunosuppression in simultaneous pancreaskidney
transplant recipients. Am J Transplant 2005;5:14231429.
73. Gupta G, Shapiro R, Thai N, et al. Low incidence of BK virus nephropathy after simultaneous kidney pancreas transplantation. Transplantation
2006;82:382388.
74. Lipshutz GS, Mahanty H, Feng S, et al. BKV in simultaneous pancreaskidney transplant recipients: a leading cause of renal graft loss in first
2 years post-transplant. Am J Transplant 2005;5:366373.
75. Paraskevas S, Coad JE, Gruessner A, et al. Posttransplant lymphoproliferative disorder in pancreas transplantation: a single-center experience.
Transplantation 2005;80:613622.
76. Venstrom JM, McBride MA, Rother KI, et al. Survival after pancreas
transplantation in patients with diabetes and preserved kidney function.
JAMA 2003;290:28172823.
77. Reddy KS, Stablein D, Taranto S, et al. Long-term survival following
simultaneous kidney-pancreas transplantation versus kidney transplantation alone in patients with type 1 diabetes mellitus and renal failure. Am J
Kidney Dis 2003;41:464470.
78. Gruessner RWG, Sutherland DER, Gruessner AG. Mortality assessment
for pancreas transplants. Am J Transplant 2006;4(12):20182026.
79. Bilous RW, Mauer SM, Sutherland DE, et al. The effects of pancreas transplantation on the glomerular structure of renal allografts in patients with
insulin-dependent diabetes. N Engl J Med 1989;321:8085.
80. Fioretto P, Steffes MW, Sutherland DE, et al. Reversal of lesions of diabetic
nephropathy after pancreas transplantation. N Engl J Med 1998;339:
6975.
81. Kennedy WR, Navarro X, Goetz FC, et al. Effects of pancreatic transplantation on diabetic neuropathy. N Engl J Med 1990;322:10311037.
82. Mehra S, Tavakoli M, Kallinikos PA, et al. Corneal confocal microscopy
detects early nerve regeneration after pancreas transplantation in patients
with type 1 diabetes. Diabetes Care 2007;30:26082612.
83. Kendall DM, Rooney DP, Smets YF, et al. Pancreas transplantation
restores epinephrine response and symptom recognition during hypoglycemia in patients with long-standing type I diabetes and autonomic neuropathy. Diabetes 1997;46:249257.
84. Walsh AW. Effects of pancreas transplantation on secondary complications
of diabetes: retinopathy. In: Gruessner RWG, Sutherland DER, eds. Transplantation of the Pancreas. New York: Springer; 2004:462470.
85. Giannarelli R, Coppelli A, Sartini MS, et al. Pancreas transplant alone has
beneficial effects on retinopathy in type 1 diabetic patients. Diabetologia
2006;49:29772982.
86. Morrissey PE, Shaffer D, Monaco AP, et al. Peripheral vascular disease
after kidney-pancreas transplantation in diabetic patients with end-stage
renal disease. Arch Surg 1997;132:358362.
87. Knight RJ, Schanzer H, Guy S, et al. Impact of kidney-pancreas transplantation on the progression of peripheral vascular disease in diabetic patients
with end-stage renal disease. Transplant Proc 1998;30:19471949.
88. Nakache R, Tyden G, Groth CG. Quality of life in diabetic patients after
combined pancreas-kidney or kidney transplantation. Diabetes 1989;
38(suppl 1):4042.
89. Gross CR, Limwattananon C, Matthees BJ. Quality of life after pancreas
transplantation: a review. Clin Transplant 1998;12:351361.
90. Owen RJ, Ryan EA, OKelly K, et al. Percutaneous transhepatic pancreatic
islet cell transplantation in type 1 diabetes mellitus: radiologic aspects.
Radiology 2003;229:165170.
91. Lau H, Reemtsma K, Hardy MA. Prolongation of rat islet allograft survival by direct ultraviolet irradiation of the graft. Science 1984;223:
607609.
92. Ryan EA, Lakey JR, Paty BW, et al. Successful islet transplantation: continued insulin reserve provides long-term glycemic control. Diabetes 2002;
51:21482157.
93. Sutherland DE, Matas AJ, Goetz FC, et al. Transplantation of dispersed
pancreatic islet tissue in humans: autografts and allografts. Diabetes 1980;
29(suppl 1):3144.
94. Brendel MD, Hering BJ, Schultz AO, et al., eds. International Islet Transplant Registry 2001. 2001;8:5.
95. Teuscher AU, Kendall DM, Smets YF, et al. Successful islet autotransplantation in humans: functional insulin secretory reserve as an estimate of surviving islet cell mass. Diabetes 1998;47:324340.
96. Shapiro AM, Lakey JR, Ryan EA, et al. Islet transplantation in seven
patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000;343:230238.
97. Shapiro AM, Ricordi C, Hering BJ, et al. International trial of the Edmonton protocol for islet transplantation. N Engl J Med 2006;355(13):
13181330.
98. Ryan EA, Paty BW, Senior PA, et al. Five year follow-up after clinical islet
transplantation. Diabetes 2005;54:20602069.
99. Markmann JF, Kaufman DB, Ricordi C, et al. Financial issues constraining
the use of pancreata recovered for islet transplantation: a white paper. Am
J Transplant 2008;8(8):15881592.
100. Close N, Alejandro R, Hering B, et al. Second annual analysis of the Collaborative Islet Transplant Registry. Transplant Proc 2007;39:179182.
101. Ricordi C, Lacy PE, Firike EH, et al. Automated method for isolation of
human pancreatic islets. Diabetes 1988;37:413420.
102. Linetsky E, Bottino R, Lehmann R, et al. Improved human islet isolation
using a new enzyme blend, LiberaseTM. Diabetes 1997;46:11201123.
103. Gerber PA, Pavlicek V, Demartines N, et al. Simultaneous islet-kidney vs
pancreas-kidney transplantation in type 1 diabetes mellitus: a 5 year single
centre follow-up. Diabetologia 2008;51(1):110119.
104. Kaufman DB, Baker MS, Chen X, et al. Sequential kidney/islet transplantation using prednisone-free immunosuppression. Am J Transplant 2002;
2:674677.
105. Lakey JR, Warnock GL, Rajotte RV, et al. Variables in organ donors that
affect the recovery of human islets of Langerhans. Transplantation 1996;
61:10471053.
106. Kneteman NM, Lakey JR, Kizilisik TA, et al. Cadaver pancreas recovery
technique. Impact on islet recovery and in vitro function. Transplantation
1994;58:114119.
607
107. Lakey JR, Tsujimura T, Shapiro AM, et al. Preservation of the human pancreas before islet isolation using a two-layer (UW solution-perfluorochemical) cold storage method. Transplantation 2002;74:18091811.
108. Ricordi C, Fraker C, Szust J, et al. Improved human islet isolation outcome
from marginal donors following addition of oxygenated perfluorocarbon
to the cold-storage solution. Transplantation 2003;75:15241527.
109. Hering BJ, Matsumoto I, Sawada T, et al. Impact of two-layer pancreas
preservation on islet isolation and transplantation. Transplantation 2002;
74:18131816.
110. Markmann JF, Deng S, Desai NM, et al. The use of non-heart-beating
donors for isolated pancreatic islet transplantation. Transplantation 2003;
75:14231429.
111. Weimar B, Rauber K, Brendel MD, et al. Percutaneous transhepatic
catheterization of the portal vein: a combined CT- and fluoroscopy-guided
technique. Cardiovasc Intervent Radiol 1999;22:342344.
112. Bretzel RG, Brandhorst D, Brandhorst H, et al. Improved survival of
intraportal pancreatic islet cell allografts in patients with type-1 diabetes
mellitus by refined peritransplant management. J Mol Med 1999;77:
140143.
113. Paty BW, Ryan EA, Shapiro AM, et al. Intrahepatic islet transplantation in
type 1 diabetic patients does not restore hypoglycemic hormonal counterregulation or symptom recognition after insulin independence. Diabetes
2002;51:34283434.
114. Frank A, Deng S, Huang X, et al. Transplantation for type I diabetes: comparison of vascularized whole-organ pancreas with isolated pancreatic
islets. Ann Surg 2004;240(4):631640.
115. Hirshberg B, Rother KI, Digon BJ III, et al. Benefits and risks of solitary
islet transplantation for type 1 diabetes using steroid-sparing immunosuppression: The National Institutes of Health experience. Diabetes Care
2003;26:32883295.
116. Casey JJ, Lakey JR, Ryan EA, et al. Portal venous pressure changes after
sequential clinical islet transplantation. Transplantation 2002;74:
913915.
117. Rafael E, Ryan EA, Paty BW, et al. Changes in liver enzymes after clinical
islet transplantation. Transplantation 2003;76:12801284.
118. Markmann JF, Rosen M, Siegelman ES, et al. Magnetic resonance-defined
periportal steatosis following intraportal islet transplantation: a functional
footprint of islet graft survival? Diabetes 2003;52:15911594.
119. Hering BJ, Kandaswamy R, Harmon JV, et al. Transplantation of cultured
islets from two-layer preserved pancreases in type 1 diabetes with antiCD3 antibody. Am J Transplant 2004;4:390401.
120. Froud T, Ricordi C, Baidal DA, et al. Islet transplantation in type 1 diabetes mellitus using cultured islets and steroid-free immunosuppression:
Miami experience. Am J Transplant 2005;5(8):20372046.
121. Gangemi A, Salehi P, Hatipoglu B, et al. Islet transplantation for brittle
type 1 diabetes: the UIC Protocol. Am J Transplant 2008;8:12501261.
122. Markmann JF, Deng S, Huang X, et al. Insulin independence following isolated islet transplantation and single islet infusions. Ann Surg 2003;237:
741750.
123 Keymeulen B, Gillard P, Mathieu C, et al. Correlation between -cell mass
and glycemic control in type 1 diabetic recipients of islet cell graft. Proc
Natl Acad Sci U S A 2006;103(46):1744417449.
124. Han D, Xu X, Pastori RL, et al. Elevation of cytotoxic lymphocyte gene
expression is predictive of islet allograft rejection in nonhuman primates.
Diabetes 2002;51:562566.
125. Shapiro AM, Hao EG, Lakey JR, et al. Novel approaches toward early
diagnosis of islet allograft rejection. Transplantation 2001;71:17091718.
TRANSPLANTATION
SECTION C
HEAD AND NECK
K E Y
P O I N T S
The most common neoplasm in the head and neck is squamous cell carcinoma.
5 Cystic neck masses in adults are metastatic oropharyngeal
carcinoma until proven otherwise.
6 In any smoker aged 35 or older with hoarseness, a neck
mass, or mucosal abnormality, carcinoma must be ruled
out.
The head and neck is a complex and intricate region of the body,
and surgical management of head and neck diseases is both
challenging and rewarding. A wide variety of benign and malignant processes are encountered by the head and neck surgeon,
and a comprehensive review of this material is well beyond the
scope of this chapter. However, head and neck complaints are
relatively common and it behooves the surgeon to familiarize
himself or herself with the processes. With that in mind, the following chapter is designed to introduce the reader to head and
neck diseases, provide a framework for diagnostic evaluation,
and discuss the treatment strategies commonly employed.
Human papillomavirus (HPV) infection is now widely recognized as a risk factor for oropharyngeal cancer. HPV is
transmitted sexually, and the risk of oropharyngeal cancers
has been strongly correlated to the lifetime number of sexual
partners.4 Consequently, the sexual history has become an
important component of the overall assessment if carcinoma is
suspectedparticularly in the absence of other risk factors.
Additional medical, surgical, family, and occupational history should also be documented at this point. While these
items may or may not have direct implications to the presenting problem, they may be critical to the overall patient evaluation and therapeutic decision-making process.
Physical Examination
Once an appropriate patient history has been obtained, a comprehensive head and neck examination should be undertaken.
Many of the techniques and equipment used in the head and
neck exam are specialized and may be unfamiliar to some pracThough a few patients will be referred to the head and neck
titioners. However, the examiner must become facile with them
surgeon for incidentally discovered abnormalities, the vast
to perform a complete and appropriate patient evaluation. At a
majority of patients will present with a specific head and neck
minimum, physicians treating head and neck disorders should
complaint. As with any medical discipline, concise history takhave at their disposal and be comfortable using a stethoscope,
ing begins with questions aimed at determining the onset,
a pneumatic otoscope, an assortment of angled mirrors, and
severity, location, and quality of the presenting symptom along
nasal specula. A headlight or head mirror should be worn. This
with any exacerbating or alleviating factors. Once this is comallows for the use of both hands during examination and propleted, a head and neck review of systems should be obtained.
vides superior visualization as compared to the omnipresent
Pertinent positives and negatives in this category will help to
single hand and flashlight technique. Though most of the
narrow the differential diagnosis and might point to the presupper aerodigestive tract is visible by direct or indirect (mirror)
ence of an underlying malignancy. Table 40.1 lists common
examination, portions of the nasal cavity, nasopharynx,
signs and symptoms that are associated with head and neck
hypopharynx, and larynx are often difficult to assess. The flexcancers. When any of these are presentparticularly in the
ible fiberoptic nasopharyngolaryngoscope (NPL scope, or
context of tobacco use or other risk factors (Table 40.2)
NPL) has become an indispensable tool for this purpose.
malignancy must be strongly considered.
Physical examination need not follow a strict sequence per
The social history is of vital importance in evaluating
patients with head and neck complaints. Tobacco and alcohol 2 se. However, the entire surface of the head, neck, and upper
1 use history must be specific and detailed. Tobacco users have
aerodigestive tract must be evaluated. It behooves the examiner
to develop his or her own systematic approach to prevent inadup to 25 times the risk of head and neck squamous cell carcivertent omissions. It is the authors practice to progress sequennoma when compared to nonusers. These carcinogenic effects
tially from the least to the most invasive portions of the exam.
are increased synergistically among heavy consumers of alcoThis allows for a gradual building of rapport and trust during
hol.1,2 Type, amount, and duration of use should be docuwhat can for many patients be a sensitive exam and an invasion
mented as well as any previous efforts to quit (including methof personal space. It generally begins by visually inspecting the
ods used). Any significant secondhand smoke exposure should
patients face, neck, and scalppaying attention to any asymalso be documented. Passive smoking either at home or at
metry or irregularity of natural contours, cutaneous lesions,
work is often overlooked during the history, but its role in the
neuromuscular deficits, scars, or other stigmata of previous
pathogenesis of many head and neck cancers is becoming
surgery and/or radiation therapy. Palpation of the neck ensues,
increasingly evident.3
609
610
TA B L E 4 0 . 1
DIAGNOSIS PROGRESSIVE SIGNS AND SYMPTOMS THAT
MAY INDICATE A HEAD AND NECK CANCER
Odynophagia
Dysphagia
II
Weight loss
Loose dentition
Oral fetor
Trismus
III
Otalgia
Neck mass
VI
IV
Facial pain
Cranial neuropathies
Secondary infections
Aspiration
Fistulization
Hemorrhage
Voice changes
FIGURE 40.1. The cervical lymph nodes are divided into six groups,
or levels. (Reproduced with permission from Robbins KT, Samant S.
Chapter 116: Neck Dissection. In: Cummings Otolaryngology-Head
& Neck Surgery, 4th ed. Philadelphia: Elsevier; 2003:2616.)
Stridor
Airway obstruction
TA B L E 4 0 . 2
ETIOLOGY
ORAL CARCINOMA
Snuff
Burns
Tobacco chewing
Riboflavin deficiencies
Reverse smoking
Syphilis
Wood dust
Leather manufacturing
Chronic irritation
Nickel refining
Asbestos
NASOPHARYNGEAL CARCINOMA
Wood dust
Nitrosamine
Riboflavin deficiency
Salted fish
Epstein-Barr virus
Fanconi anemia
Vitamin deficiency
Chinese heritage
Radiation exposure
Eskimo heritage
Eskimo heritage
THYROID CARCINOMA
Radiation exposure
Iodine deficiency
Genetic inheritance
TA B L E 4 0 . 3
DIAGNOSIS
PRIMARY SITE
Oral cavity
II
Oropharynx
Nasopharynx
Supraglottic larynx
III
Hypopharynx
Larynx
IV
Thyroid
Hypopharynx
Larynx
Subclavicular sites
Scalp
TA B L E 4 0 . 4
611
DIAGNOSIS
with attention to the salivary glands, cervical lymph nodes, thyroid, trachea, and laryngeal cartilages. Auscultation of the neck
and chest should also be accomplished. This is followed by formal cranial nerve assessment and pneumatic otoscopy. The
remainder focuses on the mucosa-covered surfaces and should
include a speculum exam of the nasal cavity, inspection of the
oral cavity using a tongue blade in each hand to manipulate the
soft tissues, bimanual palpation of the oral cavity and oropharynx, and indirect visualization of the nasopharynx, hypopharynx, and larynx with either the mirror or the NPL.
Documentation of the exam should include detailed descriptions and diagrammatic representations of any abnormality.
Size, location, extent, and character should be included for any
suspected neoplasm. When cervical adenopathy is present, the
number, size, and anatomic level (Fig. 40.1) of the involved
lymph nodes should be reported. The pattern of nodal spread
from head and neck cancers is relatively predictable. In the
presence of a neck mass, the nodal level involved may help to
identify an occult primary tumor. Conversely, finding an
unusual drainage pattern from a known primary tumor can
alert the examiner to the presence of a second primary lesion
(Table 40.3).5
The following sections review many of the conditions seen
in a surgical head and neck practice. Coupled with the information garnered through the history and physical exam, it will
provide a framework for generating and ultimately narrowing
the differential diagnosis.
AIRWAY MANAGEMENT
Many conditions affecting the head and neck can result in
upper airway obstruction. Obstruction may be chronic, as in
the case of some neoplasms, or it may be acute, as in the case
of hemorrhage or trauma. In either case, it is crucial that the
surgeon be familiar with the techniques involved in securing
an impaired airway.
Management of the difficult airway begins with early recog3
nition. The historical and clinical elements listed in Table 40.4 may
be associated with difficult intubation and/or airway obstruction. If attention is paid to these signs and symptoms, potentially hazardous situations may be anticipated and addressed in
a controlled fashion before a difficult airway becomes an emergency airway. Orotracheal intubation remains the preferred
means of accomplishing this goal. However, various conditions
NONNEOPLASTIC DISORDERS
Sialadenitis and Sialolithiasis
The three pairs of major salivary glands include the parotid,
submandibular, and sublingual glands. In addition, there are
hundreds of minor salivary glands situated diffusely throughout the oral cavity, pharynx, and larynx. A wide variety of
nonneoplastic conditions can eventuate in swelling of either
Nasopharynx
612
FIGURE 40.2. Tracheostomy. A: The incision for an elective tracheostomy is typically placed on a horizontal axis, approximately 2 finger
breadths above the sternal notch. A vertical incision allows for less bleeding when the procedure must be performed emergently. B: The strap muscles are separated in the midline. The thyroid isthmus may bulge into the wound (C), necessitating inferior retraction or division (D). E: After the
second tracheal ring is cleaned, an inferiorly based flap (i.e., Bjrk flap) is developed in the tracheal wall and sutured to the skin. This allows for
easy access to the trachea while the tract is maturing.
TA B L E 4 0 . 5
CLASSIFICATION
613
FIGURE 40.3. Axial CT scan demonstrating large bilateral hilar calculi of the submandibular glands. Stones of this size and location are
generally not amenable to transoral or minimally invasive excision
techniques. This patient underwent bilateral submandibular gland
excision and recovered uneventfully.
Sialolithiasis is a disorder that merits special attention. Salivary stones are most commonly composed of calcium salts in
the form of hydroxyapatite.7,9 They are typically seen in the
context of chronic sialadenitis, though their exact pathogenesis remains unclear. Calculi may form in any of the major salivary glands, though 80% to 90% are submandibular.9 Patients
typically present with recurrent, painful swelling of the submandibular region, often exacerbated at mealtimes. Noncontrast CT is the initial study of choice as nearly 90% of
submandibular stones will be radio-opaque.7,10
Treatment depends on the size and location of the calculus.
Occasionally, small calculi will pass through the Wharton duct
spontaneously. Initial therapy for small, distally situated
stones consists of observation and sialogogues. Dilatation of
the papilla and proximal end of the Wharton duct and may
also be performed. Stones located proximal to the mylohyoid
muscle are less likely to be amenable to transoral removal.
However, recent advances in fiberoptics have made transoral/transductal endoscopy (i.e., sialendoscopy) possible.
Several endoscopic techniques are now used for this purpose
and have been successful in treating proximal stones.9 Despite
these advances, large, hilar, or intraglandular calculi are typically not amenable to transoral approaches (Fig. 40.3).10 In
these cases, formal submandibular gland excision is usually
necessary.
Pharyngitis
Pharyngitis is one of the most common reasons for ambulatory
care visits in the United States today. Strictly defined, pharyngitis is an inflammatory process affecting the mucosa and submucosal structures of the throat. Bacterial infection with
group A beta-hemolytic streptococci (GABHS) has classically
been associated with pharyngitis (i.e., strep throat). However,
only 5% to 15% of all adult cases of pharyngitis can be attributed to GABHS. The vast majority of cases are viral in
origin.11,12 Other bacterial etiologies include nongroup A
614
TA B L E 4 0 . 6
CLASSIFICATION
Masticator Space
Peritonsillar Space
Sinusitis
Temporal Space
Infrahyoid Spaces
Anterior Visceral Space
Adapted from: Gadre AK, Gadre KC. Infections of the deep spaces of
the neck. In: Bailey BJ, Johnson JT, eds. Head & Neck Surgery
Otolaryngology, 4th ed. Philadelphia: Lippincott Williams & Wilkins;
2006:670, with permission.
TA B L E 4 0 . 7
COMPLICATIONS
COMPLICATIONS OF SINUSITIS
Local
Temporal
Submandibular
Masticator
Mucocele
Potts Puffy Tumor
Parotid
Osteomyelitis
Orbital
Peritonsillar
Pharyngomaxillary
Preseptal Cellulitis
Orbital (Postseptal) Cellulitis
Subperiosteal Abscess
Danger
Retropharyngeal
Visceral Vascular
Prevertebral
Orbital Abscess
Cavernous Sinus Thrombosis
Intracranial
Meningitis
Anterior Visceral
Mediastinum
Epidural Abscess
Subdural Abscess
FIGURE 40.5. The deep spaces of the neck are distinct but interconnected compartments. Infections in any one of these may spread to
involve other potential spaces and critical structures contained therein.
(Adapted with permission from Gadre AK, Gadre KC. Infections of
the deep spaces of the neck. In: Bailey BJ, Johnson JT, eds. Head &
Neck SurgeryOtolaryngology, 4th ed. Philadelphia: Lippincott
Williams & Wilkins; 2006:670.)
Intracerebral Abscess
Cavernous Sinus Thrombosis
Superior Sagittal Sinus Thrombosis
From: Epstein VA, Kern RC. Invasive fungal sinusitis and complications
of sinusitis. Otolaryngol Clin North Am 2008;41:497, with permission.
Salivary Neoplasms
Tumors of the salivary glands constitute 3% to 6% of all head
and neck neoplasms. The parotid gland is most commonly
affected, with 65% of all tumors arising in it. An additional
8% of tumors will be seen in the submandibular gland while
27% occur in minor salivary glands.21 Most parotid and submandibular neoplasia is benign (75%80% and 50%60%,
respectively). Conversely, more than 80% of all minor salivary
gland tumors are malignant (Table 40.8). Patients with salivary tumors typically present with an asymptomatic mass. The
presence of pain, trismus, or cranial neuropathy is suggestive
of malignancy. Evaluation begins with a comprehensive history
TA B L E 4 0 . 8
CLASSIFICATION
615
616
E
FIGURE 40.6. Superficial parotidectomy. A: The standard Blair incision or the cosmetically superior rhytidectomy incision may be used.
B: Branches of the facial nerve course between the superficial and deep lobes of the parotid. C: The main trunk of the facial nerve is identified 8 mm
deep to the tympanomastoid suture line and at the same level as the digastric muscle. D: The nerve is then dissected distally, separating it from the
substance of the parotid. E: Schematic representation of the relationship between the parotid and surrounding structures.
STAGING
TA B L E 4 0 . 1 0
MANAGEMENT
Tx
T0
T1
T2
T3
T4a
T4b
Sinonasal Neoplasms
Various epithelial and mesenchymal tumors may arise within
the sinonasal tract. Patients with sinonasal neoplasms will
FIGURE 40.7. Excision of the submandibular gland. The skin incision usually is placed in a skin crease. A: After division of platysma, the
ramus mandibularis is identified and retracted superiorly. B: Elevation of the gland allows identification of the lingual and hypoglossal nerves.
After removal of the gland, the lingual nerve is in the base of the wound.
TA B L E 4 0 . 9
617
618
and for the fact that up to 20% will harbor in situ or invasive
squamous cell carcinoma.26 Consequently, removal of these
lesions should be aggressive. Wide excision using a lateral
rhinotomy approach and medial maxillectomy provides the
greatest chance of cure, with recurrence rates ranging from 0
to 30%.27 Advances in endoscopic instrumentation and techniques over the past decade have allowed for complete excision of these lesions through minimally invasive transnasal
approaches. At centers experienced in endoscopic resection,
the rates of disease control meet and in some cases exceed
those achieved through open maxillectomy.28
Juvenile nasal angiofibromas (JNAs) are benign vascular
tumors found in the adolescent male population. These
patients present with unilateral nasal obstruction with recurrent bouts of epistaxis. Many will require repeat transfusions.
Recurrent epistaxis in a young or adolescent male necessitates
a formal endonasal and nasopharyngeal exam. On endoscopy,
these appear as friable masses along the lateral nasopharyngeal wall. They are thought to originate near the sphenopalatine foramen. Though histologically benign, these lesions may
expand into the pterygopalatine fossa, nasal cavity, orbit, and
skull baseleading to pain, swelling, trismus, cranial neuropathies, and vision changes.26,29 Management involves complete excision via a transpalatal or transmaxillary approach.
Surgery is often complicated by profuse bleeding, and preoperative embolization is recommended. Endoscopic-transnasal
approaches have demonstrated safety and efficacy in the management of JNA. These techniques continue to be investigated,
but in expert hands it appears that they may impart better cosmetic outcomes, reduced blood loss, and shorter hospital
stay.30
In many ways, squamous cell carcinoma has become synonymous with head and neck cancer. Indeed, 80% to 90% of nonthyroidal/nonsalivary head and neck cancers are squamous
cell carcinomas.2,20 Most of these tumors occur at readily visible or palpable sites.20 Despite this, many patients delay seeking treatment and present with advanced diseasethereby
dramatically reducing the chance of cure. With earlier diagnosis, many of these individuals might otherwise be rendered free
of disease. Educating patients and physicians about the risk
factors and signs associated with head and neck cancer is
imperative to the process of early detection.
As with any other patient, the diagnostic evaluation of an
individual with head and neck cancer begins with the history
and physical examination (the critical elements of which were
detailed previously). Once suspicion of a cancer exists, tissue
diagnosis is required for confirmation. In some instances, this
may be possible in the outpatient setting. As mentioned earlier,
75% of head and neck cancers occur at readily visible or palpable sites. Mucosal sites may be sampled by excisional biopsy
whereas fine-needle aspiration may be used to sample lymph
nodes or other subcutaneous masses. Alternatively, biopsy can
be undertaken under general anesthesia as a component of a
staging endoscopy procedure (panendoscopy). Panendoscopy
involves direct laryngoscopy, esophagoscopy, and tracheobronchoscopy. In addition, it provides the surgeon with the
opportunity to perform bimanual examination under anesthesia. Panendoscopy is the gold standard with respect to providing a detailed evaluation of the mucosal surfaces of the upper
aerodigestive tract and should be performed for all patients
with suspected head and neck cancers. Not only does it facilitate accurate staging and surgical planning, but it also allows
for the detection of occult synchronous primary tumors.
Second primary tumors are common in the context of head
and neck cancer and occur in approximately 20% of patients
(published reports range from 5%35%).31 Second primary tumors are more likely in heavy tobacco users (20 pack
TA B L E 4 0 . 1 1
STAGING
STAGE GROUPING
Tis, N0, M0
T1, N0, M0
II
T2, N0, M0
III
T3, N0, M0
T1-T3, N1, M0
IVA
T4a, N01, M0
T1T4a, N2, M0
IVB
T4b, Any N, M0
Any T, N3, M0
IVC
Any T, Any N, M1
619
location of cervical metastases are predictive of regional recurrence and distant metastases. Distant metastases, in turn, are
almost universally incurable. However, a recent report does
demonstrate improved survival among patients undergoing
resection of lung metastases versus those receiving conservative measures.37 Though previous attempts at metastasectomy
have not yielded positive results, these findings have sparked
optimism and warrant further investigation.
Other patient and tumor characteristics associated with
poor outcome include positive resection margins; perineural,
vascular, or extracapsular nodal extension; African American
race; malnutrition; anemia; and multiple medical comorbidities. Continued tobacco and alcohol use have significant effects
on patient outcomes. Patients who abstain from tobacco have
better locoregional control rates and are 2.5 times more likely
to survive than those who continue to smoke. Smoking and
alcohol cessation also significantly reduces the risk of second
primary tumors.38
TA B L E 4 0 . 1 2
STAGING
N0
N1
N2a
N2b
N2c
N3
620
TA B L E 4 0 . 1 3
MANAGEMENT
Oral Cavity
T2, T3, T4
Oropharynx
Hypopharynx
Supraglottic Larynx
Glottic Larynx
T2, T3, T4
FIGURE 40.8. Intraoperative photograph demonstrating the left neck after performance of a selective
(supraomohyoid) neck dissection. Selective neck dissection is generally a low-morbidity procedure. Vital
structures such as the internal jugular vein (IJV), common carotid artery (CCA), and spinal accessory nerve
(large arrow) are carefully preserved. In the context of
an N0 neck, other nonvital structures such as the sternocleidomastoid muscle (SCM), external jugular vein
(EJV), greater auricular nerve (GAN), cervical sensory
rootlets (small arrows) and ansa cervicalis (asterisks)
may also be spared.
621
TA B L E 4 0 . 1 4
CLASSIFICATION
MRND type I
MRND type II
Levels IIII
Levels IIIV
Levels IIV
SCM, sternocleidomastoid; IJV, internal jugular vein; XI, spinal accessory nerve.
TA B L E 4 0 . 1 5
STAGING
AJCC STAGING CLASSIFICATION FOR TUMORS OF THE NASAL CAVITY AND PARANASAL SINUSES
Maxillary Sinus
Tx
T0
T1
T2
Tumor erodes into the hard palate or middle meatus of the nose. Tumor does not involve the posterior maxillary wall or
pterygoid plates
T3
Tumor invades any of the following: posterior wall of the maxillary sinus, subcutaneous tissues, floor or medial wall of the
orbit, pterygoid fossa, or ethmoid sinuses
T4a
Tumor invades anterior orbital contents, skin of cheek, pterygoid plates, infratemporal fossa, cribriform plate, sphenoid
sinus, or frontal sinus
T4b
Tumor invades any of the following: orbital apex, dura, brain, middle cranial fossa, cranial nerve other than V2,
nasopharynx, or clivus
T0
T1
T2
Tumor invading two subsites within a single region or extending to involve an adjacent region within the nasoethmoidal
complex, with or without bony invasion
T3
Tumor invades the medial wall or floor of the orbit, maxillary sinus, palate, or cribriform plate
T4a
Tumor invades any of the following: anterior orbital contents, skin of nose or cheek, minimal invasion of anterior cranial
fossa, pterygoid plates, sphenoid sinus, or frontal sinus
T4b
Tumor invades any of the following: orbital apex, dura, brain, middle cranial fossa, cranial nerves other than V2,
nasopharynx, or clivus
From: American Joint Committee on Cancer. Cancer Staging Manual, 6th ed. New York: Springer-Verlag; 2002, with permission.
Tx
622
STAGING
T0
T1
T2
T3
T4
T4a
T4b
will have developed occult nodal disease at the time of presentation.46 This may be related to the depth of tumor invasion as
lesions with greater than 2 mm thickness have nearly four
times the rate of nodal metastases of thinner tumors (47% vs.
12%).47 At present, elective neck dissection is indicated for all
but the most superficially invasive T1 tumors.48 Bilateral lymphadenectomy should be performed for lesions approaching
the midline. The prognostic significance of nodal metastases
cannot be overstated. Five-year survival is approximately 75%
among patients with localized disease. In the presence of
advanced T-stage or regional nodal metastases, this drops to
25% to 48%.45,49
Oropharyngeal Carcinomas
The oropharynx extends from the anterior tonsillar pillars and
the junction of the soft and hard palate to the level of the hyoid
bone. Oropharyngeal subsites include the palatine tonsils, base
of tongue, soft palate, and posterior oropharyngeal wall. The
current primary tumor staging is listed in Table 40.17. Nearly
90% of oropharyngeal cancers are squamous cell carcinomas.54 The symptoms of oropharyngeal carcinomas are typically vague, and primary tumors may be difficult to assess.
Consequently, delay in diagnosis is common and nearly 70% of
patients will present with advanced disease.45,54 Because of the
rich vascularity of this region and bilateral lymphatic drainage
patterns, these patients often develop bilateral or even contralateral nodal metastases. The tonsillar fossa is the most common site for primary tumors of the oropharynx, followed
closely by the base of tongue. Primary tumors of the soft palate
and posterior oropharyngeal wall occur much less frequently.
For early-stage, localized disease, surgery and radiation
have approximately equal cure rates, with nearly 90% local
control rates for the pooled group of oropharyngeal cancers.57,58 Ablative surgery of the oropharynxparticularly the
tongue basecan have significant effects on speech and swallowing. Radiation therapy results in less functional impairment and is in most cases the preferred initial treatment for T1
and T2 tumors. Advanced-stage disease is typically treated
with multimodal therapy including surgery with adjuvant
radiation or chemoradiation. Among all head and neck sites,
surgical resections of the oropharynx are the most likely to
result in functional morbidity with respect to speech, deglutition, and management of airway secretions. Historically, tongue
base resections very often necessitated the performance of a
total laryngectomy as a means to prevent chronic aspiration.
For several years, pedicled pectoralis major myocutaneous flaps
were used to offset some of these difficulties. However, these
have fallen out of favor because of pedicle retraction, unpredictability of residual bulk, and their insensate nature. As
TA B L E 4 0 . 1 7
STAGING
T0
T1
T2
T3
T4a
T4b
Nasopharyngeal Carcinoma
Nasopharyngeal carcinoma (NPC) is a relatively uncommon
diagnosis in the United States, though it is prevalent in other
parts of the worldparticularly in Southern China, where the
disease is endemic. The risk of NPC remains elevated in
patients who have emigrated from these areas, suggesting that
both environmental and genetic factors contribute to its pathogenesis.65 Environmental agents include nitrosamines such as
those present in cured meats and fish, cigarette smoking,
formaldehyde, wood dust, and polycyclic hydrocarbons.66
However, Epstein-Barr virus (EBV) is the most widely implicated etiologic agent. More than 90% of endemic NPC and
over 60% of cases worldwide are associated with EBV.6769
Though NPC is a squamous cell carcinoma, there are three distinct histologic classifications based on the degree of differentiation: keratinizing, nonkeratinizing, and undifferentiated. The
World Health Organization (WHO) has designated these as
types I, II, and III, respectively. WHO type III is the most common, accounting for 63% of North American cases and 95%
of endemic cases in China. In China, types I and II account for
less than 5% of all cases. However, WHO type I NPC occurs
much more frequently in North America, where up to 40% of
the cases may be of the keratinizing variety.70,71 Endemic/EBVassociated NPC is typically WHO types II and III whereas sporadic NPC is most frequently keratinizing (type I). However,
molecular detection methods have identified EBV DNA among
a significant proportion of type I NPCs as well.72
The most common presenting symptom of a patient with
NPC is a neck mass. This is followed closely by nasal obstruction and otologic complaints.65,68,73 Advanced disease may be
623
624
TA B L E 4 0 . 1 8
STAGING
T0
T1
T2
T2a:
T2b:
T3
T4
Nx
N0
N1
N2
N3
N3a:
Larger than 6 cm
N3b:
Stage Grouping
Stage I
T1, N0, M0
Stage IIa
T2a, N0, M0
Stage IIb
T1, N1, M0
Hypopharyngeal Carcinomas
The hypopharynx is a region that extends from the hyoid bone
to the esophageal inlet and includes the pyriform sinuses, postcricoid region, and posterior hypopharyngeal walls. Squamous cell carcinoma of the hypopharynx is extremely aggressive, and the prognosis is poor irrespective of the therapeutic
regimen used. The use of tobacco and alcohol account for a
great number of hypopharyngeal carcinomas. However, several other risk factors including Plummer-Vinson syndrome,
Fanconi anemia, and gastroesophageal reflux disease have also
been reported.7577 Patients will typically present with dysphagia, odynophagia, and otalgia. In addition, the hypopharynx
has a rich lymphovascular supply and nodal metastases are
common. Nearly 65% will present with N disease and more
than three fourths of patients with clinically negative necks
will harbor occult metastases.78,79 Contralateral disease is frequent, especially among tumors approaching the midline and
those with clinically positive disease on the ipsilateral side.79
Hypopharyngeal tumors are not readily visible on routine
examination. Coupled with the vagueness of the symptoms,
this often results in a delay in diagnosis. Nearly 80% will present with stage III or IV disease.54 The primary tumor staging
system may be seen in Table 40.19.
Early-stage disease may be treated using either definitive
radiation therapy or open partial pharyngectomy/partial laryngopharyngectomy.80 Advanced disease requires a combined
approach using surgery and adjuvant radiation or chemoradiation. Surgery typically involves total laryngopharyngectomy
and flap reconstruction. The submucosal lymphatic plexus of
the hypopharynx is extensive and allows for proximal and distal spread of disease. This often necessitates a wide margin that
may extend beyond the thoracic inlet. In these cases, resection
includes not only total laryngopharyngectomy but also
esophagectomy. Gastric pullup or jejunal free flap reconstruction is necessary in this circumstance.81 Given the morbidity of
these procedures and the dismal prognosis, organ-preservation
TA B L E 4 0 . 1 9
T3, N01, M0
T13, N2, M0
Stage IVa
T4, N02, M0
Stage IVb
Any T, N3, M0
Stage IVc
Any M1
T0
T1
T2
T3
T4
T2, N01, M0
Stage III
STAGING
625
Laryngeal Carcinomas
626
TA B L E 4 0 . 2 0
STAGING
T0
T1
Tumor limited to one subsite of supraglottis with normal vocal fold mobility
T2
Tumor invades mucosa of more than one adjacent subsite of supraglottis or glottis or
region outside supraglottis (e.g., mucosa of base of tongue, vallecula, medial wall of
pyriform sinus) without fixation of the hemilarynx
T3
Tumor limited to larynx with vocal cord fixation and/or invades any of the
following: postcricoid area, preepiglottic space, and/or minor cartilage erosion (e.g.,
inner cortex)
T4a
Tumor invades through the thyroid cartilage and/or invades tissues beyond the
larynx (e.g., trachea, soft tissues of neck including deep extrinsic muscle of tongue,
strap muscles, thyroid, or esophagus)
T4b
Glottis
Tx
T0
T1a
Tumor limited to one vocal fold with normal vocal fold motion
T1b
Tumor involves both vocal folds with normal vocal fold motion
T2
T3
Tumor limited to the larynx with vocal cord fixation and/or invades paraglottic
space, and/or minor thyroid cartilage erosion (e.g., inner cortex)
T4a
Tumor invades through the thyroid cartilage and/or invades tissues beyond the
larynx (e.g., trachea, soft tissues of neck including deep extrinsic muscle of tongue,
strap muscles, thyroid, or esophagus)
T4b
Subglottis
Tx
T0
T1
T2
T3
T4a
Tumor invades through the thyroid cartilage and/or invades tissues beyond the
larynx (e.g., trachea, soft tissues of neck including deep extrinsic muscle of tongue,
strap muscles, thyroid, or esophagus)
T4b
From: American Joint Committee on Cancer. Cancer Staging Manual, 6th ed. New York: Springer-Verlag;
2002, with permission.
dations for stages I and II disease is definitive radiation therapy, with local control and survival rates of approximately
65% to 70%.93,94 Advanced disease often involves the thyroid
gland, paratracheal lymph nodes, trachea, and other structures
of the superior mediastinum. Total laryngectomy with tracheal
resection and adjuvant radiation/chemoradiation are advocated. Despite aggressive local and systemic therapy, the prognosis is poor, with overall survival nearing 25%.94
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35. Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy in high-risk squamous-cell carcinoma of the
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36. Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or
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38. Smith BD, Haffty BG. Prognostic factors in patients with head and neck
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39. Kowalski LP, Bagietto R, Lara JRL, et al. Prognostic significance of the distribution of neck node metastasis from oral carcinoma. Head Neck 2000;
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40. Robbins KT, Clayman G, Levine PA, et al. Neck dissection classification
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42. Goldenberg D, Begum S, Westra WH, et al. Cystic lymph node metastasis
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43. Persky MS, Tabaee A. Cancer of the nasal vestibule, nasal cavity, and
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44. Piero N, Battaglia P, Bignami M, et al. Endoscopic surgery for malignant
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45. SEER Cancer Database. http://seer.cancer.gov; Accessed 1 November,
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46. Spiro RH, Alfonso AE, Farr HW, et al. Cervical node metastases from epidermoid carcinoma of the oral cavity and oral pharynx: a critical assessment of current staging. Am J Surg 1974;128:562.
47. Spiro RH, Huvos AG, Wong GY, et al. Predictive value of tumor thickness
in squamous carcinoma confined to the tongue and floor of the mouth. Am
J Surg 1986;152:345.
48. Sparano A, Weinstein G, Chalian A, et al. Multivariate predictors of occult
neck metastasis in early oral tongue cancer. Otolaryngol Head Neck Surg
2004;131:472.
49. Sessions DG, Spector GJ, Lenox J, et al. Analysis of treatment results for
oral tongue cancer. Laryngoscope 2002;112:616.
50. Sessions DG, Spector GJ, Lenox J, et al. Analysis of treatment results for
floor of mouth cancer. Laryngoscope 2000;110:1764.
51. Hicks WJ, Loree TR, Garcia RI, et al. Squamous cell carcinoma of the
floor of the mouth: a 20-year review. Head Neck 1997;19:400.
52. Wallwork BD, Anderson SR, Coman WB. Squamous cell carcinoma of the
floor of the mouth: tumor thickness and the rate of cervical metastasis.
ANZ J Surg 2007;77:761.
53. Koo BS, Lim YC, Lee JS, et al. Management of the contralateral N0 neck
in oral cavity squamous cell carcinoma. Head Neck 2006;28:896.
54. Hoffman HT, Karnell LH, Funk GF, et al. The national cancer database
report on cancer of the head and neck. Arch Otolaryngol Head Neck Surg
1998;124:951.
55. Vartanian JC, Carvalho AL, Filho MJ, et al. Predictive factors and distribution of lymph node metastasis in lip cancer patients and their implications
on the treatment of the neck. Oral Oncol 2004;40:223.
56. Campbell JP. Surgical management of lip carcinoma. J Oral Maxillofac
Surg 1998;56:955.
57. Fein DA, Lee WR, Amos WR, et al. Oropharyngeal carcinoma treated
with radiotherapy: a 30-year experience. Int J Radiat Oncol Biol Phys
1996;34:289.
58. Mendenhall WM, Morris CG, Amdur RJ, et al. Definitive radiotherapy for
squamous cell carcinoma of the base of tongue. Am J Clin Oncol 2006;
29:32.
59. Rieger JM, Zalmanowitz JG, Li SY, et al. Functional outcomes after surgical reconstruction of the base of tongue using radial forearm free flap in
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60. Shirazi HA, Sivanandan R, Goode R, et al. Advanced-stage tonsillar squamous carcinoma: organ preservation versus surgical management of the
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61. Denis F, Garaud P, Bardet E, et al. Final results of the 9401 French head
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64. Fakhry C, Gillison ML. Clinical implications of human papillomavirus in
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66. Yu MC, Yuan JM. Epidemiology of nasopharyngeal carcinoma. Sem Cancer Biol 2002;12:421.
67. Liu FF, Frappier L, Kim J, et al. East-West symposium on nasopharyngeal
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81. Triboulet J, Mariette C, Chevalier D, et al. Surgical management of carcinoma of the hypopharynx and cervical esophagus. Arch Surg 2001;136:
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82. Lee M, Ho H, Hsiao S, et al. Treatment results and prognostic factors in
locally advanced hypopharyngeal cancer. Acta Otolaryngol 2008;128:103.
83. Rabbani A, Amdur RJ, Mancuso AA. Definitive radiotherapy for T1-T2
squamous cell carcinoma of the pyriform sinus. Int J Radiat Oncol 2008;
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84. Wolf GT, Hawn WK, Fisher SG, et al. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. N Engl J Med 1991;324:1685.
85. Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and
radiotherapy for organ preservation in advanced laryngeal cancer. N Engl
J Med 2003;349:209.
86. Hoffman HT, Porter K, Karnell LH, et al. Laryngeal cancer in the United
States: changes in demographics, patterns of care, and survival. Laryngoscope 2006;116(suppl 11):1.
87. Sessions DG, Lenox J, Spector GJ. Supraglottic laryngeal cancer: analysis
of treatment results. Laryngoscope 2005;115:1402.
88. Redaelli de Zinis LO, Nicolai P, Tomenzoli D, et al. The distribution of
lymph node metastases in supraglottic squamous cell carcinoma: therapeutic implications. Head Neck 2002;24:913.
89. Cabanillas R, Rodrigo JP, Llorente JL, et al. Oncologic outcomes of transoral laser surgery of supraglottic carcinoma compared with a transcervical approach. Head Neck 2008;30:750.
90. Rodrigo JP, Suarez C, Silver CE, et al. Transoral laser surgery for supraglottic cancer. Head Neck 2008;30:658.
91. Laudadio P, Presutti L, DallOlio D, et al. Supracricoid laryngectomies:
long-term oncological and functional results. Acta Otolaryngol 2006;126:
640.
92. Mendenhall WM, Wernig JW, Hinerman RW, et al. Management of T1-T2
glottic carcinomas. Cancer 2004;100:1786.
93. Paisley S, Warde PR, OSullivan B, et al. Results of radiotherapy for primary
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94. Garas J, McGuirt WF. Squamous cell carcinoma of the subglottis. Am J
Otolaryngol 2006;27:1.
SECTION D
ESOPHAGUS
ANATOMY
A detailed knowledge of the anatomic relationships of the
esophagus is essential for the surgeon to plan and perform safe
surgery, as well as to understand the significance of abnormalities detected on studies such as upper endoscopy, barium
roentgenography, or computed tomography.1 In this section,
the embryology of the esophagus is first described, then the
topographic relations of the esophagus are covered, and finally
the conduct of investigations that yield anatomic information
is addressed.
The embryology of the esophagus is important in understanding the pathogenesis of congenital malformations of the
esophagus and trachea. The embryonic esophagus forms when
P O I N T S
10
11
12
paired longitudinal grooves appear on each side of the laryngotracheal diverticulum. These grooves subsequently grow
medially and fuse to form the tracheoesophageal septum. This
septum divides the foregut into the ventral laryngotracheal
tube and the dorsal esophagus. Incomplete fusion of the two
lateral grooves was thought to be the major factor in the
pathogenesis of congenital tracheoesophageal fistula, but the
anomaly is now attributed to abnormal growth and differentiation of the lung buds. Initially the esophagus is short, but
elongation occurs rapidly, and the final relative length is
attained by the seventh gestational week. This is followed by
endodermal proliferation, resulting in near obliteration of the
esophageal lumen and subsequent recanalization by the development of large vacuoles that coalesce. The striated muscle of
629
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630
the superior vena cava. The thoracic duct ascends behind and
to the right of the distal esophagus, but at the level of T5 it
passes posterior to the aorta and ascends on the left side of the
esophagus and posterior to the left subclavian artery.
Throughout its length, the attachments of the esophagus to
its adjacent structures other than the posterior trachea are flimsy.
This accounts for the ease with which the esophagus may be
bluntly mobilized out of the mediastinum during transhiatal
esophagectomy. In general, the lower esophagus is most easily
approached through the left chest, but access to the supra-aortic
esophagus is restricted. Thus, a left thoracotomy is most useful
for performing Heller myotomy, transthoracic fundoplication,
or resection of an epiphrenic diverticulum. Access to the entire
thoracic esophagus can be obtained only from the right chest,
but access to the intra-abdominal organs is restricted by the liver
and normally requires a separate upper abdominal incision.
The abdominal esophagus begins as the esophagus enters the
abdomen through the diaphragmatic hiatus (Fig. 41.1). It is surrounded by a fibroelastic membrane, the phrenoesophageal ligament, which arises from the subdiaphragmatic fascia (Fig.
41.2). The lower limit of the phrenoesophageal membrane anteriorly is marked by a prominent fat pad, which corresponds to
the gastroesophageal (GE) junction. The lower esophageal
sphincter (LES) is a zone of high pressure 3 to 5 cm long at the
lower end of the esophagus.2 Although it does not correspond
to any macroscopic anatomic structure, its function appears to
be related to the microscopic architecture of the muscle fibers.
The esophageal hiatus is formed by the right and left crura,
which form a sling of muscular fibers arising by tendinous
bands from the anterolateral surface of the first four lumbar vertebrae. The relative contributions of the right and left crura to
the sling are variable. Surgeons name the crura from their relation to the esophagus, whereas anatomists name them from their
relation to the aorta. Thus, both right and left surgical crura
originate from the right anatomic crus. Caudally, the crura
are united by a tendinous arch, the median arcuate ligament,
just anterior to the aorta at the level of the celiac axis.
The blood supply and venous drainage are largely segmental. The inferior thyroid artery provides the main blood supply
to the cervical portion of the esophagus. This becomes important in a patient with a previous thyroidectomy, although
ligation is usually performed distal to the esophageal branch.
The thoracic portion of the esophagus receives its blood supply from two sources. Usually, branches from two to three
Chapter 41: Esophageal Anatomy and Physiology and Gastroesophageal Reflux Disease
631
632
Chapter 41: Esophageal Anatomy and Physiology and Gastroesophageal Reflux Disease
633
PHYSIOLOGY
The act of alimentation requires the passage of food and drink
from the mouth into the stomach. Food is taken into the mouth
in a variety of bite sizes, where it is broken up, mixed with
saliva, and lubricated. Swallowing, once initiated, is entirely a
reflex. When food is ready for swallowing, the tongue, acting
like a piston, moves the bolus into the posterior oropharynx
and forces it into the hypopharynx.3 Concomitantly with the
posterior movement of the tongue, the soft palate is elevated,
thereby closing the passage between the oropharynx and
nasopharynx. This partitioning prevents pressure generated in
the oropharynx from being dissipated through the nose. When
the soft palate is paralyzed, as following a cerebral vascular
accident, food is commonly regurgitated into the nasopharynx. During swallowing, the hyoid bone moves upward and
anteriorly, elevating the larynx and opening the retrolaryngeal
space, bringing the epiglottis under the tongue. The backward
tilt of the epiglottis covers the opening of the larynx to prevent
esophagus. The esophageal plexus on the anterior and posterior wall of the esophagus provides innervation for the lower
esophagus. The esophageal plexus also receives fibers from the
thoracic sympathetic chain. The single trunks located distally
contain fibers from both right and left original vagus nerves.
Efferent preganglionic sympathetic fibers supplying the
esophagus arise from the fourth to sixth thoracic spinal cord
segments and terminate in the cervical and thoracic sympathetic ganglions. Fibers from the superior cervical ganglion
arrive at the pharyngeal plexus by way of vagal nerves. The
postganglionic fibers reach the esophagus by branches from the
cervical and thoracic sympathetic chain. The distal esophageal
segments also receive direct sympathetic fibers from the celiac
ganglion.
Afferent visceral sensory pain fibers from the esophagus
terminate without synapsing in the first four segments of the
thoracic spinal cord, following both sympathetic and vagal
pathways. Pain fibers from the heart also travel in this same
pathway, which explains the similarity of the symptoms in
many esophageal and cardiac diseases.
634
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60
50
40
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60
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0
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70
60
50
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Chapter 41: Esophageal Anatomy and Physiology and Gastroesophageal Reflux Disease
Press
3*
4*
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0
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30
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GASTROESOPHAGEAL
REFLUX DISEASE
Definition and Epidemiology
Developing an accurate definition of gastroesophageal reflux
disease is surprisingly difficult. The disease can be associated
with myriad common gastrointestinal (GI) and respiratory
symptoms and there is no fully accurate diagnostic test that
can be relied upon. In an effort to provide a consensus definition, a group of experts came together in Montreal in 2004
and concluded that GERD can be best defined as a condition
2*
40
30
20
10
0
10
40
30
20
10
0
10
40
30
20
10
0
10
40
30
20
10
0
10
635
636
Europe
USA
Asia
South America
Prevalence (%)
25
20
15
10
5
0
1980
1985
1990
1995
2000
2005
2010
Date of publication
FIGURE 41.8. Time trends for the prevalence of weekly heartburn
from 1980 to 2005. (Reproduced with permission from El-Serag H.
Time trends of gastroesophageal reflux disease: a systematic review.
Clin Gastroenterol Hepatol 2007;5:1726, Figure 1.)
Most patients with mild symptoms self-medicate with overthe-counter antacids or antisecretory agents, whereas those
with more severe and persistent symptoms seek out medical
attention. Further, the prevalence and severity of GERD are
likely increasing. This is in contrast to duodenal ulcer disease,
where the prevalence has markedly decreased (Fig. 41.9).14
The diagnosis of a columnar-lined esophagus is also increasing
at a rapid rate, and deaths from end-stage benign esophageal
disease are on an upward trend.15 These changes have occurred
despite dramatic improvements in the efficacy of treatment
options.
Two epidemiologic trends may be contributing to the
increasing prevalence and severity of GERD over the past several decades. Population-based studies have shown that GERD
is positively associated with obesity and negatively associated
with gastric colonization with Helicobacter pylori. Over the
past 20 to 30 years, the former has increased and the latter has
decreased markedly in most Western countries. The relationship between GERD and body mass index (BMI) has been
evaluated in a number of well-designed clinical studies. The
frequency, duration, and severity of reflux symptoms were
studied in 10,500 women of the Nurses Health Study and a
dose-dependent relationship between increasing BMI frequency of GERD symptoms was identified.16 Compared to
normal-weight women (BMI 20 to 22.4), underweight women
(BMI 20) were one-third less likely and overweight women
(BMI 25 to 27.4) two times more likely to have frequent
GERD symptoms. Obese women (BMI 30) had a nearly
three times higher risk of frequent GERD symptoms (Fig. 41.10).
Recent meta-analyses confirm these findings, with studies from
the United States demonstrating an association between
increasing BMI and the presence of GERD.17 High-resolution
motility studies have shown a significant correlation with BMI
and both intragastric pressure and gastroesophageal pressure
gradients, providing a physiologic explanation for the BMI
GERD association.18 These studies suggest that obese subjects
are more likely to have esophagogastric junction disruption
and abnormal pressure gradients favoring the development of
reflux. Finally, the risk of Barrett esophagus has been correlated with the presence of central obesity. Measures of central
obesity, including waist circumference and waist-to-hip ratios,
were associated with both short- and long-segment Barrett
esophagus, with a 4.1 higher odds ratio of long-segment Barrett
in patients with a high waist-to-hip ratio.19
The possible pathogenic role of helical-shaped bacteria
found in gastric fluids was first suggested in the late 19th century by the Polish scientist Walery Jaworski of the University
of Krakow.20 It was the publication of two Australian scientists in 1983 that convincingly demonstrated the pathogenic role
of H. pylori.21 These pioneering studies of Barry Marshall and
Chapter 41: Esophageal Anatomy and Physiology and Gastroesophageal Reflux Disease
4.2
4.0
3.8
3.6
3.4
3.2
3.0
2.8
2.6
2.4
2.2
2.0
1.8
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
2.92 (2.353.62)
2.93 (2.243.85)
2.20 (1.812.66)
637
2.43 (1.963.01)
1.38 (1.131.67)
0.67 (0.480.93)
<20.0
20.022.4
22.524.9
25.027.4
27.529.9
30.034.9
35.0
firmed an inverse relationship between the presence of cagA positivity and adenocarcinoma of the esophagus and the GE junction.28 Most authors postulate that cagA strains may protect
from the development of adenocarcinoma by inducing more
severe mucosal inflammation and atrophic gastritis and thereby
decreasing acid reflux. Present data regarding gastric acid secretion are conflicting, however, and further studies are required to
test whether this hypothesis is true.
Studies on the natural history of GERD are rare. The few
that do exist usually involve patients who were receiving some
form of therapy. One of the most detailed studies on the natural history of the disease comes from investigators in
Europe.29 The progression or regression of GERD complications was assessed in a cohort of nearly 4,000 patients with
predominant heartburn over a 2-year period. After 2 years,
25% of patients with nonerosive GERD progressed to erosive
disease, 1.6% with mild erosive esophagitis worsened to more
severe esophagitis, and nearly 8% progressed to Barrett esophagus, the latter predominantly in patients with Los Angeles
grade C/D erosive disease at baseline. On the other hand, 50%
to 60% of patients with baseline esophagitis improved to a
milder grade or no erosive disease and 22% were off medications at 2 years. Given that virtually all patients were receiving
significant antisecretory therapy, the study shows that a substantial minority of patients will continue to worsen despite
pharmacologic treatment. Investigators in Lausanne, Switzerland, reported an intensive endoscopic follow-up of a defined
population of 959 patients over a 30-year period.30 The study
involved only patients who had endoscopic esophagitis and
did not include those who had symptoms without mucosal
injury. Esophagitis was an isolated episode and did not return
while on acid suppression therapy in roughly half of the
patients. In the remaining patients, esophagitis intermittently
recurred on acid suppression therapy, and in 42% it progressed on therapy to more severe mucosal injury. This latter
group makes up roughly one quarter of the initial population
of patients with esophagitis, similar to that reported in the
Labenz study outlined previously. The study also showed that
as many as 18% of the initial population may have acquired,
while on therapy, a columnar-lined lower esophagus with
intestinal metaplasia.
Clinical Presentation
The most common complaints in patients with GERD are
heartburn, regurgitation, and dysphagia or difficulty swallowing. These represent the so-called typical symptoms of GERD.
Although none of these are specific to GERD, dysphagia is
Body-Mass Index
638
Erosion absent
Erosion present
Chapter 41: Esophageal Anatomy and Physiology and Gastroesophageal Reflux Disease
639
TA B L E 4 1 . 1
NORMAL MANOMETRIC VALUES OF THE DISTAL ESOPHAGEAL SPHINCTER IN 50 SUBJECTS
PARAMETER
MEDIAN
VALUE
2.5TH
PERCENTILE
97.5TH
PERCENTILE
5.8
27.7
13
3.6
2.1
5.6
0.9
4.7
640
Anatomic Alterations
With the advent of clinical roentgenology, it became evident
that a hiatal hernia was a relatively common abnormality
although not always accompanied by symptoms. Philip Allison, in his classic treatise published in 1951, suggested that the
manifestations of gastroesophageal reflux disease were caused
by the presence of a hiatal hernia. For most of the next two
decades, hiatal hernia was considered the primary pathophysiologic abnormality leading to GERD. Indeed, the Allison
repair, among the first surgical attempts to treat GERD, consisted of a hernia repair only. As techniques of esophageal
manometry were developed in the late 1950s and 1960s,
allowing identification and study of the lower esophageal
sphincter, attention was slowly diverted away from the hernia
as the main pathophysiologic abnormality of GERD. In 1971,
Cohen and Harris published a study of the contributions of
hiatal hernia to lower esophageal sphincter competence in 75
patients, concluding that hiatal hernia had no effect on GE
junction competence.42 This paper, published in the New England Journal of Medicine, and the growing use of esophageal
manometry shifted the emphasis away from the hernia almost
exclusively toward features of the lower esophageal sphincter
as the primary abnormality in symptomatic GERD.
Perhaps serendipitously, studies of the phenomenon of
TLESRs identified the diaphragmatic crura as an important
factor in preventing reflux during periods of loss of LES pressure.43 In normal subjects, even with absent LES pressure,
reflux does not occur without relaxation of the crural
FIGURE 41.13. The intragastric pressure at which the lower esophagus endoscopically opened in response to gastric distention by air during endoscopy. Note that the dome architecture of a hiatus hernia
(HH) influences the ease with which the sphincter can be pulled open
by gastric distention. (Reproduced with permission from Ismail T,
Bancewicz J, Barlow J. Yield pressure, anatomy of the cardia and gastrooesophageal reflux. Br J Surg 1995;82:943.)
641
Chapter 41: Esophageal Anatomy and Physiology and Gastroesophageal Reflux Disease
9.0
7.0
pH 5.0
3.0
1.0
Fasting
9.0
7.0
pH 5.0
3.0
1.0
Postprandial
49
48
47 46 45 44 43 42
Distance from nostril (cm)
41
40
39
This is the initial step and explains why in early disease the
esophagitis is mild and commonly limited to the very distal
esophagus. The patient compensates by increased swallowing,
allowing saliva to bathe the injured mucosa and alleviate the
discomfort induced by exposure to gastric acid. Increased swallowing results in aerophagia, bloating, and repetitive belching.
The distention induced by aerophagia leads to further exposure
and repetitive injury to the terminal squamous epithelium and
the development of cardiac-type mucosa. This is an inflammatory process, commonly referred to as carditis, and explains
the complaint of epigastric pain so often registered by patients
with early disease. The process can lead to a fibrotic mucosal
ring at the squamocolumnar junction and explains the origin of
a Schatzki ring. Extension of the inflammatory process into the
muscularis propria causes a progressive loss in the length and
pressure of the distal esophageal high-pressure zone associated
with an increased esophageal exposure to gastric juice and the
Nitric oxide
concentration
after nitrate (M)
10
8
6
4
2
0
10 9 8 7 6 5 4 3 2 1 0 -1 -2 -3 -4 -5
4
3
2
1
0
10 9 8 7 6 5 4 3 2 1 0 -1 -2 -3 -4 -5
Distance from gastroesophageal pH step-up (cm)
FIGURE 41.15. Mean (SEM) nitric oxide concentrations in the
upper stomach and lower esophagus after administration of water
with 2 mmol nitrate (upper tracing) and water alone (lower tracing)
(**p 0.01, *p 0.05 compared with value at gastroesophageal junction pH step-up). (Reproduced with permission from Iljima K, Henry
E, Moriya A, et al. Dietary nitrate generates potentially mutagenic
concentrations of nitric oxide at the gastroesophageal junction. Gastroenterology 2002;122:1248.)
Nitric oxide
concentration
after water (M)
642
Reflux
Non-pH-dependent complications
Asthma
Bronchitis
Laryngitis
Aspiration pneumonia
Restrictive lung disease
symptoms of heartburn and regurgitation. The loss of the barrier occurs in a distal-to-proximal direction and eventually
results in the permanent loss of LES resistance and the explosion of the disease into the esophagus with all the clinical manifestations of severe esophagitis. This accounts for the observation that severe esophageal mucosal injury is almost always
associated with a permanently defective sphincter. At any time
during this process and under specific luminal conditions or
stimuli, such as exposure time to a specific pH range, intestinalization of the cardiac-type mucosa can occur and set the
stage for malignant degeneration.
Implications
Implications of recognizing anatomic alterations as component
of GE barrier:
1. Transient lower esophageal sphincter relaxation is the
likely underlying mechanism of belching and physiologic
reflux. It does not play a major role in patients with symptomatic gastroesophageal reflux, particularly those with
erosive disease, those with Barrett esophagus, or those
referred for surgery.
2. Efforts to augment the gastroesophageal barrier either
pharmacologically or endoscopically will commonly fail
when a hiatal hernia is present.
3. Patients with abnormal esophageal acid exposure in the
presence of normal LES characteristics and no hiatal hernia
have an uncommon reason for reflux. Gastric or esophageal
clearance failure may be present and will seriously complicate postoperative outcome.
4. Both reduction of hiatal hernia and augmentation of the
lower esophageal sphincter is necessary to maximally
restore gastroesophageal barrier competence.
5. Although acid control without regard to barrier incompetence will improve heartburn and heal esophageal erosive
disease, it results in increasing numbers of patients with
pulmonary manifestations of GERD.
Mucosal Complications. The potential injurious components that reflux into the esophagus include gastric secretions,
such as acid and pepsin; biliary and pancreatic secretions that
regurgitate from the duodenum into the stomach; and toxic
compounds generated in the mouth, esophagus, and stomach
by the action of bacteria on dietary substances.
Our current understanding of the role of the various ingredients of gastric juice in the development of esophagitis is
based on classic animal studies performed by Lillimoe et
al.53,54 These studies have shown that acid alone does minimal
damage to the esophageal mucosa, but the combination of
acid and pepsin is highly deleterious. Hydrogen ion injury to
the esophageal squamous mucosa occurs only at a pH below
2. In acid refluxate, the enzyme pepsin appears to be the major
injurious agent. Similarly, the reflux of duodenal juice alone
does little damage to the mucosa, while the combination of
duodenal juice and gastric acid is particularly noxious. Reflux
of bile and pancreatic enzymes into the stomach can either
protect or augment esophageal mucosal injury. For instance,
the reflux of duodenal contents into the stomach may prevent
the development of peptic esophagitis in a patient whose gastric acid secretion maintains an acid environment, because the
bile salts would attenuate the injurious effect of pepsin and the
acid would inactivate the trypsin. Such a patient would have
Barretts esophagus
Esophagitis III/IV
Complications of Gastroesophageal
Reflux Disease
The complications of gastroesophageal reflux result from the
damage inflicted by gastric juice on the esophageal mucosa or
laryngeal or respiratory epithelium (Fig. 41.16). These can be
conceptually divided into (a) mucosal complications such as
esophagitis and stricture; (b) extraesophageal or respiratory
complications such as chronic cough, asthma, and pulmonary
fibrosis; and (c) metaplastic (Barrett esophagus) and neoplastic
(adenocarcinoma). The prevalence and severity of complications is related to the degree of loss of the gastroesophageal
Chapter 41: Esophageal Anatomy and Physiology and Gastroesophageal Reflux Disease
643
60
40
20
Upright
Postprandial
N
su or
bj ma
ec l
ts
w P
ith at
G ien
ER ts
D
N
su or
bj ma
ec l
ts
w P
ith at
G ien
ER ts
D
N
su or
bj ma
ec l
ts
w P
ith at
G ien
ER ts
D
Supine
% ionized
644
asthma and pulmonary fibrosis in particular, have a significantly higher frequency of positive 24-hour pH studies.67,68
With dual pH monitoring of the proximal and distal esophagus, prolonged exposure of the proximal esophagus to gastric
juice occurs at a higher frequency in patients with gastroesophageal reflux and respiratory symptoms than in patients
without respiratory complaints.69,70 Fourth, simultaneous tracheal and esophageal pH monitoring in patients with reflux
disease have documented tracheal acidification in concert with
esophageal acidification.64 Finally, medications used to treat
chronic lung diseases, in particular, bronchodilators, relax
esophageal sphincter tone.71
A reflex mechanism is primarily supported by the fact that
bronchoconstriction occurs following the infusion of acid into
the lower esophagus.7274 This can be explained by the common embryologic origin of the tracheoesophageal tract and its
shared vagal innervation.
The primary challenge in implementing treatment for
reflux-associated respiratory symptoms lies in establishing the
diagnosis. In those patients with predominantly typical reflux
symptoms and secondary respiratory complaints, the diagnosis may be straightforward. However, in a substantial number
of patients with reflux-induced respiratory symptoms, the respiratory symptoms dominate the clinical scenario. Gastroesophageal reflux in these patients is often silent and is only
uncovered when investigation is initiated.68,75 A high index of
suspicion is required, notably in patients with poorly controlled asthma in spite of appropriate bronchodilator therapy.
Supportive evidence for the diagnosis can be gleaned from
endoscopy and stationary esophageal manometry. Endoscopy
may show erosive esophagitis or Barrett esophagus. Manometry may indicate a hypotensive lower esophageal sphincter or
ineffective body motility, defined by 30% or more contractions in the distal esophagus of less than 30 mm Hg in amplitude.76 DOvidio et al. studied 78 patients awaiting lung transplant for IPF, scleroderma, COPD, or CF and found that 72%
had a hypotensive lower esophageal sphincter, 33% abnormal
esophageal body motility, and 38% abnormal 24-hour pH
testing,77 although, interestingly, patients with IPF in other
series have been shown to have normal manometry.70
The current gold standard for the diagnosis of refluxinduced respiratory complaints is ambulatory dual-probe pH
monitoring, often combined with multichannel intraluminal
pH negative, no symptoms or
symptoms occurring with no change
of pH recorded in proximal or
distal probe
No antireflux therapy
Abnormal motility
Normal motility
Low probability of
relief of symptoms
with surgery
High probability
of relief of
symptoms with
surgery
ALGORITHM 41.1
ALGORITHM 41.1. Algorithm of clinical decision making based on outcome of dual-probe 24-hour pH testing and esophageal manometry in
patients with respiratory symptoms thought secondary to gastroesophageal reflux disease.
Chapter 41: Esophageal Anatomy and Physiology and Gastroesophageal Reflux Disease
645
646
Chapter 41: Esophageal Anatomy and Physiology and Gastroesophageal Reflux Disease
TA B L E 4 1 . 2
647
DIAGNOSIS
FINAL DIAGNOSIS
NO.
METAPLASIA
I/LGD
HGD
CA
Metaplasia
39
27
10
I/LGD
20
HGD
648
Antireflux Surgery
Indications. Antireflux surgery is indicated for the treatment of
objectively documented, relatively severe GERD. Candidates
for surgery include not only patients with erosive esophagitis,
stricture, and Barrett esophagus but also those without severe
mucosal injury who are dependent on PPIs for symptom relief.
Patients with atypical or respiratory symptoms who have a
good response to intensive medical treatment are also candidates. The option of antireflux surgery should be given to all
patients who have demonstrated the need for long-term medical therapy, particularly if escalating doses of PPIs are needed
to control symptoms. Antireflux surgery may be the preferred
option in patients younger than 50 years, those who are noncompliant with their drug regimen, those for whom medications are a financial burden, and those who favor a single
intervention over long-term drug treatment. It may be the
treatment of choice in patients who are at high risk of progression despite medical therapy. Although this population is
not well defined, risk factors that predict progressive disease
and a poor response to medical therapy include (a) nocturnal
reflux on 24-hour esophageal pH study, (b) a structurally deficient LES, (c) mixed reflux of gastric and duodenal juice, and
(d) mucosal injury at presentation.132
Preoperative Evaluation. Successful antireflux surgery is
largely defined by two objectives: the achievement of longterm relief of reflux symptoms and the absence of complications or complaints after the operation. In practice, achieving
these two deceptively simple goals is difficult. Both are critically dependent on establishing that the symptoms for which
the operation is performed are the result of excess esophageal
exposure to gastric juice, as well as the proper performance of
the appropriate antireflux procedure. Success can be expected
in the vast majority of patients if these two criteria are met.
The status of the LES is not as important a factor as in the days
of open surgery. Patients with normal resting sphincters are
often selected for antireflux surgery in the era of laparoscopic
fundoplication. The outcome is not dependent on sphincter
function. There are four important goals of the diagnostic
approach to patients suspected of having GERD and being
considered for antireflux surgery (Table 41.3).
The introduction of laparoscopic access, coupled with the
growing recognition that surgery is a safe and durable treatment for GERD, has dramatically increased the number of
patients being referred for laparoscopic fundoplication compared to the prelaparoscopic era. Recent data suggest that the
peak use of antireflux surgery in the United States occurred in
1999, with an estimated 15.7 cases per 100,000 adults at that
time.133 Since then, the frequency of antireflux surgery has
declined, such that an estimated 11 antireflux procedures were
performed per 100,000 adults in 2003. This recent decline
may reflect the availability of generic and over-the-counter
PPIs, a constantly evolving menu of endoscopic antireflux
therapies, increased utilization of Roux-en-Y gastric bypass
for control of GERD in morbidly obese individuals, and the
long-term efficacy of fundoplication being called into question. Given the various therapies for GERD, each with its
potential advantages and shortcomings, accurate and contemporary data regarding outcomes after antireflux surgery are
necessary as a basis against which other established and novel
therapies must be judged.
TA B L E 4 1 . 3
DIAGNOSIS
649
Chapter 41: Esophageal Anatomy and Physiology and Gastroesophageal Reflux Disease
TA B L E 4 1 . 4
PREDICTORS OF OUTCOME AFTER LAPAROSCOPIC FUNDOPLICATION: STEPWISE LOGISTIC REGRESSION RESULTS
OF 199 PATIENTS
PREDICTOR
Composite acid score
Symptom
Response to medical therapy
STATUS
WALDS p VALUE
5.4 (1.915.3)
0.001
Normal
Typical
5.1 (1.913.7)
0.001
Atypical
3.3 (1.38.7)
0.02
Increased
Complete/partial
Minor/none
Odds ratios and corresponding p values are adjusted for age and for all other factors in the model.
From Campos GMR, Peters JH, DeMeester TR, et al. Multivariate analysis of the factors predicting outcome after laparoscopic Nissen
fundoplication. J Gastrointest Surg 1999;3:292300.
TA B L E 4 1 . 5
CLASSIFICATION
LESION
Given the large number of surgical referrals, the importance of selecting patients for surgery who are likely to have a
successful outcome cannot be overemphasized. Although a
Nissen fundoplication will reliably and reproducibly halt the
return of gastroduodenal juice into the esophagus, little benefit is likely if the patients symptoms are not caused by this specific pathophysiologic derangement. Thus, in large part, the
anticipated success rate of laparoscopic fundoplication is
directly proportional to the degree of certainty that GERD is
the underlying cause of the patients complaints.
Three factors predictive of a successful outcome following
12
antireflux surgery have emerged (Table 41.4).134 These are (a)
an abnormal score on 24-hour esophageal pH monitoring;
(b) the presence of typical symptoms of GERD, namely,
heartburn or regurgitation; and (c) symptomatic improvement in response to acid suppression therapy prior to
surgery. It is immediately evident that each of these factors
helps to establish that GERD is indeed the cause of the
patients symptoms and that they have little to do with the
severity of the disease.
650
degree of unfolding or deterioration of the normal valve architecture. This grading system has been correlated with the presence of increased esophageal acid exposure, occurring predominantly in patients with a grade III or IV valve.
A hiatal hernia is endoscopically confirmed by finding a
pouch lined with gastric rugal folds lying 2 cm or more above
the margins of the diaphragmatic crura. A prominent sliding
hernia is frequently associated with increased esophageal
exposure to gastric juice. When a paraesophageal hernia
exists, particular attention is given to exclude a gastric ulcer or
gastritis within the pouch. The term Cameron erosions refers
to such mucosal erosions occurring in large sliding or paraesophageal hernias, typically at the level of the diaphragmatic
hiatus. The intragastric retroflex or J maneuver is important
in evaluating the full circumference of the mucosal lining of
the herniated stomach. As the endoscope is removed, the
esophagus is again examined and biopsies taken. The location
of the cricopharyngeus is identified and the larynx and vocal
cords are visualized. Acid reflux may result in inflammation of
the larynx. Vocal cord movement is recorded both as a reference for subsequent surgery and an assessment of the patients
ability to protect the airway.
Twenty-four Hour Ambulatory pH Monitoring. The most
direct method of assessing the relationship between symptoms
and GERD is to measure the esophageal exposure to gastric
juice with an indwelling pH electrode. Miller136 first reported
prolonged esophageal pH monitoring in 1964, although it was
not until 1973 that its clinical applicability and advantages
were demonstrated by Johnson and DeMeester.137 Ambulatory
pH testing is considered by many to be the gold standard for
the diagnosis of GERD, because it has the highest sensitivity
and specificity of all tests currently available. Some experts
have suggested that 24-hour pH monitoring be used selectively, limited to patients with atypical symptoms or no endoscopic evidence of GE reflux. Given present-day referral patterns, more than half of the patients referred for antireflux
surgery will have no endoscopic evidence of mucosal injury.
For these patients, 24-hour pH monitoring provides the only
objective measure of the presence of pathologic esophageal
acid exposure. Although it is true that most patients with typical symptoms and erosive esophagitis have a positive 24-hour
pH result, the pH study provides other useful information. It
quantifies the actual time that the esophageal mucosa is
exposed to gastric juice, measures the ability of the esophagus
to clear refluxed acid, and correlates esophageal acid exposure
with the patients symptoms. It is the only way to quantitatively express the overall degree and pattern of esophageal acid
exposure, both of which may impact the decision toward
surgery.138 Patients with nocturnal or bipositional reflux have
a higher prevalence of complications and failure of long-term
TA B L E 4 1 . 6
NORMAL VALUES FOR ESOPHAGEAL EXPOSURE TO pH 4 IN 50 SUBJECTS
COMPONENT
MEAN
STANDARD
DEVIATION
95TH
PERCENTILE
Total time pH 4
1.51
1.36
4.45
Upright time pH 4
2.34
2.34
8.42
Supine time pH 4
0.63
1.0
3.45
No. episodes
19.00
12.76
No. 5 min
0.84
1.18
Longest episode
6.74
7.85
46.9
3.45
19.8
From Johnson LF, DeMeester TR. Development of the 24-hour intraesophageal pH monitoring composite
scoring system. J Clin Gastroenterol 1986;8(suppl 1):5258.
Chapter 41: Esophageal Anatomy and Physiology and Gastroesophageal Reflux Disease
MII measuring
segments
15 cm
9 cm
7 cm
5 cm
Oesophageal pH
sensor 5 cm
3 cm
LOS
Gastric pH
sensor 10 cm
17 cm
651
652
TA B L E 4 1 . 7
DIAGNOSIS
PURPOSE
TECHNIQUE
Prone RAO
Esophageal diameter
Gastric function
Supine
Relationship of GE
junction to hiatus
Erect
Cricopharyngeal function
Mucosal injury
Reducibility of hernia
the bolus. Residual material can stimulate a secondary peristaltic wave, but usually a second pharyngeal swallow is
required. Motility disorders with disorganized or simultaneous esophageal contractions have tertiary waves and provide a segmented appearance to the barium column, often
referred to as beading or corkscrewing. In dysphagic patients,
a barium-impregnated marshmallow, bread, or hamburger is a
useful adjunct, which can discern a functional esophageal
transport disturbance not evident on the liquid barium study.
Reflux is not easily seen on video esophagram, and motility
disorders that cause retrograde barium transport may be mistaken for reflux.
Assessment of the stomach and duodenum during the barium study is a necessity for proper preoperative evaluation of
the patient with GERD. Evidence of gastric or duodenal ulcer,
neoplasm, or poor gastroduodenal transit has obvious importance in the proper preoperative evaluation.
Assessment of Esophageal Function. The presence of poor
esophageal body function can impact the likelihood of relief of
regurgitation, dysphagia, and respiratory symptoms following
surgery and may influence the decision to undertake a partial
rather than a complete fundoplication. When peristalsis is
absent or severely disordered, many surgeons would opt for a
partial fundoplication, although recent studies would suggest
a complete fundoplication may be appropriate even in this setting. The less favorable response of atypical, compared with
typical, reflux symptoms after fundoplication may be related
to persistent poor esophageal propulsive function and the continued regurgitation of esophageal contents.148,149
The function of the esophageal body is assessed with
esophageal manometry. Conventional water-perfused or solidstate manometry is performed with five pressure transducers
located in the esophagus (Fig. 41.24). To standardize the procedure, the most proximal pressure transducer is located 1 cm
below the well-defined cricopharyngeal sphincter. With this
method, a pressure response along the entire esophagus can be
obtained during one swallow. The study consists of recording
10 wet swallows with 5 mL of water. Amplitude, duration,
Chapter 41: Esophageal Anatomy and Physiology and Gastroesophageal Reflux Disease
cm
100
30
50
11
70
16
90
21
100
80
60
40
20
Respiration
Time
18
Pressure
mm Hg
Length
653
654
FIGURE 41.27. Pulsox-300i with finger probe used to assess ambulatory oxygen saturation (Konica Minolta Sensing, Inc.).
Chapter 41: Esophageal Anatomy and Physiology and Gastroesophageal Reflux Disease
655
studies of unselected patients undergoing laparoscopic fundoplication have shown equivalence of complete and partial fundoplications, anterior in one study156 and posterior in the
other,83 in terms of operative time, perioperative morbidity, and
hospital stay. Watson et al.156 noted that resting and residual
LES pressures were greater after complete fundoplication and
that esophageal clearance of liquid radioisotope was prolonged
in these patients compared with after partial fundoplication.
Six months after operation, partial fundoplication was linked
to a greater overall level of patient satisfaction manifested by a
lower incidence of the symptoms of dysphagia, inability to
belch, and excessive flatus. Laws et al.157 did not identify any
difference in symptomatic outcome between patients treated by
complete and those treated by posterior partial fundoplication
at a mean follow-up time of 27 months.
Hagedorn et al. reported on the results of a randomized,
controlled trial comparing total (Nissen-Rosetti) and posterior
100
p<0.0001
80
60
40
20
0
respiratory
symptoms
esophageal
symptoms
20
0:56:05 desaturation
656
TA B L E 4 1 . 8
MANAGEMENT
particularly in patients with Barrett esophagus. Currently, partial fundoplication is best reserved for patients with severe
esophageal dysmotility approaching aperistalsis, such as
occurs in scleroderma, or in combination with a distal
esophageal myotomy for achalasia.162
Laparoscopic Nissen Fundoplication. The performance of
laparoscopic fundoplication should include the steps identified
in Table 41.8.
Port Placement. Five ports are used (Fig. 41.30). The camera is
placed above and to the left of the umbilicus, roughly one third
of the distance to the xiphoid process. In most patients, placement of the camera in the umbilicus is too low to allow adequate visualization of the hiatal strictures once dissected. A
transrectus location is preferable to midline to minimize the
prevalence of port site hernia formation. Two lateral retracting
ports are placed, one for the liver retractor in the right midabdomen (anterior axillary line), at or slightly below the camera
port. This allows the proper angle toward the left lateral segment of the liver and thus the ability to push the retractor
toward the operating table, lifting the liver. A second retraction
port is placed slightly above the level of the umbilicus, in the
left anterior axillary line. Placement of these ports too far lateral or too low on the abdomen will compromise the excursion
of the instruments and thus the ability to retract. The left-sided
operating port (surgeons right hand) is placed 1 to 2 cm below
the costal margin approximately at the lateral rectus border.
Such placement allows triangulation between the camera and
the two instruments and avoids the difficulty associated with
the instruments being in direct line with the camera. The rightsided operating port (surgeons left hand) is placed last, after
the left lateral segment of the liver has been retracted. This
placement prevents sword fighting between the liver retractor and the left-handed instrument. The falciform ligament
hangs low in many patients and provides a barrier around
which the left-handed instrument must be manipulated.
Hiatal Dissection. A fan or similar suitable retractor is placed
into the right anterior axillary port and positioned to hold the
left lateral segment of the liver toward the anterior abdominal
wall. We prefer to use a table retractor to hold this instrument
once properly positioned. Trauma to the liver should be meticulously avoided, because subsequent bleeding will obscure the
field. Mobilization of the left lateral segment by division of the
triangular ligament is not necessary. A Babcock or fundus
clamp placed through the left anterior axillary port is used to
grasp the GE fat pad and retract the stomach toward the
patients left foot. This maneuver exposes the esophageal hiatus. Commonly a hiatal hernia will need to be reduced. Atraumatic clamps should be used and care taken not to grasp the
stomach too vigorously, as gastric perforations can occur.
Crural Dissection. Crural dissection begins with identification
of the right crus. Metzenbaum-type scissors and fine grasping
forceps are preferred for dissection. In all except the most
obese patients, there is a very thin portion of the gastrohepatic
omentum overlying the caudate lobe of the liver. The dissection is begun by incising the portion of the gastrohepatic
omentum above and below the hepatic branch of the anterior
vagal nerve (which some authors routinely spare). A large left
hepatic artery arising from the left gastric artery is present in
up to 25% of patients (Fig. 41.31); it should be identified and
avoided. A right crural branch is occasionally seen, which can
Liver
Esophagus
Caudate lobe
of liver
Right crus
Chapter 41: Esophageal Anatomy and Physiology and Gastroesophageal Reflux Disease
Anterior
crura
confluence
Left crus
Esophagus
Left crus
esophageal shortening, or a large posterior fat pad, this dissection may be particularly difficult. If unduly difficult, abandon
this route of dissection and approach the hiatus from the left
side by dividing the short gastric vessels at this point in the
procedure rather than later. After completing the posterior dissection, pass a grasper (through the surgeons left-handed
port) behind the esophagus and over the left crus and pull a
Penrose drain around the esophagus to be used as an esophageal
retractor for the remainder of the procedure.
Fundic Mobilization. Complete fundic mobilization allows
construction of a tension-free fundoplication. This is best done
by suspending the gastrosplenic omentum anteroposteriorly,
in a clothesline fashion via two Babcock forceps, and opening
into the lesser sac approximately one-third the distance down
the greater curvature of the stomach (Fig. 41.34). The short
Fundus
Spleen
Divided
short gastric
vessels
Gastric
omentum
Caudate lobe
of liver
Right crus
FIGURE 41.34. Illustration of the proper retraction of the gastrosplenic omentum facilitating the initial steps in short gastric division.
Complete fundic mobilization is continued by retraction of the stomach rightward and the spleen and omentum left and downward. These
maneuvers allow opening of the lesser sac and facilitate division of the
high short gastric vessels.
be divided. After incising the gastrohepatic omentum, the outside of the right crus will become evident. The peritoneum
overlying the anterior aspect of the right crus is incised with
scissors and electrocautery, and the right crus dissected from
anterior to posterior as far as possible. The medial portion of
the right crus leads into the mediastinum and is entered by
blunt dissection with both instruments.
At this juncture the esophagus usually becomes evident.
The right crus is retracted laterally with the surgeons lefthanded grasper and a modest dissection of the tissues posterior
to the esophagus is performed. In most patients it is best not to
dissect behind the GE junction at this time. Meticulous hemostasis is critical. Blood and fluid tend to pool in the hiatus and
are difficult to remove. Irrigation should be avoided. Modest
bleeding can be controlled by placing a 4 4 sponge into the
abdomen. A large hiatal hernia often makes this portion of the
procedure easier because it accentuates the diaphragmatic
crura. On the other hand, dissection of a large mediastinal hernia sac can be difficult.
Following dissection of the right crus, attention is turned
toward the anterior crural confluence. The tissues anterior to
the esophagus are held upward by the left-handed grasper and
the esophagus is swept downward and to the right, separating
it from the left crus (Fig. 41.32). The anterior crural tissues are
then divided and the left crus identified. The anterior vagus
nerve often hugs the left crus and can be injured in this portion of the dissection if not carefully searched for and protected. The left crus is dissected as completely as possible,
including taking down the angle of His and the attachments of
the fundus to the left diaphragm (Fig. 41.33). A complete dissection of the lateral and inferior aspect of the left crus and
fundus of the stomach is the key maneuver allowing circumferential mobilization of the esophagus. Failure to do so will
result in difficulty encircling the esophagus, particularly if
approached from the right. Repositioning of the Babcock
retractor toward the fundic side of the stomach facilitates
retraction for this portion of the procedure. The posterior
vagus nerve may be encountered in the low left crural dissection and should be protected.
A window behind the GE junction can generally now be
easily created. Attention is returned to the right side of the
esophagus where the left-handed instrument is used to retract
the esophagus anteriorly. This allows the right hand to perform the dissection behind the esophagus. The posterior vagus
nerve should be identified and left on the esophagus. The left
crus is identified and the dissection kept caudal to it. There is
a tendency to dissect into the mediastinum and left pleura. In
the presence of severe esophagitis, transmural inflammation,
657
658
Liver
Caudate lobe
of liver
Divided short
gastric
vessels
Crural closure
FIGURE 41.35. The fundic mobilization is continued to include pancreaticogastric branches as well as the short gastric branches. Dissection continues until the crura and the caudate lobe can be seen from
left posterior.
Chapter 41: Esophageal Anatomy and Physiology and Gastroesophageal Reflux Disease
Right
upper
Right
lower
Left
upper
Left
lower
Camera
(midline)
659
Transthoracic Nissen Fundoplication. The indications for performing an antireflux procedure by a transthoracic approach
are given in Table 41.9.
In the thoracic approach the hiatus is exposed through a
left posterior lateral thoracotomy incision in the sixth intercostal space (i.e., over the upper border of the seventh rib).
When necessary, the diaphragm is incised circumferentially 2
to 3 cm from the lateral chest wall for a distance of approximately 10 to 15 cm. The esophagus is mobilized from the level
of the diaphragm to underneath the aortic arch. Mobilization
up to the aortic arch is usually necessary to place the repair in
a patient with a shortened esophagus into the abdomen without undue tension. Failure to do this is one of the major causes
for subsequent breakdown of a repair and return of symptoms. The cardia is then freed from the diaphragm. When all
the attachments between the cardia and diaphragmatic hiatus
are divided, the fundus and part of the body of the stomach are
drawn up through the hiatus into the chest. The vascular fat
pad that lies at the GE junction is excised. Crural sutures are
then placed to close the hiatus though are not tightened until
later. The fundoplication is constructed by enveloping the fundus around the distal esophagus in a manner similar to that
described for the abdominal approach. When complete, the
fundoplication is placed into the abdomen by compressing the
fundic ball with the hand and manually maneuvering it
through the hiatus. The previously placed crural stitches are
then tightened and knotted.
Collis Gastroplasty. In patients with a short esophagus secondary to a stricture, Barrett esophagus, or a large hiatal hernia,
Anterior
fundus
Stomach
Posterior
fundus
660
TA B L E 4 1 . 9
INDICATIONS/CONTRAINDICATIONS
EXPLANATION
Concomitant procedure
Short esophagus
This is usually associated with a stricture or Barrett esophagus. In this situation, the
thoracic approach is preferred to allow maximum mobilization of the esophagus, the
performance of a Collis gastroplasty, or, if necessary, placement of the repair without
tension below the diaphragm.
This can indicate esophageal shortening and, again, a thoracic approach is preferred for
maximum mobilization of the esophagus and, if necessary, the performance of a Collis
gastroplasty.
The nature of the pulmonary pathology can be evaluated and the proper pulmonary
surgery, in addition to the antireflux repair, can be performed.
Obesity
The abdominal repair is difficult because of poor exposure, whereas the thoracic approach
gives better exposure and allows a more precise repair.
the esophagus is lengthened with a Collis gastroplasty. The gastroplasty lengthens the esophagus by forming a gastric tube or
neoesophagus along the lesser curvature. The procedure
allows a tension-free construction of a total or partial fundoplication around the newly formed gastric tube, with placement of the repair in the abdomen. A gastroplasty can be readily performed via either an abdominal or thoracic approach. A
number of techniques have been reported for the laparoscopic
performance of Collis gastroplasty, and the surgeon opting to
manage the shortened esophagus laparoscopically must be able
to perform such a procedure should the need arise.167
Outcomes Following Antireflux Surgery. Any discussion
regarding results following fundoplication must consider:
1.
2.
3.
4.
5.
As with any laparoscopic procedure, instrumental perforation of the hollow viscera may occur. Early esophageal perforation may arise during passage of the bougie, during the
retroesophageal dissection, or during suture pull-through.
Late esophageal perforation is related to diathermy injury at
the time of mobilization. Gastric perforations usually result
from excessive traction on the fundus for retraction purposes.
Recognition of the problem at the time of surgery requires
repair, which may be performed either laparoscopically or by
an open technique.
Hemorrhage during the course of laparoscopic fundoplication usually arises from the short gastric vessels or spleen. Rarer
causes include retractor trauma to the liver, injury to the left
inferior phrenic vein, an aberrant left hepatic vein, or the inferior vena cava. Cardiac tamponade as a result of right ventricular trauma has also been reported. Major vascular injury mandates immediate conversion to an open procedure to achieve
hemostasis. One complication that has been virtually eliminated
since the advent of laparoscopic fundoplication is incidental
splenic injury necessitating splenectomy (0.06%), which
occurred with a frequency of around 2% to 5% during the open
era. The mortality rate for primary minimally invasive antireflux surgery has fortunately been quite low, reported at 0.08%.
Symptomatic Outcomes Following Antireflux Surgery. Studies
of long-term outcome following both open and laparoscopic
fundoplication document the ability of laparoscopic fundoplication to relieve typical reflux symptoms (heartburn, regurgitation, and dysphagia) in more than 90% of patients at followup intervals averaging 2 to 3 years and 80% to 90% of
patients 5 years or more following surgery.169177 The data
include evidence-based reviews of antireflux surgery,174
prospective randomized trials comparing antireflux surgery to
PPI therapy175 and open to laparoscopic fundoplication,176
and analysis of U.S. national trends in utilization and outcomes.177 The results of laparoscopic fundoplication compare
favorably with those of the modern era of open fundoplication. They also indicate the less predictable outcome of atypical reflux symptoms (cough, asthma, laryngitis) after surgery
being relieved in only two thirds of patients.178
A few recent trials deserve emphasis. Results were updated
on a prospective, randomized trial comparing PPI therapy to
antireflux surgery.179 The outcome of the study previously had
been reported at a follow-up of 5 years,175 while the latest
Chapter 41: Esophageal Anatomy and Physiology and Gastroesophageal Reflux Disease
661
662
FUTURE DIRECTIONS
Medical therapy for GERD and antireflux surgery both have
inherent drawbacks. Major limitations of acid suppressive
medications include the inability to prevent regurgitation of
weakly acidic or nonacidic refluxate and the need for chronic,
continual therapy, not to mention the cost, inconvenience,
potential side effects, and need for ongoing dietary and lifestyle
modifications. In addition, current therapy does not address
the main pathophysiologic contributor to the presence of
GERD, the mechanically defective LES. Fundoplications, while
intended to permanently restore the LES, suffer from the potential for perioperative complications, a high initial cost, the risks
inherent in general anesthesia, possible short- and long-term
side effects, and inconsistent reflux control across centers. In
addition, proper patient selection is critical and the operative
technique is not well standardized, perhaps adversely affecting
outcomes, particularly in inexperienced hands.
For all of these reasons, an interest remains to create means
of restoring LES competence by medical or less invasive surgical or endoscopic techniques that are easily applied and highly
reproducible. Medications such as baclofen, a -aminobutyric
acidB receptor agonist, have been utilized to decrease TLESRs,
thereby decreasing GERD.195 Similar investigational drugs are
in the pipeline and likely will reach clinical practice soon. A
number of endoluminal therapies have been devised and tested
to date, including endoscopically injected agents for bulking of
the LES, endoluminal suturing or valvuloplasty, and radiofrequency energy application to the LES, though most have been
withdrawn from the marketplace.196
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82. Boeree MJ, Peters FTM, Postma DS, et al. No effects of high-dose omeprazole in patients with severe airway hyperresponsiveness and symptomatic
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83. Harding SM, Richter JE, Guzzo MR, et al. Asthma and gastroesophageal
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84. Raghu G, Yang ST, Spada C, et al. Sole treatment of acid gastroesophageal
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794800.
85. Sontag SJ, OConnell S, Khandelwal S, et al. Asthmatics with gastroesophageal reflux: long term results of a randomized trial of medical and
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86. Lau CL, Palmer SM, Howell DN, et al. Laparoscopic antireflux surgery in
the lung transplant population. Surg Endosc 2002;16:16741678.
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664
87. Linden PA, Gilbert RJ, Yeap BY, et al. Laparoscopic fundoplication in
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88. Patti MG, Tedesco P, Golden J, et al. Idiopathic pulmonary fibrosis: how
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89. Fernando HC, El-Sherif A, Landreneau RJ, et al. Efficacy of laparoscopic
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92. Chandrasoma P. Norman Barrett: so close, yet 50 years away from the
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93. Campos GMR, DeMeester SR, Peters JH, et al. Predictive factors of Barretts esophagus: multivariate analyses of 502 patients with GERD. Arch
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94. Kauer WK, Stein HJ. Bile reflux in the constellation of gastroesophageal
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96. Ouatu-Lascar R, Triadafilopolous G. Complete elimination of reflux
symptoms does not guarantee normalization of intraesophageal acid reflux
in patients with Barretts esophagus. Am J Gastroenterol 1998;93:
711716.
97. Sampliner RE, Fennerty B, Garewal HS. Reversal of Barretts esophagus
with acid suppression and multipolar electrocoagulation: preliminary
results. Gastrointest Endos 1996;44:532535.
98. Hofstetter WA, Peters JH, DeMeester TR, et al. Long term outcome of
antireflux surgery in patients with Barretts esophagus. Ann Surg
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99. Lord RV, DeMeester SR, Peters JH, et al. Hiatal hernia, lower esophageal
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100. Farrell TM, Smith CD, Metreveli RE, et al. Fundoplication provides effective and durable symptom relief in patients with Barretts esophagus. Am J
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102. Mehta S, Bennett J, Mahon D, et al. Prospective trial of laparoscopic Nissen
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103. Dallemagne B, Weerts J, Markiewicz S, et al. Clinical results of laparoscopic
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105. Wijnhoven BP, Lally CJ, Kelly JJ, et al. Use of antireflux medication after
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106. Lurje G, Vallbohmer D, Collet PH, et al. COX-2 mRNA expression is significantly increased in acid-exposed compared to nonexposed squamous
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107. Vallbhmer D, DeMeester SR, Oh DS, et al. Antireflux surgery normalizes
cyclooxygenase-2 expression in squamous epithelium of the distal esophagus. Am J Gastroenterol 2006;101:14581466.
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111. Pacifico RJ, Wang KK, Wongkeesong LM, et al. Combined endoscopic
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151. Schwizer W, Hinder RA, DeMeester TR. Does delayed gastric emptying
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154. Johnston N, Knight J, Dettmar PW, et al. Pepsin and carbonic anhydrase
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155. Kim TH, Lee KJ, Yeo M, et al. Pepsin detection in the sputum/saliva for the
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156. Watson DI, Jamieson GG, Pike GK, et al. Prospective randomized doubleblind trial between laparoscopic Nissen and anterior partial fundoplication. Br J Surg 1999;86:123.
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158. Hagedorn C, Lonroth H, Rydberg L, et al. Long-term efficacy of total
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a randomized clinical trial. J Gastrointest Surg 2002;6:540.
159. Cai W, Watson DI, Lally CJ, et al. Ten-year clinical outcome of a prospective randomized clinical trial of laparoscopic Nissen versus anterior 180
665
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176. Nilsson G, Wenner J, Larsson S, et al. Randomized clinical trial of laparoscopic versus open fundoplication for gastroesophageal reflux. Br J Surg
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177. Finlayson SRG, Laycock WS, Birkmeyer JD. National trends in utilization
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179. Lundell L, Miettinen P, Myrvold HE, et al. Seven-year follow-up of a randomized clinical trial comparing proton-pump inhibition with surgical
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180. Mehta S, Bennett J, Mahon D, et al. Prospective trial of laparoscopic Nissen fundoplication versus proton pump inhibitor therapy for gastroesophageal reflux disease: seven-year follow-up. J Gastrointest Surg
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181. Lundell L, Attwood SE, Ell C, et al. Comparing laparoscopic antireflux
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182. Spechler SJ. Comparison of medical and surgical therapy for complicated
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recurrence after laparoscopic paraesophageal hernia repair: a multicenter,
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197. Jobe BA, ORourke RW, McMahon BP, et al. Transoral endoscopic fundoplication in the treatment of gastroesophageal reflux disease: the anatomic
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198. Bonavina L, Saino GI, Bona D, et al. Magnetic augmentation of the lower
esophageal sphincter: results of a feasibility clinical trial. J Gastrointest
Surg 2008;12:21332140.
Chapter 41: Esophageal Anatomy and Physiology and Gastroesophageal Reflux Disease
AND INJURY
PHILIP A. RASCOE, JOHN C. KUCHARCZUK, AND LARRY R. KAISER
K E Y
1
P O I N T S
6
10
666
667
ESOPHAGEAL INJURY
Despite decades of clinical experience and surgical innovation,
perforation of the esophagus continues to present diagnostic
and therapeutic challenges. Accurate diagnosis and early treatment are essential to the successful management of patients
with esophageal perforation. Outcome is determined by the
cause and location of the injury, the presence of concomitant
esophageal disease, and the interval between perforation and
initiation of therapy.
The causes of esophageal perforation are listed in Table 42.1.
Over the past decade, the incidence of esophageal perforation
FIGURE 42.1. Barium contrast esophagography showing the con- 2 has increased, and the most common etiology has become
striction caused by the cricopharyngeal muscle, aortic arch, and the
iatrogenic, due to the increasing use of invasive diagnostic and
left mainstem bronchus. Indentations of the esophagus made by extertherapeutic endoscopic procedures. In our review of the literanal structures are important anatomic landmarks and are often the
ture, we found that iatrogenic injury to the esophagus by
sites of perforation due to instrumentation.
instrumentation accounted for 59% of all cases and spontaneous perforations accounted for only 15%.8
Other, less common injuries include foreign body ingestion
(12%) and trauma (9%). Ingestion of foreign bodies or causSURGICAL APPROACHES
tic materials can produce perforation most commonly in areas
of anatomic narrowing including the cricopharyngeus, the segTO THE ESOPHAGUS
ment where the aortic arch and left mainstem bronchus
Multiple factors influence the surgical approach to the esophimpinge on the esophagus, and at the distal esophageal sphincagus. These include the nature of the injury or neoplasm
ter. External penetrating trauma causes perforations mainly in
(benign vs. malignant), the overall health of the patient, and
the cervical esophagus, the portion not protected by the
the expertise of the surgeon.
A complete working knowledge of the anatomic relationships between the esophagus and adjacent structures is vital to
TA B L E 4 2 . 1
ETIOLOGY
planning surgical therapy. The upper thoracic esophagus is in
contact with the posterior membranous trachea, the left mainCAUSES OF ESOPHAGEAL PERFORATION
stem bronchus, and the aortic arch. Patients with cancers
involving the upper thoracic esophagus must undergo preoperINSTRUMENTAL
ative bronchoscopy to rule out invasion of the posterior memEndoscopy
branous trachea, because this precludes resection. Although
Dilation
flexible bronchoscopy may demonstrate gross airway invasion,
rigid bronchoscopy is much more sensitive in determining
Intubation
adherence to the membranous trachea. Loss of the normal ripSclerotherapy
ple effect as the rigid scope slides over the membranous traLaser therapy
chea suggests the tumor is fixed to the airway and is not
resectable. This is equally important where the esophagus
NONINSTRUMENTAL
passes under the left mainstem bronchus.
Barogenic trauma
From a surgical perspective, the esophagus is divided into
Postemetic (Boerhaave syndrome)
thirds. The upper third can be reached through a cervical incision. The middle third is best approached through the right
Blunt chest or abdominal trauma
chest, as access to the middle third of the esophagus from the
Other (e.g., labor, convulsions, defecation)
left chest is obscured by the aorta. The distal third of the
Penetrating
neck, chest, or abdominal trauma
esophagus is best approached through the left chest. The short
Operative
trauma
segment of intra-abdominal esophagus may be approached
through the upper abdomen.
Esophageal reconstruction (anastomotic disruption)
When esophagectomy is required, several surgical
Vagotomy, pulmonary resection, hiatal hernia repair,
approaches have been described. These include the transhiatal
esophagomyotomy
2
approach, the transabdominal transthoracic approach (Ivor
3
4
Corrosive injuries (acid or alkali ingestion)
Lewis), the three-stage or three-hole approach (McKeown),
the thoracoabdominal approach, and the minimally invasive
Erosion by adjacent infection
approach. Each approach has its own set of risks and benefits as
Swallowed foreign body
well as outspoken opponents and proponents. Selection of the
Perforation
668
669
Contained
perforation
Uncontained
Perforation
No improvement
<24 hr
Broad-spectrum antibiotics
parenteral nutrition
Cervical
Thoracic
Drainage
Primary repair
Evaluation of perforation
Controlled
fistula
Abdominal
Exclusion
and
diversion
Malignancy
Resection
ALGORITHM 42.1
ALGORITHM 42.1. Evaluation and treatment of esophageal perforation. (Adapted with permission from Brinster CJ, Singhal S, Lawrence L,
et al. Evolving options in the management of esophageal perforation. Ann Thorac Surg 2004;77:1475.)
670
FIGURE 42.2. A: Barium swallow and (B) computed tomography scan showing cervical esophageal perforation. The
patient was treated with drainage and 1 week of gastrostomy tube feeding. The follow-up swallow at 1 week showed resolution.
671
Foreign Body
Foreign body ingestion typically occurs in pediatric, psychiatric, alcoholic, and elderly patients. Most objects remain in
the cervical esophagus; blunt objects as well as small sharp
objects usually can be removed either by flexible and/or rigid
esophagoscopy. Objects such as fish and chicken bones can be
reoriented with a long grasper and easily brought out through
a rigid esophagoscope. Large, rigid foreign bodies with sharp
edges embedded in the mucosa and those that exceed the
diameter of the rigid endoscope in all orientations pose a particularly difficult problem and may require esophagotomy for
removal. Following endoscopic removal of a foreign body,
completion esophagoscopy and contrast esophagography
should be performed to rule out esophageal perforation. If a
perforation is present, the patient is managed according to the
esophageal protocol presented in Algorithm 42.1.
Caustic Injury
Caustic injury to the esophagus occurs following ingestion of
either strong acids or strong base chemicals, usually household
cleaning products. Ingestions in children are usually accidental
and the quantities involved small. Ingestions in adults are
often associated with a suicide attempt or psychiatric illness.
The quantities swallowed in this group can be quite large and
the injury extensive. Fortunately, these types of ingestion
injuries are relatively rare today when compared to the number formerly seen.
Management of caustic ingestion injuries requires experienced surgical judgment.21 The first step in caring for any
patient following caustic ingestion is airway protection. Burns
to the oropharynx result in ongoing edema and may cause loss
of the airway. A tracheostomy should be performed early if
this is suspected. The second step is to determine the type of
agent, the approximate quantity, and the time since ingestion.
672
Caustic Ingestion
*Severe injury
h/o Exposure
ABCs, upright
chest x-ray,
Abd Films
Perforation
Symptoms
<24 hr stay
Immediate
discharge
No perforation
Follow-up
Esophagoscopy
Bronchoscopy
Injury
Grade
Full-Thickness
IIB/III
Antibiotics
Steroids
TPN
Close observation
for deterioration
Asymptomatic
Mild
Grade I
Grade IIA
Worsening
symptoms
48 hr observation
NPO, advance diet
as tolerated
Emergency resection
via thorax and/or
abdominal approach
ALGORITHM 42.2
ALGORITHM 42.2. Evaluation and management of acute caustic ingestion. (Adapted with permission from Paidas CN. Caustic burns of the
esophagus. In: Yang SC, Cameron DE, eds. Current Therapy in Thoracic and Cardiovascular Surgery. St. Louis: Mosby; 2004:99.)
TA B L E 4 2 . 2
CLASSIFICATION
ENDOSCOPIC
APPEARANCE
DEPTH OF
INJURY
Superficial hyperemia
Mucosal
II A
Sloughing mucosa,
superficial ulceration
Patch partial
thickness
II B
Deep ulceration
Circumferential
III
Eschar, necrosis
Full thickness
In symptomatic patients or those with suspected large ingestions of strong caustic agents, immediate esophagoscopy
should be performed. The esophageal injury is graded endoscopically as shown in Table 42.2. This information is used to
determine the appropriate treatment. The acute management
is summarized in Algorithm 42.2.
BENIGN NEOPLASMS
Table 42.3 shows a complete listing of the benign neoplasms
of the esophagus. All are rare. Leiomyoma is the most common benign esophageal neoplasm and is subsequently discussed in detail. Esophageal polyps are also seen with some
frequency at referral centers and deserve mention. Other
benign neoplasms occur so infrequently that they are not individually discussed in this chapter.
Leiomyoma
Leiomyomas account for roughly two thirds of all benign
tumors of the esophagus.22 The incidence of leiomyoma
reported in autopsy series ranges from 0.005% to 5.1%.23
Approximately 80% of leiomyoma are located intramurally
and originate in the muscularis propria. Roughly 90% are
TA B L E 4 2 . 3
673
CLASSIFICATION
located in the middle and lower esophagus, reflecting the relative paucity of smooth muscle in the upper esophagus. They
are slow-growing tumors, and therefore the size of the lesion
may not change for many years. Leiomyomas usually present
as single lesions, although cases of multiple lesions have been
reported.24 Figure 42.5 shows the typical esophagogram of a
midthoracic esophageal leiomyoma; note the smooth-walled
appearance of the lesion, indicating that the mucosa is not
involved by this submucosal lesion. Figure 42.6 shows the
endoscopic appearance of a distal esophageal leiomyoma.
Evaluation of a patient with a suspected leiomyoma usually
includes a barium swallow, endoscopy, endoscopic ultrasound
(EUS), and a CT scan of the chest. The utility of EUS lies in its
ability to ascertain the layer of origin of a submucosal mass. In
cases where the diagnosis of leiomyoma is in question, EUSguided fine-needle aspiration (EUS-FNA) may be used to
obtain tissue for histologic study including immunohistochemical (IHC) analysis. IHC in particular can differentiate leiomyoma from more aggressive entities such as gastrointestinal
stromal tumor (GIST) and leiomyosarcoma and therefore
assist in surgical planning.25 However, FNA should not be routinely performed in the evaluation of suspected leiomyoma, as
preoperative biopsy has been shown to increase the risk of
mucosal perforation at the time of surgical enucleation.26
674
Barium swallow
(filling defect)
Endoscopy
(normal mucosa covering mass)
EUS
(homogeneous, hypoechoic mass)
CT
(hypodense mass)
Clinically diagnose
leiomyoma
Surgery
Radiological
monitoring
ALGORITHM 42.3
ALGORITHM 42.3. Evaluation and treatment of esophageal leiomyoma. (Adapted with permission from Lee LS, Singhal S, Brinster CJ, et al.
Current management of esophageal leiomyoma. J Am Coll Surg 2004;198:136.)
675
Malignant neoplasms of the esophagus include adenocarcinoma, squamous cell carcinoma, small cell carcinoma,
leiomyosarcoma, rhabdomyosarcoma, fibrosarcoma, liposarcoma, lymphomas, and metastatic lesions from distant primary
sites. Adenocarcinoma and squamous cell carcinoma are the
most frequent malignant lesions, and adenocarcinoma has
emerged in recent years as the more common lesion (Fig. 42.8).
6 In fact, the incidence of esophageal adenocarcinoma has
increased in the last 25 years greater than the incidence of any
other major malignancy in the United States (Fig. 42.9).30 Most
thoracic surgeons will complete an entire career without seeing
the less common types of esophageal malignancies.
The goal of esophageal resection, whether as primary
7
treatment or as part of a multimodality plan, is cure, though
this goal remains elusive. Palliative esophagectomy is associated with mortality rates in excess of 20% and morbidity
rates as high as 50% and should therefore be avoided.31 Very
effective palliation can be obtained with chemotherapy, radiation therapy, and endoscopic interventions such as stenting.
Surveillance, epidemiology and end results (SEER) data from
the National Cancer Institute estimate that 16,470 Americans will be diagnosed with and 14,280 will die of esophageal
cancer annually. The lifetime risk of developing esophageal
cancer is about 0.5%, being slightly higher for men than
women.
Tobacco, alcohol, and obesity are all risk factors associated
with the development of esophageal cancer. Table 42.4 shows
the additional risk factors associated with esophageal cancer
and their contributions to the development of either squamous
cell carcinoma or adenocarcinoma.
Although many have postulated a genetic predisposition
to esophageal cancer, tylosis is the only recognized familial
syndrome that predisposes to the development of esophageal
cancer. This is an autosomal dominant disorder that has
been mapped to chromosome 17q25. 32 Patients have
hyperkeratosis of the palms of their hands and the soles of
their feet. The risk of developing squamous cell carcinoma
of the esophagus by age 70 is 95% in this cohort of
patients.33
35
30
25
20
15
10
5
0
1975
1980
1985
1990
1995
2000
7
6
5
4
3
2
1
0
1975
1980
1985
1990
1995
2000
FIGURE 42.9. Relative change in incidence of esophageal adenocarcinoma and other malignancies (19752001). Data from the National
Cancer Institutes Surveillance, Epidemiology, and End Results program with age-adjustment using the 2000 U.S. standard population.
Baseline was the average incidence between 1973 and 1975. Blue line,
esophageal adenocarcinoma; green line, melanoma; orange line,
prostate cancer; yellow line, breast cancer; purple line, lung cancer;
red line, colorectal cancer. (Adapted with permission from Pohl H,
Welch G. The role of overdiagnosis and reclassification in the marked
increase of esophageal adenocarcinoma incidence. J Natl Cancer Inst
2005;97:142146.)
Diagnosis
Unfortunately, early esophageal carcinomas are largely asymptomatic. As a distensible muscular tube, a significant portion
of the esophageal lumen must be obstructed to impede passage
of a food bolus and produce symptoms. Dysphagia is the primary manifestation of esophageal cancer in 80% of patients,
and up to 20% have odynophagia. Vague symptoms of retrosternal discomfort and transient dysphagia are often overlooked by the patient and the physician. On retrospective evaluation, many patients have significantly altered their eating
habits by avoiding foods such as meats and breads while
increasing their intake of semisolid foods and liquids. About
one half of patients have significant weight loss. Weight loss of
more than 10% of body mass is an independent predictor of
poor prognosis.34
Pulmonary symptoms may be caused by aspiration of
regurgitated food or by direct invasion of the airway by
esophageal tumor. Direct airway invasion can occur with
locally advanced lesions at the location where the left mainstem bronchus passes anterior to the esophagus. New hoarseness due to vocal cord paralysis is indicative of left recurrent
nerve involvement and suggests unresectability. The Virchow
node, a palpable left supraclavicular lymph node, may be
apparent in some patients. Fine-needle aspiration with positive
cytology confirms the pathologic involvement of the Virchow
node, which is considered distant metastatic disease and precludes resection.
The evaluation of a patient with suspected esophageal cancer involves securing the diagnosis, clinically staging the
patient, and determining the medical operability of patients
with stage-appropriate lesions for resection. Barium swallow
and esophagoscopy remain the most important diagnostic tools
for assessing the patient with esophageal symptoms. Barium
swallow is usually the first study obtained. It provides both
anatomic and functional information. Flexible esophagoscopy
is used to precisely locate the lesion and provide tissue confirmation of malignancy. In patients considered for surgical
resection, endoscopic ultrasonography (EUS) is the single most
MALIGNANT NEOPLASMS
676
TA B L E 4 2 . 4
ETIOLOGY
SQUAMOUS CELL
CARCINOMA
ADENOCARCINOMA
Tobacco use
Alcohol use
Barrett esophagus
Obesity
Poverty
Nonepidermolytic palmoplantar
keratoderma (tylosis)
Plummer-Vinson syndrome
Achalasia
, Increase in the risk by a factor of less than two; , increase by a factor of two to four; , increase
by a factor of more than four to eight; , increase by a factor of more than eight; , conflicting
results have been reported; , no proven risk.
Reproduced with permission from Enzinger C, Mayer J. Esophageal cancer. N Engl J Med 2003; 349:2241
Copyright 2003 Massachusetts Medical Society. All rights reserved.
valuable test in determining tumor size and depth of penetration (T stage). EUS successfully predicts the T stage in greater
than 80% of cases confirmed at surgery and generally performs better for advanced (T4) than local (T1) disease.
Regional lymph nodes are also visualized during EUS and can
be sampled by FNA to determine the cytologic presence or
absence of metastatic nodal disease (N stage). The sensitivity
of EUS alone to predict N stage is 85% and improves to
greater than 95% with FNA.35 Figure 42.10 shows an example of EUS for esophageal cancer.
A computed tomographic (CT) scan of the chest, abdomen,
and pelvis with intravenous contrast is valuable for assessing
lung and liver metastasis. However, it is not accurate for determining T stage or assessing regional lymph node involvement.
Positron emission tomography (PET) with 18 F-fluorodeoxyglucose (FDG) is a physiologic test unique in its ability
to detect increased metabolic activity within tissues. It is
increasingly used to detect distant metastasis (M stage) in
patients with esophageal cancer. It has been reported that PET
will detect otherwise radiographically occult metastatic disease in up to 15% of patients who were thought to have only
localized disease by conventional studies, thus making them
more appropriately managed by non-surgical interventions.36
We now routinely obtain a PET scan as part of the preoperative staging evaluation in patients under consideration for
esophagectomy. Increasingly, PET is being used to restage
patients and evaluate response after neoadjuvant chemoradiation. Several studies have shown promising results in demonstrating that decreased FDG-avidity after neoadjuvant therapy
predicts pathologic response and increased survival.37,38
677
FIGURE 42.10. Endoscopic image (A) and endoscopic ultrasound (B) showing a transmural adenocarcinoma of the esophagus associated with a
Barrett esophagus (short arrows), with lymph node metastasis (long arrow). (Reproduced with permission from Enzinger C, Mayer J. Esophageal
cancer. N Engl J Med 2003;349:2245. Copyright 2003 Massachusetts Medical Society. All rights reserved.)
as intestinalization of the mucosa. With progression to dysplasia, the nuclei become crowded and the normal glandular
architecture is lost. Histologically, patients with high-grade
dysplasia carry a significant risk for esophageal carcinoma and
should be considered candidates for resection. Ten percent to
thirty percent of patients with high-grade dysplasia will
develop invasive adenocarcinoma within 5 years of the initial
FIGURE 42.11. A: The typical endoscopic appearance of Barrett changes at the gastroesophageal (GE) junction. Note the salmon-colored areas
of erosion extending from the GE junction. Also note the intervening areas of normal appearing mucosa. B: Vital staining with methylene blue.
Vital stains are used to highlight the mucosal changes at the time of endoscopy. (Courtesy of Michael L. Kochman, M.D., University of Pennsylvania, Philadelphia.)
or so-called skip areas. Figure 42.11A shows the typical endoscopic appearance; Figure 42.11B shows the same patient with
methylene blue vital stain, which can be used to highlight the
mucosal changes. Microscopic evaluation reveals replacement
of the normal stratified squamous epithelium of the esophagus
with columnar epithelium more typical of other parts of the
gastrointestinal tract. Thus, these changes are often referred to
678
Neoadjuvant Therapy
The current information on neoadjuvant treatment can be
divided into studies evaluating preoperative radiation, preoperative chemotherapy, and combined preoperative chemoradi8 ation therapy. In operable patients with resectable tumors, the
results of any preoperative therapy followed by resection must
be compared with the results of primary resection alone. It is
important that this analysis must take into account the toxicities associated with multimodality therapy and the impact on
the intended resection and quality of life.
Several randomized trials have failed to show any benefit
from preoperative radiation therapy alone. Proponents of preoperative radiotherapy argue that the trials are too small to
demonstrate the advantages of this approach. A meta-analysis
TA B L E 4 2 . 5
STAGING
DESCRIPTION
T0
Tis
Carcinoma in situ
T1
T2
T3
T4
N0
N1
M0
No distant metastasis
M1
Distant metastasis
M1b
Not applicable
M1b
M1b
TA B L E 4 2 . 6
679
STAGING
TNM DESIGNATION
TREATMENT
Tis, N0, M0
Surgery alone
95
T1, N0, M0
Surgery alone
75
T2, N0, M0
Surgery alone
30
20
T3, N1, M0
1015
T4, any N, M0
IVA
IVB
IIA
T3, N0, M0
IIB
T1, N1, M0
T2, N1, M0
III
Operative Management
Approaches to Esophagectomy. There are several surgical
approaches to esophagectomy. Selecting the appropriate procedure for an individual patient depends on the overall medical
condition of the patient, the location of the tumor, and the
expertise and experience of the surgeon. Possible approaches
include the transhiatal approach, the transabdominal transthoracic approach (Ivor Lewis), the three-stage or three-hole
approach (McKeown), the thoracoabdominal approach, and
the minimally invasive approach. Options for reconstruction
include a gastric tube, a colonic interposition, and in selected
cases small intestinal free graft. Because of its ample blood supply, ease of mobilization, and sufficient length to reach the
neck, the gastric tube is the usual conduit of choice for reconstruction. The use of colon is more complex and has increased
morbidity when compared to gastric pull-up.54 We reserve the
use of colon or jejunum for patients with an unusable stomach
due to previous surgery, tumor extension, or other technical
considerations.
The esophageal anastomosis requires meticulous attention.
Many esophageal operations are plagued by high anastomotic
leak rates and a significant number of postoperative strictures.
At present, the modified stapled anastomosis as described by
Orringer et al.55 appears to have the lowest leak rate, about
3% as compared with sutured techniques, which are as high as
15%. The technique is shown in Figure 42.12; many thoracic
surgeons have adopted this anastomotic technique.
The Transhiatal Approach. The transhiatal esophagectomy
was reintroduced by Orringer and Sloan2 in 1978 and continues to be refined.56,57 The procedure is performed through an
only 25% had either distal esophageal or GE junction adenocarcinoma. Also, only 41.6% of patients randomized to perioperative chemotherapy were able to complete all six prescribed cycles of therapy. In the most recent Cochrane review
of the topic, 11 randomized controlled trials with 2,051
patients suggested that preoperative chemotherapy plus
surgery may offer a survival advantage compared to surgery
alone for resectable esophageal cancer.50 There was no demonstrable difference in the rate of resection, tumor recurrence, or
postoperative morbidity. There was some chemotherapyrelated morbidity. Presumably based on the relative success of
the MRC and MAGIC trials, chemotherapy alone is used quite
commonly as neoadjuvant therapy in Europe, whereas combined chemotherapy and radiation is used more commonly in
the United States.
Several small randomized trials have evaluated combined
preoperative chemoradiation followed by surgical resection.
The most widely cited trial to justify the use of combined treatment followed by surgery was published by Walsh et al.51 in
1996. This study projected a 3-year survival of 32% in the
neoadjuvant treatment group as compared to 6% in the
surgery alone group for patients with adenocarcinoma. Critics
were quick to point out the lack of appropriate staging, the
poor survival in the surgical group as compared with other
surgical series, and the small study size. A more recent study
found equivalent median and 3-year survival in patients with
squamous cell carcinoma of the esophagus randomized to
either preoperative chemoradiation followed by surgery or
surgery alone.52 An increased complication rate was noted in
the patients undergoing preoperative chemoradiation therapy.
A recent meta-analysis of 10 randomized controlled trials of
neoadjuvant chemoradiotherapy versus surgery alone demonstrated an absolute survival advantage of 13% at 2 years
favoring neoadjuvant therapy.53 Despite a paucity of conclusive data, there seems to be an evolving consensus at most centers that patients with T3 and/or N1 disease should receive
neoadjuvant chemoradiation. This issue remains unresolved,
and operation remains the standard treatment for localized
680
FIGURE 42.12. The stapled technique for cervical esophageal anastomosis. This technique results in lower anastomotic leak rates and
fewer postoperative strictures. (Adapted with permission from Orringer MB, Marshall B, Iannettoni MD. Eliminating the cervical esophagogastric anastomotic leak with a side-to-side stapled anastomosis. J Thorac Cardiovasc Surg 2000;119:277.)
chest can lead to life-threatening mediastinitis should an anastomotic leak occur. Additionally, a large amount of thoracic
esophagus is retained with this approach and may be at risk of
recurrent disease, specifically in the setting of severe Barrett
esophagus.
Three-Field Esophagectomy. This approach is carried out
through separate laparotomy, right thoracotomy, and cervical
incisions.4 Proponents of this approach fall into two categories.
The first group uses this approach to resect large intrathoracic
lesions of the midesophagus. Exposure especially at the level of
the carina and left mainstem bronchus is superior as compared
with the transhiatal approach. Because visualization is
improved, the injury rate to nearby structures, especially the
airway and azygous vein, is lower. The second group uses this
approach to perform a complete two- or three-field lymph node
dissection, suggesting that this approach provides a more complete resection and thus improves long-term survival. This
approach has been shown to have acceptable morbidity and
mortality as compared with other approaches; however, the
often-cited report was from a single U.S. center.58 On the other
hand, a large randomized Dutch trial comparing transhiatal
resection with extended transthoracic resection showed that
the transhiatal approach was associated with a lower morbidity
and no statistically different overall, disease-free, and qualityadjusted survival.59 Patients who underwent thoracotomy had
an increased incidence of chyle leak and pulmonary complications, as well as longer ventilator dependence, ICU stay, and
hospital stay (Table 42.7). In a recent retrospective review of
2,303 esophageal cancer patients treated with R0 resection
without adjuvant or neoadjuvant therapy, the number of nodes
removed was an independent predictor of survival. The authors
concluded that to maximize this survival benefit, a minimum of
23 nodes should be removed at esophagectomy.60 The true
value of extensive lymphadenectomy in esophageal cancer
remains undefined.
The Thoracoabdominal Approach. The left thoracoabdominal approach is probably the least used of all approaches to
681
FIGURE 42.13. A: Transhiatal mobilization of the thoracic esophagus from the posterior mediastinum with the use of blunt dissection and traction on rubber drains placed around the esophagogastric junction and cervical esophagus. The volar aspects of the fingers are kept against the
esophagus to reduce the risk for injury to adjacent structures. B: Lateral view showing transhiatal mobilization of the esophagus away from the
prevertebral fascia. Half of a sponge on a stick is inserted through the cervical incision and advanced until it makes contact with the hand inserted
from below through the diaphragmatic hiatus. Arterial pressure is monitored as the heart is displaced forward by the hand in the posterior mediastinum. (Adapted with permission from Orringer MB. Surgical options for esophageal resection and reconstruction with stomach. In: Baue AE,
Geha AS, Hammond GL, eds. Glenns Thoracic and Cardiovascular Surgery, 5th ed. Norwalk, CT: Appleton & Lange; 1991:799.)
682
Aorta
Pylorus
FIGURE 42.14. Final position of the mobilized stomach in the posterior mediastinum after transhiatal esophagectomy and cervical esophagogastric anastomosis. The gastric fundus has been suspended from
the cervical prevertebral fascia, and an end-to-side cervical esophagogastrostomy has been performed. The pylorus is now located several centimeters below the level of the diaphragmatic hiatus. (Adapted
with permission from Orringer MB, Sloan H. Esophagectomy without
thoracotomy. J Thorac Cardiovasc Surg 1978;76:643.)
Palliation
Several palliative therapies are available for patients who have
unresectable disease, have metastatic disease, or are medically
10 unfit for surgery. The intent of palliation is to maintain comfort, restore swallowing function if possible, and support
nutrition.
Establishment of alternative enteral access is helpful in
maintaining nutritional status and hydration. When possible,
this is provided by a percutaneous gastrostomy (PEG) tube
placed under endoscopic guidance. For patients with bulky
obstructing lesions who cannot undergo PEG, an open gastrostomy or jejunostomy tube is required.
Photodynamic Therapy. Intraluminal photodynamic therapy (PDT) is a nonthermal ablative technique that can be used
to palliate patients. This technique requires the systemic
administration of a hematoporphyrin, which is concentrated
within the malignant cells. Approximately 48 hours after
administration of the photosensitizer, patients undergo
endoscopy and an argon-pump dye-laser is used to deliver
endoluminal light at a wavelength of 630 nm. This results in
the generation of oxygen radicals, which quickly lead to tumor
necrosis. The depth of penetration is relatively limited, and
this decreases the risk of full-thickness necrosis with perforation. Unfortunately, the photosensitizing agents are retained
by the reticuloendothelial system in skin; thus, patients are
sensitive to infrared wavelength light, including sunlight, radiant heat, fluorescent light, and strong incandescent light.
Depending on the photosensitizing agent used, this sensitivity
can persist up to 3 months, a challenging problem in patients
with short life expectancies.
A recent series of 215 patients treated with palliative endoluminal PDT revealed a procedure-related mortality rate of
1.8%, effective palliation for patients with obstructing cancers
in 85% of the treatment courses, and median survival of 4.8
months.63 Some patients in this series also required stenting,
suggesting that PDT has a role in multimodality palliation of
obstructing esophageal cancers.
TA B L E 4 2 . 7
COMPLICATIONS
TRANSTHORACIC
(n 114)
TRANSHIATAL
(n 106)
P VALUE
Pulmonary complications
57%
27%
0.001
Chylothorax
10%
2%
0.02
076
019
079
038
19
15
7154
463
0.001
0.001
0.001
683
Anastomotic leak
16%
14%
0.85
21%
13%
0.15
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SECTION E
STOMACH AND DUODENUM
K E Y
The stomach is an extremely well-vascularized organ, supplied by a number of major arteries and protected by a
large number of extramural and intramural collaterals.
2 Oxyntic glands occupy the fundus and body of the stomach and contain the oxyntic or parietal cells, which are the
sites of acid production. Oxyntic glands also contain chief
cells, the site of gastric pepsinogen synthesis.
3 The most important stimulant of gastrin release is a meal.
Postprandial luminal pH also strongly affects gastrin
secretion.
4 Ghrelin is the only known circulating hormone that causes
the sensation of hunger and stimulates oral intake.
1
P O I N T S
The basolateral membrane of the parietal cell contains specific receptors for histamine, gastrin, and acetylcholine, the
three major stimulants of acid production.
6 Pepsins are a heterogeneous group of proteolytic enzymes
that are secreted by the gastric chief cells.
7 The gastric mucosa is the site of production of intrinsic
factor, which is necessary for the absorption of cobalamin
from the ileal mucosa. Total gastrectomy is regularly followed by cobalamin malabsorption, as is resection of the
proximal stomach or atrophic gastritis that involves the
oxyntic mucosa.
GROSS ANATOMY
685
GASTROINTESTINAL
PHYSIOLOGY
686
vature drains through suprapyloric nodes. The proximal portion of the greater curvature is supplied by lymphatic vessels
that traverse pancreaticosplenic nodes, whereas the antral portion of the greater curvature drains into the subpyloric and
omental nodal groups. Secondary drainage from each of these
systems eventually traverses nodes at the base of the celiac
axis. These discrete anatomic groupings are misleading. The
lymphatic drainage of the human stomach, like its blood supply, exhibits extensive intramural ramifications and a number
of extramural communications. As a consequence, disease
processes that involve the gastric lymphatics often spread
687
GASTROINTESTINAL
tric wall. The posterior vagus nerve branches into the celiac
division, which passes to the celiac plexus, and a posterior gastric division, which innervates the posterior gastric wall.
Approximately 90% of the fibers in the vagal trunks are
afferent, transmitting information from the gastrointestinal
tract to the central nervous system (CNS). Parasympathetic
afferent fibers are not responsible for the sensation of gastric
pain. Only 10% of vagal nerve fibers are motor or secretory
efferents. Parasympathetic efferent fibers contained in the
vagus originate in the dorsal nucleus of the medulla. Vagal
efferent fibers pass without synapse to contact postsynaptic
neurons in the gastric wall in the myenteric and submucous
plexuses. Secondary neurons directly innervate gastric smooth
muscle or epithelial cells. Acetylcholine is the neurotransmitter
of primary vagal efferent neurons.
The gastric sympathetic innervation is derived from spinal
segments T5 through T10. Sympathetic fibers leave the corresponding spinal nerve roots by way of gray rami communicantes and enter a series of bilateral prevertebral ganglia (Fig.
43.5). From these ganglia, presynaptic fibers pass through the
greater splanchnic nerves to the celiac plexus, where they
synapse with secondary sympathetic neurons. Postsynaptic
sympathetic nerve fibers enter the stomach in association with
blood vessels. Afferent sympathetic fibers pass without synapse
from the stomach to dorsal spinal roots. Pain of gastroduodenal origin is sensed through afferent fibers of sympathetic
origin.
MICROSCOPIC ANATOMY
688
FIGURE 43.6. Resting and stimulated parietal cell, emphasizing morphologic transformation with increase in secretory canalicular membrane surface area that occurs with acid secretion.
689
GASTROINTESTINAL
GASTRIC PEPTIDES
The stomach contains a number of biologically active peptides
in nerves and mucosal endocrine cells, including gastrin,
somatostatin, ghrelin, gastrin-releasing peptide, vasoactive
intestinal polypeptide (VIP), substance P, glucagon, and calcitonin generelated peptide. The peptides with the greatest
importance to human disease and clinical surgery are gastrin,
somatostatin, and ghrelin.
Gastrin
The synthesis, secretion, and action of gastrin have been extensively studied, and many aspects of the biology of gastrin appear
to be shared by other gastrointestinal peptide hormones.1 The
gene that encodes for gastrin has been isolated using a human
DNA library. The human gastrin gene contains three exons; two
exons consist of coding sequences. The major active product is
encoded by a single exon. In adults, the gastrin gene is expressed
primarily in mucosa cells of the gastric antrum, with lower levels of expression in the duodenum, pituitary, and testis. During
embryonic development, the gastrin gene is transiently active in
pancreatic islets and colonic mucosa.
The human gene encompasses approximately 4,100 base
pairs and directs the synthesis of a peptide of 101 amino
acids (Fig. 43.8). The resulting peptide, preprogastrin, contains the sequence of gastrin within its amino acid sequence.
Preprogastrin consists of a signal peptide of 21 amino acids,
an intervening peptide of 37 amino acids, the 34-residue
region of the gastrin molecule, and a carboxyl-terminal
extension of nine amino acids. Gastrin is derived from its
preprohormone by the sequential enzymatic cleavage of the
signal peptide, the intervening peptide, and the carboxyl-terminal extension.
The signal peptide region of preprogastrin consists of a
series of hydrophobic amino acids that direct the nascent peptide into the endoplasmic reticulum as it is translated from
messenger RNA. After directing the preprogastrin molecule
into the rough endoplasmic reticulum, the signal peptide is
removed. The remaining peptide is termed progastrin. Progastrin is further processed as it traverses the endoplasmic reticulum to mature secretory vesicles. Enzymatic cleavage at a pair
of basic amino acid residues proximal to the gastrin 34 (G34)
sequence removes the intervening peptide. A similar cleavage
removes a six-amino-acid fragment at the carboxyl-terminal
end. The peptide that remains has a Gly-Arg-Arg sequence at
690
In addition to stimulating acid secretion from gastric parietal cells (detailed later in this chapter), gastrin has important
physiologic actions in the control of gastrointestinal mucosal
growth. The acid-secreting oxyntic mucosa is particularly sensitive to the trophic actions of gastrin, but the mucous membranes of the duodenum, colon, and pancreatic parenchyma
are also affected. Stimulation of mucosal growth by gastrin is
enhanced by the presence of solid food in the diet. The 17- and
34-amino-acid forms of gastrin are equipotent in stimulating
mucosal growth. In humans, the relative importance of gastrin
and other influences, such as the composition and form of the
diet and the actions of other trophic hormones, have not been
completely established. Prolonged stimulation by high levels of
gastrin, as seen in the Zollinger-Ellison syndrome, is associated
with hypertrophy of the gastric mucosa. Smaller increases in
circulating gastrin, such as those that follow vagotomy, do not
cause mucosal hypertrophy.
Somatostatin
Somatostatin, like gastrin, is very significant in gastric physiology. Somatostatin was first isolated from hypothalamic tissues
and was named for its ability to inhibit the release of growth
hormone. The peptide was subsequently localized in neurons
in central and peripheral nervous systems, and in endocrine
cells in the pancreas, stomach, and intestine. The wide tissue
distribution of somatostatin suggested important regulatory
functions, a concept validated by many investigations.
The human somatostatin gene is located on chromosome 3
and encodes for a precursor of 116 amino acids (Fig. 43.9). The
somatostatin molecule is contained in the carboxyl-terminal
sequence of this preprohormone. The first 24 amino acids of
the amino terminus of preprosomatostatin constitute a signal
peptide; cleavage of this signal peptide leaves prosomatostatin.
Enzymatic cleavage of an additional 64-amino-acid segment
from prosomatostatin forms somatostatin 28. Further processing of somatostatin 28 to somatostatin 14 is tissue-specifically
regulated. In the stomach, most somatostatin exists as the
shorter peptide.
Gastric somatostatin release responds to luminal, hormonal, and neural signals. Luminal acidification is associated
with increased somatostatin release, whereas somatostatin
release decreases when luminal pH is increased. A number of
peptides have been demonstrated experimentally to release
somatostatin from the stomach, including gastrin, cholecystokinin, and secretin. -Adrenergic agonists have also been
691
shown to release somatostatin. In contrast, electrical stimulation of vagal nerves inhibits somatostatin release, as does the
cholinergic agonist methacholine.
The most important gastric function of somatostatin
appears to be regulation of acid secretion and gastrin release.
Circulating somatostatin appears to be important in modulating gastric acid secretion; locally released somatostatin functions to regulate gastrin release. In each instance, somatostatin
serves an inhibitory function, decreasing acid secretion and
diminishing the release of gastrin. In animals, antral or duodenal acidification has been associated with an increase in circulating somatostatin. Increases in circulating somatostatin are
followed, in turn, by decreased gastric acid secretion. Infusion
of exogenous somatostatin in doses that produce somatostatin
levels similar to those observed postprandially has also been
shown to inhibit acid secretion. In humans, concentrations of
somatostatin capable of inhibiting acid secretion can do so
without altering serum gastrin levels, indicating a direct action
on the acid-secreting fundic mucosa.
Somatostatin is believed to influence gastrin secretion through
a locally active intramucosal mechanism. Local actions of somatostatin are supported by ultrastructural studies of antral somatostatin cells, which demonstrate long cytoplasmic processes
that make intimate cell-to-cell contact with antral gastrin cells.
The presence of somatostatin at these sites of cellular contact
implies that somatostatin cells influence the function of gastrin
cells through local release of the peptide. Somatostatin can also
reach neighboring gastrin cells through diffusion or local blood
flow. A number of experiments have suggested that release of
somatostatin and gastrin is functionally, although reciprocally,
linked. For example, in anesthetized animals, an increase in gastric pH or ingestion of a meal is associated with increases in gastrin and decreases in somatostatin in antral venous blood.
Cholinergic agents stimulate gastrin release while inhibiting
somatostatin release. Prostaglandin E2, in contrast, inhibits
gastrin release and stimulates somatostatin secretion. These and
similar observations suggest that increases in somatostatin
release are often associated with decreased gastrin secretion. A
family of five somatostatin receptors has been cloned. Inhibition
of gastrin-stimulated gastric acid secretion is mediated by
somatostatin receptor subtype 2.
Ghrelin
The control of feeding behavior and nutrient intake is an
extremely important, and highly regulated, biologic process.
GASTROINTESTINAL
692
A
Hypothalamus
ARC
NTS Satiety center
Food
intake
Food
intake
Vagus nerve
CCK
Gut
Vagus nerve
Satiety
Satiety
Ghrelin
ARC
Insulin
POMC/
CART
AgRP/
NPY
CCK
Leptin
Leptin
Insulin
Ghrelin
FIGURE 43.10. Source of hormones that act within the brain to regulate appetite and energy homeostasis. The arcuate nucleus of the hypothalamus (ARC) contains neurons that reciprocally influence ingestive behavior. Activation of NPY/AgRP neurons increases appetite and metabolism. Activation of POMC/CART neurons suppresses appetite and energy expenditure. The vagal nucleus of the tractus solitarius receives
input from the hypothalamus as well as from the periphery via the vagus nerve.
693
phate (PIP2) within the plasma membrane to liberate watersoluble inositol triphosphate (IP3) and diacylglycerol. A major
action of IP3 is to increase intracellular calcium, mainly from
intracellular stores in the endoplasmic reticulum. The resulting increased cytosolic calcium interacts with calmodulin or
other calcium-binding proteins. Calmodulin kinase type II is
involved in parietal cell activation by acetylcholine. Intracellular calcium in this form is postulated to modulate parietal
cell function through protein phosphorylation or enzyme activation. Diacylglycerol, the second product released by hydrolysis of PIP2, activates a class of protein kinases that are phospholipid dependent and Ca2 activated, protein kinase C.
Protein kinase C in turn acts to phosphorylate a set of proteins that are distinct from those affected by the calmodulindependent system. The ultimate result of this protein phosphorylation is parietal cell activation and hydrogen ion
secretion.
Parietal cells can also be activated by occupation of specific
gastrin receptors. As with cholinergic stimulation, gastrin
exposure increases membrane PIP2 turnover (see Fig. 43.12).
Like acetylcholine, the actions of gastrin depend highly on
increases in intracellular calcium and activation of protein
kinase C.
Although histamine, acetylcholine, and gastrin occupy
separate receptors on the parietal cell and activate differing
second-messenger systems, each secretagogue ultimately acts by
means of a specialized ion transport system called the parietal
cell proton pump. This membrane-bound protein is located in
the secretory canaliculus of the parietal cell; the peptide has not
been identified in other gastric cells or in significant amounts in
other organs. The proton pump is an H-K-adenosine triphosphatase (ATPase) that electroneutrally exchanges cytosolic H for
luminal K. Hydrogen ions are concentrated 2.5-million-fold
within the secretory canaliculus, and the hydrolysis of ATP is the
energy source for transport against the steep electrochemical
gradient generated. For each H ion transported to the luminal
FIGURE 43.11. Interactions of cell types that affect parietal cell acid secretion.
GASTROINTESTINAL
694
FIGURE 43.12. Cellular mechanisms controlling parietal cell acid secretion. ADP, adenosine diphosphate; ATP, adenosine
triphosphate; cAMP, cyclic adenosine monophosphate; PI, phosphatidylinositol; PIP, phosphatidylinositol-4,5-phosphate; PIP2,
phosphatidylinositol-4,5-bisphosphate; RER, rough endoplasmic reticulum.
surface of the canalicular membrane, one K ion is transported to the cytosolic surface (Fig. 43.13). This cotransport
requires that K be continuously supplied to the luminal surface of the secretory membrane. This requirement is satisfied
by conductance of K across the canalicular membrane from
intracellular stores. Chloride ions also enter the secretory
canaliculus by diffusion.
695
GASTROINTESTINAL
696
PEPSIN
6
697
GASTROINTESTINAL
GASTRIC MOTILITY
Gastric Smooth Muscle
Consideration of gastric motility requires that the stomach be
viewed in functional terms as two different regions, the proximal one third and the distal two thirds. These areas are distinct
in terms of smooth muscle anatomy, electrical activity, and
contractile function. The regions do not correspond to the traditional anatomic divisions of fundus, corpus, and antrum.
In the proximal stomach, three layers of gastric smooth
muscle can be distinguished: an outer longitudinal layer, a
middle circular layer, and an inner oblique layer. In the distal
two thirds of the stomach, the longitudinal layer is most
clearly defined, and the inner oblique layer is usually not distinct. The gastric smooth muscle ends at the pylorus.
The smooth muscle of the proximal stomach is electrically
stable, whereas the smooth muscle of the distal stomach
demonstrates spontaneous, repeated electrical discharges.
Gastric smooth muscle exhibits myoelectric activity that is
based on a highly regular pattern called the slow wave.13 In the
698
churning action that results mixes ingested food particles, gastric acid, and pepsin, and contributes to the grinding function
of the stomach. Solid food particles do not ordinarily pass the
pylorus unless they are no larger than 1 mm.
A consistent finding in humans ingesting a mixed solid
liquid meal is that liquids empty more quickly than solids.
Characteristically, solid food empties only after a lag period,
whereas liquid emptying begins almost immediately. A traditional interpretation of these human observations has been
that the proximal stomach is the dominant force in determining how quickly a liquid meal empties by the gastroduodenal
pressure gradient generated by proximal gastric contractions.
The actions of the proximal stomach in liquid emptying are
also regulated by the sieving actions of the antropyloric segment and are modified by the nutrient composition of the
ingested meal. The distal gastric segment has been postulated
to control solid emptying through its grinding and peristaltic
actions. This traditional concept of the two-component stomach is useful in considering observations in patients who have
undergone gastric operative procedures. Patients who have
undergone proximal gastric vagotomy exhibit accelerated
emptying of liquids but have normal solid emptying. Because
of loss of receptive relaxation, the denervation of the proximal
stomach is presumed to increase intragastric pressure and
accelerate liquid emptying while leaving the distal gastric segment unaffected. Conversely, vagal denervation of the antrum
interrupts gastric emptying of solids to a greater degree than
liquids. Although this model of gastric emptying oversimplifies
the many mechanisms (gastric, pyloric, and intestinal) that
work in concert to control gastric emptying, it provides a useful framework for considering the effects of gastric surgical
procedures.
References
Coordination of Contraction
Important vagally mediated reflexes influence intragastric
pressure, presumably by affecting contractile activity of
smooth muscle in the proximal stomach. The most important
reflex is termed receptive relaxation and occurs with ingestion
of a meal. Increasing gastric volumes are accommodated with
little increase in intragastric pressure by relaxation of the
proximal stomach. This receptive relaxation allows the proximal stomach to act as a storage site for ingested food in the
immediate postprandial period. Afferent impulses, presumed
to originate from stretch receptors in the gastric wall, are carried along vagal fibers; efferent vagal discharges are inhibitory.
Receptive gastric accommodation is lost after either truncal or
proximal gastric vagotomy. After the meal has been ingested,
proximal contractile activity increases; alterations in proximal
gastric tone cause the compressive movement of gastric content from the fundus to the antrum.
Food that enters the antrum from the proximal stomach is
propelled peristaltically toward the pylorus. A number of
observations indicate that the pylorus closes 2 or 3 seconds
before the arrival of the antral contraction ring. This coordinate closing of the pylorus allows a small bolus of liquid and
suspended food particles to pass while retropulsing the main
mass of gastric contents back into the proximal antrum. The
1. Dockray GJ, Varro A, Dimaline R. Gastric endocrine cells: gene expression, processing, and targeting of active products. Phys Rev 1996;76:767
798.
2. Magee DF. Pyloric antral inhibition of gastrin release. J Gastroenterol 1996;
31:758763.
3. Debas HT, Carvajal SH. Vagal regulation of acid secretion and gastrin
release. Yale J Biol Med 1994;67:145151.
4. DeValle J. The stomach as an endocrine organ. Digestion 1997;58(suppl
1):47.
5. Sachs G, Meyer-Rosberg K, Scott DR, et al. Acid secretion and Helicobacter pylori. Digestion 1997;58(suppl 1):813.
6. Date Y, Kojima M, Hosoda H, et al. Ghrelin, a novel growth hormonereleasing acylated peptide, is synthesized in a distinct endocrine cell type in
the gastrointestinal tracts of rats and humans. Endocrinology 2000;141:
42554261.
7. van der Lely AJ, Tschop M, Heiman ML, et al. Biological, physiological,
and pathophysiological aspects of ghrelin. Endocr Rev 2004;25:426457.
8. Otto B, Cuntz U, Fruehauf E, et al. Weight gain decreases elevated plasma
ghrelin concentrations of patients with anorexia nervosa. Eur J Endocrinol
2001;145:669673.
9. Cummings DE, Weigle DS, Frayo RS, et al. Plasma ghrelin levels after dietinduced weight loss or gastric bypass surgery. N Engl J Med 2002;346:
16231630.
10. Gao Q, Horvath TL. Neuronal control of energy homeostasis. FEBS Lett
2008;582:132141.
11. Urushidani T, Forte JG. Signal transduction and activation of acid secretion
in the parietal cell. J Membr Biol 1997;59:99111.
12. Waldum HL, Brenna E, Kleveland PM, et al. Gastrinphysiological and
pathophysiological role: clinical consequences. Dig Dis 1995;13:2538.
13. Quigley EM. Gastric and small intestinal motility in health and disease.
Gastroenterol Clin North Am 1996;25:113145.
K E Y
Mucosal infection with Helicobacter pylori is the factor
that contributes to ulcer pathogenesis in most patients.
2 H. pylori virulence factors include vacuolating cytotoxin A
(VacA) and cytotoxin-associated gene A (CagA).
3 As a group, patients with duodenal ulcers have an increased
capacity for gastric acid secretion relative to normal people.
4 Current treatment of peptic ulceration involves a combination of an antisecretory drug, usually a proton pump
inhibitor, with antibiotics.
1
P O I N T S
Hemorrhage is the leading cause of death associated with
peptic ulcer. Patients with recurrent hemorrhage and
elderly patients are at greatest risk of death.
6 For perforation, current therapy includes omental patch
closure with postoperative antiH. pylori therapy. Minimally invasive approaches are becoming standard practice.
7 Major trauma accompanied by shock, sepsis, respiratory
failure, hemorrhage, or multiorgan injury is often accompanied by acute stress gastritis.
EPIDEMIOLOGY
Helicobacter pylori
PATHOPHYSIOLOGY
The pathogenesis of peptic ulceration is complex and multifactorial but increasingly understood. Approximately 85% of
peptic ulcer cases are caused by Helicobacter pylori, with
almost all other cases due to use of nonsteroidal antiinflammatory drugs (NSAIDs).1 The development of peptic
ulceration is often depicted as a balance between chronic
inflammatory injury, acidpeptic secretion, and mucosal
defense, with the equilibrium shifted toward disease. Although
acidpeptic secretion is crucial in the development of ulcers,
1 usually a defect in mucosal defense induced by bacterial infection also exists to tip the balance away from health. Mucosal
infection with H. pylori is the factor that contributes to ulcer
pathogenesis in most patients.
699
GASTROINTESTINAL
MICHAEL W. MULHOLLAND
700
TA B L E 4 4 . 1
HELICOBACTER PYLORI VIRULENCE FACTORS
Vacuolating cytotoxin A (VacA)
Forms ring structure in the shape of a flower
Inserts into gastric cell membrane, forming pore
Inserts into endosomal membranes, causing cellular
swelling
Damages mitochondrial membranes
Causes leakage of ions and small molecules
Cytotoxin-associated gene A (CagA)
Contained within pathogenicity island DNA sequence
Injected into host cells
Phosphorylated by cellular oncogenes
Activates growth factor receptorlike signaling
Disturbs normal proliferation, adhesion, cytoskeletal
function
Disturbs intercellular junctions, causing disruption of
epithelial permeability
Elicits inflammatory response
TA B L E 4 4 . 2
ETIOLOGY
701
that abnormalities of mucosal defense might result in ulceration. In addition, several agents that are useful in the treatment
of peptic ulceration are cytoprotective, which is defined as the
ability to protect the mucosa from injury at doses lower than
the threshold dose needed to inhibit acid secretion. The ability
of cytoprotective agents to heal ulcers has suggested that
abnormalities in mucosal defense are responsible for some
instances of ulceration. Most investigative efforts have focused
on the role of mucosally secreted bicarbonate and on mucosal
prostaglandin production.
Gastric surface epithelial cells secrete mucus and bicarbonate, creating a pH gradient within the mucous layer that is
nearly neutral at the mucous cell surface, even when the lumen
is highly acidic. Failure of normal bicarbonate secretion locally
would, in theory, result in exposure of surface epithelial cells
to the peptic activity of gastric secretions at low pH. Patients
with duodenal ulcers have been demonstrated to have significantly lower basal bicarbonate secretion in the proximal duodenum than normal subjects. In addition, in response to a
physiologically relevant amount of hydrochloric acid instilled
into the duodenal bulb, stimulated bicarbonate output was
approximately 40% of the normal response. Abnormalities in
duodenal bicarbonate secretion normalize after elimination of
H. pylori in infected patients. These results suggest one mechanism by which ulceration could occur, even in patients secreting normal amounts of acid.
Diminished mucosal prostaglandin production has also
been proposed to exist in subsets of patients with duodenal
ulcer. Prostaglandins and prostaglandin analogues have been
shown to exert cytoprotective effects, to accelerate healing of
established duodenal ulcers, and to decrease acid secretion. In
the duodenum, locally produced prostaglandins stimulate
mucosal bicarbonate secretion. In patients with active duodenal ulceration, gastric mucosal production of prostaglandin E2
and other prostanoids has been shown to be diminished. An
increase in prostanoid synthesis within the gastric mucosa
characterizes ulcer healing. Duodenal bicarbonate responses
to prostaglandin E2 are impaired in patients with duodenal
ulcer.
Inflammatory responses to H. pylori infection are central
to the pathogenesis of peptic ulceration. While H. pylori
infection always induces inflammation, the patterns of
response are not uniform. Three major patterns have been
recognized.7 The most common pattern is a mild to moderate
inflammation of all regions of the stomach. This form is not
associated with major alterations in gastric acidity and most
individuals are asymptomatic and do not develop peptic
ulceration. Approximately 15% of infected individuals
develop an antral-predominant form of gastritis. These individuals exhibit an intense inflammation limited to the antrum
without involvement of the mucosa of the gastric corpus.
Gastrin levels are elevated and acid secretion is high.
Inhibitory control of gastric acid production is impaired in
this form of gastritis. As a result, duodenal and prepyloric
ulcers are common. The third form of inflammatory response,
occurring in 1% of infected individuals, is least common but
most serious. This form is characterized by corpus-predominant
gastritis, hypochlorhydria, and gastric atrophy. This form of
inflammatory response is considered a precursor state for
gastric cancer. Individuals with the third pattern of inflammation demonstrate hypergastrinemia, low acid secretion, and
diminished secretion of pepsinogen.
Environmental Factors
Substantial evidence implicates cigarette smoking as an additive risk factor in the development of duodenal ulcers. Cigarette smoking impairs ulcer healing and increases the recurrence of ulcers. Continued smoking attenuates the effectiveness
of active ulcer therapy. Cigarette smoking increases both the
GASTROINTESTINAL
702
distinguished include nonulcerative dyspepsia, gastric neoplaprobability that surgery will be required and the risks of opersia, cholelithiasis and related diseases of the biliary system,
ative therapy. Cessation of smoking is a key element of antiuland both inflammatory and neoplastic disorders of the pancer therapy.
creas. In dyspeptic patients, the principal diagnoses that must
NSAIDs have emerged as a significant risk factor for the
be differentiated definitively are peptic ulceration and gastric
development of acute ulceration.8 Although acute mucosal
cancer.
injury caused by NSAIDs is more common in the stomach than
The evaluation of patients with suspected peptic ulceration
in the duodenum, NSAID-induced ulcer complications occur
usually involves endoscopy, the standard against which other
with equal frequency in these two sites. NSAIDs produce a
diagnostic modalities are measured. Endoscopy is employed
variety of lesions, ranging from hemorrhage, to superficial
because it permits biopsy of the esophagus, stomach, and duomucosal erosions, to deeper ulcerations. In the duodenum, it
denum. Endoscopy must be recommended with discretion
appears likely that invasive NSAID-associated ulcers result
because of associated morbidity (approximately 1 per 5,000
from underlying peptic ulcer diathesis compounded by the
cases) and higher costs.
direct injurious effects of these drugs.
Duodenal ulcer is characterized by lesions that are erosive
The ulcerogenic actions of NSAIDs have been attributed to
to the bowel wall. When viewed endoscopically, the ulcers
their systemic suppression of prostaglandin production.
have a typical appearance. The edges are usually sharply
Numerous experimental models have demonstrated the ability
demarcated and the underlying submucosa is exposed. The
of NSAIDs to injure the gastroduodenal mucosa. Ulcers resemulcer base is often clean and smooth, although acute ulcers
bling those caused by NSAIDs can be produced experimentally
and those with recent hemorrhage can demonstrate eschar or
by antibodies to prostaglandins. Conversely, NSAID-associated
adherent exudate. Surrounding mucosal inflammation is
gastric ulcers can be prevented by the coadministration of
common. The most frequent site for peptic ulceration is the
prostaglandin analogues. Ulcers associated with NSAIDs usufirst portion of the duodenum, with the second portion less
ally heal rapidly when the drug is withdrawn, corresponding
commonly involved. Ulceration of the third or fourth porto the reversal of antiprostaglandin effects. All available
tions of the duodenum is unusual, and occurrence in these
NSAIDs appear to pose the hazard of gastroduodenal ulcerasites should arouse suspicion of an underlying gastrinoma.
tion. Clinically important ulceration (of both the stomach and
Ulceration in the pyloric channel or the prepyloric area is
duodenum) is estimated by the U.S. Food and Drug Adminissimilar in endoscopic appearance to duodenal ulceration,
tration to occur at a rate of 2% to 4% per patient-year. The
and ulcers in these areas demonstrate other clinical features
risks inherent with NSAID use appear to be increased by a hissimilar to duodenal ulcers. Endoscopic demonstration of a
tory of H. pylori infection, by cigarette smoking, and by alcoduodenal ulcer should prompt mucosal biopsy of the gastric
hol use. The incidence of NSAID-caused ulcer complications is
antrum to demonstrate the presence of H. pylori and guide
highest in older patients, as is the attendant mortality rate.
subsequent therapy.
Peptic ulcer disease is rare in individuals who are H. pylori
The hallmarks of the histologic appearance of duodenal
negative and who are not receiving NSAID medications.
ulcers are chronicity and invasiveness. Chronic injury is sugA role of NSAIDs in upper gastrointestinal (GI) hemorgested by surrounding fibrosis; collagen is deposited in the
rhage is widely recognized. The risk of bleeding is particularly
submucosa during each round of ulcer relapse and healing.
acute for peptic ulceration. In three reports, spanning two
The adjacent mucosa often demonstrates evidence of chronic
decades, NSAIDs were linked to 50% to 75% of bleeding pepinjury with infiltration of acute and chronic inflammatory
tic ulcers, one third of deaths due to hemorrhage, and 30% of
cells. Gastric metaplasia, in which the duodenum exhibits hishospitalizations.810 Use of NSAIDs increases the risk of bleedtologic features of gastric mucosa, is common in the surrounding from peptic ulcer threefold for those under 65 years of age,
ing nonulcerated mucosa. The ulcer can extend for a variable
but by eightfold for individuals over 75 years of age. The odds
distance through the wall of the duodenum, including the full
ratio for bleeding is 13 for patients with a prior history of
thickness of the bowel in cases of perforation.
bleeding ulcer.
Because of the risk of gastrointestinal side effects, a selective class of cyclooxygenase-2 (COX-2) inhibitors was developed for long-term pain relief and anti-inflammatory therapy.
DRUG TREATMENT
Selective COX-2 inhibitors have reduced potential to injure
the gastrointestinal mucosa relative to standard NSAIDs.11
OF ULCER DISEASE
The incidence of upper GI bleeding for celecoxib or rofecoxib
therapy was reported to be fourfold less than standard
In the absence of active treatment, H. pylori infection is lifeNSAID therapy. Nonetheless, a definite risk for upper GI
long. Spontaneous healing of infected mucosa is very rare,
hemorrhage is still present, and is higher in aged patients. 4 occurring in less than 0.5% per patient-year. Current treatConcurrent use of aspirin with COX-2 inhibitors significantly
ment of peptic ulceration involves a combination of an antiseundermines the safety advantages of the COX-2 agents, as
cretory drug, usually a proton pump inhibitor, with antibidoes smoking. An increased incidence of adverse cardiovascuotics.12 This therapy is rational for most patients who are
lar events caused the withdrawal of rofecoxib and valdecoxib
H. pylori positive and results in a high rate of sustained ulcer
from the market.
healing.
A large number of drug regimens have been described, but
the most widely used treatment protocols combine a proton
pump inhibitor, usually omeprazole, with two antibiotics,
DIAGNOSIS
usually clarithromycin and metronidazole or amoxicillin. A
combination of antibiotics is more effective than one antibiThe cardinal feature of duodenal ulceration is epigastric pain.
otic alone in almost all series. This triple therapy is adminisThe pain is usually confined to the upper abdomen and is
tered for 7 or 14 days. Triple-drug therapy is cost effective
described as burning, stabbing, or gnawing. Unless perforaand associated with a low rate of side effects, low rates of
tion or penetration into the head of the pancreas has occurred,
antibiotic resistance, and acceptable levels of patient complireferral of pain is not common. Many patients report pain on
ance. H. pylori eradication rates of greater than 90% have
arising in the morning. Ingestion of food or antacids usually
been reported.
provides prompt relief. In uncomplicated cases, abnormal
After elimination of H. pylori, ulcer recurrence rates reflect
physical findings are minimal. The differential diagnosis is
the rate of reinfection. In developed countries, reinfection rates
broad and includes a variety of diseases originating in the
of less than 10% at 5 years have been reported. Eradication of
upper gastrointestinal tract. The most common disorders to be
HISTAMINE-RECEPTOR
ANTAGONISTS
Histamine, released into the interstitial fluid by cells in the
fundic mucosa, diffuses to the mucosal parietal cell. Histamine
stimulates acid production by occupying a membrane-bound
receptor and activating parietal cell adenylate cyclase. Histamine is released in response to a number of physiologic stimuli; blockade of histamine receptors inhibits most forms of
stimulated acid secretion in humans. Parietal cell histamine
receptors are classified as H2 receptors because they are activated by agonists such as 4-methylhistamine and are selectively blocked by agents such as cimetidine. Some H2 receptor
antagonists also possess nongastric actions by binding to
androgen receptors, by interacting with the hepatic microsomal oxidase system, and by crossing the bloodbrain barrier.
All clinically useful gastric histamine receptor antagonists are
of the H2 type.
H2-receptor antagonists bind competitively to parietal cell
H2 receptors to produce a reversible inhibition of acid secretion.
An enormous worldwide experience has accumulated with the
use of H2-receptor antagonists. The agents are effective and safe
when used in the treatment of peptic ulcer. The various compounds have similar efficacy in terms of ulcer healing when used
in doses that produce similar reductions in acid output. It is
clear that H2-receptor blockers do not affect the underlying
ulcer diathesis; if H2-receptor antagonists are stopped, recurrent
ulceration occurs in more than half of patients within 1 year.
The current understanding of the role of H. pylori in ulcer
pathogenesis has changed the role of H2-receptor antagonists
from primary therapy to that of a substitute for proton pump
inhibitors in conjunction with antibiotic treatment.
SUCRALFATE
Sucralfate is the aluminum salt of sulfated sucrose. In the
acidic environment of the stomach, sucralfate polymerizes,
becoming viscous and adhering to the gastroduodenal mucosa.
Coating of the ulcer base by the polymer has been claimed to
provide a protective barrier, binding bile salts and inhibiting
the actions of pepsin. Sucralfate also stimulates the production
of mucus. Sucralfate stimulates increased mucosal prostaglandin
E2 production and increases bicarbonate secretion. Sucralfate
binds epidermal growth factor and may protect the mitogen
from acid degradation. Sucralfate stimulates epithelial proliferation at the ulcer margin. The drug has almost no buffering
capacity. Virtually no systemic absorption occurs, and because
of this property, sucralfate is safe for the treatment of peptic
ulcer in pregnancy.
OPERATIVE TREATMENT
OF ULCER DISEASE
Surgical Goals
Operative intervention is reserved for the treatment of complicated ulcer disease. Three complications are most common and
constitute the indications for peptic ulcer surgeryhemorrhage,
perforation, and obstruction.13 The first goal in the surgical
treatment of the complications of ulcer disease is treatment of
coexisting anatomic complications, such as pyloric stenosis or
perforation. The second major goal should be patient safety
and freedom from undesirable chronic side effects. To achieve
these goals, the gastric surgeon can direct therapy through
endoscopic or operative means, the appropriate choice depending on the clinical circumstances.
Operative Procedures
A number of operative procedures have been used to treat peptic ulcer, but with decreasing frequency in the past decade.
There is currently no indication for surgical treatment of
uncomplicated ulcer disease. Operative treatment of gastric
outlet obstruction has decreased by approximately 50%. Most
surgical patients are now treated emergently for the complications of bleeding or perforation.
Three procedurestruncal vagotomy and drainage, truncal
vagotomy and antrectomy, and proximal gastric vagotomy
have been widely used in the past in the operative treatment of
peptic ulcer disease. With increasing frequency, surgical therapy of peptic ulcer is directed exclusively at correction of the
immediate problem (e.g., closure of duodenal perforation)
without gastric denervation. The underlying ulcer diathesis is
then addressed after surgery by antibiotic therapy directed at
H. pylori. This approach is applicable to most patients with
peptic ulcer undergoing emergent operation and predicts a
rapidly diminishing role for vagotomy in the future.
Division of both vagal trunks at the esophageal hiatus
truncal vagotomydenervates the acid-producing fundic
mucosa as well as the remainder of the vagally supplied viscera
(Fig. 44.1). Because denervation impedes normal pyloric coordination and can result in impairment of gastric emptying,
GASTROINTESTINAL
703
704
FIGURE 44.1. Truncal vagotomy and proximal gastric vagotomy. A: With truncal vagotomy, both nerve trunks are divided at the level of
the diaphragmatic hiatus. B: Proximal gastric vagotomy involves division of the vagal fibers that supply the gastric fundus. Branches to the
antropyloric region of the stomach are not transected, and the hepatic and celiac divisions of the vagus nerves remain intact.
truncal vagotomy must be combined with a procedure to eliminate pyloric sphincteric function. Usually, gastric drainage is
ensured by performance of a pyloroplasty (Fig. 44.2).
Truncal vagotomy can also be combined with resection of
the gastric antrum to effect a further reduction in acid secretion, presumably by removing antral sources of gastrin. The
limits of antral resection are usually defined by external landmarks, rather than the histologic transition from fundic to
antral mucosae. The stomach is divided proximally along a
line from a point above the incisura angularis to a point along
the greater curvature midway from the pylorus to the gastroesophageal junction. Restoration of gastrointestinal continuity
by a gastroduodenostomy is termed a Billroth I reconstruction.
A Billroth II procedure uses a gastrojejunostomy (Fig. 44.3).
Proximal gastric vagotomy differs from truncal vagotomy
in that only the nerve fibers to the acid-secreting fundic
mucosa are divided (see Fig. 44.1). Vagal nerve fibers to the
antrum and pylorus are left intact, and the hepatic and celiac
divisions are not transected. The operation has also been
called parietal cell vagotomy to emphasize its most important
functional consequence.
The role of vagotomy in clinical surgery diminished significantly in the 1990s. In 1998, only 7,000 vagotomies were performed in the United States, of more than 41 million operative
procedures.14
705
GASTROINTESTINAL
FIGURE 44.2. (Continued) B: The Finney pyloroplasty is performed as a gastroduodenostomy with division of the pylorus.
C: The Jaboulay pyloroplasty differs from the Finney procedure in that the pylorus is not transected.
706
TA B L E 4 4 . 3
RESULTS
TV P
(%)
TV A
(%)
0.51
12
Acid reduction
Basal
80
70
85
Stimulated
50
50
85
Ulcer recurrence
10
12
12
Gastric emptying
Liquids
Accelerated
Accelerated
Accelerated
Solids
No change
Accelerated
Slowed
5
10
1015
12
5
25
20
12
Dumping
Mild
Disabling
Diarrhea
Mild
Disabling
of dumping after truncal vagotomy and antrectomy or pyloroplasty. Persistent or disabling diarrhea is present in less than
1% of patients after proximal gastric vagotomy.
Proximal gastric vagotomy has the lowest operative mortality rate. Collected series of proximal gastric vagotomies
have reported an operative mortality rate of less than 0.05%,
lower than the reported mortality rate for any other gastric
procedure for peptic ulcer. Truncal vagotomy and pyloroplasty
has a reported mortality rate of 0.5% to 0.8%, whereas the
mortality rate after truncal vagotomy and antrectomy approximates 1.5%.
Most prospective surgical series were reported in the era
before the pathogenic role of H. pylori was appreciated. With
appropriate use of postoperative antimicrobials directed
against H. pylori, ulcer recurrence rates are currently much
lower than historical standards. Although recurrence rates
(without H. pylori treatment) as low as 5% have been
reported, a more generally accepted figure is 10%.15 This rate
is similar to that of reinfection with H. pylori after its successful eradication. The reported ulcer recurrence rates after proximal gastric vagotomy can be adversely affected by the inclusion of prepyloric and pyloric channel ulcers. For reasons that
are not clear, proximal gastric vagotomy is significantly less
effective when used to treat ulcers in this position than when
used for duodenal ulceration.
707
TA B L E 4 4 . 4
INDICATIONS/CONTRAINDICATIONS
Perforation
The lifetime risk for perforation in patients with duodenal
ulceration who do not receive therapy approximates 10%. In
contrast, ulcer perforation is unusual if initial ulcer healing has
been achieved.
Perforation of a duodenal ulcer is usually accompanied by
sudden and severe epigastric pain. The pain, caused by the
100
H. pylori
negative
90
80
H. pylori
positive
70
60
50
0
10
20
30
40
50
Months after index bleeding
60
70
GASTROINTESTINAL
708
Upper GI bleeding
Resuscitation
Early endoscopy
No stigmata of hemorrhage
Clean ulcer base
Stigmata of hemorrhage
Active bleeding, oozing,
adherent clog, visible vessel
Endoscopic hemostasis
Biopsy of antral mucosa
Recurrent bleeding
Inability to perform
Endoscopic therapy
Hemodynamic instability
Operative treatment
Inpatient observation
followed by omeprazole
and antibiotics
Inpatient recovery
followed by
treatment for H. pylori
ALGORITHM 44.1
ALGORITHM 44.1 Treatment of bleeding duodenal ulceration.
spillage of highly caustic gastric secretions into the peritoneum, rapidly reaches peak intensity and remains constant.
Radiation to the right scapular region is common because of
right subphrenic collection of gastric contents. Occasionally,
pain is sensed in the lower abdomen if gastric contents travel
caudally through the paracolic gutter. Peritoneal irritation is
usually intense, and most patients avoid movement to minimize
discomfort.
Physical examination reveals low-grade fever, diminished
bowel sounds, and rigidity of the abdominal musculature.
Usually, upright abdominal radiographs reveal pneumoperitoneum, but up to 20% of perforated ulcers do not show free
intraperitoneal air. Computed tomography of the abdomen is
very sensitive for demonstrating perforation if pneumoperitoneum is not demonstrated but perforation is still suspected.
Although occasional reports have described the nonoperative treatment of this complication, perforation remains a
strong indication for surgery in most circumstances. Laparotomy or laparoscopy affords the opportunity to relieve
intraperitoneal contamination and to close the perforation
(Fig. 44.5).
Signs of antecedent duodenal ulceration, in terms of history
of prior symptoms and anatomic evidence of duodenal scarring, should be sought. A lack of antecedent symptoms is not
protective. Reports suggest that patients without antecedent
symptoms are also at risk for recurrent ulceration. By 5 to
6 years, symptomatic ulcer recurrence in patients with acute
ulcer perforation is similar to that for patients with chronic
disease. Before the role of H. pylori was appreciated, simple
omental closure of duodenal perforation resulting from
chronic ulceration did not provide satisfactory long-term
results; up to 80% of patients so treated had recurrent ulceration, and 10% experienced reperforation if untreated.
Approximately four fifths of all patients with perforation have
709
GASTROINTESTINAL
Obstruction
Gastric outlet obstruction can occur acutely or chronically
in patients with duodenal ulcer disease. Acute obstruction is
caused by edema and inflammation associated with ulcers in
the pyloric channel and the first portion of the duodenum.
Pyloric obstruction is suggested by recurrent vomiting,
dehydration, and hypochloremic alkalosis due to loss of gastric secretions. Acute gastric outlet obstruction is treated
with nasogastric suction, rehydration, and intravenous
administration of antisecretory agents. In most instances,
acute obstruction resolves with such supportive measures
within 72 hours.
Repeated episodes of ulceration and healing can lead to
pyloric scarring and a fixed stenosis with chronic gastric outlet
obstruction.23 In cases of untreated duodenal ulceration, the
lifetime risk of chronic pyloric stenosis approximates 10%.
GASTRIC ULCER
Benign gastric ulcers are a form of peptic ulcer disease, occurring with one-third the frequency of benign duodenal ulceration. In the United States, gastric ulcer is somewhat more common in men than in women and occurs in a patient cohort
approximately 10 years older than for duodenal ulceration.
Endoscopic Diagnosis
Upper gastrointestinal endoscopy is the preferred method for
diagnosing gastric ulceration. The ulcer base in benign disease
is commonly smooth and flat and often covered by a gray,
fibrous exudate. The margin is usually slightly raised, erythematous, and friable. Differentiation of benign and malignant
gastric ulcers is reliably made only by histologic examination.
Visual endoscopic differentiation of benign from malignant
ulcers is not reliable. All gastric ulcers should have multiple
biopsies taken from the perimeter of the lesion. The addition
of lesional brushings to biopsy increases diagnostic accuracy
to approximately 95%.
Benign gastric ulcers may occur in any location in the stomach, but approximately 60% are located along the lesser curvature proximal to the incisura angularis. Less than 10% of
benign gastric ulcers are located on the greater curvature. Virtually all gastric ulcers lie within 2 cm of the histologic transition between fundic and antral mucosa. With increasing age,
this mucosal transition zone moves proximally along the lesser
710
Therapy
The primary therapy for benign gastric ulceration in most
patients is antimicrobial treatment of H. pylori infection. The
treatment protocols are similar to those used for benign duodenal ulceration. For many patients, cessation of NSAID therapy is also required.
Indications for surgical treatment of gastric ulcer include
hemorrhage, perforation, failure of a recurrent ulcer to
respond to medical therapy, and inability to exclude malignant
disease.
For benign gastric ulcers, the elective operation of choice is
usually a distal gastrectomy with gastroduodenal (Billroth I)
anastomosis. The ulcer should be included in the gastrectomy
specimen. With this approach, operative mortality rates of 2%
to 3%, with ulcer recurrence rates of less than 5%, have been
reported. Because benign gastric ulcers are not associated with
gastric acid hypersecretion, inclusion of vagotomy is not necessary.
The occurrence of a gastric ulcer near the gastroesophageal
junction represents a difficult surgical problem. When possible, the ulcer should be excised. This usually requires a distal
gastrectomy with an extension along the lesser curvature near
the esophageal wall and reconstruction with gastrojejunostomy.
Emergency operations performed for hemorrhage or perforation require ulcer excision. Distal gastrectomy, performed
with gastroduodenal reconstruction, is usually the procedure
of choice. Operative mortality rates average 10% to 20% in
the presence of hemorrhage or perforation.
POSTGASTRECTOMY
SYNDROMES
A number of syndromes have been described that are associated with distressing symptoms after gastric operations performed for peptic ulcer or gastric neoplasm. The occurrence of
severe postoperative symptoms is fortunately low, perhaps 1%
to 3% of cases, but the disturbances can be disabling. The two
most common postgastrectomy syndromes, categorized
according to predominant manifestation, are dumping and
alkaline reflux gastritis.
Dumping
The term dumping denotes a clinical syndrome with both gastrointestinal and vasomotor symptoms. The precise cause of
dumping is not known but is believed to relate to the
unmetered entry of ingested food into the proximal small
STRESS GASTRITIS
7
Major trauma accompanied by shock, sepsis, respiratory failure, hemorrhage, or multiorgan injury is often accompanied
by acute stress gastritis.26 Acute stress gastritis is particularly
prevalent after thermal injury with greater than 35% total
surface area burned. A similar entity is also observed as a
711
GASTROINTESTINAL
FIGURE 44.7. Conversion of Billroth II gastrojejunostomy to Roux-en-Y gastrojejunostomy. The afferent limb is divided (A),
and intestinal continuity is re-established by anastomosis 50 to 60 cm downstream from the original gastrojejunostomy (B).
result of central nervous system injury or intracranial hypertension. Multiple superficial ulcerations and erosions are
noted in the proximal, acid-secreting portion of the stomach,
with fewer lesions in the antrum and only rare ulcerations in
the duodenum.
The most sensitive diagnostic test for stress ulceration is
endoscopic examination. If patients are examined within 12
hours of the onset of injury, acute mucosal ulcerations may be
observed that appear as multiple, shallow areas of erythema
and friability, often accompanied by focal hemorrhage. The
lesions are progressive during the first 72 hours after injury.
When lesions are examined histologically, they are seen to consist of coagulation necrosis of the superficial endothelium with
infiltration of leukocytes into the lamina propria. Chronic disease, characterized by fibrosis and scarring, is not observed.
With resolution of the underlying injury or sepsis, healing is
accompanied by mucosal restitution and regeneration.
712
long-bone fractures, a major burn over 35% of the body surface, transfusion requirement above 6 units, hepatic dysfunction, sepsis, hypotension, and oliguric renal failure. Scoring
systems of critical illness, exemplified by the Acute Physiology
and Chronic Health Evaluation (APACHE) system, accurately
predict risk for acute stress gastritis.
The major complication of stress gastritis is hemorrhage.
Admission to an intensive care unit is not an independent risk
factor for bleeding. However, the development of respiratory
failure or coagulopathy (platelet count less than 50,000/mm3,
international normalized ratio [INR] 1.5, or partial thromboplastin time [PTT] greater than two times normal) imparts
the greatest risk for hemorrhage.
Diagnosis
Clinical studies that use bloody nasogastric discharge as a
sign of stress gastritis probably underestimate its incidence in
critically ill patients. Conversely, studies based on endoscopy
overestimate the incidence of clinically important stress
gastritis. In one endoscopically controlled study, 100% of
patients with life-threatening injuries had evidence of gastric
erosions by 24 hours. Severely burned patients have endoscopic evidence of gastric erosions in greater than 90% of
cases, whereas significant upper gastrointestinal hemorrhage
occurs in between 25% and 50% of patients with burn
wound infection.
Barium contrast examinations have no role in the diagnosis
of stress gastritis and interfere with subsequent endoscopic
examination. Analysis of gastric contents for titration of acid
production is not informative.
References
1. Suerbaum S, Michetti P. Helicobacter pylori infection. N Engl J Med
2002;347(15):11751186.
2. Kokoska ER, Kauffman GL Jr. Helicobacter pylori and the gastroduodenal
mucosa. Surgery 2001;130:1316.
3. Maeda S, Mentis AF. Pathogenesis of helicobacter pylori infection. Helicobacter 2007;12(suppl 1):1014.
4. Reyrat JM, Rappouli R, Telford JL. A structural overview of the Helicobacter cytotoxin. Int J Med Microbiol 2000;290:375379.
5. Censini S, Lange C, Xiang Z, et al. Cag, a pathogenicity island of Helicobacter pylori encodes type I-specific and disease-associated virulence factors. Proc Natl Acad Sci U S A 1996;93:12591264.
6. Gillen D, El-Omar EM, Wirz AA, et al. The acid response to gastrin distinguishes duodenal ulcer patients from Helicobacter pylori-infected
healthy subjects. Gastroenterology 1998;114:5057.
7. Amieva MR, El-Omar EM. Host-bacterial interactions in Helicobacter
pylori infection. Gastroenterology 2008;134;306323.
8. Lanas A, Perex-Aisa MA, Feu F, et al. A nationwide study of mortality
associated with hospital admission due to severe gastrointestinal events
and those associated with nonsteroidal antiinflammatory drug use. Am J
Gastroenterol 2005;100:16851693.
9. Cebollaro-Santamaria F, Smith J, Gioe S, et al. Selective outpatient management of upper gastrointestinal bleeding in the elderly. Am J Gastroenterol 1999;94:12421247.
10. Pilotto A, Franceshi M, Leandro G, et al. NSAID and aspirin use by the
elderly in general practice: effect on gastrointestinal symptoms and therapies. Drugs Aging 2003;20:701710.
11. Lanas A, Garcia-Rodriguez LA, Arroyo MT, et al. Risk of upper gastrointestinal ulcer bleeding associated with selective cyclooxygenase-2
inhibitors, traditional non-aspirin non-steroidal anti-inflammatory drugs,
aspirin and combinations. Gut 2006;55;17311738.
12. Bazzoli F, Bianchi Porro G, Maconi G, et al. Treatment of Helicobacter
pylori infection: indications and regimens: an update. Dig Liver Dis 2002;
34:7083.
13. Millat B, Fingerhut A, Borie F. Surgical treatment of complicated duodenal
ulcers: controlled trials. World J Surg 2000;24:299306.
14. Kleeff J, Friess H, Bchler MW. How Helicobacter pylori changed the life
of surgeons. Dig Surg 2003;20:93102.
15. Johnson AG. Proximal gastric vagotomy: does it have a place in the future
management of peptic ulcer? World J Surg 2000;24:259263.
16. Zullo A, Hassan C, Campo SMA, et al. Bleeding peptic ulcer in the elderly:
risk factors and prevention strategies. Drugs Aging 2007;24:815828.
17. Sandel MH, Kolkman JJ, Kuiper EJ, et al. Nonvariceal upper gastrointestinal bleeding: differences in outcome for patients admitted to internal
medicine and gastroenterological services. Am J Gastroenterol 2000;95:
23572362.
18. Machicado GA, Jensen DM. Thermal probes alone or with epinephrine for
the endoscopic haemostasis of ulcer haemorrhage. Baillieres Clin Gastroenterol 2000;14:443458.
19. Hepworth CC, Swain CP. Mechanical endoscopic methods of haemostasis
for bleeding peptic ulcers: a review. Baillieres Clin Gastroenterol 2000;14:
467476.
20. Sharma VK, Sahai AV, Corder FA, et al. Helicobacter pylori eradication is
superior to ulcer healing with or without maintenance therapy to prevent
further ulcer haemorrhage. Ailment Pharmacol Ther 2001;15:19391947.
21. Boey J, Choi SKY, Alagaratnam TT, et al. Risk stratification for perforated
duodenal ulcers: a prospective validation of predictive factors. Ann Surg
1987;205:2228.
22. Lunevicius R, Morkevicius M. Systematic review comparing laparoscopic
and open repair for perforated peptic ulcer. Br J Surg 2005;92:11951207.
23. Sanabria AE, Morales CH, Villegas MI. Laparoscopic repair for perforated
peptic ulcer disease. Cochrane Database Syst Rev 2005:CD004778.
24. Ellis H. Pyloric stenosis complicating duodenal ulceration. World J Surg
1987;11:198202.
25. Atherton JC. The pathogenesis of Helicobacter pylori-induced gastroduodenal disease. Annu Rev Pathol 2006;1:6396.
26. Hiramoto JS, Terdiman JP, Norton JA. Evidence-based analysis: postoperative gastric bleeding: etiology and prevention. Surg Oncol 2003;12:919.
27. Mutlu GM, Mutlu EA, Factor P. GI complications in patients receiving
mechanical ventilation. Chest 2001;119:12221238.
28. Tryba M. Role of acid suppressants in intensive care medicine. Best Pract
Res Clin Gastroenterol 2001;15:447461.
29. Yang Y, Lewis JD. Prevention and treatment of stress ulcers in critically ill
patients. Semin Gastrointest Dis 2003;14:1119.
K E Y
Overweight and obesity can be quantified by body mass
index (BMI), which is calculated as weight in kilograms
divided by the square of the height in meters.
2 Two thirds of the U.S. adult population is considered overweight (BMI 25 kg/m2) and half of these are obese (BMI
30 kg/m2).
3 Obesity is associated with numerous comorbidities including diabetes and atherosclerosis, respiratory and cardiac
failure, venous thromboembolic disease, cholelithiasis,
degenerative joint disease, pseudotumor cerebri, and nonalcoholic steatohepatitis.
4 Patients are considered eligible for surgical treatment of
obesity if they have a BMI greater than or equal to 40 kg/m2
Obesity and overweight have now reached epidemic proportions, and their associated conditions have serious implications for global health. Traditionally, categories of obesity and
overweight have been defined using body mass index (BMI),
which is calculated as weight in kilograms divided by the square
of the height in meters. Thresholds to classify overweight, obesity, and morbid obesity have been created based on long-term
outcome.
According to this classification, more than two thirds of the
U.S. adult population is overweight and half of these are obese,
which has important public health implications because obesity
is clearly associated with increased morbidity and mortality.1,2
In addition, this crisis now involves the developing world, and
the World Health Organization (WHO) currently estimates
that 1.7 billion people worldwide are overweight or obese.3
Alarmingly, obesity has become increasingly prevalent in the
pediatric population, and 30% of U.S. children have a BMI
greater than the 85th percentile for their age.4
Severe obesity is associated with a large number of associated comorbidities, many of which are associated with an
increased risk of mortality (Table 45.1) and include coronary
artery disease, hypertension, heart failure, type 2 diabetes mellitus, obesity hypoventilation and sleep apnea syndromes,
hypercoagulability and venous thromboembolic disease,
necrotizing panniculitis, diverticulitis, and necrotizing pancreatitis. In addition, morbidly obese patients have an increased
risk of colon, prostate, breast, and uterine carcinoma.
The 1991 National Institutes of Health (NIH) Consensus
Panel (Table 45.2) established eligibility criteria for surgical
management. In general, a BMI greater than or equal to 40
kg/m2 without an associated comorbidity and a BMI greater
than or equal to 35 kg/m2 with an established comorbidity are
considered general criteria for consideration of surgical management of obesity.
P O I N T S
ETIOLOGY
The causes of morbid obesity are not entirely known but likely
include a combination of genetic, endocrinologic, behavioral,
713
GASTROINTESTINAL
714
TA B L E 4 5 . 1
MORBIDITY OF OBESITY
Cardiovascular dysfunction
Hypertension
Coronary artery disease
Heart failure
Type 2 diabetes mellitus (adult onset or noninsulin dependent)
Nonalcoholic steatohepatitis
Respiratory insufficiency of obesity (pickwickian syndrome)
Obesity hypoventilation syndrome
Obstructive sleep apnea syndrome
Increased intra-abdominal pressure
Stress overflow urinary incontinence
Gastroesophageal reflux
Venous disease
Thrombophlebitis
Respiratory Disorders
Associated with Obesity
There are two components of respiratory dysfunction in obesityobstructive sleep apnea syndrome (OSA) and obesity
hypoventilation syndrome (OHS)and collectively these conditions comprise the pickwickian syndrome. Both of these conditions may be present before operation but may be exacerbated by a surgical procedure. Following gastric surgery for
obesity, OSA and OHS can completely resolve.14
OSA is a potentially fatal complication of morbid obesity
and is characterized by frequent daytime somnolence and
heavy snoring. The frequent episodes of apnea result in inadequate stage IV and rapid eye movement (REM) sleep, leading
to somnolence during the day. Patients with suspected sleep
apnea syndrome should undergo preoperative polysomnography at a sleep center to confirm the diagnosis and to guide
therapy. During surgical procedures, patients with OSA are at
great risk for acute upper airway obstruction and respiratory
arrest at the time of anesthetic induction. In severe cases, it
may be worthwhile to consider elective tracheostomy prior to
bariatric surgery.
Stasis ulcers
Pulmonary embolism
Nephrotic syndrome
Pseudotumor cerebri
Degenerative osteoarthritis
Cholelithiasis
Infectious complications
Difficulty recognizing peritonitis
Necrotizing subcutaneous infections
Wound infections or dehiscence
Sexual hormone dysfunction
Polycystic ovary (Stein-Leventhal) syndrome
Cardiac Dysfunction
CONDITIONS ASSOCIATED
WITH MORBID OBESITY
An important consequence of central obesity is increased intraabdominal pressure, which contributes to many of the conditions associated with morbid obesity. In addition to the conditions in this section, gastroesophageal reflux, stress or urge
urinary incontinence, nephrotic syndrome, and incisional and
inguinal hernias are common problems in obese patients.12,13
TA B L E 4 5 . 2
INDICATIONS/CONTRAINDICATION
Gallstones
Approximately one third of morbidly obese patients have
cholelithiasis. Many have either had a cholecystectomy or had
gallstones noted during another intra-abdominal operative
procedure. In addition, rapid weight loss has been associated
with development of gallstones in 25% to 40% of patients
who undergo gastric bypass procedures. The risk of cholelithiasis in this setting can be reduced to 2% by administering
ursodeoxycholic acid, 300 mg orally twice daily.24
Preoperative evaluation of the gallbladder may be technically quite difficult in morbidly obese patients because gallstones may be missed with transcutaneous ultrasonography.
Among patients with symptoms of cholelithiasis, intraoperative sonography is a useful procedure to characterize cholelithiasis. Consideration should be given to cholecystectomy in a
patient undergoing gastric operation for obesity.
Pseudotumor Cerebri
Pseudotumor cerebri is an unusual complication of morbid
obesity that is associated with benign intracranial hypertension, papilledema, blurred vision, headache, and elevated cerebrospinal fluid pressures.25 Currently, there is no evidence that
patients with pseudotumor cerebri are at any additional perioperative risk, and cerebrospinal fluid does not have to be
removed or shunted before anesthesia and major abdominal
operations. Importantly, successful weight reduction will lead
to resolution of pseudotumor cerebri.26,27
Degenerative Osteoarthritis
Degenerative osteoarthritis of the knees, hips, and back is a
common complication of morbid obesity. In addition, podiatric pain is quite common. Weight reduction alone may
greatly reduce the pain and immobility that afflict these
patients, although many patients may require total joint
replacement. Of note, joint replacement in patients who weigh
more than 250 lb is associated with an unacceptable incidence
of loosening, highlighting the importance of weight reduction
prior to aggressive orthopedic interventions in morbidly obese
patients.28 Given the significant limitations of conservative
weight loss programs in patients with severe degenerative joint
disease, weight reduction by means of a gastric bariatric operation may be the most sensible initial approach, followed by
repeat orthopedic evaluation if pain and dysfunction persist.
SURGICAL MANAGEMENT
OF MORBID OBESITY
Eligibility for Obesity Surgery
The mortality risk for patients undergoing gastric bypass can
now be assessed by the Obesity Surgery Mortality Risk Score
(OS-MRS), which is composed of five independent, preoperative clinical variables and predicts 90-day mortality after gastric bypass surgery (Table 45.3). The OS-MRS was derived
from 2,075 patients undergoing gastric bypass surgery at a single institution, and validation of the OS-MRS has been completed in a multicenter study involving 4,431 patients from
four institutions. The OS-MRS is a valuable tool that can be
used to stratify risk and aid in surgical decision making and
patient discussion in bariatric surgery.6
While morbid obesity does impose greater perioperative
risk, the risk can be markedly reduced by appropriate preoperative and postoperative care. Specifically, these risks include
wound infection, dehiscence, thrombophlebitis, pulmonary
embolism, anesthetic calamities, acute postoperative asphyxia
in patients with OSA, acute respiratory failure, right ventricular or biventricular cardiac failure, and missed acute catastrophes of the abdomen, such as an anastomotic leak (Table 45.4).
Periprocedure Considerations
Morbidly obese patients are at significant risk of coronary
artery disease as a result of the increased prevalence of coronary risk factors including systemic hypertension, dyslipidemia, insulin resistance, and diabetes. Thus, preoperative
TA B L E 4 5 . 3
THE OBESITY SURGERY MORTALITY RISK SCORE
Body mass index 50 kg/m2
Male gender
Hypertension
Increased risk of pulmonary embolus:
Previous thrombosis
Previous pulmonary embolus
Inferior vena caval filter
Right heart failure
MEDICAL MANAGEMENT
OF MORBID OBESITY
There are many dietary programs for weight reduction,
including hospital-supervised programs, psychiatric behavioral modification programs, commercial organizations, commercial diets, protein-sparing fast programs, and medications. Unfortunately, while many people can lose weight
successfully through dietary manipulation, only 5% to 10%
of patients with extreme obesity are able to sustain significant
5 weight reduction.29 An NIH Technology Assessment Conference in 1992 concluded that dietary management of severe
Mortality Risk
01
0.2%
23
1.1%
45
2.4%
GASTROINTESTINAL
715
716
TA B L E 4 5 . 4
COMPLICATIONS OF BARIATRIC OPERATIONS
Wound infection
Incisional hernia
Thrombophlebitis
Pulmonary embolism
Acute postoperative asphyxia
Acute respiratory failure
Cardiac failure
Marginal ulcer
Anastomotic leak
Death
Jejunoileal Bypass
The first popular surgical procedure for morbid obesity was
the jejunoileal bypass. This operation produced an obligatory
malabsorption state through bypass of a major portion of the
absorptive surface of the small intestine. The procedure connected a short length of proximal jejunum (8 to 14 inches) to
the distal ileum (4 to 12 inches) as an end-to-end or end-toside anastomosis. The end-to-end procedures, which were
associated with a better weight loss, required decompression
717
GASTROINTESTINAL
population (BMI 50 kg/m2) with a 150-cm Roux limb (longlimb gastric bypass).27
Gastroplasty
Gastric Bypass
7
718
Adjustable
gastric band
Subcutaneous
port
250 cm
50 cm
FIGURE 45.2. Biliopancreatic diversion. A distal gastrectomy is performed, followed by division of the distal small bowel 250 cm proximal to the ileocecal valve. The proximal bypassed bowel is anastomosed to the ileum 50 cm from the ileocecal valve.
5 mm
5 mm
5 mm
12 mm
5 mm
719
COMPLICATIONS OF GASTRIC
SURGERY FOR MORBID OBESITY
The most feared complication of gastric surgery for morbid
obesity is gastrointestinal leak (Algorithm 45.1). This occurs
most commonly at the gastrojejunostomy, although other
potential sites include the jejunojejunostomy, excluded stomach, and inadvertent enterotomies. Following gastric bypass,
Anastomotic leak
Not contained
Contained
Operative
re-exploration
Percutaneous drainage,
antibiotics, observation
ALGORITHM 45.1
ALGORITHM 45.1. Management of anastomotic leak after gastric surgery for obesity.
GASTROINTESTINAL
720
the excluded stomach can perforate because of marked dilatation resulting from biliopancreatic limb obstruction. This
complication is often heralded by frequent hiccups and can be
diagnosed by noting a large gastric bubble on abdominal radiographs. Impending gastric perforation requires urgent percutaneous or operative decompression. In patients undergoing
revisional gastric surgery for obesity, a gastrostomy tube should
be inserted prophylactically for decompression.
Leaks can be extremely difficult to detect in the morbidly
obese patient. If patients complain of increasing pain in the
abdomen, back, or shoulder (consistent with irritation of the
left hemidiaphragm) or of pelvic pressure or hiccups, the clinician must suspect a leak. Tachycardia, tachypnea, fever, anxiety, and leukocytosis are often present, although it is not
uncommon for a leak to manifest as unexplained persistent
tachycardia in an asymptomatic patient. This complication
can often be confirmed with an emergent upper gastrointestinal series using water-soluble contrast. If the study is negative
but suspicion is high, the patients abdomen should be reexplored urgently. An attempt to repair the leak should be made,
and a large sump drain should be placed nearby because the
repair frequently breaks down. This leads to a controlled fistula, which usually heals with total parenteral nutrition or
tube feeds via gastrostomy or jejunostomy. Some gastrojejunal
leaks can be managed nonoperatively in situations where the
leak is drained (via a drain placed at the time of operation or
radiographically guided) or contained; in either circumstance,
Algorithm 45.1 is appropriate only in stable patients without
signs of systemic toxicity. Factors associated with leak include
increasing age, revisional surgery, male gender, and sleep
apnea.39
Marginal ulcers develop in approximately 10% of patients
with gastric bypass even when treated with postoperative acid
suppression. This complication usually responds to additional
medical therapy with proton pump inhibitors. Stomal stenosis
can occur following gastric bypass or vertical banded gastroplasty. Outpatient endoscopic dilatation is usually successful
in patients with gastric bypass, although more than one treatment may be necessary.
Rapid weight loss following bariatric surgery is associated with
a high incidence (up to 35%) of gallstone formation and need for
subsequent cholecystectomy for biliary colic or acute cholecystitis.
Some surgeons recommend prophylactic cholecystectomy at the
time of bariatric surgery, whereas others perform cholecystectomy
only if sonographic evidence of gallstones is identified. Ursodeoxycholic acid (300 mg orally twice daily) administered for 6 months
following gastric bypass (the period of rapid weight loss) reduces
the risk of gallstone formation to 2%.40 Compliance with this
medication can be difficult secondary to adverse side effects (nausea, diarrhea, and pruritus).
Nutritional follow-up is mandatory after gastric bypass
because these patients are at risk for deficiency states and their
sequelae. Vitamin B12, iron, and calcium supplements are often
necessary along with routine administration of multivitamins.
A high-protein diet (50 g/d for women and 65 g/d for men) is
required to avoid protein malnutrition.
The incidence of perioperative venous thrombosis and
pulmonary embolism can be reduced with prophylactic subcutaneous heparin, sequential compression boots, and early
ambulation. Pulmonary embolism nonetheless occurs in 0.9%
of patients despite these measures; independent risk factors
include extreme obesity (BMI of 50 kg/m2 or greater), obesity
hypoventilation syndrome, and venous stasis. It has been recommended that prophylactic vena caval filters be placed in
these high-risk patients at the time of obesity surgery.
The operative mortality rate after gastric surgery is now
approximately 0.5% in most series. Independent risk factors
associated with increased risk of death include gastrointestinal
leak, pulmonary embolus, hypertension, and preoperative
weight.41
FAILED GASTRIC
SURGERY FOR OBESITY
Revision of a failed gastroplasty is often unsuccessful because
of recurrence of stomal dilation and problems with gastric
emptying; conversion to gastric bypass provides better results.
Laparoscopic gastric banding with ineffective weight loss can
likewise be converted to gastric bypass, but the complication
rate with this and any revision is higher than for a primary gastric bypass. Revision of a dilated gastrojejunal stoma has not
been effective, but application of an adjustable band to the
pouch above the stoma has been suggested as an option for
this problem. Most patients who fail a gastric bypass do so as
a result of dietary indiscretion. If a patient has significant
obesity-related comorbidities that have failed to resolve or
have returned with weight gain, conversion to long-limb gastric bypass can be performed. This modification can be associated with steatorrhea, fat-soluble vitamin deficiency, and
osteoporosis.
TA B L E 4 5 . 5
R E S U LT S
RATE (%)
73
100
75
56
91
90
94
Pseudotumor cerebri
100
Joint pain
71
permit successful total artificial joint replacement. Patient selfimage is often markedly improved after gastric surgery for
obesity.
Treatment of morbidly obese patients requires a multidisciplinary approach including psychologists, nutritionists, and
experienced physicians and ward personnel. Patients must be
willing to make a lifelong commitment to behavioral modification, regular exercise, and long-term medical follow-up.
References
1. National Center for Health Statistics NHANES IV report. Available at:
http://www.cdc.gov/nchs/product/pubs/pubd/hestats/obes/obese99.htm20
02. Accessed November 29, 2004.
2. Fontaine KR, Redden DT, Wang C, et al. Years of life lost due to obesity.
JAMA 2003;289:187193.
3. Deitel M. Overweight and obesity worldwide now estimated to involve 1.7
billion people. Obes Surg 2003;13:329330.
4. Ogden CL, Flegal KM, Carroll MD, et al. Prevalence and trends in overweight among US children and adolescents, 19992000. JAMA 2002;288:
17281732.
5. Stunkard AJ, Sorensen TA, Hanis C, et al. An adoptive study of human
obesity. N Engl J Med 1986;314:193198.
6. Vogler GP, Sorensen TI, Stunkard AJ, et al. Influences of genes and shared
family environment on adult body mass index assessed in an adoption
study by a comprehensive path model. Int J Obes Relat Metab Disord
1995;19:4045.
7. Stunkard AJ, Harris JR, Pedersen NL, et al. The body-mass index of twins
who have been reared apart. N Engl J Med 1990;322:14831487.
8. Austin MA, Friedlander Y, Newman B, et al. Genetic influences on changes
in body mass index: a longitudinal analysis of women twins. Obes Res
1997;5:326331.
9. Neary NM, Small CJ, Bloom SR. Gut and mind. Gut 2003;52:918921.
10. Jequier E. Leptin signaling, adiposity, and energy balance. Ann N Y Acad
Sci 2002;967:379388.
11. van Gemert WG, Westerterp KR, van Acker BA, et al. Energy, substrate
and protein metabolism in morbid obesity before, during and after massive
weight loss. Int J Obes Relat Metab Disord 2000;24:711718.
12. Sugerman H, Windsor A, Bessos M, et al. Intra-abdominal pressure, sagittal abdominal diameter, and obesity co-morbidity. J Intern Med 1997;241:
7179.
13. Sugerman H, Windsor A, Bessos M, et al. Effects of surgically induced
weight loss on urinary bladder pressure, sagittal abdominal diameter,
and obesity co-morbidity. Int J Obes Relat Metab Disord 1998;22:
230235.
14. Bjorntorp P, Rosmond R. The metabolic syndromea neuroendocrine disorder? Br J Nutr 2000;83:S49S57.
15. Sugerman HJ, Felton WL III, Salvant JB, et al. Effects of surgically induced
weight loss on idiopathic intracranial hypertension in morbid obesity.
Neurology 1995;45:16551659.
16. Wong CY, OMoore-Sullivan T, Leano R, et al. Alterations of left ventricular myocardial characteristics associated with obesity. Circulation 2004;
110:30813087.
17. Alpert MA. Obesity cardiomyopathy: pathophysiology and evolution of
the clinical syndrome. Am J Med Sci 2001;321:225236.
18. Wang TJ, Parise H, Levy D, et al. Obesity and the risk of new-onset atrial
fibrillation. JAMA 2004;292:24712477.
19. Frey WC, Pilcher J. Obstructive sleep-related breathing disorders in
patients evaluated for bariatric surgery. Obes Surg 2003;13:676683.
20. Rubino F, Gagner M, Gentileschi P, et al. The early effect of the Roux-enY gastric bypass on hormones involved in body weight regulation and glucose metabolism. Ann Surg 2004;240:236242.
721
21. Sugerman HJ, Sugerman EL, Wolfe L, et al. Risks and benefits of gastric
bypass in morbidly obese patients with severe venous stasis disease. Ann
Surg 2001;234:4146.
22. Bump RC, Sugerman HJ, Fantl JA, et al. Obesity and lower urinary tract
function in women: effect of surgically induced weight loss. Am J Obstet
Gynecol 1992;167:392397.
23. NIH Technology Assessment Conference Panel. NIH conference: methods
for voluntary weight loss and control. Ann Intern Med 1992;116:
942949.
24. Hocking MP, Duerson MC, OLeary JP, et al. Jejunoileal bypass for morbid obesity. Late follow-up in 100 cases. N Engl J Med 1983;308:995999.
25. Griffen WO Jr, Young VL, Stevenson CC. A prospective comparison of
gastric and jejunoileal bypass procedures for morbid obesity. Ann Surg
1977;186:500509.
26. Sugerman HJ, Wolper JL. Failed gastroplasty for morbid obesity. Revised
gastroplasty versus Roux-Y gastric bypass. Am J Surg 1984;148:331336.
27. Brolin RE, Kenler HA, Gorman JH, et al. Long-limb gastric bypass in the
superobese. A prospective randomized study. Ann Surg 1992;215:
387395.
28. Sugerman HJ, Starkey J, Birkenhauer R. A randomized prospective trial of
gastric bypass versus vertical banded gastroplasty for morbid obesity and
their effects on sweets versus non-sweets eaters. Ann Surg 1987;205:
613624.
29. Fisher BL, Schauer P. Medical and surgical options in the treatment of
severe obesity. Am J Surg 2002;184:9S16S.
30. Alpert MA, Terry BE, Mulekar M, et al. Cardiac morphology and left ventricular function in normotensive morbidly obese patients with and without congestive heart failure, and effect of weight loss. Am J Cardiol 1997;
80:736740.
31. Sugerman HJ, Baron PL, Fairman RP, et al. Hemodynamic dysfunction in
obesity hypoventilation syndrome and the effects of treatment with surgically induced weight loss. Ann Surg 1988;207:604613.
32. Huang B, Rodreiguez BL, Burchfiel CM, et al. Associations of adiposity
with prevalent coronary heart disease among elderly men: the Honolulu
Heart Program. Int J Obes Relat Metab Disord 1997;21:340348.
33. Sugerman HJ, DeMaria EJ, Felton WL III, et al. Increased intra-abdominal
pressure and cardiac filling pressures in obesity associated pseudotumor
cerebri. Neurology 1997;49:507511.
34. Scopinaro N, Gianetta E, Civalleri D, et al. Two years of clinical experience with biliopancreatic bypass for obesity. Am J Clin Nutr 1980;33:
506514.
35. Hess DS, Hess DW. Biliopancreatic diversion with a duodenal switch.
Obes Surg 1998;8:267282.
36. Ren CJ, Weiner M, Allen JW. Favorable early results of gastric banding for
morbid obesity: the American experience. Surg Endosc 2004;18:543546.
37. DeMaria EJ, Sugerman HJ, Meador JG, et al. High failure rate after
laparoscopic adjustable silicone gastric banding for treatment of morbid
obesity. Ann Surg 2001;233:809818.
38. Nguyen NT, Goldman C, Rosenquist CJ, et al. Laparoscopic versus open
gastric bypass: a randomized study of outcomes, quality of life, and costs.
Ann Surg 2001;234:279289.
39. Fernandez AZ Jr, DeMaria EJ, Tichansky DS, et al. Experience with over
3,000 open and laparoscopic bariatric procedures: multivariate analysis of
factors related to leak and resultant mortality. Surg Endosc 2004;18:
193197.
40. Sugerman HJ, Brewer WH, Shiffman ML, et al. A multicenter, placebocontrolled, randomized, double-blind, prospective trial of prophylactic
ursodiol for the prevention of gallstone formation following gastricbypass-induced rapid weight loss. Am J Surg 1995;169:9196.
41. Fernandez AZ Jr, Demaria EJ, Tichansky DS, et al. Multivariate analysis of
risk factors for death following gastric bypass for treatment of morbid
obesity. Ann Surg 2004;239:698702.
42. Buchwald H, Avidor Y, Braunwald E, et al. Bariatric surgery: a systematic
review and meta-analysis. JAMA 2004;292:17241737.
43. Jones DB, Provost DA, DeMaria EJ, et al. Optimal management of the
morbidly obese patient SAGES appropriateness conference statement. Surg
Endosc 2004;18:10291037.
GASTROINTESTINAL
K E Y
The presence of a gastric adenomatous polyp is a marker
of increased risk for the development of cancer in the
remaining gastric mucosa, and therefore these patients
should be enrolled in an appropriate endoscopic surveillance program.
2 Helicobacter pylori infection is the predominant risk factor
for gastric carcinogenesis; however, additional cofactors
also play an important role and likely drive the progression
from a premalignant condition to adenocarcinoma in most
individuals.
3 The symptoms produced by gastric cancer are not specific
and can mimic those associated with several nonneoplas-
P O I N T S
Gastric cancer is a relatively common, frequently lethal affliction and remains a serious and unsolved problem in general
surgery. The disease often is not recognized until it is at an
advanced stage. Gastric cancer usually cannot be controlled by
surgery alone, and surgical cure rates have remained disappointingly low. Increasingly, a multidisciplinary approach is
being applied to these difficult neoplasms, with some modest
improvements in outcome finally being observed. Technical
innovations and basic scientific investigations continue to be
applied to this disease, and cautious optimism for the future is
appropriate.
ADENOCARCINOMA
Epidemiology
Starting in 1930, the incidence of gastric cancer declined dramatically in the United States (Fig. 46.1). By 1980, the incidence of gastric cancer (10 cases per 100,000 population) was
approximately one fourth the incidence recorded in 1930. The
incidence of the disease remained relatively constant in the
decades from 1980 to 2000.1 By 1997, reported new cases of
gastric cancer had declined to 22,000. While this is a small
number relative to the 150,000 estimated deaths from cancer
of the lung,2 gastric cancer remains among the top 10 causes of
cancer-related deaths for both men and women in the United
States. In 2008, it is estimated that 21,500 new cases of gastric
cancer will be diagnosed in the United Statesthus the incidence remains fairly stable over the last decade.3 An increase
in the proportion of proximal gastric cancers has been
observed, with young white men being much more likely to
present with proximal gastric cancers whereas distal cancers
are more likely to occur in Asian, African American, and Hispanic patients.4 While the reasons for the decline in the incidence of gastric cancer in the 1930s are not entirely known
(though some attribute the decreased incidence to the introduction of refrigeration and widespread access to fresh fruits
and vegetables), we now have a better understanding of the
factors contributing to its persistence.
722
5
6
7
723
GASTROINTESTINAL
724
Clinical Features
3
TA B L E 4 6 . 1
DIAGNOSIS
PHYSICAL FINDINGS
Weight loss
Guaiac-positive stool
Pain
Cachexia
Abdominal mass
Anorexia
Abdominal tenderness
Dysphagia
Hepatomegaly
Melena
20% of patients with proximal gastric lesions. Overt gastrointestinal hemorrhage is present in only 5%. Perforation is rare
(1%).
In most patients with early gastric cancers, physical examination is negative. Stool is guaiac positive in one third.
Abnormal physical findings usually reflect advanced disease
(Table 46.1). Cachexia, abdominal mass, hepatomegaly, and
supraclavicular adenopathy usually indicate metastatic disease.19 There are no simple laboratory tests specific for gastric
neoplasms.
725
GASTROINTESTINAL
726
Metabolic Imaging
Metabolic imaging with positive emission tomography (PET)
using 18 F-fluorodeoxyglucose has been found to be less accurate than cross-sectional imaging and EUS for staging locoregional involvement, but more sensitive for detecting distant
metastases in patients with gastric cancer.3 A metanalysis comparing PET, ultrasound, CT, and magnetic resonance imaging
(MRI) found that PET scan was the most sensitive imaging
modality for detecting hepatic metastases.22 A separate study
found that tumors which responded metabolically on PET to
neoadjuvant chemotherapy correlated highly with histopathologic response and improved patient survival.23 Therefore, current recommendations regarding the use of PET for staging
gastric cancer are for selective use for patients with locally
advanced tumors where the metastatic potential is high, and in
cases where neoadjuvant therapy is being considered.3
Pathology
Gastric adenocarcinoma occurs in two distinct histologic subtypesintestinal and diffuse. These subtypes are characterized
by differing pathologic and clinical features and by differing
patterns of metastatic spread.
In the intestinal form of gastric cancer, the malignant cells
tend to form glands. The intestinal form of malignancy is more
TA B L E 4 6 . 2
C L A S S I F I C AT I O N A N D S TA G I N G
T0
Tis
T1
T2a
T2b
T3
T4
N0
N1
N2
N3
DISTANT METASTASIS
MX
M0
No distant metastasis
M1
Distant metastasis
Stage Grouping
Stage 0
Tis N0 M0
Stage IA
T1 N0 M0
Stage IB
T1 N1 M0
T2 N0 M0
Stage II
Curative Treatment
Surgical resection is the only hope for cure in gastric cancer,
but an advanced stage of disease at the time of diagnosis precludes curative resection for most patients. The surgical
objectives in gastric cancer must, therefore, be two: (a) to
maximize chances for cure in patients with localized tumor
T1 N2 M0
T2 N1 M0
T3 N0 M0
Stage IIIA
Stage IIIB
T2 N2 M0
T3 N1 M0
T4 N0 M0
T3 N2 M0
Stage IV
T4 N1 M0
T1 N3 M0
T2 N3 M0
T3 N3 M0
T4 N2 M0
T4 N3 M0
Any T Any N M1
Reproduced with permission from Greene FL, Page DL, Fleming ID,
et al. AJCC Cancer Staging Manual, 6th ed. New York: Springer; 2002.
727
GASTROINTESTINAL
5.0
25
4.5
23
21
4.0
19
Gastric resections
3.5
27
17
3.0
8
19 9
9
19 0
91
19
92
19
93
19
9
19 4
95
19
9
19 6
97
19
98
19
99
20
00
15
88
29
5.5
19
6.0
19
Gastric resections
728
Year
FIGURE 46.9. Incidence of gastric cancer and gastric cancer resection
in the United States, per 100,000 adults, over the time period 1988
through 2000.
9
8
7
8.3
7.1
6
In-hospital
mortality (%)
6.5
5
4
3
2
1
0
LVH
MVH
Hospital volume
HVH
FIGURE 46.10. In-hospital mortality as a function of varying hospital volume. Low-volume hospitals are defined as performing four or
fewer resections per year. Medium-volume hospitals are defined as
performing five to eight resections per year. High-volume hospitals are
defined as performing nine or more resections per year.
729
19
97
-1
99
99
-1
93
19
19
88
-1
99
TA B L E 4 6 . 3
C O M P L I C AT I O N S
LAPAROSCOPIC GROUP
[no. (%)]
Perioperative mortality
2 (6.7%)
1 (3.3%)
Overall morbidity
8 (27.6%)
7 (23.3%)
1 (12.5%)
Edematous pancreatitis
1 (14.3%)
Pleural effusion
3 (37.5%)
3 (42.8%)
Bronchopneumonia
2 (25%)
1 (14.3%)
Wound infection
2 (25%)
2 (28.6%)
Reproduced with permission from Huscher CG, Mingoli A, Sgarzini G, et al. Laparoscopic versus open
subtotal gastrectomy for distal gastric cancer: five-year results of a randomized prospective trial. Ann Surg
2005;241(2):232237.
GASTROINTESTINAL
40
730
FIGURE 46.12. Surgical options for resection of gastric neoplasms. A: Subtotal gastrectomy with gastrojejunal reconstruction. B: Total gastrectomy with
esophagojejunostomy. C: Esophagogastrectomy with
anastomosis in cervical or thoracic position.
A
80% resection
Esophagus
Pyloromyotomy
TA B L E 4 6 . 4
731
MANAGEMENT
DESCRIPTION
R1
R2
R3
TA B L E 4 6 . 5
MANAGEMENT
DESCRIPTION
D0
D1
D2
D3
GASTROINTESTINAL
LEVEL
732
Palliative Treatment
When preoperative evaluation demonstrates disseminated disease, palliation of symptoms becomes a primary consideration.
Palliation does not usually require surgery. Obstruction and
bleeding can be managed nonoperatively by the use of endoscopic laser fulguration in selected patients. Dysphagia and
bleeding caused by proximal lesions can also be controlled in
80% of patients using this modality. Successful application of
laser treatment requires adequate visualization, and is hampered by circumferential tumor growth that impedes passage
of the endoscope, by sharp angulation of the esophagogastric
junction, and by lesions more than 6 cm long.
In the setting of metastatic gastric cancer, palliative resection does not improve survival. Nonetheless, resection appears
to provide superior relief of symptoms, particularly dysphagia,
as compared with surgical bypass. Bypass of obstructing distal
gastric cancers without resection provides relief to less than
half of patients, and mean survival is less than 6 months. For
proximal obstructing lesions, total gastrectomy with Roux-en-Y
esophagojejunal reconstruction may be necessary. An operative mortality rate of less than 5% has been reported, and
introduction of stapling devices has reduced the rate of anastomotic leaks to less than 5% in several series. Mean survival
after palliative gastric resection approximates 9 months. For
symptomatic unresectable gastric adenocarcinoma, radiation
therapy with or without concomitant chemotherapy can also
provide significant palliation.
5
GASTRIC LYMPHOMA
Clinical Features
The stomach is the site of more than half of gastrointestinal
lymphomas and is the most common organ involved in extranodal lymphomas. Non-Hodgkins lymphomas account for
approximately 5% of malignant gastric tumors; lymphoma
represents an increasing proportion of gastric neoplasms diagnosed currently. Patients are considered to have primary gastric lymphoma if initial symptoms are gastric and the stomach
is exclusively or predominantly involved with the tumor.
Patients who do not fulfill these criteria are considered to have
secondary gastric involvement from systemic lymphoma.
Gastric lymphoma is distinctly uncommon in children and
young adults. The peak incidence is in the sixth and seventh
decades. Symptoms are indistinguishable from those of gastric
adenocarcinoma. Epigastric pain, weight loss, anorexia, nausea, and vomiting are common.72 Although gross bleeding is
uncommon, occult hemorrhage and anemia are observed in
more than half of patients. Patients rarely have spontaneous
perforation.
Diagnosis
Radiologic findings are similar to those for adenocarcinoma.
Endoscopic examination has become the diagnostic method of
733
Endoscopic confirmation
of healing
Localized disease
Metastatic disease
Chemotherapy
Palliative care
Adjuvant
chemoradiation
ALGORITHM 46.1
ALGORITHM 46.1. Treatment of gastric adenocarcinoma.
choice. The endoscopic appearance of lesions may be ulcerated, polypoid, or infiltrative. Gastric lymphoma is most commonly localized to the middle or distal stomach and unusually
involves the proximal stomach, in contrast to gastric adenocarcinoma. Endoscopic biopsy, combined with endoscopic
brush cytology and ultrasonography, provides positive diagnosis in 90% of cases. Submucosal growth without ulceration of
the overlying mucosa can occasionally render endoscopic
biopsy nondiagnostic. Endoscopic ultrasound-guided biopsy is
useful in this circumstance.
When gastric lymphoma is first diagnosed by endoscopic
means, evidence of systemic disease should be sought. CT of
the chest and abdomen (to detect lymphadenopathy), bone
marrow biopsy, and biopsy of enlarged peripheral lymph
nodes are all appropriate.
6
interleukin-2 production by antigenically stimulated nonneoplastic T cells. Progressive genetic rearrangements lead to Bcell proliferation that is independent of H. pyloristimulated
interleukin-2. With cumulative genetic defects, low-grade
MALT lymphoma progresses to high-grade MALT lymphoma.
Low-grade MALT lymphomas resemble Peyers patches.
Lymphoma cells invade between follicles and into gastric
epithelium; invasion of gastric glands forms characteristic lymphoepithelial lesions. Low-grade lesions are often multifocal.
Low-grade MALT lesions are less likely than high-grade
tumors to invade transmurally, involve perigastric lymph
nodes, or invade adjacent organs.75 Approximately 40% of
gastric lymphomas are low-grade MALT lymphomas.76 Highgrade MALT lymphomas cannot be distinguished histologically from non-MALT, high-grade B-cell lymphomas.
The concept that low-grade lymphoma depends on continued H. pylori antigenic stimulation supports eradication of H.
pylori with antibiotics as first-line antineoplastic therapy.
Complete regression of low-grade MALT lymphomas with
antibiotic treatment has been reported in 70% to 100% of
cases.77,78 The median time to complete response averaged 5
months.79 Most patients with partial responses were subsequently determined also to have foci of high-grade lymphoma.
Radiation and chemotherapy have been proposed as salvage
for antibiotic treatment failures.
GASTROINTESTINAL
734
Survival (%)
100
Chemotherapy
Surgery and
chemotherapy
50
Surgery and
radiotherapy
Surgery
0
0
5
Years
10
GASTRIC CARCINOIDS
Gastric carcinoid tumors were previously considered to be very
rare tumors; more recent studies have reported that as many as
1030% of all carcinoids occur in the stomach and they account
for at least 1% of all gastric neoplasms.83 Most patients with
small gastric carcinoids are asymptomatic and these tumors are
most commonly diagnosed incidentally. Occasionally, larger
tumors can present with abdominal pain, bleeding, or symptoms related to the secretion of bioactive substances which can
be produced by the tumor. When viewed endoscopically at an
early stage, carcinoids are reddish-pink to yellow submucosal
nodules in the proximal stomach. Endoscopic biopsy is usually
diagnostic if deep enough to sample submucosal tumor cells.
Gastric carcinoids arise from enterochromaffin cells which
mediate the secretion of histamine, which in turn stimulates
parietal cells to secrete acid. Hypergastrinemia is thought to
cause enterochromaffin cell hyperplasia, and may lead to the
development of gastric carcinoids over time.84 Four types of
gastric carcinoids have been described. Type I is the most common, and is associated with chronic atrophic gastritis and pernicious anemia. These tumors tend to be slow growing with
less malignant potential. Type II tumors are described as having
an intermediate malignant potential and occur in patients with
Zollinger Ellison syndrome and multiple endocrine neoplasia I.
Both Type I and Type II gastric carcinoid tumors are associated
with hypergastrinemia. These tumors tend to be small
(1 cm) and are often multi-focal. Type III gastric carcinoids
tend to be larger, solitary lesions, are associated with normal
gastrin levels, and behave much more aggressively.84 Type IV
are also larger, solitary, aggressive lesions which are associated
with parietal cell hyperplasia. Histologically, the tumors appear
as nests of monotonous hyperchromatic cells originating in the
submucosa or in the basal area of gastric glands.
A recent review of 1,543 patients with gastric carcinoid identified from the Surveillance Epidemiology and End Results (SEER)
database found that the mean tumor size was 1.73 cm, with 12%
and 7.9% of patients presenting with lymph node metastasis and
distant metastasis, respectively.84 Greater depth of tumor invasion
and the presence of lymph node or distant metastasis adversely
affected survival. Overall, 5-year survival for Types I and II gastric
carcinoids is 81% (95% for Type I lesions), while Type III and
IV tumors have only a 33% overall 5-year survival.83 Given the
potential for invasion by all gastric carcinoids, attempts at curative
resection with appropriate gastric resection and lymphadenectomy is indicated in all patients deemed fit for surgery.
GASTROINTESTINAL STROMAL
TUMORS OF THE STOMACH
Gastrointestinal stromal tumors (GIST) were historically misclassified as leiomyomas, leiomyosarcomas, and leiomyoblastomas
due to a mistaken belief that they arose from the smooth muscle in the bowel wall. It is now recognized that GISTs represent
a distinct mesenchymal tumor type, and arise from the interstitial cells of Cajal, an intestinal pacemaker cell located in and
around the myenteric plexus in the bowel wall. Additionally,
9599% of GISTs also express the CD117 antigen (KIT), and
express the c-kit receptor. c-kit is the receptor for the KIT ligand, also known as cytokine stem cell factor. c-kit is a tyrosine
kinase that acts as a growth factor or developmental antigen
receptor; occupation of the receptor acts to stimulate cellular
proliferation; positive staining for c-kit is diagnostic of a GIST.
While GISTs can arise anywhere within the gastrointestinal
tract, approximately 50% of these tumors are found in the
stomach. With a slight male predominance, GIST most commonly are identified in individuals in the fourth to eighth
decades of life, with a median presentation of approximately
60 years of age. The majority of these tumors are asymptomatic, and are most commonly identified incidentally during
endoscopy performed for other reasons. Endoscopically, they
typically appear as a submucosal mass. If these tumors become
large, they may present with symptoms of abdominal pain and
bleeding. GISTs frequently have prominent extraluminal
growth patterns, and central necrosis is common as these
tumors become large and outgrow their blood supply (Fig.
46.16). If the majority of the growth is extraluminal, endoscopic examination may be unrevealing or only demonstrate
umbilication of the mucosa possibly indicate an underlying
mass. Endoscopic ultrasound or CT imaging may be helpful for
diagnosis in these cases. With large tumors, symptoms related
to mass effects with compression of adjacent structures are
most common. Additionally, ulceration of the overlying gastric
mucosa may occur with tumor necrosis, and these patients may
present with significant and intermittent gastrointestinal
hemorrhage.
Determination of whether an isolated primary GIST is
benign or malignant is difficult, and only the evidence of
metastatic disease is diagnostic of a malignant tumor. Certain
morphologic features have been identified as being associated
with increased risk of local recurrence or distant metastasis.
Tumor size (2 cm) and mitotic index (510 mitoses/high
power field) are the most important prognostic variables, as
well as site of origin within the gastrointestinal tract; however,
all GISTs should be viewed as having malignant potential
with the possible exception of very small tumors measuring
1 cm.85 As compared to other sites of origin, gastric GISTs
tend to have a more favorable prognosis.
If GISTs do metastasize, it is by a hematogenous route
(most commonly to peritoneal surfaces and the liver), therefore, associated lymphadenectomy is typically not performed
FIGURE 46.16. CT scan of GIST of stomach arising from lesser curvature. The arrow indicates central tumor necrosis. The lesion caused
mucosal erosion with gastrointestinal hemorrhage.
735
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25. Katano M, et al. Prognostic value of platelet-derived growth factor-A
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26. Harrison LE, Karpeh MS, Brennan MF. Proximal gastric cancers resected
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27. Kodama I, et al. Gastrectomy with combined resection of other organs for
carcinoma of the stomach with invasion to adjacent organs: clinical efficacy in a retrospective study. J Am Coll Surg1997;184(1):1622.
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29. Blackshaw GR, et al. Laparoscopy significantly improves the perceived
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30. Lowy AM, et al. Laparoscopic staging for gastric cancer. Surgery 1996;
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31. Sarela AI, et al. Clinical outcomes with laparoscopic stage M1, unresected
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32. DUgo DM, et al. Immediately preoperative laparoscopic staging for gastric cancer. Surg Endosc 1996;10(10):996999.
33. Badgwell B, et al. Does neoadjuvant treatment for gastric cancer patients
with positive peritoneal cytology at staging laparoscopy improve survival?
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34. Wainess RM, et al. Epidemiology of surgically treated gastric cancer in the
United States, 19882000. J Gastrointest Surg 2003;7(7):879883.
35. Adachi Y, Shiraishi N, Kitano S. Modern treatment of early gastric cancer:
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36. Kunisaki C, et al. Prognostic factors in early gastric cancer. Hepatogastroenterology 2001;48(37):294298.
37. Nakamura K, et al. An early gastric carcinoma treatment strategy based on
analysis of lymph node metastasis. Cancer 1999;85(7):15001505.
38. Ono H, et al. Endoscopic mucosal resection for treatment of early gastric
cancer. Gut 2001;48(2):225229.
39. Korenaga D, et al. Pathological appearance of the stomach after endoscopic mucosal resection for early gastric cancer. Br J Surg 1997;84(11):
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40. Cuschieri A. Laparoscopic gastric resection. Surg Clin North Am 2000;
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41. Kitano S, et al. A multicenter study on oncologic outcome of laparoscopic
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42. Huscher CG, et al. Laparoscopic versus open subtotal gastrectomy for distal gastric cancer: five-year results of a randomized prospective trial. Ann
Surg 2005;241(2):232237.
43. Kim SH, et al. Effect of microscopic resection line disease on gastric cancer
survival. J Gastrointest Surg 1999;3(1):2433.
44. Bozzetti F, et al. Adequacy of margins of resection in gastrectomy for cancer. Ann Surg 1982;196(6):685690.
45. Schwarz RE, Karpeh MS, Brennan MF. Factors predicting hospitalization
after operative treatment for gastric carcinoma in patients older than 70
years. J Am Coll Surg 1997;184(1):915.
46. Daly JM, et al. Enteral nutrition during multimodality therapy in upper
gastrointestinal cancer patients. Ann Surg 1995;221(4):327338.
47. Bozzetti F, et al. Comparing reconstruction with Roux-en-Y to a pouch following total gastrectomy. J Am Coll Surg 1996;183(3):243248.
48. Chareton B, et al. Prospective randomized trial comparing Billroth I and
Billroth II procedures for carcinoma of the gastric antrum. J Am Coll Surg
1996;183(3):190194.
49. de Almeida AC, dos Santos NM, Aldeia FJ. Long-term clinical and endoscopic assessment after total gastrectomy for cancer. Surg Endosc 1993;
7(6):518523.
50. Nakane Y, et al. Jejunal pouch reconstruction after total gastrectomy for
cancer. A randomized controlled trial. Ann Surg 1995;222(1):2735.
51. Shiu MH, et al. Influence of the extent of resection on survival after curative treatment of gastric carcinoma. A retrospective multivariate analysis.
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52. Maruyama K, Okabayashi K, Kinoshita T. Progress in gastric cancer
surgery in Japan and its limits of radicality. World J Surg 1987;11(4):
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53. Noguchi Y, et al. Radical surgery for gastric cancer. A review of the Japanese experience. Cancer 1989;64(10):20532062.
54. Adachi Y, et al. Role of lymph node dissection and splenectomy in nodepositive gastric carcinoma. Surgery 1994;116(5):837841.
55. Baba H, et al. Effect of lymph node dissection on the prognosis in patients
with node-negative early gastric cancer. Surgery 1995;117(2):165169.
56. Bonenkamp JJ, et al. Extended lymph-node dissection for gastric cancer. N
Engl J Med 1999;340(12):908914.
57. Cuschieri A, et al. Postoperative morbidity and mortality after D1 and D2
resections for gastric cancer: preliminary results of the MRC randomised
controlled surgical trial. The Surgical Cooperative Group. Lancet 1996;
347(9007):995999.
58. Maeta M, et al. A prospective pilot study of extended (D3) and superextended para-aortic lymphadenectomy (D4) in patients with T3 or T4 gastric cancer managed by total gastrectomy. Surgery 1999;125(3):325331.
59. Robertson CS, et al. A prospective randomized trial comparing R1 subtotal gastrectomy with R3 total gastrectomy for antral cancer. Ann Surg
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60. Siewert JR, et al. Relevant prognostic factors in gastric cancer: ten-year
results of the German Gastric Cancer Study. Ann Surg 1998;228(4):
449461.
61. Lee JS, Douglass HO Jr. D2 dissection for gastric cancer. Surg Oncol
1997;6(4):215225.
62. Pacelli F, et al. Extensive versus limited lymph node dissection for gastric
cancer: a comparative study of 320 patients. Br J Surg 1993;80(9):
11531156.
63. Kodera Y, et al. The number of metastatic lymph nodes: a promising prognostic determinant for gastric carcinoma in the latest edition of the TNM
classification. J Am Coll Surg 1998;187(6):597603.
64. Maehara Y, et al. Clinical significance of occult micrometastasis lymph
nodes from patients with early gastric cancer who died of recurrence.
Surgery 1996;119(4):397402.
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ed. New York: Springer; 2002.
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68. Kunisaki C, et al. Impact of splenectomy in patients with gastric adenocarcinoma of the cardia. J Gastrointest Surg 2007;11(8):10391044.
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70. Macdonald JS, et al. Chemoradiotherapy after surgery compared with
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86. Antonescu CR. Targeted therapies in gastrointestinal stromal tumors.
Semin Diagn Pathol 2008;25(4):295303.
SECTION F
SMALL INTESTINE
K E Y
1
4
5
The small intestines intrinsic design serves to provide a maximum amount of surface area for absorption of nutrients,
water, and electrolytes. Specialized areas provide neurohormonal stimulation to the digestive tract. Its structure and vast
surface area also provide an important physical barrier to
potential pathogens, and certain areas are critical in immune
surveillance.
GROSS ANATOMY
AND EMBRYOLOGY
The small intestine spans from the pylorus to the ileocecal
valve and includes three distinct regions: the duodenum, the
jejunum, and the ileum. These areas combined measure, on
average, approximately 5 meters and comprise nearly 62% of
the entire length of the alimentary tract. The gastrointestinal
tract is formed from the endodermal layer of the developing
embryo. The small intestine is derived from the distal foregut
(proximal duodenum), the midgut, and the adjacent splanchnic mesenchyme. Epithelium and glands develop from the
embryonic endoderm, while connective tissue, muscle, and
serosa develop from the mesoderm. During the fifth and sixth
weeks of development, the duodenal lumen is temporarily
obliterated due to proliferation of its mucosal lining. During
the subsequent weeks, luminal vacuolization and degeneration
of some of the proliferating cells result in recanalization of the
1 duodenal lumen. From the 4th to the 10th week of development, a large portion of the midgut is herniated through the
umbilicus. This may be due to the rapid growth of the intestinal tract at this time in relation to the abdominal cavity. At
approximately 8 weeks of gestation, the midgut begins to
P O I N T S
The coordination of movements of the gastrointestinal
tract is necessary for the proper digestion of food. Welltimed contraction and relaxation patterns are initiated in
the gastrointestinal nervous system causing coordinated
electrical activity and muscular movements.
7 The lumen of the gastrointestinal tract is connected to the
outside environment and comes in direct contact with
many potentially pathogenic microorganisms. Consequently, the small intestine has a complex defense
mechanism to battle against these exposures in different
ways.
8 The small intestine reabsorbs nearly 80% of the fluid that
passes through it. This dynamic process is accomplished
by a rapid bidirectional movement of fluid in the intestinal
lumen. This ebb and flow of fluid in the intestinal lumen is
critical in maintaining normal homeostasis. Minor
changes in intestinal permeability or rate of flow of the
intestinal contents can result in net secretion and diarrheal
states.
6
Duodenum
The duodenum makes up the first portion of the small intestine
and plays an important role in connecting the foregut organs
to the midgut. It anatomically begins at the duodenal bulb,
which is immediately adjacent to the pylorus and terminates at
the ligament of Treitz, where it joins the jejunum. The duodenum is approximately 20 to 30 cm in length and is divided into
four distinct areas.
The first portion of the duodenum is approximately 5 cm in
length and is referred to as the bulb or cap. This area is directly
attached to the pylorus and extends laterally and cephalad. It
serves as an attachment for the hepatoduodenal ligament and
traverses over the common bile duct, portal vein, pancreatic
head, and gastroduodenal artery. The mucosal surface of the
duodenal bulb is smooth until its junction with the second
portion of the duodenum, where the concentric Kerckring
folds begin. This portion of the duodenum is prone to ulceration, with approximately 90% of duodenal ulcers occurring
here. Unfortunately, due to its anatomic positioning, these
ulcers may erode into the gastroduodenal artery, which lies
737
GASTROINTESTINAL
738
739
MICROSCOPIC ANATOMY
General Considerations
The wall of the small intestine is composed of four distinct
layers: mucosa, submucosa, muscle, and serosa. The role of
the mucosa is absorption and secretion. The luminal mucosal
surface forms circular folds known as plica circularis or
valvulae conniventes in all segments of the small intestine
distal to the first portion of the duodenum. The submucosa
contains an elaborate network of blood vessels, lymphatics,
3 and nerves. The muscular portion of the wall includes outer
longitudinal and inner circular muscle layers. Between the
muscle layers lies the myenteric (Auerbach) plexus. The muscular layers are responsible for coordinating peristaltic
movements. The outermost layer, the serosa, is composed of
a thin layer of mesothelial cells overlying loose connective
tissue. The serosa covers only the anterior surface of the
retroperitoneal segments of small bowel, but it completely
covers the portions of small bowel that are invested with
mesentery.
GASTROINTESTINAL
Mucosa
740
Submucosa
4
PHYSIOLOGY
5
The small intestine plays important physiologic roles in motility, blood flow, growth, digestion, absorption, immune function, and endocrine secretion. In fact, the small intestine is the
largest endocrine organ in the human body.7 The secretion of
these numerous hormones and neurotransmitters is specific to
distinct anatomic zones within the small intestine (Fig. 47.3).
There is no specific cell mass that produces these hormones,
741
Motility
6
Nodose
ganglia
Dorsal-root
ganglia
Sympathetic
ganglia
Parasympathetic
nervous system
Parasympathetic
nervous system
Parasympathetic
ganglia
Intermediate
cells
Effector systems
(muscle, secretory, epithelium, endocrine cells, vasculature)
GASTROINTESTINAL
duodenum and jejunum. Secretin is released into the circulation and intestinal lumen in response to low intraluminal pH,
fatty acids, and bile salts. Water and bicarbonate are secreted
by the pancreas in response to secretin. Bicarbonate is also
released from the biliary ductal epithelium and Brunners glands
in response to secretin. In turn, pancreatic enzymes are
released from the pancreas. The increased pH and the presence
of pancreatic enzymes aids in the digestion of lipids. The
increased pH also provides a negative feedback loop to inhibit
further production of secretin. Secretin produces a paradoxical
release of gastrin in patients with gastrinomas, but does not
produce this effect on normal individuals.
Somatostatin is a peptide hormone consisting of 14 or 28
amino acids and is produced by D cells in the pancreatic islets,
gastric antrum, and duodenum. Its primary role is inhibition
of other gastrointestinal hormones and inhibition of pancreatic, biliary, and gastric secretion. In addition, somatostatin
decreases splanchnic and portal blood flow. Somatostatin is
stimulated by the presence of fat, proteins, acid, glucose,
amino acids, and cholecystokinin. Octreotide, a long-acting
synthetic somatostatin analogue, is used in the treatment of
variceal bleeding, hormone-secreting neuroendocrine tumors,
carcinoid syndrome, and enterocutaneous and pancreatic fistulas.8
Gastrin-releasing peptide, the mammalian homologue of
bombesin, is a 27-amino-acid peptide that is produced by the
small intestine and is released in response to vagal stimulation.
It is a prostimulatory molecule that causes the release of most
gastrointestinal hormones, with the exception of secretin. It
also has a promotility effect and stimulates endothelial proliferation. GIP or glucose-dependent insulinotropic peptide is a
42-amino-acid peptide produced by the K cells of the duodenum and jejunum. It is released in response to glucose, fat,
protein, and adrenergic stimulation. It stimulates secretion of
insulin and inhibits gastric acid and pepsin production. Type 2
diabetics are resistant to the effects of GIP.
Motilin is a 22-amino-acid peptide produced by the
enteroendocrine cells in the duodenum and jejunum. Release
of motilin occurs during the interdigestive and fasting periods.
Release may also be related to alkalinization of the duodenum.
Motilins main function is to stimulate the migrating myoelectric complex. Motilin agonists such as erythromycin are used
clinically as stimulants of gastrointestinal motility.
VIP is a 28-amino-acid peptide that is produced by gastrointestinal tract neurons. It serves as a neurotransmitter
stimulating pancreatic exocrine and intestinal secretion. Conversely, it has an inhibitory effect on gastric acid secretion. VIP
is a potent vasodilator and relaxant of smooth muscle.
Neurotensin is a 13-amino-acid peptide that is produced by
the N cells primarily in the ileum, but also in the proximal
small intestine and colon in response to the presence of intraluminal fat. It stimulates pancreatic bicarbonate secretion and
intestinal motility. Neurotensin also serves as a trophic factor
on the small-intestinal mucosa and inhibits gastric secretion.
Pancreatic glucagon and enteroglucagon are 29- and 37amino-acid peptides produced by the -islet cells of the pancreas and the L cells of the small intestine, respectively. Pancreatic glucagon is released in response to low serum glucose and
subsequently induces glycogenolysis, lipolysis, gluconeogenesis, and ketogenesis. Enteroglucagon is released in response to
the presence of a mixed meal and inhibits gastric emptying and
small-bowel motility.
742
Immunology
7
Spike potentials present a second mode of electrical stimulation of the small intestine, and result in rapid depolarization
of the membrane potential. Repeated bursts of spike potentials
cause a short area of contraction. In contrast to the always
present slow waves, spike potentials occur at discrete time
intervals. The coordination of a slow wave and a spike potential leads to the initiation, duration, and frequency of rhythmic
migratory small-intestinal contractions (Fig. 47.5).
During the interdigestive period between feeding, the small
intestine follows a well-defined rhythmic pattern. This pattern
consists of muscular contractions that migrate from the stomach or duodenum, continue on to the terminal ileum, and are
regulated by the migrating motor complex (MMC). This pattern can be broken down into four distinct phases. Phase I is a
period of relative quiescence, phase II is a period of accelerated
irregular electrical spiking and muscular activity, phase III is a
series of high-amplitude rapid electrical spikes corresponding
to rhythmic gut contractions, and phase IV is a period of
subsiding activity. This process occurs over a period of 90 to
120 minutes and progresses from the proximal small bowel
and terminates in the ileum. Once the MMC reaches the terminal ileum, the process starts over again in the proximal small
bowel. The circular muscles provide segmental contraction
over a 1-cm length of small intestine. These contractions occur
approximately 11 to 13 times per minute in the duodenum and
decrease to 8 to 10 times in the ileum. This creates functional
compartments where prolonged exposure to the mucosa and
mixing of the intestinal chyme occur, aiding the process of
digestion and absorption. The circular muscles are also responsible for the peristaltic waves, which propagate regularly at a
rate of 1 to 2 cm per second. These regular waves may be interspersed with rushes of contractions followed by periods of no
motor activity. This rate becomes progressively slower in the
distal small intestine. These peristaltic movements serve as a
method of propelling chyme through the length of the small
intestine. The total transit time from the duodenum to the terminal ileum is approximately 220 minutes ( 53 minutes).10
Serum motilin levels have been found to mirror the activity of
the MMC. Exogenous motilin administration has been found
to increase MMC activity.
During and immediately following times of feeding, the
intestinal movements are not rhythmic, with complexes of
peristaltic and antiperistaltic contractions. This is thought to
be a disruption of the MMC from bolus feeding. This seemingly random pattern of movements allows for effective mixing of chyme. Hormonal changes are thought to play a role in
Principles of Gut Immunology. The lumen of the gastrointestinal tract is connected to the outside environment and
comes in direct contact with many potentially pathogenic
microorganisms. Lymphocytes, macrophages, polymorphic
granulocytes, and other cells that take part in the immune
response are distributed throughout the whole gut. The commensal microflora have many benefits to the host by supporting digestion and keeping the appropriate balance among different microbial species.11 The immune system is highly
effective at responding selectively to invading pathogens yet on
the other hand tolerating a much larger number of harmless
food antigens and commensal organisms. Many bacteria,
viruses, and parasites are digested and enter the small intestine
every day.12 Consequently, the small intestine needs a complex
defense mechanism to battle against these exposures in different ways.13
While the immune system in the small intestine is important
for host defense, other mechanisms within the small intestine
also participate in host defense. Proteolytic and lipolytic
enzymes are produced in high concentrations by extraintestinal
cells in the pancreas and degrade different pathogenic agents at
an early phase of digestion. In addition, mucin is produced by
the enterocytes, which protects them and inhibits bacterial
growth. Actively increased peristalsis functions to mechanically
get rid of pathogenic agents and potentially dangerous gut content. In addition, tight junctions between epithelial cells prevent
penetration of bacteria in between cells. Potential pathogens
vary greatly in size, from very small viruses that are nanometers
in size to parasites such as helminths that are macroscopically
visible and quite large. To put this into the broader picture of
evolution, a large range of defense mechanisms is essential for
survival of each individual.
The primary cellular barrier in the gut that prevents antigens from encountering the immune system is the single layer
of gut epithelium. The total surface area of the small intestine
is 400 m2, due not only to intestinal length but also to the formation of millions of villi in the small bowel, which contribute
significantly to the overall surface area.14 In the upper small
intestine, the bulk of antigen exposure comes from the diet,
whereas in the ileum and colon, the additional antigenic load
of an abundant and highly complex commensal microflora is
prevalent. The epithelial cells of the gut mucosa have developed features that make the intestinal epithelium an active
immunologic as well as anatomic barrier. For example, these
nonclassical immune cells express major histocompatibility
complex (MHC) class I and II molecules, consistent with their
ability to participate in adaptive immune recognition of pathogenic bacteria. Small-intestinal epithelial cells also express
Toll-like receptors on their apical surface that enables them to
detect bacterial products and to initiate an innate immune
response. Antigen-presenting dendritic cells (DCs) also send
processes between gut epithelial cells without disturbing tight
junction integrity and sample commensal and pathogenic gut
bacteria.15,16 The gut epithelial barrier therefore represents a
highly flexible structure that limits antigens from entering the
systemic circulation.
The gut-associated immune system represents one of the
largest immunologic compartments in the body. Lymphoid
743
GASTROINTESTINAL
744
GASTROINTESTINAL
745
by the presence of hydrochloric acid in the gastric lumen. Calcium, phosphate, magnesium, sulfur, sodium, chloride, and
potassium are considered macrominerals, with daily requirements exceeding 100 mg/d. Microminerals (trace minerals)
include iron, zinc, copper, manganese, iodine, selenium, fluoride, molybdenum, chromium, and cobalt with daily requirements of less than 15 mg/d.
Approximately 1 g of calcium is consumed per day, mainly
from dairy products. Once in its ionized form, calcium is primarily absorbed in the duodenum, although this process occurs
throughout the length of the small intestine. When calcium is
present intraluminally at low levels, it is transported across the
apical membrane of the enterocyte by carrier-mediated facilitated diffusion. Once calcium is in the cytoplasm, it is bound
to calcium-binding proteins and delivered to the basal membrane. Calcium is then transferred into the interstitium by a
Ca2-ATPase pump. This process is indirectly regulated by
parathyroid hormone (PTH). PTH in low-calcium states promotes conversion of vitamin D to its active form, 1,25(OH)2
vitamin D. This activated form of vitamin D causes an increase
in the expression of both calcium-binding proteins and Ca2ATPase, causing an increase in the absorption of calcium by
the small intestine.23,24 When intraluminal calcium is in excess
of its capacity to be actively transferred by the apical membranes carrier-mediated mechanism, passive paracellular calcium absorption occurs in the distal small intestine.
Absorbable dietary sources of iron are typically either contained within a protein, such as heme, or as a ferrous Fe2 ion.
Iron-containing proteins are usually from ingested meats,
whereas ferrous forms are typically present in vegetables,
grains, and fruits. Vitamin C (ascorbic acid) increases iron
absorption by reducing the ferric (Fe3) ion into the more soluble ferrous state. Absorption of iron is facilitated by carriermediated translocation across the apical membrane of the enterocyte in the duodenum and proximal jejunum. Once in the
cytoplasm, the ferrous ion is released by enzymatic cleavage.
Ferrous ions may be stored intracellularly by ferritin or transported into the circulation by transferrin. The process of iron
absorption is regulated in the enterocyte by hypoxia-inducible
factor signaling and iron-regulatory proteins. Systemically, the
central iron-regulatory hormone is hepatic hepcidin. Hepatic
hepcidin regulates iron absorption and mobilization from systemic stores by inhibiting ferroportin, a cellular iron exporter.25
Carbohydrate Digestion and Absorption. Carbohydrates are a staple in many diets and provide a major source of
746
transported across the apical cell membrane. A sodiumdependent hexose transporter (SGLUT-1) is required for the
transport of glucose and galactose as they utilize the same carrier mechanism. The cotransportation of these monosaccharides with sodium is dependent on the Na-K-ATPase pump
on the basolateral membrane to maintain a sodium gradient
allowing for this influx. Fructose is transported in a carriermediated diffusion-dependent manner by GLUT5 and does
not require sodium as a cotransporter (Fig. 47.9). The movement of monosaccharides into the cellular cytoplasm provides
an additional gradient by which water is absorbed by the enterocytes from the intestinal lumen. The monosaccharides are
then transported across the basolateral membrane by GLUT2.
This hexose transporter allows for the diffusion of all three
monosaccharides into the extracellular space and ultimately
into the portal blood flow. A small portion of these monosaccharides may be used by the enterocyte, but the majority are
transported through the cell.
Nondigestible carbohydrates (dietary fiber) such as cellulose are thought to be an important part of a normal diet even
though they do not provide dietary calories. Dietary fiber is
present in grains, vegetables, and pulpy fruits. Dietary fiber
helps decrease bowel transit time by absorbing water in the
intestinal lumen. In addition, fiber can absorb organic materials such as lipids and bile salts and inorganic minerals such as
zinc, calcium, and magnesium. These actions of fiber are
thought to play a role preventing carcinogenesis and in helping
to maintain normal serum lipid profiles. Unfortunately, fiber is
underrepresented in most Western diets.
Fat Digestion and Absorption. Forty percent of the average daily caloric intake (60 to 90 g) in a Western diet is in the
form of fat. Ninety percent of these ingested fats are triglycerides, while the remainder is composed of cholesterol, phospholipids, and fat-soluble vitamins. The initiation of lipid
digestion occurs when CCK is stimulated by the presence of
fatty acids on the duodenal mucosa. CCK in turn stimulates
pancreatic secretion of lipase and its cofactor colipase. Lipase
hydrolyzes triglycerides at the 1 and 3 position of the glycerol
backbone, yielding two fatty acids and a monoglyceride (a
fatty acid esterified to glycerol). Cholesterol and fat-soluble
vitamins are hydrolyzed by pancreatic cholesterol esterase and
phospholipids by phospholipase A2. The products of lipolysis
interact with bile salts to form water-soluble micelles. Mixed
micelles are 50 to 400 in diameter and are a combination of
fatty acids, bile salts, and monoglycerides. The structure of a
micelle is composed of an inward-facing hydrophobic region
and a hydrophilic region facing outward toward the aqueous
environment of the intestinal lumen. Due to the hydrophobic
core, cholesterol, phospholipids, and fat-soluble vitamins can
reside within the micelle structure. Micelles are able to interact
with the mucosal cells and empty their contents into the cytoplasm. This occurs by the process of dissolution of the micelles
747
into the lipid bilayer of the mucosal cell. Once this is completed, the components of the micelle are ready to re-form
with new lipid components to repeat this process. There is no
energy consumed directly in the transfer of lipids into the cell
cytoplasm.
Once in the cytoplasm, long-chain fatty acids and monoglycerides are carried by cytosolic fatty acidbinding proteins to the smooth endoplasmic reticulum (SER). In the SER,
resynthesis of triglycerides occurs. These triglycerides are further processed in the Golgi apparatus where a phospholipid
and an apoprotein coat are added to form a chylomicron. Chylomicrons are 90% triglyceride; the remaining 10% is composed of phospholipid, cholesterol, and protein. These large
particles are 750 to 6,000 in diameter. Before exiting the
Golgi apparatus, the chylomicrons are packaged into secretory
vesicles. They exit the cell membrane by exocytosis and enter
the central lacteal of the villus and the intestinal lymphatic system. In addition, enterocytes also produce smaller lipoprotein
particles, very-low-density lipoproteins, which contain a higher
cholesterol/triglyceride ratio and provide the major route of
entry for dietary cholesterol into the lymphatic system.
Short-chain fatty acids contain less than eight carbon atoms
and are water soluble. This allows these molecules to enter and
exit the enterocyte by simple diffusion independent of bile
micelles or chylomicrons. Medium-chain triglycerides consist
of 6 to 12 carbon atoms and can be absorbed by simple diffusion or through the previously mentioned process of transport
of long-chain fatty acids via the formation of bile micelles and
chylomicrons. Both short- and medium-chain fatty acids may
enter the portal circulation without entering into the lymphatics. The majority of dietary fat is processed and absorbed in
the duodenum and upper jejunum.
GASTROINTESTINAL
748
called transcobalamins. Cobalamin is essential for DNA synthesis, and a deficiency usually presents with megaloblastic
anemia. Inability to absorb sufficient amounts of cobalamin
may be due to lack of intrinsic factor after proximal or total
gastrectomy, autoimmunity to gastric parietal cells or intrinsic
factor, or atrophic gastritis. In addition, cobalaminintrinsic
factor complexes may fail to be absorbed due to distal ileal disease or resection, and cobalamin deficiency may occur from
bacterial overgrowth due to bacterial overconsumption of
cobalamin.
References
1. Kluth D, Jaeschke-Melli S, Fiegel H. The embryology of gut rotation.
Semin Pediatr Surg 2003;12:275279.
2. Cohen S, Harris LD, Levitan R. Manometric characteristics of the human
ileocecal junctional zone. Gastroenterology 1968;54:7275.
3. Holmes R, Lobley RW. Intestinal brush border revisited. Gut 1989;30:
16671678.
4. Rubin DC. Spatial analysis of transcriptional activation in fetal rat jejunal
and ileal gut epithelium. Am J Physiol 1992;263:G853G863.
5. Trier JS. Studies on small intestinal crypt epithelium. I. The fine structure
of the crypt epithelium of the proximal small intestine of fasting humans.
J Cell Biol 1963;18:599620.
6. Garabedian EM, Roberts LJ, McNevin MS, et al. Examining the role of
Paneth cells in the small intestine by lineage ablation in transgenic mice.
J Biol Chem 1997;272:2372923740.
7. Englander E, Greeley J. Postpyloric Gastrointestinal Peptides. San Diego:
Elsevier; 2005.
8. Weckbecker G, Lewis I, Albert R, et al. Opportunities in somatostatin
research: biological, chemical and therapeutic aspects. Nat Rev Drug
Discov 2003;2:9991017.
9. Casteels R. Membrane Potential in Smooth Muscle Cells. Austin, TX:
University of Texas Press; 1981.
10. Ofori-Kwakye K, Fell JT, Sharma HL, et al. Gamma scintigraphic evaluation of film-coated tablets intended for colonic or biphasic release. Int
J Pharm 2004;270:307313.
11. Xavier RJ, Podolsky DK. Microbiology. How to get alongfriendly
microbes in a hostile world. Science 2000;289:14831484.
12. Kraehenbuhl JP, Corbett M. Immunology. Keeping the gut microflora at
bay. Science 2004;303:16241625.
13. Macdonald TT, Monteleone G. Immunity, inflammation, and allergy in the
gut. Science 2005;307:19201925.
14. Hayday A, Viney JL. The ins and outs of body surface immunology.
Science 2000;290:97100.
15. Niess JH, Reinecker HC. Lamina propria dendritic cells in the physiology
and pathology of the gastrointestinal tract. Curr Opin Gastroenterol
2005;21:687691.
16. Pasare C, Medzhitov R. Toll-like receptors: balancing host resistance with
immune tolerance. Curr Opin Immunol 2003;15:677682.
17. Niess JH, Brand S, Gu X, et al. CX3CR1-mediated dendritic cell access to
the intestinal lumen and bacterial clearance. Science 2005;307:254258.
18. Macpherson AJ, Uhr T. Induction of protective IgA by intestinal dendritic
cells carrying commensal bacteria. Science 2004;303:16621665.
19. Charney AN, Donowitz M. Functional significance of intestinal Na-KATPase: in vivo ouabain inhibition. Am J Physiol 1978;234:E629636.
20. Barrett KE, Keely SJ. Chloride secretion by the intestinal epithelium: molecular basis and regulatory aspects. Annu Rev Physiol 2000;62:535572.
21. Minhas BS, Sullivan SK, Field M. Bicarbonate secretion in rabbit ileum:
electrogenicity, ion dependence, and effects of cyclic nucleotides. Gastroenterology 1993;105:16171629.
22. Agarwal R, Afzalpurkar R, Fordtran JS. 1994. Pathophysiology of potassium absorption and secretion by the human intestine. Gastroenterology
1993;107:548571.
23. Cai Q, Chandler JS, Wasserman RH, et al. Vitamin D and adaptation to
dietary calcium and phosphate deficiencies increase intestinal plasma
membrane calcium pump gene expression. Proc Natl Acad Sci U S A 1993;
90:13451349.
24. Walters JR. Calbindin-D9k stimulates the calcium pump in rat enterocyte
basolateral membranes. Am J Physiol 1989;256:G124G128.
25. Zhang AS, Enns CA. Molecular mechanisms of normal iron homeostasis.
Hematology Am Soc Hematol Educ Program 2009;207214.
26. Said HM. Recent advances in carrier-mediated intestinal absorption of
water-soluble vitamins. Annu Rev Physiol 2004;66:419446.
K E Y
P O I N T S
Peritoneal adhesions account for more than half of smallbowel obstruction cases.
4 Ileus denotes underlying alterations in motility of the gastrointestinal tract, leading to functional obstruction.
5 Postoperative ileus can be differentiated from small-bowel
obstruction with the use of contrast computed tomography
and enteroclysis imaging techniques.
6 Postoperative ileus (POI) is often self-limiting; less frequent
interventions are required for prolonged POI if proper precautions have been taken during surgery.
INTRODUCTION AND
HISTORICAL PERSPECTIVE
749
FIGURE 48.1. Schematic illustration of different forms of simple mechanical obstruction. Simple obstruction is most often due to adhesion
(A), groin hernia (B), or neoplasm (C). The hernia can act as a tourniquet, causing a closed-loop obstruction and strangulation.
GASTROINTESTINAL
750
TA B L E 4 8 . 1
CLASSIFICATION OF ADULT MECHANICAL INTESTINAL OBSTRUCTIONS
INTRALUMINAL
INTRAMURAL
EXTRINSIC
Foreign bodies
Adhesions
Web
Postoperative
Intestinal duplication
Meckel diverticulum
Inspissated feces
Hernias
Inflammatory process
Abdominal wall
Crohn disease
Internal
Diverticulitis
Gallstone ileus
Volvulus
Enterolith
Intussusception
Secondary (metastasis or
carcinomatosis)
Annular pancreas
Pancreatic pseudocyst
Carcinomatosis
Endometriosis
Pregnancy
obstruction, blood flow to the obstructed segment is compromised and tissue necrosis and gangrene are imminent. Strangulation usually implies that the obstruction is complete, but
some forms of partial obstruction can also be complicated by
strangulation.
The various forms of mechanical intestinal obstruction can
be classified according to different but overlapping schemes.
Most commonly, obstruction is classified according to etiology. As detailed in Table 48.1, distinctions are drawn between
intraluminal obturators such as foreign bodies or gallstones,
intramural lesions such as tumors or intussusceptions, and
extrinsic or extramural lesions such as adhesions. In order to
highlight the pathophysiology, presentation, and natural history, however, it is useful to classify obstruction according to
the location of the obstructing lesion. Proximal or high
obstructions involve the pylorus, duodenum, and proximal
jejunum. Intermediate levels of obstruction involve the intestine from the midjejunum to the midileum. Distal levels of
obstruction arise in the distal ileum, ileocecal valve, and proximal colon, whereas the most distant or low obstructions
would arise in regions beyond the transverse colon. As shown
in Table 48.2, clinical symptoms and signs of obstruction
(pain, vomiting, abdominal distention, gas pattern on abdominal radiographs) vary with the level of obstruction.
TA B L E 4 8 . 2
SYMPTOMS AND SIGNS OF BOWEL OBSTRUCTION
SYMPTOM/
SIGN
PROXIMAL SMALL
BOWEL (OPEN LOOP)
DISTAL SMALL
BOWEL (OPEN LOOP)
SMALL BOWEL
(CLOSED LOOP)
Pain
Intermittent, intense,
colicky, often relieved
by vomiting
Intermittent to constant
Progressive, intermittent
to constant, rapidly
worsens
Continuous
Vomiting
May be prominent
(reflex)
Intermittent, not
prominent; when
present, feculent
Tenderness
Epigastric or periumbilical;
quite mild, unless
strangulation is present
Diffuse, progressive
Diffuse, progressive
Diffuse
Distention
Absent
Moderate to marked
Often absent
Marked
Obstipation
Present
Present
COLON/RECTUM
Adapted from Schuffler MD, Sinanan MN. Intestinal obstruction and pseudo-obstruction. In: Sleisenger MH, Fordtran JS, eds. Gastrointestinal
Disease, 5th ed. Philadelphia, PA: WB Saunders; 1993:898916.
751
Intestinal Flora. An important contribution to normal digestive function comes from its bacterial population. In patients
with normal gastric acid secretion, the chyme entering the
duodenum is sterile. The small numbers of bacteria that are
found in the stomach and proximal intestine are aerobic,
gram-positive species found in the oropharynx. Distally, in the
ileum and colon, gram-negative aerobes are present and
anaerobic organisms predominate. Total bacterial counts in
normal feces reach 1011 organisms per gram of fecal matter.
Control of the bacterial populations depends on intact motor
activity of the intestines and the interactions of all species present. This ecology can be disturbed by antibiotic therapy or by
surgical reconstructions that result in stasis within intestinal
segments. Intestinal bacteria serve several functions, including
metabolism of fecal sterols, releasing the small-chain fatty
acids that are an important food source for colonocytes;
metabolism of fecal bile acids, fat-soluble vitamins (e.g., vitamin K), and vitamin B12; and breakdown of complex carbohydrates and organic matter, leading to formation of CO2, H2,
and CH4 gases.9 Considerable evidence suggests that the normal flora may contribute to baseline levels of intestinal secretion and, perhaps, normal intestinal motility. Under baseline
conditions, the small intestines in germ-free animals are frequently dilated, fluid filled, and without peristalsis.11,12
In recent years, the role of bacterial toxins in mediating the
mucosal response to obstruction has received increasing attention. In germ-free dogs, luminal accumulation of fluid is not
observed and absorption continues.12 In addition, it is well recognized that bacterial endotoxins can stimulate secretion, possibly via release or potentiation of activity of neuroendocrine
substances and prostaglandins.11 Finally, since a substantial
part of systemic microvascular and hemodynamic responses to
endotoxemia appears to be attributable to heightened synthesis of nitric oxide,13,14 it seems likely that mucosal response to
local inflammation and endotoxin release will also be altered
by conditions modifying the synthesis or activity of nitric
oxide. The role of nitric oxide in mucosal fluid and electrolyte
movements is currently under active investigation.15,16
Intestinal Fluid. Classical experimental studies established that
fluid accumulates intraluminally with open- or closed-loop
small-intestinal obstruction.9,17 Factors contributing to the
accumulation of fluid include intraluminal distention and pressure, release of prosecretory and antiabsorptive hormones and
paracrine substances, changes in mesenteric circulation, and
elaboration and luminal release of bacterial toxins. Experimental studies and clinical investigation18,19 demonstrated that
elevation of luminal pressures above 20 cm H2O inhibits
absorption and stimulates secretion of salt and water into the
lumen proximal to an obstruction. In closed-loop obstructions, luminal pressures may exceed 50 cm H2O and may
account for a substantial proportion of luminal fluid accumulation.20 In simple, open-loop obstructions, distention of the
lumen by gas rarely leads to luminal pressures higher than 8 to
12 cm H2O.21 Thus, in open-loop obstructions, the contributions of high luminal pressures to hypersecretion may not be
important.
The release of endocrine/paracrine substances remains relatively uncharacterized in states of mechanical bowel obstruction.22,23 Suggestions have been made that vasoactive intestinal
polypeptide (VIP) may be released from the submucosal and
myenteric plexuses within the gut wall, promoting epithelial
secretion and inhibiting absorption.23 Use of prostaglandin
GASTROINTESTINAL
752
753
GASTROINTESTINAL
FIGURE 48.3. Plain supine abdominal film of a patient with smallintestinal obstruction. Note the multiple dilated loops of small intestine (black arrow) in the left upper quadrant, characterized by complete markings of the plicae. Also note absence of air in colon and
rectum.
FIGURE 48.4. Plain upright abdominal film of a patient with smallintestinal obstruction. Note the airfluid levels in the stomach and
multiple dilated loops of small intestine (black arrows), and absence of
air in the colon or rectum.
754
and can elicit fluid translocation into the gut. When the obstruction of the small intestine is incomplete (as discussed later), the
use of these agents may facilitate resolution. In two randomized trials, diagnostic and therapeutic use of water-soluble
contrast agents such as Gastrografin reduced the need for
operation by 74%.38,39 Gastrografin is hyperosmolar and
causes mobilization of fluid into the bowel lumen and occasionally is therapeutic in cases of incomplete obstruction.
Assalia et al.38 divided 99 patients including 107 episodes of
adhesive partial small-bowel obstruction into two groups:
conservative management versus administration of 100 mL of
Gastrografin via nasogastric tube. The group of patients who
received Gastrografin had their first bowel movement, on average, in 6 hours versus 23 hours in the control group. Operative
intervention was required in only 10% of the Gastrografin
group (six episodes) compared with 21% (10 episodes) in
the control group. The mean intervals of hospital stay were
2.2 days and 4.4 days, respectively. The authors suggested that
orally administered Gastrografin is safe and therapeutic in
adhesive partial small-bowel obstruction, though further studies were required to confirm the significance of the reduction in
need for an operation.
755
GASTROINTESTINAL
reinforce the dictum that when there are clinical signs of strangulation, surgery should be performed without additional
imaging studies. In patients with equivocal findings or uncertain clinical diagnosis, CT can be highly useful in confirming
the diagnosis, localizing the site, and detecting the cause of
intestinal obstruction and strangulation.42
756
TA B L E 4 8 . 3
MANAGEMENT OF BOWEL OBSTRUCTION IN THREE HYPOTHETICAL PATIENTS
PATIENT III
OPEN-LOOP OBSTRUCTION
OF THE DISTAL SMALL
INTESTINE OR CECUM
PATIENT I
CLOSED-LOOP
OBSTRUCTION
PATIENT II
INTESTINAL OBSTRUCTION
WITH STRANGULATION
Clinical:
Crampy periumbilical
pain worsening over
last 12 h. Two to three
episodes of emesis.
No distention, minimal
flatus
Lab:
No leukocytosis, pH, or
electrolyte disturbances
Radiography:
Differential
Dx:
Broad: includes
appendicitis, closed-loop
SBO, pancreatitis,
nonsurgical conditions
Initial Rx:
Indications
for surgery:
CT, computed tomography; Dx, diagnosis; IVF, intravenous fluids; NG, nasogastric; OR, operating room; P, pulse; T, temperature; SBO, small-bowel
obstruction; WBC, white blood cell.
are not evolving rapidly and when identification of the underlying lesion might alter the operative strategy (see specific
lesions later).
The initial management of all patients with suspected bowel
obstruction includes designating the patient NPO and starting intravenous fluids composed of isotonic Ringer or normal
saline solutions. Restoration of fluid and electrolyte balance is a
priority, often requiring frequent evaluation of serum electrolytes and pH. In rapidly evolving cases or patients with significant dehydration, an indwelling urinary catheter should be
placed to monitor urine output. Invasive hemodynamic monitoring (e.g., a Swan-Ganz catheter) may be necessary to monitor
the response to fluid resuscitation in patients with underlying
cardiac, pulmonary, or renal insufficiency. Nasogastric decompression is indicated in most cases. The nasogastric tube, typically a 16- or 18-French sump tube, serves to prevent distal passage of swallowed air and minimizes the discomfort of refluxing
intestinal content. The use of longer tubes has been advocated in
certain settings, especially for patients with chronic but intermittent obstruction arising from Crohn disease, peritoneal carcinomatosis, radiation enteritis, or many previous laparotomies
for obstruction. The underlying rationale is that advancement
of the tip of the long tube to the obstructed loop would permit
more effective decompression, perhaps resulting in relaxation of
the loop and relief of the obstruction. Although this concept is
appealing, there is no evidence to suggest a benefit for the use of
a long tube in such settings.45,46
The use of intravenous antibiotics in the initial management
of bowel obstruction should be discussed as well. Clinically, it
has been recognized that antibiotics can ameliorate the evolution of symptoms and signs of strangulation in closed-loop
obstruction and appendicitis. Studies in humans have demonstrated that, even in simple obstruction, bacterial counts in succus rise from under 106 organisms/L to over 109 organisms/L47
and are not necessarily reduced with short-term administration
of antibiotics.48 Moreover, experimental studies indicate that
bacteria can translocate across the intestinal mucosa, passing
into lymph channels.49 Further studies have demonstrated that
germ-free animals can survive strangulation obstruction longer
than normal animals and that luminal fluid taken from
obstructed segments in germ-free animals is much less toxic
than fluid taken from normal animals.50,51
For all these reasons, it is a well-established practice to
administer antibiotics perioperatively, in order to reduce wound
infection and abdominal sepsis rates in patients undergoing
operation to relieve intestinal obstruction, simple or strangulated. Once the decision has been made to proceed with surgery,
broad-spectrum antibiotics, covering gram-negative aerobes and
anaerobes, should be given. A second-generation cephalosporin
or a combination of a first-generation cephalosporin and metronidazole is rational practice for perioperative coverage in both
simple and strangulation obstruction. Nevertheless, the use of
antibiotics in patients who have not yet been committed to operation has not been evaluated systematically. Giving antibiotics to
patients who are being observed can obscure the underlying
process and, in the end, delay optimal therapy.
The decision to perform abdominal exploration to relieve
intestinal obstruction should be made expeditiously, but not in
the absence of critical information or before adequate resuscitation. Indications for surgery are outlined in Table 48.3, for
each of the thumbnail vignettes. It should be emphasized that
once a diagnosis of complete obstruction is made, simple or
strangulated, the operation should proceed without undue
delay. It is reasonable to commit the patient to a period of
observation when the diagnosis is uncertain (i.e., there is a
possibility of a nonsurgical diagnosis or that the obstruction is
not complete). A practical point is that obstruction occurring
in a patient without a previous history of laparotomy is not
likely to be caused by peritoneal adhesions. This is known as
de novo obstruction and, whatever the underlying cause, will
not usually resolve without operation.
757
minimizes severity, and decreases density and vascularity of adhesions.55,57 Other trials corroborate decreased severity, density, and
vascularity of adhesions but not total prevention of adhesions or
reduction of the incidence of subsequent bowel obstruction.58
Seprafilm and similar barriers have been advocated for use in
patients in whom a second abdominal procedure is planned or
significant adhesions anticipated (e.g., Hartmann procedure, ileal
pouch anal anastomosis with protecting ileostomy, pelvic surgery,
gynecologic procedures, and colon surgery), though it has been
proposed for all surgeries by the manufacturers. Meta-analyses in
gynecologic procedures support claims that numbers and density
of adhesions are reduced, without necessarily improving the incidence of subsequent intestinal obstruction.
More important than pharmacologic approaches, however,
are the efforts of the surgeon to pay meticulous attention to
hemostasis and surgical technique, and to carefully inspect for
and remove foreign material from the peritoneal cavity. It is
also possible that the use of monofilament sutures for fascial
closure and avoidance of closure of the peritoneum as a separate layer may lower the formation of adhesions between viscera and the abdominal wall.59
Early Postoperative Adhesions. Obstruction in the immediate period following abdominal surgery is uncommon but may
occur in up to 1% of patients in the 4 weeks following laparotomy. Adhesions are responsible for approximately 90% of such
cases and hernias for approximately 7%.60 Intussusception,
abscess, or technical errors may be responsible for the remainder
of cases.61,62 Most cases occur after surgery of the colon, especially abdominoperineal resections, or operations in the lower
abdomen. It is rare for upper abdominal surgery to cause such
obstructions. A common scenario is that a patient will undergo
colectomy uneventfully, pass flatus, and have bowel sounds by
postoperative day 3. On the fourth postoperative day the patient
suddenly becomes distended and uncomfortable, and stops passing flatus and stool. Patients with acutely evolving symptoms
and signs represent complete obstruction and should be managed as such. In this latter setting, the mortality may be as high
as 15% due to delays in recognition and operative intervention.
The loss of bowel sounds after a short period of normal or
hyperactive activity is worrisome for ischemia of the obstructed
segment. The vast majority of such cases may be treated as partial intestinal obstruction; nasogastric suction and intravenous
fluids will help resolve symptoms within a few days (Algorithm
48.1). When the clinical course does not demand earlier intervention, a nonoperative approach may be tried for 10 to 14 days
and will resolve the obstruction in over 75% of such cases.60,62,63
GASTROINTESTINAL
758
Colic
Active bowel sounds
X-ray, air-fluid levels
Suspect ileus
Suspect mechanical
obstruction
Expectant observation
Intravenous fluids, nasogastric tube, serial evaluations
Improvement
Clamp tube
Tolerated, passes flatus
and stool
No change
Deterioration
Not
tolerated
Colic
White blood cells
Mass
Tenderness
Continued expectant
management
Gradual
resolution
No resolution
after 10 days
Laparotomy
ALGORITHM 48.1
ALGORITHM 48.1. Approach to recognition and management of early postlaparotomy obstruction of the small intestine. (Adapted from Welch
JP. Bowel Obstruction: Differential Diagnosis and Clinical Management. Philadelphia, PA: WB Saunders; 1989.)
Gallstone Ileus. As a result of intense inflammation surrounding a gallstone, a fistula may develop between the biliary
tree and the small or large intestine. Most fistulas develop
between the gallbladder fundus and duodenum. If the stone is
greater than 2.5 cm in diameter, it can lodge in the narrowest
759
GASTROINTESTINAL
Transverse
mesocolon
Jejunum
Inferior
mesenteric vein
Paraduodenal
fossa
Duodenum
portion of the terminal ileum, which is just proximal to the ileocecal valve. This complication is rare, accounting for less than 6
in 1,000 cases of cholelithiasis and no more than 3% of cases of
intestinal obstruction. Typically, the patient is elderly and presents with intermittent symptoms over several days, as the stone
FIGURE 48.9. Richter hernia. A: Computed tomography scan showing contrast and air in the incarcerated segment within the left groin.
B: Schematic diagram showing Richter hernia, in which the antimesenteric border (but not the whole wall) of the intestine is incarcerated.
760
C
FIGURE 48.10. A: Plain radiograph of a patient with gallstone ileus, showing obstructed loops of small intestine (black arrow) in the abdomen
and a gallstone (white arrow) in the pelvis (gallstone was initially misinterpreted as an EKG lead [black arrow]). B: Computed tomography (CT)
scan showing a cholecystoduodenal fistula (black arrow) with air in the biliary tree (D, duodenum). C: CT scan showing gallstone (white arrow)
in the distal ileum and fecalization of luminal content adjacent to the stone.
761
FIGURE 48.12. Axial (A) and coronal CT scan (B) images of an ileocolic intussusception secondary to colon carcinoma (M) as a lead
point. Intussusceptum (long arrows) and intussuscipiens (arrowhead).
Mesenteric vessels and fat (white arrowhead) accompany the intussusceptum.
GASTROINTESTINAL
762
tube if possible. They are encouraged to eat as soon as obstructive symptoms resolve using a low-fiber diet. Antiemetics and
opioids via continuous subcutaneous infusions are used to
manage nausea and vomiting and colic, respectively. In addition,
octreotide, a somatostatin analogue, is used in palliation of
refractory malignant intestinal obstruction by improving
intestinal mucosal absorption, improving motility, reducing
gastrointestinal hormone levels and intestinal secretions, and
having a direct antineoplastic effect on the obstructing
tumor.74 This allows true palliative care outside a hospital setting saving patients the pain, discomfort, and complications of
hospitalization and unproductive surgery.73
twisted more than 180 degrees about the axis of its mesentery.
Volvulus has been reported for the cecum, transverse colon,
splenic flexure, and sigmoid colon. A special variant of volvulus, complicating a condition known as Chilaiditi syndrome,
can occur when redundant loops of the transverse colon slip
between the liver and diaphragm and then torse.75 Generally,
the condition is asymptomatic, but when associated with
volvulus it must be relieved surgically.
The most common site for volvulus is the sigmoid colon,
accounting for 65% of cases.76 By definition, a volvulus is a
form of closed-loop obstruction of the colon. Air is always present in the colon and rectum, and thus volvulus of any segment of
the colon is associated with abdominal distention and, usually,
severe abdominal pain. As shown in Figure 48.5, the most common radiographic feature is the bent inner tube appearance of
the sigmoid, which is located in the upper abdomen. The preferred method of management involves endoscopic decompression. A rigid or flexible proctosigmoidoscope is advanced gently
into the rectum until a rush of air and feces indicate that the loop
has been untorsed. A rectal tube is then advanced well into the
loop as a stent to prevent retorsion. Gangrene of the colon does
not usually complicate the picture if the patient is seen and
treated promptly. This conservative approach resolves the volvulus in 85% to 90% of cases and elective resection or fixation of
the redundant segment can then be planned. Following endoscopic decompression, recurrence of the volvulus is higher than
60%.77 Thus, an operation to remove the sigmoid should be performed if the patient is fit for surgery.78 However, a majority of
these patients are elderly and infirm and approximately 15%
have a history of psychiatric disorder. As a result, the patient may
present with peritoneal findings, sepsis, and shock. In this setting, rapid resuscitation followed by urgent resection and
colostomy is warranted. Other forms of volvulus generally cannot be detorsed without operation. Fixation of the torsed segment (e.g., via cecostomy or cecopexy) is generally a less satisfactory solution than resection of the involved segment and is
not generally recommended.76
763
SURGICAL BYPASS OR
ENTEROSTOMY
MEDICAL PALLIATION OF
SYMPTOMS
PEG
Multiple sites of obstruction
Small bowel obstruction
beyond duodenum
PERCUTANEOUS
ENDOSCOPIC
GASTROSTOMY (PEG)
v.s.
OPEN GASTROSTOMY
ENDOSCOPIC SELF
EXPANDING METAL STENTS
(SEMS)
Continuous pain
Opioids
Colicky pain
Anti-Cholinergics:
Scopolamine
Nausea and vomiting
Anti-Cholinergics:
Scopolamine
Glycopyrrolate
Octreotide
Metoclopramide
Neuroleptics:
Haloperidol
Methotrimeprazine
Prochlorperazine
Chlorpromazine
Antihistamines
Cyclizine
ALGORITHM 48.2
ALGORITHM 48.2. Algorithm for management of malignant obstruction. (Contributed by William Peranteau, M.D.)
TA B L E 4 8 . 5
FORMS OF INTESTINAL OBSTRUCTION SELECTIVELY
AMENABLE TO LAPAROSCOPIC MANAGEMENT
Diaphragmatic (hiatal) hernia
Gallstone ileus
Inguinal hernia
Intussusception
Incisional hernia
Adenocarcinoma of colon
Femoral hernia
Diverticulitis
Spigelian hernia
Internal hernia
Volvulus
Adhesions
Crohn disease
Periappendicular abscess
Small-bowel tumor
Carcinomatosis
Meckel diverticula
Ogilvie syndrome
Bezoar
GASTROINTESTINAL
PATIENT
764
TA B L E 4 8 . 6
OUTCOMES OF LAPAROSCOPIC OPERATIONS FOR OBSTRUCTION OF THE SMALL INTESTINE DUE TO ADHESIONS
REFERENCES
OPERATIVE
TIME (min)
Pekmezci et al.85
Levard et al.
CONVERSION (%)a
99
83
BOWEL
INJURY
(%)
6.7
LOS
(d)
REOPERATION
(%)
SUCCESS
(%)
MORTALITY
(%)
100
6.7
NR
40.9
8.4
4.5
95
2.2
Sato et al.86
105
17.6
17.6
10.4
5.8
88
Suter et al.87
NR
43
15.6
5.9
NR
2.4
Al-Mulhim88
58
32
NR
100
Chosidow et al.89
71.7
16
Strickland et al.90
68
32.5
Leon et al.
91
108
Bailey et al.92
93
Navez et al.
Ibrahim et al.94
Overall
35
64
21.5
5.03
10
7.5
NR
77
40
NR
15
9.1
58108
6.743
317.6
NR
80
3.6
97
2.9
17.5
81
10.8
NR
6.6
2.9
1.8
85.3
NR
NR
2.910.4
017.5
80100
2.9
3
03
TA B L E 4 8 . 7
OUTCOMES, COMPLICATIONS, AND COSTS IN LAPAROSCOPIC MANAGEMENT OF INTESTINAL OBSTRUCTION
DUE TO ADHESIONS
REFERENCE
CONVERSION (%)
Wullstein et al.f
52a
Laparoscopic
COMPLICATION
(%)
TIME TO
RBF (d)
LOS
(DAYS)
OPERATIVE
TIME (min)
COST
($)
Intraop: 29b
P 0.156
3.5
p 0.001
11.3
p 0.001
103
p 0.05
NR
4.4
18.1
84
NR
Postop: 19.2c
P 0.032
Open
Intraop: 15d
Postop: 40.4e
Mancini et al.g
17.2
Laparoscopic
19.2
p 0.008
NR
6
p 0.0001
NR
9,412
p 0.0003
Open
30.1
NR
NR
11,858
GASTROINTESTINAL
time between the onset of symptoms and diagnosis (1.6 vs. 3.1
days), and the presence of a pathologic lead point.96 Although
these early retrospective studies are encouraging, prospective
studies evaluating laparoscopic management of small-bowel
obstruction are required to definitively document its benefits
over the traditional open approach.
765
766
TA B L E 4 8 . 8
FACTORS CONTRIBUTING TO PROLONGED ILEUS
NEUROGENIC
Spinal cord lesions or injury
Retroperitoneal process
hematoma, tumor
Ureteral colic
METABOLIC
PHARMACOLOGIC
INFECTIOUS
Hypokalemia
Anticholinergics
Systemic sepsis
Uremia
Opiates
Pneumonia
Autonomic blockers
Peritonitis
Hypothyroidism
Antihistamines
Herpes zoster
Psychotropics
Tetanus
Phenothiazines
Haloperidol
Tricyclic antidepressants
Clonidine
Vincristine
Management. A normal POI is usually self-limiting. Nevertheless, there are a number of interventions that are effective
TA B L E 4 8 . 9
767
MANAGEMENT
TREATMENT
BENEFIT
DRAWBACK
Nasogastric tube
Peripheral acting
FDA approved to hasten postoperative
ileus following partial large- or smallbowel resection with primary anastomosis
Laparoscopic procedures
Epidural anesthetics/analgesics
Gum chewing
Limited data
Laxatives
Nonsteroidal anti-inflammatory
drugs (COX-2 inhibitors)
function. Mastication stimulates the vagal cholinergic pathways that increase gastrointestinal hormone secretion such as
gastrin, pancreatic polypeptide, and neurotensin, which affect
gastrointestinal motility.131,132 Since the initial publication of
one small and underpowered study,133 a number of prospective
randomized trials have been conducted to test the hypothesis
that gum chewing results in earlier passage of flatus and bowel
movement in patients undergoing laparoscopic colectomy.134,135
No conclusive evidence has been obtained to demonstrate a
clear benefit of gum chewing, although subgroup analysis suggests some patients may benefit.135 According to one hypothesis,
sorbitol and other hexitols, the key gradients of sugar-free
chewing gums, may also play a role in the earlier recovery of
postoperative ileus.136 This hypothesis and its putative benefits
are intriguing.
Salt and water disturbances in the body also may influence
return of bowel function following laparotomy. In one initial
study, patients undergoing colectomy received a restricted perioperative fluid resuscitation regimen or a standard, more liberal fluid resuscitation. The restricted group had a quicker
passage of flatus and moved their bowels earlier, leading in part
to shorter hospital stays.137 Subsequent studies138,139 have not
uniformly suggested that recovery from ileus is faster with temperance in fluid resuscitation, or have indicated that there is a
GASTROINTESTINAL
768
TA B L E 4 8 . 1 0
MANAGEMENT
Colonic Pseudo-obstruction
(Ogilvie Syndrome)
Etiologic Factors. Acute pseudo-obstruction of the colon,
also known as Ogilvie syndrome,152 is a paralytic ileus of the
large bowel, characterized by rapidly progressive abdominal
distention, often painless.153 Although the distention of the
colon is not due to mechanical obstruction, the wall of the
bowel, particularly that of the cecum, can become sufficiently
distended so that its blood supply is compromised. Gangrene,
perforation, peritonitis, and shock can follow. In 95% of the
cases, there is an underlying disease.153,154
Major risk factors for development of Ogilvie syndrome
include traumatic injury (11%); infections such as pneumonia
and sepsis (10%); obstetric/gynecologic conditions (10%);
myocardial infarction and congestive heart failure (10%);
abdominal and pelvic surgery (9%); neurologic conditions
such as Parkinson disease, spinal cord injury, multiple sclerosis, and Alzheimer disease (9%); orthopedic procedures (7%);
other medical conditions including metabolic imbalances (e.g.,
hypokalemia, hypocalcemia, hypomagnesemia) (32%); and
other surgical conditions (12%).152,154 Evidence suggests that
Ogilvie syndrome is thought to be related, at least in part, to
sympathetic nervous overactivity or interference with sacral
parasympathetic efferents, although there is little direct experimental evidence for this.153 It is postulated that the distal
colon becomes atonic on interruption of the S2 to S4 parasympathetic nerve fibers.
Diagnosis. This syndrome is commonly encountered in
patients hospitalized over 3 to 7 days, often in men older than
60 years of age. Primary manifestations include gastrointestinal symptoms such as nausea, vomiting, abdominal pain, constipation, or even diarrhea with great variability.153,154
Labored breathing, caused by abdominal distention, is often
part of the clinical picture. Other than distention, there are no
characteristic physical or laboratory findings for this syndrome. The abdomen resonates with percussion. Sounds from
the small intestine are present and may not be high pitched, as
they are in intestinal obstruction.
Laboratory findings associated with this syndrome may
include hypokalemia, hypocalcemia, and hypomagnesemia,
which are implicated as etiologic factors. Leukocytosis, elevation of the sedimentation rate, or C-reactive protein is also
present if inflammation is initiated or perforation is impending.
The diagnosis is usually apparent from plain films. Radiographs of the abdomen may reveal air in the small bowel and
distention of discrete segments of the colon (i.e., cecum or
transverse colon often up to the splenic flexure) or the entire
abdominal colon. Haustral markings disappear with increasing distention. In doubtful cases in which bowel necrosis is not
a significant worry, a Hypaque contrast enema can establish
the nonmechanical nature of the dilatation. Alternatively,
colonoscopy can be diagnostic as well as therapeutic. Features
suggesting the complication of bowel ischemia may include
localized tenderness, worsening leukocytosis, metabolic acidosis, evidence of sepsis, or a rapidly deteriorating clinical
course.
It is important to differentiate this syndrome from toxic
megacolon and mechanical obstruction before establishing a
final diagnosis. Mechanical obstruction of the colon, occurring in volvulus or obturator obstructions from cancer or
diverticular disease, presents with acute pain along with distention. In contrast, pseudo-obstruction is less often associated
with acute pain and more likely to present with discomfort due
to distention. However, lack of pain in postoperative patients
on opiates or elderly patients cannot exclude mechanical
obstruction. In plain radiographs, the pathognomonic signs of
mechanical obstruction such as lack of gas in the distal colon
or rectum and airfluid levels in the small intestine can also be
TA B L E 4 8 . 1 1
MANAGEMENT
BENEFIT
Nasogastric tube
Neostigmine
Erythromycin
Required in case of
refractory medical therapy
769
GASTROINTESTINAL
770
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156. Sloyer AF, Panella VS, Demas BE, et al. Ogilvies syndrome. Successful
management without colonoscopy. Dig Dis Sci 1988;33:13911396.
157. Cowlam S, Watson C, Elltringham M, et al. Percutaneous endoscopic
colostomy of the left side of the colon. Gastrointest Endosc 2007;65:
10071014.
158. Armstrong DN, Ballantyne GH, Modlin IM. Erythromycin for reflex ileus
in Ogilvies syndrome. Lancet 1991;337:378.
159. Jiang DP, Li ZZ, Guan SY, et al. Treatment of pediatric Ogilvies syndrome
with low-dose erythromycin: a case report. World J Gastroenterol 2007;
13:20022003.
160. Lee JT, Taylor BM, Singleton BC. Epidural anesthesia for acute pseudoobstruction of the colon (Ogilvies syndrome). Dis Colon Rectum 1988;31:
686691.
161. Sgouros SN, Vlachogiannakos J, Vassiliadis K, et al. Effect of polyethylene
glycol electrolyte balanced solution on patients with acute colonic pseudo
obstruction after resolution of colonic dilation: a prospective, randomised,
placebo controlled trial. Gut 2006;55:638642.
162. Korsten MA, Rosman AS, Ng A, et al. Infusion of neostigmine-glycopyrrolate for bowel evacuation in persons with spinal cord injury. Am J Gastroenterol 2005;100:15601565.
163. Child CS. Prevention of neostigmine-induced colonic activity. A comparison of atropine and glycopyrronium. Anaesthesia 1984;39:1083
1085.
164. Ponec RJ, Saunders MD, Kimmey MB. Neostigmine for the treatment of
acute colonic pseudo-obstruction. N Engl J Med 1999;341:137141.
165. Lynch CR, Jones RG, Hilden K, et al. Percutaneous endoscopic cecostomy
in adults: a case series. Gastrointest Endosc 2006;64:279282.
K E Y
Crohn disease is a chronic inflammatory disorder of the
gastrointestinal tract with varied presentations.
2 Although no cure exists for Crohn disease, symptoms can
be ameliorated with medical therapy, and surgical intervention is reserved for when medical treatment fails or to
treat complications of disease.
3 Understanding medical therapies for Crohn disease is imperative for the appropriate perioperative care of patients.
1
cure for this disease. Treatment of Crohn disease consists primarily of medical management and modulation of symptoms,
with surgical involvement when complications or escalations
of symptoms occur. The course and severity of Crohn disease
is affected by its location and disease characteristics, and are
difficult to generalize. Patterns of disease and involved segments vary from ileocolic disease, the most common surgical
manifestation, to colon disease, to pan-intestinal tract disease.
Over 70% of patients will require a surgical intervention at
some point in their lives and over half of patients will require
*This chapter has been adapted from the fourth edition of Greenfields 3 multiple surgical interventions. A comprehensive understanding of the disease process and surgical options is imperative for
Surgery and the authors are grateful for the contributions of previous
appropriate treatment of the disease.
authors Roger D. Hurst and Alessandro Fichera.
Crohn disease is a chronic inflammatory disorder of the gastrointestinal tract that can affect patients from the mouth to
the anus. Crohn disease was first described by Dalziel in 19131
but derives its name from Burill Crohn, the first author of the
2 now classic paper published in 1932.2 Although much has
been discovered regarding the etiology and treatment of Crohn
disease in recent years, there remains no medical or surgical
1
P O I N T S
773
EPIDEMIOLOGY
GASTROINTESTINAL
varied location and pathologic features may complicate diagnosis. Approximately 60% of patients have involvement of the
ileum, with or without cecal disease. Colonic disease presents
in 15% to 20% of patients. Ten percent of patients have proximal small bowel involvement and 15% of patients have multiple sites of disease throughout the gastrointestinal tract.10 The
peak age of diagnosis is between 15 and 25 years of age with a
second peak between 55 and 65 years. Crohn disease is uncommon prior to the age of 6 years.
DISEASE PATTERNS
Crohn disease is categorized by three general disease categories: inflammatory disease, stricturing disease, and perforating disease. It is believed that these patterns do not represent
distinct disease entities but rather a continuum of the disease.
An inflammatory disease pattern is typically characterized by
mucosal ulceration and thickening of the bowel wall, resulting
in narrowing of the intestinal lumen (Fig. 49.1). Symptoms of
the inflammatory pattern of disease are characteristic of chronic
obstruction and include weight loss, nausea, abdominal pain,
bloating, and change in bowel habits. A stricturing disease pattern is characterized by intestinal luminal narrowing, forming
cicatricial strictures surrounded by fibrotic scar tissue. Unlike
the inflammatory pattern, stricturing disease is rarely amenable
to medical management.
Perforating disease is characterized by the macroscopic or
microscopic presence of fistulas and abscesses. Perforating disease typically begins on the mesenteric portion of the intestinal
lumen and bores through the bowel wall. Tracks may penetrate
for only a short distance and form blind tracks or sinuses, or
continue into an adjacent segment of intestine, into an abdominal organ, or through the abdominal wall. Abscesses may cause
obstructive symptoms, fevers, abdominal pain, or sepsis. Fistulas are often asymptomatic but, depending on the location, can
result in diarrhea, fecaluria, pneumaturia, or enteric drainage
through the abdominal wall or the vagina.
DIAGNOSIS
CLINICAL PRESENTATION
Diagnosis is based on a combination of clinical history, physical examination, and laboratory, endoscopic, and radiographic
findings, but no definitive test for Crohn disease exists. The
774
EXTRAINTESTINAL DISEASE
Extraintestinal manifestations of Crohn disease occur in up to
25% of patients with Crohn disease and are most likely to occur
in patients with ileal disease.11 Patients may present with dermatologic disorders, ocular disease, arthralgias, hepatic dysfunction, and deep venous thrombosis. Some other manifestations, including peripheral arthritis, episcleritis, aphthous
ulcers, and erythema nodosum, which generally parallel the
activity of the intestinal disease, and symptoms often regress
with successful medical or surgical treatment. Surgical intervention is occasionally advocated when these extraintestinal manifestations fail to resolve. Ankylosing spondylitis, uveitis, pyoderma gangrenosum, and primary sclerosing cholangitis do not
correlate with bowel disease activity, and their clinical course is
not attenuated by surgical resection of intestinal Crohn disease.
ENDOSCOPY
The evaluation of Crohn disease should survey the entire gastrointestinal tract. Endoscopic evaluation includes upper endoscopy for evaluation of gastroduodenal ulcers and colonoscopy
with ileal intubation to investigate colonic and ileal disease. Findings typical of Crohn disease include ulcerations, cobblestoning,
and skip lesions. The presence of ileal disease may differentiate
Crohn disease from ulcerative colitis, though backwash ileitis
(present in ulcerative colitis) may make differentiating the two
entities challenging. Rectal sparing or fistulous perianal disease
may help differentiate Crohn disease from ulcerative colitis. The
presence of aphthous ulcers, cobblestoning, and strictures are
highly suggestive of Crohn disease.
SMALL-BOWEL RADIOGRAPHY
Small-bowel follow-through and enteroclysis were traditionally used to evaluate the small bowel between the duodenum
and the terminal ileum. In both these studies, oral contrast is
ingested and serial radiographic imaging is performed with fluoroscopy or still images. Radiographic findings may be distinctive.12 Mucosal granularity, ulceration, and blunting of normal
intestinal architecture may be seen. Abnormal spacing of bowel
loops on enterography is characteristic of mesenteric and
bowel wall thickening found in Crohn disease. Fistulas may be
demonstrated between loops of bowel; strictures and skip
lesions may also be visualized.
COMPUTED TOMOGRAPHY
Computed tomography (CT) allows for identification of extraluminal pathology, unavailable on traditional small-bowel
studies. CT can evaluate ureteric obstruction, air within the
urinary bladder, inflammatory masses, and abscesses. Information provided by the CT scan is integral for planning percutaneous drainage of abscesses. Recent advancements in the use
of CT enterography have increased the sensitivity of CT scan
for intraluminal pathology. Using a multidetector CT scanner
with oral and intravenous (IV) contrast, CT enterography can
evaluate the bowel wall for enhancement and the presence or
absence of strictures and fistulas. The sensitivity and specificity
of CT enterography still falls behind that of traditional smallbowel follow-through and enteroclysis, but are improving
with increasing experience.13
CAPSULE ENDOSCOPY
Capsule endoscopy is a recent advancement in gastrointestinal
endoscopy. Patients swallow a small capsule, which transmits
continuous images to a monitor, which is placed on the patient
for the duration of the study. This provides direct imaging of the
small bowel between the ligament of Treitz and ileocecal valve,
not previously accessible by endoscopy. Patients who undergo
capsule endoscopy should first be evaluated for the presence of
strictures and chronic obstruction, as cases of retained capsule
requiring surgical retrieval have been reported.
PATHOLOGY
Pathologic findings of Crohn disease tend to progress from
small aphthous ulcers to full-thickness inflammation and fistulas. Aphthous ulcers are small red spots or depressions in the
intestine that represent mucosal ulceration over microscopic
lymphoid aggregates and are the earliest manifestation of
Crohn disease.14 As the disease progresses, the ulcers enlarge,
forming longitudinal ulcerations on the mesenteric aspect of
the bowel wall. Further disease progression leads to a serpiginous network of thin, linear ulcerations surrounding islands of
edematous mucosa, producing a classic cobblestone appearance. Pseudopolyps, which are actually formed by the paucity
of normal surrounding mucosa secondary to severe disease,
may be seen in Crohn disease (Fig. 49.2A).
775
DIFFERENTIAL DIAGNOSIS
B
FIGURE 49.2. A: Pseudopolyps and full-thickness ulceration in a
patient with Crohn disease of the ileum. B: Fat wrapping or creeping
fat is seen extending over the serosal surface of the bowel of a stenotic,
diseased segment of ileum. Fibrotic changes are noted on the cut surface
of ileum, extending to all layers of the bowel wall.
FIGURE 49.3. A: Deep fissure extending through layers of the bowel wall with preservation of surrounding
villi and crypts. B: Diffuse lymphoid aggregates characteristic of Crohn disease. C: Noncaseating granulomas
are a valuable diagnostic feature of the disease.
GASTROINTESTINAL
776
TREATMENT
Neither medical nor surgical therapy is curative for Crohn disease. Management of Crohn disease is focused on the relief of
5 symptoms and prevention of recurrence. As patients with
Crohn disease often have multiple recurrences and escalation
of symptoms, avoidance of surgical resection to preserve
bowel length is an important component in treatment. Medical therapy represents first-line treatment for most symptoms
of Crohn disease and is based on the severity of symptoms.
The understanding of medical treatments for patients with
Crohn disease is imperative for the surgeon, as many medications affect postoperative physiology and risks for surgical
complications.
MEDICAL MANAGEMENT
The first line of treatment in Crohn disease is symptomatic
supportive care. Many patients find that a bland, low-fiber diet
may alleviate the symptoms of bloating and abdominal pain.
Bowel rest can decrease disease activity, but remission is often
transient. Antidiarrheal and antimotility agents, such as diphenoxylate, loperamide, and diluted tincture of opium, are used
for chronic diarrhea related to colitis, ileal disease, or prior
bowel resection. These medications decrease intestinal cramping and diarrhea by decreasing intestinal motility. In the presence of severe colitis, these medications are contraindicated as
they may precipitate toxic megacolon.
Patients with severe malnutrition may benefit from parenteral nutrition. Data extrapolated from the literature on
cancer patients suggest that 1 week to 10 days of preoperative
total parenteral nutrition may prevent weight loss, improve
nitrogen balance, and reduce perioperative complications.15
The risks of total parenteral nutrition must be weighed carefully against the benefits of nutritional optimization.
Aminosalicylates or 5-aminosalicylic acid (5-ASA) derivatives are commonly used as first-line treatment for patients
with mild to moderate Crohn disease of the large and small
intestine. These medications inhibit proinflammatory mediators and are designed to deliver medications to a specific bowel
segment. Diffusion-dependent medications (Pentasa) target the
distal small intestine and are effective in patients with diarrhea. pH-dependent medications (Asacol) are effective in the
terminal ileum and ascending colon where the bowel pH
reaches 6 to 7. Flora-dependent derivatives (Colazal, sulfasalazine) rely on colonic flora to break the diazobond and
work most effectively in the colon.
Aminosalicylates may be taken orally or rectally and have
been shown to be effective to prevent relapse after medically
induced remission or surgical resection.16 Patients on ASA
derivatives are not at increased risk of postoperative complications and may be started early in the postoperative period to
help decrease recurrence rates and maintain remission.17 It is
critical that 5-ASA derivatives not be confused with acetylsalicylic acid (aspirin) or other NSAIDs frequently used in postoperative patients. NSAIDs have the potential to exacerbate
disease activity and should be avoided in patients with Crohn
disease.18
Antibiotics have been demonstrated to improve symptoms
of Crohn disease. They are used to treat intra-abdominal and
perianal infection and abscesses and to obtain and retain
remission in inflammatory and fistulizing disease.19 The mechanism of action is theorized to be due to altering indigenous
luminal bacteria and modifying the aerobic and anaerobic bacteria concentrations in the gastrointestinal tract. Fluoroquinolones, metronidazole, and rifaximin are used commonly.
Historically, steroids were the first-line treatment of acute
flares of Crohn disease and were used for medically refractory
disease. Recent medical literature has de-emphasized the use of
steroids in favor of antibiotics and biologic and immunologic
pharmacotherapies. Multiple studies have demonstrated that
steroids may be helpful in achieving remission, but only about
30% of patients will maintain remission without continued
steroids.20 Steroids may be administered orally, intravenously,
or rectally.
A limitation of steroids is the extensive side effect profile,
which includes osteonecrosis, diabetes, myopathy, infection,
and adrenal suppression. Intravenous and oral medications
with systemic absorption have a high risk of steroid-induced
side effects. Orally available budesonide and topical enemas
have decreased systemic absorption and side effects. In general, chronic use of doses of 20 mg/d or higher portends a
worse prognosis, with an increased risk of surgical intervention.21
The thiopurines azathioprine (AZA) and 6-mercaptopurine
(6-MP) are used for treatment of moderate to severe disease
and have been particularly useful for patients with fistulizing
disease. Studies have shown 6-mercaptopurine and azathioprine to be effective in decreasing recurrence, ameliorating fistulizing disease, and maintaining remission.22 The mechanism
of action is induction of apoptosis and inhibition of ribonucleotide synthesis. Side effects of these agents include bone
marrow suppression, hepatitis, pancreatitis, and lymphoma,
which can be severe and limit usage. Approximately 20% of
patients are intolerant to the medications. These medications
are not thought to be a major risk factor for patients undergoing surgical intervention.
Methotrexate has been used in patients to facilitate weaning from steroids, particularly in patients intolerant to 6MP/AZA. Studies in Crohn disease demonstrate an increased
rate of remission and ability to wean steroids when compared
to placebo.23 Side effects include bone marrow suppression,
pneumonitis, and cirrhosis. Methotrexate is not thought to be
a particular risk factor for postoperative complications.
One of the most important recent advances in the medical
treatment of Crohn disease is the use of biologic agents. Infliximab
Intestinal Obstruction
Intestinal obstruction generally occurs secondary to inflammatory or stricturing disease. Partial or complete obstruction is a
common indication for surgery in patients with Crohn disease,10 but acute obstruction is rare. Initial treatment usually
involves bowel rest, antibiotics, and supportive therapy. Partial small-bowel obstruction related to acute inflammation can
often be managed with medical therapy. Traditionally steroids
were used, but recently, new therapies such as infliximab and
adalimumab have proven useful in inflammatory disease.
Stricturing disease is less likely to respond to medical treatTA B L E 4 9 . 1
INDICATIONS
777
Enteric Fistulas
Fistulization is a common manifestation of Crohn disease and
results from full-thickness rupture into an adjacent hollow
organ or through the abdominal wall. Fistulas may occur at
the site of prior anastomoses; ileocolic resection often fistulizes
to the duodenum, and colon resections can fistulize to the
stomach. Crohn disease may form symptomatic fistulas between
proximal and distal loops of bowel or between the small bowel
and colon. Enteric fistulas may be found in as many as one
third of patients with Crohn disease, but constitute an indication for surgery in only a small minority of patients. Immunologics such as anti-TNF chimeric monoclonal antibody (infliximab) may be used for the medical treatment of fistulous
disease.30
Most fistulas between loops of bowel are asymptomatic
and are noted incidentally at the time of surgery or on radiographic studies. Up to two thirds of ileosigmoid fistulas are
not diagnosed prior to surgery, and the surgeon and patient
should be prepared for this possibility.31 Occasionally, fistulas
may be symptomatic and warrant surgical intervention or
escalation of medical therapy. Most commonly this occurs
when a large-diameter fistula forms between the ileum and sigmoid secondary to the proximity of these loops of bowel. The
large-diameter fistulas may cause shunting of the fecal stream
and significant diarrhea. Often, the sigmoid is only secondarily
GASTROINTESTINAL
778
Hemorrhage
Enterocutaneous Fistulas
Enterocutaneous fistulas occur in approximately 4% of
patients with Crohn disease,32 typically from direct penetration
of a sinus through the abdominal wall or rupture of a superficial abscess. Prior scars are common sites of drainage. Evaluation of the fistulas with radiographic imaging may demonstrate
the existence of an abscess requiring drainage or an obstruction
preventing spontaneous healing. The presence of an enterocutaneous fistula does not necessarily dictate the need for surgical
intervention; sepsis must be cleared, abscesses drained, and
nutritional support supplied if necessary. Enterocutaneous fistulas are often slow to heal, and surgery is ultimately required
in many cases. The general principles of management include
resection of diseased segment and dbridement of the fistulous
tract and abdominal wall.
Perforation
Free perforation with peritonitis is a rare complication of Crohn
disease, occurring in 1% of patients, and is a clear indication for
urgent operation.34 Perforation can occur in the large or small
bowel. Resection of the diseased segment is favored over simple
Toxic Colitis
Patients with Crohn disease occasionally develop severe colitis. Severe colitis is defined by Truelove and Witts37 as dilation
on radiography (typically defined as transverse colon 5.5 cm
in diameter), abdominal tenderness, more than 10 bloody
bowel movements per day, fever, tachycardia, anemia, and elevated sedimentation rate. Failure to respond to medical therapy or progression on medical therapy is accepted as an indication for therapy. Subtotal colectomy with ileostomy should
be performed.
779
Growth Retardation
GASTROINTESTINAL
780
in several studies.43,44 Long-term follow-up has not demonstrated an increased rate of surgical recurrence or intervention
in patients who underwent laparoscopic resection. A long-term
follow-up series demonstrated that as many as 50% of patients
with Crohn disease who had their operation performed laparoscopically were able to undergo a second surgery laparoscopically.45 Many patients with Crohn disease are young healthy
patients and the cosmetic advantages of a laparoscopic
approach can be considerable.
Laparoscopic surgery for Crohn disease may be challenging. Thickened mesentery, abscesses, and fistulas may make
dissection difficult. Conversion rates are typically higher in
Crohn surgery than other types of laparoscopic bowel surgery,
with rates of conversion cited between 4.8% and 29.2%.42 It
is estimated that surgeons require 10 to 50 cases per year to
obtain minimum proficiency, and laparoscopic cases for Crohn
disease are recommended only for experienced laparoscopic
surgeons.46
1-2 cm
B
SPECIFIC SCENARIOS
OF CROHN DISEASE
FIGURE 49.6. Heineke-Mikulicz strictureplasty. This technique is
limited to patients with short-segment disease in close proximity.
(Adapted from Milsom JW. Strictureplasty and mechanical dilation in
strictured Crohns disease. In: Michelassi F, Milsom JW, eds. Operative Strategies in Inflammatory Bowel Disease. New York: SpringerVerlag; 1999:259267.)
GASTROINTESTINAL
781
has been associated with the occurrence or worsening of diarrhea in patients with Crohn disease.48 Distal duodenal disease
may be amenable to Roux-en-Y duodenojejunostomy. Both of
these procedures can be performed using either an open or
laparoscopic technique with a high rate of success. Surgical
resection is generally avoided secondary to a high rate of complications.
Secondary involvement of the second or third portion of
the duodenum typically occurs from recurrent disease in the
neoterminal ileum after a prior ileocolic anastomosis. Secondary disease of the fourth portion of the duodenum or the
stomach usually occurs from primary disease of the transverse
colon. Although most fistulas are asymptomatic, shunting of
enteric contents may cause malabsorption and diarrhea. Surgical management involves resection of the primary diseased
intestine. The duodenum or stomach edges may be dbrided to
healthy bowel and repaired primarily. In cases of large defect
or tension on the repair site, closure with jejunal serosal patch
or duodenojejunostomy may be necessary.
782
Fistulas are abnormal connections between the anus or rectum and the perianal skin. Fistulas may be low lying or involve
a portion of the internal sphincter muscles. Continence may be
severely affected. Fistulas may extend to the vagina or urinary
tract. Patients with abscesses should have surgical drainage
and treatment with antibiotics including metronidazole and
ciprofloxacin. Placement of setons, in the form of suture material or plastic loops, through the fistulous tract can stent the
track and prevent formation of abscesses (Fig. 49.10).
Recent advances in medical therapies such as anti-TNF
antibody (infliximab) have been shown to be effective in promoting the healing of complex Crohn perianal fistulas.
Although short-term data show improvement, longer followup shows a low rate of sustained healing, even when combined
with surgical drainage of abscess.57 Local injection of immunologics may also be used, especially in the setting of painful skin
tags and fissures.
When medical therapy fails to improve symptoms, or in the
case of fistulizing disease to the vagina, surgical therapy is
advocated. Fistulotomies, or laying open of the fistulous tract,
may be used for low-lying fistulas, but the risk of incontinence
limits its use in Crohn patients at risk for recurrent fistulas.
Puborectalis
muscle
External
sphincter
muscle
Seton
FIGURE 49.10. Placement of a seton suture through a transsphincteric fistula-in-ano. (Adapted from Gordon PH, Nivatvongs S, eds.
Principles and Practice of Surgery for the Colon, Rectum, and Anus.
St. Louis, MO: Quality Medical; 1992:221265.)
RECURRENCE
The most common long-term complication following surgery
for Crohn disease is recurrent disease. Reported recurrence
rates vary greatly. Endoscopic recurrence, which is often
asymptomatic, has been reported to vary from 28% to 73% at
1 year and from 77% to 85% at 3 years after ileal resection.59
Symptomatic recurrence occurs in 60% of patients at 5 years
and 75% to 95% of patients at 20 years. Reports vary, but the
rate of reoperation to treat recurrent disease is approximately
20% at 5 years, 33% at 10 years, and 50% at 20 years.60
Research has focused on the prevention of recurrence.
Some evidence indicates that the use of NSAIDs or nicotine
both promote recurrence of disease. All patients with Crohn
disease should be strongly advised to refrain from smoking
cigarettes or taking NSAIDs.
Patients are often placed on maintenance therapy within
days or weeks of surgery. The most common maintenance
therapies recommended are controlled-release 5-ASA (Pentasa) and 6-MP, but newer regimens include the use of metronidazole and infliximab. The degree to which postsurgical
maintenance therapy lessens the risk for recurrent disease is in
some cases only marginal. The effects on long-term quality of
life and the cost-effectiveness of postoperative maintenance
therapy have not been fully determined. Thus, the decision to
recommend maintenance therapy must be individualized for
each patient.
References
1. Dalziel TK. Chronic interstitial enteritis. Br Med J 1913;2:10681070.
2. Crohns BB, Ginzburg L, Oppenheimer GD. Regional ileitis: a pathological
and clinical entity. JAMA 1932;99:13231329.
3. Sandler RS, Glenn ME. Epidemiology of inflammatory bowel disease. In:
Kirsner JB, ed. Inflammatory Bowel Disease, 5th ed. Philadelphia: WB
Saunders; 2000:89112.
4. Economou M, Pappas G. New global map of Crohns disease: genetic,
environmental and socioeconomic correlations. Inflamm Bowel Dis 2008;
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5. Yang H, McElree C, Roth MP, et al. Familial empiric risks for inflammatory bowel disease: differences between Jews and non-Jews. Gut 1993;34:
517524.
6. Sands BR. Inflammatory bowel disease: past present and future. J Gastroenterol 2007;42:1625.
7. Schreiber S, Hampe J. Genomics and inflammatory bowel disease. Curr
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8. Inohara N, Ogura Y, Fontalba A, et al. Host recognition of bacterial
muramyl dipeptide mediated through NOD2. Implications for Crohns
disease. J Biol Chem 2003;278:55095512.
9. Thomas GA, Rhodes J, Green JT. Inflammatory bowel disease and
smokinga review. Am J Gastroenterol 1998;93:144149.
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52. Farmer RG, Hawk WA, Turbull RG. Clinical patterns of Crohns disease:
a statistical study of 615 cases. Gastroenterology 1975;68:627635.
53. Longo WE, Ballantyne GH, Cahow E. Treatment of Crohns colitis. Segmental of total colectomy? Arch Surg 123;588590.
54. Prabhakar LP, Laramee C, Nelson H, et al. Avoiding a stoma: role for segmental or abdominal colectomy in Crohns colitis. Dis Colon Rectum
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55. Moscovitz I, Belin BM, Wexner SD. Colonic Crohns disease. Tech Coloproctol 2000;4:3944.
56. Trickett JP, Tilney HS, Gudgeon AM, et al. Management of the rectal
stump after emergency subtotal colectomy: which surgical option is associated with the lowest morbidity? Colorectal Dis 2005;7:519522.
57. Hyder SA, Travis SPL, Jewell DP, et al. Fistulizing anal Crohns disease:
results of combined surgical and infliximab treatment. Dis Colon Rectum
2006;49:18371841.
58. OConnor L, Champagne BJ, Ferguson MA, et al. Efficacy of anal fistula
plug in closure of Crohns anorectal fistulas. Dis Colon Rectum 2006;49:
15691573.
59. Mekhjian HS, Switz DM, Watts HD, et al. National Cooperative Crohns
Disease Study: factors determining recurrence of Crohns disease after
surgery. Gastroenterology 1979;77(4 Pt 2):907913.
60. Post S, Herfarth C, Bohm E, et al. The impact of disease pattern, surgical
management, and individual surgeons on the risk for relaparotomy for
recurrent Crohns disease. Ann Surg 1996;223:253260.
K E Y
Although the small bowel accounts for 75% of the length and
90% of the mucosal surface of the gastrointestinal tract, it is
the site of only 1% to 3% of gastrointestinal malignancies.
2 As in the colon, small-bowel adenomas may be histologically classified as tubular, tubulovillous, or villous. Adenomas occur predominantly in the duodenum with the
majority found in the periampullary region.
3 Like adenomas, adenocarcinomas have a predilection for
the duodenum, with a marked decrease in frequency moving axially along the small bowel. Approximately 80% of
tumors are located in the duodenum or proximal jejunum.
4 The gastrointestinal tract is the site of 4% to 20% of all
non-Hodgkin lymphomas, being the most common extra1
Small-bowel tumors, both benign and malignant, are uncommon. Although the small bowel accounts for 75% of the length
and 90% of the mucosal surface of the gastrointestinal tract,
less than 5% of primary gastrointestinal malignancies arise
from the small intestine.1 Although they are unusual, benign
small-bowel lesions have been incidentally discovered in 0.2%
to 0.3% of autopsy specimens, 15 times more than the number
discovered in surgical specimens, attesting to the frequently
asymptomatic nature of these neoplasms.2 Recent data have
reported an increase in the incidence of small-intestinal tumors, a
factor at least partly due to improved imaging modalities and
to an increasing number of immunocompromised patients.1,3
Small-intestinal tumors may originate from cells of epithelial
origin (adenomas, adenocarcinomas, or carcinoids), lymphatic
tissues (lymphomas), or mesenchymal or neural elements (gastrointestinal stromal tumors, leiomyomas, lipomas, hemangiomas, neuromas, and a wide variety of sarcomas). From
1975 to 2000, the rates increased by almost 50%. This trend
reflected increases for adenocarcinomas, malignant carcinoid
tumors, and lymphomas in men, and for carcinoid tumors and
lymphomas in women.4 The small intestine is also a rare site for
metastasis from other primary tumors.
P O I N T S
nodal site. The stomach harbors the most lymphomas, followed by the small bowel and then the colon.
5 Carcinoids are indolent malignant neuroendocrine tumors
that arise from the enterochromaffin cells at the base of the
crypts of Lieberkhn.
6 Gastrointestinal stromal tumors are characterized by
expression of c-kit and PDGFR gene mutations. While
surgical resection is the only curative treatment, adjuvant
therapy with imatinib and other tyrosine kinase antagonists can decrease the risk of relapse in patients after resection of high-risk tumors.
EPIDEMIOLOGY
While the relative incidence rates of small-bowel tumors in the
United States appear to be increasing,3 there are clearly geographic variations in incidence worldwide. Carcinoid tumors
are virtually nonexistent in Asian populations, yet represent
about 30% of malignant small-bowel neoplasms in Western
series.3,5,6 The proportion of benign small-bowel tumors varies
from 14% to 52% in various international series, a disparity
likely explained by failure to detect the typically asymptomatic
benign lesions. Reported rates of non-Hodgkin lymphoma of
the small bowel vary from 27% to 72%, a discrepancy due in
part to inconsistent categorization of lymphomas as primary
or metastatic tumors, but also due partly to geographic variation. Given the rarity of small-bowel tumors and the wide variety of histologies, there are no large case series for any specific
histologic subtype in the world literature, making comparisons
difficult and definitive incidence rates difficult to confirm.7
Although generalizations regarding these rare tumors can be
difficult to formulate, certain patterns can be discerned. Smallbowel neoplasms are less common in women than in men: a
785
PATHOGENESIS
Several hypotheses have been proposed to explain the low incidence of small-bowel tumors, particularly those derived from
cells of the intestinal epithelium. These hypotheses postulate
that small-bowel neoplasms may arise from disruption of normal small-bowel flora, pH, transit times, or mucosal integrity.
Although none of these hypotheses have been verified, they are
plausible given what is known about the pathogenesis of other
gastrointestinal tumors. The dilute alkaline liquid contents of
healthy small bowel are potentially less capable of inducing
direct mechanical mucosal injury and disruption than the
more solid contents of the colon. The luminal content of the
healthy small-bowel lumen does not harbor pathogenic bacteria and their potentially toxic metabolites are not present to
induce the genetic alterations implicated in colon carcinogenesis. Rapid transit time through the small-bowel lumen, normally 30 minutes to 2 hours, may limit mucosal exposure to
potential carcinogens, whereas the presence of the enzyme
benzopyrene hydroxylase in the brush border of the small
intestine may provide protection against mucosal damage by
detoxifying the carcinogen benzopyrene. The greater concentration and distribution of lymphoid tissue in the intestinal
epithelium and submucosa and high levels of luminal
immunoglobulin A may provide an immunologic protective
mechanism against neoplasia. Some investigators suggest that
the high rate of metachronous primary malignancies, observed
in up to 20% of patients, and the frequency of multicentric
small-bowel malignancies support an alteration in host
defenses or a breakdown in this immunologic protective
mechanism as an important etiologic factor.
CONDITIONS ASSOCIATED
WITH INCREASED RISK FOR
SMALL-BOWEL TUMORS
Although the small bowel develops few tumors, risk factors
for the development of malignant lesions have been identified.
As shown in Table 50.1, several conditions carry an increased
risk of neoplasia.
Crohn Disease
Crohn disease is associated with up to a 10- to 12-fold
increased risk of developing small-bowel adenocarcinoma,9
with carcinoma developing in diseased segments of the bowel
with preexisting dysplasia. Three quarters of these smallintestinal cancers arise in the ileum, the area most commonly
involved with Crohn disease but the segment of small bowel
least commonly affected by adenocarcinoma in healthy individuals. The remaining small-intestinal tumors in patients with
Crohn disease are found in the duodenum and the jejunum,
following the usual distribution of sporadic carcinoma, which
tends to develop in the duodenum. Crohn-associated carcinomas carry a particularly poor prognosis because the tumors
are frequently diagnosed at an advanced stage, likely because
the abdominal symptoms of the tumor are initially attributed
to the underlying inflammatory bowel disease.10
TA B L E 5 0 . 1
ETIOLOGY
POTENTIAL
MALIGNANCY
Adenomatous polyps
Adenocarcinoma
Familial adenomatous
polyposis
Adenocarcinoma
Peutz-Jeghers syndrome/
hamartomatous polyps
Adenocarcinoma
Leiomyomas
Possible leiomyosarcoma
Neurofibromatosis
Leiomyosarcoma, carcinoid,
adenocarcinoma
Crohn disease
Adenocarcinoma
Celiac sprue
Lymphoma, adenocarcinoma
Immunosuppression
Lymphoma
Human immunodeficiency
virus infection
Low-grade lymphoma
(mucosal-associated
lymphoid tissue)
Lymphoma
GASTROINTESTINAL
786
CLINICAL PRESENTATION
There are no pathognomonic signs or symptoms of smallbowel tumors. Complaints, if reported, are nonspecific. As
shown in Table 50.2, the most common symptomsabdominal pain, weight loss, anemia, nausea, and vomitingdo not
suggest specific localization and are usually present in about
45% of patients. These vague complaints often lead to diagnostic delay before the correct diagnosis of small-bowel neoplasm is established. Tumor location may influence the time
required for detection. Smaller lesions often present earlier in
the ileum, where the lumen is narrower and obstruction more
likely to develop. As tumors enlarge, symptoms are more likely
to develop. Of all lesions measuring at least 4 cm, 75% will
cause symptoms, whereas 92% of malignant lesions of that
size will be symptomatic. Overall, malignant lesions tend to be
more symptomatic than benign lesions, eliciting complaints of
abdominal pain and weight loss. In contrast, benign tumors
more often present with acute hemorrhage as the primary
TA B L E 5 0 . 2
DIAGNOSIS
FREQUENCY (%)
Benign Neoplasms
Asymptomatic
4760
Abdominal pain
2450
2944
Anemia
2858
Intermittent obstruction
1228
Malignant Neoplasms
Asymptomatic
612
Abdominal pain
6283
Weight loss
3855
Nausea/vomiting
2364
631
1238
Abdominal mass
532
DIAGNOSIS
Diagnosis of a small-bowel neoplasm can be challenging. In
most series, the average duration of symptoms prior to
diagnosis ranges from weeks to many months. Diagnosis is
hindered by the infrequency of these tumors and failure to
consider small-bowel neoplasm in the differential diagnosis
for patients with nonspecific abdominal complaints. More
importantly, diagnosis is delayed because imaging modalities
available to study the small bowel are limited. Accurate preoperative diagnosis is rarely established prior to surgery.1
Plain abdominal radiography is rarely helpful unless the
patient presents with obstructive symptoms. For patients being
evaluated for gastrointestinal complaints or gastrointestinal
bleeding, the diagnosis of small-bowel tumor is usually considered after negative endoscopic evaluation of the foregut and
colon. The diagnostic workup should then proceed to computed
tomography (CT) scan of the abdomen. In addition to readily
identifying bulky mass lesions, imaging allows detection of subtle findings that are highly suggestive of small-bowel tumors.
Neoplastic disease must be strongly suspected if the small bowel
wall is thicker than 1.5 cm or if there are discrete mesenteric
lymph nodes or masses greater than 1.5 cm in diameter. The CT
scan may reveal a transition zone, demarcating dilated proximal
bowel from decompressed distal bowel. If associated with
bowel wall thickening, a tumor is likely, except in patients with
clinical characteristics more typical of Crohn disease or those
who carry a known diagnosis of Crohn disease.
Tumors of the distal small bowel may show CT findings of
ileocolic or jejunoileal intussusception. Diagnosis of intussusception in adult patients warrants operative intervention without further delay. During intussusception, the small-bowel
tumor serves as the lead point to pull the small bowel into the
Small-bowel Enteroscopy
Endoscopic modalities include push enteroscopy, intraoperative enteroscopy, VCE, and DBE. The older modality of Sonde
pull-through enteroscopy is no longer in clinical use. Push
enteroscopy utilizes a pediatric colonoscope for direct examination of the mucosa of the proximal small bowel.21 Biopsy of
identified lesions can be performed with this instrument,
787
SURGICAL MANAGEMENT
Surgical approaches have changed as laparoscopic procedures
for abdominal conditions have been disseminated throughout
the surgical community. Laparoscopic approaches are suitable
GASTROINTESTINAL
788
BENIGN TUMORS OF
THE SMALL INTESTINE
Accounting for 30% to 50% of primary neoplasms of the small
bowel, benign tumors are poorly characterized. Half the patients
with benign tumors are symptom free, even in retrospect, until
the need for emergency surgery. Up to 60% of benign smallbowel tumors will be diagnosed at the time of presentation with
a surgical emergency including obstruction, massive gastrointestinal hemorrhage, or perforation. For patients who do present
with symptoms necessitating evaluation, vague abdominal pain
and recurrent gastrointestinal bleeding are the most common. In
one series,2 29% of patients with benign lesions presented with
an acute hemorrhage and 40% in another series,8 a feature that
may help differentiate benign from malignant lesions, the latter
of which bleed less often. Many more lesions are never identified
because they elicit no symptoms.
As noted previously, the diagnostic workup is challenging.
In patients with symptoms, investigations should proceed as
outlined previously. The sequelae of the neoplasms (obstruction, hemorrhage, perforation) will dictate the pathway of
evaluation.
Regardless of the location, the treatment of benign smallbowel tumors is local excision or limited resection. As gross
appearance in the operating room may not definitively establish a small-bowel tumor as benign, segmental resection is
often the most appropriate surgical approach. Endoscopic
resection or submucosal excision via operative enterotomy
may be appropriate for small lesions with obvious benignappearing features such as a lipoma or for multiple symptomatic lesions as occurs with Peutz-Jeghers syndrome24; however,
segmental limited resection is usually the most appropriate
intervention. Intraoperative examination of the small bowel
with careful palpation, including the possible use of intraoperative enteroscopy for evaluation of suspected abnormalities, is
essential to rule out synchronous lesions.
ADENOMAS
Unique to the duodenum, Brunner gland adenomas are rare
tumors of the proximal duodenum.25 Brunner glands are normally found in the duodenal submucosa and secrete an alkaline bicarbonate-rich fluid and mucus that aids in the neutralization of gastric acid. The pathogenesis of the glandular
hyperplasia that is linked to adenoma formation remains
unknown. Brunner gland adenomas appear to have minimal, if
any, malignant potential. Once identified, local resection via
endoscopic means or duodenotomy with submucosal excision
should be performed to prevent intussusception or biliary
obstruction as the adenoma grows.
2
As in the colon, small-bowel adenomas may be histologically classified as tubular, tubulovillous, or villous. Adenomas
LIPOMAS
Lipomas are true fatty neoplasms of the small bowel that are
typically asymptomatic. These tumors are most often found
incidentally on abdominal CT scans completed for evaluation
of other clinical conditions. Lipomas are identified as wellcircumscribed lesions of fat density on CT imaging. Unless
associated with bleeding or obstruction, small tumors under
2 cm can be safely observed, while larger lesions or growing
lesions should be resected to rule out malignant liposarcoma.
Because these tumors are polypoid, compressible intraluminal
lesions, they are predisposed to induce intussusception. If
surgery is performed either for a complication of the lipoma or
an unrelated condition, local excision is adequate treatment.
HAMARTOMAS
MALIGNANT NEOPLASMS
Malignant neoplasms in the small bowel are either primary or
metastatic. Primary malignancies include adenocarcinoma,
gastrointestinal stromal tumors (GISTs), leiomyosarcoma,
non-Hodgkin lymphoma (NHL), and carcinoid tumors, with
rare reports of other lesions including liposarcoma, myxoliposarcoma, and lymphangiosarcoma. Metastatic tumors of the
small bowel have been reported from many primary solid
tumors, but melanoma and lymphoma are the most common.
Compared with benign tumors, malignant lesions are more
likely to present with pain, weight loss, and anorexia. Although
nonspecific, these findings are more ominous than other symptoms shared with benign tumors, such as nausea and vomiting
and acute or chronic blood loss. As a group, patients with
malignant small-bowel tumors present at advanced stages and
have a poor prognosis. High rates of metastatic spread are
noted on initial surgical operation.
The diagnosis of small-bowel malignancy should prompt a
thorough diagnostic evaluation. Second primary malignancies
are found in 20% to 30% of patients. This association is especially relevant for carcinoid tumors, where the incidence rate
of second primaries is as high as 30% to 50%. The second
primary cancer may arise in any organ, but the most frequent
second primary sites are the colorectum and breast.29
Peutz-Jeghers syndrome (PJS) is an autosomal dominant condition characterized by multiple gastrointestinal hamartomas
ADENOCARCINOMA
and mucocutaneous pigmentation. The polyps arise predominantly in the jejunum and ileum and often present as an intusEpidemiology
susception. Although hamartomas rarely if ever undergo malignant transformation, the condition is associated with the
Adenocarcinoma accounts for about 30% of small-bowel
development of adenocarcinoma.17 Double-balloon enteroscopy
3 tumors.1 Like adenomas, sporadic adenocarcinomas have a
and video capsule endoscopy have provided effective screening
predilection for the duodenum, with a marked decrease in fretechnologies for patients with PJS. Endoscopic mucosal resecquency moving axially along the small bowel.3 Approximately
tion of hamartomas or polyps in patients with PJS via double80% of tumors are located in the duodenum or proximal
balloon enteroscopy has been described. Surveillance is recomjejunum. Most studies report a slight male preference.
mended with endoscopic removal of lesions when they are
There are several risk factors for the development of adenoidentified. Patients who are diagnosed with PJS are at
carcinoma.
Malignant transformation of villous and tubulovilincreased risk for developing a number of cancer types, includlous adenomas is likely the most important and occurs preing colorectal, gastric, small-bowel, ovarian/testicular, and
dominantly in the periampullary region of the duodenum.
pancreatic cancer. Patients who are diagnosed with this disease
Crohn disease increases the risk up to 100-fold and predisshould undergo genetic counseling and have first-degree relaposes to cancer in the more distal small bowel in regions of
tives screened. Screening for duodenal and small-bowel tumors
dysplasia.
in patients who are positive for the genetic mutation that
causes PJS can include interval esophagogastroduodenoscopy
and small-bowel contrast studies beginning in childhood (as
Clinical Presentation
early as age 8).24 Although no consensus exists regarding the
exact screening guidelines for these patients, close follow-up by
The presenting symptoms of small-bowel adenocarcinoma
a gastroenterologist is warranted given the high risk for a
depend on the location and size of the tumor. Because tumors
number of malignancies.
tend to arise in the proximal small bowel and to encompass
the bowel wall, adenocarcinomas cause obstruction with associated anorexia. The majority of tumors cause crampy abdominal pain. Periampullary duodenal adenocarcinomas may
HEMANGIOMAS
cause obstructive jaundice or pancreatitis as they grow. In this
case, the physical complaints and findings help guide the direcHemangiomas are rare lesions of the small bowel, developing
tion of the diagnostic evaluation. Often, the only complaint is
predominantly in the jejunum and ileum. They are congenital
vague, persistent abdominal pain.
lesions that grow slowly, typically coming to medical attention
GASTROINTESTINAL
789
790
FIGURE 50.2. A 73-year-old woman who presented with gastric outlet obstruction was found on this small-bowel follow-through study to
have apple-core lesion of the proximal jejunum. At exploration, she
was found to have jejunal adenocarcinoma.
Diagnosis
If obstruction is present, plain abdominal films may reveal gastric distention or near-complete proximal small-bowel obstruction. More commonly, however, these films are unrevealing. For
the jaundiced patient, ultrasound or abdominal CT or magnetic
resonance cholangiopancreatography may demonstrate the
duodenal mass and site of biliary obstruction. Esophagogastroduodenoscopy is the diagnostic modality of choice, with diagnostic rates of 85% to 90%.
Of small-bowel adenocarcinomas, 70% are polypoid, 20%
are ulcerated, and 10% are infiltrative. Comparable to other
segments of the gastrointestinal tract, adenocarcinomas of the
jejunum and ileum are usually annular constricting tumors
seen as apple-core lesions, as demonstrated on luminal contrast studies or esophagogastroduodenoscopy (Fig. 50.2).
Long lesions, especially when ulcerated, may be mistaken for
lymphomas. On CT scan, adenocarcinomas may attenuate
heterogenously and have moderate contrast enhancement.
Again, usually only a short segment of small bowel is involved,
and occasionally they are associated with an ulcer. Despite the
array of diagnostic modalities, preoperative diagnosis remains
infrequent, achieved in only 20% to 50% of cancers.
Management
The only potential cure for adenocarcinoma is complete surgical resection. At operation, the resectability rate for cure
approaches 60%. For proximal and midduodenal lesions, pancreaticoduodenectomy is necessary to completely resect the
tumor and lymphatic basin. In the third and fourth portions of
the duodenum and in the mesenteric small bowel, a segmental
resection with lymphadenectomy should be performed to
attempt surgical cure. In patients with metastatic or unresectable disease, palliative procedures to relieve obstruction or
control hemorrhage should be considered. Segmental resection
or intestinal bypass is appropriate in some patients. Duodenal
obstruction may be palliated with endoscopic placement of
expandable stents, although recurrent obstruction and hemor-
NON-HODGKIN LYMPHOMA
4
TA B L E 5 0 . 3
791
S TA G I N G
STAGE
5-YEAR SURVIVAL
RATE
Tx
Unknown primary
T0
No evidence of primary
Tis
Carcinoma in situ
T1
70%
T2
T3
II
50%
T4
Nx
N0
20%
IV
10%
N1
Mx
Mo
No distant metastases
M1
On physical examination, there should be no superficial adenopathy, and chest radiograph (CT or x-ray) should reveal no mediastinal adenopathy. Peripheral blood cell counts must be normal, and there may be no evidence of splenic or hepatic
involvement. Finally, at laparotomy, disease must be restricted
to the primary tumor with mesenteric lymph node involvement.
Multiple histologic variations of lymphoma exist, showing
significant geographic variability. The majority of primary
intestinal NHLs are of the B-cell type, with T-cell lymphoma
comprising only 10% to 25% of cases. Further classifications
of B-cell and T-cell tumors have been proposed, but none has
been uniformly adopted. A significant number of gastrointestinal lymphomas appear to be low-grade lymphomas derived
from mucosal-associated lymphoid tissue. These lymphomas
arise predominantly in the stomach but also occur in the small
bowel. In the stomach they are associated with Helicobacter
pylori infection and may regress with treatment of this infection. In the small bowel these low-grade lymphomas should be
resected. T-cell lymphomas tend to have a worse prognosis
than B-cell tumors.
Clinical Presentation
Similar to other small-bowel malignancies, the majority of
patients with NHL present with abdominal pain that is nonspecific and unlocalized. Malabsorption, obstruction, and evidence of a palpable mass may be present. Although rare, perforation is a more common presentation for gastrointestinal
NHL than for adenocarcinoma, possibly related to a lack of a
vigorous desmoplastic response in lymphoma. Signs that are
common in nodal lymphoma, such as adenopathy and
splenomegaly, are unusual in primary gastrointestinal NHL.
Diagnosis
Most small-bowel lymphomas will be demonstrable on CT
scan, as these lymphomas may grow to be quite large. CT scan
will demonstrate the mass as well as marked luminal dilata-
Treatment
With no randomized series and small numbers of cases at single
institutions, the optimal treatment of gastrointestinal NHL
remains controversial. Previously, surgical resection of localized
gastrointestinal lymphomas followed by systemic chemotherapy
was considered to be standard first-line therapy.3335 The data
regarding the efficacy of primary surgical therapy with or without adjuvant chemotherapy versus systemic therapy alone are
limited since gastrointestinal lymphomas are relatively rare. In
many case series reporting outcomes after surgical resection of
gastrointestinal lymphoma, the diagnosis of lymphoma was not
known preoperatively and discovered only after intervention for
a symptomatic small-bowel lesion. It is not clear, however,
GASTROINTESTINAL
TNM
792
TA B L E 5 0 . 4
S TA G I N G
EXTENT OF DISEASE
II
IIE
II1
II2
III
IV
routinely treated primarily with anthracycline-based chemotherapy regimens, in combination with monoclonal-based antibody
therapies such as rituximab and/or irradiation.36 The majority of
small-bowel lymphomas are also large-cell, non-Hodgkin, Bcelltype lymphomas. Although they may appear to be localized,
biologically these tumors tend to be more aggressive and often
require systemic therapy for definitive management. Increasingly, systemic therapy is considered to be the mainstay for management of these lesions. Surgical intervention can still be considered for patients who are refractory to chemotherapy or as
primary therapy for localized small-bowel lymphoma with
favorable histology.37 Decisions regarding the management of
small-bowel lymphomas that do not require emergent surgical
management should be made in a multidisciplinary setting with
input from surgeons, medical oncologists, and pathologists, as
there is currently no definitive consensus regarding standard
first-line therapy for small-bowel lymphomas.3,3739
whether surgery should be the first line of treatment if a diagnosis of lymphoma can be made prior to any operative interventions. Indeed, for most lymphomas, systemic therapy and/or
radiation has been considered to be standard first-line therapy,
rather than surgical resection, because lymphoma is recognized
to have the potential for systemic dissemination. For other gastrointestinal lymphomas, such as gastric lymphoma, chemotherapy and/or radiation is now considered to be the first-line therCARCINOID TUMORS
apy of choice, with surgical interventions being reserved for
complications such as bleeding, perforation, obstruction, or fail- 5 Carcinoids are indolent malignant neuroendocrine tumors that
ure to respond. Indeed, non-Hodgkin, diffuse B-cell lymphoma
arise from the enterochromaffin cells at the base of the crypts of
is the most common type of gastric lymphoma, and it is now
Lieberkhn. These cells are part of the amine precursor uptake
and decarboxylation (APUD) system and can secrete peptides
responsible for the carcinoid syndrome. Although 80% of carcinoids arise in the gastrointestinal tract, 10% of primary carcinoids occur in the bronchus or lung. Other sites, such as the
ovaries, testicles, pancreas, and kidney, are far less common.
Within the gastrointestinal tract, carcinoids are most often
identified in the appendix, followed by the small bowel, which
harbors approximately 30% of all gastrointestinal carcinoids.
Almost half of these arise in the distal 2 feet of ileum.
A recently published series (the largest to date) evaluated all
small-bowel malignancies reported to the National Cancer
Database from 1985 to 2005. Analysis of 67,000 patients with
small-intestinal tumors revealed that the incidence of smallbowel cancer of all histologies has increased, but most of the
change is a result of a more than fourfold increase in the incidence of carcinoid tumors. In this particular series, carcinoid
tumors accounted for the majority of small-intestinal cancers,
surpassing adenocarcinoma of the small intestine.3 Of all the
FIGURE 50.4. The computed tomography scan similarly demonpatients evaluated, 25,339 patients (37.4%) had carcinoid
strated a thickened ileal loop with dilatation. No adenopathy was
tumors and 25,053 patients (36.9%) had adenocarcinomas. In
noted. At surgery, the patient was found to have a primary lymphoma
various series, carcinoid tumors comprise 30% to 35% of
of the small bowel.
small-bowel neoplasms, and carcinoids are found slightly
more often in men than in women.3,40 The mean age of presentation is 60 years. The tumors are frequently asymptomatic;
in fact, the autopsy rate in one study was over 2,000 times that
of the annual incidence rate, indicating the potential for longstanding slow growth. When symptomatic, carcinoids typically
present with pain or obstructive symptoms. Because these
tumors are typically slow growing, symptoms may be present
for 2 to 20 years prior to diagnosis. Ulceration is rare in carcinoids, so gastrointestinal bleeding is uncommon. Patients present with carcinoid syndrome in up to 40% of cases and only
in the presence of symptoms of carcinoid syndrome is the diagnosis consistently made preoperatively.
There are five histologic patterns that correlate embryologically with the location of the tumor.41 The foregut, or duodenal, lesions usually demonstrate a trabecular or ribbon pattern. An insular pattern predominates in the midgut or
small-bowel lesions, and a mixed pattern is typical of the
hindgut or colorectal lesions. The least common patterns are
glandular or tubular and undifferentiated, both of which have a
much poorer prognosis than the three more common variations.
The histologic pattern does not affect treatment, but with other
factors, appears to impact on long-term survival.
793
Carcinoid Syndrome
Carcinoid syndrome refers to vasomotor, gastrointestinal, and
cardiac manifestations induced by systemic circulation of a variety of peptides elaborated by carcinoid tumors. The amine precursor uptake and decarboxylation cells of carcinoid tumors
can produce vasoactive products including serotonin, histamine, kallikrein, bradykinin, and prostaglandins, although the
specific mediator or mediators of the syndrome remain
unknown. Carcinoid syndrome is most reliably confirmed by
finding elevated 24-hour 5-hydroxyindoleacetic acid (5-HIAA)
urinary excretion, the primary stable metabolite of serotonin.
Attacks are initiated by stimuli including stress, alcohol, a
large meal, or sexual intercourse, all of which manipulate the
liver in some capacity. Flushing is the most common finding
and affects approximately 80% of syndrome patients. The
flush varies slightly by the location of the tumor, but in midgut
carcinoids the flush is usually short-lived, lasting 5 to 10 minutes. Classically, the erythematous flush begins on the face and
spreads to the trunk and limbs. Diarrhea, found in 75% of
patients, seems to be caused by serotonin release. The diarrhea
is intermittent, watery, and at times explosive. It may be associated with abdominal cramps and the patient may experience
a certain degree of malabsorption. Cardiac manifestations are
present in 60% to 70% of patients due to tricuspid and pulmonary valve fibrosis, possibly secondary to high levels of 5hydroxyindoleacetic acid. As the disease progresses, the fibrotic
plaque stiffens, leading eventually to right heart failure.
GASTROINTESTINAL
794
GASTROINTESTINAL
STROMAL TUMORS
Although GISTs are the most common nonepithelial cell
tumors of the small bowel, they are rare tumors of the gastrointestinal tract, representing only about 5,000 cases nationwide per year.51 Approximately 25% of GISTs arise in the
small bowel, with 50% gastric, 15% rectal, and 10% colonic
in origin.52 GISTs are diagnosed equally in men and women,
with a median age at onset of 64 years. Arising from the interstitial cell of Cajal, the pacemaker cells of the gastrointestinal
tract situated between the intramural neurons and the smooth
muscle cells, GISTs are characterized by the presence of activating c-kit mutations, a transmembrane receptor tyrosine
kinase involved in the regulation of cellular proliferation,
apoptosis, and differentiation. More than 95% of GISTs
express kit (CD117) mutations.51 This molecular marker
allows for distinction of GISTs from histologically similar mesenchymal tumors of the small bowel including leiomyomas,
leiomyosarcomas, and schwannomas. This molecular feature
has led to reclassification of up to 70% of small-bowel tumors
as GISTs that had previously been classified as a variety of
mesenchymal tumors. Those GISTs that do not express c-kit
mutations may express a mutation in another tyrosine kinase
receptor, platelet-derived growth factor receptor- (PDGFR).53 Present in approximately 5% to 7% of GISTs, these activating mutations also result in abnormal cellular proliferation.
Like other primary small-bowel tumors, GISTs are characterized by indolent clinical symptoms including vague abdominal pain, weight loss, and occult gastrointestinal bleeding.
Although acute hemorrhage, perforation, or obstruction may
lead to an emergency presentation, GISTs may grow to a massive size prior to surgical presentation. Usually they grow
insidiously as extraluminal masses from their submucosal origin in a noninvasive manner, characteristically pushing adjacent organs away from the expanding mass.
Diagnostic strategies are the same as for other tumors of the
small bowel. Given the propensity of GIST to grow to a large
size prior to diagnosis, CT scan is most likely to be the initial
positive test. A characteristic finding is the presence of a large
space-occupying mass, occasionally with calcification and
hypervascularity and often with evidence of central necrosis and
compression of adjacent organs (Fig. 50.7A). Smaller tumors
are detected with esophagogastroduodenoscopy in the stomach
and duodenum and with video capsule endoscopy or doubleballoon enteroscopy in the small bowel. 18F-fluorodeoxyglucose
(18F-FDG) positron emission tomography (PET) testing has also
been utilized for assessing response to adjuvant therapies but is
not employed generally for initial staging of the disease.51
All GISTs should be considered to be malignant.54 Malignant
potential is based on two major criteria, as reported from the
National Institutes of Health consensus workshop: tumor size
and mitotic rate (Table 50.5). Biologically aggressive tumors are
large lesions with a high mitotic index, whereas tumors with
benign features are small and exhibit a low mitotic index.
Tumors are thus classified into very-low- to high-risk lesions for
malignant potential, a classification that has prognostic significance. Additional reports have suggested negative factors for
prognosis including high Ki-67 index and male gender, but these
parameters have not consistently been predictive.51
Treatment
Surgery is the primary therapeutic option with the goal being
complete resection. Preoperative biopsy is controversial, and a
presumed diagnosis of GIST is enough to warrant surgery if
the disease appears resectable. At operation, wide local excision of the primary tumor with in continuity resection of
adherent organs is appropriate to attain curative resection
795
GASTROINTESTINAL
FIGURE 50.7. A: Computed tomography image of a 76-year-old man with abdominal distention demonstrating a complex abdominal mass with
varying degrees of thickness, central necrosis, and compression of adjacent organs. This was found to be a gastrointestinal stromal tumor with
markedly increased mitotic activity. B: Intraoperative photograph of the same patient, showing displacement of adjacent organs.
SIZE
MITOTIC RATE
High
Any size
10/50 HPF
10 cm
Any rate
10-YEAR SURVIVAL
30%
5 mm
5/50 HPF
510 cm
5/50 HPF
5 cm
610/50 HPF
Low
25 cm
5/50 HPF
75%
Very low
2 cm
5/50 HPF
80%
Normal population
80%
Intermediate
60%
796
METASTATIC LESIONS
TO THE SMALL BOWEL
The small bowel is the site of metastatic disease from multiple
other primary sites. Metastatic spread can occur by direct
invasion, hematogenous spread, or intraperitoneal seeding.
Direct invasion from a colon or pancreatic cancer represents
the most common mode of involvement. Hematogenous spread
arises most frequently from bronchogenic or breast carcinoma or
malignant melanoma. Peritoneal seeding has been documented
from primary tumors of the stomach, liver, ovary, appendix, and
colon.
A CT scan often demonstrates not only the degree of
involvement of the small bowel but also the primary tumor. In
metastatic small-bowel tumors, one may see bowel wall thickening as well as lesions in the mesentery or retroperitoneal fat.
For small lesions, CT scan may be negative, while video capsule
endoscopy or double-balloon enteroscopy may reveal a luminal
mass. Carcinomatosis may be difficult to identify even on body
CT imaging.
Optimal management is based on clinical criteria. Palliative
intestinal resection or bypass to relieve hemorrhage, obstruction, or pain is indicated except in the most terminal stages of
disease. Case reports of prolonged survival after intestinal
resection of solitary metastases have been reported, although
progression of metastatic disease is more common.57
Management of patients with carcinomatosis, regardless of
tumor origin, remains difficult. Palliative measures to maintain
intestinal continuity and liberal use of decompressive gastrostomy tubes are indicated.
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9. Xie J, Itzkowitz SH. Cancer in inflammatory bowel disease. World J Gastroenterol 2008;14:378389.
10. Freeman HJ. Colorectal cancer risk in Crohns disease. World J Gastroenterol 2008;14:18101811.
11. Howe JR, Karnell LH, Menck HR, et al. The American College of Surgeons Commission on Cancer and the American Cancer Society. Adenocarcinoma of the small bowel: review of the national cancer data base,
19851995. Cancer 1999;86:26932706.
12. OBoyle CJ, Kerin MJ, Feeley K, et al. Primary small intestinal tumours:
increased incidence of lymphoma and improved survival. Ann R Coll Surg
Engl 1998;80:332334.
13. Freeman HJ. Failure of added dietary gluten to induce small intestinal
histopathological changes in patients with watery diarrhea and lymphocytic colitis. Can J Gastroenterol 1996;10:436439.
14. Freeman HJ. Lymphoproliferative and intestinal malignancies in 214
patients with biopsy-defined celiac disease. J Clin Gastroenterol 2004;38:
429434.
15. Freeman HJ. Malignancy in adult celiac disease. World J Gastroenterol
2009;15:15811583.
16. Green PH, Fleischauer AT, Bhagat G, et al. Risk of malignancy in patients
with celiac disease. Am J Med 2003;115:191195.
17. Dong K, Li B. Peutz-Jeghers syndrome: case reports and update on diagnosis and treatment. Chin J Dig Dis 2004;5:160164.
18. Crump M, Gospodarowicz M, Shepherd FA. Lymphoma of the gastrointestinal tract. Semin Oncol 1999;26:324337.
19. Svoboda J, Kotloff R, Tsai DE. Management of patients with posttransplant lymphoproliferative disorder: the role of rituximab. Transpl Int
2006;19:259269.
20. Everly MJ, Bloom RD, Tsai DE, et al. Posttransplant lymphoproliferative
disorder. Ann Pharmacother 2007;41:18501858.
21. Waye JD. Small-bowel endoscopy. Endoscopy 2003;35:1521.
22. Rondonotti E, Villa F, Mulder CJ, et al. Small bowel capsule endoscopy in
2007: indications, risks and limitations. World J Gastroenterol 2007;13:
61406149.
23. Ersoy O, Sivri B, Bayraktar Y. How helpful is capsule endoscopy to surgeons? World J Gastroenterol 2007;13:36713676.
24. Calva D, Howe JR. Hamartomatous polyposis syndromes. Surg Clin
North Am 2008;88:779817, vii.
25. Zangara J, Kushner H, Drachenberg C, et al. Iron deficiency anemia due to
a Brunners gland hamartoma. J Clin Gastroenterol 1998;27:353356.
26. Beger HG, Treitschke F, Gansauge F, et al. Tumor of the ampulla of Vater:
experience with local or radical resection in 171 consecutively treated
patients. Arch Surg 1999;134:526532.
27. Brosens LA, Keller JJ, Offerhaus GJ, et al. Prevention and management of duodenal polyps in familial adenomatous polyposis. Gut 2005;54:10341043.
28. Farnell MB, Sakorafas GH, Sarr MG, et al. Villous tumors of the duodenum: reappraisal of local vs. extended resection. J Gastrointest Surg
2000;4:1321, discussion 2223.
29. Cunningham JD, Aleali R, Aleali M, et al. Malignant small bowel neoplasms: histopathologic determinants of recurrence and survival. Ann Surg
1997;225:300306.
30. Sohn TA, Lillemoe KD, Cameron JL, et al. Adenocarcinoma of the duodenum:
factors influencing long-term survival. J Gastrointest Surg 1998;2:7987.
31. Abrahams NA, Halverson A, Fazio VW, et al. Adenocarcinoma of the
small bowel: a study of 37 cases with emphasis on histologic prognostic
factors. Dis Colon Rectum 2002;45:14961502.
32. Singhal N, Singhal D. Adjuvant chemotherapy for small intestine adenocarcinoma. Cochrane Database Syst Rev 2007:CD005202.
33. Koniaris LG, Drugas G, Katzman PJ, et al. Management of gastrointestinal lymphoma. J Am Coll Surg 2003;197:127141.
34. Huang WT, Hsu YH, Yang SF, et al. Primary gastrointestinal follicular
lymphoma: a clinicopathologic study of 13 cases from Taiwan. J Clin Gastroenterol 2008;42:9971002.
35. Yamaguchi T, Takahashi H, Kagawa R, et al. Surgical resection combined
with chop chemotherapy plus rituximab for a patient with advanced
mesenteric diffuse large B cell lymphoma. Hepatogastroenterology 2008;
55:891894.
36. Psyrri A, Papageorgiou S, Economopoulos T. Primary extranodal lymphomas of stomach: clinical presentation, diagnostic pitfalls and management. Ann Oncol 2008;19:19921999.
37. Cheung MC, Housri N, Ogilvie MP, et al. Surgery does not adversely affect survival in primary gastrointestinal lymphoma. J Surg Oncol 2009;100:5964.
38. Pandey M, Wadhwa MK, Patel HP, et al. Malignant lymphoma of the gastrointestinal tract. Eur J Surg Oncol 1999;25:164167.
39. Gollub MJ. Imaging of gastrointestinal lymphoma. Radiol Clin North Am
2008;46:287312, ix.
40. Horton KM, Kamel I, Hofmann L, et al. Carcinoid tumors of the small
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182:559567.
41. Memon MA, Nelson H. Gastrointestinal carcinoid tumors: current management strategies. Dis Colon Rectum 1997;40:11011118.
42. Yantiss RK, Odze RD, Farraye FA, et al. Solitary versus multiple carcinoid
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43. Modlin IM, Shapiro MD, Kidd M. Carcinoid tumors and fibrosis: an association with no explanation. Am J Gastroenterol 2004;99:24662478.
44. Sheth S, Horton KM, Garland MR, et al. Mesenteric neoplasms: CT
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45. Soreide JA, van Heerden JA, Thompson GB, et al. Gastrointestinal carcinoid tumors: long-term prognosis for surgically treated patients. World J
Surg 2000;24:14311436.
46. Schell SR, Camp ER, Caridi JG, et al. Hepatic artery embolization for control of symptoms, octreotide requirements, and tumor progression in
metastatic carcinoid tumors. J Gastrointest Surg 2002;6:664670.
47. Roche A, Girish BV, de Baere T, et al. Trans-catheter arterial chemoembolization as first-line treatment for hepatic metastases from endocrine
tumors. Eur Radiol 2003;13:136140.
48. Roche A, Girish BV, de Baere T, et al. Prognostic factors for chemoembolization in liver metastasis from endocrine tumors. Hepatogastroenterology 2004;51:17511756.
48a. Moertel et al. Proc Am Soc Clin Oncol 1982.
49. Modlin IM, Kidd M, Latich I, et al. Current status of gastrointestinal carcinoids. Gastroenterology 2005;128:17171751.
50. Anthony LB, Woltering EA, Espenan GD, et al. Indium-111-pentetreotide
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51. Hueman MT, Schulick RD. Management of gastrointestinal stromal
tumors. Surg Clin North Am 2008;88:599614, vii.
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52. Miettinen M, Lasota J. Gastrointestinal stromal tumorsdefinition, clinical, histological, immunohistochemical, and molecular genetic features
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53. Heinrich MC, Corless CL, Duensing A, et al. PDGFRa activating mutations in gastrointestinal stromal tumors. Science 2003;299:708710.
54. von Mehren M. New therapeutic strategies for soft tissue sarcomas. Curr
Treat Options Oncol 2003;4:441451.
55. Kingham TP, DeMatteo RP. Multidisciplinary treatment of gastrointestinal
stromal tumors. Surg Clin North Am 2009;89:217233, x.
56. Andtbacka RH, Ng CS, Scaife CL, et al. Surgical resection of gastrointestinal stromal tumors after treatment with imatinib. Ann Surg Oncol 2007;
14:1424.
57. Cipollone G, Santarelli G, Quitadamo S, et al. Small bowel metastases
from lung cancer. Chir Ital 2004;56:639648.
GASTROINTESTINAL
SECTION G
PANCREAS
PHYSIOLOGY
TAYLOR S. RIALL
1
2
5
6
The pancreas is an elongated digestive organ that lies transversely in the retroperitoneum at the level of the second
1 lumbar vertebra. It is a glandular organ that has both
exocrine and endocrine function. The exocrine pancreas is
composed of acinar cells and ductal networks that function
to deliver alkaline solution (pH 8.0) containing over 20
enzymes and zymogens to the small intestine daily. The pancreatic secretions provide the optimal pH for the enzymes
and zymogens to carry out the major digestive activity of the
small intestine.
The endocrine pancreas is composed of islets of Langerhans. The islets secrete hormones including insulin, glucagon,
and somatostatin directly into the bloodstream in endocrine
fashion. These hormones regulate glucose homeostasis and
also play a role in the complex regulation of pancreatic secretion and digestion.
The pancreas is divided anatomically into four parts: the
pancreatic head, neck, body, and tail (Fig. 51.1). The pancreatic head includes the uncinate process, which is an extension
of the pancreatic head wrapping posterior to the superior
mesenteric vessels. An understanding of the close relationship of the pancreas to adjacent organs (duodenum, stomach,
spleen, transverse colon, bile duct, and left adrenal gland)
and major vessels (celiac axis, superior mesenteric artery,
superior mesenteric vein, splenic artery and vein, portal vein,
inferior mesenteric vein, and vena cava) is critical when performing surgical procedures on the pancreas. In addition,
understanding of the embryology is critical for recognizing
congenital anomalies, understanding their significance, and
treating them appropriately. Knowledge of the normal pancreatic physiology provides insight into the pathologic processes
P O I N T S
10
11
12
and subsequent treatments that can affect the normal function of the pancreas.
EMBRYOLOGY
Normal Pancreatic Embryology
During the fifth week of gestation, the pancreas begins forming at the junction of the foregut and midgut. The formation
begins as two endodermal pancreatic buds, the dorsal bud and
the ventral bud, which eventually fuse to form the pancreas
(Fig. 51.2). Both the acinar cells and islet cells differentiate
from the endodermal cells found in the embryonic buds. The
endocrine function of the pancreas begins between 10 and
15 weeks gestation, whereas the exocrine function does not
begin until after birth.
The dorsal and ventral buds are composed of endoderm
covered in splanchnic mesoderm. The splanchnic mesoderm
eventually develops into the dorsal and ventral mesentery.
The dorsal bud forms first and is larger. It ultimately forms
much of the head, body, and tail of the pancreas. As the duodenum grows and rotates, the ventral bud rotates clockwise
(Fig. 51.2) and fuses with the dorsal bud, forming the uncinate
process and inferior head of the pancreas. In the majority of
cases, the duct in the ventral bud fuses with the duct in the dorsal bud to become the main pancreatic duct (duct of Wirsung),
which drains the majority of the pancreas into the duodenum
through the major papilla, or ampulla of Vater. The proximal
duct of the dorsal bud forms the lesser or minor pancreatic duct
799
PANCREAS/LIVER
K E Y
800
Abnormalities in the rotation and fusion of the pancreas during embryonic development can result in specific congenital
anomalies that have surgical significance (Table 51.1). Approx-
TA B L E 5 1 . 1
CONGENITAL DISORDERS RESULTING FROM ABNORMALITIES IN THE ROTATION OR FUSION OF THE
DEVELOPING PANCREAS
DISORDER
DESCRIPTION
PRESENTATION
TREATMENT
Pancreas divisum
Often asymptomatic
Adults: recurrent acute pancreatitis,
chronic pancreatitis, or chronic
abdominal pain
Operative or endoscopic
sphincteroplasty of the
minor papilla and
accessory duct in
symptomatic patients
Annular pancreas
In utero: polyhydramnios
Infancy: duodenal obstruction, low
birth weight, feeding intolerance
Adults: often asymptomatic and
found incidentally
Duodenal bypass
(duodenoduodenostomy
or gastrojejunostomy)
Heterotopic
pancreas
Treatment directed at
presenting symptoms
Ikeda Y, Irving IM. Annular pancreas in a fetus and its three-dimensional reconstruction. J Pediatr Surg 1984;19(2):160164.
801
PANCREAS/LIVER
FIGURE 51.2. AD: Schematic drawings of the successive stages in the development of the pancreas from the fifth through the eighth weeks.
EG: Diagrammatic transverse sections through the duodenum and the developing pancreas. Growth and rotations (arrows) of the duodenum
bring the ventral pancreatic bud toward the dorsal bud and they subsequently fuse. The bile duct initially attaches to the ventral aspect of the
duodenum and is carried around to the dorsal aspect as the duodenum rotates. The main pancreatic duct is formed by the union of the distal
part of the dorsal pancreatic duct and the entire ventral pancreatic duct. (After Moore KL. The Developing Human, 3rd ed. Philadelphia, PA:
WB Saunders; 1982.)
802
the main pancreatic duct, this is of little to no clinical significance and most often found only at autopsy.
In 5% to 14% of cases, the fusion of the ventral and
dorsal pancreatic ducts is incomplete (pancreas divisum, Fig.
51.3C).13 As a result, the lesser duct drains the majority of the
pancreas into the duodenum through the minor papilla. Only
the small remnant duct of the ventral bud drains the uncinate
process into the duodenum via the ampulla of Vater. Pancreas
divisum is often asymptomatic. Whether this anomaly is
causative in producing pancreatitis and abdominal pain is
unclear.1,4,5 However, there is evidence that inadequate
drainage of the pancreas associated with mucosal stenosis of
the minor papilla is associated with amylase elevations and
abdominal pain.1,6,7 Patients can have recurrent episodes of
acute pancreatitis or chronic pancreatitis with chronic pain,
most often seen in young females. If no other causes of pan-
creatitis are identified and a patient has abdominal pain, elevated amylase levels, and pancreas divisum, this is considered
causative and an endoscopic or operative papillotomy of the
minor papilla and accessory duct is indicated. As most patients
with pancreas divisum do not develop acute or recurrent pancreatitis, it is thought that stenosis at the minor papilla or a
cystic dilatation of the distal dorsal duct just proximal to the
papilla may be the additional factors necessary for developing
pancreatitis in the setting of pancreas divisum.8
Annular pancreas is a rare congenital anomaly of the pancreas first recognized in 1818. Early autopsy and surgical series
estimate the incidence to be approximately 3 in 20,000.9,10
However, with better imaging modalities such as computed
tomography (CT), magnetic resonance cholangiopancreatography (MRCP), and endoscopy, the incidence is thought to be
closer to 1 in 1,000.1113 People with annular pancreas have a
Aorta
Celiac trunk
Duodenum
Pancreas
Superior
mesenteric artery
Jejunum
FIGURE 51.4. Annular pancreas. The ring of pancreatic tissue surrounds the duodenum. This ring contains a large duct and may be
heavily fixed to the duodenal musculature. The duodenum beneath the
annulus is often stenosed. As a result, dividing the ring of pancreatic
tissue may not provide relief of duodenal obstruction. There is also the
danger of creating a pancreatic fistula or duodenal perforation. Duodenojejunostomy bypassing the annulus is the procedure of choice for
duodenal obstruction caused by annular pancreas. (After Gray SW,
Skandalakis JE. Atlas of Surgical Anatomy for General Surgeons.
Baltimore, MD: Williams and Wilkins; 1985.)
The pancreas has two major components: the exocrine structure and the endocrine structure. The exocrine structure of the
pancreas accounts for 80% to 90% of the pancreatic mass,
while the endocrine structure accounts for approximately 2%
of the pancreatic mass. The remainder of the pancreas is composed of extracellular matrix, blood vessels, and major ductal
structures. The exocrine component secretes the enzymes
responsible for digestion, and the endocrine component is critical in glucose homeostasis.
Exocrine Structure
The exocrine structure of the pancreas is composed of two
main components: the acinar cells and the ductal network. The
acinar cells produce and secrete the enzymes responsible for
digestion. The acinar cells are pyramidal cells with an apex
that faces the pancreatic ductal network. Within the apex
of the cells there are numerous zymogen granules, which contain the digestive enzymes for secretion into the ductal system.
There are approximately 20 to 40 acinar cells that cluster
together to form the functional unit called an acinus (Fig.
51.5A, B). A second cell type in the acinus, the centroacinar
cell, functions to secrete fluid and electrolytes of the correct
pH into the pancreatic ductal system. The role of the ductal
system is to carry the digestive secretions to the duodenum.
The acinus drains into small intercalated ducts, which join to
form interlobular ducts that also secrete fluid and electrolytes
(Fig. 51.5A). These interlobular ducts form secondary ducts
that drain into the main pancreatic ductal system and eventually the duodenum at the ampulla of Vater.
thin band of normal pancreatic parenchyma completely surrounding the second portion of the duodenum. This band is in
continuity with the head of the pancreas and causes variable
degrees of duodenal compression and stenosis (Fig. 51.4). In
1910, Lecco postulated that annular pancreas resulted from
abnormal fusion of the ventral pancreatic bud to the duodenum, leading to improper rotation of the ventral bud around
the duodenum.14
Annular pancreas represents a spectrum of disease, presenting at varying time points from in utero to adulthood. The
disease differs significantly in adults and children.13 When
annular pancreas presents in childhood, it tends to be severe,
presenting at a median age of 1 day. In children it is more comEndocrine Structure
monly associated with other congenital anomalies including
Down syndrome, cardiac anomalies, and other intestinal
The pancreatic islet cells are of neural crest origin and part of
anomalies. When diagnosed in utero, the most common prethe family of amine precursor uptake and decarboxylation
sentation is polyhydramnios due to duodenal obstruction.
(APUD) cells. The most critical role of the pancreatic islet cells
Newborns present most commonly with duodenal obstruction
is the secretion of insulin and glucagon to maintain glucose
as evidenced by low birth weight and feeding intolerance.
homeostasis, although the islets secrete other hormones with
Duodenal bypass (duodenoduodenostomy or gastrojejunosvarying roles in digestion. Each pancreatic islet is approxitomy) is the treatment of choice in children.
mately 40 to 900 mm and contains an average of 3,000 cells.
Fifty percent of cases of annular pancreas occur in adults. 4 The islets are composed of four cell types. Alpha (A) cells
Adults are less likely to have significant obstruction and less
secrete glucagon, beta (B) cells secrete insulin and amylin,17
likely to require surgical intervention. In adults, annular pandelta (D) cells secrete somatostatin, and F cells secrete pancrecreas is more commonly associated with pancreas divisum and
atic polypeptide.
pancreatic neoplasia than in children.13 This abnormal ring of 5
B cells are located centrally within the islets and constitute
pancreatic tissue may contain a pancreatic duct. Therefore, the
approximately 70% of the islet cell mass. F cells and A cells are
surgeon must be aware of this anomaly since division of the
located peripherally within the islets and constitute 15% and
abnormal ring can result in pancreatic fistula or obstruction of
10% of the islet cell mass, respectively. D cells are located
pancreatic ductal drainage.
both centrally and peripherally and constitute 5% of the islet
Heterotopic pancreas is pancreatic tissue outside the 6 cell mass.18 The distribution of endocrine cell types is not unibounds of the normal pancreas without anatomic or vascular
form throughout the pancreas. B and D cells are uniformly disconnections to the pancreas itself. Heterotopic pancreas
tributed throughout the gland. However, A cells are concenoccurs in 0.5% to 14% of autopsy series. The heterotopic pantrated in the body and tail of the pancreas, and F cells are
creatic tissue is functional and can occur in a variety of sites
concentrated in the uncinate process. This distribution is
including the stomach, duodenum, ileum, umbilicus, colon,
important clinically, since resection of different parts of the
appendix, and gallbladder, and even within a Meckel diverticpancreas will have varying endocrine effects.
ulum. This tissue is usually submucosal and uniformly conThe islet cells have a rich blood supply with the afferent
tains acini and ducts. Up to one third contain islet cells. Hetarteriole entering the islet in an area of discontinuity in the
erotopic pancreas is usually an incidental finding, but can
non-B cells surrounding the periphery. The afferent arteriole
present with ulceration, obstruction, or intussusception, in
then breaks into a capillary bed within the islet and then exits
which case treatment is directed at the presenting symptoms
the islet through an efferent arteriole (Fig. 51.6). The horand may require resection. In incidental and asymptomatic
mones from the islet cells are secreted directly into this rich
cases, no treatment is required. The pancreas is susceptible to
capillary network within the islet.
PANCREAS/LIVER
Portal vein
Superior
mesenteric
vein
803
804
The pancreas lies in the retroperitoneum at the level of the second lumbar vertebra. It lies obliquely and transversely from its
most caudal point at the duodenal C loop on the right to its
most cranial point in the splenic hilum on the left. The pancreas is composed of four anatomic parts: the head (including
the uncinate process), neck, body, and tail (Fig. 51.1).
The understanding of the pancreatic anatomy in relation to adjacent structures is critical when performing operative procedures
on the pancreas or surrounding structures including the duodenum, bile duct, and spleen. The pancreatic head, further subdivided into the head and uncinate process, is embraced by the C
loop of the duodenum (Fig. 51.1). The pancreatic head is the
portion of the pancreas extending to the right of the superior
mesenteric vessels. The uncinate process is a projection from the
inferior portion of the pancreas head that extends medially to
the left, posterior to the superior mesenteric vessels. The head of
the pancreas is attached to the medial aspect of the descending
duodenum and its horizontal third portion, and the two organs
share a blood supply. Posterior to the pancreatic head lie the inferior vena cava, right renal artery and vein, and left renal vein. In
order for these structures to be exposed, the pancreas must be
mobilized out the retroperitoneum (Kocher maneuver). The bile
duct runs through the posterior and superior aspect of the pancreatic head, joining the pancreatic duct and draining into the
duodenum medially at the ampulla of Vater.
The pancreatic neck is the 1.5 to 2.0 cm of pancreatic tissue that overlies the superior mesenteric artery and vein anteriorly. These vessels form a vascular groove in the posterior
aspect of the gland. The anterior surface of the pancreatic
neck is covered by peritoneum and lies directly posterior to
the pylorus of the stomach. The splenic vein joins the superior mesenteric vein posterior to the pancreatic neck forming
the portal vein, which drains the intestinal blood supply to
the liver.
The body of the pancreas continues left from the pancreatic
neck. The anterior surface of the pancreatic body is covered
with peritoneum and forms the floor of the omental bursa
within the lesser sac. The stomach overlies the pancreatic
body/lesser sac anteriorly. The posterior surface of the pancreatic body is not peritonealized and directly contacts the aorta,
left adrenal gland, left kidney, and left renal artery and vein.
The body of the pancreas is the portion overlying the second
lumbar vertebrae.
The tail of the pancreas begins anterior the left kidney and
extends superolaterally to the hilum of the spleen. The splenic
artery and vein run along the posterior surface of the pancreas.
The tail of the pancreas is in close proximity to the spleen and
splenic flexure of the colon.
PANCREAS/LIVER
PANCREATIC ANATOMY
805
806
Common
hepatic artery
Celiac trunk
Splenic
artery
Portal vein
Gastroduodenal
artery
Aberrant
common
hepatic artery
Gastroduodenal
artery
Superior
mesenteric
artery
B
C
2
Left hepatic
artery
Aberrant right
hepatic artery
Venous Drainage
The venous drainage of the pancreas follows the arterial blood
supply and is eventually returned to the portal circulation and
delivered back to the liver. There are four main routes of
venous drainage in the pancreas. In the pancreatic head, superior venous arcades drain either directly into the suprapancreatic portal vein or laterally into the retropancreatic portal vein.
The anterior and inferior branches of the pancreaticoduodenal
arcades of the pancreatic head drain directly into the infrapancreatic superior mesenteric vein. There are rarely any anterior
branches from the pancreatic head and neck into the superior
mesenteric and portal veins. When they do occur, it is most
commonly at the superior border of the pancreatic neck. The
body and tail of the pancreas have many venous tributaries that
drain into the splenic vein, which joins the superior mesenteric
vein posterior to the pancreatic neck, forming the portal vein.
The three named tributaries of the splenic vein are the inferior
pancreatic vein, the caudal pancreatic vein, and the great
Lymphatic Drainage
Throughout the pancreas there is a rich periacinar network of
lymphatic vessels that drain to five major nodal groups.19 The
first is the superior nodal group along the superior border of
the pancreas and celiac trunk. These lymph nodes drain the
superior portion of the pancreatic head. The inferior nodal
group along the inferior border of the head and body of the
pancreas drains the inferior pancreatic head and uncinate
process, eventually draining to the superior mesenteric and paraaortic lymph nodes. The anterior lymphatics drain to the
prepyloric and infrapyloric nodes. The posterior lymph nodes
include the distal common bile duct and ampullary lymphatics
and drain directly into the para-aortic lymph nodes. Lastly, the
splenic lymph nodes drain the lymphatics of the pancreatic
body and tail into the interceliomesenteric lymph nodes.
The Japanese Pancreas Society has classified the pancreatic
lymphatic drainage into 18 lymph node stations.20 The greater
and lesser curves of the stomach drain into lymph node stations
1 through 4. The anterior lymphatics described earlier drain
into lymph node stations 5 and 6. The superior nodal group
includes lymph node stations 7 through 9 along the left gastric
Innervation
The innervation to the pancreas is derived from the vagus and
thoracic splanchnic nerves as well as peptidergic neurons that
secrete amines and peptides.21 Parasympathetic and sympathetic
fibers reach the pancreas by passing along the arteries from the
celiac axis and superior mesenteric arteries (Fig. 51.8). These
fibers give rise to periacinar plexuses within the pancreatic
parenchyma, which send fibers directly to the acinar cell group.
The pancreatic islets and islet vasculature are similarly innervated. The parasympathetic nerves stimulate both exocrine and
endocrine secretion, while the sympathetic fibers have a predominantly inhibitory effect (Fig. 51.9).22 The peptidergic neurons
secrete hormones including somatostatin, vasoactive intestinal
peptide (VIP), calcitonin generelated peptide (CGRP), and
galanin. While the peptidergic neurons influence exocrine and
endocrine secretion, their precise physiologic role is unclear. The
pancreas also has a rich network of afferent sensory fibers.
PANCREAS/LIVER
807
808
SURGICAL SIGNIFICANCE
OF PANCREATIC ANATOMY
The proximity of the pancreas to major visceral arteries, veins,
and other abdominal organs makes the understanding of pancreatic anatomy critical for the general and pancreaticobiliary
surgeon. Knowledge of the anatomy and anatomic variants
can give clues to the diagnosis of pancreatic disease based on
signs and symptoms and prevent injury to surrounding structures in the operating room.
Blood Supply
Knowledge of the normal pancreatic blood supply is critical in
order to perform an adequate cancer operation. As the duodenum and head of the pancreas share a blood supply, it is necessary to remove these organs en bloc when performing an operation for carcinoma. While the duodenum can be preserved in
PANCREAS/LIVER
809
810
TA B L E 5 1 . 2
JAPANESE LYMPH NODE STATIONS
STATION
NUMBER
NAME
STANDARD
RADICAL
Noa
Yesb
Noa
Yesb
Superior pyloric
No
Yes
Inferior pyloric
Noa
Yes
No
No
Celiac origin
No
Yesc
Nod
Nod
Yes
Yese
Yes
Yes
No
Nod
Posterior pancreaticoduodenal
Yes
Yes
No
No
12
12a2
12b2
12c
12p2
13
Hepatoduodenal ligament
Proper hepatic artery near GDA
14
14a
Origin of SMA
14b
Yes
Yese
14c
No
No
14d
No
No
14v
SMV nodes
Yese
Yese
No
Yesf
16
Aortocaval nodes
16a2
16b1
No
Yes
Anterior pancreaticoduodenal
Yes
Yes
17
GDA, gastroduodenal artery; IMA, inferior mesenteric artery; SMA, superior mesentery artery;
SMV, superior mesenteric vein.
a
Unless a distal gastrectomy is performed as part of standard resection.
b
Some of these nodes may accompany the distal gastrectomy specimen.
c
Sampled only.
d
Not formally resected.
e
Some of these nodes may accompany the pancreaticoduodenectomy specimen.
f
Some of these nodes, cephalad to the left renal vein, but not required to dissect the celiac axis origin.
Reproduced with permission from Yeo CJ, Cameron JL, Lillemoe KD, et al. Pancreaticoduodenectomy
with or without distal gastrectomy and extended retroperitoneal lymphadenectomy for periampullary
adenocarcinoma, part 2: randomized controlled trial evaluating survival, morbidity, and mortality. Ann
Surg 2002;236:355368.
PANCREATIC PHYSIOLOGY
Exocrine Function
The pancreas secretes 1.5 to 3 liters of a colorless, odorless,
isosmotic, and alkaline solution daily containing over 20
enzymes and zymogens. The enzymes and zymogens play a
major role in the digestive activity of the gastrointestinal tract.
Bicarbonate Secretion
Bicarbonate is the most physiologically important ion secreted
by the pancreas. Bicarbonate is formed from carbonic acid by
the enzyme carbonic anhydrase. The secretion of water and
electrolytes originates in the centroacinar and intercalated duct
cells (Fig. 51.5). These cells secrete 20 mmol of bicarbonate per
liter in the basal state and up to 150 mmol/L in the maximally
stimulated state.36 The bicarbonate secreted from the ductal
cells is primarily derived from the plasma and not from intracellular metabolism. Chloride efflux through the cystic fibrosis
transmembrane conductance regulator (CFTR) leads to depolarization and bicarbonate entry through the sodium bicarbonate cotranporter.36 As a result, chloride secretion varies inversely
with bicarbonate secretion, with the sum of these two anions
balancing the sodium and potassium cations and remaining
constant and equal to that of the plasma.
10
Both secretin and VIP stimulate bicarbonate secretion by
increasing intracellular cyclic adenosine monophosphate, which
acts on the CFTR.36 Secretin is released from the duodenal
mucosa in response to a duodenal lumen pH of less than 3.0 due
to gastric acid. CCK is a weak direct stimulator of bicarbonate
secretion, but it acts as a neuromodulator and potentiates the
stimulatory effects of secretin. Gastrin and acetylcholine are
also weak stimulators of bicarbonate secretion.37 Bicarbonate
secretion is inhibited by atropine (vagal stimulation) and can
be reduced by 50% after truncal vagotomy.38 Islet peptides
including somatostatin, pancreatic polypeptide, glucagon,
galanin, and pancreastatin are thought to inhibit exocrine
secretion.
811
Enzyme Secretion
Pancreatic enzymes originate in the acinar cells, which are
highly compartmentalized. Proteins are synthesized in the
rough endoplasmic reticulum, processed in the Golgi apparatus, then targeted to the appropriate cell compartment (zymogen granules, lysosomes, etc.). The acinar cells secrete enzymes
that fall into three major enzyme groups: amylolytic enzymes,
lipolytic enzymes, and proteolytic enzymes. Amylolytic
enzymes such as amylase hydrolyze starch to oligosaccharides
and the disaccharide maltose. Lipolytic enzymes such as lipase,
phospholipase A, and cholesterol esterase function work in
conjunction with bile salts to digest fats and cholesterol.
Proteolytic enzymes include endopeptidases (trypsin and chymotrypsin), which act on the internal peptide bonds of
proteins and polypeptides, and exopeptidases (carboxypeptidases), which act on the free carboxy- and amino-terminal ends
of proteins. The proteolytic enzymes are secreted as inactive
precursors. Enterokinase cleaves the lysineisoleucine bond in
trypsinogen to create the active enzyme trypsin. Trypsin then
activates the other proteolytic enzyme precursors.36
The enzyme groups are not secreted in a fixed ratio. Dietary
alterations and stimulation by specific nutrients can result in
812
and proteins. Autodigestion of the pancreas by these proteolytic enzymes is prevented by packaging of proteases in an
inactive precursor form and by the synthesis of protease
inhibitors including pancreatic secretory trypsin inhibitor
(PSTI), serine protease inhibitor kazal type 1 (SPINK1), and
protease serine 1 (PRSS1). These enzymes are found in the acinar cell and loss of these protective mechanisms can lead to
activation, autodigestion, and acute pancreatitis. Mutations in
the SPINK1 and PRSS1 genes are known to cause one of the
aggressive familial forms of chronic pancreatitis, leading to
recurrent episodes of pancreatitis with associated exocrine and
endocrine insufficiency.39,40
Endocrine Function
Insulin Synthesis, Secretion, and Action. Insulin is a
56-amino-acid polypeptide with a molecular weight of 6 kD. It
consists of two polypeptide chains (A and B) joined by two
disulfide bridges. The amino acid sequence varies among
species, but the location of the disulfide bridges are highly conserved and are critical for its biologic activity. Insulin is synthesized by the B cells within the islets of Langerhans. Insulin
functions to promote glucose transport in all cells except B
cells, hepatocytes, and central nervous system cells. Insulin
inhibits glycogenolysis and fatty acid breakdown but stimulates protein synthesis. There is a significant secretory reserve
of insulin within the pancreas. Destruction or removal of 80%
of the pancreatic islet cell mass is necessary before endocrine
dysfunction becomes clinically apparent in the form of type 1
(insulin-dependent) diabetes.41
In response to pancreatic B-cell stimulation, proinsulin
(precursor peptide to insulin) is synthesized in the endoplasmic
reticulum and transported to the Golgi. In the Golgi, the
proinsulin is packaged into granules, where it is cleaved into
insulin and the residual connecting peptide, C peptide (Fig.
51.11). The granules are then released directly into the intervascular space. Defects in the synthesis and cleavage of insulin
can lead to rare forms of diabetes mellitus such as Wakayama
syndrome and proinsulin syndrome.42
The secretion of insulin is tightly regulated by nutrient,
neural, and hormonal factors. In response to glucose, the predominant nutrient regulator, insulin is secreted in two phases.
The first phase is a short burst of stored insulin that lasts 4 to
6 minutes. This is followed by a sustained secretion of insulin,
which requires active synthesis of the hormone within the islet
cell. The B cell is sensitive to even small changes in glucose
concentration and is maximally stimulated at concentrations
of 400 to 500 mg/dL. Insulin is released in an oscillatory or
pulsatile pattern controlled by an internal pacemaker, which is
present even in isolated islet cells.43 Insulin has a short half-life
of 7 to 10 minutes after secretion, when it is primarily metabolized by the liver. Forty percent to 70% of insulin secreted
into the portal venous system is cleared by hepatocytes on the
first pass through the liver. Excess insulin is then slowly metabolized by the liver, kidneys, and skeletal muscles. Both brain
cells and red blood cells do not take up insulin.
Like all hormones, insulin binds to specific cell surface receptors that have been isolated and well characterized. The insulin
receptor is a 300-kD glycoprotein. Stimulation of the insulin
receptor is dependent on insulin concentration. Insulin resistance, present in type 2 diabetes, can be the result of decreased
numbers of receptors or a decreased affinity for insulin.
Glucose is actively transported across cell membranes
throughout the body by 55-kD membrane-bound facilitator
peptides called glucose transporters (Fig. 51.12). There are
several classes of glucose transporters with varying affinities
for glucose. The GLUT-2 transporter located on B cells
has a low affinity for glucose. This results in a low rate of
transport at physiologic concentrations of glucose but an
increased rate of transport at higher concentrations, with
subsequent higher insulin secretion rates.44 The loss of B-cell
GLUT-2 transporter can contribute to the development of
diabetes mellitus.45
Orally administered glucose has a greater effect on insulin
secretion than an equivalent amount of glucose administered
intravenously. This effect is called the enteroinsular axis and is
related to the release of enteric hormones in response to glucose that also potentiate insulin secretion. Gastric inhibitory
polypeptide (GIP) is an important regulator of this effect.46
Additional gut peptides and hormones that stimulate insulin
secretion include glucagon, glucagonlike peptide-1, and CCK,
while somatostatin, amylin, and pancreastatin inhibit insulin
secretion. Nutrients including certain amino acids (arginine,
lysine, and leucine) and free fatty acids also regulate insulin
secretion. Sulfonylurea compounds, which act independently
of glucose concentration, also stimulate insulin secretion and
are used in the treatment of type 2 diabetes, where the primary
defect is peripheral insulin resistance, not insulin production
or decreased islet cell mass.
B cells are also neuronally regulated. Both cholinergic and
b-sympathetic fibers stimulate insulin secretion, whereas asympathetic fibers are inhibitory. A loss of pancreatic innervation in the setting of pancreatic transplantation can therefore
result in changes in the pattern and quality of insulin secretion.
813
hormone because it increases metabolic fuel in the form of glucose during stress. Secretion of pancreatic glucagon is tightly
controlled by neural, hormonal, and nutrient factors. Like
insulin, glucose is the primary regulator, but the two hormones
respond to glucose in reciprocal fashion. It has a strong suppressive effect on glucagon secretion. The two hormones are
counterregulatory and function together to tightly control
blood glucose levels. Excess glucagon can lead to hyperglycemia, whereas insufficient glucagon can lead to profound
hypoglycemia. For this reason, the diabetes resulting from
total pancreatectomy is very brittle and difficult to control due
to the lack of endogenous glucagon to balance exogenously
administered insulin.
Glucagon secretion is also stimulated by the amino acids
arginine and alanine. Through paracrine effects within the
islets, both insulin and somatostatin have a suppressive effect
on glucagon secretion. The neural regulation of glucagon parallels that of insulin, with cholinergic fibers being strongly
stimulatory, B-sympathetic fibers being weakly stimulatory,
and A-sympathetic fibers being inhibitory.
DIAGNOSTIC APPROACH
TO PATIENTS WITH
PANCREATIC DISEASE
Pancreatic Imaging (Studies of
Pancreatic Structure)
If pancreatic disease is suspected, the pancreas can be imaged
by several radiographic modalities including plain abdominal
radiographs, upper gastrointestinal series, abdominal ultrasonography, CT, MRCP, endoscopic retrograde cholangiopancreatography (ERCP), and EUS.
PANCREAS/LIVER
814
Endoscopic Ultrasound
Upper Gastrointestinal Series
In the setting of a mass or mass effect on plain film, an upper
gastrointestinal series can demonstrate displacement of the
stomach or duodenum by a retroperitoneal mass. Displacement or narrowing of the duodenal C loop suggests the
presence of a pancreatic mass. However, the character of the
mass (inflammatory, neoplastic, cystic, etc.) cannot be further
defined on upper gastrointestinal series.50 For this reason, the
upper gastrointestinal series has been largely replaced by ultrasound and other three-dimensional imaging modalities such as
CT or MRCP.
Ultrasonography
Abdominal ultrasound can be useful in the setting of acute
pancreatitis, chronic pancreatitis, pancreatic cystic lesions,
pancreatic pseudocysts, and pancreatic cancer. In acute pancreatitis, the abdominal ultrasound may demonstrate gallstones, suggesting a potential etiology. In addition, the ultrasound can identify an enlarged pancreas, pancreatic edema,
and peripancreatic fluid collections consistent with the diagnosis of acute pancreatitis. Ultrasound can also identify pancreatic pseudocysts, cystic lesions, and other pancreatic
masses.50 Pancreatic pseudocysts usually appear as a smooth,
round fluid collection without acoustic shadowing. A pancreatic cancer is more likely to distort the underlying pancreatic
anatomy and appear as a localized, solid lesion on ultrasound, also without acoustic shadowing. Cystic neoplasms of
the pancreas can have both solid and cystic components. They
can be uniloculated or multiloculated and contain cysts of
varying size.
Ultrasound examination can be limited by obesity, overlying bowel gas, and recently performed barium contrast studies. Small masses or fluid collections can be easily missed. The
presence of a mass on ultrasound is an indication for more
extensive workup via CT or MRCP imaging.
Computed Tomography
Contrast-enhanced, helical three-dimensional CT is the most
commonly performed study for the detection and characterization of pancreatic solid and cystic tumors. It is also useful in
defining the pancreatic anatomy in the presence of chronic
Magnetic Resonance
Cholangiopancreatography
MRCP using three-dimensional turbo spin-echo techniques
is now being used more commonly as a noninvasive way to
image both the bile duct and pancreatic duct. This imaging
modality can provide excellent images and detect abnormalities of the common bile duct and main pancreatic duct, but it
is more limited in its ability to detect abnormalities in the secondary ducts. This noninvasive imaging technique is very useful in high-risk patients and pregnant patients. It is also useful
in diagnosis, especially in settings where interventions such as
biopsy or biliary drainage are unnecessary. MRCP can be a
good modality for defining pancreatic ductal anatomy in
patients with chronic pancreatitis and pancreatic pseudocysts
to help plan operative management.
815
PANCREAS/LIVER
Endoscopic Retrograde
Cholangiopancreatography
816
TA B L E 5 1 . 4
CHARACTERISTIC RESULTS OF SECRETIN TESTING: VOLUME, BICARBONATE CONCENTRATION, AND ENZYME SECRETION
CHANGES IN PANCREATIC DISEASE PROCESSES
DISORDER
TOTAL
VOLUME
PATTERN
MAXIMUM
BICARBONATE
SECRETION
ENZYME
SECRETION
End-stage pancreatitis
Total insufficiency
Decreased
Decreased
Decreased
Advanced pancreatic
cancer
Total insufficiency
Decreased
Decreased
Decreased
Chronic pancreatitis
Qualitative insufficiency
Normal
Decreased
Normal
Pancreatic cancer
Quantitative insufficiency
Decreased
Normal
Normal
Malnutritiona
Normal
Normal
Decreased
Hemochromatosis,
Zollinger-Ellison
syndrome, cirrhosis
Hypersecretion
Increased
Normal
Normal
TA B L E 5 1 . 5
DIFFERENTIAL DIAGNOSIS OF INTESTINAL AND PANCREATIC STEATORRHEA
PARAMETER
INTESTINAL
STEATORRHEA
PANCREATIC
INSUFFICIENCY
D-xylose
Abnormal (low)
Normal
Secretin test
Normal
Abnormal
Small-bowel series
Abnormal
Normal
Small-bowel biopsy
Abnormal
Normal
PABA test
Normal
Abnormal
PP response to meal
Normal
Abnormal
Abnormal (low)
Normal
No change
Improvement
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K E Y
1
2
In the United States, more than 75% of cases of acute pancreatitis are attributable to either gallstones or alcohol.
Approximately 80% of cases of acute pancreatitis are
mild, are associated with minimal systemic derangements,
and generally resolve within 5 to 7 days, even with minimal therapy.
Severe acute pancreatitis accounts for about 20% of cases
and is defined as acute pancreatitis associated with one or
more of the following: pancreatic necrosis, distant organ
failure, and the development of local complications such as
hemorrhage, abscess, or pseudocyst.
The mortality rate associated with severe acute pancreatitis
ranges from 10% to 20%, with half of the deaths in the first
2 weeks as the result of systemic inflammatory response syndromeinduced multisystem organ failure and the remaining
occurring later as the result of pancreatic necrosis/infection.
Computed tomography scanning is the most important
imaging test for acute pancreatitis and is useful in confirming the diagnosis, assessing disease severity, and detecting
complications.
P O I N T S
6
7
10
CLASSIFICATION
TERM
DEFINITION
Mild acute
pancreatitis
PATHOLOGY AND
PATHOPHYSIOLOGY
Severe acute
pancreatitis
Acute fluid
collections
Pancreatic
necrosis
Pseudocyst
Pancreatic
abscess
The typical pathologic correlate of mild acute pancreatitis is interstitial (edematous) pancreatitis, in which the pancreatic
parenchyma is edematous and infiltrated with inflammatory cells.
Gross architectural features are preserved. In contrast, severe
acute pancreatitis (SAP) can be associated with necrotizing pancreatitis, in which variable amounts of pancreatic parenchyma
and peripancreatic fat have undergone tissue necrosis, with vascular inflammation and thrombosis being prominent features.
Studies using experimental models suggest that prototypical molecular and cellular derangements lead to pancreatic
injury, regardless of the specific etiology or inciting event that
triggers an episode of acute pancreatitis. Among the earliest of
these derangements appears to be abnormal activation of proteolytic enzymes within pancreatic acinar cells.4 Under normal
conditions, trypsinogen and other digestive zymogens are
stored in granules that are segregated from lysosomal enzymes
(e.g., cathepsin B) and acid. Early in the course of acute pancreatitis, cytoplasmic vacuoles containing activated proteolytic
enzymes appear. How the digestive enzymes are activated, and
what role these vacuoles play, has been the subject of much
investigation. In the prevailing model, trypsinogen is believed
to be activated to yield trypsin either by colocalization with
the lysosomal hydrolase cathepsin B5 or through autoactivation due to a moderately acidic pH.6 Recently, it has been
noted that the cytoplasmic vacuoles appearing in the acinar
cell in experimental acute pancreatitis share expression of proteins with autophagosomes. Autophagosomes are vacuoles
that degrade cellular components such as organelles in the
process of autophagy. Highlighting the possible importance of
autophagy in the development of pancreatitis, mice lacking
expression of the autophagy-related gene Atg5 in the pancreas
fail to exhibit prototypical features of acute pancreatitis.7
Acinar cell injury induced by active trypsin allows it to be
released into the pancreatic parenchyma (Fig. 52.1), where it
activates more trypsin and other digestive enzymes (e.g., chymotrypsin, phospholipase, and elastase). Trypsin can also activate the complement, kallikrein-kinin, coagulation, and fibrinolysis cascades within the pancreatic parenchyma. Activation
of these enzymes is believed to initiate a vicious cycle in which
Acute pancreatitis is an acute inflammatory process of the pancreas with variable involvement of other regional tissues or
remote organ systems.1 In the United States, more than 200,000
patients are hospitalized annually with acute pancreatitis as the
primary diagnosis.2 It is the principal cause of approximately
3,200 deaths per year and a contributing factor in an additional
4,000 deaths. The direct cost attributable to acute pancreatitis
exceeds $2 billion per year in the United States.
CLASSIFICATION
AND DEFINITIONS
A useful and widely accepted system for defining and classifying the severity and complications of acute pancreatitis was
PANCREAS/LIVER
TA B L E 5 2 . 1
819
820
Other Etiologies
A wide range of other etiologies of acute pancreatitis have
been identified (Table 52.2). Ongoing investigations are beginning to reveal specific gene abnormalities (e.g., mutations in
cationic trypsinogen PRSS1, pancreatic secretory trypsin
inhibitor SPINK1, and the cystic fibrosis transmembrane
conductance regulator CFTR) that can be associated with pancreatitis. Patients for whom no etiology can be identified
despite thorough evaluation are classified as having idiopathic
pancreatitis.
CLINICAL PRESENTATION
FIGURE 52.2. Illustration of the common channel concept. A gallstone lodged at the ampulla of Vater can cause reflux of bile into the
pancreatic duct.
ETIOLOGY
pancreatitis in a patient with cirrhosis). Evidence of retroperitoneal hemorrhage may become apparent if blood dissects into
the subcutaneous tissues of the flanks (Grey-Turner sign),
umbilicus (Cullen sign), or inguinal region (Fox sign); however, these findings are unusual.
2
Approximately 80% of cases of acute pancreatitis are mild,
are associated with minimal systemic derangements, and generally resolve within 5 to 7 days, even with minimal therapy.
The mortality rate associated with mild acute pancreatitis is
less than 1%.
3
Approximately 20% of cases are classified as severe acute
pancreatitis (SAP), defined as acute pancreatitis associated
with one or more of the following: (a) necrosis of greater than
one third of the pancreas; (b) distant organ failure (indicated
by systolic blood pressure 90 mm Hg, serum creatinine 2.9
mg/dL, gastrointestinal blood loss exceeding 500 mL in volume within a 24-hour period, and/or partial pressure of arterial oxygen [PaO2] 60 mm Hg); and/or (c) the development of
local complications, such as hemorrhage, abscess, or pseudo-
DIAGNOSIS
The differential diagnosis of acute pancreatitis includes other
conditions causing acute upper abdominal pain, such as biliary colic and cholecystitis, acute mesenteric ischemia, smallbowel obstruction, visceral perforation, and ruptured aortic
aneurysm. Acute exacerbations of chronic pancreatitis can
also be associated with clinical features resembling those of
acute pancreatitis. The diagnosis of acute pancreatitis usually
can be made by confirming biochemical evidence of pancreatic
injury. Imaging tests should be used selectively to rule out
other diagnoses and for the indications discussed later.
Laboratory Tests
With pancreatic injury, a variety of digestive enzymes escape
from acinar cells and enter the systemic circulation. Of these
enzymes, amylase is the most widely assayed to confirm the
diagnosis of acute pancreatitis. Amylase levels rise within several hours after onset of symptoms and typically remain elevated for 3 to 5 days during uncomplicated episodes of mild
acute pancreatitis. Because of the short serum half-life of amylase (10 hours), levels can normalize as soon as 24 hours after
disease onset. The sensitivity of this test depends on what
threshold value is used to define a positive result (90% sensitivity with a threshold value just above the normal range vs.
60% sensitivity with a threshold value at three times the upper
limit of normal). Specificity (which also varies with the threshold values selected) is limited because a wide range of disorders
can cause elevations in serum amylase concentration. Assays
that detect increases in the serum concentration of amylase of
pancreatic origin (P-isoamylase) alone are associated with
greater specificity. Increased urinary amylase concentrations
and amylase-to-creatinine clearance ratios occur with acute
pancreatitis; however, these parameters offer no advantage
over serum amylase concentrations, except in the evaluation of
macroamylasemia (in which urinary amylase excretion is not
increased despite elevations in serum amylase concentration).
Serum lipase concentrations increase with kinetics similar
to those of amylase. It has a longer serum half-life than amylase, however, and may be useful for diagnosing acute pancreatitis late in the course of an episode (at which time serum
amylase concentrations may have already normalized).
Although lipase is more specific than amylase in the diagnosis
of acute pancreatitis, note that lipase is produced at a range of
nonpancreatic sites, including the intestine, liver, biliary tract,
stomach, and tongue.
The magnitude of the increases in amylase or lipase concentrations has no correlation with severity of pancreatitis. In
general, the magnitude of increases in amylase concentrations
tends to be greater in patients with gallstone pancreatitis than
in those with alcohol-induced pancreatitis; however, this finding is unreliable in distinguishing between these two etiologies.
Imaging Tests
Findings on plain radiographs associated with acute pancreatitis are nonspecific and include ileus that may be generalized or localized to a segment of small intestine (sentinel
loop) or transverse colon (colon cut-off sign), psoas muscle margins that are obscured by retroperitoneal edema, an
PANCREAS/LIVER
TA B L E 5 2 . 2
821
822
ASSESSMENT OF
DISEASE SEVERITY
Accurate prediction of severity early in the course of disease
offers potential benefits in that complications can be anticipated and detected early through the use of intensive monitoring and frequent clinical assessment, and early and aggressive
therapies can be instituted to attempt to prevent these complications. Routine clinical assessment at the time of admission is
associated with low sensitivities (50%) in identifying patients
with SAP.10 Therefore, alternative methods for assessing disease
severity based on scoring systems, CT scanning, and serum
markers have been widely studied. In addition to these meth-
Scoring Systems
The Ranson criteria (Table 52.3) are easily tabulated, and the
resulting scores are well correlated with morbidity and mortality rates.12 The presence of three or more of these criteria is
indicative of SAP. Important limitations of the Ranson criteria
are that the predictive score cannot be determined prior to 48
hours following admission and that it can only be used once.
Furthermore, because these criteria were developed using a
cohort of patients for whom alcohol was the predominant etiology of pancreatitis, their generalizability may be limited. A
similar predictive scoring system developed in Glasgow using
a cohort of patients for whom gallstones were the predominant etiology of pancreatitis is available.13
TA B L E 5 2 . 3
STAGING
55 y
WBC count
16,000/mm3
Glucose
200 mg/dL
LDH
350 IU/L
AST
250 IU/L
WITHIN 48 H
Hematocrit decrease
10 pt
BUN increase
5 mg/dL
Calcium
8 mg/dL
PaO2
60 mm Hg
Base deficit
4 mEq/L
Fluid requirement
6 L
Minimizing Progression of
Pancreatic Inflammation and Injury
The diagnostic application of CT scanning was discussed previously. For assessment of disease severity, dynamic intravenous
contrast-enhanced CT scanning should be obtained. This technique is associated with greater than 90% sensitivity in the
detection of pancreatic necrosis, a finding that is predictive of
severe disease, and is indicated if clinical deterioration occurs or
if one of the scoring systems discussed earlier suggests severe disease (e.g., presence of three or more Ranson criteria or APACHE
II score 8). Because necrosis takes time to develop, a contrastenhanced CT scan obtained too early in the disease course (e.g.,
at the time of admission) is unlikely to have predictive value. In
addition, concerns that early administration of iodinated intravenous contrast agents used in CT scanning may exacerbate pancreatic injury have been raised, although these agents have not
been shown to cause or exacerbate pancreatitis in humans.15
MANAGEMENT
The goals of management for patients with acute pancreatitis
are summarized next.
823
PANCREAS/LIVER
824
incidence of recurrent pancreatitis and gallstone-related complications in patients with biliary pancreatitis whose cholecystectomy is delayed even 2 weeks after hospital discharge.20
Therefore, cholecystectomy should be performed during the
same hospitalization for most patients with mild gallstone
pancreatitis. In severe biliary pancreatitis, the risk of deferring
surgery needs to be balanced against the risk of performing
early surgery in patients who are debilitated and nutritionally
compromised. Endoscopic sphincterotomy is another option;
however, the high risk of recurrent gallstone-related complications and the higher mortality compared to cholecystectomy
suggest that this strategy should be reserved for patients with
severe comorbidities precluding safe surgery.21
Examples of other measures directed at correcting the
underlying cause of pancreatitis include cessation of drugs
known to cause pancreatitis and treatment of hypercalcemia
or hyperlipidemia.
Infected Necrosis. Infection of pancreatic and peripancreatic necrosis complicates 30% to 70% of cases of acute necrotizing pancreatitis and most commonly becomes established
during the second to third weeks after onset of disease. Historical data suggest that mortality rates associated with untreated
9 infected necrosis approach 100%. The diagnosis of infected
necrosis is made based on cultures of aspirates of fluid or
necrotic tissue obtained during CT-guided fine-needle aspiration (FNA) or specimens collected during surgery. The concordance rate between bacteriologic results of FNA and those of
surgical specimens is greater than 95%.22 In addition, the visualization of air bubbles within necrotic tissue on CT scans is
highly suggestive of infection. Because the presence or absence
of infection has a strong impact on surgical decision making,
FNA should be obtained in patients with acute necrotizing pancreatitis who exhibit clinical features of sepsis or whose clinical
course deteriorates beyond 1 to 2 weeks after onset of disease.
If FNA indicates the presence of infected necrosis, surgical
intervention is indicated. Infected necrosis consists of thick and
tenacious material that is most effectively treated with mechanical dbridement. Traditionally, the abdomen is entered through a
vertical midline or bilateral subcostal incision. The anterior surface of the pancreas can be exposed by dividing the gastrocolic
ligament (greater omentum) and entering the lesser sac. If inflammatory changes have obliterated the lesser sac, this approach
may be hazardous. In such cases, an alternative route to the pan8
TA B L E 5 2 . 4
COMPLICATIONS
Initial clinical trials failed to demonstrate a benefit of prophylactic antibiotics; however, these studies were flawed by the
inclusion of patients with mild disease who were at low risk
for developing infected necrosis and the use of antibiotics
with poor penetration into the pancreas. Trials were published in the 1990s showing a significant reduction in the incidence of pancreatic infection among patients receiving antibiotic prophylaxis, and based on this evidence, the use of
antibiotic prophylaxis in patients documented to have necrotizing pancreatitis has become a widespread practice. Several
recent trials that failed to show a benefit for prophylactic
antibiotics have now been published.25,26 Similarly, recent
meta-analyses of the available trials have failed to demonstrate a benefit for patients receiving prophylactic antibiotics.27,28 Disadvantages of using prophylactic antibiotics
include the risks of fungal superinfection and the selection of
resistant organisms. Another strategy for prophylaxis against
infection in patients with acute pancreatitis has been the
administration of probiotic bacteria to reduce the load of
pathogenic bacteria in the bowel; however, prospective evaluation has yielded disappointing results.29
825
An algorithm for the general management of acute pancreatitis and pancreatic necrosis is shown in Algorithm 52.1.
Severe acute
pancreatitis suspected
Observation and
support until
resolution
CT scan
PANCREAS/LIVER
Signs of infection or
clinical deterioration
Resolution
No necrosis on CT
Necrosis on CT
Repeat CT
CT-guided FNA
Sterile necrosis
Infected necrosis
Resolution
Failure to improve
CT = computed tomography, ICU = intensive care unit, FNA = fine needle aspiration
ALGORITHM 52.1
ALGORITHM 52.1. Algorithm for the management of acute pancreatitis.
Dbridement
826
References
1. Bradley EL III. A clinically based classification system for acute pancreatitis. Summary of the International Symposium on Acute Pancreatitis,
Atlanta, Ga, September 11 through 13, 1992. Arch Surg 1993;128:
586590.
2. Frossard JL, Steer ML, Pastor CM. Acute pancreatitis. Lancet 2008;371:
143152.
3. Bollen TL, van Santvoort HC, Besselink MG, et al. The Atlanta classification of acute pancreatitis revisited. Br J Surg 2008;95:621.
4. Steer ML. Pathogenesis of acute pancreatitis. Digestion 1997;58(suppl 1):
4649.
5. Saluja AK, Donovan EA, Yamanka K, et al. Cerulein-induced in vitro activation of trypsinogen in rat pancreatic acini is mediated by cathepsin B.
Gastroenterology 1997;113:304310.
6. Leach SD, Modlin IM, Scheele GA, et al. Intracellular activation of digestive zymogens in rat pancreatic acini. Stimulation by high doses of cholecystokinin. J Clin Invest 1991;87:362366.
7. Hashimoto D, Ohmuraya M, Hirota M, et al. Involvement of autophagy
in trypsinogen activation within the pancreatic acinar cells. J Cell Biol
2008;181:10651072.
8. Ashley SW, Perez A, Pierce EA, et al. Necrotizing pancreatitis: contemporary analysis of 99 consecutive cases. Ann Surg 2001;234:572579.
9. Bchler MW, Gloor B, Muller CA, et al. Acute necrotizing pancreatitis:
treatment strategy according to the status of infection. Ann Surg 2000;
232:619626.
10. Corfield AP, Cooper MJ, Williamson RC, et al. Prediction of severity in
acute pancreatitis: prospective comparison of three prognostic indices.
Lancet 1985;2:403407.
11. Banks PA. Epidemiology, natural history, and predictors of disease outcome in acute and chronic pancreatitis. Gastrointest Endosc 2002;56:
S226S230.
12. Ranson JH, Rifkind KM, Roses DF, et al. Prognostic signs and the role of
operative management in acute pancreatitis. Surg Gynecol Obstet 1974;
139:6981.
13. Imrie CW, Benjamin IS, et al. A single-centre double-blind trial of Trasylol
therapy in primary acute pancreatitis. Br J Surg 1978;65:337341.
14. Larvin M, McMahon MJ. APACHE-II score for assessment and monitoring of acute pancreatitis. Lancet 1989;2:201205.
15. Johnson CD, Stephens DH, Sarr MG. CT of acute pancreatitis: correlation
between lack of contrast enhancement and pancreatic necrosis. AJR Am
J Roentgenol 1991;156:9395.
16. Marik PE, Zaloga GP. Meta-analysis of parenteral nutrition versus enteral
nutrition in patients with acute pancreatitis. BMJ 2004;328:1407.
17. Eatock FC, Chong P, Menezes N, et al. A randomized study of early nasogastric versus nasojejunal feeding in severe acute pancreatitis. Am J Gastroenterol 2005;100:432439.
18. Fan ST, Lai EC, Mok FP, et al. Early treatment of acute biliary pancreatitis
by endoscopic papillotomy. N Engl J Med 1993;328:228232.
19. Flsch UR, Nitsche R, Ldtke K, et al. Early ERCP and papillotomy compared with conservative treatment for acute biliary pancreatitis. The German
Study Group on Acute Biliary Pancreatitis. N Engl J Med 1997;336:237242.
20. Ito K, Ito H, Whang EE. Timing of cholecystectomy for biliary pancreatitis: do the data support current guidelines? J Gastrointest Surg 2008;12:
21642170.
21. McAlister VC, Davenport E, Renouf E. Cholecystectomy deferral in
patients with endoscopic sphincterotomy. Cochrane Database Syst Rev
2007;(4):CD006233.
22. Gerzof SG, Banks PA, Robbins AH, et al. Early diagnosis of pancreatic
infection by computed tomography-guided aspiration. Gastroenterology
1987;93:13151320.
29.
30.
31.
32.
33.
34.
827
P O I N T S
Surgical therapy may be required to treat mechanical complications of chronic pancreatitis such as biliary and duodenal stricture; however, the most common surgical indication is for treatment of pain.
6 Pancreatic anatomic changes in chronic pancreatitis are
widely heterogeneous; selecting the proper operation for
individual patients is crucial to obtain excellent outcomes.
7 Pancreas-directed operations may involve resection (pancreaticoduodenectomy, distal pancreatectomy, Beger operation),
drainage (lateral pancreaticojejunostomy), or a combination
of both resection and drainage (Frey operation).
PANCREAS/LIVER
K E Y
828
TA B L E 5 3 . 1
CLASSIFICATION OF CHRONIC PANCREATITIS BY THE
TIGAR-O SYSTEM
T
Idiopathic
Early onsetmean age 20; pain predominant;
calcification rare
Late onsetmean age 56; relatively painless; calcification,
endocrine, and exocrine insufficiency present
Minimal changeabdominal pain syndrome; minimal
pancreatic changes on imaging studies
Tropical pancreatitistropical calcific and fibrocalculous
pancreatic diabetes
Genetic predispositions
PRSS1cationic trypsinogen cannot be inactivated
CFTRcystic fibrosis transmembrane conductance
regulator mutation; cannot hydrolyze mucus
SPINK1inactivates trypsin inhibitor
Autoimmune
Lymphoplasmacytic sclerosing pancreatitis; increased
IgG-4; increased association with other autoimmune
diseases
Obstructive
Stricture in main pancreatic duct leads to upstream (to
the tail) ductal dilation, acinar atrophy, and chronic
pancreatitis
Caused by trauma, sphincter of Oddi dysfunction,
pancreas divisum, sequelae of acute pancreatitis
CLINICAL PRESENTATION
The clinical presentation of patients with CP involves pain,
malabsorption (exocrine insufficiency), and diabetes mellitus
(endocrine insufficiency). It is surprising that the interval
between symptom onset and time of CP diagnosis ranges from
30 to 60 months.14 Several factors likely play a role in this
delay in diagnosis, including (i) unreliability of alcoholic
patients (the most common etiology of CP); (ii) nonspecificity
of abdominal pain; (iii) difficulty in diagnosing idiopathic CP;
and (iv) difficulty in diagnosing the small percentage (7%) of
patients with painless CP. It is not unusual for morphologic
changes of CP to exist for some time before symptoms occur.
The vast majority of patients with CP experience abdominal
2
pain. Typical CP pain is described as located in the epigastrium
and boring through the abdomen to the midback. In some
cases, the pain is felt to wrap around the right or left flank in a
bandlike nature. The pain may or may not be exacerbated by
eating and is often worse at night.
More than 90% of acinar function must be lost before
symptoms of malabsorption appear.15 Steatorrhea (fat malabsorption) usually precedes azotorrhea (protein malabsorption). Patients with steatorrhea complain of loose foulsmelling stools that appear greasy and float on the surface of
the toilet bowl. Fat malabsorption may be accompanied by
crampy abdominal pain and bloating. Weight loss and proteincalorie malnutrition commonly accompany malabsorption.
Most patients with CP will experience glucose intolerance at
some point of their disease, and up to 60% will require insulin
replacement. Endocrine insufficiency is due to a combination of
decreased insulin production (as disease progresses and islet cell
volume decreases) as well as a blunted insulin response. Diabetic
ketoacidosis is rare; it seems that only a small amount of endogenous insulin/glucagon is necessary to prevent brittle diabetes.
DIAGNOSIS
The diagnosis of chronic pancreatitis is notoriously difficult in
the early stages of the disease. The ideal gold standard for diagnosis of CP is histologic tissue analysis. Biopsy of the pancreas,
however, is hazardous and not commonly available. Four principal modalities are currently used to image the pancreatic duct
and pancreatic parenchyma: abdominal computed tomography
(CT), magnetic resonance imaging (MRI), endoscopic retrograde
pancreatography (ERP), and endoscopic ultrasound (EUS).
Endoscopic Imaging
Historically, ERP has played an important role not only in diagnosis but also in treatment of patients with chronic pancreatitis.
Changes in the pancreatic ducts observed on ERP include dilation and irregularity of side branches in early disease, with significant main duct changes (stricturing, irregularity, tortuosity,
calcification, and cysts) occurring as CP progresses (Fig. 53.3).
The small but significant potential for complications (bleeding,
perforation, acute pancreatitis) accompanying ERP must be
weighed against the potential benefits of diagnosis (in more difficult cases) and the ability to provide therapeutic intervention.
Tremendous recent advances in the technique and application of endoscopic ultrasound have led to its increased use for
diagnosing CP. Sonographic features of CP include irregularity
of the pancreatic duct, hyperechoic duct margins, and hyperechoic stranding in the pancreatic parenchyma (Fig. 53.4). Data
are accumulating that attempt to correlate these changes with
parenchymal histology.16 Advantages of EUS include its relative noninvasive nature, the ability to biopsy discrete lesions
with great precision, and the ability to collect tissue (by fineneedle or core-needle biopsy) and pancreatic juice. The major
disadvantage of EUS is the potential for significant intraobserver variability. Nevertheless, as further work to standardize
definitions of sonographic CP evolves, it is likely that EUS will
play an increasingly important role in the future.
Functional Tests
Pancreatic exocrine insufficiency invariably accompanies
chronic pancreatitis; however, it is not necessarily diagnostic of
CP. Tests of pancreatic exocrine function are mostly invasive
PANCREAS/LIVER
FIGURE 53.1. Abdominal computed tomography scan without contrast in a patient with chronic pancreatitis demonstrating marked
parenchymal calcification.
829
830
TA B L E 5 3 . 2
Pseudoaneurysm
90%
Pseudocyst
25%30%
Biliary stricture
10%15%
5%10%
Duodenal stricture
4%5%
Pseudoaneurysm
2%3%
Pancreatic adenocarcinoma
2%4%a
Extrapancreatic malignancy
10%15%
COMPLICATIONS
A wide variety of symptomatic and anatomic complications
accompany the progression of CP. Of these complications,
pain, pseudocyst, and biliary stricture are the most common
(Table 53.2).
Pain
More than 90% of patients with CP have symptoms of abdominal pain at some point during the course of their disease. The
mechanisms responsible for CP pain are incompletely understood but likely involve multiple factors including acute and
chronic inflammation of pancreatic nerves as well as increased
pancreatic ductal and interstitial pressure.17
Exocrine/Endocrine Insufficiency
Virtually all patients with CP demonstrate impaired exocrine
function. This exocrine insufficiency is generally mild in the early
course of the disease process. Patients with moderate to severe
exocrine insufficiency should be treated by pancreatic enzyme
replacement. Glucose intolerance appears later in the course of
the disease (usually after 810 years). Patients with CP should
undergo regular screening for endocrine insufficiency.
Pseudocyst
The true incidence of pseudocyst complicating CP is difficult to
accurately identify, but likely ranges from 25% to 30%.18,19
Pseudocysts by definition arise after disruption of main or sidebranch ducts and may be solitary or multiple. Treatment of
pseudocysts is informed by defining the underlying pancreatic
ductal anatomy. It is worth mention that the classic teaching
that all pseudocysts greater than 5 to 6 mm in size should be
treated is no longer accepted by most pancreatic surgeons.
Currently, indications for treating pseudocysts are related
strictly to symptoms.20
Biliary Stricture
Chronic inflammation and scarring in the pancreatic head leads
to stricture of the intrapancreatic bile duct in up to 50% of
patients. Many of these strictures are mild (in fact, clinical jaundice is generally preceded by asymptomatic elevation of alkaline
phosphatase); however, between 10% and 15% of patients with
CP will develop symptomatic jaundice requiring treatment.
Duodenal Obstruction
Pancreatic head inflammatory changes and/or compression by
pseudocysts lead to duodenal obstruction in 4% to 5% of
patients with CP.
Cancer
The specter of pancreatic cancer looms large in all patients
with CP. Lowenfels et al.22 showed the incidence of pancreatic
cancer to be 1.8% after 10 years with CP and 4% after 20
years. Chronic inflammatory changes and fibrosis of the pancreatic parenchyma make the diagnosis of pancreatic cancer
quite difficult in the setting of CP. It is notable that CP patients
have a significantly elevated risk of developing extrapancreatic
malignancy (10%15%), primarily in the upper and lower airway and gastrointestinal tract.
THERAPY
Pain is the main symptom in CP, and although concomitant
treatment of the physiologic derangements that occur in these
patients such as diabetes mellitus (endocrine insufficiency) and
steatorrhea (exocrine insufficiency) are important factors in
improving an individuals overall quality of life, pain control
remains the central focus for most patients. Due to the poorly
understood nature of pain in patients with chronic pancreatitis and the lack of high-quality controlled clinical trials in
treatment, no established standards of care exist. To fill this
void, the American Gastroenterological Association developed
an algorithm for treatment guidelines progressing from less4 invasive to more-invasive therapies.23 The first step in management of patients with CP should be targeted at lifestyle
SURGERY FOR
COMPLICATIONS OF CP
Biliary Obstruction
This local complication of CP results from either fibrotic stricturing of the distal common bile duct as it traverses the head of
the pancreas or through compression of the intrapancreatic biliary segment by the inflammatory enlargement and microcystic
disease in the pancreatic head. It is reported to occur in approximately 6% (3%32%) of hospitalized patients with CP and is
found in 35% (15%60%) of patients undergoing surgical
intervention for CP.34 Significant biliary obstruction is commonly defined as an elevated alkaline phosphatase greater than
two times the upper limit of normal values in the laboratory
used associated with radiographic evidence of biliary dilatation.
Although it is tempting to manage these fibrotic biliary strictures initially with endoscopic therapy, the long-term success
rates with this modality are disappointing.35 Self-expanding
metal stents have been used in a highly selected population of 13
patients unable to undergo operative bypass, with good results
reported after a mean of 50 months.36 Choledochoduodenostomy or hepaticojejunostomy Roux-en-Y are the operations of
choice to simply relieve the biliary tract obstruction,34 although
most surgeons would employ a pancreatic head resection as
described below to treat both the inflammatory pancreatic head
mass as well as the concomitant biliary tract obstruction.
Duodenal Obstruction
Obstruction of the duodenum due to CP is either acute or
chronic. Acute obstruction is usually transient and related to
the severe inflammatory process occurring in the pancreas and
retroperitoneum during an acute attack and as such, has the
potential to resolve once the pancreatic inflammation subsides.
Chronic duodenal obstruction occurs from repeated inflammatory insults resulting in cicatricial stenosis and fibrosis of
the duodenum. These structural alterations will not resolve
when the pancreatic inflammation subsides. Although chronic
duodenal obstruction is a rare complication, occurring in
1.2% (0.5%13%) of hospitalized patients with CP, it can be
found in up to 13% (2%36%) of patients requiring surgical
intervention.34 Similar to biliary obstruction, its specific treatment is a gastrojejunostomy, although most surgeons would
relieve this obstruction using a pancreatic head resection.
Pancreatic Pseudocysts\Pseudoaneurysms
Complicated pseudocysts that frequently occur in patients with
CP are commonly associated with an underlying pancreatic
duct abnormality, and their surgical treatment should take
these facts into account.18 Patients with pseudocysts and CP
should not be treated by cyst drainage solely, as is often the case
in patients with a pseudocyst following a bout of acute pancreatitis, because the underlying anatomic and morphologic
abnormalities are left untreated, leading to a high incidence of
recurrence.19 Patients with CP frequently require some form of
pancreatic duct drainage, and at times, a parenchymal resection to treat the underlying anatomic abnormality that contributed to the formation of the pancreatic pseudocyst.
Less common complications occur as a consequence of fibrotic
stricturing of adjacent organs including the biliary tract (elevated
alkaline phosphatase, transaminases, and a dilated common bile
duct) or duodenum (early satiety, weight loss, inability to eat);
most of these complications can be addressed by the judicious
application of one of the aforementioned operative procedures.
Pseudoaneurysms that occur as a consequence of severe
inflammation and in patients with chronic pancreatitis are
commonly related to a pseudocyst. Their presentation is that
of bleeding, either into an established pseudocyst causing an
increase in abdominal pain, or rarely through the ampulla of
Vater (hemosuccus pancreaticus) or freely into the abdominal
cavity (hemoperitoneum). Mesenteric angiography can detect
the source of bleeding from the splenic, gastroduodenal, superior and inferior pancreaticoduodenal arteries in 94% of
cases.37 Angiographic embolization for control is generally the
treatment of choice. Following control of hemorrhage and stabilization of the patients clinical course, formal pancreatic
resection of the involved pancreas may be carried out.
PANCREAS/LIVER
831
832
Minimal change
Small duct
Puestow
Frey
Denervation
(Thoracoscopic
splanchnlcectomy)
Whipple
Beger
Frey
6
Whipple/total
Pancreatectomy
with Islet cell Tx.
Distal pancreatectomy
833
PANCREAS/LIVER
tissue in the head and uncinate process (Fig. 53.7) while preserving the normal relationship and function of the duodenum and distal common bile duct.47 This operation is
applied to patients with small duct chronic pancreatitis and
a large, hypertrophic pancreatic head. It has also been selectively used with good overall results in patients with small
duct chronic pancreatitis and normal pancreatic heads (pancreas divisum).48
Distal pancreatectomy removes pancreatic parenchyma to
the left of the confluence of the splenic vein with the portal vein
(body and tail of the pancreas). This operation is used very
selectively in patients with obstructive chronic pancreatitis.45,49
834
TA B L E 5 3 . 3
RESULTS OF PANCREATIC HEAD RESECTION IN PATIENTS
WITH CHRONIC PANCREATITIS; COMPARISON OF DPPHR
VS. PD FOR PATIENTS WITH CHRONIC PANCREATITIS
MEASURED VARIABLE
DPPHR
PD
Pain relief
Overall morbidity
Endocrine insufficiency
Hospital stay
Quality of life
Operative time
FIGURE 53.9. Operative photograph of the Frey operation: longitudinal pancreaticojejunostomy with coring-out of the pancreatic
head. The patients head is at the 12 oclock position; the asterisk is on
the junction of the second and third portion of the duodenum.
TA B L E 5 3 . 4
RESULTS OF PATIENTS UNDERGOING FREY OPERATION VS. BEGER OPERATION
MEASURED
VARIABLE
FREY OPERATION
(N 36)
BEGER OPERATION
(N 38)
Quality of life
58.35 (0100)
66.7 (0100)
Pain score
11.25 (099.75)
11.25 (075)
Exocrine insufficiency
78%
88%
Endocrine insufficiency
60%
56%
Late mortality
32% (8/25)
31% (8/26)
TA B L E 5 3 . 5
RESULTS OF PATIENTS SUBJECTED TO LONGITUDINAL PANCREATICOJEJUNOSTOMY FOR CHRONIC PANCREATITIS
REFERENCE
Greenlee et al.53
Adloff et al.
59
NO.
PATIENTS
86
COMPLETE OR
PARTIAL PAIN RELIEF (%)
80
MORTALITY
(%)
3
MEAN F/U
(mos)
95
105
93
65
85
55
76
Sielezneff et al.61
57
84
65
Sakorafas et al.62
120
81
96
Mean results
453
72
79
Adams et al.60
835
TA B L E 5 3 . 6
RESULTS OF PATIENTS UNDERGOING THORASCOPIC SPLANCHNICECTOMY FOR
CHRONIC PANCREATITIS
REFERENCE
NO.
PATIENTS
MEAN F/U
(mos)
COMPLETE
OR PARTIAL
PAIN RELIEF (%)
Moodley et al.63
17
12
94
Ihse et al.64
21
43
50
Buscher et al.
44
36
46
Howard et al.55
55
32
35
20
15
60
157
30
50
66
Hammond et al.
Mean results
Drainage Operation. The Partington-Rochelle modification of the Puestow procedure, a longitudinal pancreaticojejunostomy is the classic operation used to treat patients with
large duct pancreatitis by decompressing the entire length of
the pancreatic duct (head to tail) into a defunctionalized
(Roux-en-Y) limb of jejunum (Fig. 53.8).53
Denervation Operations. Bilateral thoracoscopic splanchnicectomy is a minimally invasive approach to splanchnic denervation used to treat pain in patients with chronic pancreati-
CONCLUSION
Various operations are available to treat the heterogeneous
complications of chronic pancreatitis. Surgeons who accept
care of these challenging patients must be well versed in several therapeutic strategies, and committed to following these
patients closely for the long term to ensure optimal clinical
outcomes. Future advances in the therapy of chronic pancreatitis will be predicated on obtaining a better understanding of
the underlying pathophysiology.
PANCREAS/LIVER
65
836
References
1. Sarner M, Cotton PB. Classification of pancreatitis. Gut 1984;25(7):
756759.
2. Andersen BN, Pedersen NT, Scheel J, et al. Incidence of alcoholic chronic
pancreatitis in Copenhagen. Scand J Gastroenterol 1982;17(2):247252.
3. De las Heras G, Pons F. Epidemiologia y aspectos etiopatogenicos de la
pancreatitis alcoholica cronica. Rev Esp Enferm Dig 1993;84:253258.
4. Etemad B, Whitcomb DC. Chronic pancreatitis: diagnosis, classification,
and new genetic developments. Gastroenterology 2001;120(3):682 707.
5. Whitcomb DC, Gorry MC, Preston RA, et al. Hereditary pancreatitis is
caused by a mutation in the cationic trypsinogen gene. Nat Genet 1996;
14(2):141145.
6. Comfort M, Gambill E, Baggenstoss A. Chronic relapsing pancreatitis: a
study of twenty-nine cases without associated disease of the biliary or gastro-intestinal tract. Gastroenterology 1946;6(4):239408.
7. Sarles H, Sahel J. Pathology of chronic calcifying pancreatitis. Am J Gastroenterol 1976;66(2):117139.
8. Bordalo O, Goncalves D, Noronha M, et al. Newer concept for the pathogenesis of chronic alcoholic pancreatitis. Am J Gastroenterol 1977;68(3):
278285.
9. Kloppel G, Maillet B. The morphological basis for the evolution of acute
pancreatitis into chronic pancreatitis. Virchows Arch A Pathol Anat
Histopathol 1992;420(1):14.
10. Shimizu K. Pancreatic stellate cells: molecular mechanism of pancreatic
fibrosis. J Gastroenterol Hepatol 2008;23(suppl 1):S119S121.
11. Witt H, Luck W, Hennies HC, et al. Mutations in the gene encoding the
serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Nat Genet 2000;25(2):213216.
12. Sharer N, Schwarz M, Malone G, et al. Mutations of the cystic fibrosis gene
in patients with chronic pancreatitis. N Engl J Med 1998;339(10): 645652.
13. Cohn JA, Friedman KJ, Noone PG, et al. Relation between mutations of
the cystic fibrosis gene and idiopathic pancreatitis. N Engl J Med 1998;
339(10):653658.
14. Lankisch PG. The problem of diagnosing chronic pancreatitis. Dig Liver
Dis 2003;35(3):131134.
15. DiMagno EP, Go VL, Summerskill WH. Relations between pancreatic
enzyme outputs and malabsorption in severe pancreatic insufficiency. N
Engl J Med 1973;288(16):813815.
16. Wiersema MJ, Hawes RH, Lehman GA, et al. Prospective evaluation of
endoscopic ultrasonography and endoscopic retrograde cholangiopancreatography in patients with chronic abdominal pain of suspected pancreatic
origin. Endoscopy 1993;25(9):555564.
17. Sarr MG, Sakorafas GH. Incapacitating pain of chronic pancreatitis: a surgical perspective of what is known and what needs to be known. Gastrointest Endosc 1999;49(3 Pt 2):S85S89.
18. Nealon WH, Walser E. Duct drainage alone is sufficient in the operative
management of pancreatic pseudocysts in patients with chronic pancreatitis. Ann Surg 2003;237:614620.
19. Nealon WH, Walser E. Surgical management of complications associated
with percutaneous and\or endoscopic management of pseudocysts of the
pancreas. Ann surg 2005;241:948957.
20. Vitas GJ, Sarr MG. Selected management of pancreatic pseudocysts: operative versus expectant management. Surgery 1992;111(2):123130.
21. Heider TR, Azeem S, Galanko JA, et al. The natural history of pancreatitis-induced splenic vein thrombosis. Ann Surg 2004;239(6):876880; discussion 880882.
22. Lowenfels AB, Maisonneuve P, Cavallini G, et al. Pancreatitis and the risk
of pancreatic cancer. International Pancreatitis Study Group. N Engl J Med
1993;328(20):14331437.
23. AGA treatment Guidelines. American Gastroenterological Association
Medical Position Statement: treatment of pain in chronic pancreatitis.
Gastroenterology 1998;115:763764.
24. Ihse I, Lankisch PG. Treatment of chronic pancreatitis. Current status.
Acta Chir Scand 1988;154:553558.
25. Miyake H, Harada H, Kunichika K, et al. Clinical course and prognosis of
chronic pancreatitis. Pancreas 1987;2:378385.
26. Maisonneuve P, Lowenfels AB, Mullhaupt B, et al. Cigarette smoking accelerates progression of alcoholic chronic pancreatitis. Gut 2005;54: 510514.
27. Talamini G, Bassi C, Falconi M, et al. Pain relapses in the first 10 years of
chronic pancreatitis. Am J Surg 1996;171:565569.
28. Talamini G, Bassi C, Galconi M, et al. Smoking cessation at the clinical
onset of chronic pancreatitis and risk of pancreatic calcifications. Pancreas
2007;35:320326.
29. Dominguez-Munoz JE, Hieronymus C, Sauerbruch T, et al. Fecal elastase
test: evaluation of a new noninvasive pancreatic function test. Am J Gastroenterol 1995;90(10):18341837.
30. Winstead NS, Wilcox CM. Clinical trials of pancreatic enzyme replacement
for painful chronic pancreatitisa Review. Pancreatology 2009;9: 344350.
31. Attasaranya S, Abdel Aziz AM, Lehman GA. Endoscopic management of
acute and chronic pancreatitis. Surg Clin North Am 2007;87:13791402.
32. Michaels AJ, Draganov PV. Endoscopic ultrasonography guided celiac
plexus neurolysis and celiac plexus block in the management of pain due
to pancreatic cancer and chronic pancreatitis. World J Gastroenterol 2007;
13:35753580.
33. Santosh D, Lakhtakia S, Gupta R, et al. Clinical trial: a randomized trial
comparing fluoroscopically guided percutaneous tchnique vs. endoscopic
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
EXOCRINE PANCREAS
ATTILA NAKEEB AND KEITH D. LILLEMOE
P O I N T S
incidence of pancreatic cancer has been real. The risk for the
development of pancreatic cancer is related to age, race, sex,
tobacco use, diet, and specific genetic syndromes (Table 54.1).
The incidence increases with advancing age. More than 80%
of cases occur in persons between the ages of 60 and 80 years,
and pancreatic cancer is rare in people younger than 40 years.
The incidence and mortality rates for pancreatic cancer in
African Americans of both sexes are higher than those in
whites. The gender differences in pancreatic cancer have been
equalizing during recent years. Pancreatic cancer is still more
common in men than in women, but the incidence and mortality rates have increased in women, while they have stabilized or slightly decreased in men.1
Environmental and dietary factors have also been implicated as risk factors for the development of pancreatic cancer.
The most consistently observed environmental risk for the
development of pancreatic cancer is cigarette smoking. It has
been estimated that cigarette smoking can increase the risk for
pancreatic cancer between one and a half and five times. The
mechanism is unknown, but carcinogens in cigarette smoke
have been shown to produce pancreatic cancers in laboratory
animals. In addition, autopsy studies have documented hyperplastic changes in pancreatic ductal cells with atypical nuclear
patterns in smokers. Alcohol consumption does not seem to be
a risk factor for pancreatic cancer despite conflicting past
reports. Recent studies suggest that past studies linking pancreatic cancer to alcohol use may have been confounded by
tobacco use. Similarly, coffee consumption and exposure to
ionizing radiation have been shown not to be associated with
an increased pancreatic cancer risk.
Several epidemiologic investigations have suggested that
diet may play an important role in the development of pancreatic cancer. An apparent association has been noted between
pancreatic cancer and an increased consumption of total calories, carbohydrate, cholesterol, meat, salt, dehydrated food,
EPIDEMIOLOGY AND
RISK FACTORS
In the United States, approximately 11 new cases of pancreatic
cancer are diagnosed per 100,000 population annually.1
Although the incidence rate of pancreatic cancer has been relatively stable during the last two decades, it has increased nearly
threefold since the beginning of the last century (Fig. 54.1). It
has been argued that the apparent increase in the incidence of
pancreatic cancer may represent a misclassification of pancreatic cancer as other types of upper gastrointestinal cancer,
particularly gastric cancer, in the past. However, several analyses indicate that a portion of the threefold increase in the
837
PANCREAS/LIVER
K E Y
838
20
16
12
0
1965
Overall
Male
Female
1970
1975
1980
1985
1990
1995
2000
2005
Year
TA B L E 5 4 . 1
RISK FACTORS FOR PANCREATIC CANCER
Demographic factors
Host factors
INCREASED RISK
POSSIBLE
RISK
UNPROVED
RISK
Advancing age
Geography
Male sex
Socioeconomic
status
Black race
Migrant status
Hereditary nonpolyposis
colorectal cancer
Peptic ulcer
surgery
Tobacco
Diet
Alcohol
Occupation
Coffee
Radiation
Modified from Gold EB, Goldin SB. Epidemiology of and risk factors for pancreatic cancer. Surg Oncol
Clin North Am 1998;7:67.
839
TA B L E 5 4 . 2
GENETIC SYNDROMES ASSOCIATED WITH HEREDITARY PANCREATIC CANCER
SYNDROME
MODE OF
INHERITANCE
GENE
FOLD INCREASE
IN RISK
MANIFESTATION OF
PANCREATIC CANCER
Peutz-Jeghers
AD
STKll
140
Hereditary
pancreatitis
AD
PRSSl
60
Familial
pancreatic cancer
Unknown
Unknown
18
FAMMM
AD
p16
20
Familial breast
cancer 2
AD
BRCA2
10
HNPCC
AD
MSH2
Unknown
HLHl
Most cases of pancreatic cancer have no obvious predisposing factors. However, it is believed that between 5% and 10%
of pancreatic cancers arise because of a familial predisposition.
Six genetic syndromes have been associated with an increased
risk for the development of pancreatic cancer (Table 54.2).
These include hereditary nonpolyposis colon cancer, familial
breast cancer associated with the BRCA2 mutation, PeutzJeghers syndrome, ataxia-telangiectasia syndrome, familial
atypical multiple mole melanoma syndrome, and hereditary
pancreatitis.
MOLECULAR GENETICS
Tremendous advances have been made in understanding the
molecular genetics of pancreatic cancer in recent years. In
general, the genes involved in the pathogenesis of pancreatic
cancer can be divided into three categories: tumor-suppressor
genes, oncogenes, and DNA mismatch-repair genes (Table
54.3).
Tumor-suppressor genes normally function to control cellular proliferation. When these genes are inactivated by genetic
events such as mutation, deletion, chromosome rearrangements, or mitotic recombination, their function as growth suppressors can be lost, and abnormal growth regulation is the
result. The tumor-suppressor genes p53, p16, DPC4, and
BRCA2 are frequently inactivated in sporadic adenocarcinoma of the pancreas. The function of p53 appears to be inactivated in up to 75% of all pancreatic cancers. The p53 gene
product is a DNA-binding protein that acts as both a cell cycle
checkpoint and an inducer of apoptosis. Inactivation of the
p53 gene in pancreatic cancer leads to the loss of two important controls of cell growth: regulation of cellular proliferation
and induction of cell death. The p16 gene encodes a protein
that binds cyclin to cyclin DCdk4 complexes. When the p16
gene product binds to these complexes, it inhibits the phosphorylation of a number of growth and regulatory proteins.
Inactivation of p16 leads to the loss of an important cell cycle
checkpoint and therefore relatively unchecked proliferation.
DPC4 is a tumor-suppressor gene that has been identified on
chromosome 18q. This chromosome has been shown to be
missing in nearly 90% of pancreatic cancers. The DPC4 gene
is inactive in almost 50% of pancreatic carcinomas. The mutation appears to be a homozygous deletion in 30% of pancre-
TA B L E 5 4 . 3
GENETIC ALTERATIONS IN PANCREATIC
ADENOCARCINOMAS
GENE
CHROMOSOME FREQUENCY
LOCUS
(%)
ONCOGENES
K-ras
12
90
TUMOR-SUPPRESSOR GENES
p16
9p
95
p53
17p
5075
DPC4
18q
55
BRCA2
13q
LKB1
17p
MKK4
19p
ALK4
12q
Genome maintenance
4 genes bMSH2,
hMLH1
2P, 3P
PANCREAS/LIVER
AD, autosomal dominant; FAMMM, familial atypical multiple mole melanoma; HNPCC, hereditary nonpolyposis colorectal cancer.
840
codons 12, 13, or 61 of the K-ras oncogene impair the intrinsic guanosine triphosphatase activity of its gene product; the
result is a protein that is constitutively active in signal transduction. Mutations of K-ras have been found in 80% to 100%
of pancreatic cancers and therefore may prove useful in the
development of a molecular screening test for pancreatic
cancer.
Mismatch-repair genes function to ensure the accuracy of
DNA replication, and when these genes are mutated, errors in
DNA replication are not repaired. The human mismatch-repair
genes are hMSH2, hMLH1, hPMS1, hPMS2, hMSH6/GTBP,
and hMSH3. The enzymes encoded by these genes repair single
base-pair changes and small insertions and deletions that occur
during DNA replication. Approximately 4% of pancreatic cancers can be characterized by disorders of DNA mismatch-repair
genes.6
FIGURE 54.2. Microscopic appearance of ductal adenocarcinoma of
the head of the pancreas demonstrating glands from an adenocarcinoma embedded in a fibrous matrix.
PATHOLOGY
Tumors of the exocrine pancreas can be classified based on
their cell of origin (Table 54.4). The most common neoplasms
of the exocrine pancreas are ductal adenocarcinomas. Approximately 65% of pancreatic ductal cancers arise in the head,
neck, or uncinate process of the pancreas; 15% originate in the
body or the tail of the gland; and 20% diffusely involve the
whole gland.
TA B L E 5 4 . 4
CLASSIFICATION
NUMBER
572 (89%)
494
28
Adenosquamous carcinoma
20
Microadenocarcinoma
16
Mucinous carcinoma
Mucinous cystadenocarcinoma
8 (1%)
7
1
61 (9%)
Pancreaticoblastoma
1
58
4 (1%)
Adenosquamous Carcinomas. Adenosquamous carcinoma is a rare variant of ductal adenocarcinoma that shows
both glandular and squamous differentiation. This variant
appears to be more common in patients who have undergone
Mucinous Cystic Neoplasms. Mucinous cystic neoplasms (MCNs) are neoplasms composed of mucin-producing
epithelial cells associated with an ovarian type of stroma.
These cysts usually do not communicate with the larger pancreatic ducts. MCNs are relatively uncommon but account for
almost 30% of all cystic neoplasms. The mean age at diagnosis is between 40 and 50 years. MCNs are more common in
women, with a female-to-male ratio of 9:1. Most patients with
MCNs present with vague abdominal symptoms that include
epigastric pain or a sense of abdominal fullness. The majority
(70% to 90%) of MCNs arise in the body or tail of the pancreas, and only a minority (10% to 30%) involve the head of
the gland. Microscopically, the cysts are lined by tall, columnar, mucin-producing epithelium. These columnar cells have
basal nuclei and abundant intracytoplasmic apical mucin and
can form flat sheets or papillae. The walls of the cysts contain
a very distinctive ovarian-type stroma. This stroma is composed of densely packed spindle cells with sparse cytoplasm
and uniform elongated nuclei. All MCNs are considered to be
premalignant lesions and should be completely resected to prevent progression to malignancy.
Invasive mucinous cystadenocarcinomas are MCNs associated with an invasive carcinoma, whereas noninvasive mucinous neoplasms can be categorized into mucinous cystic
neoplasms with low-grade dysplasia (adenoma), mucinous
cystic neoplasms with moderate dysplasia (borderline), and
mucinous cystic neoplasms with high-grade dysplasia (carcinoma in situ) based on the degree of architectural and cytologic atypia of the epithelial cells. Approximately one third of
all MCNs are associated with invasive carcinoma. Patients
with mucinous cystadenocarcinomas tend to be 5 to 10 years
older than patients with benign MCNs. The extent of invasive
and in situ carcinomas in MCNs can be very focal. Therefore,
a benign diagnosis cannot be established on biopsy alone and
the lesions should be completely resected. The prognosis for
patients with resected benign or borderline tumors is excellent.
Patients with mucinous cystadenocarcinoma tend to do better
than patients with ductal adenocarcinoma, with a 5-year survival of approximately 50%.
PANCREAS/LIVER
841
842
TA B L E 5 4 . 5
DIAGNOSIS
IPMN
Age (y)
4050
6080
Gender
Location
Body/tail
Head
No
Yes
Mucin at ampulla
No
Yes
Ovarianlike stroma
Yes
No
CLINICOPATHOLOGIC STAGING
Accurate pathologic staging of pancreatic cancer is important for providing prognostic information to patients and for
TA B L E 5 4 . 6
843
STAGING
IA
T1
N0
M0
2030
IB
T2
N0
M0
2030
IIA
T3
N0
M0
1025
IIB
T1, T2, T3
N1
M0
1015
III
T4
Any N
M0
05
IV
Any T
Any N
M1
TUMOR (T)
TX: Primary tumor cannot be assessed
T0: No evidence of primary tumor
Tis: Carcinoma in situ
T1: Tumor limited to the pancreas, 2 cm or less in greatest dimension
T2: Tumor limited to the pancreas, more than 2 cm in greatest dimension
T3: Tumor extends beyond the pancreas but without involvement of the celiac axis or the
superior mesenteric artery
T4: Tumor involves the celiac axis or the superior mesenteric artery (unresectable primary
tumor)
PANCREAS/LIVER
comparing the results of various therapeutic trials. The American Joint Committee on Cancer (AJCC) staging for pancreatic
cancer is shown in Table 54.6. This system, based on the TNM
classification, takes into account the extent of the primary
tumor (T), the presence or absence of regional lymph node
involvement (N), and the presence or absence of distant
metastatic disease (M).
DIAGNOSIS
Clinical Presentation
Many of the difficulties associated with the management of
pancreatic cancer result from our inability to make the diagnosis at an early stage. The early symptoms of pancreatic cancer include anorexia, weight loss, abdominal discomfort, and
nausea. Unfortunately, the nonspecific nature of these symptoms often leads to a delay in the diagnosis. Specific symptoms
usually develop only after invasion or obstruction of nearby
structures has occurred. Most pancreatic cancers arise in the
head of the pancreas, and obstruction of the intrapancreatic
portion of the common bile duct leads to progressive jaundice,
acholic stools, darkening of the urine, and pruritus. Pain is a
common symptom of pancreatic cancer. The pain usually
starts as vague upper abdominal or back pain that is often
ignored by the patient or attributed to some other cause. It is
usually worse in the supine position and is often relieved by
Laboratory Studies
In patients with cancer of the head of the pancreas, laboratory
studies usually reveal a significant increase in serum total
bilirubin, alkaline phosphatase, and -glutamyl transferase,
844
TA B L E 5 4 . 7
DIAGNOSIS
PATIENTS (%)
HEAD
Weight loss
92
Jaundice
82
Pain
72
Anorexia
64
Dark urine
63
Light stools
62
Nausea
45
Vomiting
37
Weakness
35
Pruritus
24
Diarrhea
18
Melena
12
Constipation
11
Fever
11
Hematemesis
100
Pain
87
Weakness
43
Nausea
43
Vomiting
37
Anorexia
33
Constipation
27
Hematemesis
17
Melena
17
Jaundice
Fever
Diarrhea
TA B L E 5 4 . 8
DIAGNOSIS
PATIENTS (%)
HEAD
Jaundice
87
Palpable liver
83
Palpable gallbladder
29
Tenderness
26
Ascites
14
Abdominal mass
13
33
Tenderness
27
Abdominal mass
23
Ascites
20
Jaundice
13
Diarrhea
Radiologic Investigations
Radiologic imaging plays a crucial role in the diagnosis, staging,
and follow-up of patients with pancreatic cancer. In addition to
identifying the primary tumor, the goals of imaging include the
assessment of local and regional invasion, evaluation of lymph
nodes and vascular structures, identification of distant metastatic disease, and determination of tumor resectability. Ultrasonography, CT, and magnetic resonance imaging (MRI) are all
useful noninvasive tests in the patient suspected of having a pancreatic cancer.
Transabdominal ultrasonography is operator dependent
but can demonstrate dilated intrahepatic and extrahepatic bile
ducts, liver metastases, pancreatic masses, ascites, and enlarged
peripancreatic lymph nodes. Pancreatic cancer typically
appears as a hypoechoic mass on ultrasonography. Ultrasonography will reveal a pancreatic mass in 60% to 70% of
patients with cancer. Because helical CT is just as sensitive as
ultrasonography and provides more complete information
about surrounding structures and the local and distant extent
of the disease, transabdominal ultrasonography has been
largely replaced by CT.
3
Helical or spiral CT is currently the preferred noninvasive
imaging test for the diagnosis of pancreatic cancer. Pancreatic
cancer usually appears as an area of pancreatic enlargement
with a localized hypodense lesion (Fig. 54.3). For pancreatic
lesions, a dual-phase intravenous contrast study is ideal. Thin
cuts are obtained through the pancreas and liver during both an
arterial phase and portal venous phase after the administration
845
of intravenous contrast. In addition to determining the primary tumor size, CT is used to evaluate invasion into local
structures or metastatic disease.
In general, MRI offers no significant advantages over CT
because of a low signal-to-noise ratio, motion artifacts, lack of
bowel opacification, and low spatial resolution. MRI can be
considered an alternative preoperative staging exam in
patients with allergies to iodinated contrast agents and in
patients with renal insufficiency. On MRI, a typical pancreatic
adenocarcinoma appears hypointense on T1-weighted,
unenhanced images, and has a variable appearance on T2weighted sequences. The T2 signal of the tumor is often
dependent on the amount of desmoplastic response associated
PREOPERATIVE STAGING
PANCREAS/LIVER
FIGURE 54.3. Computed tomogram of the abdomen of a patient with adenocarcinoma of the pancreas. A: The obstructed and dilated common
bile duct (light arrow) and pancreatic duct (dark arrow) can be seen. In the adjacent cross section (B), a large mass is present in the head of the
pancreas (arrow).
846
STAGING LAPAROSCOPY
TA B L E 5 4 . 9
DIAGNOSIS
847
Spiral CT
Unresectable
Resectable
Biliary or
duodenal
(consider)
obstruction
Absent
Present
Operative
candidate
No
Laparoscopic
staging
Peritoneal or
hepatic
metastases
No
Yes
Duodenal obstruction
+/ biliary obstruction
Life expectancy
< 6 mo
> 6 mo
Endobiliary
stent
Observation
+/ chemotherapy
Yes
Nonoperative
palliation
Biliary stent
Chemo/radiotherapy
Operative palliation
Biliary bypass
Gastrojejunostomy
Celiac plexus block
ALGORITHM 54.1
ALGORITHM 54.1. Diagnosis and management of pancreatic cancer. (After Tsiotis GG, Sarr MG. Diagnosis and clinical staging of pancreatic
cancer. In: Howard JM, Idezuki Y, Ihse I, et al., eds. Surgical Disease of the Pancreas, 3rd ed. Baltimore: Williams & Wilkins; 1998:510.)
RESECTION OF PANCREATIC
CARCINOMA
Carcinoma of the Head, Neck,
or Uncinate Process
In 1912, Kaush18 reported the first successful resection of the
duodenum and a portion of the pancreas for an ampullary
cancer. In 1935, Whipple et al.19 described a technique for radical excision of a periampullary carcinoma. The operation was
originally performed in two stages. A cholecystogastrostomy
to decompress the obstructed biliary tree and a gastrojejunostomy to relieve gastric outlet obstruction comprised the first
stage. The second stage was performed several weeks later
when the jaundice had resolved and the nutritional status had
improved. During the second stage, an en bloc resection of the
second portion of the duodenum and head of the pancreas was
performed without reestablishing pancreaticenteric continuity. Although earlier contributions had been made, the report
by Whipple et al. began the modern-day approach to the treatment of pancreatic carcinoma.
Since Whipples original description, pancreaticoduodenal
resection has undergone numerous modifications and technical
refinements. Unfortunately, during most of the first 50 years
when the procedure was performed, the reported morbidity
and mortality rates were unacceptably high, and long-term
survival rates were disappointing. During the late 1960s and
1970s, the high operative morbidity and mortality and poor
PANCREAS/LIVER
Body/Tail
Head
848
Extent of Resection. Several technical aspects of pancreaticoduodenectomy remain controversial: (a) whether or not a
radical lymph node dissection is necessary, (b) whether a
pylorus-preserving or classic pancreaticoduodenectomy should
be performed, and (c) whether or not there is a role for laparoscopic pancreatic resections.
Several nonrandomized retrospective studies have advocated adding a radical (extended) retroperitoneal lymph node
dissection to pancreaticoduodenectomy in an attempt to
improve survival. However, results from four randomized
prospective trials2023 (Table 54.10) have shown extended
lymph node dissections not to be beneficial. The prospective
trial performed by Pedrazzoli et al.20 suggested a survival
advantage to extended retroperitoneal lymph node dissection
in patients with positive lymph nodes. Eighty-one patients
with pancreatic adenocarcinoma were randomized to either
standard or radical lymphadenectomy over 3 years at six different institutions. While the two groups were similar with
respect to preoperative parameters, operative morbidity, and
overall survival, a subgroup analysis of the 48 patients with
positive lymph nodes showed a statistically significant survival
advantage for patients undergoing the extended lymph node
dissection. However, the largest prospective randomized trial
from the Johns Hopkins Hospital failed to demonstrate a survival advantage for a radical resection as compared with a
classic pancreaticoduodenectomy.21 Two hundred and ninetyfour patients undergoing resection for periampullary adenocarcinoma were randomized between a standard resection
(pylorus-preserving pancreaticoduodenectomy with en bloc
resection of the anterior and posterior pancreaticoduodenal
lymph nodes, lower hepatoduodenal lymph nodes, and nodes
along the right lateral aspect of the superior artery and vein)
and a radical resection (standard resection plus distal gastrectomy and retroperitoneal lymph node dissection extending
from the right renal hilum to the left lateral border of the aorta
and from the portal vein to the inferior mesenteric artery). The
groups did not differ with respect to age, gender, site of primary tumor, lymph node status, or margin status. There were
no significant differences in 1-, 3-, or 5-year and median survival
when comparing the standard and radical groups (Fig. 54.7).
However, the radical group had a higher overall morbidity
(43% vs. 29%) with significantly higher rates of delayed gastric emptying and pancreatic fistula in addition to a longer
postoperative hospital stay.
In 1978, Traverso and Longmire24 popularized the pyloruspreserving modification of the Whipple procedure. Preserving
antral and pyloric function, the pylorus-preserving Whipple
procedure reduces the incidence of troublesome postgastrectomy symptoms. A number of studies have documented that
849
PANCREAS/LIVER
TA B L E 5 4 . 1 0
TREATMENT
RANDOMIZED PROSPECTIVE TRIALS OF STANDARD VERSUS EXTENDED LYMPHADENECTOMY FOR PANCREATIC CANCER
AUTHOR
YEAR
Pedrazzoli et al.20
1998
Yeo et al.21
2002
Nimura et al.22
2004
Farnell et al.23
2005
PROCEDURE
OP
TIME (h)
MORBIDITY
(%)
MORTALITY
(%)
3-Y SURVIVAL
(%)
12
Standard
40
6.2
35
Extended
41
6.6
45
Standard
146
5.9
29
36
Extended
148
6.4
43
38
Standard
51
7.0
12
29
Extended
50
9.0
20
17
Standard
34
6.2
35
41
Extended
31
7.6
45
2.6
25
1.0
0.9
Radical (n = 145)
Standard (n = 140)
0.8
Proportion surviving
850
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
12
24
36
48
60
Months
and the mean number of lymph nodes removed in the specigastrointestinal function is better preserved in the pylorusmen was 13 (range, 8 to 21). These results are comparable to
sparing modification than in the traditional operation. In addithose of open pancreaticoduodenectomy. The authors emphation, compared with the classic Whipple operation, the
size the importance of patient selection in attempting laparopylorus-preserving procedure is less time-consuming and techscopic PD. They recommend limiting the procedure to othernically easier to perform. Concerns exist in the use of the
wise healthy, nonobese patients with early ampullary or distal
pylorus-preserving Whipple procedure for the management of
bile duct cancers or patients with small (2 cm) pancreatic
periampullary tumors because of the possibility of compromiscancers with minimal inflammatory changes in the pancreas
ing the already small proximal surgical margin of resection.
and no evidence of superior mesenteric vein/portal vein
This question has been addressed by a number of authors, and
involvement by preoperative imaging. In addition, they state
no difference appears to be found in survival among those
that it should be attempted only after obtaining considerable
patients treated with the pylorus-sparing Whipple procedure and
experience in laparoscopic pancreatic surgery and not simply
those managed by the traditional Whipple resection.2527 Thereadvanced laparoscopic surgery.
fore, many pancreatic surgeons favor pylorus-preserving pancreaticoduodenectomy because it shortens the operative time, retains
the entire stomach as a reservoir, and has a similar survival rate as
compared with the classic pancreaticoduodenectomy.
Carcinoma of the Body and Tail
In recent years significant advances have been made in the
application of minimally invasive techniques to the manageThe surgical management of adenocarcinoma of the body and
ment of both benign and malignant pancreatic disorders. Initail of the pancreas is much more limited than that of the head
tially, laparoscopic pancreatic surgery was limited to diagnosof the pancreas because of the extent of the disease usually prestic staging in patients with pancreatic cancer prior to resection.
ent at the time of symptomatic presentation. Most patients are
More recently minimally invasive techniques have been used
unable to undergo resection, based on findings of major vascuto manage benign and malignant lesions of the pancreas.
lar involvement on CT or peritoneal or liver metastases on
While laparoscopic distal pancreatic resections are being perlaparoscopy. If an attempt at open exploration for possible cure
formed with increasing frequency,28 the role of laparoscopic
is undertaken, the exploration should be started with a search
for evidence of either metastatic disease to the liver or peripancreaticoduodenectomy (PD) remains controversial.
toneal implants. If this is not the case, the lesser sac is opened,
Laparoscopic PD is a technically demanding procedure due to
and the SMV is identified as it passes under the neck of the panthe retroperitoneal location of the pancreas, its intimate assocreas. If this vessel is normal, and if the splenic vein does not
ciation with surrounding gastrointestinal and major vascular
appear to be obstructed preoperatively, a distal pancreatectomy
structures, and the need for three separate anastomoses to
with splenectomy is performed. The spleen is mobilized, as is
complete the reconstruction. In addition, it is unclear whether
the distal pancreas, and an en bloc resection of the structure,
an adequate cancer operation can be performed with respect
including the mass, is obtained. The resection should be
to lymph node harvest and margin status in patients with
extended as proximally as possible, with the transected panmalignancy. Currently, laparoscopic PD is only performed in a
creas simply oversewn. The tumor bed should be marked with
handful of specialized centers. The procedures are performed
the placement of clips for postoperative radiation therapy. If, as
as either pure laparoscopic, hand assisted or as laparoscopicin most cases, the tumor cannot be resected, a tissue biopsy
assisted procedures with the resection being performed laparoshould be performed, in addition to a chemical splanchnicecscopically and the reconstruction being completed via a
tomy with alcohol for pain management. In some cases, a promini laparotomy or through a hand port.
phylactic gastrojejunostomy may be indicated because of the
Palanivelu et al.29 describe 42 patients who successfully
potential for obstruction by tumor at the ligament of Treitz.
underwent laparoscopic PD for ampullary carcinoma (n
24), pancreatic cystadenocarcinoma (n 4), pancreatic adenocarcinoma (n 9), distal cholangiocarcinoma (n 3), and
chronic pancreatitis (n 2). All of the procedures were able to
Postoperative Results
be completed with a totally laparoscopic technique and there
were no conversions to open. There was one perioperative 4 During the 1960s and 1970s, many centers reported operative
mortality (2.4%) and the complication rate was 31%. The opermortality following pancreaticoduodenectomy in the range of
ative time averaged 370 minutes and the postoperative length
20% to 40%, with postoperative morbidity rates as high as
of stay was 10.1 days. All patients underwent an R0 resection
40% to 60%. During the last two decades, a dramatic decline
TA B L E 5 4 . 1 1
COMPLICATIONS
851
ADJUVANT AND
NEOADJUVANT THERAPY
Duodenal
PANCREAS/LIVER
Gastric
852
Tumor Diameter
1.0
1.0
0.9
0.9
0.8
Proportion surviving
Proportion surviving
p < 0.0001
0.7
0.6
< 3 cm
0.5
0.4
0.3
3 cm
0.2
p < 0.0001
0.7
0.6
No positive nodes
0.5
0.4
0.3
Positive nodes
0.2
0.1
0.1
0.0
0.8
12
24
36
48
0.0
60
12
24
Months
Margin Status
1.0
0.9
0.9
0.8
p < 0.0001
0.7
0.6
Negative margin
0.5
0.4
0.3
Positive margin
0.2
0.1
0.0
12
24
60
0.8
p < 0.0001
0.7
0.6
Well or moderate
0.5
0.4
0.3
Poor or
undifferentiated
0.2
0.1
48
Histologic Grade
1.0
Proportion surviving
Proportion surviving
36
Months
36
48
0.0
60
12
24
Months
36
48
60
Months
E
1.0
0.9
1970s
1980s
1990s
2000s
Proportion surviving
0.8
0.7
0.6
n = 514
0.5
n = 573
0.4
0.3
n = 65
n = 23
0.2
0.1
0
12
36
24
48
60
Months
FIGURE 54.8. Survival of patients with pancreaticoduodenectomy based on tumor size (A), lymph node status (B), margin status (C), histologic
grade (D), and historical context (E). (Reproduced with permission from Winter JM, Cameron JL, Campbell KA, et al. 1,423 pancreaticoduodenectomies for pancreatic cancer: a single-institution experience. J Gastrointest Surgery 2006;10:11991210.)
853
TA B L E 5 4 . 1 2
TREATMENT
STUDY
TREATMENT
ARM
GITSG35
Surg
11
18
18
43
19
EORTC36
ESPAC-137
RTOG38
CONKO39
MEDIAN
SURVIVAL (mo)
2-Y OVERALL
SURVIVAL (%)
5-Y OVERALL
SURVIVAL (%)
Surg
13
23
10
17
37
20
Surg
17
11
Surg, 5-FU
20
40
21
16
29
10
17
21 (3 y)
19
31 (3 y)
Surg
20
42
12
Surg, Gemcitabine
22
48
23
TA B L E 5 4 . 1 3
TREATMENT
41
YEAR
REGIMEN
1997
91
XRT, 5-FU
RESECTED
(%)
MEDIAN
SURVIVAL (mo)
45
19
1998
53
45
16
Pisters et al.42
2002
37
XRT, Paclitaxel
54
19
Wolff et al.43
2002
86
XRT, Gemcitabine
73
36
Talamonti et al.44
2006
20
XRT, Gemcitabine
85
26
PANCREAS/LIVER
5-FU, 5-fluorouracil; EORTC, European Organization for Research and Treatment of Cancer; ESPAC, European Study Group for Pancreatic Cancer;
GITSG, Gastrointestinal Tumor Study Group; Surg, surgical; ROTC, Radiation Therapy Oncology Group; XRT, radiation therapy.
854
potential benefits, including (a) delivery of treatment to welloxygenated tissue, which enhances efficacy of chemoradiation; (b) downstaging, which can enhance ability to achieve a
negative margin resection and thereby reduce local recurrence; and (c) avoidance of surgery in patients with rapidly
progressive disease. Neoadjuvant therapy can be completed
without increasing the subsequent morbidity and mortality
of surgical resection. The group from the M.D. Anderson
Cancer Center has reported on the multimodality treatment
of 142 consecutive patients with localized adenocarcinoma
of the pancreatic head.40 A subset of 41 patients treated by
preoperative chemoradiation and pancreaticoduodenectomy
were compared with 19 patients receiving pancreaticoduodenectomy and postoperative adjuvant chemoradiation.
Surgery was not delayed for any patient who received preoperative chemoradiation because of chemoradiation toxicity,
but 24% of the eligible patients did not receive their intended
postoperative chemoradiation because of delayed recovery
following pancreaticoduodenectomy. The patients treated
with rapid fractionation were reported to have a significantly shorter duration of treatment (median, 62.5 days)
than patients who received postoperative chemoradiation
(median, 98.5 days). In early follow-up, no patient who
received preoperative chemoradiation experienced a local
recurrence, and peritoneal recurrence developed in only
10% of these patients. Local or regional recurrence developed in 21% of patients who received postoperative
chemoradiation. The overall survival curves were similar for
both cohorts.
Wolff et al.43 examined 86 patients treated with weekly
gemcitabine at a dose of 400 mg/m2 and 30 Gy of radiation.
Sixty-one patients ultimately underwent resection (71%). The
median survival in the resected patients was 36 months,
which is significantly longer than those seen in regimens using
5-FU or paclitaxel as the radiation sensitizer. Analysis of the
specimens revealed two pathologic complete responses and
more than 50% nonviable tumor cells in 36 (59%). A gemcitabine-based regimen was also used in a multi-institutional
study of 20 patients reported by Talamonti et al.44 This group
used full-dose gemcitabine and limited-field radiation to 36
Gy (2.4 Gy/fraction). The authors described 14 patients as
resectable and six as borderline resectable. Ultimately, all
patients were explored and 17 resected (85%), again representing a very high rate of resectability. A single pathologic
complete response was observed and, in 24% of tumors,
greater than 90% of the tumor cells were felt to be nonviable.
Also notable was the low incidence, 6%, of margin positivity
in this trial. The median survival in the resected patients was
26 months. Based on the results of these initial trials, gemcitabine-based neoadjuvant regimens remain of considerable
interest.
PALLIATION
7
Jaundice
Obstructive jaundice is present in most patients who have
pancreatic cancer. If left untreated, it can result in progressive
liver dysfunction, hepatic failure, and early death. In addi-
Duodenal Obstruction
At the time that pancreatic cancer is diagnosed, approximately
one third of patients have symptoms of nausea or vomiting.
Although true mechanical obstruction of the duodenum seen
by radiologic or endoscopic examination is much less frequent, duodenal obstruction develops in almost 20% of
patients before they die as the disease progresses.46 Duodenal
obstruction can be caused in the C-loop by cancers of the head
or at the ligament of Treitz by cancers of the body and tail. In
patients with evidence of duodenal obstruction or impending
obstruction, a gastrojejunostomy is indicated for palliation.
This is typically performed as a retrocolic, isoperistaltic loop
gastrojejunostomy with a loop of jejunum 20 to 30 cm distal
to the ligament of Treitz.
In patients with unresectable pancreatic cancer who do
not have symptoms of gastric outlet obstruction, whether or
not to perform a prophylactic gastric bypass at the time of
biliary bypass is a matter of debate. Surgeons who do not
perform a prophylactic bypass feel that it needlessly
increases the postoperative length of stay and can be associated with delayed gastric emptying and increased morbidity
and mortality. However, data from a prospective randomized trial of prophylactic gastrojejunostomy in patients with
unresectable cancer do not support this view.47 In this study,
44 patients were randomized to a gastrojejunostomy, and
43 did not undergo gastric bypass. No mortality occurred in
either group. No difference was observed in either the
855
TA B L E 5 4 . 1 4
MANAGEMENT
MORBIDITY
(%)
MORTALITY
(%)
POSTOPERATIVE
LENGTH OF
STAY (d)
LATE GASTRIC
OUTLET
OBSTRUCTION (%)
Gastrojejunostomy
44
32
8.5
No gastrojejunostomy
43
33
8.0
19
Adapted from Lillemoe KD, Cameron JL, Hardacre JM, et al. Is prophylactic gastrojejunostomy indicated for unresectable periampullary cancer?
Ann Surg 1999;230:322330.
Pain
Tumor-associated pain can be incapacitating in patients with
unresectable pancreatic cancer. The postulated causes of
tumor-associated pain are many and include tumor infiltration
into the celiac plexus, increased parenchymal pressure caused
by pancreatic duct obstruction, pancreatic inflammation, gallbladder distention resulting from biliary obstruction, and gastroduodenal obstruction. The management of pain in patients
dying of carcinoma of the pancreas is one of the most important aspects of their care. The appropriate use of oral agents
can be successful in most patients. Patients with significant
pain should receive their medication on a regular schedule and
not an as needed basis. The use of long-acting morphine
derivative compounds appears to be best suited for such treatment. Percutaneous neurolytic block of the celiac axis, performed under either fluoroscopic or CT guidance, is also successful in the majority of patients at eliminating pain. Patients
with unresectable cancer at the time of surgical exploration
should receive a chemical splanchnicectomy, with 20 mL of
50% alcohol injected on either side of the aorta at the level of
the celiac axis.49
Summary
The decision to perform nonoperative versus surgical palliation
for pancreatic cancer is influenced by a number of factors,
including the patients symptoms, overall health status, predicted procedure-related morbidity and mortality, and projected survival. Surgical palliation can be completed with
acceptable perioperative morbidity and mortality and postoperative length of stay. The avoidance of late complications of
recurrent jaundice, duodenal obstruction, and disabling pain
would strengthen the argument in favor of surgical palliation in
those patients expected to survive 6 months or more. Nonoperative methods of palliation should be considered for patients
in whom preoperative staging suggests distant metastatic disease or a locally unresectable tumor, patients who are not candidates for operative intervention, and those not expected to
survive more than 3 months.
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21. Yeo CJ, Cameron JL, Lillemoe KD, et al. Pancreaticoduodenectomy with
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trial evaluating survival, morbidity, and mortality. Ann Surg 2002;236:
355.
22. Nimura Y, Nagino M, Kato H, et al. Regional vs extended lymph node
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23. Farnell MB, Pearson RK, Sarr MG, et al. A prospective randomized trial
comparing standard pancreatoduodenectomy with pancreatoduodenectomy with extended lymphadenectomy in resectable pancreatic head adenocarcinoma. Surgery 2005;138:618630.
24. Traverso LW, Longmire WP Jr. Preservation of the pylorus in pancreaticoduodenectomy. Surg Gynecol Obstet 1978;146:959.
25. Kozuschek W, Reith HB, Waleczek H, et al. A comparison of long term
results of the standard Whipple procedure and the pylorus preserving pancreatoduodenectomy. J Am Coll Surg 1994;178:443.
26. Takada T, Yasuda H, Amano H, et al. Results of a pylorus-preserving pancreatoduodenectomy for pancreatic cancer: a comparison with results of
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27. Tran KT, Smeenk HG, van Eijck CH, et al. Pylorus-preserving pancreaticoduodenectomy versus standard Whipple procedure a prospective randomized multicenter analysis of 170 patients with pancreatic and periampullary tumors. Ann Surg 2004;240:738.
28. Kooby D, Gillespie T, Bentrem D, et al. Left-sided pancreatectomy: a multicenter comparison of laparoscopic and open approaches. Ann Surg 2008;
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29. Palanivelu C, Jani K, Senthilnathan P, et al. Laparoscopic pancreaticoduodenectomy: technique and outcomes. J Am Coll Surg 2007;205:
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32. Schmidt CM, Powell ES, Yiannoutsos CT, et al. Pancreaticoduodenectomy: a 20-year experience in 516 patients. Arch Surg 2004;139:718.
33. Sosa JA, Bowman HM, Gordon TA, et al. Importance of hospital volume in the overall management of pancreatic cancer. Ann Surg 1998;
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36. Kinkenbijl JH, Jeekel J, Sahmoud T, et al. Adjuvant radiotherapy and 5fluorouracil after curative resection of cancer of the pancreas and periampullar region. Ann Surg 1999;230:776.
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38. Regine WF, Winter KW, Abrams R, et al. RTOG 9704 a phase III study of
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39. Oettle H, Post S, Neuhaus P, et al. Adjuvant chemotherapy with gemcitabine vs. observation in patients undergoing curative-intent resection of
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40. Spitz FR, Abbruzzese JL, Lee JE, et al. Preoperative and postoperative
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41. Hoffman JP, Lipsitz S, Pisansky T, et al. Phase II trial of preoperative radiation therapy and chemotherapy for patients with localized, resectable
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42. Pisters PW, Wolff RA, Janjan NA, et al. Preoperative paclitaxel and concurrent rapid-fractionation radiation for resectable pancreatic adenocarcinoma: toxicities, histologic response rates, and event-free outcome. J Clin
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44. Talamonti MS, Small W Jr, Mulcahy MF, et al. A multi-institutional phase
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658.
46. Sarr MG, Cameron JL. Surgical management of unresectable carcinoma of
the pancreas. Surgery 1982;91:123.
47. Lillemoe KD, Cameron JL, Hardacre JM, et al. Is prophylactic gastrojejunostomy indicated for unresectable periampullary cancer? Ann Surg
1999;230:322.
48. Van Heek NT, De Castro SM, van Eijck CH, et al. The need for a prophylactic gastrojejunostomy for unresectable periampullary cancer: a prospective randomized multicenter trial with special focus on assessment of quality of life. Ann Surg 2003;238:894.
49. Lillemoe KD, Cameron JL, Kaufman HS, et al. Chemical splanchnicectomy in patients with unresectable pancreatic cancer: a prospective randomized trial. Ann Surg 1993;217:447.
50. Burris HA, Moore MJ, Anderson J, et al. Improvements in survival and
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7:347.
PANCREAS
EUGENE P. KENNEDY, JONATHAN R. BRODY, AND CHARLES J. YEO
P O I N T S
5
6
10
Endoscopic ultrasonography is particularly useful in localizing tumors in patients with gastrinoma and insulinoma.
Insulinomas may present with either neuroglycopenic
symptoms (confusion, seizure, obtundation, coma) or
hypoglycemic-induced symptoms (palpitations, diaphoresis, tachycardia).
Ninety percent of insulinomas are solitary, 90% are sporadic, and 90% are benign with location evenly distributed
throughout the pancreas.
Seventy-five percent of gastrinomas are sporadic (25% are
associated with multiple endocrine neoplasia type 1 syndrome), and all should be considered to be of malignant
potential.
Most gastrinomas are located in the gastrinoma triangle
and may be intrapancreatic, within the wall of the duodenum, or in a peripancreatic lymph node, and in most cases
local resection (enucleation) may be adequate therapy.
Glucagonomas usually present with a characteristic severe
dermatitis (termed necrolytic migratory erythema) and are
typically large and bulky and often with metastatic disease.
PENs measuring greater than 0.5 cm in diameter and havPancreatic endocrine neoplasms (PENs) are rare tumors that
ing a low mitotic rate of less than 10 mitoses per 10 highaccount for 1% to 2% of pancreatic neoplasms.1 First
power fields are referred to as well-differentiated pancreatic
described by Nicholls in 1902 as a tumor arising from pancreendocrine neoplasms. This group comprises the large majority
atic islet cells, these islet cell adenomas were long thought to
1 arise from the islets of Langerhans.2 Recent investigations
of clinically relevant PENs. They are uncommon, with an estimated incidence of approximately 1 out of 100,000 peohave revealed that PENs more likely originate from multipople.10,11 Although rare in children, cases have been described at
tential stem cells in pancreatic ductules.3,4 This nonislet cell
origin has been further demonstrated in tumors arising in
all ages, and the peak incidence occurs between the ages of 40
patients with multiple endocrine neoplasia type 1.5 Therefore,
and 60 years.6 Overall distribution is equal between men and
use of the older terms islet cell tumor and islet cell carcinoma
women with some differences in ratio among different funcis now discouraged, in favor of the terms pancreatic endocrine
tional types.
neoplasms or pancreatic endocrine tumors.6,7
No well-established staging system exists for PENs.12 Mul2
tiple studies have been performed attempting to establish progOverall, PENs are best classified according to the size and
nostic characteristics such as size, mitotic count, vascular and
the mitotic rate of the tumor (Table 55.1). This system places
perineural invasion, nuclear polymorphisms, and Ki-67 labelPENs into one of three categories: pancreatic endocrine
microadenomas, well-differentiated pancreatic endocrine neo- 3 ing index.1316 The most recent World Health Organization
plasms, and poorly differentiated or high-grade endocrine car(WHO) classification divides well-differentiated PENs into
cinomas. Additionally, they can be classified by the presence
well-differentiated endocrine tumors and well-differentiated
(i.e., functional tumors) or absence (i.e., nonfunctional
endocrine carcinomas based on their clinical behavior.1 Any
tumors) of a syndrome due to hormone production. The prolocal invasion beyond the pancreas or metastatic spread to
duction of certain hormones and the resulting syndromes lead
lymph nodes or distant locations results in classification as carto well-described clinical syndromes, which are detailed later
cinoma. The WHO well-differentiated endocrine tumors are
in this chapter.
further subclassified as having predicted benign behavior or
PENs less than 0.5 cm in diameter are classified as pancreuncertain behavior. This subdivision (benign vs. uncertain) is
atic endocrine microadenomas. Oncologically, they are conbased on size (2 cm or 2 cm), mitotic count (less than two
sidered to be benign lesions. Their prevalence is estimated to
or two or more mitotic figures per 10 high-power fields), Ki-67
be as high as 10% of the population in autopsy series.8,9 Most
labeling index (2% or 2%), and absence or presence of perineural and vascular invasion (Table 55.2).
pancreatic endocrine microadenomas are noted as incidental
Well-differentiated PENs can also be classified as functional
findings in pancreata resected for other indications and, by
or nonfunctional based on the presence or absence of an assodefinition, produce no neoplastic syndromes (i.e., are nonfuncciated clinically recognizable syndrome (Table 55.3). These
tional). Functional PENs less than 0.5 cm are classified with
syndromes are the result of the secretion of biologically active
well-differentiated pancreatic endocrine neoplasms.
857
PANCREAS/LIVER
K E Y
858
TA B L E 5 5 . 1
C L A S S I F I C AT I O N
SIZE
MITOTIC RATE
CLINICAL BEHAVIOR
0.5 cm
2 per 10 HPF
Benign
0.5 cm
Indeterminate
Any
Malignant
hormones by the tumors and are confirmed by measurable elevations of the hormones in the blood. The most common functional PENs include insulinomas, gastrinomas, vasoactive
intestinal polypeptide-omas (VIPomas), glucagonomas, and
somatostatinomas. The incidence of these lesions ranges from
1 per 1 million for insulinomas to 1 per 40 million for somatostatinomas.17 Even less common PENs secreting calcitonin,18,19 parathyroid hormonerelated protein,20 growth
hormonereleasing factor, and adrenocorticotropic hormone21
have been reported. Nonfunctional PENs are classified as such
due to their lack of an associated clinical syndrome. Some of
the tumors in this group do secrete elevated amounts of hormones, including chromogranin A, which can be detected in
either the serum or surgical specimens using immunohistochemistry.22 These secreted hormones either produce no clinical syndromes, as is seen with tumors that secrete pancreatic
polypeptide,23 or secrete hormones in subclinical amounts or
inactive forms. Traditionally, functional PENs were reported
to comprise the majority of PENs. As methods of detecting
these lesions and patterns of presentation have evolved, due
primarily to the widespread use of high-quality cross-sectional
imaging, nonfunctional PENs now comprise more than half of
surgically resected cases.13,24
The least common group of PENs is the poorly differentiated or high-grade endocrine carcinomas. These are aggressive
tumors characterized by their high mitotic count (10 mitotic
figures per 10 high-powered fields).25 These tumors primarily
occur in adults and have a male predominance. Some have
been reported to be functional, producing varied clinical syndromes (commonly gastrinoma, VIPoma, glucagonoma, and,
less frequently, insulinoma). Prognosis is often poor, with the
clinical course varying from a rapid decline to a more indolent,
prolonged survival.
MOLECULAR GENETICS
The majority of PENs are sporadic. Some of them, however,
occur as part of inherited familial syndromes such as multiple
endocrine neoplasia type 1 (MEN-1), von Hippel-Lindau
(VHL) syndrome, neurofibromatosis (NF-1), and tuberous
sclerosis (TSC) (Table 55.4). Recent technical advances in
Familial Syndromes
Significant progress has been made in the genetic understanding of the MEN-1 syndrome in relation to PENs.26 Chromosomal linkage studies have localized the genetic defect to the
11q13 locus, and studies of DNA markers have localized the
MEN-1 gene between PYGM and D11S97. The gene contains
10 exons that code for a 610-amino-acid protein called menin,
whose function is unknown, although it is classically labeled
as a tumor suppressor gene. Some studies provide a possible
explanation for loss of this gene in neuroendocrine tumors.27
The menin protein is expressed in diverse tissues and is highly
conserved evolutionarily. Menin is predominately a nuclear
protein, which binds to JunD and may repress JunD-mediated
transcription. Studies in patients with MEN-1 have shown
allelic deletions at chromosome 11q13 in nearly 100% of
parathyroid tumors, 85% of nongastrinoma islet cell tumors,
and up to 40% of gastrinomas. In patients with sporadic
tumors (without MEN-1), 11q13 deletions are seen in about
25%, 20%, and almost 50% of parathyroid tumors, nongastrinoma PENs, and gastrinomas, respectively. Recently it has
been shown that a comprehensive genetic testing program for
patients at risk for MEN-1 can identify patients harboring a
MEN-1 mutation almost 10 years before the development of
clinical signs or symptoms of disease.28 Since MEN-1 loss has
been detected in both the sporadic and the familial forms of
PENs, the menin pathway is most likely involved in the pathogenesis of this disease.27
Less frequently than MEN-1, PENs may be associated with
VHL syndrome. VHL syndrome is another autosomal dominant
inheritance disease that includes many clinical disorders,29 including retinal hemangioblastomas, cerebellar and medullary
hemangioblastomas, and PENs. PENs are found in a small percentage of patients with VHL syndrome. A mutation in the VHL
gene, a tumor suppressor located on chromosome 3p2526,
TA B L E 5 5 . 2
C L A S S I F I C AT I O N
CLINICAL BEHAVIOR
SIZE
MITOTIC COUNT
Ki-67 INDEX
Benign
2 cm
2 per 10 HPF
2%
Absent
Uncertain
2 cm
2 per 10 HPF
2%
Present
859
TA B L E 5 5 . 3
C L A S S I F I C AT I O N
EXTRAPANCREATIC
LOCATION
CLINICAL FEATURES
Hypoglycemia
MALIGNANCY
RATE
Rare
10%
Frequent
50%
10%
Most
Rare
Most
Rare
Most
Anabolic state
Gastrinoma (Zollinger-Ellison)
Peptic ulcer
Diarrhea
VIPoma (Verner-Morrison;
WDHA; pancreatic cholera)
Watery diarrhea
Hypokalemia
Achlorhydria/acidosis
Glucagonoma
Hyperglycemia
Catabolic state
Dermatitis
Somatostatinoma
Hyperglycemia
Steatorrhea
Gallstones
which regulates hypoxia-induced cell proliferation, is responsible. Although germline mutations with loss of heterozygosity
(LOH) are associated with this disease, it has been proposed that
other tumor suppressors most likely cooperate with VHL in
order to form PENs.
NF-1 (von Recklinghausen disease) is an autosomal dominant disorder that produces a well-described clinical syndrome
characterized by caf-au-lait spots and neurofibromas. These
patients may develop pancreatic somatostatinomas. The NF-1
gene is a tumor suppressor gene located on 17q11.2 that
encodes for neurofibromin, a regulator of the mammalian target of rapamycin (mTOR) pathway. Loss of NF-1 results in
mTOR activation and tumor development.30
TA B L E 5 5 . 4
ETIOLOGY
CHROMOSOMAL
LOCATION
11q13
GENE PRODUCT
Menin
PEN TYPE
Gastrinoma
Nonfunctional
VHL syndrome
3p2526
VHL gene
Various
NF-1
17q11.2
Neurofibromin
Somatostatinomas
PANCREAS/LIVER
860
found a strong correlation between CIN, specific chromosomal alterations, and metastatic disease and poor tumor-free
survival in insulinomas and noninsulinomas. The authors also
note that CK19 is a strong indicator of tumor-specific death in
all PENs.36 Other epigenetic studies have correlated altered
methylation patterns in well-characterized tumor suppressor
genes (e.g., APC, E-cadherin, p16) with tumor staging.38 Further, Chan et al. assessed differences between methylation patterns in a similar set of genes between carcinoid and pancreatic
endocrine tumors. This study found distinct differences
between these uncommon tumor types.39
In summary, PENs are most likely difficult to characterize
molecularly (and clinically) due to molecular and thus cellular
heterogeneity within the tumor. Ongoing efforts to search for
candidate genes that lay the foundation for CIN in these
tumors will aid in unraveling the molecular etiology of this disease. It was suggested in one study that FANCD2 is a good
candidate gene since it resides in a chromosomal region of loss
for PENs (chromosome 3p25).36,40 However, it should be
noted that loss of FANCD2 has been shown previously to be
lethal (i.e., counterproductive) to cancer cells.41 Further studies are needed to explore the connection between the FANCD2
gene and PENs. Currently, using modern techniques such as
comparative genomic hybridization (CGH) along with tumor
sizing and markers such as CK19 may provide clinically relevant information.
PRESENTATION AND
EVALUATION
There are three primary ways by which patients with PENs
come to clinical attention: the incidental discovery of a mass in
the pancreas during cross-sectional imaging, symptoms secondary to the mass effect of a lesion in the pancreas (i.e.,
obstructive jaundice or pain), and, as a consequence of the
symptoms of, a syndrome associated with a functional PEN. As
Nonfunctional
Functional
Abdominal pain,
peptic ulcer,
diarrhea
Hypoglycemic
symptoms
Diarrhea,
hypokalemia
Rash
Spiral CT scan
Suspected
Gastrinoma
Insulinoma
Incidental finding
Pain, jaundice
VIPoma
Glucagonoma
Localized
Metastatic
Resection
Chemotherapy
Pancreaticoduodenectomy,
distal pancreatectomy, other
Localized, resectable
Metastatic, operable
Metastatic, inoperable
Enucleation,
pancreaticoduodenectomy,
distal pancreatectomy
Debulking,
liver resection
Octreotide,
chemotherapy
ALGORITHM 55.1
ALGORITHM 55.1. Diagnosis and management of pancreatic endocrine neoplasms.
Endoscopic Ultrasound
shown utility in
MRI is increasingly used in the detection of PENs, particularly 5 Endoscopic ultrasonography (EUS) has also
localizing pancreatic endocrine neoplasms.5660 Rosch et al.59
small lesions. They are especially well visualized on T1- and
were able to localize 32 of 39 tumors (82%) correctly with
T2-weighted images with fat suppression. MRI has the advanEUS after CT had failed to locate the tumor (Fig. 55.3). In
tage of increased soft tissue contrast without the administratheir experience, EUS was more sensitive than the combination
tion of intravenous contrast when compared to CT.42 PENs
of CT and visceral angiography. A more recent study by Proye
characteristically have high signal intensity on T2-weighted
et al.61 evaluated preoperative EUS and SRS in 41 patients
images.47 On dynamic contrast-enhanced T1-weighted images,
with insulinoma and gastrinoma. The sensitivity and positive
the tumors show the same typical enhancement pattern as on
predictive value of EUS were 77% and 94%, respectively, for
CT scan. The sensitivity of MRI has been reported to be
pancreatic tumors; 40% and 100%, respectively, for duodenal
between 74% and 100%.43,44
gastrinomas; and 58% and 78%, respectively, for metastatic
lymph nodes. These results indicate that EUS is best at detecting lesions in the head of the pancreas. It is less successful at
Somatostatin Receptor Scintigraphy
evaluating the distal pancreas and the duodenal wall. Additionally, the procedure is operator dependent.62 These results
(Octreoscan)
have been duplicated by others and have led some to suggest
that EUS should serve as the initial localization procedure in
Somatostatin receptor scintigraphy (SRS) also plays an imporpatients with insulinoma and gastrinoma. Of note, the drawtant role in imaging patients with pancreatic endocrine
back to EUS is that it does not evaluate accurately for hepatic
tumors.4854 In this technique, the octapeptide analogue of
metastatic disease; rather, it is more sensitive than CT for
somatostatin (Octreotide) labeled with indium-111 is adminis-
PANCREAS/LIVER
861
862
FIGURE 55.4. Schematic depiction of data from percutaneous transhepatic portal venous sampling (PTPVS) in a patient with an insulinoma. Insulin levels are given in microunits per milliliter. These data
localize the neoplasm to the head of the pancreas. (Adapted from Norton JA, Sigel B, Baker AR, et al. Localization of an occult insulinoma
by intraoperative ultrasonography. Surgery 1985;97:381.)
FIGURE 55.3. Endoscopic ultrasonographic image from a patient
with an insulinoma (arrows) in the body of the pancreas. SV, splenic
vein. (From Rosch T, Lightdale CJ, Botet JF, et al. Localization of pancreatic endocrine tumors by endoscopic ultrasonography. N Engl J
Med 1992;326:1721, with permission.)
imaging the duodenal wall, pancreatic parenchyma, and peripancreatic lymph nodes.
Intraoperative Ultrasound
Historically, the primary methods of localizing PENs intraoperatively have been visualization and palpation. With the
advent of laparoscopic exploration for PENs, intraoperative
ultrasound has been substituted for palpation. Results have
been promising, with sensitivities reported between 75% and
90%.63,64
Venous Sampling
Percutaneous transhepatic portal venous sampling (PTPVS)
and arterial stimulation with venous sampling (ASVS) are two
techniques that are used exclusively for the diagnosis and localization of PENs. In a small number of cases, CT, MRI, SRS,
and EUS are unsuccessful at localizing a pancreatic endocrine
neoplasm. When insulinoma or gastrinoma are suspected,
PTPVS may help in localizing the occult neoplasm.6569 The
technique involves placing a catheter percutaneously through
the liver into the portal vein and then sequentially sampling for
hormone levels in the splenic vein, superior mesenteric vein,
and portal vein, thereby regionalizing the location of hormone
production (Fig. 55.4). The overall accuracy of this test ranges
from 70% to greater than 95% depending on the number of
samples obtained, the persistence of autonomous hormone
production by the tumor, and the careful handling and assaying
of all samples. ASVS involves the selective visceral arterial
injection of secretin or calcium with concurrent hepatic venous
sampling for either gastrin or insulin.70,71 Gastrinoma cells are
known to respond to secretin by releasing gastrin,72,73 and
insulinoma cells are known to respond to calcium by releasing
insulin. The provocative secretogogue is serially injected
through an arterial catheter into at least three sitesthe
splenic, gastroduodenal, and inferior pancreaticoduodenal
arteries. Samples are drawn from a hepatic vein catheter before
863
associated with gastrectomy or gastroenterostomy, nonpancreatic tumors, pleural mesothelioma, sarcoma, adrenal carcinoma, hepatocellular carcinoma, carcinoid, hypopituitarism,
chronic adrenal insufficiency, extensive hepatic insufficiency,
and surreptitious self-administration of insulin or ingestion of
SURGICAL EXPLORATION
oral hypoglycemic agents.
A common error made in evaluating a patient with susAt the time of surgical exploration for PEN, a complete evalupected insulinoma is to begin with an oral glucose tolerance
ation of the pancreas and peripancreatic regions is performed.
test. Instead, insulinoma is most reliably diagnosed by means
The body and tail of the pancreas are exposed by dividing the
of a monitored fast. During a monitored fast, blood is sampled
gastrocolic ligament. This portion of the pancreas can be parfor glucose and insulin determinations every 4 to 6 hours and
tially elevated out of the retroperitoneum by dividing the infewhen symptoms appear. Hypoglycemic symptoms typically
rior retroperitoneal attachments to the gland. After the second
occur when glucose levels are below 50 mg/dL, with concurportion of the duodenum has been elevated out of the
rent serum insulin levels often exceeding 25 microunits/mL.
retroperitoneum by means of the Kocher maneuver, the panAdditional support for the diagnosis of insulinoma comes
creatic head and uncinate process are palpated bimanually.
from the calculation of the insulin-to-glucose ratio at different
The liver is carefully assessed for evidence of metastatic distimes during the monitored fast. Normal persons have insulinease. Potential extrapancreatic sites of tumor are evaluated in
to-glucose ratios below 0.3, whereas patients with insulinoma
all cases, with particular attention paid to the duodenum,
typically demonstrate insulin-to-glucose ratios above 0.4 after
splenic hilum, small intestine and its mesentery, peripancreatic
a prolonged fast. Other measurable -cell products synthelymph nodes, and reproductive tract in women. The goals of
sized in excess in patients with insulinoma include C peptide
surgical therapy for pancreatic endocrine neoplasms include
and proinsulin. Elevated levels of both are typically found in
controlling the symptoms of hormone excess, safely resecting
the peripheral blood of patients with insulinoma.
maximal tumor mass, and preserving maximal pancreatic
The possibility of the surreptitious administration of
parenchyma. Management strategies, including preoperative,
insulin or oral hypoglycemic agents should be considered in all
intraoperative, and postoperative considerations, vary for the
patients with suspected insulinoma. Levels of C peptide and
different types of endocrine neoplasms of the pancreas.
proinsulin are not elevated in patients who self-administer
insulin. Additionally, patients self-administering either bovine
or porcine insulin may demonstrate anti-insulin antibodies in
INSULINOMA
circulating blood. The ingestion of oral hypoglycemic agents,
such as sulfonylureas, can be assessed by means of standard
Insulinoma is the most common functional neoplasm of the
toxicologic screening.
endocrine pancreas (Table 55.5). The insulinoma syndrome is
Insulinomas are evenly distributed throughout the pancreas,
associated with the following features, known as Whipples
with one third found in the head and uncinate process, one
triad76:
third in the body, and one third in the tail of the gland.77 Less
1. Symptoms of hypoglycemia during fasting
than 3% are located outside the pancreas, with these lesions
2. Documentation of hypoglycemia, with a serum glucose
7 located in the peripancreatic area.78 Ninety percent are found
level below 50 mg/dL
to be benign solitary adenomas amenable to surgical cure.
3. Relief of hypoglycemic symptoms following administration
Ninety percent of insulinomas are sporadic, with approxiof exogenous glucose
mately 10% being associated with the MEN-1 syndrome. In
6
patients with MEN-1, the possibility of multiple insulinomas
Autonomous insulin secretion in insulinomas leads to sponmust be considered, and recurrence rates are higher. In approxtaneous hypoglycemia, with symptoms that can be classified into
imately 10% of patients, insulinoma is metastatic to the peritwo groups (see Table 55.5). Neuroglycopenic symptoms include
pancreatic lymph nodes or liver, making the diagnosis of maligconfusion, seizure, obtundation, personality change, and coma.
nant insulinoma.
Hypoglycemia-induced symptoms, related to a surge in cateAfter the diagnosis of insulinoma has been confirmed biocholamine levels, include palpitations, trembling, diaphoresis,
chemically, the appropriate localization and staging studies
and tachycardia. In most cases, patients consume carbohydratedescribed earlier are performed (typically CT and EUS). Once
rich meals and snacks to relieve or prevent these symptoms.
the lesion has been localized,79 patients undergo surgical exploWhipples triad is not specific for insulinoma. The differential diagnosis of adult hypoglycemia is extensive and includes
ration, where the pancreas is assessed not only by operative
the following: reactive hypoglycemia, functional hypoglycemia
palpation but also by intraoperative ultrasonography. This
allows for confirmation of preoperative localization and evaluates for the presence or absence of multiple primary tumors.
Small, benign tumors that are not close to the main pancreatic
duct can be removed by enucleation80 (Fig. 55.6), regardless of
TA B L E 5 5 . 5
DIAGNOSIS
their location in the gland. Larger tumors in the neck or proxiINSULINOMA
mal body may be resected via central pancreatectomy.8183 In
the body and tail of the pancreas, insulinomas more than 2 cm
PARAMETER
DESCRIPTION
in diameter and those close to the pancreatic duct are most
commonly removed via distal pancreatectomy. Large lesions in
Symptoms
Neuroglycopenia causes confusion,
the head or uncinate process of the gland may not be amenable
personality change, coma
to local resection and may occasionally require pancreaticoCatecholamine surge causes
duodenectomy for complete excision.84,85 Increasingly, experitrembling, diaphoresis, tachycardia
enced surgeons are utilizing a laparoscopic approach to these
tumors. Both laparoscopic pancreatectomy and enucleation are
Anabolic state: weight gain
now performed on a routine basis with excellent results.8690
Diagnostic tests
Monitored fast
In rare instances, preoperative localization studies and
Insulin-to-glucose ratio
intraoperative ultrasound fail to identify the tumor. Intraoperative biopsy of the pancreatic tail may help make the diagnosis
Anatomic localization
Evenly distributed throughout
of nesidioblastosis as the cause of hyperinsulism. Some authors
pancreas
have recommended a blind distal pancreatic resection to the
PANCREAS/LIVER
864
Cauterize vessels
on tumor
Clip vessels
on pancreas
Tumor
Tumor
Body of
pancreas
Pancreatic bed
of islet tumor
FIGURE 55.6. The technique for enucleating a benign pancreatic endocrine neoplasm with scissors (A) or electrocautery (B).
C: After enucleation, the site of excision is drained. (Adapted
from Cameron JL. Atlas of Surgery. Vol 1. Philadelphia, PA: BC
Decker/Mosby; 1990:441.)
level of the superior mesenteric vein (60% to 70% pancreatecpancreatic tumor.99101 It has been estimated that approxitomy), in the hope of excising an unidentified insulinoma in the
mately 1 in 1,000 patients with primary duodenal ulcer disease
body and tail. Others have suggested blind pancreaticoduoand 2 in 100 patients with recurrent ulcer after ulcer surgery
denectomy, because the thickness of the gland in this region 8 harbor gastrinomas.102 Seventy-five percent of gastrinomas
makes it more likely to harbor an occult neoplasm. The favored
occur sporadically, and 25% are associated with the MEN-1
approach at the current time is to defer any blind resection,
syndrome. Historically, the majority of gastrinomas were
close the patient without pancreatectomy, and perform postopfound to be malignant, with metastatic disease present at the
erative selective arterial calcium stimulation with hepatic
time of initial workup. With increased awareness and screenvenous insulin sampling to allow for specific tumor localization
ing for hypergastrinemia, the diagnosis of gastrinoma is made
and directed surgical excision at a second operation.91
earlier and a higher percentage of patients present with benign
Approximately 10% of insulinomas are malignant, preand potentially curable neoplasms.103
senting with lymph node or liver metastases. In the presence of
The clinical symptoms of patients with gastrinoma are a
hepatic metastases, resection of the primary tumor and accesdirect result of increased levels of circulating gastrin (Table
sible metastases should be considered if it can be performed
55.6). Abdominal pain and peptic ulceration of the upper gassafely.9294 Such tumor debulking can be helpful in reducing
trointestinal (UGI) tract are seen in up to 90% of patients.
hypoglycemic symptoms and improving long-term survival. In
Diarrhea is seen in 50% of patients, with 10% having diarrhea
patients with unresectable disease, medications such as diaas their only symptom. Esophageal symptoms or endoscopic
zoxide and octreotide can be used to reduce insulin secretion
abnormalities resulting from gastroesophageal reflux are seen
from the tumor, minimizing hypoglycemia. One promising
in up to half of patients. The diagnosis of gastrinoma should
new treatment is everolimus, an oral rapamycin analogue that
inhibits mammalian target of rapamycin (mTOR). In a pilot
study of patients with refractory hypoglycemia due to metastatic insulinoma, everolimus resulted in improved glycemic conTA B L E 5 5 . 6
DIAGNOSIS
trol.95 Dietary manipulations, including judicious spacing of
GASTRINOMA
carbohydrate-rich meals and the consumption of nighttime
snacks, can also reduce the number of hypoglycemic episodes.
Multiple chemotherapeutic regimens have been used including
PARAMETER
DESCRIPTION
streptozocin, dacarbazine, doxorubicin, and 5-fluorouracil.9698
Symptoms
Peptic ulcer disease
Combination chemotherapy has yielded the highest response
rates but has not been shown to be curative.
Diarrhea
Esophagitis
Diagnostic tests
Anatomic localization
TA B L E 5 5 . 7
865
DIAGNOSIS
PANCREAS/LIVER
866
in the parenchyma may require partial resection by pancreaticoduodenectomy or distal pancreatectomy. If no pancreatic tumor
is identified, a longitudinal duodenotomy should be performed
at the level of the second portion of the duodenum in search of
duodenal microgastrinomas.109,110 Small gastrinomas in the
duodenal wall can be locally resected with primary closure of
the duodenal defect. The routine use of duodenotomy increases
the short- and long-term cure rates in patients with sporadic
gastrinoma, because such a duodenotomy allows detection of
more duodenal gastrinomas.111 Duodenotomy did not impact
the occurrence of hepatic metastases or disease-related mortality. In a small percentage of patients, gastrinoma is found only
in peripancreatic lymph nodes, with these lymph nodes harboring the apparent primary tumor. Resection of these apparent
lymph node primary gastrinomas has been associated with
long-term eugastrinemia and biochemical cure in up to half of
cases.112 A review from the National Institutes of Health identified likely primary lymph node gastrinomas in 26 of 176 gastrinoma patients (14.7%), with 69% being eugastrinemic at a
mean of 10 years after resection.113
Occasionally, preoperative localization studies may identify
the tumor in the gastrinoma triangle, but at the time of exploration, the tumor is not demonstrable. Several surgical options
are available at this point. First, a parietal cell vagotomy has
been proposed as a way to reduce antisecretory drug dose
requirements in patients on high-dose antisecretory drug therapy but without prior life-threatening complications.114 However, this approach leaves behind potentially resectable gastrinoma and has lost favor as an option. A second option is total
gastrectomy; however, the availability of PPIs has drastically
reduced the need to perform this operation for gastrinoma. It
may have a limited role in patients whose tumors cannot be
localized, if they cannot or will not take their PPIs. Like parietal cell vagotomy, this leaves tumor behind. A third, controversial option in patients with localization to the gastrinoma
triangle is blind pancreaticoduodenectomy. Some argue this
should include distal gastrectomy, as duodenal gastrinomas
may arise close to the pylorus and be left behind during a
pylorus-preserving resection.
Patients with sporadic gastrinomas tend to fare better following resection than those with MEN-1. In a series of 151
patients reported by Norton et al.,115 123 had sporadic gastrinoma and 28 had MEN-1associated gastrinoma. Of those
with sporadic gastrinoma, 34% were free of disease 10 years
following resection. None of the MEN-1 patients were free of
disease at 10 years. A more recent review of 195 patients from
the same institution demonstrated clear superiority of surgical
intervention over other treatment strategies.116 The rate of
disease-related death was increased 23-fold in the group of
patients treated without surgery. These data provide compelling evidence that patients with sporadic gastrinoma benefit
from surgical exploration and complete tumor resection.
The management of gastrinoma in MEN-1 is not as clear.
The surgical treatment of hypercalcemia caused by parathyroid
hyperplasia should precede any surgery for hypergastrinemia in
patients with MEN-1. In these patients, gastrin-secreting
tumors are often multicentric and associated with lymph node
metastases. Although some groups have favored exploration
only when MEN-1 gastrinoma tumors exceed 3 cm, it seems
that earlier intervention may be warranted.117,118 Unfortunately, more data from an appropriate clinical trial are needed
to better define the timing of surgery for MEN-1 gastrinoma.
In the 1950s and 1960s, most gastrinomas were diagnosed
late in the course of the disease, when the tumor burden was
already significant. At that time, effective medical therapy did
not exist, nor did sophisticated radiographic localization and
staging techniques. Patients often suffered multiple ulcer complications, required total gastrectomy to control the ulcer
diathesis, and typically succumbed to continued tumor growth
following gastrectomy. Recent reviews of patients with surgically treated gastrinoma provide room for optimism.119122
VIPOMA (VERNER-MORRISON
SYNDROME)
Synonyms for VIPoma include WDHA syndrome (watery diarrhea, hypokalemia, and either achlorhydria or acidosis) and
pancreatic cholera syndrome (Table 55.8). Verner and Morrison131 characterized this secretory diarrheal syndrome in a 1958
report. Patients characteristically present with intermittent,
severe, watery diarrhea averaging up to 5 L/d. Hypokalemia
results from fecal loss of large amounts of potassium. Low serum
potassium levels lead to lethargy, muscle weakness, and nausea.
A metabolic acidosis may be present, due to loss of bicarbonate
in the diarrhea. Half of the patients may have hyperglycemia or
hypercalcemia, and cutaneous flushing can be observed in a
minority. The diagnosis of VIPoma is made after other common
causes of diarrhea have been excluded (Table 55.9)132 and an elevated serum VIP level is documented.
VIP secretion can be episodic, so repeated fasting levels
should be measured if there is a strong clinical suspicion. Preoperative tumor localization is critical, because 10% of
patients may have extrapancreatic tumors located in the
retroperitoneum or chest. Most tumors are located in the distal pancreas where they are amenable to resection via distal
pancreatectomy (Fig. 55.9). In most cases, hepatic metastases
accompany the primary tumor. Therapies directed at debulking these metastases such as resection or ablative strategies are
appropriate.
Surgical excision is appropriate in nearly all patients with
Verner-Morrison syndrome. Prior to surgery, fluid and electrolyte imbalances must be corrected. Octreotide can serve as
a treatment adjunct, reducing the levels of circulating VIP,
TA B L E 5 5 . 8
DIAGNOSIS
VIPOMA
PARAMETER
Symptoms
DESCRIPTION
Watery diarrhea
Weakness
Lethargy
Nausea
Diagnostic tests
Hypokalemia
Achlorhydria
Metabolic acidosis
Serum VIP levels elevated
Anatomic localization
TA B L E 5 5 . 9
DIAGNOSIS
TA B L E 5 5 . 1 0
WORKUP
Villous adenoma
Lower GI endoscopy
Laxative abuse
Celiac disease
GLUCAGONOMA
Carcinoid syndrome
DESCRIPTION
Symptoms
Dermatitis manifested as
necrolytic migratory erythema
Catabolic state: weight loss
Diagnostic tests
Hyperglycemia
Hypoproteinemia
Stool culture
Anatomic localization
Lower GI endoscopy
Upper GI and small bowel series
Urinary 5-HIAA
PARAMETER
Stomatitis
DIAGNOSIS
GLUCAGONOMA
10
FIGURE 55.9. Several computed tomographic images from a patient with a primary vasoactive intestinal polypeptide-oma (VIPoma) in the tail
of the pancreas. The tumor is nearly spherical. Its location is posterior to the stomach and adjacent to the spleen.
PANCREAS/LIVER
Parasitic and
infectious diseases
867
868
NONFUNCTIONAL ISLET
CELL TUMORS
SOMATOSTATINOMA
The somatostatinoma syndrome is the least common of the
five generally accepted functional pancreatic endocrine neoplasia syndromes, occurring in less than 1 in 40 million people. The clinical features are nonspecific including steatorrhea,
diabetes, hypochlorhydria, and cholelithiasis (Table 55.11).
Fasting plasma somatostatin levels of greater than 100 pg/mL
can be used to confirm the diagnosis.
Most somatostatinomas are located in the pancreatic head
or periampullary region.134 Tumors are of variable size and are
often easily localized. Metastatic disease may be present at the
time of diagnosis. Safe resection of the primary tumor (often
TA B L E 5 5 . 1 1
DIAGNOSIS
SOMATOSTATINOMA
PARAMETER
Symptoms
DESCRIPTION
Steatorrhea
Right upper quadrant pain
Diagnostic tests
Hyperglycemia
Hypochlorhydria
Gallstones
Serum somatostatin level
Anatomic localization
METASTATIC PANCREATIC
ENDOCRINE TUMORS
At least one third of patients with malignant PENs present with
synchronous liver metastases at the time of diagnosis.138 A subset of these patients remain asymptomatic and experience prolonged survival even without aggressive therapy.96 However,
overall 5-year survival with liver metastases is less than
50%.139 PENs are one of the few tumors for which a survival
advantage for surgical debulking has been shown.127,138,140142
In those selected patients where safe surgical resection of
greater than 90% of the tumor burden can be achieved, 5-year
survival rates of 60% to 75% have been reported.
Those with unresectable disease have shown partial
responses to chemotherapy. In 1992, the results of a trial conducted by the Eastern Cooperative Oncology Group (ECOG)
were published.96 In this study, 105 patients with advanced
nonfunctional endocrine tumors were randomly assigned to
one of three groups. The lowest response rate (30%) was seen
in patients receiving chlorozotocin alone, an intermediate
response rate (45%) was seen in patients receiving the combination of streptozotocin plus 5-fluorouracil, and the highest
response rate (69%) was noted in patients receiving streptozotocin plus doxorubicin. The last regimen also showed significant survival advantage in comparison with the other two
treatments. More recent attempts to replicate these results
have been disappointing.143
Somatostatin analogues are another approach to treating
metastatic PENs. Results are more favorable in tumors that
have high-affinity receptors (gastrinomas, VIPomas, glucagonomas, and some nonfunctional tumors) as compared to insulinomas. Symptomatic improvement occurs in 60% to 90% of
patients. However, an objective tumor response is seen in only
5% to 15% of patients, with stabilization of disease in 50% or
more of patients.144146
Multiple investigational agents have been tried in the setting
of advanced metastatic PEN. One promising agent is sunitinib
malate (Sutent, Pfizer Inc.), an oral multikinase inhibitor
approved for the treatment of advanced renal cell carcinoma
and refractory gastrointestinal stromal tumors. Interim analysis
of a phase III trial showed significant benefit in the group taking sunitinib and the trial was halted early.147
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871
SECTION H
HEPATOBILIARY AND PORTAL VENOUS SYSTEM
P O I N T S
6
10
or abdominal wall and liver may jointly be involved in a pathologic process. Posteriorly, the right adrenal gland or upper pole
of the right kidney may involve or be involved by the liver.
Inferiorly, the gallbladder, colon, duodenum, or periportal lymphatics may be involved. Cancers of the stomach or gastroesophageal junction may involve the left liver or vice versa.
TOPOGRAPHIC ANATOMY
MORPHOLOGIC AND
FUNCTIONAL ANATOMY
873
PANCREAS/LIVER
K E Y
874
Cantlies line
Right anterior
sector
Right liver
Right posterior
sector
Left medial
section
Left lateral
section
Falciform
ligament
Left liver
875
VIII
II
VII
III
IV
V
VI
The most widely accepted nomenclature is based on Couinauds description of the discrete anatomic segments of the liver
(Fig. 56.4).6 The eight segments of a liver can be determined
using surface anatomy and location of the three main hepatic
veins, the portal pedicle bifurcation into right and left, and the
umbilical fissure and falciform ligament. As described, the right
and left halves of the liver are delineated by a plane through the
middle hepatic vein and IVC. Segments II, III, and IV lie to the
left of this plane and form the left half of the liver. Segments V,
VI, VII, and VIII lie to the right of this plane and form the right
half of the liver. Segment I, or the caudate process, is morphologically distinct from the two halves of the liver and emanates
from a process of liver lying posterior to the portal pedicle and
anterior to the IVC. Whereas the right and left halves of the liver
derive blood supply from the corresponding right and left portal veins and hepatic arteries, segment I derives blood supply
from both. Additionally, the right half of the liver has venous
drainage primarily through the right and middle hepatic veins,
and the left half of the liver primarily through the left and middle hepatic veins. Segment I, however, drains directly via small
branches into the IVC. The left liver and especially the right liver
usually have small accessory hepatic venous branches draining
directly into the inferior vena cava. Occasionally on the right,
the accessory branch is significant in size.
The right half of the liver can be further subdivided using a
plane through the right hepatic vein and the IVC. Liver anterior to this plane forms the right anterior sector, and liver posterior to this plane forms the right posterior sector. The right
anterior sector of the liver is composed of segment V (inferior
to the portal bifurcation) and segment VIII (superior to the
portal bifurcation). The right posterior sector of the liver is
composed of segment VI (inferior to the portal bifurcation)
and segment VII (superior to the portal bifurcation).
The left half of the liver can be further subdivided using a
plane through the umbilical fissure and falciform ligament.
Liver medial to this plane forms the left medial section of the
liver or segment IV, and liver lateral to this plane forms the left
lateral section of the liver. The left medial section of the liver is
sometimes divided into two halves, with IVa closer to the inferior vena cava and IVb farther. The left lateral section of the
liver is further subdivided into segment II (which is superior)
and segment III (which is inferior).
Hepatic Veins
2
Three major hepatic veins carry blood from the liver to the
IVC. Most patients have a right hepatic vein that joins the
right anterior wall of the IVC and a middle and left hepatic
vein that converge into a common trunk about 1 cm from the
IVC that enters the left anterior wall of the IVC (Fig. 56.5). In
some patients, the three main hepatic veins join the IVC via
three distinct trunks. These hepatic veins usually lie within the
hepatic parenchyma. Usually, a definable extraparenchymal
segment of the hepatic veins, especially the right, can be dissected out before it empties into the IVC, which makes outflow
control safer and easier. Usually, multiple accessory right
hepatic veins empty from the right half of the liver directly into
the IVC as it courses posterior to the liver (Fig. 56.6). On occasion, these accessory right hepatic veins are sizable and may
even support venous outflow should the native right hepatic
vein need to be taken. Additionally, sometimes an umbilical
vein can be appreciated running to the falciform ligament
between the middle and left hepatic veins and emptying into
the terminal portion of the left hepatic vein.
Portal Veins
The superior mesenteric and splenic veins join posterior to the
neck of the pancreas to form the main portal vein. It receives
pyloric and coronary vein branches as it courses cephalad and
obliquely to the right to form the most posterior structure
within the hepatoduodenal ligament (portal triad). In the hilus
of the liver, the main portal vein bifurcates into a short oblique
right portal vein and a longer, more transverse, and more superficial left portal vein (Fig. 56.7). These branches then enter the
parenchyma and become invested along with the other components of the portal triad by extensions of the Glisson capsule.
Both the right and left portal veins give off small branches to
dually supply segment I. The right portal vein usually enters the
hepatic parenchyma immediately and is quick to divide into a
right anterior portal vein supplying segments V and VIII and a
right posterior portal vein supplying segments VI and VII. The
left portal vein may remain near the surface of the left half of the
liver in the hilar plate for a significant distance as it courses to
the umbilical fissure to give off medial branches to segment IV
and lateral branches to segments II and III.
Hepatic Arteries
There is much variability in the hepatic arterial supply to the
liver. The most common anatomy is a common hepatic artery
that arises from the celiac trunk and courses near the superior
border of the neck of the pancreas. After the origins of the
PANCREAS/LIVER
FIGURE 56.4. Functional divisions of the liver and liver segments according to Couinauds nomenclature.
876
Left
Middle
Right
Caudate
Cantlies line
Ligation of
accessory retroheaptic
veins
Cantlies
line
877
A Normal anatomy
Cystic artery
Replaced left
hepatic artery
Hepatic duct
Proper
hepatic artery
Splenic artery
Gastroduodenal
artery
Portal vein
Gallbladder
Cystic artery
Proper
hepatic artery
Portal vein
Aorta
Celiac trunk
Gastroduodenal artery
Right gastric artery
Pylorus
Duodenum
Stomach
Pancreas
Accessory
left hepatic
artery
Proper
hepatic artery
Portal vein
Aorta
Gastroduodenal
artery
Splenic artery
Replaced right
hepatic artery
Superior
mesenteric
artery
F Anterior location of right hepatic artery
Left gastric
artery
Splenic artery
Gastroduodenal artery
Right hepatic
artery
Proper
hepatic artery
Gastroduodenal artery
Replaced
hepatic artery
Portal vein
Aorta
Celiac trunk
Lienogastric
trunk
Splenic artery
Hepatomesenteric
trunk
Stomach
Pancreas
PANCREAS/LIVER
878
VI, VII, and VIII, which constitute the right liver. Usually, the
bile ducts from segments V and VIII join to first form the anterior sectoral duct and the bile ducts from segments VI and VII
join to first form the posterior sectoral duct prior to forming
the right hepatic duct (Fig. 56.9).
Gallbladder
The gallbladder is a reservoir for bile located on the undersurface of the liver at the confluence of the right and left halves of
the liver. It is separated from the hepatic parenchyma by a cystic plate, which is constituted of connective tissue applied to
the Glisson capsule. The gallbladder may be deeply imbedded
into the liver or occasionally presents on a mesenteric attachment, but usually lays in a gallbladder fossa. The gallbladder
varies in size and consists of a fundus, a body, and an
infundibulum. The tip of the fundus usually reaches the free
edge of the liver and is closely applied to the cystic plate. The
infundibulum of the gallbladder makes an angle with the body
FIGURE 56.9. Intrahepatic divisions of the bile ducts and hepatic
arteries.
and may obscure the common hepatic duct, constituting a danger point during cholecystectomy. The cystic duct arises from the
infundibulum of the gallbladder and extends to join the common
hilus. Bile ducts are usually located above the corresponding
hepatic duct. The lumen measures between 1 and 3 mm in diamportal branches, whereas hepatic arterial branches run inferieter, and its length varies depending on the type of union with the
orly to the veins. The left hepatic duct directly drains the bile 4 common hepatic duct (Fig. 56.10). Callots triangle is bounded
ducts to segments II, III, and IV, which constitute the left liver.
by the common hepatic duct on the left, the cystic duct inferiorly,
The right hepatic duct drains the bile ducts from segments V,
and the cystic artery superiorly. Arterial blood reaches the
A Normal
E Low insertion of
F Short and wide
G Cystic duct coursing
H Cystic duct coursing
cystic duct passing
cystic duct
anterior to common
posterior to common
anterior to common
bile duct before insertion
hepatic duct before
hepatic duct
insertion
FIGURE 56.10. Variations in the junction of the cystic duct and common hepatic duct.
B Off gastroduodenal
artery (GDA)
E Anterior to common
bile duct
PANCREAS/LIVER
879
LIVER IMAGING
Computed Tomography
880
FIGURE 56.12. Anatomy of the extrahepatic biliary tree and pancreatic duct.
Right hepatic duct
881
left pedicle. The portal pedicles are invested with the Glisson
capsule and have a very echogenic covering to them in contrast
to hepatic vein branches. The main right portal pedicle is followed toward the right where it gives off an anterior and posterior branch (Fig. 56.17A). The right anterior branch gives off
separate pedicles to segment V (caudad) and to segment VIII
(cephalad). The right posterior branch gives off separate pedicles to segment VI (caudad) and to segment VII (cephalad).
The main left pedicle is usually much longer and courses intact
to the base of the umbilical fissure before branching into various segmental pedicles (Fig. 56.17B). At the base of the umbilical fissure, the main left pedicle courses anteriorly toward the
round ligament and gives off a pedicle to segment IV medially
and pedicles to segments II and III laterally. Next, if the falciform ligament has been divided, the hepatic veins can easily be
visualized using intraoperative ultrasonography (Fig. 56.17C).
As described previously, usually a larger right hepatic vein can
be delineated and smaller left and middle hepatic veins joining
into a common trunk before emptying into the IVC are seen.
Commonly, an umbilical hepatic vein branch can be identified
coursing between the middle and left hepatic veins and running under the falciform ligament. Not uncommonly, significant accessory right hepatic veins can be seen emptying from
the posterior surface of the right liver directly into the IVC as
it courses posterior to the liver. The identification of these
accessory right hepatic veins is potentially important for both
vascular control and preservation of outflow from the liver (in
occasional cases where outflow of the remnant right liver can
be supported by a very large accessory vein). Lastly, the
hepatic parenchyma is systematically scanned to identify
lesions within the liver (Fig. 56.17D). It is sometimes useful to
adjust the ultrasound settings on a known lesion defined preoperatively to maximize the echogenicity in the hopes of identifying other occult lesions not identified preoperatively.
B
FIGURE 56.14. Portal venous phase of computed tomography (CT)
scan from a patient with a history of colorectal cancer and three
lesions in the liver. Lesion 1 in segment VIII is irregular and rim
enhancing and was a colorectal cancer metastasis. Lesion 2 straddling
segments IV and VIII has smooth borders, is not rim enhancing, and
was found to be a cyst. Lesion 3 straddling segments IV and III across
the umbilical fissure is irregular and rim enhancing and was a colorectal cancer metastasis.
Positron emission tomography (PET), especially when combined with CT (PET-CT), has become a valuable tool in helping to select patients who will most benefit from aggressive
liver resection. This technique is based on the increased metabolism of glucose in neoplastic tissues. A glucose analogue, fluorodeoxyglucose, that is tagged with fluorine 18 is injected
intravenously before scanning and is retained preferentially in
metabolically active tumors over normal tissue. Sometimes
PET scans will identify areas of occult disease within the liver,
but more importantly, they can identify areas of extrahepatic
occult disease previously unsuspected. When combined with a
CT scanner within the same machine and the ability to fuse
images, the areas of increased activity can be more precisely
anatomically identified (Fig. 56.18).
PREOPERATIVE EVALUATION
OF HEPATIC RESERVE
Whenever a surgical resection is planned, an important consideration is whether the remnant liver will be sufficient to
regenerate and sustain the patient long term. In patients with
PANCREAS/LIVER
882
FIGURE 56.15. A, B: T1-weighted magnetic resonance imaging (MRI) with gadolinium from the same patient as in Figure 58.14 with history of
colorectal cancer and three lesions in the liver. Lesion 1 in segment VIII is irregular and rim enhancing and was a colorectal cancer metastasis.
Lesion 2 straddling segments IV and VIII has smooth borders, is not rim enhancing, and was found to be a cyst. Lesion 3 straddling segments IV
and III across the umbilical fissure is irregular, rim enhancing, and was a colorectal cancer metastasis. C, D: T2-weighted MRI from same patient
with history of colorectal cancer and three lesions in liver. Lesion 1 in segment VIII is irregular and mildly bright and was a colorectal cancer
metastasis. Lesion 2 straddling segments IV and VIII has smooth borders, is very bright, and was found to be a cyst. Lesion 3 straddling segments
IV and III across the umbilical fissure is mildly bright and was a colorectal cancer metastasis. Colorectal metastases and many tumors are mildly
bright on T2-weighted MRI, whereas cysts and hemangiomas are typically very bright.
relatively normal hepatic parenchyma (without active hepatitis, cirrhosis, or metabolic defects), up to 75% of the hepatic
volume can be resected with good recovery as long as the remnant liver has adequate portal venous and hepatic arterial
inflow, adequate hepatic venous outflow, and adequate biliary
drainage. Many groups around the world have used various
strategies to predict hepatic reserve (Tables 56.1 and 56.2).
None of these tests or strategies has been demonstrated to
clearly better predict outcome than another. Many centers in
the United States rely simply on the Child-Pugh score and the
prediction of adequate liver remnant volume after resection. In
select circumstances, it may be of benefit to perform portal
vein embolization to the right or left half (rare) of the liver in
the hopes of obtaining compensatory hypertrophy of the other
side before resection. This is especially useful when the predicted liver remnant after resection is small or if the patient has
an underlying hepatic dysfunction that may not allow the remnant to fully regenerate and sustain the patient long term. To
gain maximal growth of the left lateral section of the liver,
some centers will also embolize the portal vein branches to
segment IV in addition the main right portal vein. The disadvantages of portal vein embolization include the need to wait
883
TA B L E 5 6 . 2
CHILD-PUGH CLASSIFICATION
1 POINT 2 POINTS 3 POINTS
Bilirubin (mg/dL)
2
23
3
Albumin (g/dL)
3.5
2.83.5
2.8
Ascites
Absent
Moderate
Severe
Encephalopathy
Absent
Moderate
Severe
Seconds
prolonged
4
46
6
INR
1.7
1.72.3
2.3
Prothrombin time
PANCREAS/LIVER
FIGURE 56.17. A, B: Intraoperative ultrasound images of liver demonstrating right hepatic pedicle (RHP), right anterior sector pedicle (RASP),
right posterior sector pedicle (RPSP), left hepatic pedicle (LHP), segment II pedicle (SIIP), segment IV pedicle (SIVP), segment I (SI), and inferior
vena cava (IVC). C, D: Intraoperative ultrasound images of liver demonstrating inferior vena cava (IVC), right hepatic vein (RHV), middle hepatic
vein (MHV), left hepatic vein (LHV), segment I (SI), and a metastatic gastrointestinal stromal tumor lesion straddling segments IV and V of the liver.
884
FIGURE 56.18. Positron emission tomography and computed tomography (PETCT) scan images of patient in Figure
56.17B and C with solitary gastrointestinal
stromal tumor metastasis straddling segments IV and V. Noncontrast CT images
(left). PET images (center). Fusion images
(right).
885
INTRAOPERATIVE ASSESSMENT
Incisions for hepatic resections usually involve a right subcostal incision. Significant exposure can be obtained with a trifurcated incision as shown in Figure 56.20. In the majority of
cases, however, all that is needed is an extended right subcostal
incision with a vertical extension to the base of the xiphoid.
The xiphoid can be resected for better exposure. For bulky
lesions on the left or if the left half of the liver extends signifi-
PANCREAS/LIVER
ONCOLOGIC CONSIDERATIONS
IN HEPATIC RESECTION
886
vein(s) and IVC, it may be easier and safer to divide the hepatic
vein(s) within the hepatic parenchyma after most of the
parenchymal transection has been performed. The use of
endoscopic vascular stapling devices has made the ligation of
hepatic veins, whether extra- or intraparenchymally, much
quicker and safer10 (Fig. 56.24). It is often useful to keep the
central venous pressure (CVP) of the patient low (5 mm Hg)
until after parenchymal transection as this will decrease bleeding from the IVC and hepatic vein branches.11
MAJOR HEPATECTOMIES
To develop a uniform nomenclature understood by all, the
American and International Hepato-Pancreato-Biliary Associations (AHPBA and IHPBA) have adopted the Brisbane 2000
terminology of hepatic anatomy and resections. Right hepatectomy or right hemihepatectomy involves the resection of segments V through VIII. Left hepatectomy or hemihepatectomy
involves the resection of segments II through IV. Either of these
resections may or may not include resection of segment I,
which should be stated. Extended right hepatectomy involves
the resection of segments IV through VIII. Extended left hepaFIGURE 56.21. Lowering the hilar plate. A: The inferior border of
tectomy involves the resection of segments II through V plus
segment IV overlies the hepatic duct confluence. B: Division of the
VIII. Again, either of these extended resections may or may
connective tissue investment allows elevation of segment IV, which
not include resection of segment I, which should be stipulated.
results in a lower hilar plate and surgical exposure to the hepatic
Right anterior sectorectomy includes segments V and VIII.
duct confluence. (From Blumgart LH, ed. Surgery of the Liver and Biliary Tract. New York: Churchill Livingstone; 1994, with permission.)
Right posterior sectorectomy includes segments VI and VII.
Left medial sectionectomy removes segment IV. Left lateral
sectionectomy includes segments II and III. A segmentectomy
involves the resection of a single segment and a bisegmentectomy involves the resection of two contiguous segments.
portal triad structure may be aided by exposing the hilar plate
The steps involved in each of these major hepatectomies
(Fig. 56.21) and dividing the Glisson capsule at the most 10
include optimal exposure of the liver, vascular inflow control,
inferior border of segment IV. Inflow control to the liver can
vascular outflow control, and parenchymal transection. Vascular
also be obtained by pedicle ligations in which small hepatoinflow control can be obtained by directly ligating the main right
tomies are made around the main right pedicle, main left pedior left branches of the hepatic artery and portal vein in the hilum
cle, right anterior pedicle, or right posterior pedicle after idenor by intermittent 10- to 20-minute intervals of a Pringle maneutification with ultrasound (Fig. 56.22).10 The pedicle of interest
ver with 3 minutes in between to reestablish blood flow (or
can be dissected out bluntly with a right angle or by palpation.
both). It is the authors preference to encircle the hepatoduodenal
The pedicle can then be clamped to confirm that it does indeed
ligament twice with a quarter-inch Penrose drain that is tightsupply the area of liver of interest (i.e., right half, left half, right
ened and clamped for a Pringle maneuver. Pedicle ligation can
anterior section, or right posterior section). Once confirmed,
also be performed, as described previously, or the pedicles can be
the pedicle can be divided. Alternatively, the inflow pedicles can
controlled as they are encountered during parenchymal transecbe divided as they are encountered while transecting hepatic
tion. It is the authors preference to obtain vascular inflow by liparenchyma. With this technique, hemorrhage can be minigating the appropriate vessels in the hilum or by pedicle ligations
mized by intermittent portal inflow occlusion, which is accomand to supplement this with intermittent Pringle maneuvers, as
plished by gently clamping the main portal triad within the
necessary, during parenchymal transection. Often the Pringle
hepatoduodenal ligament (Pringle maneuver).
maneuver is not required, but if bleeding from inflow vessels
Outflow control of the hepatic veins can be obtained before
becomes significant, then it should be performed. Vascular outor after hepatic transection and should be decided on a caseflow to the right or left liver can be obtained by exposing and liby-case basis. When there is a significant extraparenchymal
gating the hepatic veins, as previously described, or by ligating the
component to the hepatic vein(s), often it is easier to divide the
vessels intraparenchymally during transection of the liver tissue.
hepatic vein(s) early and before parenchymal transection (but
Parenchymal transection can be performed using a multitude of
after inflow control) (Fig. 56.23). When the extraparenchymal
techniques including finger fracture, using a Kelly clamp to fraccomponent to the hepatic vein(s) is very short or absent and
ture, Cavitron Ultrasonic Surgical Aspirator (CUSA), harmonic
when the tumor margin is not near the junction of the hepatic
FIGURE 56.22. Hepatotomies to access pedicles for
ligation: right hepatectomy, 1 and 2; left hepatectomy,
3 and 5; right anterior sectorectomy, 2 and 4; and right
posterior sectorectomy, 1 and 4. (From Fong Y, Blumgart LH. Useful stapling techniques in liver surgery. J
Am Coll Surg 1997;185:93100, with permission.)
Segment IV
Segment V
2
Segment VI
4
1
Segment I
887
Right
hepatic vein
Right liver
Diaphragm
Vena cava
SEGMENTAL RESECTIONS
To maximize functional reserve, (multi)segmental or subsegmental (or nonanatomic) hepatectomies can be performed. For
example, left lateral sectionectomy (segments II and III),
central hepatectomy to remove the right anterior section
(segments V and VIII) and left medial section (segment IV),
right posterior sectionectomy (segments VI and VII), or caudate resection (segment I) are examples in which one, two, or
three contiguous segments are removed to eradicate tumors
within those regions of the liver. These resections are often
done with intermittent Pringle maneuvers until the specific
pedicles supplying these areas are controlled.
References
1. McIndoe AH, Counseller VX. A report on the bilaterality of the liver. Arch
Surg 1927;15:589.
2. Hjrtsj CH. The topography of the intrahepatic duct systems. Acta Anat
(Basel) 1931;11:599615.
3. Tung TT. La vascularixation veineuse du foie et ses applications aux resections hepatiques. Thse Hanoi, 1939.
4. Healy JE, Schroy PC. Anatomy of the biliary ducts within the human liver.
Analysis of the prevailing pattern of branchings and the major variations
of the biliary ducts. AMA Arch Surg 1953;66:599616.
5. Goldsmith NA, Woodvurne RT. Surgical anatomy pertaining to liver resection. Surg Gynecol Obstet 1957;195:310318.
6. Couinaud C Le Foi. Etudes anatomogiques et chirurgicales. Paris: Masson;
1957.
7. Bismuth J, Houssin D, Castaing D. Major and minor segmentectomies
rglesin liver surgery. World J Surg 1982;6:1024.
8. Blumgart LH, Hann LE. Surgical and radiologic anatomy of the liver and
biliary tract. In: Blumgart LH, Fong Y, eds. Surgery of the Liver and Biliary Tract, 3rd ed. New York: WB Saunders; 2000.
9. Michels NA. Newer anatomy of the liver and its variant blood supply and
collateral circulation. Am J Surg 1966;112:337.
10. Fong Y, Blumgart LH. Useful stapling techniques in liver surgery. J Am
Coll Surg 1997;185:93100.
11. Melendez JA, Arslan V, Fischer ME, et al. Perioperative outcomes of major
hepatic resections under low central venous pressure anesthesia: blood
loss, blood transfusion, and the risk of postoperative renal dysfunction. J Am
Coll Surg 1998;187:620625.
PANCREAS/LIVER
HEPATIC FAILURE
ARUNA SUBRAMANIAN, AHMET GURAKAR, ANDREW KLEIN, AND ANDREW CAMERON
K E Y
Gram-negative anaerobes account for two thirds of the
cases of pyogenic liver abscesses, with anaerobes isolated
in 30% of cases.
2 First-line treatment of hepatic amebic abscesses is oral
metronidazole, with percutaneous drainage considered if
there is a poor response to therapy or when superinfection
is suspected.
3 The treatment of choice for hydatid cysts is surgical resection of the intact cyst, often preceded by injection of ethyl
chloride, 95% ethanol, or 20% sterile saline solution.
Surgery should occur after antiparasitic medication has
begun.
1
P O I N T S
Viral hepatitis, especially hepatitis B and C, represents a
principal cause of chronic liver disease, cirrhosis, and
hepatocellular carcinoma in the United States and worldwide.
5 Liver transplantation is the treatment of choice for patients
with liver failure resulting from viral hepatitis, although
recurrence of viral infection in the allograft is universal
with hepatitis C virus.
6 About one third of patients with acute liver failure will
die without liver transplant, usually secondary to cerebral
edema and sepsis, with 25% of patients surviving with medical treatment and 40% undergoing transplantation.
4
888
889
most prevalent in tropical and subtropical regions with poor sanitation, and it is estimated that 40 million to 50 million people
are infected annually worldwide. In the United States, the highest incidence of infection is encountered in immigrants from and
travelers to endemic areas. Most infection is asymptomatic, but
amebic dysentery, amebic liver abscesses, and, rarely, pulmonary,
cardiac, or brain involvement can occur. Hepatic abscesses occur
in only 3% to 7% of individuals with amebiasis. The peak incidence of amebic abscesses is observed in patients in their third or
fourth decade of life. Men are affected 7 to 10 times more frequently than women, and corticosteroid use is a risk factor for
invasive amebiasis.2,12
Fecal-oral transmission is the most frequent route of infection. Ingested cysts, containing four nuclei, pass unaltered
through the stomach and reach the intestine. Once in the intestine, the cyst wall is degraded by trypsin and eight trophozoites are released. These infective forms multiply in the
colonic lumen, especially in the cecum. While living within the
colonic lumen, E. histolytica may become tissue invasive. Invasion may range from superficial mucosal ulceration to perforation. Amebic trophozoites that enter the mesenteric veins or
lymphatics reach other organs. The portal vein is the route via
which they reach the liver, the most frequent site of extraintestinal involvement. Amebic trophozoites cause obstruction of
venules, thrombosis and infarction of the corresponding areas
of hepatic parenchyma, and eventually abscesses (Fig. 57.2). In
the distal colon they become cystic, undergo two consecutive
divisions, are excreted in the feces as tetranucleate cysts, and
remain viable for 8 to 30 days after being shed. Cysts are susceptible to acetic acid, iodine, chlorine, and temperatures
greater than 68C.2,6,12
Liver abscesses range in size from several millimeters to
gigantic masses (Fig. 57.3). Differential diagnosis is with pyogenic abscess and malignancies. Abscesses are encountered
more frequently in the right lobe and tend to be single lesions.
Amebic abscesses show slight inflammation on the periphery,
and many times contain a dark hemorrhagic fluid known as
anchovy paste (Fig. 57.4). Patients most frequently present
with fever and right upper quadrant abdominal pain. Other
findings include hepatomegaly, weight loss, diarrhea, chills,
and afternoon and night sweats. Jaundice is less frequent than
in pyogenic abscesses. Abscesses have been classified into acute
PANCREAS/LIVER
890
B
FIGURE 57.3. Sonogram (A) and computed tomogram (B) in a patient with multiple amebic abscesses (arrows).
or chronic and benign or aggressive. The most feared comChest radiographs are abnormal in the majority of patients
plication is rupture into surrounding tissues or spaces. Bacwith amebic hepatic abscesses. Findings include elevation of
terial superinfection of initially amebic abscesses may
the right hemidiaphragm, right pleural effusion, atelectasis in
occur.1,2,4,6,1214
the region of the base of the right lung, and a right pleural
effusion. CT scanning is probably the imaging technique of
Most patients with amebic abscesses have elevated white
choice, given the detailed information it provides. An enhancing
blood cell counts with no eosinophilia. Serum alkaline phoswall and surrounding edema are usually observed in contrastphatase is elevated in approximately 75% of cases. Hypoalbuenhanced CT scans. Ultrasonography is very useful as well,
minemia may be seen, and serum bilirubin and transaminase
but its accuracy is associated with the skills of the operator,
levels are slightly elevated. E. histolytica is not found in fecal
is influenced by physiologic changes such as hepatic steatosis,
specimens of most patients with hepatic abscesses. Antibodies
and has a resolution inferior to that of CT scans. Amebic
in serum are encountered in 92% to 99% of patients with
abscesses usually lack wall echoes by ultrasound. MRI shows
amebic liver abscesses and are detectable 7 to 10 days after the
homogeneous low signal intensity on T1- and high signal
appearance of symptoms. Indirect hemagglutination and
intensity on T2-weighted images. Technetium Tc99m nuclear
enzyme-linked immunosorbent assay (ELISA) have reported
scanning displays a photopenic area. Gallium scanning shows
sensitivities of 99% and 97.9% and specificities of 99.8% and
amebic abscesses as cold spots, because they do not contain
94.8%, respectively. Other available diagnostic tests include
leukocytes, which may aid in differentiating them from pyoindirect immunofluorescence, latex agglutination, complement
genic abscesses.2,6,12
fixation, gel diffusion, and counterimmunoelectrophoresis.
Gel diffusion and counterimmunoelectrophoresis remain posi- 2
Treatment of hepatic amebic abscesses is based on amebicitive for only 6 to 12 months after infection and are used to disdal drugs. Metronidazole is the drug of choice. Standard dosing
tinguish current from previous infection.2,12,15
is 750 mg orally three times daily or 500 mg intravenously every
6 hours for 7 to 10 days, with oral administration being the preferred route. Metronidazole has been shown to effectively treat
both intestinal and extraintestinal sites. In patients who are
slow to respond to therapy or with relapsed disease, a prolonged course of metronidazole may be considered, or a
nitroimidazole with a longer half-life (e.g., tinidazole) can be
given at a dose of 2 g for 3 days. Following therapy for invasive
amebiasis, a luminal agent must be given, such as paromomycin
for 10 days or iodoquinol for 20 days. Amebic liver abscesses
can almost always be treated with medical therapy alone. Percutaneous drainage is considered in cases of poor response to
antiamebic agents, when superinfection is suspected, or when
there is a risk of rupture. Open surgical drainage is almost never
required and is recommended only in severe, complicated
cases.2,12,13
ECHINOCOCCUS
(HYDATID DISEASE)
FIGURE 57.4. Amebic abscesses of the liver. The cut surface of the liver
shows multiple abscesses containing anchovy paste material. (Reproduced with permission from Rubin E, Farber JL. Pathology, 3rd ed.
Philadelphia, PA: Lippincott Williams & Wilkins; 1999.)
891
PANCREAS/LIVER
892
FIGURE 57.7. Hepatic schistosomiasis. A hepatic granuloma surrounds a degenerating egg of Schistosoma mansoni. (Reproduced with
permission from Rubin E, Farber JL. Pathology, 3rd ed. Philadelphia,
PA: Lippincott Williams & Wilkins; 1999.)
SCHISTOSOMA
result of regurgitated heme-derived pigments from the schistoSchistosomiasis constitutes a health risk for inhabitants of
some gut.6,17,18,26
endemic regions as well as for visitors to these sites. Schistosoma
Imaging studies are not useful in the diagnosis of acute
mansoni, S. japonicum, and S. hematobium are the species of
infection.
Ultrasound examination in chronic S. mansoni
this trematode fluke that most frequently infect humans. Liver
infection shows echogenic thickening of the wall of the portal
disease, although encountered with all species, is especially
vein and its branches, in a bulls-eye pattern. Hypertrophy of
severe with S. mansoni, S. japonicum, and S. mekongi. Endemic
the left hepatic lobe, splenomegaly, and engorged venous colareas where these trematodes are encountered are also frequently
laterals are also observed. On noncontrast CT scan the fibrosis
associated with a high prevalence of hepatitis B and C. The life
around the portal vein branches presents as low-attenuation
cycle of Schistosoma species alternates between sexual reproducrings throughout the liver. Administration of intravenous contion in humans and asexual multiplication in water snails. Certrast material leads to marked enhancement of the lesions.
cariae enter the human host by penetrating the skin. An irritating
The periportal bands appear isointense on magnetic resomaculopapular rash that lasts for several days is one of the early
nance T1-weighted images and hyperintense on T2-weighted
manifestations. Schistosomes live in the intestinal lumen. Eggs
images.6
reach the liver via the portal circulation and cause an inflamma17,18,24
The preferred treatment of schistosomiasis is administratory reaction.
tion
of praziquantel, though this is ineffective in early infecInfection is characterized by the presence of inflammatory
tion. The reported cure efficacy is approximately 90%. It is
granulomata surrounding schistosomal eggs. Acute schistosoessential that patients with chronic schistosomiasis undergo
miasis is seen most frequently in nonimmune visitors to
evaluation and treatment of esophageal varices.17,18
endemic areas. Inflammatory hepatic schistosomiasis causes
hepatomegaly and severe splenomegaly, usually in children
and adolescents. With very intense egg infestation, it can lead
to widespread granulomatous necrosis of the liver and even
VIRAL HEPATITIDES
death. In contrast, chronic schistosomiasis is seen in young
and middle-aged adults. It is usually asymptomatic until 4 Viral hepatitis represents a principal cause of chronic liver disvariceal hemorrhage occurs as a result of presinusoidal portal
ease, cirrhosis, and hepatocellular carcinoma. Infection is panhypertension. These patients exhibit hepatosplenomegaly, no
demic in the United States and worldwide, representing one of
ascites, and relatively normal hepatic synthetic function.
the significant global public health problems of our time.
Hepatomegaly involves mainly the left lobe. Severe decom- 5 Hepatitis C virus (HCV) has become the most common indipensation tends to be observed in cases where schistosomal
cation for liver transplant in the United States and recurrent
infections and viral hepatitis coexist. Hepatocellular carciHCV disease after transplant is a major unmet challenge in the
noma, colon cancer, and follicular lymphoma of the spleen
field. Liver transplant for hepatitis B, in distinction, has shown
have been reported in association with hepatic schistosomiagreatly improved results in recent years due to improved pharsis.6,17,18,25,26
macologic treatment options.
Active infection is usually diagnosed by the presence of
The pathophysiology of liver injury is largely host response
schistosomal eggs in the stool (Kato-Katz smears), epidemioto noncytopathic virus. Table 57.1 summarizes the characterislogic data, and biochemical or serologic findings. Laboratory
tics of the five viruses most commonly associated with clinical
features include eosinophilia, hypoalbuminemia, hypergamhepatitis, their modes of transmission, and the consequences of
maglobulinemia, and elevated serum alkaline phosphatase.
infection.
Serum transaminase levels are usually normal. ELISA serum
Hepatitis G virus (HGV) does not appear to be injurious to
antibody tests are highly sensitive but may not correlate with
the liver and will not be considered further. Other viral infecactivity of the infection. Histologically, heavy infection can
tions can produce acute hepatitis in a fraction of patients (e.g.,
lead to prominent granulomata formation, normal liver archiEpstein-Barr virus, cytomegalovirus, herpes simplex virus, and
tecture, and severe portal fibrosis (Symmers pipestem fibrosis).
varicella virus). In some cases the hepatitis caused by these
In mild infections small white granulomata, each with a schisviruses generally associated with more systemic illness may be
tosomal egg at its center, are observed throughout the liver
severe, and in fact liver involvement may be the dominant
(Fig. 57.7). The hepatic parenchyma is darker than usual as a
component of the infected patients illness.
893
TA B L E 5 7 . 1
CLASSIFICATION OF VIRAL HEPATITIS
THE VIRAL HEPATITIDES
VIRUS
HEP A
PICORNAVIRUS
(RNA)
HEP B
HEPADNAVIRUS
(DNA)
HEP C
FLAVIVIRUS
(RNA)
HEP D
VIROID
(RNA)
HEP E
CALICIVIRUS
(RNA)
Transmission
Fecal-oral
Parenteral
Parenteral
Parenteral
Fecal-oral
Acute disease
Common
Common
Uncommon
Common
Yes
Evolution to
chronic disease
Never
Infrequent in adults
Frequent
(70%)
Yes
Described in
organ transplant
recipients
New cases/year
180,000
180,000
40,000
# Infected (U.S.)
1,250,000
4,000,000
Worldwide
350,000,000
170,000,000
Unknown, found
in approximately
5% of cases of
HBV infection
Treatment
None
Lamivudine
Interferon
Ribavirin
Treatment of HBV
Mainly sanitary
preventative
Adefovir
300
Unknown,
uncommon
Prophylaxis
Vaccine and Ig
Vaccine and Ig
None
Vaccinate against
HBV
In development
Fulminant failure
Rare
Yes
Never
With HBV, as
coinfection or
superinfection
Especially in
pregnant women
HEPATITIS A VIRUS
Molecular Structure
Hepatitis A virus (HAV) was identified in 1973.27 HAV
belongs to the Picornaviridae family, genus Hepatovirus. Four
distinct genotypes have been identified, though no clinical difference between them has been appreciated and all four genotypes belong to a single serotype.28 HAV is a single-stranded
RNA virus. It is 27 nm in diameter and nonenveloped. The
viral genome is 7,474 nucleotides in length and is divided into
5 and 3 untranslated regions and a single long open reading
frame that encodes a 2,227-amino-acid polypeptide. Upon
processing this peptide yields four structural and seven nonstructural proteins.
Clinical Features
Hepatitis A infection almost universally results in an acute
self-limited illness and can produce either icteric or anicteric
syndromes (Fig. 57.8). The incubation period is 28 days. The
anicteric prodrome lasts from 2 days to 3 weeks and typically
consists of fatigue, malaise, nausea, vomiting, anorexia, fever,
and right upper quadrant pain; the diagnosis of hepatitis may
be missed when it does not progress to jaundice. In cases
where jaundice becomes manifest, it persists for 1 to 6 weeks.
Transaminase levels are usually above 1,000 IU/mL and serum
bilirubin (10 mg/dL) and alkaline phosphatase values are
elevated as well. Serum IgM antibodies are detected in 95% of
patients and are the gold standard of diagnosis. IgG antibodies become elevated as jaundice subsides and may persist
for years.
HAV infection leads to fulminant liver failure in 0.01% to
0.35% of cases of acute hepatitis A. This rare event mostly
occurs in patients with underlying liver disease, especially
hepatitis C and less commonly hepatitis B or alcoholic liver
disease. The risk of fulminant failure is also higher in people
over 40 years of age, intravenous drug users, homosexual men,
and inhabitants of endemic areas.32
Treatment
Most patients with HAV infection recover with supportive
care (approximately 20% require hospitalization in large outbreaks). Hygiene should be a top priority to prevent spread of
PANCREAS/LIVER
Entecavir
894
Clinical Features
The incubation period in cases of acute infection is approximately 8 weeks. The presence of serum hepatitis B surface antigen (HBsAg) may precede the clinical onset of jaundice. Acute
infection is associated with serum HBV DNA, HBV DNA polymerase, hepatitis B early antigen (HBeAg), and liver HBV DNA
and hepatitis B core antigen (HBcAg). HBeAg is a useful
marker of viral replication, except in individuals infected with
mutant viruses where it may be undetectable despite active
viral replication (Fig. 57.9). In such circumstances, serum HBV
DNA is detected by hybridization techniques. Serum anti-HBc
IgM becomes detectable with the onset of jaundice. In most
individuals, when HBV does not develop into chronic hepatitis,
anti-HBc IgM becomes undetectable beyond 6 months. On
occasion, however, it may persist for years after the acute infection or may recur as an amnestic phenomenon in reactivating
chronic hepatitis B, thus limiting its usefulness as a marker of
acute hepatitis B infection.
Although HBV accounts for 40% of cases of acute liver
failure in developing countries, it is estimated that the incidence in the United States is approximately 10%. Hepatitis B
becomes fulminant in approximately 1% of acute cases.
Women, elderly individuals, and those who sustain superinfection with another virus (such as HCV) seem to be at greater
risk. Furthermore, the risk of acute liver failure is directly proportional to the antibody titers to HBcAg and HBsAg. Some
cases of acute liver failure may be due to reactivation of HBV
in patients with chronic infection. In cases of reactivation,
reappearance of HBc IgM antibodies (Abs) aids in the diagnosis. Spontaneous survival after HBV acute liver failure ranges
from 15% to 36%.38,39
Most patients with acute HBV infection in the Western world
(low carrier rates) recover completely. Approximately 25% of
adult cases in the Western world develop clinical jaundice but do
HEPATITIS B VIRUS
Molecular Structure
Hepatitis B virus (HBV) is a DNA virus that belongs to the
hepadnavirus family. It is the smallest DNA virus with the
ability to infect humans. HBV virions are 40 to 42 nm in diameter, with a double shell and an outer lipoprotein envelope.
The viral nucleocapsid, or core, contains a 3.2-kb partially
duplex DNA and a polymerase. Replication resembles that of
retroviruses, in which the viral DNA polymerase acts as a
reverse transcriptase. The HBV polymerase lacks proofreading
activity. This finding is associated with an estimated frequency
of 105 to 106 mutations per nucleotide per year and the resultant development of mutant forms of the virus.3537
895
Treatment
Primary prevention by means of vaccination constitutes the
best treatment approach for HBV infection. Individuals at
high risk include health care workers, visitors to highly
endemic areas, sexual contacts of chronic carriers or acutely
infected people, and household contacts of those at high risk
of infection (intravenous drug users, hemophiliacs, patients
with thalassemia). The hepatitis B vaccine is given as a series of
three intramuscular doses and has an almost 100% efficacy
among immunocompetent persons with antibody levels of at
least 10 mIU/mL. Since the World Health Organization in
1991 called for all children to receive the vaccine, 116 countries have adopted it as a routine immunization. Hepatitis B
PANCREAS/LIVER
FIGURE 57.10. Clinical course of chronic hepatitis B. A: A benign chronic carrier has continued production of hepatitis B surface antigen but there is an absence of serum markers of viral replication. B: A pattern of continuing liver injury and serum
markers of active viral replication.
896
HEPATITIS C VIRUS
Molecular Structure
Hepatitis C virus (HCV) is a lipid-enveloped, 9.4-kb, singlestranded RNA virus of the family Flaviviridae, genus
Hepacivirus. Six genotypes have been identified, which differ
from one another by as much as 30% at the sequence level.44
Quasispecies within genotypes demonstrate further genetic
heterogeneity and reflect the high rate of mutation seen in viral
replication. Over 70% of U.S. cases are due to genotype 1
virus.
most cases undetected until the appearance of overt liver failure decades after the initial infection (Fig. 57.12). The incidence of hepatic decompensation (variceal hemorrhage,
ascites, jaundice, encephalopathy) in the setting of cirrhosis is
approximately 5% per year. Hepatitis C cirrhosis is strongly
associated with the development of hepatocellular carcinoma.
Extrahepatic manifestations of hepatitis C include membranoproliferative glomerulonephritis, cryoglobulinemia, diabetes, porphyria cutanea tarda, lichen planus, vitiligo, and
non-Hodgkin lymphoma.45
The diagnosis of hepatitis C is based on serologic demonstration of HCV RNA and/or antibodies. HCV RNA can be
detected weeks earlier than antibodies, which are not observed
until approximately 18 weeks after the initial illness.
Treatment
Therapy is indicated in cases of chronic hepatitis C with elevated serum aminotransferase concentrations and chronic
hepatitis on liver biopsy. The current treatment of chronic
hepatitis C is via a combination of pegylated interferon alfa
and ribavirin. Pegylation of interferon alfa optimizes its
pharmacodynamics and pharmacokinetics by providing sustained concentrations after single weekly injections. Its principal mechanism of action seems to be the immune clearance
of infected cells, perhaps via mobilization of endogenous
Clinical Features
The usual incubation period is 5 to 10 weeks. Most acutely
infected patients are asymptomatic and therefore the infection
goes unappreciated. Initial laboratory findings after infection
include hepatitis characterized by elevated ALT levels (500 to
1,000 IU/mL) and high HCV RNA titers (Fig. 57.11). HCV is
thought to be cleared spontaneously in 20% of individuals following primary infection. Hepatitis C infection by itself is
almost never associated with acute liver failure. Liver damage
in the setting of chronic infection is due to host immune
response rather than to viral hepatotoxicity. Ongoing chronic
hepatic injury leads to progressive fibrosis and cirrhosis, in
897
HEPATITIS D VIRUS
Clinical Features
Acute infection is diagnosed by the presence of anti-HDV IgM.
Anti-HBc IgM distinguishes coinfection from superinfection
(Figs. 57.13 and 57.14). The diagnosis in patients with chronic
liver disease is made by the presence of HBsAg and antibodies
against HDV in the serum and confirmed by the presence of
HDV antigen in the liver or HDV RNA in the serum (Fig. 57.15).
Acute liver failure is seen with both coinfection (HDV and HBV
simultaneously infect the host) and superinfection (HDV infects
a host already infected with HBV). Superinfection seems to be
associated with a higher mortality rate. Chronic HDV and HBV
infection may coexist. Cirrhosis is observed in at least two thirds
of patients and occurs at a younger age than in patients infected
with HBV alone.50,51
Treatment
Treatment and prevention of HDV are associated with that of
hepatitis B, with which it always coexists. Vaccination with
the hepatitis B vaccine is contributing to the decline in the
incidence of HDV. -Interferon (IFN) is the only currently
PANCREAS/LIVER
Molecular Structure
898